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.
We conducted a large-scale genetic analysis on giant cell arteritis (GCA), a polygenic immune-mediated vasculitis. A case-control cohort, comprising 1,651 case subjects with GCA and 15,306 unrelated control subjects from six different countries of European ancestry, was genotyped by the Immunochip array. We also imputed HLA data with a previously validated imputation method to perform a more comprehensive analysis of this genomic region. The strongest association signals were observed in the HLA region, with rs477515 representing the highest peak (p = 4.05 × 10(-40), OR = 1.73). A multivariate model including class II amino acids of HLA-DRβ1 and HLA-DQα1 and one class I amino acid of HLA-B explained most of the HLA association with GCA, consistent with previously reported associations of classical HLA alleles like HLA-DRB1(∗)04. An omnibus test on polymorphic amino acid positions highlighted DRβ1 13 (p = 4.08 × 10(-43)) and HLA-DQα1 47 (p = 4.02 × 10(-46)), 56, and 76 (both p = 1.84 × 10(-45)) as relevant positions for disease susceptibility. Outside the HLA region, the most significant loci included PTPN22 (rs2476601, p = 1.73 × 10(-6), OR = 1.38), LRRC32 (rs10160518, p = 4.39 × 10(-6), OR = 1.20), and REL (rs115674477, p = 1.10 × 10(-5), OR = 1.63). Our study provides evidence of a strong contribution of HLA class I and II molecules to susceptibility to GCA. In the non-HLA region, we confirmed a key role for the functional PTPN22 rs2476601 variant and proposed other putative risk loci for GCA involved in Th1, Th17, and Treg cell function.
ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.
Objective To compare the efficacy of abatacept to placebo for the treatment of Takayasu’s arteritis (TAK). Methods In this multicenter trial, patients with newly-diagnosed or relapsing TAK 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, reaching 20 mg daily at week 12 with discontinuation of prednisone at week 28 and 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 Thirty-four eligible patients with TAK were enrolled and treated with prednisone and abatacept; 26 reached the week 12 randomization and underwent a blinded randomization to abatacept or placebo. The relapse-free survival 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 (abatacept 5.5 months, placebo 5.7 months). There was no difference in the frequency or severity of adverse events between treatment arms, including infection. Conclusions In patients with TAK the addition of abatacept to a treatment regimen with prednisone did not reduce the risk of relapse.
Objective Interleukin-6 (IL-6) is a pivotal cytokine in the pathogenesis of polymyalgia rheumatica (PMR), yet the efficacy of IL-6 blockade with tocilizumab (TCZ) for the treatment of PMR is unknown. The aim of this study was to assess the efficacy and safety of TCZ in newly diagnosed PMR. Methods In a single-center open-label study, patients with newly diagnosed PMR who had been treated with glucocorticoids (GCs) for <1 month were treated monthly with intravenous (IV) TCZ 8 mg/kg for 1 year, with a rapid tapering of GCs according to standardized protocol. The primary end point was the proportion of patients in relapse-free remission without GC treatment at 6 months. Secondary outcome measures included duration of GC use and cumulative GC dose. Patients were followed up for 15 months. Results Ten patients were enrolled in the study. One patient withdrew after 2 months, leaving 9 patients in whom the primary end point was assessed. The primary end point of relapse-free remission without GC treatment at 6 months was achieved by all 9 of these patients. All patients who received TCZ treatment were able to discontinue GCs within 4 months of study entry. The cumulative mean ± SD prednisone dose was 1,085 ± 301 mg and the total duration of GC exposure was 3.9 ± 0.9 months. Remission persisted without relapse, in all 9 patients, throughout the entire 15-month study. Conclusion Our findings suggest that TCZ may be an effective, safe, and well-tolerated treatment for newly diagnosed patients with PMR, with a robust steroid-sparing effect.
Rheumatoid arthritis (RA) is a prototypical autoimmune disease that causes destructive tissue inflammation in joints and elsewhere. Clinical challenges in RA include the empirical selection of drugs to treat patients, inadequate responders with incomplete disease remission, and lack of a cure. We profiled the full spectrum of cells in inflamed synovium from patients with RA with the goal of deconstructing the cell states and pathways characterizing pathogenic heterogeneity in RA. Our multicenter consortium effort used multi-modal CITE-seq, RNA-seq, and histology of synovial tissue from 79 donors to build a >314,000 single-cell RA synovial cell atlas with 77 cell states from T, B/plasma, natural killer, myeloid, stromal, and endothelial cells. We stratified tissue samples into six distinct cell type abundance phenotypes (CTAPs) individually enriched for specific cell states. These CTAPs demonstrate the striking diversity of RA synovial inflammation, ranging from marked enrichment of T and B cells (CTAP-TB) to a congregation of specific myeloid, fibroblast, and endothelial cells largely lacking lymphocytes (CTAP-EFM). Disease-relevant cytokines, histology, and serology metrics are associated with certain CTAPs. This comprehensive RA synovial atlas and molecular, tissue-based CTAP stratification reveal new insights into RA pathology and heterogeneity, which could lead to novel targeted-treatment approaches in RA.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.