Carlos D. Rose

Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor–negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10−8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10−6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10−6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.

Primary Sjögren syndrome in the paediatric age: a multicentre survey.

Abstract Primary Sjögren syndrome (SS) is very rare in childhood. We collected a series of primary paediatric SS cases from different centres. A data collection form was prepared and sent to rheumatologists who were willing to participate. Data on 40 cases of primary SS with onset before the 16th birthday were collected. Almost all patients (35/40) were females, age at onset varied from 9.3 to 12.4 years (mean 10.7 years). Signs and symptoms at disease onset were mainly recurrent parotid swelling followed by sicca symptoms. Abnormal laboratory tests were found in the majority of cases. Regarding treatment, 22 patients were treated at some time with oral corticosteroids, seven with non-steroidal anti-inflammatory drugs, and five with hydroxychloroquine; two patients needed cyclosporine and one cyclophosphamide. Follow-up varied from 0 to 7.5 years from onset, without major complications in the majority of patients. Conclusion: recurrent parotid swelling is a common feature of primary Sjögren syndrome in childhood and often occurs as a presenting feature. Sicca symptoms may be rarer.

An International registry on Autoinflammatory diseases: the Eurofever experience

Objective To report on the demographic data from the first 18 months of enrollment to an international registry on autoinflammatory diseases in the context of the Eurofever project. Methods A web-based registry collecting baseline and clinical information on autoinflammatory diseases and related conditions is available in the member area of the PRINTO web-site. Anonymised data were collected with standardised forms. Results 1880 (M:F=916:964) individuals from 67 centers in 31 countries have been entered in the Eurofever registry. Most of the patients (1388; 74%), reside in western Europe, 294 (16%) in the eastern and southern Mediterranean region (Turkey, Israel, North Africa), 106 (6%) in eastern Europe, 54 in Asia, 27 in South America and 11 in Australia. In total 1049 patients with a clinical diagnosis of a monogenic autoinflammatory diseases have been enrolled; genetic analysis was performed in 993 patients (95%): 703 patients have genetically confirmed disease and 197 patients are heterozygous carriers of mutations in genes that are mutated in patients with recessively inherited autoinflammatory diseases. The median diagnosis delay was 7.3 years (range 0.3–76), with a clear reduction in patients born after the identification of the first gene associated with autoinflammatory diseases in 1997. Conclusions A shared online registry for patients with autoinflammatory diseases is available and enrollment is ongoing. Currently, there are data available for analysis on clinical presentation, disease course, and response to treatment, and to perform large scale comparative studies between different conditions.

Clinical characteristics of antiphospholipid antibody syndrome in children

OBJECTIVE To evaluate the clinical features and outcome of antiphospholipid syndrome (APS) in children. STUDY DESIGN Retrospective chart review of patients seen at the Childrens Hospital of Philadelphia and Childrens Seashore House Pediatric Rheumatology Center between 1988 and 1993. RESULTS Nine patients with ages ranging from 8 months to 17 years are presented. Clinical features of five patients with primary APS, described in detail, were digital ischemia, stroke, chorea, Addison disease, and pulmonary vaso-occlusive disease. The four children with secondary APS had systemic lupus erythematosus. Clinical features of these patients include livedo reticularis, deep venous thrombosis, and pulmonary hypertension. Antiphospholipid titers, results of coagulation studies, and serologic findings did not predict outcome. CONCLUSION APS in children has diverse clinical features similar to those in adults and should be considered in cases of unexplained vaso-occlusive disease.

Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis

Twenty-nine children with juvenile rheumatoid arthritis were studied to determine the safety and efficacy of methotrexate therapy. The initial dose of methotrexate averaged 7.1 mg/m2/wk and was given as a single, oral weekly dose or as three divided doses, each separated by 12 hours. Current antiinflammatory medications were continued; 25 of 29 children had had lack of efficacy, and 8 of 29 had toxic effects, with one or more prior drugs such as intramuscularly or orally administered gold, hydroxychloroquine, or D-penicillamine. Intolerable corticosteroid dependency or toxic effects were present in 18 of 29 cases. Methotrexate-treated patients were examined monthly; minimum treatment duration required to assess efficacy and toxicity was 6 months. The range of treatment duration was 8 to 39 months (mean 18.5 months). Efficacy was assessed by comparing pretreatment versus posttreatment fever and rash, swollen-joint counts, articular indexes, duration of morning stiffness, functional class, hemoglobin levels, and platelet counts. Treatment with methotrexate effectively controlled fever and rash in 83% of children with systemic juvenile rheumatoid arthritis, reduced morning stiffness by 63%, eliminated recalcitrant joint restriction in 48%, and reduced numbers of swollen joints and swelling indexes by 46% and 52%, respectively. No significant toxic effects were observed. Juvenile rheumatoid arthritis of long duration, or with major erosions, was more likely to be refractory to methotrexate therapy. We recommend earlier consideration of methotrexate in place of other slow-acting antirheumatic drugs for juvenile rheumatoid arthritis not responding well to usual therapy. Future studies should address potential methotrexate toxic effects in the lungs and reproductive system, as well as outcome after discontinuation of methotrexate treatment.

The NOD2 defect in Blau syndrome does not result in excess interleukin 1 activity

OBJECTIVE Blau syndrome is a rare, autosomal-dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetics studies have shown that the disease is caused by single nonsynonymous substitutions in NOD-2, a member of the NOD-like receptor or NACHT-leucine-rich repeat (NLR) family of intracellular proteins. Several NLRs function in the innate immune system as sensors of pathogen components and participate in immune-mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD-2, NLRP3, are responsible for excess caspase 1-dependent interleukin-1beta (IL-1beta) in cryopyrinopathies such as Muckle-Wells syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1beta also involves NOD-2. The aim of this study was to test the hypothesis that IL-1beta may mediate the inflammation seen in patients with Blau syndrome. METHODS IL-1beta release was measured in peripheral blood mononuclear cells cultured in vitro, obtained from 5 Blau syndrome individuals with a NOD2 (CARD15) mutation. RESULTS We observed no evidence for increased IL-1beta production in cells obtained from subjects with Blau syndrome compared with healthy control subjects. Furthermore, we presented 2 cases of Blau syndrome in which recombinant human IL-1 receptor antagonist (anakinra) was ineffective treatment. CONCLUSION Taken together, these data suggest that in contrast to related IL-1beta-dependent autoinflammatory cryopyrinopathies, Blau syndrome is not mediated by excess IL-1beta or other IL-1 activity.

Blau syndrome revisited.

Purpose of reviewBlau syndrome is a monogenic disease resulting from mutations in nucleotide oligomerization domain 2 (NOD2) and is phenotypically characterized by granulomatous polyarthritis and uveitis. Not only there has been significant progress in disease characterization but also the biological pathways associated with NOD2 and related proteins of the innate immunity are better understood. Recent findingsThe phenotype of Blau syndrome has proven to be more complex than initially thought. A discussion on those manifestations will be provided in the clinical sections of this review. As more patients and pedigrees are found new mutations in the NOD2 gene have emerged and we discuss them in some detail. Due to its importance in Crohns disease NOD2 has become the focus of intense research. A brief review of more recent advances in relevant pathways is presented and published reviews referenced for the interested reader. The granulomatous character of Blau syndrome provides an opportunity to look at possible pathogenic effects of NOD2 ‘gain of function’. New immunohistochemical data are briefly reviewed as well. SummaryElucidation of downstream effects of NOD2 mutations could provide valuable clues to mechanisms of arthritis and uveitis in general as well as granulomatous diseases in particular.

Lyme disease and seventh nerve paralysis in children

PURPOSE This study was undertaken to determine the frequency of Lyme disease (LD) as a cause of transient facial nerve palsy (FNP) in children. Acute onset FNP in children has been primarily associated with acute otitis media (AOM). Recently, LD has emerged in regions where the deer-tick vector is present and has been associated with multiple cranial neuropathies. PATIENTS AND METHODS Fifty children with transient FNP were evaluated and treated at our institution over a 5.5-year period. RESULTS The rank of etiologies confirmed LD to now be the most common (50%), followed by AOM (12%), varicella (6%), Herpes zoster (4%), and coxsackievirus (2%). Thirteen children (26%) had idiopathic FNP consistent with Bells palsy. CONCLUSION We conclude that transient FNP in children is most commonly caused by LD for regions with endemic infections caused by Borrelia burgdorferi.

Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13

OBJECTIVE In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. METHODS The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. RESULTS Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10(-6) ) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10(-8) ], rs12411988 [OR 1.57, P = 1.16 × 10(-7) ], and rs10995450 [OR 1.31, P = 6.74 × 10(-5) ]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10(-7) for rs4688011, P = 4.33 × 10(-5) for rs6479891, P = 2.71 × 10(-5) for rs12411988, and P = 5.39 × 10(-5) for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. CONCLUSION Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.

Blau Syndrome, the prototypic auto-inflammatory granulomatous disease

Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau granuloma. Finally, emerging insights into pathogenic mechanisms including activation of NOD2 signal transduction, and potential biomarkers of disease activity are discussed.