The association of PTPN22 rs2476601 with juvenile idiopathic arthritis is specific to females.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (Pinteraction=0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.

Effects of obesity on health-related quality of life in juvenile-onset systemic lupus erythematosus.

OBJECTIVE: This study evaluated the effects of obesity on health-related quality of life (HRQOL) measures in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: Obesity was defined as a body mass index (BMI) ≥ 95 th percentile according to the Sex-specific Center for Disease Control BMI-For-Age Charts and determined in a multicenter cohort of jSLE patients. In this secondary analysis, the domain and summary scores of the Pediatric Quality of Life (PedsQL) Inventory and the Child Health Questionnaire (CHQ) of obese jSLE patients were compared to those of non-obese jSLE patients as well as historical obese and non-obese healthy controls. Mixed-effects modeling was performed to evaluate the relationship between obesity and HRQOL measures. RESULTS: Among the 202 jSLE patients, 25% (n = 51) were obese. Obesity had a significant negative impact on HRQOL in jSLE, even after adjusting for differences in current corticosteroid use, disease activity, disease damage, gender and race between groups. Obese jSLE patients had lower physical functioning compared to non-obese jSLE patients, and to non-obese and obese healthy controls. Compared to their non-obese counterparts, obese jSLE patients also had worse school functioning, more pain, worse social functioning and emotional functioning. Parents of obese jSLE patients worry more. The CHQ scores for obese jSLE patients were also worse compared to non-obese jSLE patients in several other domains. CONCLUSION: Our study demonstrates the detrimental effects of obesity on patient-reported outcomes in jSLE. This supports the importance of weight management for the therapeutic plan of jSLE.

Use of atorvastatin in systemic lupus erythematosus in children and adolescents.

OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.

Severe cochlear inflammation and vestibular syndrome in an experimental model of Streptococcus suis infection in mice.

Hearing impairment is a common and frequently permanent sequel of Streptococcus suis meningitis in humans. Nevertheless, mechanisms underlying the development of cochlear damage have not been addressed so far. In the present work, we characterized a mouse model of suppurative labyrinthitis and meningitis induced by a systemic infection with S. suis and studied the impact of the injected bacterial dosage on the progression of such inflammatory events. We observed that high infection doses of bacteria lead to sustained bacteremia, with an increase in the permeability of the blood-labyrinth and blood-brain barriers, causing suppurative labyrinthitis and meningitis, respectively. However, in mice infected with a low dose of S. suis, bacteria disappeared quickly from blood, hence, cochlear inflammation and meningitis were not consistent features. This model of S. suis infection seems ideal to evaluate novel drugs that may help alleviate the negative consequences of such important sequelae of S. suis-induced meningitis and labyrinthitis.

Clinical comparison of early-onset psoriatic and non-psoriatic oligoarticular juvenile idiopathic arthritis.

OBJECTIVES: Among the seven subtypes of juvenile idiopathic arthritis (JIA), oligoarticular JIA (oJIA) and psoriatic JIA (psJIA) display a predilection for onset in early childhood. We examined whether meaningful differences in clinical phenotype justify the distinction between these conditions. METHODS: We performed a chart review to identify children with psoriatic and non-psoriatic oligoarticular-onset JIA. Clinical and demographic features of the two groups of children were compared. RESULTS: Of the 390 children included in the study, 303 met the criteria for oJIA and 87 met the criteria for oligoarticular-onset psJIA. Both groups had a peak age of onset at 2-3 years, though psJIA had appreciable incidence into adolescence. Onset before 5 years of age was observed in 215 (71%) and 38 (44%) children respectively (p<0.001). Within this age category, children with psJIA demonstrated similar gender ratio and anti-nuclear antibody status to those with oJIA but exhibited a distinctive clinical pattern, with a tendency to involve the wrists and small joints of the hands and feet. Conversely, among all children presenting with oligoarthritis in early childhood, those with wrist or small joint involvement were more likely to have nail pits, psoriasis, or a family history of psoriasis than those without (p<0.05), supporting the association of this joint pattern with the psoriatic diathesis. CONCLUSIONS: Even taking into account age of onset and number of joints, oJIA and psJIA remain clinically distinct, though important demographic overlap remains. These findings support separate diagnostic categories but justify further investigation into the similarities as well as differences among these children.

Elevated IgG autoantibody production in oligoarticular juvenile idiopathic arthritis may predict a refractory course.

OBJECTIVES: Although oligoarticular juvenile idiopathic arthritis (oJIA) is considered to carry the best prognosis among the JIA subtypes, many children evolve to a chronic course. A few studies have identified clinical risk factors for disease extension, and recent studies have evaluated synovial fluid markers. However, the only biological marker from the serum studied to date is the anti-nuclear antibody (ANA), regarding which there is mixed data regarding prognosis. No studies have evaluated whether additional autoantibodies may affect the articular prognosis of oJIA. METHODS: Microarrays containing candidate autoantigens were printed on slides, which were used to profile 36 children with oJIA and 18 controls. Unsupervised cluster analysis was used to identify distinct subgroups of JIA patients. Response to therapy after a mean interval of 4.9 months was evaluated. RESULTS: Cluster analysis revealed two subgroups of oJIA patients, with identical clustering observed when children with onset over age six were excluded. Cluster 1 had higher levels of multiple autoantibodies compared to both cluster 2 as well as controls, including antibodies against several extracellular matrix (ECM) and nuclear antigens. Although the two patient clusters were similar with respect to clinical features and treatment decisions, children in cluster 1 were less likely to have attained remission by the follow-up visit. CONCLUSIONS: Antibodies against ECM and possibly other antigens may identify a sub-group of children with oJIA who will require more aggressive therapy to attain control of the arthritis.

Disruption of srtA gene in Streptococcus suis results in decreased interactions with endothelial cells and extracellular matrix proteins.

Streptococcus suis, a major pathogen of swine, is an emerging zoonotic agent which causes meningitis and septic shock. In this study, we investigated the ability of S. suis mutant strain (SRTDeltaA) lacking the sortase A gene (srtA) to interact with host cells and extracellular matrix (ECM) proteins, as well as its virulence in a mouse infection model. We demonstrated that mutant SRTDeltaA had reduced capacity to adhere to and invade porcine brain microvascular endothelial cells compared to the wild-type strain. In addition, mutant SRTDeltaA also showed significantly less adherence to plasma fibronectin, cellular fibronectin and collagen type I. However, disruption of srtA had little effect on the virulence of S. suis in a mouse intraperitoneal model of infection. These results indicate that surface proteins anchored by sortase A are required for a normal level of bacterial binding. However, other factors may also be important for S. suis virulence and interaction with host tissues.

Lymphocyte subpopulations in Kawasaki disease.

The relative percentages of subpopulations of peripheral T lymphocytes in children with Kawasaki Disease (KD) was investigated using matched antibodies directed against the T3, T4 and T8 antigens. The percentage of B cells was determined with antibodies against human surface immunoglobulins. Subjects were six children with acute KD who were compared to normal, age matched controls. The percentage of peripheral lymphocytes positive for OKT3 was 61% for KD children and 64% for controls; for OKT4 they were 41% and 44% respectively and for OKT8 both were 19%. The B cell percentages were 13% in KD and 11% in controls. Thus no abnormalities in the distribution of lymphocyte subtypes in children with KD was found. Previous studies of immune function in KD are reviewed.

Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritis.

OBJECTIVE: To investigate the association of NLRP3, NOD2, MEFV, and PSTPIP1, genes that cause 4 of the autoinflammatory hereditary periodic fever syndromes (HPFS), with juvenile idiopathic arthritis (JIA). METHODS: Fifty-one single-nucleotide polymorphisms (SNPs) across the 4 loci were investigated using MassArray genotyping in 950 Caucasian patients with JIA living in the UK and 728 ethnically matched healthy controls. RESULTS: Prior to Bonferroni correction for multiple testing, significant genotype associations between 6 SNPs in MEFV and JIA were observed and, in subgroup analysis, associations between 12 SNPs across all 4 loci and the subgroup of patients with psoriatic JIA were found. After Bonferroni correction for multiple testing, 2 genotype associations remained significant in the subgroup of patients with psoriatic JIA (MEFV SNP rs224204 [corrected P = 0.025] and NLRP3 SNP rs3806265 [corrected P = 0.04]). CONCLUSION: These findings support the use of monogenic loci as candidates for investigating the genetic component of complex disease and provide preliminary evidence of association between SNPs in autoinflammatory genes and psoriatic JIA. Our findings raise the interesting possibility of a shared disease mechanism between the HPFS and psoriatic JIA, potentially involving abnormal production of interleukin-1beta.

Unusual neurologic manifestations (II): posterior reversible encephalopathy syndrome (PRES) in the context of juvenile systemic lupus erythematosus.

Posterior reversible encepalopathy syndrome (PRES), or reversible posterior leukoencephalopathy, is a neurologic condition characterized by recognizable pattern of altered mental status, headache, visual changes and seizures in association with findings indicating a predominantly posterior leucoencephalopathy on imaging studies. It has rarely been described in children. We report two cases of pediatric systemic lupus erythematosus (SLE) complicated by PRES and review the literature.

Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study.

OBJECTIVE: Juvenile localized scleroderma (JLS) includes a number of conditions often grouped together. With the long-term goal of developing uniform classification criteria, we studied the epidemiological, clinical and immunological features of children with JLS followed by paediatric rheumatology and dermatology centres. METHODS: A large, multicentre, multinational study was conducted by collecting information on the demographics, family history, triggering environmental factors, clinical and laboratory features, and treatment of patients with JLS. RESULTS: Seven hundred and fifty patients with JLS from 70 centres were enrolled into the study. The disease duration at diagnosis was 18 months. Linear scleroderma (LS) was the most frequent subtype (65%), followed by plaque morphea (PM) (26%), generalized morphea (GM) (7%) and deep morphea (DM) (2%). As many as 15% of patients had a mixed subtype. Ninety-one patients (12%) had a positive family history for rheumatic or autoimmune diseases; 100 (13.3%) reported environmental events as possible trigger. ANA was positive in 42.3% of the patients, with a higher prevalence in the LS-DM subtype than in the PM-GM subtype. Scl70 was detected in the sera of 3% of the patients, anticentromere antibody in 2%, anti-double-stranded DNA in 4%, anti-cardiolipin antibody in 13% and rheumatoid factor in 16%. Methotrexate was the drug most frequently used, especially during the last 5 yr. CONCLUSION: This study represents the largest collection of patients with JLS ever reported. The insidious onset of the disease, the delay in diagnosis, the recognition of mixed subtype and the better definition of the other subtypes should influence our efforts in educating trainees and practitioners and help in developing a comprehensive classification system for this syndrome.