A prospective, multicenter, randomized trial ... - Wiley Online Library

ARTHRlTlS & RHEUMATISM Vol 40, No 12. December 1997, pp 2187-2198 0 1997. American Collcge of Rheumatology

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A PROSPECTIVE, MULTICENTER, RANDOMIZED TRIAL COMPARING STEROIDS AND PULSE CYCLOPHOSPHAMIDE VERSUS STEROIDS AND ORAL CYCLOPHOSPHAMIDE IN THE TREATMENT OF GENERALIZED WEGENER'S GRANULOMATOSIS LOIC GUILLEVIN, JEAN-FRANCOIS CORDIER, FRANCOIS LHOTE, PASCAL COHEN, BERNARD JARROUSSE, ISABELLE ROYER, PHILIPPE LESAVRE, CHRISTIAN JACQUOT, PASCAL BINDI, PHILIPPE BIELEFELD, JEAN-FRANCOIS DESSON, FREDERICK DETREE, ALAIN DUBOIS, ERIC HACHULLA, BRUNO HOEN, DOMINIQUE JACOMY, CHRISTIAN SEIGNEURIC, DOMINIQUE LAUQUE, MARC STERN, and MAITE LONGY-BOURSIER Objective. To investigate the effectiveness and side effects of oral versus pulse cyclophosphamide (CYC) in combination with corticosteroids (CS) in the treatment of systemic Wegener's granulomatosis (WG). Methods. Patients with newly diagnosed systemic WG were enrolled in a prospective, randomized trial. At the time of diagnosis, prior to randomization, every patient received a daily injection of methylprednisolone for 3 days, followed by daily oral prednisone (1 mg/kg/ day) and a 0.7-gm/m2 pulse of CYC. Patients were then randomly assigned to receive either prednisone plus intravenous pulse CYC (group A) or prednisone plus Presented in part at the 58th National Scientific Meeting of the American College of Rheumatology, Minneapolis, MN, October l Y Y 4 and at the 6th International ANCA Workshop, Paris, France, June 28-July 1, 1995. Supported by grants from the Institut National pour la SantC et la Recherche Medicale (TNSERM), the Assistance PubliqueHBpitaux de Paris (AP-HP), and the Association pour la Recherchc sur lcs Angeites Necrosantes (ARAN). LoIc Guillevin. MD: HBpital Aviccnnc, Bobigny, France; Jean-Franpis Cordier, MD: HApital Louis Pradel, Lyon, France; Franpis Lhote, MD: HBpital Delafontaine, Saint-Denis, France; Pascal Cohen, MD, Bernard Jarroussc, MD, Isabelle Royer, MD: HBpital Avicenne, Hobigny, France; Philippe Lesavre, MD: HBpital Neckcr, Paris, France; Christian Jacquot, MD: HBpital Broussais, Paris, France; Pascal Bindi, MD: Verdun, France; Philippe Bielefeld, MD: Dijon, France; Jean-FranGois Desson, MD: Caen, France; FrCdCrick DttrCc, MD: Reims, France; Alain Dubois, MD: Nimes, France; Eric Hachulla, MD: Lille, France; Bruno Hoen, MD: Nancy, France; Dominique Jacomy, MD: LaVal, France; Christian Seigneuric, MD: Montauban, Francc; Dominique Lauque, MD: Toulouse, France; Marc Stern, MD: Suresnes, France; Malt6 Longy-Boursier, MD: Bordcaux, France. Address reprint requests to Loi'c Guillcvin, MD, Service de Medecine Interne, I-IBpital Avicenne, Facult6 de Medecine ParisNord, 125, rue de Stalingrad, 93009 Bobigny Cedex, France. Submitted lor publication October 29, 1996; accepted in revised form June 26, 1997.

oral CYC (group B) as first-line treatment. CYC was given for a t least 1 year and was then progressively tapered and discontinued. Results. Fifty patients were included in the study: 27 in group A and 23 in group B. At 6 months, 24 group A patients (88.9%) were in remission, versus 18 group B patients (78.3%). At the end of the trial, 18 group A patients (66.7%) and 13 group B patients (56.5%) were in remission. In group A, 66.7% of the patients experienced side effects, versus 69.6% in group B. Infectious side effects were significantly more frequent in group B (69.6%) than in group A (40.7%) (P C 0.05). The incidence of Pneumocystis curinii pneumonia was higher in oral CYC-treated patients (30.4%) than in pulse CYC-treated patients (11.1%). Nine group A patients (33.3%) and 10 group B patients (43.5%) died. Actuarial curves showed that relapses were significantly more frequent in group A (59.2%) than in group B (13%) ( P = 0.02). Conclusion. Our results indicate that pulse CYC is as effective as oral CYC in achieving initial remission of WG and is associated with fewer side effects and lower mortality. However, in the long term, treatment with pulse CYC does not maintain remission or prevent relapses as well as oral CYC. Wegener's granulomatosis (WG) was described in 1936 by Friedriech Wegener (1) and is characterized by involvement of lung (nodules and infiltrates), ear, nose, and throat (ENT), and kidneys (rapidly progressive glomerulonephritis [RPGN]); the necrotizing vasculitis involves medium- and small-sized arteries, veins, and capillaries, and extravascular granulomas are

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present. The association between antibodies directed against components of neutrophil cytoplasm (ANCA) and WG was first reported in 1985 (2) and triggered intense interest in these antibodies, which may be involved in the pathophysiology of the disease. Indirect immunofluorescence (IIF) labeling of ANCA can show a diffuse cytoplasmic staining pattern (cANCA) or a perinuclear pattern (pANCA) (3). By enzyme-linked immunosorbent assay (ELISA), antibodies directed against proteinase 3 (PR3) are usually detected in cANCA-positive patients, and antibodies against myeloperoxidase (MPO) in pANCA-positive patients. The sensitivity of ANCA, mainly cANCA, is -90% in patients with active WG and 40% when the disease is in remission or in those with localized disease. The specificity of cANCA in the diagnosis of WG is -90%. Use of the combination of cyclophosphamide (CYC) and corticosteroids (CS) to treat WG has dramatically improved patient outcome (4). High rates of remission have been achieved with daily oral low-dose CYC and CS (43). However, the outcome of WG can be poor, with multiple relapses, and sequelae are common. This widely used treatment regimen was initially considered to be safe, generating an extraordinarily low incidence of treatment-related infections and malignancies (4). Nonetheless, several reports have suggested that WG patients are at greater risk for infection than previously indicated (6,7) and have emphasized that long-term CYC treatment could predispose to the occurrence of malignancies. Recently, Hoffman et a1 ( 5 ) described their extended experience with 158 WG patients referred to the National Institutes of Health (NIH). They observed a greater frequency of disease activity and treatment-related morbidity during longterm followup, compared with patients followed up for shorter periods of time. Furthermore, because lifethreatening symptoms and death can occur very early, even at the time of diagnosis of WG, severely ill patients are not always taken into consideration and recruited into referral center trials. The initial treatment of WG generally consists of CYC, which is usually given orally (5,8). Administration of CYC by other approaches has been used in the treatment of various connective tissue disorders, and pulse CYC combined with CS (9-15) or with plasma exchange (16) has been shown to be effective and well tolerated. However, the ability of CYC to better control WG when given as a pulse (17) rather than orally has not yet been confirmed. Since the total dose of CYC administered as a pulse is lower than that given orally, the pulse regimen could limit long-term side effects, espe-

GUILLEVIN ET AL

cially the risk of developing malignancy, which seems to be correlated with the cumulative dose (18). The present study was undertaken to compare pulse and oral CYC, in combination with CS, in the treatment of systemic WG. The short- and long-term efficacy and tolerability of each of these treatments were evaluated in an attempt to identify the better protocol. PATIENTS AND METHODS Patients. Only patients with newly diagnosed systemic W G (within a week after diagnosis and prior to treatment initiation) were included in the trial. All patients fulfilled the following inclusion criteria: 1) age >15 years; 2) systemic W G diagnosed clinically based on the presence of multiorgan involvement (ENT and/or lung and/or RPGN associated with severe general symptoms); or 3) monovisceral involvement, representing a potential risk of severe morbidity or fatality; and 4) histopathologic characterization of necrotizing granulomatous vasculitis or evidence of either granulomatous inflammation and vasculitis or segmental necrotizing glomerulonephritis. To avoid the bias of disease severity, patients were recruited from a large panel of French hospitals, most of which are general hospitals, to identify those with W G diagnosed in primary care hospitals, and not only in referral centers. Every hospital had an intensive care unit and the technical equipment necessary for patient treatment. The study protocol was approved by the Biomedical Ethics Committee of the University of Paris-Nord. Prior to formal enrollment in the trial, the study was explained to all patients and written informed consent was obtained. Treatment protocol. Initial regimen. The initial regimen was identical for all patients and consisted of intravenous (IV) methylprednisolone, 15 mglkgiday for 3 consecutive days, followed by oral prednisone, 1 mgikgiday. One pulse of 1V CYC, at a dose of 0.7 gmim2, was administered the day after the last IV methylprednisolone administration and concurrently with the first day of oral prednisone treatment. Prednisone. Every patient received prednisone. The CS regimen was the same in both treatment groups (see below) and similar to that we used in a study of patients with polyarteritis nodosa or Churg-Strauss syndrome (19). Oral prednisone was prescribed at an initial dosage of 1 mg/kg/day for 6 weeks. For those patients in whom complete remission was achieved, the daily dosage was tapered gradually by 2.5 mg every 10 days until a level equivalent to half the initial dosage was reached. This dosage was maintained for 3 weeks, and was then further decreased by 2.5 mg every 10 days to 20 mgiday. A more gradual tapering schedule was then used for doses