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Objective: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA)., Methods: Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples., Results: Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2., Conclusion: A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus-negative idiopathic PAN., (© 2020 American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function., Results: Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%., Conclusion: This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To compare the efficacy of abatacept to that of placebo for the treatment of Takayasu arteritis (TAK)., Methods: In this multicenter trial, patients with newly diagnosed or relapsing TAK were treated with abatacept 10 mg/kg intravenously on days 1, 15, and 29 and week 8, together with prednisone administered daily. At week 12, patients in remission underwent a double-blinded randomization to continue to receive abatacept monthly or switch to placebo. Patients in both study arms received a standardized prednisone taper, reaching a dosage of 20 mg daily at week 12, with discontinuation of prednisone at week 28. All patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary end point was duration of remission (relapse-free survival)., Results: Thirty-four eligible patients with TAK were enrolled and treated with prednisone and abatacept; of these, 26 reached the week 12 randomization and underwent a blinded randomization to receive either abatacept or placebo. The relapse-free survival rate at 12 months was 22% for those receiving abatacept and 40% for those receiving placebo (P = 0.853). Treatment with abatacept in patients with TAK enrolled in this study was not associated with a longer median duration of remission (median duration 5.5 months for abatacept versus 5.7 months for placebo). There was no difference in the frequency or severity of adverse events, including infection, between the treatment arms., Conclusion: In patients with TAK, the addition of abatacept to a treatment regimen with prednisone did not reduce the risk of relapse., (© 2017, American College of Rheumatology.)

Objective: To compare the efficacy of abatacept to that of placebo for the treatment of giant cell arteritis (GCA)., Methods: In this multicenter trial, patients with newly diagnosed or relapsing GCA were treated with abatacept 10 mg/kg intravenously on days 1, 15, and 29 and week 8, together with prednisone administered daily. At week 12, patients in remission underwent a double-blinded randomization to continue to receive abatacept monthly or switch to placebo. Patients in both study arms received a standardized prednisone taper, with discontinuation of prednisone at week 28. All patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary end point was duration of remission (relapse-free survival rate)., Results: Forty-nine eligible patients with GCA were enrolled and treated with prednisone and abatacept; of these, 41 reached the week 12 randomization and underwent a blinded randomization to receive abatacept or placebo. Prednisone was tapered using a standardized schedule, reaching a daily dosage of 20 mg at week 12 with discontinuation in all patients at week 28. The relapse-free survival rate at 12 months was 48% for those receiving abatacept and 31% for those receiving placebo (P = 0.049). A longer median duration of remission was seen in those receiving abatacept compared to those receiving placebo (median duration 9.9 months versus 3.9 months; P = 0.023). There was no difference in the frequency or severity of adverse events, including infection, between the treatment arms., Conclusion: In patients with GCA, the addition of abatacept to a treatment regimen with prednisone reduced the risk of relapse and was not associated with a higher rate of toxicity compared to prednisone alone., (© 2017, American College of Rheumatology.)