CAR T cell therapy for refractory pediatric systemic lupus erythematosus: a new era of hope?

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition that can affect multiple organ systems and is heterogenous in its presentation and response to therapy. When diagnosed in childhood, SLE is associated with increased morbidity and mortality compared to adult SLE, often requiring substantial immunosuppression with the risk of significant side effects. There remains a significant unmet need for new therapies that can improve disease control and reduce glucocorticoid and other toxic medication exposure for patients with severe or refractory disease. The pathogenesis of SLE involves B cell dysregulation and autoantibody production, which are a hallmark of the disease. Currently approved B cell directed therapies often result in incomplete B cell depletion and may not target long-lived plasma cells responsible for SLE autoantibodies. It is hypothesized that by persistently eliminating both B cells and plasmablasts, CAR T therapy can halt autoimmunity and prevent organ damage in patient's refractory to current B cell-depleting treatments. Herein we summarize the current preclinical and clinical data utilizing CAR T cells for SLE and discuss the future of this treatment modality for lupus.

Multisystem Inflammatory Syndrome in Children and Cardiac Involvement: A Quaternary Center Experience.

We prospectively analyzed clinical and laboratory characteristics associated with cardiac involvement and severe presentation in multisystem inflammatory syndrome in children. Of 146 patients, 66 (45.2%) had cardiac dysfunction and 26 (17.8%) had coronary artery abnormalities. Lower serum albumin levels, absolute lymphocyte and platelet counts, and elevated ferritin, fibrinogen, d-dimer and interleukin-6 levels were associated with cardiac dysfunction. Possible treatment complications were identified.

Case report and review of the literature: immune dysregulation in a large familial cohort due to a novel pathogenic RELA variant.

OBJECTIVE: To explore and define the molecular cause(s) of a multi-generational kindred affected by Bechet's-like mucocutaneous ulcerations and immune dysregulation. METHODS: Whole genome sequencing and confirmatory Sanger sequencing were performed. Components of the NFκB pathway were quantified by immunoblotting, and function was assessed by cytokine production (IL-6, TNF-α, IL-1ß) after lipopolysaccharide (LPS) stimulation. Detailed immunophenotyping of T-cell and B-cell subsets was performed in four patients from this cohort. RESULTS: A novel variant in the RELA gene, p. Tyr349LeufsTer13, was identified. This variant results in premature truncation of the protein before the serine (S) 536 residue, a key phosphorylation site, resulting in enhanced degradation of the p65 protein. Immunoblotting revealed significantly decreased phosphorylated [p]p65 and pIκBα. The decrease in [p]p65 may suggest reduced heterodimer formation between p50/p65 (NFκB1/RelA). Immunophenotyping revealed decreased naïve T cells, increased memory T cells, and expanded senescent T-cell populations in one patient (P1). P1 also had substantially higher IL-6 and TNF-α levels post-stimulation compared with the other three patients. CONCLUSION: Family members with this novel RELA variant have a clinical phenotype similar to other reported RELA cases with predominant chronic mucocutaneous ulceration; however, the clinical phenotype broadens to include Behçet's syndrome and IBD. Here we describe the clinical, immunological and genetic evaluation of a large kindred to further expand identification of patients with autosomal dominant RELA deficiency, facilitating earlier diagnosis and intervention. The functional impairment of the canonical NFκB pathway suggests that this variant is causal for the clinical phenotype in these patients.

Reintroduction of immunosuppressive medications in pediatric rheumatology patients with histoplasmosis: a case series.

BACKGROUND: Children with rheumatic diseases (cRD) receiving immunosuppressive medications (IM) are at a higher risk for acquiring potentially lethal pathogens, including Histoplasma capsulatum (histoplasmosis), a fungal infection that can lead to prolonged hospitalization, organ damage, and death. Withholding IM during serious infections is recommended yet poses risk of rheumatic disease flares. Conversely, reinitiating IM increases risk for infection recurrence. Tumor necrosis factor alpha inhibitor (TNFai) biologic therapy carries the highest risk for histoplasmosis infection after epidemiological exposure, so other IM are preferred during active histoplasmosis infection. There is limited guidance as to when and how IM can be reinitiated in cRD with histoplasmosis. This case series chronicles resumption of IM, including non-TNFai biologics, disease-modifying anti-rheumatic drugs (DMARDs), and corticosteroids, following histoplasmosis among cRD. CASE PRESENTATION: We examine clinical characteristics and outcomes of 9 patients with disseminated or pulmonary histoplasmosis and underlying rheumatic disease [juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and mixed connective tissue disease (MCTD)] after reintroduction of IM. All DMARDs and biologics were halted at histoplasmosis diagnosis, except hydroxychloroquine (HCQ), and patients began antifungals. Following IM discontinuation, all patients required systemic or intra-articular steroids during histoplasmosis treatment, with 4/9 showing Cushingoid features. Four patients began new IM regimens [2 abatacept (ABA), 1 HCQ, and 1 methotrexate (MTX)] while still positive for histoplasmosis, with 3/4 (ABA, MTX, HCQ) later clearing their histoplasmosis and 1 (ABA) showing decreasing antigenemia. Collectively, 8/9 patients initiated or continued DMARDs and/or non-TNFai biologic use (5 ABA, 1 tocilizumab, 1 ustekinumab, 3 MTX, 4 HCQ, 1 leflunomide). No fatalities, exacerbations, or recurrences of histoplasmosis occurred during follow-up (median 33 months). CONCLUSIONS: In our cohort of cRD, histoplasmosis course following reintroduction of non-TNFai IM was favorable, but additional studies are needed to evaluate optimal IM management during acute histoplasmosis and recovery. In this case series, non-TNFai biologic, DMARD, and steroid treatments did not appear to cause histoplasmosis recurrence. Adverse events from corticosteroid use were common. Further research is needed to implement guidelines for optimal use of non-TNFai (like ABA), DMARDs, and corticosteroids in cRD following histoplasmosis presentation.

Improving eye screening practice among pediatric rheumatology patients receiving hydroxychloroquine.

OBJECTIVE: Hydroxychloroquine (HCQ) is commonly used in the treatment of various autoimmune diseases related to its many benefits and favorable safety profile. Although HCQ retinopathy was considered to be uncommon, a prevalence of 7.5% was described in a recent study making early detection critical. The most updated screening guidelines by the American Academy of Ophthalmology were published in 2016; however, it lacked pediatric-specific recommendations and the overall compliance with screening guidelines was poor in previous studies. We developed a quality improvement (QI) initiative aiming to create institutional screening recommendations. Additionally, to increase eye screening in pediatric rheumatology clinic for patients receiving HCQ from 65% to 85% in 12 months and to sustain that rate for at least 6 months. METHODS: We formed a multidisciplinary team of pediatric rheumatologists and ophthalmologists, clinical pharmacist, clinic nurses, QI specialist, quality data technician and administrative staff. We included patients receiving HCQ and who were evaluated at Nationwide Children's Hospital rheumatology clinic. A key driver diagram was formulated to identify barriers to compliance and determine possible interventions. Main interventions included summarizing screening guidelines in a step by step algorithm, increasing awareness of these guidelines among patients and providers, improving collaboration and communication with ophthalmologists, and initiating pre-visit planning. RESULTS: Baseline performance data included 164 patients. Fifty-four (33%) of those patients were at high risk for HCQ retinopathy. Of them, 50% were on HCQ dose of >5 mg/kg/day and 31.5% had been taking HCQ for ≥5 years. Two center line shifts were noticed over the course of the project. The target of 85% compliance was reached in February 2019 and was sustained until December 2019. CONCLUSIONS: Our study highlights the importance of interdisciplinary communication to increase awareness of screening guidelines among medical providers and patients. Pre-visit planning played a major role in identifying patients and opportunities for optimizing eye screening in patients at risk for HCQ retinopathy. Collaboration between rheumatologists and ophthalmologists is crucial in managing patients on HCQ. The implementation of same-day eye screening allowed this collaboration to be more efficient. Future efforts are being directed at monitoring and improving utilization of the effective interventions.

Secondary Intracranial Hypertension in Pediatric Patients With Cryopyrin-Associated Periodic Syndrome.

BACKGROUND: Cryopyrin-associated periodic syndrome is characterized by periodic fever, rash, and joint pain. Papilledema rarely occurs. We present our series of patients with cryopyrin-associated periodic syndrome who clinically met the diagnostic criteria for Muckle-Wells syndrome and our experience with secondary intracranial hypertension. METHODS: Retrospective review of all patients with cryopyrin-associated periodic syndrome at Nationwide Children's Hospital from October 2015 to September 2017. RESULTS: Eighteen children met inclusion criteria: 15 females and three males, aged 1.5 to 16.2 years. Fifteen had periodic fever genetic testing; three had a known genetic defect identified, eight had a defect identified not currently known to be associated with cryopyrin-associated periodic syndrome, and four had no defect identified. Six patients (30%) developed headaches and were diagnosed with secondary intracranial hypertension. Lumbar puncture opening pressures ranged from 28 to 45 cm H2O. Only one patient had papilledema. Initial treatment was medical in all cases, by increasing interleukin-1 inhibitor dose and/or acetazolamide. One patient required a ventriculoperitoneal shunt for headache management. No visual acuity loss was detected. All six patients with secondary intracranial hypertension had a known genetic mutation or genetic variant of unknown significance; five involved the NLRP3 gene. CONCLUSIONS: In our series of 18 patients with cryopyrin-associated periodic syndrome, secondary intracranial hypertension occurred at a higher than expected rate. We suspect that genetic defects involving the NLRP3 gene may be a risk factor. Papilledema was present in only one patient. Physicians treating cryopyrin-associated periodic syndrome should be aware of this vision-threatening association and potential therapeutic approach.