Janus kinase (JAK) inhibitors have emerged as a promising therapeutic option for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), a severe extra-articular manifestation with significant morbidity and mortality. This review synthesizes current evidence on the mechanisms and clinical efficacy of JAK inhibitors in RA-ILD.

This review was conducted by drawing from preclinical studies, observational cohorts, meta-analyses, and real-world data up to 2025.

Preclinical studies reveal a dual mechanism of action: JAK inhibitors suppress the pro-fibrotic interleukin-17A (IL-17A)/JAK2/nuclear factor kappa B (NF-κB) axis in lung fibroblasts and modulate pulmonary immunity by expanding myeloid-derived suppressor cells (MDSCs), thereby attenuating both inflammatory and fibrotic processes. These effects are particularly relevant given the role of tertiary lymphoid structures and local autoantibody production in RA-ILD pathogenesis.

Clinical evidence, primarily from observational studies and systematic reviews, indicates that JAK inhibitors do not increase the risk of incident ILD and may even reduce it compared to certain biologic agents such as adalimumab. In patients with established RA-ILD, JAK inhibitor therapy is associated with stabilization or modest improvement in forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLCO), and high-resolution computed tomography (HRCT) findings. Pooled analyses demonstrate a mean increase of +2.07% in predicted FVC and +3.12% in predicted DLCO, with radiological improvement in approximately 11% of patients. Comparative studies suggest efficacy and safety profiles similar to abatacept and rituximab, with no significant differences in drug persistency or pulmonary outcomes.

However, recent large-scale real-world data raise important safety considerations. A 2025 propensity-matched study involving over 1,600 RA-ILD patients found that JAK inhibitors were associated with higher all-cause mortality (HR 1.46), hospitalization (HR 1.17), and mechanical ventilation (HR 2.61) compared to tumor necrosis factor (TNF) inhibitors. These risks were particularly pronounced in patients aged over 65 years and those with cardiovascular comorbidities, underscoring the need for careful patient selection.

Emerging evidence on combination therapy, such as tofacitinib with iguratimod, shows promise in improving lung function and HRCT fibrosis scores in usual interstitial pneumonia (UIP) pattern RA-ILD, though data remain preliminary. The potential for combining JAK inhibitors with antifibrotic agents like nintedanib represents an unexplored avenue that warrants future investigation.

Despite accumulating evidence, significant gaps remain. The overall quality of data is moderate to low, with no randomized controlled trials specifically designed for JAK inhibitors in RA-ILD. Heterogeneity in study design, outcome definitions, and follow-up durations limits direct comparability. Ongoing prospective trials (e.g., PULMORA, RAILDTo) may provide higher-certainty evidence in the coming years.

In conclusion, JAK inhibitors offer a mechanistically rational and clinically effective oral option for RA-ILD, with evidence supporting disease stabilization and potential superiority over TNF inhibitors in reducing ILD risk. However, their use requires individualized risk-benefit assessment, particularly in older adults and those with cardiovascular risk factors, where alternative agents such as abatacept or rituximab may be preferred. Dedicated randomized trials are urgently needed to establish their definitive role and optimize treatment sequencing in this vulnerable population.