Tacrolimus-induced pulmonary injury in rheumatoid arthritis patients

https://doi.org/10.1016/j.pupt.2011.01.016Get rights and content

Abstract

Background

Tacrolimus (TAC) was approved in Japan in 2005 for rheumatoid arthritis (RA) patients having inadequate response to other disease-modifying anti-rheumatic drugs. As of May 2007, spontaneous reports identified twenty-seven cases of exacerbation or new development of interstitial pneumonia among RA patients given TAC in Japan.

Objective

To describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI).

Patients and methods

Eleven RA patients diagnosed with de novo pulmonary injury or exacerbation of IP during treatment with TAC were identified. Clinical, radiological, and laboratory data of ten of these cases were retrospectively analyzed.

Results

Baseline data for the ten patients were a mean age of 69.7 years; gender, 70% female; mean RA disease duration, 9.1 years; and pulmonary comorbidities, 90%. Six cases were classified as presumptive TAC-induced pulmonary injury (TIPI) and four as probable TIPI. Among the six presumptive cases, TIPI developed at an average of 84 days after initiation of treatment (n = 5) or four days after reinstitution of TAC (n = 1). Five cases were an exacerbation of pre-existing interstitial pneumonia and one was a de novo pulmonary injury. Radiological patterns of thoracic computed tomography (CT) scans of patients in the presumptive TIPI cases were hypersensitivity pneumonia like-pattern (n = 3), ground-glass opacity (n = 2), and organizing pneumonia-pattern (n = 1). All patients with presumptive TIPI were treated with high dosage glucocorticosteroids and one received concomitant immunosuppressants. Two of the six presumptive TIPI patients died.

Conclusion

Rheumatologists should be aware of this rare but potentially life-threatening adverse event in RA patients receiving TAC.

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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