Azathioprine as Effective as Cyclophosphamide for Maintenance in ANCA-Associated Vasculitis CME

News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd

Authors and Disclosures
To earn CME credit, read the news brief, the paragraphs that follow, and answer the questions below.

Release Date: July 2, 2003; Valid for credit through July 2, 2004

Credits Available
Physicians - up to 0.25 AMA PRA category 1 credit(s)

July 2, 2003 — Azathioprine was as effective as cyclophosphamide in the maintenance phase of vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCA), according to the results of a randomized controlled trial published in the July 3 issue of the New England Journal of Medicine. Substituting azathioprine allows reduction in long-term exposure to the toxicity of cyclophosphamide, which the investigators suggest has immediate relevance to clinical practice. The editorialist concurs.

"The standard therapy for generalized ANCA-associated vasculitis has comprised at least one year of corticosteroid and oral cyclophosphamide therapy," write David Jayne, FRCP, and colleagues from the European Vasculitis Study Group. "The resultant exposure to cyclophosphamide causes hemorrhagic cystitis and increases the risk of bladder cancer and lymphoproliferative disease, myelodysplasia, and infertility."

Of 155 patients newly diagnosed with generalized vasculitis, with serum creatinine concentration of 5.7 mg/dL or less, 144 patients (93%) entered remission after receiving at least three months of therapy with oral cyclophosphamide and prednisolone. Patients in remission were then randomized to treatment with azathioprine or continued cyclophosphamide.

Eight patients (5%) died, including seven who died during the first three months. Relapses occurred in 11 patients (15.5%) in the azathioprine group and in 10 patients (13.7%) in the cyclophosphamide group (P = .65). Relapses were fewer in patients with microscopic polyangiitis than in those with Wegener's granulomatosis (P = .03).

During induction, 15 patients (10%) had severe adverse events. During the remission phase, eight patients (11%) in the azathioprine group and seven patients (10%) in the cyclophosphamide group had severe adverse events (P = .94).

"It is possible to reduce patients' exposure to cyclophosphamide and its toxic effects without increasing the rate of relapse," the authors write. "These findings have immediate relevance for the daily management of vasculitis."

One of the authors reports receiving consulting or lecture fees from GlaxoSmithKline and AstraZeneca.

In an accompanying editorial, Carol A. Langford, MD, MHS, from the National Institutes of Health (NIH) in Bethesda, Maryland, praises this trial and recommends additional controlled trials "to provide data of direct relevance to current patient care and form the foundation for the design of future investigations."

N Engl J Med. 2003;349:3-5, 36-44
Learning Objectives
Upon completion of this activity, participants will be able to:

* Describe the morbidity and mortality associated with ANCA-positive generalized vasculitis and its treatment.
* List the current recommendations for maintenance therapy after induction of remission.

Clinical Context

ANCA-positive vasculitis occurs in the majority of patients with Wegener's granulomatosis and microscopic angiitis. These vasculitides are associated with a mortality of more than 90% in the first two years if untreated. A landmark NIH study in the March 15, 1992, issue of the Annals of Internal Medicine, with follow-up of 6 months to 24 years, resulted in standard therapy with combination prednisolone and cyclophosphamide for induction, achieving remission rates of up to 90%, with 75% of patients achieving complete remission. However, of the patients who received cyclophosphamide, 50% developed cystitis, 5.6% developed bladder cancer, and 57% developed amenorrhea, while prednisolone caused opportunistic infection, cataracts, diabetes, and other steroid-induced complications. Typical induction duration ranged from several months to two years. Prednisolone or cyclophosphamide alone or in lower doses had much lower efficacy for induction or prevention of relapse. Without maintenance therapy, relapse rates of more than 50% may occur. Thus, recent research has focused on transitioning from this toxic prednisolone-cyclophosphamide combination to less toxic regimens such as azathioprine or methotrexate for maintenance. In a 1999 supplement to Arthritis & Rheumatism, the European Vasculitis Study Group first reported a multicenter randomized trial of cyclophosphamide vs. azathioprine during remission demonstrating equivalent efficacy of azathioprine, with the possibility of lower long-term toxicity.

This prospective, randomized, open study examined the efficacy of oral azathioprine compared with oral cyclophosphamide after induction was achieved in patients with newly diagnosed, generalized ANCA-positive or tissue-confirmed vasculitis.
Study Highlights

* 155 patients were recruited from 39 hospitals in 11 European countries and followed up for 18 months.
* 144 patients, aged 18 to 75 years, with ANCA-positive or tissue-confirmed vasculitis, serum creatinine of <5.7 mg/dL, who had not been treated with cytotoxic agents, and without multisystem autoimmune disease, completed the study. Of the 155 recruited, seven patients died during induction, and four were either withdrawn or ineligible.
* Clinical remission was achieved by 93%, 77% by 3 months, and an additional 16% by 6 months.
* After an induction period of 3 to 6 months using standard prednisolone-cyclophosphamide therapy, patients were randomized to receive cyclophosphamide (n = 71) or azathioprine (n = 73) while continuing on prednisolone. At 12 months, all patients continued on azathioprine with a reduced dose of prednisolone. Both groups of patients were similar in age and sex distribution, proportion with Wegener's granulomatosis vs. microscopic polyangiitis, disease severity, systems involved, renal function, and percentage achieving successful remission by 3 and 6 months. Neither patients nor investigators were blinded to treatment allocation.
* Primary outcome was disease relapse defined by the validated Vasculitis Damage Index (using the Birmingham Vasculitis Activity score) and the Medical Outcomes Study 36-item short form (SF-36) for quality of life (physical and mental health). Secondary outcomes were inflammatory markers, including erythrocyte sedimentation rate and C-reactive protein. Disease relapse was defined as major or minor relapse. Assessment for disease relapse was conducted by the investigators and thus not blinded.
* Outcomes were assessed at 0, 1.5, 3, 6, 9, 12, 15, and 18 months after randomization. Prophylaxis against steroid- and cyclophosphamide-induced conditions was recommended but not required during maintenance. Adverse events were continuously monitored.
* There was one death from stroke during the maintenance phase. Three patients were lost to follow-up and five withdrew from the study (two in the cyclophosphamide group and three in the azathioprine group) during maintenance.
* Relapse rates were similar in both groups at 15.5% for azathioprine and 13.7% for cyclophosphamide (P = .65). Adverse events were also similar in the two groups, at 11% for azathioprine vs. 10% for cyclophosphamide (P = .94). Overall, for both groups, relapse rate was lower in patients with microscopic polyangiitis compared with those with Wegener's granulomatosis (P = .03).
* There were no between-group differences in the SF-36 index of general health. At entry, both groups scored more than 30% below the general population. Overall, values for physical health remained below the norm throughout maintenance in both groups. Mental health measures improved and increased significantly for both groups (P < .001) during maintenance, but they were still 14% below the general population.

Pearls for Practice

* After successful induction of remission for generalized vasculitis, azathioprine is as effective as cyclophosphamide in preventing major and minor relapse.
* The use of azathioprine as a substitute for cyclophosphamide, for maintenance therapy in vasculitis, has the potential to reduce long-term toxicity associated with cyclophosphamide therapy.