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


CONCLUSIONS
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.
Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), Notre-Dame Hospital, Montreal, Quebec, Canada.
Camille
C
Roubille
Department of Medicine, Rheumatic Disease Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada; Institut de rhumatologie de Montréal, 1551 Ontario St East, Montreal, Quebec, Canada H2L 1S6. Electronic address: boulos.haraoui@ssss.gouv.qc.ca.
Boulos
B
Haraoui
D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D001685:Biological Factors / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000139:chemically induced*
D018501:Antirheumatic Agents; D001685:Biological Factors
Interstitial lung disease; Leflunomide; Methotrexate; Pneumonitis; Pulmonary fibrosis; Rheumatoid arthritis; Rituximab; TNF inhibitors; Tocilizumab