Tacrolimus-induced pulmonary injury in rheumatoid arthritis patients
Introduction
Tacrolimus (TAC), a potent calcineurin inhibitor derived from Streptomyces species found in soil [1], is an immunosuppressant used widely for treating graft-versus-host disease following organ or bone marrow transplantation [2]. It has been proven that TAC is clinically effective for some autoimmune diseases, including rheumatoid arthritis (RA) [3], [4], [5], systemic lupus erythematosus [6], and dermatomyositis [7], [8]. Accordingly, TAC was approved since 2005 in Japan for RA patients having inadequate response to other disease-modifying anti-rheumatic drugs (DMARDs).
Although several clinical trials of the drug revealed that TAC significantly improved the signs and symptoms of RA, implementation of a post-marketing surveillance program was required as a condition for approval to collect safety data in actual practice. The post-marketing surveillance program and spontaneous reports to a pharmaceutical company (Astellas Pharma, Inc.) identified 27 cases of exacerbation or new development of interstitial pneumonia among RA patients receiving TAC in Japan as of May 2007 [9], [10].
'The main differential diagnosis of TAC-induced pulmonary injury (TIPI) includes (i) the exacerbation of interstitial pneumonia due to RA (rheumatoid lung), (ii) an opportunistic pulmonary infection with interstitial lesions seen on chest X-ray, and (iii) pulmonary injury due to treatment with concomitant drugs. The diagnosis of pulmonary injury during RA treatment is challenging, and often puzzling, for clinical rheumatologists and pulmonologists.
The present study is a case series of TIPI in RA patients. The objective of this study was to analyze clinical and radiological data of RA patients with TIPI and to extract characteristics of the adverse event.
Section snippets
Patients and diagnostic criteria
RA was diagnosed according to the revised classification criteria for RA by American College of Rheumatology [11] in each institution. In August, 2008, letters requesting participation in our goal to describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI) were sent to attending physicians who either reported interstitial pneumonia as an adverse event in the post-marketing surveillance program or sent spontaneous reports to the pharmaceutical company. We
Demographic characteristics of the enrolled patients
One of the eleven cases was eliminated from the analysis because of a lack of radiological data other than a standard chest X-ray. Baseline data of the remaining ten patients were a mean age of 69.7 years; 70% were female; the mean disease duration of RA was 9.1 years; and pulmonary comorbidities were observed in 90% of the patients. Pre-existing pulmonary lesions of seven patients were compatible with those observed in collagen diseases including RA and they were expressed as the collagen
Discussion
Drug-induced pulmonary injury is particularly important in the management of RA because most chemical and biological DMARDs are known to cause pulmonary injuries [15], [16]. Methotrexate is known to induce pulmonary injury not only by direct toxicity to alveolar epithelial cells but also by possible allergic effects, independent of dose [17]. Leflunomide has been regarded as a DMARD with low pulmonary toxicity based on the results from clinical trials [18], [19]. Unfortunately, de novo or
Funding
This work was supported by a grant-in-aid for scientific research (KAKENHI) from the Japan Society for the promotion of science (grant-in-aid #20390158 to M.H. and #19590530 to R.K.). This work was also supported by a grant-in-aid from the Ministry of Health, Labor and Welfare, Japan (#2401980) to N.M. and M.H. This work was also supported by Global Center of Excellence (GCOE) program, ‘International Research Center for Molecular Science in Tooth and Bone Diseases’.
Conflict of interest
Nobuyuki Miyasaka and Masayoshi Harigai received a research grant from Astellas. Masayoshi Harigai received honoraria from Astellas. There is no other competing interest for the other authors regarding this article.
Acknowledgments
We would like to thank Drs. Koichi Amano (Saitama Medical University), Masahiro Iwamoto (Jichi Medical University), and Noriyoshi Ogawa (Hamamatsu University School of Medicine) for their critical discussion as members of sub-committee of tacrolimus post-marketing surveillance in Japan College of Rheumatology (JCR).
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