Gil Amarilyo

IL-17 Promotes Murine Lupus

The proinflammatory activity of IL-17–producing Th17 cells has been associated with the pathogenesis of several autoimmune diseases. In this article, we provide direct evidence for a role of IL-17 in the pathogenesis of systemic lupus erythematosus (SLE). The induction of SLE by pristane in IL-17–sufficient wild-type mice did not occur in IL-17–deficient mice, which were protected from development of lupus autoantibodies and glomerulonephritis. The protection from SLE in IL-17–deficient mice was associated with a reduced frequency of CD3+CD4−CD8− double-negative T cells and an expansion of CD4+ regulatory T cells, and did not depend on Stat-1 signaling. These data affirm the key role of IL-17 in the pathogenesis of SLE and strengthen the support for IL-17 blockade in the therapy of SLE.

miRNA in systemic lupus erythematosus

Since their recent discovery, the small noncoding RNA known as microRNAs (miRNA) have been reported to play a major role in the physiological control of gene expression and in the pathogenesis of malignant, infectious, and autoimmune disorders. In systemic lupus erythematosus (SLE), an autoimmune disease characterized by the presence of autoantibodies to multiple antigens, the role of miRNA as post-transcriptional regulators of different aspects of the disease process has recently emerged. This article reviews the pertinent literature and mechanisms of action of miRNA that have so far been associated with the pathogenesis of SLE.

Leptin promotes lupus T-cell autoimmunity.

In systemic lupus erythematosus (SLE), the impairment in apoptosis can facilitate the initiation and maintenance of autoimmune responses to self antigens. Here we show that the adipocytokine leptin, which is abnormally elevated in SLE, promotes the survival and proliferation of autoreactive T-cells in mice with an autoreactive T-cell repertoire, including (NZB x NZW)F1 lupus-prone mice. This ability of leptin to promote lupus T-cell autoimmunity suggests the possibility of a therapeutic targeting of leptin in SLE.

Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: a systematic review and meta-analysis of randomized trials

OBJECTIVE To define the optimal biologic agent for systemic JIA (sJIA) based on safety and efficacy data from a randomized controlled trial (RCT). METHODS Through a systematic literature search, sJIA RCTs evaluating biologic agents were identified. The primary efficacy outcome was defined as a 30% improvement according to the modified American College of Rheumatology Paediatric 30 response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. The quality of evidence between biologic agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. RESULTS From the 493 citations originally identified, 5 RCTs were eligible for inclusion-one each for anakinra, canakinumab and tocilizumab and two for rilonacept: all vs placebo. While all were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab [odds ratio (OR) 0.10 (95% CI 0.02, 0.38), P = 0.001] or tocilizumab [OR 0.12 (95% CI 0.03, 0.44), P = 0.001]. Risks of SAEs were similar among the biologic agents (supported by very low-quality evidence) and not different from placebo. CONCLUSION Despite heterogeneous eligibility criteria and study designs across the five studies and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Biologic agents in sJIA seem safe and comparable with respect to SAE risk in the short term.

Orotracheal Tube Insertion in Extremely Low Birth Weight Infants

Thirty-one consecutive infants <1000 g at birth were intubated according to Tochens rule; placement was verified/modified after auscultation and by radiology. Depth measurements were by caliper and radiology. Tochens rule alone would lead to inadequate tube placement in 47% of infants. Auscultation allows adequate placement in only three-fourths of patients.

Diagnostic accuracy of clinical symptoms and signs in children with meningitis.

Background: The diagnostic accuracy of the classic symptoms and signs of meningitis in infants and children has not been established. Methods: All children aged 2 months to 16 years with clinically suspected meningitis were eligible for this prospective cohort study at 2 large medical centers between February 2006 and October 2007. Exclusion criteria were severe chronic disease, severe immune deficiency, or idiopathic intracranial hypertension. The emergency department physician obtained information on clinical symptoms and signs and cerebrospinal fluid analysis. Meningitis was defined as white blood cell count of 6 or higher per microliter of cerebrospinal fluid. Results: A total of 108 patients with suspected meningitis were enrolled. Meningitis was diagnosed in 58 patients (53.7%; 6 bacterial and 52 aseptic). Sensitivity and specificity were 76% and 53% for headache (among the verbal patients) and 71% and 62% for vomiting, respectively. Photophobia was highly specific (88%) but had low sensitivity (28%). Clinical examination revealed nuchal rigidity (in patients without open fontanel) in 32 (65%) of the patients with meningitis and in 10 (33%) of the patients without meningitis. Brudzinski and Kernig signs were present in 51% and 27% of the patients with meningitis, respectively, and had relatively high positive predictive values (81% and 77%, respectively). Bulging fontanel in patients with open fontanel was present in 50% of the patients with meningitis but had a positive predictive value of only 38%. Conclusions: Classic clinical diagnostic signs have limited value in establishing the diagnosis of meningitis in children and should not be the sole determinants for referral to further diagnostic testing and lumbar puncture.

Leptin enhances availability of apoptotic cell-derived self-antigen in systemic lupus erythematosus.

In systemic lupus erythematosus (SLE), the availability of self-antigen promotes and fuels self-reactive immune responses. Apoptotic cells represent a major source of self-antigens, and an impairment of the removal of apoptotic material containing self-antigen can contribute to the development of autoimmunity. To address whether the adipocytokine leptin - which favors autoimmune responses through little understood mechanisms - could modulate the handling of apoptotic cells in SLE, we evaluated the ability of leptin to modulate the capacity of macrophages to phagocytose apoptotic bodies in (NZB×NZW)F1 lupus mice. It was found that leptin promoted phagocytosis of apoptotic cells by macrophages by modulating cAMP levels in macrophages. This finding associated with an increased availability of antigen that favored the development of T cell responses to apoptotic-derived antigen. As leptin promotes macrophage phagocytosis of apoptotic bodies in SLE and subsequent availability of apoptotic-derived antigen to T cells, an inhibition of this process via leptin blockade might have a therapeutic potential in SLE.

Publication Outcomes of Abstracts Presented at an American College of Rheumatology/Association of Rheumatology Health Professionals Annual Scientific Meeting

The American College of Rheumatology (ACR) and the Association of Rheumatology Health Professionals (ARHP) Annual Scientific Meeting is an important forum for early dissemination of novel ideas. However, unlike published studies in peer‐reviewed journals, reviewers select abstracts based solely on a general summary of the research. Analyses of the scientific impact and the publication record of the ACR/ARHP Annual Meeting have not been previously described. This study characterizes publication trends and outcomes associated with abstracts presented at the ACR/ARHP Annual Scientific Meeting.

Biological agents in polyarticular juvenile idiopathic arthritis: A meta-analysis of randomized withdrawal trials ☆ ☆☆

BACKGROUND AND OBJECTIVE Although various biological agents are in use for polyarticular juvenile idiopathic arthritis (pJIA), head-to-head trials comparing the efficacy and safety among them are lacking. We aimed to compare the efficacy and safety of biological agents in pJIA using all currently available randomized withdrawal trials (wRCTs). METHODS A systematic search of MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov was performed. Eligible wRCTs: patients with pJIA where a biological agent was compared with another biological agent or placebo. Efficacy was evaluated using disease flare as a measure. Adverse events (AEs) and serious AEs were evaluated. Network meta-analysis compared biological agents based on a (empirical Bayes) mixed-effects logistic regression model that combines statistical inference from both direct and indirect comparisons of the treatment effects between biological agents. RESULTS Of 496 references identified, five wRCTs were included-abatacept, adalimumab, anakinra, etanercept, and tocilizumab, one trial each, all vs. placebo. There were no differences in efficacy among biological agents and most showed statistically significant efficacy compared with placebo (nearly all exceptions were in agreement with the original study data). Serious AEs occurred very infrequently (0-8%) and an analysis was not possible. There were no differences for AEs when compared among biological agents or to placebo. CONCLUSION There were no statistical differences among biological agents for efficacy or safety. Overall, biological agents were effective and safe when compared to placebo. Based on these data, other considerations such as price and availability may need to be used to decide among biological agents when treating pJIA patients.

Consensus Treatment Plans for Chronic Nonbacterial Osteomyelitis Refractory to Nonsteroidal Antiinflammatory Drugs and/or With Active Spinal Lesions.

To develop standardized treatment regimens for chronic nonbacterial osteomyelitis (CNO), also known as chronic recurrent multifocal osteomyelitis (CRMO), to enable comparative effectiveness treatment studies.