Rheumatoid Arthritis: Laxer RM

Laxer RM. · Department of Pediatrics and Medicine, University of Toronto, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. · Pediatr Clin North Am. · Pubmed #15820370 No free full text.

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Laxer RM, Harrison C. · No affiliation provided · J Rheumatol. · Pubmed #11669147 links to  free full text

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Hashkes PJ, Laxer RM. · Department of Rheumatic Diseases A50, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Curr Rheumatol Rep. · Pubmed #17092444 No free full text.

Abstract: Many exciting developments in the treatment of juvenile idiopathic arthritis (JIA) have emerged recently, including new tools to assess the results of clinical trials (eg, the definition of remission and a radiologic scoring tool). New controlled studies examined the equivalence of meloxicam to naproxen, the efficacy of leflunomide but the superiority of methotrexate, and the use of infliximab in polyarthritis JIA. Initial studies have shown the potential of anti-interleukin (IL)-1 and anti-IL-6 receptor antibody therapy for systemic JIA. Corticosteroid-sparing medications including the use of "biologic modifiers" for JIA-associated uveitis have been described. Evidence-based guidelines for the main subtypes of JIA have been published. However, good evidence on the treatment of several disease subtypes is still lacking. Studies of new medications and the use of combination therapy, including aggressive induction therapy early in the disease course, are necessary to continue improving the outcome of JIA patients.

Tse SM, Laxer RM. · The Hospital for Sick Children, Toronto, Ontario, Canada. · Pediatr Rev. · Pubmed #16651274 No free full text.

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Hashkes PJ, Laxer RM. · Section of Pediatric Rheumatology, Department of Rheumatic Diseases, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. · JAMA. · Pubmed #16204667 links to  free full text

Abstract: CONTEXT: The treatment of juvenile idiopathic arthritis (JIA) has changed markedly in the last 15 years. Many children with JIA are not treated by pediatric rheumatologists. OBJECTIVE: To review the best evidence for the treatment of JIA. DATA SOURCES: English-language trials of JIA between 1966 and 2005 were searched using MEDLINE, EMBASE, the Cochrane database, and abstracts from recent rheumatology and pediatric scientific meetings. STUDY SELECTION: Randomized controlled trials and open studies including at least 10 patients for medications without controlled trials. DATA EXTRACTION: For studies after 1997, the American College of Rheumatology Pediatric 30 outcome measure was used to define patients as responders. For older studies, the primary response outcome measure defined by the authors was used. DATA SYNTHESIS: Thirty-four controlled studies were identified. Nonsteroidal anti-inflammatory drugs are effective only for a minority of patients, mainly those with oligoarthritis. Intra-articular corticosteroid injections are very effective for oligoarthritis. Methotrexate is effective for the treatment of extended oligoarthritis and polyarthritis and less effective for systemic arthritis. Sulfasalazine and leflunomide may be alternatives to methotrexate. Antitumor necrosis factor medications are highly effective for polyarticular course JIA not responsive to methotrexate but are less effective in systemic arthritis. There is a lack of evidence for the optimal treatment of systemic and enthesitis-related arthritis. CONCLUSIONS: Despite many advances in the treatment of JIA, there is still a lack of evidence for treatment of several disease subtypes. The treatment plan needs to be individualized based on the JIA subtype.

Tse SM, Laxer RM. · Department of Pediatrics, Hospital for Sick Children, University of Toronto, Ontario, Canada. · Curr Opin Rheumatol. · Pubmed #12819463 No free full text.

Abstract: The juvenile-onset spondyloarthropathies are a group of pediatric disorders characterized by arthropathy and enthesopathy and a variety of extra-articular symptoms. With the application of new classification criteria, there is an increasing recognition of these diseases. This review summarizes recent advances in etiologic factors, clinical manifestations, therapeutics, and prognosis. Improved recognition of juvenile-onset spondyloarthropathies has allowed systematic and rigorous treatment trials to evaluate clinical outcomes relevant to pediatric medicine. Thus far, current therapeutic options allow for symptomatic control only. Further treatment studies are needed to examine the possibility of disease modification of juvenile-onset spondyloarthropathies.

Laxer RM, Clarke HM. · Division of Rheumatology, University of Toronto, Ontario, Canada. · Hand Clin. · Pubmed #11117055 No free full text.

Abstract: Rheumatic diseases are common in the pediatric population. Because the hand surgeon is often the first specialist to whom children with rheumatic disease involving the upper extremity are referred, it is important they are aware of the wide variety of disorders that can present with joint complaints to facilitate prompt referral and treatment of these patients.

Uziel Y, Berkovitch M, Gazarian M, Koren G, Silverman ED, Schneider R, Laxer RM. · Divisions of Rheumatology and Clinical Pharmacology and Toxicology, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #12610822 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of eutectic lidocaine/prilocaine cream (EMLA) in reducing the pain associated with steroid joint injection in children with juvenile arthritis. METHODS: A randomized, double blind, placebo controlled parallel group trial. Thirty-one children (ages 8-18 yrs) scheduled for steroid injection into a knee were randomized into groups having either 2.5 g lidocaine/prilocaine cream or placebo cream applied to the injection site 60-90 min before the procedure. Patients assessed the pain associated with initial needle insertion and subsequent steroid injection using a 10 cm visual analog scale. RESULTS: No significant difference was found in the pain reported after needle insertion or steroid injection between the lidocaine/prilocaine cream group (n = 17) and the placebo group (n = 14). There was a trend toward an association of lower median scores with the pain of steroid injection in the lidocaine/prilocaine group (6 mm) compared with the placebo group (22 mm). CONCLUSION: Application of 2.5 g lidocaine/prilocaine cream for 60-90 min had no statistically significant analgesic effect on pain associated with injections of steroids into the knees of children with juvenile arthritis.

Singh-Grewal D, Schneiderman-Walker J, Wright V, Bar-Or O, Beyene J, Selvadurai H, Cameron B, Laxer RM, Schneider R, Silverman ED, Spiegel L, Tse S, Leblanc C, Wong J, Stephens S, Feldman BM. · The Hospital for Sick Children, Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #17907238 links to  free full text

Abstract: OBJECTIVE: To examine the effectiveness of high-intensity aerobic training compared with low-intensity training in terms of energy cost of locomotion, peak oxygen uptake, peak power, and self-reported physical function in children with juvenile idiopathic arthritis (JIA). METHODS: Eighty children with JIA, ages 8-16 years, were enrolled in a randomized, single-blind controlled trial. Both groups participated in a 12-week, 3-times-weekly training program consisting of high-intensity aerobics in the experimental group and qigong in the control group. Subjects underwent exercise testing measuring submaximal oxygen uptake at 3 km/hour (VO(2submax)) as the primary outcome, maximal oxygen uptake, and peak power at the beginning and end of the program. Physical function was measured using the Child Health Assessment Questionnaire (C-HAQ). RESULTS: The exercise program was well tolerated in both groups. There was no difference in VO(2submax) or any other exercise testing measures between the groups through the study period and no indication of improvement. Both groups showed significant improvements in C-HAQ with no difference between the groups. Adherence was higher in the control group than the experimental group. CONCLUSION: Our findings suggest that activity programs with or without an aerobic training component are safe and may result in an important improvement in physical function. The intensity of aerobic training did not seem to provide any additional benefits, but higher adherence in the qigong program may suggest that less intensive regimens are easier for children with JIA to comply with, and provide a degree of benefit equivalent to more intensive programs.

Saurenmann RK, Rose JB, Tyrrell P, Feldman BM, Laxer RM, Schneider R, Silverman ED. · Zurich University Children's Hospital, Zurich, Switzerland. · Arthritis Rheum. · Pubmed #17530723 links to  free full text

Abstract: OBJECTIVE: To study the influence of ethnicity on the risk of developing juvenile idiopathic arthritis (JIA) in a multiethnic community of patients with unrestricted access to health care. METHODS: A questionnaire on ethnicity was distributed to all patients with JIA being followed up at the Hospital for Sick Children in Toronto, Ontario, Canada. Of 1,082 patients, 859 (79.4%) responded to the questionnaire. To calculate the relative risk (RR) of developing JIA in this study cohort, the results were compared with data from the age-matched general population of the Toronto metropolitan area (TMA) as provided in the 2001 census from Statistics Canada. RESULTS: European descent was reported by 69.7% of the patients with JIA compared with a frequency of 54.7% in the TMA general population, whereas a statistically significantly lower than expected percentage of the patients with JIA reported having black, Asian, or Indian subcontinent origin. Children of European origin had a higher RR for developing any of the JIA subtypes except polyarticular rheumatoid factor (RF)-positive JIA, and were particularly more likely to develop the extended oligoarticular and psoriatic subtypes. A higher frequency of enthesitis-related JIA was observed among patients of Asian origin, while those of black origin or native North American origin were more likely to develop polyarticular RF-positive JIA. CONCLUSION: In this multiethnic cohort, European descent was associated with a significantly increased risk of developing JIA, and the distribution of JIA subtypes differed significantly across ethnic groups.

Saurenmann RK, Levin AV, Feldman BM, Rose JB, Laxer RM, Schneider R, Silverman ED. · Department of Pediatrics, University Children's Hospital, Zurich, Switzerland. · Arthritis Rheum. · Pubmed #17265500 links to  free full text

Abstract: OBJECTIVE: To assess the prevalence, risk factors, and long-term outcome of uveitis in patients with juvenile idiopathic arthritis (JIA). METHODS: An inception cohort of all 1,081 patients diagnosed as having JIA at a single tertiary care center was established. A questionnaire and followup telephone calls were used to confirm the diagnosis of uveitis. Ophthalmologists' records of patients with uveitis were collected. Kaplan-Meier and Cox regression analyses were used to assess risk factors for developing uveitis and for complications of uveitis. RESULTS: After a mean followup time of 6.9 years, 142 of 1,081 patients (13.1%) had developed uveitis. Risk factors were young age at diagnosis, female sex, antinuclear antibody positivity, and the subtype of JIA. The relative contribution of these risk factors was different for the different subtypes of JIA. Until the end of the study, uveitis complications had developed in 53 of 142 patients with uveitis (37.3%; 4.9% of the total cohort). Only 16 of 175 involved eyes (9.1%) in 14 of 108 patients (13%; 1.3% of the total cohort) for whom ophthalmology reports were available had best corrected visual acuity less than 20/40 (mean followup time for uveitis of 6.3 years). Abnormal vision was associated with synechiae or cataract. CONCLUSION: Risk factors for developing uveitis were different among subtypes of JIA. The long-term outcome of JIA-associated uveitis in our cohort was excellent despite the high rate of complications.

Saurenmann RK, Levin AV, Feldman BM, Laxer RM, Schneider R, Silverman ED. · Division of Rheumatology, the Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. · J Pediatr. · Pubmed #17137902 No free full text.

Abstract: OBJECTIVE: To determine whether treatment with tumor necrosis factor alpha (TNFalpha)-blocking agents alters the incidence of new-onset uveitis in patients with juvenile idiopathic arthritis (JIA). STUDY DESIGN: Cohort study based on retrospective chart review. The charts of all 1109 patients with a diagnosis of JIA seen between January 1, 1996, and June 30, 2003, at our clinic were reviewed for diagnosis of uveitis and treatment with TNFalpha inhibitors. Cox regression analysis was performed with anti-TNFalpha treatment as a time-dependent covariate for risk of development of uveitis. RESULTS: We identified 70 patients treated with anti-TNFalpha without a prior diagnosis of uveitis. Two of these 70 patients (2.9%), both treated with etanercept, had development of new-onset uveitis during anti-TNFalpha therapy. One had juvenile psoriatic arthritis diagnosed 4.1 years before onset of uveitis. The other had extended oligoarticular JIA diagnosed 6.4 years before onset of uveitis. We found no statistically significant difference in the risk for development of uveitis between patients with or without anti-TNFalpha treatment. CONCLUSIONS: In our patients with JIA, anti-TNFalpha treatment did not alter the risk for development of new-onset uveitis. However, anti-TNFalpha therapy with etanercept did not prevent the development of uveitis in 2 patients.

Tse SM, Laxer RM, Babyn PS, Doria AS. · Department of Pediatrics, Division of Rheumatology, The Hopital for Sick Children, Tonoto, Ontario, M5G IX8 Canada. · J Rheumatol. · Pubmed #16755667 No free full text.

Abstract: Children with juvenile spondyloarthropathy, classified as enthesitis-related arthritis (ERA) under the International League of Associations for Rheumatology classification of juvenile idiopathic arthritis, usually experience both arthritis and enthesitis. Treatment with anti-tumor necrosis factor-alpha (TNF-alpha) agents has resulted in dramatic clinical improvement. Radiologic imaging methods useful in the detection, diagnosis, and grading of arthritis and enthesitis include magnetic resonance imaging and ultrasonography. We describe the serial radiologic improvements of arthritis and enthesitis in a child with ERA in response to treatment with the anti-TNF-alpha agent etanercept.

Saurenmann RK, Levin AV, Rose JB, Parker S, Rabinovitch T, Tyrrell PN, Feldman BM, Laxer RM, Schneider R, Silverman ED. · Division of Rheumatology, Hospital for Sick Children, Toronto, Canada. · Rheumatology (Oxford). · Pubmed #16461435 links to  free full text

Abstract: OBJECTIVE: To describe the efficacy of anti-TNF-alpha agents in the treatment of childhood uveitis. METHODS: We performed a retrospective chart review of all children with uveitis treated with TNF-alpha blockers at The Hospital for Sick Children, Toronto. RESULTS: Twenty-one children with uveitis were treated with the anti-TNF-alpha agents etanercept (11 patients) and infliximab (13 patients), resulting in 24 treatment courses. All patients had persistently active uveitis despite treatment with at least one standard immunosuppressive drug before the start of anti-TNF-alpha therapy. Six of 21 patients (29%) had idiopathic uveitis. In the other 15 patients, the underlying disease was juvenile idiopathic arthritis in 12 (57%), Behçet disease in two (9%) and sarcoidosis in one (5%). Response to etanercept treatment was good in 27%, moderate in 27% and poor in 45% of patients. Response to infliximab treatment was good in 38%, moderate in 54% and poor in 8% of patients. The difference in the percentage of patients with a moderate or good response was statistically significant (P = 0.0481). We also observed a lower rate of complications, such as new-onset or worsening glaucoma or cataract in the infliximab-treated group. CONCLUSION: Anti-TNF-alpha treatment was beneficial in a high percentage of patients with childhood uveitis refractory to standard immunosuppressive treatment. Infliximab resulted in better clinical responses with less ocular complications than etanercept.

Duffy CM, Colbert RA, Laxer RM, Schanberg LE, Bowyer SL. · Montreal Children's Hospital of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada. <> · Arthritis Rheum. · Pubmed #15692991 links to  free full text

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Ramanan AV, Rosenblum ND, Feldman BM, Laxer RM, Schneider R. · Department of Pediatrics, Health Policy Management and Evaluation, and Public Health Sciences, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #15468377 No free full text.

Abstract: Systemic-onset juvenile rheumatoid arthritis (SoJRA) constitutes about 10-20% of all JRA. However more than two-thirds of the mortality seen in JRA patients is accounted for by SoJRA. Macrophage activation syndrome (MAS), which can also be considered as a form of secondary hemophagocytic lymphohistiocytosis, is a major cause of morbidity and mortality in children with SoJRA. MAS is characterized by persistent high fever, pancytopenia, mild to serious derangements of liver cell function, encephalopathy, and disseminated intravascular coagulation. Renal involvement in MAS is a rarely recognized feature. In 2 recently reported case series of MAS in SoJRA, renal involvement appeared to be associated with poor prognosis. We describe 3 children with SoJRA who had renal involvement complicating MAS and had a favorable outcome.

Muzaffer MA, Dayer JM, Feldman BM, Pruzanski W, Roux-Lombard P, Schneider R, Laxer RM, Silverman ED. · Division of Rheumatology, Hospital for Sick Children, Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #12022325 No free full text.

Abstract: OBJECTIVE: To determine whether levels of soluble tumor necrosis factor receptor 55 (sTNFR55), sTNFR75, and interleukin 1 receptor antagonist (IL-1Ra) can differentiate different subtypes of juvenile rheumatoid arthritis (JRA), and to determine if the levels of these proteins correlate with disease activity. METHODS: Serum sTNFR (55 and 75) and IL-1Ra levels were measured by ELISA in 34 patients with JRA and these values were correlated with disease subtype and activity. RESULTS: Serum sTNFR55 levels were significantly elevated in patients with systemic onset JRA (SoJRA) (mean +/- 2 SD, 2.9 +/- 1.8 ng/ml) (p < or = 0.05) compared to rheumatoid factor positive (RF+) polyarticular JRA (2.1 +/- 0.6), RF-polyarticular JRA (1.5 +/- 0.6), and pauciarticular JRA (1.4 +/- 0.4). There was a trend for elevation of sTNFR75 levels in patients with SoJRA compared to other subtypes (p = 0.08). More patients had elevated levels of sTNFR75 than sTNFR55 (15 vs 7). This was true for all subsets (SoJRA 7 vs 5; polyarticular JRA 4 vs 2; and pauciarticular JRA 4 vs 0). In contrast to sTNFR, IL-1Ra levels were significantly elevated in RF+ polyarticular JRA compared to the other subgroups (p < or = 0.001). We found statistically significant Pearson correlations between (1) sTNFR75 and hemoglobin concentration: and (2) IL-1Ra and number of active joints and number of joints with effusions. CONCLUSION: The increased serum level of sTNF receptors in SoJRA suggests that TNF is likely more important than IL-1 in systemic inflammation and in particular in SoJRA. Conversely, IL-1 is likely more important in the inflammatory arthritis of JRA and in particular in the pathogenesis of RF+ polyarticular JRA. Our results suggest that cytokines have differing roles in JRA subtypes and likely reflect JRA subtype heterogeneity.

Tse S, Lubelsky S, Gordon M, Al Mayouf SM, Babyn PS, Laxer RM, Silverman ED, Schneider R, Feldman BM. · Department of Pediatrics, Medicine, Immunology, Diagnostic Imaging, and Public Health Sciences, Hospital for Sick Children, University of Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #11196524 No free full text.

Abstract: OBJECTIVE: Arthritis has been an associated finding in juvenile dermatomyositis (JDM), but its prevalence, course, and response to therapy has not been well described. We investigated the frequency, course, and clinical and radiographic features in a large cohort of patients with JDM. METHODS: The charts of 94 patients with idiopathic myositis (1984-99) were reviewed: 80 JDM, 3 juvenile polymyositis (JPM), 5 amyopathic JDM, and 6 overlap myositis syndromes. Compiled data included demographics, clinical features, a detailed description of the arthritis, investigations (radiographs, autoantibodies), course, and response to therapy. All radiographs were independently reviewed by a single radiologist. RESULTS: Sixty-one percent (95% CI 50-72%) of patients with JDM had arthritis. The arthritis was reported a median 4.5 mo (range -73.6 to 76.6 mo) after the JDM onset. When compared to patients with no arthritis, the occurrence of arthritis was not significantly related to sex, race, positive antinuclear antibody or rheumatoid factor, calcinosis, nodules, vasculitis, or Raynaud's phenomenon. The initial involvement was pauciarticular in 67% and polyarticular in 33%. In the pauci group, asymptomatic knee effusions were the predominant finding (n = 19, 58%), and in 18 patients may have been the result of steroid therapy. Two patients evolved from a pauci onset to a polyarticular course. All responded to therapy (corticosteroids; 47 were taking other medications) with remission of the arthritis within a median of 2.0 mo (range 0.1-64.5 mo). However, the arthritis recurred in 39% as the corticosteroids were tapered. Four patients with JDM eventually required corticosteroid wrist injections, with resolution of the arthritis. The arthritis was nonerosive in all cases. No patient with JPM had arthritis. Three of 5 patients with amyopathic JDM and 4 of 6 with overlap myositis syndrome had a nonerosive polyarthritis. CONCLUSION: Nonerosive arthritis involving the knees, wrists, elbows, and fingers is a frequent manifestation of JDM and other idiopathic childhood myositis. The arthritis is seen early in the course of JDM and often responds to treatment. However, the arthritis may recur with tapering of corticosteroids despite remission of the JDM. In a significant proportion of JDM cases, arthritis is the major sequela and may warrant further medical therapy or intraarticular corticosteroid injections.

Spiegel LR, Schneider R, Lang BA, Birdi N, Silverman ED, Laxer RM, Stephens D, Feldman BM. · The Hospital for Sick Children, University of Toronto, Ontario, Canada. · Arthritis Rheum. · Pubmed #11083261 links to  free full text

Abstract: OBJECTIVE: To examine the ability of a previously described set of criteria to predict poor functional outcome in a large, multicenter cohort of children with systemic-onset juvenile rheumatoid arthritis (JRA). METHODS: All children who were diagnosed with systemic-onset JRA since 1980 at the Hospital for Sick Children (Toronto), since 1983 at the Isaac Walton Killam Hospital for Children (Halifax), and since 1981 at the Children's Hospital of Eastern Ontario (Ottawa) were evaluated. Patients were included in the study if they had been evaluated clinically within 6 months of diagnosis and had been followed up for at least 2 years. Patients were divided into 4 cohorts according to their length of followup: 2-4 years, 4-7 years, 7-10 years, and >10 years. Using previously described criteria for destructive arthritis in children with systemic-onset JRA, the patients were classified as either high risk or low risk for poor functional outcome based on the data from their 6-month visit. High-risk patients had active systemic disease (persistent fever or corticosteroid requirement for control of systemic disease) and a platelet count > or =600 x 10(9)/liter. Poor outcome was defined as moderate or severe disability (defined as a score of > or =0.75 on the Childhood Health Assessment Questionnaire) or disease-associated death. RESULTS: Among 122 eligible patients with systemic-onset JRA, we were able to contact 111 (91%) for outcome data. The mean followup period was 7.7 years (SD 3.7). The mean age at outcome assessment was 13.5 years (SD 5.3). There were 51 boys and 60 girls. Twenty-four patients (22%) had moderate-to-severe disability and 2 patients died; these 26 patients were considered to have had a poor outcome. We could determine risk classification for 104 patients. Twenty-four patients (23%) met the criteria for high risk at the 6-month visit. Overall, the risk of a poor functional outcome was significantly higher in the high-risk group (relative risk 3.3, 95% confidence interval [95% CI] 1.73-6.43, P = 0.0004). This risk was most marked in the cohort with > 10 years of followup (relative risk 4.3, 95% CI 1.82-10.29, P = 0.006). CONCLUSION: The presence of active systemic disease at 6 months, as characterized by fever or the need for corticosteroids, and thrombocytosis strongly predicted the development of a poor functional outcome in these patients. This was especially apparent with longterm followup. Our study validates the previously developed prognostic criteria for systemic-onset JRA.

Marcelino J, Carpten JD, Suwairi WM, Gutierrez OM, Schwartz S, Robbins C, Sood R, Makalowska I, Baxevanis A, Johnstone B, Laxer RM, Zemel L, Kim CA, Herd JK, Ihle J, Williams C, Johnson M, Raman V, Alonso LG, Brunoni D, Gerstein A, Papadopoulos N, Bahabri SA, Trent JM, Warman ML. · Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA. · Nat Genet. · Pubmed #10545950 No free full text.

Abstract: Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.