D. M. C. Brinkman

Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis

OBJECTIVE Juvenile idiopathic arthritis (JIA) is characterized by chronic arthritis and an autoimmune etiology. In several autoimmune diseases, including rheumatoid arthritis (RA), an association with the 4q27 locus has been reported. We undertook this study to investigate the possible role of the 4q27 locus in JIA. METHODS A case-control association study was conducted, with a total of 655 Caucasian JIA patients and 791 healthy controls divided into 2 independent sample sets. The rs6822844 marker in the 4q27 locus was genotyped. RESULTS In the first and larger sample set, a 5% decrease in T allele frequency was observed in patients compared with controls (allelic odds ratio [OR] 0.72 [95% confidence interval 0.55-0.95], P = 0.019), and in the second set, a 3% decrease was observed (allelic OR 0.81 [95% confidence interval 0.61-1.09], P = 0.169). The combined data set generated an OR of 0.76 (95% confidence interval 0.62-0.93, P = 7.08 x 10(-3)). When the different JIA subtypes were analyzed individually, significant decreases were seen in the subtypes with a polyarticular course of disease (extended oligoarthritis [P = 0.019] and rheumatoid factor-negative polyarthritis [P = 0.038]). CONCLUSION Our findings suggest that the 4q27 locus, previously reported to be associated with RA, type 1 diabetes mellitus, celiac disease, and psoriatic arthritis, is also associated with susceptibility to JIA.

Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation

Objectives: To determine whether myeloid related proteins (MRP8/MRP14), a complex of two S100 proteins related to neutrophil and monocyte activation, might be used as a marker for disease activity, and as an early indicator of relapse in juvenile idiopathic arthritis. Patients and methods: A group of 12 patients who underwent an autologous haematopoietic stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JIA) were studied. MRP8/MRP14 serum concentrations were determined by a sandwich enzyme linked immunosorbent assay (ELISA) as described. Improvement from baseline was described by a definition of improvement employing a core set of criteria as detailed previously by Giannini. Results: After ASCT, MRP8/MRP14 serum concentrations in JIA showed a positive correlation with the Child Health Assessment Questionnaire (CHAQ; r=0.80) and erythrocyte sedimentation rate (r=0.45), but not with the total leucocyte count (r=0.26). Mean MRP8/MRP14 serum concentrations dropped markedly in the first three months after ASCT (p=0.0039) and clinical parameters of disease activity such as CHAQ markedly improved (p=0.0039). During a transient relapse there was an increase in MRP8/MRP14. Conclusions: MRP8/MRP14 serum concentration can be used as a marker for disease activity in patients who receive an ASCT for refractory JIA. This indicates a role of macrophage activation in the pathogenesis of JIA. The occurrence of MAS in three patients in this study was not preceded by significant changes in MRP8/MRP14 concentration.

Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis

Summary:Since 1997, autologous stem cell transplantation (ASCT) had been applied to more than 40 children with polyarticular or systemic juvenile idiopathic arthritis (JIA). For this review, results of the follow-up are available from 25 children with systemic JIA and six with polyarticular JIA that were reported in detail from eight different pediatric European transplant centers. Before ASCT all children had progressive disease despite the use of corticosteroids, methotrexate (MTX) up to 1 mg/kg/week, cyclosporin (2.5 mg/kg/day) and/or anti-TNFα therapy. The clinical follow-up of these children ranges from 8 to 60 months (median 33 months).

Vaccination with Rabies to Study the Humoral and Cellular Immune Response to a T-Cell Dependent Neoantigen in Man

We investigated the humoral (antigen-specific immunoglobulin isotypes, IgG subclasses, and avidity maturation) and cellular (antigen-specific in vitro proliferation) immune response in 18 healthy adult volunteers, following a primary and a single booster vaccination with the T-cell dependent neoantigen rabies administered at a 3-months interval. The IgG antibody titer showed a mean 31-fold increase (range 3–154) 4 weeks after the first vaccination and a memory response was observed after booster vaccination, i.e. high IgG titers, switch from IgM to IgG and IgA and increased antibody avidity. All healthy adults showed a rabies-induced proliferative response with a mean stimulation index of 45 (range 3.5–200) after in vitro stimulation of PBMC obtained at 4 weeks after booster vaccination. The results obtained in this study provide a frame of reference for the interpretation of specific immune responses to the T-cell dependent neoantigen rabies in patients suspected of a primary or secondary immunodeficiency. Humoral and cellular immune responses to the rabies neoantigen provide complementary information on the condition of the immune system of an individual. Five patients diagnosed with a combined immunodeficiency were vaccinated using the same protocol and showed a number of abnormalities, either in the humoral or the cellular immune response to the rabies neoantigen.

Resetting the Adaptive Immune System After Autologous Stem Cell Transplantation: Lessons from Responses to Vaccines

Autologous stem cell transplantation (ASCT) to treat autoimmune diseases (AID) is thought to reset immunological memory directed against autoantigens. This hypothesis can only be studied indirectly because the exact nature of the pathogenetic autoantigens is unknown in most AID. Therefore, 19 children with juvenile idiopathic arthritis (JIA) or systemic lupus erythematodes (SLE) and 10 adults with multiple sclerosis (MS) were vaccinated with the T-cell-dependent neoantigen rabies and the recall antigen tetanus toxoid after, respectively before, bone marrow harvest. Both vaccinations were repeated after ASCT. All except two of the responders mounted a primary antibody response to rabies after revaccination, and 44% of the responders mounted a primary antibody response to tetanus boost after ASCT. These data show that immunological memory to a neoantigen is lost in most patients with AID after immunoablative pretreatment; however, memory to a recall antigen boosted before bone marrow harvest is only lost in part of the patients. Disease progression was arrested in all patients with JIA/SLE except one, but only in a minority of MS patients. Clinical outcome on a per case basis was not associated with the profile of the immune response toward the vaccination antigens after ASCT.

Anticarbamylated protein (anti-CarP) antibodies are present in sera of juvenile idiopathic arthritis (JIA) patients

In juvenile idiopathic arthritis (JIA) patients there is a lack of markers that predict severe disease. Although anticitrullinated protein antibodies (ACPA) have contributed substantially to the understanding of rheumatoid arthritis (RA),1 their detection in JIA has not been equally useful as incidence rates in JIA patients are low2 and merely confined to the polyarticular immunoglobulin (Ig)M-rheumatoid factor (RF)-positive category resembling RA. Recently, anticarbamylated protein (anti-CarP) antibodies were detected in 45% of RA patients and importantly also in 16%–20% ACPA-negative patients.3–5 Within the ACPA-negative patients, anti-CarP antibodies were associated with more severe radiographic progression.3 Since most JIA patients are ACPA-negative we investigated whether anti-CarP antibodies are present in the sera of JIA patients and how they are related to ACPA and IgM-RF. JIA patients from three Dutch sources were included: the BeSt for Kids trial (NTR 1574, a treatment strategy study) (n=33), a previously described cohort6 (n=48) and the Arthritis and Biologicals in Children (ABC) register7 (n=153). Healthy controls (n=107) (mean age/range 11/(2–20)) are stem-cell graft …

CD226 (DNAM-1) is associated with susceptibility to juvenile idiopathic arthritis

Objectives Juvenile idiopathic arthritis (JIA) is considered a complex genetic autoimmune disease. We investigated the association of genetic variants previously implicated in JIA, autoimmunity and/or immunoregulation, with susceptibility to JIA. Methods A genetic association study was performed in 639 JIA patients and 1613 healthy controls of northwest European descent. Ninety-three single nucleotide polymorphisms (SNP) were genotyped in a candidate gene approach. Results of the entire JIA patient group (all subtypes) were compared with results obtained, alternatively, with a clinically homogeneous patient group including only oligoarticular and rheumatoid factor (RF) negative polyarticular JIA patients (n=493). Meta-analyses were performed for all SNPs that have been typed in other Caucasian JIA cohorts before. Results SNPs in or near PTPN22, VTCN1, the IL2-IL21 region, ANKRD55 and TNFA were confirmed to be associated with JIA (p<0.05), strengthening the evidence for involvement of these genes in JIA. In the majority of these replicated SNPs, effect sizes were larger when analysing a homogeneous patient cohort than when analysing all subtypes. We identified two novel associations with oligoarticular and RF-negative polyarticular JIA: CD226 rs763361 (OR 1.30, 95% CI 1.12 to 1.51, p=0.0006) and CD28 rs1980422 (OR 1.29, 95% CI 1.07 to 1.55, p=0.008). Meta-analyses including reported studies confirmed the association of both SNPs with susceptibility to JIA (OR 1.16, p=0.001 and OR 1.18, p=0.001, for rs763361 and rs1980422, respectively). Conclusions The CD226 gene has been identified as novel association with JIA, and a SNP near CD28 as a suggestive association. Both genes are probable candidate risk factors, since they are involved in costimulation of T cells.

Genetic variation in VTCN1 (B7-H4) is associated with course of disease in juvenile idiopathic arthritis

Objective The course of disease in juvenile idiopathic arthritis (JIA) is unpredictable with episodes of activity and remission. In order to identify predictive factors, 93 SNPs, JIA subtype, age at onset and ANA status were studied in relation to disease course. Methods Genetic and clinical parameters were analysed in a cohort of 272 Caucasian patients with persistent oligoarthritis (n=129), extended oligoarthritis (n=57) and rheumatoid factor negative polyarthritis (n=86). Categories of disease course (remitting (n=65), intermediate (n=96) and unremitting (n=111)) were designed based on the cumulative time spent in active disease in the first 2 years. Results Univariate analysis revealed association of the course of disease with JIA subtype (p=5.7*10–5) and three SNPs; VTCN1 rs10 923 223 (p=4.4*10−5), VTCN1 rs12 046 117 (p=0.017) and CDK6 rs42 041 (p=0.038). In a subsequent multivariate ordinal logistic regression analysis, VTCN1 rs10 923 223 (OR 0.41, 95%-CI 0.26 to 0.63) and JIA subtype (OR 3.8, 95%-CI 2.0 to 7.2; OR 2.5, 95%-CI 1.4 to 4.2, for extended oligoarthritis and RF-negative polyarthritis vs persistent oligoarthritis, respectively) were the strongest independent factors for course of disease. Conclusions This study provides evidence that VTCN1, encoding B7-H4, is associated with course of disease in selected subtypes of JIA. VTCN1 might be useful in predicting the course of disease.

PReS-FINAL-2109: Genetic variations in patients with juvenile idiopathic arthritis and uveitis

Juvenile Idiopathic Arthritis (JIA) is accompanied by uveitis in approximately 20% of the cases. This is a serious complication with risk of impaired vision or even blindness. Both conditions are considered to be autoimmune diseases. Since uveitis is often asymptomatic, frequent ophthalmologic checks are needed to diagnose this complication at an early stage. Identification of risk factors for uveitis (besides presence of antinuclear antibodies (ANA)) could contribute to understanding of the pathogenesis of both diseases, and could be used as prognostic tool in an individual patient.

Association of the CD226 ( DNAM-1 ) Gly307Ser polymorphism with juvenile idiopathic arthritis

Background Recent genetic studies have reported an association of the Gly307Ser single nucleotide polymorphism (SNP) in the CD226 gene with susceptibility to multiple autoimmune diseases. CD226 or DNAM-1 is a type 1 membrane protein belonging to the Ig-superfamily and is involved in the adhesion and co-stimulation of T cells and NK cells. A trend towards association of this SNP with Juvenile Idiopathic Arthritis (JIA) was recently reported, but was not statistically significant (p=0.13) (Genes Immun. 2010 Mar;11(2):194-8).