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Objective To compare the efficacy of abatacept to placebo for giant cell arteritis (GCA). Methods In this multicenter trial, patients with newly-diagnosed or relapsing GCA were treated with abatacept 10 mg/kg IV on days 1, 15, 29, week 8, together with prednisone. At week 12, patients in remission underwent a double-blinded randomization to continue monthly abatacept or switch to placebo. Patients in both study arms received a standardized prednisone taper with discontinuation of prednisone at week 28. Patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary endpoint was duration of remission (relapse-free survival). Results Forty-nine eligible patients with GCA were enrolled and treated with prednisone and abatacept; forty-one reached the week 12 randomization and underwent a blinded randomization to abatacept or placebo. Prednisone was tapered using a standardized schedule reaching 20 mg daily at week 12 with discontinuation in all patients at week 28. The relapse-free survival 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 with abatacept (9.9 months) compared to placebo (3.9 months, p=0.023). There was no difference in the frequency or severity of adverse events between treatment arms, including infection. Conclusions 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.

ObjectiveTo identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).MethodsA 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.ResultsAmong 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%.ConclusionThis 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.

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).