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Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case–control study

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Abstract

The objective of the study was to identify risk factors for acute exacerbation of interstitial lung disease (ILD) during tocilizumab treatment in patients with rheumatoid arthritis (RA). This is a retrospective, case–control study. We reviewed 395 consecutive RA patients who received tocilizumab. First, we divided the patients according to the presence (RA-ILD) or absence of ILD (non-ILD) assessed by chest X-ray or high-resolution computed tomography, and compared them for characteristics relevant to RA-ILD. Subsequently, focusing on the patients with RA-ILD, we assessed their baseline characteristics and clinical courses comparing patients with acute exacerbation to those without. Comparing 78 with ILD and 317 without ILD, the following were identified as factors related to RA-ILD on multivariate analysis: age 60 years or older (OR 4.5, 95 % CI 2.2–9.4, P < 0.0001), smoking habit (OR 2.9, 95 % CI 1.5–5.5, P = 0.002), and high rheumatoid factor levels (OR 2.8, 95 % CI 1.4–5.5, P = 0.002). Of 78 RA-ILD patients, six developed acute exacerbation during tocilizumab treatment. The median duration between the initiation of tocilizumab treatment and the acute exacerbation occurrence was 48 weeks. While baseline characteristics did not differ between acute exacerbation and non-acute exacerbation groups, patients experiencing acute exacerbation had significantly higher Clinical Disease Activity Index (CDAI) at 24 weeks (20.8 vs. 6.2, P = 0.019). Univariate analysis showed that CDAI > 10 at 24 weeks was a risk factor for acute exacerbation (OR 4.7, 95 % CI 2.1–10.4, P = 0.02). Uncontrolled arthritis activity during tocilizumab treatment may be associated with acute exacerbation of RA-ILD, suggesting post-treatment monitoring of disease activity is important not only with respect to RA itself but also for RA-ILD.

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Acknowledgments

We sincerely thank all the physicians and others caring for the patients enrolled in this study.

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Mitsuhiro Akiyama, Yuko Kaneko, Kunihiro Yamaoka, Harumi Kondo & Tsutomu Takeuchi

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  1. Mitsuhiro Akiyama
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  2. Yuko Kaneko
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  3. Kunihiro Yamaoka
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  4. Harumi Kondo
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  5. Tsutomu Takeuchi
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Correspondence to Tsutomu Takeuchi.

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Conflict of interest

Yuko Kaneko has received consultancies, speaking fees, and honoraria from Astellas Pharma, Astellas Pharma, Chugai Pharmaceutical Co, Ltd., Bristol–Myers K.K., Eisai Co., Ltd., Kissei Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Taisho Toyama Pharma Co., and UCB. Kunihiro Yamaoka has received consultancies, speaking fees, and honoraria from Pfizer Japan Inc., Chugai Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd, GlaxoSmithkline, Nipponkayaku Co., Ltd, Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Eisai Co., Ltd., Astellas Pharma, and Acterlion Pharmaceuticals. Tsutomu Takeuchi has received consultancies, speaking fees, and honoraria from Astellas Pharma, Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahikasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd, Nipponkayaku Co., Ltd, Astra Zeneca K.K., Eli Lilly Japan K.K., and Novartis Pharma K.K. Mitsuhiro Akiyama and Harumi Kondo declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and with the 1964 Helsinki declaration and comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Supplementary Figure

Clinical courses in patients with rheumatoid arthritis–interstitial lung disease after initiation of tocilizumab. a. Changes in the disease activity score in 28 joints (DAS28) with and without acute exacerbation. Line in the non-acute exacerbation group shows the mean ± SD. b. Comparison of disease activity based on DAS28 at 24 weeks after tocilizumab initiation between RA-ILD patients with and without acute exacerbation. c. Comparison of proportions of remission or low disease activity in DAS28 at 24 weeks after tocilizumab initiation between RA-ILD patients with and without acute exacerbation. d. Comparison of the proportion of acute exacerbation events between the “remission and low disease activity” group and the “moderate and high disease activity” group in DAS28. * P < 0.05 by the Mann–Whitney U test. Abbreviations: RA, rheumatoid arthritis; CDAI, the Clinical Disease Activity Index (TIFF 103 kb)

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Akiyama, M., Kaneko, Y., Yamaoka, K. et al. Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case–control study. Rheumatol Int 36, 881–889 (2016). https://doi.org/10.1007/s00296-016-3478-3

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