Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: A systematic literature review
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.
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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.
References (139)
- et al.
Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate
Semin Arthritis Rheum
(1987) - et al.
Pneumonitis complicating low-dose methotrexate therapy for rheumatoid arthritis. Discrepancies between lung biopsy and bronchoalveolar lavage findings
Chest
(1993) - et al.
Pulmonary function in patients receiving long-term low-dose methotrexate
Chest
(1996) - et al.
A case of acute pneumonitis associated with leflunomide treatment
Respiry Med Extra
(2005) - et al.
An elderly man with rheumatoid arthritis and dyspnea
Chest
(2009) - et al.
Sulfasalazine-induced pulmonary disease
Chest
(1992) - et al.
Acute organizing interstitial pneumonia and interstitial nephritis due to salazosulfapyridine in a patient with rheumatoid arthritis
Allergol Int
(2003) - et al.
Exacerbation of interstitial lung disease during etanercept therapy: two cases
Joint Bone Spine
(2008) - et al.
Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition
Chest
(2002) - et al.
Organizing pneumonia after rituximab therapy: two cases
Joint Bone Spine
(2008)
Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial
Lancet
Methotrexate pulmonary toxicity
Rheum Dis Clin North Am
High-resolution computed tomography of drug-induced lung disease
Clin Radiol
Extra-articular rheumatoid arthritis
Curr Opin Rheumatol
Risk of serious bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha antagonists
Arthritis Rheum
Incidences of overall and site specific cancers in TNFalpha inhibitor treated patients with rheumatoid arthritis and other arthritides—a follow-up study from the DANBIO Registry
Ann Rheum Dis
Gold-induced hypersensitivity pneumonitis in a patient with rheumatoid arthritis
Clin Exp Rheumatol
Methotrexate pulmonary toxicity
Expert Opin Drug Saf
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA Statement
Br Med J
Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis
Arthritis Rheum
Methotrexate pneumonitis after low-dose therapy for rheumatoid arthritis
Arthritis Rheum
Pneumonitis complicating low-dose methotrexate therapy in rheumatoid arthritis
Arch Intern Med
Low dose methotrexate pneumonitis in rheumatoid arthritis
Thorax
Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature
J Rheumatol
Fatal methotrexate pneumonitis in rheumatoid arthritis
Arthritis Rheum
Life threatening acute pneumonitis during low dose methotrexate treatment for rheumatoid arthritis: a case report and review of the literature
Ann Rheum Dis
Toxicity of methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. A case-control study of 131 patients
Arch Intern Med
Successful reintroduction of methotrexate after pneumonitis in two patients with rheumatoid arthritis
Ann Rheum Dis
Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports
Thorax
Methotrexate pneumonitis in rheumatoid arthritis—a dramatic response to treatment
Br J Rheumatol
Concurrent acute megaloblastic anaemia and pneumonitis: a severe side-effect of low-dose methotrexate therapy during rheumatoid arthritis
Clin Rheumatol
Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis
Thorax
Methotrexate-related pulmonary complications in patients with rheumatoid arthritis: cluster of five cases in a period of three months
Ann Rheum Dis
Occurrence of pulmonary complications during methotrexate therapy in rheumatoid arthritis
Br J Rheumatol
Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review
Arthritis Rheum
Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pneumonitis
J Rheumatol
Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature
Clin Rheumatol
Rheumatoid arthritis associated with methotrexate-induced pneumonitis: improvement with i.v. cyclophosphamide therapy
Clin Exp Rheumatol
Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients
Eur Respir J
Two fatal cases of methotrexate-induced interstitial pneumonitis
Nihon Kokyuki Gakkai Zasshi
Methotrexate pneumonitis in a patient with rheumatoid arthritis
J Microbiol Immunol Infect
Methotrexate pneumonia lacking dyspnea and radiographic interstitial patterns during treatment for early rheumatoid arthritis: bronchoalveolar lavage and transbronchial lung biopsy in a differential diagnosis
Mod Rheumatol
Methotrexate pneumonitis precipitated by switching from oral to parenteral administration
Rheumatology (Oxford)
Methotrexate-induced diffuse interstitial pulmonary fibrosis
South Med J
Fatal pulmonary fibrosis complicating low dose methotrexate therapy for rheumatoid arthritis
J Rheumatol
Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study
Br J Rheumatol
Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests
Rheumatology (Oxford)
Effect of methotrexate on pulmonary function in patients with rheumatoid arthritis—a prospective study
Rheumatol Int
Rheumatoid arthritis complicated with acute interstitial pneumonia induced by leflunomide as an adverse reaction
Intern Med
Leflunomide induced acute interstitial pneumonia
J Rheumatol
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