The safety of biologic therapies in RA-associated interstitial lung disease

Key Points

  • Anti-TNF therapy has improved outcomes in rheumatoid arthritis (RA), but has also been associated with serious respiratory adverse events (SRAEs)

  • Biologic therapy might cause SRAEs by inducing idiosyncratic reactions, accelerating pre-existing ILD, modifying ILD into a more injurious phenotype or increasing susceptibility to infection

  • The risks associated with anti-TNF therapy in patients with RA-associated ILD (RA-ILD) remain uncertain; whether other biologic agents are safer is also still unclear

  • Given this uncertainty, careful assessment of patients before treatment and strict subsequent monitoring is required, particularly in patients at high risk of ILD progression, regardless of chosen treatment

  • We need to move towards a better understanding of the natural history of RA-ILD and the roles of new therapies in the management of this disease, which requires well-conducted research


Interstitial lung disease (ILD) is a common extra-articular manifestation associated with increased morbidity and mortality in patients with rheumatoid arthritis (RA). Early case reports of serious respiratory adverse events (SRAEs) following treatment with anti-TNF agents have led to concerns about biologic therapy in patients with RA-associated ILD (RA-ILD), and a tendency for biologic agents targeting factors other than TNF to be prescribed in such patients. At present, the appropriateness of such decisions is not clear. Given that the therapeutic goal for RA is remission, clinicians increasingly face the challenge of choosing the optimal biologic agent in patients with RA-ILD and uncontrolled joint disease. However, no evidence-based guidelines exist to guide physicians in deciding whether to commence biologic therapy in this setting, or in selecting which drug is most appropriate. Herein, we review the evidence for the comparative pulmonary safety of anti-TNF agents and non-TNF-targeting biologic agents in RA-ILD. In addition, we propose a framework for assessment of baseline disease severity to guide treatment decisions, and for monitoring during therapy. Because of substantial gaps in the available evidence, we also describe a research agenda aimed at obtaining data that will help inform future clinical practice.

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Figure 1: Classification of ILDs.
Figure 2: Suggested algorithm for assessment, monitoring and management of patients with RA-ILD on biologic therapy.


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The authors thank J. Ryu for reviewing the draft manuscript before submission. M. Jani is a Medical Research Council (MRC) Clinical Training Fellow supported by the North West England MRC Fellowship Scheme in Clinical Pharmacology and Therapeutics, which is funded by the MRC (grant number G1000417/94,909), with additional financial support from ICON, GSK, AstraZeneca and the Medical Evaluation Unit. W. G. Dixon acknowledges research funding from the MRC (Clinician Scientist Fellowship; G0902272).

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M. Jani and W. G. Dixon contributed to all stages of the preparation of the manuscript for submission, N. Hirani and E. L. Matteson made substantial contributions to discussion of content and review/editing of the manuscript before submission.

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Correspondence to William G. Dixon.

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Competing interests

M. Jani has received reimbursement for attending symposia from UCB and Pfizer. N. Hirani has received reimbursement for attending symposia from Boehringer-Ingelheim and has received research funding from the AstraZeneca. E. L. Matteson and W. G. Dixon declare no competing interests.

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Jani, M., Hirani, N., Matteson, E. et al. The safety of biologic therapies in RA-associated interstitial lung disease. Nat Rev Rheumatol 10, 284–294 (2014).

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