Large network meta-analysis challenges longstanding concerns over methotrexate while highlighting potential roles for abatacept combinations, antifibrotics, and JAK inhibitors in rheumatoid arthritis-associated interstitial lung disease.
Methotrexate may deserve a fresh look in patients with rheumatoid arthritis-associated interstitial lung disease, with a major network meta-analysis finding the conventional DMARD was associated with the lowest all-cause mortality despite decades of concern about pulmonary toxicity.
The analysis, published in the Journal of Autoimmunity, compared 14 pharmacological regimens across 27 studies involving 8186 patients with RA-ILD, making it one of the largest comparative assessments of treatment options for this serious extra-articular manifestation of rheumatoid arthritis.
Investigators found methotrexate was associated with an 85% reduction in all-cause mortality compared with standard therapy (OR 0.15), while tocilizumab (OR 0.28) and rituximab (OR 0.33) were also associated with significantly lower mortality.
However, the researchers cautioned that these findings were largely based on observational data and should be regarded as hypothesis-generating rather than practice-changing.
The results add to a growing body of evidence challenging the long-held belief that methotrexate should routinely be avoided in RA-ILD because of concerns about lung toxicity.
The researchers noted that patients selected for methotrexate in observational studies may have had milder lung disease or fewer contraindications, creating the potential for confounding by indication.
“Therefore, the observed association between MTX and lower mortality should not be interpreted as definitive evidence of a causal protective effect,” they wrote.
“Rather, it supports the hypothesis that MTX may not be uniformly harmful in selected RA-ILD patients and warrants confirmation in prospective controlled studies.”
For slowing disease progression, abatacept combined with methotrexate ranked highest, with a markedly reduced risk of ILD progression compared with control therapy (OR 0.07).
The researchers said the combination’s complementary immunomodulatory effects may explain the benefit.
Among antifibrotic therapies, both nintedanib and pirfenidone were associated with better preservation of forced vital capacity or slower decline in lung function, consistent with previous randomised trials. Immunoglobulin therapy produced the largest improvement in predicted forced vital capacity, although evidence came from relatively few patients.
Janus kinase inhibitors emerged as the most tolerable option overall, recording the lowest treatment discontinuation rate at 7.9% and the highest drug retention rate of 81.7%.
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However, the authors cautioned that tolerability should not be confused with safety. Although patients were less likely to stop JAK inhibitor treatment, serious adverse events including respiratory failure and intensive care admission remained a concern, underscoring the need for careful patient selection and monitoring.
The findings broadly align with recent European Respiratory Society and EULAR guidance supporting antifibrotic therapy in progressive fibrosing disease while providing comparative estimates across a wider range of immunosuppressive and targeted therapies.
The researchers said the analysis may help clinicians individualise treatment decisions according to the dominant clinical problem.
Patients at high risk of ILD progression might be candidates for abatacept plus methotrexate with close safety monitoring, while those with progressive fibrosing disease may benefit from antifibrotic therapy.
JAK inhibitors could represent an alternative for patients requiring better treatment persistence who do not have significant infection risk factors.
Despite its size, the researchers emphasised that the evidence base remains limited. Twenty-five of the 27 included studies were observational, leaving results vulnerable to confounding, treatment selection bias and differences in baseline disease severity.
Rather than establishing a new treatment hierarchy, they concluded that the findings identified promising signals that should guide future prospective trials
