Source: GUIPCAR Group. In: Clinical practice guideline for the
	management of rheumatoid arthritis. Madrid: Spanish Society of
	Rheumatology; 2001. 146 p.


	GUIPCAR
	CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF RHEUMATOID ARTHRITIS


	- Translated from the Spanish


	Contents

	   * PARTICIPATING INSTITUTIONS 
	   * HOW TO CITE THIS GUIDELINE 
	   * GUIPCAR GROUP
	   * ACKNOWLEDGEMENTS 
	   * SUMMARY 
	   * PREFACE 
	   * BACKGROUND 
	   * GUIDELINE OBJECTIVES 
	   * METHODOLOGY 
	   * HOW TO USE THIS GUIDELINE 
	   * CONTENTS AND LIMITATIONS OF THE GUIDELINE 
	   * CHAPTER 1. DIAGNOSING RHEUMATOID ARTHRITIS 
	   * CHAPTER 2. INITIAL EVALUATION 
	   * CHAPTER 3. CLASSIFYING RHEUMATOID ARTHRITIS 
	   * CHAPTER 4. MEDICAL TREATMENT OF RHEUMATOID ARTHRITIS 
	   * CHAPTER 5. CRITERIA FOR RESPONSE TO TREATMENT 
	   * CHAPTER 6. ADVERSE EFFECTS OF DRUGS USED IN THE TREATMENT OF RHEUMATOID
 	                ARTHRITIS 
	   * CHAPTER 7. OTHER TREATMENTS 
	   * CHAPTER 8. EXTRA-ARTICULAR COMPLICATIONS OF RHEUMATOID ARTHRITIS 
	   * ACRONYMS 
	   * APPENDICES 
	   * TABLES 
	   * REFERENCES 
	   * QUICK REFERENCE GUIDE 


	Rheumatoid arthritis (RA) is a highly prevalent disease in Spain, and
	its management consumes a large amount of health and social resources.
	The disease often has serious repercussions on the quality of life of
	those affected, provoking chronic pain, limitations in the activities of
	daily living, and work disability. Although there is currently no cure
	for the disease, its symptoms can be controlled by early detection and
	the initiation of appropriate treatment. In recent years, however, the
	appearance of new drugs, new forms of combined treatment, and a plethora
	of studies on the efficacy of different therapeutic modalities means
	that the clinician is not always sure which treatment strategy to follow
	for a particular patient.

	Faced with this explosion of new information, it is not surprising that
	there is large variability in the treatment of patients with RA, which
	cannot always be explained by characteristics of the disease. Thus, the
	Spanish Society of Rheumatology (SER), aware of the difficulties
	involved in making decisions about the management of RA, decided to
	develop this Clinical Practice Guideline for the Management of
	Rheumatoid Arthritis in Spain (Guía de Práctica Clínica para el manejo
	de Artritis Reumatoide en España - GUIPCAR). The aim of the guideline
	is to help clinicians make decisions about their patients. The guideline
	recommendations are based on the best available scientific evidence and,
	when this is lacking, on the work of an expert panel that developed a
	series of detailed recommendations on the diagnosis, management, and
	treatment of patients with RA. The recommendations on disease-modifying
	antirheumatic drugs (DMARDs) are the result of an exhaustive review and
	synthesis of the published randomized clinical trials meeting strict
	methodological criteria for these types of studies.

	Clinical practice guidelines are one of the most appropriate tools for
	improving the quality of care and decreasing unnecessary variability in
	clinical practice. Their objective is to offer systematically developed
	recommendations to aid the physician and patient in decision making.
	Although these recommendations aim to include most patients who would
	present to a physician, there may be particular circumstances in which
	they do not apply.

	With this work, the SER hopes to offer the clinician a practical tool
	that will prove useful in daily clinical practice. We hope the
	information included here will be of assistance to physicians, will help
	improve the quality of care, and, above all, will help patients who
	suffer from RA. Should this be so, we will have achieved an important
	objective for the year 2001, designated by the Society as the "Year of
	Rheumatoid Arthritis."

	Armando Laffón Roca
	Emilio Martín Mola


	PARTICIPATING INSTITUTIONS

	This guideline is an initiative of the Spanish Society of Rheumatology.
	A number of institutions have collaborated in carrying out this initiative:

	Spanish Society of Rheumatology (Sociedad Española de Reumatología -
	SER). The SER promoted the idea for this guideline, chose the research
	group to develop it, helped select the panel of experts, sponsored its
	development, and presented the project to the financing organization.

	Health Services Research Unit (Unidad de Investigación en Servicios de
	Salud - UISS). When the SER decided to produce the guideline in late
	1998, the Society proposed that it be developed by the UISS. At that
	time the UISS was a research unit within the Carlos III Health Institute
	(ISCIII). The UISS began to develop the guideline, but organizational
	changes in the ISCIII took place at the end of 2000. The UISS then
	became a private company with the name of TAISS, part of whose research
	staff came from the UISS.

	Ignacio de Mercado Foundation (Fundación Ignacio de Mercado - FIdeM)
	for research and education in the health services. The FIdeM contracted
	project personnel who were not on the staff of the UISS.

	Advanced Research Techniques in the Health Services (Técnicas
	Avanzadas de Investigación en Servicios de Salud, S.L. - TAISS). TAISS
	is a company devoted to producing knowledge to improve decision making
	in the health sector at the macro (policy) level, as well as at the meso
	(management) and micro (physician-patient) levels. Its research staff
	came from the UISS. All the investigators who participated in the
	project at its inception have continued to work on it.

	Novartis. Novartis is the organization that financed the development
	of this guideline. It also oversaw each project activity and, together
	with the SER, monitored project tasks to ensure they were carried out in
	a correct and timely fashion.

	Abbott. This English-language version of GUIPCAR was made possible
	thanks to Abbott, which provided financing for the translation.


	HOW TO CITE THIS GUIDELINE

	The following format is suggested for citation of this guideline:

	GUIPCAR Group. Clinical Practice Guideline for the Management of
	Rheumatoid Arthritis in Spain. Spanish Society of Rheumatology. Madrid,
	2001.


	GUIPCAR GROUP

	The following persons are members of the GUIPCAR Group, which authored
	this guideline:

	1. Principal Investigator

	Pablo Lázaro y de Mercado, Director of TAISS. Founder and director
	of the Health Services Research Unit (UISS) of the Carlos III Health
	Institute (1993-2000). Vice-Director General of Health and Technological
	Evaluation of the Ministry of Health and Consumer Affairs (1997-98).
	University graduate in Medicine (Complutense University of Madrid,
	1973). Doctor of Medicine (Autonomous University of Madrid, 1989).
	Specialist in Internal Medicine and in Respiratory Diseases (1977).
	Residency in Respiratory Diseases at the 12 de Octubre Hospital in
	Madrid (1974-77), and associate in Respiratory Diseases at the Ramón y
	Cajal Hospital in Madrid (1978-86). Master of Business Administration
	from the IESE (1989). Post-doctoral studies in health policy analysis at
	the RAND/UCLA Center for Health Policy Analysis, Santa Monica,
	California (USA), where he helped develop clinical practice guidelines
	(1990-93). His areas of expertise include research in the health
	services, socioeconomic evaluation, medical technology evaluation,
	development of clinical practice guidelines, and development of
	appropriateness criteria for clinical procedures.

	2. Expert Panel

	The experts who developed the recommendations in this guideline, listed
	in alphabetical order, are:

	José Luis Andréu Sánchez, rheumatologist, Clínica Puerta de Hierro,
	Madrid.
	University graduate in Medicine and Surgery (Autonomous University of
	Madrid, 1983), specialist in Rheumatology via the MIR (Puerta de Hierro
	Clinic, Madrid, 1984-87) and Doctor of Medicine with special honors
	(Autonomous University of Madrid, 1990). Has participated in different
	research projects related with Immunology at the Center of Molecular
	Biology (Professor Martínez-Alonso) and has been a member of various
	expert groups (e.g., the Strategic Plan of the Spanish Society of
	Rheumatology and the Consensus Conference on the use of biological
	therapies in rheumatoid arthritis) sponsored by the Spanish Society of
	Rheumatology, of which he was Secretary (1998-2000). Formerly or
	currently serving on the editorial boards of various clinical journals
	such as Annals of the Rheumatic Diseases, Revista Española de
	Reumatología and Revista Clínica Española. Has published over 100 book
	chapters, 54 articles in national scientific journals, and 30 articles
	in the most prestigious international journals such as Nature, Journal
	of Experimental Medicine, and Arthritis and Rheumatism. Editor of 8
	books. Has given over 40 post-graduate seminars on different subjects
	related with his speciality. Currently works as a rheumatologist at the
	Puerta de Hierro Clinic in Madrid, is honorary professor of Rheumatology
	at the Faculty of Medicine of the Autonomous University of Madrid and
	the Hospital for Rheumatic Diseases of Barcelona, and is President of
	the Society of Rheumatology of the Community of Madrid.

	Enrique Batlle Gualda, rheumatologist, University Hospital General of
	Alicante, Alicante.
	University graduate in Medicine and Surgery by the Autonomous University
	of Barcelona (1978), specialist in Rheumatology via the MIR (1984),
	Doctor of Medicine (University of Alicante, 1992), and University
	Specialist in Health Economics and Management of Health and Social
	Services (University of Alicante, 1993). Trained in epidemiology and
	statistics. Experienced as a teacher, evaluator, and advisor for
	different agencies, organizations, and research groups. Research
	experience in brucelar arthritis and clinical epidemiology in the
	evaluation of health-related quality of life, clinical methodology, and
	clinical trials. Currently associate in the Rheumatology Section and
	Secretary of the Clinical Research Ethics Committee of the General
	University Hospital of Alicante, and Associate Professor of the Miguel
	Hernández University.

	Loreto Carmona Ortells, rheumatologist and epidemiologist, Spanish
	Society of Rheumatology, Madrid.
	University graduate in Medicine and Surgery (Autonomous University of
	Madrid, 1990) and specialist in Rheumatology via the MIR (La Princesa
	Hospital, Madrid, 1991-94). Carried out the project "Clinical
	Epidemiology and Application to the Study of Rheumatic Diseases" (FIS
	BAE grant 96/5485 and 97/5090) in the Arthritis Research Group (directed
	by Edward Yelin) and the Departments of Rheumatology and Epidemiology
	and Biostatistics of the University of California in San Francisco. Has
	worked in the Spanish Medicines Agency (grant FC1 1999- 2000) as
	technical evaluator for various recently developed drugs in
	rheumatology. Coordinator since 1998 for various epidemiological
	projects of the Spanish Society of Rheumatology. Currently contracted as
	investigator of the Health Research Fund in the Research Unit of La
	Princesa Hospital to develop a line of Research in Rheumatic Diseases
	and coordinate the installation of a Cochrane Centre in Madrid for the
	diffusion of Evidence-Based Medicine.

	Federico Díaz González, rheumatologist, University Hospital of the
	Canary Islands, Santa Cruz de Tenerife.
	University graduate in Medicine and Surgery (La Laguna University,
	1986), specialist in Rheumatology via the MIR (La Princesa Hospital,
	1991), and Doctor of Medicine from the Autonomous University of Madrid
	(1994). Post-doctoral training under grants from the Ministry of Health
	and the Spanish Ministry of Education and Science at the Laboratory of
	Dr. Mark H. Ginsberg in the Department of Vascular Biology of the
	Scripps Research Institute, La Jolla, California. Has published 28
	articles in Spanish and international journals, has authored 2 book
	chapters and has wide experience in research. Formerly, specialist in
	the Rheumatology Department of La Princesa Hospital of Madrid, and
	currently occupies the same position in the University Hospital of the
	Canary Islands.

	Juan José Domínguez Reboiras, orthopedist, La Paz University
	Hospital, Madrid.
	University graduate in Medicine and Surgery by the Santiago de
	Compostela University (1968); Doctor of Medicine and Surgery from the
	Autonomous University of Madrid (1974); specialist in Orthopedic Surgery
	and Traumatology, in Physical Education and Sports Medicine and in
	Occupational Medicine, and Advanced Degree in the Management of Health
	Institutions. Tenured Professor in Anatomy and Physiology in the La Paz
	University School of Nursing. Formerly, Chief of the Orthopedic Surgery
	and Traumatology Department in the Xeral Cies Hospital of Vigo.
	Currently, Chief of the Shoulder and Elbow Diseases Unit in the La Paz
	University Hospital of Madrid.

	Ángel Elena Ibáñez, rheumatologist, San Millán-San Pedro Hospital,
	Logroño.
	University graduate in Medicine and Surgery (Autonomous University of
	Madrid 1979), specialist in Rheumatology via the MIR (Ramón y Cajal
	Hospital, Madrid, 1980-1984), and Doctor in Medicine and Surgery
	(Autonomous University of Madrid, 1994). Area specialist of the
	Rheumatology Section, San Millán-San Pedro Hospital of La Rioja, since
	1987. Degree in Clinical Research (Autonomous University of Madrid, 1997
	and National School of Health, 1999). Formerly responsible for the
	Clinical-Epidemiological Research Unit of La Rioja from 1995 to 1999.
	Currently working in the Rheumatology Section of the San Millán-San
	Pedro Hospital of La Rioja, Logroño.

	Juan Gómez-Reino Carnota, rheumatologist, University Clinical
	Hospital, Santiago de Compostela.
	Residency in Medicine and Fellowship in Rheumatology at the State
	University of New York at Stony Brook (USA). Previously Chief of Section
	of Rheumatology and Director of the Research Centre of the 12 de Octubre
	University Hospital of Madrid. Formerly responsible for the Area of
	Biomedicine at the National Agency of Planning and Evaluation (ANEP) and
	member of evaluation committees for national and international research.
	Has published numerous articles in speciality journals in the area of
	autoimmune diseases and inflammation. Currently, Chief of the
	Rheumatology Department in the Santiago University Clinical Hospital.

	Agustún Gómez de la Cámara, epidemiologist, Research Unit, 12 de
	Octubre Hospital, Madrid.
	Doctor in Medicine and Surgery from the Autonomous University of Madrid.
	Currently, Chief of the Clinical Epidemiology Unit of the Research Unit
	in the 12 de Octubre Hospital. His training in clinical epidemiology was
	received, among other centres, at the Houston Medical Center, University
	of Texas (USA). Has worked mainly in teaching and research in the Health
	Research Fund, Carlos III Health Institute, and 12 de Octubre Hospital
	in diagnostic, prognostic, and therapeutic research areas from the
	perspective of clinical epidemiology. Actively promotes the use and
	development of Evidence-Based Medicine and has translated its basic
	texts. Technical advisor to the Health Research Fund and ANEP, and
	member of the Spanish Medicines Agency as advisor to the Committee on
	Drug Safety.

	Nuria Guañabens Gay, rheumatologist, Clinical and Provincial
	Hospital, Barcelona.
	University graduate in Medicine and Surgery (1978), specialist in
	Rheumatology (Clinical Hospital, Barcelona, 1979-1984), and Doctor of
	Medicine (University of Barcelona, 1987). Responsible for the Bone
	Metabolic Disease Team of the Agust Pi I Sunyer Biomedical Research
	Institute (IDIBAPS), Clinical Hospital, Barcelona. Currently, medical
	rheumatology adviser at the Clinical Hospital and Associate Professor of
	Medicine of the University of Barcelona.

	César Hernández García, rheumatologist, San Carlos Clinical Hospital,
	Madrid.
	University graduate in Medicine and Surgery (Complutense University of
	Madrid, 1987), Doctor of Medicine (Complutense University of Madrid,
	1996, special honors), and specialist in Rheumatology via the MIR (San
	Carlos Clinical Hospital, Madrid, 1988-91). Visiting Fellow at the
	Division of Arthritis and Rheumatism, Oregon Health Sciences University.
	FIS fellow (1992-94) at the San Carlos Clinical Hospital, Madrid, and
	Area Specialist in the Rheumatology Department of that hospital since
	1994. Current major research area is rheumatoid arthritis, involving
	both clinical research and health services projects.

	M^a Victoria Irigoyen Oyarzábal, rheumatologist, Carlos Haya General
	Hospital, Málaga.
	University graduate in Medicine and Surgery (University of Malaga, 1979)
	and specialist in Rheumatology via the MIR (Ramón y Cajal Hospital,
	Madrid 1981-1984). One year of specialization via the MIR in
	Anesthesiology (Carlos Haya Hospital, Malaga 1980). Area specialist in
	Rheumatology (Hospital of Navarra, Pamplona 1987-1992) and area
	specialist in Rheumatology (Carlos Haya Hospital, Malaga, Connective
	Tissue Diseases Unit, from 1992 to present).

	José Luis Marenco de la Fuente, rheumatologist, Hospital
	Universitario de Valme, Sevilla.
	University graduate in Medicine and Surgery (University of
	Sevilla,1974-80), specialist in Rheumatology via the MIR (Puerto de
	Hierro Clinic, Autonomous University of Madrid, 1981-84). Doctorate cum
	laude in 1986 for the thesis "Synoviorthesis with yttrium-90 in knees.
	Long-term results" (directed by Professor Noguera Hernando). Responsible
	for the creation of the Rheumatology Section in the Hospitals of Jerez
	(1987-91) and Valme of Sevilla (1992) and Chief of Rheumatology Section
	in the latter hospital since 1994. Associate Professor of Rheumatology
	in the Faculty of Medicine of Sevilla.

	Víctor Manuel Martínez Taboada, rheumatologist, Marqués de Valdecilla
	University Hospital, Santander.
	University graduate in Medicine and Surgery (University of Zaragoza,
	1988) and specialist in Rheumatology via the MIR (Marqués de Valdecilla
	University Hospital, Santander, 1992). Completed clinical and research
	training in the Lupus Research Unit (The Rayne Institute, St. Thomas
	Hospital) in London (UK) and in the Rheumatology Research Unit (Mayo
	Clinic) of Rochester, Minnesota (USA). Doctor of Medicine from the
	University of Cantabria (1998). Since 1994, associate physician of the
	Rheumatology Department at the Marqués de Valdecilla University Hospital
	in Santander.

	Cristina Riera Riezu, rehabilitation therapist, Germans Trias i Pujol
	Hospital of Badalona, Barcelona.
	University graduate in Medicine and Surgery (Central University of
	Barcelona, 1983), specialist in Physical Therapy and Rehabilitation via
	the MIR (Germans Trias i Pujol University Hospital, 1989), and Doctor of
	Medicine (Autonomous University of Barcelona, 2000). Member of the
	Medical Commission of the International Para-Olympics Committee and of
	the Catalan and Spanish Sports Federations for the Physically
	Handicapped. Member of the Catalan Society of Rheumatology; received
	first prize from the Catalan Society of Rehabilitation Therapy for her
	work "Rehabilitation therapy in rheumatoid arthritis: protocol for
	action." Has published 12 articles in national journals and 8 in
	international journals, in addition to 93 conference contributions.
	Worked as associate physician for the Department of Rehabilitation
	Therapy at the General Hospital of Cataluña (1990-91), and is currently
	associate physician for the Department of Rehabilitation Therapy at the
	Germans Trias i Pujol University Hospital, where she is responsible for
	the Rheumatological Rehabilitation Unit.

	José María Salazar Vallinas, rheumatologist, Infanta Cristina
	Hospital, Badajoz.
	University graduate in Medicine and Surgery (Autonomous University of
	Madrid,1977), specialist in Rheumatology via the MIR (Ramón y Cajal
	Hospital, Madrid 1980-83), and in Family and Community Medicine
	(Ministry of Education and Science, 1987). Master of Public Health
	(National School of Health, Madrid, 1986). Formerly, President and
	Founding Member of the Rheumatological Association of Extremadura and
	spokesperson for the Spanish Society of Rheumatology, and responsible
	for residency training in Family and Community Medicine and member of
	the Teaching Commission (1988-95) and the Clinical Chart Commission
	(1990-1996) of the Infanta Cristina de Badajoz University Regional
	Hospital. Also Associate Professor of the Health Sciences in the
	Department of Human Clinical Pathology, Area of Medicine/Rheumatology,
	of the University of Extremadura.

	3. Investigators

	The research team, originally from the UISS (most of whom currently work
	at TAISS), that was responsible for designing the study methodology,
	coordinating the work of the expert panel, carrying out the synthesis of
	the scientific evidence, and producing the final guideline document, was
	made up of the following persons:

	Setefilla Luengo Matos (UISS). Design of the synthesis of the evidence.
	Doctor of Medicine (Autonomous University of Madrid, 1990) and
	specialist in Preventive Medicine and Public Health (La Paz Hospital,
	1985). Master of Public Health (National School of Health). Area Chief
	at the Agency for Health Technology Evaluation, Carlos III Health
	Institute, Madrid.

	José Manuel Estrada Lorenzo (TAISS). Bibliographic search.
	University graduate in Geography and History from the Complutense
	University of Madrid (1986), specializing in documentation in the Health
	Sciences.

	Santiago Alonso Corral (UISS). Database design.
	University graduate in Medicine and Surgery (University of Salamanca,
	1987) and specialist in Preventive Medicine and Public Health (San
	Carlos Clinical Hospital, Madrid, 2001). Master of Public Health
	(National School of Health, 1997). Specialist in Health Information
	Systems (Complutense University of Madrid, 1994) and Master in Applied
	Electronics (School of Industrial Organisation, 1992).

	Miguel Ángel Abad Hernández (FIdeM). Analysis of the scientific
	evidence.
	University graduate in Medicine (Complutense University of Madrid, 1991)
	and specialist in Rheumatology via the MIR (Gregorio Marañón University
	General Hospital of Madrid, 1997).
	
	Hildegarda Godoy Tundidor (FIdeM). Analysis of the scientific evidence.
	University graduate in Medicine (Complutense University of Madrid 1994)
	and specialist in Rheumatology via the MIR (Gregorio Marañón University
	General Hospital of Madrid, 1998).

	Sandra García Armesto (UISS). Analysis of the scientific evidence.
	University graduate in Medicine (Autonomous University of Madrid) and
	Master of Public Health, specializing in Health Services Management and
	Evaluation, from the University Center of Public Health (CUSP) in Madrid.

	Yesenia Tordecillas Echenique (FIdeM). Analysis of the scientific
	evidence.
	University graduate in Medicine (University of Cartagena, Colombia,
	1997). Has participated in various research projects in Colombian
	hospitals. Trained in the methodology of scientific research and the
	critical review of medical literature.

	Yira Tordecillas Echenique (FIdeM). Analysis of the scientific evidence.
	University graduate in Medicine (University of Cartagena, Colombia,
	1996). Has participated in various research projects in Colombian
	hospitals. Trained in the methodology of scientific research and the
	critical review of medical literature.

	Milena Gobbo Montoya (TAISS). General coordinator and editor of GUIPCAR.
	University graduate in Psychology (Autonomous University of Madrid,
	1984). Previous training and experience related with the practice of
	clinical psychology and the administration and management of hospital units.


	ACKNOWLEDGEMENTS

	This guideline is the fruit of collaboration among a number of
	institutions and persons, all of whom have helped to make it possible.

	The SER, for its initiative in promoting the development of this
	guideline, monitoring activities, and providing the meeting ground for
	strategic discussions.

	Novartis should receive special thanks, not only for its sensitivity
	in sponsoring the guideline, but also for not influencing its content or
	development except to ensure its timely completion. The investigators
	and panelists can thus confirm that their freedom of opinion and
	criteria was preserved so that this guideline is free of financing bias.

	The ISCIII made a significant contribution to making this guideline
	possible, both by carrying out research activities in the UISS, and for
	generously allowing the use of its installations for various research
	meetings, including those of the panel.

	TAISS, which assumed responsibility from the UISS for producing the
	guideline, contracted the UISS investigators to continue its
	development, and provided the site for various research meetings,
	including the last meeting of the panel.

	FIdeM, for handling the contracting of non-UISS staff.

	The panelists, who so generously dedicated their time, energy, and
	knowledge to producing this guideline, are responsible for developing
	the key parts of the guideline.

	The investigators, who overcame difficult moments and maintained their
	enthusiasm throughout all phases of the project, from its initial
	design, to the synthesis of the evidence, and the final assemblage of
	the pieces that make up this guideline.

	María Dolores Aguilar and Kathy Fitch, who provided suggestions in
	previous versions of the guideline, and Ignacio Lázaro, for his silent
	miracles in solving computer-related mysteries.

	The librarians at the National Library of the Health Sciences and at the
	libraries of the 12 de Octubre and the Ramón y Cajal Hospitals, who
	helped locate the documents necessary for the synthesis of the evidence.


	SUMMARY

	Rheumatoid arthritis (RA) affects some 200,000 persons in Spain, with
	20,000 new cases emerging each year. RA reduces quality of life and
	functional capacity, produces work disability, and increases mortality.
	It has been estimated that the annual social cost of RA in Spain exceeds
	200 billion pesetas (US$1.04 billion), of which 65 billion pesetas
	($338.5 million) are devoted to health expenditures. There is evidence
	of large variability in the management of RA in Spain; this variability
	depends not only on patient or disease characteristics, but also on
	characteristics of the hospital, department, or physician providing
	patient care. These facts suggest that some diagnostic or therapeutic
	procedures are overused, while others may be underused.

	For these reasons, in 1998 the Spanish Society of Rheumatology (SER)
	decided to develop a clinical practice guideline for the management of
	rheumatoid arthritis (GUIPCAR) to help physicians make decisions about
	the diagnosis and treatment of patients with RA. The objective of
	GUIPCAR is to develop standards of quality for the treatment of RA and
	to reduce the variability that does not depend on patient characteristics.

	This guideline, aimed at rheumatologists, describes the diagnostic and
	management strategies for the evaluation and treatment of patients with
	RA. It focuses on RA in adults (excluding juvenile RA) and includes
	diagnosis, evaluation, prognosis, and treatments such as drugs,
	rehabilitation, and surgery. It does not cover other treatments such as
	acupuncture, and only briefly treats extra-articular complications of RA
	such as amyloidosis, anemia, or Sjögren's syndrome.

	The guideline begins with a description of its origin and justification
	in the preface and an explanation of its objectives. The methodology
	followed to develop the recommendations is then described. The
	recommendations for treatment with disease-modifying antirheumatic drugs
	(DMARDs) in this guideline are based on a synthesis of the best
	available scientific evidence, after making a systematic review of the
	clinical trials and meta-analyses that have been published. A total of
	2,281 articles was identified, 103 of which met the inclusion criteria
	for this review. The rest of the recommendations or considerations are
	based on scientific evidence obtained without a systematic literature
	review, or on the opinions of the expert panel. The experts were chosen
	by the SER, applying a series of criteria designed to support their
	validity at the national level and to avoid conflicts of interest. The
	guideline describes how it can be used, its contents, and its limitations.

	Chapter 1 focuses on the diagnosis of RA, chapter 2 on the initial
	evaluation, based on which, in chapter 3, patients are classified
	according to the number of swollen joints and the presence of erosions.
	The classification is further broken down by acute phase reactants, the
	health assessment questionnaire (HAQ), and rheumatoid factor (RF). The
	recommendations on medical treatment are presented in chapter 4, the
	criteria for response to treatment in chapter 5, and the adverse effects
	of medical treatment in chapter 6. Surgical, rehabilitative, and local
	treatments are covered in chapter 7. Chapter 8 describes the
	extra-articular complications of RA. The guideline includes an appendix
	with instruments to facilitate the clinician's data collection for the
	initial classification and follow-up of patients with RA, and another
	appendix with the complete patient classification. To make it easier to
	follow the guideline recommendations, readers may wish to make use of a
	simplified algorithm or the other, complete algorithm. The key features 
	of the guideline are contained in a summary version, the "rapid reference 
	guide."

	The bibliography has been divided into two sections, one listing all the
	references provided by the panelists or the investigators without a
	systematic search, and the other listing all the references used in the
	systematic review.

	The Health Services Research Unit (Unidad de Investigación en Servicios
	de Salud - UISS) of the Carlos III Health Institute was commissioned by
	the SER to develop GUIPCAR. The project took 2 years to complete. During
	this time, the UISS became a private entity under the name of Advanced
	Research Techniques in the Health Services (Técnicas Avanzadas de
	Investigación en Servicios de Salud -TAISS). Novartis financed this
	project. The investigators established the necessary mechanisms to
	ensure that the guidelines would have no financing bias and that the
	persons involved in its development would have no conflicts of interest.


	PREFACE

	In 1998 the Spanish Society of Rheumatology (SER) undertook the
	development of a Clinical Practice Guideline (CPG) to help physicians
	make decisions about the diagnosis and treatment of patients with
	rheumatoid arthritis (RA). This initiative of the SER was in response to
	a phenomenon frequently seen in clinical practice: the large variability
	in the use of diagnostic, therapeutic, and rehabilitative procedures. RA
	is a disease with a relatively high prevalence, affecting from 0.2 to
	0.8% of the population in Spain. The different specialties and levels of
	care involved in its treatment are not always well coordinated.
	Furthermore, recent years have seen rapid innovation in medical
	treatment, with the appearance of new drugs, new forms of combined
	treatment, and numerous studies on the effects of the drugs utilized.
	The large amount of information produced as a result of the ever-growing
	growing number of studies, their variable methodological quality, and
	the complexity of comparing the results of different studies constitutes
	a major obstacle for clinicians in keeping up to date on important
	knowledge in their field. Thus came about the project to produce a CPG
	for the management of RA (GUIPCAR), which was undertaken by the Health
	Services Research Unit (UISS) of the Carlos III Health Institute. This
	project took 2 years to complete. During this time, the UISS became a
	private company with the name of Advanced Research Techniques in the
	Health Services (TAISS).

	CPGs should be based on scientific evidence, but when such evidence is
	absent or contradictory, they may be complemented by unbiased techniques
	of handling expert opinion. This guideline uses both methods, and is
	based on three central tasks: 1) a synthesis of the evidence on the
	efficacy of disease-modifying antirheumatic drugs (DMARDs); 2) specific
	recommendations on the diagnosis, evaluation, and treatment of patients
	with RA made by a panel of experts, generally rheumatologists with
	scientific prestige proposed by the SER, following a methodology
	designed to produce CPG recommendations; and 3) assignment of the level
	of scientific evidence that supports each recommendation for treatment
	with DMARDs.

	The ultimate objective of this guideline is to aid clinical decision
	making by offering recommendations for the therapeutic management of RA
	that are based on the best available evidence. We have tried to present
	the recommendations in a clear and agreeable manner, so that it is easy
	to find the information sought. We hope it will prove useful to those
	who face the difficult task of making decisions about different courses
	of treatment and that, in the final analysis, it will result in better
	outcomes for patients with RA.


	BACKGROUND

	RA is a systemic disease of unknown etiology, which is characterized by
	chronic inflammation of the diarthrodial joints. It is frequently
	associated with severe morbidity, functional abnormalities involving
	work disability, reduced quality of life, and increased mortality. RA
	affects all populations, with an estimated prevalence of about 0.8% and
	an incidence of approximately 0.5/1,000 population per year [Silman,
	1993]. In Spain, RA affects about 5 of every 1,000 adults [Villaverde,
	2000] and causes 5% of all permanent work disability [Tornero, 1998].

	The economic impact of this disease is reflected in direct costs
	(physician visits, diagnostic tests, drugs, hospitalization) and
	indirect costs (loss of income due to work disability). In one health
	district of Madrid it has been estimated that the mean annual cost of a
	patient with RA is 1.11 million pesetas (about US $5,700) Some 70% of
	these costs are direct costs - 32% for patient care and 38% not for
	patient care - and 30% are indirect costs, that is, lost hours of work.
	If these results are extrapolated to the whole Spanish population, based
	on the estimated prevalence of RA in this country, the annual social
	costs of this disease would reach more than 200 billion pesetas ($1.04
	billion), of which 65 billion ($338.5 million) would be for health costs.

	As with most diseases, there is enormous variability in the management
	of RA - among countries, among institutions, among physicians, and even
	within the same physician - and in the use of diagnostic procedures,
	follow-up methods, and therapeutic and rehabilitative measures. At times
	it may be thought that health resources are used inappropriately, or
	that a variety of different recommendations are followed due to the
	large amount of information about the disease that appears in different
	publications or other channels of communication. Sometimes modifications
	in disease management are introduced even though they do not have a
	clear advantage over existing strategies, while at other times effective
	strategies may be ignored. Health professionals caring for RA patients
	are faced not only with a disease whose etiology, management, and
	diagnosis are complicated, but also with an enormous amount of
	information that is not always easy to interpret.

	CPGs are one of the most appropriate instruments to decrease unnecessary
	variability and improve clinical practice. A CPG is defined as a set of
	"systematically defined statements to assist practitioner and patient
	decisions about appropriate health care for specific clinical
	circumstances." A good CPG should have the attributes of validity,
	reliability, reproducibility, clinical applicability, flexibility,
	clarity, multidisciplinarity, and periodic review [IOM, 1990a; IOM,
	1992]. CPGs are part of a cultural change which consists of moving from
	unsubstantiated confidence in the opinions of professionals to a more
	structured and well-founded support for clinical decisions.

	The US Institute of Medicine (IOM) has suggested various criteria for
	selecting the contents of a CPG: first, the guideline should be applied
	to a clinical condition for which there is the potential to improve
	health for a significant number of persons; second, it should reduce
	clinically significant variations in services and procedures; third, it
	should reduce clinically significant variations in the outcomes of
	health care; and fourth, policies for guideline development should
	reflect the needs and priorities of the health system. Following these
	criteria, the SER considers that RA is a clinical condition that would
	benefit from the development of a CPG.


	GUIDELINE OBJECTIVES

	The objectives of this guideline are to improve the quality of care, to
	reduce variability in the management of RA, to move toward the integral
	management of RA, and to align clinical practice more closely with the
	best available scientific evidence.

	Improving the Quality of Care

	The quality of care can be seen, defined, and measured in many ways
	[Donabedian, 1980; OTA, 1988; Lohr, 1990; Rubenstein, 1990; Chassin,
	1991; Brook, 1991; Keeler, 1992; Kassirer, 1993; Burstin, 1993; Gates,
	1993; Miller, 1993; Hayward, 1993]. The IOM defines it as "the degree to
	which health services for individuals and populations increase the
	likelihood of desired health outcomes and are consistent with current
	professional knowledge" [IOM, 1990b]. According to the characteristics
	implicit in this definition, quality refers both to the
	physician-patient (individual) level and to the social (population)
	level; it can be measured in probabilistic terms (quantification of
	uncertainty); and it is based on scientific knowledge. Donabedian, who
	conceives quality of care as based on three dimensions (structure,
	process, and result), emphasizes the degree to which technology is used
	well in different centers or places [Donabedian, 1988].

	Evaluating the quality of care is a critical component of the correct
	functioning of health systems. Quality of care can be evaluated and can
	dramatically improve medical practice [Brook, 1990]. It is rarely
	evaluated, however, even though sufficient methodological instruments
	are available.

	Measuring outcomes is critically important in evaluating the quality of
	care. Two classic measures of the outcomes of clinical practice are
	efficacy and effectiveness. Efficacy refers to the patient outcome
	produced under ideal conditions (e.g., in a clinical trial), while
	effectiveness is the outcome produced under real conditions (e.g., in
	daily practice). The difference between efficacy and effectiveness can
	be produced by random error, by systematic error or bias (for example,
	the inventors of a drug or technology, consciously or subconsciously,
	may make it appear better than it really is), by variability in the
	quality of care, or by personal health characteristics that may or may
	not be controlled by the individual [Brook, 1990]. For this reason, the
	degree to which effectiveness (the effect achieved) approximates
	efficacy (the maximum achievable effect) can be considered as an
	indicator of the quality of care. This guideline will deal with both
	concepts.

	Implementing quality measures involves constructive actions to establish
	a relation between the process of care and patient outcomes [Brook,
	1990]. For example, statistically significant and clinically important
	differences have been shown in clinical outcomes depending on whether
	procedures are applied with a good or poor process of care [Kahn, 1990].
	The evidence showing that improving the process of care leads to better
	outcomes and that CPGs are one of the instruments designed to improve
	the process of care is one of the reasons behind the development of this
	guideline.

	Reducing Variability in the Management of Rheumatoid Arthritis

	There is evidence that decisions made in identical clinical situations
	may differ depending on individual, institutional, or geographic factors
	that are unrelated with patient characteristics [IOM, 1990a; IOM, 1992].
	This does not mean that variability in clinical practice is
	unacceptable. It may be acceptable when there is uncertainty about the
	advantages of one technique over another, when patient characteristics
	or preferences are different, when the characteristics of the center or
	its resources are different, or because of changing science or social
	and individual values. Such variability is not acceptable, however, when
	it is due to inadequate medical skill, poor institutional organization,
	ignorance, or the deliberate decision not to use procedures for which
	there is proven evidence of their superiority. Unacceptable clinical
	practice does not benefit patients; it may harm them, and it consumes
	resources unnecessarily.

	In Spain there is large inter- and intra-hospital variability in the use
	of health resources, diagnostic procedures, and therapeutic procedures
	in patients with RA. For example, in one comparison among centers, the
	mean number of visits per person over a 2-year period ranged from a low
	of 5.1 (range 1-11) to a high of 10.2 (range 2-31). These differences
	remained after adjusting for disease severity and functional class,
	according to the preliminary results of the "Study of RA Management"
	(emAR). In the same study, the percentage of patients who underwent some
	orthopedic surgical procedure during the course of their disease ranged
	from 0 to 71%, depending on the center. Even though most patients were
	being treated with nonsteroidal anti-inflammatory drugs (NSAIDs),
	corticosteroids, and DMARDs, the use of specific drugs varied
	significantly, independently of the patient's clinical situation. That
	is, the variability observed cannot be explained solely by differences
	related with the disease itself, but is also associated with variables
	related with the hospital center, department, or physician responsible
	for the patient. This variability in RA management that cannot be
	explained by patient characteristics justifies the development of
	standards of quality for the treatment of RA.

	Moving Toward Integral Management of Rheumatoid Arthritis

	At any given time, a variety of specialists may collaborate in managing
	specific disease aspects, from diagnosis to treatment to follow-up.
	Primary care physicians, rheumatologists, radiologists,
	ophthalmologists, orthopedic surgeons, rehabilitation specialists,
	orthopedists, psychologists or psychiatrists, and even other,
	non-medical health personnel, should be aware of the need to unify
	criteria and to integrate care in accordance with the best available
	scientific evidence. One way to avoid RA patients' receiving
	contradictory messages from different specialists is the development of
	CPGs that are easy to understand, and with a strong enough scientific
	basis to earn the support of all specialists who help manage patients
	with this disease.

	Aligning Clinical Practice with the Best Available Scientific Evidence

	Clinical practice in RA treatment has varied considerably in recent
	years, despite the fact that therapeutic resources have remained almost
	constant. There is growing use of early and aggressive treatment, which
	is supported by evidence that such measures may delay disease progression.

	The controlled clinical trials showing the short-term efficacy of a
	treatment intervention in selected populations initially led to
	disparate treatment practices and options, which have not subsequently
	been supported by studies of effectiveness in persons with RA. For
	example, in clinical trials of short-term efficacy, the efficacy of all
	the available DMARDs is higher than that of placebo (PCB). In
	comparative studies of a similar duration, it is difficult to find
	evidence that one DMARD is better than others. In studies evaluating
	compliance with long-term treatment, the number of patients who continue
	taking a specific DMARD after 5 years is significantly higher for
	methotrexate. This type of evidence has led to the generalized use of
	methotrexate as the drug of choice in most centers that care for these
	patients.

	There is insufficient scientific to support certain clinical decisions,
	however, and not all the scientific evidence is within easy reach of
	clinicians. Furthermore, the evidence available is of varying
	methodological quality, thus its scientific validity may be more or less
	solid. The use of more highly developed instruments to analyze
	information may facilitate changes in clinical practice as important as
	that of early intervention, based on the best available scientific
	evidence. Thus, this guideline is an attempt to base the process of care
	on the best available scientific evidence and, where this does not exist
	or is contradictory, applies the collective judgments of an expert panel
	selected according to specific criteria and using a scientific
	methodology developed to avoid biases.


	METHODOLOGY


	1. Synthesis of the Evidence


	1.1 Objective

	The synthesis of the evidence in the development of CPGs has three
	objectives: 1) to base the recommendations on the best available
	scientific evidence; 2) to allow users to obtain the information on
	which the recommendations are based; and 3) to make it possible to
	evaluate the quality of the guideline.

	One problem in carrying out a synthesis of the evidence is that the
	amount of information may be so extensive as to be impossible to cover.
	There are more than 35,000 medical journals in the world, which publish
	over 3 million articles every year. In addition, these journals are
	published in many different languages, the designs of the studies may be
	very heterogeneous, the methodological quality is highly variable, the
	patients selected may be very different, the measure of results may
	refer to different outcomes, and different subjects may be treated for
	the same intervention (e.g., whereas one study focuses on clinical
	outcomes, others may focus on complications, utilization,
	physiopathological mechanisms, or costs). This makes it necessary to
	limit the search for scientific evidence. Limiting such searches is
	justified not only by real limitations on resources and time, but also
	because a search aimed specifically at key aspects of disease management
	may constitute one of the strengths of a CPG. This naturally depends on
	achieving an intelligent balance among the topics searched, the quality
	of the review process, and the available resources. Thus, once the large
	number of RA publications had been explored, it was agreed that, for
	this guideline, the synthesis of the evidence would focus on the
	efficacy of DMARDs.


	1.2 Drugs included in the synthesis of the evidence

	After making an initial estimate of the volume of literature to be
	reviewed, the project investigators and the members of the expert panel
	agreed to focus the synthesis of the evidence on studies evaluating the
	efficacy of treatment with DMARDs (clinical trials) by means of a
	systematic review. Table 1 shows the DMARDs included in the review.


	Table 1. Disease modifying antirheumatic drugs included in the
	systematic literature review

	   * Antimalarials: Chloroquine (CLQ) and Hydroxychloroquine (HCQ)
	   * Azathioprine (AZA)
	   * Cyclophosphamide (CPA)
	   * Cyclosporin A (CSA)
	   * D-penicillamine (DP)
	   * Anti-tumor necrosis factor (anti-TNF) agents: infliximab (IFM) 
	     and etanercept (ETN)
	   * Leflunomide (LEF)
	   * Methotrexate (MTX)
	   * Gold salts: Oral gold (OG) and injectable gold (IG)
	   * Sulphasalazine (SSZ)


	1.3 Search strategy for identifying the scientific evidence

	The literature search for the synthesis of the evidence on the efficacy
	of DMARDs in RA was made in four databases, for the time periods noted
	below:

	   * MEDLINE: 1966-2000
	   * EMBASE (Drugs and Pharmacology section): 1984-2000
	   * Spanish Medical Index (Indice Médico Español - IME): 1971-2000
	   * Cochrane Library: year 2000 version.

	The articles for the bibliographic search had to meet the following
	inclusion criteria: 1) controlled clinical trial, meta-analysis, or
	systematic review; 2) study referring to one or more of the selected
	DMARDs; 3a) comparison of the efficacy of a drug or combined therapy vs.
	another drug or combined therapy including at least one of the drugs
	listed in Table 1, or comparison of LEF or TNF with placebo; 3b) if a 
	systematic review or meta-analysis, comparison of a drug or combined 
	therapy vs. another drug or combined therapy including at least one of 
	the drugs listed in table 1, or with placebo; 4) study carried out in 
	patients with RA; 5) trial carried out in humans; and 6) published in 
	English or Spanish.

	The descriptors used were those specified in each database with regard
	to the research methodology (e.g., RANDOMIZED-CONTROLLED-TRIAL),
	rheumatoid arthritis (e.g., RHEUMATOID ARTHRITIS), and specific drugs
	(e.g., METHOTREXATE ).


	1.4 Selection of articles

	We first identified all existing systematic reviews on DMARDs. Nine
	systematic reviews were located in the Cochrane Library that compared
	placebo with the following drugs: methotrexate, sulphasalazine,
	cyclosporin, oral gold salts, injectable gold salts, cyclophosphamide,
	d-penicillamine, azathioprine, and anti-malarials.

	Using the search strategy described, we then located 982 bibliographic
	records in MEDLINE, 968 in EMBASE, 268 in the Cochrane Library, and 63
	in IME, for a total of 2,281 records; of these, 666 were found in more
	than one database. Thus, the final number of records selected was 1,615.

	All the bibliographic records selected were read independently by two
	reviewers (a rheumatologist and a physician with training in
	epidemiology), both of whom had received training in how to carry out a
	synthesis of the evidence. The objective of reading the title of the
	bibliographic record was to verify that the article met the inclusion
	criteria.

	A 4-phase strategy was used to screen the records:

	   1. Review of the title. Resulting in the following two possibilities:
          	a. The record was rejected because it did not meet the
                   inclusion criteria.
          	b. The record was accepted either because it met the criteria
                   described or because it was not possible to decide whether
                   or not it met the inclusion criteria based on the data provided.

	Of the 1,615 records selected, 289 were rejected during the first phase;
	thus, 1,326 bibliographic records went on to the second phase.

	   2. Review of the abstract. In those cases in which the record
              passed the first phase and had an abstract, the abstract was read,
              which led to two options:
          	a. It was rejected because it did not meet the inclusion criteria.
          	b. It was accepted, either because it met the criteria
                   described or because it was not possible to decide whether
                   or not it met the inclusion criteria based on the data provided.

	All the articles passing the first phase that did not have an abstract
	passed directly to the third stage.

	Of the 1,326 articles that passed to the second phase, 1,225 had an
	abstract and 101 did not. After reading the abstract, 1,039 were
	eliminated and 186 were accepted and passed to the third phase, together
	with the 101 records with no abstract. That is, 287 articles passed to
	the "request for articles" stage.

	In the first two stages of screening the records, each
	rheumatologist-methodologist team compared the records read and, in case
	of discrepancy, the two reviewers discussed the article. If no agreement
	was reached, the record was read by another pair of reviewers.
	Discrepancies between reviewers occurred in 4% of records, and agreement
	was reached in 100% of cases.

	   3. Request for articles. In this phase the articles that had not
              been rejected after phases 1 and 2 were requested. The requests
              were directed first to the National Library of the Health Sciences
              (Biblioteca Nacional de Ciencias de la Salud - BNCS) of the
              ISCIII, to which the UISS also belonged. If the article was not in
              the BNCS, it was requested from the library of a Madrid hospital,
              generally the 12 de Octubre Hospital or the Ramón y Cajal
              Hospital. If the article could not be found in any Madrid library,
              the Loan Service of the BNCS requested it through a biomedical
              library within Spain, and if it could not be found in any Spanish
              library of the health sciences, it was requested from the British
              Library or from the Netherlands Institute for Scientific
              Information Services (Nederlands Instituut voor Wetenschappelijke
              Informatiediensten - NIWI).
	   4. Data collection and evaluation of the quality of the evidence.
              The relevant information for each article was collected using a
              form designed with four objectives in mind: 1) to identify the
              bibliographic information included in the review; 2) to verify
              that the article, in its complete text, met the inclusion criteria
              for the review; 3) to collect the relevant clinical information
              for each article accepted; and 4) to evaluate the methodological
              quality and the level of evidence of the trials.

	Objective 1: To identify the bibliographic information for each
	article included in the review. General information was obtained on the
	relevant bibliographic data of the article (e.g., first author, year of
	publication, journal). Each article was coded to facilitate its location
	in the database.

	Objective 2: To verify that the article, in its complete text, met the
	inclusion criteria for the review. This verification process resulted in
	four possibilities:

	   1. All inclusion criteria were met, in which case the article was
              included.
	   2. At least one of the inclusion criteria was not met, in which case
              it was excluded.
	   3. The inclusion criteria were met, but the article was redundant.
              Articles were considered to be redundant if they were published on
              successive occasions, generally in a different journal from the
              first publication, but referred to the same clinical trial and did
              not provide additional information in comparison to the first
              publication. In this case, one of the publications was selected to
              complete the form with the study data, and the redundant one was
              excluded.
	   4. The inclusion criteria were met but the article was a complement
              to a previous one. Articles were considered to be complementary
              if, in comparison with another previous publication of the same
              trial, they included different outcome measures or, if they
              included the same outcome measures, these were collected for a
              different period of time (e.g., clinical variables in one journal
              and radiographic variables in another; or radiographic variables
              up to 6 months in one journal and up to 3 years in another). In
              these cases, the results of both publications were combined; the
              complete information from one of the articles was used to fill out
              the form, adding the new and complementary information provided by
              the other article on the same form.

	Redundant or complementary articles were identified a posteriori after
	reading the articles, by verifying that the study was written by the
	same authors, used the same guidelines for the treatments compared, and
	used the same study design.

	Objective 3: To collect the relevant clinical information from each
	article accepted. If the article met the inclusion criteria, data were
	collected on the number and characteristics of the participants (gender,
	age, mean time of disease progression, previous use of NSAIDs and
	DMARDs), interventions, outcome measures evaluated, persons lost to
	follow-up and withdrawals from the study, reliability of the measurement
	instruments used, follow-up of the groups, and statistical analysis.

	Objective 4: To assess the methodological quality and level of
	evidence of the trials. The methodological quality of the trials was
	assessed using the Jadad scale for rating the quality of clinical trials
	(Table 2 [Jadad, 1996a]. The level of evidence was assessed in accordance 
	with the Hadorn scale designed to evaluate the quality of the evidence of 
	publications used to develop CPGs (Table 3) [Hadorn, 1996].


	Table 2. Jadad scale for rating the quality of evidence from clinical trials

	------------------------------------------------------------------------

	To rate the quality of a clinical trial, three questions are posed:

	   1. Was the study described as randomized?
	   2. Was the study described as double blind?
	   3. Was there a description of withdrawals and drop outs?

	------------------------------------------------------------------------

	One point is given for each "yes" and 0 points for each "no". There are
	no intermediate scores.

	An additional point is given in question 1 if the randomization method
	is described and is appropriate, and an additional point is given in
	question 2 if the method for making the study double blind is described
	and is appropriate.

	One point is subtracted in question 1 if the randomization method is
	described but is inappropriate, and one point is subtracted in question
	2 if the study is described as double blind, but the blinding method is
	inappropriate.

	An article can receive a score of 0 to 5 points. An article is
	considered to be of good quality if the score is 3 or higher, and of
	poor quality if the score is less than 3.


	Table 3. Hadorn scale for rating the quality of scientific evidence from 
	articles for CPGs

	   1. Well-conducted multicenter randomized controlled trials including 100
	      or more patients
	   Level of evidence
          	* A
	   2. Well-conducted randomized controlled trials with fewer than 100
	      patients, in one or more institutions
	   Level of evidence
          	* A
	   3. Well-conducted cohort studies
          	* A
	   4. Well-conducted case-control studies 	
	   Level of evidence
          	* B
	   5. Poorly controlled or uncontrolled studies
	   Level of evidence
          	* B
	   6. Conflicting evidence in favor of the recommendation
          	* B
	   7. Expert opinion
          	* C

	Levels 1, 2, and 3 refer to a high level of evidence (A); levels 4, 5,
	and 6 refer to a level of evidence with potential biases that could
	invalidate the results (B); and level 7 is the evidence most vulnerable
	to potential biases (C).

	Since only clinical trials were evaluated in the synthesis of the
	evidence for this guideline, the levels of evidence assigned are A1 (1
	on the Hadorn scale ), A2 (2 on the Hadorn scale), and B (5 on the
	Hadorn scale).

	Data collection form. A form was designed to collect the bibliographic
	data for each article, information about the study methodology, clinical
	data, the quality of the methodology, and the level of evidence. The
	first version of the form was evaluated by three reviewers (two
	rheumatologists and one methodologist) who applied it to 10 articles.
	After introducing the appropriate modifications, the reviewers began to
	use the form. It was necessary to change the form for later articles,
	however, in order to adapt it to the peculiarities of each trial (for
	example, the number of interventions compared, outcomes measured, and so
	on) and to be able to create homogeneous and unbiased evidence tables.
	After 13 successive versions, the definitive form was obtained, which
	was sufficiently valid to permit inclusion and categorization of the
	relevant information from each article. This form is available to
	interested readers (milena@taiss.com).

	Evaluation of the articles. Five reviewers read and evaluated the
	articles: two specialists in rheumatology and three in research
	methodology. All had been trained in techniques for the critical review
	of the scientific literature. Each article was read independently by two
	reviewers, one physician with training in epidemiology and one
	rheumatologist. Each reviewer completed one form for each article. Each
	epidemiologist-rheumatologist team then compared the individual forms
	and, if they agreed, completed the final form. The two reviewers
	discussed any discrepancies in an attempt to reach consensus. If they
	did not agree, the article was read and discussed by all the reviewers
	until agreement was reached, at which point the final form was completed.

	Each form made up one record in the database designed for the synthesis
	of the evidence. The form describes a comparison between two different
	treatment interventions. This means that a trial assessing more than two
	treatment interventions, making different comparisons among them, would
	give rise to more than one form. Thus, the number of forms is larger
	than the number of clinical trials included in the synthesis of the
	evidence.

	Of the 287 articles requested, 162 did not meet at least one of the
	inclusion criteria, 13 were redundant and 9 were articles comparing
	drugs with placebo that had already been included in the systematic
	reviews of the Cochrane Library. Consequently, a total of 103 articles
	was included in the review, 91 of which were different clinical trials
	(12 were complementary articles), allowing 140 comparisons between
	different treatment strategies (single drugs or combinations thereof).
	Thus, there are 140 records in the database for the efficacy of DMARDs
	(see Table 4).

	(Table 4 of the GUIPCAR CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT
	OF RHEUMATOID ARTHRITIS guideline is available in the original guideline
	document.)

	These 91 trials and the 140 resulting comparisons are grouped by the
	Jadad and Hadorn scales for classifying the quality of the evidence as
	shown in Tables 5 and 6, respectively.


	Table 5. Clinical trials and comparisons by the Jadad scale for rating 
	the quality of the evidence

	LEVEL OF EVIDENCE (Jadad Scale)
	   * 1	
	CLINICAL TRIALS
	   * 7 (8%)	
	COMPARISONS
	   * 7 (5%)

	LEVEL OF EVIDENCE (Jadad Scale)
	   * 2	
	CLINICAL TRIALS
	   * 19 (21%)	
	COMPARISONS
	   * 24 (17%)	
 	 	
	LEVEL OF EVIDENCE (Jadad Scale)
	   * 3	
	CLINICAL TRIALS
	   * 18 (20%)	
	COMPARISONS
	   * 31 (22%)	
 	 	
	LEVEL OF EVIDENCE (Jadad Scale)
	   * 4	
	CLINICAL TRIALS
	   * 32 (35%) 	
	COMPARISONS
	   * 53 (38%)	
 	 	
	LEVEL OF EVIDENCE (Jadad Scale)
	   * 5	
	CLINICAL TRIALS
	   * 15 (16%) 	
	COMPARISONS
	   * 25 (18%)	
 	 	
	LEVEL OF EVIDENCE (Jadad Scale)
	   * TOTAL	
	CLINICAL TRIALS
	   * 91 (100%)
	COMPARISONS
	   * 140 (100%)	
 

	Table 6. Clinical trials and comparisons by the Hadorn scale for rating 
	the quality of the evidence

	LEVEL OF EVIDENCE (Hadorn Scale) 	
	   * A1	
	CLINICAL TRIALS 	
	   * 13 (14%) 		
	COMPARISONS
	   * 25 (18%)
	   
	LEVEL OF EVIDENCE (Hadorn Scale) 	
	   * A2	
	CLINICAL TRIALS 	
	   * 13 (14%) 		
	COMPARISONS
	   * 20 (14%)
	   
	LEVEL OF EVIDENCE (Hadorn Scale) 	
	   * B 	
	CLINICAL TRIALS 	
	   * 65 (72%) 		
	COMPARISONS
	   * 95 (68%)

	LEVEL OF EVIDENCE (Hadorn Scale) 	
	   * TOTAL 		
	CLINICAL TRIALS 	
	   * 91 (100%)  		
	COMPARISONS
	   * 140 (100%)



	Thirty-eight of the 140 comparisons assessed a DMARD vs. certain drugs
	not included in the systematic review (e.g., collagen II, tiopronin, or
	pyrithinol). These 38 comparisons were excluded because the expert panel
	believed they were not relevant. Thus, the final 102 comparisons refer
	only to the DMARDs listed in Table 1.

	For the purposes of the synthesis of the evidence, the comparisons were
	grouped by drug to make it easier to find the clinical trials comparing
	a specific drug (alone or in combination) with any of the other drugs in
	table 1 (also alone or in combination).

	For each possible comparison we identified the number of existing
	studies, their level of evidence, and the intervention favored by the
	outcome measures collected in each study. (The tables synthesizing the
	outcome measures collected in each study for the comparisons are
	available to interested readers by contacting milena@taiss.com).

	The panel was consulted when a) different studies comparing the same
	drugs included different outcome measures, some (e.g., clinical effect)
	in favor of one treatment intervention and others (e.g., radiographic
	results) in favor of the other intervention; and b) to assess the
	clinical relevance of some outcome measures with statistically
	significant differences when the differences were not significant for
	many other outcomes. In these divergent cases, greater weight was given
	to outcome measures in agreement with the American College of
	Rheumatology (ACR) criteria, especially the number of swollen joints and
	radiographic damage. For example, a study with A2 level evidence
	comparing chloroquine with oral gold salts shows significant differences
	in favor of chloroquine with regard to strength of grip and morning
	stiffness; however, functional status is significantly better in the
	group with oral salts, and no significant differences are found between
	the two groups with regard to the number of swollen joints, pain, or
	acute phase reactants. In this case it was concluded that there were no
	important clinical differences in the efficacy of chloroquine and oral
	gold salts.

	Evidence tables

	The results of the synthesis of the evidence are shown in Tables 7
	and 8. Table 7 includes the comparisons of DMARDs used in monotherapy. 
	Table 8 includes the comparisons of single or combined drugs vs. combinations 
	of drugs.

	For those comparisons for which evidence exists, there are three lines
	in the corresponding box with the following data:

	Line 1.  Number of studies and level of evidence of these studies (e.g.,
		 "3-A1; 2-B" means there are three studies with an A1 level of 
		 evidence and two with level B).
	Line 2.  The identification numbers for these articles (used as the
		 bibliographic reference). Numbers separated by a dash (e.g., 7-9) 
		 mean that all articles in the interval are included (7, 8, and 9).
		 Numbers separated by a comma (e.g., 7, 9) represent references only to
		 those specific articles (7 and 9).
	Line 3.  One of the following possibilities is shown in bold print: 
	         - The drug or combination of drugs (COMB) which the evidence favors
		   (using the abbreviations shown in table 1.)
		 - NS: if the differences are not significant.


	Table 7. Comparisons of DMARDs used only in monotherapy

  	CPA
	   PCB 
          	*	   
	   AUR
          	*
           AZA 	
          	* 1-B
          	  1
          	  CPA                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	*	   
	   CSA
          	*	   
	   DP
          	*	   
	   ETN
          	*	   
	   HCQ
          	*	   
	   IFM
          	*	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   

	CLQ
	   PCB 
          	*	   
	   AUR
          	* 1-A2
          	  2
          	  NS
           AZA 	
          	* 1-B
          	  3
          	  NS 	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	*	   
	   CSA
          	*	   
	   DP
          	*	   
	   ETN
          	*	   
	   HCQ
          	*	   
	   IFM
          	*	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
  	  	  	  	  	  	  	  	  	 
 	CSA
	   PCB 
          	*	   
	   AUR
          	* 
           AZA 	
          	* 1-B
          	  4
          	  NS  	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 1-A2
          	  5
          	  NS 	  	  	  	  		   
	   CSA
          	*	   
	   DP
          	*	   
	   ETN
          	*	   
	   HCQ
          	*	   
	   IFM
          	*	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
  	  		  	  	  	  	  	  	  	 
	DP
	   PCB 
          	*	   
	   AUR
          	* 1-B
          	  6
          	  DP
           AZA 	
          	* 3-B
          	  7-9
          	  NS  	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 1-B
          	  10
          	  NS 	  	  	  	  		   
	   CSA
          	* 1-A2
          	  11
          	  NS 		   
	   DP
          	*	   
	   ETN
          	*	   
	   HCQ
          	*	   
	   IFM
          	*	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
 
	ETN
	   PCB 
          	* 2A1;1B
          	  12-14
          	  ETN 	 	   
	   AUR
          	* 
           AZA 	
          	*   	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 	  	  	  	  		   
	   CSA
          	* 		   
	   DP
          	*	   
	   ETN
          	* 2-A1
          	  15,72
          	  NS 	  	  	  	  	 	   
	   HCQ
          	*	   
	   IFM
          	*	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
  	  	  		  	  	  	  	 
	HCQ
	   PCB 
          	*  	 	   
	   AUR
          	* 1-B
          	  16
          	  NS 	  	 
           AZA 	
          	*   	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 	  	  	  	  		   
	   CSA
          	* 		   
	   DP
          	* 2-B
          	  17-18
          	  NS 	  	  	  	  		   
	   ETN
          	*  	  	  	  	  	 	   
	   HCQ
          	*	   
	   IFM
          	*	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
  	  	 	  	  	  	 
	IFM
	   PCB 
          	* 2-A2
          	  19,20
          	  IFM 	   	 	   
	   AUR
          	*  	  	 
           AZA 	
          	*   	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 	  	  	  	  		   
	   CSA
          	* 		   
	   DP
          	*  	  	  	  	  		   
	   ETN
          	*  	  	  	  	  	 	   
	   HCQ
          	*	   
	   IFM
          	* 1-A2
          	  21
          	  DOSE=10 	  	  	 	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
 
	LEF
	   PCB 
          	* 2-A1;3-B
          	  22-26
          	  LEF 		   	 	   
	   AUR
          	*  	  	 
           AZA 	
          	*   	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 	  	  	  	  		   
	   CSA
          	* 		   
	   DP
          	*  	  	  	  	  		   
	   ETN
          	*  	  	  	  	  	 	   
	   HCQ
          	*	   
	   IFM
          	* 	  	  	 	   
	   LEF
          	*	   
	   MTX
          	*	   
	   IG
          	*	   
  	 	  	  	  	  	  	  	  	
	MTX 
	   PCB 
          	*  		   	 	   
	   AUR
          	* 1-A1;1-B
          	  27, 28
          	  MTX  	  	 
           AZA 	
          	* 2-A2;2-B
          	  29-32
          	  MTX 	  	  	  	  	  	                     	
	   CPA 	  	
          	*	   
	   CLQ 	
          	* 1-B
          	  33
          	  NS	  	  	  	  		   
	   CSA
          	* 		   
	   DP
          	*  	  	  	  	  		   
	   ETN
          	* 2-A1
          	  72
          	  NS 	  	  	  	  	 	   
	   HCQ
          	*	   
	   IFM
          	* 3-B
          	  34-36
          	  NS 	  	  	 	   
	   LEF
          	* 1-A1;2-B
          	  37-39
          	  NS 	  	 	   
	   MTX
          	*	   
	   IG
          	*	   
  	  	  	  	  	  	  	  	  	  	  	  	 
	IG
	   PCB 
          	*  		   	 	   
	   AUR
          	* 1-A1;1-A2;
          	  8-B
          	  40-49
          	  NS 
           AZA 	
          	* 2-B
          	  50,51
          	  AZA          	  	  	  	  	  	  	                     	
	   CPA 	  	
          	* 1-B
          	  52
          	  CPA	   
	   CLQ 	
          	* 1-B
          	  53
          	  NS 	  	  	  	  		   
	   CSA
          	* 1-A2
          	  54
          	  NS 		   
	   DP
          	* 3-B
          	  55-57
          	  NS  	  	  	  	  		   
	   ETN
          	*  	 	  	  	  	  	 	   
	   HCQ
          	*	   
	   IFM
          	*  	  	  	 	   
	   LEF
          	* 	  	 	   
	   MTX
          	* 1-A2;4-B
          	  58-62
          	  NS	   
	   IG
          	*	   
 
	SSZ
	   PCB 
          	*  		   	 	   
	   AUR
          	* 1-B
          	  63
          	  NS 	  	
           AZA 	
          	*          	  	  	  	  	  	  	                     	
	   CPA 	  	
          	* 	   
	   CLQ 	
          	*  	  	  	  	  		   
	   CSA
          	*  		   
	   DP
          	* 2-B
          	  64, 65
          	  NS	  	  	  	  		   
	   ETN
          	*  	 	  	  	  	  	 	   
	   HCQ
          	* 2-A2
          	  66, 67
          	  SSZ	   
	   IFM
          	*  	  	  	 	   
	   LEF
          	* 1-A1
          	  68
          	  NS 	  	 	   
	   MTX
          	* 1-A1;1-A2
          	  69, 70
          	  NS 	   
	   IG
          	* 1-B
          	  71
          	  NS	   

	* Compares doses of 1 mg/kg vs. 10 mg/kg


	Table 8. Comparisons of single or combined DMARDs vs. drug combinations
	
	AUR
	   AUR+MTX
          	* 1-B
          	  73
          	  NS 	 	   
	   AZA+MTX
          	* 	   
	   CLQ+DP
          	* 	   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
  	 	  	  	  	  	  	  	  	  	  	  	  	 
	AZA
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	* 1-B
          	  74
          	  COMB 	  		   
	   CLQ+DP
          	* 	   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  

 	CPA 	  	  	  	  	  	  	  	  	  	  	  	 
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	* 	   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
 
	CLQ
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	* 1-B
          	  75
          	  NS 	  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
  	  	  	  	  	  	  	  	  	  	  	  	  	  	 
	CSA 
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	* 	  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  

	DP
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	* 1-B
          	  76
          	  NS 	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 1-B
          	  77
          	  NS          		  	  	  	 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
  	  	  	  	  	  	  	  	  	  	  	 
	ETN
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
 
	HCQ
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	* 1-B
          	  78
          	  NS          		  	  	  	 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	*  	   
	   SSZ+HCQ
          	* 1-A2
          	  79
          	  COMB 	   
	   HCQ+MTX
          	* 1-B
          	  80
          	  COMB 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
  	  	  	  	  	  	  	  	  	  	  	  	  	  	 
	IFM
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	*  	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
 
	LEF
	   AUR+MTX
          	* 	 	   
	   AZA+MTX
          	*  	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 	   
	   HCQ+IG
          	*  	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  
  	  	  	  	 	  	  	 
	MTX 
	   AUR+MTX
          	* 1-B
          	  81
          	  NS 	 	   
	   AZA+MTX
          	* 1-B
          	  82
          	  COMB 	 	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 1-A2
          	  83
          	  COMB	   
	   CSA+IG
          	* 	   
	   CSA+MTX
          	* 1-A1
          	  84
          	  COMB 	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 1-B
          	  85
          	  COMB 	  	   
	   HCQ+IG
          	*  	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 1-A2
          	  86
          	  COMB	   
	   IFM+MTX
          	* 7-B
          	  87-93
          	  COMB	   
	   MTX+SSZ
          	* 1-A1:1-A2
          	  94,95
          	  NS 
  	  	  	  	  	  	  	  	  	  	  	  	  	  	 
	IG
	   AUR+MTX
          	*  	 	   
	   AZA+MTX
          	*  	 	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	* 1-B
          	  96
          	  NS 	   
	   CSA+MTX
          	*  	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 	  	   
	   HCQ+IG
          	* 1-A1;1-B
          	  97,98
          	  NS 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	* 
 
	SSZ
	   AUR+MTX
          	*  	 	   
	   AZA+MTX
          	*  	 	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	*  	   
	   CSA+MTX
          	*  	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 	  	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 1-A2
          	  99
          	  NS	   
	   HCQ+MTX
          	* 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	* 1-A1:1-A2
          	  100, 101
          	  NS
  	  	  	  	  	  	  		  	  		
	SSZ+HCQ
	   AUR+MTX
          	*  	 	   
	   AZA+MTX
          	*  	 	  		   
	   CLQ+DP
          	*  	  	  		  	  		   
	   MTX+CLQ
          	* 	   
	   CSA+IG
          	*  	   
	   CSA+MTX
          	*  	   
	   HCQ+DP
          	*           		  	  	  	 	   
	   MTX+ETN
          	* 	  	   
	   HCQ+IG
          	* 	   
	   SSZ+HCQ
          	* 	   
	   HCQ+MTX
          	* 	  	  	 	   
	   MTX+SSZ+HCQ
          	* 1-A2
          	  102
          	  COMB. TRIP.	   
	   IFM+MTX
          	* 	   
	   MTX+SSZ
          	*  	  	  	  	  	  	  	  	  	  	 	  	  	  	
 

	Tables 9a and 9b show the mean time of disease progression, previous use of 
	DMARDs (if the box is blank, this data was not included in the article), 
	duration of treatment in the trial (if the box is blank, this data was not 
	included in the article), the level of evidence, the bibliographic reference 
	for each comparison (cited in references 2.2, 2.3, and 2.4), and the 
	identification number for each article (used to locate it in Tables 7 and 8).


	Table 9a. Mean time of RA progression, previous DMARD use, duration of treatment 
	in the trial, level of evidence, bibliographic reference, and ID number in the 
	comparisons of DMARDs used in monotherapy included in the synthesis of the evidence

	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * Cyclophosphamide	   
	Mean time of RA progression (in months) 	
	   * 60	
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 72	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 1, R1	
	ID N°
	   * 1	
	
	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Chloroquine	   
	Mean time of RA progression (in months) 	
	   * 39.4	
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 2	
	ID N°
	   * 2	
 	 	 	  	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * Chloroquine	   
	Mean time of RA progression (in months) 	
	   * 23	
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 3	
	ID N°
	   * 3	
 	 	 	  	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Cyclosporin
	   * Azathioprine	   
	Mean time of RA progression (in months) 	
	   * 79.2	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 4	
	ID N°
	   * 4	
 	 	 	  	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Cyclosporin
	   * Chloroquine	   
	Mean time of RA progression (in months) 	
	   * 78	
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 5	
	ID N°
	   * 5	
  	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 83	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 6	
	ID N°
	   * 6	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 113.4	
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 7, R2	
	ID N°
	   * 7	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 134	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 8	
	ID N°
	   * 8	
 	 	 	  	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 132	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 9	
	ID N°
	   * 9	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * D-penicillamine
	   * Chloroquine	   
	Mean time of RA progression (in months) 	
	   * 30	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 10	
	ID N°
	   * 10	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Cyclosporin
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 86.4	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 11	
	ID N°
	   * 11	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Etanercept
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 150	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 12	
	ID N°
	   * 12	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Etanercept
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 138	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 12	
	ID N°
	   * 13	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Etanercept
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 12	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 13	
	ID N°
	   * 14	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Etanercept
	   * Etanercept	   
	Mean time of RA progression (in months) 	
	   * 144	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 12	
	ID N°
	   * 15	
  	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Hydroxychloroquine	   
	Mean time of RA progression (in months) 	
	   * 124.5	
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 14	
	ID N°
	   * 16	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Hydroxychloroquine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 71.4	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 15	
	ID N°
	   * 17	
 	 	 	  	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Hydroxychloroquine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 	
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 16	
	ID N°
	   * 18	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Infliximab
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 99	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 4	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 17	
	ID N°
	   * 19	
  	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Infliximab
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 97.8 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 4	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 17	
	ID N°
	   * 20	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Infliximab
	   * Infliximab	   
	Mean time of RA progression (in months) 	
	   * 88.8 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 4	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 17	
	ID N°
	   * 21	
	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 79.8 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 18	
	ID N°
	   * 22	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 83.4 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 19, R3 		
	ID N°
	   * 23	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 96 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 20 		
	ID N°
	   * 24	

	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 100.8 	
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 20 		
	ID N°
	   * 25	

	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Placebo	   
	Mean time of RA progression (in months) 	
	   * 102.6 		
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 20 		
	ID N°
	   * 26	
 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Methotrexate
	   * Oral gold salts	   
	Mean time of RA progression (in months) 	
	   * 70.3 		
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 36	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 21, C1 		
	ID N°
	   * 27	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Methotrexate
	   * Oral gold salts	   
	Mean time of RA progression (in months) 	
	   * 59.5 		
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 22, C2		
	ID N°
	   * 28	

	DMARDs compared (used in monotherapy) 	
	   * Methotrexate
	   * Azathioprine	   
	Mean time of RA progression (in months) 	
	   * 104.4 		
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 23		
	ID N°
	   * 29	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Methotrexate
	   * Azathioprine	   
	Mean time of RA progression (in months) 	
	   * 133.2		
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 24, R4, R5		
	ID N°
	   * 30	
 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Methotrexate
	   * Azathioprine	   
	Mean time of RA progression (in months) 	
	   * 96 			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 25, R6, R7	
	ID N°
	   * 31	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Methotrexate
	   * Azathioprine	   
	Mean time of RA progression (in months) 	
	   * 156 			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 26
	ID N°
	   * 32	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Cyclosporin
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 25.8 			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 27
	ID N°
	   * 33	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Infliximab
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 91.2 			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 28
	ID N°
	   * 34	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Infliximab
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 92.4			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 28
	ID N°
	   * 35	
 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Infliximab
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 103.8			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 28
	ID N°
	   * 36	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 81			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 19
	ID N°
	   * 37	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 45			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 29
	ID N°
	   * 38	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 43.8			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 104	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 29
	ID N°
	   * 39	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 76			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 21	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 30, C3, R8, R9
	ID N°
	   * 40	
 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 115.8			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 31
	ID N°
	   * 41	
 	 	 	 	 	 	 	
	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 83.4			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 32
	ID N°
	   * 42	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 61.8			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 33, C4
	ID N°
	   * 43	
	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 144			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 34
	ID N°
	   * 44	
 	 	 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 63.6			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 35
	ID N°
	   * 45	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 109.2			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 36
	ID N°
	   * 46	
 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 45.6			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 37, C5
	ID N°
	   * 47	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 63			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 38
	ID N°
	   * 48	

 	DMARDs compared (used in monotherapy) 	
	   * Oral gold salts
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 24			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 39, C6, R10
	ID N°
	   * 49	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 60			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 72	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 1
	ID N°
	   * 50	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Azathioprine
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 25			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 3
	ID N°
	   * 51	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Cyclophosphamide
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 48			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 72	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 1
	ID N°
	   * 52	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Chloroquine	   
	Mean time of RA progression (in months) 	
	   * 20			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 3
	ID N°
	   * 53	
 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Cyclosporin
	   * Injectable gold	   
	Mean time of RA progression (in months) 	
	   * 11.76			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 72	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 40
	ID N°
	   * 54	
 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 66			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 41, R11
	ID N°
	   * 55	
 	 	 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 14.8 			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 42
	ID N°
	   * 56	
 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   *  			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 21	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 43
	ID N°
	   * 57	
 	 	 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   *  			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 44
	ID N°
	   * 58	
 	 	 	  	 		 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 14			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 45
	ID N°
	   * 59	
 	 	 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 17.5			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 46
	ID N°
	   * 60	
 	 	 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 23.9			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 144	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 47, C7, C8
	ID N°
	   * 61	
	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 68.4			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 26	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 48
	ID N°
	   * 62	
  	  	 		 	
 	DMARDs compared (used in monotherapy) 	
	   * Sulphasalazine
	   * Oral gold salts	   
	Mean time of RA progression (in months) 	
	   * 114			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 240	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 49, C9 	
	ID N°
	   * 63	
 	 	  	 	 		 	
 	DMARDs compared (used in monotherapy) 	
	   * Sulphasalazine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 84			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 576	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 50, C10 	
	ID N°
	   * 64	
 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Sulphasalazine
	   * D-penicillamine	   
	Mean time of RA progression (in months) 	
	   * 105			
	Previous DMARD use
	   * 	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 51 	
	ID N°
	   * 65	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Hydroxychloroquine
	   * Sulphasalazine	   
	Mean time of RA progression (in months) 	
	   * 12.8			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 52, C11, C12, R12 	
	ID N°
	   * 66	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Hydroxychloroquine
	   * Sulphasalazine	   
	Mean time of RA progression (in months) 	
	   * 75.6			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 53 	
	ID N°
	   * 67	
 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Leflunomide
	   * Sulphasalazine	   
	Mean time of RA progression (in months) 	
	   * 90			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 24	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 18 	
	ID N°
	   * 68	
 	 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Sulphasalazine
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 3.05			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 54 	
	ID N°
	   * 69	
 	 	 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Sulphasalazine
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 14.6			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 52	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 55 	
	ID N°
	   * 70	
 	  	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Injectable gold
	   * Sulphasalazine	   
	Mean time of RA progression (in months) 	
	   * 68			
	Previous DMARD use
	   * NO	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 56 	
	ID N°
	   * 71	
 	 	 	 	 	 	 	
 	DMARDs compared (used in monotherapy) 	
	   * Etanercept
	   * Methotrexate	   
	Mean time of RA progression (in months) 	
	   * 11.5			
	Previous DMARD use
	   * YES	
	Duration of treatment (in weeks) 	
	   * 48	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 57 	
	ID N°
	   * 72	
 	 	 	 	 	

	Table 9b. Mean time of RA progression, previous DMARD use, duration of treatment 
	in the trial, level of evidence, bibliographic referenc,e and ID number in the 
	comparisons of DMARDs used in monotherapy or combined therapy vs. drug combinations 
	included in the synthesis of the evidence

	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Oral gold salts 
          	* Methotrexate
          	* Oral gold salts         	
	Mean time of RA progression (in months) 	
	   * 64.5	
	Previous DMARD use 	
	   * NO	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 22	
	ID N°
	   * 73	
	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Azathioprine 
          	* Methotrexate
          	* Azathioprine         	
	Mean time of RA progression (in months) 	
	   * 96	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 25, R6, R7	
	ID N°
	   * 74	
	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Chloroquine 
          	* Chloroquine
          	* D-penicillamine         	
	Mean time of RA progression (in months) 	
	   * 24	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 10	
	ID N°
	   * 75	
 	 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * D-penicillamine 
          	* Chloroquine
          	* D-penicillamine         	
	Mean time of RA progression (in months) 	
	   * 18	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 10	
	ID N°
	   * 76	

	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * D-penicillamine 
          	* Hydroxychloroquine
          	* D-penicillamine         	
	Mean time of RA progression (in months) 	
	   * 72.6	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 15	
	ID N°
	   * 77	
 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Hydroxychloroquine 
          	* Hydroxychloroquine
          	* D-penicillamine         	
	Mean time of RA progression (in months) 	
	   * 70.8	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 96	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 15	
	ID N°
	   * 78	
 	 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Hydroxychloroquine 
          	* Sulphasalazine
          	* Hydroxychloroquine        	
	Mean time of RA progression (in months) 	
	   * 75.6	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 53	
	ID N°
	   * 79	
 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Hydroxychloroquine 
          	* Hydroxychloroquine
          	* Methotrexate        	
	Mean time of RA progression (in months) 	
	   * 	
	Previous DMARD use 	
	   * 	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 58	
	ID N°
	   * 80	
	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Oral gold salts        	
	Mean time of RA progression (in months) 	
	   * 69	
	Previous DMARD use 	
	   * NO	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 22	
	ID N°
	   * 81	
 	 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Azathioprine        	
	Mean time of RA progression (in months) 	
	   * 96	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 25	
	ID N°
	   * 82	

	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Chloroquine        	
	Mean time of RA progression (in months) 	
	   * 92.58	
	Previous DMARD use 	
	   * 	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 59	
	ID N°
	   * 83	
 	 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Cyclosporin        	
	Mean time of RA progression (in months) 	
	   * 122.4	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 60	
	ID N°
	   * 84	
 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Etanercept        	
	Mean time of RA progression (in months) 	
	   * 156	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 61	
	ID N°
	   * 85	
 	 	  	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Sulphasalazine 
          	* Hydroxychloroquine          	
	Mean time of RA progression (in months) 	
	   * 120	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 96	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 62	
	ID N°
	   * 86	
 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 103.8	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 54	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 63, R13	
	ID N°
	   * 87	
 	 	 	 	 	 		
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 96.6	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 54	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 63, R13	
	ID N°
	   * 88	
 	 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 107.4	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 54	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 63, R13	
	ID N°
	   * 89	
 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 105.6	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 54	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 63, R13	
	ID N°
	   * 90	
 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 131.4	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 28	
	ID N°
	   * 91	
 	 	 		 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 118.2	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 28	
	ID N°
	   * 92	
 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Infliximab
          	* Methotrexate 
	Mean time of RA progression (in months) 	
	   * 112.2	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 26	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 28	
	ID N°
	   * 93	
 	 	 		 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Sulphasalazine 
	Mean time of RA progression (in months) 	
	   * 14.5	
	Previous DMARD use 	
	   * NO	
	Duration of treatment (in weeks)
	   * 52	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 55	
	ID N°
	   * 94	
 	 	 	 	 	
	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Methotrexate 
          	* Methotrexate
          	* Sulphasalazine 
	Mean time of RA progression (in months) 	
	   * 2.8	
	Previous DMARD use 	
	   * NO	
	Duration of treatment (in weeks)
	   * 52	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 54	
	ID N°
	   * 95	
 	
 	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Injectable gold 
          	* Injectable gold
          	* Cyclosporin 
	Mean time of RA progression (in months) 	
	   * 133.2	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 64	
	ID N°
	   * 96	
	 	 	 	 	 	
  	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Injectable gold 
          	* Hydroxychloroquine
          	* Injectable gold 
	Mean time of RA progression (in months) 	
	   * 24	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 48	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 65	
	ID N°
	   * 97	
	 	 	 	 	
  	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Injectable gold 
          	* Hydroxychloroquine
          	* Injectable gold 
	Mean time of RA progression (in months) 	
	   * 78	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * B	
	Bibliographic reference 	
	   * 66	
	ID N°
	   * 98	
 	
  	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Sulphasalazine 
          	* Sulphasalazine
          	* Hydroxychloroquine
	Mean time of RA progression (in months) 	
	   * 75.6	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 24	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 53	
	ID N°
	   * 99	
 	 	 	 	 	 	
  	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Sulphasalazine 
          	* Methotrexate
          	* Sulphasalazine
	Mean time of RA progression (in months) 	
	   * 75.6	
	Previous DMARD use 	
	   * NO	
	Duration of treatment (in weeks)
	   * 52	
	Level of evidence 	
	   * A1	
	Bibliographic reference 	
	   * 55	
	ID N°
	   * 100	
 	
  	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Sulphasalazine 
          	* Methotrexate
          	* Sulphasalazine
	Mean time of RA progression (in months) 	
	   * 2.9	
	Previous DMARD use 	
	   * NO	
	Duration of treatment (in weeks)
	   * 52	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 54	
	ID N°
	   * 101	
 	 	 	 	 	 	
   	DMARDs compared (used in monotherapy or combined therapy vs. drug combinations) 	
	   * Sulphasalazine 
	   * Hydroxychloroquine	   
          	* Methotrexate
          	* Sulphasalazine
          	* Hydroxychloroquine          	
	Mean time of RA progression (in months) 	
	   * 96	
	Previous DMARD use 	
	   * YES	
	Duration of treatment (in weeks)
	   * 96	
	Level of evidence 	
	   * A2	
	Bibliographic reference 	
	   * 62	
	ID N°
	   * 102	
	 	 	 	
	 	 	 	 	 	
	Evaluation of the methodological quality of meta-analyses

	The quality of the Cochrane Library meta-analyses was rated using the
	index of the quality of review articles, as revised by Oxman and Guyatt
	[Oxman, 1991a; Oxman, 1991b; Jadad, 1996b].

	This index is based on answers to the following questions:

	   1. Were the search methods used to find evidence on the primary
	      question stated?

		No 	Partially 	Yes

	   2. Was the search for evidence reasonably comprehensive?

		No 	Can't tell 	Yes

	   3. Were the criteria used for deciding which studies to include in
	      the review reported?

		No 	Partially 	Yes

	   4. Was bias in the selection of studies avoided?

		No 	Can't tell 	Yes

	   5. Were the criteria used for assessing the validity of the included
	      studies reported?

		No 	Partially 	Yes

	   6. Was the validity of all of the studies referred to in the text
	      assessed using appropriate criteria (either in selecting studies
	      for inclusion or in analyzing the studies that are cited)?

		No 	Can't tell 	Yes

	   7. Were the methods used to combine the findings of the studies reported?

		No 	Partially 	Yes

	   8. Were the findings of the relevant studies combined appropriately
	      relative to the primary question the overview addresses?

		No 	Can't tell 	Yes

	   9. Were the conclusions made by the author(s) supported by the data
	      and/or analysis reported in the overview?

		No 	Can't tell 	Yes

	   10. How would you rate the scientific quality of this overview?
	
		Extensive flaws    |    Major flaws    |    Minor flaws    |    Minimal flaws
						
		     - 1 -       - 2 -     - 3 -     - 4 -      - 5 -    - 6 -       - 7 -


	The score for question 10 (overall scientific quality) is based on the
	replies to the previous 9 questions. If the answer to one or more
	questions is "Can't tell" the overview probably has, at the very least,
	minor flaws, and it is difficult to exclude major flaws (score of 4 or
	less). If the answer to questions 2, 4, 6, or 8 is "No," the overview
	probably has major flaws (score of 3 or less), depending on the number
	and severity of the flaws). The score for the quality of the overview
	can range from 1 to 7, as shown in the figure for question 10.

	In accordance with the previously described methodology, the quality of
	the scientific evidence for the nine meta-analyses found is shown in
	Table 10.


	Table 10. Evaluation of the quality of the meta-analyses of DMARDs

	DMARD [Systematic review citation]*
	Questions in meta-analysis ratings
	   * 1
	   * 2 
	   * 3
	   * 4
	   * 5
	   * 6
	   * 7
	   * 8
	   * 9
	   * 10
	   	 
	* Auranofin [RS1] 	 	 	 	 	 	 	 	 	 	
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   
	
	* Azathioprine [RS2] 	
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   
	
	* Cyclophosphamide [RS3]
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   
	
	* Cyclosporin [RS4] 
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* No
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 3	   
		
	* D-penicillamine [RS5]
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   

	* Hydroxychloroquine [RS6]
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   
	
	* Methotrexate [RS7] 
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   
	
	* Injectable gold [RS8]
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* Can't tell
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 4	   
	
	* Sulphasalazine [RS9] 
	   * 1
          	* Yes
	   * 2
          	* Yes	   
	   * 3
          	* Yes
           * 4
          	* No
           * 5
          	* Yes        
	   * 6
          	* Yes	   
	   * 7
          	* Yes	   
	   * 8
          	* Yes	   
	   * 9
          	* Yes	   
	   * 10
          	* 3	   

	* The citation for each systematic review is shown in reference list 2.1.

	Table 11 shows the conclusions of the systematic reviews of the 
	Cochrane Library and the quality of these reviews.


	Table 11. Conclusions of the Cochrane Library meta-analyses and their 
	level of evidence

	DMARD [Systematic review citation]*
	   * Auranofin [RS1]
	Conclusions 	
	   * Auranofin appears to be efficacious in the short-term treatment of 
	     patients with RA. It has a small clinically and statistically significant 
	     benefit on disease activity. It may be more appropriate for patients with 
	     early and mild disease, who probably respond to less aggressive treatments.
	 Level of Evidence (1-7)
	   * 4
	   
	DMARD [Systematic review citation]*
	   * Azathioprine [RS2]
	Conclusions 	
	   * Appears to be beneficial in the short term in the treatment of patients with
	     RA. It cannot be considered more efficacious than other DMARDs, however, and 
	     its toxicity is greater. This suggests that other DMARDs should be used before 
	     considering azathioprine.
	 Level of Evidence (1-7)
	   * 4

	DMARD [Systematic review citation]*
	   * Cyclophosphamide [RS3]
	Conclusions 	
	   * Cyclophosphamide appears to be an effective drug in treating patients with RA,
	     but its use is limited due to its toxicity. Since its efficacy appears to be 
	     similar to that of other, less toxic antirheumatic drugs, its use should be 
	     limited to patients who do not respond to other treatments.
	 Level of Evidence (1-7)
	   * 4
	   
	DMARD [Systematic review citation]*
	   * Cyclosporin [RS4]
	Conclusions 	
 	   * Cyclosporin has an important clinical benefit in the short-term treatment 
 	     of patients with progressive RA. 
	Level of Evidence (1-7)
	   * 3 	 
	   
	DMARD [Systematic review citation]*
	   * D-penicillamine [RS5]
	Conclusions 	
 	   * D-penicillamine appears to be efficacious for the short term treatment of
 	     patients with RA. It has a clinically and statistically significant benefit 
 	     on disease activity. Its effects on long-term functional status and radiographic 
 	     progression are not clear at this time. There does not appear to be any clear 
 	     advantage to using doses higher than 500 mg/day. 
	Level of Evidence (1-7)
	   * 4	 
 	
	DMARD [Systematic review citation]*
	   * Hydroxychloroquine [RS6] 
	Conclusions 	
 	   * Hydroxychloroquine appears to be efficacious in the treatment of RA. Its total 
 	     effect appears to be moderate, but its low toxicity profile should be considered 
 	     in treating RA patients. 
	Level of Evidence (1-7)
	   * 4	 
 	 	
	DMARD [Systematic review citation]*
	   * Methotrexate [RS7] 	 
	Conclusions 	
 	   * Methotrexate has a clinical and statistically significant benefit in the 
 	     short-term treatment of patients with RA. 
	Level of Evidence (1-7)
	   * 4	 
	 	
	DMARD [Systematic review citation]*
	   * Injectable gold [RS8] 	 
	Conclusions 	
 	   * Although its use may be limited due to the incidence of serious toxicity, 
 	     injectable gold has a clinical and statistically significant benefit in the 
 	     short-term treatment of patients with RA. 
	Level of Evidence (1-7)
	   * 4	 
 	
 	 	
	DMARD [Systematic review citation]*
	   * Sulphasalazine [RS9] 
	Conclusions 	
 	   * Sulphasalazine appears to be efficacious in the short-term treatment of patients
 	     with RA. It has a clinically and statistically significant benefit on disease 
 	     activity. Its effects on functional status and radiographic progression are not 
 	     clear at this time, but they appear to be modest.  
	Level of Evidence (1-7)
	   * 3	 

	* The citation for each systematic review is shown in reference list 2.1.


	2. Development of the Recommendations

	Several of the tasks involved in making this guideline, including the
	development of the recommendations, were carried out by the expert panel.


	2.1 Selection of the expert panel

	Panel nominations were provided by the SER, by independent
	rheumatologists, and by investigators familiar with the methodology for
	producing CPG recommendations.

	To help make the guideline more valid, the principal investigator
	proposed to those responsible for nominations that the panel should meet
	the following criteria: 1) multidisciplinarity, that is, the panel
	should include not only rheumatologists, but also other specialists
	whose opinions would help improve RA management or improve the
	methodology for developing the recommendations (e.g., rehabilitation
	specialists, orthopaedists, or epidemiologists); 2) professional
	prestige, that is, that by virtue of their professional trajectory the
	opinions of the expert panel would be respected by the scientific
	community; 3) geographic diversity, that is, if the guideline is to be
	applied at the national level, an attempt should be made to have a
	reasonable representation of Spain's different autonomous communities;
	4) diversity in levels of care, so that the recommendations would make
	sense in both hospital and outpatient settings; 5) diversity of
	academic level, so as to represent the viewpoints of teaching centers
	and highly developed academic and research centers, as well as the
	perspectives of professionals who manage patients in less academic
	centers; and 6) representation of both men and women on the panel.

	Although it was not easy to incorporate all these criteria, a list of
	nominees was produced. Panelists were contacted to request their
	participation, and a panel of 15 members was formed: 12 rheumatologists,
	one rehabilitation specialist, one orthopaedist, and two epidemiologists
	(one of the rheumatologists is also an epidemiologist). The autonomous
	communities from which there was at least one panel member were:
	Andalucía, Canary Islands, Cantabria, Cataluña, Extremadura, Galicia,
	Madrid, La Rioja, and Comunidad Valenciana. Finally, there were 4 women
	and 11 men on the panel.

	The most important individual criterion for selection was the explicit
	absence of conflicts of interest. Each panelist signed a document
	assuring that he or she was not affected by any of the conflicts
	described in a comprehensive list of possible conflicts of interest.
	Nominees with conflicts of interest were excluded. Another individual
	criterion for acceptance was availability during the time needed to
	carry out the tasks. Panelists received no remuneration for their work.


	2.2 Panel tasks

	The panel's tasks were: 1) to define the contents of the guideline; 2)
	to develop the recommendations; 3) to write the definitions; 4) to
	review and contribute to the synthesis of the evidence; 5) to write
	parts of the guideline that had not originally been foreseen (for
	example, the most frequent extra-articular complications); and 6) to
	review the text written by the investigators.

	The panelists were asked to write recommendations that would provide
	practical and specific advice on the subjects covered. They were
	explicitly told that their recommendations should be based on the
	risk-benefit balance for the patient and that costs were not to be taken
	into account. That is, the recommendation should be made considering
	what would be best for the patient, consistent with the objective of
	improving the quality of care.


	2.3 Formulation of the recommendations

	The 15 panelists formed 10 working groups of 3 persons each; thus, each
	panelists could serve on more than one group The working groups were
	responsible for writing different chapters of the guideline. The draft
	recommendations made by each group were sent to the investigators, who
	edited and circulated them to the rest of the panelists for suggestions,
	and in subsequent interactions the pre-definitive version of the
	recommendation was written. A joint document was written based on all
	this information, which was submitted to all the panel members for
	discussion and correction. Panelists interacted by telephone, email,
	regular mail, and small group meetings; the project investigators held
	four joint meetings with the whole panel. Thus, although each group
	wrote the initial version of a specific part of the guideline, all the
	panelists had the opportunity to contribute their knowledge and opinions
	in the rest of the guideline recommendations.

	There was large inter-panelist variability with relation to patient
	classification and the treatment approach in managing RA. Part of this
	variability may have been due to the fact that one panelist was thinking
	of a patient with certain characteristics while another was thinking of
	a patient with different characteristics. To classify patients by
	disease characteristics and to group them in a clinically meaningful
	way, various clinical variables were used. The variables considered for
	patient classification were: a) receipt of NSAIDs and/or corticosteroids
	in the previous 3 months (2 categories); b) number of swollen joints
	(less than 6, 6-10 or greater than 10) (3 categories); c) presence of 
	erosions (0, 1-3 or greater than 3 erosions) (3 categories); d) presence 
	of elevated acute-phase reactants (2 categories); Health Assessment 
	Questionnaire (HAQ) score (less than 1 or greater than or equal to 1)
	(2 categories); and f) rheumatoid factor (less than 40, 40-100 or greater
	than 100 UI/mL) (3 categories). Combining the categories of these clinical 
	variables yielded 144 different patient scenarios that might call for 
	different treatment. The panelists provided anonymous and independent
	recommendations about the initial treatment for each of these 144
	clinical scenarios.

	If the recommendations differed, panelists were free to express their
	arguments and the evidence supporting their opinion to try to convince
	the rest of the panel, but they were not obliged to reach consensus.
	That is, this guideline is based not on consensus, but rather on the
	best available scientific evidence and, when this was absent or
	contradictory, on the judgment of an expert panel that was not forced to
	reach a consensus. In other words, since part of the variability in
	clinical practice may be due to the fact that there is insufficient
	scientific evidence on the efficacy of the different DMARDs, this
	guideline recognizes that fact and considers that it is admissible for
	different professionals to have different opinions.

	The panel members chose the best treatment for each of the 144 different
	patient scenarios. Their recommendations were analyzed mathematically,
	especially the proportion of panelists who suggested each treatment
	recommendation. Since the recommended treatment was similar for many of
	the 144 different patient scenarios, these were grouped into 52
	scenarios in which the treatment decisions were the same. Reducing the
	number of options seems more reasonable for guideline users, and these
	are the classification options reflected in the decision algorithm
	for the initial treatment of RA that is included at the end of this 
	guideline. (Both the panel votes and the mathematical analysis are 
	available to interested readers by contacting TAISS at milena@taiss.com.)

	The treatment decisions are further simplified in the text of the
	recommendations, where the use of corticosteroids and/or NSAIDs is
	treated separately from DMARD treatment, since the former are used only
	in particular, very specific situations. Thus, it is necessary to
	consider only the two objective parameters (number of swollen joints and
	presence of erosions) that have been shown to be the most important in
	disease classification due to their treatment implications.

	The reduced scenario classification was used to establish the
	alternative treatment in case of toxicity or unsatisfactory response to
	initial treatment. The panelists again voted individually, and the
	alternative treatment options with the most votes were chosen, ordered
	by preference of use.

	The systematic scientific review of the literature on DMARDs made it
	possible to identify the level of evidence supporting the panel
	recommendations for medical treatment. In the other chapters, each
	panelist or group provided the evidence on which they had based their
	recommendations. In other words, support for the recommendations based
	on a systematic review and evaluation of the scientific evidence in this
	guideline is limited to management with DMARDs. The rest of the
	recommendations are based on a non-systematic review of the scientific
	evidence, which is cited as the bibliographic reference, or on expert
	opinion.


	HOW TO USE THIS GUIDELINE

	This guideline is organized by chapters. Each chapter shows the
	recommendations in bold print, followed by a more detailed justification
	or explanation of the recommendations.

	We have tried to make the recommendations clear and practical, without
	losing flexibility. Thus, at times the choice between various
	possibilities considered equally valid by the panel is left to the
	judgment of the rheumatologist (e.g., various methods to evaluate RA
	severity). One of the attributes of this guideline is its flexibility,
	allowing it to be applied to the real world where situations may vary,
	for example with regard to local characteristics of the center
	(availability of certain technologies, training, etc.), personal
	preferences of the patient, or other situations that may affect clinical
	decision making in patients with RA.

	Rheumatologists using this guideline for the first time may find it
	useful to read the chapters in order, since this is the natural order of
	a medical evaluation: diagnosis, initial evaluation, classification,
	treatment, criteria for response to treatment, adverse effects of drug
	treatment, and possible extra-articular complications.

	Several documents are included with this guideline that may be of use to
	readers in evaluating and monitoring patients: data collection forms for
	initial patient evaluation and follow-up (Appendix 1) and an algorithm 
	to aid treatment choices (Appendix 2). This algorithm allows the user to 
	follow a logical decision-making process in patient management.

	The user of this guideline can consult the quality of the scientific
	evidence supporting the use of DMARDs and identify the articles from
	which the evidence was obtained.

	Also included is a "Rapid Reference Guide," which is a brief version of 
	the guideline recommendations and includes the simplified algorithm.


	CONTENTS AND LIMITATIONS OF THE GUIDELINE

	RA is a disease that can affect different patient subgroups, can be
	managed in different settings, can be treated with a variety of
	therapeutic approaches, and can affect various organs or systems. To
	cover all these aspects in a guideline, besides being an endless task,
	would be impractical. Thus, the SER, together with the expert panel and
	the investigators, agreed to limit its contents as follows:

	   * It is intended for rheumatologists.
	   * It focuses on RA in adults (juvenile RA is excluded).
	   * It includes diagnosis, evaluation, prognosis, treatments (drugs,
  	     rehabilitation, etc.), and extra-articular complications
  	     (amyloidosis, anemia, Sjögren's syndrome, etc.).
	   * The synthesis of the scientific evidence based on a systematic
      	     review of the literature focuses on the efficacy of DMARDs.
	   * The remaining recommendations or considerations are based on
	     scientific evidence obtained without systematic review or on
      	     expert opinion.


	CHAPTER 1. DIAGNOSING RHEUMATOID ARTHRITIS

	The diagnosis of RA is essentially a clinical task. RA should be
	suspected in patients over 16 years of age who have joint inflammation
	or effusion of more than 6 weeks duration in three or more joints,
	preferably of the hands and feet. To date, the only universally accepted
	and used diagnostic criteria for RA are those proposed for
	classification of the disease by the American College of Rheumatology
	(ACR) in 1987 [Arnett, 1988].

	According to the ACR, the diagnosis of RA requires confirmation of at
	least four of the following criteria:

	   1. Morning stiffness lasting at least one hour before maximal
              improvement, for at least 6 consecutive weeks.
	   2. Soft tissue swelling or fluid, observed by a physician, in at
              least three of the following joint areas (right or left): proximal
              interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow,
              knee, ankle, or metatarsophalangeal (MTP) joints, for at least 6
              consecutive weeks.
	   3. Swelling or fluid, observed by a physician, in the proximal
              interphalangeal, metacarpophalangeal, or wrist joints, for at
              least 6 consecutive weeks.
	   4. Symmetrical (right and left sides) swelling or fluid in the joints
              mentioned in point 2, observed by a physician, for at least 6
              consecutive weeks.
	   5. Subcutaneous nodules over bony prominences or extensor surfaces,
              or in juxta-articular regions, observed by a physician.
	   6. Demonstration of serum rheumatoid factor (RF) detected by any
              method that has been positive in less than 5% of control subjects.
	   7. Radiographic evidence in the hands or wrists of articular erosions
              or osteopenia in or around the affected joints.

	These criteria have a sensitivity of 91% and a specificity of 89%.
	However, their predictive value varies depending on the prevalence of RA
	in the clinical or population setting, as can be seen in Table 12
	[Balsa, 1996; Villaverde, 2000].


	Table 12. Predictive values (%) for RA diagnostic criteria in different settings

	Population 	
	   * General	
	RA prevalence 	
	   * 0.5	
	Positive predictive value 	
	   * 4.7	
	Negative predictive value
	   * 99.9	
	
	Population 	
	   * Primary care medical consultation for osteomuscular pain	
	RA prevalence 	
	   * 19	
	Positive predictive value 	
	   * 69.9	
	Negative predictive value
	   * 97.2	
 	 	
	Population 	
	   * Specialized consultation for polyarthritis	
	RA prevalence 	
	   * 67	
	Positive predictive value 	
	   * 95.3	
	Negative predictive value
	   * 80.3	
 	 	 	
 	 	 	

	Thus, if a patient in the general population does not meet the RA
	criteria, for all practical purposes the disease can be ruled out
	(probability of error 1/1000). If the criteria are positive, however,
	the patient is unlikely to have the disease, which makes it necessary to
	confirm or rule out the diagnosis using additional techniques. In a
	consultation for polyarthritis, on the other hand, patients meeting the
	criteria are highly likely to have RA (95%), and if they do not meet the
	criteria, the probability of having RA is 20%.


	CHAPTER 2. INITIAL EVALUATION


	2.1 Patients with RA should be evaluated and treated by physicians who 
	are familiar with the clinical management and treatment of the disease.

	RA is a chronic disease, with an estimated prevalence of 0.5% (0.2-0.8%)
	in the Spanish adult population [Villaverde, 2000]. Its evaluation and
	treatment are somewhat complex, especially when the disease is
	clinically active. For this reason it is recommended that the diagnosis,
	monitoring, and treatment of RA be carried out by physicians who can
	identify patients in the early stages of the disease, evaluate the
	disease stage correctly, plan appropriate treatment for each stage of
	disease evolution, and measure the response to treatment.

	The recommendations in the following sections should always be followed
	in the initial evaluation and monitoring of patients. This systematic
	evaluation of patients is needed to plan appropriate treatment in
	accordance with disease characteristics and to measure the response to
	the treatment undertaken.


	2.2 The initial evaluation of a patient with RA should include a clinical 
	history and physical examination.

	The same as in any other clinical process, the first evaluation should
	include a clinical history and physical examination. The history
	should include a personal and family history (of diseases, surgical
	interventions, allergies), with special emphasis on processes that were
	life threatening or required medical treatment or hospitalization. The
	history should review life styles with regard to exercise, nutrition,
	smoking, and alcohol use. Gynecological history and date of first
	menstruation should also be recorded.

	The sociodemographic data to be collected include age, gender,
	educational level, main occupation, and work setting, because of their
	importance as prognostic factors in RA.

	In the initial evaluation of a patient with RA, the rheumatologist
	should keep in mind the previous history of the disease. Some patients
	will have RA of short evolution, for which hardly any medical treatment
	has been received, while others may visit the physician following a more
	or less prolonged period of arthritis, with a clinical and therapeutic
	history that must be considered. In these cases, the clinical
	characteristics of the disease should be obtained by interviewing the
	patient and reviewing reports and other documents provided by the
	patient, such as radiographs and certain laboratory tests.

	To understand the evolution of RA, it is critically important to
	identify any previous or concurrent treatment, especially with
	analgesics, NSAIDs, corticosteroids, and DMARDs. A detailed history
	should be taken of DMARDs received to date, the dosage, duration, and
	reasons for discontinuing the medication. The same information should be
	obtained for corticosteroid use. With regard to NSAIDs, the physician
	should ask about their observed tolerance and side effects, with special
	regard to digestive problems.

	In the physical examination, in addition to the signs that would be
	observed for any patient, careful note should be taken of the presence
	of pain, joint inflammation, deformities, and subcutaneous nodules.


	2.3 The evaluation and monitoring of RA should be based on a systematic 
	evaluation of a minimum set of parameters including joint pain and 
	inflammation (2.3.1), the patient's global assessment of pain (2.3.2), 
	global assessment of disease (2.3.3), functional disability (2.3.4), 
	acute phase reactants (2.3.5), and radiologic evidence of damage (2.3.6).

	The clinical evaluation of RA has been the subject of interesting
	debate. At the first conference of OMERACT (Outcome Measures in
	Rheumatoid Arthritis Clinical Trials), held in Maastricht in 1992, North
	Americans [Felson, 1993a; Felson 1993b] and Europeans [Scott, 1992]
	reached a historic consensus, with experts from different countries
	agreeing on a minimum set of parameters to be used in evaluating RA
	patients included in clinical trials [OMERACT, 1993]. These
	recommendations were subsequently ratified by the ACR [Felson, 1993a],
	the World Health Organization (WHO), the European Leagues Against
	Rheumatism (EULAR), and the International Leagues Against Rheumatism
	(ILAR) [Boers, 1994]. The parameters were chosen by consensus after
	examining the reliability, validity, and sensitivity of those most
	frequently used in the clinical evaluation of RA, with the aim of
	obtaining a set of parameters that would allow evaluation of all
	relevant aspects of the disease, without redundancy. This core set of
	parameters, which was originally selected for use in clinical trials,
	has been shown to be useful in daily clinical practice.

	The core set of parameters recommended by the OMERACT conference
	includes: 1) number of painful joints, 2) number of swollen joints, 3)
	pain, 4) the patient's overall assessment of disease, 5) the physician's
	overall assessment of disease, 6) physical functional capacity, and 7)
	acute phase reactants. Another parameter recommended in this conference
	for studies lasting at least 1 year was radiologic evaluation of damage,
	although more recent investigations have shown that radiographs of the
	hands and feet can detect changes in periods of 6 months [Sharp, 2000].
	In any case, radiologic evidence of damage is not a parameter that can
	be clinically evaluated very often, therefore it should not be
	systematically assessed at all visits, but only once a year (see section
	2.3.6.).

	There are clear advantages to using these parameters to monitor patients
	[Pincus, 1996; Wolfe, 1999a]. Nevertheless, rheumatologists do not
	systematically monitor patients with RA, and their use of different
	parameters for disease evaluation varies greatly [Bellamy, 1998;
	Bellamy, 1999]. According to the emAR study [Hernández-García, 2001],
	the use of quantitative measures of disease activity or functional
	damage is very limited in Spain. For example, joint counts were made at
	all or most visits in only 23% of 1,379 patients over a 2-year period;
	the figures for pain assessment or global assessment of disease status
	by visual analogue scale or the use of functional capacity
	questionnaires were still lower. The infrequent use of the OMERACT
	parameters and part of this variability could be explained by the fact
	that the application of standardized clinical instruments in daily
	practice involves additional time and effort in a high pressure setting.
	However, variability in the results of different treatments and the
	emergence of new, more costly and efficacious therapies with uncertain
	adverse events in the medium term will require closer patient monitoring
	if we aim to make more effective decisions at a socially acceptable cost.


	2.3.1 Validated methods should be used to assess the number of painful 
	joints and the number of swollen joints. For individual assessment of 
	disease activity the use of a complete index is recommended, based on the 
	examination of 68 joints for pain and 66 for swelling (excluding the hip).

	Articular indices assess the degree of pain and swelling by counting the
	number of painful joints and the number of swollen joints. Three
	different methods have been described, varying in the number of joints
	evaluated, although only four are in widespread use:

	   * ACR Count. The ACR (previously the ARA - American Rheumatism
	     Association) count can be defined as the most complete index
	     [Deandrade, 1965; Williams, 1983; Ward, 1983; Paulus, 1984]. It is
	     the US standard. It includes evaluation of tenderness in 68 joints
	     and swelling in 66 joints (excluding both hips). The following
	     joints are assessed: distal interphalangeal, proximal
	     interphalangeal, metacarpophalangeal, wrist, elbow, shoulder,
	     acromioclavicular, sternoclavicular, temporomandibular, hip (only
	     for pain), knee, ankle, subtalar-midtarsal, metatarsophalangeal,
	     and proximal interphalangeal joints.
	   * Ritchie Index. This is the European index most commonly used. It
	     includes assessment of pain alone in 53 joints and is calculated
	     based on 26 joints, since some joints are considered together
	     [Ritchie, 1968]. The following joints or groups of joints are
	     evaluated: right and left proximal interphalangeal,(2), right and
	     left metacarpophalangeal (2), wrist (2), elbow (2), shoulder (2),
	     cervical spine (1), acromioclavicular (1), sternoclavicular (1),
	     temporomandibular (1), hip (2), knee (2), ankle (2), subtalar (2),
	     midtarsal (2), and right and left metatarsophalangeal (2) joints.
	     This method quantifies joint tenderness or pain on motion only in
	     the case of the cervical spine, hip, subtalar and midtarsal
	     joints. Pain is scored on a 4-level scale: 0 = no pain; 1 = pain;
	     2 = pain and wincing; 3 = pain, wincing, and withdrawal (maximum
	     score: 78). In the case of joint groups, the highest score
	     assigned to any of the joints in the group is assigned to the
	     whole group.
	   * 44-Joint Index. Swelling is evaluated in the following 44
	     joints: proximal interphalangeal, metacarpophalangeal, wrist,
	     elbow, shoulder, acromioclavicular, sternoclavicular, knee, ankle,
	     and metatarsophalangeal joints. The fact that swollen joints are
	     included in this index makes it a complement to the Ritchie index.
	   * 28-Joint Index. Fuchs et al. [Fuchs, 1989] observed that a
	     simple evaluation of tenderness and swelling in 28 joints provided
	     the same sensitivity to change in clinical trials as more complex
	     indices [Fuchs, 1994]. The index includes the following joints:
	     proximal interphalangeal, metacarpophalangeal, wrist, elbow,
	     shoulder, and knee joints.

	When counting joints, one can either make a simple count of the number
	of painful and swollen joints (present/absent) or semi-quantify the
	degree of pain and swelling in each joint using a 4-level ordinal scale
	(0-3). This guideline recommends counting painful and swollen joints
	without adding any type of quantification. The advantages obtained by
	quantifying are lost in the increased variability of the measurements.

	The ACR recommends the use of complete counts of 68 joints, although it
	later accepted the use of counts based on 28 joints in clinical trials.
	The same committee emphasized, however, that indices based on 28 joints
	exclude those in the foot and ankle, which are affected in over 50% of
	patients, therefore they provide less information at the individual
	level in daily clinical practice [OMERACT, 1994]. The use of a reduced
	index does not mean that these joints should not be examined. Thus, this
	guideline recommends the use of the ACR index with 68 joints.


	2.3.2 Pain should be assessed by the patient him or herself. It is 
	recommended that pain be measured using a horizontal visual analog scale, 
	10 cm in length, divided by vertical marks into ten equal 1-cm segments. 
	The measurements should be accompanied by numeric descriptors from 0 to 10,
	with indicators at each end showing no pain (0) and worst pain (10).

	Pain is a subjective experience, therefore it should be quantified by
	the individual patient. Among the different methods used to measure
	pain, those that stand out due to their simplicity and ease of use are
	visual scales, or Likert-type scales, which usually have five or seven
	levels. The visual analog scale (VAS), with a horizontal 10 cm line and
	descriptors at each end, is the most widespread method. The ACR/OMERACT
	recommendations advise the use of either of the two methods, although
	there is a clear preference in studies for the VAS. Most patients are
	able to complete this scale. It is first necessary to devote some time
	to explaining the scale and giving a specific example; patients then
	answer quickly and with confidence. Some modifications, such as the use
	of numeric descriptors, may improve reliability in persons with a low
	educational level [Ferraz, 1990]. The VAS for pain shows a good
	correlation with the Likert scale, and both are sensitive to clinically
	important changes, with the VAS showing certain advantages [Langley,
	1984; Anderson, 1993; Buchbinder, 1995].


	2.3.3 A global assessment of disease should be made from the medical point 
	of view and another one from the patient's point of view. For this 
	measurement, the use of a 10 cm horizontal visual analog scale is recommended,
	with vertical marks dividing it into 10 equal 1-cm segments. The measurements
        should be accompanied by numeric descriptors from 0 to 10, indicating at each 
        end "very good" (0) and "very poor" (10).

	Global disease assessments by both the physician and the patient are
	useful because their evaluations may be quite different. The global
	assessment is very sensitive to clinical changes [Anderson 1989;
	Buchbinder, 1995].


	2.3.4 Self-perceived functional disability attributed to the disease should 
	be evaluated using specific, previously validated questionnaires such as the 
	Health Assessment Questionnaire (HAQ) (see Appendix 1).

	There are various ways to estimate functional capacity based on joint
	mobility or the ability to perform certain tasks as evaluated by an
	observer. The most widespread methods currently used consist of specific
	questionnaires for rheumatic disease such as the HAQ, the Modified
	Health Assessment Questionnaire (MHAQ) (shortened version of the HAQ),
	or the Arthritis Impact Measurement Scales (AIMS). They are based on the
	patient's own opinion about his or her disease. These questionnaires are
	standardized instruments, which have been shown to be valid and
	reliable. They evaluate those health dimensions that are most affected
	by RA, particularly disability, especially in relation to physical
	function, and pain.

	The HAQ is a 20-item, self-administered questionnaire that evaluates
	self-perceived physical disability to perform certain basic activities
	of daily living, grouped into eight areas: dressing and grooming,
	arising, eating, walking, hygiene, reach, grip, and other activities
	[Fries, 1980]. A Spanish version of the questionnaire has been validated
	[Esteve-Vives, 1993]. The MHAQ is a shortened version of the HAQ, with
	only eight items. Its main advantage is its simplicity, which makes it
	possible to use it in routine patient monitoring [Pincus, 1983]. The
	Spanish version of the MHAQ can be self administered by most patients
	with RA [Esteve-Vives, 1994].

	This guideline recommends the use of the HAQ as a standardized
	instrument to evaluate disability because of its widespread
	dissemination, acceptance, and proven metric characteristics.

	Persons interested in evaluating broader aspects of health-related
	quality of life can also use the so-called generic questionnaires, such
	as the Short-Form 36 (SF-36), the Nottingham Health Profile (NHP), the
	Sickness Impact Profile (SIP), or the EuroQoL-5D. These questionnaires
	provide an estimate of self-perceived physical, psychological, and
	social health status based on questions about activities, feelings, and
	emotions covering a large number of daily life situations. The generic
	questionnaires provide complementary information and make it possible to
	compare the level of health with other diseases.


	2.3.5 Laboratory tests should include two acute phase reactants (APRs): 
	erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The 
	behavior of these two APRs is closely related with the inflammatory 
	activity of the disease.

	Laboratory tests should consist of a complete blood count, acute phase
	reactants (ESR, CRP), rheumatoid factor (RF), liver function (GOT, GPT,
	GGT, alkaline phosphate, albumin), kidney function (creatinine),
	calcium, and urinalysis. The presence of hepatitis B and C virus should
	be evaluated (in relation to the hepatotoxicity of some of the drugs
	used in treatment).

	These basic tests will facilitate RA monitoring and early detection of
	disease complications and side effects of treatment (see chapter 6).

	Measurement of APRs is very helpful in monitoring inflammatory processes
	in general, and of articular inflammation in particular. Their levels
	are associated with the intensity of underlying inflammation. There are
	several acute phase reactants but, in practice, the ESR and CRP are the
	most widely used. Both were included in the ACR recommendations and have
	been shown to be about equally useful in the evaluation of inflammatory
	activity [Paulus, 1999]. The advantage of the ESR is that it is
	inexpensive and available in any laboratory, and its disadvantage is its
	low specificity, since its levels can be modified by factors that are
	independent of articular inflammation. The advantage of the CRP is that
	its levels are virtually non-existent in the absence of inflammation,
	and its synthesis is closely related with inflammatory activity, with a
	very short half life. The techniques for measuring CRP are currently
	available in most laboratories. Persistent elevation of acute phase
	reactants with respect to normal reference values, especially for CRP,
	has been associated with poorer disease outcome [Dawes, 1986; van
	Leeuwen 1993; van Leeuwen, 1997].

	Whether to include other complementary tests is left to the judgment of
	the individual physician, who should evaluate each case in terms of
	history, age, associated treatments, the possibility of using preventive
	interventions (e.g., cholesterol, glucose control), and associated
	co-morbidity.


	2.3.6 Radiographs of the hands, feet, and chest are recommended at the 
	initial evaluation. Radiographs of the feet and hands should be repeated 
	annually for the first 3 years of disease evolution, and thereafter as 
	deemed appropriate.

	One of the findings to be looked for in the radiographs are bony
	erosions, which are more frequent at the onset of disease. About 70% of
	patients have erosions in the hands or feet by the end of the first 2 or
	3 years [Van der Heijde, 1995b; Hulsmans, 2000]. Their presence and the
	speed of onset are associated with poorer outcome. Radiographic changes
	are moderately associated with physical disability [Drossaers-Bakker,
	1999; Scott, 2000].

	Numerous methods have been described to quantify radiographic changes in
	the joints. Almost all of them are based on radiograph readings of the
	hands, although some authors have pointed out the importance of
	including a systematic evaluation of the feet [Van der Heijde, 1992b].
	Most of these methods are based on the Larsen method [Larsen, 1977;
	Larsen, 1995; Edmonds, 1999] or on the Sharp method [Sharp, 1971; Sharp,
	1985; Kaye, 1987; van der Heijde, 1992b; Sharp, 1995]. There is no clear
	preference for either one [Pincus, 1995], although the van der Heijde
	method [Van der Heijde, 1992b], which includes hands and feet, appears
	to have some advantage. The disadvantage of all these methods is that
	they are very time-consuming to apply, therefore they are generally
	reserved for use in research.

	This guideline recommends a simple qualitative evaluation to identify
	the presence of new erosions or their progression. Radiographs of both
	hands and feet are justified by the fact that asymmetrical erosions
	(right or left) may appear, and by the observation that in the first 2-3
	years of the disease, erosions appear only on the feet, without clinical
	symptoms, in up to 23-36% of patients [Brook, 1977; Paimela, 1992; van
	der Heijde, 1999].

	Other imaging techniques, such as magnetic resonance and sonography,
	have shown promising results in the early detection of inflammatory
	changes and structural damage like bony erosions [Wakefield, 2000].
	These techniques involve the use of advanced technology that is not
	available in the vast majority of clinical centers. In addition, there
	is not enough evidence to date to make recommendations in this respect,
	thus their use remains reserved, for the moment, to the field of
	experimentation [Grassi, 2001].

	With regard to the chest X-ray, a baseline radiograph is recommended,
	both to have knowledge of the baseline situation and to identify
	possible problems as the disease evolves and is treated.


	Table 13. Summary of instruments for the measurement of parameters in RA evaluation

	PARAMETER 	
	   * Joint inflammation and pain	
	VALID OPTIONS 	
	   * ACR count
	   * Ritchie index
	   * 44-joint index
	   * 28-joint index	   
 	RECOMMENDATION
	   * ACR count
	   
	PARAMETER 	
	   * Global assessment of pain	
	VALID OPTIONS 	
	   * VAS for pain rated by the patient
	   * Likert scale
 	RECOMMENDATION
	   * VAS for pain rated by the patient
	   
	PARAMETER 	
	   * Global assessment of disease by the patient	
	VALID OPTIONS 	
	   * VAS
	   * Likert scales for severity and/or activity
 	RECOMMENDATION
	   * VAS for disease rated by the patient
	   
	PARAMETER 	
	   * Global assessment of disease by the physician	
	VALID OPTIONS 	
	   * VAS
	   * Likert scales for severity and/or activity
 	RECOMMENDATION
	   * VAS for disease rated by the physician
 
 	PARAMETER 	
	   * Functional capacity	
	VALID OPTIONS 	
	   * HAQ
	   * MHAQ
	   * AIMS 
 	RECOMMENDATION
	   * HAQ
  		
 	PARAMETER 	
	   * Laboratory tests	
	VALID OPTIONS 	
	   * ESR
	   * CRP
 	RECOMMENDATION
	   * ESR and CRP
 
  	PARAMETER 	
 	   * Radiographic damage	
 	VALID OPTIONS 	
 	   * Presence of absence of erosions
 	   * Sharp index
 	   * Larsen index
  	RECOMMENDATION
 	   * Presence or absence of erosions evaluated qualitatively by radiography


	2.4 An alternative procedure that is useful and valid in assessing disease
	activity is the use of composite indices summarizing the information for 
	various parameters in a single indicator. If this method is preferred, 
	this guideline recommends the use of the Disease Activity Score (DAS).

	Different composite indices have been published, and their validity has
	been reviewed in the framework of the OMERACT conference [OMERACT,
	1993]. Some good examples are the Pooled index, the Mallya and Mace
	index, the Stoke index, the Scott index, and the DAS. These indices
	differ in the number of parameters included as well as the methods used
	for their calculation. Their advantages in comparison to conventional
	evaluation using single parameters are that they avoid duplicate
	measurements and are more sensitive to change. Their disadvantages are a
	certain degree of complexity in the calculations, difficulty of
	interpretation, and some problems related with how they are constructed.

	The DAS deserves particular mention [Van der Heijde, 1990; van der
	Heijde, 1992a]. It includes the Ritchie index (RI), number of swollen
	joints out of 44 joints (NSJ44), erythrocyte sedimentation rate (ESR),
	and the patient's global assessment of health (PGA) on a visual analog
	scale (0 cm "very good" - 10 cm "very poor"). The patient's global
	assessment of disease can be substituted for the global assessment of
	health, using the same scale. The DAS is calculated using the following
	formula:

		DAS=0.54 (RI) + 0.065 (NSJ44) + 0.33 (In ESR) +0.0072 (PGA)

	There is a modified DAS based on the number of painful joints (NPJ28)
	and swollen joints (NSJ28) out of 28 joints [Prevoo, 1995]:

		DAS28=0.56(NPJ28)+0.28(NSJ28)+0.70(In ESR)+0.014(PGA)

	The score for the complete DAS and the DAS28 can range from 0 to 10. The
	DAS is of particular interest because it is the basis for the EULAR
	improvement criteria [Van Gestel, 1996].


	2.5 The initial and subsequent evaluation of patients with RA should 
	include a continual estimate of disease prognosis.

	The outcome of RA varies considerably among patients. Some treatment
	strategies, more aggressive and therefore more toxic, improve RA outcome
	when used early in patients with a high risk of serious disease,
	understood as functional disability, structural damage, and/or
	mortality. The decision of whether or not to use these aggressive
	strategies should be based on the prognosis in each individual patient.
	Since most radiographic changes and, to a lesser extent, loss of
	functional capacity, occur in the first 2 or 3 years of evolution, the
	earlier a disease prognosis is formulated, the sooner an informed
	decision can be made on the most appropriate treatment strategy.

	The factors that predict serious disease can be classified into three
	types: sociodemographic, disease-dependent and treatment-dependent. No
	single parameter, by itself, will permit estimation of RA outcome,
	therefore a combination of several parameters should be used.
	Furthermore, it is difficult to separate the individual effect of a
	particular risk factor from its interrelation with other factors
	associated with poor outcome.

	The following factors are considered to be predictive of functional
	disability, radiographic erosions, and/or mortality, and therefore of
	poor outcome:

	Sociodemographic factors:
	
	Female gender. Being a woman is associated with presentation of
	functional disability 4 years after disease onset (Odds Ratio=3.01)
	[Pease, 1999]. Not all cohort studies have reproduced this finding.
	Female gender is probably related with other prognostic factors.
	
	Age at disease onset. This is a controversial prognostic factor.
	Different groups have shown poorer, better, or equal outcome in elderly
	patients.
	
	Low educational level. This is associated with increased mortality.
	Less than secondary level education is associated with over 50% decrease
	in functional status or with mortality at 9 years (OR=7.5) [Pincus,
	1985]. In Mexican patients with RA, fewer than 6 years of formal
	education is associated with severe forms of RA (OR=3.52) [Glave
	Testino, 1994].
	
	Genetic markers. These have not been confirmed in all populations.
	They are limited to experimental use.

	Disease-dependent factors:
	
	Positive RF. Positive RF from 1/80 or = 60 IU by nephelometry is
	associated with the development of erosions (OR: 4.2 - 12) [Van der
	Heijde, 1995a]. The persistence of elevated RF is associated with
	erosions at 6 years follow-up. At 3 years from symptom onset, the
	presence of positive RF IgA is associated with more erosions, worse HAQ
	score, and more painful and swollen joints.
	
	Large number of swollen joints. A large number of swollen joints (greater
	than 20 at disease onset) is predictive of future activity, including 
	mortality [Van Zeben, 1992]. Cumulative joint inflammation is associated 
	with progression to radiographic damage in 1 year (OR=2) [Pincus, 1985].
	
	Elevated acute phase reactants. A CRP of twice the normal value at the
	patient's initial evaluation is associated with the development of
	erosions in 4 years (OR=1.81) [Glave Testino, 1994]. A continuous ESR
	higher than 60 mm in the first hour is associated with the presence of
	disability at 18 years (OR=4.88) [Furst, 1994a].
	
	Elevated HAQ at initial visit (Greater than or equal to 1 out of 3). This 
	is associated with disability at 4 years (OR=3.02) [Pincus, 1985]. For 
	each HAQ unit over 0 at the baseline visit, the OR for disability increases 
	by 1.60 to 2.94 [Wolfe, 1998]. In patients with a baseline HAQ of at least 
	2.5, the relative risk for developing disability is 2.15 [Wolfe, 1991].
	
	Early involvement of large joints (Greater than or equal to 2) is associated 
	with the presence of erosions at 1 year (OR=2.03) [Brennan, 1996].
	
	Rapid appearance of erosions (Greater than or equal to 2/year). The speed 
	with which erosions appear is associated with poorer outcome.
	
	Presence of extra-articular manifestations (rheumatoid nodules, vasculitis,
	scleritis, or others). In general, these manifestations are associated with 
	seropositive RF, therefore their prognostic value by themselves is unclear. 
	The presence of extra-articular manifestations is associated above all with 
	increased mortality [Gordon, 1973].

	Treatment-dependent factors:
	
	Length of treatment. Longer treatment time with DMARDs is associated with 
	better long-term functional outcome. For example, the difference between 
	patients treated with DMARDs throughout the course of their disease and those
	who never received treatment is 0.53 HAQ units. [Fries, 1996].
	
	Early treatment with DMARDs. Patients who delay beginning DMARD treatment have
	poorer functional outcome than those who begin treatment early. The longer the
	delay in beginning treatment, the smaller the probability of reaching a 
	satisfactory response (OR=5.57), and this in turn implies poorer functional 
	outcome (with a mean increase of 0.12 HAQ units for each visit in which a 50% 
	improvement is not reached) [Tsakonas, 2000].


	2.6 Consideration should be given to the psychological and social effects on 
	the patient, since these factors are involved in pain assessment and the 
	development of disability.

	In addition to the evaluation of structural damage, disability, and
	health-related quality of life, certain important psychological and
	social factors should be evaluated.

	Psychological disturbances (depression and anxiety) are very frequent in
	RA from the time of disease onset [Van der Heijde, 1994], due to the
	impact of confronting its diagnosis and evolution. There is a close
	relation between depression, anxiety, and chronic pain. This can make
	the assessment (VAS rating by the patient and physician) more difficult
	and should be taken into account when planning treatment. In addition,
	anxiety and depression appear to play an important role in the
	development of disability [Escalante, 1999].

	It is currently thought that some psychological characteristics of the
	patient (level of perceived helplessness, coping ability, level of
	self-management) play an important role as factors predictive of
	disability and health status. A high level of helplessness makes for a
	poorer outcome, whereas a greater coping ability and level of
	self-management improves it [Scharloo, 1999].

	With regard to social factors, one third of patients lose their job
	during the first year of the disease [Jantti, 1999], in close
	association with their inflammatory activity [Wolfe, 1998; Reisine,
	1998]. The reduced income associated with job loss affects all members
	of the family unit [Wolfe, 1998]. Patients who receive substantial
	social support from family and friends, especially from their spouses,
	have better outcomes and less disability [Fitzpatrick, 1991, Kraaimaat,
	1995]. Some clinical manifestations, such as pain or fatigue, are more
	frequent in persons who lack social support [Riemsma, 1998].


	2.7 A detailed evaluation should be made to rule out latent tuberculosis 
	infection before beginning treatment with immunosuppresants, anti-TNF 
	agents, or corticosteroids in doses higher than 15 mg/day. If latent 
	tuberculosis infection is present, prophylactic treatment with isoniazide 
	is recommended.

	Treatment with anti-TNF agents or corticosteroids is a risk factor for
	tuberculosis (TB) in persons who have a primary infection with the Koch
	bacillus. A chest X-ray and tuberculin test should be included in the
	initial evaluation, with a repeat test (booster) in a week if the result
	is negative. A positive result is considered to be an induration larger
	than 10 mm, or larger than 5mm if the patient has a history of TB, or
	radiographic signs on a simple chest X-ray. If the tuberculin test is
	negative, the patient should be monitored for TB. If it is positive, the
	eradication treatment to use is isoniazide for a minimum of 4 months,
	and preferably 6. Prophylaxis can be given concomitantly with RA
	treatment if there is no evidence of liver toxicity.


	CHAPTER 3. CLASSIFYING RHEUMATOID ARTHRITIS


	3.1 General classification

	The two characteristics that have the most influence on the initial
	classification between serious and mild disease, and therefore on the
	treatment decision, are the presence or absence of erosions and the
	number of swollen joints. The classification may be made more precise if
	other factors, such as APR, HAQ, and RF, are taken into account. The
	subsequent classification will depend on the response to treatment.

	Two types of RA with special characteristics are not included in this
	classification: "burnt-out" RA and pseudopolymyalgic RA (sections 3.2
	and 3.3).

	RA cannot be neatly classified into different categories. In this
	guideline, the classification of patients is based on two principles:
	first, classifying RA is useful for making treatment decisions and
	estimating patient outcome; second, the classification should help the
	physician in actual practice. In accordance with these two principles,
	RA is classified based on the two parameters that, in the panel's
	opinion, have the most influence on the treatment decision and on
	outcome: the presence of erosions and the number of swollen joints. The
	use of two categories for the presence of erosions (yes/no) and two
	categories for the number of swollen joints (less than 6/greater than 
	or equal to 6), gives four types of RA which, on a scale of increasing 
	severity, would go from non-erosive disease with few swollen joints to 
	erosive disease with swelling of multiple joints at clinical presentation. 
	This simple alternative makes it possible to classify patients rapidly and 
	is proposed in the recommendation for initial treatment in this guideline.

	While this guideline was being developed, we found that panelist
	disagreement about the initial treatment proposed was often due, not to
	a true difference of opinion, but to the fact that there are many
	different forms of RA. The differences arose because panelists were
	thinking about different types of patients within the same category.
	Thus, it was decided to include more variables in the categorization to
	be able to discriminate more precisely among different types of
	patients. Other factors were taken into account, such as APRs, HAQ, RF,
	and previous treatment with corticosteroids and/or NSAIDs. The
	combination of these factors resulted in 144 different scenarios
	describing different types of patients, from the mildest clinical
	presentation (no erosions, less than 6 swollen joints, normal APRs, HAQ 
	less than 1 and negative RF) to the most severe form of disease (erosions 
	present, greater than 10 swollen joints, elevated APRs, HAQ greater than 
	or equal to 1 and high titers of positive RF). Each patient, according to
	the initial disease characteristics, should begin a specific treatment 
	option (see chapter 4).	If the response to initial treatment is 
	unsatisfactory, the disease is considered to have a poor prognosis and 
	thus should be considered as severe.

	The parameters that the physician should consider when classifying a
	patient within the continuous spectrum of disease severity are probably
	more extensive than those proposed in this guideline. The inclusion of
	characteristics such as age and time of evolution, among others, or the
	inclusion of additional categories for the parameters used would be
	feasible, however it would lead to an exponential increase in the number
	of types of RA.

	It is also debatable which parameters are most useful in classifying RA
	and which cut-off points best discriminate the milder forms of disease
	from those that are more severe. Since the evaluation and follow-up of
	RA patients should be based on longitudinal monitoring of measures of
	disease activity, joint damage, and health status, any classification
	should be made as a function of these parameters. Based on these
	parameters, we propose the two classifications of RA (simpler and more
	complex) included in this guideline. Nevertheless, new research may lead
	to a more precise classification of RA with implications for the
	clinical management of these patients.


        3.2 "Burnt-out" or end-stage rheumatoid arthritis

	In "burnt-out" or end-stage RA there is no inflammatory activity and
	there is complete or practically complete destruction of the patient's
	joints. It is characterized clinically by joint pain at rest or with
	minimal exertion, joint deformities, significant muscular atrophy,
	extreme functional disability, and radiographic evidence of major joint
	destruction (erosions, subluxations, and ankylosis) [Schur, 1999].

	The evaluation should rule out the possible presence of the
	extra-articular complications or manifestations of RA that most
	frequently appear at this stage of the disease, for example, skin
	ulcers, vasculitis, and amyloidosis [Gordon, 1973; Thurtle, 1983;
	Vollertsen, 1986; Breedveld, 1989].

	Their management will be based on symptomatic treatment and repair of
	function. Special considerations should be taken into account for
	elderly patients (section 4.7).


	3.3 Pseudopolymyalgic rheumatoid arthritis

	Pseudopolymyalgic rheumatoid arthritis is a disease that affects
	patients over 60 years of age and is characterized by the sudden onset
	of symptoms, mainly affecting the proximal joints (shoulders and hips)
	as well as the knees and carpal joints. It is accompanied by
	considerable morning stiffness, negative RF, and a marked increase in
	acute phase reactants. Erosions do not usually develop, and the
	prognosis is generally good. The disease may remit spontaneously in 6-24
	months [Healey, 1986].

	The main problem with pseudopolymyalgic RA is the difficulty of making a
	differential diagnosis since it is very similar to polymyalgia rheumatica.

	Cases diagnosed as pseudopolymyalgia may include cases of polymyalgia
	rheumatica and RS3PE (remitting seronegative symmetrical synovitis with
	pitting edema), and perhaps some atypical forms of other arthropathies
	that are clinically indistinguishable from RA, a fact that may partially
	explain the good evolution in this subgroup.

	It is usually managed effectively only with corticosteroids (section
	4.5). If a satisfactory response is not obtained, it should be treated
	the same as RA in general, taking special considerations into account
	for elderly patients (section 4.7).


	CHAPTER 4. MEDICAL TREATMENT OF RHEUMATOID ARTHRITIS


	4.1 Initial treatment of rheumatoid arthritis


	4.1.1 In general, all patients with RA should be treated with a DMARD as 
	soon as the disease is diagnosed.

	The aim of RA treatment is to induce complete disease remission or,
	alternatively, to achieve the best possible response. Treatment with
	DMARDs is the only way to ensure the most favorable evolution for the
	patient and to improve the quality of life.

	The function of each drug prescribed should be explained to patients so
	that they know to discontinue or reduce symptom-modifying drugs (NSAIDs
	or analgesics) if pain and inflammation subside, but that a DMARD should
	never be discontinued without medical consultation, and that
	instructions for the use of corticosteroids should be followed closely.

	All patients with RA should initiate DMARD treatment as soon as possible
	during the course of the disease. An attempt may be made to treat only
	with NSAIDs and/or corticosteroids for a maximum of 3 months, and only
	in patients who have not used these drugs during the 3 months before the
	disease was diagnosed, who have fewer than 6 swollen joints, no
	erosions, negative RF, and normal APRs.

	Many patients in Spain experience an unacceptably long delay before the
	first DMARD treatment. According to the emAR study, the time from first
	symptoms to first treatment with any DMARD is high, ranging from 7 to 48
	months, with a median of 16 months [Hernández-García, 2001].
	Furthermore, this interval increases with increasing time between first
	symptoms and the patient's first visit for specialized care.
	[Hernández-García, 2000].

	The time between first symptoms and initiation of DMARD treatment is one
	of the few variables that the physician can modify. Early commencement
	of treatment is associated with a higher probability of favorable
	response [Anderson, 2000; Villaverde, 2000] and a lower probability of
	functional and radiologic deterioration [Fries, 1996; Abu-Shakra, 1998].
	Thus, it is essential not only that all patients with RA be treated with
	DMARDs, but that this treatment should be initiated as early as possible
	in the course of the disease.

	All the DMARDs in Table 1 have been shown to be more efficacious than 
	placebo (Table 11). However, not all possible drug combinations in 
	monotherapy or combined therapy have been compared in clinical trials 
	(Tables 7 and 8).

	For years DMARDs were used as monotherapy. If the response to one DMARD
	was not complete, it was discontinued and a second DMARD was initiated.
	This strategy often caused a reactivation of disease between the time
	one drug was withdrawn and the other begun. The fact that many RA
	patients are refractory to treatment led to the first use of
	combinations of two or more DMARDs [Ehrlich, 1982; Bitter, 1984; Gibson,
	1987; Taggart, 1987; Scott, 1989; Williams, 1992; McCarty, 1995;
	Willkens, 1995]. The use of combined treatments slowed down, however,
	partly due to the results of a meta-analysis of five initial studies
	which concluded that combined therapy was no more efficacious and
	furthermore was more toxic than monotherapy [Felson, 1994]. The
	publication in the last decade of various clinical trials with sound
	methodology and a sufficient number of patients has encouraged renewed
	use of combined therapies in RA treatment [Tugwell, 1995; O'Dell, 1996;
	Stein, 1997; Boers, 1997; Haagsma, 1997].

	The good results obtained using combined treatment in patients
	refractory to monotherapy have led some authors to propose they be used
	as sustained initial treatment or by sequentially discontinuing some of
	the drugs [Wilske, 1989; Boers, 1997]. The corticosteroids have also
	gained renewed acceptance as part of this "aggressive" strategy,
	especially while waiting for the DMARDs to take effect [Kirwan, 1995].
	The introduction of new DMARDs opens the range of possibilities in RA
	treatment even wider. Some of these strategies are moving into daily
	practice. For example, in Spain almost 28% of patients included in the
	emAR study [Hernández-García, 2001] used some combination of two or more
	DMARDs throughout the study period. Another 72% followed some kind of
	treatment with corticosteroids. The impact of new treatments on the
	treatment strategy for RA is unknown. Whatever the case may be, with the
	limitations derived from our imperfect knowledge, RA patients have
	recourse to a wide range of strategies aimed at controlling their
	disease, which can be used pending the results of new comparative studies.


	4.1.2 In addition to DMARD treatment, all RA patients should be treated
	with optimum doses of steroidal or nonsteroidal anti-inflammatory agents
	and/or analgesics if symptoms (pain and swelling) persist (sections 4.4, 
	4.5 and 4.6).

	Regardless of DMARD treatment, all patients also require treatment with
	symptom-modifying drugs (NSAIDs and/or corticosteroids and/or
	analgesics) so long as there are persistent symptoms of joint pain
	and/or swelling.


	4.1.3 Because of its efficacy and toxicity profile, methotrexate is the 
	recommended initial treatment in all patients who have not previously 
	received DMARD treatment. Nevertheless, initial treatment with other 
	drugs is considered acceptable, depending on the clinical classification of
	disease (Table 14 or Appendix 2).

	The advantages of methotrexate over other DMARDs with similar short-term
	efficacy are a well-known toxicity profile, easy management, and a lower
	rate of withdrawal from treatment in the medium and long term. For all
	these reasons, it is recommended as the drug of choice in this guideline.

	The administration of 5 to 10 mg/wk of folic acid is recommended for RA
	patients treated with MTX [American College of Rheumatology, 1996].
	Despite this recommendation, only slightly more than half of RA patients
	who receive MTX in Spain are treated with folic acid or folinic acid
	[Hernández-García, 2001].

	Due to the clinical complexity of RA, the panel considers that the use
	of other DMARDs or DMARD combinations of proven efficacy is valid as
	initial treatment in some clinical situations, in accordance with the
	treatment scheme in Appendix 2 or Table 14.

	Although the vast majority (93%) of RA patients who receive specialized
	care are treated with DMARDs, there is wide variability in their use in
	Spain. According to data from the emAR study, during a 2-year period and
	considering both monotherapy and combined therapy, 46% of patients had
	taken MTX, 21% anti-malarials, 14% IG, 8% SSZ, and 6% CSA. Among the
	factors associated with the use of each DMARD are patient age; some
	disease characteristics, such as functional class, rheumatoid factor, or
	disease activity; and the existence of associated disease. However,
	there is also significant variability that is associated, not with
	patient characteristics, but with physician specialty or
	characteristics, or with geographic region. Thus, for the same patient,
	the probability of receiving a particular DMARD depends on whether or
	not the prescribing physician is a specialist in rheumatology, his or
	her age, or the autonomous community of residence. About one-forth of
	patients treated with DMARDs use a combination of two or more drugs,
	although this percentage varies considerably between and among
	autonomous communities. The most frequent combinations include MTX and
	anti-malarials, followed by MTX with SSZ, MTX with CSA, and MTX with IG
	[Hernández-García, 2001].


	Table 14. Initial treatment by simplified clinical classification of RA

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions	
          	* less than 6 swollen joints	
	Recommended initial treatment, by order of preference (supporting evidence)
	   * Methotrexate (1)
	   * Sulphasalazine (2)
	   * Chloroquine (3)	   

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions	
          	* Greater than or equal to 6 swollen joints	
	Recommended initial treatment, by order of preference (supporting evidence)
	   * Methotrexate (1)
	   * Injectable gold (4)

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present 	
          	* less than 6 swollen joints	
	Recommended initial treatment, by order of preference (supporting evidence)
	   * Methotrexate (1)

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present 
          	* Greater than or equal to 6 swollen joints 		
	Recommended initial treatment, by order of preference (supporting evidence)
	   * Methotrexate (1)
	   * Leflunomide (5) 	 	
	   * Methotrexate + injectable gold (6)


	   1. Methotrexate is more efficacious than oral gold (A1 evidence )
	      or azathioprine (A2 evidence). No significant differences have
	      been found in the efficacy of methotrexate compared with
	      etanercept, leflunomide, sulphasalazine (A1 evidence), injectable
	      gold (A2 evidence), cyclosporin, or infliximab (B evidence).
	   2. Sulphasalazine is more efficacious than hydroxychloroquine (A2
	      evidence), and no significant differences have been found in the
	      efficacy of sulphasalazine compared with leflunomide, methotrexate
	      (A1 evidence), oral or injectable gold, and D-penicillamine (B
	      evidence).
	   3. Chloroquine is not significantly different in efficacy from
	      cyclosporin, oral gold (A2 evidence), azathioprine, injectable
	      gold and D-penicillamine (B evidence).
	   4. Injectable gold is not significantly different in efficacy from
	      oral gold (A1evidence), cyclosporin and methotrexate (A2
	      evidence), or chloroquine, D-penicillamine and sulphasalazine (B
	      evidence). It is less efficacious than azathioprine and
	      cyclophosphamide (B evidence).
	   5. Leflunomide (A1 evidence) shows no differences in efficacy as
	      compared to methotrexate and sulphasalazine (A1 evidence).
	   6. No clinical trials have evaluated the efficacy of treatment with
	      methotrexate+injectable gold (C evidence).


	4.2 Changes in treatment

	After initiating any treatment, it is necessary to evaluate the
	response (chapter 5) and to monitor its toxicity (chapter 6). Treatment
	failure or toxicity should be evaluated within a maximum of 3 months,
	and a consequent change in treatment should be considered.

	Whatever initial treatment is chosen, the patient should be monitored
	closely. If a satisfactory response is not obtained within 3 months, or
	if there is evidence of DMARD-related toxicity, consideration should be
	given to the possibility of a change in treatment by adding a new drug
	or modifying the dosage. It is critically important that a patient with
	RA who has not responded to a particular treatment with single or
	combined DMARDs have the option to try other treatments of proven
	efficacy in the shortest possible period of time.


	4.2.1 If serious adverse effects appear, an alternative treatment should 
	be substituted for the treatment of first choice, in accordance with Table 15.


	Table 15. Alternative treatment in case of severe toxicity to initial treatment

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Injectable gold (2)
	   * Sulphasalazine (4)	
	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Sulphasalazine	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Methotrexate (3)
	   * Injectable gold (2)
 	 	 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Chloroquine	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Methotrexate (3)
	   * Injectable gold (2)
 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Injectable gold (2)

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Injectable gold	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Methotrexate (3)
	   * Leflunomide (1)
 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Injectable gold (2)
	   * Sulphasalazine (4) 	 	

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Injectable gold (2)
	   * Sulphasalazine (4) 	 	
 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Leflunomide	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Methotrexate (3)
	   * Anti-TNF (5)

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate+injectable gold	
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Anti-TNF (5)


	The evidence supporting the alternative treatments proposed in case of
	toxicity or unsatisfactory response is as follows:

	   1. Leflunomide (A1 evidence) shows no differences in efficacy as
	      compared to methotrexate and sulphasalazine (A1 evidence).
	   2. Injectable gold has not been shown to have significant
	      differences in efficacy as compared to oral gold (A1 evidence),
	      cyclosporin and methotrexate (A2 evidence), or chloroquine,
	      D-penicillamine and sulphasalazine (B evidence). It is less
	      efficacious than azathioprine and cyclophosphamide (B evidence).
	   3. Methotrexate is more efficacious than oral gold (A1 evidence) or
	      azathioprine (A2 evidence). No significant differences in the
	      efficacy of methotrexate have been found in comparison with
	      etanercept, leflunomide, sulphasalazine (A1 evidence), injectable
	      gold (A2 evidence), cyclosporin, or infliximab (B evidence).
	   4. Sulphasalazine is more efficacious than hydroxychloroquine (A2
	      evidence) and no significant differences have been found in the
	      efficacy of sulphasalazine compared with leflunomide, methotrexate
	      (A1 evidence), oral or injectable gold, and D-penicillamine (B
	      evidence).
	   5. Anti-TNF agents (infliximab and etanercept) have been shown to
	      be efficacious in the treatment of RA (A1 evidence), and they show
	      no significant differences in efficacy with respect to
	      methotrexate (B evidence for infliximab and A1 for etanercept).


	4.2.2 If the treatment shows no toxicity but the response is unsatisfactory, even 
	after using the maximum dosage (see 4.3), an alternative treatment should be 
	substituted for the treatment of first choice, in accordance with Table 16.


	Table 16. Alternative treatment in case of unsatisfactory response to initial treatment

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Leflunomide (1) 	
	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Sulphasalazine
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Methotrexate (2)
	   * Leflunomide (1)	   
 	 	 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Chloroquine
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Methotrexate (2)
	   * Leflunomide (1)	   
 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Leflunomide (1)

	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * No erosions
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Injectable gold
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Methotrexate (2)
	   * Leflunomide (1) 	
 	 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* less than 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Leflunomide (1)
 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Anti-TNF (3)
	   * Methotrexate+ anti-TNF (4)
	   * Methotrexate+chloroquine+sulphasalazine (5)
 	 	 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Leflunomide
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Methotrexate (2)
	   * Anti-TNF (3)
	   * Methotrexate+ anti-TNF (4)
 	 	
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA 	
	   * Erosions present
          	* Greater than or equal to 6 swollen joints	   
	First-choice treatment used 	
	   * Methotrexate+injectable gold
	Alternative treatment in unsatisfactory response, in order of preference (supporting evidence)
	   * Leflunomide (1)
	   * Anti-TNF (3)


	   1. Leflunomide (A1 evidence) has not shown differences in efficacy
	      compared with methotrexate and sulphasalazine (A1 evidence).
	   2. Methotrexate is more efficacious than oral gold (A1 evidence) or
	      azathioprine (A2 evidence). No significant differences in efficacy
	      have been found in methotrexate as compared to etanercept,
	      leflunomide, sulphasalazine (A1 evidence), injectable gold (A2
	      evidence), cyclosporin, or infliximab (B evidence).
	   3. Anti-TNF agents (infliximab and etanercept) have been shown to
	      be efficacious in the treatment of RA (A1 evidence) in comparison
	      with placebo, and they show no significant differences in efficacy
	      as compared to methotrexate (B evidence for infliximab and A1 for
	      etanercept).
	   4. The combination of methotrexate+anti-TNF agents (infliximab or
	      etanercept) has been shown to be more efficacious than
	      methotrexate alone (B evidence).
	   5. The combination of methotrexate+chloroquine+sulphasalazine has
	      been shown to be more efficacious than methotrexate alone or
	      chloroquine+sulphasalazine (A2 evidence).

	In addition to the panel's recommendations, there is scientific evidence
	regarding the efficacy of several drug combinations in case of failure
	of treatment with methotrexate or the antimalarials.

	In case of failure with methotrexate, the following combinations have
	been shown to be more efficacious:

	   * Methotrexate+cyclosporin (A1 evidence)
	   * Methotrexate+chloroquine (A2 evidence)
	   * Methotrexate+azathioprine (B evidence)

	In case of failure with the antimalarials, the following combinations
	have been shown to be more efficacious:

	   * Sulphasalazine+hydroxychloroquine (A2 evidence)
	   * Methotrexate+hydroxychloroquine (B evidence)


	4.2.3 In patients for whom the preceding guidelines are not useful, due to 
	lack of efficacy, toxicity, or other causes, this guideline recommends the 
	use of any DMARD or DMARD combination of proven efficacy; if these fail, 
	experimental treatments are recommended.

	The natural history of RA is long and no treatment has been shown to
	cure all patients. Thus, regardless of the recommendations in the
	preceding sections, it is admissible to introduce alternative treatments
	whose efficacy has been shown in clinical trials (Tables 7 and 8.)

	If disease control is not achieved with any of the proposed treatments,
	experimental treatments may be explored (new drugs or new combinations
	of existing drugs) so that the patient is never without some type of
	disease-modifying treatment.


        4.3 Dosage for disease-modifying antirheumatic drugs


	Table 17. Recommended doses and commercial names of DMARDs

	DRUG
	   * AZATHIOPRINE	
	DOSE
	   * 1.5 - 2.5 mg/kg/day, by mouth
	   * Begin with low dose of around 1 mg/kg/day and increase in 4-6 weeks 
	     to maintenance dose of 100-150 mg/day. 	
	COMMERCIAL NAMES 
	   * IMURAN® Tab. 50 mg
	   * IMURAN®, Freeze-dried vial, 50 
 
	DRUG
	   * CYCLOPHOSPHAMIDE	
	DOSE
	   * 1.5 - 2.5 mg/kg/day, by mouth
	   * Begin with 50 mg/day and increase dose every 4-6 weeks until a 
	     response is obtained, without exceeding 2.5 mg/kg/day. 	
	COMMERCIAL NAMES 
	   * GENOXAL® Amp. IV 1000 mg
	   * GENOXAL® Amp. IV 200 mg
	   * GENOXAL® Tab. 50 mg
  	 	
	DRUG
	   * CHLOROQUINE	
	DOSE
	   * 250 mg/day, by mouth
	   * Do not exceed 4 mg/kg/day.	
	COMMERCIAL NAMES 
	   * RESOCHIN® Tab. 250 mg
	  
	DRUG
	   * CYCLOSPORIN	
	DOSE
	   * 2.5 - 5.0 mg/kg/day, by mouth
	   * The initial dose can be increased by 0.5mg/kg/day every 2 weeks up to 5
	     mg/kg/day.	
	COMMERCIAL NAMES 
	   * SANDIMMUNE NEORAL® 100 mg
	   * SANDIMMUNE NEORAL® 50 mg
	   * SANDIMMUNE NEORAL® 25 mg
	   * SANDIMMUNE NEORAL® Oral sol. 100mg/ml
	  
	DRUG
	   * D-PENICILLAMINE	
	DOSE
	   * 125 - 500 mg/day, by mouth
	   * Begin treatment with 125-250 mg/day and if there is no improvement, 
	     increase dose at 8 weeks by 125 mg/day. Dose can be increased
	     gradually every 8 weeks up to 500-750 mg/day. Should be administered 
	     2 hrs before the main meal. 
	COMMERCIAL NAMES 
	   * CUPRIMENE® Caps .250 mg
	   * CUPRIMENE® Caps .125 mg
	   * CUPRIMENE® Tab.50 mg
	   * SUFORTANON® Tab. 250 mg
	  
	DRUG
	   * ETANERCEPT	
	DOSE
	   * 25 mg, reconstituted in 1 ml water, in subcutaneous injection, twice 
	     a week at intervals of 72-96 hours
	   * One dose of 25 mg administered once a week offers a slower response 
	     and may be less effective.  
	COMMERCIAL NAMES 
	   * ENBREL® Vial 25 mg
 
	DRUG
	   * HYDROXYCHLOROQUINE	
	DOSE
	   * 400 mg/day, by mouth
	   * Do not exceed 6.5 mg/kg/day 
	COMMERCIAL NAMES 
	   * PLAQUENIL® Tab. 200 mg
 
	DRUG
	   * INFLIXIMAB	
	DOSE
	   * 3 mg/kg intravenous perfusion for 2 hours
	   * Then administer additional doses of 3 mg/kg in perfusion at weeks 
	     2 and 6 following the first week, and one dose every 8 weeks thereafter.
	     Dose may be increased to 5 mg/kg if ineffective or in case of relapse. 
	     Some patients require a shorter interval of infusion every 4-6 weeks, 
	     instead of the recommended 8 weeks for maintenance. Infliximab should be
	     administered together with methotrexate.
	COMMERCIAL NAMES 
	   * REMICADE® Freeze-dried vial 100 mg
 
	DRUG
	   * LEFLUNOMIDE	
	DOSE
	   * 20 mg/day, by mouth
	   * Begin with 100 mg/day for 3 days and then 20 mg/day continuously.
	COMMERCIAL NAMES 
	   * ARAVA® Tab.100 mg
	   * ARAVA® Tab.20 mg
	   * ARAVA® Tab.10 mg

	DRUG
	   * METHOTREXATE	
	DOSE
	   * 7.5-10 mg/week, by mouth for 4 weeks, 15 mg/week for the next 4 weeks,
	     and then increase up to 20 mg/week. In case of inefficacy or 
	     gastrointestinal toxicity, consider parenteral administration.
	   * Administer folic acid (5-10 mg/week) 24 hours after methotrexate.
	COMMERCIAL NAMES 
	   * METHOTREXATE ALMIRALL® Inj. sol. Vial 50 mg , A.D.1000 mg, 5000 mg, 
	     and 500 mg
	   * METHOTREXATE LEDERLE® Tab. 2,5 mg; Inj. sol. 25 mg/ml (2, 20, 40 and 
	     200 ml); Freeze-dried vial 50 and 500 mg
	   * METHOTREXATE WASSERMANN® Inj. sol. 25 mg/ml (2 and 20 ml)
	   * EMTHEXATE® Vial 50 and 500mg/2ml

	DRUG
	   * ORAL GOLD	
	DOSE
	   * 6 mg/day by mouth 2 tablets per day.
	COMMERCIAL NAMES 
	   * RIDAURA® Tab. 3 mg
	   * CRISINOR® Tab. 3 mg
 
	DRUG
	   * INJECTABLE GOLD	
	DOSE
	   * 50 mg/week in intramuscular injections
	   * Increasing doses of 10, 25 and 50 mg/week, maintaining the dose (from 6
	     to 24 months) or adjusting it depending on clinical response or adverse effects. 
	COMMERCIAL NAMES 
	   * MIOCRIN® Inj. sol. IM 10 mg
	   * MIOCRIN® Inj. sol. IM 25 mg
	   * MIOCRIN® Inj. sol. IM 50 mg
   	
	DRUG
	   * SULPHASALAZINE	
	DOSE
	   * 2-3 g/day, by mouth
	COMMERCIAL NAMES 
	   * SALAZOPYRIN® Tab. 500 mg


	4.4 Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs)


	4.4.1 The NSAIDs are used to modify the symptoms of RA. The use of NSAIDs is 
	recommended at disease onset, when a new DMARD is introduced, and when 
	uncontrolled isolated symptoms persist despite good response to a DMARD.

	The NSAIDs are used to modify the symptoms of RA. They have not been
	shown to have any additional effect on disease outcome.

	The use of NSAIDs is recommended:

	   * At disease onset. If the disease is low risk (less than 6 swollen 
	     joints, no erosions, negative RF, and normal APRs), they can be 
	     used alone or in combination with corticosteroids for a maximum 
	     of 3 months.
	   * When a new DMARD is introduced. NSAIDs should be used until the
	     disease and its symptoms can be controlled by the DMARD alone.
	     NSAIDs should be used for 2-12 weeks, depending on the time needed
	     for the DMARD to reach effective therapeutic levels. The period of
	     combined use may sometimes be prolonged until the DMARD dose is
	     adjusted.
	   * When uncontrolled symptoms persist. NSAIDs should be used when,
	     despite treatment with a DMARD, some isolated symptom (painful
	     inflammation or swelling or morning stiffness) is not sufficiently
	     controlled, and there is no evidence of inflammatory activity that
	     justifies increasing the DMARD dose or changing to a new treatment.

	NSAIDs should not be used without first trying other analgesics such as
	acetaminophen for mechanical pain (pain that worsens with exercise and
	improves with rest, becomes worse during the day, with no joint
	stiffness after rest).

	It is important to weigh the benefit-risk relation for the patient
	whenever an NSAID is used. The side effects and interactions of the
	NSAIDs used should be known.


	4.4.2 All NSAIDs should be used at the full dose for at least 1 week before 
	considering the treatment to have failed. Once symptoms have been controlled,
	the minimum effective dose should be used.

	When the NSAIDs are withdrawn after prolonged use (over 3 months), they
	should be discontinued gradually to avoid the effects of rebound pain.
	No guidelines for withdrawal have been shown to be more effective than
	others.

	Length of treatment with NSAIDs is a risk factor for gastric erosion.


	Table 18. Usual dosage and frequency of administration of NSAIDs

	DRUG 	
	   * AAS	
	TOTAL DOSE (mg/24 h) 	
	   * 3,000 - 6,000	
	FREQUENCY OF ADMINISTRATION
	   * 6-8 h.	
	
	DRUG 	
	   * Ibuprofen	
	TOTAL DOSE (mg/24 h) 	
	   * 1,200 - 2,400	
	FREQUENCY OF ADMINISTRATION
	   * 8 h.	
 	 	
	DRUG 	
	   * Flurbiprofen
	   * Flurbiprofen Retard 
	TOTAL DOSE (mg/24 h) 	
	   * 200 - 300
	   * 200
	FREQUENCY OF ADMINISTRATION
	   * 12 h.
	   * 24 h.

	DRUG 	
	   * Mefenamic acid	
	TOTAL DOSE (mg/24 h) 	
	   * 750 - 1,500	
	FREQUENCY OF ADMINISTRATION
	   * 8 h.	
 	 	
	DRUG 	
	   * Meclofenamic acid	
	TOTAL DOSE (mg/24 h) 	
	   * 200 - 400 	
	FREQUENCY OF ADMINISTRATION
	   * 8 h.	

	DRUG 	
	   * Diflunisal	
	TOTAL DOSE (mg/24 h) 	
	   * 500 - 1,000	
	FREQUENCY OF ADMINISTRATION
	   * 12 h.	

	DRUG 	
	   * Sodium Tolmetin	
	TOTAL DOSE (mg/24 h) 	
	   * 800 - 1,200
	FREQUENCY OF ADMINISTRATION
	   * 6-8 h.	
	
	DRUG 	
	   * Naproxen	
	TOTAL DOSE (mg/24 h) 	
	   * 500 - 1,000
	FREQUENCY OF ADMINISTRATION
	   * 12 h.	
 	
	DRUG 	
	   * Ketoprofen
	   * Ketoprofen Retard 
	TOTAL DOSE (mg/24 h) 	
	   * 200
	   * 200
	FREQUENCY OF ADMINISTRATION
	   * 8-12 h.
	   * 24 h.
 	 	
	DRUG 	
	   * Aceclofenac	
	TOTAL DOSE (mg/24 h) 	
	   * 200
	FREQUENCY OF ADMINISTRATION
	   * 12 h.
 		
	DRUG 	
	   * Diclofenac
	   * Diclofenac Retard
	TOTAL DOSE (mg/24 h) 	
	   * 150 - 200
	   * 100
	FREQUENCY OF ADMINISTRATION
	   * 8-12 h.
	   * 24 h.
 	 	
	DRUG 	
	   * Phenylbutazone	
	TOTAL DOSE (mg/24 h) 	
	   * 200 - 400
	FREQUENCY OF ADMINISTRATION
	   * 12-24 h.
 	
	DRUG 	
	   * Indomethacin	
	TOTAL DOSE (mg/24 h) 	
	   * 75 - 150
	FREQUENCY OF ADMINISTRATION
	   * 8 h.

	DRUG 	
	   * Sulindac	
	TOTAL DOSE (mg/24 h) 	
	   * 200 - 400 
	FREQUENCY OF ADMINISTRATION
	   * 12 h.

	DRUG 	
	   * Piroxicam	
	TOTAL DOSE (mg/24 h) 	
	   * 20
	FREQUENCY OF ADMINISTRATION
	   * 24 h.
 	
	DRUG 	
	   * Tenoxicam	
	TOTAL DOSE (mg/24 h) 	
	   * 20
	FREQUENCY OF ADMINISTRATION
	   * 24 h.

	DRUG 	
	   * Droxicam	
	TOTAL DOSE (mg/24 h) 	
	   * 20
	FREQUENCY OF ADMINISTRATION
	   * 24 h.
 	 	
	DRUG 	
	   * Meloxicam	
	TOTAL DOSE (mg/24 h) 	
	   * 7.5 - 15 
	FREQUENCY OF ADMINISTRATION
	   * 24 h.
 	 	
	DRUG 	
	   * Nimesulide	
	TOTAL DOSE (mg/24 h) 	
	   * 200
	FREQUENCY OF ADMINISTRATION
	   * 12 h.

	DRUG 	
	   * Nabumetone	
	TOTAL DOSE (mg/24 h) 	
	   * 1,000-2,000
	FREQUENCY OF ADMINISTRATION
	   * 12-24 h.
 		
	DRUG 	
	   * Rofecoxib	
	TOTAL DOSE (mg/24 h) 	
	   * 12.5 - 25 
	FREQUENCY OF ADMINISTRATION
	   * 24 h
 	 	
	DRUG 	
	   * Celecoxib	
	TOTAL DOSE (mg/24 h) 	
	   * 200 - 400
	FREQUENCY OF ADMINISTRATION
	   * 12-24 h


	4.4.3 There is no evidence that some NSAIDs are better than others, 
	therefore the one that best fits the patient characteristics should be used.

	There is no evidence that the efficacy of combined NSAIDs is greater
	than each NSAID alone. In a recent review of different meta-analyses and
	trials comparing the efficacy of the NSAIDs, it was not possible to show
	that some NSAIDs are more efficacious than others, although it was shown
	that they have different safety profiles, in favor of ibuprofen
	[Gotzsche, 2000a]. No controlled clinical trial of sufficient size has
	compared the efficacy of the NSAIDs to acetaminophen.

	There are no convincing studies showing that specific patients benefit
	more from some NSAIDs than from others. Generally, different NSAIDs are
	tried until symptom control is reached. A large number of different
	NSAIDs is available in Spain, thus it is important to know them all,
	especially their different pharmacokinetic profiles, in order to adapt
	them to the patient's needs. Some NSAIDs, such as naproxen or
	acetylsalicylic acid (ASA) have more rapid uptake (about 20 minutes),
	and thus would be indicated for acute pain. Others with delayed uptake
	and prolonged action (retard forms) can be administered at night so they
	will act when the patient wakes up.

	Selective cyclooxigenase inhibitors of the COX-2 isoenzyme, or coxibs
	(refecoxib, celecoxib, and others under investigation), have not been
	shown to have a safety profile significantly better than other NSAIDs,
	except in the gastrointestinal system [Schnitzer, 1999; Simon, 1999;
	Emery, 1999; Langman, 1999]. They should be used in patients at risk for
	gastroduodenal ulcers. Patients with cardiovascular disease can benefit
	from the platelet-inhibitory action of the NSAIDs, which is not shared
	by the coxibs. The SER (Spanish Society of Rheumatology) guidelines for
	the rational use of coxibs are recommended [SER, 2000a].


	4.4.4 The need for co-treatment with gastric protectors should be 
	evaluated on an individual basis.

	Since the NSAIDs are associated with a high frequency of
	gastrointestinal adverse effects and are often used for prolonged
	periods, the need for a gastric protector should be evaluated in
	accordance with other existing risk factors for gastroduodenal ulcers.


	4.5 Treatment with corticosteroids


	4.5.1 The use of oral corticosteroids at low doses is recommended in 
	patients in whom NSAIDs are not effective or are contraindicated for 
	any reason. They can be used instead of NSAIDs or in association with them.

	The corticosteroids should never replace treatment with DMARDs, unless
	their possible role as a disease modifying agent should be shown. They
	are indicated as the treatment of choice only in the case of
	pseudopolymyalgic RA (section 3.3).

	Corticosteroids should be used:

	   * When NSAIDs are contraindicated or have a high risk of adverse
	     effects (the elderly, associated morbidity).
	   * As bridge therapy until the onset of DMARD action.
	   * When NSAIDs do not effectively control inflammation (generally, by
	     adding corticosteroids to the NSAID treatment).
	   * In the treatment of pseudopolymyalgic RA.

	It is not clear what role the corticosteroids should play in RA
	treatment. More studies are needed to analyze their efficacy in
	comparison with the NSAIDs. However, it is doubtful that corticosteroids
	alone should constitute an alternative to NSAIDs if the latter treatment
	fails and cannot be considered as first-line treatment when rapid
	control of inflammation is needed. Some studies that have used a high
	initial dose, especially in very aggressive RA [Boers, 1997], indicate
	that treatment with methylprednisolone pulses may constitute an
	alternative for the initial control of disease activity (always in
	association with a DMARD and pending the onset of its effect).


	4.5.2 Low-doses of oral corticosteroids (less than 15 mg/day of prednisone
	or the equivalent) are an effective anti-inflammatory treatment in RA. Doses 
	not exceeding 15 mg/day of prednisone should be used during the shortest 
	possible period of time, and maintenance doses should not exceed 10 mg/day 
	of prednisone or the equivalent.

	The use of corticosteroids in RA treatment is controversial, but they
	are used frequently, especially in the long term. The corticosteroids
	are better than placebo and similar to or better than NSAIDs or
	chloroquine in controlling RA activity [Saag, 1997; Criswell, 2000;
	Gotzsche, 2000b]. Several authors have studied the role of the
	corticosteroids in RA management from different perspectives: as disease
	modifiers [Kirwan, 1995; Hickling, 1998; Weiss, 1989] and as "bridge"
	therapy while waiting for the DMARDs to take effect [Harris, 1983;
	Caldwell, 1991; Van Gestel, 1995].

	The use of corticosteroids has been associated with increased mortality,
	and their chronic use, at low doses, is related with increased
	morbidity. It is difficult, however, to separate the effect of
	corticosteroid use from the fact that patients who usually take them
	have more severe disease that cannot be controlled with NSAIDs alone.


	4.5.3 No corticosteroid preparation has been shown to be superior to any 
	other, thus any of them can be used at equivalent doses.

	There is currently no evidence that the most commonly used preparations
	(prednisone, prednisolone, methylprednisolone, and deflazacort) are
	significantly different in efficacy or adverse effects when used at
	equivalent doses.

	The dosage of corticosteroids always depends on the underlying disease
	for which they are prescribed, and on its clinical and biological
	activity. Whenever possible, a single daily dose should be recommended
	at the beginning of the day. The dose should be progressively reduced
	(changing fractionated doses to a single dose before decreasing the dose).


	Table 19. Classification of the corticosteroids by duration of action

	Short-acting corticosteroids
	   * Hydrocortisone, prednisone, and prednisolone
	Intermediate-acting corticosteroids
	   * Methylprednisolone, paramethasone, triamcinolone, and deflazacort
	Long-acting corticosteroids
	   * Betamethasone and dexamethasone


	4.5.4 Given the association between corticosteroid use and rapid loss of
	bone mass, the use of vitamin D plus calcium is recommended as a minimum 
	measure; if treatment is expected to exceed 3 months, other preventive 
	osteoporosis treatments (section 8.4) should be evaluated.


	4.6 Treatment for pain


	4.6.1 Analgesics are indicated to control pain. If there is no response, 
	surgical treatment can be considered, especially to restore function and 
	mobility.

	Pain control treatment should be instituted if pain persists despite the
	adoption of previous disease-control measures. Simple analgesics (e.g.,
	acetaminophen, ASA) should be used first, increasing to the maximum dose
	of 3-4 g/day in the case of acetaminophen and up to 4gr/day for ASA. If
	pain persists, dipyridamole, NSAIDs, or codeine may be used.

	If pain is due to neuropathy, tricyclic antidepressants (amitryptiline)
	and some anticonvulsants (gabapentine or carbamazepine) may be used.

	When pain is very localized, local analgesics such as capsaicin cream
	may be used. The ideal dose is 0.75 mg of cream (not available in Spain).

	Surgical treatment should be considered when pain does not respond to
	pharmacological treatments and is due to joint destruction, producing
	changes in the patient's functional capacity [Dunbar, 1998].

	If pain is intense, there is no response to previous analgesic
	treatments, and surgery is not an option, opiate analgesics may be
	administered. [Hazes, 1994; Schur, 1999].


	4.7 Special considerations in the treatment of elderly patients


	4.7.1 Kidney and liver function should be monitored in elderly patients, 
	and the dosage intervals of the drugs eliminated by these routes should be 
	adapted accordingly.

	Aging may be accompanied by changes in various organs, especially those
	responsible for metabolizing and excreting different drugs. This means
	that the pharmacokinetic and pharmacodynamic properties of a large
	number of drugs used in elderly patients may be different than in
	younger individuals [Morgan, 1986; Bird, 1990]. Optimal pharmacological
	treatment in a particular patient depends on a variety of factors, which
	are frequently not well known or are difficult to determine; this fact
	may contribute to the large variability among different individuals in
	the response to the same drug, a phenomenon that is especially notable
	in the elderly [Bird, 1990].

	The dosage of drugs eliminated by the renal route should be adjusted so
	that it is similar to what is used in patients with renal failure
	(decreasing the dose and/or lengthening the intervals between doses).
	Even in the absence of kidney disease, renal clearance in elderly
	individuals is decreased by 35-50%. The elderly, and especially those
	who suffer RA, have reduced muscular mass, which produces a decline in
	the production of creatinine. Thus, an elderly individual may have a
	normal creatinine value even though creatinine clearance is altered.
	[Oates, 1998].

	Aging may also produce alternations in hepatic function, thus the
	metabolization of drugs that are broken down in the liver may also be
	reduced [Morgan, 1986].


	4.7.2 The possible appearance of adverse effects and drug interactions 
	should be monitored in elderly patients.

	Adverse drug effects have traditionally been considered more frequent in
	elderly individuals [Hurwitz, 1969; Dahl, 1990], although little
	information is available about most drugs in this age group, including
	those used in RA patients. The lack of data is due to the frequent
	exclusion of extreme age groups in clinical trials. For this reason,
	unexpected side effects are not uncommon in individuals with late onset
	RA, once the drugs have come into generalized use [Morgan, 1986; Dahl,
	1990].

	In general, elderly patients have more than one disease and need
	treatment with multiple drugs. This means there is an increased
	probability of drug interactions and contributes to a larger number of
	side effects [Buchan, 1991]. The use of multiple drugs in elderly
	patients is often accompanied by a lack of treatment compliance, which
	has been estimated at 10% [Bird, 1990].

	The DMARDs and the immunosuppressors have a similar efficacy and safety
	profile in young and old individuals, although for the reasons mentioned
	above, toxicity should be monitored more closely in the elderly
	[O´Callaghan, 1986].


	4.8 Special considerations in the treatment of rheumatoid arthritis during 
	pregnancy


	4.8.1 Women of childbearing age should be informed of the possible effects 
	of RA on pregnancy, in particular, because of the implications for treatment.

	There is no evidence that RA has a negative effect on pregnancy outcome.
	However, treatment with DMARDs can have negative consequences on
	pregnancy, the fetus, and breastfeeding. Thus, women of childbearing age
	should know the risk so they can act accordingly.

	The symptoms of RA disappear during pregnancy in 70% of cases, to
	reappear early in the postpartum period [Nicholas, 1988]. When there is
	improvement, this usually occurs in the first trimester. Nevertheless,
	the disease commonly fluctuates and, at the very least, cycles of
	analgesics will be required. The disease almost always recurs early in
	the postpartum period, and this does not seem to depend either on
	breastfeeding or on the return of menstruation. Most patients need full
	doses of NSAIDs in the postpartum period.

	Children of mothers with Sjögren's syndrome with Ro antibodies have an
	increased risk of neonatal lupus.


	4.8.2 The use of NSAIDs during pregnancy and breastfeeding should be avoided 
	insofar as possible. Corticosteroids can be used under controlled conditions. 
	DMARDs should be managed on an individual basis, and should preferably be 
	continued during pregnancy.

	Teratogenic effects in the early weeks of pregnancy have been observed
	in animals receiving larger than pharmacological doses of NSAIDs. In
	both humans and animals, premature closure of the ductus arteriosus has
	also been observed in the last trimester. NSAIDs are not recommended
	near the time of delivery due to their inhibitor effects on platelets
	and the uterine musculature. All NSAIDs are transmitted, in greater or
	lesser measure, to the mother's milk. For these reasons, the NSAIDs
	should be avoided in the first and last trimester and during
	breastfeeding. If necessary, NSAIDs with a short half-life (ibuprofen or
	ketoprofen) should be used. During breastfeeding, NSAIDs should be taken
	while the baby is feeding to avoid elevated concentrations in the milk.

	There is no evidence that the corticosteroids produce serious adverse
	effects at average doses during pregnancy, except for promoting glucose
	intolerance, fluid retention, and hypertension. Consequently, they
	should be administered under controlled conditions.

	Table 20 shows the considerations to be taken into account with regard to 
	DMARD use during pregnancy and breastfeeding. The decision to withdraw 
	continuous treatment during pregnancy should be made on an individual basis.
	If the disease is aggressive, it is preferable not to withdraw the DMARD 
	(unless it has been shown to affect the embryo, fetus, or infant) and to leave 
	it at the minimum effective dose. Total withdrawal of the drug could provoke a 
	recurrence of disease during pregnancy and a poorer outcome. Thus, for women of 
	childbearing age, treatment involving the least risk for the fetus should be 
	proposed to avoid drastic, last-moment decisions.


	Table 20. Use of DMARDs during pregnancy and breast-feeding

	Drug 	
	   * Auranofin	
	FDA classification* 	
	   * C	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Insufficient data	
	Breastfeeding
	   * Compatible**
	   
	Drug 	
	   * Aurothiomalate	
	FDA classification* 	
	   * C	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Complex malformation of the central nervous system has been described 
	     in animals.
	Breastfeeding
	   * Compatible**
 	 	 	 	 	
	Drug 	
	   * Azathioprine	
	FDA classification* 	
	   * D	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Contraindicated during pregnancy	
	Effects on the fetus 	
	   * Intrauterine growth retardation, premature birth. Transitory 
	     immunosuppression in the neonate. Potential alternation of the germ cells.
	Breastfeeding
	   * Contraindicated due to potential immunosuppression
 	 	 	 	 	
	Drug 	
	   * Cyclophosphamide	
	FDA classification* 	
	   * D	
	Transmitted through the placenta 	
	   * Not studied	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Severe malformations
	Breastfeeding
	   * Contraindicated due to bone marrow depression
 	 	 	 	
	Drug 	
	   * Cyclosporin A	
	FDA classification* 	
	   * C	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Intrauterine growth retardation, premature birth 
	Breastfeeding
	   * Contraindicated due to potential immunosuppression

	Drug 	
	   * Antimalarials: Chloroquine, Hydroxychloroquine	
	FDA classification* 	
	   * C	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Rare	
	Effects on the fetus 	
	   * Rare 
	Breastfeeding
	   * Compatible, with precautions***
  	 	 	 		
	Drug 	
	   * D-penicillamine	
	FDA classification* 	
	   * D	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Connective tissue abnormalities, cutis laxa. 
	Breastfeeding
	   * Not studied
 	 	 	 	
	Drug 	
	   * Etanercept	
	FDA classification* 	
	   * B	
	Transmitted through the placenta 	
	   * Not studied	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Unknown 
	Breastfeeding
	   * Not studied

	Drug 	
	   * Infliximab	
	FDA classification* 	
	   * C	
	Transmitted through the placenta 	
	   * Not studied	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Unknown 
	Breastfeeding
	   * Not studied
 	 	 	 	 	
	Drug 	
	   * Leflunomide	
	FDA classification* 	
	   * X	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Contraindicated in pregnancy	
	Effects on the fetus 	
	   * Unknown 
	Breastfeeding
	   * Not studied
 	 	 		 	
 	Drug 	
	   * Methotrexate	
	FDA classification* 	
	   * X	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Spontaneous abortion 	
	Effects on the fetus 	
	   * Fetal abnormalities (including cleft palate and hydrocephaly) 
	Breastfeeding
	   * Contraindicated. Potential accumulation in the infant's tissues
	 	
 	Drug 	
	   * Sulphasalazine	
	FDA classification* 	
	   * B and D near time of delivery 	
	Transmitted through the placenta 	
	   * Yes	
	Effects on the mother 	
	   * Not studied	
	Effects on the fetus 	
	   * Kernicterus if administered near delivery
	Breastfeeding
	   * Compatible, with precautions***
 	
 	* FDA classification of drug teratogenicity:
 	
	Category A: Appropriate and well controlled trials have not shown risk
	for the fetus in the first trimester of pregnancy, and there is no
	evidence of risk in subsequent trimesters.

	Category B: Indicates one of the following: 
	a) No evidence of teratogenic effects in animal studies, but this has
	   not been confirmed in humans.
	b) Some evidence of teratogenic effects in animal studies, but this has
	   not been confirmed in humans.

	Category C: Indicates one of the following:
	a) Teratogenic effects have been detected in animal studies, but no
	   studies in humans have been carried out.
	b) No studies have been carried out (either in animals or in humans).

	Category D: Studies have shown teratogenic effects on the human fetus,
	but at times the benefit obtained with the use of these drugs may exceed
	the expected risk (use in extreme situations of possible maternal death).
	
	Category X: Drugs that have unquestionably been shown to have clear
	teratogenic effects and whose risks greatly exceed the possible benefit
	obtained.
		
	** 20 % of the dose administered is excreted in the milk. Rashes,
	hepatitis, and blood disorders have been described in infants.
	*** 7% of the dose is secreted in the milk. There is evidence of
	accumulation in the infant if renal excretion is reduced.
	**** Between 40% and 60% of the dose administered is secreted in the
	milk. Bloody diarrhea in the infant has been described.


	CHAPTER 5. CRITERIA FOR REPONSE TO TREATMENT


	5.1 The objective of RA treatment is to induce complete disease remission 
	or, alternatively, to achieve the best possible response.

	RA patients who have spontaneous or drug-induced remissions in the
	course of their disease have a better medium-term outcome than those who
	have persistent clinical activity [Eberhardt, 1998]. However, the rates
	of complete remission with DMARDs and/or corticosteroids are low
	(18-25%) [Wolfe, 1985; Prevoo, 1996; Harrison, 1996; Eberhardt, 1998]
	and are rarely prolonged. Consequently, criteria to evaluate the
	patient's clinical improvement are needed to aid the clinician in making
	treatment decisions. Complete disease remission, or at least attainment
	of the lowest possible level of inflammatory activity, is the only way
	to improve disease outcome and to assure the most favorable evolution
	for the patient.

	Two basic approaches to defining clinical remission in RA have been
	described: the ACR criteria and the EULAR criteria.


	5.1.1 ACR criteria for clinical remission

	   * Morning stiffness absent or not exceeding 15 minutes
	   * No fatigue
	   * No joint pain (by clinical history)
	   * No joint tenderness
	   * No soft tissue swelling in joints or tendon sheaths
	   * Normal erythrocyte sedimentation rate

	The presence of five or more of these criteria for at least 2 months is
	sufficient to classify a patient as in complete remission, with a
	sensitivity of 72-80% and a specificity of 96-100% [Pinals, 1981; Wolfe,
	1985]. The predictive values of these criteria may vary in different
	populations [Alarcón, 1987]. Their main disadvantages are the lack of
	guidelines on how to measure them, the fact that they are dichotomous
	(meaning that small changes in disease activity may change the
	classification), and that two of the criteria (fatigue and morning
	stiffness) are not included in the parameters recommended for the
	evaluation of RA patients [van Riel, 1992; Tugwell, 1993; Felson, 1993b;
	Boers, 1994; Wolfe, 1999b].


	5.1.2 EULAR criteria for clinical remission

	The EULAR criteria use the DAS as a continuous variable of disease
	activity [Van der Heijde, 1990]. A cut-off point below 1.6 on the DAS is
	consistent with the ACR definition of remission [Prevoo, 1996]. Since
	the measurement scale is continuous, the cut-off point recommended by
	the EULAR may vary depending on future investigations.


	5.2 Patients with RA should be clinically monitored for an indefinite period
	of time. Patients in complete disease remission should be seen every 6 months
	or 1 year, and patients with recent disease onset, frequent flare-ups, or 
	persistent activity should be seen "on demand" ( in general, every 1 or 2
        months), depending on the treatment used and disease activity, until control 
        is achieved.

	No treatment has been shown to cure RA, thus all patients who suffer
	this disease should be monitored clinically for an indefinite period.

	Patients in complete disease remission should be seen every 6 or 12
	months. To avoid an overload of patients, they can be seen in primary
	care during the periods between rheumatologist appointments so as to
	assure clinical and laboratory monitoring and permit rapid referral to
	the specialist in case of disease reactivation and/or adverse effects.

	Patients with recent disease onset, frequent flare-ups, or persistent
	activity should be seen "on demand," depending on treatment used and
	disease activity, until the best possible control is achieved. These
	patients should be monitored every 1 or 2 months, at the same time as
	laboratory tests are done.


        5.3 Follow-up of patients with RA should be based on longitudinal monitoring 
        of the parameters described in the initial evaluation: joint pain and 
        inflammation, global pain assessment by the patient, global disease 
        assessment, functional disability, acute phase reactants, and radiologic damage.

	No studies have established the core set of parameters to be used in the
	routine clinical monitoring of patients with RA.

	The quantitative measurement of disease characteristics (e.g., the
	Ritchie index) offers several advantages: it provides information about
	disease severity that is valid, reliable, and of proven sensitivity; it
	can be used to classify the patient within the continuous spectrum of
	disease; and it can be used to guide the decisions that must be made by
	the physician, patient, and/or third parties.

	One way to improve the quality of care for patients is to apply the
	treatment response criteria designed for use in clinical trials to daily
	clinical practice. Thus, it is proposed that the same parameters
	assessed at the initial evaluation be used to monitor patients and
	evaluate their response to treatment: pain and joint inflammation,
	global pain assessed by the patient, global disease activity assessed by
	the patient and by the physician, functional disability, and acute phase
	reactants. The same instruments used in the initial evaluation should be
	used in follow-up.


        5.4 The criteria for treatment response applied to individual patients 
        should take into account: a) changes in disease activity and b) current 
        level of activity. The clinician should evaluate the response to treatment, 
        classifying it as satisfactory (complete remission of disease or sufficient 
        even if not complete remission) or unsatisfactory (complete or almost
        complete lack of improvement). The evaluation can be made in accordance with 
        any of the response criteria proposed in sections 5.4.1, 5.4.2, 5.4.3, and 5.4.4.

	Many approaches to defining clinical improvement in RA have been
	described, most of them focusing on the application to clinical trials.
	There is no published clinical experience in daily practice with any of
	the response indices developed for clinical trials. Although there is no
	scientific evidence to support a uniform recommendation, in the near
	future it is likely that these types of studies will be carried out, new
	indices will appear, or existing ones will be modified for application
	in daily practice.

	The treatment response criteria used throughout this guideline are based
	on two categories: satisfactory response, meaning complete remission
	of disease or a "sufficient" response, even though complete remission is
	not achieved, and unsatisfactory response, meaning complete or almost
	complete lack of improvement. The clinician can apply different response
	criteria to classify a patient in one of these categories. The following
	sections describe four approaches that have been explored in the
	literature on rheumatology: the ACR criteria for improvement [Felson,
	1995], the EULAR definition of response [Boers, 1994], the simplified
	Scott index [Scott, 1993], and the modified Paulus criteria [Paulus, 1990].


	5.4.1 ACR response criteria [Felson, 1995]

	The ACR response criteria define a dichotomous result (response/no
	response) according to the following criteria:

	   * At least 20% improvement in the painful joint count and in the
	     swollen joint count; and
	   * At least 20% improvement in at least three of the following
	     parameters: ESR or CRP, physician's global assessment of disease
	     activity, patient's global assessment of disease activity,
	     patient's assessment of pain, and physical disability.

	These criteria are known as the ACR20, reflecting the need for a 20%
	improvement in each parameter, which is considered the clinically
	relevant cut-off point. Some authors have proposed that this requirement
	be raised to 50% (ACR50) or 70% (ACR70). The ACR improvement criteria
	use the core variables proposed by the ACR itself, which can be applied
	without major problems in daily practice [Felson, 1993b]. The fact that
	the criteria do not consider the current activity level, however, limits
	their application in daily clinical practice unless they are adapted to
	take this factor into account. The ACR improvement criteria are likely
	to be modified in the near future; in the meantime, it is proposed that
	they be adapted as follows [SER, 2000b]:

	   * Satisfactory response: Meeting the ACR20 criteria, fewer than 6
	     swollen joints, and no impairment of any joint that, for the
	     particular patient, produces intolerable loss of functional
	     capacity in the opinion of the patient or physician.
	   * Unsatisfactory response: Not meeting the criteria for
	     satisfactory response.


	5.4.2 EULAR response criteria

	The EULAR response criteria use the Disease Activity Scale (DAS), which
	combines different clinical information into a single index that can be
	used to classify patients in different categories. Although the
	proliferation of modified DAS scales [Van der Heijde, 1998] has caused
	some confusion, two basic formulas have been validated [Van Gestel,
	1998] and can be applied to the EULAR improvement criteria: the original
	DAS [Van der Heijde, 1990; van der Heijde, 1992a], which uses the
	Ritchie articular index [Ritchie, 1968] and a count of the number of
	swollen joints out of 44 joints, and the DAS28, which uses a
	non-graduated count of 28 joints (Appendix 1).

	Unlike the ACR criteria, the EULAR definition takes into account both
	the patient's current status and the amount of improvement. It has been
	shown to have comparable validity to the ACR response criteria in
	clinical trials of RA patients [Van Gestel, 1999]. The definitions of
	satisfactory and unsatisfactory response as a function of the original
	DAS and the DAS28 are shown in Table 21.


	Table 21. EULAR definition of response

	EULAR DEFINITION OF RESPONSE (DAS)
	Current DAS 	
	   * less than 2.4 
	DAS decrease
	   * greater than 1.2
          	* Satisfactory	   
	   * 0.6 - 1.2 
          	* Unsatisfactory
	   * less than 0.6
          	* Unsatisfactory	   
          	
	Current DAS 	
	   * 2.4 - 3.7 
	DAS decrease
	   * greater than 1.2
          	* Unsatisfactory	   
	   * 0.6 - 1.2 
          	* Unsatisfactory
	   * less than 0.6
          	* Unsatisfactory	   
 		
	Current DAS 	
	   * greater than 3.7
	DAS decrease
	   * greater than 1.2
          	* Unsatisfactory	   
	   * 0.6 - 1.2 
          	* Unsatisfactory
	   * less than 0.6
          	* Unsatisfactory	   


	EULAR DEFINITION OF RESPONSE (DAS28)
	Current DAS28 	
	   * less than 3.2	
	DAS28 decrease
	   * greater than 1.2
          	* Satisfactory
	   * 0.6 - 1.2
          	* Unsatisfactory
	   * less than 0.6          	
          	* Unsatisfactory 	 	
 	 	 	
	Current DAS28 	
	   * 3.2 - 5.1	
	DAS28 decrease
	   * greater than 1.2
          	* Unsatisfactory
	   * 0.6 - 1.2
          	* Unsatisfactory
	   * less than 0.6          	
          	* Unsatisfactory 	 	
 	 	
	Current DAS28 	
	   * greater than 5.1	
	DAS28 decrease
	   * greater than 1.2
          	* Unsatisfactory
	   * 0.6 - 1.2
          	* Unsatisfactory
	   * less than 0.6          	
          	* Unsatisfactory 	 	


	5.4.3 Simplified Scott index [Scott, 1993]

	The simplified Scott index takes into account the change in disease
	activity and the current activity level, which makes it possible to
	apply it to individual patients. It is easy to apply, which facilitates
	its use during physician visits, but it requires further validation
	before it can be recommended for routine use. Its scoring system from 0
	to 6 (a total of 7 categories) may be too wide for classification of
	treatment response.

	It is based on the following criteria:

	   * Morning stiffness absent or lasting no more than 15 minutes
	   * At least 50% reduction in pain
	   * No more than 3 painful joints
	   * No more than 3 swollen joints
	   * ESR less than or equal to 30
	   * Functional improvement greater than or equal to 40%.

	For each category, the patient receives 1 point if the response
	criterion is met after 6 months of treatment; this gives a range of
	possibilities from 0 (no improvement) to 6 (complete improvement).


	5.4.4 Modified Paulus criteria [Paulus, 1990]

	These criteria have been used in recent clinical trials [O´Dell, 1996].
	They define a dichotomous result (response/no response) in accordance
	with the following criteria:

	   * Morning stiffness absent or reduced by 50%
	   * 50% decrease in the number of tender joints
	   * 50% decrease in the number of swollen joints
	   * ESR less than 30 mm/hr for women and less than 20 mm/hr for men.

	These criteria combine reduction in disease activity with the patient's
	current status.


	5.4.5 Physician's subjective assessment of disease activity

	This is the most commonly used clinical criterion in daily practice. It
	is not recommended for use as the only criterion of response. If the
	physician's assessment of disease activity is the only criterion used to
	judge response to treatment, this assessment needs to be adapted to the
	treatment objectives (complete remission of disease or achieving the
	best possible response). It should be a combination of objective and
	quantifiable parameters evaluating disease activity, joint pain, and
	health status, with the final results classified into the categories of
	satisfactory or unsatisfactory response.


	CHAPTER 6. ADVERSE EFFECTS OF DRUGS USED IN THE TREATMENT OF RHEUMATOID ARTHRITIS


	6.1 Antimalarials


	6.1.1 The antimalarials are relatively safe drugs if they are used at the 
	recommended doses. The most frequent side effects are gastrointestinal 
	toxicity, skin rashes, and constitutional symptoms. Most of these side 
	effects are reversible and do not require discontinuation of treatment 
	[Maksymowych, 1987).


	6.1.2 Monitoring: A baseline opthalmological examination should be made in 
	patients over 40 years of age andor with a family history of ocular disease 
	[ACR Committee, 1996]. All patients should receive an opthalmological examination
	including funduscopic and visual field evaluation every 6-12 months. Patients 
	with kidney failure or those who take the drug for more than 10 years should be 
	monitored more frequently.


	6.1.3 Contraindications: Allergy to 4-aminoquinoline derivatives. Retinopathy or 
	visual field deterioration.

	Hydroxychloroquine is generally better tolerated and less toxic than
	chloroquine [Finbloom, 1985]. Toxicity is more closely related with
	daily dose than with cumulative dose or duration of treatment [Rynes, 1983].

	The most frequent contraindication is gastrointestinal toxicity with
	nausea, vomiting, pain, and bloated abdomen. In these cases, if the
	patient was taking chloroquine, the dosage can be reduced by half or the
	patient can be switched to hydroxychloroquine. Since its bioavailability
	is not reduced by taking it with food, it can be administered with
	meals, which improves tolerance.

	Skin toxicity rarely leads to withdrawal of the medication. Side
	effects include maculopapular, scaly, or morbilliform rashes, urticaria
	and pruritus; loss and graying of hair; lichenoid reaction; and
	exfoliative dermatitis. In cases of yellowish hyperpigmentation of the
	skin and mucosa, which generally appears after periods of prolonged
	treatment, especially in patients treated with quinacrine, it may be
	useful to reduce the dose by half.

	Ocular toxicity is very infrequent if the recommended doses are not
	exceeded. It can be detected early if periodic ophathalmological
	(funduscopic and visual field) examinations are performed.

	There are two types of ocular toxicity:

	   * Deposits on the corneas or the ciliary bodies, accompanied by
	     blurry vision, photophobia, visual halos, or difficulty in
	     focusing, which generally disappear when treatment is discontinued.
	   * Retinopathy, which may lead to lasting loss of vision and may
	     progress despite withdrawal of treatment.

	Other rare side effects, such as neuromyopathy (less than 1%), usually with
	symptoms of myopathy predominating, resolve by discontinuing treatment.
	In patients with a deficiency of glucose 6-phosphase dehydrogenase
	(G6PD), antimalarials, and especially chloroquine, can lead to hemolytic
	anemia. Cases of aplastic anemia in patients treated with quinacrine
	have also been reported.


	6.2 Anti-TNF agents


	6.2.1 The safety profiles of the two commercial preparations (etanercept 
	and infliximab) are not sufficiently well known. Their potential adverse 
	effects, however, may be related with increased risk of infection, tumors, 
	hematologic changes, and multiple sclerosis.


	6.2.2 Monitoring: Rule out acute or chronic infection before initiating 
	treatment. Rule out the presence of active or latent tuberculosis. Do not 
	use live vaccines. Monitor the appearance of neoplasms.


	6.2.3 Contraindications: Sepsis or clinically manifest infections and/or 
	abscesses. Past medical history of hypersensitivity to infliximab or other 
	murine proteins.

	Infections are infrequent [CCOHTA, 1999]. Although the use of anti-TNF
	agents exacerbates the outcome of sepsis [Fisher, 1996], there is no
	evidence to confirm a higher incidence of serious infections in patients
	treated with these drugs [Moreland, 1997; Maini, 1998; Maini, 1999;
	Moreland, 1999; Weinblatt, 1999a].

	To date, 28 cases of tuberculosis infection have been reported, both
	miliary and extrapulmonary (9 in the United States and 19 in Europe),
	one of which had a fatal outcome. In most cases, the infection presents
	shortly after the second or third infusion. Given the severity of these
	complications, the Spanish Medicines Agency, in agreement with the
	European Agency for the Evaluation of Medicinal Products, recommends
	evaluation for active or latent (inactive) tuberculosis before beginning
	treatment with infliximab. The evaluation should include previous
	history of and/or contact with the disease, chest X-ray, and tuberculin
	test. Tuberculin tests in severely ill or immunodepressed patients may
	have a false negative result. If latent (inactive) tuberculosis is
	diagnosed, preventive measures should be taken to avoid activating the
	tuberculosis and to evaluate the benefit-risk relation before beginning
	treatment with infliximab. The patient should be instructed to inform
	the physician of the appearance of signs and/or symptoms that suggest
	tuberculosis, for example, persistent cough, weakness/weight loss, and
	low-grade fever. If active tuberculosis is suspected, infliximab
	treatment should be discontinued until the diagnosis is ruled out or the
	infection has been treated according to accepted guidelines.

	For both preparations (infliximab and etanercept), upper respiratory
	infection is the most frequently reported side effect; this is usually
	mild and does not require discontinuation of treatment.

	Since the potential immunosuppressive effect of anti-TNF agents may
	favor infection, vaccination with live vaccines while they are being
	used is not recommended. (Although this guideline focuses on RA in
	adults, children should be up-to-date on all their vaccinations before
	beginning treatment with etanercept [CCOHTA, 1999].)

	Some authors have mentioned the development of neoplasia as an adverse
	effect [Koopman, 1998; Camussi, 1998], although there is no evidence of
	a higher incidence of tumors in patients treated with anti-TNF agents.
	Pending the results of long-term studies on the use of anti-TNF agents
	and their association with tumors, it is essential to monitor the
	patient clinically for possible neoplasms.

	In pharmacological surveillance studies following the commercialization
	of etanercept, 10 cases of blood disorders have been reported in
	patients treated with this drug (of an estimated total of 5,500
	patients, 3 aplastic anemias and 7 pancytopenias), with 5 deaths
	attributed to this cause (Pharmacological surveillance report from Wyeth).

	Nine cases treated with etanercept have presented with abnormalities,
	detected by magnetic resonance imaging, compatible with demyelinating
	disease of the central nervous system. Five of these patients were
	diagnosed with multiple sclerosis and one with possible multiple
	sclerosis. It is difficult at present to establish a causal relation
	between the drug and multiple sclerosis, although anti-TNF agents are
	known to exacerbate the clinical course of this disease [LMSSG, 1999].

	Local reactions at the injection site (erythema, localized pain, edema)
	occurred in 49% of patients treated with 25 mg of etanercept [Moreland,
	1999] and in 42% of those who received etanercept plus methotrexate
	[Weinblatt, 1999a]. These complications are generally self-limiting,
	lasting 3-5 days; they tend to appear in the first month of treatment
	and do not require its interruption. Five percent of patients treated
	with infliximab have had non-specific symptoms during intravenous
	administration such as fever, chills, chest pain, hypertension or
	hypotension, pruritus/urticaria, headache, sinusitis, rhinitis, and
	non-specific cardiorespiratory symptoms. In 16% of this 5% of patients,
	the infusion had to be discontinued [Remicade, 1999].

	The appearance of antinuclear and anti-DNA antibodies has been described
	for both preparations more frequently than in control groups; in the
	case of etanercept, this was not associated with autoimmune disease.


	6.3 Azathioprine


	6.3.1 The most frequent side effects of azathioprine are gastrointestinal 
	intolerance, blood disorders, and infections.


	6.3.2 Monitoring: Baseline laboratory tests should be performed, including 
	a complete blood count (leukocytes, hemoglobin, and platelets), creatinine, 
	and liver function tests. Thereafter, a blood count should be made every 1-2
	weeks while the dosage is being adjusted, and every 1-3 months upon reaching 
	a stable dose [ACR Committee, 1996]. Liver function tests are recommended 
	every 6-8 weeks. The dose should be reduced in patients with renal failure. 
	Extreme precaution should be taken if it is used concurrently with allopurinol 
	or with the angiotensin-converting enzyme inhibitors.


	6.3.3 Contraindications: Known neoplastic disease.

	The most frequent gastrointestinal symptoms (20%) are anorexia,
	nausea, and vomiting. Less frequent are diarrhea (less than 1%) or elevated
	liver enzymes (5%). Although these side effects may make it necessary to
	discontinue the drug (10%), they usually improve or resolve by reducing
	the dose.

	Blood disorders are dose-dependent; the most frequent are leukopenia
	(25%) and thrombocytopenia (5%), although cases of pure red-cell aplasia
	have been described. Mild blood disorders may resolve by reducing the
	dose. A xanthine oxidase deficiency increases side effects in general
	and hematologic ones in particular [Black, 1998]. The use of allopurinol
	(a xanthine oxidase inhibitor) should be avoided; if it must be used,
	the AZA dose should be reduced (50-75%), and the leukocyte count should
	be monitored more frequently.

	Infections appear in about 10% of patients treated with AZA. Viral
	infections are the most frequent, especially herpes zoster. Bacterial
	infections usually develop in patients with neutropenia [Singh, 1989].

	A hypersensitive reaction has been described in the first weeks of
	treatment, which includes fever, general malaise, arthralgias/myalgias,
	skin lesions, leukocytosis, elevated liver enzymes, and even hypotension
	and shock [Blanco, 1996].

	The risk of neoplasia appears to be increased in RA patients (relative
	risk 2.2-8.7), mainly skin cancers and hematologic neoplasias [Silman,
	1988].


	6.4 Cyclophosphamide


	6.4.1 Cyclophosphamide has frequent adverse effects, which vary in relation
	with dose and route of administration [Decker, 1973;Williams, 1980]. 
	Intravenous administration is recommended. Most side effects are reversible 
	by discontinuing the drug. The most frequent side effects are gonadal, urologic,
	and bone marrow toxicity, neoplasms, and infections. Other frequent but less 
	important effects are alopecia, nausea, and vomiting.


	6.4.2 Monitoring: Complete blood count every 1-2 weeks during the first 2-3 
	months of treatment, then every 2-4 weeks once the dosage has been stabilized 
	[Clements, 1986]. In patients with pulses of intravenous therapy, a blood count
	should be obtained before each infusion of cyclophosphamide. Monthly tests should
	be obtained for liver enzymes, urinalysis, and urinary sediment. If microscopic 
	hematuria is detected, other, more specific studies are indicated, such as 
	cystoscopy and urinary cytology.


	6.4.3 Contraindications: Pregnancy, chronic or active infection, liver disease, or 
	history of neoplasia. Renal failure is a relative contraindication that requires
	adjustment of the dosage.

	CPA is a useful drug in the treatment of serious RA complications.
	Administration by intravenous pulses is recommended, since they are as
	effective as oral administration and have less serious side effects.

	Gonadal toxicity from CPA is produced in women at the level of the
	primordial and antral follicles, giving rise to oligomenorrhea and
	amenorrhea [Warne, 1973]. In men it is produced in the epithelial germ
	layer of the seminal vesicles, causing azoospermia or oligospermia, and
	testicular atrophy or reduction in size [Fairley, 1972; Schilsky, 1980].
	Libido and sexual function are normally not affected [Sherins, 1973;
	Schilsky, 1980]. Accepted risk factors for infertility are age over 25
	years, concomitant radiation therapy, and prolonged treatment
	[Roubenoff, 1988].


	Table 22. CPA dosage producing toxicity

	Gender 	
	   * Men [Kovarsky,1983]	
	Age (years) 	
	   * 	
	CPA dosage producing toxicity
	   * Greater than or equal to 18 g	
 	  	
	Gender 	
	   * Women [Damewood, 1986] 	
	Age (years) 	
	   * 20-29	
	CPA dosage producing toxicity
	   * 20.4 g	

	Gender 	
	   * Women [Damewood, 1986] 	
	Age (years) 	
	   * 30-39	
	CPA dosage producing toxicity
	   * 9.3 g	

	Gender 	
	   * Women [Damewood, 1986] 	
	Age (years) 	
	   * Greater than or equal to 40	
	CPA dosage producing toxicity
	   * 5.2 g
	 	
 	Intravenous treatment with CPA entails a risk of sustained amenorrhea
	(understood as lasting over 1 year), which is associated with patient
	age, dose administered, and duration of treatment [Schilsky, 1980;
	Damewood, 1986; Boumpas, 1993; Ramsey-Goldman, 1997]. Women who do not
	develop amenorrhea may experience early menopause [Fosdick, 1968;
	Miller, 1971; Roubenoff, 1988].
	
	Oral CPA administration may provoke amenorrhea in up to 36% of cases,
	and is irreversible in 27% [Wang, 1995].
	
	
	Table 23. Percentage of women treated with CPA who develop amenorrhea

 	Age
	   * Less than or equal to 25 years
  	% of women with amenorrhea
	   * 12  	
 	
 	Age
	   * 26-30 years
  	% of women with amenorrhea
	   * 27  	
  	
 	Age
	   * Greater than or equal to 31 years 
  	% of women with amenorrhea
	   * 62  	
 	 	
 	Duration of treatment
	   * Short cycles (less than 7 bolus injections) 
  	% of women with amenorrhea
	   * 12  	
 	
 	Duration of treatment
	   * Long cycles (greater than 15 bolus injections)
  	% of women with amenorrhea
	   * 39  	

	 	
	Although recovery of spermatogenesis has been described after suspending
	treatment in young patients treated with CPA for short periods [Fairley,
	1972; Trompeter, 1981], recovery of ovarian function or spermatogenesis
	is uncertain, and irreversible sterility may result [Fosdick, 1968;
	Miller, 1971; Fairley, 1972] Thus, freezing of ova or sperm is
	recommended before beginning treatment with CPA.

	The risk of infertility in women may be reduced by treatment with
	gonadotropin inhibitors [Langevitz, 1992; Ataya, 1993] or by using oral
	contraceptives [Chapman, 1981], and in men by the use of testosterone
	[Masala, 1997].

	The urologic toxicity of CPA consists basically of the development of
	hemorrhagic cystitis [Hutter, 1969; Decker, 1973; Aptekar, 1973; Townes,
	1976; Plotz, 1979; Fauci, 1983; Ansher, 1983; Hansen, 1983], vesicle
	fibrosis [Johnson, 1971], and squamous cell and transitional cell
	bladder cancer [Worth, 1971; Wall, 1975; Ansell, 1975; Plotz, 1979;
	Baker, 1987; Pedersen-Bjergaard, 1988; Thrasher; 1990].

	Hemorrhagic cystitis is present in 15-30% of patients treated with CPA
	[Fauci, 1983], and its appearance, the same as with vesicle fibrosis, is
	directly related with oral administration. Patients treated
	intravenously do not develop hemorrhagic cystitis or neoplasms [Plotz,
	1979; Austin, 1986; Balow, 1987; Klippel, 1987a].

	There is a high risk of developing malignant vesicle neoplasm with total
	doses exceeding 80 g. Tumors may appear early or several years after
	initiation of treatment. The risk remains even years after discontinuing
	treatment [Baker, 1987; Hoffman, 1992; Radis, 1995]. The development of
	carcinoma of the bladder does not appear to be related to pre-existing
	hemorrhagic cystitis [Pedersen-Bjergaard, 1988].

	Abundant oral (2-3 liters in 24 hours) or intravenous hydration and
	frequent urination are recommended to decrease vesicle toxicity [Ahmed,
	1984; Balow, 1987; Klippel, 1987b]. The use of acetyl cysteine
	[Steinberg, 1981] or 2-mercaptoethane sodium sulfonate together with
	intravenous CPA also reduces vesicle toxicity [Bryant, 1980; Brock;
	1982; Hows, 1984; Ehrlich, 1984; Nashel, 1985].

	If the patient shows signs of reduced vesicular volume (e.g.,
	polakiuria), CPA should be discontinued and cystometry performed. If
	there is hematuria suggesting the presence of incipient hemorrhagic
	cystitis or other urological complications, treatment should be
	discontinued and cystoscopy and urinary cytology should be performed.

	The inhibition of DNA replication produces bone marrow toxicity, which
	is cumulative.

	Its hematologic effects are:

	   * Neutropenia. 32% of patients treated with high doses (150 mg) and
	     6% of those treated with low doses (75 mg).
	   * Leukopenia [Weinstein, 1985]. Dose-dependent. Maximum suppression
	     occurs 8-12 days after intravenous administration [Klippel, 1998].
	     Avoid leukocyte count dropping below 3,000/mm^3 and neutrophils
	     below 1,000/mm^3 , adjusting the dosage until the desired levels
	     are regained. Avoid concomitant treatment with allopurinol due to
	     the increased risk of leukopenia [Clements, 1986].
	   * Anemia and thrombopenia are less frequent, and aplasia, if it
	     occurs, is transitory.

	Several authors have studied tumor development in association with the
	use of CPA. Whereas some have found a high incidence of neoplasms
	[Baltus, 1983], others have not found significant increases [Kirsner,
	1982]. There have been reports in the literature of leukemias and
	malignant lymphomas [Love, 1975; Grunwald, 1979; Penn, 1981; Wheeler,
	1981; Baltus, 1983; Baker, 1987], sarcomas [Steinberg, 1981], and skin
	cancer [Baltus, 1983; Baker, 1987; Radis, 1995]. The factors that appear
	to be related with the development of carcinomas are total CPA dose
	[Greene, 1986; Baker, 1987] and duration of treatment
	[Pedersen-Bjergaard, 1985; Baker, 1987].

	Upper respiratory tract infections are related with the use of CPA, as
	are bacterial, fungal, and viral infections [Bradley, 1989;
	Kattwinkel, 1991], especially with herpes zoster (incidence from 21 to
	33%) [Moutsopoulos, 1978; Balow, 1987; Klippel, 1987a; Klippel, 1998].
	Risk factors are considered to be the involvement of multiple organs,
	concomitant treatment with high-dose steroids, and leukocyte counts
	under 3,000 cells/mm^3 [Pryor, 1996]. Patients being treated with CPA
	and high-dose steroids should receive prophylaxis for Pneumocystis
	carinii with trimethoprim-sulphamethoxazol [Ognibene, 1995].

	Other adverse effects that have been observed are gastrointestinal
	toxicity (mainly nausea and vomiting) [Belmonte, 1988; Fox, 1994;
	Klippel, 1998], pulmonary toxicity [Patel, 1976; Medrano, 1986; Klippel,
	1998], cardiac toxicity [Appelbaum, 1976; Klippel, 1998], hepatic
	toxicity [Bacon, 1982; Goldberg, 1985; Fox, 1994 Klippel, 1998],
	ophthalmological toxicity [Jack, 1981], hypersensitive reactions
	[Klippel, 1988; Knisack, 1994], hypogammaglobulinemia [Fauci, 1989],
	alopecia [Kovarsky, 1983; Belmonte, 1988; Fauci, 1989], nail
	abnormalities [Klippel, 1998], and inadequate secretion of the
	antidiuretic hormone [De Fronzo, 1973; Steinberg, 1981; Bressler, 1985;
	Klippel, 1998]. These effects are dose-dependent, occurring more
	frequently at high drug doses.


	6.5 Cyclosporin A


	6.5.1 The most serious and relatively frequent adverse effects are 
	nephrotoxicity and hypertension. Both are dose-dependent and constitute the 
	most important limitation to their use.


	6.5.2 Monitoring: Before beginning treatment, the following tests should be 
	obtained: blood pressure (two measurements), complete blood count, liver and 
	kidney biochemistry (with special attention to serum urea and creatinine), and
        urinalysis with sediment.

	Blood pressure, renal function, and K^+ and Mg^++ electrolytes should
	be monitored every 2 weeks during the first trimester and monthly
	thereafter.

	If the dose is changed or if there is an increase in creatinine levels
	or blood pressure, the patient should be monitored weekly until
	stabilization. If the levels of serum creatinine increase by more than
	30% with respect to baseline, the dose should be reduced by 25-50%.

	If renal function does not improve in 1 month, cyclosporin should be
	discontinued; it may be resumed if creatinine returns to levels within
	10% of the pre-treatment value.

	If hypertension is detected, treatment with angiotensin converting
	enzyme inhibitors or beta-blockers may be initiated. The drug of choice
	is nifedipine (which does not increase the levels of cyclosporinemia).


	6.5.3 Contraindications: co-existing cancer (except non-melanoma skin cancer), 
	uncontrolled hypertension, renal dysfunction, uncontrolled infections, and 
	primary or secondary immunodeficiency [Cush, 1999].

	The nephrotoxicity produced by CSA may provoke:

	   * Reversible functional changes: tubular dysfunction (reduced
	     reabsorption of Mg^+ , reduced secretion of K^+ , and reduced
	     excretion of uric acid with resulting hypomagnesemia,
	     hypercalcemia, and hyperuricemia) and vascular dysfunction
	     (vasoconstriction, reduced renal perfusion and filtration with
	     elevated serum urea and creatinine).
	   * Structural changes: reversible proximal tubular disease and vessel
	     disease (affecting the afferent arterioles that condition
	     glomerulosclerosis; ischemia, tubular atrophy, and interstitial
	     fibrosis.

	Reversible changes are frequent, while persistent structural changes are
	rare and usually present with elevated serum levels of CSA and
	associated risk factors such as concurrent treatment with nephrotoxic
	drugs, pre-existing nephropathy, and hypertension [Grant, 1987; Land,
	1988; Morris, 1988; Mihatsch, 1989; Landewé, 1996; Rodríguez, 1996]. At
	the usual doses (2.5 to 5 mg/kg/day), renal dysfunction is not severe
	and is rapidly reversible [Dougados, 1989; Tugwell, 1990; Boers, 1990;
	Van Rijthoven, 1991; Landewé, 1994]. High doses (from 10 mg/kg/day at
	initiation of treatment) produce more severe and less reversible changes
	in renal function (Boers, 1988; Berg, 1989].

	To prevent structural nephropathy the following recommendations are made:

	   * Exclusion of patients with potential risk factors such as renal
	     dysfunction
	   * Limitation of the maximum dose to 5 mg/kg/day
	   * Use of the smallest possible maintenance dose, depending on the
	     level of serum creatinine
	   * Frequent and careful monitoring of renal function
	   * Routine clinical examination and laboratory tests [Panayi, 1993;
	     Panayi, 1994; Tugwell, 1995a].

	The frequency of hypertension is 10-20% [Cohen, 1992]. The patient
	should have normal blood pressure before beginning therapy. If diastolic
	BP is higher than 95 mmHg or systolic BP higher than 160, the dose
	should not be increased. If hypertension is present (diastolic BP 
	greater than 105 mmHg or sustained at more than 95 mmHg) at two consecutive
	measurements, antihypertensive treatment should be initiated or the CSA 
	dose reduced [Panayi, 1993; Panayi, 1994].

	Other non-renal adverse effects related with the use of CSA are
	gastrointestinal effects (dyspepsia, nausea, vomiting, abdominal pain,
	and diarrhea), hypertrichosis, gingival hypertrophy, and paresthesias.
	These are usually dose-dependent and are reversible by reducing the dose
	of the drug. Less frequent manifestations are fatigue, leukopenia,
	sinusitis, arthralgias/myalgias, flushing, ocular pain, gynecological
	symptoms (menorrhagia, breast hypertrophy or pain), hyperlipidemia,
	hepatic abnormalities (hyperbilirubinemia and hypertransaminemia), and
	neurological effects (headache, tremor). Other rare adverse reactions,
	present in 2% or less of patients are: conjunctivitis, fever, allergic
	reactions (exanthema, angioedema with reduced C1-esterase inhibitor),
	anemia, thrombocytopenia, anorexia, confusion, convulsions, weak and
	broken nails, and peptic ulcer [Klintmalm, 1981; Maddux 1986; Grant,
	1987; Tindall, 1987; Lin, 1989; Cairns, 1992; Arellano, 1993; Fauci,
	1993; Forre, 1994; Furst, 1994b; Tugwell, 1995b; Klippel, 1998;
	Rodríguez, 1998].


	6.6 D-penicillamine


	6.6.1 The most frequent side effects of D-penicillamine are skin lesions, 
	gastrointestinal symptoms, and renal involvement.


	6.6.2 Monitoring: Baseline tests should be performed, including a complete 
	blood count, creatinine, and urinalysis (including sediment). These tests 
	should be repeated every 2 weeks until a stable dose is reached and every 
	1-3 months thereafter (ACR Committee, 1996].


	6.6.3 Contraindications: Kidney disease, blood disorders (leukopenia, 
	thrombocytopenia).

	All types of skin lesions may appear (25-50%), from morbilliform and
	pruritic rashes to pemphigus-like lesions [Willemsen, 1990]. These
	generally disappear when medication is withdrawn [Munro, 1997]. Muscosal
	lesions, especially mouth ulcers, are less frequent.

	About 30% of patients have gastrointestinal symptoms (nausea,
	anorexia, abdominal pain, and diarrhea) during the first months of
	treatment. These symptoms usually disappear even though DP is continued,
	although it is sometimes necessary to suspend it [Munro, 1997].

	About one fourth of patients report dysgeusia (altered sense of taste)
	during the first months of treatment. This symptom usually disappears
	spontaneously despite continued treatment, or it may improve following
	the administration of zinc [Jaffe, 1977].

	Some 30% of RA patients treated with DP have some type of renal
	involvement. This most frequently takes the form of proteinuria
	accompanied by microscopic hematuria [Stein, 1980]. About 7% of patients
	develop a nephrotic syndrome secondary to membranous glomerulonephritis
	which disappears completely in a variable period of time after
	discontinuing treatment [Hall, 1988a]. Much less frequent is the
	development of acute renal failure secondary to a rapidly progressive
	"half-moon" glomerulonephritis [Ntoso, 1986].

	Other side effects are blood disorders (thrombocytopenia 8-10% and
	leukopenia), pulmonary toxicity (bronchiolitis obliterans less than 1%), 
	breast hyperplasia [Taylor, 1981], development of autoimmune processes,
	systemic lupus erythematosus [Chalmers, 1982], inflammatory myopathies
	[Lund, 1983], myasthenia gravis [Andonopoulos, 1994], and Goodpasture
	syndrome [Munro, 1997].


	6.7 Leflunomide


	6.7.1 The most frequent adverse effects in published clinical trials are 
	gastrointestinal and respiratory. These effects are generally mild, are 
	not dose-dependent, and do not require discontinuation of treatment.


	6.7.2 Monitoring: Liver enzymes should be monitored, initially every 4 
	weeks until a stable treatment dose is reached. If they are elevated to 
	over twice the maximum reference value, the dose should be reduced to 10 
	mg/day. If a reduction to 1.2 times the maximum reference value is not
	obtained, leflunomide should be discontinued and cholysteramine or 
	charcoal administered. If the transaminases remain elevated, a liver 
	biopsy should be performed [Weinblatt, 1999b; Arava, 1999]. Periodic 
	monitoring for possible anemia and leukopenia is recommended.


	6.7.3 Contraindications: Serious immunodeficiency, dysplasias, uncontrolled 
	infection (due to the theoretical possibility of immunosuppression), 
	moderate or severe renal failure (there is no experience in this group of 
	patients), liver function disorder, significant bone marrow disorder,
	severe hypoproteinemia.

	The most frequent adverse effects in published clinical trials are
	gastrointestinal (diarrhea 17%, nausea 9%, and abdominal pain 6%) and
	respiratory (upper tract infections 15% and bronchitis 7%). These
	effects are generally mild, are not dose-dependent, and do not require
	that treatment be discontinued. [Mladenovic, 1995; Weinblatt, 1999b;
	Arava, 1999; Smolen, 1999; Strand, 1999;].

	Elevated transaminases have been described in about 6% of RA patients
	treated with 25 mg/day, and are reversible on discontinuing treatment.
	Generally these elevations do not exceed twice the normal maximum value
	and they tend to remit over time [Mladenovic, 1995; Smolen, 1999;
	Weinblatt, 1999b; Strand, 1999]. Cases of severe liver disease have been
	reported, some resulting in death, most of which occurred during the
	first 6 months of treatment.

	Other less frequent effects are hypertension (10%), headache (7%),
	vertigo (4%), weight loss (4%), and reversible alopecia (1% with a dose
	of 10 mg/day and 7% with 25 mg/day) [Mladenovic, 1995; Furst, 1995;
	Strand, 1999]. One case of anaphylaxis has been reported.

	In experimental models, treatment with leflunomide has been associated
	with anemia and leukopenia [Yuh, 1995]. This toxic effect has not been
	produced in clinical trials in humans, but until long-term
	pharmacological surveillance data are available, the patient should be
	monitored periodically for the possible appearance of anemia and leukopenia.

	In animal models, leflunomide has severe teratogenic effects and
	increases the risk of fetal death [Arava, 1999]. As its safety in humans
	is unknown, contraceptive measures are recommended before beginning
	treatment, not only in women of childbearing age but also in men, due to
	the possibility of teratogenic effects caused by the paternal route. If
	pregnancy occurs or if a man wishes to have children, it is recommended
	that the drug be immediately discontinued, and the patient should be
	treated with 8 g of cholestyramine, three times a day, for 11 days.

	Because it is potentially immunosuppressive, it is assumed to promote or
	exacerbate infection, but so far no serious infections during clinical
	use have been reported. Due to its potential immunosuppressive effect,
	and in the absence of safety and efficacy studies on the concomitant use
	of leflunomide and live vaccines, vaccination is not recommended during
	treatment with this drug.


        6.8 Methotrexate


	6.8.1 The most important side effects of MTX are pulmonary, hepatic, and 
	hematologic toxicity. Other adverse effects are carcinogenesis, infections, 
	nodules, gastrointestinal toxicity, and neurological toxicity.


	6.8.2 Monitoring: Before beginning treatment a complete blood count, liver
	and kidney biochemistry, and serum albumin should be obtained, together 
	with hepatitis A, B, and C serology. If pre-existing liver disease or 
	exposure to liver toxins is suspected, a liver biopsy should be performed 
	before beginning treatment. If the patient has a history of pleuropulmonary
	disease, a chest X-ray, as well as folic acid and vitamin B12 levels should
	be obtained. Follow-up tests should be obtained every 4 to 8 weeks to 
	monitor blood count and liver and kidney biochemistry. A follow-up liver 
	biopsy should be performed if there are persistent abnormalities in liver 
	biochemistry that can not be attributed to concomitant treatment with 
	nonsteroidal anti-inflammatories. Other non-routine studies are indicated
	if symptoms suggestive of specific complications appear (e.g., blood gas 
	analysis and chest X-ray if pneumonia is suspected).


	6.8.3 Contraindications: Pregnancy, alcohol abuse, hepatitis B or C, and 
	cirrhosis of any origin are considered to be absolute contraindications. 
	Relative contraindications are renal failure, chronic pulmonary disease, 
	and active infection not associated with Felty's syndrome.

	Six MTX-induced clinical syndromes of pulmonary toxicity are known:
	acute interstitial pneumonitis, interstitial fibrosis, pulmonary
	nodules, non-cardiogenic pulmonary edema, pleuritis, and pleural
	effusion [Cannon, 1997]. The first three have been described in RA
	patients and the latter three in patients with neoplasms. The most
	frequent type of pulmonary toxicity (from 2 to 6%) is acute interstitial
	pneumonitis or hypersensitivity pneumonitis [Furst, 1994b]. This is a
	potentially lethal complication [Furst, 1990] by itself or as a result
	of pulmonary superinfection [Searles, 1987]. It is not associated with
	either duration of treatment, weekly dose, or cumulative dose received
	[White, 1989; Hargreaves, 1992; Alarcón, 1995; Kremer, 1995; Cannon,
	1997]. Pre-existing pulmonary disease is a risk factor [Golden, 1995].
	Treatment consists basically of withdrawing MTX, administering
	corticosteroids, and managing the respiratory insufficiency.

	The hepatic toxicity of MTX manifests as fibrosis and cirrhosis,
	especially in patients who consume excessive amounts of alcohol (more
	than 100 g/week) or have pre-existing liver disease [Farell, 1998].
	Nonetheless, although transaminases are frequently elevated
	[Songsiridej, 1990], fibrosis rarely progresses to cirrhosis [Furst,
	1990], even after cumulative MTX doses exceeding 5 g [West, 1997]. The
	main risk factors are diabetes mellitus [Erickson, 1995; Bass, 1996;
	Farrell, 1998], alcohol abuse, obesity, fatty liver, underlying liver
	disease (chronic liver disease due to hepatitis B, C, or other viruses),
	age over 60 years, renal failure, cumulative doses of MTX exceeding
	1.5-2 g, concomitant treatment with NSAIDs, and related systemic disease
	[Walker, 1993; O´Dell, 1997; Farrell, 1998]. It has been suggested that
	patients with a deficiency of alpha-1 antitrypsin are more susceptible
	to MTX hepatotoxicity [Hilsden, 1995; O´Dell, 1997]. Hepatotoxicity is
	reduced by using low doses and following recommended guidelines for
	weekly administration of the drug [Sznol, 1987]. Pre-treatment biopsy is
	indicated only in patients with a history of excessive alcohol
	consumption, persistent transaminase elevation, or pre-existing liver
	disease [Kremer, 1992; Kremer, 1994]. If liver biopsy shows acute
	fibrosis or cirrhosis (Roegnick stages class III-b or IV), the treatment
	is contraindicated [Kremer, 1994]. It should also be discontinued in
	patients who refuse biopsy if they have persistent liver test
	abnormalities (5 of 9 GOT measurements above the normal range in a
	12-month period, or 6 of 12 if tested monthly) or hypoalbuminemia
	[Kremer, 1994].

	Hemotologic toxicity (5-25%), consists of leukopenia,
	thrombocytopenia, megaloblastic anemia, and pancytopenia (1-2%)
	[Gutiérrez Ureña, 1996]. It is usually mild or moderate and remits when
	the dosage is reduced. Pancytopenia responds to folic acid and
	supportive treatment (steroids, transfusions, antibiotics, and
	hematopoietic stimulating factors) [McKendrey, 1997]. Probable risk
	factors are considered to be folate deficiency and macrocytosis
	[Al-Awadhi, 1993], concomitant treatment with other antifolate drugs
	such as sulphasalazine [Morgan, 1993] or trimethoprim-sulphanotoxazol,
	concurrent viral infections [Naides, 1995], advanced age, and renal
	failure [Al-Awadhi, 1993, RACTAG, 1995].

	Increased risk of cancer has not been shown in numerous studies of
	patients with diseases other than RA who were treated with MTX. Tumors
	of the liver [Ruymann, 1977] and lymphomas [Ellman, 1991; Shiroky, 1991;
	Kingsmore, 1992; Kamel, 1993; Bachman, 1996], however, have been
	observed in RA patients. Studies of lung cancer incidence in RA patients
	treated with MTX have yielded contradictory results, with increases
	shown in some cases [McKendry, 1993] and normal incidence in others
	[Alarcón, 1994]. It does not appear to increase the risk of hematologic
	malignancies [Moder, 1995].

	MTX treatment may increase the risk of bacterial, viral, herpes zoster,
	or opportunistic infections in patients with RA. The risk is higher
	with combined steroid treatment [Kanik, 1997].

	Some 60% of patients treated with MTX have gastrointestinal toxicity
	(stomatitis, nausea, vomiting, dyspepsia, abdominal pain, indigestion,
	diarrhea, anorexia, or weight loss) [McKendry, 1997]. These effects are
	generally reversible by reducing the drug dosage or changing from the
	oral to the parenteral route of administration [O´Dell, 1997]. They can
	be prevented and treated with folic acid supplements. Exceptionally,
	hemorrhagic enteritis may occur.

	Neurotoxicity occurs at high doses (more than 1 g/m^2 ) in 15% of
	patients. It may manifest as depression, confusion, memory loss,
	drowsiness, headache, fatigue, or discomfort; it most frequently occurs
	within 24 hours of drug administration [McKendry, 1997]. Exceptionally,
	hallucinations or leukoencephalopathy may appear [Worthley, 1995].

	Nodules are histologically indistinguishable from rheumatoid nodules;
	they regress when treatment is discontinued and reappear when it is
	renewed [Kerstens, 1992]. They may be associated with vasculitis [Segal,
	1988], pleural effusion, and pericardial tamponade [Abu-Shakra, 1994].

	Other toxic manifestations are rashes [Neiman, 1985; Bannwarth, 1994],
	alopecia, osteopathy [McKendry, 1997], arthralgias/myalgias, general
	malaise on the first or second day of treatment, or even fever unrelated
	with infection. These "post-dose" effects are the second most common
	cause of MTX withdrawal [Halla, 1994].


	6.9 Gold salts


	6.9.1 The most important clinical side effects are hematologic and renal 
	toxicity. Both are more frequent with intramuscular treatment. They require
	careful clinical monitoring and the immediate discontinuation of treatment
	to prevent irreversible sequelae.


	6.9.2 Monitoring: Periodic testing for proteinuria by routine urinalysis 
	(qualitative or semiquantitative) every 4 weeks during the first 6 months
	and every 3 months thereafter. If proteinuria is detected, a 24-hour urine 
	quantification should be obtained. If the proteinuria exceeds 500 mg/24 h,
	treatment should be discontinued until it disappears or drops below 200 mg/24 h,
	after which it may be renewed. If the proteinuria is severe (above 1 g/24 h),
	treatment should be discontinued permanently.


	6.9.3 Contraindications: Severe liver or kidney disease and blood or bone
	marrow disorders.

	The most frequent hematologic effects are related with the
	hematopoietic system: eosinophilia and thrombocytopenia (1-3%), followed
	by neutropenia [Lockie, 1985; Ridaura, 1995; Myochrysine, 1997].
	Aplastic anemia and pure red-cell aplasia have also been reported. Of
	all these effects, the only one that does not require discontinuation of
	treatment is eosinophilia, which some authors consider a warning sign
	for the presentation of other toxic effects [Davis, 1974; Bretza, 1983].
	Thrombocytopenia may appear suddenly or progressively; treatment should
	be discontinued if platelet counts drop below 100,000 platelets/mm^3
	[Ridaura, 1995].

	The most frequent renal toxicity is membranous glomerulonephritis,
	usually preceded by proteinuria and/or hematuria, followed in frequency
	by nephrotic syndrome and acute renal failure, which may be secondary to
	acute tubular necrosis [Robbins, 1980; Hall, 1988b].

	Other adverse effects are skin toxicity (dermatitis, pruritus)
	[Ridaura, 1995]; ulcers of the mouth, gums, or tongue, including the
	upper palate and pharynx; abnormal taste sensations (dysgeusia, metallic
	taste); hepatic toxicity (jaundice with or without intrahepatic
	cholestasis); pulmonary toxicity (hypersensitivity pneumonitis,
	bronchiolitis obliterans); gastrointestinal toxicity (diarrhea,
	especially with auranofin - 47%, toxic enterocolitis); neurologic
	toxicity (peripheral neuropathy, cranial neuropathy, Guillan-Barré
	syndrome, encephalopathy); vaso-vagal hypotension; conjunctivitis
	(auranofin); and corneal ulcers and gold deposits (sodium aurothiomalate).


	6.10 Sulphasalazine


	6.10.1 The most frequent sites of adverse reactions (33%) to sulphasalazine 
	are the central nervous system and gastrointestinal tract. These are usually
	mild and do not require discontinuation of treatment. Other less frequent
	adverse effects are hematologic and hepatic toxicity.


	6.10.2 Monitoring: Blood cell count every 4 weeks during the first 3 months
	and every 3 months thereafter.


	6.10.3 Contraindications: Allergy to salicylates or sulfonamides.

	The adverse effects on the central nervous system (headache, vertigo)
	and gastrointestinal tract (anorexia, nausea, vomiting, abdominal
	pain) are generally mild and do not require discontinuation of treatment
	[Amos, 1986; Farr, 1986; Williams, 1988].

	Hematologic toxicity occurs particularly in the hematopoietic system:
	macrocytosis (9%), leukopenia (3.7%), neutropenia (2%) and megaloblastic
	anemia (less than 1%). Isolated episodes of aplastic anemia, agranulocytosis,
	thrombocytopenia, and leukocytosis have been reported. Hematologic
	toxicity may present at any time during treatment, although it usually
	appears early (between the 5th and 12th week), except for macrocytosis
	and megaloblastic anemia, which may present after prolonged periods of
	treatment [Drugex, 1999].

	These effects are reversible if the drug is discontinued and treatment
	is initiated [Guillemin, 1989; Canvin, 1993]. Folic acid treatment (5-10
	mg/day) should be used in the case of megaloblastic anemia. A deficiency
	of glucose 6-phosphase dehydrogenase (G6PD) may produce hemolytic anemia
	[ACR Committee, 1996].

	Hepatic toxicity manifests as acute, febrile episodes, with pruritic
	skin lesions, lymphadenopathy, hepatomegaly, lymphocytosis,
	eosinophilia, and elevated transaminases [Williams, 1979; Losek, 1981;
	Boyer, 1989; Marinos, 1992; Vyse, 1992]. This situation is serious and
	can lead to death [Pears, 1989; Marinos, 1992]. Discontinuing medication
	is not sufficient to prevent the patient's deterioration, and
	corticosteroids are needed.

	Continued treatment with sulphasalazine has been associated with male
	infertility (spermiogram abnormalities in 86% and oligospermia in 72%)
	[Birnie, 1981]. These abnormalities are reversible after discontinuing
	treatment for 3 months [Toovey, 1981].

	There have been isolated reports of cases of altered taste (ageusia and
	metallic taste), skin abnormalities (drug-induced exanthema, pruritic
	maculopapular rashes, Stevens-Johnson syndrome, toxic epidermic
	necrolysis), pulmonary disorders (eosinophilic pneumonia, fibrosing
	alveolitis, subacute hypersensitivity pneumonitis), neurologic disorders
	(motor and sensory neuropathy, aseptic meningitis), muscular disorders
	(myopathy), and renal disorders (hemolytic-uremic syndrome, nephrotic
	syndrome, bilateral kidney stones).


	Table 24. Adverse effects of DMARDs

	Drug 	
	   * Antimalarials	
	Toxicity 	
	   * Gastrointestinal, retina, skin	
	Initial evaluation 	
	   * Funduscopic examination in persons over 40 years of age, visual field.	
	Clinical effects 	
	   * Visual disturbances, skin lesions.	
	Tests 	
	   * Funduscopic examination every 6-12 months.	
	Most common reasons for suspending treatment 
	   * Corneal deposits, retinopathy.	
	
	Drug 	
	   * Anti-TNF agents	
	Toxicity 	
	   * Hematologic, central nervous system, immune system (toxicity assumed).	
	Initial evaluation 	
	   * Rule out acute or chronic infection (particularly TB). Rule out multiple
	     sclerosis.	
	Clinical effects 	
	   * Local or anaphylactic reactions. Signs or symptoms of infection or neoplasm,
	     myelosuppression or demyelinating disease. 	
	Tests 	
	   * CBC on administration of infliximab, and every 4-6 weeks with etanercept
	     treatment.	
	Most common reasons for suspending treatment 
	   * Systemic infection.	
	
	Drug 	
	   * Azathioprine	
	Toxicity 	
	   * Hematologic, gastrointestinal.	
	Initial evaluation 	
	   * Baseline CBC, creatinine, liver function.
	Clinical effects 	
	   * Signs or symptoms of infection or neoplasm.	
	Tests 	
	   * CBC every 1-2 weeks until dosage stable, then every 1-3 months. 
	     Liver function tests every 6-8 weeks.
	Most common reasons for suspending treatment 
	   * Leukopenia (less than 3,000 leukocytes and/or less than 1,000 neutrophils).
	     Thrombocytopenia (less than 150,000 /mm^3 ). Systemic infection.
	
	Drug 	
	   * Cyclophosphamide	
	Toxicity 	
	   * Gonadal, urological, bone marrow.
	Initial evaluation 	
	   * Rule out pregnancy, infections, neoplasms, or re-existing liver disease.
	Clinical effects 	
	   *  Signs or symptoms of infection or neoplasm, alopecia, nausea, vomiting.	
	Tests 	
	   * CBC every 1-2 weeks until dosage stable, then every 2-4 weeks.
	     Liver enzymes, urinalysis, urinary sediment, monthly.
	Most common reasons for suspending treatment 
	   * Leukopenia (less than 3,000 leukocytes and/or less than 1,000 neutrophils).
	     Thrombocytopenia (less than 150,000 /mm^3 ). 
	     Systemic infection, hemorrhagic cystitis.
 
	Drug 	
	   * Cyclosporin A	
	Toxicity 	
	   * Kidney, hypertension.
	Initial evaluation 	
	   * Rule out neoplasms or premalignant lesions.
	     Two BP tests for hypertension. CBC, hepato-renal biochemistry, 
	     routine urinalysis with sediment.
	Clinical effects 	
	   * Signs or symptoms of infection or neoplasm.
	Tests 	
	   * Monitor for hypertension, renal and electrolyte function every 2
	     weeks the first 3 months, and then monthly.
	Most common reasons for suspending treatment 
	   * Greater than or equal to 30% increase in creatinine not reversed 
	     after halving dose. Development of uncontrolled hypertension.

	Drug 	
	   * D-penicillamine	
	Toxicity 	
	   * Skin, gastrointestinal, kidney.
	Initial evaluation 	
	   * CBC, creatinine, urinalysis. 
	Clinical effects 	
	   * CBC, creatinine, urinalysis every 2 weeks until dosage stable, and
	     then every 1-3 months.
	Tests 	
	   * Skin lesions, anaphylactic reactions.
	Most common reasons for suspending treatment 
	   * Proteinuria greater than 500 g/24 h. Leukopenia (less than 3,000 
	     leukocytes and/or less than 1,000 neutrophils). Thrombocytopenia 
	     (less than 150,000 /mm^3 ).
 
	Drug 	
	   * Leflunomide
	Toxicity 	
	   * Pulmonary, gastrointestinal, hepatic.
	Initial evaluation 	
	   * Begin contraceptive use. Rule out active infection, liver disease, 
	     and renal failure.
	Clinical effects 	
	   * Skin lesions, hair loss, weight loss, hypertension.
	Tests 	
	   * CBC and GOT, GPT every 4 weeks until dosage stable. 
	Most common reasons for suspending treatment 
	   * Liver enzymes persistently elevated to more than twice the reference 
	     values.
 
	Drug 	
	   * Methotrexate
	Toxicity 	
	   * Pulmonary, hepatic, hematologic, gastrointestinal, and neurological.
	Initial evaluation 	
	   * CBC, liver and kidney biochemistry, serum albumin, hepatitis A, B, C
             serology. If there is history of pleuropulmonary disease: chest X-ray,
             folic acid and vitamin B12 levels. If excessive alcohol consumption or
             previous liver disease, liver biopsy.
	Clinical effects 	
	   * Dry cough, shortness of breath, fever, hemorrhage, nausea, vomiting,
             diarrhea, nodules, adenopathy.
	Tests 	
	   * CBC and kidney and liver biochemistry every 4-8 weeks. If liver
             function abnormalities persist: follow-up liver biopsy.
	Most common reasons for suspending treatment 
	   * Pregnancy, pulmonary toxicity, liver enzymes persistently elevated to
             more than twice the reference values.
             Leukopenia (less than 3,000 leukocytes and/or less than 1,000 neutrophils).
             Thrombocytopenia (less than 150,000 mm^3 ).
  	 	
	Drug 	
	   * Gold salts
	Toxicity 	
	   * Hematologic and renal.
	Initial evaluation 	
	   * Baseline
	Clinical effects 	
	   * Skin lesions, mouth ulcers, edema, diarrhea, signs or symptoms of
             myelosuppression.
	Tests 	
	   * CBC and proteinuria every 4 weeks for the first 6 months, and then
             every 3 months.
	Most common reasons for suspending treatment 
	   * Proteinuria greater than 500mg/24 h. Leukopenia (less than 3,000 
	     leukocytes and/or less than 1,000 neutrophils).
             Thrombocytopenia (less than 150,000 /mm^3 ).

	Drug 	
	   * Sulphasalazine
	Toxicity 	
	   * Central nervous system, gastrointestinal, hematologic.
	Initial evaluation 	
	   * Hypersensitivy to sulfonamides. History compatible with G6PD deficiency.
	Clinical effects 	
	   * Skin lesions, signs or symptoms of myelosuppression.
	Tests 	
	   * CBC every 4 weeks for 3 months, and then every 3 months.
	Most common reasons for suspending treatment 
	   * Hypersensitivity syndrome. Leukopenia (less than 3,000 leukocytes 
	     and/or less than 1,000 neutrophils). Thrombocytopenia (less than 
	     150,000 /mm^3 ).
  	
	* Because there has been little experience with its use, it is not possible
	  to recommend a specific period of time for monitoring adverse effects once
	  a stable dose has been reached (3 months would seem to be prudent).


	CHAPTER 7. OTHER TREATMENTS


	7.1 Surgical treatment


	7.1.1 The rheumatologist should consider surgical treatment when articular 
	function does not improve or is notably worse, when incapacitating pain persists,
	or when there are potentially serious or limiting neurological complications
	[Dreyer, 1999; Grob, 1999].

	Appropriate medical treatment will reduce the indications for surgery
	and will improve the likelihood of surgical success. Consultation with
	an orthopedic surgeon should not always be an indication for surgery,
	but the exchange of opinions and clinical evaluation will help improve
	the patient's clinical and functional status.

	A number of factors should be considered before surgical treatment: bone
	quality, the patient's level of motivation and preferences, the
	probability that surgery will modify the course of the disease, and an
	estimate of the extent to which surgical treatment can reconstruct
	articular function and make the patient more independent [Bogoch, 1999].

	In deciding on surgical intervention, clinical and functional evaluation
	should predominate over simple radiographic change in the disease.

	RA patients who consult the orthopedic surgeon often have various joints
	needing surgical evaluation, therefore priorities need to be
	established. The joint that the patient finds most incapacitating will
	usually be treated first.

	Patients who cannot walk due to lower limb pain or deformity need to
	have functional upper limbs to facilitate the post-surgical period. When
	the upper limbs are affected (pain, deformity, or stiffness) to the
	point that they would impede the use of walking aids, the upper limbs
	should be reconstructed first. If the joints are affected with different
	degrees of severity, the one with the best prognosis should be
	reconstructed first.


	7.1.2 The joint prosthesis is the most efficient surgical means to arrest
	progressive loss of functional capacity. Prosthetic implant in any joint 
	should be performed before irreparable deformities occur (e.g., flexus or axial
	deviations and instabilities) because these will limit the success of 
	arthroplasty [Waldman, 1998; Creighton, 1998; Hargreaves, 1999].

	Synovectomy may produce slight improvement in the synovectomized joints,
	but this effect is not maintained at 3 years.

	Arthrodesis is a good control measure but is more limited from the
	functional point of view. It remains a commonly used technique in RA to
	palliate damage from joint destruction, especially in the
	interphalangeal joints of the hand, the metacarpophalangeal joint of the
	thumb, the wrist, ankle, and hindfoot [Bogoch, 1999]. Arthrodesis of
	other joints is less acceptable.

	Surgical success or complications in RA are associated with the
	surgeon's experience, the patient's previous status, and post-operative
	care, especially rehabilitation and occupational therapy. The latter two
	factors are an important aid in establishing optimal joint function,
	especially after arthroplasy of the knee or shoulder and hand surgery.

	The incidence of infection in orthopedic surgery may increase during the
	perioperative period, although this has not been conclusively
	established. A reasonable course of action is to omit the weekly dose of
	MTX in the week before and after surgery, which reduces the small
	possibility of perisurgical complications, at the expense of the also
	small risk of reactivating the disease [Bridges, 1991; Carpenter, 1996].


	7.2 Rehabilitative therapy


	7.2.1 The objective of a rehabilitation program in RA patients is to improve 
	pain relief, joint mobility, and the performance of the activities of daily 
	living. This is intended to prevent disability and maintain maximum personal 
	independence [Sutej, 1991]. Rehabilitative techniques that may be used in 
	treating RA patients are thermotherapy, physical exercise, prescription of 
	splints, and occupational therapy.

	Although rehabilitation is prescribed relatively frequently in RA
	patients, few studies with sound methodology have demonstrated its
	benefits with respect to control groups.

	Several studies show that patients who undergo a rehabilitation program
	have a 25 to 40% improvement in function. Other benefits that have also
	been attributed to rehabilitation are improvement in "disease
	perception" as well as in indicators of disease "activity" [Conaty,
	1971; Spiegel, 1986].

	Rehabilitation techniques that may be used in treating RA patients are
	thermotherapy, physical exercise, prescription of splints, and
	occupational therapy.


	7.2.2 Thermotherapy (the use of heat or cold as an analgesic method in joints
	with symptoms of inflammation) is useful in the treatment of RA. Superficial 
	heat is indicated in RA, whereas deep heat is formally contraindicated. The 
	local application of cold increases the pain threshold in the inflamed joints.

	Heat can be applied superficially (hot compresses, paraffin, infrared
	rays) or deeply (microwaves, ultrasound). Deep heat raises the
	temperature of the inflamed joints, while superficial heat,
	paradoxically, decreases it and thus reduces pain. Consequently,
	superficial heat is indicated in RA, while deep heat is formally
	contraindicated.

	Superficial heat increases the blood flow to the inflamed joints,
	producing a cooling effect, whereas deep heat does not increase blood
	flow [Lehmann, 1966; Harris, 1974; Feibel, 1976].

	Cold should only be applied superficially in the form of cold
	compresses, ice massage, or cold spray. The local application of cold
	increases the pain threshold in inflamed joints [Benson, 1974].

	The application of cold is contraindicated in the case of Raynaud's
	phenomenon, hypersensitivity to cold, cryoglobulinemia, or paroxysmal
	nocturnal hemoglobinuria [Olson, 1972].


	7.2.3 The ideal type of physical exercise in patients with RA is 
	static or isometric active exercise, which involves minimal increase
	in intra-articular pressure or bone destruction. Resistance active 
	exercises (lifting weights) are formally contraindicated because they
	increase joint inflammation, pain, muscular fatigue, temperature, and 
	intra-articular pressure.

	In passive exercise there is no voluntary muscular contraction on the
	part of the patient. The physiotherapist moves the joints. Its main
	objective is to maintain articular balance in joints at risk of
	developing ankylosis or contractures. Its efficacy in RA patients,
	however, is uncertain. If used, it should never cause pain [Merritt, 1983].

	In active exercise there is voluntary muscular contraction by the
	patient. There are three types:

	   * Static or isometric active exercise: limited muscular contraction
	     without joint motion but with maximal muscular tension.
	   * Dynamic or isotonic active exercise: muscular contraction
	     associated with joint motion that may act with or against the
	     force of gravity.
	   * Resistance active exercise: exercise performed against the force
	     of gravity and with added weight.

	The ideal type of physical exercise for RA patients is static or
	isometric active exercise, which involves a minimal increase in
	intra-articular pressure or bone destruction [Castillo, 1965; Jaison,
	1970]. Isometric exercise of the quadriceps has been shown to be
	beneficial for the knee joint [Ekblom, 1975a].

	Resistance active exercises (lifting of weights) are formally
	contraindicated in RA patients because they increase joint inflammation,
	pain, muscular fatigue, temperature, and intra-articular pressure.

	Patients without active disease who have developed sufficient muscular
	strength through isometric exercise may benefit from repetitive isotonic
	active exercises with minimal resistance, so long as they are performed
	with a reduced range of joint motion. Some ways of practicing these
	exercises would be swimming, stationary bicycling, or gardening, with
	the stipulation that fatigue should be avoided [Ekblom, 1975b; Minor, 1989].


	7.3 Local therapy


	7.3.1 Local therapy in RA is indicated in joints with persistent disease
	activity despite adequate systemic control of the disease. The smaller
	the radiographic damage in a joint and the less systemic inflammatory 
	activity of RA, the higher the probability that local treatment will have
	good results.

	Local treatment in RA is understood as therapy applied to an individual
	joint. During the course of RA it is frequently found that, although the
	disease's systemic inflammatory activity is controlled with the use of
	DMARDs and anti-inflammatories (steroidal or nonsteroidal), some joints
	still have active inflammation characterized by the presence of pain at
	rest, tenderness, pain on motion, swelling, and localized warmth. In
	these situations the systemic medication that is controlling the disease
	should be maintained, adding a local treatment to reduce inflammation in
	the joint where it is not controlled.


	7.3.2 Intra-articular steroid injection is the procedure of choice. The 
	most effective corticosteroid preparation is triamcinolone hexacetonide 
	due to its prolonged intra-articular duration. If corticosteroid 
	infiltration fails, radioisotopic synoviolisis and chemical synoviolisis
	with osmic acid may be useful procedures before referring the patient for
	arthroscopic or surgical synovectomy.

	The first step is to obtain synovial liquid for testing. The presence of
	infection should be ruled out by Gram stain and appropriate cultures.

	The administration of intra-articular corticosteroids is the local
	therapy of choice for an out-of-phase joint when infection has been
	ruled out. A number of drugs exist, including methylprednisolone
	acetate, paramethasone acetonide, triamcinolone acetonide, and
	triamcinolone hexacetonide. This guideline recommends the use of
	triamcinolone hexacetonide because of its prolonged action, lasting
	several months [Bain, 1972; Bird, 1979; Blyth, 1994]. After
	administering the corticosteroid, it is a good idea to prescribe joint
	rest for at least 24 hours [Chakravarty, 1994].

	Radioisotopic synovectomy consists of the intra-articular administration
	of a radioactive drug that emits high energy beta particles. The
	synovial membrane receives local radiation, destroying the synovial
	membrane cells and reducing their thickness, which improves the symptoms
	of inflammation in the medium- and long term. The most commonly used
	drugs in large joints such as the knee are dysprosium-165, 90-yttrium,
	and samarium-153. For medium-sized joints such as the elbows, carpals,
	or ankles, rhenium-186 has been used. For small joints such as the
	metacarpophalangeal or proximal interphalangeal joints, erbium-169 has
	been used [Muller, 1975; Gumpel, 1979; Sledge, 1984; Sledge, 1986;
	Sledge 1987; Jones, 1993; Barnes, 1994; Clunie, 1996; Asavatanabodee,
	1997; Jahangier, 1997; O´Duffy, 1999].

	Chemical synovectomy refers to the intra-articular administration of a
	chemical agent capable of destroying the synovial membrane by metabolic
	or abrasive action on the cells or extracellular material. Osmic acid is
	the most commonly used agent [Bontoux, 1978].


	CHAPTER 8. EXTRA-ARTICULAR COMPLICATIONS OF RHEUMATOID ARTHRITIS


	8.1 Amyloidosis


	8.1.1 Secondary amyloidosis should be suspected in RA patients who develop
	proteinuria, renal failure, gastrointestinal symptoms, myocardiopathy 
	and/or hepatomegaly, and in those having elevated phase reactants 
	concurrent with little clinical activity.


	8.1.2 The recommended treatment is chlorambucil at a dosage of 0.1-0.2 
	mg/kg/day [Berglund, 1993; David, 1993].

	Background:	
	Amyloidosis is a syndrome characterized by the presence of insoluble
	deposits of normal serum proteins in the extracellular material of one
	or more organs. Secondary amyloidosis, produced by the serum amyloid A,
	a phase reactant, is the most frequent form of amyloidosis. It occurs in
	association with a large number of chronic inflammatory diseases such as
	RA. The inflammatory response tends to increase the production of serum
	amyloid A in the liver, which is broken down in the circulating
	macrophages into smaller fragments that are deposited in the tissues
	[Glenner, 1980]. Amyloidosis increases RA mortality by causing organ
	dysfunction.

	When to suspect:	
	Secondary amyloidosis should be suspected in RA patients who develop
	proteinuria, renal failure, gastrointestinal symptoms, myocardiopathy
	and/or hepatomegaly [Okuda, 1994; Hazenberg, 1994], as well as in those
	having elevated phase reactants concurrent with little clinical activity.

	Clinical description:	
	The prevalence of amyloidosis in RA in post-mortem studies ranges
	between 10 and 25% [Husby, 1985; Pai, 1993]; it becomes symptomatic in
	only 2-10 %. It is more frequent in patients with severe long-standing
	disease [Okuda, 1994]. One of the most frequent indicators of amyloid
	deposits in RA patients is the presence of proteinuria, which may
	progress to nephrotic syndrome. Other organs that may be affected are
	the heart, liver, spleen, gut, and skin.

	Diagnosis:	
	The diagnosis of amyloidosis requires documentation of an extracellular
	fibrillar deposit with green birefringence under polarized light in
	biopsies stained with Congo red [Glenner, 1980]. It is recommended that
	biopsies be made of abdominal fat [Duston, 1989] or of rectal or
	gingival mucosa [Kyle, 1983], which is safe and accessible. It has
	recently been suggested that scintigraphy with serum amyloid P component
	(a phase reactant that coprecipitates in all forms of amyloidosis)
	marked with iodine-123 may be a reliable alternative to biopsy in the
	diagnosis of secondary amyloidosis [Tan, 1995].

	Treatment:	
	Treatment should always aim to suppress RA activity [Gerts, 1991;
	Berglund, 1993; David, 1993; Lovat, 1997]. Chlorambucil at a dosage of
	0.1-0.2 mg/kg/day has been shown to play a beneficial role in the
	treatment of secondary amyloidosis in patients with chronic arthritis
	[Berglund, 1993; David 1993].


        8.2 Anemia


	8.2.1 Anemia in RA is usually asymptomatic, therefore periodic blood 
	cell counts should be obtained including erythrocyte, leukocyte, and
	platelet counts; calculation of the mean corpuscular volume (MCV); 
	reticulocyte count; and general liver and kidney function tests.


	8.2.2 There is no specific treatment for anemia in RA. It should be 
	considered for possible changes in RA treatment guidelines.

	Background:
	Anemia is one of the hematologic disorders that can appear during the
	course of RA. It may be related with the disease's inflammatory
	character and chronic nature, with associated iron-deficiency, or it may
	be an undesired effect of treatment. The severity depends on its intensity.

	If the anemia is severe (hemoglobin less than 80 g/l), not only iron
	deficiency, but also other, infrequent causes of anemia should be
	considered, such as autoimmune hemolytic anemia and drug-induced
	aregenerative anemia. In the absence of blood loss, the diagnosis of
	hemolytic anemia is based on reticulocytosis, and the diagnosis of
	aregenerative anemia is based on the drug used in treatment and its
	association with leukopenia and thrombocytopenia.

	When to suspect:	
	The anemia is usually moderate and asymptomatic, and is detected in
	routine tests. Typical symptoms may also develop at times, such as
	fatigue, increasing difficulty in normal physical exertion,
	palpitations, and/or pale skin and mucosa. The range of symptoms depends
	on the intensity of the anemia and on the organism's possible
	development of adaptive mechanisms.

	Diagnosis:	
	A blood count should be obtained, including erythrocyte, leukocyte, and
	platelet counts; calculation of the mean corpuscular volume (MCV);
	reticulocyte count; and general liver and kidney function tests. If
	anemia exists, a second round of tests may be obtained to diagnose its
	etiology. These tests may include:

	   * Determination of the serum levels of ferritin and transferrin and
             their saturation index, indicated to evaluate associated iron
             deficiency (Table 25). Iron deficiency is also
             accompanied by elevated transferrin levels, with a low saturation
             index (less than 16%).
	   * Myelogram. Indicated only in cases where there is unconfirmed
             suspicion of coexisting iron-deficiency anemia.
	   * Bone marrow biopsy. Only if aregenerative anemia is suspected.


	Table 25. Definition and characteristics of anemia in RA
	
	DEFINITION
	   * Hemoglobin
	   * less than 130 g/l (men); less than 120 g/l (women)
	CHARACTERISTICS
	   * Normocytic
	   * MCV: 83-97 fl
	CHARACTERISTICS	   
	   * Normochromic 
	   * MCH: 27-33 pg
	CHARACTERISTICS	   
	   * Transferrinemia 
	   * Slightly reduced saturation index
	CHARACTERISTICS	   
	   * Reticulocytes 
	   * Normal or low
	CHARACTERISTICS	   
	   * Ferritin (serum values) 
	   * greater than 60 ng/ml
	     less than 12 ng/ml (iron deficiency anemia)
	     12-60 ng/ml (anemia associated with iron deficiency)
 	

	Treatment:	
	Transfusions of concentrated red blood cells are contraindicated, except
	in exceptional cases of severe anemia with high cardiocirculatory risk.
	Iron (oral ferrous salt compounds) should only be administered when
	there is evidence of coexisting iron-deficiency anemia. The cause of
	blood loss should also be investigated.

	The usefulness of administering erythropoietin has not been defined,
	although it could be indicated prior to surgery, particularly before
	joint prosthesis. The treatment required for pure red cell aplasia is
	complex and should be carried out in a hematology unit.


	8.3 Cardiological complications


	8.3.1 Cardiac involvement should be suspected if there is pericardial 
	pain, heart failure, or conduction abnormalities. The two most frequent 
	complications are pericarditis and myocarditis.


	8.3.2 Pericarditis should be treated with full doses of NSAIDs (150 mg/day
	of indomethacin). If this treatment is not effective, prednisone 
	(1 mg/kg/day) is useful to control symptoms. Myocarditis is treated with 
	high-dose steroids, diuretics, digitalis, vasodilatador agents, and 
	antiarrhythmia drugs.

	Background:
	The heart and adjacent structures (pericardium and vessels) may be
	affected by nodular lesions or fibrosis in RA patients. In these
	patients, however, heart involvement is likely to be due to causes other
	than rheumatoid disease itself. The cardiac lesions derived from RA have
	little clinical expression, and are usually mild alterations not
	requiring treatment.

	When to suspect:
	Pericardial-type pain, heart failure, or conduction abnormalities should
	be a warning of possible cardiac involvement in an RA patient. The two
	types of cardiac involvement in RA patients are pericarditis and
	myocarditis.

	Pericarditis

	Clinical description:
	This is the most frequent type, with an annual incidence of 0.3-0.4%
	[Jurik, 1986]. Echocardiographic studies show asymptomatic pericardial
	effusion in over 30% of RA patients. In some exceptional cases of
	massive effusions or rapid onset, cardiac tamponade manifesting as shock
	is produced. Most RA patients with symptomatic pericarditis are males
	with positive RF.

	Diagnosis:
	Pericardial effusion seen on echography.

	Treatment:
	Full doses of NSAIDs (150 mg/day of indomethacin). If this is not
	effective, prednisone (1 mg/kg/day) is useful to control symptoms. Cases
	of cardiac tamponade should be treated with evacuation by
	pericardiocentesis.

	Myocarditis

	Clinical description:
	Myocarditis may be interstitial or granulomatous and is rare in RA
	[Lebowitz, 1963]. The granulomatous variety is highly specific in RA,
	while the interstitial variety is more frequent in lupus. Myocarditis
	presents as progressive shortness of breath. The physical examination
	reveals tachycardia, reduced differential blood pressure, and frequently
	a third heart sound. The coronary valves may be affected by granulomas
	leading to valve insufficiency and affecting, in this order, the mitral,
	aortic, tricuspid, and pulmonary valves. The coronary arteries may be
	affected in RA, especially the small intramyocardial vessels. Coronary
	arteritis is not usually expressed clinically, thus the presence of
	symptoms of ischemia in RA patients is practically always due to
	associated coronary arteriosclerosis.

	Diagnosis:
	Reduced contractility shown on echocardiography. Biopsy of the right
	ventricle may be indicated in these patients.

	Treatment:
	High-dose steroids, combined with diuretics, digitalis, vasodilators,
	and antiarrhythmia drugs.


        8.4 Osteoporosis


	8.4.1 Osteoporosis should be suspected in the presence of vertebral or
	peripheral fractures not due to trauma. When RA is first diagnosed, all 
	patients should be evaluated for the main risk factors for fracture and 
	loss of bone mass; this analysis should include both RA-associated and 
	independent risk factors (Tables 26 and 27).


	8.4.2 First-line agents for the specific treatment of osteoporosis are 
	alendronate, risedronate, or hormone replacement therapy or, alternatively,
	cyclical etidronate or calcitonine.

	Background:
	A large percentage of RA patients have low bone mass in the axial and
	peripheral skeleton. These patients are considered to have twice the
	risk of the general population for developing fractures of the vertebra
	and femur, with a relative risk of 2.1 for fracture of the vertebra and
	1.5-2.1 for fracture of the femur, rising to 4.4 in patients with marked
	alternation of functional capacity.

	Many risk factors are involved in the development of osteoporosis: age,
	post-menopause (in women), disease activity, functional capacity,
	immobility, and the influence of drugs used in treatment, especially the
	corticosteroids. Major bone mass loss has been described even in the
	initial phases of RA. Despite this evidence, no CPG for osteoporosis
	treatment in RA has been developed to date.

	When to suspect:
	Vertebral or peripheral fractures, excluding those caused by trauma.

	Diagnosis:
	At the initial examination an analysis should be made of the main risk
	factors for fracture and loss of bone mass, both risk factors that are
	associated with RA and those that are independent of the disease (Tables
	26 and 27). If one or more of these factors is present, a bone 
	densitometry of the lumbar spine and femur is indicated, according to 
	the recommendations of the National Osteoporosis Foundation (US), the 
	International Committee for Osteoporosis Clinical Guidelines in 
	post-menopausal women, the ACR (US), and the National Osteoporosis 
	Society (Great Britain) for the prevention and treatment of
	corticosteroid-induced osteoporosis.

	Since a large percentage of vertebral fractures are asymptomatic, a
	lateral radiograph should be made of the dorsal and lumbar spine to
	evaluate the existence of vertebral fractures in accordance with the
	following criterion for fracture: a 20% or greater reduction of the
	anterior, mid, or posterior height of the vertebral body. Laboratory
	tests will usually also be obtained to rule out associated processes
	that may be causing the osteoporosis.


	Table 26. RA-independent risk factors for osteoporosis

	   * Age over 65 years
	   * History of fracture due to bone fragility after 40 years of age
	   * Body weight under 58 kg
	   * Fractures due to bone fragility in nuclear family members
	   * Smoking
	   * Early menopause
	   * Prolonged amenorrhea
	   * Hypogonadism in males
	   * Other predisposing diseases


	Table 27. RA-associated risk factors for osteoporosis

	   * Active disease
	   * HAQ greater than 1.25
	   * Treatment with corticosteroids greater than 7.5 mg/day for over 6 
	     months, or cumulative doses over 30 g
	   * Treatment with methotrexate

	In accordance with the WHO criteria for the diagnosis of osteoporosis in
	women, osteopenia or osteoporosis is considered to exist when the
	T-scale value is between -1 and -2.5, or is less than -2.5,
	respectively. Although there is no official consensus, these diagnostic
	criteria appear to be valid in men.

	Treatment:
	Since all RA patients are at risk for osteoporosis, the following
	recommendations for preventive treatment are made for all such patients:

	   * Stop smoking and excessive alcohol consumption.
	   * Maintain physical activity.
	   * Take necessary precautions to avoid falls.
	   * Calcium supplements sufficient to reach a daily intake, including
             diet, of 1,500 mg, plus 400-800 IU of vitamin D3.
	   * If hypercalciuria is present, thiazides should be administered.

	Begin specific treatment of osteoporosis if:

	   * There is a history of fracture of the vertebra or femur.
	   * Bone mineral density is less than -1.5 on the T scale.
	   * The patient is over 65 years of age.
	   * The dose of corticosteroids is higher than 7.5 mg/day of
             prednisone for more than 6 months, and there are other risk
             factors (Tables 26 and 27).

	Treatment with alendronate, residronate, or hormone replacement therapy
	(estrogens either alone or in association with progestogens - depending
	on whether or not the uterus is intact - in postmenopausal women, or
	testosterone in hypogonadal men). If contraindicated, cyclical
	etidronate or calcitonine can be used as an alternative.

	At the time this guideline was written, no information was available on
	the efficacy of raloxifene in secondary osteoporosis.

	Monitoring:
	Patients who have a baseline densitometry should repeat the test one
	year later, and every 1-3 years thereafter. If annual bone loss is more
	than 4% in the lumbar spine or 7% in the femur, treatment should be
	initiated or modified.


        8.5 Lung complications


	8.5.1 The appearance of pleuritic pain, shortness of breath (either 
	progressive or of recent onset), or hemoptysis suggests pulmonary 
	disease in RA patients. Lung complications may include pleural disease, 
	rheumatoid nodules, interstitial fibrosis, or bronchiolitis obliterans 
	with organizing pneumonia (BOOP).


	8.5.2 Treatment for pleural disease includes thoracocentesis to obtain 
	an exudate and rule out other pathologies (infection or neoplasm), 
	NSAIDs at full doses, or steroids at half doses (10-20 mg/day of 
	prednisone). Rheumatoid nodules do not require treatment in the absence 
	of complications. Recent onset (acute) interstitial involvement is treated 
	with prednisone (1-1.5 mg/kg/day). If there is no response, patients may be
	treated with cyclophosphamide or azathioprine. BOOP is treated with 
	prednisone (1.5 mg/kg/day).

	Background:
	It is not clear how pulmonary disease is associated with RA [Kelly,
	1993]. Pleuritis (with or without effusion), pulmonary nodules (with or
	without cavitation), rheumatoid pneumoconiosis (Caplan's syndrome), and
	BOOP are accepted rheumatoid manifestations. The association of RA with
	bronchiectasis or with diffuse interstitial fibrosis, however, is
	questionable [McMahon, 1993; Shadick, 1994]. In any case, the appearance
	of pulmonary lesions in a patient with RA makes it necessary to rule out
	the presence of a neoplastic process, infection, or a drug side effect
	(pneumonitis due to gold salts or methotrexate).

	When to suspect:
	Pulmonary disease should be suspected in the event of pleuritic pain,
	shortness of breath, either progressive or of recent onset, or hemoptysis.

	Pleural disease:
	
	Clinical description: The incidence of pleuritis in RA patients is
	nearly 20% [Jurik, 1982]. It is usually asymptomatic and especially
	affects male patients with seropositive and nodular RA. When it is
	symptomatic, it manifests as pleuritic pain and pleural effusion.
	Diagnosis: Low cell count in the pleural fluid (less than 5,000 
	leukocytes/mm^3), low concentration of glucose (less than 40 mg/dl) and 
	complement, together with a high total protein content.
	
	Treatment: Treatment includes thoracocentesis to obtain an exudate and
	rule out other pathologies (infection or neoplasm), full doses of
	NSAIDs, and half-doses of steroids (10-20 mg/day of prednisone).

	Rheumatoid nodules:
	
	Clinical description: Intrapulmonary rheumatoid nodules usually remain
	asymptomatic, except when they cavitate, in which case they may become
	superinfected or produce hemoptysis. The presence of pulmonary nodules
	has most frequently been described in RA patients exposed to inorganic
	dust (Caplan's syndrome in coal miners). All pulmonary nodules should be
	biopsied to rule out neoplasia.
	
	Diagnosis: The only certain diagnosis of rheumatoid nodules is
	histological.
	
	Treatment: The nodules have not been shown to respond to
	pharmacological treatment, nor do they usually require surgical
	treatment unless complications occur (pneumothorax).

	Interstitial fibrosis:
	
	Clinical description: Diffuse interstitial fibrosis affects 10% of
	patients with RA [Jurik, 1982]. Its clinical presentation is no
	different from the idiopathic syndrome, and it presents as a slowly
	progressing shortness of breath.
	
	Diagnosis: In all RA patients with pulmonary findings on the physical
	examination (fine basal crepitations) or on the radiography (reticular
	or reticulo-nodular pattern), the physician should request blood gas
	analysis and respiratory function tests (diffusion test). High
	resolution tomography, although it does not detect pulmonary
	inflammation, is a highly specific and sensitive technique for the
	diagnosis of pulmonary interstitial fibrosis.
	
	Treatment: Interstitial disease of recent onset (acute) is an
	indication for prednisone therapy (1-1.5 mg/kg/day). Patients who do not
	respond can be treated with cyclophosphamide or azathioprine, although
	there is no evidence that these agents reduce the progression of fibrosis.

	Bronchiolitis obliterans with organizing pneumonia (BOOP):
	
	Clinical description: BOOP is a rare pulmonary disease that has been
	related with RA [Rees, 1991]. It presents with cough and severe
	shortness of breath of recent onset.
	
	Diagnosis: Chest X-ray shows bilateral opacities of the pulmonary
	parenchyma without loss of volume. High resolution tomography reveals
	patchy areas in the pulmonary parenchyma, which are usually peripheral.
	A definitive diagnosis requires thoracoscopic lung biopsy, with the
	observation of intraluminal plugs in the bronchioles.
	
	Treatment: Oral prednisone (1.5 mg/kg/day) in a single daily dose for
	4-6 weeks, then slowly tapering off until discontinuing the drug in 4-6
	months.


        8.6 Felty's syndrome


	8.6.1 Felty's syndrome is characterized by the presence of splenomegaly,
	leukopenia (less than 3,500/mm^3), and neutropenia (less than 2,000/mm^3)
	in patients meeting RA criteria.


	8.6.2 The use of filgastrim is recommended when the absolute neutrophil 
	count is less than 1,000/mm^3 and the patient has a history of associated
	severe infection.

	Background and diagnosis:
	Felty's syndrome is an infrequent but serious extra-articular
	manifestation of RA. Patients with this syndrome meet the criteria for
	RA and in addition have splenomegaly, leukopenia (less than 3,500/mm^3), and
	neutropenia (less than 2,000/mm^3). Its prognosis is largely governed by the
	higher incidence of systemic manifestations, mainly bacterial
	infections. This higher incidence of infection is due both to
	neutropenia and to defective functioning of the neutrophils.

	Treatment:
	There are no controlled studies showing the efficacy of any specific
	treatment for Felty's syndrome, thus the patient should be managed the
	same as for RA, together with prophylactic measures against infection
	and empirical treatment for fever the same as those used in patients
	with secondary neutropenia due to the use of cytotoxic drugs. These
	recommendations will vary in each center depending on the frequency of
	isolation of particular infectious agents, thus each center should use
	its own guidelines.

	Filgastrim is recommended when the absolute neutrophil count is lower
	than 1,000/mm^3 and the patient has a history of severe infection
	associated with the course of Felty's syndrome. A bone marrow biopsy
	should be performed before using filgastrim, since myeloid processes may
	simulate Felty's syndrome. In refractory cases surgical splenectomy or
	embolization of the splenic artery is indicated.


        8.7 Secondary Sjögren's syndrome


	8.7.1 A patient with RA is considered to have secondary Sjögren's 
	syndrome (SSS) if there are signs and symptoms indicative of 
	xerophthalmia and xerostomia.


	8.7.2 There are no specific recommendations for modifying the course
	of SSS in RA. This guideline recommends symptomatic treatment of 
	xerophthalmia and xerostomia. Dental and ophthalmological 
	examinations are recommended every 6 months.

	Background and diagnosis:
	An RA patient is considered to have SSS if there are objective signs and
	symptoms of xerophthalmia together with objective signs and symptoms of
	xerostomia.

	Objective signs of xerophthalmia are considered to be an altered
	Schirmer test, together with a diagnosis of keratoconjunctivitis sicca
	by rose Bengal staining or fluorescein.

	Objective signs of xerostomia are considered to be reduced production of
	saliva measured by Lashley cup or other methods, together with a
	positive minor salivary gland biopsy and a lymphoid foci count of 2 or
	higher, measured as the average of four salivary gland lobules.

	A differential diagnosis should be made in patients with sarcoidosis,
	lymphoma, AIDS, hepatitis, autonomous neuropathy, and salivary gland
	hypertrophy.

	Treatment:
	There are no specific recommendations for modifying the course of SSS in RA.

	Dryness of the eyes should be treated with:

	   * Withdrawal, if possible, of drugs that produce ocular dryness,
             such as drugs for hypertension, diuretics, and psychotropic drugs
	   * Use of artificial tears
	   * Avoidance of dry areas, those that are excessively warm, or
             contain irritating gases, including tobacco smoke
	   * Temporary or permanent surgical occlusion of the tear duct.

	Dryness of the mouth should be treated with:

	   * Withdrawal, if possible, of drugs that produce mouth dryness, such
             as drugs for hypertension, diuretics, and psychotropic drugs
	   * Use of artificial saliva
	   * Use of sugar-free lemon drops
	   * Use of oral pilocarpine (5 mg/6 h).

	Multidisciplinary teams should be created consisting of a
	rheumatologist, a dentist, and an ophthalmologist. Dental and
	opthalmological examinations are recommended every 6 months.


	8.8 Vasculitis


	8.8.1 Rheumatoid vasculitis is understood to be a set of vascular 
	processes (periungual splinter hemorrhages, palpable purpura, 
	polyarteritis nodosa) with variable prognosis and treatment.


	8.8.2 Palpable purpura should be treated with full doses of NSAIDs and
	medium to low doses of prednisone (15-30 mg/day). Polyarteritis nodosa 
	is treated initially with high- dose steroids (40-120 mg/day of prednisone). 
	If there is no response, cyclophosphamide can be added, either 2-3 mg/kg/day
	orally or 0.5-1 g/m^2 in intravenous pulses of 2 to 4 weeks.

	Background:
	Rheumatoid vasculitis is an infrequent extra-articular manifestation of
	RA. It appears in RA of long evolution, often with little or no joint
	inflammation. Risk factors for rheumatoid vasculitis are male gender,
	positive RF, the presence of other extra-articular manifestation of RA,
	and time of disease evolution.

	Palpable purpura:
	
	Diagnosis: Diagnosed clinically. Systematic skin punch biopsy is not
	recommended for histopathological confirmation, unless a vascular
	process other than small vessel leukocytoclastic vasculitis is
	suspected. Recently prescribed drugs should be reviewed to identify a
	possible pharmacological cause of the palpable purpura.
	
	Treatment: Generally disappears spontaneously. The most important
	factor in treatment is rest. If it does not disappear, palpable purpura
	should be treated with full doses of NSAIDs and medium to low doses of
	prednisone, beginning with 15 to 30 mg/day and progressively reducing
	the dosage depending on disease evolution.

	Polyarteritis nodosa-type rheumatoid vasculitis:
	
	Diagnosis: This is the most severe form of rheumatoid vasculitis and
	is life threatening in many patients. Histopathological confirmation is
	recommended whenever possible, since treatment of this form of
	vasculitis is frequently accompanied by severe adverse effects.
	Nevertheless, the physician can initiate treatment without
	histopathological confirmation in the most common and typical clinical
	presentations such as distal necrosis, skin ulceration, or multiple
	mononeuritis. Depending on the clinical manifestations, various
	complementary studies should be made, such as liver and kidney tests,
	arteriography, electromyogram-electroneurogram, skin biopsy,
	subcutaneous tissue biopsy, or biopsy of the sural nerve.
	
	Treatment: Initial treatment is with high-dose steroids: from 40 to
	120 mg of prednisone or its equivalent, in single or divided doses. The
	dosage selected for a particular patient will depend on the severity of
	the process and the threat to life. If the clinical manifestations are
	not controlled with high-dose prednisone or if they reappear when trying
	to reduce the dosage, cyclophosphamide can be added, either 2-3
	mg/kg/day orally or 0.5 to 1 g/m^2 in intravenous pulses every 2 to 4 week.

	Periungual splinter hemorrhages:
	
	Although periungual splinter hemorrhages are traditionally included in
	the vascular manifestations associated with RA, they are not
	histologically related with vasculitis.
	
	Diagnosis: They are diagnosed clinically and do not require
	complementary examinations.
	
	Treatment: No specific treatment is required. Close clinical
	monitoring is recommended for the early identification and treatment of
	vascular phenomena that may develop in the future.


	ACRONYMS

	   * ACR 
          	* American College of Rheumatology
	   * AIMS 	
          	* Arthritis Impact Measurement Scales
	   * APR
          	* Acute phase reactants
	   * ARA
          	* American Rheumatism Association
	   * ASA 
          	* Acetylsalicylic acid
	   * AUR
          	* Auranofin
	   * AZA
          	* Azathioprine
	   * BNCS
          	* Biblioteca Nacional de Ciencias de la Salud (National Library of
                  the Health Sciences)
	   * BOOP
          	* Bronchiolitis obliterans with organizing pneumonia
	   * BP
          	* Blood pressure
	   * CLQ 	
          	* Chloroquine
	   * CPA
          	* Cyclophosphamide
	   * CPG 
          	* Clinical practice guideline
	   * CRP
          	* C-reactive protein
	   * CS
          	* Corticosteroids
	   * CSA 
          	* Cyclosporin A
	   * DAS
          	* Disease activity score
	   * DAS 28
          	* Disease activity score counting 28 joints
	   * DP 
          	* D-penicillamine
	   * ESR
          	* Erythrocyte sedimentation rate
	   * ETN
          	* Etanercept
	   * EULAR 
          	* European Leagues Against Rheumatism
	   * FDA
          	* Food and Drug Administration
	   * FIdeM
          	* Fundación Ignacio de Mercado (Ignacio de Mercado Foundation)
	   * GUIPCAR
          	* Guía de Práctica Clínica para el manejo de Artritis Reumatoide en
                  España (Clinical Practice Guideline for the Mangement of Rheumatoid 
                  Arthritis in Spain)
	   * HAQ
          	* Health Assessment Questionnaire
	   * HCQ 
          	* Hydroxychloroquine
	   * IFM
          	* Infliximab
	   * IG
          	* Injectable gold
	   * ILAR 
          	* International Leagues Against Rheumatism
	   * IOM 
          	* Institute of Medicine (National Academy of Sciences)
	   * ISCIII
          	* Instituto de Salud Carlos III (Carlos III Health Institute)
	   * LEF
          	* Leflunomide
	   * MCH
          	* Mean corpuscular hemoglobin
	   * MCP 
          	* Metacarpophalangeal joint
	   * MCV 
          	* Mean corpuscular volume
	   * MHAQ
          	* Modified Health Assessment Questionnaire
	   * MTP
          	* Metatarsophalangeal joint
	   * MTX
          	* Methotrexate
	   * NIWI
          	* Nederlands Instituut voor Wetenschappelijke Informatiediensten
                  (Netherlands Institute for Scientific Information Services)
	   * NPJ 	
          	* Number of painful joints
	   * NPJ28 	
          	* Number of painful joints out of 28 joints
	   * NPJ44 	
          	* Number of painful joints out of 44 joints
	   * NSAIDs
          	* Nonsteroidal anti-inflammatory drugs
	   * NSJ
          	* Number of swollen joints
	   * NSJ28 	
          	* Number of swollen joints out of 28 joints
	   * NSJ44 	
          	* Number of swollen joints out of 44 joints
	   * OMERACT
          	* Outcome Measures in Rheumatoid Arthritis Clinical Trials
	   * OR 
          	* Odds ratio
	   * PCB 
          	* Placebo
	   * PGA 
          	* Patient's global assessment (of disease or health)
	   * PIP 
          	* Proximal interphalangeal joint
	   * RA 	
          	* Rheumatoid arthritis
	   * RF 
          	* Rheumatoid factor
	   * RI
          	* Ritchie index
	   * SER 
          	* Sociedad Española de Reumatología (Spanish Society of Rheumatology)
	   * SSS 
          	* Secondary Sjögren's syndrome
	   * SSZ
          	* Sulphasalazine
	   * TAISS
          	* Técnicas Avanzadas de Investigación en Servicios de Salud
                  (Advanced Research Techniques in the Health Services)
	   * TB 
          	* Tuberculosis
	   * TNF 
          	* Tumor necrosis factor
	   * UISS
          	* Unidad de Investigación en Servicios de Salud (Health Services
          	  Research Unit)
	   * VAS 
          	* Visual analog scale
	   * WHO 
          	* World Health Organization


	APPENDICES


	Appendix 1. Data collection instruments for parameters used in initial 
	evaluation and monitoring of RA patients

	This appendix contains a model data collection sheet for the evaluation
	and monitoring of RA patients. This model can be adapted to each
	specialist's needs in accordance with the way the particular hospital or
	clinical practice is run, and can be added to the patient's usual
	clinical record.

	First, there are three scales that the patient should fill out with
	reference to the previous week: change with respect to the last visit,
	pain, and global assessment of disease. The bottom half is for the
	physician. It is useful to mark the swollen joints with a dot (*) and
	the painful joints with an X.

	The usual procedure is to give this sheet to the patient at the end of
	the visit, and ask the patient to fill it out at home the day before
	returning for the next appointment. The physician should emphasize that
	this is not to be done any sooner, and that the patient should fill out
	the form thinking only of the previous 7 days. The bottom half is for
	the physician's evaluation.

	The HAQ, also included in this appendix, should be printed on the back
	of the same sheet.

	Finally, this appendix also includes instructions on how to correct the
	HAQ, the most commonly used joint indices, and different ways of
	calculating the DAS.


	Patient Home Worksheet

	Complete this section only
	
	Clinical History |__|__|__|__|__| 	Date ________________
	
	Please answer the following questions one day before your appointment
	with the rheumatologist.
	
	1. How is your arthritis in comparison with your last visit?

	Much better 	
	Somewhat better 	
	The same 	
	Somewhat worse 	
	Much worse

	2. How much pain have you noted during this past week?
	No pain 							Worse pain
	1 	2 	3 	4 	5 	6 	7 	8 	9 	10
	
	3. In general, how has your arthritis been during this past week?
	Very good 							Very bad
									PGA (0-100)
	1 	2 	3 	4 	5 	6 	7 	8 	9 	10
	------------------------------------------------------------------------

	Physician
	Physician's global assessment of disease.
	Very good 							Very bad
	1 	2 	3 	4 	5 	6 	7 	8 	9 	10

	   * NSJ:
	   * NPJ:
	   * RI:
	   * ESR:          /CPR:

	DAS=0.54(R1)+0.065(NSJ)+0.33(In ESR)+0.0072(PGA)

	DAS28=0.56(NPJ28)+0.28(NSJ28)+0.70(In ESR)+0.014(PGA)

	NOTE: Original Spanish evaluation sheet provided by Enrique Batlle Gualda. 
	University General Hospital of Alicante.


        Health Assessment Questionnaire (HAQ)

	Name ________________________________________  Date ________________
	
	We are interested in learning how your illness affects your ability to
	function in daily life.
	
	Please feel free to add any comments at the end of this form.

	Please check the response which best describes your usual abilities
	OVER THE PAST WEEK:
  	
  	Without ANY difficulty
  	Score = 0 
  	
  	With SOME difficulty 	
  	Score = 1
  	
  	With MUCH difficulty 	
  	Score = 2
  	
  	UNABLE to do
 	Score = 3
 
  		 	 	
	DRESSING AND GROOMING -
	Are you able to: 	  	  	  	 
	   - Dress yourself, including tying shoelaces and doing buttons? 				
	   - Shampoo your hair? 				
	ARISING - Are you able to: 	  	  	  	 
	   - Stand up from a straight chair? 				
	   - Get in and out of bed? 				
	EATING - Are you able to: 	  	  	  	 
	   - Cut your meat? 				
	   - Lift a full cup or glass to your mouth? 				
	   - Open a new milk carton? 				
	WALKING - Are you able to: 	  	  	  	 
	   - Walk outdoors on flat ground? 				
	   - Climb up five steps? 				
	
	Please check any AIDS OR DEVICES that you usually use for any of these
	activities:
	   * Cane 
	   * Devices used for dressing (buttonhook, zipper pull, long handled shoe horn, etc.)
	   * Walker
	   * Built up or special utensils
	   * Crutches 	
	   * Special or built up chair
	   * Wheelchair
	   * Other (Specify: __________________)
	   
	Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
	   * Dressing and grooming 	
	   * Eating
	   * Arising 	
	   * Walking
  	
  	Without ANY difficulty 	
  	Score = 0 
  	
  	With SOME difficulty 	
  	Score = 1 
  	
  	With MUCH difficulty 
  	Score = 2 
  	
  	UNABLE to do
 	Score = 3
  				
	HYGIENE - Are you able to: 	  	  	  	 
	   - Wash and dry your entire body? 				
	   - Take a tub bath? 				
	   - Get on and off the toilet? 				
	REACH - Are you able to: 	  	  	  	 
	   - Reach and get down a 5-pound object (such as a bag of sugar) from just above
	     your head? 				
	   - Bend down to pick up clothing from the floor? 				
	GRIP - Are you able to: 	  	  	  	 
	   - Open car doors? 				
	   - Open jars which have been previously opened? 				
	   - Turn faucets on and off? 				
	ACTIVITIES - Are you able to: 	  	  	  	 
	   - Run errands and shop? 				
	   - Get in and out of a car? 				
	   - Do chores such as vacuuming or yardwork? 
	   
	Please check any AIDS OR DEVICES that you usually use for any of these activities:
	   * Raised toilet seat 
	   * Bathtub bar
	   * Bathtub seat
	   * Long-handled appliances for reach
	   * Jar opener (for jars previously opened) 	
	   * Long-handled appliances in bathroom
	   * Other (Specify: __________________)
	   
	Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
	   * Hygiene
	   * Gripping and opening things
	   * Reach
	   * Errands and chores
 
	SCORING OF HAQ
	Add the maximum score for each of the 8 sections and divide by 8 to give
	a score between 0-3. 
	
	If aid/device or help is needed the score for that activity
	automatically = 2 (unless 3 has already been ticked).
	
	Normal function = 0
	Most affected function = 3


	Indices for the evaluation of joint inflammation and pain

  	Cervical spine
  	ACR (66/68)
	   *  -  	
  	Ritchie (53) 
	   * +*m   	
  	NSJ (44) 
	   * -  	
  	Fuchs (28)
	   * -   	

  	Temporomandibular
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*  	
  	NSJ (44) 
	   * -  	
  	Fuchs (28)
	   * -   	

  	Sternoclavicular
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * -   	

  	Acromioclavicular
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * -   	

  	Shoulder
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * +    	

  	Elbow
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * +    	
 			 	
  	Wrist
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * +    	
 	 	 	
  	Metacarpophalangeal
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * +    	
 	 			
  	Proximal interphalangeal
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*  	
  	NSJ (44) 
	   * +   	
  	Fuchs (28)
	   * +    	
 	 	
  	Distal interphalangeal
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * -  	
  	NSJ (44) 
	   * -  	
  	Fuchs (28)
	   * -    	
 	
  	Hip
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +m   	
  	NSJ (44) 
	   * -  	
  	Fuchs (28)
	   * -    	
 	
  	Knee
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +   	
  	NSJ (44) 
	   * +  	
  	Fuchs (28)
	   * +    	

  	Ankle
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +   	
  	NSJ (44) 
	   * +  	
  	Fuchs (28)
	   * -    	

  	Subtalar
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +m   	
  	NSJ (44) 
	   * -  	
  	Fuchs (28)
	   * -    	
 	 	 	 	
  	Midtarsal
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*m   	
  	NSJ (44) 
	   * -  	
  	Fuchs (28)
	   * -    	

  	Metatarsophalangeal
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * +*   	
  	NSJ (44) 
	   * +  	
  	Fuchs (28)
	   * -    	

  	Interphalangeal (foot)
  	ACR (66/68)
	   *  +  	
  	Ritchie (53) 
	   * -   	
  	NSJ (44) 
	   * - 	
  	Fuchs (28)
	   * -    	

	- The joints marked with an asterisk (*) are counted as a single joint.
	- In the ARA/ACR index the subtalar and midtarsal joints are counted as
          a single joint.
	- The Ritchie index counts (0-3) the presence of tenderness or pain on
          motion (*m*)

	
	Disease Activity Score

	Ranges from 0 (no disease activity) to 10 (maximum disease activity)

	DAS28 with four variables:

		DAS28=0.56(NPJ28)+0.28(NSJ28)+0.70(In ESR)+0.014(PGA)

	DAS28 with three variables:

		DAS28=0.56 (NPJ28) + 0.28 (NSJ28) + 0.70 (In ESR) + 1.08 + 0.16

	Formula to transform original DAS to DAS28:

		DAS28 = 1.072 (DAS) + 0.938

	Original DAS with four variables:

		DAS=0.54(RI) +0.065(NSJ44) + 0.33(In ESR) + 0.0072(PGA)

	Original DAS with three variables:

		DAS = 0.54 (RI) + 0.065 (NSJ44) + 0.33 (In ESR) + 0.224

	------------------------------------------------------------------------

	NPJ28: Number of painful joints based on a count of 28 joints
	NSJ28: Number of swollen joints based on a count of 28 joints
	ln: Natural logarithm
	ESR: Erythrocyte sedimentation rate
	PGA: Patient's global assessment of health or disease on a VAS from 0
	(very good) to 100 (very poor). Either of the two scales produces the same 
	results, although the latter one is preferable.
	RI: Ritchie index
	NSJ44: Number of swollen joints based on a count of 44 joints


	Appendix 2. Initial RA treatment with DMARDs, according to the complete 
	classification scheme (144 patient scenarios)

	The following list shows how the 144 different patient scenarios were
	classified as a function of disease characteristics, together with the
	recommended treatment/s in each case.


	I. PATIENT WITH less than 6 SWOLLEN JOINTS

	A.1. No erosions and has NOT taken NSAIDs and/or corticosteroids during
	the last 3 months
	
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or chloroquine
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or chloroquine or sulphasalazine
	
	b.  HAQ greater than or equal to 1 	  	 
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or chloroquine or sulphasalazine
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or chloroquine or sulphasalazine
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or chloroquine or sulphasalazine
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or chloroquine or sulphasalazine
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or methotrexate or chloroquine
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or methotrexate

	A.2. No erosions and HAS taken NSAIDs and/or corticosteroids during the
	last 3 months
	
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Chloroquine
	   - RF 40-100 	  	
          	Chloroquine or methotrexate
	   - RF greater than 100 	  	
          	Chloroquine or methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate or sulphasalazine or chloroquine
	   - RF 40-100 	  	
          	Methotrexate or sulphasalazine
	   - RF greater than 100 	  	
          	Methotrexate or sulphasalazine
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Chloroquine or sulphasalazine or methotrexate
	   - RF 40-100 	  	
          	Methotrexate or sulphasalazine
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate or sulphasalazine
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	B. From 1 to 3 erosions
	
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	C. More than 3 erosions
	1.  Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate


	II. PATIENT WITH 6-10 SWOLLEN JOINTS

	A.1. No erosions and has NOT taken NSAIDs and/or corticosteroids during
	the last 3 months
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or methotrexate
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	A.2. No erosions and HAS taken NSAIDs and/or corticosteroids during the
	last 3 months
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate or injectable gold
	b. 	HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate or injectable gold
	   - RF greater than 100 	  	
          	Methotrexate or injectable gold
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	B. From 1 to 3 erosions
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	C. More than 3 erosions
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate


	III. PATIENT WITH greater than 10 SWOLLEN JOINTS

	A.1 No erosions and has NOT taken NSAIDs and/or corticosteroids during
	the last 3 months
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	   - RF 40-100 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  
          	Methotrexate
	   - RF greater than 100 	  
          	Methotrexate
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	   - RF 40-100 	  
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	   - RF greater than 100 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	NSAIDs and/or corticosteroids or methotrexate or injectable gold
	   - RF 40-100 	  	
          	Methotrexate or injectable gold
	   - RF greater than 100 	  	
          	Methotrexate or injectable gold

	A.2 No erosions and HAS taken NSAIDs and/or corticosteroids during the
	last 3 months
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate

	B. From 1 to 3 erosions
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate or injectable gold
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate or methotrexate + injectable gold
	   - RF greater than 100 	  	
          	Methotrexate or methotrexate + injectable gold
          	
	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate or leflunomide
	   - RF 40-100 	  	
          	Methotrexate or leflunomide
	   - RF greater than 100 	  	
          	Methotrexate or leflunomide
	b.  HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate or methotrexate + injectable gold
	   - RF greater than 100 	  	
          	Methotrexate or methotrexate + injectable gold

	C. More than 3 erosions
	1. Normal acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate
	   - RF greater than 100 	  	
          	Methotrexate or injectable gold or leflunomide
	b. HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate
	   - RF 40-100 	  	
          	Methotrexate or methotrexate + injectable gold
	   - RF greater than 100 	  	
          	Methotrexate or methotrexate + injectable gold

	2. Elevated acute phase reactants
	a.  HAQ less than 1
	   - RF less than 40 	  	
          	Methotrexate or methotrexate + sulphasalazine
	   - RF 40-100 	  	
          	Methotrexate or leflunomide
	   - RF greater than 100 	  	
          	Methotrexate or leflunomide
	b. HAQ greater than or equal to 1
	   - RF less than 40 	  	
          	Methotrexate or injectable gold
	   - RF 40-100 	  	
          	Methotrexate or methotrexate + injectable gold
	   - RF greater than 100 	  	
          	Methotrexate or methotrexate + injectable gold


	TABLES

	Table 1. 	
	Disease modifying antirheumatic drugs included in the systematic literature review
	
	Table 2. 	
	Jadad scale for rating the quality of evidence from clinical trials
	
	Table 3.
	Hadorn scale for rating the quality of scientific evidence from articles for CPGs
	
	Table 4.
	Outline of article selection process
	
	Table 5.
	Clinical trials and comparisons by the Jadad scale for rating the quality of the evidence
	
	Table 6.
	Clinical trials and comparisons by the Hadorn scale for rating the quality of the evidence
	
	Table 7.
	Comparisons of DMARDs used only in monotherapy
	
	Table 8.
	Comparisons of single or combined DMARDs vs. drug combinations
	
	Table 9a.
	Mean time of RA progression, previous DMARD use, duration of treatment in the trial, level
	of evidence, bibliographic reference, and ID number in the comparisons of DMARDs used in 
	monotherapy included in the synthesis of the evidence 
	
	Table 9b.
   	Mean time of RA progression, previous DMARD use, duration of treatment in the trial, level 
   	of evidence, bibliographic reference, and ID number in the comparisons of DMARDs used in 
   	monotherapy or combined therapy vs. drug combinations included in the synthesis of the 
   	evidence
   	
	Table 10.
	Evaluation of the quality of the meta-analyses of DMARDs
	
	Table 11.
	Conclusions of the Cochrane Library meta-analyses and their level of evidence
	
	Table 12.
	Predictive values (%) for RA diagnostic criteria in different settings
	
	Table 13.
	Summary of instruments for the measurement of parameters in RA evaluation
	
	Table 14.
	Initial treatment by simplified clinical classification of RA
	
	Table 15.
	Alternative treatment in case of severe toxicity to initial treatment
	
	Table 16.
	Alternative treatment in case of unsatisfactory response to initial treatment
	
	Table 17.
	Recommended doses and commercial names of DMARDs 
	
	Table 18.
	Usual dosage and frequency of administration of NSAIDs
	
	Table 19.
	Classification of the corticosteroids by duration of action
	
	Table 20.
	Use of DMARDs during pregnancy and breast-feeding 
	
	Table 21.
	EULAR definition of response 
	
	Table 22.
	CPA dosage producing toxicity 
	
	Table 23.
	Percentage of women treated with CPA who develop amenorrhea 
	
	Table 24.
	Adverse effects of DMARDs 
	
	Table 25.
	Definition and characteristics of anemia in RA 
	
	Table 26.
	RA-independent risk factors for osteoporosis 
	
	Table 27.
	RA-associated risk factors for osteoporosis 
	
	
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	2. References used in the studies included in the synthesis of the evidence


	2.1. Systematic reviews (SR)

	SR1.
	Suarez Almazor ME, Spooner CH, Belseck E, Shea B. Auranofin versus
	placebo in rheumatoid arthritis. Cochrane Database Syst Rev 2000; (2):
	CD002048.

	SR2.
	Suarez Almazor ME, Spooner C, Belseck E. Azathioprine for rheumatoid
	arthritis. Cochrane Database Syst Rev 2000; (2): CD001461.

	SR3.
	Suarez Almazor ME, Belseck E, Shea B, Wells G, Tugwell P.
	Cyclophosphamide for rheumatoid arthritis. Cochrane Database Syst Rev
	2000; (2): CD001157.
	
	SR4.
	Wells G, Haguenauer D, Shea B, Suarez Almazor ME, Welch VA, Tugwell
	P. Cyclosporin for rheumatoid arthritis. Cochrane Database Syst Rev
	2000; (2): CD001083.

	SR5.
	Suarez Almazor ME, Spooner C, Belseck E. Penicillamine for rheumatoid
	arthritis. Cochrane Database Syst Rev 2000; (2): CD001460.

	SR6.
	Suarez Almazor ME, Belseck E, Shea B, Homik J, Wells G, Tugwell P.
	Antimalarials for rheumatoid arthritis. Cochrane Database Syst Rev 2000;
	(2): CD000959.

	SR7.
	Suarez Almazor ME, Belseck E, Shea B, Wells G, Tugwell P.
	Methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2000;
	(2): CD000957.
	
	SR8.
	Clark P, Tugwell P, Bennet K, Bombardier C, Shea B, Wells G, Suarez
	Almazor ME. Injectable gold for rheumatoid arthritis. Cochrane Database
	Syst Rev 2000; (2): CD000520.

	SR9.
	Suarez Almazor ME, Belseck E, Shea B, Wells G, Tugwell P.
	Sulfasalazine for rheumatoid arthritis. Cochrane Database Syst Rev 2000;
	(2): CD000958.


	2.2. Articles on clinical trials referenced in the evidence tables
        (Tables 7, 8, and 9)

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	      22(7): 1235-40.
	   3. Dwosh IL, Stein HB, Urowitz MB, Smythe HA, Hunter T, Ogryzlo MA.
	      Azathioprine in early rheumatoid arthritis: comparison with gold
	      and chloroquine. Arthritis Rheum 1977; 20(2): 685-92.
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	      preliminary report. Arthritis Rheum 1987; 30(1): 88-92.
	   5. Landewé RBM, Goei-The HS, Rijthoven AWAM, Breedveld FC, Dijkmans
	      BAC. A randomized, double-blind, 24-week controlled study of
	      low-dose cyclosporin versus chloroquine for early rheumatoid
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	   6. Hochberg MC. Auranofin or D-penicillamine in the treatment of
	      rheumatoid arthritis. Ann Intern Med 1986; 105(4): 528-35.
	   7. Berry H, Liyanage SP, Durance RA, Barnes CG, Berger LA, Evans S.
	      Azathioprine and penicillamine in treatment of rheumatoid
	      arthritis: a controlled trial. BMJ 1976; 1(6017): 1052-4.
	   8. Paulus HE, Williams HJ, Ward JR, Reading JC, Egger MJ. Coleman ML,
	      et al. Azathioprine versus D-penicillamine in rheumatoid arthritis
	      patients who have been treated unsuccessfully with gold. Arthritis
	      Rheum 1984; 27(7): 721-7.
	   9. Halberg P, Bentzon MW, Crohn O, Gad I, Halskov O, Heyn J, et al.
	      Double-blind trial of levamisole, penicillamine and azathioprine
	      in rheumatoid arthritis: clinical, biochemical, radiological and
	      scintigraphic studies. Dan Med Bull 1984; 31(5): 403-9.
	  10. Gibson T, Emery P, Armstrong RD, Crisip AJ, Panayi GS. Combined
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	  11. Rijthoven AWAM, Dijkmans BAC, Goei Thé HS, Meijers KAE,
	      Montnor-Beckers ZLBM, Moolenburgh JD, et al. Comparison of
	      cyclosporin and D-penicillamine for rheumatoid arthritis: a
	      randomized, double blind, multicenter study. J Rheumatol 1991;
	      18(6): 815-20.
	  12. Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann
	      RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthritis:
	      a randomized, controlled trial. Ann Intern Med 1999; 130: 478-86.
	  13. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann
	      RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a
	      recombinant human tumor necrosis factor receptor (p75)-Fc fusion
	      protein. N Engl J Med 1997; 337(3): 41-7.
	  14. Bird HA, Le Gallez P, Dixon JS, Surrall KE, Cole DS, Goldman MH,
	      et al. A single-blind comparative study of auranofin and
	      hydroxychloroquine in patients with rheumatoid arthritis. Clin
	      Rheumatol 1984; 3(suppl. 1): 57-66.
	  15. Bunch TW, O'Duffy JD, Tompkins RB, O'Fallon WM. Controlled trial
	      of hydroxychloroquine and D-penicillamine singly and in
	      combination in the treatment of rheumatoid arthritis. Arthritis
	      Rheum 1984; 27(3): 267-76.
	  16. Scott DL, Greenwood A, Davies J, Maddison PJ, Maddison MC, Hall
	      ND. Radiological progression in rheumatoid arthritis: do
	      d-penicillamine and hydroxychloroquine have different effects? Br
	      J Rheumatol 1990; 29(2): 126-7.
	  17. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS,
	      et al. Ramdomized double-blind comparison of chimeric monoclonal
	      antibody to tumour necrosis factor alfa (cA2) versus placebo in
	      rheumatoid arthritis. Lancet 1994; 34: 1105-10.
	  18. Smolen JS. Efficacy and safety of leflunomide compared with
	      placebo and sulphasalazine in active rheumatoid arthritis: a
	      double-blind, randomized, multicentre trial: European Leflunomide
	      Study Group. Lancet 1999; 353(9149): 259-66.
	  19. Strand V, Cohen S, Schiff M, Weaver A, Fleischmann R, Cannon G, et
	      al. Treatment of active rheumatoid arthritis with leflunomide
	      compared with placebo and methotrexate. Arch Intern Med 1999;
	      159(21): 2542-50.
	  20. Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic
	      J, et al. Safety and effectiveness of leflunomide in the treatment
	      of patients with active rheumatoid arthritis: results of a
	      randomized, placebo-controlled, phase II study. Arthritis Rheum
	      1995; 38(11): 1595-1603.
	  21. Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon SD, et
	      al. Low-dose methotrexate compared with auranofin in adult
	      rheumatoid arthritis: a thirty-six-week, double-blind trial.
	      Arthritis Rheum 1990; 33(3): 330-8.
	  22. Williams HJ, Ward JR, Reading JC, Brooks RH, Clegg DO, Skosey JL,
	      et al. Comparison of auranofin, methotrexate, and the combination
	      of both in the treatment of rheumatoid arthritis: a controlled
	      clinical trial. Arthritis Rheum 1992; 35(3): 259-69.
	  23. Hamdy H, McKendry RJR, Mierins E, Liver JA. Low-dose methotrexate
	      compared with azathioprine in the treatment of rheumatoid
	      arthritis: a twenty-four-week controlled clinical trial. Arthritis
	      Rheum 1987; 30(4): 361-8.
	  24. Jeurissen MEC, Boerbooms AMT, Van de Putte LBA, Doesburg WH,
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	      the treatment of rheumatoid arthritis: a forty-eight-week
	      randomized, double-blind trial. Arthritis Rheum 1991; 34(8): 961-72.
	  25. Willkens RF, Sharp JT, Stablein D, Marks C, Wortmann R. Comparison
	      of azathioprine, methotrexate, and the combination of the two in
	      the treatment of rheumatoid arthritis: a forty-eight-week
	      controlled clinical trial with radiologic outcome assessment.
	      Arthritis Rheum 1995; 38(12): 1799-1806.
	  26. Arnold MH, O'Callaghan J, McCredie M, Beller EM, Kelly DE, Brooks
	      PM. Comparative controlled trial of low-dose weekly methotrexate
	      versus azathioprine in rheumatoid arthritis: 3-year prospective
	      study. Br J Rheumatol 1990; 29: 120-5.
	  27. Drosos AA, Voulgari PV, Papadopoulos IA, Politi EN, Georgiou PE,
	      Zikou AK. Cyclosporin A in the treatment of early rheumatoid
	      arthritis: a prospective, randomized 24-month study. Clin Exp
	      Rheumatol 1998; 16(6): 695-701.
	  28. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane
	      JD, et al. Therapeutic efficacy of multiple intravenous infusions
	      of anti-tumor necrosis actor alfa monoclonal antibody combined
	      with low-dose weekly methotrexate in rheumatoid arthritis.
	      Arthritis Rheum 1998; 41(9): 1552-63.
	  29. Emery P, Breedveld FC, Lemmel EM, Kaltwasser JP, Dawes PT, Gömör
	      B, et al. A comparison of the efficacy and safety of leflunomide
	      and methotrexate for the treatment of rheumatoid arthritis.
	      Rheumatology 2000; 39: 655-65.
	  30. Ward JR, Williams HJ, Egger MJ, Reading JC, Boyce E, Altz-Smith M,
	      et al. Comparison of auranofin, gold sodium thiomalate, and
	      placebo in the treatment of rheumatoid arthritis: a controlled
	      clinical trial. Arthritis Rheum 1983; 26(11): 1303-15.
	  31. Prete PE, Zane J, Krailo M, Bulanowski M. Randomized trial of
	      switching rheumatoid arthritis patients in remission with
	      injectable gold to auranofin. Clin Rheumatol 1994; 13(1): 60-9.
	  32. Smith PR, Brown GMM, Meyers OL. An open comparative study of
	      auranofin versus gold sodium thiomalate. J Rheumatol Suppl 1982;
	      8: 190-6.
	  33. Harth M, Davis P, Thompson JM, Menard H, Beaudet F. Comparison
	      between sodium aurothiomalate and auranofin in rheumatoid
	      arthritis: results of a two-year open randomized study. Scand J
	      Rheumatol 1987; 16(3): 177-84.
	  34. Hull RG, Morgan SH, Parke AL, Childs L, Goldman M, Hughes GRV. A
	      double-blind study comparing sodium aurothiomalate and auranofin
	      in patients with rheumatoid arthritis previously stabilized on
	      sodium aurothiomalate. Int J Clin Pharmacol Res 1984; 4(6): 395-401.
	  35. Rau R, Schattenkirchner M, Müller-Fass-Bender H, Kaik B, Zeidelr
	      H. A three year comparative multicenter study of auranofin (AF)
	      and gold sodium thiomalate (GST) in the treatment of rheumatoid
	      arthritis (RA). Clin Rheumatol 1987; 6(suppl. 2): 43-52.
	  36. Yamamoto S, Mitomo T, Saito T, Inoue K, Uchida S, Namiki O, et al.
	      Randomized comparative study in early rheumatoid arthritis with
	      gold sodium thiomalate versus auranofin. Jpn J Rheumatol 1992;
	      4(1): 33-53.
	  37. Van Riel PL, Van de Putte LBA, Gribnau FWJ, Macrae KD. Comparison
	      of auranofin and aurothioglucose in the treatment of rheumatoid
	      arthritis: a single blind study. Clin Rheumatol 1984; 3(suppl. 1):
	      51-6.
	  38. Lewis D, Capell HA. Oral gold: a comparison with placebo and with
	      intramuscular sodium aurothiomalate. Clin Rheumatol 1984; 3(suppl.
	      1): 83-96.
	  39. Rau R, Schattenkirchner M, Muller-Fassbender H, Kaik B, Zeidler H,
	      Missler B. A three year comparative study of auranofin and gold
	      sodium thiomalate in rheumatoid arthritis. Clin Rheumatol 1990;
	      9(4): 461-74.
	  40. Zeidler HK, Kvien TK, Hannonen P, Wollheim FA, Forre O, Geidel H,
	      et al. Progression of joint damage in early active severe
	      rheumatoid arthritis during 8 months of treatment: comparison of
	      low-dose cyclosporin and parenteral gold. Br J Rheumatol 1998; 37:
	      874-82.
	  41. Huskisson EC, Gibson TJ, Balme HW, Berry H, Burry HC, Grahame R,
	      et al. Trial comparing D-penicillamine and gold in rheumatoid
	      arthritis: preliminary report. Ann Rheum Dis 1974; 33(6): 532-5.
	  42. Mäkisara P, Nissilä M, Kajander A, Martio J, Essen R, Anttila P,
	      et al. Comparison of penicillamine and gold treatment in early
	      rheumatoid arthritis. Scand J Rheumatol 1978; 7(3): 166-70.
	  43. Thomas MH, Rothermich NO, Philips VK, Bergen W, Hedrick SW. Gold
	      versus D-penicillamine double-blind study and followup. J
	      Rheumatol 1984; 11(6): 764-7.
	  44. Suarez Almazor ME, Fitzgerald A, Grace M, Russell AS. A randomized
	      controlled trial of parenteral methotrexate compared with sodium
	      aurothiomalate (Myochrysine registered) in the treatment of
	      rheumatoid arthritis. J Rheumatol 1988; 15(5): 753-6.
	  45. Rau R, Herborn G, Karger T, Menninger H, Elhardt D, Schmitt J. A
	      double-blind comparison of parenteral methotrexate and parenteral
	      gold in the treatment of early erosive rheumatoid arthritis: an
	      interim report on 102 patients after 12 months. Semin Arthritis
	      Rheum 1991; 21(2 Suppl 1): 13-20.
	  46. Rau R, Herborn G, Karger T, Menninger H, Elhardt D, Schmitt J. A
	      double blind randomized parallel trial of intramuscular
	      methotrexate and gold sodium thiomalate in early erosive
	      rheumatoid arthritis. J Rheumatol 1991; 18(3): 328-33.
	  47. Menninger H, Herborn G, Sander O, Blechschmidt J, Rau R. A 36
	      month comparative trial of methotrexate and gold sodium thiomalate
	      in the treatment of early active and erosive rheumatoid arthritis.
	      Br J Rheumatol 1998; 37: 1060-8.
	  48. Morassut P, Goldstein R, Cyr M, Karsh J, McKendry RJ. Gold sodium
	      thiomalate compared to low dose methotrexate in the treatment of
	      rheumatoid arthritis: a randomized, double blind 26-week trial. J
	      Rheumatol 1989; 16(3): 302-6.
	  49. McEntegart A, Porter D, Capell HA, Thomson EA. Sulphasalazine has
	      a better efficacy/toxicity profile than auranofin: evidence from a
	      5 year prospective, randomized trial. J Rheumatol 1996; 23(11):
	      1887-90.
	  50. Capell HA, Maiden N, Madhok R, Hampson R, Thomson EA. Intention to
	      treat analysis of 200 patients with rheumatoid arthritis 12 years
	      after random allocation to either sulfasalazine or penicillamine.
	      J Rheumatol 1998; 25(10): 1880-6.
	  51. Carroll GJ, Will RK, Breidahl PD, Tinsley LM. Sulphasalazine
	      versus penicillamine in the treatment of rheumatoid arthritis.
	      Rheumatol Int 1989; 8(6): 251-5.
	  52. Nuver-Zwart IH, Van Riel PLCM, Van de Putte LBA, Grignau FWJ. A
	      double blind comparative study of sulphasalazine and
	      hydroxychloroquine in rheumatoid arthritis: evidence of an earlier
	      effect of sulphasalazine. Ann Rheum Dis 1989; 48(5): 389-95.
	  53. Faarvang KL, Egsmose Ch, Kryger P, Podenphant J, Ingeman-Nielsen
	      M, Hansen TM. Hydroxychloroquine and sulphasalazine alone and in
	      combination in rheumatoid arthritis: a randomized double blind
	      trial. Ann Rheum Dis 1993; 52(10): 711-5.
	  54. Haagsma CJ, Van Riel PLCM, De Jong AJL, Van de Putte LBA.
	      Combination of sulphasalazine and methotrexate versus the single
	      components in early rheumatoid arthritis: a randomized,
	      controlled, double-blind 52 week clinical trial. Br J Rheumatol
	      1997; 36: 1082-8.
	  55. Dougados M, Combe B, Cantagrel A, Goupille P, Olive P,
	      Schattenkirchner M, et al. Combination therapy in early rheumatoid
	      arthritis: a randomized, controlled, double-blind 52 week clinical
	      trial of sulphasalazine and methotrexate compared with the single
	      components. Ann Rheum Dis 1999; 58: 220-5.
	  56. Peltomaa R, Paimela L, Helve T, Leirisalo-Repo M. Comparison of
	      intramuscular gold and sulphasalazine in the treatment of early
	      rheumatoid arthritis: a one year prospective study. Scand J
	      Rheumatol 1995; 24(6): 330-5.
	  57. Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH,
	      Keystone EC, et al. A comparison of etanercept and methotrexate in
	      patients with early rheumatoid arthritis. N Engl J Med 1994;
	      343(22): 1586-93.
	  58. Trnavsky K, Gatterová J, Linduskova M, Pelisková Z. Combination
	      therapy with hydroxychloroquine and methotrexate in rheumatoid
	      arthritis. Z Rheumatol 1993; 52(5): 292-6.
	  59. Ferraz MB, Pinheiro GRC, Helfenstein M, Albuquerque E, Rezende C,
	      Roimicher L, et al. Combination therapy with methotrexate and
	      chloroquine in rheumatoid arthritis: a multicenter randomized
	      placebo-controlled trials. Scand J Rheumatol 1994; 23: 231-6.
	  60. Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, et al.
	      Combination therapy with cyclosporin and methotrexate in severe
	      rheumatoid arthritis. N Engl J Med 1995; 333(3): 137-41.
	  61. Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM,
	      Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis
	      factor receptor: Fc fusion protein, in patients with rheumatoid
	      arthritis receiving methotrexate. N Engl J Med 1999; 340(4): 253-9.
	  62. O'Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ,
	      et al. Treatment of rheumatoid arthritis with methotrexate alone,
	      sulfasalazine and hydroxychloroquine, or a combination of all
	      three medications. N Engl J Med 1996; 334(20): 1287-91.
	  63. Lipsky PE, Van der Heijde DMFM, St. Clair W, Furst DE, Breedveld
	      FC, Kalden JR. Infliximab and methotrexate in the treatment of
	      rheumatoid arthritis. N Engl J Med 1994; 343(22): 1594-1602.
	  64. Bendix G, Bjelle A. Adding low-dose cyclosporin A to parenteral
	      gold therapy in rheumatoid arthritis: a double-blind
	      placebo-controlled study. Br J Rheumatol 1996; 35: 1142-9.
	  65. Scott DL, Dawes PT, Tunn E, Fowler PD, Shadforth MF, Fisher J, et
	      al. Combination therapy with gold and hydroxychloroquine in
	      rheumatoid arthritis: a prospective, randomized,
	      placebo-controlled study. Br J Rheumatol 1989; 28(2): 128-33.
	  66. Porter DR, Capell HA, Hunter J. Combination therapy in rheumatoid
	      arthritis: no benefit of addition of hydroxychloroquine to
	      patients with a suboptimal response to intramuscular gold therapy.
	      J Rheumatol 1993; 20(4): 645-9.


	2.3. Articles that complement one of the articles on the clinical 
	trials (Tables 7, 8, and 9)

	Complement of 21
	
	C1.
	Weinblatt ME, Polisson R, Blotner SD, Sosman JL, Aliabadi P, Baker N,
	et al. The effects of drug therapy on radiographic progression of
	rheumatoid arthritis: results of a 36-week randomized trial comparing
	methotrexate and auranofin. Arthritis Rheum 1993; 36(5): 613-9.
	
	Complement of 22
	
	C2.
	Lopez-Mendez A, Daniel WW, Reading JC, Ward JR, Alarcon GS.
	Radiographic assessment of disease progression in rheumatoid arthritis
	patients enrolled in the cooperative systematic studies of the rheumatic
	diseases program randomized clinical trial of methotrexate, auranofin,
	or a combination of the two. Arthritis Rheum 1993; 36(10): 1364-9.

	Complement of 30

	C3.
	Ward JR, Williams HJ, Boyce E, Egger MJ, Reading JC, Samuelson CO.
	Comparison of auranofin, gold sodium thiomalate, and placebo in the
	treatment of rheumatoid arthritis: subsets of responses. Am J Med 1983;
	75(6A): 133-7.

	Complement of 33

	C4.
	Davis P, Menard H, Thompson J, Harth M, Beaudet F. One-year
	comparative study of gold sodium thiomalate and auranofin in the
	treatment of rheumatoid arthritis. J Rheumatol 1985; 12(1): 60-7.

	Complement of 37

	C5.
	Van Riel PLCM, Larsen A, Van de Putte LBA, Gribnau FWJ. Effects of
	aurothioglucose and auranofin on radiographic progression in rheumatoid
	arthritis. Clin Rheumatol 1986; 5(3): 359-64.

	Complement of 39

	C6.
	Schattenkirchner M, Kaik B, Muller-Fassbender H, Rau R, Zeidler H.
	Auranofin and sodium aurothiomalate in the treatment of rheumatoid
	arthritis: a double-blind, comparative multicenter study. J Rheumatol
	Suppl 1982; 8: 184-9.

	Complement of 47

	C7.
	Rau R, Herborn G, Menninger H, Sangha O. Progression in early erosive
	rheumatoid arthritis: 12 month results from a randomized controlled
	trial comparing methotrexate and gold sodium thiomalate. Br J Rheumatol
	1998; 37(11): 1220-6.

	C8.
	Rau R, Herborn G, Menninger H, Blechschmidt J. Comparison of
	intramuscular methotrexate and gold sodium thiomalate in the treatment
	of early erosive rheumatoid arthritis: 12 month data of a double-blind
	parallel study of 174 patients. Br J Rheumatol 1997; 36(3): 342-52.

	Complement of 49

	C9.
	Porter D, Madhok R, Hunter JA, Capell HA. Prospective trial comparing
	the use of sulphasalazine and auranofin as second line drugs in patients
	with rheumatoid arthritis. Ann Rheum Dis 1992; 51(4): 461-4.

	Complement of 50

	C10.
	Capell HA, Marabani M, Madhok R, Torley H, Hunter JA. Degree and
	extent of response to sulphasalazine or penicillamine therapy for
	rheumatoid arthritis: results from a routine clinical environment over a
	two-year period. Q J Med 1990; 75(276): 335-44.

	Complement of 52

	C.11.
	Heijde DM, Riel PL, Nuver-Zwart IH, Gribnau FW, Putte LB. Effects of
	hydroxychloroquine and sulphasalazine on progression of joint damage in
	rheumatoid arthritis. Lancet 1989; 1(8646): 1036-8.

	C12.
	Van der Heijde DM, Van Riel PLCM, Van de Putte LBA. Sensitivity of a
	Dutch Health Assessment Questionnaire in a trial comparing
	hydroxychloroquine vs sulphasalazine. Scand J Rheumatol 1990; 19(6):
	407-12.


	2.4. Articles that are redundant with one of the articles on clinical 
	trials (Tables 7, 8, and 9)

	Redundant with 1
	
	R1.
	Woodland J, Mason RM, Harris J, Dixon AS, Currey HL, Brownjohn AM, et
	al. Trial of azathioprine, cyclophosphamide, and gold in rheumatoid
	arthritis. Ann Rheum Dis 1974; 33(4): 399-401.
	
	Redundant with 7
	
	R2.
	Berry H, Liyanage S, Durance R, Barnes CG, Berger L. Trial comparing
	azathioprine and penicillamine in treatment of rheumatoid arthritis. Ann
	Rheum Dis 1976; 35(6): 542-3.
	Redundant with 19
	
	R3.
	Strand V, Tugwell P, Bombardier C, Maetzel A, Crawford B, Dorrier C,
	et al. Function and health-related quality of life: results from a
	randomized controlled trial of leflunomide versus methotrexate or
	placebo in patients with active rheumatoid arthritis. Arthritis Rheum
	1999; 42(9): 1870-8.
	
	Redundant with 24
	
	R4.
	Jeurissen MEC, Boerbooms AMT, Van de Putte LBA, Doesburg WH, Lemmens
	AM. Influence of methotrexate and azathioprine on radiologic progression
	in rheumatoid arthritis: a randomized, double-blind study. Arch Intern
	Med 1991; 114: 999-1004.
	
	R5.
	Kerstens PJSM, Boerbooms AMT, Jeurissen MEC, Westgeest TAA, Van Erp
	A, Mulder J, et al. Antiperinuclear factor and disease activity in
	rheumatoid arthritis: longitudinal evaluation during methotrexate and
	azathioprine therapy. J Rheumatol 1994; 21(12): 2190-4.
	
	Redundant with 25
	
	R6.
	Willkens RF, Stablein D. Combination treatment of rheumatoid
	arthritis using azathioprine and methotrexate: a 48-week controlled
	clinical trial. J Rheumatol 1996; 23(Suppl 44): 64-8.
	
	R7.
	Willkens RF, Urowitz MB, Stablein DM, McKendry RJR, Berger RG, Box
	JH, et al. Comparison of azathioprine, methotrexate, and the combination
	of both in the treatment of rheumatoid arthritis: a controlled clinical
	trial. Arthritis Rheum 1992; 35(8): 849-56.
	
	Redundant with 30
	
	R8.
	Williams HJ, Ward JR, Egger MJ, Reading JC, Samuelson CO, Altz-Smith
	M, et al. Auranofin, gold sodium thiomalate, and placebo in the
	treatment of rheumatoid arthritis: cooperative systematic studies of
	rheumatic diseases. Clin Rheumatol 1984; 3(suppl.1): 39-50.
	
	R9.
	Williams HJ, Ward JR. Comparison of oral and parenteral gold therapy
	and placebo in the treatment of rheumatoid arthritis. Scand J Rheumatol
	Suppl 1983; 51: 92-9.
	
	Redundant with 39
	
	R10.
	Schattenkirchner M, Bröll H, Kaik B, M¨ller-Fassbender H, Rau R,
	Zeidler H. Auranofin and gold sodium thiomalate in the treatment of
	rheumatoid arthritis: a one-year, double-blind, comparative multicenter
	study. Klin Wochenschr 1988; 66(4): 167-74.
	
	Redundant with 41
	
	R11.
	Huskisson EC, Gibson TJ, Wykeham Balme H, Berry H, Burry HC, Grahame
	R, et al. Penicillamine or gold for rheumatoid arthritis?: multicentre
	trial using 'blind' observers: the first six months. Ann Rheum Dis 1974;
	33(4): 399.
	
	Redundant with 52
	
	R12.
	Van der Heijde DMFM, Van Riel PLCM, Nuwer-Zwart IH, Van de Putte LBA.
	Alternative methods for analysis of radiographic damage in a randomized,
	double blind, parallel group clinical trial comparing hydroxychloroquine
	and sulfasalazine. J Rheumatol 2000; 27(2): 535-8.
	
	Redundant with 63
	
	R13.
	Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et
	al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal
	antibody) versus placebo in rheumatoid arthritis patients receiving
	concomitant methotrexate: a randomised phase III trial. ATTRACT Study
	Group. Lancet 1999; 354(9194): 1932-9.

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