Citation Information :
Suraj K, Jyothi E, Jayarajan P, George B. Cyclophosphamide Pulse Therapy in the Treatment of Systemic Sclerosis Associated Interstitial Lung Disease: An Observational Study. Indian J Chest Dis Allied Sci 2022; 64 (4):263-268.
Introduction: Scleroderma is a multisystem autoimmune connective tissue disease with approximately 90% of patients having lung involvement. It is the leading cause of morbidity and mortality in scleroderma. There is no effective treatment once there is lung involvement in the form of fibrosis.
Study setting: Conducted in a tertiary care center between January 2017 and December 2019.
Aim: To evaluate the efficacy of intravenous cyclophosphamide in patients with scleroderma-associated interstitial lung disease (ILD).
Study population: Symptomatic patient with scleroderma with high-resolution computed tomography (HRCT)-proven non-specific interstitial pneumonia (NSIP)-pattern ILD.
Methodology: Patients received 12 cycles of cyclophosphamide at a dose of 10 mg/kg every 4 weeks. Patients were followed up for 1 year after treatment completion. A six-minute walk test (6MWT) and spirometry were done at baseline and then every 6 months up to 2 years. Diffusing capacity of lung for carbon monoxide (DLCO) was done at baseline and then yearly for up to 2 years.
Results: A total of 38 patients completed the study. The majority of patients had diffuse cutaneous type of systemic sclerosis. Throughout the study period, there was a gradual worsening of dyspnea as measured by the Modified Medical Research Council (mMRC) scale. Mean forced vital capacity (FVC) improved with 1 year of treatment, but later steadily decreased during follow-up. Similarly, DLCO also improved during 1-year treatment, but the improvement was not sustained during follow-up. There was a statistically significant improvement in 6MWD at the end of 6 months. This was followed by a gradual fall in 6MWD during follow-up. The only adverse event noted was persistent leukopenia in one patient.
Conclusion: Intravenous pulse cyclophosphamide therapy in patients with scleroderma-associated ILD is associated with stabilization of pulmonary function during the treatment period, but not maintained during follow-up.
Schurawitzki H, Stiglbauer R, Graninger W, et al. Interstitial lung disease in progressive systemic sclerosis: High-resolution CT versus radiography. Radiology 1990;176(3):755–759. DOI: 10.1148/radiology.176.3.2389033.
Walker UA, Tyndall A, Czirják L, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: A report from the EULAR Scleroderma Trials And Research group database. Ann Rheum Dis 2007;66(6):754–763. DOI: 10.1136/ard.2006.062901.
Steen VD, Conte C, Owens GR, et al. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum 1994;37(9):1283–1289. DOI: 10.1002/art.1780370903.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006;354(25):2655–2666. DOI: 10.1056/NEJMoa055120.
Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016;4(9):708–719. DOI: 10.1016/S2213-2600(16)30152-7.
Silver RM, Warrick JH, Kinsella MB, et al. Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 1993;20(5):838–844. PMID: 8336309.
Hoyles RK, Ellis RW, Wellsbury J, et al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006;54(12):3962–3970. DOI: 10.1002/art.22204.
Tashkin DP, Elashoff R, Clements PJ, et al. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med 2007;176(10):1026–1034. DOI: 10.1164/rccm.200702-326OC.
Kowal–Bielecka O, Fransen J, Avouac J, et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheum Dis 2017;76(8):1327–1339. DOI: 10.1136/annrheumdis-2016-209909.
Kundu S, Paul S, Hariprasath K, et al. Effect of sequential intravenous pulse cyclophosphamide–azathioprine in systemic sclerosis–interstitial lung disease: An open-label study. Indian J Chest Dis Allied Sci 2016;58(1):7–10. PMID: 28368564.
Haubitz M, Schellong S, Göbel U, et al. Intravenous pulse administration of cyclophosphamide versus daily oral treatment in patients with antineutrophil cytoplasmic antibody-associated vasculitis and renal involvement: A prospective, randomized study. Arthritis Rheum 1998;41(10):1835–1844. DOI: 10.1002/1529-0131(199810)41:10<1835::AID-ART16>3.0.CO;2-Q. PMID: 9778225.
Madelon C Vonk. Is there still a role for cyclophosphamide in the treatment of systemic sclerosis?. J Scleroderma Rel Disord 2021;6(2):117–122. DOI: 10.1177/2397198320961673.
Khanna D, Albera C, Fischer A, et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: The LOTUSS trial. J Rheumatol 2016;43(9):1672–1679. DOI: 10.3899/jrheum.151322.
Distler O, Highland KB, Gahlemann M, et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019; 380(26):2518–2528. DOI: 10.1056/NEJMoa1903076.
Pretorius E, Davids MR, du Toit R. Oral v. pulse intravenous cyclophosphamide: A retrospective analysis of adverse events in a setting with a high burden of infectious disease. S Afr Med J 2015;105(3):209–214. DOI: 10.7196/samj.8785.
Yee CS, Gordon C, Dostal C, et al. EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis. Ann Rheum Dis 2003;6(5)3:525–529. DOI: 10.1136/ard.2002.003574.
van den Brand JAJG, van Dijk PR, Hofstra JM, et al. Cancer risk after cyclophosphamide treatment in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2014;9(6):1066–1073. DOI: 10.2215/CJN.08880813.
Radis CD, Kahl LE, Baker GL, et al. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year follow-up study. Arthritis Rheum 1995;38(8):1120–1127. DOI: 10.1002/art.1780380815.