Becker, Mara L.

ObjectiveJuvenile localized scleroderma (jLS) is a chronic autoimmune disease commonly associated with poor outcomes, including contractures, hemiatrophy, uveitis, and seizures. Despite improvements in treatment, >25% of patients with jLS have functional impairment. To improve patient evaluation, our workgroup developed the Localized scleroderma Total Severity Scale (LoTSS), an overall disease severity measure.MethodsLoTSS was developed as a weighted measure by a consensus process involving literature review, surveys, case vignettes, and multicriteria decision analysis. Feasibility was assessed in larger Childhood Arthritis and Rheumatology Research Alliance groups. Construct validity with physician assessment and inter‐rater reliability was assessed using case vignettes. Additional evaluation was performed in a prospective patient cohort initiating treatment.ResultsLoTSS severity items were organized into modules that reflect jLS disease patterns, with modules for skin, extracutaneous, and craniofacial manifestations. Construct validity of LoTSS was supported by a strong positive correlation with the Physician Global Assessment (PGA) of severity and damage and weak positive correlation with PGA‐Activity, as expected. LoTSS was responsive, with a small effect size identified. Moderate‐to‐excellent inter‐rater reliability was demonstrated. LoTSS was able to discriminate between patient subsets, with higher scores identified in those with greater disease burden and functional limitation.ConclusionWe developed a new LS measure for assessing cutaneous and extracutaneous severity and have shown it to be reliable, valid, and responsive. LoTSS is the first measure that assesses and scores all the major extracutaneous manifestations in LS. Our findings suggest LoTSS could aid assessment and management of patients and facilitate outcome evaluation in treatment studies.image

Background/Purpose:Genome‐wide association studies have identified susceptibility loci for many autoimmune diseases, including rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). About 5% of children with JIA have rheumatoid factor positive arthritis that is phenotypically similar to adult seropositive RA, thus representing childhood onset RA (CORA). To understand the genetic architecture of CORA risk relative to other autoimmune diseases, we genotyped CORA cases and controls on the Immunochip, a custom array designed by the Immunochip Consortium to fine map autoimmune disease‐associated loci shared across 11 autoimmune phenotypes.Methods:Genotyping was completed on 340 CORA cases (mean onset age: 10.2 ± 4.2 yrs) and 11624 controls. Standard SNP and sample QC was performed (e.g., removing samples with call rate <98%, admixture outliers). To test for SNP association with CORA a logistic regression model was computed with Caucasian admixture proportions (ADMIXTURE) as covariates (SNPLash). False discovery rate (FDR) adjusted p‐values (PFDR) are reported to account for the actual number of tests computed.Results:SNP rs3129769, near HLA DRB1 was the most significantly associated (PFDR <3×10‐25), and is in linkage disequilibrium with the HLA DRB1 SNP reported in RA (rs660895, PFDR <1×10‐24). Outside the HLA region, 28 regions had ≥1 SNP meeting genome‐wide significance (PFDR<0.05). The best signal of association was on 22q13 (rs9610687, OR = 0.57, PFDR < 0.0002) near IL2RB, followed by the PTPN22 locus (rs6679677, OR = 1.83, PFDR < 0.0005), an intergenic SNP on chromosome 4 (rs970036, OR = 1.78, PFDR < 0.002) and an intronic SNP (19p13, rs3787016 PFDR < 0.002) in the POLR2E gene, which encodes a subunit of RNA polymerase II. Some loci which have previously been implicated in RA had evidence of association including MMEL (rs751358 PFDR < 0.003), IRF5 (rs4731531 PFDR < 0.006) and CCR6 (rs11575078 PFDR < 0.03). In addition using the FDR‐based threshold we identified several potential SNPs (rs10918214, 1q23; rs28491312, 14q31) not previously implicated in RA.Conclusion:Immunochip analysis of the largest cohort of CORA investigated to date has confirmed the HLA DRB1 association and identified several other loci associated with CORA. Comparisons among loci associated with CORA and those identified in RA and other forms of JIA are underway and will help delineate the unique genetic factors for CORA susceptibility.

Objective To investigate aspects of juvenile dermatomyositis (DM), including disease characteristics and treatment, through a national multicenter registry. Methods Subjects meeting the modified Bohan and Peter criteria for definite juvenile DM were analyzed from the cross‐sectional Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry between 2010 and 2012 from 55 US pediatric rheumatology centers. Demographics, disease characteristics, diagnostic assessments, and medication exposure data were collected at enrollment. Results A total of 384 subjects met the criteria for analysis. At enrollment, the median Childhood Myositis Assessment Scale score was 51 (interquartile range [IQR] 46–52), the median Childhood Health Assessment Questionnaire score was 0 (IQR 0–0.5), and the median physician and subject global assessment scores were 1 (IQR 0–2) and 1 (IQR 0–3), respectively, out of a maximum of 10. Of the diagnostic assessments, magnetic resonance imaging was more likely than electromyography or muscle biopsy to show abnormalities. A total of 329 subjects had ≥2 diagnostic studies performed, and >34% of these subjects reported ≥1 negative study. Ninety‐five percent had been treated with corticosteroids and 92% with methotrexate, suggesting that these medications were almost universally prescribed for juvenile DM in the US. Conclusion In 2 years, the ongoing CARRA Registry has collected clinical data on 384 children with juvenile DM and has the potential to become one of the largest juvenile DM cohorts in the world. More research is needed about prognostic factors in juvenile DM, and differences in therapy based on manifestations of disease need to be explored by practitioners. This registry provides the infrastructure needed to advance clinical and translational research and represents a major step toward improving outcomes of children with juvenile DM.