Reduction of adenosine deaminase 2 (ADA2) activity due to autosomal-recessive loss-of-function mutations in the ADA2 gene (previously known as CECR1) results in a systemic vasculitis known as deficiency of ADA2 (DADA2). Neutrophils and a subset of neutrophils known as low-density granulocytes (LDGs) have been implicated in the pathogenesis of vasculitis, at least in part, through the formation of neutrophil extracellular traps (NETs). The study objective was to determine whether neutrophils and NETs play a pathogenic role in DADA2. In vivo evidence demonstrated NETs and macrophages in affected gastrointestinal tissue from patients with DADA2. An abundance of circulating LDGs prone to spontaneous NET formation was observed during active disease in DADA2 and were significantly reduced after remission induction by anti–tumor necrosis factor (TNF) therapy. Increased circulating LDGs were identified in unaffected family members with monoallelic ADA2 mutations. Adenosine triggered NET formation, particularly in neutrophils from female patients, by engaging A1 and A3 adenosine receptors (ARs) and through reactive oxygen species– and peptidylarginine deiminase–dependent pathways. Adenosine-induced NET formation was inhibited by recombinant ADA2, A1/A3 AR antagonists, or by an A2A agonist. M1 macrophages incubated with NETs derived from patients with DADA2 released significantly greater amounts of TNF-α. Treatment with an A2AAR agonist decreased nuclear translocation of NF-κB and subsequent production of inflammatory cytokines in DADA2 monocyte-derived macrophages. These results suggest that neutrophils may play a pathogenic role in DADA2. Modulation of adenosine-mediated NET formation may contribute a novel and directed therapeutic approach in the treatment of DADA2 and potentially other inflammatory diseases.

SYNOPSIS Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever, rash and disease-specific patterns of organ inflammation. Mutations in innate immune sensors that include the IL-1β activating inflammasomes, NLRP3, pyrin and NLRC4, pointed to the importance of innate immune dysregulation leading to excessive production or stimulation of the proinflammatory cytokine, IL-1β, and provided the concept of targeting proinflammatory cytokines as therapeutic intervention. Recently, increased cytokine amplification loops of Type I interferon and IL-18 signaling are the cause of a spectrum of Type-I IFN mediated diseases (interferonopathies) and IL-18 mediated conditions. Many genetically defined autoinflammatory disorders present with cutaneous neutrophilic inflammation associated with systemic manifestations. Innate danger sensing pathways that include inflammasomes and nucleic acid sensing pathways play critical roles in pathogenesis of IL-1 mediated and IFN-mediated disorders and justify a grouping of the genetically-defined autoinflammatory disorders by cytokine mediators, their clinical manifestations, histologic findings and treatment.

In this survey of ACR members, we found self-reported differences in the type of corticosteroid used for MSK injections. There was general agreement on frequency of injections, but more experienced practitioners reported using lower doses of corticosteroid.