Shenoy et al.

Arthritis Research & Therapy (2016) 18:123

DOI 10.1186/s13075-016-1015-0

RESEARCH ARTICLE Open Access

Cyclophosphamide versus mycophenolate

mofetil in scleroderma interstitial lung
disease (SSc-ILD) as induction therapy: a
single-centre, retrospective analysis
Padmanabha D. Shenoy1*, Manish Bavaliya2, Sujith Sashidharan3, Kaveri Nalianda1 and Sreelakshmi Sreenath1

Abstract
Background: Scleroderma is a systemic autoimmune disease characterized mainly by skin manifestations and
involvement of various visceral organs, especially the lungs. Lung involvement is the leading cause of mortality in
patients with scleroderma. There are data to suggest that cyclophosphamide (CYC) and mycophenolate mofetil
(MMF) are effective in the management of scleroderma interstitial lung disease (SSc-ILD) but no head to head
comparative data are available to date.
Methods: For the last 3 years, patients with SSc-ILD have been treated at our centre by protocol-based administration
of intravenous CYC and MMF. Results of lung function tests (spirometry) were recorded at baseline, 3 months and
6 months in every patient. The clinical records of patients with systemic sclerosis and significant ILD, who were not
previously exposed to any immunosuppressant and were treated with MMF OR CYC, were reviewed. The efficacy of
treatment was assessed by the change in forced vital capacity on spirometry.
Results: Of the total 57 patients included in the analysis, 34 were treated with MMF and 23 were treated with
CYC. Mean duration of illness was 4.19 ± 2.82 years in the MMF and 6.04 ± 5.96 years in the CYC group. After
6 months of therapy, FVC increased by 10.84 ± 13.81 % in the CYC group and by 6.07 ± 11.92 % in the MMF
group. This improvement from baseline was statistically significant in both groups (P < 0.01). The improvement
was comparable with no statistically significant differences between groups (P = 0.373). There were no major
adverse events reported in either arm.
Conclusion: Both MMF and CYC were equally effective in stabilizing lung function in patients with scleroderma and ILD.
Keywords: Scleroderma interstitial lung disease, Cyclophosphamide, Mycophenolate mofetil

Background rates of patients with SSc in an Italian study involving

Lung diseases in scleroderma (SSc) are the leading dis- 915 patients was 64.9 % in those with lung involvement
ease-related cause of mortality, most typically including in comparison to 80.6 % in those without lung involve-
interstitial lung disease (ILD) and/or pulmonary arterial ment [4].
hypertension (PAH) [1]. Approximately 80 % of patients For more than 15 years, cyclophosphamide (CYC) is
have evidence of pulmonary fibrosis at postmortem exam- used in the treatment of SSc-ILD. CYC is a cytotoxic
ination [2] or on high-resolution computed tomography immunosuppressive agent that suppresses lymphokine
(HRCT), although clinically evident disease is present only production and modulates lymphocyte function by al-
in approximately 40 % of patients [3]. The 10-year survival kylating various cellular constituents and depressing
the inflammatory response via normalization of neutro-
* Correspondence: [email protected]
philia and healing of vascular endothelial cells [5]. CYC
1
Centre For Arthritis & Rheumatism Excellence (CARE), NH-47, Nettoor, Kochi, is the only agent shown to at least stabilize lung func-
Kerala 682040, India tion in a randomized, controlled trial [6].
Full list of author information is available at the end of the article

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Shenoy et al. Arthritis Research & Therapy (2016) 18:123 Page 2 of 6

Mycophenolic acid, the active metabolite of mycophe- or serum creatinine >2.0 mg/dl), or who had already been
nolate mofetil (MMF) and mycophenolate sodium (MS), treated with CYC or MMF or other immunosuppressants
inhibits inosine monophosphate dehydrogenase and de- such as cyclosporin or rituximab, or had severe cardiac dis-
pletes guanosine nucleotides. It is thus thought to decrease ease, with moderate to severe PAH (right ventricle systolic
the activity of inflammatory cells and to produce anti- pressure (RVSP) >50 mm Hg) measured by transthoracic
fibrotic and immunomodulatory effects. Mycophenolic echocardiography (TTE), or were chronic smokers, or were
acid has emerged recently as a promising therapy for pregnant or lactating. Those patients who were unable to
SSc [7]. Evidence supporting its use derives from small, perform spirometry or whose data were missing were not
uncontrolled, single-arm studies, suggesting that myco- included in the study.
phenolate is a safe therapeutic modality associated with The study was performed in accordance with the Dec-
functional stabilization of SSc-ILD [8–15]. laration of Helsinki and received approval from the insti-
No head to head data comparing the efficacy of CYC tutional ethics committee of Amrita institute of medical
and MMF are available to date. The objective of the science and research institute. Informed consent was not
study was to compare the efficacy of MMF and CYC in relevant as it was a retrospective study.
patients with SSc-ILD for improvement in lung function.
Lung function test
Methods Spirometry (MicroQuark-Cosmed PFT suit) was per-
Study design formed by a highly trained and experienced technician
A single-centre, retrospective study in all the patients so as to minimize interobserver variabil-
ity to achieve a high degree of reproducibility (interclass
Patients and treatment regimes At our centre MMF correlation coefficient of 0.96). The results were expressed
and CYC were used, in a protocol-based manner, for the as percentage of predicted for each patient. Depending on
treatment of SSc-ILD. MMF was initiated with 500 mg the FVC values, the severity of ILD was classified as mild
once a day and was increased to maximum tolerable (70–80 %), moderate (50–69 %) and severe (<50 % pre-
dose or to a maximum dose of 3 g daily. Patients were dicted values) according to Medsger’s severity scale [16]. In
advised to take MMF 30 minutes before food or 2 h after order to evaluate the response to treatment by means of
food. The starting dose of CYC was 600 mg/m2 given as spirometry values, the recommendations of the American
an intravenous (IV) infusion. Six monthly pulses of CYC Thoracic Society (ATS) [17] were followed. According
were given and the dose was increased to 1.2 g as toler- to these recommendations, improvement is defined by
ated. Adequate hydration was maintained. Selection of an increase in FVC ≥10 %, stabilization by change in
the drug for induction therapy was based on the patient’s FVC <10 % and worsening by a reduction in FVC ≥10 %.
willingness to receive a particular drug after explaining Spirometry was carried out in all patients at baseline (be-
the side effects and treatment costs of each of the drugs in fore treatment was started) and repeated at 3 and 6 months.
detail to the patient. After detailed baseline evaluations Baseline and 6-month data were used for comparisons.
every patient underwent a monthly clinical examination.
Forced vital capacity (FVC) was assessed by spirometry at Statistical analysis
baseline, 3 and 6 months. Data were presented as mean ± standard deviation for
We carried out a retrospective analysis of clinical records numerical variables. Continuous variables were analysed
of the patients attending the rheumatology outpatient de- within groups using the paired t test, and the independent
partment (OPD), who had ILD and had undergone treat- two-sample t test or the Mann–Whitney test (non-parametric
ment with intravenous pulses of CYC or MMF in the last data) was used to compare variables in the two groups.
3 years. Patients were included for analysis if they were The chi square test was used to test the associations be-
over 18 years of age, fulfilled the American College of tween categorical variables. Differences were considered
Rheumatology (ACR) 2013 classification criteria for SSc significant at P ≤ 0.05. Data were analysed using IBM SPSS
with significant ILD as defined by FVC ≤80, and had evi- Version 20 software.
dence of ILD on thoracic HRCT. Patients were excluded if
they had end-stage lung disease and FVC <20 % and were Results
oxygen dependent, clinically significant abnormalities on As summarized in Table 1, both groups were comparable
HRCT that were not attributable to SSc, clinically signifi- in terms of demographic data and other baseline vari-
cant cytopoenia (Hb <10 g %, leucocyte count <4000 per ables. There were 23 patients with SSC-ILD (18 female
cubic millimeter, platelet count <1,50000 per cubic milli- and 5 male) in the CYC group and 34 patients (31 female
meter), altered liver function on tests (liver enzymes >2 and 3 male) in the MMF group. The mean age was
times normal and/or bilirubin >1.5 times the upper limit of around 46 years in both groups. The mean disease dur-
normal) or altered renal function (unexplained haematuria ation, defined as the time from initiation of the first
Shenoy et al. Arthritis Research & Therapy (2016) 18:123 Page 3 of 6

Table 1 Demographic and baseline clinical characteristics of patients in the cyclophosphamide (CYC) and mycophenolate mofetil
(MMF) groups
Characteristics CYC (n = 23) MMF (n = 34) P value for significance
Age, mean ± SD 46 ± 10.34 45.24 ± 13.87 0.82
Female, n (%) 18 (78.2) 31 (91.18) 0.24
Disease duration in years, mean ± SD 6.04 ± 5.96 4.19 ± 2.82 0.11
Clinical features, n (%)
Breathlessness 21 (91.3) 30 (88.2) 0.53
Arthritis 23 (100) 28 (82.4) 0.07
Skin changes 21 (91.3) 30 (88.2) 0.53
Raynaud’s symptoms 17 (74) 18 (52.9) 0.16
Baseline FVC %, mean ± SD 48.74 ± 15.67 53.44 ± 13.69 0.23
Pulmonary artery hypertension, n (%) 2 (2.7) 4 (11.8) 0.63
Anti-scl-70-positive, n (%) 12 (52.17) 16 (47.18) 0.41
FVC forced vital capacity

non- Raynaud’s symptom, was around 5 years. During the (P = 0.003) in the CYC group. The mean percentage in-
study period 17 patients in the CYC and 30 patients in the crease in FVC at 6 months compared to baseline was
MMF group were on low-dose steroids (≤5 mg/day). The 10.84 ± 13.81 % in the CYC group and 6.07 ± 11.92 % in
average cumulative dose of CYC was 7.2 g and the average the MMF group. Both improvements were statistically
maximum dose of MMF was 2.62 g/day. significant when compared to baseline. Hence, as per
Both the groups had similar lung function at baseline the ATS recommendation, the CYC group had an im-
as evidenced by a baseline FVC of 48.74 ± 15.67 % in the provement, as the percentage increase in FVC was >10 %,
CYC group and 53.44 ± 13.69 % in the MMF group. but FVC was only stabilized in the MMF group (FVC
PAH was detected in two patients in the CYC group and change <10 %). When the change in FVC at 6 months was
four patients in the MMF group. compared in the two groups, there was no significant dif-
As shown in Fig. 1, the mean FVC increased to 55.99 ± ference (P = 0.232). As shown in Fig. 2, when numerical
13.47 % from the baseline value of 53.44 ± 13.69 % in the values were considered, 68.57 %, 28.57 % and 2.85 % of
MMF group (P = 0.003). Similarly, mean FVC improved to patients in the CYC group had increased, decreased and
53.09 ± 14.93 % from the baseline value of 48.74 ± 15.67 % unchanged percentage FVC, respectively, and 78.26 %,

Fig. 1 Mean change in percentage forced vital capacity (FVC) at baseline and 6 months in the mycophenolate mofetil (MMF) and cyclophosphamide
(CYC) groups
Shenoy et al. Arthritis Research & Therapy (2016) 18:123 Page 4 of 6

Fig. 2 Change from baseline in percentage forced vital capacity (FVC%) at 6 months in the mycophenolate mofetil (MMF) and cyclophosphamide
(CYC) groups: 68.57 %, 28.57 % and 2.85 % of patients in the CYC group had increased, decreased and unchanged FVC% respectively, and 78.26 %,
17.39 % and 4.35 % of patients in the MMF group had increased, decreased and unchanged FVC% after 6 months of treatment

17.39 % and 4.35 % of patients in the MMF group had in- To date, all the available information on the use of
creased, decreased and unchanged percentage FVC after mycophenolate in the treatment of SSc-related ILD
6 months of treatment. comes from small-scale, single-arm and open-label stud-
Both drugs were generally well tolerated in all patients ies. A recent meta-analysis, which includes six studies and
except for nine patients in the CYC group and four pa- a total of 69 patients, the majority of whom had diffuse
tients in the MMF group who developed lower respira- cutaneous SSc-related ILD, confirmed the acceptable
tory tract infection; this was treated with a short course safety and tolerability profile of mycophenolate. In the
of antibiotics. No exacerbation of ILD, hospital admissions, primary analysis, four out of six studies reported statistically
or fatalities occurred in either group during treatment. significant functional improvement following 12-month
oral administration of MMF or MS, and the remaining
Discussion two studies reported stabilization of disease; however, a
The results of this retrospective analysis demonstrate pooled analysis did not corroborate this finding. In par-
that both CYC and MMF were equally effective in pre- ticular, in the overall analysis of 69 patients, MMF or
serving lung function in patients with SSc-ILD. Pre- MS treatment was not associated with a statistically sig-
vention of disease progression is considered the most nificant beneficial functional effect as assessed by both
important aim in SSc-ILD [18]. FVC and the diffusing capacity of the lungs for carbon
In a landmark study, The Scleroderma Lung Study Re- monoxide (DLCO) [20]. A more recent, study by Fischer
search Group noted that oral CYC achieved a modest et al. [9], including 125 patients with connective tissue
but significant beneficial effect on lung function and pa- disease-associated ILD (of whom 44 patients had SSc-
tients’ quality of life, but unfortunately, it also provoked ILD) treated with mycophenolate for a median of
a serious adverse event in six patients [6]. After the first 897 days, showed stabilization or improvement of lung
year these patients were observed without any immuno- function.
suppression and by 2 years the improvement in lung The results of the current study show both MMF and
function that had been observed in the CYC arm was CYC were not only able to stabilize lung function but
lost [19]. The modest and transitory benefit of CYC in also there was a numerical increase in FVC in the major-
patients with SSc-ILD and the substantial toxicity of the ity of patients. In view of the expected annual decline in
drug compels us to search for safer alternatives, espe- lung function over time among patients with SSc-ILD
cially for younger patients with mild disease, who would [21], it is reasonable to state that a marginal increase in
benefit from longitudinal administration of therapeutic FVC or even a stabilization of functional status through
modalities with minimal side effects, and to reserve more the disease course is a great achievement, especially
aggressive and potentially more beneficial cytotoxic when the therapeutic agent used presents with an excel-
regimens for later stages of the disease course. lent safety profile tested longitudinally.
Shenoy et al. Arthritis Research & Therapy (2016) 18:123 Page 5 of 6

Besides this, it is important to note that in our study Shah medical college Surendranagar) for his valuable comments in the
the enrolled patients had a mean disease duration of statistical analysis of the study.

around 5 years with moderate to severe ILD prior to ad- Author details
ministration of CYC or MMF. It can be argued that 1
Centre For Arthritis & Rheumatism Excellence (CARE), NH-47, Nettoor, Kochi,
stabilization can happen in a group of patients with SSc Kerala 682040, India. 2Department of Rheumatology, Amrita Institute of
Medical Sciences, Ponekkara, Kochi, Kerala, India. 3Department of Medicine,
and the results of the study merely reflect the natural Amrita Institute of Medical Sciences, Ponekkara, Kochi, Kerala, India.
course of disease. But to prove this point we need a pla-
cebo arm, which appears to be unethical in a deadly Received: 5 January 2016 Accepted: 9 May 2016

disease like SSc-ILD. Moreover, improvement in lung

function is not part of the natural course of the disease
References
and the patients with FVC <70 % are more likely to de- 1. Taylor J, Bolster M. Bronchiolitis obliterans with organizing pneumonia
teriorate than others. Scleroderma lung study 2 (SLS2), associated with scleroderma and scleroderma spectrum diseases. J Clin
the results of which are currently available in abstract Rheumatol. 2003;9(4):239–45.
2. D’Angelo W, Fries J, Masi A, Shulman L. Pathologic observations in systemic
form, compared oral cyclophosphamide with MMF. sclerosis (scleroderma). Am J Med. 1969;46(3):428–40.
The results showed that the improvement in FVC is 3. Todd N, Lavania S, Park M, Iacono A, Franks T, Galvin J, et al. Variable
comparable in both the arms at the end of 2 years. prevalence of pulmonary hypertension in patients with advanced interstitial
pneumonia. J Heart Lung Transplant. 2010;29(2):188–94.
These results are in concurrence with ours, although in 4. Ferri C, Valentini G, Cozzi F, Sebastini M, Michelassi C, La Montagna G, et al.
SLS 2 oral CYC was used instead of IV CYC. Systemic sclerosis. Medicine. 2002;81(2):139–53.
Our study is limited by the lack of a control arm for 5. Simeon-Aznar C, Fonollosa-Plá V, Tolosa-Vilella C, Selva-O’ Callaghan A,
Solans-Laqué R, Palliza E, et al. Intravenous cyclophosphamide pulse therapy
those who were not treated, randomization and long fol- in the treatment of systemic sclerosis-related interstitial lung disease: a long
low up. The 6-minute walking test was not used as an term study. TORMJ. 2008;2(1):39–45.
outcome measure as it has been proven that features like 6. Tashkin D, Elashoff R, Clements P, Goldin J, Roth M, Furst D, et al.
Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J
pain and musculoskeletal involvement can influence the Med. 2006;354(25):2655–66.
result [22], and HRCT could not be performed in all pa- 7. Nihtyanova S, Brough G, Black C, Denton C. Mycophenolate mofetil in
tients at 6 months due to financial constraints. As the diffuse cutaneous systemic sclerosis–a retrospective analysis. Rheumatology.
2007;46(3):442–5.
reproducibility of FVC is better than that of DLCO and 8. Tzouvelekis A, Galanopoulos N, Bouros E, Kolios G, Zacharis G, Ntolios P, et al.
DLCO is less specific than FVC for lung function, Effect and safety of mycophenolate mofetil or sodium in systemic sclerosis-
DLCO was not chosen as an outcome measure. associated interstitial lung disease: a meta-analysis. Pulm Med. 2012;2012:
143637. doi:10.1155/2012/143637.
9. Fischer A, Brown K, Du Bois R, Frankel S, Cosgrove G, Fernandez-Perez E,
Conclusion et al. Mycophenolate mofetil improves lung function in connective tissue
We support the use of immunosuppressants in patients disease-associated interstitial lung disease. J Rheumatol. 2013;40(5):640–6.
10. Gerbino A, Goss C, Molitor JA. Effect of mycophenolate mofetil on pulmonary
with scleroderma ILD. Although MMF and CYC may be function in scleroderma-associated interstitial lung disease. Chest.
equally effective, MMF may be preferred due to the 2008;133(2):455–60.
long-term toxicity of CYC. Larger randomized controlled 11. Koutroumpas A, Ziogas A, Alexiou I, Barouta G, Sakkas L. Mycophenolate
mofetil in systemic sclerosis-associated interstitial lung disease. Clin Rheumatol.
studies are sorely needed to support this premise. 2010;29(10):1167–8.
12. Liossis S, Bounas A, Andonopoulos A. Mycophenolate mofetil as first-line
Abbreviations treatment improves clinically evident early scleroderma lung disease.
ACR: American college of rheumatology; ATS: American Thoracic Society; Rheumatology. 2006;45(8):1005–8.
CYC: cyclophosphamide; DLCO: diffusing capacity of the lungs for carbon 13. Swigris J, Olson A, Fischer A, Lynch D, Cosgrove G, Frankel S, et al.
monoxide; FVC: forced vital capacity; HRCT: high-resolution computed Mycophenolate mofetil is safe, well tolerated, and preserves lung function
tomography; ILD: interstitial lung disease; IV: intravenous; in patients with connective tissue disease-related interstitial lung disease.
MMF: mycophenolate mofetil; MS: mycophenolate sodium; PAH: pulmonary Chest. 2006;130(1):30–6.
arterial hypertension; RVSP: right ventricle systolic pressure; 14. Zamora A, Wolters P, Collard H, Connolly M, Elicker B, Webb W, et al. Use of
SLS2: Scleroderma lung study 2; SSc: scleroderma; SSc-ILD: scleroderma mycophenolate mofetil to treat scleroderma-associated interstitial lung
interstitial lung disease; TTE: transthoracic echocardiography. disease. Respir Med. 2008;102(1):150–5.
15. Vanthuyne M, Blockmans D, Westhovens R, Roufosse F, Cogan E, Coche E,
Competing interests et al. A pilot study of mycophenolate mofetil combined to intravenous
The authors declare that they have no competing interests. methylprednisolone pulses and oral low-dose glucocorticoids in severe
early systemic sclerosis. Clin Exp Rheumatol. 2007;25(2):287–92.
Authors’ contributions 16. Medsger TA, Bombardieri S, Czirjak L, Scorza R, Della Rossa A, Bencivelli W,
PDS designed the study and gave his valuable comments while drafting et al. Assessment of severity and prognosis in SSc. Clin Exp Rheumatol.
this article. MB, KN, SSu and SSr collected the data and drafted the article. 2003;21:S42–6.
All authors approved the final version to be submitted for publication. 17. Collard H, Loyd J, King T, Lancaster L. Current diagnosis and management
of idiopathic pulmonary fibrosis: a survey of academic physicians. Respir Med.
Acknowledgements 2007;101(9):2011–6.
The authors are thankful to Ms Prasanna (PFT-spirometry technician) 18. Antoniou K, Wells A. Scleroderma lung disease: evolving understanding in
Pulmonology department and Mr Unnikrishnan (Statistician), Amrita light of newer studies. Curr Opin Rheumatol. 2008;20(6):686–91.
institute of medical science, Kochi, for their valuable contribution in 19. Tashkin D, Elashoff R, Clements P, Roth M, Furst D, Silver R, et al. Effects of
performing spirometry and data calculation, respectively. The authors are 1-year treatment with cyclophosphamide on outcomes at 2 years in
also thankful to Dr Nishant Bhimani (Resident-community medicine, C.U. scleroderma lung disease. Am J Respir Crit Care Med. 2007;176(10):1026–34.
Shenoy et al. Arthritis Research & Therapy (2016) 18:123 Page 6 of 6

20. Tzouvelekis A, Galanopoulos N, Bouros E, Kolios G, Zacharis G, Ntolios P,

et al. Effect and safety of mycophenolate mofetil or sodium in systemic
sclerosis-associated interstitial lung disease: a meta-analysis. Pulm Med.
2012;2012:1–7.
21. Steen V. Predictors of end stage lung disease in systemic sclerosis. Ann
Rheum Dis. 2003;62(2):97–9.
22. Khanna D, Seibold J, Wells A, Distler O, Allanore Y, Denton C, et al. Systemic
sclerosis-associated interstitial lung disease: lessons from clinical trials,
outcome measures, and future study design. CRR. 2010;6(2):138–44.

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