Sheila T. Angeles-Han

Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.

Risk Markers of Juvenile Idiopathic Arthritis-associated Uveitis in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry

Objective. To characterize the epidemiology and clinical course of children with juvenile idiopathic arthritis-associated uveitis (JIA-U) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry and explore differences between African American (AA) and non-Hispanic white (NHW) children. Methods. There were 4983 children with JIA enrolled in the CARRA Registry. Of those, 3967 NHW and AA children were included in this study. Demographic and disease-related data were collected from diagnosis to enrollment. Children with JIA were compared to those with JIA-U. Children with JIA-U were also compared by race. Results. There were 459/3967 children (11.6%) with JIA-U in our cohort with a mean age (SD) of 11.4 years (± 4.5) at enrollment. Compared to children with JIA, they were younger at arthritis onset, more likely to be female, had < 5 joints involved, had oligoarticular JIA, and were antinuclear antibody (ANA)-positive, rheumatoid factor (RF)-negative, and anticitrullinated protein antibody-negative. Predictors of uveitis development included female sex, early age of arthritis onset, and oligoarticular JIA. Polyarticular RF-positive JIA subtype was protective. Nearly 3% of children with JIA-U were AA. However, of the 220 AA children with JIA, 6% had uveitis; in contrast, 12% of the 3721 NHW children with JIA had uveitis. Conclusion. In the CARRA registry, the prevalence of JIA-U in AA and NHW children is 11.6%. We confirmed known uveitis risk markers (ANA positivity, younger age at arthritis onset, and oligoarticular JIA). We describe a decreased likelihood of uveitis in AA children and recommend further exploration of race as a risk factor in a larger population of AA children.

The genetics of juvenile idiopathic arthritis: what is new in 2010?

Juvenile idiopathic arthritis (JIA), the most common cause of chronic arthritis in children, is believed to be influenced by genetic factors. Recent studies on the genetics of JIA have not only validated proposed genetic associations but have also led to the recognition of novel genetic associations. Studies of specific genes have been modeled on the premise of shared autoimmunity, wherein genetic variants that predispose to other autoimmune phenotypes may also confer susceptibility to JIA. The advent of genome-wide association studies has accelerated the detection of non-HLA susceptibility loci in other autoimmune phenotypes and is likely to uncover novel JIA-associated variants as well. This review highlights recent genetic investigations of JIA.

Hierarchy of risk of childhood onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope

OBJECTIVE Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. METHODS High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S(2) , S(3P) , or L alleles, based on amino acid sequences in position 70-74 of the DRβ1 chain, as proposed by Tezenas du Montcel et al. RESULTS We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10(-7) ). We also observed associations between individual SE alleles (HLA-DRB1*0101, *0401, *0404, *0405, *0408, and *1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S(2) /S(3P) (OR 22.3, 95% CI 9.9-50.5, P < 0.0001). CONCLUSION We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S(2) and S(3P) risk alleles suggests that children with DRβ1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.

The importance of visual function in the quality of life of children with uveitis

BACKGROUND Studies of quality of life (QOL) in children with juvenile idiopathic arthritis (JIA) have focused on changes in musculoskeletal function secondary to arthritis. The role of visual functionality as a result of JIA-associated uveitis and its complications has not been examined. We evaluated the individual impact of physical and visual disability on QOL in children with and without uveitis. METHODS We administered patient-based questionnaires that measured visual function, physical function, and overall QOL to 27 children with JIA or idiopathic uveitis. Demographic data, assessed joint involvement, and reviewed medical records were recorded. Groups with and without uveitis were compared for differences in arthritis and uveitis disease characteristics with use of the Wilcoxon-Mann-Whitney, chi2, and Fisher exact tests. Associations between physical or visual function, and overall QOL were measured with use of Pearsons correlation coefficient. RESULTS Of 27 patients, 85.2% had had arthritis and 51.9% had had uveitis. The group without uveitis had increased morning stiffness (p = 0.036). Patients with uveitis reported more eye redness (p = 0.033) and photophobia (p = 0.013) than those without uveitis. We observed moderate associations between overall QOL and visual function in the uveitis group (r = -0.579) and overall QOL and physical function in the nonuveitis group (r = -0.562). CONCLUSIONS This study demonstrates that visual impairment is an important component of QOL in children with uveitis. It suggests that QOL studies should incorporate both visual and physical function measures in their analyses, especially because many children with JIA also suffer from uveitis and visual impairment.

Adding Canakinumab to the Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for Systemic Juvenile Idiopathic Arthritis: Comment on the Article by DeWitt et al

The Childhood Arthritis and Rheumatology Research Alliance (CARRA) previously published an article in Arthritis Care & Research describing the consensus treatment plans (CTPs) for new-onset systemic juvenile idiopathic arthritis (JIA) (1). Since its publication, canakinumab, an interleukin-1 (IL-1) beta monoclonal antibody, was approved for use by US and European regulatory authorities following the publication of studies demonstrating its efficacy and safety in this disease (2). The CARRA systemic JIA workgroup had previously decided that new medications that become commonly available for this disease would be added to the CTPs. The CTPs are meant to be used when treating new-onset systemic JIA patients so that the comparative effectiveness of the CTPs can be studied through data entered into the CARRA registry. Once canakinumab became available for systemic JIA patients, the workgroup decided to revise the IL-1 inhibitor CTP to include this medication so that the patient may start either IL-1 inhibitor (anakinra or canakinumab) at any point during the course of the CTP (Figure 1). This revised IL-1 inhibitor CTP was then circulated via an electronic survey to all CARRA JIA Disease Committee members (n 188) to ensure acceptability. Of these members, 98 responded (52%), of whom 6 were not clinicians and were excluded. Of the remaining 92 members, 90 (98%) agreed with the IL-1 inhibitor CTP as presented and would use it when treating new-onset systemic JIA patients. We anticipate that this new IL-1 inhibitor CTP that allows the use of canakinumab or anakinra will be considered going forward by pediatric rheumatologists for new-onset systemic JIA patients when it is decided that an IL-1 inhibitor is indicated. A pilot study funded by the Arthritis Foundation is currently under way in a limited number of sites to assess the feasibility of using the systemic JIA CTPs in daily practice. In the future, we anticipate that, by widely disseminating the use of these CTPs to all CARRA sites and collecting the resulting data through the CARRA registry, their comparative effectiveness in patients with this disease will be able to be studied. Supported by the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, the Wasie Foundation, and Friends of the Childhood Arthritis and Rheumatology Re-

Prevention and Management of Cataracts in Children with Juvenile Idiopathic Arthritis–Associated Uveitis

Juvenile idiopathic arthritis (JIA)-associated uveitis can be associated with vision-compromising complications such as cataracts, glaucoma, synechiae, and band keratopathy. Of these, cataracts are one of the most common sequelae of JIA-associated uveitis and can result in significant visual disability. Risk factors for cataracts include posterior synechiae and longstanding ocular inflammation. Prevention of cataract development is crucial through appropriate control of uveitis. However, not all preventive measures are successful, and further management consisting of medical and surgical techniques is often necessary. Various factors should be taken into consideration when deciding on cataract management, including timing of surgery and placement of an intraocular lens. Continued partnership between pediatric rheumatologists and pediatric ophthalmologists can help ensure favorable visual outcomes.

Updates on the risk markers and outcomes of severe juvenile idiopathic arthritis-associated uveitis

Uveitis is the most common extra-articular manifestation of juvenile idiopathic arthritis, which is the most common systemic cause of uveitis in children. Known risk factors for uveitis include antinuclear antibody seropositivity, young age of arthritis onset, specific juvenile idiopathic arthritis subtype and short duration of disease. Risk markers for severe ocular disease include gender, age and complications at initial visit. Due to the risk for vision-compromising sequelae such as cataracts, band keratopathy, glaucoma, vision loss and blindness, an understanding of the risk factors for uveitis development and severe ocular disease is crucial to help prevent serious visual disability and complications. This paper reviews the pathogenesis of uveitis, known risk factors for uveitis development and severe visual outcome, and addresses the need for additional biomarkers of uveitis risk, prognosis and remission.

Meta-analysis confirms association between TNFA-G238A variant and JIA, and between PTPN22-C1858T variant and oligoarticular, RF-polyarticular and RF-positive polyarticular JIA

BackgroundAlthough more than 100 non-HLA variants have been tested for associations with juvenile idiopathic arthritis (JIA) in candidate gene studies, only a few have been replicated. We sought to replicate reported associations of single nucleotide polymorphisms (SNPs) in the PTPN22, TNFA and MIF genes in a well-characterized cohort of children with JIA.MethodsWe genotyped and analyzed 4 SNPs in 3 genes: PTPN22 C1858T (rs2476601), TNFA G-308A, G-238A (rs1800629, rs361525) and MIF G-173C (rs755622) in 647 JIA cases and 751 healthy controls. We tested for association between each variant and JIA as well as JIA subtypes. We adjusted for multiple testing using permutation procedures. We also performed a meta-analysis that combined our results with published results from JIA association studies.ResultsWhile the PTPN22 variant showed only modest association with JIA (OR = 1.29, p = 0.0309), it demonstrated a stronger association with the RF-positive polyarticular JIA subtype (OR = 2.12, p = 0.0041). The MIF variant was not associated with the JIA as a whole or with any subtype. The TNFA-238A variant was associated with JIA as a whole (OR 0.66, p = 0.0265), and demonstrated a stronger association with oligoarticular JIA (OR 0.33, p = 0.0006) that was significant after correction for multiple testing. TNFA-308A was not associated with JIA, but was nominally associated with systemic JIA (OR = 0.33, p = 0.0089) and enthesitis-related JIA (OR = 0.40, p = 0.0144). Meta-analyses confirmed significant associations between JIA and PTPN22 (OR 1.44, p <0.0001) and TNFA-238A (OR 0.69, p < 0.0086) variants. Subtype meta-analyses of the PTPN22 variant revealed associations between RF-positive, RF-negative, and oligoarticular JIA, that remained significant after multiple hypothesis correction (p < 0.0005, p = 0.0007, and p < 0.0005, respectively).ConclusionsWe have confirmed associations between JIA and PTPN22 and TNFA G-308A. By performing subtype analyses, we discovered a statistically-significant association between the TNFA-238A variant and oligoarticular JIA. Our meta-analyses confirm the associations between TNFA-238A and JIA, and show that PTPN22 C1858T is associated with JIA as well as with RF-positive, RF-negative and oligoarticular JIA.

Limitations in the Classification of Childhood-onset Rheumatoid Arthritis

Objective. Rheumatoid factor-positive polyarthritis (RF+ poly) is the juvenile idiopathic arthritis (JIA) category that resembles adult seropositive rheumatoid arthritis (RA). We studied children with RF+ and/or anticyclic citrullinated peptide antibody (anti-CCP)+ JIA to determine what proportion of those children meet International League of Associations for Rheumatology (ILAR) criteria for RF+ poly JIA and to assess for significant differences between children who meet RF+ poly criteria and those who are classified in other categories. Methods. Charts of children with JIA who were RF+ and/or anti-CCP+ were reviewed. Children with RF+ poly JIA were compared to children in other categories. Statistical analysis was performed using chi-square, Fisher’s exact test, and the Student’s t-test. Results. Of 56 children with RF+ and/or anti-CCP+ JIA, 34 (61%) met ILAR criteria for RF+ poly JIA. Twelve children had RF–/anti-CCP+ JIA with low anti-CCP titers. When these 12 children were excluded, there were few significant differences between children who met criteria for RF+ poly and those who were classified in other categories. The American College of Rheumatology/European League Against Rheumatism criteria for RA identified more RF+ children than did the ILAR RF+ poly classification (100% vs 77%). Conclusion. A number of children with RF+ arthritis were excluded from the RF+ poly JIA classification, though many demographic features and disease measures were similar to those of children who met criteria for RF+ poly JIA. We propose prioritization of RF/anti-CCP positivity over specific exclusions, along with inclusion of anti-CCP, in future revisions of the JIA classification criteria, to improve the sensitivity of diagnosing childhood-onset RA.