Mycophenolate and azathioprine efficacy in interstitial lung disease: a systematic review and meta-analysis

Abstract

Objectives: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.

Design: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.

Eligibility criteria: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.

Data synthesis: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I² evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.

Results: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I²=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I²=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I²=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DL_CO (95% CI 2.05 to 6.79, I²=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.

Conclusions: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.

Prospero registration number: CRD42023423223.

Keywords: Interstitial Fibrosis; Respiratory Function Test.

Figure 1

Preferred reporting items for systematic review and meta-analysis (PRISMA) flow of study search and inclusion. AZA, azathioprine; MMF, mycophenolate mofetil.

Figure 2

Qualitative synthesis: risk of bias. (A) Risk of bias in RCTs assessed using Cochrane ROB2.0 tool. (B) Risk of bias assessed using Newcastle-Ottawa Quality assessment scale for cohort studies. Green has been assessed as: three or four stars in selection bias; two stars in comparability, three stars in outcome. Yellow has been assessed as: two stars in selection bias; one star in comparability, two stars in outcome. RCTs, randomised controlled trial; ROB2.0, Risk of Bias 2.0.

Figure 3

Primary endpoint analysis of efficacy on pulmonary function relative to comparator. (A) Forest plot of difference in %FVC in treatment of MMF versus comparators at follow-up. (B) Forest plot of difference in %DLco in treatment of MMF versus comparators at follow-up. Positive values indicate improvement relative to comparator, negative values indicate decline relative to comparator. Presented with cohort size (N) for intervention and comparator, weighted mean difference (WMD) and 95% CI. Follow-up time reported in months. %DLco, per cent predicted diffusion lung capacity of carbon monoxide; %FVC, per cent predicted forced vital capacity; MMF, mycophenolate mofetil.

Figure 4

Secondary endpoint analysis of efficacy on pulmonary function compared with baseline. Subgroup analysis of MMF overall and summary estimates presented by study design of trial or prospective observational study. (A) Forest plot of change in %FVC at follow-up versus baseline. (B) Forest plot of change in %DLco versus baseline. Positive values indicate improvement relative to baseline, negative values indicate decline relative to baseline. Presented with cohort size (N) for intervention and comparator, weighted mean difference (WMD) and 95% CIs. Follow-up time reported in months. %DLco, per cent predicted diffusion lung capacity of carbon monoxide; %FVC, per cent predicted forced vital capacity; MMF, mycophenolate mofetil.