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Thiopurine methyltransferase genotype and activity cannot predict outcomes of azathioprine maintenance therapy for antineutrophil cytoplasmic antibody associated vasculitis: A retrospective cohort study.

ABSTRACT: Azathioprine is a widely used immunosuppressive drug. Genetic polymorphisms and activity of the enzyme thiopurine methyltransferase (TPMT) have been associated with azathioprine efficacy and toxicity in several populations. We investigated whether these associations also exist for ANCA associated vasculitis (AAV) patients, who receive azathioprine maintenance therapy after remission induction with cyclophosphamide.207 AAV patients treated with cyclophosphamide induction and azathioprine maintenance therapy were included and followed for 60 months. TPMT genotype and tertiles of TPMT activity were compared to relapse free survival and occurrence of adverse events, particularly leukopenia. Multivariable regression was performed to account for confounders.In univariable analysis, relapse free survival was not significantly associated with TPMT genotype (P = 0.41) or TPMT activity (P = 0.07), although it tended to be longer in lower tertiles of TPMT activity. There was no significant association of TPMT genotype and activity with occurrence of any adverse event. In multiple regression, leukocyte counts at the end of cyclophosphamide induction were related to risk of leukopenia during azathioprine therapy [P<0.001; OR 0.54 (95% CI 0.43-0.68)] and risk of relapse during follow-up [P = 0.001; HR 1.17 (95% CI 1.07-1.29)] irrespective of TMPT genotype or activity.TPMT genotype and activity were not independent predictors of relapse, and could not predict leukopenia or other adverse effects from azathioprine. Leukocyte counts after cyclophosphamide induction were related to both outcomes, implying a greater influence of cyclophosphamide response compared to azathioprine and TPMT in AAV patients.

SUBMITTER: Hessels AC

PROVIDER: S-EPMC5890988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate the safety and efficacy of belimumab as adjunctive therapy to maintain remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).MethodsIn this multicenter, double-blind, placebo-controlled study, patients with AAV (ages ≥18 years) were randomized 1:1 to receive azathioprine (2 mg/kg/day), low-dose oral glucocorticoids (≤10 mg/day), and either intravenous belimumab (10 mg/kg) or placebo, following remission induction with rituximab or cyclophosphamide along with glucocorticoids. The primary end point was time to first protocol-specified event (PSE), with first PSE defined as a Birmingham Vasculitis Activity Score (BVAS) of ≥6, presence of ≥1 major BVAS item, or receipt of prohibited medications for any reason, resulting in treatment failure (adjusted for ANCA type [proteinase 3 (PR3) or myeloperoxidase (MPO)], disease stage at induction, and induction regimen). Vasculitis relapse was defined as the PSE of either a BVAS activity score of ≥6 or receipt of prohibited medications for vasculitis. Changes in treatment practice led to truncation of the study population from ~300 patients to ~100 patients.ResultsThe intent-to-treat population totaled 105 patients with AAV, of whom 52 (40 with PR3-ANCAs, 12 with MPO-ANCAs) received placebo and 53 (41 with PR3-ANCAs, 12 with MPO-ANCAs) received belimumab; 27 of the patients were in rituximab-induced disease remission, while 78 were in cyclophosphamide-induced disease remission at baseline. Compared with placebo, treatment with belimumab did not reduce the risk of a PSE (adjusted hazard ratio [HR] 1.07, 95% confidence interval [95% CI] 0.44-2.59; P = 0.884) or vasculitis relapse (adjusted HR 0.88, 95% CI 0.29-2.65; P = 0.821). The overall rate of PSEs was low (11 [21.2%] of 52 patients receiving placebo, 10 [18.9%] of 53 patients receiving belimumab). Vasculitis relapse in the placebo group (n = 8) occurred independent of the induction regimen, disease stage, or ANCA type. All vasculitis relapses in the belimumab group (n = 6) occurred in patients who had PR3-ANCA-associated vasculitis with cyclophosphamide-induced disease remission. Adverse events occurred in 49 (92.5%) of 53 patients receiving belimumab and 43 (82.7%) of 52 patients receiving placebo, with no new safety concerns.ConclusionBelimumab plus azathioprine and glucocorticoids for the maintenance of remission in AAV did not reduce the risk of relapse.

Project description:OBJECTIVE:To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]). METHODS:A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest. RESULTS:Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor ? [sIL-2R?], and nerve growth factor ? [NGF?]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2R?, and NGF?) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-?, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis. CONCLUSION:Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.

Project description:IntroductionTo compare the efficacy and safety of different regimens used for maintenance of remission in patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis.MethodsThis network meta-analysis studied adult patients with ANCA vasculitis in complete remission, who were maintained with various regimens, excluding patients with eosinophilic granulomatosis with polyangiitis (GPA) and those who have ended up in end-stage kidney disease. Outcomes of interest included relapse (any/major), relapse-free survival, and adverse effects. PubMed, Scopus, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Google Scholar were systematically searched from inception.ResultsOverall, the meta-analysis was based on 10 reports, describing the outcomes of 7 randomized controlled trials (RCTs) including 752 patients with ANCA vasculitis. Relapse-free survival was significantly worse with the use of azathioprine (hazard ratio [HR]: 2.11, 95% CI: 1.19-3.74), methotrexate (HR: 2.51, 95% CI: 1.24-5.08), and mycophenolate mofetil (HR: 3.57, 95% CI: 1.70-7.46) compared with the use of rituximab. Outcomes estimated for azathioprine (HR: 0.59, 95% CI: 0.37-0.94), cyclophosphamide (HR: 0.39, 95% CI: 0.20-0.75), and leflunomide (HR: 0.30, 95% CI: 0.11-0.84) were better than those for mycophenolate mofetil. When examining relapse-free survival, relapses were more likely with use of azathioprine (odds ratio [OR]: 2.15, 95% CI: 1.00-4.59) and mycophenolate mofetil (OR: 4.42, 95% CI: 1.63-11.94) compared with the use of rituximab. The risk of major relapse calculated for azathioprine (OR: 2.39, 95% CI: 1.10-5.19), methotrexate (OR: 3.18, 95% CI: 1.14-8.89), and mycophenolate mofetil (OR: 5.20, 95% CI: 1.65-16.37) was higher than that for rituximab. The rates of serious adverse effects did not differ significantly among interventions.ConclusionRituximab appears predominant in maintaining remission in patients with ANCA vasculitis with no cost in adverse events.

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Thiopurine methyltransferase genotype and activity cannot predict outcomes of azathioprine maintenance therapy for antineutrophil cytoplasmic antibody associated vasculitis: A retrospective cohort study.

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