Efficacy and Safety of Combined Immunosuppressive Therapy with High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Disease Accompanied By Anti-MDA5-Positive Dermatomyositis -a Multicenter Prospective Study

Hideaki Tsuji¹, Ran Nakashima¹, Yoshitaka Imura², Masato Yagita², Hajime Yoshifuji¹, Shintaro Hirata³, Takaki Nojima³, Eiji Sugiyama⁴, Kazuhiro Hatta⁵, Yoshio Taguchi⁶, Masaki Katayama⁷, Shuji Akizuki¹, Kosaku Murakami¹, Motomu Hashimoto⁸, Masao Tanaka⁸, Koichiro Ohmura¹ and Tsuneyo Mimori⁹, ¹Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan, ²Department of Clinical Immunology and Rheumatology, The Tazuke-Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan, ³Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan, ⁴Department of Clinical Immunology and Rheumatology, Department of Clinical Immunology and Rheumatology, Hiroshima University Hospital, Hiroshima, Japan, ⁵Department of General Medicine, Tenri Hospital, Tenri, Japan, ⁶Department of Respiratory Medicine, Tenri Hospital, Tenri, Japan, ⁷Department of Rheumatology and Clinical Immunology, Osaka Red Cross Hospital, Osaka, Japan, ⁸Department of Advanced Medicine for Rheumatic Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan, ⁹Department of Rheumatology and Clinical Immunology, Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: autoantibodies, clinical trials, dermatomyositis, immunosuppressants and interstitial lung disease

Session Information

Date: Sunday, October 21, 2018

Title: 3S037 ACR Abstract: Plenary Session I (835–839)

Session Type: ACR Plenary Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Interstitial lung disease (ILD) accompanied by anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis (DM) is often rapidly progressive and associated with poor life prognosis in Japanese patients. However, the standard treatment for such intractable cases had not been established, although some case reports have suggested possible efficacy of combined immunosuppressive therapy. Therefore, we evaluated the efficacy and safety of combined immunosuppressive regimen as a prospective trial for anti-MDA5-positive DM with ILD.

Methods: Anti-MDA5 was detected by protein-immunoprecipitation using ³⁵S-methionine-labeled HeLa cells. Newly onset adult Japanese anti-MDA5-positive DM patients with ILD were enrolled in multi-centers from July 2014 to September 2017. They were treated with combined immunosuppressive regimen of high-dose glucocorticoids (GC), tacrolimus, and intravenous cyclophosphamide. Plasmapheresis was also added if the patients got worse and needed oxygenation even after the regimen started. As the primary endpoint, their six-month survival was compared with a historical control of anti-MDA5-positive DM with ILD who received step-up treatment started with high-dose GC and gradually intensified by the addition of immunosuppressants. The alteration of serum ferritin level, anti-MDA5 titer (MESACUP™ anti-MDA5 test), and respiratory functions were also compared before and after treatment.

Results: The combined immunosuppressive regimen group (n=26) showed significantly better survival than the historical control (n=15) (6-month survival; 89% and 33%, respectively, p<0.0001) (Figure 1). At week 52, anti-MDA5-titer and serum ferritin level were decreased and %vital capacity was increased (Figure 2). During 52 weeks, cytomegalovirus reactivation was frequently observed in the combined immunosuppressive regimen group (90% vs 33%, respectively, p=0.0002). When the survived (18 cases) and the deceased (4 cases) in combined immunosuppressive regimen group were compared, frequency of skin ulcer (11% vs 75%, respectively, p=0.01), positivity of CRP (39% vs 100%, respectively, p=0.01), and serum ferritin level (468.3±561.8 ng/mL vs 2050.3±1772.8 ng/mL, respectively, p=0.01) before treatment were significantly higher in the deceased patients.

Conclusion: Early treatment with combination immunosuppressive therapy improves the survival of anti-MDA5-positive DM with ILD. Opportunistic infections such as cytomegalovirus reactivation should be carefully monitored and treated during the treatment.

Disclosure: H. Tsuji, None; R. Nakashima, Medical & Biological Laboratories Co., Ltd., 9; Y. Imura, None; M. Yagita, None; H. Yoshifuji, None; S. Hirata, None; T. Nojima, None; E. Sugiyama, None; K. Hatta, None; Y. Taguchi, None; M. Katayama, None; S. Akizuki, None; K. Murakami, None; M. Hashimoto, Astellas, 2,Bristol-Myers Squibb, 2,Mitsubishi-Tanabe, Chugai, Ayumi, and UCB Japan, 3; M. Tanaka, Mitsubishi-Tanabe, Chugai, AYUMI and UCB Japan, 3,Pfizer, Astellas, AbbVie GK, Taisyo Toyama, Takeda and Eisai, 9; K. Ohmura, None; T. Mimori, Acterion, Astellas, Asahi Kasei Pharma, Ayumi, Chugai, Daiichi Sankyo, Eisai, JB, Mitsubishi-Tanabe, MSD, Nippon Shinyaku, Pfizer, Sanofi, and Takeda, 2,Bristol-Myers Squibb, Chugai, and Mitsubishi-Tanabe, 8,the Japan Society for the Promotion of Science (JP25293222 and 16H05341), 9.

To cite this abstract in AMA style:

Tsuji H, Nakashima R, Imura Y, Yagita M, Yoshifuji H, Hirata S, Nojima T, Sugiyama E, Hatta K, Taguchi Y, Katayama M, Akizuki S, Murakami K, Hashimoto M, Tanaka M, Ohmura K, Mimori T. Efficacy and Safety of Combined Immunosuppressive Therapy with High-Dose Glucocorticoid, Tacrolimus, and Cyclophosphamide in Interstitial Lung Disease Accompanied By Anti-MDA5-Positive Dermatomyositis -a Multicenter Prospective Study – [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/efficacy-and-safety-of-combined-immunosuppressive-therapy-with-high-dose-glucocorticoid-tacrolimus-and-cyclophosphamide-in-interstitial-lung-disease-accompanied-by-anti-mda5-positive-dermatomyositis/. Accessed .

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