Kiem Oen

Epidemiology of Chronic Arthritis in Childhood

This study was performed to review reports of the descriptive epidemiology of chronic arthritis in childhood and to analyze the factors that may explain differences in its reported frequency. Articles were retrieved by searching MEDLINE and EMBASE under the following index terms: juvenile rheumatoid arthritis (JRA), juvenile chronic arthritis (JCA), spondyloarthropathy, epidemiology, prevalence, and incidence. For reports published between 1977 to 1982, the Index Medicus was used. All original articles that provided prevalence or incidence rates, population size, or number of cases, were reviewed and entered into the analysis. Variables analyzed were disease prevalence and incidence. Modifier variables investigated were diagnostic criteria, source population, geographic origin of the report (Europe or North America), duration of the study, and race of the population studied. Diagnostic criteria had no effect on reported prevalence or incidence rates. Prevalence per 100,000 at risk obtained from population studies (132, 95% CI: 119, 145) was significantly higher than values derived from practitioner- (26, 95% CI: 23, 29) or clinic-based studies (12, 95% CI: 10, 15) (P = .02). North American clinic-based studies had higher prevalence values compared with European reports (32, 95% CI: 26, 38 versus 8, 95% CI: 5, 11, P = .009). None of the factors analyzed accounted for the variability in reported incidence rates. An effect of race was detected only in the distribution of patients among onset subsets. Thus, the percentage of patients with pauciarticular JRA was highest in series of North American and European caucasian patients (58, 95% CI: 56, 60) compared with series of East Indian (25, 95% CI: 20, 31), native North American Indian (26, 95% CI: 15, 37), or other races (31, 95% CI: 28, 35) (P = .001). In contrast, the percentage of patients with polyarticular JRA was lowest in the former (27, 95% CI: 25, 28) compared with the other racial groups (East Indian, 61, 95% CI: 55, 66; native North American Indian, 64, 95% CI: 53, 76; other races, 34, 95% CI: 30, 38) (P = .004). Although an effect of source population on reported prevalence was confirmed, the effect of geographic origin suggests that environmental or ethnic differences also may influence the prevalence of chronic arthritis in children. Differences in the percentages of patients with pauciarticular and polyarticular JRA may reflect racial differences in the prevalence of these conditions.

Incident vertebral fractures among children with rheumatic disorders 12 months after glucocorticoid initiation: a national observational study.

To determine the frequency of incident vertebral fractures (IVF) 12 months after glucocorticoid (GC) initiation in children with rheumatic diseases and to identify children at higher risk.

The outcomes of juvenile idiopathic arthritis in children managed with contemporary treatments: results from the ReACCh-Out cohort

Objective To describe clinical outcomes of juvenile idiopathic arthritis (JIA) in a prospective inception cohort of children managed with contemporary treatments. Methods Children newly diagnosed with JIA at 16 Canadian paediatric rheumatology centres from 2005 to 2010 were included. Kaplan–Meier survival curves for each JIA category were used to estimate probability of ever attaining an active joint count of 0, inactive disease (no active joints, no extraarticular manifestations and a physician global assessment of disease activity <10 mm), disease remission (inactive disease >12 months after discontinuing treatment) and of receiving specific treatments. Results In a cohort of 1104 children, the probabilities of attaining an active joint count of 0 exceeded 78% within 2 years in all JIA categories. The probability of attaining inactive disease exceeded 70% within 2 years in all categories, except for RF-positive polyarthritis (48%). The probability of discontinuing treatment at least once was 67% within 5 years. The probability of attaining remission within 5 years was 46–57% across JIA categories except for polyarthritis (0% RF-positive, 14% RF-negative). Initial treatment included joint injections and non-steroidal anti-inflammatory drugs for oligoarthritis, disease-modifying antirheumatic drugs (DMARDs) for polyarthritis and systemic corticosteroids for systemic JIA. Conclusions Most children with JIA managed with contemporary treatments attain inactive disease within 2 years of diagnosis and many are able to discontinue treatment. The probability of attaining remission within 5 years of diagnosis is about 50%, except for children with polyarthritis.

Immunogenetic Risks of Anti-Cyclical Citrullinated Peptide Antibodies in a North American Native Population with Rheumatoid Arthritis and Their First-degree Relatives

Objective. To determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in unaffected relatives of North American Native probands with rheumatoid arthritis (RA); and the associations of the shared epitope (SE) and HLA-DRB1*0901 with RA and anti-CCP antibodies. Methods. The subjects were RA probands, affected relatives, unaffected first-degree (FDR) and more distant relatives, and unaffected controls from the same population. HLA-DRB1 typing was determined by DNA sequencing and anti-CCP antibodies were determined by ELISA. Results. DRB1*0901, SE, and SE/DRB1*0901 genotypes were all associated with RA. SE/DRB1*0901, but not other SE genotypes, was associated with disease onset at age < 16 years. The frequency of anti-CCP antibodies was 82% in RA probands, 17% in FDR, 11% in more distant relatives, and 3% in controls. Among unaffected relatives, a significant increased risk of anti-CCP was associated with SE/DRB1*0901 genotype, but not with SE. Conclusion. An independent association of the non-SE allele DRB1*0901 with RA was confirmed in this population, and this allele in combination with a SE allele was associated with younger age at disease onset. FDR of RA probands have a higher prevalence of anti-CCP antibodies than more distant relatives and unrelated controls, suggesting a gradient of risk for disease development. Immunogenetic risks may act early in disease pathogenesis at the level of initiation of RA autoantibody formation; however, it is not clear what additional genetic and environmental risks are involved in progression to clinical disease.

Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort

To determine early outcomes and early improvements in a prospective inception cohort of children with juvenile idiopathic arthritis (JIA) treated with current standard therapies.

Predictors of early inactive disease in a juvenile idiopathic arthritis cohort: Results of a Canadian multicenter, prospective inception cohort study

OBJECTIVE To determine early predictors of 6-month outcomes in a prospective cohort of patients with juvenile idiopathic arthritis (JIA). METHODS Patients selected were those enrolled in an inception cohort study of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study, within 6 months after diagnosis. The juvenile rheumatoid arthritis core criteria set and quality of life measures were collected at enrollment and 6 months later. Outcomes evaluated included inactive disease, Juvenile Arthritis Quality of Life Questionnaire (JAQQ) scores, and Childhood Health Assessment Questionnaire (C-HAQ) scores at 6 months. RESULTS Thirty-three percent of patients had inactive disease at 6 months. Onset subtype and most baseline core criteria set measures correlated with all 3 outcomes. Relative to oligoarticular JIA, the risks of inactive disease were lower for enthesitis-related arthritis, polyarthritis rheumatoid factor (RF)-negative JIA, and polyarthritis RF-positive JIA, and were similar for psoriatic arthritis. In multiple regression analyses, the baseline JAQQ score was an independent predictor of all 3 outcomes. Other independent baseline predictors included polyarthritis RF-negative and systemic JIA for inactive disease; C-HAQ score and polyarthritis RF-positive JIA for the 6-month C-HAQ score; and active joint count, pain, and time to diagnosis for the 6-month JAQQ score. CONCLUSION Clinical measures soon after diagnosis predict short-term outcomes for patients with JIA. The JAQQ is a predictor of multiple outcomes. Time to diagnosis affects quality of life in the short term.

Malignancies in Juvenile Idiopathic Arthritis: A Preliminary Report

Objective. To present preliminary data on incidence of malignancy in juvenile idiopathic arthritis (JIA), compared to general population rates. Methods. We examined cancer occurrence within JIA registries at 3 Canadian pediatric rheumatology centers. The subjects in the clinic registries were linked to regional tumor registries to determine the occurrence of invasive cancers over the observation period (spanning 1974–2006). The total number of cancers expected was determined by multiplying the person-years in the cohort by age, sex, and calendar year-specific cancer rates. The standardized incidence ratio (SIR, ratio of cancers observed to expected) was generated, with 95% confidence intervals. Results. The study sample consisted of 1834 patients. The female proportion was 67.6%; average age at entry to cohort was 8.6 years (SD 5.1). The majority were Caucasian. Subjects contributed 22,341 patient-years (average 12.2, SD 7.8). Within this observation period, one invasive cancer occurred, compared to 7.9 expected (SIR 0.12, 95% CI 0.0, 0.70). This was a hematological cancer (Hodgkin’s lymphoma), representing a SIR for hematological malignancies of 0.76 (95% CI 0.02, 4.21). Conclusion. Only one invasive cancer was identified in this large sample of individuals with JIA, observed for an average of 12.2 years each. These data suggest that, at least in the initial years following diagnosis of JIA, the risk of invasive cancers overall is not markedly increased. The results do not rule out the possibility of a baseline increased risk of hematological malignancies.

Seasonal onset of systemic-onset juvenile rheumatoid arthritis☆☆☆★

OBJECTIVE This study was undertaken to investigate the recent finding of a seasonal difference in the onset of systemic-onset juvenile rheumatoid arthritis (SoJRA). We hypothesized that a seasonal onset pattern might implicate on infectious agent as a cause of SoJRA. METHODS The date of onset was collected from the records of all patients with SoJRA from 1980 to 1992 at presentation to pediatric rheumatology clinics across Canada. The onset pattern of SoJRA was then compared with incidence data on viral infections obtained for the same period. RESULTS Across Canada the onset of SoJRA was constant across the seasons. However, in the Prairie region there was a statistically significant seasonal pattern, with peaks in autumn and early spring. We could find no evidence that viral incidence correlated with disease incidence either throughout Canada or in the Prairie region. CONCLUSIONS If a seasonal infectious agent causes SoJRA, then it is likely only one of several causes and may act only in certain regions. Future studies should be carried out in those areas where SoJRA does have a seasonal onset pattern.

Non-HLA genes modulate the risk of rheumatoid arthritis associated with HLA-DRB1 in a susceptible North American Native population

Most of the genetic risk for rheumatoid arthritis (RA) is conferred by ‘shared epitope’ (SE), encoding alleles of HLA-DRB1. Specific North American Native (NAN) populations have RA prevalence rates of 2–5%, representing some of the highest rates estimated worldwide. As many NAN populations also demonstrate a high background frequency of SE, we sought to determine whether other genetic factors contribute to disease risk in this predisposed population. RA patients (n=333) and controls (n=490) from the Cree/Ojibway NAN population in Central Canada were HLA-DRB1 typed and tested for 21 single-nucleotide polymorphisms (SNPs) that have previously been associated with RA, including PTPN22, TRAF1-C5, CTLA4, PADI4, STAT4, FCRL3, CCL21, MMEL1-TNFRSF14, CDK6, PRKCQ, KIF5A-PIP4K2C, IL2RB, TNFAIP3, IL10-1082G/A and REL. Our findings indicate that SE is prevalent and represents a major genetic risk factor for RA in this population (82% cases versus 68% controls, odds ratio=2.2, 95% confidence interval 1.6–3.1, P<0.001). We also demonstrate that in the presence of SE, the minor allele of MMEL1-TNFRSF14 significantly reduces RA risk in a dominant manner, whereas TRAF1-C5 increases the risk. These findings point to the importance of non-HLA genes in determining RA risk in a population with a high frequency of disease predisposing HLA-DRB1 alleles.

Incident vertebral fractures and risk factors in the first three years following glucocorticoid initiation among pediatric patients with rheumatic disorders

Vertebral fractures are an important yet underrecognized manifestation of osteoporosis in children with chronic, glucocorticoid‐treated illnesses. Our goal was to determine the incidence and clinical predictors of vertebral fractures in the 3 years following glucocorticoid initiation among pediatric patients with rheumatic disorders. Incident vertebral fractures were evaluated according to the Genant semiquantitative method on lateral radiographs at baseline and then annually in the 3 years following glucocorticoid initiation. Extended Cox models were used to assess the association between vertebral fractures and clinical risk predictors. A total of 134 children with rheumatic disorders were enrolled in the study (mean ± standard deviation (SD) age 9.9 ± 4.4 years; 65% girls). The unadjusted vertebral fracture incidence rate was 4.4 per 100 person‐years, with a 3‐year incidence proportion of 12.4%. The highest annual incidence occurred in the first year (6.0%; 95% confidence interval (CI) 2.9% to 11.7%). Almost one‐half of the patients with fractures were asymptomatic. Every 0.5 mg/kg increase in average daily glucocorticoid (prednisone equivalents) dose was associated with a twofold increased fracture risk (hazard ratio (HR) 2.0; 95% CI 1.1 to 3.5). Other predictors of increased vertebral fracture risk included: (1) increases in disease severity scores between baseline and 12 months; (2) increases in body mass index Z‐scores in the first 6 months of each 12‐month period preceding the annual fracture assessment; and (3) decreases in lumbar spine bone mineral density Z‐scores in the first 6 months of glucocorticoid therapy. As such, we observed that a clinically significant number of children with rheumatic disorders developed incident vertebral fractures in the 3 years following glucocorticoid initiation. Almost one‐half of the children were asymptomatic and thereby would have been undiagnosed in the absence of radiographic monitoring. In addition, discrete clinical predictors of incident vertebral fractures were evident early in the course of glucocorticoid therapy.