, Volume 191, Issue 5, pp 483–489 | Cite as

Mycophenolate Versus Cyclophosphamide for Progressive Interstitial Lung Disease Associated with Systemic Sclerosis: A 2-Year Case Control Study

  • Stylianos T. PanopoulosEmail author
  • Vassiliki-Kalliopi Bournia
  • Georgia Trakada
  • Irene Giavri
  • Charalambos Kostopoulos
  • Petros P. Sfikakis



Cyclophosphamide is considered the treatment of choice for interstitial lung disease (ILD) secondary to systemic sclerosis (SSc), albeit having a minimal effect. Although controlled evidence does not exist, mycophenolate is used increasingly in clinical practice as an alternative. We aimed to compare the long-term efficacy of these drugs.


Patients from our SSc cohort who received mycophenolate for over 1 year for progressive ILD were 1:1 matched for age, gender, and baseline forced vital capacity (FVC ±3 %) with cyclophosphamide-treated patients. Changes in FVC, total lung capacity (TLC), diffusion capacity for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) scans were compared between groups. Changes in pulmonary function tests (PFTs) over at least 1 year in six unmatched control patients, who had denied mycophenolate or cyclophosphamide, also were examined.


FVC, TLC, and DLCO did not change significantly in either mycophenolate (from 79.0 ± 12.5 to 80.2 ± 8.1 to 81.2 ± 11.4, from 71.5 ± 16.1 to 74.3 ± 10.8 to 71.8 ± 13.0, from 56.8 ± 12.0 to 55.2 ± 9.9 to 50.6 ± 8.5, respectively) or cyclophosphamide group (from 77.3 ± 12.5 to 79.7 ± 10.3 to 82.5 ± 12.9, from 64.7 ± 14.9 to 68.6 ± 16.0 to 66.1 ± 15.5, from 53.1 ± 14.3 to 56.4 ± 13.5 to 56.3 ± 6.7, respectively), after 1 or 2 years of treatment. PFTs also remained stable in the control group. In either the mycophenolate or cyclophosphamide groups, six patients remained stable, three improved, and one deteriorated according to the definitions of the American Thoracic Society. However, and despite the fact that patients in the cyclophosphamide group had more extended ILD at baseline, a deterioration of lung HRCT findings at 2 years was noticed after mycophenolate (from 10.0 ± 8.9 to 12.7 ± 8.2, p = 0.039) but not after cyclophosphamide.


Although these results derive from patients selected for receiving at least 1 year of treatment and therefore they do not represent an intention-to-treat cohort, an eagerness to replace cyclophosphamide by mycophenolate in SSc-associated ILD treatment is not supported.


Systemic sclerosis Interstitial lung disease Cyclophosphamide Mycophenolate mofetil Mycophenolate sodium 



Supported by ELKE Grant no. 097, Athens University, Greece.

Conflict of interest

The authors have no conflict of interest to declare with regard to the present work.


  1. 1.
    Solomon JJ, Olson AL, Fischer A, Bull T, Brown KK, Raghu G (2013) Scleroderma lung disease. Eur Respir Rev 22(127):6–19. doi: 10.1183/09059180.00005512 PubMedCrossRefGoogle Scholar
  2. 2.
    Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M (2006) Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 354(25):2655–2666. doi: 10.1056/NEJMoa055120 PubMedCrossRefGoogle Scholar
  3. 3.
    Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ, Foley NM, Pearson SB, Emery P, Veale DJ, Denton CP, Wells AU, Black CM, du Bois RM (2006) 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 54(12):3962–3970. doi: 10.1002/art.22204 PubMedCrossRefGoogle Scholar
  4. 4.
    Nihtyanova SI, Brough GM, Black CM, Denton CP (2007) Mycophenolate mofetil in diffuse cutaneous systemic sclerosis—a retrospective analysis. Rheumatology (Oxford) 46(3):442–445. doi: 10.1093/rheumatology/kel244 CrossRefGoogle Scholar
  5. 5.
    Tzouvelekis A, Galanopoulos N, Bouros E, Kolios G, Zacharis G, Ntolios P, Koulelidis A, Oikonomou A, Bouros D (2012) Effect and safety of mycophenolate mofetil or sodium in systemic sclerosis-associated interstitial lung disease: a meta-analysis. Pulm Med 2012:143637. doi: 10.1155/2012/143637 PubMedGoogle Scholar
  6. 6.
    Simeon-Aznar CP, Fonollosa-Pla V, Tolosa-Vilella C, Selva-O’Callaghan A, Solans-Laque R, Vilardell-Tarres M (2011) Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol 30(11):1393–1398. doi: 10.1007/s10067-011-1823-1 PubMedCrossRefGoogle Scholar
  7. 7.
    Gerbino AJ, Goss CH, Molitor JA (2008) Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease. Chest 133(2):455–460. doi: 10.1378/chest.06-2861 PubMedCrossRefGoogle Scholar
  8. 8.
    Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas LI (2010) Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol 29(10):1167–1168. doi: 10.1007/s10067-010-1498-z PubMedCrossRefGoogle Scholar
  9. 9.
    Liossis SN, Bounas A, Andonopoulos AP (2006) Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease. Rheumatology (Oxford) 45(8):1005–1008. doi: 10.1093/rheumatology/kei211 CrossRefGoogle Scholar
  10. 10.
    Swigris JJ, Olson AL, Fischer A, Lynch DA, Cosgrove GP, Frankel SK, Meehan RT, Brown KK (2006) Mycophenolate mofetil is safe, well tolerated, and preserves lung function in patients with connective tissue disease-related interstitial lung disease. Chest 130(1):30–36. doi: 10.1378/chest.130.1.30 PubMedCrossRefGoogle Scholar
  11. 11.
    Zamora AC, Wolters PJ, Collard HR, Connolly MK, Elicker BM, Webb WR, King TE Jr, Golden JA (2008) Use of mycophenolate mofetil to treat scleroderma-associated interstitial lung disease. Respir Med 102(1):150–155. doi: 10.1016/j.rmed.2007.07.021 PubMedCrossRefGoogle Scholar
  12. 12.
    Vanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E, Nzeusseu Toukap A, Depresseux G, Houssiau FA (2007) A pilot study of mycophenolate mofetil combined to intravenous methylprednisolone pulses and oral low-dose glucocorticoids in severe early systemic sclerosis. Clin Exp Rheumatol 25(2):287–292PubMedGoogle Scholar
  13. 13.
    Panopoulos ST, Bournia VK, Sfikakis PP (2013) Is vasculopathy associated with systemic sclerosis more severe in men? J Rheumatol 40(1):46–51. doi: 10.3899/jrheum.120667 PubMedCrossRefGoogle Scholar
  14. 14.
    American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS), and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161(2 Pt 1):646–664Google Scholar
  15. 15.
    Warrick JH, Bhalla M, Schabel SI, Silver RM (1991) High resolution computed tomography in early scleroderma lung disease. J Rheumatol 18(10):1520–1528PubMedGoogle Scholar
  16. 16.
    Desai SR, Veeraraghavan S, Hansell DM, Nikolakopolou A, Goh NS, Nicholson AG, Colby TV, Denton CP, Black CM, du Bois RM, Wells AU (2004) CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology 232(2):560–567. doi: 10.1148/radiol.2322031223 PubMedCrossRefGoogle Scholar
  17. 17.
    de Lauretis A, Veeraraghavan S, Renzoni E (2011) Review series: aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ? Chron Respir Dis 8(1):53–82. doi: 10.1177/1479972310393758 PubMedGoogle Scholar
  18. 18.
    Khanna D, Furst DE, Clements PJ, Tashkin DP, Eckman MH (2008) Oral cyclophosphamide for active scleroderma lung disease: a decision analysis. Med Decis Making 28(6):926–937. doi: 10.1177/0272989X08317015 PubMedCrossRefGoogle Scholar
  19. 19.
    Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, Hirani N, Hubbard R, Lake F, Millar AB, Wallace WA, Wells AU, Whyte MK, Wilsher ML (2008) Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 63(Suppl 5):v1–v58. doi: 10.1136/thx.2008.101691 PubMedGoogle Scholar
  20. 20.
    Papiris SA, Manali ED, Kolilekas L, Kagouridis K, Triantafillidou C, Tsangaris I, Roussos C (2010) Clinical review: idiopathic pulmonary fibrosis acute exacerbations—unravelling Ariadne’s thread. Crit Care 14(6):246. doi: 10.1186/cc9241 PubMedCrossRefGoogle Scholar
  21. 21.
    du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, King TE Jr, Lancaster L, Noble PW, Sahn SA, Thomeer M, Valeyre D, Wells AU (2011) Forced vital capacity in patients with idiopathic pulmonary fibrosis: test properties and minimal clinically important difference. Am J Respir Crit Care Med 184(12):1382–1389. doi: 10.1164/rccm.201105-0840OC PubMedCrossRefGoogle Scholar
  22. 22.
    Behr J (2011) A small change in FVC but a big change for IPF: defining the minimal clinically important difference. Am J Respir Crit Care Med 184(12):1329–1330. doi: 10.1164/rccm.201110-1794ED PubMedCrossRefGoogle Scholar
  23. 23.
    Khanna D, Roth MD, Furst DE, Clements PJ, Goldin J, Arriola E, Kotlerman J, Tseng C, Kim G, Elashoff G, Tashkin, Scleroderma Lung Study II Research Group (2013) Double-blind comparison of mycophenolate mofetil and oral cyclophosphamide for treatment of scleroderma-related interstitial lung disease (Scleroderma Lung Study [SLS] II): rationale, design, methods, baseline characteristics and patient disposition. Paper presented at the EULAR Conference, Madrid, Spain, June 2013Google Scholar
  24. 24.
    Fischer A, Brown KK, Du Bois RM, Frankel SK, Cosgrove GP, Fernandez-Perez ER, Huie TJ, Krishnamoorthy M, Meehan RT, Olson AL, Solomon JJ, Swigris JJ (2013) Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. doi: 10.3899/jrheum.121043 Google Scholar
  25. 25.
    Mendoza FA, Nagle SJ, Lee JB, Jimenez SA (2012) A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J Rheumatol 39(6):1241–1247. doi: 10.3899/jrheum.111229 PubMedCrossRefGoogle Scholar
  26. 26.
    Herrick AL, Lunt M, Whidby N, Ennis H, Silman A, McHugh N, Denton CP (2010) Observational study of treatment outcome in early diffuse cutaneous systemic sclerosis. J Rheumatol 37(1):116–124. doi: 10.3899/jrheum.090668 PubMedCrossRefGoogle Scholar
  27. 27.
    Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, Corte TJ, Sander CR, Ratoff J, Devaraj A, Bozovic G, Denton CP, Black CM, du Bois RM, Wells AU (2008) Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med 177(11):1248–1254. doi: 10.1164/rccm.200706-877OC PubMedCrossRefGoogle Scholar
  28. 28.
    Khanna D, Seibold JR, Wells A, Distler O, Allanore Y, Denton C, Furst DE (2010) Systemic sclerosis-associated interstitial lung disease: lessons from clinical trials, outcome measures, and future study design. Curr Rheumatol Rev 6(2):138–144PubMedCrossRefGoogle Scholar
  29. 29.
    Au K, Khanna D, Clements PJ, Furst DE, Tashkin DP (2009) Current concepts in disease-modifying therapy for systemic sclerosis-associated interstitial lung disease: lessons from clinical trials. Curr Rheumatol Rep 11(2):111–119PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Stylianos T. Panopoulos
    • 1
    Email author
  • Vassiliki-Kalliopi Bournia
    • 1
  • Georgia Trakada
    • 2
  • Irene Giavri
    • 1
  • Charalambos Kostopoulos
    • 2
  • Petros P. Sfikakis
    • 1
  1. 1.First Department of Propedeutic and Internal MedicineAthens University Medical SchoolAthensGreece
  2. 2.Department of TherapeuticsAthens University Medical SchoolAthensGreece

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