Repression of CTSG, ELANE and PRTN3-mediated histone H3 proteolytic cleavage promotes monocyte-to-macrophage differentiation.

Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.

Hyperferritinemia Screening to Aid Identification and Differentiation of Patients with Hyperinflammatory Disorders.

High ferritin is an important and sensitive biomarker for the various forms of hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system at UPMC Children's Hospital where serum ferritin > 1000 ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.

Safety and efficacy of tofacitinib for the treatment of patients with juvenile idiopathic arthritis: preliminary results of an open-label, long-term extension study.

OBJECTIVES: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study. METHODS: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0. RESULTS: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48. CONCLUSIONS: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48. TRIAL REGISTRATION NUMBER: NCT01500551.

Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project.

OBJECTIVE: To assess current treatment in macrophage activation syndrome (MAS) worldwide and to highlight any areas of major heterogeneity of practice. METHODS: A systematic literature search was performed in both Embase and PubMed databases. Paper screening was done by two independent teams based on agreed criteria. Data extraction was standardized following the PICO framework. A panel of experts assessed paper validity, using the Joanna Briggs Institute appraisal tools and category of evidence (CoE) according to EULAR procedure. RESULTS: Fifty-seven papers were finally included (80% retrospective case-series), describing 1148 patients with MAS: 889 systemic juvenile idiopathic arthritis (sJIA), 137 systemic lupus erythematosus (SLE), 69 Kawasaki disease (KD) and 53 other rheumatologic conditions. Fourteen and 11 studies specified data on MAS associated to SLE and KD, respectively. All papers mentioned glucocorticoids (GCs), mostly methylprednisolone and prednisolone (90%); dexamethasone was used in 7% of patients. Ciclosporin was reported in a wide range of patients according to different cohorts. Anakinra was used in 179 MAS patients, with a favourable outcome in 83% of sJIA-MAS. Etoposide was described by 11 studies, mainly as part of HLH-94/04 protocol. Emapalumab was the only medication tested in a clinical trial in 14 sJIA-MAS, with 93% of MAS remission. Ruxolitinib was the most reported JAK-inhibitor in MAS. CONCLUSION: High-dose GCs together with IL-1 and IFNγ inhibitors have shown efficacy in MAS, especially in sJIA-associated MAS. However, global level of evidence on MAS treatment, especially in other conditions, is still poor and requires standardized studies to be confirmed.

Genetics of Acquired Cytokine Storm Syndromes : Secondary HLH Genetics.

Secondary hemophagocytic lymphohistiocytosis (sHLH) has historically been defined as a cytokine storm syndrome (CSS) occurring in the setting of triggers leading to strong and dysregulated immunological activation, without known genetic predilection. However, recent studies have suggested that existing underlying genetic factors may synergize with particular diseases and/or environmental triggers (including infection, autoimmune/autoinflammatory disorder, certain biologic therapies, or malignant transformation), leading to sHLH. With the recent advances in genetic testing technology, more patients are examined for genetic variations in primary HLH (pHLH)-associated genes, including through whole exome and whole genome sequencing. This expanding genetic and genomic evidence has revealed HLH as a more complex phenomenon, resulting from specific immune challenges in patients with a susceptible genetic background. Rather than a simple, binary definition of pHLH and sHLH, HLH represents a spectrum of diseases, from a severe complication of common infections (EBV, influenza) to early onset familial diseases that can only be cured by transplantation.

Comparison of disease phenotypes and mechanistic insight on causal variants in patients with DADA2.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) results in heterogeneous manifestations including systemic vasculitis and red cell aplasia. The basis of different disease phenotypes remains incompletely defined. OBJECTIVE: We sought to further delineate disease phenotypes in DADA2 and define the mechanistic basis of ADA2 variants. METHODS: We analyzed the clinical features and ADA2 variants in 33 patients with DADA2. We compared the transcriptomic profile of 14 patients by bulk RNA sequencing. ADA2 variants were expressed experimentally to determine impact on protein production, trafficking, release, and enzymatic function. RESULTS: Transcriptomic analysis of PBMCs from DADA2 patients with the vasculitis phenotype or pure red cell aplasia phenotype exhibited similar upregulation of TNF, type I interferon, and type II interferon signaling pathways compared with healthy controls. These pathways were also activated in 3 asymptomatic individuals with DADA2. Analysis of ADA2 variants, including 7 novel variants, showed different mechanisms of functional disruption including (1) unstable transcript leading to RNA degradation; (2) impairment of ADA2 secretion because of retention in the endoplasmic reticulum; (3) normal expression and secretion of ADA2 that lacks enzymatic function; and (4) disruption of the N-terminal signal peptide leading to cytoplasmic localization of unglycosylated protein. CONCLUSIONS: Transcriptomic signatures of inflammation are observed in patients with different disease phenotypes, including some asymptomatic individuals. Disease-associated ADA2 variants affect protein function by multiple mechanisms, which may contribute to the clinical heterogeneity of DADA2.

New developments related to lung complications in pediatric rheumatic disease.

PURPOSE OF REVIEW: While substantial progress has been made understanding lung disease in adult patients with rheumatic disease, pediatric lung disease has not been well addressed. Several recent studies provide new insights into diagnosis, management and treatment of lung disease in children with rheumatic disease. RECENT FINDINGS: Building on previous research, newly diagnosed patients may have abnormalities in pulmonary function tests and chest computed tomography imaging even when asymptomatic. New guidelines for screening for rheumatic-associated lung disease provide important recommendations for clinicians. New theories have been proposed about immunologic shifts leading to the development of lung disease in children with systemic juvenile idiopathic arthritis. Additionally, there are new antifibrotic agents that are being explored as treatments in pediatric patients with fibrotic lung diseases. SUMMARY: Patients appear to have frequent lung function abnormalities while being clinically asymptomatic, emphasizing importance for rheumatologists to refer for pulmonary function tests and imaging at diagnosis. New advances are helping define optimal approaches to treatment of lung disease, including use of biologic agents and antifibrotic medicines for pediatric patients with rheumatologic diseases.

Secukinumab in enthesitis-related arthritis and juvenile psoriatic arthritis: a randomised, double-blind, placebo-controlled, treatment withdrawal, phase 3 trial.

BACKGROUND: Treatment options in patients with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA) are currently limited. This trial aimed to demonstrate the efficacy and safety of secukinumab in patients with active ERA and JPsA with inadequate response to conventional therapy. METHODS: In this randomised, double-blind, placebo-controlled, treatment-withdrawal, phase 3 trial, biologic-naïve patients (aged 2 to <18 years) with active disease were treated with open-label subcutaneous secukinumab (75/150 mg in patients <50/≥50 kg) in treatment period (TP) 1 up to week 12, and juvenile idiopathic arthritis (JIA) American College of Rheumatology 30 responders at week 12 were randomised 1:1 to secukinumab or placebo up to 100 weeks. Patients who flared in TP2 immediately entered open-label secukinumab TP3 that lasted up to week 104. Primary endpoint was time to disease flare in TP2. RESULTS: A total of 86 patients (median age, 14 years) entered open-label secukinumab in TP1. In TP2, responders (ERA, 44/52; JPsA, 31/34) received secukinumab or placebo. The study met its primary end point and demonstrated a statistically significant longer time to disease flare in TP2 for ERA and JPsA with secukinumab versus placebo (27% vs 55%, HR, 0.28; 95% CI 0.13 to 0.63; p<0.001). Exposure-adjusted incidence rates (per 100 patient-years (PY), 95% CI) for total patients were 290.7/100 PY (230.2 to 362.3) for adverse events and 8.2/100 PY (4.1 to 14.6) for serious adverse events in the overall JIA population. CONCLUSIONS: Secukinumab demonstrated significantly longer time to disease flare than placebo in children with ERA and JPsA with a consistent safety profile with the adult indications of psoriatic arthritis and axial spondyloarthritis. TRIAL REGISTRATION NUMBER: NCT03031782.

Efficacy and safety of emapalumab in macrophage activation syndrome.

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria. METHODS: We studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator's assessment of response. Patients entered a long-term (12 months) follow-up study. RESULTS: Fourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed. CONCLUSIONS: Neutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus. TRIAL REGISTRATION NUMBER: NCT02069899 and NCT03311854.

The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.