Progressive pulmonary fibrosis (PPF) is a disabling condition characterized by worsening symptoms, lung function, and fibrosis of HRCT. PPF imposes a substantial burden on affected individuals and healthcare systems worldwide, highlighting the urgent need for novel therapeutic approaches to halt or reverse disease progression. Understandably, due to the fibrotic nature of PPF, antifibrotic (nintedanib and pirfenidone) are used commonly for the treatment. Although the US-FDA has  approved both these drugs; both these drugs show modest efficacy in slowing disease progression of PPF. Hence, there remains a significant unmet need for more effective therapies to improve outcomes in patients with progressive pulmonary fibrosis.

PPF is a heterogeneous disease with varying diseases with varied underlying pathogenic mechanisms. In fact, the majority of the diseases that encompass PPF (connective disease associated-interstitial lung diseases (ILD), hypersensitivity pneumonitis, sarcoidosis, NSIP etc.) are inflammatory to begin with and the ongoing inflammation may play an important role in the development and further progression of PPF. Therefore, a one-size-fits-all approach to treatment is unlikely to be optimal. 

Both immunosuppressive agents and antifibrotic drugs have been investigated as potential treatments for many fibrotic ILDs. While immunosuppressants (prednisolone, MMF, azathioprine, cyclophosphamide etc.) may target inflammation and immune dysregulation, antifibrotics primarily aim to inhibit fibroblast activation and collagen deposition. However, few patients have an overlap of varying degree of fibrosis and inflammation, as pathologically, PPF is a spectrum that consists of inflammation at the one end and fibrosis at the other end. It is almost impossible to categorize PPF patients in these categories with currently available tools. The comparative efficacy and safety of these treatment approaches remain unclear, necessitating head-to-head randomized trials.

Current guidelines suggest use of nintedanib (only conditional recommendation, low level of evidence) and recommend further research in efficacious treatment of PPF. Potentially, combining nintedanib with immunosuppressive therapy might be a better approach for the treatment of PPF. Also, currently, it is not known which is the group of PPF who would respond to nintedanib, or first a trial of immunosuppressive followed by nintedanib, or simultaneous introduction of immunosuppressive and nintedanib. Tailoring treatment strategies based on individual patient characteristics, including biomarkers predictive of treatment response, may improve therapeutic outcomes. Therefore, identifying biomarkers predictive of treatment response is crucial for personalized medicine in pulmonary fibrosis. By stratifying patients based on their likelihood of responding to specific therapies, clinicians can optimize treatment selection and improve clinical outcomes.

In summary, this randomized study aims to address the unmet need for effective therapies in PPF by comparing the efficacy of immunosuppressive therapy (prednisolone plus MMF), antifibrotic (nintedanib), and combination of immunosuppressive and antifibrotic treatment, while also investigating predictive biomarkers to guide treatment selection and optimize therapeutic outcomes.