Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-18 years with rheumatoid factor (RF)-positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (> or =10 mg/m(2)/week [ approximately 0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. RESULTS: A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. CONCLUSION: These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

Cyclosporine A in juvenile idiopathic arthritis. Results of the PRCSG/PRINTO phase IV post marketing surveillance study.

OBJECTIVE: To investigate the clinical use patterns, clinical effect and safety of cyclosporine A (CSA) in juvenile idiopathic arthritis (JIA) in the setting of routine clinical care. METHODS: An open-ended, phase IV post marketing surveillance study was conducted among members of the Pediatric Rheumatology Collaborative Study Group (PRCSG) and of the Paediatric Rheumatology International Trials Organisation (PRINTO) to identify patients with polyarticular course JIA who had received CSA during the course of their disease. RESULTS: A total of 329 patients, half of whom had systemic JIA, were collected in 21 countries. Data were collected during 1240 routine clinic visits. CSA was started at a mean of 5.8 years after disease onset and was given at a mean dose of 3.4 mg/kg/day. The drug was administered in combination with MTX in 61% and along with prednisone in 65% of the patients who were still receiving CSA. Among patients who were still receiving CSA therapy at the last reported visit, remission was documented in 9% of the patients, whereas in 61% of the patients the disease activity was rated as moderate or severe. The most frequent reason for discontinuation of CSA was insufficient therapeutic effect (61% of the patients); only 10% of the patients stopped CSA because of remission. In 17% of the patients, side effects of therapy was given as the primary reason for discontinuation. CONCLUSION: This survey suggests that CSA may have a less favourable efficacy profile than MTX and etanercept, whereas the frequency of side effects may be similar. The exact place of CSA in the treatment of JIA can only be established via controlled clinical trial.

Gene expression in juvenile arthritis and spondyloarthropathy: pro-angiogenic ELR+ chemokine genes relate to course of arthritis.

OBJECTIVE: To evaluate the ability of microarray-based methods to identify genes with disease-specific expression patterns in peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) of juvenile arthritis patients and healthy controls. METHODS: Microarray data (Affymetrix U95Av2) from 26 PBMC and 20 SFMC samples collected from patients with active disease (classified by course according to ACR criteria) were analysed for expression patterns that correlated with disease characteristics. For comparison, PBMC gene expression profiles were obtained from 15 healthy controls. Real-time PCR was used for confirmation of gene expression differences. RESULTS: Statistical analysis of gene expression patterns in PBMC identified 378 probe sets corresponding to 342 unique genes with differing expression levels between polyarticular course patients and controls (t test, P<0.0001). The genes represented by these probe sets were enriched for functions related to regulation of immune cell functions, receptor signalling as well as protein metabolism and degradation. Included in these probe sets were a group of CXCL chemokines with functions related to angiogenesis. Further analysis showed that, whereas angiogenic CXCL (ELR+) gene expression was elevated in polyarticular PBMC, expression of angiostatic CXCL (ELR-) chemokines was lower in polyarticular SFMC compared with corresponding pauciarticular samples (t test, P<0.05). CONCLUSIONS: This pilot study demonstrates that juvenile arthritis patients exhibit complex patterns of gene expression in PBMC and SFMC. The presence of disease-correlated biologically relevant gene expression patterns suggests that the power of this approach will allow better understanding of disease mechanisms, identify distinct clinical phenotypes in disease subtypes, and suggest new therapeutic approaches.

Expression of angiogenic factors in juvenile rheumatoid arthritis: correlation with revascularization of human synovium engrafted into SCID mice.

OBJECTIVE: Although increased vascularity was noted in early histopathologic studies of juvenile rheumatoid arthritis (JRA) synovium, the available data on angiogenesis in JRA are very limited. The main purposes of this study were to assess expression of the key angiogenic factors in JRA synovium, and to evaluate a SCID mouse model of JRA as an approach to study in vivo regulation of the expression of these factors in JRA. METHODS: RNase protection assay was used to assess the expression of the key angiogenic factors in fresh JRA synovium and in JRA synovial tissue fragments that had been minced and then implanted into SCID mice. Vascularity of the samples was assessed by immunohistochemical staining for von Willebrand factor. Synovial specimens obtained from patients with osteoarthritis (OA) or other noninflammatory arthropathies were used as controls. RESULTS: Detectable levels of messenger RNA for vascular endothelial growth factor and angiopoietin 1 and their respective receptors, as well as endoglin and thrombin receptors, were present in all JRA tissue specimens studied. The levels of expression of these factors in JRA tissues were significantly higher than those in tissues obtained from patients with OA or other noninflammatory arthropathies. Furthermore, increased expression of the key angiogenic factors in the fresh JRA tissues correlated with the exuberant revascularization of JRA minced tissue fragments implanted into SCID mice. This was in sharp contrast to the poor revascularization of implanted OA tissues. CONCLUSION: JRA synovium is characterized by high angiogenic activity. SCID mouse-human JRA synovium chimeras may provide a good approach to study the in vivo regulation of angiogenesis in JRA.

Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs.

OBJECTIVE: To test for linkage between the HLA region and juvenile rheumatoid arthritis (JRA), with stratification by onset and course types, in a cohort of affected sibling pairs (ASPs). METHODS: Eighty pairs of siblings with JRA who were registered with the Research Registry for JRA ASPs (sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases) were typed for HLA-DR. The observed ratio of sharing of none, one, or both parental DR alleles was compared against the expected ratio of 1:2:1 by goodness-of-fit chi-square tests. A group of 265 unrelated control subjects served as a comparison population for HLA-DR allele frequencies among patients, by Fisher's exact test. RESULTS: Overall, there was excess sharing of 2 DR alleles among ASPs with JRA. The observed ratio of sharing 0, 1, or 2 DR alleles was 8:40:32, instead of the expected ratio of 20:40:20 (P < 0.001). When stratified by JRA onset type, excess allele sharing was demonstrated among ASPs who were concordant for onset type (P = 0.002). This was true for both pauciarticular and polyarticular onset. When stratified by disease course, excess allele sharing was also demonstrated among ASPs who were concordant for disease course (P < 0.001). This was true for both the pauciarticular and the polyarticular course. Among the 32 ASPs who shared two DR alleles, 5 pairs had both DR8 and DR11, which was significantly more frequent (P < 0.0001) than the incidence in the control group (n = 0). CONCLUSION: This study of an independent cohort of multiplex families confirms the previously reported linkage between pauciarticular JRA and the HLA-DR region that was identified using a different analytic method in a cohort of simplex families. Additionally, this study establishes evidence for linkage between polyarticular JRA and the HLA-DR region.

Evidence-based medicine in pediatric rheumatology.

Evidence-based medicine (EBM) has increasingly gained importance over the past two decades. This review defines and discusses EBM in the light of specific issues relating to pediatrics and pediatric rheumatology. The efforts of pediatric rheumatologists to practice and promote EBM are summarized.

Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.

BACKGROUND: We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. METHODS: Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. RESULTS: At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. CONCLUSIONS: Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

In vivo survival of autoreactive B cells: characterization of long-lived B cells.

To determine the effects of chronic Ag stimulation on B cell survival and phenotype, we compared survival and surface markers of hen egg lysozyme (HEL)-specific B cells in Ig transgenic (Tgn) mice, which lack HEL, and in HEL-Ig transgenic mice, which express soluble HEL. Serum HEL levels were maximized in HEL-Ig Tgn mice by feeding them zinc, which activates the metallothionein promoter that regulates HEL expression. B cell age was characterized by expression of heat-stable Ag, and B220 and B cell survival was studied by evaluating changes in B cell number when lymphopoiesis was suppressed with anti-IL-7 mAb and by identifying newly generated B cells through 5-bromo-2'-deoxyuridine incorporation. Our observations show that the mean B cell life span is considerably reduced in HEL-Ig Tgn compared with Ig Tgn mice, but also demonstrate that some HEL-Ig Tgn B cells survive to maturity. Some of these surviving B cells have undergone receptor editing (substitution of an endogenous Ig light chain for the transgenic Ig light chain), so that their ability to bind HEL is decreased or absent. Surviving HEL-Ig Tgn B cells that retain HEL specificity express decreased mIgD and little or no mIgM. mIgD expression progressively decreases with increasing HEL-Ig Tgn B cell age. These observations suggest that self Ag-specific B cells can survive in the presence of soluble self Ag by down-regulating mIg expression, which should limit B cell signaling by Ag that might otherwise cause deletion of these cells.

Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer.

Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are anti-inflammatory proteins that can suppress collagen-induced arthritis (CIA). These and related proteins have shown efficacy in the treatment of human rheumatoid arthritis; however, neither alone is able to completely suppress disease. Furthermore, they have short half-lives, necessitating frequent administration. To determine the ability of these proteins to act synergistically following gene transfer, arthritis was induced in DBA/1 male mice by immunization with type II collagen on days 0 and 21. Mice were injected i.v. either before disease onset (day 20) or after disease onset (day 28) with 1010 particles of adenovirus encoding vIL-10, a soluble TNF receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both vectors, or a control vector lacking a transgene. Significant synergism was observed with the combination of vIL-10 and sTNFR-Ig, with a substantial reduction in both the incidence and severity of disease as well as inhibition of progression of established disease. sTNFR-Ig alone had no effect on CIA. vIL-10 alone inhibited disease when given before disease onset, but had minimal effect on established disease. Both proteins inhibited spleen cell proliferation and IFN-gamma secretion in response to stimulation with type II collagen, but only vIL-10 reduced the synovial mRNA levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6. These findings demonstrate that vIL-10 and sTNFR-Ig act synergistically in suppressing CIA and suggest that gene transfer offers a potential therapeutic modality for the treatment of arthritis.

Development of validated disease activity and damage indices for the juvenile idiopathic inflammatory myopathies. II. The Childhood Myositis Assessment Scale (CMAS): a quantitative tool for the evaluation of muscle function. The Juvenile Dermatomyositis Disease Activity Collaborative Study Group.

OBJECTIVE: To develop, validate, and determine the measurement characteristics of a quantitative tool for assessing the severity of muscle involvement in children with idiopathic inflammatory myopathies. METHODS: The Childhood Myositis Assessment Scale (CMAS) was developed from 2 existing observational functional assessment tools to assess muscle function in the areas of strength and endurance across a wide range of ability and ages. The 14 ordinal items included were chosen to assess primarily axial and proximal muscle groups and are ranked with standard performance and scoring methods. Following the development of the CMAS, a training video and written instructions were developed and reviewed by the physicians participating in this study. Subsequently, utilizing a randomized block design, 12 physicians independently scored 10 children (9 with dermatomyositis, 1 with polymyositis; ages 4-15 years) twice in one day (morning and afternoon) on the CMAS. A pediatric physical therapist performed quantitative manual muscle strength testing (MMT) twice on each child (morning and afternoon), including the neck, trunk, and proximal and distal extremity muscle groups. RESULTS: The CMAS has a potential range of 0-51, with higher scores indicating greater muscle strength and endurance. The observed mean for the 10 patients was 36.4 (median 44, SD 14.1, observed range 5-51). The total score for the CMAS correlated with the physician's global assessment (by visual analog scale) of disease activity, the MMT score, serum creatine kinase level, and the Juvenile Arthritis Functional Assessment Report score. The score on the CMAS was not correlated with patient age. Interrater reliability (Kendall's coefficient of concordance) ranged from 0.77 to 1.0 for individual items (all P < 0.001), and overall, it was 0.95 (P < 0.001). Intrarater reliability for the individual physicians was measured by correlation of the CMAS scores for each patient on 2 separate evaluations and ranged from 0.97 to 0.99, with an overall correlation for all physicians of 0.98 (all P < 0.001). CONCLUSION: The CMAS demonstrated an acceptable range of observed scores, excellent convergent validity, and excellent inter- and intrarater reliability. The CMAS is validated to quantitatively assess muscle function in the areas of strength and endurance in children with idiopathic inflammatory myopathies. It can be used in routine clinical care as well as therapeutic trials.

Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles.

OBJECTIVE: To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. METHODS: We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. RESULTS: Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. CONCLUSION: These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.

Cross-cultural adaptation and validation of an Argentine Spanish Version of the Stanford Childhood Health Assessment Questionnaire.

OBJECTIVES: To translate into Argentine Spanish and cross-culturally adapt the Childhood Health Assessment Questionnaire (CHAQ) and validate the adapted instrument in Argentine patients with juvenile rheumatoid arthritis (JRA). METHODS: Five bilingual Argentine pediatric rheumatologists translated into Argentine Spanish and cross-culturally adapted the United States English CHAQ. Pretesting was done in a sample of 23 parents using a probe question technique. Parents of 70 patients with JRA and 21 healthy children (controls) participated in the validation phase. All were from Argentina. RESULTS: The mean disability index (DI) scores for patients with systemic, polyarticular, or pauciarticular onset JRA were 0.64, 0.32, and 0.1, respectively. Healthy controls averaged 0.2. Intercomponent correlations were between 0.4 and 0.9, suggesting internal consistency, but also some redundancy. Test-retest reliability, studied at a 1-week interval, was moderate (mean DI 0.44 [in clinic] and 0.29 [one week later], Pearson's correlation = 0.82). We compared CHAQ scores from 15 parents with those of their children > 10 years of age. Significantly higher DI scores were given by patients than their respective parents (P > 0.019), but the pairwise scores (parent-patient) were highly correlated (r = 0.986). CONCLUSIONS: Cross-cultural adaptation of the US CHAQ to Argentina required few changes. Although DI scores for all patient subgroups were higher than for controls subjects, the scores were low, particularly for those with pauciarticular disease. Prospective studies designed to examine the sensitivity to change and predictive validity will help to assess further the usefulness of the adapted CHAQ in the Argentine population.

Transmission disequilibrium as a test of linkage and association between HLA alleles and pauciarticular-onset juvenile rheumatoid arthritis.

OBJECTIVE: To determine if HLA class I and II alleles previously found to be associated with (or protective against) pauciarticular-onset juvenile rheumatoid arthritis (pauci-onset JRA) in population-association studies are transmitted from heterozygous parents to an extent different from the expected 50%. METHODS: One hundred one Caucasian North American families that had a child with pauci-onset JRA and at least 1 parent who was heterozygous for the allele of interest were available for analysis. Both biologic parents and all children (affected and unaffected) were typed for HLA class I and II alleles. The transmission disequilibrium test (TDT) was used to determine if affected offspring received the disease-associated (or protective) allele more (or less) frequently than its alternate allele. In families in which an unaffected sibling was available, the unmatched chi-square test was used to determine if a meiotic segregation distortion bias existed. RESULTS: HLA class I alleles A2, B27, and B35 showed a significantly higher than expected frequency of transmission to affected offspring, as did class II alleles DR5 and DR8. HLA-DR4 was found to be transmitted significantly less frequently than expected to affected, but not unaffected, offspring. All alleles that showed an excess transmission to affected offspring were transmitted to unaffected offspring at expected rates. When the data were stratified by age and sex, the likelihood of transmission of some of the alleles was strongly influenced by these variables. For example, excess transmission of HLA-DR5 was found exclusively in female patients who were younger at the time of disease onset. CONCLUSION: Results from these family-based studies rule out the possibility that HLA disease associations found in earlier studies were a result of population stratification and establish linkage and association between the major histocompatibility complex and pauci-onset JRA.

Inhibition of collagen-induced arthritis in mice by viral IL-10 gene transfer.

Autoimmune arthritides are characterized by an imbalance between pro- and anti-inflammatory cytokines. Viral IL-10 (vIL-10) shares many of the anti-inflammatory properties of mouse and human IL-10, but lacks their immunostimulatory properties and may therefore offer superior immunosuppression. Viral IL-10 has a short half-life; however, genetic modification of cells in vivo offers a potential means of achieving prolonged therapeutic titers. To determine the effects on collagen-induced arthritis of vIL-10 gene transfer, DBA/1 mice were administered i.v. or intra-articular injections of Av(vIL-10), a replication-deficient adenovirus encoding vIL-10. The i.v. injection of Av(vIL-10) before disease onset delayed the onset and reduced the severity of collagen-induced arthritis, but treatment of established disease was ineffective. The preventative effects were not due to decreased anti-type II collagen Ab production. Rather, T cells from mice treated with Av(vIL-10) demonstrated a decreased in vitro proliferative response to type II collagen, and a delay was observed in up-regulation of synovial mRNA for the proinflammatory cytokines IL-2 and IL-1beta. Intra-articular injection of Av(vIL-10) into knee joints did not reduce arthritis in the knees, but inhibited the development of arthritis in the paws. Humoral and cellular immune responses against Av(vIL-10) were observed. These results demonstrate that vIL-10 can significantly alter the course of autoimmune arthritis and emphasize the complexities of using gene transfer as a method of drug delivery for arthritis.

Estimates of the discriminant ability of definitions of improvement for juvenile rheumatoid arthritis.

OBJECTIVE: To investigate the ability of various definitions of improvement to distinguish between patients with juvenile rheumatoid arthritis (JRA) treated with active drug from those given placebo in randomized trials. METHODS: A core set of 6 response (outcome) variables for use in JRA has been reported. These core variables were combined into a number of "definitions of improvement" for the purpose of classifying individual patients as either "clinically significantly improved" or "not improved." We used a large dataset from randomized controlled trials to test the discriminant ability (sensitivity to change) of the definitions. We calculated the proportion of patients classified as "improved" by each definition in each of the treatment and control groups. RESULTS: Effect sizes were weak in 4 of the treatment regimens used (D-penicillamine, hydroxychloroquine, auranofin, and very low dose methotrexate) and no definition discriminated well between drug and placebo treated groups. Definitions that required 20 to 30% improvement in 3 to 4 of the 6 core set variables showed statistically significant differences in the proportions of patients who were classified as improved in the group treated with low dose methotrexate (10 mg/m2 body surface area/wk) compared to placebo. A definition resembling the Paulus criteria used in adult RA trials (4 of 6 core set variables improved by > or = 20%) performed well, as did the definition selected previously as the best for JRA (3 of 6 core set variables improved by > or = 30%, not more than one worsening by > 30%). CONCLUSION: Definitions that require 20 to 30% improvement in 3 to 4 core outcome variables are sensitive to change and are able to clearly distinguish between treated and control groups when an effective drug is being tested. Further testing of their validity is under way.

Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States.

OBJECTIVE: To provide a single source for the best available estimates of the national prevalence of arthritis in general and of selected musculoskeletal disorders (osteoarthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, the spondylarthropathies, systemic lupus erythematosus, scleroderma, polymyalgia rheumatica/giant cell arteritis, gout, fibromyalgia, and low back pain). METHODS: The National Arthritis Data Workgroup reviewed data from available surveys, such as the National Health and Nutrition Examination Survey series. For overall national estimates, we used surveys based on representative samples. Because data based on national population samples are unavailable for most specific musculoskeletal conditions, we derived data from various smaller survey samples from defined populations. Prevalence estimates from these surveys were linked to 1990 US Bureau of the Census population data to calculate national estimates. We also estimated the expected frequency of arthritis in the year 2020. RESULTS: Current national estimates are provided, with important caveats regarding their interpretation, for self-reported arthritis and selected conditions. An estimated 15% (40 million) of Americans had some form of arthritis in 1995. By the year 2020, an estimated 18.2% (59.4 million) will be affected. CONCLUSION: Given the limitations of the data on which they are based, this report provides the best available prevalence estimates for arthritis and other rheumatic conditions overall, and for selected musculoskeletal disorders, in the US population.

Juvenile rheumatoid arthritis in affected sibpairs.

OBJECTIVE: To describe the demographics and clinical disease in affected sibpairs (ASPs) with juvenile rheumatoid arthritis (JRA), and to compare JRA as it occurs in ASPs with that from non-ASP JRA populations described in the literature. METHODS: A rare disease research registry was established with a focus on JRA ASPs to facilitate accrual of patients for genetic, epidemiologic, and clinical studies. Physicians likely to care for patients with JRA were made aware of the registry and its goals by a variety of methods and asked to refer patients for entry. RESULTS: To date, 71 ASPs have been registered and complete information has been obtained. These affected sibs differed in age by a mean of 4.1 years (SD 3.4) and in age at disease onset by 2.8 years (SD 3.0). The actual time difference between onset in sib 1 versus sib 2 averaged 4.4 years (SD 4.2). Sixty-three percent of the sibpairs were concordant for sex, and 76% for JRA onset type. Onset type within sibpairs did not appear to be random, based upon comparisons with non-ASP populations. Greater than expected concordance was seen among those with pauciarticular-onset and polyarticular-onset JRA. Seventy-nine percent of the pairs were concordant for course type. Seven sets of twins were included (approximately 10% of the total), all were concordant for onset and course type (6 sets with pauciarticular, 1 set with polyarticular), and disease onset was separated by a mean of only 3.3 months. Within the onset and course types, the clinical disease, such as the female:male ratio, age at onset, and serologic findings, in ASPs resembled that which has been described in the literature. CONCLUSION: A higher than expected degree of concordance for onset type of JRA exists between sibpairs, indicating that genetic influences play a role. Affected sibs do not tend to develop their disease at approximately the same point in time, except for the twin sets. Clinical features of the disease within the various subtypes appear similar to those in non-ASP populations.