Risk factors for abnormal hepatic enzyme elevation by methotrexate treatment in patients with rheumatoid arthritis: A hospital based-cohort study

Abstract

Objectives: Methotrexate (MTX) is used as first-line treatment of rheumatoid arthritis (RA) worldwide. Large interindividual differences in MTX effectiveness and safety occur, and the most frequent adverse reaction is hepatotoxicity, although the main cause remains unknown. We investigated factors associated with MTX-induced hepatic enzyme elevation in a hospital-based cohort study.

Methods: Study participants were 114 Japanese adult RA outpatients prescribed MTX. Sixteen types of single-nucleotide polymorphisms were investigated using real-time PCR. Patient characteristics were collected from the electronic medical records. The onset of MTX-induced abnormal hepatic enzyme elevation was defined according to deviation from normal liver enzyme reference values during treatment. The observation period was 1 year after beginning MTX. Associations between MTX-induced hepatic enzyme elevation and patient characteristics were evaluated using the multivariate logistic regression model.

Results: Thirty-two patients experienced MTX-induced abnormal hepatic enzyme elevation. In multivariate analysis, MTX dosage, estimated glomerular filtration rate (eGFR), and genetic polymorphisms of ABCB1 3435C>T and ATIC 347C>G were associated with abnormal hepatic enzyme elevation.

Conclusions: MTX-induced abnormal hepatic enzyme elevation in Japanese RA patients was associated with dosage and eGFR as nongenetic factors, and with ABCB1 3435C>T and ATIC 347C>G as genetic factors in this hospital-based cohort study.

Keywords:

• Abnormal hepatic enzyme elevation
• allele frequency
• cohort study
• methotrexate
• rheumatoid arthritis

Acknowledgments

We are grateful to Ms. Harumi Kondo and research nurses of the Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan, for helpful assistance in collecting patient information.

Ethical approval

The study protocol was approved by the Institutional Review Board of Keio University (approval nos.: G151007-1, G161014-1, 20140445), and written informed consent was given by all patients prior to enrollment.

Conflict of interest

YK has received lecture fees from Abbvie, Eisai Pharmaceutical, Chugai Pharmaceutical, Bristol Myers Squibb, Astellas Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Pfizer, Janssen, and UCB. HO has received lecture fees from Astellas Pharma, Asahi Kasei, Takeda Pharmaceutical, Bristol Myers Squibb, MSD LLC, Chugai Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, and DS Pharma Biomedical Co., Ltd. KY has received consulting fees and speaking fees from Pfizer, Chugai Pharma, Mitsubishi-Tanabe Pharma, Takeda Industrial Pharma, GlaxoSmithkline, Nippon Shinyaku, Eli Lilly, Janssen Pharma, Eisai Pharma, Astellas Pharma, and Acterlion Pharmaceuticals. TT has received research grants and lecture fees from Abbvie, Astra Zeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Novartis, Takeda Pharmaceutical, Abbott Japan Co., Ltd., Astellas Pharma, Ltd., Daiichi Sankyo, Pfizer, Sanofi–Aventis, Santen Pharmaceutical, Teijin Pharma Ltd., Asahikasei Pharma Corp., SymBio Pharmaceuticals Ltd., Celtrion, Nipponkayaku Co., Ltd, Eli Lilly Japan K.K., and Taisho Toyama Pharmaceutical. The authors declare that they have no competing interests. The other authors have no conflict of interest.

Additional information

Funding

This study was supported in part by Keio Gijuku Academic Development Funds from Keio University.