Systemic onset juvenile idiopathic arthritis (SoJIA) encompasses approximately 10% of cases of arthritis that begin in childhood. The disease is unique in terms of clinical manifestations, severity ...of joint involvement, and lack of response to tumor necrosis factor blockade. Here, we show that serum from SoJIA patients induces the transcription of innate immunity genes, including interleukin (IL)-1 in healthy peripheral blood mononuclear cells (PBMCs). Upon activation, SoJIA PBMCs release large amounts of IL-1beta. We administered recombinant IL-1 receptor antagonist to nine SoJIA patients who were refractory to other therapies. Complete remission was obtained in seven out of nine patients and a partial response was obtained in the other two patients. We conclude that IL-1 is a major mediator of the inflammatory cascade that underlies SoJIA and that this cytokine represents a target for therapy in this disease.
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.
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 (SRTΔA) ...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 SRTΔA had reduced capacity to adhere to and invade porcine brain microvascular endothelial cells compared to the wild-type strain. In addition, mutant SRTΔA 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.
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.
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) ≥95th 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.
Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 ...agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.
Severe pain and impairments in functioning are commonly reported for youth with juvenile fibromyalgia. The prevalence and impact of pain in other diseases commonly managed in pediatric rheumatology ...comparatively have been rarely systematically studied. The objective of the current study was to determine the extent to which high levels of pain and functional limitations, and the strength of their association, are unique to youth with juvenile primary fibromyalgia syndrome/JPFS) relative to other pediatric rheumatic diseases.
Using data from 7753 patients enrolled in the multinational Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry, we compared the levels and association of pain and functional limitations between youth with JPFS and those with other rheumatic diseases.
Pain levels were rated highest among youth with JPFS (M = 6.4/10, SD = 2.4) and lowest for juvenile dermatomyositis (M = 1.7/10, SD = 2.2), with pain significantly higher in the JPFS group than any other pediatric rheumatic disease (effect sizes = .22 to 1.05). Ratings on measures of functioning and well-being also were significantly worse for patients with JPFS than patients with any other rheumatic disease (effect sizes = .62 to 1.06). The magnitude of association between pain intensity and functional disability, however, generally was higher in other rheumatic diseases than in JPFS. Pain was most strongly associated with functional limitations in juvenile dermatomyositis, juvenile idiopathic arthritis, and mixed connective tissue disease.
JPFS is unique among conditions seen in pediatric rheumatology with regard to ratings of pain and disability. However, pain appears to be comparably or more highly associated with level of functional impairment in other pediatric rheumatic diseases. Pain in childhood rheumatic disease thus would benefit from increased prioritization for research and treatment.
Global disease activity scores (gVAS) capture patient or family (PF) and physician (MD) assessments of disease. This study sought to measure discordance between PF and MD global activity scores in ...juvenile dermatomyositis (JDM), and determine factors associated with discordance.
Patients with JDM were included from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry (N = 563). PF and MD gVAS were assessed for discordance, defined as a ≥ 2-point difference. Factors associated with discordant gVAS were compared in univariate analysis. Multivariable regression analysis was used to identify predictors of discordance.
Almost 40% (N = 219) of PF and MD gVAS were discordant. Among discordant scores, 68% of PF rated gVAS ≥2-points above MD, which was associated with calcinosis and lower quality of life and functional scores (p < 0.01). MD gVAS rated ≥2-points above PF in 32%, which was associated with abnormal laboratory results, weakness, arthritis, rash and other skin changes, and current intravenous steroid treatment (p < 0.01). In multivariate analysis, predictors for higher PF rating included calcinosis, lower quality of life and functional scores, while predictors for higher MD rating included rash, calcinosis, nailfold capillaroscopy changes, and current intravenous steroid treatment.
Discordance between PF and MD gVAS was common in this JDM cohort. Overall, higher PF rating was associated with poorer patient reported outcome (PRO) scores, while higher MD rating was associated with poorer objective measures. This suggests PF and MD assessments of gVAS may be measuring different aspects of disease, highlighting the importance of integrating PROs into clinical practice and research.
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.
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.
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.
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.
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.
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