Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: A systematic literature review

https://doi.org/10.1016/j.semarthrit.2013.09.005Get rights and content

Abstract

Objective

To review published cases of induced or exacerbated interstitial lung disease (ILD) in rheumatoid arthritis (RA) associated with non-biologic disease-modifying antirheumatic drugs (nbDMARDs) and biologics and to discuss clinical implications in daily practice.

Methods

We performed a systematic literature review from 1975 to July 2013 using Medline, Embase, Cochrane, and abstracts from the ACR 2010–2012 and EULAR 2010–2013 annual meetings. Case reports and series that suggest a causative role of nbDMARDs (methotrexate [MTX], leflunomide [LEF], gold, azathioprine [AZA], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) and biologic agents (TNF inhibitors [TNFi], rituximab [RTX], tocilizumab [TCZ], abatacept [ABA], and anakinra) in causing ILD or worsening a pre-existing ILD in RA patients were included. Results from observational and postmarketing studies as well as reviews on this topic were excluded from the qualitative analysis but still considered to discuss the implication of such drugs in generating or worsening ILD in RA patients. Comparisons were made between MTX-induced ILD in RA and the cases reported with other agents, in terms of clinical presentation, radiological features, and therapeutic management and outcomes.

Results

The literature search identified 32 articles for MTX, 12 for LEF (resulting in 34 case reports), 3 for gold, 1 for AZA, 4 for SSZ, 27 for TNFi (resulting in 31 case reports), 3 for RTX, 5 for TCZ (resulting in 8 case reports), and 1 for ABA. No case was found for HCQ or anakinra. Common points are noted between LEF- and TNFi-related ILD in RA: ILD is a rare severe adverse event, mostly occurs within the first 20 weeks after initiation of therapy, causes dyspnea mostly in older patients, and can be fatal. Although no definitive causative relationship can be drawn from case reports and observational studies, these data argue for a pulmonary follow-up in RA patients with pre-existing ILD, while receiving biologic therapy or nbDMARDs.

Conclusion

As previously described for MTX, growing evidence highlights that LEF, TNFi, RTX, and TCZ may induce pneumonitis or worsen RA-related pre-existing ILD. Nonetheless, identifying a causal relationship between RA therapy and ILD-induced toxicity clearly appears difficult, partly because it is a rare condition.

Introduction

Rheumatoid arthritis (RA) has long been considered a systemic disease with extra-articular involvement including interstitial lung disease (ILD) [1]. Biologics and non-biological disease-modifying antirheumatic drugs (nbDMARDs) are the mainstay in the management of RA. Their symptomatic and structural efficacy is well established. On the other hand, especially since the advent of biologics, several observations have stressed certain adverse effects, some of them potentially life-threatening such as infections and malignancy [2], [3].

With regard to pulmonary toxicity, drug-induced ILD has been reported in the past as a rare but severe adverse event with almost all nbDMARDs, such as gold [4] and methotrexate (MTX) [5], and clinicians are usually aware of MTX-induced pneumonitis. By analogy, other nbDMARDs, such as leflunomide (LEF), and biologics were subsequently suspected to induce lung injury given that unexpected multiple cases of new-onset or exacerbation of ILD have been reported in association with almost every RA treatment. We decided to undertake a systematic literature research (SLR) in order to better characterize the magnitude of this problem.

Section snippets

Data sources and searches

We performed a systematic review [6] of articles published from 1975 to July 2013, restricted to English and French languages and to human adults, in Medline (via PubMed), Cochrane, and Embase databases, as well as abstracts presented at the American College of Rheumatology (ACR) 2010–2012 and European League Against Rheumatism (EULAR) 2010–2013 annual meetings, with the help of an experienced librarian. We also hand searched for relevant additional references. Main search terms were

Results

A total of 910 references were identified through database searching (Fig.). An additional 43 references from conference abstracts and hand-search screening were found. Of the 786 references screened after removing duplicates, the first step of the systematic review excluded 619 references that were not relevant to our topic. Of the remaining 167 references, 137 were selected for full-text review. Finally, 88 full case reports or series were selected for qualitative analysis. The other 49

Methotrexate

MTX-induced ILD is the prototype of drug-induced lung toxicity in RA patients. MTX-induced lung toxicity was first described in children treated for leukemia in 1969 [94], and later, in 1983, low doses of MTX were reported to induce pneumonitis in RA patients [7]. Acute pneumonitis can occur at any time during MTX therapy; its exact incidence is difficult to assess, but it is estimated to be between 0.3% and 8% of patients receiving MTX for rheumatic disorders including RA [28]. In a SLR of 88

Conclusion

Based on the recent multiple case reports and reviews, there was a general impression of increased pulmonary toxicity induced by the biologics and especially the TNFi, alone or in combination with MTX. However, this adverse effect, even potentially fatal, seems to be relatively rare based on this literature review. For MTX or LEF or TNFi, the estimated prevalence of possible induced ILD is around 1%. For comparison, estimates of the prevalence of ILD in RA range widely between 1% and 58% [135],

Acknowledgment

The authors are grateful to Virginia Wallis for her assistance with the manuscript preparation.

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