Up to 40 percent of patients with connective tissue disease–associated interstitial lung disease (CTD-ILD) develop progressive pulmonary fibrosis, which requires more intensive management beyond immunosuppressants to control the decline in lung function. At the International Conference of Chinese Rheumatologists 2025, Professor Rohit Aggarwal from the Division of Rheumatology, University of Pittsburgh, US, discussed the therapeutic role of nintedanib as an antifibrotic in CTD-ILD management and shared recent updates from international guidelines.
CTD-ILD: Pathophysiology and treatment challenges
ILD is common among autoimmune diseases, where inflammation drives pulmonary fibrosis, and fibrosis in turn feeds back into inflammation. Even when inflammation is controlled with immunosuppressants, self-sustaining fibrosis may persist. [Arthritis Res Ther 2010;12:213; Rheumatology (Oxford) 2018;57:204-205; EBioMedicine 2019;50:379-386; Eur Respir J 2019;54:1900161]
“Patients whose rheumatoid arthritis [RA] is controlled with resolution of inflammation may continue to experience ILD progression. ILD contributes to irreversible lung damage and early mortality in CTDs, and patients with RA-associated ILD [RA-ILD] face significantly lower survival than those with RA alone,” explained Aggarwal. “Therefore, rheumatologists play an important role in ILD management by using antifibrotics in addition to immunosuppressants to keep the fibrosis under control.” [Arthritis Rheum 1994;37:1283-1289; Arthritis Rheum 2010;62:1583-1591; Ann Rheum Dis 2025;S0003-4967(25)04320-1]
Why initiate antifibrotics early?
“When monitoring lung function, it is important to note that periods of relative stability in forced vital capacity [FVC] do not mean that lung function will remain stable in the future. The overall trend should be assessed to determine whether progression is occurring,” Aggarwal emphasized. “If progression is identified, immunosuppressive therapy should be started and optimized, followed by addition of antifibrotics to slow the decline in FVC.” [Chest 2014;145:579-585; Ann Rheum Dis 2020;80:219-227; Ann Rheum Dis 2025;S0003-4967(25)04320-1; Arthritis Care Res (Hoboken) 2024;76:1051-1069]
In Hong Kong, nintedanib is the only antifibrotic approved for progressive pulmonary fibrosis and systemic sclerosis associated ILD (SSc-ILD). As a small-molecule tyrosine kinase inhibitor, nintedanib targets multiple kinases, including platelet-derived growth factor receptor α and β, fibroblast growth factor receptor 1–3, and vascular endothelial growth factor receptor 1–3, thereby inhibiting intracellular signalling pathways that drive fibrotic tissue remodelling in ILD. [Ofev Hong Kong Prescribing Information; Pirfenidone US prescribing information]
In the double‑blind, placebo‑controlled, phase III INBUILD trial involving 663 patients with progressive fibrosing ILD, of whom 25.6 percent had autoimmune ILDs (including RA-ILD, SSc-ILD, mixed CTD [MCTD]-ILD), nintedanib significantly reduced the rate of FVC decline by 107 mL/year vs placebo over 52 weeks (p<0.001). (Figure) In patients with autoimmune-ILD , the reduction difference was 104.0 mL/year with nintedanib vs placebo. [N Engl J Med 2019;381:1718- 1727; Lancet Respir Med 2020;8:453-460]
The benefit of combining nintedanib with immunosuppressants was further explored in the SENSCIS trial. In patients with SSc-ILD, nintedanib reduced the annual rate of FVC decline by 41 mL vs placebo (p=0.04). A subgroup analysis showed that in patients already receiving mycophenolate at baseline, nintedanib still provided a numerical reduction of 26.3 mL in the annual rate of FVC decline vs placebo, suggesting an additive benefit of the combination in slowing ILD progression. [N Engl J Med 2019;380:2518-2528; Lancet Respir Med 2021;9:96-106]
Beyond slowing FVC decline, nintedanib has demonstrated survival benefits in real-world setting when initiated early in combination with immunosuppressive therapy. In a retrospective study of patients with idiopathic inflammatory myopathy–associated ILD (IIM-ILD), patients who received nintedanib in combination with immunosuppressant after diagnosis had better survival than those receiving immunosuppression alone, even after propensity score matching (p=0.016). [Front Med (Lausanne) 2021;8:626953]
“Initiating nintedanib early was protective for survival,” commented Aggarwal. “Treat all CTD‑ILD patients with immunosuppressive drugs, maximize and optimize that as best as you can, and then determine which patients, under which conditions, need additional antifibrotic therapy.”
Common adverse events (AEs) associated with nintedanib include diarrhoea, nausea, vomiting, and decreased weight. In addition to symptomatic treatment, dose reduction or temporary interruption may be used to manage these AEs until they resolve to a level that allows continuation of therapy. [Ofev Hong Kong Prescribing Information]
International guideline re-commendations for CTD-ILD
The use of antifibrotics is recommended by the European Respiratory Society/European Alliance of Associations for Rheumatology (ERS/EULAR) 2025 and American College of Rheumatology/College of Chest Physicians (ACR/CHEST) 2023 guidelines for managing CTD-ILD. [Ann Rheum Dis 2025;S0003-4967(25)04320-1; Arthritis Care Res (Hoboken) 2024;76:1051-1069]
According to ERS/EULAR, in SSc-ILD, nintedanib should be used in patients with ≥10 percent fibrosis on high-resolution CT (HRCT) or in those at high risk of progression. “If ILD is the main clinical problem, starting nintedanib early is beneficial. In patients at high risk of progression, nintedanib should be added to immunosuppressive therapy, even before progression occurs,” said Aggarwal. [Ann Rheum Dis 2025;S0003- 4967(25)04320-1]
In IIM-ILD and RA-ILD with well-controlled arthritis, antifibrotics or a combination of immunosuppressive therapy and nintedanib are recommended for patients who develop progressive pulmonary fibrosis despite maximized immunosuppression. [Ann Rheum Dis 2025;S0003-4967(25)04320-1]
“Nintedanib alone or combined with an immunosuppressant is also recommended for other CTD-ILDs in patients with progressive pulmonary fibrosis,” stated Aggarwal. [Ann Rheum Dis 2025;S0003- 4967(25)04320-1]
Additionally, ACR/CHEST recommends ILD screening primarily in patients with systemic autoimmune rheumatic diseases (SARDs) who have an increased risk of developing ILD, while ERS/EULAR strongly recommends ILD screening in all patients with SSc or MCTD, or patients with IIM and risk factors for ILD. Both HRCT and pulmonary function tests (PFTs) are recommended as screening modalities by ACR/CHEST, while HRCT is supported by ERS/EULAR. To determine ILD risk, patients should be assessed using risk factors unique to each SARD according to ACR/CHEST and to each CTD according to ERS/EULAR. [Arthritis Rheumatol 2024;76:1201-1213; Ann Rheum Dis 2025;S0003-4967(25)04320-1]
Both guidelines also provide recommendations on monitoring frequency. ACR/CHEST recommends PFTs every 3–6 months in SSc-ILD and IIM-ILD, or every 3–12 months in RA/MCTD/Sjögren disease-ILD, with HRCT performed as clinically indicated. In high-risk patients, ERS/ EULAR advises PFTs every 3–6 months early in the disease course and then every 6–12 months, with HRCT at 12 months and annually thereafter. [Arthritis Rheumatol 2024;76:1201-1213; Ann Rheum Dis 2025;S0003-4967(25)04320-1]
Conclusion
Antifibrotic therapy with nintedanib slows lung function decline and provides potential survival benefit, with its use supported by international guidelines for CTD-ILD management.
