Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: preliminary results of an open-label, long-term extension study.

OBJECTIVES: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study. METHODS: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0. RESULTS: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48. CONCLUSIONS: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48. TRIAL REGISTRATION NUMBER: NCT01500551.

Feasibility of Conducting Comparative Effectiveness Research and Validation of a Clinical Disease Activity Score for Chronic Nonbacterial Osteomyelitis.

OBJECTIVE: Prospective comparative effectiveness research (CER) in chronic nonbacterial osteomyelitis (CNO) is lacking. Our objectives were to (1) determine the use and safety of each consensus treatment plan (CTP) regimen for CNO, (2) assess the feasibility of using the Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) data for CER, and (3) develop and validate a CNO clinical disease activity score (CDAS) using CHOIR. METHODS: Consenting children or young adults with CNO were enrolled into CHOIR. Demographic, clinical, and imaging data were prospectively collected. The CNO CDAS was developed through a Delphi survey and nominal group technique. External validation surveys were administered to CHOIR participants. RESULTS: One hundred forty (78.2%) CHOIR participants enrolled between August 2018 and September 2020 received at least 1 CTP regimen. Baseline characteristics from different CTP groups were well matched. Patient pain, patient global assessment, and clinical CNO lesion count were key variables included in the CNO CDAS. The CDAS showed a strong correlation with patient/parent report of difficulty using a limb, back, or jaw and patient/parent report of disease severity, but a weak correlation with patient/parent report of fatigue, sadness, and worry. The change in CDAS was significant in patients reporting disease worsening or improvement (P < 0.001). The CDAS significantly decreased after initiating second-line treatments from median 12.0 (IQR 8.0-15.5) to 5.0 (IQR 3.0-12.0; P = 0.002). Although second-line treatments were well tolerated, psoriasis was the most common adverse event. CONCLUSION: The CNO CDAS was developed and validated for disease monitoring and assessment of treatment effectiveness. CHOIR provided a comprehensive framework for future CER.

Determination of Relative Weightings for Sacroiliac Joint Pathologies in the OMERACT Juvenile Arthritis Magnetic Resonance Imaging Sacroiliac Joint Score.

This study aims to determine the relative weights (point value) of items of the juvenile idiopathic arthritis magnetic resonance imaging-sacroiliac joint scoring system (JAMRIS-SIJ). An adaptive multicriteria decision analysis was performed using the 1000Minds web application to determine the relative weights of the items in the JAMRIS-SIJ inflammation and damage domains. Experts in imaging and rheumatology independently completed a conjoint analysis survey (CAS) to determine the point value of the measurement items of the JAMRIS-SIJ. Each CAS survey question asked the expert to compare two hypothetical patient profiles, which were otherwise similar but different at two items at a time, and to select which item showed a more severe stage of inflammation or osteochondral damage. In addition, experts ranked 14 JAMRIS-SIJ grade only or image + grade patient vignettes while blinded to the CAS-derived weights. The validity of the weighted JAMRIS-SIJ was tested by comparing the expert CAS-weighted score and the image + grade ranking method. Seventeen experts completed the CAS (11 radiologists and 6 rheumatologists). Considering the point value for inflammation domain items, osteitis (24.7%) and bone marrow edema (24.3%) had higher group-averaged percentage weights compared to inflammation in erosion cavity (16.9%), joint space enhancement (13.1%), joint space fluid (9.1%), capsulitis (7.3%), and enthesitis (4.6%). Similarly, concerning the damage domain, ankylosis (41.3%) and erosion (25.1%) showed higher group-averaged weights compared to backfill (13.9%), sclerosis (10.7%), and fat metaplasia lesion (9.1%). The Spearman correlation coefficients of the CAS-weighted vignette order and unweighted JAMRIS-SIJ grade only order vignettes for all experts were 0.79 for inflammation and 0.80 for damage. The correlations of image vignettes among imaging experts to CAS were 0.75 for inflammation and 0.90 for damage. The multicriteria decision analysis identified differences in relative weights among the JAMRIS-SIJ measurement items. The determination of the relative weights provided expert-driven score scaling and face validity for the JAMRIS-SIJ, enabling the future evaluation of its longitudinal construct validity.

Childhood Sjögren syndrome: features of an international cohort and application of the 2016 ACR/EULAR classification criteria.

OBJECTIVE: Sjögren syndrome in children is a poorly understood autoimmune disease. We aimed to describe the clinical and diagnostic features of children diagnosed with Sjögren syndrome and explore how the 2016 ACR/EULAR classification criteria apply to this population. METHODS: An international workgroup retrospectively collected cases of Sjögren syndrome diagnosed under 18 years of age from 23 centres across eight nations. We analysed patterns of symptoms, diagnostic workup, and applied the 2016 ACR/EULAR classification criteria. RESULTS: We identified 300 children with Sjögren syndrome. The majority of patients n = 232 (77%) did not meet 2016 ACR/EULAR classification criteria, but n = 110 (37%) did not have sufficient testing done to even possibly achieve the score necessary to meet criteria. Even among those children with all criteria items tested, only 36% met criteria. The most common non-sicca symptoms were arthralgia [n = 161 (54%)] and parotitis [n = 140 (47%)] with parotitis inversely correlating with age. CONCLUSION: Sjögren syndrome in children can present at any age. Recurrent or persistent parotitis and arthralgias are common symptoms that should prompt clinicians to consider the possibility of Sjögren syndrome. The majority of children diagnosed with Sjögren syndromes did not meet 2016 ACR/EULAR classification criteria. Comprehensive diagnostic testing from the 2016 ACR/EULAR criteria are not universally performed. This may lead to under-recognition and emphasizes a need for further research including creation of paediatric-specific classification criteria.

Vaccinations Do Not Increase Arthritis Flares in Juvenile Idiopathic Arthritis: A Study of the Relationship between Routine Childhood Vaccinations on the Australian Immunisation Schedule and Arthritis Activity in Children with Juvenile Idiopathic Arthritis.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a collective term for a group of inflammatory conditions of uncertain origin, which causes chronic arthritis in one or more joints. The clinical course of JIA is characterised by episodes of increased activity, termed flares. Vaccinations have previously been proposed as a "trigger" for some flares, although evidence supporting this is scant. OBJECTIVE: To explore whether routine childhood vaccinations are associated with an increased risk of flares of arthritis activity in children with JIA. METHODS: Patients aged below 6 years with a diagnosis of JIA were recruited from the Rheumatology Clinical Database at the Royal Children's Hospital, Melbourne, Australia, from 1 January 2010 to 30 April 2016. Patient immunisation status was cross-checked with the Australian Childhood Immunisation Register (ACIR). The self-controlled case series methodology (Rowhani-Rahbar et al., 2012) was applied to determine whether the risk of arthritis flares in the three months following immunisation was greater than the baseline risk for each patient. RESULTS: 138 patients were included in the study. 32 arthritis flares occurred in the 90 days following immunisation. The risk of arthritis flares during the 90 days following immunisation was reduced compared with patients' baseline risk (RR 0.59 (95% CI 0.39-0.89, p = 0.012)). CONCLUSION: Routine childhood immunisations were not associated with arthritis flare onset in patients with JIA. The risk of arthritis flares in the 90 days following vaccination was lower than the baseline risk. In the context of COVID19, vaccination will not increase interaction with the healthcare system beyond the immunisation encounter.

Live attenuated MMR/V booster vaccines in children with rheumatic diseases on immunosuppressive therapy are safe: Multicenter, retrospective data collection.

PURPOSE: To collect retrospective data of patients with Juvenile Idiopathic Arthritis (JIA) and other rheumatic diseases who received live attenuated booster measles-mumps-rubella (MMR) or measles-mumps-rubella-varicella (MMR/V) during treatment with immunosuppressive therapy. RESULTS: Data from 13 pediatric rheumatology centers in 10 countries, including 234 patients, were collected. Mean age at diagnosis was 5 ± 2.7 years, 67% were girls. Among them, 211 (90.2%) had JIA and 110 (47%) were in remission on medication. Disease activity was low in 37%, high in 8%, and moderate in 8%. One hundred-twenty-four received MMR/V booster while on methotrexate (MTX); 3 reported local mild adverse events (AE). Among 62 on MTX + biologics and 9 patients who received a combination of 2 disease modifying antirheumatic drugs (DMARDs), 9 reported mild AE. Among 39 on biologics, 1 reported fever one day after booster vaccination. No vaccine-related infection of measles, rubella, mumps or varicella was reported, none of the patients developed disease flare, including those with high disease activity. CONCLUSIONS: In this retrospective study, live-attenuated MMR/V booster vaccines were safe for children with rheumatic diseases, on immunosuppressive therapies. This strengthens the Paediatric Rheumatology European Society (PReS) recommendation that vaccination with live attenuated vaccines in patients on immunosuppressive therapies can be considered individually, weighing the benefit of vaccination against the risk of inducing infection through vaccination. These data provide the basis for a prospective data collection study, planned by the PReS vaccination study group.

Association of Increased Sun Exposure Over the Life-course with a Reduced Risk of Juvenile Idiopathic Arthritis.

Cutaneous sun exposure is an important determinant of circulating vitamin D. Both sun exposure and vitamin D have been inversely associated with risk of autoimmune disease. In juvenile idiopathic arthritis (JIA), low circulating vitamin D appears common, but disease-related behavioral changes may have influenced sun exposure. We therefore aimed to determine whether predisease sun exposure is associated with JIA. Using validated questionnaires, we retrospectively measured sun exposure for 202 Caucasian JIA case-control pairs born in Victoria Australia, matched for birth year and time of recruitment. Measures included maternal sun exposure at 12 weeks of pregnancy and child sun exposure across the life-course prediagnosis. We converted exposure to UVR dose and looked for case-control differences using logistic regression, adjusting for potential confounders. Higher cumulative prediagnosis UVR exposure was associated with reduced risk of JIA, with a clear dose-response relationship (trend P = 0.04). UVR exposure at 12 weeks of pregnancy was similarly inversely associated with JIA (trend P = 0.011). Associations were robust to sensitivity analyses for prediagnosis behavioral changes, disease duration and knowledge of the hypothesis. Our data indicate that lower UVR exposure may increase JIA risk. This may be through decreased circulating vitamin D, but prospective studies are required to confirm this.

Treating juvenile idiopathic arthritis to target: recommendations of an international task force.

Recent therapeutic advances in juvenile idiopathic arthritis (JIA) have made remission an achievable goal for most patients. Reaching this target leads to improved outcomes. The objective was to develop recommendations for treating JIA to target. A Steering Committee formulated a set of recommendations based on evidence derived from a systematic literature review. These were subsequently discussed, amended and voted on by an international Task Force of 30 paediatric rheumatologists in a consensus-based, Delphi-like procedure. Although the literature review did not reveal trials that compared a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated development of recommendations. The group agreed on six overarching principles and eight recommendations. The main treatment target, which should be based on a shared decision with parents/patients, was defined as remission, with the alternative target of low disease activity. The frequency and timeline of follow-up evaluations to ensure achievement and maintenance of the target depend on JIA category and level of disease activity. Additional recommendations emphasise the importance of ensuring adequate growth and development and avoiding long-term systemic glucocorticoid administration to maintain the target. All items were agreed on by more than 80% of the members of the Task Force. A research agenda was formulated. The Task Force developed recommendations for treating JIA to target, being aware that the evidence is not strong and needs to be expanded by future research. These recommendations can inform various stakeholders about strategies to reach optimal outcomes for JIA.

The DNA methylation landscape of CD4+ T cells in oligoarticular juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is presumed to be driven by an adverse combination of genes and environment. Epigenetic processes, including DNA methylation, act as a conduit through which the environment can regulate gene activity. Altered DNA methylation has been associated with adult autoimmune rheumatic diseases such as rheumatoid arthritis, but studies are lacking for paediatric autoimmune rheumatic diseases including JIA. Here, we performed a genome-scale case-control analysis of CD4+ T cell DNA methylation from 56 oligoarticular JIA (oJIA) cases and 57 age and sex matched controls using Illumina HumanMethylation450 arrays. DNA methylation at each array probe was tested for association with oJIA using RUV (Remove Unwanted Variation) together with a moderated t-test. Further to this 'all-inclusive' analysis, we stratified by age at diagnosis (≤6yrs, >6yrs) and by sex as potential sources of heterogeneity. Following False Discovery Rate (FDR) adjustment, no probes were associated with oJIA in the all-inclusive, >6yrs-diagnosed, or sex-stratified analyses, and only one probe was associated with oJIA in the ≤6yrs-diagnosed analysis. We attempted technical validation and replication of 14 probes (punadj<0.01) at genes of known/potential relevance to disease. At VPS53, we demonstrated a regional shift towards higher methylation in oJIA (all-inclusive) compared to controls. At REEP3, where polymorphism has been previously associated with JIA, we demonstrated higher DNA methylation in male oJIA compared to male controls. This is the most comprehensive JIA case-control analysis of DNA methylation to date. While we have generated some evidence of altered methylation in oJIA, substantial differences are not apparent in CD4+ T cells. This may indicate a lesser relevance of DNA methylation levels in childhood, compared to adult, rheumatic disease.

Two-year Efficacy and Safety of Etanercept in Pediatric Patients with Extended Oligoarthritis, Enthesitis-related Arthritis, or Psoriatic Arthritis.

OBJECTIVE: The main objective was to determine the 2-year clinical benefit and safety of etanercept (ETN) in children with the juvenile idiopathic arthritis (JIA) categories of extended oligoarthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). METHODS: CLIPPER was a 96-week, phase IIIb, open-label, multicenter study. Patients with eoJIA, ERA, or PsA received ETN 0.8 mg/kg once weekly (50 mg max) for up to 96 weeks. The proportions of patients reaching the JIA American College of Rheumatology (ACR) 30/50/70/90/100 and inactive disease responses at Week 96 were calculated. Adverse events (AE) were collected throughout the study (intention-to-treat sample). RESULTS: There were 127 patients (eoJIA n = 60, ERA n = 38, PsA n = 29) who received ≥ 1 dose of ETN. The mean disease duration was 31.6 (eoJIA), 23.0 (ERA), and 21.8 (PsA) months. At Week 96, JIA ACR 30/50/70/90/100/inactive disease responses (95% CI) were achieved by 84.3% (76.7, 90.1), 83.5% (75.8, 89.5), 78.7% (70.6, 85.5), 55.1% (46.0, 63.9), 45.7% (36.8, 54.7), and 27.6% (20.0, 36.2) of patients, respectively. The most common AE (no. events, events per 100 patient-yrs) overall were headache (23, 10.7), pyrexia (12, 5.6), and diarrhea (10, 4.6). The most common infections were upper respiratory tract infection (83, 38.6), pharyngitis (50, 23.2), gastroenteritis (22, 10.2), bronchitis (19, 8.8), and rhinitis (17, 7.9). No cases of malignancy, active tuberculosis, demyelinating disorders, or death were reported. CONCLUSION: Over 96 weeks of therapy, ETN demonstrated sustained efficacy at treating the clinical symptoms of all 3 JIA categories, with no major safety issues.

DNA methylation at IL32 in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease of childhood. We recently showed that DNA methylation at the gene encoding the pro-inflammatory cytokine interleukin-32 (IL32) is reduced in JIA CD4+ T cells. To extend this finding, we measured IL32 methylation in CD4+ T-cells from an additional sample of JIA cases and age- and sex-matched controls, and found a reduction in methylation associated with JIA consistent with the prior data (combined case-control dataset: 25.0% vs 37.7%, p = 0.0045). Further, JIA was associated with reduced IL32 methylation in CD8+ T cells (15.2% vs 25.5%, p = 0.034), suggesting disease-associated changes to a T cell precursor. Additionally, we measured regional SNPs, along with CD4+ T cell expression of total IL32, and the γ and ß isoforms. Several SNPs were associated with methylation. Two SNPs were also associated with JIA, and we found evidence of interaction such that methylation was only associated with JIA in minor allele carriers (e.g. rs10431961 p(interaction) = 0.011). Methylation at one measured CpG was inversely correlated with total IL32 expression (Spearman r = -0.73, p = 0.0009), but this was not a JIA-associated CpG. Overall, our data further confirms that reduced IL32 methylation is associated with JIA, and that SNPs play an interactive role.

Sibling Exposure and Risk of Juvenile Idiopathic Arthritis.

OBJECTIVE: Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail. METHODS: We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case-hospital control sample (302 cases and 676 controls) from Victoria, Australia. RESULTS: We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28-0.74) (P = 0.001). The protective association appeared to increase with increasing number of siblings (e.g., for ≥3 siblings, adjusted OR 0.25 [95% CI 0.13-0.48], P < 0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g., for ≥3 years of exposure versus no exposure, adjusted OR 0.49 [95% CI 0.30-0.79], P = 0.003). We also compared cases to a second control sample (n = 341) collected from the community and weighted to represent the child population of Victoria. Data remained supportive of an association between sibling exposure and protection against JIA, particularly for exposure to younger siblings. CONCLUSION: Increased exposure to siblings is associated with a reduced risk of disease in our sample. This suggests that increased microbial exposure in childhood may confer protection against the development of JIA.

Epistasis amongst PTPN2 and genes of the vitamin D pathway contributes to risk of juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a leading cause of childhood-onset disability. Although epistasis (gene-gene interaction) is frequently cited as an important component of heritability in complex diseases such as JIA, there is little compelling evidence that demonstrates such interaction. PTPN2, a vitamin D responsive gene, is a confirmed susceptibility gene in JIA, and PTPN2 has been suggested to interact with vitamin D pathway genes in type 1 diabetes. We therefore, tested for evidence of epistasis amongst PTPN2 and the vitamin D pathway genes GC, VDR, CYP24A1, CYP2R1, and DHCR7 in two independent JIA case-control samples (discovery and replication). In the discovery sample (318 cases, 556 controls), we identified evidence in support of epistasis across six gene-gene combinations (e.g., GC rs1155563 and PTPN2 rs2542151, ORint=0.45, p=0.00085). Replication was obtained for three of these combinations. That is, for GC and PTPN2, CYP2R1 and VDR, and VDR and PTPN2, similar epistasis was observed using the same SNPs or correlated proxies in an independent JIA case-control sample (1008 cases, 9287 controls). Using SNP data imputed across a 4 MB region spanning each gene, we obtained highly significant evidence for epistasis amongst all 6 gene-gene combinations identified in the discovery sample (p-values ranging from 5.6×10(-9) to 7.5×10(-7)). This is the first report of epistasis in JIA risk. Epistasis amongst PTPN2 and vitamin D pathway genes was both demonstrated and replicated.

Complicated Henoch-Schönlein purpura.

We present a case of Henoch Schonlein pupura in a 6-year-old boy demonstrating some of the diagnostic pitfalls, complications and management challenges of this common paediatric condition.

Independent confirmation of juvenile idiopathic arthritis genetic risk loci previously identified by immunochip array analysis.

BACKGROUND: Our understanding of the genetic factors underlying juvenile idiopathic arthritis (JIA) is growing, but remains incomplete. Recently, a number of novel genetic loci were reported to be associated with JIA at (or near) genome-wide significance in a large case-control discovery sample using the Immunochip genotyping array. However, independent replication of findings has yet to be performed. We therefore attempted to replicate these newly identified loci in the Australian CLARITY JIA case-control sample. FINDINGS: Genotyping was successfully performed on a total of 404 JIA cases (mean age 6.4 years, 68% female) and 676 healthy child controls (mean age 7.1 years, 42% female) across 19 SNPs previously associated with JIA. We replicated a significant association (p < 0.05, odds ratio (OR) in a direction consistent with the previous report) for seven loci, six replicated for the first time--C5orf56-IRF1 (rs4705862), ERAP2-LNPEP (rs27290), PRR5L (rs4755450), RUNX1 (rs9979383), RUNX3 (rs4648881), and UBE2L3 (rs2266959). CONCLUSIONS: We have carried out the first independent replication of association for six genes implicated in JIA susceptibility. Our data significantly strengthens the evidence that these loci harbor true disease associated variants. Thus, this study makes an important contribution to the growing body of international data that is revealing the genetic risk landscape of JIA.

Vaccination in paediatric rheumatology.

As awareness of the risk of vaccine-preventable diseases for children with rheumatic diseases has increased, vaccination has become an important clinical consideration and focus of research in paediatric rheumatology. Conflicting reports in the literature and differing advice from national bodies regarding the safety of different vaccines for this patient population have led to confusion in the minds of many rheumatologists as to what is appropriate. This article will provide an overview of crucial aspects of the recently published European League Against Rheumatism recommendations regarding vaccination of paediatric patients with rheumatic disease, and will review advances in this field since their publication.

Recurrent fevers in children: TRAPS for young players.

We present the case of an 11-month-old girl who presented with recurrent febrile episodes and was found to have tumour necrosis factor receptor-associated periodic syndrome due to a novel mutation in the TNFRSF1A gene. The concept of autoinflammatory diseases is discussed and the management of this condition reviewed.

Clinical features and disease course of patients with juvenile dermatomyositis.

OBJECTIVE: To describe the clinical features and course of a cohort of patients with juvenile dermatomyositis (JDM) at a tertiary referral pediatric centre in Australia and examine changes in diagnostic and therapeutic approach over time. METHODS: Retrospective review of patients diagnosed with JDM at the Royal Children's Hospital, Melbourne, between 1989 and 2010. RESULTS: Fifty-seven patients were identified. The female : male ratio was 2 : 1 and median age at diagnosis was 7.1 years (2.2-15.3). At diagnosis, 95% had weakness, all had typical rash and 68% had nailfold capillary changes. Calcinosis was not present in any patients at diagnosis and occurred in 18% over time. Creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and aldolase levels were abnormal in 65%, 92%, 88%, 58% and 100%, respectively. Magnetic resonance imaging (MRI) was abnormal in 97% of patients, electomyograph (EMG) in 83% and muscle biopsy in all four patients in whom it was performed. MRI was used in 86% (24/28) of patients diagnosed after 2000. Muscle biopsy was used in four and EMG in no patients over the same period. Treatment used throughout the disease course included oral steroids (93%), high-dose pulse intravenous steroids (82%), methotrexate (63%), intravenous immunoglobulin (32%) and cyclosporin (18%). The disease was monophasic in 46.7% (21/45), polyphasic in 17.7% (8/45) and chronic in 35.5% (16/45). CONCLUSIONS: Australian patients with JDM have similar characteristics to previously described cohorts. In practice, MRI has replaced the invasive diagnostic tests included in the Bohan and Peter criteria for the diagnosis of JDM. The early use of disease-modifying anti-rheumatic drugs has become the most common treatment approach.

Independent replication analysis of genetic loci with previous evidence of association with juvenile idiopathic arthritis.

BACKGROUND: Over the last five years, there have been numerous reports of association of juvenile idiopathic arthritis with single nucleotide polymorphisms (SNPs) at various loci outside the major histocompatibility complex (MHC) region. However, the majority of these association findings have been generated using a limited number of international cohorts, and thus there is benefit in further independent replication. To address this, we examined a total of 56 SNPs in 42 non-MHC gene regions previously reported to be associated with JIA, in the ChiLdhood Arthritis Risk factor Identification sTudY (CLARITY), a new Australian collection of cases and healthy child controls. FINDINGS: Genotyping was performed on a total of 324 JIA cases (mean age 9.7 years, 67.3% female) and 568 controls (mean age 7.8 years, 40.7% female). We demonstrated clear evidence for replication of association of JIA with SNPs in or around c12orf30, c3orf1, PTPN22, STAT4, and TRAF1-C5, confirming the involvement of these loci in disease risk. Further, we generated evidence supportive of replication of association of JIA with loci containing AFF3, CD226, MBL2, PSTPIP1, and RANTES (CCL5). These results were robust to sensitivity analyses for ethnicity. CONCLUSION: We have provided valuable independent data as to the underlying genetic architecture of this understudied pediatric autoimmune disease, further confirming five loci outside the MHC, and supporting a role for a further five loci in determining disease risk.