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Annals of the American Thoracic Society logoLink to Annals of the American Thoracic Society
. 2024 Jan 1;21(1):136–150. doi: 10.1513/AnnalsATS.202301-054OC

Mycophenolate in Patients with Systemic Sclerosis–associated Interstitial Lung Disease: A Systematic Review and Meta-Analysis

Derrick Herman 1, Marya Ghazipura 2,3,4,✉, Hayley Barnes 6,7,8, Madalina Macrea 9,10, Shandra L Knight 11, Richard M Silver 12, Sydney B Montesi 13, Ganesh Raghu 14,15, Tanzib Hossain 5
PMCID: PMC12056972  PMID: 37027538

Abstract

Rationale

The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis–associated interstitial lung disease (SSc-ILD).

Objective

To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with mycophenolate.

Methods

A literature search was conducted across the MEDLINE, EMBASE, and CENTRAL databases through June 2022 for studies using mycophenolate to treat patients with SSc-ILD. Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group method was used to assess the quality of evidence.

Results

The literature review resulted in seven studies fitting the inclusion criteria. The systematic review and meta-analyses revealed changes in forced vital capacity % predicted (mean difference [MD], 5.4%; 95% confidence interval [95% CI]: 3.3%, 7.5%), diffusing capacity of the lung for carbon monoxide % predicted (MD, 4.64%; 95% CI: 0.54%, 8.74%), and breathlessness score (MD, 1.99; 95% CI: 0.36, 3.62) favored mycophenolate over placebo. The risk of anemia (relative risk [RR], 2.3; 95% CI: 1.2, 71.4) was higher with mycophenolate. There were no significant differences between mycophenolate and cyclophosphamide, except risk of premature discontinuation (RR, 0.6; 95% CI: 0.4, 0.9), and leukopenia (RR, 0.1; 95% CI: 0.05, 0.4) favored mycophenolate. The quality of evidence was moderate to very low per GRADE.

Conclusions

Mycophenolate use in patients with SSc-ILD is associated with statistically significant improvements in disease progression and quality-of-life measures compared with placebo. There were no differences in mortality, disease progression, or quality of life compared with cyclophosphamide, but there were fewer adverse events. The quality of evidence is very low.

Keywords: mycophenolate, ILD, SSc, SSc-ILD, systematic review

Interstitial lung disease (ILD) is highly prevalent in patients with systemic sclerosis (SSc), occurring in up to 80% of all patients (1, 2). Although the progression is highly variable, SSc-associated ILD (SSc-ILD) becomes clinically significant in up to 30% of patients and is the most common cause of death in patients with SSc (1, 3). SSc-ILD is also associated with significant morbidity and burden of symptoms (1). Although evidence-based reviews and consensus statements exist on the diagnosis and management of patients with SSc-ILD, no evidence-based clinical practice guidelines exist regarding SSc-ILD treatment. In response, the American Thoracic Society (ATS) convened a multidisciplinary committee of experts to publish a clinical practice guideline for the treatment of SSc-ILD (G. Raghu and colleagues, Am J Respir Crit Care Med [online ahead of print] 29 Sep 2023; DOI:10.1164/rccm.202306-1113ST). To inform the guideline, this systematic review examined the existing literature to determine the treatment effect, if any, that mycophenolate exhibits in patients with SSc-ILD. Mycophenolate, an inhibitor of inosine monophosphate dehydrogenase that impairs T and B cell proliferation, has been established as the standard of care for SSc-ILD on the basis of the Scleroderma Lung Study (SLS) II (4–6).

Methods

Research Question and Outcomes

This systematic review was conducted to provide evidence for the ATS 2023 clinical practice guidelines on SSc-ILD (G. Raghu and colleagues, Am J Respir Crit Care Med [online ahead of print] 29 Sep 2023; DOI:10.1164/rccm.202306-1113ST). It was registered with the PROSPERO database (registration number CRD42022330684) and conducted in accordance with the Cochrane Handbook for Systemic Reviews of Intervention (7). The overarching research question asked by the guideline committee was: “Should patients with SSc-ILD be treated with mycophenolate?”

For the purposes of the associated clinical practice guideline and this systematic review, SSc is strictly defined by the American Rheumatology Association 1980 criteria or the 2013 American College of Rheumatology criteria/European League Against Rheumatism criteria (8, 9). ILD is defined by radiological criteria, as noted in the guideline document (G. Raghu and colleagues, Am J Respir Crit Care Med [online ahead of print] 29 Sep 2023; DOI:10.1164/rccm.202306-1113ST). Patients with SSc-ILD are those meeting either set of criteria for SSc plus ILD, as defined in the guideline document (G. Raghu and colleagues, Am J Respir Crit Care Med [online ahead of print] 29 Sep 2023; DOI:10.1164/rccm.202306-1113ST).

Given the heterogeneity of the patient population with SSc-ILD and the recognition that not all patients with SSc-ILD have progressive disease, several subpopulations of patients with SSc-ILD were defined by disease status, resulting in the following, more specific, research subquestions: 1) “Should patients with SSc-ILD at initial diagnosis of SSc-ILD be treated with mycophenolate?” 2) “Should patients with stable SSc-ILD be treated with mycophenolate?” and 3) “Should patients with progressive SSc-ILD be treated with mycophenolate?” Derived from the 2022 clinical practice guideline for progressive pulmonary fibrosis, progressive SSc-ILD was defined as having at least two of the following three criteria occurring in patients with SSc-ILD over the prior year: 1) worsening dyspnea or cough, 2) physiological evidence of disease progressions (⩾5% absolute decline in forced vital capacity [FVC] or ⩾10% absolute decline in diffusing capacity of the lung for carbon monoxide [DlCO] adjusted for hemoglobin), or 3) radiological evidence of disease progression (radiological interpretation of increase in the extent of ILD features on computed tomography assessed visually) (10). Patients who did not meet criteria for progressive SSc-ILD (i.e., stable dyspnea or cough, stable lung function measurements, and stable radiological ILD) were deemed to have stable SSc-ILD (G. Raghu and colleagues, Am J Respir Crit Care Med [online ahead of print] 29 Sep 2023; DOI:10.1164/rccm.202306-1113ST).

The intervention of interest for this review was mycophenolate. The guideline committee identified potential heterogeneity in the intervention, as mycophenolate exists in different formulations; specifically, mycophenolate mofetil and mycophenolic acid. This led to two additional research questions regarding mycophenolate by formulation: 1) “Should patients with SSc-ILD be treated with mycophenolate mofetil?” and 2) “Should patients with SSc-ILD be treated with mycophenolic acid?”

The appropriate comparator to mycophenolate was selected to be either placebo or cyclophosphamide. Before the publication of the SLS I in 2006, there was no established or recognized standard of care (SOC) for patients with SSc-ILD. The SLS I, which compared cyclophosphamide with placebo in patients with SSc-ILD, established cyclophosphamide as the SOC (11). As a result, the acceptable and appropriate comparator groups for mycophenolate for this systematic review were either placebo or cyclophosphamide, the historical SOC.

Critical outcomes of interest included mortality and disease progression (determined by changes in FVC and DlCO on pulmonary function testing; radiological progression; or changes in the modified Rodnan Skin Score [mRSS], an indirect measure because of its use with SSc). Important outcomes included quality-of-life indices such as St. George’s Respiratory Questionnaire (SGRQ), Transition Dyspnea Index (TDI), Leicester Cough Questionnaire (LCQ), and adverse events (12).

Literature Search, Study Selection, and Data Extraction and Synthesis

The literature search was conducted with the assistance of a medical librarian across MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases, with a broad focus on the use of mycophenolate in patients with SSc-ILD through June 2022. Additionally, one study that met our search criteria and that was still in press was included for review (Figure 1). Two authors (D.H. and T.H.) independently screened all studies, from title to full text screens, with disagreements resolved by consensus. Studies that enrolled patients with SSc-ILD and provided treatment with mycophenolate were included. To document SSc-ILD at enrollment, studies were required to define SSc and ILD. Randomized controlled trials (RCTs) were prioritized, but all trials with an appropriate comparator, either placebo or cyclophosphamide, were included.

Figure 1.

Figure 1.

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Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.

Once studies were selected for inclusion, data were extracted by two authors (D.H. and T.H.) and verified for accuracy by additional authors. The data extracted included key study background characteristics (including year, location, study type, duration, and funding source), population characteristics (including diagnostic criteria for SSc-ILD, number of patients in intervention and control arms, and treatment details), and all relevant outcomes (Table 1). When possible, data from individual studies were pooled to create a meta-analysis, using the generic inverse variance method; RevMan 5 was used for all calculations. Individual effect estimates were pooled using random-effects models. Relative risk (RR) scores were obtained to report the results for binary outcomes, and mean differences (MDs) were obtained to report the results for continuous outcomes, accompanied with a 95% confidence interval (95% CI). Statistical heterogeneity was assessed using the I2 test, with I2 of 50% or higher indicating significant heterogeneity.

Table 1.

Characteristics of studies evaluating mycophenolate versus placebo or cyclophosphamide in systemic sclerosis–associated interstitial lung disease

Study Name or Author, Year (Reference Number); Type Study Details SSc-ILD Population Study Size Treatment Detail Study Outcomes Risk of Bias
Panopoulos et al., 2013 (22); case control Location: single center
Funding: NA
Duration: 2 yr		 Mixed population of SSc-ILD – included both patients at time of initial ILD diagnosis and progressive ILD, defined as >10% decline over prior 1 yr.
SSc-ILD defined as ILD confirmed by HRCT imaging.		 Total N = 20;
intervention: n = 10;
control n = 10		 Intervention: mean dose, 1.5 g/d, 22–72 mo; MMF, n = 7; MS, n = 3
Control: CYC, mean dose, 90 mg/d, 17–55 mo		 1) Difference in FVC % predicted at 12 mo;
2) difference in FVC % predicted at 24 mo;
3) difference in TLC % predicted at 12 mo;
4) difference in TLC % predicted at 24 mo;
5) difference in % predicted DlCO at 12 mo;
6) difference in % predicted DlCO at 24 mo;
7) difference in HRCT score Warrick et al. (24) at 12 mo;
8) difference in HRCT score Warrick et al. (24) at 24 mo;
9) difference in HRCT score Desai et al. (25) coarseness at 12 mo;
10) difference in HRCT score Desai et al. (25) coarseness at 24 mo;
11) difference in HRCT score Desai et al. (25) disease extent at 12 mo;
12) difference in HRCT score Desai et al. (25) disease extent at 24 mo;
13) difference in ILD exacerbations;
14) difference in hospital admissions;
15) difference in fatalities; and
16) difference in pneumonia		 Serious (nonrandomized, small study size)
Shenoy et al., 2016 (21); case control Location: single center
Funding: NA
Duration: 6 mo		 SSc-ILD defined by FVC ⩽80% and evidence of ILD on HRCT imaging Total N = 57;
intervention, n = 34;
control n = 23		 Intervention: MMF, oral, 500 mg–3 g/d
Control: CYC, i.v., 6 × 0.6–1.2 g/m2/mo		 1) Change in % predicted FVC;
2) death;
3) ILD exacerbations;
4) hospital admissions; and
5) pneumonia		 Serious (nonrandomized, small study size)
SLS II 2016; RCT Location: multicenter, United States
Funding: NHLBI-NIH
Duration: 2 yr		 SSc-ILD defined as FVC <80% but ⩾45% predicted value, exertional dyspnea Grade 2 or higher on the Magnitude of Task Component of the BDI, any GGO on HRCT imaging whether associated with reticulations or not; and the onset of their first non–Raynaud’s symptom of SSc within the previous 7 yr Total N = 126;
intervention, n = 63;
control, n = 63		 Intervention: 1.5 g 2×/d for 24 mo
Control: CYC, 2 mg/kg/d for 12 mo, followed by placebo for 12 mo		 Primary outcome: mean change from baseline to 24 mo in % predicted FVC.
Secondary outcomes: mean changes in the course from 3 to 24 mo of the % predicted DlCO, % predicted TLC, % predicted DL/VA, TDI, and modified Rodnan skin score. Mean change from baseline in QLF and QILD scores for whole lung and lobe most affected.
Additional outcomes: adverse events (leukopenia, neutropenia, anemia, thrombocytopenia, hematuria, pneumonia), SAEs; no. of patients and total no. of events), SAEs related to treatment, SAEs related to underlying disease, SAEs due to other causes. Overall premature discontinuation, premature discontinuation due to adverse event, premature discontinuation due to patient request, premature discontinuation due to noncompliance, premature discontinuation due to loss to follow-up, premature discontinuation due to death, premature discontinuation due to treatment failure. Death.		 Not serious
Volkmann et al., 2017 (23); post hoc of SLS I and SLS II SLS I
Location: multicenter, United States
Funding: NIH
Duration: 2 yr
SLS II
Location: multicenter, United States
Funding: NHLBI-NIH
Duration: 2 yr		 SLS I:
SSc-ILD defined as active alveolitis on BAL (neutrophilia ⩾3%, eosinophilia ⩾2%, or both) OR any GGO on HRCT imaging; onset of the first symptom of scleroderma other than Raynaud’s within the previous 7 yr; an FVC between 45% and 85%, and Grade 2 exertional dyspnea according to the baseline instrument of the MDI
SLS II:
SSc-ILD defined as FVC <80% but ⩾45% predicted value, exertional dyspnea ⩾Grade 2 on the Magnitude of Task Component of the BDI, any GGO on HRCT imaging whether associated with reticulations or not; and the onset of their first non–Raynaud’s symptom of SSc within the previous 7 yr		 Total N = 148; intervention, n = 69 from SLS II; control, n = 79 from SLS I Intervention: MMF, 3 g
Control: Placebo		 Primary: difference in % predicted FVC
Secondary: mean changes in the course from 3 to 24 mo % predicted FVC, % predicted DlCO, TDI, and mRSS; adverse outcomes (drug discontinuation, leukopenia, neutropenia, anemia, thrombocytopenia, hematuria, pneumonia); SAEs; SAEs related to treatment; SAEs not related to treatment; death.		 Serious (post hoc)
Goldin et al., 2018 (19); post hoc of SLS II Location: multicenter, United States
Funding: NHLBI-NIH
Duration: 2 yr		 SSc-ILD defined as FVC <80% but ⩾45% predicted value, exertional dyspnea Grade 2 or higher on the Magnitude of Task Component of the BDI, any GGO on HRCT imaging whether associated with reticulations or not; and the onset of their first non–Raynaud’s symptom of SSc within the previous 7 yr Total N = 97; intervention, n = 50; control, n = 47 Intervention: MMF, 3 g
Control: CYC 1.8–2.3 mg/kg		 1) Mean difference in QLF whole lung score;
2) mean difference in QGG whole lung score;
3) mean difference in QILD whole lung score;
4) mean difference in QLF most severe lobe score;
5) mean difference in QGG most severe lobe score; and
6) mean difference in QILD most severe lobe score		 Serious (post hoc)
Naidu et al., 2020 (5); RCT Location: single center
Funding: NA
Duration: 6 mo		 Mild SSc-ILD defined as features of ILD on HRCT imaging with <20% involvement on visual inspection, FVC ⩾70% predicted Total N = 41; intervention, n = 20; control, n = 21 Intervention: MMF, 2 g
Control: placebo		 1) Median difference in % predicted FVC;
2) mean difference in % predicted FVC;
3) improvement in FVC;
4) median difference in % predicted DlCO;
5) median difference in 6MWD;
6) median difference in % predicted FVC in patients with a usual interstitial pneumonia pattern;
7) median difference in % predicted FVC in patients with a nonspecific interstitial pneumonia pattern;
8) median difference in the focal TDI score;
9) median difference in the PCS score;
10) median difference in the MCS;
11) mean difference in any adverse event;
12) mean difference in any SAEs;
13) mean difference in infections;
14) mean difference in upper respiratory tract infections;
15) mean difference in pneumonia;
16) mean difference in urinary tract infection;
17) mean difference in skin infections;
18) mean difference in acute gastroenteritis;
18) mean difference in diarrhea;
19) mean difference in anemia;
20) mean difference in thrombocytopenia; and
21) mean difference in elevated transaminases		 Serious (bias-baseline imbalances, small study size)
Volkmann et al., 2020 (20); post hoc of SLS II Location: Multicenter, United States
Funding: NHLBI-NIH
Duration: 2 yr		 SSc-ILD defined as FVC <80% but ⩾45% predicted value, exertional dyspnea Grade 2 or higher on the Magnitude of Task Component of the BDI, any GGO on HRCT imaging whether associated with reticulations or not; and the onset of their first non–Raynaud’s symptom of SSc within the previous 7 yr Total N = 126;
intervention, n = 63;
control, n = 63		 Intervention: MMF, 3 g
Control: CYC, 1.8–2.3 mg/kg		 1) Mean change in SF-36 PCS;
2) mean change in SF-36 MCS;
3) mean change in HAQ-DI;
4) mean change in TDI;
5) mean change in SGRQ;
6) mean change in LCQ;
7) mean change in GIT 2.0 total score;
8) mean change in GIT 2.0 reflux score;
9) participants meeting the MCID for SF-36 PCS;
10) participants meeting the MCID for SF-36 MCS;
11) participants meeting the MCID for TDI;
12) participants meeting the MCID for LCQ;
13) participants meeting the MCID for SGRQ; and
14) participants meeting the MCID for GIT 2.0 total score		 Serious (post hoc)
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Definition of abbreviations: 6MWD = 6-minute-walk distance; BAL = bronchoalveolar lavage; BDI = Maher Baseline Dyspnea Index; CYC = cyclophosphamide; DlCO = diffusion capacity of the lung for carbon monoxide; DL/VA = DlCO adjusted for alveolar volume; FVC = forced vital capacity; GGO = ground-glass opacity; GIT = gastrointestinal tract; HAQ-DI = Health Assessment Questionnaire-Disability Index; HRCT = high-resolution computed tomographic; ILD = interstitial lung disease; i.v. = intravenously; LCQ = Leicester Cough Questionnaire; MCID = minimal clinically important difference; MCS = mental component score; MMF = mycophenolate; MS = mycophenolate sodium; mRSS = modified Rodnan Skin Score; NA = not applicable; NHLBI-NIH = National Heart, Lung, and Blood Institute-National Institutes of Health; QGG = quantitative ground glass; QILD = quantitative interstitial lung disease; QLF = quantitative lung fibrosis; RCT = randomized controlled trial; SAEs = serious adverse events; SF-36 PCS = Short Form 36 Physical Component Score; SGRQ = St. George’s Respiratory Questionnaire; SLS I = Scleroderma Lung Study I; SLS II = Scleroderma Lung Study II; SSc= systemic sclerosis; TDI = Transitional Dyspnea Index; TLC = total lung capacity.

The method proposed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group was used to assess the risk of bias for each individual study and then the certainty of evidence (either very low, low, moderate, or high) for each intervention on the outcomes of interest (13–18). RCTs started as high quality of evidence, and all observational studies started as low quality of evidence. Study quality was downgraded for high risk of bias (e.g., baseline differences in demographics between intervention and control groups in randomized trials), inconsistency in data (present if there is significant heterogeneity), indirectness to interventions and outcomes of interest, imprecision of results (wide confidence intervals and small sample sizes), and likelihood of publication bias (15, 18). The evidence tables summarize the effect estimates of the study outcomes with the corresponding assessments of quality (Tables 2 and 3; see Tables E3 and E4 in the data supplement), which were used by the guideline committee to inform their recommendations.

Table 2.

Critical outcome summary for mycophenolate versus placebo

Outcome Group Outcome Outcome Measure (95% CI) Arm Favored Total N (Intervention n; Control n) No. of Studies (Reference Number); Type Evidence Quality
Mortality Mortality at 24 mo RR: 0.95 (0.30, 2.99) Neither N = 148 (69; 79) 1 (23); 1 RCT post hoc Very low*†
Disease progression Improvement in FVC % predicted at 24 mo RR: 2.28 (1.54, 3.38)‡ Mycophenolate N = 109 (53; 56) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 3 mo MD: 0.90 (−3.70, 1.90) Neither N = 143 (62; 72) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 6 mo MD: 2.27 (−0.55, 5.09) Neither N = 130 (60; 70) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 9 mo MD: 2.75 (−0.20, 5.70) Neither N = 120 (54; 66) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 12 mo MD: 4.29 (0.92, 7.66)‡ Mycophenolate N = 124 (58; 66) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 15 mo MD: 7.84 (4.31, 11.37)‡ Mycophenolate N = 107 (51; 56) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 18 mo MD: 6.85 (3.30, 10.40)‡ Mycophenolate N = 105 (49; 56) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 21 mo MD: 3.4 (−0.70, 7.50) Neither N = 98 (47; 51) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in DlCO % predicted at 24 mo MD: 4.64 (0.54, 8.74‡ Mycophenolate N = 107 (52; 57) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 3 mo MD: 0.70 (−0.76, 2.2) Neither N = 134 (64; 73) 1 (23); 1 RCT post hoc Very low*†
Mean Change from Baseline in FVC % Predicted at 6 mo MD: 3.45 (0.96, 1.58)‡ Mycophenolate N = 131 (60; 71) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 9 mo MD: 4.86 (2.11, 7.61)‡ Mycophenolate N = 120 (54; 66) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 12 mo MD: 5.11 (2.37, 7.85)‡ Mycophenolate N = 125 (59; 66) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 15 mo MD: 6.18 (3.61, 8.75)‡ Mycophenolate N = 107 (51; 56) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 18 mo MD: 6.78 (3.61, 9.95)‡ Mycophenolate N = 106 (49; 57) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 21 mo MD: 7.02 (3.58, 10.46)‡ Mycophenolate N = 98 (47; 51) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in FVC % predicted at 24 mo MD: 5.44 (3.33, 7.55)‡ Mycophenolate N = 109 (53; 56) 1 (23); 1 RCT post hoc Very low*†
Mean change from baseline in mRSS at 6 mo MD: −0.03 (−1.86, 1.80) Neither N = 131 (59; 72) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS at 12 mo MD: −2.66 (−4.67, −0.65)‡ Mycophenolate N = 120 (57; 63) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS at 18 mo MD: −2.65 (−4.94, −0.36)‡ Mycophenolate N = 104 (49; 55) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS at 24 mo MD: −2.44 (−4.92, 0.04) Neither N = 109 (53; 56) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS - diffuse at 6 mo MD: −0.18 (−2.82, 2.46) Neither N = 81 (38; 43) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS - diffuse SSc-ILD at 12 mo MD: −3.43 (−6.32, −0.54)‡ Mycophenolate N = 75 (38; 37) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS - diffuse SSc-ILD at 18 mo MD: −3.24 (−6.19, −0.29)‡ Mycophenolate N = 65 (32; 33) 1 (23); 1 RCT post hoc Very low*†§
Mean change from baseline in mRSS - diffuse SSc-ILD at 24 mo MD: −2.37 (−5.78, 1.04) Neither N = 69 (35; 34) 1 (23); 1 RCT post hoc Very low*†§
Disease progression (mild SSc-ILD)ǁ Improvement in FVC % predicted at 6 mo RR: 0.98 (0.77, 1.26) Neither N = 42 (20; 22) 1 (5); 1 RCT Low*†
Mean change from baseline in % predicted FVC, NSIP radiology patients at 6 mo MD: −2.5 (P = 0.390) Neither N = 42 (20; 22) 1 (5); 1 RCT Low*†
Mean change from baseline in % predicted FVC, UIP radiology patients at 6 mo MD: −6.0 (P = 0.515) Neither N = 42 (20; 22) 1 (5); 1 RCT Low*†
Median change from baseline in DlCO % predicted at 6 mo MD: −0.5 (P = 0.412) Neither N = 42 (20; 22) 1 (5); 1 RCT Low*†
Median change from baseline in FVC % predicted at 6 mo MD: −3.7 (P = 0.131) Neither N = 42 (20; 22) 1 (5); 1 RCT Low*†
Mean change from baseline in mRSS at 6 mo MD: −4.0 (P = 0.042)‡ Mycophenolate N = 42 (20; 22) 1 (5); 1 RCT Very low*†§
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Definition of abbreviations: CI = confidence interval; DlCO = diffusing capacity of the lung for carbon monoxide; FVC = forced vital capacity; MD = mean difference; mRSS = modified Rodnan Skin Score; medianD = median difference; MD = mean difference; NSIP = nonspecific interstitial pneumonia; RCT = randomized controlled trial; RR = relative risk; SSc-ILD = systemic sclerosis–associated interstitial lung disease; UIP = usual interstitial pneumonia.

*

Downgraded for single study.

†

Downgraded for bias-baseline demographic imbalances.

‡

Statistical significance.

§

Downgraded for indirectness.

ǁ

Mild SSc-ILD is defined as features of ILD on high-resolution computed tomographic imaging with <20% involvement on visual inspection and an FVC ⩾70% predicted.

Table 3.

Critical outcome summary for mycophenolate versus cyclophosphamide

Outcome Group Outcome Outcome Measure (95% CI) Arm Favored Total N (Intervention n; Control n) No. of Studies (Reference Number); Type Evidence Quality
Disease progression Improvement in FVC % predicted at 24 mo RR: 1.10 (0.85, 1.44) Neither N = 104 (53; 51) 1 (4); 1 RCT Moderate*
Mean change from baseline in FVC % predicted at 6 mo MD: −0.32 (−2.53, 1.89) Neither N = 173 (94; 79) 2 (5, 21); 1 RCT, 1 case control Low†
Mean change from baseline in FVC % predicted at 15 mo MD: 6.18 (3.61, 8.75)‡ Mycophenolate N = 107 (51; 56) 1 (4); 1 RCT Moderate*
Mean change from baseline in FVC % predicted at 18 mo MD: −0.62 (−2.7, 1.4) Neither N = 95 (49; 46) 1 (4); 1 RCT Moderate*
Mean change from baseline in FVC % predicted >10% at 24 mo RR: 1.25 (0.60, 2.59) Neither N = 104 (53; 51) 1 (4); 1 RCT Moderate*
Mean change from baseline in FVC % predicted >15% at 24 mo RR: 0.14 (0.01, 2.60) Neither N = 104 (53; 51) 1 (4); 1 RCT Moderate*
Mean change from baseline in FVC % predicted >5% at 24 mo RR: 1.11 (0.70, 1.75) Neither N = 104 (53; 51) 1 (4); 1 RCT Moderate*
Mean change from baseline in DlCO % predicted at 6 mo MD: 3.67 (1.1, 6.3)‡ Mycophenolate N = 116 (60; 56) 1 (4); 1 RCT Moderate*
Mean change from baseline in DlCO % predicted at 18 mo MD: 3.26 (0.41, 6.10)‡ Mycophenolate N = 93 (49; 44) 1 (4); 1 RCT Moderate*
Mean change from baseline in DL/VA % predicted at 6 mo MD: 4.88 (2.5, 7.3)‡ Mycophenolate N = 116 (60; 56) 1 (4); 1 RCT Moderate*
Mean change from baseline in DL/VA % predicted at 12 mo MD: 5.90 (3.4, 8.4)‡ Mycophenolate N = 109 (59; 52) 1 (4); 1 RCT Moderate*
Mean change from baseline in DL/VA % predicted at 18 mo MD: 5.71 (3.06, 8.36)‡ Mycophenolate N = 94 (49; 45) 1 (4); 1 RCT Moderate*
Mean change from baseline in DL/VA % predicted at 24 mo MD: 0.96 (−2.2, 4.1) Neither N = 103 (52; 51) 1 (4); 1 RCT Moderate*
Mean change in quantitative ground glass - most severe lobe score at 24 mo MD: −0.79 (−3.94, 2.36) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change in quantitative ground glass - whole lung score at 24 mo MD: −0.28 (−2.74, 2.18) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change in quantitative ILD - lobe most involved score at 24 mo MD: 0.27 (−3.09, 3.67) Neither N = 98 (51; 47) 1 (4); 1 RCT Moderate*
Mean change in quantitative ILD - most severe lobe score at 24 mo MD: 0.73 (−3.34, 4.70) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change in quantitative ILD - whole lung score at 24 mo MD: 0.89 (−3.58, 5.36) Neither N = 98 (51; 47) 1 (4); 1 RCT Moderate*
Mean change in quantitative ILD - whole lung score at 24 mo MD: −0.21 (−2.85, 2.43) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change in quantitative lung fibrosis - lobe most involved at 24 mo MD: 0.39 (−1.27, 2.05) Neither N = 98 (51; 47) 1 (4); 1 RCT Moderate*
Mean change in quantitative lung fibrosis - most severe lobe score at 24 mo MD: 1.45 (−2.73, 5.63) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change in quantitative lung fibrosis - whole lung score at 24 mo MD: 1.02 (−2.99, 5.03) Neither N = 98 (51; 47) 1 (4); 1 RCT Moderate*
Mean change in quantitative lung fibrosis - whole lung score at 24 mo MD: 0.44 (−0.68, 1.56) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change in quantitative lung fibrosis - whole lung score at 24 mo MD: 0.44 (−0.68, 1.56) Neither N = 97 (50; 47) 1 (19); 1 RCT post hoc Very low*
Mean change from baseline in mRSS at 6 mo MD: 0.75 (−0.9, 2.4) Neither N = 118 (60; 58) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS at 12 mo MD: 0.24 (−1.7, 2.2) Neither N = 113 (58; 55) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS at 18 mo MD: 0.25 (−1.6, 2.1) Neither N = 79 (40; 39) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS at 24 mo MD: 0.45 (−1.7, 2.6) Neither N = 106 (53; 53) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - diffuse SSc-ILD at 6 mo MD: 1.02 (−5.77, 3.72) Neither N = 69 (39; 30) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - diffuse SSc-ILD at 12 mo MD: 0.61 (−1.7, 2.2) Neither N = 66 (38; 28) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - diffuse SSc-ILD at 18 mo MD: 0.78 (−1.6, 2.1) Neither N = 58 (33; 25) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - diffuse SSc-ILD at 24 mo MD: 1.90 (−1.7, 2.6) Neither N = 62 (35; 27) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - limited SSc-ILD at 6 mo MD: 0.11 (−1.5, 1.7) Neither N = 49 (21; 28) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - limited SSc-ILD at 12 mo MD: -0.21 (−2.2, 1.8) Neither N = 47 (20; 27) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - limited SSc-ILD at 18 mo MD: 0.15 (−1.7, 2.0) Neither N = 39 (17; 22) 1 (4); 1 RCT Low*†
Mean change from baseline in mRSS - limited SSc-ILD at 24 mo MD: −1.19 (−3.5, 1.1) Neither N = 44 (18; 26) 1 (4); 1 RCT Low*†
Mortality Mortality at 24 mo RR: 0.48 (0.18, 1.31) Neither N = 219 (113; 106) 3 (4, 21, 22); 1 RCT, 2 case control Low†
Disease progression Mean change from baseline in FVC % predicted MD: −0.50 (−2.17, 1.18) Neither N = 187 (103; 84) 3 (4, 21, 22); 1 RCT, 2 case control Low†
Mean change from baseline in FVC % predicted at 12 mo MD: 0.10 (−1.93, 2.12) Neither N = 130 (69; 61) 2 (4, 22); 1 RCT, 1 case control Low†
Mean change from baseline in FVC % predicted at 24 mo MD: −0.79 (−3.14, 1.56) Neither N = 120 (63; 61) 2 (4, 22); 1 RCT, 1 case control Low†
Mean change from baseline in DlCO % predicted at 12 mo MD: 1.19 (−8.24, 10.62) Neither N = 129 (68; 61) 2 (4, 22); 1 RCT, 1 case control Low†
Mean change from baseline in DlCO % predicted at 24 mo MD: −2.33 (−12.84, 8.18) Neither N = 116 (62; 58) 2 (4, 22); 1 RCT, 1 case control Low†
Mean change in coarseness of high-resolution chest CT imaging score at 12 mo MD: 0.90 (−0.92, 2.72) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in coarseness of high-resolution chest CT imaging score at 24 mo MD: 0.50 (−1.47, 2.47) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in disease extent of high-resolution chest CT imaging score at 12 mo MD: −0.25 (−5.00, 4.50) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in disease extent of high-resolution chest CT imaging score at 24 mo MD: −0.35 (−5.63, 4.93) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in high-resolution chest CT imaging score at 12 mo MD: 0.40 (−2.50, 3.30) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in high-resolution chest CT imaging score at 24 mo MD: 0.70 (−2.76, 4.16) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in coarseness of high-resolution chest CT imaging score at 12 mo MD: 0.90 (−0.92, 2.72) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
Mean change in coarseness of high-resolution chest CT imaging score at 24 mo MD: 0.50 (−1.47, 2.47) Neither N = 20 (10; 10) 1 (22); 1 case control Very low*
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Definition of abbreviations: CI = confidence interval; CT = computed tomographic; DlCO = diffusing capacity of the lung for carbon monoxide; DL/VA = DlCO adjusted for alveolar volume; FVC = forced vital capacity; MD = mean difference; mRSS = modified Rodnan Skin Score; RCT = randomized controlled trial; RR = relative risk; SSc-ILD = systemic sclerosis–associated interstitial lung disease.

*

Downgraded for single study.

†

Downgraded for indirectness.

‡

Statistical significance.

Results

Literature Review and Characteristics of Included Studies

The literature review resulted in 506 total articles. After 31 duplicates were removed, 395 were excluded on initial title and abstract screen (Figure 1). Eighty full-text publications were assessed for eligibility, resulting in seven publications meeting the inclusion criteria for data extraction (Table 1) (4, 5, 19–23). The primary reason for exclusion was that the study was a conference abstract only. Of the seven publications included in the study, two were RCTs (4, 5), three were post hoc analyses of RCTs (19, 20, 23), and two were nonrandomized studies (21, 22). Two publications, one an RCT and the other an RCT post hoc analysis, compared mycophenolate with placebo (5, 23). Five studies compared mycophenolate with cyclophosphamide, which included one RCT, two post hoc analyses of RCTs, and two nonrandomized trials (4, 19–22).

The primary study comparing mycophenolate with cyclophosphamide, the SOC at the time of that study, was the SLS II (4). SLS II was a phase 3 RCT funded by the National Institutes of Health that observed 126 patients across multiple centers in the United States of America over a 2-year period of time. Inclusion criteria included limited or diffuse SSc defined by American College of Rheumatology criteria and the presence of ground-glass opacification on chest high-resolution computed tomographic (HRCT) imaging. The intervention arm consisted of mycophenolate mofetil titrated to a dose of 1.5 g twice daily for 24 months. The control arm received oral cyclophosphamide with a target dose of 2 mg/kg/d for 12 months, followed by placebo for 12 months. The primary outcome was mean change from baseline to 24 months in % predicted FVC. Secondary outcomes included changes in DlCO % predicted, total lung capacity (TLC) % predicted, TDI, mRSS, quantitative lung fibrosis (QLF) score, quantitative interstitial lung disease (QILD) score, and adverse events.

Two publications, one by Goldin and colleagues and one by Volkmann and colleagues, were post hoc analyses of the SLS II (19, 23). Goldin and colleagues examined the effect of mycophenolate versus cyclophosphamide on radiological progression in SSc-ILD. Outcomes of interest included differences in QLF scores, quantitative ground-glass (QGG) scores, and QILD scores, both in the whole lung and the most severely affected lobe. Volkmann and colleagues examined the effect of mycophenolate versus cyclophosphamide on several patient-reported outcomes in the SLS II, some of which were TDI, SGRQ, and LCQ scores.

Two nonrandomized case-control studies compared mycophenolate to cyclophosphamide (21, 22). The study by Panopoulos and colleagues was a single-center study including 20 patients with newly diagnosed or progressive SSc-ILD over 2 years (22). Seven patients received mycophenolate mofetil, and 3 patients received mycophenolic acid; the outcomes for different formulations were not reported separately. All 10 controls received oral cyclophosphamide. The reported outcomes included differences in % predicted FVC at 12 and 24 months, differences in TLC % predicted at 12 and 24 months, differences in radiological progression per two different chest HRCT scoring systems, and adverse events. The study by Shenoy and colleagues was the second single-center case-control study occurring in India that included 57 patients over a 6-month time period comparing mycophenolate with monthly intravenous cyclophosphamide (21). Reported outcomes included change in % predicted FVC and adverse events.

The comparator to mycophenolate was placebo in two studies (5, 23). The study by Naidu and colleagues was a single-center RCT in India that included patients with mild SSc-ILD, defined as features of ILD on chest HRCT imaging with <20% involvement on visual inspection and an FVC ⩾70% predicted (5). Forty-one patients were included; the intervention was mycophenolate mofetil titrated to a target dose of 2 g/d. There were baseline differences in FVC and DlCO % predicted between the intervention and control groups. The primary outcome for this study was the median change from baseline in FVC at 6 months. Secondary outcomes included median change from baseline in DlCO, 6-minute-walk distance, mRSS, TDI, FVC changes in usual interstitial pneumonia versus nonspecific interstitial pneumonia radiological pattern, and adverse events.

The second publication comparing mycophenolate to placebo, that of Volkmann and colleagues, was a post hoc analysis of both the SLS I and SLS II (23). The SLS I and SLS II had similar, albeit not identical, inclusion criteria and outcomes. The SLS I was a multicenter RCT of symptomatic patients with SSc-ILD and impaired lung function that compared oral cyclophosphamide with placebo for 1 year. The notable difference in inclusion criteria between the SLS I and SLS II is that patients in the SLS I could be enrolled in the absence of abnormalities on chest HRCT imaging if active alveolitis was present on bronchoalveolar lavage, defined as neutrophils ⩾3% or eosinophils ⩾2%. Volkmann and colleagues compared the 79 patients who received placebo in the SLS I to the 69 patients who received mycophenolate in the SLS II. There were several baseline differences in demographics between these two groups across the two studies; patients who received mycophenolate were older (52.6 vs. 48.1 yr) and had a higher DlCO % predicted (54.0% vs. 46.2%). Patients who received placebo had more dyspnea per the Maher Baseline Dyspnea Index and more extensive radiological fibrosis as per baseline QILD score for the whole lung. The primary outcome for Volkmann and colleagues was the difference in FVC % predicted. Other reported outcomes included DlCO % predicted, TDI, mRSS, and adverse events.

No studies were identified that addressed the predefined subgroups of interest by disease status; specifically, patients with SSc-ILD at initial diagnosis, those with stable disease and those with progressive disease, or subgroups of interest by mycophenolate formulation. Panopoulos and colleagues’ inclusion criteria were those with SSc-ILD at the time of diagnosis or with progressive disease; however, results for these two groups were not reported separately, so data could not be extracted to address the subgroups by disease status. Only one study, that of Panopoulos and colleagues included patients who received either mycophenolate mofetil or mycophenolic acid. All others used mycophenolate mofetil. Consequently, the reported results address one heterogeneous population of patients with SSc-ILD who predominantly received mycophenolate mofetil.

Systematic Review Outcomes

Critical outcomes

Mycophenolate versus placebo

A summary of the critical outcomes for all patients with SSc-ILD comparing mycophenolate with placebo can be found in Table 2. Critical outcomes were mortality and disease progression. Disease progression was defined by changes in FVC % predicted, DlCO % predicted, radiological disease, and mRSS changes. The key critical outcomes extracted from the available studies included mortality, mean change in FVC % predicted at 12 and 24 months, overall improvement in FVC % predicted at 12 and 24 months, mean change in DlCO % predicted at 12 and 24 months, and mRSS score changes.

There was no difference in mortality at 24 months between mycophenolate and placebo (RR, 0.95; 95% CI: 0.30, 2.99). This outcome had very low-quality evidence per GRADE. Differences in mean change from baseline in FVC % predicted at 12 months (MD, 5.11%; 95% CI: 2.37%, 7.85%) and 24 months (MD, 5.44%; 95% CI: 3.33%, 7.55%), overall improvement in FVC % predicted at 12 months (RR, 2.28; 95% CI: 1.54, 3.38) and 24 months (RR, 2.25; 95% CI: 1.52, 3.33), and mean change from baseline in DlCO % predicted at 12 months (MD, 4.29%; 95% CI: 0.92%, 7.66%) and 24 months (MD, 4.64%; 95% CI: 0.54%, 8.74%) all favored mycophenolate. All outcomes had very low-quality evidence per GRADE. There was a statistically significant difference in mRSS score at 12 months (MD, −3.43; 95% CI: −6.32, −0.29), favoring mycophenolate, but there was no significant difference at 24 months (MD, −2.44; 95% CI: −5.87, 1.04).

For patients with mild SSc-ILD, there were no statistically significant differences in median change from baseline to 6 months in FVC % predicted (−3.7%; P = 0.13), overall improvement in FVC % predicted (RR, 0.98; 95% CI: 0.77, 1.26), or median change in DlCO % predicted (−0.5; P = 0.412) between those who received mycophenolate or placebo. However, the median mRSS score at 6 months (−4.0; P = 0.042) favored mycophenolate.

Mycophenolate versus cyclophosphamide

A summary of the critical outcomes for all patients with SSc-ILD comparing mycophenolate with cyclophosphamide can be found in Table 3. There was no significant difference in mortality at 24 months (RR, 0.48; 95% CI: 0.18, 1.31; see Figure E1). This outcome had low-quality evidence per GRADE. There were no differences between mycophenolate or cyclophosphamide in mean change in FVC % predicted at 6 months (MD, −0.32%; 95% CI: −2.53%, 1.89%), 12 months (MD, 0.10%; 95% CI: −1.93%, 2.12%), 24 months (MD, −0.79%; 95% CI: −3.14%, 1.56%), or overall improvement in FVC % predicted (MD, −0.50%; 95% CI: −2.17%, 1.18%) (Table 3; see Figures E2–E5). Although there were statistical differences between mycophenolate and cyclophosphamide in unadjusted DlCO % predicted at 6 and 18 months, there were no differences in unadjusted DlCO % predicted at 12 months (MD, 1.19%; 95% CI: −8.24, 10.62) or 24 months (MD, −2.33%; 95% CI: −12.84, 8.18) (see Figures E6 and E7). When adjusted for alveolar volume, DlCO % predicted at 6 months (MD, 4.88; 95% CI: 2.5, 7.3), 12 months (MD, 5.90; 95% CI: 3.4, 8.4), and 18 months (MD, 5.71; 95% CI: 3.06, 8.36) favored mycophenolate, but the difference did not remain statistically significant at 24 months (MD, 0.96; 95% CI: −2.2, 4.1). There were no differences between mycophenolate and cyclophosphamide in several different measures of radiological progression, including QLF, QILD, and QGG scores. All outcomes had low- or moderate-quality evidence per GRADE.

Important outcomes

Mycophenolate versus placebo

A complete summary of the important outcomes for all patients with SSc-ILD comparing mycophenolate with placebo can be found in Table E3. The key reported important outcomes extracted were changes in quality of life, such as TDI score, and adverse events. There were significant differences in TDI score at 6, 12, 18, and 24 months (MD, 1.99; 95% CI: 0.36, 3.62), favoring mycophenolate. There were no significant differences in adverse events between mycophenolate or placebo in premature discontinuation, serious adverse events, hematuria, leukopenia, neutropenia, or thrombocytopenia. However, there was a significant difference in anemia (RR, 9.16; 95% CI: 1.17, 71.41), favoring placebo. All outcomes had very low-quality evidence per GRADE.

Mycophenolate versus cyclophosphamide

A complete summary of the important outcomes for all patients with SSc-ILD comparing mycophenolate to cyclophosphamide can be found in Table E4. The key important outcomes extracted were: other parameters of lung function, such as changes in TLC % predicted; quality-of-life measures, such as SGRQ, LCQ, Health Assessment Questionnaire-Disability Index, and gastrointestinal tract reflux score; and adverse events. There was no difference in mean change in TLC % predicted at any time point, including 24 months (MD, 0.61; 95% CI: −2.05, 3.27; see Figures E8 and E9). There were no differences in quality-of-life measures between mycophenolate and cyclophosphamide.

There were significant differences in the adverse events of premature discontinuation for any reason (RR, 0.59; 95% CI: 0.38, 0.91) and leukopenia (RR, 0.14; 95% CI: 0.05, 0.38) favoring mycophenolate. These outcomes had moderate-quality evidence per GRADE. There were no statistically significant differences in any other adverse event.

Discussion

The aim of this systematic review was to identify the treatment effect of mycophenolate on patients with SSc-ILD to inform expert panelists from the ATS in formulating clinical practice recommendations on the treatment of patients with SSc-ILD (G. Raghu and colleagues, Am J Respir Crit Care Med [online ahead of print] 29 Sep 2023; DOI:10.1164/rccm.202306-1113ST). This systematic review and meta-analysis identified a consistent treatment effect of mycophenolate on patients with SSc-ILD over placebo. Although there was no difference identified in the critical outcome of mortality, there were consistent benefits of mycophenolate in regard to reducing disease progression—specifically, changes in FVC % predicted and DlCO % predicted—at multiple time points, including 12 and 24 months. Furthermore, there were benefits to mycophenolate compared with placebo in improving quality of life—specifically, breathlessness as measured by TDI at all time points. Differences in adverse events were also identified, with an increased risk of anemia in patients receiving mycophenolate over placebo.

When compared with cyclophosphamide, there were no significant differences in the critical outcomes of mortality or disease progression. Although there were some differences identified between mycophenolate and cyclophosphamide at intermediate time points—specifically, FVC % predicted at 18 months and DlCO % predicted at 6, 12, and 18 months—no differences were identified at the key time point of 24 months. No differences were identified between mycophenolate or cyclophosphamide in any quality-of-life measures. However, patients who received mycophenolate were less likely to develop leukopenia and also less likely to discontinue the treatment prematurely.

A strength of this systematic review and meta-analysis is the identification of studies allowing mycophenolate to be compared with both placebo and cyclophosphamide. In comparing mycophenolate with placebo, the preponderance of evidence suggests a consistent treatment effect across multiple outcomes in patients with SSc-ILD. Publication of the SLS I led to cyclophosphamide as the SOC, but comparing mycophenolate with cyclophosphamide identified no difference in efficacy and, instead, highlighted improved tolerability and less leukopenia with mycophenolate.

There are many limitations to this systematic review. Although seven publications were identified, only two were RCTs and three were post hoc analyses, and the preponderance of data is derived from only two publications: one an RCT and the other a post hoc analysis (4, 23). As a result, the quality of evidence for most outcomes was downgraded, and the overall quality of evidence for all outcomes ranged from very low to moderate per GRADE. In particular, the comparison of mycophenolate with placebo is noteworthy. Because cyclophosphamide was the SOC at the time of SLS II, the comparison of mycophenolate with placebo is primarily from a post hoc study comparing the placebo group from SLS I with the mycophenolate group from the SLS II. Although the inclusion criteria were similar across the SLS I and SLS II, there were differences in baseline demographics between the placebo and mycophenolate groups, introducing potential bias from confounding in the results. Although there was one RCT that compared mycophenolate to placebo, it was a small trial in which there were also baseline demographic differences between groups.

An additional limitation was the absence of research addressing specific subpopulations of patients with SSc-ILD (an initial diagnosis of SSc-ILD, stable SSc-ILD, progressive SSc-ILD) and for the different formulations of mycophenolate. Because most data are derived from the SLS I and SLS II trials, the results of this review are most applicable to patients with SSc-ILD who are similar to the study populations, and who may differ from many patients with SSc-ILD in clinical practice. Regarding drug formulation, all studies except one, a small nonrandomized trial, included mycophenolate mofetil; therefore, the results of the systematic review and meta-analysis are most directly applicable to mycophenolate mofetil. The review was unable to identify whether mycophenolic acid has an efficacy similar to that of mycophenolate mofetil.

Despite the findings from this review, many unknowns still exist with regard to treating patients with SSc-ILD with mycophenolate. The scope of this review focused on comparing mycophenolate with placebo or cyclophosphamide. Separate systematic reviews and meta-analyses were prepared for the guideline committee to evaluate alternative treatments to mycophenolate, including cyclophosphamide (26), rituximab (27), tocilizumab (28), and nintedanib (29). This review does not address the management of patients with SSc-ILD who have a progression of disease while on mycophenolate. As a result, the optimal management strategy for patients with progressive SSc-ILD while on therapy with mycophenolate remains unknown.

Additionally, the ideal dosing of mycophenolate and presence of a dose response are unclear. Most of the data in this review are derived from the mycophenolate arm in the SLS II trial, which had a target dose of 3 g/d of mycophenolate in divided doses. The publication comparing mycophenolate with placebo using these data demonstrated many benefits to mycophenolate over placebo (4). The only other RCT, which compared mycophenolate with placebo in early SSc-ILD, had a target dose of 2 g/d in divided doses (5). In this study, there was not a clear benefit to mycophenolate. It is unknown whether the absence of a benefit was due to the lower target dose of mycophenolate, treatment of patients with SSc-ILD with more mild disease, or the study’s small sample size. Further unknowns include the optimal duration of treatment with mycophenolate. If disease stability is obtained, how long should patients remain on the medication before attempting to discontinue—should therapy remain lifelong? Finally, high-quality long-term efficacy or safety data beyond 24 months of therapy with mycophenolate in patients with SSc-ILD are not available.

Conclusion

Mycophenolate has a beneficial effect compared with that of placebo in patients with SSc-ILD with regard to disease progression, as measured by FVC % predicted and DlCO % predicted, and quality-of-life measures, but did have an increased risk of anemia. Compared with cyclophosphamide, there are no significant differences in measures of disease progression or quality of life, but mycophenolate had fewer instances of leukopenia and premature treatment discontinuation. These findings are based on low-quality evidence.

Footnotes

Supported by the U.S. Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service, Grant/Award Number: Career Development Award 1IK2RX003535-01A2 (to M.M.).

Author Contributions: M.G., G.R., S.B.M., and R.M.S. conceived the manuscript. S.L.K. performed the literature search. D.H. and T.H. screened articles and performed data extraction. D.H., M.G., and T.H. drafted the manuscript. All authors contributed to changes and approved the final manuscript.

This article has a data supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org.

Author disclosures are available with the text of this article at www.atsjournals.org.

References

  • 1. Perelas A, Silver RM, Arrossi AV, Highland KB. Systemic sclerosis-associated interstitial lung disease. Lancet Respir Med . 2020;8:304–320. doi: 10.1016/S2213-2600(19)30480-1. [DOI] [PubMed] [Google Scholar]
  • 2. Denton CP, Khanna D. Systemic sclerosis. Lancet . 2017;390:1685–1699. doi: 10.1016/S0140-6736(17)30933-9. [DOI] [PubMed] [Google Scholar]
  • 3. Hoffmann-Vold AM, Allanore Y, Alves M, Brunborg C, Airó P, Ananieva LP, et al. EUSTAR collaborators Progressive interstitial lung disease in patients with systemic sclerosis-associated interstitial lung disease in the EUSTAR database. Ann Rheum Dis . 2021;80:219–227. doi: 10.1136/annrheumdis-2020-217455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al. Sclerodema Lung Study II Investigators 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;4:708–719. doi: 10.1016/S2213-2600(16)30152-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Naidu GSRSNK, Sharma SK, Adarsh MB, Dhir V, Sinha A, Dhooria S, et al. Effect of mycophenolate mofetil (MMF) on systemic sclerosis-related interstitial lung disease with mildly impaired lung function: a double-blind, placebo-controlled, randomized trial. Rheumatol Int . 2020;40:207–216. doi: 10.1007/s00296-019-04481-8. [DOI] [PubMed] [Google Scholar]
  • 6. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology . 2000;47:85–118. doi: 10.1016/s0162-3109(00)00188-0. [DOI] [PubMed] [Google Scholar]
  • 7. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. Cochrane Bias Methods Group Cochrane Statistical Methods Group. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ . 2011;343:d5928. doi: 10.1136/bmj.d5928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum . 1980;23:581–590. doi: 10.1002/art.1780230510. [DOI] [PubMed] [Google Scholar]
  • 9. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum . 2013;65:2737–2747. doi: 10.1002/art.38098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, et al. Idiopathic pulmonary fibrosis (an update) and progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med . 2022;205:e18–e47. doi: 10.1164/rccm.202202-0399ST. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al. Scleroderma Lung Study Research Group Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med . 2006;354:2655–2666. doi: 10.1056/NEJMoa055120. [DOI] [PubMed] [Google Scholar]
  • 12. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al. American Thoracic Society European Respiratory Society; Japanese Respiratory Society; Latin American Thoracic Association. An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med . 2015;192:e3–e19. doi: 10.1164/rccm.201506-1063ST. [DOI] [PubMed] [Google Scholar]
  • 13.Schünemann H, Brożek J, Guyatt G, Oxman A, editors. GRADE handbook. Handbook for grading quality of evidence and strength of recommendations. GRADE Working Group; 2013. https://gdt.gradepro.org/app/handbook/handbook.html [Google Scholar]
  • 14. Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, et al. GRADE Working Group GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ . 2016;353:i2089. doi: 10.1136/bmj.i2089. [DOI] [PubMed] [Google Scholar]
  • 15. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE Working Group GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ . 2008;336:924–926. doi: 10.1136/bmj.39489.470347.AD. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Moberg J, Oxman AD, Rosenbaum S, Schünemann HJ, Guyatt G, Flottorp S, et al. GRADE Working Group The GRADE Evidence to Decision (EtD) framework for health system and public health decisions. Health Res Policy Syst . 2018;16:45. doi: 10.1186/s12961-018-0320-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Zhang Y, Akl EA, Schünemann HJ. Using systematic reviews in guideline development: the GRADE approach. Res Synth Methods . 2018 doi: 10.1002/jrsm.1313. [DOI] [PubMed] [Google Scholar]
  • 18. Schünemann HJ, Jaeschke R, Cook DJ, Bria WF, El-Solh AA, Ernst A, et al. ATS Documents Development and Implementation Committee An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. Am J Respir Crit Care Med . 2006;174:605–614. doi: 10.1164/rccm.200602-197ST. [DOI] [PubMed] [Google Scholar]
  • 19. Goldin JG, Kim GHJ, Tseng CH, Volkmann E, Furst D, Clements P, et al. Longitudinal changes in quantitative interstitial lung disease on computed tomography after immunosuppression in the Scleroderma Lung Study II. Ann Am Thorac Soc . 2018;15:1286–1295. doi: 10.1513/AnnalsATS.201802-079OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Volkmann ER, Tashkin DP, LeClair H, Roth MD, Kim G, Goldin J, et al. Treatment with mycophenolate and cyclophosphamide leads to clinically meaningful improvements in patient-reported outcomes in scleroderma lung disease: results of Scleroderma Lung Study II. ACR Open Rheumatol . 2020;2:362–370. doi: 10.1002/acr2.11125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Shenoy PD, Bavaliya M, Sashidharan S, Nalianda K, Sreenath S. Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: a single-centre, retrospective analysis. Arthritis Res Ther . 2016;18:123. doi: 10.1186/s13075-016-1015-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Panopoulos ST, Bournia VK, Trakada G, Giavri I, Kostopoulos C, Sfikakis PP. Mycophenolate versus cyclophosphamide for progressive interstitial lung disease associated with systemic sclerosis: a 2-year case control study. Lung . 2013;191:483–489. doi: 10.1007/s00408-013-9499-8. [DOI] [PubMed] [Google Scholar]
  • 23. Volkmann ER, Tashkin DP, Li N, Roth MD, Khanna D, Hoffmann-Vold AM, et al. Mycophenolate mofetil versus placebo for systemic sclerosis-related interstitial lung disease: an analysis of Scleroderma Lung Studies I and II. Arthritis Rheumatol . 2017;69:1451–1460. doi: 10.1002/art.40114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Warrick JH, Bhalla M, Schabel SI, Silver RM. High resolution computed tomography in early scleroderma lung disease. J Rheumatol . 1991;18:1520–1528. [PubMed] [Google Scholar]
  • 25. Desai SR, Veeraraghavan S, Hansell DM, Nikolakopolou A, Goh NS, Nicholson AG, et al. CT features of lung disease in patients with systemic sclerosis: comparison with idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Radiology . 2004;232:560–567. doi: 10.1148/radiol.2322031223. [DOI] [PubMed] [Google Scholar]
  • 26. [Google Scholar]
  • 27. [Google Scholar]
  • 28. [Google Scholar]
  • 29. [Google Scholar]

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