Granulomatosis With Polyangiitis (Wegener’s)

To determine outcomes in relation to duration of maintenance therapy in patients with granulomatosis with polyangiitis (Wegener’s) (GPA), we conducted a retrospective chart review of patients with GPA seen at a single vasculitis center from 1992 to 2010. All patients achieved remission defined by a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS/WG) of 0 with either cyclophosphamide or methotrexate. After achieving remission all patients were started on maintenance therapy with either methotrexate or azathioprine. The study comprised 157 patients with a median follow-up of 3.1 years. Using a univariate model, the continuation of maintenance medications for >18 months showed a 29% reduction in hazard ratio (HR) for relapse (HR, 0.71; 95% confidence interval [CI], 0.42–1.19; p = 0.19). Treatment for >36 months showed a 66% reduction in hazard ratio for relapse (HR, 0.34; 95% CI, 0.15–0.76; p = 0.008). When length of treatment was considered as a continuous factor, longer courses had an inverse relationship with the risk of relapse (HR, 0.70; 95% CI, 0.58–0.84; p < 0.001), which remained significant after adjusting for prednisone dose (HR, 0.59; 95% CI, 0.42–0.83; p = 0.003). Fifty-two percent of relapses occurred while the patients were off maintenance therapy. Among all patients who relapsed on therapy, 52% of those receiving methotrexate were on <15 mg/week, and 67% of those receiving azathioprine were on ≤50 mg/d. There were no differences between the shortand long-term maintenance therapy groups in overall adverse events or GPA-related morbidity. Discontinuation or use of low doses of maintenance therapy is associated with a higher relapse rate. (Medicine 2014;93: 82–90) Abbreviations:ANCA= antineutrophil cytoplasmic antibody, AZA = azathioprine, BVAS/WG = Birmingham Vasculitis Activity Score for Wegener Granulomatosis, CI = confidence interval, CYC = cyclophosphamide, GPA = granulomatosis with polyangiitis, HR = hazard ratio, IV = intravenous, MMF = mycophenolate mofetil, MPA = microscopic polyangiitis, MPO = myeloperoxidase, MTX = methotrexate, PR3 = proteinase 3, RTX = rituximab. From Department of Rheumatic and Immunologic Diseases (JS); Department of Quantitative Health Sciences (BN); and Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Diseases (CAL, GSH, AVF), Cleveland Clinic, Cleveland, Ohio. *Current affiliation: University of KansasMedical Center, Kansas City, Kansas. Financial support and conflicts of interest: Funding for this research was provided by the Research Program Committee Award from the Cleveland Clinic Foundation. The following authors have received financial support (personal or institutional) from the listed companies, unrelated to the present work: GSH: Roche, Sanofi-Aventis; CAL: Genentech. The authors have no conflicts of interest to disclose. Correspondence: Jason Springer, MD, University of Kansas Medical Center, 3901 Rainbow Boulevard, MS 2026, Kansas City, KS 66160 (e‐mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0000000000000020 82 www.md-journal.com Copyright © 2014 Lippincott Williams & Wilkins. Unau INTRODUCTION Granulomatosis with polyangiitis (Wegener’s) (GPA) is a systemic inflammatory disease histologically characterized by the presence of granulomas, necrosis, and vasculitis. While GPA typically affects the upper and lower respiratory tracts as well as the kidneys, any organ system can be involved. The disease has been associated with significant mortality and morbidity if untreated. Current treatment regimens lead to remission in up to 93% of patients. Severe disease, defined as lifeor critical organ-threatening illness, is initially treated with glucocorticoids and cyclophosphamide (CYC) or rituximab (RTX) to induce remission. In mild to moderate disease, remission can be achieved with glucocorticoids and methotrexate (MTX). MTX has been shown to be as effective as CYC at inducing remission in this setting. Despite high rates of remission, patients with GPA often experience relapses. This has led to longer treatment with agents such as MTX or azathioprine (AZA) to maintain remission. Over the last 50 years there has been a decline in mortality, relapse rate, and death related to therapy in GPA. This is likely due to changes in treatment strategies that include avoiding or limiting the duration of CYC use. Results from recent prospective trials reveal relapse rates of 15%–35% at 12–18 month followup in patients continued on maintenance therapy. However, higher frequencies of relapse are reported in the setting of withdrawal and discontinuation of therapy. Frequently, questions arise about when and if maintenance therapy can be safely discontinued following a prolonged period of remission. Published data addressing long-term outcomes in patients treated for >18 months are scant. To our knowledge, guidelines for duration of maintenance therapy for patients who never had a disease relapse do not exist. We conducted the current study to compare long-term outcomes in regard to duration and dose of maintenance immunosuppressive therapy in GPA patients without a history of relapse. PATIENTS AND METHODS We retrospectively reviewed the medical records of newly diagnosed patients with GPA who received care at the Cleveland Clinic from January 1992 to August 2010. Patients were included only if they met all the following inclusion criteria: 1) met the 1990 American College of Rheumatology criteria for Wegener granulomatosis; 2) received induction therapy with CYC, RTX, or MTX at diagnosis; 3) achieved remission as defined as a BirminghamVasculitis Activity Score forWegener Granulomatosis (BVAS/WG) of 0; 4) received initial maintenance therapy with eitherMTXor AZA (patients were not excluded if theywere changed to mycophenolate mofetil [MMF] because of medication intolerance); 5) sustained remission for a period of at least 18 months, regardless of treatment duration, and 6) had adequate data available to determine dates of remission and relapse. “Maintenance therapy” was defined as treatment with AZA, MTX, or MMF after patients achieved remission. Patients were excluded if maintenance therapy was not started for >1 month after the date of remission. Medicine • Volume 93, Number 2, March 2014 thorized reproduction of this article is prohibited. Medicine • Volume 93, Number 2, March 2014 Maintenance Therapy in GPA Remission was defined as a BVAS/WG score of 0, and relapse was defined as a score of ≥1, after a period of remission. Patient information was gathered from onset of initial symptoms until remission was achieved after the first relapse or until the last follow-up. Patients on maintenance therapy for >18 months were categorized as the “long-term maintenance group,” while those receiving maintenance therapy for ≤18 months were categorized as the “short-term maintenance group.” A separate analysis was performed for patients on maintenance therapy for 18–36 months and for those treated for >36 months. Adverse events included those attributed to medications for the treatment of GPA. Serious adverse events were defined as those that were life threatening, required hospitalization, or resulted in death. Infections requiring antibiotics or hospitalization and chronic organ damage related to GPAwere recorded. This study received approval from the ethics committee of the Cleveland Clinic Foundation. The study was conducted in accordance with the Declaration of Helsinki. Statistical Analysis Numerical measures were summarized by median values and quartiles. Categorical values were summarized by frequency and percentage. Univariable comparisons were conducted using Wilcoxon rank sum test for numerical values and either a chisquare test or Fisher exact test (where appropriate). Significance was determined by a p value ≤ 0.05. Duration of relapse-free remission was evaluated using cox proportional hazard models. Three models were constructed to illustrate the effect of duration of maintenance therapy on time to relapse. The first model used duration of maintenance therapy as a categorical factor, comparing fewer than 18months of therapy to more than 18months of therapy. The secondmodel used duration of therapy as a continuous FIGURE 1. Cohort diagram. Patients were initially excluded if they rela the inclusion and exclusion criteria. Patients were then divided based long-term group was further divided into patients on maintenance be therapy for >36 months. © 2014 Lippincott Williams & Wilkins Copyright © 2014 Lippincott Williams & Wilkins. Unau factor, eliminating the arbitrary dichotomy of less than or equal to and more than 18 months. The third model adjusted the continuous duration of therapy for prednisone as a time-dependent covariate.