Background While dramatic progress has been made in this decade with treatments for rheumatoid arthritis (RA), such as methotrexate (MTX) and biological agents, concern about the safety, including the occurrence of malignancy, of these highly effective drugs still exists in daily clinical practice. There has not been an evident association between the use of biological agents and the occurrence of malignancy in most reports from clinical trials¹ and observational studies², although MTX use might be associated with the development of malignant lymphoma, called MTX-associated lymphoproliferative disorder³, in patients with RA. In an analysis of risk factors for overall and site-specific malignancies in Japanese patients with RA, higher disease activity was identified to be a risk factor for overall malignancies (hazard ratio [HR] 1.10, 95% CI 1.02–1.19), suggesting that tight control of RA disease activity would reduce the occurrence of malignancies in patients with RA⁴. However, the risk of malignancies with RA treatments including MTX and biological agents was not assessed in that analysis.

Objectives We investigated the association between the occurrence of malignancies (overall and malignant lymphoma) and drug use (MTX and biological agents) in a large observational cohort of Japanese patients with RA over a long-term period.

Methods Among Japanese patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort from April 2000 to September 2013, data for all malignancies were extracted from patients' self-reports and confirmed by medical records. Data for malignancies occurring in patients who dropped out of the IORRA study during the subsequent three months were also collected from medical information from affiliated hospitals. We analysed whether MTX and biological agents were risk factors for overall malignancy and malignant lymphoma using a marginal structural Cox proportional hazards model⁵ adjusted for age, gender, smoking history, body mass index, RA disease duration, rheumatoid factor positivity and disease activity (28-joint disease activity score).

Results Among 11,106 Japanese patients with RA representing 68,483 person-years, 507 overall malignancies, including 68 malignant lymphomas, were confirmed. Neither MTX nor biological agent use was a significant risk factor for overall malignancy, with an HR (95% CI) of 1.18 (0.77–1.81) and 1.01 (0.65–1.57), respectively, or for malignant lymphoma, with an HR (95% CI) of 1.17 (0.55–2.48) and 1.26 (0.43–3.64), respectively.

Conclusions The use of MTX and biological agents was not significantly associated with the occurrence of overall malignancy or malignant lymphoma during long-term longitudinal observation of Japanese patients with RA.

References

1. Moulis G, et al. PLoS One. 2012;7:e48991.

2. Mariette X, et al. Ann Rheum Dis. 2011;70:1895–904.

3. Kameda T, et al. Arthritis Care Res (Hoboken). 2014;66:1302–9.

4. Sugimoto N, et al. EULAR Congress 2016;FRI0143.

5. Choi HK, et al. Lancet. 2002;359:1173–7.

References

Disclosure of Interest N. Sugimoto Speakers bureau: Takeda Pharmaceutical and Bristol Myers Squibb., E. Tanaka Consultant for: Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Pfizer, Takeda Pharmaceutical, and Ayumi Pharmaceutical., Speakers bureau: Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Pfizer, Takeda Pharmaceutical, and Ayumi Pharmaceutical., E. Inoue: None declared, M. Kawano: None declared, M. Ochiai: None declared, Y. Shimizu: None declared, R. Yamaguchi: None declared, K. Ikari Grant/research support from: Astellas, UCB, Bristol-Meyers, Pfizer, Eisai, Tanabe-Mitsubishi, Chugai, AbbVie, Janssen Pharmaceutical, Otsuka, Kaken, Asahi-Kasei, Hisamitsu and Takeda., Speakers bureau: Astellas, UCB, Bristol-Meyers, Pfizer, Eisai, Tanabe-Mitsubishi, Chugai, AbbVie, Janssen Pharmaceutical, Otsuka, Kaken, Asahi-Kasei, Hisamitsu and Takeda., A. Nakajima Consultant for: Bristol-Meyers, Mitsubishi Tanabe Pharma, Nippon Kayaku Co. Ltd., Novartis Pharma, Pfizer, Siemens Healthcare Diagnostics K.K. and Takeda Pharmaceutical Company., Speakers bureau: Bristol-Meyers, Mitsubishi Tanabe Pharma, Nippon Kayaku Co. Ltd., Novartis Pharma, Pfizer, Siemens Healthcare Diagnostics K.K. and Takeda Pharmaceutical Company., A. Taniguchi Grant/research support from: AbbVie, Eisai, Takeda, Tanabe-Mitsubishi, Teijin Pharma, Pfizer., Speakers bureau: AbbVie, Eisai, Takeda, Tanabe-Mitsubishi, Teijin Pharma, Pfizer., H. Yamanaka Grant/research support from: MSD, Ayumi, AbbVie, Eisai, Ono, Astellas, Daiichi-Sankyo, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, Torii, Nippon Shinyaku, Pfizer. UCB. Nippon Kayaku, YL biologics, Bayer and Bristol-Meyers., Consultant for: MSD, Ayumi, AbbVie, Eisai, Ono, Astellas, Daiichi-Sankyo, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, Torii, Nippon Shinyaku, Pfizer. UCB. Nippon Kayaku, YL biologics, Bayer and Bristol-Meyers., Speakers bureau: MSD, Ayumi, AbbVie, Eisai, Ono, Astellas, Daiichi-Sankyo, Taisyo-Toyama, Takeda, Tanabe-Mitsubishi, Chugai, Teijin Pharma, Torii, Nippon Shinyaku, Pfizer. UCB. Nippon Kayaku, YL biologics, Bayer and Bristol-Meyers.