Abstract
Introduction:
There is a paucity of real-world data on mycophenolate mofetil/mycophenolate sodium in systemic sclerosis-related interstitial lung disease.
Aim:
To study the efficacy of mycophenolate mofetil/ mycophenolate sodium in systemic sclerosis-related interstitial lung disease.
Methods:
In this single-centre study, clinical, laboratory and imaging details of consecutive patients with systemic sclerosis-related interstitial lung disease receiving mycophenolate mofetil/mycophenolate sodium from rheumatology and pulmonology clinics between January 2008 and March 2017 were retrospectively retrieved. The change in percentage of predicted normal forced vital capacity at last follow-up visit as compared with baseline was studied. In addition, high-resolution computed tomography scans at baseline and 2-year follow-up visit were scored as either stable/improved or worsened by experienced thoracic radiologists blinded to the clinical details of patients.
Results:
Altogether, 88 patients (85.2% females) with mean age (SD) of 33.8 years (± 11.3) and median (interquartile range) duration of disease since non-Raynaud’s symptoms of 36 months (13.5–60) were studied. Diffuse systemic sclerosis comprised 85.2% of them. The mean baseline forced vital capacity was 61.2 ± 17.9% and median scores for ground glass opacities and fibrosis in high-resolution computed tomography were 0.5 (0–1.3) and 1 (0–1.3), respectively. At a median follow-up duration of 30 months (interquartile range = 16.5–49), the percentage of forced vital capacity improved by 1.8% (–3.82 to 9.07) as compared with baseline visit (p = 0.02). In the 2-year follow-up, the ground glass opacity and fibrosis scores in high-resolution computed tomography improved in 17.3% and 7.7% of patients and stabilized in 63.5% and 78.8% patients, respectively.
Conclusion:
Mycophenolate mofetil/mycophenolate sodium was efficacious in improving /stabilizing forced vital capacity irrespective of the baseline high-resolution computed tomography lung scores in our patients with systemic sclerosis-related interstitial lung disease during the ⩾ 2-year follow-up period.
Keywords: Scleroderma-ILD, mycophenolate, outcomes
Introduction
Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microvasculopathy, fibrosis and autoimmunity, involving skin, lungs, gastrointestinal tract and other systems. The reported prevalence of interstitial lung disease (ILD) varies from 50% to 70% depending on the population studied and the definition of ILD used.1–3 ILD is responsible for 33%–35% of SSc-related death.4,5
Among the immunosuppressants used for SSc-related ILD (SSc-ILD), mycophenolate mofetil (MMF)/mycophenolate sodium (MMS) has a better safety profile than cyclophosphamide (CYC). Its efficacy was established in scleroderma lung study-II (SLS-II) and other small series.6–8 The aim of the present study was to assess the efficacy and safety of MMF/MMS in management of SSc-ILD in a real-world setting.
Methods
Prospectively documented electronic medical records of consecutive patients aged > 18 years with symptomatic SSc-ILD fulfilling American College of Rheumatology (ACR) 1980 classification criteria for scleroderma, were retrospectively retrieved. 9 Patients with SSc-ILD on MMF/MMS from the out patient and inpatient services of clinical immunology and rheumatology department in our tertiary care teaching hospital in southern India, between January 2013 and March 2017 comprised the study cohort. By unit policy, we screen all newly diagnosed scleroderma patients by spirometry and high-resolution computed tomography (HRCT) thorax at baseline. Six monthly spirometry and HRCT after 2 years are done for SSc-ILD cases. Gas exchange studies are variably done, hence these values were not available for all patients.
Convenience sampling was used to select patients for this study.
Inclusion criteria
(1) Confirmation of the diagnosis of ILD by HRCT, (2) patients who had undergone lung function tests, including forced vital capacity (FVC) at their baseline and follow-up visits and (3) patients who were initiated in our centre on MMF at a dose of 2 g/day (or equivalent dose of MMS), the dose tapered only after 2 years and maintained at 1 g/day of MMF or equivalent dose of MMS. Initiation of MMF/MMS was by clinician’s discretion. All patients included were immunosuppression naive for preceding 2 years before enrolment, nor were they treated with any other steroid sparing immunosuppressant during the study period.
Exclusion criteria
Patients receiving other immunosuppressants within 2 years prior to our initiation of MMF/MMS.
FVC. Retrieved data included those related to lung function tests, including FVC using standard protocols. 10 Absolute change in FVC in percentage of predicted normal value (FVC%) compared with baseline was documented and represented as median (interquartile range) according to the American Thoracic Society (ATS) recommendations.10,11 According to these recommendations, improvement was defined by an increase in FVC ⩾ 10%, stabilization by change in FVC < 10%, and worsening by a reduction in FVC ⩾ 10%.
HRCT. Two millimetre-sliced HRCT scans of thorax at baseline and follow-up were interpreted by two independent dedicated thoracic radiologists with expertise in chest imaging. The scans were scored using the scheme suggested by Kazarooni et al. 12 Briefly, the extent of ground glass opacity (GGO), fibrosis and honey combing of three zones of lung parenchyma on either side were scored from 0 to 4 using Likert-type scale. The involvement of none, 1%–25%, 26%–50%, 51%–75% and 76%–100% of lung were scored as 0, 1, 2, 3 and 4 respectively. The inter-rater reliability was determined.
Study definitions and outcome
The patients were sub-classified as having diffuse, limited or sine scleroderma on the basis of criteria proposed by Le Roy et al. 9 Limited ILD was defined as FVC ⩾ 70% and/or fibrosis in < 25% of lung with a score of ⩽ 1 in HRCT, while extensive disease was defined as FVC values < 70% and/or disease extent of > 25% in imaging. 13
The change in HRCT scoring from baseline in terms of each of the variables (GGO, fibrosis and honey combing) was dichotomously scored as either stable/improved or worsened. 14
Primary outcome. The absolute change in FVC as a percentage of predicted normal value (FVC%) at last follow-up visit as compared with baseline.
Secondary outcome. Changes in modified Rodnan skin score (mRSS), New York Heart Association (NYHA) dyspnoea and radiological scores as described above were the secondary outcome measures.
A change of ± 4 in mRSS was considered as a meaningful change; any change less than that was considered as stable score. 15
Change in NYHA dyspnoea score of 1+ was considered as meaningful.
Statistical analysis
The descriptive data are reported as mean (± SD) or median (interquartile range (IQR)). Paired T-test was used to compare FVC change at various time points from baseline. Wilcoxon signed rank test was used to compare HRCT scores at various time points. For all comparisons, p-value < 5% was considered as significant. For data with non-normal distribution and significant outliers, Huber covariance analysis was used to assess treatment effects, which was adjusted for baseline values of FVC. Logistic regression analysis was performed to assess independent association between baseline variables and change in FVC. All analyses were performed using STATA version 14.2.
The study conformed to the rules laid by declaration of Helsinki, 2013 and was approved by the Institutional Review Board and Ethics Committee of Christian Medical College, Vellore (IRB min no 13415). 16 Patients’ consent was not feasible as the study design comprised of retrospective chart review.
Results
We studied 88 patients (75 females) with symptomatic SSc-ILD. The mean age of the patients was 33.8 years (±11.3; Table 1). The median disease duration was 36 (13.5–60) months. Of these, 75 (85.2%) were of diffuse SSc variety, five (5.7%) were having limited SSc and six (6.8%) were cases with sine scleroderma. Mean FVC was 61.2% (± 17.9). Majority of the patients (86.4%) had nonspecific interstitial pattern (NSIP) in HRCT. Clinically significant pulmonary arterial hypertension (PAH) at baseline was seen in three patients.
Table 1.
Baseline characteristics.
| Clinical and laboratory features | Value (n = 88) | Outcome features and treatment characteristics | Value (n = 88) |
|---|---|---|---|
| Mean age in year (± SD) | 33.8 (± 11.3) | Mean FVC% predicted (± SD) | 61.2 (± 17.9) |
| Number of female patients (%) | 75 (85.2%) | Mean mRSS (± SD); n = 52 | 20.4 (± 13.2) |
| Median disease duration in months (IQR) | 36 (13.5–60) | Number of patients as per MMF* dose at last follow-up | |
| Median duration of follow-up in months (IQR) | 30 (16.5–49) | 2 g/day | 66 (75%) |
| 1 g/day | 15 (17.1%) | ||
| Off MMF/MMS | 7 (7.9%) | ||
| Number of patients as per type of SSc (%) | HRCT determined disease extent ((median (IQR)) at baseline | ||
| Limited | 5 (5.7%) | Median fibrosis score | 0.5 (0–1.3) |
| Diffuse | 75 (85.2%) | Median GGO | 1 (0–1.3) |
| Sine scleroderma | 6 (6.8%) | Maximum fibrosis score | 1 (0–2) |
| Data not available | 2 (2.3%) | ||
| Number of patients with antibody positivity (%) | Maximum fibrosis score at baseline; n = 87 | ||
| ANA | 80 (90.9%) | No fibrosis (score 0) | 29 (33.3%) |
| Scl-70 | 70 (79.5%) | 1%–25% (score 1) | 18 (20.7%) |
| Anti-centromere | 1 (1.1%) | 26%–50% (score 2) | 24 (27.6%) |
| Negative | 14 (15.9%) | 51%–75% (score 3) | 14 (16.1%) |
| 76%–100% (score 4) | 2 (2.3%) | ||
FVC: forced vital capacity; mRSS: modified Rodnan skin scoring; MMF: mycophenolate mofetil (* or equivalent dose of MMS); HRCT: high-resolution computed tomography; IQR: interquartile range; GGO: ground glass opacity.
Median (IQR) duration of follow-up was 30 months (16.5–49); 22 were lost to follow-up during this duration. MMF dose at last follow-up was as follows: full dose (at least 2 g/day) in 66 patients, tapered and maintained at 1 g/day in 15 patients, and tapered and stopped in seven patients.
Of the 88 patients, 66 patients had a 1-year follow-up, 46 patients had a 2-year follow-up and 29 patients had a 3-year follow-up data. The absolute median (IQR) increase in the FVC% value at the end of 1, 2 and 3 years was 4.15% (–2.4 to 10.6), 2.85% (–3.5 to 7.9) and 3.8% (–0.6 to 10.4), respectively and were significant as compared with baseline (Table 2). At a median follow-up duration of 30 months (IQR = 16.5–49), the FVC% improved by 1.8% (–3.82 to 9.07) as compared with baseline visit (p = 0.02).
Table 2.
FVC% change following treatment with MMF/MMS.
| Follow-up duration | Number of patients | Median (IQR) FVC change (as compared with baseline) | p- value | Improved FVC [≥10% FVC% change]N (%) |
Stable FVC [<10% FVC % change]N (%) |
|---|---|---|---|---|---|
| 1 year | 66 | 4.15 (–2.4 to 10.6) | .00006 | 19 (28.8) | 45 (68.2) |
| 2 years | 46 | 2.85 (–3.5 to 7.9) | .02 | 10 (21.7) | 31 (67.4) |
| 3 years | 29 | 3.8 (–0.6 to 10.4) | .007 | 10 (34.5) | 17 (58.6) |
| Last follow-up | 88 | 1.8 (–3.82 to 9.07) | .02 | 21 (23.9) | 53 (60.2) |
MMF/MMS: mycophenolate mofetil/mycophenolate sodium; FVC: forced vital capacity; IQR: interquartile range.
At the end of 1-, 2- and 3-year follow-ups, stable or improved relative FVC was noted in 89.4% (68.2% had stable and 28.8% had improvement), 82.6% (65.2% had stable and 23.9% had improvement) and 75.9% (58.6% had stable and 34.5% had improved) of patients, respectively, as compared with baseline (Table 2, Figure 1).
Figure 1.
Absolute change in FVC% at 2 years.
Nearly, half (46%) of the patients had more than 25% of the fields with fibrotic involvement. Of the 52 individuals with a baseline as well as repeat HRCT data, stable and/or improved scores in GGO, fibrosis and honey combing were seen in 80.8% (17.3% improved and 63.5% stabilized), 86.5% (7.7% improved and 78.8% stabilized) and 86.5% (3.8% improved and 82.7% stabilized) of the cases, respectively; the corresponding figures for worsening were 17.3%, 13.5% and 13.5%, respectively (Table 3).
Table 3.
Change in radiological scores following treatment with MMF/MMS.
| Radiological feature n = 52 | Baseline score median (IQR) | Follow-up score median(IQR) | p-value | Improved N (%) | Stable N (%) |
|---|---|---|---|---|---|
| GGO | 0.58 (0–1.33) | 0.33 (0–1.28) | NS | 9 (17.3) | 33 (63.5) |
| Fibrosis | 1 (0–1.5) | 1 (0–1.66) | NS | 4 (7.7) | 41 (78.8) |
| Honey combing | 0 (0–0.12) | 0 (0–0.33) | NS | 2 (3.8) | 43 (82.7) |
GGO: ground glass opacity; MMF/MMS: mycophenolate mofetil/mycophenolate sodium; NS: not significant.
Of the full cohort, 35 had a baseline as well as a follow-up mRSS recorded at least 6 months apart. Among them, 23 (65.7%) had a clinically meaningful improvement as defined in methods, seven (20%) had stable and five (14.3%) had worsening over time in mRSS. Mean change in mRSS from baseline was –7.7 (± 10.1).
Of the 32 patients who had documented NYHA dyspnoea scores at baseline and last follow-up visits, 30 (93.7%) had stable or improved scores and 2 (6.3%) had worsened scores.
None of the baseline parameters like age of the patient, disease duration, FVC and extent of fibrosis on HRCT study had any association with treatment outcome (Table 4).
Table 4.
Association of baseline variables with FVC% change at 2 years.
| Variable | FVC% change at 2 year | p-value |
|---|---|---|
| Baseline FVC% < 70% vs > = 70% | 2.9 (± 10.1) vs 4.7 (± 11.5) | 0.306 |
| Baseline extensive vs limited GGO | 5.45 (–6.6 to 17) vs 4.02 (–9.3–16) | 0.49 |
| Baseline extensive vs limited fibrosis | 4.02 (–8.7 to 25) vs 6.07 (–11.7–25) | 0.84 |
| Baseline extensive vs limited honey combing | –0.06 (–7.4 to 6.1) vs 4.7 (–9.3–25) | 0.54 |
| Disease duration at initiation of MMF < 4 vs > 4 years | 2.6 (± 9.9) vs 4.7 (± 11) | 0.25 |
| Age of the patient < 40 vs > 40 years | 2.18 (± 9.9) vs 6.28 (± 14.7) | 0.17 |
FVC: forced vital capacity; GGO: ground glass opacity; MMF: mycophenolate mofetil.
In 46 patients who were followed for more than 2 years, MMF was tapered in 20 individuals. Of them, disease worsened after tapering in six patients and remained stable in 14 individuals.
Except for a single patient in whom MMF was discontinued after 6 years because of development of invasive aspergillosis, there was no other major limiting toxicity.
Discussion
Our cohort represents the largest single-centre SSc-ILD series on MMF, while the largest data so far in published literature come from SLS-II study. 6
Our study demonstrates stabilization and/or improvement in FVC scores as well as radiological scores in the majority of patients with SSc-ILD on MMF/MMS.
Our cohort predominantly consists of early scleroderma (median disease duration is 36 months (13.5–60)) with a spectrum of severity of ILD comparable with clinic population elsewhere; hence it has wide applicability.
More than 80% of patients in our cohort have shown stabilization and/or improvement in FVC at 1, 2 and 3-year follow-ups. Minimal clinically important difference (MCID) estimates for absolute FVC improvement over 1-year period reported in literature range from 3.0% to 5.3% and for worsening, it ranges between –3.0% and –3.3%. 17 We have an absolute median (IQR) increase in the FVC% value at the end of 1, 2 and 3 years of 4.15 (–2.3 to 10.5), 2.85 (–3.4 to 7.2) and 3.8 (–0.6 to 10.4), respectively, which closely matches the reported MCID for FVC% change in published literature.
Our figures of improvement in median FVC scores at 2 years [2.85 (–3.5 to 7.9)] is also comparable with that seen in SLS-II [2.19 (0.53–3.84)]. 6 In addition, a sustained median improvement in FVC% of 3.8% (–0.2% to 10.4%) was present in 93.1% of our patients with 3 years of follow-up.
Stabilization of radiological scoring during the follow-up period further substantiates the other results related to outcome in our study. We have also used surrogate outcome measures corroborating the beneficial effect of MMF/MMS in SSc-ILD, like improvement in NYHA functional class, stabilization in fibrosis and GGO scores on HRCT over 2-year period as well as improvement in mRSS during the follow-up in majority of our patients.
In our study, the beneficial response to MMF/MMS at ⩾ 2 years was not differential for patients with baseline limited versus extensive fibrosis. In SLS-I trial also, immunosuppression resulted in stabilization of FVC% at 12 months across all patients irrespective of baseline scores (0–4) of fibrosis; in fact, extensive lung fibrosis (fibrosis score ⩾ 2) has been one of the three baseline characteristics predictive of a superior response to CYC in SLS-I.18,19 In contrast, placebo arm showed statistically significant progression of disease in those with higher baseline fibrosis score. Therefore, both improvements in FVC with immunosuppression and progression of fibrosis in absence of immunosuppression in SSc-ILD are directly proportional to degree of baseline fibrosis, as per SLS-I.
However, such an analysis was not done for MMF in SLS-II; hence our data fills in this lacunae in literature. 6
Considering the existing literature reporting annual progressive decline of FVC almost as a rule in SSc-ILD patients, stabilization and the modest improvement of FVC scores over a 3-year period in our study is clearly a positive outcome with meaningful clinical implications. 20 First, this may indirectly imply an improved long-term survival of patients with SSc-ILD on MMF/MMS, as earlier studies had reported a worse 10-year mortality in patients with extensive fibrosis and/or progressive disease at baseline.2,20 Second, initiation of MMF/MMS therapy in early disease is the key to improving/stabilizing ILD in SSc, rather than the extent of baseline lung fibrosis. Radiological extent of fibrosis may represent a spectrum of the same underlying pathology. In our cohort too, the majority of the patients with limited fibrosis by baseline HRCT had baseline FVC% of < 70%, and hence, they were already at a higher risk of progression. Immunological basis of radiological fibrosis may also be similar between radiologically limited and extensive subsets, as studies have shown significant, ongoing, underlying inflammatory activity even in presence of extensive radiological fibrosis; and this may be the biological basis of beneficial response to immunosuppression even in the presence of extensive radiological fibrosis, as discussed above.21,22 Radiological fibrosis, therefore, may not imply a totally burnt out biological fibrosis in SSc-ILD. Concurrent immunohistochemical studies with longitudinal follow-up may throw more light.
MMF with its better safety profile described in SLS-II is, therefore, preferred to CYC by many in SSc-ILD (6). In our cohort too, there was no limiting toxicity except one patient with invasive aspergillosis.
Limitations include retrospective design affecting comprehensive documentation of adverse events and compliance with intake of MMF/MMS, as well as possible sampling bias from convenient sampling.
Conclusion
MMF/MMS initiated early in SSc-ILD significantly stabilizes or improves FVC and numerically betters / stabilizes HRCT lung scores in > 80% of the patients over a ⩾ 2-year follow-up period, irrespective of baseline radiological extent of fibrosis, with good safety profile.
Acknowledgments
The authors sincerely thank Mr John Michael Raj, Assistant Professor, Department of Biostatistics, St John’s Medical College Hospital, Bengaluru, India, for his help in statistical analysis.
Footnotes
Data availability statement: Data supporting findings of this study are available on request from the first author (R.J.) and the corresponding author (D.D.).
Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship and/or publication of this article.
ORCID iD: Debashish Danda 
https://orcid.org/0000-0002-2121-0942
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