Efficacy of Cyclophosphamide in the Treatment of Interstitial Lung Disease Associated with Systemic Sclerosis

Espinosa, Gerard; Pilar Simeon, Carmen; Angel Plasin, Miguel; Xaubet, Antoni; Muñoz, Xavier; Fonollosa, Vicent; Cervera, Ricard; Vilardell, Miquel

doi:10.1016/S1579-2129(11)70059-3

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Abstract

Background

Cyclophosphamide (CYC) stabilizes the parameters of lung function tests (LFT) of patients with systemic sclerosis (SSc) and interstitial lung disease (ILD) treated for 12 months. There is little information about long-term treatment (24 months). The aim of this study is to analyze the effect of intravenous CYC in LFT parameters in patients with SSc and ILD treated for 24 months.

Patients and method

Retrospective study of 37 patients with ILD associated with scleroderma treated with intravenous CYC for 24 months and regularly assessed by LFT (at baseline, 6, 12 and 24 months) including forced vital capacity (FVC) and transfer capacity of carbon monoxide (DLCO).

Results

The differences between FVC and DLCO values performed at baseline and those performed at 6, 12, and 24 months were less than 10%, which meant that CYC stabilized functional parameters. There were no differences in FVC or DLCO when patients treated for 6 months were evaluated according to the type of SSc skin involvement of (diffuse or limited) or according to the evolution time of ILD before the start of treatment. Although patients with severe restriction (FVC<70%) showed more improvement, it was less than 10% in all cases

Conclusion

In this series of patients with ILD associated with SSc, intravenous CYC was effective in stabilizing lung function parameters in long-term treatment.

Keywords:

Interstitial lung disease

Systemic sclerosis

Cyclophosphamide

Treatment

Resumen

Introducción

La ciclofosfamida (CFM) estabiliza los parámetros del estudio funcional respiratorio (EFR) de los pacientes con esclerosis sistémica (ES) y enfermedad pulmonar intersticial (EPI) tratados durante 12 meses. Existe poca información acerca del tratamiento a largo plazo (24 meses). El objetivo del estudio es analizar el efecto de la CFM endovenosa en los parámetros del EFR de los pacientes con ES y EPI tratados durante 24 meses.

Pacientes y método

Estudio retrospectivo de 37 pacientes con EPI asociada a esclerodermia, tratados con CFM endovenosa durante 24 meses y evaluados de forma periódica mediante EFR (basal, a los 6, 12 y 24 meses). En este se evaluó la capacidad vital forzada (FVC) y la capacidad de transferencia de monóxido de carbono (DLCO).

Resultados

Las diferencias entre los valores de FVC y DLCO basales y los realizados a los 6, 12 y 24 meses fueron menores del 10%, lo que significa que la CFM estabilizó los parámetros funcionales. Tampoco se detectaron diferencias en la FVC ni en la DLCO cuando se valoró a los pacientes tratados durante 6 meses de acuerdo al tipo de afectación cutánea de la ES (difusa o limitada), o según el tiempo de evolución de la EPI antes del inicio del tratamiento. Si bien los pacientes con restricción grave (FVC < 70%) al inicio mostraron mayor mejoría, esta fue en todos los casos inferior al 10%.

Conclusión

En esta serie de pacientes con EPI asociada a ES, la CFM endovenosa estabilizó los parámetros funcionales respiratorios en el tratamiento a largo plazo.

Palabras clave:

Enfermedad pulmonar intersticial

Esclerosis sistémica

Ciclofosfamida

Tratamiento

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References

[1.]

A. Gabrielli, E.V. Avvedimento, T. Krieg.

Mechanisms of disease: Scleroderma.

N Engl J Med, 360 (2009), pp. 1989-2003

http://dx.doi.org/10.1056/NEJMra0806188 | Medline

[2.]

A.U. Wells, V. Steen, G. Valentini.

Pulmonary complications: one of the most challenging complications of systemic sclerosis.

Rheumatology, 48 (2009), pp. iii40-iii44

http://dx.doi.org/10.1093/rheumatology/kep109 | Medline

[3.]

V.D. Steen, T.A. Medsger.

Changes in causes of death in systemic sclerosis, 1972-2002.

Ann Rheum Dis, 66 (2007), pp. 940-944

http://dx.doi.org/10.1136/ard.2006.066068 | Medline

[4.]

D. Bouros, A.U. Wells, A.G. Nicholson, T.V. Colby, V. Polychronopoulos, P. Pantelidis, et al.

Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome.

Am J Respir Crit Care Med, 165 (2002), pp. 1581-1586

http://dx.doi.org/10.1164/rccm.2106012 | Medline

[5.]

D.J. Abraham, T. Krieg, J. Distler, O. Distler.

Overview of pathogenesis of systemic sclerosis.

Rheumatology, 48 (2009), pp. iii3-iii7

http://dx.doi.org/10.1093/rheumatology/ken481 | Medline

[6.]

P. Ostojic, M. Matucci Cerinic, R. Silver, K. Highland, N. Damjanov.

Intersticial lung disease in systemic sclerosis.

Lung, 185 (2007), pp. 211-220

Medline

[7.]

I. Miniati, G. Valentini, M. Matucci Cerinic.

Cyclophosphamide in systemic sclerosis: still in search of a ‘real life’ scenario.

Arthritis Res Ther, 11 (2009), pp. 103

http://dx.doi.org/10.1186/ar2576 | Medline

[8.]

O. Nadashkevich, P. Davis, M. Fritzler, W. Kovalenko.

A randomized unblinded trial of cyclophosphamide versus azathioprine in the treatment of systemic sclerosis.

Clin Rheumatol, 25 (2006), pp. 205-212

http://dx.doi.org/10.1007/s10067-005-1157-y | Medline

[9.]

D.P. Tashkin, R. Elashoff, P.J. Clements, J. Goldin, M.D. Roth, D.E. Furst, Scleroderma Lung Study Research Group, et al.

Cyclophosphamide versus Placebo in Scleroderma Lung Disease.

N Eng J Med, 354 (2006), pp. 2655-2666

Article

[10.]

R.K. Hoyles, R.W. Ellis, J. Wellsbury, B. Lees, P. Newlands, N.S. Goh, 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, 54 (2006), pp. 3962-3970

http://dx.doi.org/10.1002/art.22204 | Medline

[11.]

C. Nannini, C.P. West, P.J. Erwin, E.L. Matteson.

Effects of cyclophosphamide on pulmonary function in patients with scleroderma and interstitial lung disease: a systematic review and meta-analysis of randomized controlled trials and observational prospective cohort studies.

Arthritis Res Ther, 10 (2008), pp. R124

http://dx.doi.org/10.1186/ar2534 | Medline

[12.]

R. Giacomelli, G. Valentini, F. Salsano, P. Cipriani, P. Sambo, M.L. Conforti, et al.

Cyclophosphamide pulse regimen in the treatment of alveolitis in systemic sclerosis.

J Rheumatol, 29 (2002), pp. 371-376

[13.]

B. Griffiths, S. Miles, H. Moss, R. Robertson, D. Veale, P. Emery.

Systemic sclerosis and interstitial lung disease: A pilot study using pulse intravenous methylprednisolone and cyclophosphamide to assess the effect on high resolution computed tomography scan and lung function.

J Rheumatol, 29 (2002), pp. 2371-2378

Medline

[14.]

O. Kowal-Bielecka, R. Landewé, J. Avouac, S. Chwiesko, I. Miniati, L. Czirjak, et al.

EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR).

Ann Rheum Dis, 68 (2009), pp. 620-628

http://dx.doi.org/10.1136/ard.2008.096677 | Medline

[15.]

A.U. Wells, N. Hirani, and on behalf of the BTS Interstitial Lung Disease Guideline Interstitial lung disease guideline Group, a subgroup of the British Thoracic Society Standards of Care Committee, in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society.

Thorax, 63 (2008), pp. v1-v58

http://dx.doi.org/10.1136/thx.2008.101691 | Medline

[16.]

P. Airò, E. Danieli, M. Rossi, M. Frassi, I. Cavazzana, M. Scarsi, et al.

Intravenous cyclophosphamide for interstitial lung diases associated to systemic sclerosis: results with an 18-month protocol including a maintenance phase.

Clin Exp Rheumatol, 25 (2007), pp. 293-296

Medline

[17.]

R.M. Silver, J.H. Warrick, M.B. Kinsella, L.S. Staudt, M.H. Baumann, C. Strange.

Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease.

J Rheumatol, 20 (1993), pp. 838-844

Medline

[18.]

A.T. Masi, G.P. Rodnan, T.A. Medsger, R. Altman, W. D’Angelo, J. Fries, et al.

Preliminary criteria for the classification of systemic sclerosis (scleroderma).

Arthritis Rheum, 23 (1980), pp. 581-590

Medline

[19.]

P.I. Latsi, A.U. Wells.

Evaluation and management of alveolitis and interstitial lung disease in scleroderma.

Curr Opin Rheumatol, 15 (2003), pp. 748-755

Medline

[20.]

R.J. Barst, M. McGoon, A. Torbicki, O. Sitbon, M.J. Krowka, H. Olschewski, et al.

Diagnosis and differential assessment of pulmonary arterial hypertension.

J Am Coll Cardiol, 43 (2004), pp. S40-S47

[21.]

T.A. Medsger, S. Bombardieri, L. Czirjak, R. Scorza, A. Della Rosa, W. Bencivelli.

Assessment of severity and prognosis in SSc.

Clin Exp Rheumatol, 21 (2003), pp. S42-S46

Medline

[22.]

American Thoracic Society/European Respiratory Society.

Idiopathic pulmonary fibrosis: diagnosis and treatment International consensus statement.

Am J Respir Crit Care Med, 161 (2000), pp. 646-664

http://dx.doi.org/10.1164/ajrccm.161.2.ats3-00 | Medline

[23.]

A. Xaubet, J. Ancochea, R. Blanquer, C. Montero, F. Morell, E. Rodríguez Becerra, et al.

Diagnóstico y tratamiento de las enfermedades pulmonares intersticiales difusas.

Arch Bronconeumol, 39 (2003), pp. 580-600

Medline

[24.]

A.U. Wells, P. Latsi, W.J. McCune.

Daily cyclophosphamide for scleroderma: are patients with the most to gain underrepresented in this trial?.

Am J Respir Crit Care Med, 176 (2007), pp. 952-953

http://dx.doi.org/10.1164/rccm.200708-1185ED | Medline

[25.]

D.P. Tashkin, R. Elashoff, P.J. Clements, M.D. Roth, D.E. Furst, R.M. Silver, et al.

Effects of 1-year treatment with cyclophosphamide on outcomes at 2years in scleroderma lung disease.

Am J Respir Crit Care Med, 176 (2007), pp. 1026-1034

http://dx.doi.org/10.1164/rccm.200702-326OC | Medline

[26.]

G. Yiannopoulos, V. Pastromas, I. Antonopoulis, G. Katsiberis, G. Kalliolias, S.N. Liossis, et al.

Combination of intravenous pulses of cyclophosphamide and methyprednisolone in patients with systemic sclerosis and interstitial lung disease.

Rheumatol Int, 27 (2007), pp. 357-361

http://dx.doi.org/10.1007/s00296-006-0217-1 | Medline

[27.]

A. Bérezné, B. Ranque, D. Valeyre, M. Brauner, Y. Allanore, D. Launay, et al.

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.

J Rheumatol, 35 (2008), pp. 1064-1072

Medline

[28.]

G.J. Gerbino, C.H. Goss, J.A. Molitor.

Effect of mycophenolate mofetil on pulmonary function in scleroderma-associated interstitial lung disease.

Chest, 133 (2008), pp. 455-460

http://dx.doi.org/10.1378/chest.06-2861 | Medline

[29.]

A. Koutroumpas, A. Ziogas, I. Alexiou, G. Barouta, L.I. Sakkas.

Mycophenolate mofetil in systemic sclerosis-associated interstitial lung disease.

Clin Rheumatol, 29 (2010), pp. 1167-1168

http://dx.doi.org/10.1007/s10067-010-1498-z | Medline