Beyond corticosteroids: A systematic review and meta-analysis of novel therapies for hypersensitivity pneumonitis.

INTRODUCTION

Hypersensitivity pneumonitis (HP) is a complex immune-mediated interstitial lung disease triggered by inhaled antigens. While corticosteroids remain the mainstay of therapy, their benefit is limited in fibrotic HP. Several novel agents-including pirfenidone, nintedanib, rituximab, azathioprine, mycophenolate mofetil (MMF), leflunomide, and roflumilast-have been investigated as alternatives.

METHODS

This meta-analysis followed PRISMA guidelines and was registered on PROSPERO (CRD42023428070). Eligible studies included clinical and non-clinical trials assessing both traditional and novel therapies in HP. Primary outcomes were mean difference from baseline (MDB) and percentage change from baseline (PCB) in forced vital capacity (FVC%) and diffusing capacity for carbon monoxide (DLCO%). Meta-analyses were performed using fixed- and random-effects models, with heterogeneity assessed via I2. Sensitivity analyses and publication bias assessments were also conducted. Risk of bias was evaluated using CASP and RoB-2 tools.

RESULTS

Twenty-three studies comprising 975 patients (aged 39.3-83 years) were included. Rituximab, azathioprine, MMF, and corticosteroids showed non-significant pooled MDBs in FVC%, with MDB of -0.87 %, 2.49 %,1.96 %, and 2.03 %, respectively. For DLCO%, rituximab and MMF showed positive effects, with a MDB of 6.69 and 5.98, respectively, while azathioprine had minimal impact. Single-study analyses suggested that pirfenidone and nintedanib may stabilize lung function; their combination improved DLCO% but not FVC%. Leflunomide and roflumilast demonstrated promising effects in single reports.

CONCLUSION

Due to heterogeneity and limited high-quality evidence, definitive conclusions about novel therapies in HP remain elusive. However, rituximab and MMF showed promising results. Long-term randomized trials with standardized endpoints are needed to guide therapeutic decisions.