Chapter IV: 
Rheumatology: 
Clinical Case Definitions/Diagnoses 
and Clinical Associations

Principal Author: 
Peter Tugwell, MBBS, MD, MSc, FRCP [Canada and United Kingdom]
Professor and Chairman, Department of Medicine
University of Ottawa
Ottawa, Ontario, Canada

Chapter IV: Rheumatology: Clinical Case Definitions/Diagnoses and Clinical Associations

I.	Introduction	IV-2
II.	Classic Accepted Connective Tissue Diseases	IV-3
		Clinical Case Definition	IV-4
		Strength of Association	IV-4
			Methodology	IV-4
			Study Results Reported for Accepted Diagnoses	IV-7
	
III.	Atypical Presentations of Connective Tissue Diseases: 
	Undifferentiated Connective Tissue Disease (UCTD)	IV-16
		Clinical Case Definition	IV-16
		Strength of Association	IV-17
			Methodology	IV-17
			Study Results Reported for Atypical Presentations (UCTD)	IV-17

IV.	Atypical Presentations of Connective Tissue Diseases; 
	Proposed Systemic Silicone Related Diseases (SSD)	IV-18
		Clinical Case Definition	IV-18

V.	Symptoms	IV-24
		Clinical Case Definition	IV-24
		Strength of Association	IV-25
			Methodology	IV-25
			Study Results Reported for Symptoms	IV-26

VI.	Concluding Comments	IV-41

References			IV-43
Table 1			IV-47
Appendix A		IV-A-75
Appendix B		IV-B-82

Rheumatology:  Clinical Case Definitions/Diagnoses and Clinical Associations

1.	Introduction

The charge from the court to the Panel is to assess whether existing studies, research and reported observations provide a reasonable scientific basis for one to conclude that silicone breast implants cause or exacerbate "classic" connective tissue diseases, atypical presentations, symptoms or immune system dysfunctions.
		The following Scope was specified in Order No 31E:  
•	Classic connective tissue disease such as systemic lupus erythematosus, Sjögren's syndrome
 etc.
•	Atypical presentations of connective tissue diseases.
•	Symptoms (a listing of symptoms and signs was appended)
•	Immune system dysfunctions (this category of immune system dysfunction is not addressed here since it is reviewed in detail in the Immunology Chapter).

		The categories specified in Order No 31E (classic connective tissue disease, atypical presentations, symptoms and signs), require case-definitions that can be used for clinical diagnosis. Clinical diagnosis is the crucial process that labels patients and classifies their diseases (Sackett, 1991).  The word "disease" is an ambiguous term but in this context it can usefully be conceptualized as an agreed upon case definition of a "target disorder" that is the objective of the diagnostic process. Target disorders consist of clusters of symptoms (manifestations of the target disorder that the subjects themselves perceive either spontaneously or on questioning), signs (manifestations perceived by their clinicians during an examination) and laboratory/radiological findings (results that reflect maladaptive alterations in structure or function). The above approach is consistent with that described by Dr. Robert Willkens in his September 10th 1996 submission to Judge Robert E. Jones (Willkens, 1996) in which he states:  "The scientific methodology of arriving at a hypothesis by observation, in the matter of symptoms in patients who have previously undergone silicone breast implantation would seem appropriate and incontestable. A clinician considers the history of the development of symptoms, performs a physical examination, obtains laboratory studies such a x-rays, electrocardiograms and additional studies in establishing a diagnosis. But in arriving at a specific diagnosis he must consider all those conditions which might

present with some or all of the findings and finally the diagnostician selects the diagnosis which best fits the findings on the basis of common knowledge. This process in called differential diagnosis. Cardinal elements of arriving at a correct diagnosis are objective determinations in any of the facets of the examination. (Degown and Degown, 1969). In arriving at a diagnosis the physician is encouraged to employ the principle called the Law of Parsimony that encourages the choice of a single disease to explain the patient's disease manifestations. This "law" must be applied cautiously since the experienced clinician recognizes the likelihood of multiple disorders contributing to the patient's symptoms. The clinician must then differentiate, if he can, the patient's symptoms as unique to a disease which he designates as being present."
	The Findings of Fact Documents, and the supporting material submitted by both legal parties provided an excellent review of the clinical studies themselves, their strengths and weaknesses. There is no dispute that there is sound documentation of the presence of a wide variety of connective tissue/autoimmune diseases and symptoms in women with silicone breast implants. However, this does not automatically lead to the conclusion that silicone breast implants are the cause of the clinical conditions. In such a large number of women with implants all of these conditions will occur independently in this population. To support the hypothesis that silicone breast implants are causing additional cases of connective tissue/autoimmune diseases, it is necessary to demonstrate an increased incidence of these conditions in women with silicone breast implants, compared to women without such implants. This is best assessed through estimating the strength of the association. Although the case series and case reports are critical to establishing a clinical case definition, assessing the strength of association requires studies with appropriate control groups using cohort, case-control, or cross-sectional designs (see also Epidemiology Chapter).
	The remainder of this chapter is structured to review each category (Classic/Accepted Diagnosis, Atypical Presentations of Connective Tissue Disease, Symptoms and Signs) first for the Clinical Case Definition/Diagnosis and then for a review of the Strength of Association.
	The categories of systemic disease specified in Order no 31E will now be reviewed.
II.  Classic/Accepted Connective Tissue Diseases, Such As Systemic Lupus Erythematosus, Sjögren's Syndrome Etc.

Clinical Case Definition/Diagnosis

We have interpreted the word 'classic' to include established connective tissue/autoimmune diseases that are described in the major textbooks and accepted by the majority of the rheumatology medical community. We have added the term autoimmune to include diseases such as Hashimoto's Thyroiditis, Multiple Sclerosis and Myasthenia Gravis which are included in the submissions submitted by legal counsel.
Established/Classic Connective Tissue/Autoimmune Diseases include:  Ankylosing Spondylitis; Arthritis Associated with Inflammatory Bowel Disease; Chronic Fatigue Syndrome; Dermatomyositis Polymyositis; Fibromyalgia; Hashimoto's Thyroiditis; Localized or Discoid Lupus; Mixed Connective Tissue Disease; Morphea Multiple Sclerosis; Myasthenia Gravis; Polyarteritis Nodosa; Polychondritis; Polyrnyalgia Rheumatica; Psoriatic Arthritis; Raynaud's Disease/Phenomenon; Rheumatoid Arthritis Sarcoidosis; Scleroderma; Sjögren's Syndrome; Systemic Lupus Erythematosus; Temporal Arteritis; Vasculitis; Wegener's Granulomatosis. 
	Explicit criteria have been established for a number of these (i.e. Dermatomyositis/Polymyositis; Fibromyalgia; Rheumatoid Arthritis; Scleroderma; Sjögren's Syndrome; Systemic Lupus Erythematosus) (The Arthritis Foundation, 1997). The standard textbooks describe in a reasonably consistent fashion, the case definition for each cluster, or constellation of the symptoms, signs and diagnostic test results.
Strength of Association
Methodology
The basic methodology for assessing the Strength of Association is described here for all three categories (Classic/Accepted, Atypical Presentations and Symptoms and Signs). 
1) Literature Search 
Three methods were used to identify potentially relevant studies:  1) screening of all legal submissions supplied by the Kobayashi legal firm; 2) a search of computerized bibliographical databases; and 3) a review of references cited in the retrieved articles. 
	For the computerized search, four search strategies designed to focus on different subsets of rheumatological/autoimmune disease, were run on five bibliographic databases. MEDLINE (1966-

September 1998), Current Contents (January 1997 - week 13 1998), HealthSTAR (1990 -December 1996), and Biological Abstracts (1990 - September 1996) were searched using OVID version 3.0. EMEBASE (1980- April 1997) was searched using Silver Platter's WinSPIRS version 2.0. The search strategies were initially developed for MEDLINE and then modified to search the indices of the other databases. In an attempt to retrieve any studies pertaining to atypical presentations, symptoms or neurological disorders that may have been missed, MEDLINE (1996-September 1998), Toxline (1965-Sept 1998) via Internet Grateful Med. and Dissertation Abstracts (1997-1998) from Dissertation Services at:  http:  //www.umii.com were searched with a fifth strategy to capture these less uniform terms. (See Appendix A for details).

2) Study Selection

The panel received over 3600 documents from the legal councils of the parties. One thousand six hundred articles were identified through the computerized searches. Some were duplicates.
	The titles of all legal submissions were screened independently by two reviewers. Each citation was categorized as:  potentially relevant, insufficient information to make a judgment, or ineligible. All citations classified, by one or both of the reviewers, as potentially relevant or as insufficient information to make a judgment were retrieved and classified as eligible or ineligible according to predetermined inclusion criteria. All ineligible citations were coded according to the reason for exclusion. Disagreements were resolved through discussion and consensus. A final list of included citations from the legal submissions was generated.
	The titles and abstracts of computerized database search printouts were screened independently by two reviewers, and categorized as eligible or ineligible according to the same predetermined criteria. Disagreements were resolved through discussion and consensus. A final list of included citations from the database search was generated.
	A priori selection criteria were:  
a)	human studies;
b)	total number of participants equal to or greater than ten;
c)	appropriate control group of either healthy or unexposed women, fulfilling the requirements of the study design (i.e. cohort, case-control, or cross-sectional studies);

d)	for multiple publications of the same data, only one publication using the same data was
	included in the review;
e)	no language restrictions were imposed;
f)	no restrictions were imposed on publication dates for the legal submissions and computerized database searches were limited to 1962-1998.

3)	Data Extraction

A standard form (see appendix B) was used to collect information from the selected manuscripts, regarding study design, population characteristics, exposure to implants (type, duration, complications, explantation, outcome measure (self-report and/or diagnostic criteria) and results. In particular, the types of breast implants included silicone gel-filled, saline-filled or polyurethanecoated. Information was extracted independently by two reviewers. Discrepancies in data extraction were discussed and resolved through consensus.

4)		Data Synthesis

The magnitude of the association between breast implants (exposure) and a connective tissue disease under consideration (outcome) is expressed as a relative risk (RR) or an odds ratio (OR). The RR is obtained directly from a cohort study and the OR from case-control and cross-sectional studies. If the estimates were corrected for the effects of confounding factors they are called adjusted estimates, otherwise unadjusted. In addition to the point estimate, the 95% confidence interval (CI) estimate are used, which defines a range within which the true value for the association between exposure and outcome is most likely to be found. If the study provided adjusted RRs or ORs, they were reported, otherwise unadjusted RRs and ORs were calculated and reported. These calculated risk estimates and confidence intervals should be interpreted with caution, since in many instances the number of cases reported are small and approximate methods need to be used.

	A RR or OR of 1.0 indicates no observed association between exposure and outcome; a number appreciably larger than 1.0 indicates a likely increase in risk associated with the exposure, whereas a number appreciably smaller than 1.0 indicates a likely risk reduction. As indicated in the Epidemiology

Chapter, the decision that a value is 'appreciably' larger than 1.0 is generally based on whether the lower boundary of the 95% confidence interval exceeds 1.0 for increased risks or the upper boundary is less than 1.0 for decreased risks.
	For meta-analysis of adjusted effects, approximate large-sample statistical methods were used. These methods are outlined in Appendix B, Section B.1 of the Epidemiology Chapter.

Study Results Reported For Accepted Diagnoses

Twenty studies using cohort, case-control or cross-sectional designs were identified, namely:  (Burns, 1996; Dugowson, 1992; Edworthy, 1998; Englert, 1996; Friis, 1997; Gabriel, 1994; Goldman, 1995; Hennekens, 1996; Hochberg, 1996; Lacy, 1997; Macdonald, 1996; Nyren, 1998a; Nyren, 1998b; Park, 1998; Sanchez-Guerrero, 1995; Strom, 1994; Teel 1997; Wells, 1994; Winther, 1998; Wolfe, 1995). Details regarding these studies may be found in Table 1.
	Although some individual studies show some degree of elevation of risk, as given by the relative risk or odds ratio, these are not substantial or consistent for any of these conditions. For the studies reported here, no risk estimate has a lower confidence interval greater than one.
	The details, analysis and results for the following diagnoses are given in the Epidemiology Chapter.

Dermatomyositis/Polymyositis-see Epidemiology Chapter for details

Friis 1997
Goldman 1995
Hennekens 1996
Nyren 1998a
Sanchez-Guerrero 1995
Teel 1997

Rheumatoid Arthritis-see Epidemiology Chapter for details

Dugowson 1992
Edworthy 1998
Friis 1997
Gabriel 1994
Goldman 1995
Hennekens 1996
Nyren 1998
Park 1998

Sanchez-Guerrero 1995
Wolfe 1995

Scleroderma-see Epidemiology Chapter for details

Burns 1996
Edworthy 1998
Englert 1996
Friis 1997
Gabriel 1994
Goldman 1995
Hennekens 1996
Hochberg 1996
Lacey 1997
Nyren 1998
Sanchez-Guerrero 1995
Wells 1994

Sjögren's Syndrome - see Epidemiology chapter three for details

Edworthy 1998
Friis 1997
Gabriel 1994
Goldman 1995
Hennekens 1996
Nyren 1998a
Sanchez-Guerrero 1995

Systemic Lupus Erythematosus - see Epidemiology Chapter for details

Edworthy 1998
Friis 1997
Goldman 1995
Hennekens 1996
Nyren 1998a
Sanchez-Guerrero 1995
Strom 1994
Wells 1994

	Diagnoses not discussed in the Epidemiology chapter are divided into and discussed in the following categories:  

1) Diagnoses for which there are no data reported;

2) Diagnoses for which there is no study reporting an estimate with a lower confidence limit of greater than one (or the limit could not be calculated with information provided); 
3) Diagnoses for which there are discordant results (i.e. at least one but not all studies report an estimate with a lower confidence limit of greater than one); and 
4) Diagnoses for which there are concordant results (i.e. all studies report an estimate with a lower confidence limit of greater than one).

1) Diagnoses for which there are no data reported

Morphea

2) Diagnoses for which there is no study reporting an estimate with a lower confidence limit of greater than one

Ankylosing Spondylitis

Friis 1997	Design:  Cohort
	Implant Type:  any
	Factors Controlled:  none
	Frequencies:  0 cases in 2570 exposed (0.0%); unexposed not reported
	Relative Risk:  na

Gabriel 1994	Design:  Cohort
	Implant Type:  any
	Factors Controlled:  Design - age, duration of medical care, index year
	Frequencies:  0 cases in 749 exposed (0.0%); 3 cases in 1498 unexposed (0.26%)
	Relative Risk (adjusted/calculated):  0.29 (0.01, 5.52)

Nyren 1998a	Design:  Cohort
	Implant Type:  any
	Factors Controlled:  none
	Frequencies:  1 case in 7442 exposed (0.01%); 0 cases in 3353 unexposed (0.0%)
	Relative Risk (unadjusted/calculated):  1.35 (0.06, 33.18)

Arthritis Associated with Inflammatory Bowel Disease

Gabriel 1994	Design:  Cohort
	Implant Type:  any
	Factors Controlled:  Design - age, duration of medical care, index year
	Frequencies:  1 case in 749 exposed (0. 13%); 0 cases in 498 unexposed (0.0%)
	Relative Risk (adjusted/calculated):  2.00 (0.08, 48.90)

Chronic Fatigue Syndrome

Macdonald		Design:  Case-Control
1996		Implant Type:  any
		Factors Controlled:  Design - neighbourhood, age
		Frequencies:  1 exposure in 35 cases (2.86%); 2 exposures in 35 controls (5.71%)
		Odds Ratio (adjusted/calculated):  0.49 (0.01,9.84)

Fibromyalgia

Nyren 1998a		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  Analysis - age, length of follow up
		Frequencies:  9 cases in 7442 exposed (0.12%); 5 cases in 3353 unexposed (0.15%)
		Relative Risk (adjusted/article):  1.0 (0.3, 3.0)

Wolfe 1995		Design:  Case-Control
		Implant Type:  silicone breast implants
		Factors Controlled:  Analysis - age
		Frequencies:  4 exposures in 533 cases (0.57%); 4 exposures in 1134 controls
		(0.35%)
		Relative Risk (adjusted/article):  2.11 (0.51, 8.77)

Hashimoto's Thyroiditis

Friis 1997		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 2570 exposed (0.0%); unexposed not reported
		Relative Risk:  na

Gabriel 1994		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  Design - age, duration of medical care, index year; Analysis 			-age, index year
		Frequencies:  10 cases in 749 exposed (1.34%); 21 cases in 1498 unexposed
		(1.40%)
		Relative Risk (adjusted/article):  1.00 (0.47, 2.13)

Localized or Discoid Lupus

Friis 1997		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 2570 exposed (0.0%); unexposed not reported
		Relative Risk:  na

Nyren 1998a		Design:  Cohort:  
		Implant Type:  any

		Factors Controlled:  none
		Frequencies:  I case in 7442 exposed (0.01%); 0 cases in 3353 unexposed (0.0%)
		Relative Risk (unadjusted/calculated):  1.35 (0.06, 33.18)

Mixed Connective Tissue Disease

Goldman		Design:  Cross-Sectional
1995		Implant Type:  any
		Factors Controlled:  Analysis-age at first visit, income
		Frequencies:  0 cases in 150 exposed (0.0%); 49 cases in 4097 unexposed (1.20%)
		Odds Ratio (unadjusted/article):  0.00 (0.00, 2.68)

Sanchez-		Design:  Cohort
Guerrero		Implant Type:  any
1995		Factors Controlled:  none
		Frequencies:  0 cases in 1183 exposed (0.0%); 0 cases in 86,318
		unexposed (0.0%)
		Relative Risk (unadjusted/calculated):  17.55 (0.35, 884.24)

Teel l997		Design:  Case-Control
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 exposed in 3 cases (0.0%); 40 unexposed in 3249 controls
		Odds Ratio (unadjusted/calculated):  11.32 (0.58, 222.74)

Multiple Sclerosis

Nyren 1998b		Design:  Cohort
		Implant type:  any
		Factors Controlled:  Analysis - age, follow-up
		Frequencies:  3 cases in 7429 exposed (0.04%); 4 cases in 3351
		unexposed (0. 12%)
		Relative Risk (adjusted/article):  0.5 (0.2, 0.9)

Winther 1998		Design:  Cohort
		Implant type:  unspecified
		Factors Controlled:  none
		Frequencies:  2 cases in 1135 exposed (0. 18%); 2 cases in 7071
		unexposed (0.03%)
		Relative Risk (unadjusted/calculated):  6.23 (0.88, 44.18)

Myasthenia Gravis

Winther 1998		Design:  Cohort
		Implant type:  unspecified
		Factors Controlled:  none
		Frequencies:  0 cases in 1135 exposed (0.0%); 1 case in 7071 unexposed (0.01%)

		Relative Risk (unadjusted/calculated):  2.08 (0.08, 50.91)

Polyarteritis Nodosa

Friis 1997		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 2570 exposed (0.0%); unexposed not reported
		Relative Risk:  na

Nyren 1998a		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 7442 exposed (0.0%); 0 cases in 3353 unexposed (0.0%)
		Relative Risk (unadjusted/calculated):  0.45 (0.01, 22.71)

Polychondritis

Gabriel 1994		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  Design - age, duration of medical care, index year
		Frequencies:  1 case in 749 exposed (0. 13%); 0 cases in 1498 unexposed (0.0%)
		Relative Risk (adjusted/calculated):  6.00 (0.24, 147.01)

Polymyalgia Rheumatica

Gabriel 1994		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  Design - age, duration of medical care, index year
		Frequencies:  2 cases in 749 exposed (0.27%); 1 case in 1498 unexposed (0.07%)
		Relative Risk (adjusted/calculated):  4.00 (0.36, 44.04)

Friis 1997		Design:  Cohort
		Implant Type:  any
(combined		Factors Controlled:  none
with Temporal		Frequencies:  3 cases in 2570 exposed (11.7%); 10 cases in 11023 unexposed
Arteritis)		(0.09%)
		Relative Risk (unadjusted/calculated):  1.29 (0.35, 4.67)

Psoriatic Arthritis

Friis 1997		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 2570 exposed (0.0%); unexposed not reported
		Relative Risk:  na

Gabriel 1994		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  Design - age, duration of medical care, index year
		Frequencies:  0 cases in 749 exposed (0.0%); 1 case in 1498 unexposed (0.07%)
		Relative Risk (adjusted/calculated):  0.67 (0.03, 16.33)

Nyren 1998a		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 7442 exposed (0.0%); 2 cases in 3353 unexposed (0.06%)
		Relative Risk (unadjusted/calculated):  0.09 (0.00, 1.88)

Raynaud's Disease/Phenomenon

Giltay 1994		Design:  Cohort
		Implant Type:  silicone gel-filled
		Factors Controlled:  Design - age, year of operation
		Frequencies:  12 cases in 325 exposed (3.69%); 7 cases in 210 unexposed (3.33%)
		Relative Risk (adjusted/calculated):  1. 11(0.44, 2.77)

Park 1994		Design:  Cohort
		Implant Type:  silicone gel-filled
		Factors Controlled:  Design - Augmentation - "similar aged"; Reconstruction -
		partially matched on age, stage of disease and time of operation
		Frequencies:  
			Augmentation:  1 case in 110 exposed (0. 91%); 3 cases in 128 unexposed (2.34%)
			Reconstruction:  7 cases in 207 exposed (3.38%);5 cases in 88 unexposed (5.68%)
		Relative Risk (adjusted/calculated):  
			Augmentation:  0.39 (0.04, 3.68);
			Reconstruction:  0.60 (0.19, 1.82)

Wells 1994		Design:  Cohort
		Implant Type:  silicone breast implants
		Factors Controlled:  none
		Frequencies:  1% cases in exposed group; 0% cases in unexposed group
		Relative Risk:  na

Sarcoidosis

Friis 1997		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 2570 exposed (0.0%); unexposed not reported
		Relative Risk:  na

Nyren 1998a 		Design:  Cohort

		Implant Type:  any 
		Factors Controlled:  none 
		Frequencies:  2 cases in 7442 exposed (0.03%); 2 cases in 3353 
		unexposed (0.06%) 
		Relative Risk (unadjusted/calculated):  0.45 (0.06,3.20)

Temporal Arteritis

Friis 1997		Design:  Cohort
(combined with		Implant Type:  any
Polymyalgia		Factors Controlled:  none
Rheumatica)		Frequencies:  3 cases in 2570 exposed (0. 12%); 10 cases in 11023
		unexposed (0.09%)
		Relative Risk (unadjusted/calculated):  1.29 (0.35, 4.67)

Nyren 1998a		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  1 case in 7442 exposed (0.01%); 0 cases in 3353 unexposed (0.0%)
		Relative Risk (unadjusted/calculated):  1.35 (0.06, 33.18)

Vasculitis

Gabriel 1994		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  Design - age, duration of medical care, index year
		Frequencies:  0 cases in 749 exposed (0. 0%); 2 cases in 1498 unexposed (0.13%)
		Relative Risk (adjusted/calculated):  0.40 (0.02, 8.32)

Wegener's Granulomatosis

Friis 1997		Design:  Cohort
		Implant Type:  any
		Factors Controlled:  none
		Frequencies:  0 cases in 2570 exposed (0.0%); 0 cases in 11023 unexposed (0.0%)
		Relative Risk (unadjusted/calculated):  4.29 (0.09, 216.04)

A meta-analysis was possible for four diagnoses, and the results, as given by the pooled relative risk and confidence interval, are as follows:  

	Relative Risk (95% Confidence Interval)
Multiple Sclerosis
(including unadjusted estimates)
Nyren 1998b	0.5 (0.2, 0.9)
Winther 1998	6.23 (0.88, 44.18)
Overall	0.69 (0.34, 1.40)
Raynaud's Disease/Phenomenon
Giltay 1994	1.11 (0.44, 2.77)
Park 1994 Augmentation	0.39 (0.04, 3.68)
Overall	0.96 (0.41, 2.25)
Fibromyalgia
Nyren 1998	1.0 (0.3,3.0)
Wolfe 1995	2.11 (0.51, 8.77)
Overall	1.34 (0.55, 3.29)

Polymyalgia Rheumatica
(including unadjusted estimates)
Gabriel 1994	4.00 (0.36, 44.04)
Fries 1997	1.29 (0.35, 4.67)
Overall	1.66 (0.53, 5.21)

3)  Diagnoses for which there are discordant results (i.e. at least one but not all studies report an
estimate with a lower confidence limit of greater than one)
None

4)  Diagnoses for which there are concordant results (i. e. all studies report an estimate with a lower confidence limit of greater than one)
None

This data does not provide any evidence for an association between silicone breast implants and
these Classic/Accepted connective tissue diseases.

III.  Atypical Presentations of Connective Tissue Diseases:  Undifferentiated Connective Tissue Disease (UCTD)

Two constellations of symptoms, signs and laboratory test abnormalities have been proposed that are not in the majority of textbooks, namely Undifferentiated Connective Tissue Disease and Systemic Silicone Related Disease.

Clinical Case Definition/Diagnosis

In order to be able to study such atypical presentations there needs to be an accepted case definition that has been shown to differ from other conditions in its constituent clinical presentation, impact upon prognosis, severity or response to therapy.

	Undifferentiated connective tissue disease provides a good example of how a case definition is established and the natural history assessed. The term has been used since the early 1980s (Leroy, 1980; Rich, 1984; Strongwater, 1989) to describe patients who do not meet the criteria for other accepted connective tissue diseases, but who have a constellation of the symptoms that are found in the accepted connective tissue diseases.

	An important study (Williams, 1998) has been conducted to standardize the case definition, and to follow a cohort of 410 patients with well defined and undifferentiated connective tissue diseases over 5 years to assess the natural history and outcome. The case definition was defined by a group of experienced rheumatologists under the auspices of the Coordinating Center of the Cooperative Systemic Studies of the Rheumatic Diseases, funded under the National Institute of Arthritis, Musculoskeletal and Skin Diseases. A protocol was developed at the Coordinating Center with the assistance and approval of participating clinics and under the direction and guidance of an external advisory committee. Early Undifferentiated Connective Tissue Disease was defined as patients with disease manifestations of less than one year in duration that met at least one of the following criteria:  1) Raynaud's phenomenon; 2) isolated keratoconjunctivitis SICCA; 3) unexplained polyarthritis (including possible and probable rheumatoid arthritis); or 4) at

least three other criteria that could not be attributed to other disease processes, which included myalgias, rash, pleuritis, pericarditis, central nervous system symptoms, pulmonary symptoms, peripheral neuropathy, elevated erythrocyte rate, and a false positive serologic test for syphilis.
	The above group of investigators followed 115 undifferentiated patients over five years. Thirty four patients were lost to follow-up. Of the remaining 81 patients, the five year actuarial survival was 94%, similar to patients with rheumatoid arthritis, systemic lupus erythematosus or dermatomyositis/polymyositis. Ten patients experienced complete remission, 34 patients persisted with undifferentiated disease, 18 patients went on to fulfill the diagnostic or classification criteria for a specific disease. The response to therapy of patients with UCTD is not well documented with the exception of one study by Wise (1996) in which patients with UCTD (defined as having two to three criteria for Systemic Lupus Erythematosus (SLE)), respond as well to methotrexate, as do those who meet the full criteria for SLE.
	The Panel is comfortable with including UCTD as a constellation given that it has a case definition, is distinct from the other established connective tissue diseases, has been studied longitudinally, and has substantive symptoms, which in many patients have been shown to be stable over time. In addition, the criteria do not require the presence of silicone gel. This allows studies to be conducted to assess its putative association with silicone gel (Liang, 1996).

Strength of Association
Methodology

The same methods were applied as for the Classic/Accepted diseases and the results are shown below.

Study Results Reported For Atypical Presentations:  UCTD

UCTD was included explicitly in one case control study (Liang, 1996) and although not analyzed separately would possibly apply to a number of the patients included in cross sectional or cohort studies. (Edworthy, 1998; Friis, 1997; Gabriel, 1994; Giltay, 1994; Hennekens, 1996; Nyren, 1998; Park, 1998; Wells, 1994)
	The study addressing this outcome had an estimate with lower confidence interval greater

than one indicating no appreciably increased risk.

Liang 1996	Design:  Case Control						
		Implant Type:  unspecified
		Factors Controlled:  Design - age, race, geographic location:  
		Analysis - year of birth
		Frequencies:  3 exposures in 205 cases (1.46%); 27 exposures in 2220 controls (1.21%)
		Odds Ratio (adjusted/article):  2.27 (0.67, 7.71)

	This study was only available as an abstract. The study found only 3 cases out of 205 women with implants. The confidence limits for the adjusted odds ratio are very wide with the lower bound of 0.67, well below the criteria level of 1.0 for defining an appreciable association. This is insufficient to substantiate an association with silicone breast implants.

IV.  Atypical Presentation of Connective Tissue Diseases:  Proposed Systemic Silicone Related Disease (SSRD)

Clinical Case Definitions

The second constellation of atypical presentation of connective tissue diseases for which a case definition has been proposed, that is not in the majority of textbooks, is that of the proposed Systemic Silicone Related Disease.
	The history of SSRD being proposed as a disease is well summarized in the Findings of Fact from the plaintiffs. In the early 1990s, rheumatologists were reporting an increasing number of case series of women with implants with a wide variety of rheumatological symptoms. It was noted that many of these women did not have classical connective tissue disease and it was suggested that perhaps they were experiencing an atypical disease (Bridges, 1993; Love, 1992).
	Weiner et al, (1992) reported on 50 patients with Silicone Breast Implants (SBIs) all of whom had arthralgias, and many of whom had myalgias, neuralgias, recurrent flu-like sensations and profound fatigue. Sixty percent reported dry eyes/mouth and Anti-nuclear Antibodies (ANAs) were positive in 70% of women. None met ACR criteria, and none responded to traditional therapy.
	Osborn (1992) described symptoms of breast pain and hardening, fatigue, weakness, muscle aches, widespread pain, and breast lumps in 50% of 100 women with Silicone Breast Implants. Less than 20% met American College of Rheumatology (ACR) criteria for classical Connective Tissue

Disease (CTD).  Subsequently, Osborn and colleagues (1993) reported a series of 126 women with rheumatological complaints, none of whom fulfilled ACR criteria for classical Connective Tissue Disease.
	Vasey (1994) reported the clinical findings of 50 Silicone Breast Implant patients between 1977 and 1991. The most common clinical findings included chronic fatigue, muscle pain, joint pain, joint swelling and lymphadenopathy. Twenty percent were judged to have classical connective tissue disease.
	By 1995, the reports of atypical connective tissue disease were growing and the literature contained an increasing number of case series. Freundlich (1994) reviewed 50 consecutive women with Silicone Breast Implant and found 50% had complaints of dry eyes and dry mouth. The same year, Borenstein described symptoms of fatigue, myalgias and arthralgias reported by a proportion of 100 patients, who on average reported the onset of clinical symptoms 5.6 years after mammaplasty. In 1995, Davis reported on 343 patients with arthralgias (71%), chronic fatigue (85%), dry eyes (69%) and numbness (69%). Mease and colleagues (1995) reported a series of 128 symptomatic women with Silicone Breast Implants. The average interval between implantation and onset of symptoms was 5.8 years. The authors concluded that their results suggested the presence of a syndrome marked by fatigue, polyarthralgias, myalgias, cognitive dysfunction, SICCA syndrome, rash, chest wall pain, sleep and mood disturbance and occasional serologic abnormalities. Baker reported on 145 patients with Silicone Breast Implant who reported symptoms of Sjögren's syndrome, alopecia, arthralgia and skin rashes which seemed to represent a clustering that is different from fibromyalgia or primary generalized osteoarthritis. Cuellar (1995) reported on 813 patients with Silicone Breast Implants, many with an ill-defined connective tissue diseases. Predominant complaints were malaise, fatigue, lymphadenopathy, arthralgia and myalgia.

	Solomon reported similar findings in 1994 on his first 176 patients. By 1996 he reported on a patient base of 639 symptomatic women. The mean implant duration was 12.4 years. Four hundred and fifty six of the women had a history of Baker Grade IV contracture and 216 had documented implant rupture. The most frequently reported symptoms were fatigue, cognitive dysfunction, arthralgias, and dry mouth. Three hundred and thirty two of the patients had their implants removed. Of these, 215 were followed for six months following explantation with clinical improvement seen in 36%. Solomon (1994) concluded that these women had a unique disease which tends to occur in women with long-standing implants who have antecedent pathology in the form of capsular contracture

and implant rupture.
	The Executive Committee of the Silicone Related Disorders Research Group (1996) have
proposed the following set of preliminary operational criteria for a syndrome/disease that they term Systemic Silicone Related Disease.

Inclusion Criteria:  

A.	Presence of a silicone gel filled breast implant either currently or in the past

B.	Presence of local disease:  Any of the following
1 .	Capsular contracture (Baker 11 or greater)
2.	Rupture documented by imaging technique (sonograrn or MRI), operative findings, or presence of siliconoma
3.	Persistent (more than 6 weeks) chest wall pain
4.	Persistent (more than 6 weeks) breast pain unrelated to menses
5.	Axillary adenopathy
6.	Entrapment neuropathy or thoracic outlet syndrome documented by physical exam (positive Adson's sign) or by electrodiagnostic studies
7.	Immune mediated skin rash (petechiae, telangiectasia, or poikiloderma not related to sun 
	exposure) on the chest wall
8.	Histopathologic finding in capsule of immune granuloma (foamy macrophages, plasma cells, or
	lymphoid infiltrates)

To be considered definite SSRD, both A and B must be present unless the implant is polyurethane coated in which case only A must be present.

Exclusion Criteria:  

A.	Presence of classic connective tissue disease
1 .	Rheumatoid Arthritis by ACR criteria
2.	Systemic Lupus Erythematosis by ACR criteria
3.	Primary Systemic Sclerosis (PSS) by ACR criteria or biopsy
4.	Mixed Connective Tissue Disease with positive anti-RNP antibody
5.	Dermatomyositis/Polymyositis by Bohan criteria
6.	Primary Sjögren's Syndrome by Fox Criteria

B.	Presence of local or metastatic malignancy excluding skin cancer or carcinoma in situ.

C.	Exposure to another environmental agent or drug know to produce systemic rheumatic disease

D.	Documented chronic and persistently active infection prior to implantation. Does not exclude

patients with positive serologies for past viral or bacterial infection who lack evidence of active infection at time of implantation.

Major Criteria:  

(Defined as those signs or symptoms present in 50% or more women in 2 or more published series). The symptom must be either objectively verifiable or sufficiently severe to interfere with activities of daily living, vocational activities, and/or recreational activities.

A.	Symmetrical myalgia with 4-11 tender points, including four or more tender points above the waist. Ascertainment of tender points includes appropriate negative control points.

B.	Chronic fatigue of six month duration or longer interfering with activities of daily living or occupational and/or recreational activities.

C.	Cognitive dysfunction of six month duration or longer which can either be objectively demonstrated on neuropsychiatric testing or which is of sufficient severity to interfere with activities of daily living and occupational and/or recreational activities.

D.	Objective SICCA complex defined by abnormal Schirmer testing, abnormal Rose Bongal
	staining, salivary scintography, sialogram or abnormal labial biopsy.

Minor Criteria:  

(Defined as those signs, symptoms or laboratory findings seen in 50% or more symptomatic women in two or more published series without objective confirmation or in 25-50% of symptomatic women with objective confirmation).

A.	Local disease (see above) after onset of systemic disease. (This criteria may only be applied to
	patients with polyurethane implants who did not satisfy inclusionary criteria B)

B.	Arthralgia (pain lasting for six months or longer in four or more upper extremity joints which do
	not have radiographic evidence of osteoarthritis).

C.	Enthesopathy in 2 or more sites in the upper extremities

D.	Subjective SICCA complex (2 of 3:  dry eye, dry mouth, dry vagina)

E.	Cerebello-vestibular dysfunction demonstrated on physical examination or by electrophysiologic
	testing.

F.	Non-scarring alopecia not attributable to pregnancy

G.	Raynaud's phenomenon with observed 2 or 3 color change

H.	Photosensitive skin rash

I.	Immune mediated skin rash (petechiae, telangiectasia, or livedo reticularis) involving both the trunk and extremities)

J.	Improvement of two Major or one Major and four Minor criteria within 18 months of 
	explantation

K.	Positive ANA at a titer of 1:  40 or greater on a Hep-2 cell line

L.	Elevated ESR (Westergren>25)

M.	Abnormal quantitative immunoglobulins (one or more isotypes)

Definite SSRD requires:  

1)	Presence of the inclusion criterion

2)	Absence of the exclusion criterion

3)	Presence of three major criteria, or presence of two major criteria and four minor criteria, or 	presence of one major and seven minor criteria.

	These criteria were derived from the clinical experience with 639 patients reported by Solomon and the patients that had been seen by other members of the Silicone Related Disorders Study Group, a non-profit clinical research organization. The requirement that there be a history of breast implant is of concern to the Panel, since the requirement of the inclusion of the putative cause of silicone exposure as one of the criteria, does not allow the criteria set to be tested objectively without knowledge of the presence of implants thus incurring 'incorporation bias' (Sackett, 1979).
	Another concern of the Panel is that there are few objective signs and that the constellation proposed is not unique. The majority of components of the proposed SSRD criteria are already part of other accepted diseases (e.g, scleroderma, Sjögren's, lupus, fibromyalgia, chronic fatigue syndrome) with the only differentiating feature being that SSRD requires the presence of a breast implant.
	A consensus statement was developed following a meeting of a consensus panel of nine practicing rheumatologists with extensive experience with patients having silicone exposure in October 1995. An abstract at the 1996 ACR describes the application of preliminary operational criteria to 100 cases with what is termed atypical connective tissue disease (ACTD), another 60 cases with implants and no systemic complaints, and 37 patients with a diagnosis of fibromyalgia without implants. The authors

state that "the selection of the cases of ACTD were obtained by random or consecutive selection from four university based urban practices." The exact criteria for the selection of these patients are not stated in this abstract. All charts were reviewed by two of the authors and a given patient was considered to have fulfilled these putative criteria for SSRD if the two reviewers found the documentation to meet these criteria. Sensitivity and specificity were calculated. An abstract from the 1996 ISEE Annual Conference provides similar information although some patients with classic connective disease are included. This latter abstract describes the approach but does not include any results. This study does not provide the needed information around patients presenting with none or a more of the exact symptoms proposed to assess whether these are more frequent in those with implants. The patients with implants but no symptoms are by definition not going to contribute to this, and the patients with fibrositis will have been selected out on the basis of their own constellation of signs and symptoms.
	The authors have called for a large multicenter disease classification study, but this has not been completed to our knowledge. Such a study will require an evaluation of a representative sample of women with implants (that are not self selected from those with complaints) compared with a matched population group to examine the frequency of the presence of the proposed criteria.
	The Panel has carefully considered the above information, as well as presentations at the hearings by Drs. Solomon and Silverman, complemented by Plaintiff Exhibit 434 by Solomon (1996) that presents evidence in support of there being a unique atypical connective tissue disease in women with silicone breast implants.
	The Panel has concluded that they do not yet support SSRD being included in the list of accepted diseases for the following reasons:  

1.  That the requirement of the inclusion of the putative cause (silicone exposure) as one of the criteria does not allow the criteria set to be tested objectively without knowledge of the presence of implants thus incurring incorporation bias.

2. There are few objective signs, and the constellation proposed is not unique. That is a majority of
components of the proposed SSRD criteria are already part of other accepted diseases (e.g.
scleroderma, Sjögren's, lupus, fibromyalgia, chronic fatigue syndrome) with the only differentiating
feature being that SSRD requires the presence of a breast implant.

3.  There is no proven association of the criteria set, with the putative cause - exposure to silicone gel and/or silica, through well controlled studies. If a cohort design is used, this requires study of a representative sample of women with implants that are not self selected from those with complaints compared with a matched population group to examine the frequency of such symptoms. Although this conclusion is subject to revision if the appropriate well designed studies are conducted. The Panel, on balance, concludes that at present the scientific basis is insufficient to accept this as a established disease or syndrome.

V.	Symptoms

Clinical Case Definition

The mandate from Judge Pointer in Order 31E states:  Listed in the appendix to this order are various diseases, symptoms, conditions or complaints that have sometimes been asserted as possibly associated with silicone gel implants. To the extent you believe appropriate - and without being asked to address separately each of these diseases, symptoms, conditions, and complaints- you are encouraged to comment on the scientific basis, if any, for any such claimed linkage. The Appendix to Order 31E from Judge Pointer lists the following symptoms and signs reported in women exposed to Silicone Breast Implants, but in whom the accepted criteria for any of the above conditions are not met:  
Allergies; Alopecia; Arthralgias; Breathing difficulties/shortness of breath/pulmonary symptoms; Bruising easily; Burning in chest/heartburn/esophageal symptoms; Chronic fatigue/low energy; Chronic inflammation; Cognitive dysfunctions/memory problems; Concentration difficulties; Constipation; Coughing; Diarrhea; Decrease in sex drive; Fever/low grade; Flu-like feelings; Headaches; Heart palpitations; Hot flashes; Incontinence; Infections Lymphadenopathy; Malaise/general; Mood swings/irritability/anxiety/panic attacks; Mucosal ulcers; Muscle cramps; Muscle weakness; Myalgias ; Nausea/vomiting; Neurologic deficits; Night sweats; Pain (abdominal, back, chest, intestinal, joint, muscle); Paraesthesia/numbness and tingling; Sensitivity to heat/cold; SICCA symptoms (dry eyes/mouth/skin/vagina); Skin changes/rashes/hives; Sleep disorders; Sore throat; Stiffness; Swallowing difficulties/dysphagia; Swelling/fluid retention/bloating; Tenderness/tender points; TMJ problems;

Urination/frequency/burning/incontinence; Vertigo/dizziness/ringing in ears/vestibular dysfunction; Vision problems/blurred vision/light sensitivity; Weight loss; Weight gain.
	The more than 50 case reports and clinical series describing these in the Findings of Fact of the Plaintiffs were reviewed. The precision of the Case Definition of the symptoms and signs varied across the studies, with few providing reproducible definitions or evidence of validation by medical records and/or rheumatologist's evaluation

Prognosis
	The prognosis influences the clinical importance of symptoms and signs in patients not fulfilling criteria for a Classic/Accepted Disease. For this review the author's categorization was accepted. It is known that in most cases single symptoms or signs are not predictive of accepted connective diseases -for example polyarthralgias have numerous causes and rarely and in the majority no diagnosis is ever made (Williams, 1998; Mukeji, 1993). In patients presenting with monoarthritis of three months duration that do not have the associated features to meet the criteria for an accepted connective tissue diseases, the majority fail to attain a definitive diagnosis in the ensuing two years (Blocka, 1987). In patients with Raynaud's Phenomenon two studies have reported that only 3-19% go on to attain diagnoses of defined connective tissue diseases (Harper, 1982; Fitzgerald, 1988; Williams, 1998).
	The same is true of individuals with positive anti-nuclear antibodies. As described in the chapter on immunology, Aho et al showed that in healthy women less than one in 100 with a positive Antinuclear Antibodies will develop systemic lupus erythematosus. Schoenfeld et al, found that over five years only 12% of women with a high level of Anti-nuclear Antibodies developed symptoms and none had developed an established connective tissue disease. Thus the evidence to date suggests that the majority of these symptoms and signs resolve spontaneously, and the abnormal laboratory tests do not lead to symptomatic disease in the majority of patients.

Strength of Association

Methodology

The same methods were applied as for the Classic/Accepted diseases and the results are listed below. 
The symptoms and signs in the eligible controlled studies were categorized according to the Appendix

to Order 31E. Some categories included a number of different symptoms or signs. It should be appreciated that many studies do present the results as a frequency of symptoms rather than by individual women, so that women with multiple symptoms will be represented in several analyses

Study Results Reported for Symptoms
Nine cohort studies reporting endpoints, which could be classified according to the appendix of order
31E were found. (Edworthy, 1998; Friis, 1997; Gabriel, 1994; Giltay, 1994; Kim, 1998; Nyren,
1998b; Park, 1998; Wells, 1994; Winther, 1998)

	Symptoms are divided into the following categories:  
1)	Symptoms for which there are no data reported
2)	Symptoms for which there is no study reporting an estimate with a lower confidence limit
	of greater than one (or the limit could not be calculated with information provided).
3)	Symptoms for which there are discordant results (i.e. at least one but not all studies report
	an estimate with a lower confidence limit of greater than one).
4)	Symptoms for which there are concordant results (i.e. all studies report an estimate with a
	lower confidence limit of greater than one).

1)  Symptoms for which there are no data reported

Allergies
Bruising Easily
Burning In Chest/Heartburn/Esophageal Symptoms
Chronic Inflammation
Cognitive Dysfunction/Memory Problems
Coughing
Decrease in Sex Drive
Diarrhea
"Flu-Like " Feelings
Heart Palpitations
Hot Flashes
Incontinence
Infections
Malaise (General)
Muscle Cramps
Nausea/Vomiting
Night Sweats

Pain (Abdominal, Back, Chest, Intestinal, Joint, Muscle)-see arthralgias, myalgias
Sensitivity To Heat/Cold
Sleep Disorders
Sore Throat
Tenderness/Tender Points-see myalgias
TMJ problems
Urination - Frequency/Burning/Incontinence
Vision Problems - Blurred Vision/Light Sensitivity

2)  Symptoms for which there is no study reporting a point estimate with a lower confidence limit of greater than one.

Alopecia

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  hair loss arms and legs
			Frequencies:  0% cases in exposed group; 1% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 0.32 (0.01,8.30)

Breathing Difficulties/Shortness of Breath/Pulmonary Symptoms

Giltay 1994		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - age, year of operation

			Endpoint:  pleuritis
			Frequencies:  4 cases in 235 exposed (1.7%); 5 cases in 210 unexposed (2.38%)
			Relative Risk (adjusted/calculated):  0.71 (0.19, 2.63)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  breathing difficult
			Frequencies:  2% cases in exposed group; 7% cases in unexposed group
			Odds Ratio(adjusted/article):  (Relative Risk not reported) 0.22 (0.067, 0.731)

Chronic Fatigue/Low Energy

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Endpoint:  fatigue

			Factors Controlled:  Design - Augmentation - "similar aged"; Reconstruction -
			partially matched on age, stage of disease and time of operation 
			Frequencies:  
				Augmentation - 13 cases in 110 exposed (11. 82%); 
				8 cases in 128 unexposed (6.25%) 
				Reconstruction -28 cases in 207 exposed (13.53%); 
				15 cases in 88 unexposed (17.05%) 
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.89 (0.81, 4.39) 
				Reconstruction - 0.79 (0.45, 1.41)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  easily tire
			Frequencies:  15% cases in exposed group; 11% cases in unexposed group
			Odds Ratio(adjusted/article):  (Relative Risk not reported) 1.379 (0.547,3.310)

Concentration Difficulties

Edworthy		Study Type:  Cohort
1998			Implant Type:  silicone gel-filled
			Factors controlled:  none

			Endpoint:  thought problems
			Frequencies:  32% cases in exposed group; 17% cases in unexposed group
			Relative Risk (adjusted/calculated):  1.88 (confidence interval not available)
Constipation

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - Augmentation - "similar aged", Reconstruction -
			partially matched on age, stage of disease and time of operation

			Endpoint:  constipation
			Frequencies:  
				Augmentation - 4 cases in 110 exposed (3.62%);
				2 cases in 128 unexposed (1.56%)
				Reconstruction - 8 cases in 207 exposed (3.82%);
				4 cases in 88 unexposed (4.55%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 2.33 (0.43, 12.46)
				Reconstruction - 0.85 (0.26, 2.75)

Fever (Low Grade)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  persistent fever
			Frequencies:  1% cases in exposed group; 0% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.099 (0.164, 7.381)

Headaches

Edworthy		Study Type:  Cohort
1998			Implant Type:  silicone gel-filled
			Endpoint:  headache
			Factors controlled:  none
			Frequencies:  18% cases in exposed group; 8% cases in unexposed group
			Relative Risk (unadjusted/calculated):  2.25 (confidence interval not available)

Mood Swings/Irritability/Anxiety/Panic Attacks

	Park 1998	Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - Augmentation - "similar aged"; Reconstruction -
			partially matched on age, stage of disease and time of operation

			Endpoint:  psychiatric
			Frequencies:  
				Augmentation - 2 cases in 110 exposed (1.82%);
				0 cases in 128 unexposed(0.0%)
				Reconstruction - 3 cases in 207 exposed (1.45%);
				1 cases in 88 unexposed (1.14%)
			Relative Risk (adjusted/calculated):  
			Augmentation - 5.81 (0.28, 119.76)
			Reconstruction - 1.28 (0.13, 12.09)

Mucosal Ulcers

Gabriel 1994		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - age, duration of medical care, index year; Analysis -
			age, index year

			Endpoint:  oral ulcers 
			Frequencies:  25 cases in 749 exposed (3.34%); 39 cases in 1498 (2.60%) 					unexposed 
			Relative Risk (adjusted/article):  0.69 (0.29, 1.63)

Giltay 1994		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - age, year of operation; Analysis - none

			Endpoint:  mouth ulcers for at least three weeks
			Frequencies:  4 cases in 235 (1.70%) exposed; 2 cases in 210 (0.95%) unexposed
			Relative risk (adjusted/calculated):  1.79 (0.33, 9.66)

Muscle Weakness

Gabriel 1994		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - age, duration of medical care, index year

			Endpoint:  symmetric muscle weakness
			Frequencies:  1 case in 749 exposed (0. 13%); 5 cases in 1498 unexposed (0.33%)
			Relative Risk (adjusted/article):  0.43 (0.04, 2.67)

Neurologic Deficits

Nyren 1998b		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - none; Analysis - age, follow-up time for all endpoints
			except neuritis of the optic nerve, Guillian-Barre syndrome for which no factors
			were adjusted and amyotropic lateral sclerosis

			Endpoint:  diseases on nerve roots and plexuses 
			Frequencies:  3 cases in 7425 exposed (0.04%); 1 case in 3351 unexposed (0.03%) 			Relative Risk (adjusted/article):  1.5 (0.6,3.9)

			Endpoint:  mononeuritis of the upper limb
			Frequencies:  8 cases in 7425 (0.11%) exposed; 8 cases in 3351 unexposed (0.24%)
			Relative Risk (adjusted/article):  0.5 (0.2,1.03)

			Endpoint:  mononeuritis of the lower limb
			Frequencies:  7 cases in 7425 exposed (0.09%); 3 cases in 3351 unexposed (0.09%)
			Relative Risk (adjusted/article):  1.3 (0.6,2.5)

			Endpoint:  Guillian-Barre Syndrome
			Frequencies:  1 case in 7425 exposed (0.01%); 0 cases in 3351 unexposed (0.0%)
			Relative Risk (unadjusted/calculated):  1.35 (0.06, 33.23)

			Endpoint:  neuritis of the optic nerve
			Frequencies:  0 cases in 7425 exposed (0.0%); 0 cases in 3351 unexposed (0.0%)
			Relative Risk (unadjusted/calculated):  0.45 (0.01, 22.74)

			Endpoint:  amyotropic lateral sclerosis
			Frequencies:  0 cases in 7425 exposed (0.0%); 0 cases in 3351 unexposed (0.0%)
			Relative Risk (unadjusted/calculated):  0.45 (0.01, 22.74)

Winther 1998		Study Type:  Cohort
			Implant Type:  unspecified
			Factors Controlled:  none

			Endpoint:  motor neuropathy
			Frequencies:  0 cases in 1135 exposed (0.0%); 1 case in 7071 unexposed (0.01%)
			Relative Risk (unadjusted/calculated):  2.08 (0.08, 50.91)

			Endpoint:  peripheral neuropathies
			Frequencies:  9 cases in 1135 exposed (0.79%); 53 cases in 7071 unexposed
			(0.75%)
			Relative Risk (unadjusted/calculated):  1.06 (0.52, 2.14)

			Endpoint:  optical retino- and neuropathy
			Frequencies:  0 cases in 1135 exposed (0.0%); 1 case in 7071 unexposed (0.01%)
			Relative Risk (unadjusted/calculated):  2.08 (0.08, 50.91)

Paraesthesia/Numbness and Tingling

Edworthy		Study Type:  Cohort
1998			Implant Type:  silicone gel-filled
			Factors controlled:  none

			Endpoint:  numbness in extremities
			Frequencies:  26% cases in exposed group; 15% cases in unexposed group
			Relative Risk (unadjusted/calculated):  1.73 (confidence interval not available)

Swallowing Difficulties/Dysphagia

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design --Augmentation - "similar aged"; Reconstruction
			partially matched on age, stage of disease and time of operation

			Endpoint:  dysphagia
			Frequencies:  
				Augmentation - 2 cases in 110 exposed (1.82%);
				0 cases in 128 unexposed (0.0%)
				Reconstruction - 1 case in 207 exposed (0.48%);
				0 cases in 88 unexposed (0.0%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 5.81 (0.28, 119.76)
				Reconstruction - 1.28 (0.05, 31.21)

Swelling/Fluid Retention/Bloating

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design --Augmentation - "similar aged"; Reconstruction
			partially matched on age, stage of disease and time of operation

			Endpoint:  edema
			Frequencies:  
				Augmentation - 6 cases in 110 exposed (5.54%);
				2 cases in 128 unexposed (1.56%)
				Reconstruction - 32 cases in 207 exposed (15.46%),
				20 cases in 88 unexposed (22.73%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 3.49 (0.72, 16.95)
				Reconstruction - 0.68 (0.41, 1.12)

Vertigo/Dizziness/Ringing in Ears/Vestibular Dysfunction

Kim 1998		Study Type:  Case-Control
			Implant Type:  silicone breast implants
			Factors Controlled:  Design-age

			Endpoint:  progressive sensorineural hearing loss or Meniere's disease
			Frequencies:  5 exposures in 119 cases ( 4.20%); 3 exposures in 100 controls
			(3.0%)
			Odds Ratio (adjusted/calculated):  1.45 (0.27, 9.54)

Nyren 1998b		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Analysis-age, follow-up time

			Endpoint:  Meniere's disease
			Frequencies:  3 cases in 7425 exposed (0.04%); 1 case in 3351 unexposed (0.03%)
			Relative Risk (adjusted/article):  0.8 (0.4, 1.4)

Winther 1998		Study Type:  Cohort
			Implant Type:  unspecified
			Factors Controlled:  none

			Endpoint:  Meniere's disease
			Frequencies:  1 case in 1135 exposed (0.09%); 3 cases in 7071 unexposed (0.04%)
			Relative Risk (unadjusted/calculated):  2.08 (0.22, 19.95)

Weight gain

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  weight gain > 10 lbs
			Frequencies:  10% cases in exposed group; 3% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.307 (0.370, 4.619)

Weight loss

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  weight loss > 10 lbs
			Frequencies:  2% cases in exposed group; 4% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 0.419 (0.105, 1.676)

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design --Augmentation - "similar aged"; Reconstruction -
			partially matched on age, stage of disease and time of operation

			Endpoint:  weight loss
			Frequencies:  
				Augmentation - 0 cases in 110 exposed (0.0%);
				0 cases in 128 unexposed (0.0%)
				Reconstruction - 4 cases in 207 exposed (1.93%);
				2 cases in 88 unexposed (2.27%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.16 90.02, 58.09)
				Reconstruction - 0.85 (0.16, 4.56)

3)  Symptoms for which there are discordant results (i.e. at least one but not all studies report an estimate with a lower confidence limit of greater than one).

Arthralgias

Six studies reported arthralgias; some with increases in odds ratios, but only in Giltay 1994 did one of the analyses (of painful joints for at least three months) have a lower confidence limit exceeding 1 (1.37). The frequency of 8.5% in the unexposed group and of 19.57% in the exposed group are much higher than in other studies suggesting a different population.

Edworthy		Study Type:  Cohort
1998			Implant Type:  silicone gel-filled
			Factors controlled:  none

			Endpoint:  hand pain
			Frequencies:  26% cases in exposed group; 18% cases in unexposed group
			Relative Risk (unadjusted/calculated):  1.44 (confidence interval not available)

Friis 1997		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  none

			Endpoint:  arthritis not further specified
			Frequencies:  2 cases in 2570 (0.08%) exposed; 8 cases in 11023 unexposed (0.07%)
			Relative risk (unadjusted/calculated):  1.07 (0.23, 5.05)

			Endpoint:  rheumatism not further specified
			Frequencies:  1 case in 2570 exposed (0.04%); 1 case in 11023 unexposed (0.01%)
			Relative Risk (unadjusted/calculated):  4.29 (0.27,68.55)

Gabriel 1994		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - age, duration of medical care, index year;
			Analysis - age, index year

			Endpoint:  any arthritis (includes swelling of wrist, swelling of three or more joints,
			symmetric joint swelling or any other documented arthritis or synovitis)
			Frequencies:  25 cases in 749 exposed (3.34%); 39 cases in 1498 unexposed (2.60%)
			Relative Risk (adjusted/article):  1.38 (0.84, 2.28)

Giltay 1994		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - age, year of operation; Analysis - none

			Endpoint:  painful joints for at least three months
			Frequencies:  46 cases in 235 exposed (19.57%); 18 cases in 210 unexposed
			(8.57%)
			Relative risk (adjusted/calculated):  2.28 (1.37, 3.81)

			Endpoint:  Swelling of joints for at least one week
			Frequencies:  14 in 235 (5.96%) exposed; 10 in 210 unexposed (4.76%)
			Relative Risk (adjusted/calculated):  1.25 (0.57,2.76)

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design-Augmentation - "similar aged"; Reconstruction -
			partially matched on age, stage of disease and time of operation

			Endpoint:  joint pain
			Frequencies:  
				Augmentation - 11 cases in 110 exposed (10.00%);
				12 cases in 128 unexposed (9,38%)
				Reconstruction - 31 cases in 207 exposed (14.98%);
				13 cases in 88 unexposed (14.77%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.07 (0.49, 2.32)
				Reconstruction - 1.01 (0.56, 1.84)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implant
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  arthritis
			Frequencies:  0% cases in exposed group; 1% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.159 (0.149, 9.040)

			Endpoint:  painful joints
			Frequencies:  11% cases in exposed group; 5% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.929 (0.521, 7.142)

			Endpoint:  swollen joints
			Frequencies:  5% cases in exposed group; 3% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.477 (0.263, 8.291)

Lymphadenopathy/Swollen and Tender Glands

Park did not find an association; Wells found a small increase in the frequency of swollen or tender glands under the arms with a lower confidence limit of 1. 129 and 1.752 respectively. If this is a true increase, it is still not possible to know if these signs and symptoms occurred shortly after surgery or whether they were related to the primary indication for the implant.

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - Augmentation - "similar aged"; Reconstruction -
			partially matched on age, stage of disease and time of operation

			Endpoint:  lymphadenopathy
			Frequencies:  
				Augmentation - 1 case in 110 exposed (0.91%); 0 cases in 128
				unexposed (0.0%)
				Reconstruction - 0 cases in 207 exposed (0.0%); 1 case in 88
				unexposed (1.14%)

			Relative Risk (adjusted/calculated):  
				Augmentation - 3.49 (0.14, 84.73)
				Reconstruction - 0.14 (0.01, 3.47)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  swollen glands neck
			Frequencies:  10% cases in exposed group; 5% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.982 (0.570, 6.894)

			Endpoint:  tender glands neck
			Frequencies:  10% cases in exposed group; 7% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.433 (0.472, 4.354)

			Endpoint:  swollen glands under arm
			Frequencies:  8% cases in exposed group; 1% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 7.082 (1.129,44.439)

			Endpoint:  tender glands under arm
			Frequencies:  14% cases in exposed group; 3% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 6.898 (1.752, 27.154)

Myalgias

Friis 1997 is the only one of the three studies that has a raised odds ratios with a lower confidence limit that exceeds 1. Edworthy has a raised summary relative risk but the information was not available to allow a calculation of the confidence limits. This sample includes a variety of conditions including "muscular rheumatism, fibrositis and myalgia" so that these patients appear heterogeneous.

Edworthy		Study Type:  Cohort
1998			Implant Type:  silicone gel-filled
			Factors controlled:  none

			Endpoint:  muscle pain
			Frequencies:  25% cases in exposed group; 16% cases in unexposed group
			Relative Risk (adjusted/calculated):  1.56 (confidence interval not available)

Friis 1997		Design:  Cohort
			Implant Type:  any
			Factors Controlled:  none
			Endpoint:  muscular rheumatism, fibrositis, myalgia

			Frequencies:  63 cases in 2570 exposed (2.45%); 169 cases in 11023 
			unexposed (1.53%) 
			Relative Risk (adjusted/calculated):  1.60 (1.20, 2.13)

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - Augmentation - "similar aged"; Reconstruction
			partially matched on age, stage of disease and time of operation

			Endpoint:  muscle pain
			Frequencies:  
				Augmentation - 7 cases in 110 exposed (6.36%);
				7 cases in 128 unexposed (5.47%)
				Reconstruction - 17 cases in 207 exposed (8.21%);
				3 cases in 88 unexposed (3.41%)
			Relative Risk (unadjusted/calculated):  
				Augmentation - 1.16 (0.42, 3.2 1)
				Reconstruction - 2.41 (0.72, 8.01)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  muscle pain
			Frequencies:  15% cases in exposed group; 9% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.396 (0.541, 3.600)

SICCA Symptoms (Dry Eyes/Mouth/Skin/Vagina)

Giltay 1994 found an increase frequency of 8.5% versus 1.9% in 52 cases with a relative risk of 2.20 and a lower confidence limit of 1.25 in the symptom of "regularly burning eyes"; Gabriel also found a slightly increased frequency of 3.3% versus 2.6% in five cases giving a relative risk of 1.42, but the confidence limits straddle 1(0. 92, 2.2 1); however, these were for the symptoms of dryness of the eyes and mouth with no mention of the symptom of burning.

Gabriel 1994		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - age, duration of medical care, index year;
			Analysis -(SICCA only) age, index year

			Endpoint:  salivary gland enlargement
			Frequencies:  2 cases in 749 exposed (0.27%); 3 cases in 1498 unexposed (0.20%)
			Relative Risk (adjusted/article):  1.42 (0.22, 7.98)

			Endpoint:  SICCA 
			Frequencies:  25 cases in 749 exposed (3.34%); 39 cases in 1498 unexposed (2.60%) 			Relative Risk (adjusted/article):  1.42 (0.92, 2.21)

Giltay 1994		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - age, year of operation

			Endpoint:  regularly burning eyes
			Frequencies:  37 cases in 235 exposed (8.51); 15 cases in 210 unexposed (1.90)
			Relative risk (adjusted/article):  2.20 (1.25, 3.90)

Skin Changes/Rashes/Hives

Photosensitivity:  Giltay 1994 reported an increased frequency of 'skin abnormalities worsened by sun exposure of 8.5% versus 1.9% relative risk of 4.47 (1.55, 12.86). Gabriel, found a frequency of 0.4% in exposed and unexposed.  Park found a raised frequency in augmentation cases but a lower frequency in the reconstruction patients; this lack of consistency may be due to the small numbers of implants in this study leading to imprecise estimates.

Gabriel 1994		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - age, duration of medical care, index year;
			Analysis - age, index year only for endpoint photosensitivity

			Endpoint:  malar or discoid rash
			Frequencies:  1 case in 749 exposed (4.41%); 5 cases in 1498 unexposed (3.34%)
			Relative Risk (adjusted/article):  0.43 (0.04, 2.67)

			Endpoint:  photosensitivity
			Frequencies:  3 cases in 749 exposed (0.40%); 6 cases in 1498 unexposed (0.40%)
			Relative Risk (adjusted/article):  1.12 (0.28, 4.50)

Giltay 1994		Study Type:  Cohort
			Implant Type:  silicone gel-filled
			Factors Controlled:  Design - age, year of operation

			Endpoint:  skin abnormalities worsened by sun exposure
			Frequencies:  20 cases in 235 exposed (8.51%):  4 cases in 210 unexposed (1.90%)
			Relative risk (adjusted/calculated):  4.47 (1.55, 12.86)

Park 1998		Study Type:  Cohort
			Implant Type:  silicone gel-filled

			Factors Controlled:  Design - Augmentation - "similar aged"; Reconstruction -
			partially matched on age, stage of disease and time of operation

			Endpoint:  photosensitivity
			Frequencies:  
				Augmentation - 5 cases in 110 exposed (4.55%);
				3 cases in 128 unexposed (2.34%)
				Reconstruction - 7 cases in 207 exposed (3.38%);
				5 cases in 88 unexposed (5.68%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.94 (0.47, 7.93)
				Reconstruction - 0.60 (0.19, 1.82)

			Endpoint:  telangiectasia
			Frequencies:  
				Augmentation - 3 cases in 110 exposed (2.72%);
				2 cases in 128 unexposed (1.56%)
				Reconstruction - 2 cases in 207 exposed (0.97%);
				1 case in 88 unexposed (1. 14%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.77 (0.24, 15.41)
				Reconstruction - 0.85 (0.06, 23.96)

			Endpoint:  rash
			Frequencies:  
				Augmentation - 3 cases in 110 exposed (2.73%);
				3 cases in 128 unexposed (2.34%)
				Reconstruction - 8 cases in 207 exposed (3.68%);
				8 cases in 88 unexposed (9.09%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.16 (0.24, 5.65)
				Reconstruction - 0.43 (0.16, 1.10)

			Endpoint:  sclerodactyly
			Frequencies:  
				Augmentation - 0 cases in 110 exposed;
				12 cases in 128 unexposed
				Reconstruction - 1 case in 207 exposed;
				0 cases in 88 unexposed
			Relative Risk (adjusted/calculated):  
				Augmentation - 0.05 (0.00, 0.78)
				Reconstruction - 1.28 (0.05, 31.21)

			Endpoint:  abnormal pigment
			Frequencies:  
				Augmentation - 2 cases in 110 exposed (1.82%);
				2 cases in 128 unexposed (1.56%)

				Reconstruction - 3 cases in 207 exposed (1.45%);
				1 case in 88 unexposed (1.14%)
			Relative Risk (adjusted/calculated):  
				Augmentation - 1.16 (0.17, 8.12)
				Reconstruction - 1.28 (0.13, 12.09)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  rashes
			Frequencies:  4% cases in exposed group; 4% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 1.067 (0.273, 4.168)

			Endpoint:  skin thickening
			Frequencies:  2% cases in exposed group; 7% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 0.206 (0.043, 0.992)

			Endpoint:  skin tightness
			Frequencies:  12% cases in exposed group; 19% cases in unexposed group
			Odds Ratio (adjusted/article):  (Relative Risk not reported) 0.582 (0.264, 1.284)

Stiffness

Gabriel 1994 found an increased frequency of 4% versus 2.3% with a relative risk of 1.80 and a lower confidence limit of 1.0. The significance and importance of this is unclear. Wells 1994 did not find an association.

Gabriel 1994		Study Type:  Cohort
			Implant Type:  any
			Factors Controlled:  Design - age, duration of medical care, index year; Analysis -
			age, index year

			Endpoint:  morning stiffness 
			Frequencies:  30 cases in 749 exposed (4.01%); 35 cases in 1498 
			unexposed (2.34%) 
			Relative Risk (adjusted/article):  1.80 (1.10, 2.93)

Wells 1994		Study Type:  Cohort
			Implant Type:  silicone breast implants
			Factors Controlled:  Analysis - age, year of operation

			Endpoint:  general stiffness
			Frequencies:  10% cases in exposed group; 10% cases in unexposed group

			Odds Ratio (adjusted/article):  (Relative Risk not reported) 0.930 (0.382, 2.265)

Symptoms for which there are consistent results

None

Few studies have adequate numbers of patients, and although some individual studies show some degree of elevation of relative odds or relative risks, these are not substantial in a consistent fashion in any of these conditions.

VI.	Concluding Comments

	In this chapter the clinical case definitions have been reviewed for the three clinical categories of Classic/Accepted Diagnosis., Atypical Presentations of Connective Tissue Diseases, and Symptoms and Signs listed in the Appendix to the Court Order 31E. The prognosis of many of the Classic/Accepted diseases is poor with most patients being subjected to sustained morbidity with symptoms, reduction in ability to carry out their activities of daily living and reduced psychosocial well-being.
	In none of the Classic/Accepted diagnosis was there any 'appreciable' association (as defined in the Epidemiology Chapter) with silicone breast implants demonstrated.
	The atypical syndrome of Undifferentiated Connective Tissue Disease (UCTD) as defined by the criteria of Williams, also has sustained morbidity in a proportion of patients. In the one study of this, there were few implants and no appreciable association was found.
	Patients with one or more symptoms and signs but who do not meet the criteria for a specified Classic/Accepted connective tissue disease or the criteria for UCTD as defined by Williams, have a better prognosis and do not usually progress to a defined disease. There are few symptoms and signs for which a single study found an appreciable association, but in all cases there were other studies of the same symptom or sign that did not confirm this association. Additional caution in accepting any association in these studies is needed compared to the studies of the Classic/Accepted diagnosis and UCTD, since different symptoms are included in some of the categories, the numbers of cases are small, a single woman with more than one symptom will be represented in the analysis of each symptom that the woman has experienced.

	Other atypical syndromes have been suggested, some of which include the presence of a silicone breast implant and none of which (with the exception of UCTD as stated above) have stringent, objective diagnostic criteria. Including the exposure (i.e. breast implants), in the disease definition precluded the rigorous scientific evaluation of this proposed entity, since there is no possibility of comparing women with and without the syndrome to estimate each group's frequency of implants. Furthermore, many of the signs and symptoms including the rheumatologic and psychological complaints are so common in the general population and as presenting complaints in physician's offices, that a possible increased frequency of these complaints among those with implants would be difficult to discern.

	The literature submitted by the court was reviewed for information on the effect of silicone breast implants on the clinical course and immunologic parameters in women with diagnosed connective tissue disease. No substantive data was found that allowed a rigorous assessment of any differences in the clinical course from those with the conditions but without implants; thus no conclusion can be reached due to the uncertainty arising from a lack of research addressing this question.

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Williams HJ, Alarcon GS, Neuner R, et al:  Early Undifferentiated Connective Tissue Disease. V. An Inception Cohort 5 Years Later:  Disease Remissions and Changes in Diagnoses in Well Established and Undifferentiated Connective Tissue Diseases. J Rheumatol 1998;25:  261-268.

Winther JF, Bach FW, Friis S, et al:  Neurologic disease among women with breast implants [see comments]. Neurology 1998;50:  951-955.

Wise CM, Vuyyuru S, Roberts WN:  Methotrexate in nonrenal lupus and undifferentiated connective tissue disease-a review of 36 patients. Journal of Rheumatology. 1996;23:  1005-1010.

Wolfe P:  Silicone breast implants and the risk of fibromyalgia and rheumatoid arthritis. Arthritis and Rheumatism 1995;38:  S265.

Table 1:  Description of Included Studies

Study	Methods	Participants	Interventions	Outcomes

Burns	Case Control Study	Country:  Michigan USA	Implant Type	Diagnosis
(1996)		Cases:  N = 274	Unspecified:  N = 1(control)	Systemic sclerosis (1980 ACR
	Study Dates	Controls:  N= 1184	Silicone gel filled:  N = 14 (2	criteria or subject exhibited signs
	Cases of scleroderma diagnosed		cases, 12 controls)	and symptoms characteristic of
	between 1985-1991.	Mean age at interview:  cases 54.3 years,	Saline:  N = 1 (control)	SSc:  sclerodactyly or thick tight
	Data collection August 1992 - May	controls 52.6 years.	Polyurethane coated:  N = 2	skin, and at least one other
	1993.	Income >$ 15,000:  cases 74.8 0/., controls	(controls)	manifestation of CREST.
		81.5% (p<.05)	Separate analysis for Silicone gel	Excluded linear or localized SSc -
	Group Selection	High school education:  cases 85%, controls	filled implants:  yes	morphea)
	Case Definition:  Women diagnosed	84.3%
	with systemic sclerosis in Michigan	Race - non black:  cases 83.9%, controls	Exposure
	between 1985-1991 were recruited	88.1%	Rupture described:  yes (1 case
	from hospitals, rheumatologists and	Reconstruction due to breast cancer:  cases	had ruptured;no ruptures reported
	United Scleroderma Foundation.	50%, controls 50%	among controls although 6
	Control Definition:  Females,	Separate analysis for breast cancer subjects:  	experienced encapsulation,
	identified through random digit	no	hardness, scar tissue or
	dialing, were frequency matched to	Years since implantation:  cases (n=2) 1 and	unspecified problems)
	cases on age (5 yr. Intervals), race	12 years., controls (n=14) median 8.8 years	Explantation described:  no
	and geographic region.	Cases with breast implants:  0.7%	Duration described:  yes
		Controls with breast implants:  1.2%	Excluded injections:  no (they
	Group Determination		were enumerated as "injections to
	Cases:  medical records were	Response Rate	a body part" and reported
	reviewed by a rheumatologist to	Cases:  Investigators estimate that 80 - 87%	separately)
	determine eligibility	of incident cases in Michigan from 1985-91
	Controls:  self report (telephone	were identified. 75-80% of these responded
	interview)	to mailing, 93% of whom agreed to
		participate.
	Ascertainment of Exposure	Controls:  80%
	Cases:  self report (telephone
	interview)
	Controls:  same
	To determine the accuracy of self
	reporting of breast implants a
	validation study was carried out on
	a separate population. (94%
	accurate with respect to presence or
	absence of implant)

	Blinding
	Subjects were unaware of the 
	research hypothesis and in the case
	 of the validation study, investigators 
	were blind to implant status.

Study	Methods	Participants	Interventions	Outcomes

Dugowson	Case Control Study	Country:  Seattle, Washington USA	Implant Type	Diagnosis
(1992)		Cases:  N = 300	Unspecified	Rheumatoid Arthritis (criteria not
	Study Dates	Controls:  N = 1456		reported)
	Not reported		Exposure
		Cases with breast implants:  0.3%	Rupture described:  no
	Group Selection	Controls with breast implants 0.8%	Explantation described:  no
	Case Definition:  Women with new		Duration described:  no
	onset of rheumatoid arthritis	Response Rate	Excluded injections:  not reported
	Control Definition :  Similarly aged 	Cases:  86%,
	women were recruited co-	Controls:  Number of subjects in original
	operatively with a breast cancer	pool from which controls were drawn is not
	study	reported

	Group Determination
	not reported

	Ascertainment of exposure 
	Cases:  self report (questionnaire) 
	-history of implants prior to reference 
	date (first physician visit for
	 rheumatoid arthritis) 
	Controls:  self report (questionnaire)
	 - history of implants prior to a 
	reference date chosen randomly 
	from cases

	Blinding 
	not reported

Study	Methods	Participants	Interventions	Outcomes

Edworthy
(1998)

Retrospective Cohort Study

Study Dates
1978-1986 - Subjects were 
identified who underwent cosmetic 
surgery during this period ,
 No dates reported for recruitment 
and examination of these women. 
1982-1993 - data base searched for
 hospitalization rates and service 
use during this time period.

Group Selection 
Exposed :  Women, identified 
through the Alberta Health 
Registry, who had obtained breast 
implants, other than for 
reconstructive purposes, between 
1978 and 1986. 
Unexposed :  Women, from the
 same source, who had undergone
 non silicone related cosmetic
 surgery.

Group Determination 
Exposed :  Alberta Health Registry 
procedural codes, medical records 
(for verification of implant type), 
self report (questionnaire) 
Unexposed :  Alberta Health 
Registry procedural codes, self 
report

Ascertainment of Outcome 
Exposed :  Direct measurement 
(physical exam for those with a 
history or symptoms of disease), 
lab values, self report 
(questionnaire and for those 
attending physical exam, a detailed 
history) 
Unexposed :  same

Blinding
Rheumatologist's Physical 
assessment

Country:  Alberta, Canada
Exposed:  N = 1,576
Unexposed:  N = 727

Median Age at Assessment:  Exposed
(Silicone gel filled) 42 years, Unexposed
46 years
Median Years of Education:  Exposed 12,
Unexposed 13
Married:  Exposed 80. 1,% Unexposed
73.7%
Mean Duration of Exposure:  13.5 years
Reconstruction Due to Breast Cancer:  0%

Response Rate 
Of the 9200 implantations and 7400 other 
cosmetic surgeries identified, 60% had a 
current address. Of those contacted 3152 
implanted women 34% of those identified) 
and 2670 controls (36% of those 
identified) responded. Of those who 
responded, 41% of implanted subjects and 
69% of controls declined. An 
additional 9% of implanted subjects and
 4% of controls were ineligible.

Implant Type 
Unspecified (N=86) 
Silicone gel filled (N= 1, 112) 
Saline (N=352) 
Meme (N=26) 
Only Silicone get filled implants 
appear to have been included in 
the analyses.

Exposure
Rupture Described:  no
Explantation Described:  no
Duration Described:  yes
Excluded Injections yes

Diagnosis 
Rheumatoid Arthritis (ACR tree 
criteria)
 Systemic Lupus Erythematosus 
(ARA 4 of 11 criteria) 
Scleroderma (ACR criteria,
 CREST or variants of) 
Sjögren's Syndrome (clinical signs 
of dry eyes, dry mouth, history of 
parotitis), 
Atypical Connective Tissue 
Disease (cases which did not 
conform to expected patterns of 
presentation and had a greater 
than 50% certainty of having any 
CTD)

Lab Values 
ANAs (indirect 
immunofluorescence using HEp-2 
cells, considered positive if > 1:  40 
dilution)

Symptoms
Thought problems
Numbness in extremities
Muscle pain
Headache
Hand pain

Study	Methods	Participants	Interventions	Outcomes

Englert
 (1996)

Case Control Study (Update of
Englert 1994)

Study Dates
Study initiated 1989. Scleroderma
diagnosis must have been made
prior to Dec 31,1988 (study time
frame 1974-1988) Controls must
have attended General practitioner
since Jan 1990.

Group Selection
Case Definition:  Patients with SSc
who resided in Sydney for at least 6
consecutive months within study
time frame. Excluded were patients
with mixed CTD morphea or other
localized form of SSc. Cases were
recruited from hospitals, death
certificates, physicians, Scleroderma
Association of NSW and medical
laboratories performing ANA tests.
If patient migrated to Sydney, the
major reason must not have been for
scleroderma management, and the
diagnoses must have been made
prior to emigration
Control Definition:  Sydney residents
(for at least 6 consecutive months)
were recruited from 28 randomly
selected general practices and were
age and sex stratified (5 years) with
a living case.
Those with scleroderma CREST or
a psychiatric history were excluded.

Group Determination
Cases:  medical records
Controls:  medical records

Ascertainment of Exposure
Cases:  medical records (GP and for
those with implants surgeon's
records) for deceased and medical
records plus self report (interview)
for living subjects
Controls:  medical records plus self
report (interview)

Country:  Sydney, Australia
Cases:  N = 532
Controls:  N = 253

Explantation:  cases 50%, controls 20% Dates of implantation:  cases 1978-1983, controls 1973-1990 Cases with breast implants:  0.9% Controls with breast implants:  1.2 -1.6%

Response Rate not reported

Implant Type
Unspecified 10%
Silicone gel filled 80%
(analysed separately)
Saline:  10%

Exposure
Rupture described:  no
Explantation described:  yes
Duration described:  yes
Excluded injections:  not reported

Diagnosis 
Systemic Sclerosis (ACR criteria or patient had sclerodyctaly plus 2 of the following:  Raynaud's phenomenon, oesophageal dysmotolity, calcinosis, telangiectasia(e), bilateral basal pulmonary fibrosis or elevated ANA)

Blinding 
Both physicians and patients were blind to each others responses regarding mammaplasty status

Study	Methods	Participants	Interventions	Outcomes

Friis
(1997)

Retrospective Cohort Study

Study Dates
Identification of subjects 1977
1992
Follow up to Dec3l/93

Group Selection
Expose :  Women from Danish
Central Hospital Register who had
received implants between 1977
and 1992 for cosmetic or
reconstructive purposes.
Unexposed :  Women from the same
source who had undergone breast
reduction surgery or correction for
mammoptosis or women who had
been diagnosed with breast cancer
but had not received an implant.
Breast cancer controls were
matched to the reconstruction
patients in:  age, disease (localized,
regional, metastatic), and calendar
time (5 years)
Group Determination
Exposed :  medical records
(information on breast surgery
confirmed by authors)
Unexposed :  same as exposed

Ascertainment of Outcome
Exposed:  medical records
(diagnosis of definite CTD
validated by rheumatologists)
Unexposed :  same as exposed

Blinding
Not reported

Country:  Denmark 
Exposed:  cosmetic N = 1,335,
 reconstruction N = 1,435 
Unexposed:  breast reduction N = 7,07 1, mamoptosis N = 472 (not analysed), breast cancer N= 3,952

Median Age at Entry:  Exposed:  cosmetic 31 years, reconstruction 45 years; Unexposed:  reduction 31 years, mamoptosis 28 years, breast cancer 47years Median Length of Follow up:  Exposed:  cosmetic 8.4 years; reconstruction 7.2 years Unexposed:  reduction 7.6 years, mammoptosis 6.2 years, breast cancer 5.3 years Reconstruction due to breast cancer:  52% (analysed separately)

Response Rate All eligible women from the register were entered into the study. They were followed until the time of death, emigration or Dee 31 1993, whichever came first.

Implant
Unspecified:  16% Silicone get filled:  84% (no separate analysis) Note:  Percentages are based on an earlier sampling study

Exposure 
Rupture described:  no 
Explantation described:  no 
Duration described:  no 
Excluded Injections:  not reported

Diagnosis
 (All cases represented rheumatic 
disease requiring hospitalization 
and were classified according to 
ICD 8) 
Rheumatoid Arthritis (ICD 712.09 -39, 712.59) Dermatomyositis / Polymyositis (ICD 716.09, 716.19) 
Systemic Sclerosis (ICD 734.0.09) 
Systemic Lupus Erythematosis (ICD 734.19) 
Sjögren Syndrome (ICD 734.90) 
Polymyalgia Rheumatica and Ternperal Arteritis (446.30-39)
Muscular Rheumatism Including Fibrositis and Myalgia (717.90 717.99) 
Arthritis Not Further Specified (715.99) 
Rheumatism Not Further Specified (718.99) 
CTD Not Further Specified (734.91,734.99)

Study	Methods	Participants	Interventions	Outcomes

Gabriel
(1994)

Retrospective Cohort Study

Study Dates
Exposed:  implantation occurred
between January 1964 to December
1991
Follow up:  to December 31 1991

Group Selection
Exposed :  All women in Olmstead
county whose medical records
indicated that they had received a
breast implant.
Unexposed :  Age matched (3 years)
Olmstead women who had
undergone a medical evaluation
within 2 years of date of matched
case implantation. For each woman
who had undergone reconstruction
following mastectomy for breast
cancer an additional 2 controls were
selected who had undergone
mastectomy but had not received an
implant (analysis of data using this
control group was not reported).

Group Determination
Exposed:  medical records
Unexposed :  same

Ascertainment of Outcome
Exposed :  Medical records reviewed
by trained nurses for evidence of
clinical features, and laboratory and
radiographic studies necessary to
make diagnoses.
Unexposed:  same

Blinding
Not reported

Country:  Olmsted county Minnesota
USA
Exposed:  N = 749
Unexposed:  N = 1498

Mean age:  exposed 34.4 +/- 10.5 years, unexposed 34.3 +/- 10.5 years Caucasian:  exposed 96.8%, unexposed 92.8% (p<.05) Marital status - single:  exposed 15.21/e, unexposed 2 1.0% (p<.05) History of smoking:  exposed 53.5%, unexposed 45.6% (p<.05) Mean years since implantation or index visit:  exposed 7.8 +/- 5.5 years, unexposed:  8.3 +/- 5.8 years (36% of cohort followed for at least 10 years) Reconstruction Due to Breast Cancer:  17% (analysed both separately and combined) Bilateral implants:  83%

Response Rate All eligible records included. Follow up continued to Dec 31 1991, death or date of last health care visit.

Implant Type
Uuspecified:  N=2
Silicone gel filled:  78.3%
Saline:  5.2%
Double Lumen:  6.7%
Polyurethane coated:  9.6%
Combination of Silicone and
Saline:  6.7%
Perras Papillion:  N=2

Exposure 
Rupture described:  no 
Explantation described:  no 
Duration described:  yes. 23.6% of exposed women had undergone> 1 surgical breast implantation procedure 
Excluded Injections:  yes

Diagnosis 
determined from clinical features, 
lab and radiographic studies 
Systemic sclerosis (ACR criteria) 
Rheumatoid arthritis (ACR criteria) 
Scleroderma (ACR criteria) 
Sjögren 
SLE 
Dermatomyositis 
Polymyositis 
Vasculitis 
Ankylosing spondylitis 
Psoriatic arthritis 
Arthritis associated with inflammatory bowel disease
Polychondritis 
Polymyalgia rheumatica 
Any CTD (combined endpoint including all of the above)
Hashimoto's thyroiditis 
Primary bilary cirrhosis 
Sarcoidosis

Lab Values 
Antinuclear Antibodies (values 
considered abnormal at the time the 
test was performed)

Symptoms 
any arthritis (swelling of the wrist, 
swelling of 3 or more joints,
symmetric joint swelling or any 
other documented arthritis or 
synovitis) 
SICCA (dry eyes, dry mouth, or 
keractoconjunctivitis) 
serositis (serosal inflammation such 
as pleuritis and pericarditis) 
malar or discoid rash 
oral ulcers 
photosensitivity 
salivary gland enlargement 
symmetric muscle weakness 
morning stiffness

Study	Methods	Participants	Interventions	Outcomes

Gfltay	Retrospective Cohort Study	Country:  The Netherlands	Implant Type	Diagnosis
(1994)		Exposed:  N = 235	Implant:  Silicone gel filled	Probable inflammatory disease
	Study Dates	Unexposed:  N = 2 10	excluded polyurethane coated	with onset 1 or more years
	Surgery performed Jan 1978 - Dec			following surgery (subjects self
	1990.	Mean age:  exposed 43 years ; unexposed	Exposure	reported symptoms on
	Questionnaire regarding rheumatic	43 years	Rupture described:  no	questionnaire were assessed by
	symptoms June 1992	Mean years since implantation:  6.5 years	Explantation described:  no	rheumatologist regarding
		(range 2-14 years) for all subjects	Duration described:  yes	likelihood to have disease; likely
	Group Selection	Mean interval between surgery and	Excluded Injections:  yes	subjects were further assessed via
	Exposed :  All patients who received	symptom onset:  exposed 5.1 years		phone, plus medical records;
	silicone breast implants at Free	unexposed 5.9 years		criteria not reported.)
	University Hospital, Amsterdam.	Reconstruction due to breast cancer:  23.8%
	Unexposed:  Age matched females	(not analysed separately)		Symptoms
	who had an operation not involving	Bilateral:  68.5%		Raynaud's phenomenon
	silicone in the same year in the same			painful joints ( > 3 months)
	department.	Response Rate		swollen joints (1+ weeks)
		Exposed:  82%		regularly burning eyes
	Group Determination	Unexposed:  73%		mouth ulcers (3+ weeks)
	Exposed:  medical records,			pleuritis
	Unexposed :  same			skin abnormalities worsened by
				sunlight
	Ascertainment of Outcome			combined endpoint - subjects with
	Exposed:  Self report - mailed			at least one symptom arising after
	questionnaire and for those			surgery
	suspected of rheumatic disease,
	medical records
	Unexposed:  same

	Blinding
	Not reported

Study	Methods	Participants	Interventions	Outcomes

Goldman
(1995)

Cross Sectional Study

Study Dates 
1982 - May 1992 - Medical records of office visits between these dates 
provided data regarding both 
exposure and outcome. (1982-1986 
prior to computerization - some 
incomplete data)

Group Selection
Both exposed and unexposed subjects were identified from all female patient records in one referral based rheumatology practice.

Group Determination:  
Exposed:  Medical records -historical, physical or radiologic evidence of a breast implant. 
Unexposed:  Medical records - no evidence of breast implant

Ascertainment of outcome 
Exposed:  Medical records -independent chart review to confirm rheumatological diagnoses 
Unexposed:  same

Blinding
Not reported

Country:  Atlanta, Georgia USA
Exposed:  N = 150
Unexposed:  N = 4079

Mean age (at 1 st visit):  exposed:  43.8, unexposed 47.2 (p<.04) SES (mean income based on ZIP code):  exposed $43,744, unexposed $39,524 (p<0.0001) Race "primarily Caucasian" Mean years since implantation:  exposed who did develop disease 8.3, exposed with no disease 9.9% of cohort with breast implants:  3.5

Response Rate 
100% of eligible records reviewed

Implant Type 
Unspecified (11%) 
Silicone get fitted (85%) (no separate analysis) 
Saline (4%)

Exposure
Ruptured described:  no
Explantation described:  no
Duration described:  yes
Injections excluded:  yes

Diagnosis 
Patients were diagnosed according to ACR and Arthritis Foundation criteria. No year was reported for ICD codes. Rheumatoid Arthritis (ICD 714) 
Systemic Lupus Erythematosus (ICD 710.0) 
Systemic Sclerosis - including CREST (ICD 710.1) 
Sjögren's (ICD 710.2) 
Dermatomyositis / Polymyositis (ICD 710.3, 710.4) 
Mixed Connective Tissue Disease (ICD 710.9) 
Rheumatoid Arthritis and Connective Tissue Disease (combined endpoint comprised of all the above)

Study	Methods	Participants	Interventions	Outcomes

Hennekens
(1996)

Cross Sectional Study

Study Dates
Sept 1992 - May 1995 -Questionnaire regarding both exposure and disease was mailed to prospective participants. Aug 1, 1995 - forms completed Dec 31 1991 - only CTDs diagnosed prior to this date were included in the analysis.

Group Selection
Female health professionals age 18 - 99 residing in the USA or Puerto Rico, who completed mailed questionnaires for participation in the Women's Health Study. Excluded were women who reported an implant or CTD prior to 1962 or who provided unclear or missing information regarding implant surgery, CTD and dates

Ascertainment of Exposure
Exposed:  self report (questionnaire) - women who reported ever having had a breast implant along with the year of procedure 
Unexposed:  self report (questionnaire) - those not reporting an implant

Ascertainment of Outcome
Exposed:  self report
(questionnaire)
Unexposed:  same

Blinding
Not reported

Country:  USA and Puerto Rico
Exposed:  N = 10,830
Unexposed:  N = 384,713

Mean age:  51.7 years. Caucasian:  90.7% Reconstruction due to breast cancer:  18% (estimated from report of implantation the same year as diagnosis of breast cancer. No separate analysis of these cases) Cohort with breast implants:  3.6%

Response Rate
24% (whole cohort)

Implant Type
Unspecified

Exposure
Rupture described:  no
Explantation described:  no
Duration described:  yes
Excluded Injection:  no

Diagnosis 
All diseases were self reported. No diagnostic criteria were used Rheumatoid Arthritis Systemic Lupus Erythematosus Sjögren's Dermatomyositis / Polymyositis Other Connective Tissue Disease (including Mixed) Any Connective Tissue Disease (combined endpoint comprised of all the above)

Study	Methods	Participants	Interventions	Outcomes

Hochberg
(1996)

Case Control Study

Study Dates
July 1990 - summer of 1991 -eligible cases mailed questionnaires. 1993 - data collected from an additional 18 of the eligible cases Dec 1991 - cases diagnosed after this date were excluded July 1993 - Dec 1994 - controls interviewed

Group Selection 
Case Definition :  Women with a clinical diagnosis of SSc Identified at 3 university based scleroderma research centers:  1) Baltimore-Washington - seen at scleroderma center, referred by rheumatologists, or members of Scleroderma Foundation; 2) Pittsburgh - all patients seen by faculty members at U of Pittsburgh were consecutively enrolled; 3) San Diego/Orange County - patients followed by faculty members UCSD or community based rheumatologists. Patients < 18 years at diagnoses or Residing outside USA were excluded. 
Control Definition:  Race and sex matched local controls were identified through random digit dialing and frequency matched to cases in 3 strata:  age < 45, 45-64 and 65+. Women with a self reported diagnosis of CTD were excluded.

Group Determination 
Cases:  medical records 
Controls:  self report (telephone interview

Ascertainment of exposure 
Cases:  self report (self administered questionnaire),

Country:  USA (Multicenter)
Cases:  N = 837
Controls:  N = 2507

Mean Age at Interview:  cases:  55.3 +/- 12.9 years controls:  55.6 +/- 15. 5years SES -% High School Graduates:  cases 86.6%, controls:  85.3%% Caucasian:  cases 90.4%, controls 90.9% Mean Duration of SSc:  cases 10.0 +/- 7.2 Median years since implantation:  cases:  11 years (time to disease), controls:  10 years (time to interview) 
Complications related to implants:  Cases 0%, Controls 16% (hardening N~2, shifting N=2, leakage N= 1) Explantation:  cases 36% (Diagnosis of scleroderma N=2, hardening N= 1, leakage N=1) controls.032% (breast pain N= 1) Breast surgery (related to benign breast masses, breast cancer, fibrocystic disease and mastitis):  cases 17.9%, controls 18.5% Cases with implants:  1.3% Controls with implants:  1.2%

Response Rate
Cases:  Baltimore 61.9%  Pittsburgh 78.4%
San Diego 100%
Controls:  90% of those eligible

Implant Type
Silicone get-filled
Exposure
Rupture described:  yes
Explantation described:  yes
Duration described:  yes
Excluded Injections:  yes

Diagnosis 
Systemic Sclerosis (no diagnostic 
criteria reported)

Study	Methods	Participants	Interventions	Outcomes

Controls:  self report (telephone
interview)

Blinding
Not reported

Study	Methods	Participants	Interventions	Outcomes

Kim
(1998)

Case Control Study

Study Dates
Questionnaires collected between
July 1995 and Jan 1996

Group Selection
Case Definition:  Female patients
with a diagnosis of either Meniere's
disease or progressive sensorineural
hearing loss who had undergone
prior Western blot analysis for
reactivity to 68 kD.
Control Definition:  Women waiting
for outpatient lab results at an
ambulatory care center matched to
cases on age.

Group Determination
Cases:  Identified from a single
clinical practice.
Controls:  Mailed questionnaire.
Those reporting a history of hearing
loss were excluded.

Ascertainment of Outcome
Cases:  Self report - mailed
questionnaire.
Control :  questionnaire

Blinding
not reported

Country:  La Jolla California USA
Cases:  N=119
Controls:  N=100

Mean Age:  cases - Meniere's - 48.5 years,
cases - PSNHL - 50.2 years controls 49.7
years
Mean time from implantation to disease:  
9.23 years (range 2 months to 24 years)
Cases with breast implants:  4.2%
Controls with breast implants:  3%

Response Rate
Cases:  64.7%
Controls:  not reported

Implant Type
"Silicone breast implants"

Exposure
Rupture described:  no
Explantation described:  no
Duration described:  no
Injections excluded:  yes

Diagnoses 
Meniere's Disease (no criteria reported) 
Progressive Sensorineural Hearing Loss 
(PSNHL no criteria reported)

Lab Values 
Anti-68kD antibodies (Western blot 
analysis) - This variable was analysed 
both on its own and in combination with 
Meniere's Disease or PSNHL

Study	Methods	Participants	Interventions	Outcomes

Lacey	Case Control Study	Country:  Michigan USA	Implant Type	Diagnosis
(1997)		Cases:  N = 189	Unspecified N=4	Systemic Sclerosis (1980 ACR
	Study Dates	Controls:  N = 1043	Silicone gel filled N=11	criteria or subject exhibited signs
	1985 - 1992 diagnosis of SSc		(separate analysis provided)	and symptoms characteristic of
		Cases with implants:  1.1%		SSc:  sclerodactyly or thick tight
	Group Selection	Controls with implants:  1.2%	Exposure	skin, and at least one other
	Case Definition:  Women		Rupture described:  no 	manifestation of CREST -
	diagnosed with SSc in Ohio	Response Rate	Explantation described:  no	Excluded linear or localized SSc -
	Control Definition:  Ohio women	Not reported	Duration described:  no	morphea)
	selected by random digit dialing		Excluded injections:  no (data re
	matched to cases on age		injections was recorded but does
	geographic location and race		not appear to have been
			analysed)
	Group Determination
	Cases:  medical records - reviewed
	by rheumatologist
	Controls:  self report

	Ascertainment of Exposure
	Cases:  self report -telephone
	questionnaire
	Controls:  self report - telephone
	questionnaire

	Blinding
	Blind expert reviewed self reported
	exposure data

Study	Methods	Participants	Interventions	Outcomes

Liang	Case Control Study	Country:  Michigan and Ohio, USA	Implant Type	Diagnosis
(1996)		Cases:  N = 205	Unspecified	Undifferentiated Connective Tissue
	Study Dates	Controls:  N = 2220		Disease (Either the referring
	Diagnoses 1980-1992		Exposure	physician diagnosis or HCIA
		Mean age at interview:  Cases:  52.3	Rupture described:  no	discharge code was UCTD (ICD 9
	Group Selection	Controls:  51.4	Explantation described:  no	10.9) or the patient fulfilled all of
	Case Definition:  All women 18+	Mean age at diagnoses:  cases 41.6,	Duration described:  no	the following:  1) was diagnosed as
	years in Michigan and Ohio	Caucasian:  cases 90.7%, controls 89.4%	Excluded injections:  not reported	having Systemic Sclerosis but did
	Diagnosed with UCTD between	Cases with breast implants:  1. 5%		not meet the ACR criteria, 2) did
	1980 and 1992	Controls with breast implants:  1.2%		not meet the diagnostic criteria for
	Control Definition:  Identified			another CTD and 3) had a
	through random digit dialing	Response Rate		minimum of 2 signs, symptoms or
	Frequency matched to cases within	Not reported		lab values suggestive of a CDT.)
	each state on age race and
	geographic location.

	Group Determination
	Cases:  medical records - National
	Hospital discharge database,
	university hospital databases,
	mailing list of rheumatologists,
	Scleroderma, Foundation
	Controls:  self report

	Ascertainment of Exposure:  
	Cases:  self report - telephone
	interview
	Controls:  self report - telephone
	interview

	Blinding
	Yes - blind review of self reported
	occupational hobby exposure

Study	Methods	Participants	Interventions	Outcomes

MacDonald	Case Control Study	Country:  Minnesota USA	Implant Type	Diagnosis
(1996)		Cases:  N = 35	Silicone gel filled (1 case 1	Chronic Fatigue Syndrome (8 of
	Study Dates	Controls:  N = 35	control - numbers available to	10 symptoms identified in 1988
	Diagnosis:  Post Jan 1988		analysed separately)	CDC criteria, more than once or
	Interviews conducted Oct/93 -	Median Age at Disease Onset:  cases 37	Saline (1 control)	persistently for at least 6 months)
	Jun/94	Median Duration of Illness:  cases 54.3
		months	Exposure
	Group Determination	Mean Years Since Implantation:  cases 11,	Rupture described:  no
	Case Definition:  patients from the	controls not reported	Explantation described:  no
	Minnesota Regional CFS Research	Subjects with any breast implant:  cases	Duration described:  yes
	Program Registry whose disease	3%, controls 6%	Excluded injections:  not
	onset occurred after Jan 1988 and	Reconstruction due to breast cancer:  not	reported
	were residents of Minneapolis St.	reported
	Paul or St. Cloud. They were
	diagnosed after medical	Response Rate
	psychometric and psychiatric	Cases:  83%
	assessment could not establish	Controls:  58%
	another explanation for fatigue.
	Two investigators, a psychiatrist
	and an infectious disease specialist,
	had to agree on the diagnosis.
	Control Definition:  matched to
	cases on neighborhood (calling
	households with same 3 digit
	prefix as cases) gender and age (5
	years)

	Group Determination
	Cases:  medical records
	Controls:  self report - telephone
	interview

	Ascertainment of Exposure
	Cases:  self report - telephone
	interview
	Controls:  self report - telephone
	interview

	Blinding
	Not reported

Study	Methods	Participants	Interventions	Outcomes

Nyren
(1998)

Retrospective Cohort Study

Study Dates
Breast surgery took place from 1965 -1993 Follow up from Jan 1 1972 - Dec 31 1993

Group Selection 
Exposed:  All records in the National Swedish Inpatient register that contained the surgical code for breast augmentation with foreign material. These were divided into 2 subcohorts - those with a diagnosis of breast cancer and those who had received implants for other reasons (mainly cosmetic) 
Unexposed:  All records, of patients who had received breast reduction surgery, were selected from the same source. From these, 1 woman was selected as a control for each subject in the cosmetic implant group. They were matched on age (5 years), hospital and calendar year at operation (2 years).

Group Determination 
Exposed:  Medical records -National Swedish Inpatient Register 
Unexposed:  same

Ascertainment of Outcome 
Exposed:  Medical Records - records were reviewed to confirm diagnoses 
Unexposed:  same

Blinding
Not reported

Country:  Sweden
Exposed:  N = 7442
Unexposed:  N = 3353

Mean years since operation:  exposed cosmetic 10.3 years, exposed reconstruction 6.0 years, unexposed:  9.9 years Reconstruction Due to Breast Cancer:  53 (separate analysis provided)

Response Rate 
Medical records - 100% of those eligible. Censoring occurred at date of immigration, death or end of follow up.

Implant Type
Unspecified 7% Silicone gel filled
56% (no separate analysis)
Saline 24%
Double Lumen 12%
Polyurethane Coated <0.1%

Exposure
Rupture Described:  no
Explantation Described:  no
Duration Described:  yes
Excluded Injections:  not reported

Diagnosis 
Determined via ICD 8 and ICD 9 
codes in Swedish Inpatient Register 
Sjögren's Syndrome (ICD 8 
734,90, ICD 9 710C) 
Systemic Lupus Erythematosis 
(ICD8 734,10 ICD9 710A) 
Systemic Sclerosis (ICD8 
734,00,01,09 ICD 9 710B) 
Dermatomyositis (ICD8 716,00 
ICD 9 710D) 
Rheumatoid Arthritis (ICD8 
712,00,10,20,38,39 ICD9 
714A,B,C,D 719D) 
All Definite CTD (combined 
outcome included the proceeding 
diagnoses) 
Fibromyalgia (ICD8 712,50 
717,98 718,99 ICD 9 729A) 
Polymyositis (ICD 8 716. 10, ICD 
9 710E) 
Polyrnyalgia Rheumatica (ICD 8 
446.38, ICD 9 725) 
Polyarteritis Nodosa (codes na) 
Temporal Arteritis (ICD 8 446.30, 
ICD 9 446F) 
Other Specified CTD (ICD 
8734.98, ICD 9710W) 
CTD or Collagenosis without 
further specification (ICD 8 
734.91,734.99, ICD 9710) 
Sarcoidosis (ICD 8 135, ICD 9 
135) 
Localized Lupus (ICD 8 695.40, 
ICD 9 695E) 
Ankylosing Spondylitis (ICD 8 
712.40, ICD 9 720A) 
Psoriatic Arthritis (ICD 8 696.0,
 713D, ICD 9 696A)

Study	Methods	Participants	Interventions	Outcomes

Nyren
(1998b)

Retrospective Cohort Study

Study Dates
Breast surgery took place from 1965
to 1993.
Follow up from Jan 1972 to Dec
1993

Group Selection
Exposed:  All records in the National
Swedish Inpatient register that
contained the surgical code for
breast augmentation with foreign
material. These were divided into 2
subcohorts - those with a diagnosis
of breast cancer and those who had
received implants for other reasons
(mainly cosmetic).
Unexposed:  
All records, of patients who had
received breast reduction surgery,
were selected from the same source.
From these, 1 woman was selected
as a control for each subject in the
cosmetic implant group. They were
matched on age (5 yrs), hospital and
calendar year at operation (2 yrs).

Group Determination
Exposed:  Medical records - National
Swedish Inpatient Register
Unexposed:  same

Ascertainment of Outcome
Exposed:  Medical Records - records
were reviewed to confirm diagnoses
Unexposed:  same

Blinding:  not reported

Country:  Sweden 
Exposed:  N = 7433 
Unexposed:  N = 3353 
Mean follow up:  exposed cosmetic 10.3 years; exposed reconstruction 6.0 years; unexposed 9.9 years 
% Reconstruction Due to Breast Cancer:  53 (separate analysis provided)

Response Rate 
All eligible records included. Censoring occurred at date of immigration, death or end of follow up.

Implant Type Type Unspecified
7% Silicone Gel Filled 56% (no separate analysis) 
Saline 24% 
Double Lumen 12% 
Polyurethane Coated <0.1%

Exposure
Injections Excluded:  no mention
Rupture Described:  no
Explantation Described:  no
Duration Described:  yes

Diagnoses
Multiple Sclerosis (ICD-7 345.00, ICD-8
340.99, ICD-9 340)
Neuritis of the Optic Nerve (ICD-7345.10,
ICD-8341.01, ICD-9341A)
Amyotrophic Lateral Sclerosis (ICD
7356.10, ICD-8 348.00, ICD-9 335C)
Diseases of the Nerve Roots and Plexuses
(ICD-9 353)
Mononeuritis of the Upper Extremity
-Lesion of the Median Nerve (ICD-7
368.01, ICD-8 357.01, ICD-9354B)
-Lesion of the Ulnar Nerve (ICD-7 368.00,
ICD-8 357.00, ICD-9 354C)
-Lesion of the Radial Nerve (ICD-7 368.02,
ICD-8 354.01, ICD-9 354D)
Mononeuritis of the Lower Extremity (ICD
9 355)
Guillian-Barre Syndrome (ICD-7 364.20,
ICD-8 354.01, ICD-9 357A)
Meniere's Disease (ICD-7 395, ICD-8 385,
ICD-9 368A)

Study	Methods	Participants	Interventions	Outcomes

Park
(1998)

Retrospective Cohort Study

Study Dates
Implantation took place from 1982
1991. No other dates reported.
Group Selection
Exposed:  1) Augmentation Group -
All women in SE Scotland who had
received silicone gel implants for
reasons other than reconstruction
following mastectomy, between
1982 and 1991 were approached to
participate. 2) Reconstruction Group
- All women from the same region
who had undergone reconstruction
with silicone gel implants following
mastectomy for breast cancer.
Patients who had locally advanced
or metabolic disease at the time of
initial diagnoses were excluded.
Only those patients who had
survived 1 year following their
operations were eligible.
Unexposed:  1) Augmentation
Control Group (a) Examination
controls - Women attending the
plastic surgery out patient
department who were of similar age
as augmentation group. 2)
Augmentation Control Group (b)
Blood Sample Controls - Women of
similar age as augmentation group
recruited anonymously from local
maternity unit. 3) Reconstruction
Controls - Patients from the data
base of the Breast Unit were
matched to reconstruction patients
on age (6 months), stage of disease
at diagnosis and time of operation (3
months).

Group Determination
Exposed:  medical records -
operating books
Unexposed:  medical records
Ascertainment of Outcome:  
Exposed:  
Direct measurement (medical exam
and seroloical analysis), medical

Country:  Scotland
Exposed:  Augmentation Group N = I 10,
Reconstruction Group N = 207
Unexposed:  Augmentation -

Examination Controls N = 128, Blood Controls N = 203, Reconstruction Controls N=88 Mean Age:  Exposed:  Augmentation Group 34.1 years, Reconstruction Group 55.2 years, Unexposed:  Augmentation (a) Examination Controls 33.6 years, (b) Blood Controls 31.2 years, Reconstruction Controls 55.8 years Mean Years Since Implantation:  Augmentation Group 5.9 Reconstruction Group 5.3 Reconstruction Due to Breast Cancer:  64% (separate analysis) Cosmetic:  36% Bilateral:  77% Unilateral:  32%

Response Rate 
Augmentation Group 59% 
Augmentation controls (both groups) not reported 
Reconstruction Group 72% 
Reconstruction controls 50%

Implant Type
Silicone gel filled (average size
258 ml)

Exposure
Rupture Described:  yes
Explantation Described:  yes
Duration Described:  yes
Excluded Injections yes

Diagnosis 
Rheumatoid Arthritis (ACR 
criteria)

Lab Values
Positive ANA (human cell culture,
titre <40 considered normal)

Symptoms 
joint pain 
muscle pain 
fatigue 
Raynaud's phenomenon 
dysphagia 
weight loss 
constipation, 
psychiatric 
photosensitivity 
rash 
edema 
lyphadenopathy 
sclerodactyly 
abnormal pigment 
telangectasia

Study	Methods	Participants	Interventions	Outcomes

records, and self report (medical history and quality of life questionnaire)
Unexposed:  same

Blinding
Not reported

Study	Methods	Participants	Interventions	Outcomes

Sanchez
(1995)

Retrospective Cohort Study

Study Dates
1976 - rheumatic conditions which
occurred since this date were
enumerated
1990 - Implantation must have
taken place prior to this date.
1992- Information regarding
exposure was collected via mailed
questionnaires.
1980-1992 - Information regarding
rheumatic conditions was collected
via mailed questionnaires
(biannually).
1992 - Participants who had
completed the 1992 biannual
questionnaire and had reported
rheumatic disease prior to June 1
1990 were sent a screening
questionnaire regarding CTD.

Group Selection
Participants in Nurses Health Study
assembled in June 1976 - married
female RNs age 30-55 residing in
11 US states.
Exposed:  women reporting any
breast implants or injections on
questionnaire (surgery prior to
1990)
Unexposed:  reporting no implants or
injections on questionnaire

Group Determination
Exposed:  self report (mailed
questionnaire). Self report validated
in a random sample by blinded
physician medical record review.
Unexposed:  self report (mailed
questionnaire)
Ascertainment of Outcome:  
Exposed:  self report (questionnaire),
medical records - Women who had
reported CTD were then sent a
screening questionnaire including 30
criteria based symptoms, (sensitivity
83 -96%, specificity 83-93%) for
detecting RA, SLE, SSc, Sjögren's,

Country:  United States
Exposed:  N = 1183
Unexposed:  N = 86318

SES:  All nurses
Caucasian:  95% (whole cohort)
Reconstruction Due to Breast cancer:  33%
(no separate analysis)
Bilateral:  79%
Exposed subjects with 2+ operations:  23%
Mean years since implantation:  9.9 (+/- 6.4)
Cohort with breast implants:  1.4%

Response Rate 
Whole cohort:  
1976 baseline questionnaire 70%, 
1992 biennial questionnaire 81%, Supplementary questionnaire to those who reported breast implants in 1992 - 97.2%, Screening questionnaire to those who had reported disease 90%

Implant Type 
Unspecified:  5% Silicone gel filled:  74% (analysed separately) 
Saline:  14% 
Double lumen:  6% 
Polyurethane coated:  1%

Exposure
Rupture described:  no
Explantation described:  no
Duration described:  yes
Excluded Injections:  yes

Diagnosis 
Rheumatoid Arthritis (ACR criteria) 
Scleroderma (ACR criteria) 
Sjögren's Syndrome (Fox et al criteria) 
Polymyositis / Dermatomyocitis (Bohan and Peter criteria)
Systemic Lupus Erythematosus (ACR criteria) 
Mixed Connective Tissue Disease 
(Alarcon, Sigovis and Cardiel criteria) 
Definite CTD (combined endpoint 
comprised of all the above) 
Self Reported Connective Tissue 
Disease (women with possible 
early, milder or atypical forms of 
CTD who did not meet the 
standard classification criteria)

Symptoms 
Self Reported Signs or Symptoms 
of CTD 
Documented Signs or Symptoms of CTD

Inflammatory Myosotis, and Mixed Connective Tissue Disease. Those who had a positive questionnaire (at least 2 swollen joints for >6 weeks or 3 positive answers) had their medical records reviewed by 2 rheumatologists. Date of onset was defined as date of diagnosis in chart. Less stringent criteria were used for a separate analysis - patients who reported rheumatic disease on any biennial questionnaire, patients who had a positive screening questionnaire, or patients who had any 1 of 41 signs, symptoms or laboratory features on the medical record abstraction form were included. 
Unexposed:  same

Blinding
Data regarding implant history was entered by blinded researchers. Medical records regarding outcome were reviewed by blinded physicians.

Study	Methods	Participants	Interventions	Outcomes

Strom
(1994)

Case Control Study

Study Dates
1985-1987 - Cases and controls identified for a general risk factor study not involving implants. June 1992 - Sept 1992 Subjects were contacted again to be interviewed regarding breast implantation prior to the index date of the previous study.

Group Selection 
Case Definition:  Outpatients with a new (incident) or recent (within 3 years) clinical diagnosis of SLE or lupus-like illness were identified from Philadelphia rheumatology practices (73%) and local Lupus Foundation (27%). Cases without matched controls were excluded 
Control Definition:  
Internal Controls - Friends of cases, matched on sex and age (5 years) were randomly selected from alphabetical order and random number table. 
External Controls - Population based controls from the Cancer and Steroid Hormone study which studied events diagnosed from 1980 -1982.

Group Determination
Cases:  medical records (not specified) Controls (internal):  self report (not specified) - excluded those with SLE

Ascertainment of Exposure
Cases:  self report (telephone interview) Controls (internal):  same

Blinding
not reported

Country:  Philadelphia, USA 
Cases:  N = 133 
Controls:  Internal Controls N = 100, 
External Controls N = 4754 
Years since implantation:  cases:  8 years (only 1 case) 
Cases with breast implants:  0.75% Controls with breast implants:  internal controls 0, external controls 0. 17

Response Rate Cases:  
Original Study - 89% Implant Study - cases 75.9% of original subjects 
Controls:  Original Study - 85.1% Implant Study 77.6% of original subjects

Implant Type
Unspecified

Exposure 
Rupture described:  no 
Explantation described:  no 
Duration described:  yes 
Excluded injections:  no (external controls)

Diagnosis 
Scleroderma (4 or more revised 
ARA criteria)

Study	Methods	Participants	Interventions	Outcomes

Teel	Case Control Study	Country:  Washington State, USA	Implant Type	Diagnoses
(1997)		Cases:  N = 427	Unspecified:  N = 5 (1 case, 4	Systemic Lupus Erythematosus
	Study Dates	Controls:  "Pre-existing" N = 1688; "New"	controls)	(ACR criteria)
	Cases diagnosed between Jan 1983	N = 1577	Silicone Get-Fitted:  N = 32 (4	Systemic Sclerosis/Crest (ACR
	and Dec 1991. "Pre existing control		cases, 28 controls)	criteria)
	group" interviewed between 1986	Mean age at reference date:  cases 45.2	Saline:  N = 8 (1 case, 7 controls)	Sjögren's Syndrome (ACR criteria)
	and 1991. "New" control group	years; "pre-existing" controls 48.1 years;	Separate analysis for Silicone	Polymyositis (Bohan criteria)
	selected from 1994 - 1996.	"new" controls 41.7 years	Gel-Filled implants:  no	Mixed Connective Tissue Disease
		Race - Caucasian:  cases 79.9%; "pre		(Sharp criteria)
	Group Selection	existing" controls 89.1%; "new" controls	Exposure	Any Connective Tissue Disease
	Case Definition	93.7%	Rupture described:  no	(all cases combined)
	Female residents of King's County	Body Mass Index:  cases 23.2; "pre-	Explantation described:  no
	diagnosed by a rheumatologist as	existing" controls 23.5; "new" controls 23.2	Duration described:  no
	having one of five connective tissue	Ever Married:  cases 83. 1%; "pre existing"	Injections excluded:  not reported
	diseases.	controls 91.0%; "new" controls 81.4%
		Education:  cases 13.9 years; "pre existing"
	Control Definition	controls 13.9 years; "new" controls 14.1
	"Pre existing" controls had been	years
	identified through random digit	Breast Cancer:  :  cases 1.6%, "pre existing"
	dialing for previous epidemiologic	controls 2.3 O/o; "new" controls 1.3%
	studies.	Cases with breast implants:  1.4%
	"New" controls were selected by	Controls with breast implants:  "pre
	random digit dialing and matched	existing" 1.0%; "new" 1.1%
	to cases on age and year of
	diagnosis.	Response Rate
	All controls were residents of King	Cases:  80.3%
	County at their reference dates.	Control :  "pre existing" controls 79.0%;
	Those with a history of CTD prior	"new controls" 79.0%
	to reference date were excluded.

	Group Determination
	Cases:  Medical records were
	reviewed by trained research
	assistants. Cases were classified as
	definite (case met all diagnostic
	criteria and had been diagnosed by
	rheumatologist) or probable
	(rheumatologist made diagnosis but
	case fell one feature short of
	requisite criteria or criteria were met
	but rheumatologist had labeled the
	disease as probable). 96% of
	probable cases were re-abstracted to
	confirm eligibility
	Controls:  "Pre existing" controls -
	self report (not clear if interview or
	questionnaire). "New" controls - self
	report - mailed questionnaire (non
	respondents administered same

	questionnaire by phone)

	Ascertainment of Exposure 
	Cases:  Self report - mailed 
	questionnaire (non respondents 
	administered same questionnaire by 
	phone)
	Controls:  "Pre existing" controls -
	self report - interview "New" 
	controls same as for cases.

	Blinding 
	Not reported.

Study	Methods	Participants	Interventions	Outcomes

Wells
(1994)

Retrospective Cohort Study

Study Dates
1970-1990 - dates of implantation
Oct 13 1990 - Questionnaire
regarding symptoms was mailed to
both exposed and unexposed plastic
surgery patients.
July 11 1991 - Second questionnaire
was mailed to non responders. (In
addition, a telephone follow up for
which no dates were reported, was
conducted with a random sample of
- responding women.)

Group Selection
Subjects age 20 - 60 who had not
undergone silicone chin or nose
implant or collagen injections
selected from a single plastic surgery
practice
Exposed:  women who had "silicone
breast implants" for aesthetic or
reconstructive purposes.
Unexposed:  Women who had a
cosmetic procedure (blepharoplasty,
rhinoplasty or liposuction) other
than breast implants. Those who
subsequently obtained breast
implants were excluded.

Group Determination
Exposed:  medical records
Unexposed:  same

Ascertainment of Outcome
Exposed:  self report - mailed
questionnaire and for a random
sample of non responders (n=8)
telephone survey
Unexposed:  same (telephone survey
n=19)

Blinding
not reported

Country:  Florida, USA
Exposed:  N = 222
Unexposed:  N = 80

Median age:  exposed 37(+/- 0.67), 
unexposed 46.5 (+/-1.63) 
Caucasian:  98% (of all subjects) 
Median year of operation:  exposed 1986 (+/-0.48), unexposed 1988 (+/-0.31). 8% of implant group had surgery >10 years ago. 
None of controls had surgery > than 7 years previously. 
Good health before surgery:  exposed 98%, unexposed 100% 
Prevalence of allergies:  exposed 38%, unexposed 32% 
History of breast cancer:  0 in Cohort

Response Rate
Exposed:  59%
Unexposed:  46%

Implant Type 
Silicone gel filled (assume -article states "silicone breast implants"

Exposure
Rupture described:  no
Explantation described:  no
Duration described:  yes
Excluded Injections:  yes

Diagnosis 
Systemic sclerosis 
Raynaud's phenomenon 
Arthritis (not defined whether RA or not) 
Note:  study looked at self reported diagnoses only, no criteria reported.

Symptoms 
easily tired 
muscle pain 
swollen glands neck 
tender glands neck 
swollen glands under arm 
tender glands under arm 
rashes 
skin thickening 
skin tightness 
change in skin colour 
hair loss arms and legs 
persistent fever 
change in hand colour with cold 
breathing difficulty 
weight loss > 10 lbs. 
weight gain > 10 lbs. 
swollen joints 
painful joints 
general stillness 
Note:  patients were asked if they experienced these outcomes either before or after surgery. Only those symptoms reported as being post surgical which were not present before hand were analysed.

Study	Methods	Participants	Interventions	Outcomes

Winther	Retrospective Cohort Study:  	Country:  Denmark	Implant Type	Diagnoses
(1998)	Study Dates:  Breast surgery took	Exposed:  N = 1335	Silicone breast implants	(All cases represented neurologic disease
	place between 1977- 1992. Follow	Unexposed:  N = 7071		requiring hospitalization and were classified
	up to Dec 31 1993			according to ICD 8)
		Median Age at Entry:  Exposed 31;	Exposure	Multiple Sclerosis (ICD 340, Poser criteria)
	Group Selection	Unexposed 31	Injections Excluded:  yes	Other Demyelinating CNS Neuropathies
	Exposed:  Women identified through	Median Length of Follow up:  Exposed 8.5	Rupture Described:  no	(ICD 341)
	Danish Central National Register	yrs; Unexposed 7.7 yrs	Explantation Described:  no	Motor Neuropathy (ICD 348, includes
	of Patients (NRP) who had received		Duration Described:  yes	ALS)
	implants at public hospitals between	Response Rate		Peripheral Neuropathies
	for cosmetic reasons.	All eligible records included. Follow up		-Brachial Neuropathy (ICD 352)
	Exposed:  Women from the same	continued to Dec 31 1993, death or date of		Sciatic Neuropathy (ICD 353.99)
	source who had undergone breast	last health care visit.		Polyneuropathy (ICD 354, includes
	reduction surgery.			Guillian Barre)
				Neuropathy, NOS (ICD 355.09)
	Group Determination			Other Peripheral Neuropathies (ICD
	Exposed:  NRP records (ICD-8			357.99)
	38500, 38540)			Optical Retino, - and Neuropathy (ICD 367)
	Unexposed:  NRP records (ICD-8			Meniere's Disease (ICD 385.99)
	38400, 38460)			Myasthenia Gravis (ICD 733.09)

	Ascertainment of Outcome 
	Exposed:  NRP records. Hospital 
	medical records were reviewed to 
	validate neurologic diagnoses 
	obtained form NRP
	Unexposed:  NRP records. Hospital 
	medical records were reviewed to 
	validate neurologic diagnoses for 
	which an increased occurrence was 
	observed in the exposed cohort

	Blinding
	Medical records reviewed by 
	blinded neurologist

Study	Methods	Participants	Interventions	Outcomes

Wolfe
(1995)

Case Control Study

Study Dates
not reported 
Case Definition:  patients with fibromyalgia, patients with rheumatoid arthritis 
Control Definiton:  Two groups - 1) patients with osteoarthritis, 2) women randomly selected from the general population

Group Determination
not reported

Ascertainment of Exposure
Cases:  self report - mailed 
questionnaires 
Controls:  Osteoarthritis controls -
self report - mailed questionnaires, community controls - self report -
telephone interview

Blinding
not reported

Country:  Kansas, USA
Cases:  Fibromyalgia (FM) N = 533,
Rheumatoid Arthritis (RA) N = 637
Controls:  Osteoarthritis (OA) N = 477,
Community N = 655

Mean age at interview:  cases:  RA 64.4 years, FM 51.6 years controls:  OA 67.4 years, community 55.3 years Mean age at disease onset:  Cases:  RA 47.1 years, FM 38.5 years Controls:  OA 52.7 years Cases with implants:  Fibromyalgia 1.31%, Rheumatoid Arthritis 0.47% Controls with implants:  Community controls 0.31%. Osteoarthritis controls 0.42

Response Rate 
not reported

Implant Type
Unspecified (referred to as silicone breast implants but not specific about the filling)

Exposure 
Rupture described:  no 
Explantation described:  no 
Duration described:  no 
Excluded injections:  not reported

Diagnosis 
Rheumatoid Arthritis (criteria not reported) 
Fibromyalgia (criteria not reported)

APPENDIX A
SEARCH STRATEGY

APPENDIX A
SEARCH STRATEGY

Set   Search 1

001   breast implants/
002   (breast adj3 implant$).tw.
003   (breast adj3 (augmentation or reconstruction)).tw.
004   (breast adj3 prosthes#s).tw.
005   or/1‑3
006   breast/ or breast$.tw.
007   implants, artificial/
008   prosthesis/
009   exp silicones/ or silicone$.tw.
010   or/7‑9
011   (5 or 6) and 10
012   mammaplasty/ or mammaplasty.tw.
013   surgery, plastic/
014   breast/su
015   or/12‑14
016   (augment$ or implast$).tw.
017   (reconstruct$ or cosmetic or prosthes#s).tw.
018   15 and (16 or 17)
019   5 or 11 or 18
020   exp arthritis, rheumatoid/
021   (felty$ adJ2 syndrome).tw.
022   (caplan$ adJ2 syndrome).tw.
023   rheumatoid nodule.tw.
024   (sjogren$ adJ2 syndrome).tw.
025   (sicca adj2 syndrome).tw.
026   still$ disease.tw.
027   (spondylitis adJ2 ankylosing).tw.
028   bechterew$ disease.tw.
029   (arthritis adJ2 rheumat$).tw.
030   or/20‑29
031   19 and 30
032   scleroderma, circumscribed/
033   ((scleroderma adj localized) or progressive or diffuse or sy
034   exp sclerodenna, systemic/
035   ((crest or crst) adj syndrome).tw.
036   morphea.ti,ab,sh. or dermatosclerosis.tw.
037   sclerodacty$.tw.
038   exp calcinosis/ or calcinosis.tw.
039   exp esophageal motility disorders/
040   esophag$.tw.

041   ataxia telangiectasia/
042   telangiectasia, hereditary hemorrhagic/
043   telangiectasia.tw.
044   osler‑rendu.tw.
045   louis‑bar.tw.
046   raynaud's disease/ or raynaud$.tw.
047   or/32‑46
048   19 and 47
049   48

Set   Search 2

001   breast implants/
002   (breast adj3 implant$).tw.
003   (breast adj3 (augmentation or reconstruction)).tw.
004   (breast adj3 prosthes#s).tw.
005   or/1‑3
006   breast/ or breast$.tw.
007   implants, artificial/
008   prosthesis/
009   exp silicones/ or silicone$.tw.
010   or/7‑9
011   (5 or 6) and 10
012   mammaplasty/ or mammaplasty.tw.
013   surgery, plastic/
014   breast/su.
015   or/12‑14
016   (augment$ or implast$).tw.
017   (reconstruct$ or cosmetic or prosthes#s).tw.
018   15 and (16 or 17)
019   5 or 11 or 18
020   exp lupus erythematosus, systemic/
021   (lupus adj (nephritis or erythematosus or disseminatus)).tw.
022   libman‑sacks.tw.
023   antiphospholipid syndrome/
024   antiphospholipid.tw.
025   or/20‑24
026   19 and 25
027   dermatomyositis/ or dermatomyositis.tw.
028   19 and 27
029   polymyositis/
030   myositis.ti,ab,sh. or polymyositis.tw.
031   20 or 30
032   19 and 31
033   arthritis, psoriatic/

034   (psoriatic adJ2 (arthrit$ or arthropathica)).tw.
035   33 or 24
036   19 and 35
037   28

Set Search 3

001   breast implants/
002   (breast adj3 implant$).tw.
003   (breast adj3 (augmentation or reconstruction)).tw.
004   (breast adj3 prosthes#s).tw.
005   or/1‑3
006   breast/ or breast$.tw.
007   implants, artificial/
008   prosthesis/
009   exp silicones/ or silicone$.tw.
010   or/7‑9
011   (5 or 6) and 10
012   mammaplasty/ or mammaplasty.tw.
013   surgery, plastic/
014   breast/su
015   or/12‑14
016   (augment$ or implast$).tw.
017   (reconstruct$ or cosmetic or prosthes#s).tw.
018   15 and (16 or 17)
019   5 or 11 or 18
020   exp vasculitis/
021   angiitis.tw.
022   vasculitis, allergic cutaneous/
023   vasculitis.tw,sh.
024   arteritis.tw.
025   (thrombophlebitis or phlebitis).tw.
026   thromboangiitis.tw.
027   (behcet$ or churg‑strauss).tw.
028   wegener$.tw.
029   mucocutaneous lymph.tw.
030   or/20‑29
031   19 and 30
032   exp inflammatory bowel diseases/
033   ulcerative colitis.tw.
034   crohn$.tw.
035   (colitis or ileitis or enteritis).tw.
036   (rectocolitis or proctocolitis).tw.
037   inflammatory bowel.tw.

038     or/32‑37
039   19 and 38
040   polychondritis, relapsing/
041   polychondritis.tw.
042   40 or 41
043   19 and 42
044   fibromyalgia/
045   (fibromyalgia or fibrositis).tw.
046   muscular rheumatism.tw.
047   fatigue syndrome, chronic/
048   chronic fatigue.tw.
049   myalg$.tw.
050   encephalomyelitis.tw.
051   encephalomyelitis.tw.
052   or/44‑51
053   19 and 52
054   53

Set   Search 4

001   breast implants/
002   (breast adj3 implant$).tw.
003   (breast adj3 (augmentation or reconstruction)).tw.
004   (breast adj3 prosthes#s).tw.
005   or/ 1 ‑3
006   breast/ or breast$.tw.
007   implants, artificial/
008   prosthesis/
009   exp silicones/ or silicone$.tw.
010   or/7‑9
011   (5 or 6) and 10
012   mammaplasty/ or mammaplasty.tw.
013   surgery, plastic/
014   breast/su
015   or/12‑14
016   (augment$ or implast$).tw.
017   (reconstruct$ or cosmetic or prosthes#s).tw.
018   15 and (16 or 17)
019   5 or 11 or 18
020   connective tissue diseases/
021   exp cartilage diseases/
022   cellulitis/
023   exp collagen diseases/
024   cutis laxa/
025   dupuytren's contracture/

026   homocystinuria/
027   marfan syndrome/
028   mixed connective tissue disease/
029   exp mucinoses/
030   neoplasms, connective tissue/
031   noonan syndrome/
032   osteopoikilosis/
033   exp panniculitis/
034   pseudoxanthorna elasticum/
035   mctd.tw.
036   sharp syndrome.tw.
037   human adjuvant.tw.
038   mixed connective tissue.tw.
039   sclerosis‑like.tw.
040   fibrous banding.tw.
041   skin thickening. tw.
042   arthralgia/
043   (arthralgia or polyarthralgia).tw.
044   or/20‑43
045   19 and 44
046   scleroderma, circumscribed/
047   ((scleroderma adj localized) or progressive or diffuse or sy
048   exp scleroderma, systemic/
049   ((crest or crst) adj syndrome).tw.
050   morphea.ti,ab,sh. or dermatosclerosis.tw.
051   sclerodacty$.tw.
052   exp, calcinosis/ or calcinosis.tw.
053   exp esophageal motility disorders/
054   esophag$.tw.
055   ataxia telangiectasia/
056   telangiectasia, hereditary hemorrhagic/
057   telangiectasia.tw.
058   osler‑rendu.tw.
059   louis‑bar.tw.
060   raynaud's disease/ or raynaud$.tw.
061   or/46‑60
062   19 and 61
063   45 not 62
064   63

Set   Search 5

001   breast implants/
002   breast adj3 implant$).tw.
003   (breast adj3 (augmentation or reconstructio

004   (breast adj3 prosthes#s).tw.
005   or/1‑3
006   breast/ or breast$.tw.
007   implants, artificial/
008   prosthesis/
009   exp silicones/ or silicone$.tw.
010   or/7‑9
011   (5 or 6) and 10
012   mammaplasty/ or mammaplasty.tw.
013   surgery, plastic/
014   breast/su
015   or/12‑14
016   (augment$ or implast$).tw.
017   (reconstruct$ or cosmetic or prosthes#s).tw
018   15 and (16 or 17)
019   5 or 11 or 18
020   randomized controlled trial.pt.
021   controlled clinical trial.pt.
022   controlled clinical trials/
023   exp cross‑sectional studies/
024   cross‑sectional.tw.
025   prospective.tw.
026   retrospective. tw.
027   exp cohort studies/
028   exp case‑control studies/
029   or/20‑28
030   19 and 29
031   control$.tw.
032   19 and 31
033   30 or 32
034   limit 33 to human
035   exp arthritis, rheumatoid/
036   exp calcinosis/
037   exp scleroderma, systemic/
038   exp esophageal motility disorders/
039   exp lupus erythematosus, systemic/
040   arthritis, psoriatic/
041   vasculitis.tw.
042   exp inflammatory bowel diseases/
043   fibromyalgia/
044   fatigue syndrome, chronic/
045   connective tissue diseases/
046   mixed connective tissue disease/
047   exp collagen diseases/
048   exp cartilage diseases/

049   neoplasms, connective tissue/
050   exp Mucinoses/
051   cellulitis/
052   scleroderma.tw.
053   antiphospholipid syndrome/
054   polymyositis/
055   arteritis.tw.
056   (colitis or ileitis).ti,ab,rw,sh. or enteri
057   exp panniculitis/
058   arthralgia/
059   telangiectasia.tw.
060   raynaud's disease/ or raynaud$.tw.
061   or/35‑50
062   34 not 61
063   2 or 3 or 4 or 6 or 12 or 14
064   63 and 9
065   1 or 64
066   breast implantation/
067   65 or 66
068   29 and 67
069   31 and 67
071   limit 71 to human

Toxline Search

001   (breast implant$ or breast) and silicone$
002   exclude medline

Dissertation Abstracts

001   breast implant
002   breast implants
003   breast and silicone

APPENDIX B
DATA EXTRACTION FORMS

SILICONE BREAST IMPLANTS AND CONNECTIVE TISSUE DISEASE
CASE CONTROL STUDY

Identification	
Article # 		Review # 		Reviewer		
			
Title			

Investigator			
		Year	
Setting	Location	Language	
			
	Study Name		
Dates of			
Enrolment			
Diagnoses	‘ SSc	‘ ACR	
	‘ Morphea	‘ ACR	
	‘ RA	‘ ACR	
	‘ SLE	‘ ACR	
	‘ FM	‘ ACR	
	‘ Sjögren's	‘ ACR	
	‘ Dermatomyositis	‘ ACR	
	‘ Polymyositis	‘ ACR	
	‘ Vasculitis	‘ ACR	
	‘ Ankylosing Spondylitis		
	‘ Psoriatic Arthritis		
	‘ Arthritis Associated With Inflammatory Bowel Disease		
	‘ Polychondritis		
	‘ Mixed Connective Tissue Disease		
	‘ Raynaud's Phenomenon		
	‘ Any Connective Tissue Disease (Combined Endpoint)		
	‘ Other		
	‘ Other		
Implant	‘ Implant Type Unspecified 	‘ Injection - Silicone	
	‘ Silicone Gel Filled	‘ Injection - Collagen	
	‘ Saline		
	‘ Double lumen		
	‘ Polyurethane coated		

Comments:  	_________________________________________________________________
		
		_________________________________________________________________

		_________________________________________________________________

Methodology

	Cases	Control	
# Identified			
			
# Excluded			

			
Group N			
			
Group	Case Definition	Control Definition	
Selection			

			

			
		‘ Randomly Selected	
		‘ Excluded Hist of Disease	
		‘ Community Controls	
		‘ Hospital Controls	
		‘ Matched	
		‘ Unmatched	
	Excluded cases with Dx prior 	‘  Single Control	
	to implants? ‘ Y   ‘ N   ‘ NA 	‘ Multiple Controls	
			
Group	‘ Direct Measurement	‘ Direct Measurement	
Determination	‘ Medical Records	‘ Medical Records	
	‘ Self Report	‘ Self Report	
			
Ascertainment	‘ Direct Measurement	‘ Direct Measurement	
of Exposure	‘ Medical Records	‘ Medical Records	
	‘ Self Report	‘ Self Report	
	Blinding   ‘ Y   ‘ N	Blinding   ‘ Y   ‘ N	
			
Exposure	Rupture Described			‘ Y    ‘ N		
	Explantation Described 		‘ Y    ‘ N		
	Duration Described 			‘ Y    ‘ N		
	Excluded Injections 			‘ Y    ‘ N		

Subject Characteristics

Characteristic	Cases	Controls	
 Age
			
SES (Define)
			
% Family History of
     Disease			
% Caucasian
			
% Rupture
			
% Explantation
			
  Yrs Since Implantation
			
% Reconstruction Due to
     Breast Cancer			
% Cosmetic
			
% Bilateral
			
% Unilateral

Group Differences:  

Data Analysis:  ‘  All subjects         ‘ Excludes ascertainment exposure unknown

Exposure	N			Crude	Adjusted	Factors Adjusted	Translation	
				OR (CI)	OR (CI)			
		Case 	Control			‘ Age		
						‘ Education		
	E 					‘ Income		
						‘ Marital Status		
	E					‘ Race		
	 					‘		
	T					‘		
	 							
		Case 	Control			‘ Age		
						‘ Education		
	E 					‘ Income		
						‘ Marital Status		
	E					‘ Race		
						‘ 		
	T					‘		
								
		Case 	Control			‘ Age		
						‘ Education		
	E 					‘ Income
L) Marital Status		
						‘ Marital Status 		
	E					‘ Race		
						‘		
	T					‘		

SILICONE BREAST IMPLANTS AND CONNECTIVE TISSUE DISEASE
COHORT STUDY

Identification	
Article # 		Review # 		Reviewer		
			
Title			

Investigator			
		Year	
Setting	Location	Language	
			
	Study Name		
Dates of			
Enrolment			
Diagnoses	‘ SSc	‘ ACR	
	‘ Morphea	‘ ACR	
	‘ RA	‘ ACR	
	‘ SLE	‘ ACR	
	‘ FM	‘ ACR	
	‘ Sjögren's	‘ ACR	
	‘ Dermatomyositis	‘ ACR	
	‘ Polymyositis	‘ ACR	
	‘ Vasculitis	‘ ACR	
	‘ Ankylosing Spondylitis		
	‘ Psoriatic Arthritis		
	‘ Arthritis Associated With Inflammatory Bowel Disease		
	‘ Polychondritis		
	‘ Mixed Connective Tissue Disease		
	‘ Raynaud's Phenomenon		
	‘ Any Connective Tissue Disease (Combined Endpoint)		
	‘ Other		
	‘ Other		
Implant	‘ Implant Type Unspecified	‘ Injection - Silicone	
	‘ Silicone Gel Filled	‘ Injection - Collagen	
	‘ Saline		
	‘ Double lumen		
	‘ Polyurethane coated		

Comments:  	_______________________________________________________________

		_______________________________________________________________

		_______________________________________________________________

Methodology

Design:  	‘ Prospective Cohort		‘ Retrospective Cohort
		‘ Internal Cohort		‘ External Cohort

	Exposed	(Cohort)		Unexposed	
# Identified					
(Describe)					

# Excluded					
(Describe)					

Group N					
All S's					
Accounted ?					
Group					
Selection					
					
	Exposure:  				
	Injections Excluded ‘ Y 	‘ N			
	Rupture Described  ‘ Y 	‘ N			
	Explantation Desc.  ‘ Y 	‘ N			
	Duration Described ‘ Y 	‘ N			
Group	‘  Direct Measurement		‘ 	Direct Measurement	
Determination	‘  Medical Records		‘ 	Medical Records	
	‘  Self Report		‘ 	Self Report	
	Blinding   ‘ Yes  ‘ No			Blinding  ‘ Yes   ‘ No	
Ascertainment	‘  Direct Measurement		‘ 	Direct Measurement	
of Outcome	‘  Medical Records		‘ 	Medical Records	
	‘  Self Report		‘ 	Self Report	
	Blinding   ‘ Yes   ‘ No		Blinding   ‘ Yes   ‘ No		
					
Outcome					

					

					

Subject Characteristics

Characteristic	Cohort	Exposed	Unexposed	
 Age
				
SES (Define)
				
% Family History of
     Disease				
% Caucasian
				
% Rupture
				
% Explantation
				
  Yrs Since Implantation
				
% Reconstruction Due to
     Breast Cancer				
% Cosmetic
				
% Bilateral
				
% Unilateral

Group Differences:  

Data Analysis:  ‘  All subjects    ‘ Loss to follow up excluded

Outcome	N				Crude	Adjusted	Factors Adjusted 	Translation	
and					OR/RR 	OR/RR			
Exposure					(CI)	(CI)			
Outcome		D	D	T/PY			‘ Age		
							‘ Education		
	E						‘ Income		
							‘ Marital Status		
Exposure	E						‘ Race		
							‘		
	T						‘		
							‘		
Outcome		D	D	T/Py			‘ Age		
							‘ Education		
	E						‘ Income		
							‘ Marital Status		
Exposure	E						‘ Race		
							‘		
	T						‘		
							‘		
Outcome		D	D	T/Py			‘ Age		
							‘ Education		
	E						‘ Income		
							‘ Marital Status		
Exposure	E						‘ Race		
							‘		
	T						‘		
							‘