Adverse Effects of Sulfasalazine in Patients with Rheumatoid Arthritis Are Associated with Diplotype Configuration at the N-Acetyltransferase 2 Gene

EIICHI TANAKA, ATSUO TANIGUCHI, WAKO URANO, HIROSHI NAKAJIMA, YUKO MATSUDA, YUTAKA KITAMURA, MASAYUKI SAITO, HISASHI YAMANAKA, TERUNOBU SAITO, and NAOYUKI KAMATANI

ABSTRACT.

Objective. N-acetyltransferase 2 (NAT2) is a key enzyme for the acetylation of sulfasalazine (SSZ). We examine whether there was a correlation between diplotype configurations (combinations of 2 haplotypes for a subject) at the NAT2 gene and the adverse effects of SSZ used for the treatment of rheumatoid arthritis (RA).

Methods. The findings from 144 patients with RA who had been treated with SSZ were collected from our outpatient department and used for a retrospective study. Haplotype analysis was performed by the maximum-likelihood estimation based on the EM algorithm using the obtained polymorphism data.

Results. Sixteen patients (11.1%) had experienced adverse effects from SSZ, the most common being allergic reactions including rash and fever. The slow acetylators who had no NAT2*4 haplotype had experienced adverse effects more frequently (62.5%) than the fast acetylators who had at least one NAT2*4 haplotype (8.1%) (p < 0.001, OR 7.73, 95% CI 3.54-16.86). In 25% of the slow acetylators, the adverse effects were so severe that they were hospitalized.

Conclusion. Genotyping the NAT2 gene followed by estimation of diplotype configuration before administration of SSZ is likely to reduce the frequency of adverse effects in Japanese patients with RA. (J Rheumatol 2002;29:2492-9)

Key Indexing Terms:

SULFASALAZINE
N-ACETYLTRANSFERASE 2
POLYMORPHISM
RHEUMATOID ARTHRITIS
DIPLOTYPE CONFIGURATION
ADVERSE EFFECTS

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From the Institute of Rheumatology and Division of Statistical Genetics, Tokyo Women's Medical University, Tokyo, Japan.

Supported by the Research for the Future Program of the Japan Society for the Promotion of Science, and the Japan Research Foundation for Clinical Pharmacology.

E. Tanaka, MD, Research Associate; A. Taniguchi, MD, PhD, Assistant Professor; W. Urano, MD, Research Associate; H. Nakajima, MD, Research Associate; Y. Matsuda, MD, PhD, Research Associate, Institute of Rheumatology; Y. Kitamura, MSc; M. Saito, MSc, Division of Statistical Genetics; H. Yamanaka, MD, PhD, Associate Professor; T. Saito, MD, PhD, Professor; N. Kamatani, MD, PhD, Director and Professor, Institute of Rheumatology, Tokyo Women's Medical University.

Address reprint requests to Dr. E. Tanaka, Institute of Rheumatology, Tokyo Women's Medical University, 10-22 Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan. E-mail: tanaka@tkg.att.ne.jp

Submitted February 20, 2002; revision accepted June 17, 2002.

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