Funding

Osteoarthritis Initiative

Updated July 21, 2001

Appendix B: The European Longitudinal Studies of OA

Population-based

Patient-based

Chingford Study

PI: Tim D. Spector, MD, MSC, and Deborah J. Hart, PhD, St. Thomas Hospital, London (tim.spector@kcl.ac.uk and zmmd2386@mail.kcl.ac.uk)

Population studied: Population-based cohort of middle-class white women, ages 45-67 (mean age 54), from Chingford, London, established in 1988-89 (n=1003). At 4-year follow-up, n=840. Includes symptomatic and asymptomatic individuals.

Endpoints: Osteophytes, joint space narrowing, knee injury, pain assessment (NHANES definition), past fractures and ongoing incident fractures, bone loss, Heberden's nodes. Also, risk factors for prevalent OA -- obesity, smoking, ERT, BMD, C-reactive protein (CRP), activity -- and risk factors for incident and progressive OA.

Accessibility of data: Collaborators gain access to specific data relating to the collaborative work.

Joints evaluated: Knee, hip, hand, spine

Specimens: Serum obtained at baseline stored at -20°C, measured for CRP, sex hormones, sex hormone-binding globulin, IGF-1, and dehydroepiandrosterone sulphate. Urine and DNA also available.

Imaging studies: Anteroposterior radiograph of hands at baseline and years 1 and 2. Weight-bearing AP radiograph of knees with legs in full extension. 4 years and 10 years later, repeat AP extended-view weight-bearing knee radiograph. Annual DEXA (dual energy x ray absorptiometry) scans of the hip and spine. Whole body scans also available years 8 and 10 and central fat analysis from DEXA scan.

Status: Active and closed (84% of cohort still actively followed)

Summary of strengths and limitations:
Strengths: This is a very extensive cohort that is still actively followed. Radiography is consistent and standardized over 10 years; validated algorithm on spinal changes over 3 time points; prospective radiographs at sites to ascertain changes and timepoint of disease occurring or progression. Specimens are easily retrieved and many markers have already been done (sex hormones, IGGs, CRP, osteocalcin, pyridiniline). All women live near the center and could be recalled for extra data/blood sampling at no cost.
Limitations: Supplies of some markers are low.

Major findings:

  • About 3 percent of middle-aged women (ages 45-67) will develop radiologic knee OA every year. The importance of obesity is confirmed as the major modifiable risk factor for OA. Evidence from this study supports the notion of a protective effect of estrogen replacement therapy. Could not confirm an association between OA and smoking (Hart 1999).

  • A low-level increase in C-reactive protein, a marker of joint inflammation, occurs in early OA and is predictive of progressive loss of joint pace. Increased levels of CRP at presentation should help to identify individuals at risk of progression who may be suitable for intervention (Spector 1997).

  • Weight-bearing sports activity in women is associated with a 2- to 3-fold increased risk of radiologic OA of the knees and hip (Spector 1996).

  • A retrospective study of fractures rejects the hypothesis that increased BMD associated with radiologic OA leads to a decrease in osteoporotic fractures, with the exception of the lumbar spine, where the hypothesis was supported (Arden 1996).

  • There is a modest association between IGF-I concentrations and the development of distal interphalangeal osteoarthritis and more severe or bilateral knee osteoarthritis in women from the general population, but no association with other forms of OA, bone density, or fractures (Lloyd 1996).

  • In this community-based study, skyline views performed better than lateral views for identifying symptomatic patellofemoral joint OA (Cicuttini 1996).

  • Hypertension, hypercholesterolemia, and blood glucose are associated with both unilateral and bilateral knee OA independent of obesity, which supports the concept that OA has an important systemic and metabolic component in its etiology (Hart 1995).

  • Small increases in BMD are present in middle aged women with early radiologic OA of the hands, knees, and lumbar spine. These data support the hypothesis that the two conditions are inversely related, although mechanisms remain unclear (Hart 1994).

Relevant references:
Hart DJ, Doyle DV, Spector TD. Incidence and risk factors for radiographic knee osteoarthritis in middle-aged women: The Chingford Study. Arthritis Rheum 1999;42:17-24. [UI: 99116737]

Spector TD, Hart DJ, Nandra D, Doyle DV, Mackillop N, Gallimore JR, Pepys MB. Low-level increases in serum c-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 1997;40:723-7. [UI: 97244307]

Spector TD, Harris PA, Hart DJ, Cicuttini FM, Nandra D, Etherington J, Wolman RL, Doyle DV. Risk of osteoarthritis associated with long-term weight-bearing sports. Arthritis Rheum 1996;39:988-95. [UI: 96232429]

Arden NK, Griffiths GO, Hart DJ, Doyle DV, Spector TD. The association between osteoarthritis and osteoporotic fracture: the Chingford study. British J Rheum 1996;35:1299-1304. [UI: 97163225]

Lloyd ME, Hart DJ, Nandra D, McAlindon TE, Wheeler M, Doyle DV, Spector TD. Relation between insulin-like growth factor-I concentrations, osteoarthritis, bone density, and fractures in the general population: the Chingford study. Ann Rheum Dis 1996;55:870-4. [UI: 97166890]

Cicuttini FM, Baker J, Hart DJ, Spector TD. Choosing the best method for radiological assessment of patellofemoral osteoarthritis. Ann Rheum Dis 1996;55:134-6.
[UI: 96263577]

Hart DJ, Doyle DV, Spector TD. Association between metabolic factors and knee osteoarthritis in women: the Chingford study. J Rheumatol 1995;22:1118-23.
[UI: 95404550]

Hart DJ, Mootoosamy I, Doyle DV, Spector TD. The relationship between osteoarthritis and osteoporosis in the general population: the Chingford study. Ann Rheum Dis 1994;53:158-62. [UI: 94206096]

Malmö #1: Preventive Study

Olof Johnell, MD, PhD, is the contact for bones and joints, Malmö University Hospital, Malmö, Sweden (olof.johnell@orto.mas.lu.se)

Population studied: Population-based study of 33,000 men and women recruited in Malmo City. 22,000 men screened in 1979 (mean age 44) and 11,000 women screened in 1984 (mean age 49), for a study of prevention of cardiovascular disease, cancer, and osteoporosis. For a new osteoarthritis arm of the study, individuals who have had a total hip replacement have been identified, as have those with an x-ray showing a pathological outcome other than fracture, including osteoarthritis.

Endpoints: Incident OA, total hip or knee replacement, all fractures, death. Thorough baseline examination of risk factors.

Accessibility of data: Available with approval. Will be competing with Cancer and CHD research for blood samples.

Joints evaluated: Knee, hip, hand, spine.

Specimens: Serum stored at -20°C. DNA can be collected if a sample of the cohort is called back.

Imaging studies: BMD of 1300 participants at baseline.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: Follow-up is long-term: 20 years for men and 15 years for women. The study will enable analysis of risk factors for hip and knee OA, including severe disease indicating total hip or knee replacement.
Limitations: No baseline x-rays.

Relevant References: N/A

Malmö #2: Nutrition and Cancer Study
Olof Johnell, MD, PhD, is the contact for bones and joints, Malmö University Hospital, Malmö, Sweden (olof.johnell@orto.mas.lu.se)

Population studied: Population-based sample of 30,000 men and women from Malmo City, age range 45-70 at time of recruitment. This study was developed to evaluate the nutrition effects of diseases such as cardiovascular disease, cancer, and osteoporosis. Individuals had extensive interviews concerning their nutrition and other risk factors, as well as blood sampling. To date, follow-up is 3 years.

Endpoints: Incident OA, total hip or knee replacement, all fractures, death. Thorough baseline examination of risk factors.

Accessibility of data: Available with approval. Will be competing with Cancer and CHD research for blood samples.

Joints evaluated: Knee, hip, hand, spine.

Specimens: Serum/plasma, DNA stored at -70°C.

Imaging studies: Incident x-rays and BMD of 11000 participants at baseline.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: They have permission to run these data together with computer files of the Radiology Dept. to identify all fractures. It will be possible to identify all who had an OA examination after baseline and study risk factors and blood samples to identify those who will develop clinical OA.
Limitations: No baseline x-rays.

Relevant References: N/A

Progetto Veneto Anziani (PRO.V.A.)

PI: Maria-Chiara Corti, MD, MHS (cortic@ux1.unipd.it)

Population studied: Population-based study of a representative sample of 3000 community-dwelling men and women age 65 years and older (age and sex-stratified). Study sample drawn from one rural and one urban area of the Veneto Region of Italy. Includes symptomatic and asymptomatic individuals. Re-evaluation every 2 years for total of 4 years follow-up. Study developed in collaboration with WHAS researchers to characterize the disease-disability relationship, with special focus on cardiovascular and osteoarticular disease.

Endpoints: Radiographic (eg., joint space narrowing), hospitalizations, morbidity, mortality, nursing home admissions, change in physical function. Not clear if follow-up radiographs will be done.

Accessibility of data: Unknown.

Joints evaluated: Knee, hip, hand.

Specimens: Serum collected at baseline.

Imaging studies: X-rays include fluoro-positioned semilflexed knee films and skylines. MRI done also. Both x-rays and MRI done every 15 months.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: Extensive collateral disability data, both self-reported and physical performance measures.
Limitations:

Major findings/Relevant references:

N/A

Rotterdam Study, The Netherlands

PI: Huibert A. Pols, MD, PhD, Erasmus University Medical School, Rotterdam, The Netherlands (pols@inw3.azr.nl)

Population studied: A population-based study of men and women ages 55 and older (n=2745) from the general population of Rotterdam. The Rotterdam Study's aim is to study determinants and prognosis of chronic diseases in the elderly, focusing on cardiovascular, neurogeriatric, ophthalmologic, and locomotor diseases. Baseline data collected in 1990-93.

Endpoints: Radiographic OA (Kellgren scale), lower limb disability assessed using questionnaire modified from Stanford Health Assessment Questionnaire, BMD measured by DEXA, BMI, genotypes of IGF-1 and vitamin D3 receptor (VDR) gene.

Accessibility of data: Available with approval.

Joints evaluated: Knee, hip, hand, spine.

Specimens: Baseline serum and DNA stored at -20°C and -196°C (limited amount available). Overnight fasting urine also taken.

Imaging studies: Weight-bearing anteroposterior radiographs of the pelvis and knees at baseline and at 2-year follow-up. Also anterior-posterior radiographs of the hands and wrists and lateral radiographs of the spine. Follow-up images taken after approximately 5 years.

Status: Active and closed. Adding a cohort ages 55-65 years.

Summary of strengths and limitations:
Strengths: An extensive data set, similar to Chingford and Health ABC. Extensive data on other major diseases in the elderly available. Cohort defined to a restricted area.
Limitations:

Major findings:

  • The IGF-1 genotype is associated with the prevalence of radiographic OA in knee, hip, hand, or spine, irrespective of BMD, BMI, and age. These findings suggest that IGF-1 plays a part in OA pathogenesis (Meulenbelt 1998).

  • The vitamin D3 receptor (VDR) gene is associated with radiographic OA of the knee. The association was largely explained by the presence of osteophytes rather than joint space narrowing, which might indicate involvement of the VDR gene in the molecular mechanisms regulating the development of osteophytes (Uitterlinden 1997).

  • Radiographic OA of the knee and hip are associated with high BMD and increased rate of bone loss (Burger 1996).

Relevant References:
Meulenbelt I, Bijkerk C, Miedema HS, Breedveld FC, Hofman A, Valkenburg HA, Pols HA, Slagboom PE, van Duijn CM. A genetic association study of the IGF-1 gene and radiological osteoarthritis in a population-based cohort study (the Rotterdam Study). Ann Rheum Dis 1998 Jun;57(6):371-4. [UI: 98444152]

Uitterlinden AG, Burger H, Huang Q, Odding E, Duijn CM, Hofman A, Birkenhager JC, van Leeuwen JP, Pols HA. Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee. J Clin Invest 1997 Jul 15;100(2):259-63.
[UI: 97364791]

Burger H, van Daele PL, Odding E, Valkenburg HA, Hofman A, Grobbee DE, Schutte HE, Birkenhager JC, Pols HA. Association of radiographically evident osteoarthritis with higher bone mineral density and increased bone loss with age. The Rotterdam Study. Arthritis Rheum 1996 Jan;39(1):81-6. [UI: 96133265]

Bristol Phasic OA Knee Study Cohort 1 (TFJ)

PI: John R. Kirwan, MD, Bristol Royal Infirmary, U.K. (John.kirwan@bristol.ac.uk)

Population studied: 135 hospital-referred, caucasian, male and female patients, ages 38 to 81 (mean age 64) with radiographic changes in at least one knee compartment. Study began in 1996.

Endpoints: Joint space narrowing, progression to total knee replacement. Other endpoints are knee crepitus, bony swelling, soft tissue swelling, fixed flexion deformity, obvious instability, new disease, surgery, disability and pain (WOMAC), anxiety and depression, body mass index, current treatments. Will link radiographic changes to symptoms and signs.

Accessibility of data: Possibly accessible by mutual agreement. Data are already being used by others.

Joints evaluated: Knee

Specimens: Serum, urine collected every 6 months, stored at -70° C. Six collections are completed, two are in process, one remains.

Imaging studies: Scintigraphy of the knee; subchondral bone density measured every 6 months by DEXA. Standing anteroposterior radiograph and lateral radiographs in 30 degrees flexion for each knee at entry and after 2, 3, and 4 years of follow-up.

Status: Active and closed

Summary of strengths and limitations:
Strengths: Patients have relatively early disease. Follow-up is regular, frequent, and comprehensive. Attrition rate is low. Aliquots of stored serum and urine are available and are already being used in biomarker studies. Potential for international collaboration.
Limitations:

John Kirwan is PI for additional relevant cohorts:

Bristol Phasic OA Knee Study Cohort 2
87 men and women originally part of a randomized controlled trial of physiotherapy in patello-femoral knee OA. Primary endpoint is more than 2 mm reduction in joint space or progression to knee joint replacement surgery. Blood and urine are collected annually. Radiographs are standing AP and 15 degree lateral knee radiographs. Its usefulness is limited in that the initial assessment was not as comprehensive as might be required now and full follow-up assessments have only been introduced later in the protocol. There are, however, some remaining serum and urine samples and the group is a convenient comparator to the Bristol Phasic OA Knee Study Cohort 1. Follow up for years 3 and 4 has been approved and partially funded.

Bristol Phasic OA Knee Study Cohort 3
Hospital outpatients, ages 35 and older, with anterior knee pain. Study will enroll patients with predominantly patello-femoral OA knee as evidenced by radiographic joint space narrowing osteophytes, or sclerosis; and patients with minor or no radiographic changes but arthroscopic or MRI evidence of cartilage damage. Part of a pilot study of viscosupplementation of patello-femoral knee OA. Follow-up is planned for 1 year. Could seek approval for extension of follow-up.

Bristol, OA 500
500 symptomatic hospital-referred patients. Study is closed and inactive. No follow-up studies planned. Many patients will have died or moved by now. Not a well-characterized patient group. All joints evaluated, except spine; concentration on knees. No serum samples available. This cohort was followed by more recent, well-characterized cohorts above. X-rays available and being used by others.

Major findings (from Bristol OA500 and Bristol Phasic OA Knee Cohort 1 (TFJ):

  • Raised serum CRP reflects events that precede a period of later radiographic progression of knee OA. However, serum CRP or hyaluronic acid concentration are not good predictors of individual patient progression and have poor sensitivity and specificity (Sharif 2000).

  • There was no correlation between radiographic and clinical changes over 3 years for patients with established, symptomatic limb joint OA. Radiographic changes may not be a good surrogate for clinical outcome in established OA (Dieppe 1997).

  • There is an association between late-phase bone scintigraphic scan abnormalities and synovial fluid biochemical markers (osteocalcin) of bone turnover in OA (Sharif 1995/Arthritis Rheum, first in list).

  • Serum hyaluronic acid levels predict disease outcome in OA of the knee; a single measurement of the serum level of keratan sulfate is not useful as a prognostic marker in OA (Sharif 1995/Arthritis Rheum, second in list).

  • Changes in serum cartilage oligomeric matrix protein (COMP) may have prognostic significance and are consistent with a model of OA in which early signs of episodic clinical progression can be found in the cartilage as well as in subchondral bone (Sharif 1995, Br J Rheumatol).

Relevant references:
Sharif M, Shepstone L, Elson CJ, Dieppe PA, Kirwan JR. Increased serum C reactive protein may reflect events that precede radiographic progression in osteoarthritis of the knee. Ann Rheum Dis 2000;1:71-74. [UI: 20094611]

Dieppe PA, Cushnaghan J, Shepstone L. The Bristol 'OA500' study: progression of osteoarthritis (OA) over 3 years and the relationship between clinical and radiographic changes at the knee joint. Osteoarthritis Cartilage 1997;5:87-97. [UI: 97281512]

Sharif M, George E, Dieppe PA. Correlation between synovial fluid markers of cartilage and bone turnover and scintigraphic scan abnormalities in osteoarthritis of the knee. Arthritis Rheum 1995;38:78-81. [UI: 95118402]

Sharif M, George E, Shepstone L, Knudson W, Thonar EJ, Cushnaghan J, Dieppe P. Serum hyaluronic acid level as a predictor of disease progression in osteoarthritis of the knee. Arthritis Rheum 1995;38:760-7. [UI: 95298061]

Sharif M, Saxne T, Shepstone L, Kirwan JR, Elson CJ, Heinegard D, Dieppe PA. Relationship between serum cartilage oligomeric matrix protein levels and disease progression in osteoarthritis of the knee joint. Br J Rheumatol 1995;34:306-10.
[UI: 95307883]

ECHODIAH Study, University Rene Descartes-Paris

PI: Maxime Dougados, MD, University Rene Descartes-Paris, Hopital Cochin, Paris, France (maxime.dougados@cch.ap-hop-paris.fr)

Population studied: A patient-based study (n=508) of men and women with symptomatic hip OA (mean age 63). Recruitment for this 10-year study occurred 1993-1994.

Endpoints: Clinical (pain+function+overall) evaluated every 3 months during the first 3 years; x-rays at entry, and years 1, 2, 3, 5, 10. Total hip replacement any time during the study. Lequesne's index used to evaluate functional impairment.

Accessibility of data: Data are potentially available for collaboration with other researchers.

Joints evaluated: Hip

Specimens: Serum and urine collected at baseline, and 6-, 12-, and 36-months and stored at -20°C.

Imaging studies: Hip x-rays taken at entry, 1, 2, 3, 5, 10 years.

Status: Active and closed.

Summary of strengths and limitations:
Strengths:
Limitations:

Major findings:

  • In a 3-year study of patients with painful hip OA, changes in radiologic joint space width during the first year were highly predictive of requirement for total hip replacement during the following 2 years. These data suggest that total hip replacement could be considered a valid outcome measure of OA (Dougados 1999).

  • A number of baseline features, including distribution of joint space loss, subchondral bone production, and severity of joint space loss, are predictive of progression of hip osteoarthritis (Dougados 1997).

  • Radiologic progression of hip osteoarthritis could be defined by a change in joint space width of at least 0.6mm after a 1-year follow-up period. This is correlated with changes in clinical status of the patient, and is related not only to age and gender, but also some specific characteristics of osteoarthritis, such as localization, radiologic severity, and clinical activity (Dougados 1996).

Relevant references:
Dougados M, Gueguen A, Nguyen M, Berdah L, Lequesne M, Mazieres B, Vignon E. Requirement for total hip arthroplasty: an outcome measure of hip osteoarthritis? J Rheumatol 1999;26:855-61. [UI: 99244413]

Dougados M, Gueguen A, Nguyen M, Berdah L, Lequesne M, Mazieres B, Vignon E. Radiographic features predictive of radiographic progression of hip osteoarthritis. Rev Rhum Engl Ed 1997;64:795-803. [UI: 98136745]

Dougados M, Gueguen A, Nguyen M, Berdah L, Lequesne M, Mazieres B, Vignon E. Radiological progression of hip osteoarthritis: definition, risk factors, and correlations with clinical status. Ann Rheum Dis 1996;55:356-62. [UI: 96296821]

Lund University Hospital, Sweden

PI: L. Stefan Lohmander, MD, PhD, Lund University Hospital, Sweden (stefan.lohmander@ort.lu.se)

Population studied: Approximately 100 patients who had a meniscectomy in 1973, mean age 55, 74% male, evaluated 21 years after baseline survey. Now being longitudinally followed with repeat exams every 5 years, together with age- and sex-matched controls without injury. Additional patient cohorts followed from 1978, 1983-85, 1988, 1993, and so on, all with the same injury, same exams and sampling as the 1973 cohort. All cohorts are active.

Endpoints: Knees: joint space narrowing and osteophytes by standardized x-ray. Pain, stiffness, and function (by validated patient-relevant questionnaires), osteotomy, joint replacement. Hands: standardized x-ray.

Accessibility of data:_ Accessible by mutual agreement. Being used by academic investigators.

Joints evaluated: Knee, hand

Specimens: Serum, urine, knee synovial fluid collected at each examination (see above for schedule) and stored at -70° C. DNA will be collected at future visits.

Imaging studies: Standing radiograph of both knees in 15 degree flexion and hand x-rays taken at 21-year follow-up. Radiograph of hands as well.

Status: Active, currently enrolling new cohorts.

Summary of strengths and limitations:
Strengths: When complete, study will be uniquely able to analyze OA disease progression by x-ray, symptoms, and biomarkers from time of initiation of disease process. Both individuals with and without OA and symptoms following disease-initiating event are studied. Will provide prevalence and incidence data for radiological OA in retro-/prospective cohorts with isolated meniscus injury and surgery. Age- and sex-matched controls are available. Data on patient-relevant symptoms and function collected by validated questionnaires. Samples of synovial fluid, serum, and urine collected at each exam. Hand x-rays available on some cohorts. Consequences of partial and total meniscectomy will be compared. Additional risk factors such as age, sex, BMI, work and leisure activity are analyzed. Biomarker data will be related to prevalent disease at first exam and incident disease at subsequent visits.
Limitations: Resource consuming, requires long-term follow-up and repeat visits. Limited to post-injury OA.

Major findings:

  • Two new dimensions to WOMAC, Sports and Recreation Function and Knee-Related Quality of Life, were highly sensitive and discriminant outcomes in patients younger and older than 50 years and should be assessed in addition to WOMAC in subjects with post-traumatic OA of the knee (Roos 1999).

  • Total surgical removal of a meniscus following knee injury represents a significant risk factor for radiographic tibiofemoral OA, with a relative risk of 14.0 after 21 years compared to an age- and sex-matched control group without prior knee injury (Roos, 1998)

Relevant references:
Roos H, Lauren M, Adalberth T, Roos EM, Jonsson K, Lohmander LS. Knee osteoarthritis after meniscectomy. Arthritis Rheum 1998;41:687-693. [UI: 98209848]

Roos EM, Roos HP, Lohmander LS. WOMAC Osteoarthritis index -- additional dimensions for use in subjects with post-traumatic osteoarthritis of the knee. Osteoarthritis Cartilage 1999;7:216-21. [UI: 99240932]

Nottingham

PI: Michael Doherty, MD, City Hospital, Nottingham, United Kingdom (Michael.Doherty@nottingham.ac.uk)

Populations studied: Several cohorts are described below.

Cohort #1: Synovial fluid repository. A cohort of 225 Caucasian male and female patients with well-characterized knee OA (age range 46-94, mean age 72) to study baseline synovial fluid, serum, and, urine values in progressive versus non-progressive (x-ray) OA, variation in serial sampling, comparison in values between right and left knees in subjects with symmetrical and asymmetrical x-ray scores, and cross-sectional comparisons between OA subsets, normals, and inflammatory arthritis. A group of subjects with no knee disease (n=17), rheumatoid arthritis with knee involvement (n=26), and subjects with septic arthritis knee, acute pseudogout knee, or acute gout knee (n=23) have been similarly characterized. Full repository characterization commenced in 1996. 4 years of follow-up have occurred so far with plans to continue for an additional 10 years.

Endpoints: Knee x-rays, weight, height, drug use, and clinical indicators such as nodal and non-nodal OA, and calcium pyrophosphate crystals in knee synovial fluid. No evaluation of pain or function.

Accessibility of data: Investigators are happy to collaborate on the use of this resource for biochemical marker studies.

Joints evaluated: Knee

Specimens: Serum, urine, and synovial fluid (both knees when possible) taken every 3-12 months and stored at -80°C.

Imaging studies: Knee x-rays are AP extended standing and flexed skyline taken every 12 months.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: Detailed characterization and samples from 3 body compartments; includes normal SF samples.
Limitations: Hospital-referred subjects; predominantly elderly with severe structural knee OA. No data on pain or function.

Cohorts #2:Family studies for OA genetic markers. Subjects characterized by questionnaire regarding risk factors for OA, clinical examination of OA target joints, and x-rays (of the index, phenotypic joint, see below). Serum and DNA collected. Working with geneticists in Manchester, Oxford, and London on candidate and genome-wide gene association studies:

Nodal OA: 215 affected sibling pairs (defined by multiple bilateral Heberden's/Bouchard's nodes) and 108 vertical pairs (at least 1 parent and 1 affected offspring).

Hip OA: 160 affected sibling pairs, 200 pairs (1 affected, 1 unaffected), and 300 singletons with hip OA.

Knee OA: 200 affected sibling pairs (still ongoing, target is 300 pairs).

Controls: 300 non-OA elderly controls.

Cohort #3: Generalized OA in sibling pairs. Active recruitment of 200 affected sibling pair families with generalized OA, defined by radiographic hand and large joint OA, is part of a multicenter study financed by GlaxoWellcome to recruit 1400 families in the U.S. and U.K. Questionnaire data on risk factors for OA; x-rays obtained of hands, knees, and pelvis. DNA and serum are being obtained from all families.

Cohort #4: Knee pain and OA. A community-based case-control study of nutrition, occupation, and exercise. This provides 780 characterized subjects with knee pain (40% with x-ray OA) and 400 characterized subjects without knee pain (25% with x-ray OA). Subjects could be available for prospective marker study. A grant is under consideration for a prospective incident knee pain study over a 4-year period, which, if funded, could involve serum marker assessment.

Major findings:
[from Cohort #1/Synovial fluid repository]

  • Altered ratios of chondroitin sulphation patterns occur in OA and within OA subsets. These results further justify considering nodal generalized OA as a subset with a different etiopathogenesis (Lewis 1999).

  • Single time point estimation of chondroitin sulphate, keratan sulphate, hyaluronan, or total glycosaminoglycans in synovial fluid does not distinguish radiographically progressive and non-progressive knee osteoarthritis patients followed for 2 years (Fawthrop 1997).

  • Changed concentrations of ynovial fluid chondroitin sulfate and keratan sulfate can be detected in OA with a profile that differs from that seen in RA. Clinical subgroupings and local joint inflammation may influence these measures, supporting different pathogenesis within OA subgroups and requiring careful patient characterization in synovial fluid studies (Belcher 1997).

[from Cohorts #2/Family studies]

  • This study suggests that genetic anticipation (disease occurring at an earlier age in subsequent generations, with increased severity) in nodal OA, and if confirmed, a search for trinucleotide repeats is warranted (Wright 1998).

  • A significant association was identified between nodal OA and two loci on the short arm of chromosome 2 (2q 23-35). These findings need confirmation and further analysis of candidate genes in this region (Wright 1996).

Relevant references:
Lewis S, Crossman M, Flannelly J, Belcher C, Doherty M, Bayliss MT, Mason RM. Chondroitin sulphation patterns in synovial fluid in osteoarthritis subsets. Ann Rheum Dis 1999;58:441-5. [UI: 99310558]

Fawthrop F, Yaqub R, Belcher C, Bayliss M, Ledingham J, Doherty M. Chondroitin and keratan sulphate epitopes, glycosaminoglycans, and hyaluronan in progressive versus non-progressive osteoarthritis. Ann Rheum Dis 1997;56:119-22.
[UI: 97221239]

Belcher, C, Yaqub R, Fawthrop F, Bayliss M, Doherty M. Synovial fluid chondroitin and keratan sulphate epitopes, glycosaminoglycans, and hyaluronan in arthritic and normal knees. Ann Rheum Dis 1997;56:299-307. [UI: 97319027]

Wright GD, Regan M, Deighton CM, Wallis G, Doherty M. Evidence for genetic anticipation in nodal osteoarthritis. Ann Rheum Dis 1998;57:524-526. [UI: 99066172]

Wright GD, Hughes AE, Regan M, Doherty M. Association of two loci on chromosome 2q with nodal osteoarthritis. Ann Rheum Dis 1996;55:317-9. [UI: 96263223]

The Spenshult Cohort, Sweden

PI: Ingemar F. Petersson, Spenshult's Hospital for Rheumatic Diseases, Halmstad, Sweden and Tore Saxne, Lund University, Lund, Sweden (Tore.Saxne@reum.lu.se)

Population studied: A population-based study aimed at monitoring individuals with more than 3 months of knee pain during development of OA. A population-based postal survey of 2000 randomly selected men and women ages 35-54 in southwest Sweden in 1990 yielded 279 respondents with knee pain, who were offered a clinical exam and radiographic exam. 204 agreed to participate (180 remain at 8-year follow-up). Individuals are symptomatic.

Endpoints: Radiographic OA (Kellgren-Lawrence and Ahlback classifications) and MR changes in a subgroup of 60 randomly selected individuals. Serum evaluated for factors including cartilage oligomeric matrix protein (COMP) and bone sialoprotein (BSP).

Accessibility of data: Would likely be available if research aims and study objectives were sound.

Joints evaluated: Knee

Specimens: Serum taken at baseline, year 3, 5, and 8 so far. Synovial lavage fluid taken at baseline. Specimens stored at -80° C.

Imaging studies: Postanterior radiographs with straight knees in weight-bearing position and skyline patellofemoral radiographs. MRI and scintigraphy also done (for the subgroup of 60). Radiographs taken at 3, 5, and 8 years follow-up so far.

Status: Active and closed.

Summary of strengths and limitations:
Strengths: The cohort, although not very large, provides an opportunity to evaluate markers during early phases of developing OA. This is not possible in cohorts recruited on the basis of radiographic changes compatible with OA. Specimens are available. Age at inclusion is lower than in most other studies.
Limitations: It takes considerable time before a sufficient number of individuals have developed radiographic OA, but the study is relatively far along and the approach is proving feasible. This study does not compare individuals with and without symptoms; it monitors individuals with knee pain.

Major findings:

  • In individuals with knee pain, serum levels of COMP and bone sialoprotein differ between those with or without bone scan abnormalities in the knee joints. This suggests that measurements of the serum levels of these markers have potential as means for evaluation of tissue changes in individuals with long-standing knee pain in relation to early stages of OA (Petersson 1998, Br J Rheumatol & Osteoarthritis Cartilage).

  • A minimal joint space width of 5mm showed high specificity for MR-detected cartilage defects. Thus a minimal joint space of 5 mm proved to be a limit in the diagnosis of joint-space narrowing in the patello-femoral joint in middle-aged individuals with chronic knee pain (Boegård 1998).

  • Postero-anterior radiogram of the knee and minimal joint space width measurements in the radiograms are reproducible. A minimal joint space of 3 mm is a limit in diagnosing joint-space narrowing in knees with MR-detected cartilage defects. There was a high proportion of meniscal abnormality within the narrowed compartments in comparison with those that were not narrowed (Boegård 1997).

  • Prevalence of chronic knee pain was 15% in population ages 35-54. On further examination of 204 participants with knee pain, prevalence of radiographic tibiofemoral OA was about 1% as estimated by either Kellgren & Lawrence or Ahlback classifications. For most people with chronic knee pain, no structural changes were found on radiograph (Petersson 1997).

Relevant references:
Petersson IF, Boegård T, Svensson B, Heinegard D, Saxne T. Changes in cartilage and bone metabolism identified by serum markers in early osteoarthritis of the knee joint. Br J Rheumatol 1998;37:46-50. [UI: 98148230]

Petersson IF, Boegård T, Dahlstrom J, Svensson B, Heinegard D, Saxne T. Bone scan and serum markers of bone and cartilage in patients with knee pain and osteoarthritis. Osteoarthritis Cartilage 1998;6:33-9. [UI: 98279409]

Boegård T, Rudling O, Petersson IF, Sanfridsson J, Saxne T, Svensson B, Jonsson K. Joint-space width in the axial view of the patello-femoral joint. Definitions and comparison with MR-imaging. Acta Radiol 1998;39:24-31. [UI: 98141104]

Boegård T, Rudling O, Petersson IF, Sanfridsson J, Saxne T, Svensson B, Jonsson K. Postero-anterior radiogram of the knee in weight-bearing and semiflexion. Comparison with MR-imaging. Acta Radiol 1997;38:1063-70. [UI: 98056653]

Petersson IF, Boegård T, Saxne T, Silman AJ, Svensson B. Radiographic osteoarthritis of the knee classified by the Ahlback and Kellgren & Lawrence systems for tibiofemoral joint in people aged 35-54 years with chronic knee pain. Ann Rheum Dis 1997;56:493-6. [UI: 97452102]

Ulm Osteoarthritis Study, Germany

PI: Klaus-Peter Guenther, Ulm Germany (klaus-peter.guenther@rku.de)

Population studied: Patient-based study, enrolling from January 1995 to December 1996, white patients under age 76 from 4 hospitals in the southwest of Germany with symptomatic OA of the hip (200 men and 220 women) or knee (107 men and 282 women) severe enough to warrant unilateral total hip or knee replacement. Follow-up performed at 6- and 12-months and occurring now at 5 years.

Endpoints: Prevalence of generalized OA in patients with severe hip or knee OA.

Accessibility of data: Researchers are interested in scientific collaboration, but quantities of specimens are limited. Their availability would have to be determined individually, depending on a project's research aims, the groups involved, and the type of cooperation requested.

Joints evaluated: Knee, hip, hand

Specimens: Serum and urine collected at baseline (prior to surgery) as well as 6- and 12-months postoperatively, and stored at -80°C. At time of surgery, resected femoral heads and knee joint surfaces (cartilage, subchondral bone) together with synovial tissue and synovial fluid collected. Cartilage and synovial tissue are formalinized.

Imaging studies: Supine anteroposterior radiograph of both hip joints, anteroposterior weight bearing views in extension and supine lateral views of both knees, and bilateral posteroanterior hand radiographs all collected before joint replacement. Radiographs performed preoperatively and at 12-months postoperatively.

Status: Active and closed.

Summary of strengths and limitations:
Strengths:
Limitations: Population is limited to patients with advanced disease requiring total joint replacement.

Major findings:___

  • After adjusting for age and sex, there is no significant difference in the prevalence of generalized OA between patients with advanced hip or knee OA (Guenther 1998).

Relevant references:
Guenther KP, Sturmer T, Sauerland S, Zeissig I, Sun Y, Kessler S, Scharf HP, Brenner H, Puhl W. Prevalence of generalized osteoarthritis in patients with advanced hip and knee osteoarthritis: The Ulm osteoarthritis study. Ann Rheum Dis 1998:57:717-723. [UI: 99169423]