Larry B. Vogler

Prediction of persistent immunodeficiency in the DiGeorge anomaly

To assess the natural history of the immune defect in DiGeorge anomaly, we reviewed serial immunologic studies in 18 patients. The diagnosis was made with criteria based on the concept of the DiGeorge anomaly as a field defect. Initial or early follow-up laboratory examination suggested moderate to normal T cell function in 14 patients. None of these patients have lost T cell capability; they have never had infections characteristic of T cell deficiency. Four patients had clinical and laboratory evidence of profound immunodeficiency. A decreased number of CD4+ cells (less than 400/microliters) and a decrease in phytohemagglutinin responsiveness (stimulation index less than 10) may be useful in discriminating patients with immunodeficiency; absolute lymphocyte count and immunoglobulin values were not informative. At the time of surgery, the thymus was not found in 11 of 14 patients; however, only two of these patients had immunodeficiency. Patients with a persistently low number of CD4+ cells and decreased phytohemagglutinin response are candidates for immunologic reconstitution.

Consensus treatment plans for induction therapy of newly diagnosed proliferative lupus nephritis in juvenile systemic lupus erythematosus

To formulate consensus treatment plans (CTPs) for induction therapy of newly diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (SLE).

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.

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.

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.

Susceptibility to childhood-onset rheumatoid arthritis: Investigation of a weighted genetic risk score that integrates cumulative effects of variants at five genetic loci

OBJECTIVE Children with childhood-onset rheumatoid arthritis (RA) include those with rheumatoid factor or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. To test the hypothesis that adult-onset RA-associated variants are also associated with childhood-onset RA, we investigated RA-associated variants at 5 loci in a cohort of patients with childhood-onset RA. We also assessed the cumulative association of these variants in susceptibility to childhood-onset RA using a weighted genetic risk score (wGRS). METHODS A total of 155 children with childhood-onset RA and 684 healthy controls were genotyped for 5 variants in the PTPN22, TRAF1/C5, STAT4, and TNFAIP3 loci. High-resolution HLA-DRB1 genotypes were available for 149 cases and 373 controls. We tested each locus for association with childhood-onset RA via logistic regression. We also computed a wGRS for each subject, with weights based on the natural log of the published odds ratios (ORs) for the alleles investigated, and used logistic regression to test the wGRS for association with childhood-onset RA. RESULTS Childhood-onset RA was associated with TNFAIP3 rs10499194 (OR 0.60 [95% confidence interval 0.44-0.83]), PTPN22 rs2476601 (OR 1.61 [95% confidence interval 1.11-2.31]), and STAT4 rs7574865 (OR 1.41 [95% confidence interval 1.06-1.87]) variants. The wGRS was significantly different between cases and controls (P < 2 × 10(-16) ). Individuals in the third to fifth quintiles of wGRS had a significantly increased disease risk compared to baseline (individuals in the first quintile). Higher wGRS was associated with increased risk of childhood-onset RA, especially among males. CONCLUSION The magnitude and direction of the association between TNFAIP3, STAT4, and PTPN22 variants and childhood-onset RA are similar to those observed in RA, suggesting that adult-onset RA and childhood-onset RA share common genetic risk factors. Using a wGRS, we have demonstrated the cumulative association of RA-associated variants with susceptibility to childhood-onset RA.

The health education for lupus study: a randomized controlled cognitive-behavioral intervention targeting psychosocial adjustment and quality of life in adolescent females with systemic lupus erythematosus.

Introduction:To examine in a randomize controlled feasibility clinical trial the efficacy of a cognitive-behavioral intervention designed to manage pain, enhance disease adjustment and adaptation and improve quality of life among female adolescents with systemic lupus erythematosus. Methods:Female adolescents (n = 53) ranging in age from 12 to 18 years were randomly assigned to 1 of 3 groups including a cognitive-behavioral intervention, an education-only arm and a no-contact control group. Participants were assessed at baseline, postintervention and at 3- and 6-month intervals after completion of the intervention. Results:No significant differences were revealed among the 3 treatment arms for any of the dependent measures at any of the assessment points. For the mediator variables, a posthoc secondary analysis did reveal increases in coping skills from baseline to postintervention among the participants in the cognitive-behavioral intervention group compared with both the no-contact control group and the education-only group. Conclusion:Although no differences were detected in the primary outcome, a possible effect on coping of female adolescents with systemic lupus erythematosus was detected in this feasibility study. Whether the impact of training in the area of coping was of sufficient magnitude to generalize to other areas of functioning, such as adjustment and adaptation, is unclear. Future phase III randomized trials will be needed to assess additional coping models and to evaluate the dose of training and its influence on pain management, adjustment and health-related quality of life.

Using the Effects of Youngsters' Eyesight on Quality of Life Questionnaire to Measure Visual Outcomes in Children With Uveitis.

The Effects of Youngsters’ Eyesight on Quality of Life (EYE‐Q) is a novel measure of vision‐related quality of life (QOL) and function in children. We aim to determine the validity of the EYE‐Q in childhood uveitis.