Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis

Introduction: The aim of this work was to assess the impact of prolonged low immunoglobulin (IgG or IgM) serum concentrations on the potential cumulative serious infection (SI) risk in pediatric patients following rituximab treatment for granulomatosis with polyangiitis or microscopic polyangiitis (GPA/MPA) in PePRS. Methods: Patients aged ≥ 2 to < 18 years received four weekly intravenous rituximab infusions of 375 mg/m2 and concomitant glucocorticoid taper. After 6 months, patients could receive further rituximab and/or other immunosuppressants per investigator discretion. Immunoglobulin levels and SIs were assessed throughout the 4.5-year observation period. Prolonged low IgG or IgM was defined as below the lower limit of normal age-specific reference range for ≥ 4 months. Results: A total of 25 patients were included, of whom 19 (76%) had GPA and six (24%) had MPA; 18 (72%) had newly diagnosed disease and seven (28%) had relapsing disease. All 25 patients completed the rituximab induction regimen; 24 completed ≥ 18 months of follow-up. At month 18, eighteen patients (72%) had prolonged low IgG; 19 (76%), prolonged low IgM; and 15 (60%), both. Seven patients (28%) had nine SIs; one occurred during or after prolonged low IgG only, two during or after prolonged low IgM only, and six during or after concurrent prolonged low IgG and IgM. No patients died or discontinued the study due to SI. All patients had complete and sustained peripheral B-cell depletion for ≥ 6 months. Conclusions: The majority of pediatric patients who received rituximab for GPA/MPA with prolonged low immunoglobulin levels did not experience SIs. In patients with SIs, these events were manageable, and the number of SIs did not increase over time or with multiple rituximab treatments. These observations are consistent with the rituximab safety profile in adults with GPA/MPA. Trial registration: ClinicalTrials.gov identifier, NCT01750697

Fatal myocarditis in a child with systemic onset juvenile idiopathic arthritis during treatment with an interleukin 1 receptor antagonist

<p>Abstract</p> <p>Background</p> <p>The pathologic diagnosis of isolated myocarditis without pericardial involvement is uncommonly encountered in systemic onset Juvenile Idiopathic Arthritis (soJIA).</p> <p>Case</p> <p>An eleven year-old boy with soJIA died suddenly while being treated with the interleukin 1 (IL-1) receptor inhibitor, anakinra. His autopsy revealed an enlarged heart and microscopic findings were consistent with myocarditis, but not pericarditis. Viral PCR testing performed on his myocardial tissue was negative.</p> <p>Conclusion</p> <p>This case illustrates myocarditis as a fatal complication of soJIA, potentially enabled by anakinra.</p

Genetic architecture distinguishes systemic juvenile idiopathic arthritis from other forms of juvenile idiopathic arthritis: Clinical and therapeutic implications

Objectives Juvenile idiopathic arthritis (JIA) is a heterogeneous group of conditions unified by the presence of chronic childhood arthritis without an identifiable cause. Systemic JIA (sJIA) is a rare form of JIA characterised by systemic inflammation. sJIA is distinguished from other forms of JIA by unique clinical features and treatment responses that are similar to autoinflammatory diseases. However, approximately half of children with sJIA develop destructive, long-standing arthritis that appears similar to other forms of JIA. Using genomic approaches, we sought to gain novel insights into the pathophysiology of sJIA and its relationship with other forms of JIA. Methods We performed a genome-wide association study of 770 children with sJIA collected in nine countries by the International Childhood Arthritis Genetics Consortium. Single nucleotide polymorphisms were tested for association with sJIA. Weighted genetic risk scores were used to compare the genetic architecture of sJIA with other JIA subtypes. Results The major histocompatibility complex locus and a locus on chromosome 1 each showed association with sJIA exceeding the threshold for genome-wide significance, while 23 other novel loci were suggestive of association with sJIA. Using a combination of genetic and statistical approaches, we found no evidence of shared genetic architecture between sJIA and other common JIA subtypes. Conclusions The lack of shared genetic risk factors between sJIA and other JIA subtypes supports the hypothesis that sJIA is a unique disease process and argues for a different classification framework. Research to improve sJIA therapy should target its unique genetics and specific pathophysiological pathways

Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis

<p>Abstract</p> <p>Objective</p> <p>Cytokines play important roles in mediating inflammation in autoimmunity. Several cytokines are elevated in serum and synovial fluid samples from children with Juvenile Idiopathic Arthritis (JIA). Soluble CD154 (sCD154) is elevated in other autoimmune disorders, but has not been characterized in JIA. Our objectives were to determine if sCD154 is elevated in JIA, and to examine correlations between sCD154 and other inflammatory cytokines.</p> <p>Methods</p> <p>Serum from 77 children with JIA and 81 pediatric controls was analyzed for interleukin (IL)1β, IL2, IL4, IL5, IL6, IL8, IL10, IL12, IL13, sCD154, interferon-γ (IFNγ), soluble IL2 receptor (sIL2R), and tumor necrosis factor-α (TNFα), using the Luminex Multi-Analyte Profiling system. Differences in levels of cytokines between cases and controls were analyzed. Logistic regression was also performed.</p> <p>Results</p> <p>sCD154 was significantly elevated in cases compared to controls (p < 0.0001). IL1β, IL5, IL6, IL8, IL13, IFNγ, sIL2R, and TNFα were also significantly elevated in JIA. Levels of sCD154 were highly correlated with IL1β, IL6, IL8, and TNFα (p < 0.0001). Logistic regression analysis suggested that IL6 (odds ratio (OR): 1.4, p < 0.0001), sCD154 (OR: 1.1, p < 0.0001), and TNFα (OR: 1.1, p < 0.005) were positively associated with JIA, while IL10 (OR: 0.5, p < 0.002) was protective. sCD154 was elevated in all JIA subtypes, with highest levels among more severe subtypes. IL1β, IL6, IL8, sIL2R and TNFα were also elevated in several JIA subtypes.</p> <p>Conclusion</p> <p>Serum levels of sCD154, IL1β, IL6, IL8, sIL2R and TNFα are elevated in most JIA subtypes, suggesting a major role for sCD154, and these cytokines and cytokine receptors in the pathogenesis of JIA.</p

The Use of IL-1 Receptor Antagonist (Anakinra) in Idiopathic Recurrent Pericarditis: A Narrative Review

Recurrent pericarditis is a complication of acute pericarditis in 20–30% of the patients and is usually idiopathic in nature. The underlying pathogenesis of this condition remains unclear, although immune-mediated mechanisms seem likely. A subgroup of these patients with refractory symptoms can be challenging to manage, and multiple immunosuppressive medications have been used without consistent benefit. Anakinra, an interleukin-1 receptor antagonist, has been used in treatment of rheumatoid arthritis and autoinflammatory syndromes. Preliminary evidence suggests that anakinra could be a promising therapy for idiopathic recurrent pericarditis. In this narrative review, we summarize the current understanding of the etiopathogenesis of idiopathic recurrent pericarditis, mechanism of action of anakinra, and the preliminary evidence, supporting the use of anakinra in pericarditis

Visual recovery and vascular reperfusion after vaso-occlusive retinopathy from anti-phospholipid syndrome associated with systemic lupus erythematosus.

PurposeTo report a case of visual recovery and vascular reperfusion after vaso-occlusive retinopathy from anti-phospholipid syndrome associated with systemic lupus erythematosus.ObservationsA 15-year-old boy with a known diagnosis of systemic lupus erythematosus and a clinically significant anti-phospholipid panel presented with sudden vision loss in the left eye. Examination and ocular imaging revealed signs of vaso-occlusive retinopathy. The patient was immediately started on high dose intravenous steroids, followed by mycophenolate mofetil. He remained on aspirin. After showing no improvement in retinal arteriole and capillary perfusion he was started on therapeutic anti-coagulation with enoxaparin. He regained 20/20 vision. Intravenous fluorescein angiography demonstrated reperfusion of retinal arterioles. Optical coherence tomography angiography showed return of flow in the capillary networks.ConclusionsWe present a case of vaso-occlusive retinopathy in a patient with known systemic lupus erythematosus and a clinically significant anti-phospholipid panel, thus meeting criteria for anti-phospholipid syndrome. He was treated with intravenous methylprednisolone, mycophenolate motefil, aspirin, and enoxaparin. The patient not only had great recovery of visual acuity, but also demonstrated reperfusion of arterioles and reconstitution of flow in the retinal capillary network. These findings suggest that the vaso-occlusive disease is reversible if the diagnosis is made promptly and intensive therapy is initiated.ImportanceCurrently there are no reported cases of vaso-occlusive retinopathy from APLS and SLE with visual recovery, reperfusion, and return of capillary flow