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Therapeutic Strategy Combining Intravenous Cyclophosphamide Followed by Oral Azathioprine to Treat Worsening Interstitial Lung Disease Associated with Systemic Sclerosis: A Retrospective Multicenter Open-label Study

ALICE BÉREZNÉ, BRIGITTE RANQUE, DOMINIQUE VALEYRE, MICHEL BRAUNER, YANNICK ALLANORE, DAVID LAUNAY, VÉRONIQUE LE GUERN, JEAN-EMMANUEL KAHN, LOUIS-JEAN COUDERC, JOËL CONSTANS, PASCAL COHEN, ALFRED MAHR, CHRISTIAN PAGNOUX, ERIC HACHULLA, ANDRÉ KAHAN, JEAN CABANE, LOÏC GUILLEVIN, and LUC MOUTHON

ABSTRACT.

Objective
. To evaluate the effects and safety of 6-month intravenous cyclophosphamide (CYC) followed by 18-month oral azathioprine (AZA) therapy in patients with systemic sclerosis (SSc) and worsening interstitial lung disease (ILD).

Methods. All patients presented with ILD and worsened forced vital capacity (FVC) and/or total lung capacity of more than 10% and/or DLCO of more than 15% during the previous year. Treatment was 6 monthly pulses of 0.6 g/m2 CYC followed by oral AZA for 18 months on disease stabilization or improvement. The endpoint was the rate of percentage change in pulmonary function tests (PFT) after 6 and 24 months.

Results. Twenty-seven patients with SSc (20 females) were recruited. Age and disease duration before CYC therapy were (mean ± SD) 49.4 ± 15 years and 75.5 ± 87.8 months, respectively. Mean baseline FVC was 67% ± 19% of predicted value. At 6 months, in 7 (26%) patients disease was improved, in 12 (44%) stabilized, and in 8 (30%) worsened. Among the 19 (70%) responders, 15 received AZA and 4 declined. Twenty-three completed 2-year followup, 3 died, and one dropped out. Six (22.2%) had improved, 8 (29.6.%) were stable, and 13 (48.2%) had worsened. Evolution of the slope of FVC (in % per year) varied from -15.5 prior to treatment to 3 (p = 0.004) at 6 months and to 1 (p < 5 ´ 10-5) at 24 months.

Conclusion. Intravenous CYC followed by oral maintenance immunosuppressive therapy for worsening ILD was well tolerated and was associated with stable or improved PFT in 70% and 51.8% of SSc patients at 6 months and 2 years, respectively. (J Rheumatol First Release May 1 2008)

Key Indexing Terms:

SYSTEMIC SCLEROSIS
CYCLOPHOSPHAMIDE
AZATHIOPRINE
MYCOPHENOLATE MOFETIL
INTERSTITIAL LUNG DISEASE


From Paris Descartes University, Faculty of Medicine, Department of Internal Medicine and Reference Center for Necrotizing Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris; Paris Nord University, Faculty of Medicine; Departments of Pneumology and Radiology; Avicenne Hospital, AP-HP, Bobigny; Paris Descartes University, Faculty of Medicine, Department of Rheumatology A, Cochin Hospital and AP-HP, Paris; Lille 2 University, Faculty of Medicine, Department of Internal Medicine and National Reference Center of Vascular Manifestations of Scleroderma, Regional University Hospital Claude-Huriez Hospital, Lille; Departments of Internal Medicine and Pneumology, Foch Hospital, Suresnes; Department of Vascular Medicine, CHU-Hôpitaux de Bordeaux, Saint André Hospital, Bordeaux; and Department of Internal Medicine, Saint-Antoine Hospital, Paris, France.

Supported by the Association des sclérodermiques de France under the auspices of the Groupe Français de Recherche sur la Sclérodermie (GFRS) and the Société Nationale Française de Médecine Interne.

A. Bérezné, MD; B. Ranque*, MD; V. Le Guern, MD; P. Cohen, MD; A. Mahr, MD; C. Pagnoux, MD; L. Guillevin, MD; L. Mouthon, MD, PhD, Paris Descartes University, Faculty of Medicine; Department of Internal Medicine and Reference Center for Necrotizing Vasculitides and Systemic Sclerosis, Cochin Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP); D. Valeyre*, MD, Paris Nord University, Faculty of Medicine; Department of Pneumology, Avicenne Hospital, AP-HP; M. Brauner, MD, Paris Nord University, Faculty of Medicine; Department of Radiology, Avicenne Hospital, AP-HP; Y. Allanore, MD, PhD; A. Kahan, MD, Paris Descartes University, Faculty of Medicine, Department of Rheumatology A, Cochin Hospital and AP-HP; D. Launay, MD; E. Hachulla, MD, PhD, Lille 2 University, Faculty of Medicine, Department of Internal Medicine and National Reference Center of Vascular Manifestations of Scleroderma, Regional University Hospital Claude-Huriez Hospital; J-E. Kahn, MD, Department of Internal Medicine, Foch Hospital; L-J. Couderc, MD, Department of Pneumology, Foch Hospital; J. Constans, MD, Department of Vascular Medicine, CHU-Hôpitaux de Bordeaux, Saint André Hospital; J. Cabane, MD, Department of Internal Medicine, Saint-Antoine Hospital.

*Both authors contributed equally to the work.

Address reprint requests to Dr. L. Mouthon, Service de Médecine Interne, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris CEDEX 14, France. E-mail: luc.mouthon@cch.aphp.fr

Accepted for publication January 17, 2008.



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