title: Association of the diplotype configuration at the N-acetyltransferase 2 gene with adverse events with co-trimoxazole in Japanese patients with systemic lupus erythematosus.
abstract: Although co-trimoxazole (trimethoprim-sulphamethoxazole) is an effective drug for prophylaxis against and treatment of Pneumocystis pneumonia, patients often experience adverse events with this combination, even at prophylactic doses. With the aim being to achieve individual optimization of co-trimoxazole therapy in patients with systemic lupus erythematosus (SLE), we investigated genetic polymorphisms in the NAT2 gene (which encodes the metabolizing enzyme of sulphamethoxazole). Of 166 patients with SLE, 54 patients who were hospitalized and who received prophylactic doses of co-trimoxazole were included in the cohort study. Adverse events occurred in 18 patients; only two experienced severe adverse events that lead to discontinuation of the drug. These two patients and three additional ones with severe adverse events (from other institutions) were added to form a cohort sample and were analyzed in a case-control study. Genotype was determined using TaqMan methods, and haplotype was inferred using the maximum-likelihood method. In the cohort study, adverse events occurred more frequently in those without the NAT2*4 haplotype (5/7 [71.4%]) than in those with at least one NAT2*4 haplotype (13/47 [27.7%]; P = 0.034; relative risk = 2.58, 95% confidence interval = 1.34-4.99). In the case-control study the proportion of patients without NAT2*4 was significantly higher among those with severe adverse events (3/5 [60%]) than those without severe adverse events (6/52 [11.5%]; P = 0.024; odds ratio = 11.5, 95% confidence interval = 1.59-73.39). We conclude that lack of NAT2*4 haplotype is associated with adverse events with co-trimoxazole in Japanese patients with SLE.
authors.affiliation: Institute of Rheumatology, Tokyo Women's Medical University School of Medicine, Kawada-cho, Shinjuku-ku, Tokyo 162-0054, Japan. msoejima@ior.twmu.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Soejima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sugiura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Katsumata
authors.forename: Kae
authors.initials: K
authors.lastname: Takagi
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakajima
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Mitamura
authors.forename: Akio
authors.initials: A
authors.lastname: Mimori
authors.forename: Masako
authors.initials: M
authors.lastname: Hara
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000890:Anti-Infective Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D044466:Asian People; D001219:Aspartate Aminotransferases / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D006239:Haplotypes; D006801:Humans; D016867:Immunocompromised Host / Q000187:drug effects; D008180:Lupus Erythematosus, Systemic / Q000382:microbiology*; D011020:Pneumonia, Pneumocystis / Q000276:immunology / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000009:adverse effects*
chemical_list: D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase