Background/Purpose:

Salazosulfapyridine (SASP) is acetylated in liver by N-acetyltransferase2 (NAT2) in the track of metabolism. Previous studies have shown that genotyping of NAT2 is adequate to classify its acetylation activity into fast (FA), intermediate (IA), and slow acetylator (SA). Prediction of SASP efficacy/adverse events (AEs) based on NAT2 genotype has been demonstrated in retrospective studies, but has not been validated by prospective study. Thus, the purpose of this study is to investigate the association of efficacy and NAT2 genotype prospectively.

Methods:

NAT2 genotype was determined by typing following SNPs, C341T, G590A, and G857A, using Q-probe method (i-densy; Arkray Inc.). Wilcoxon rank-sum test and Pearson’s chi-square test were used for statistical analysis.

1.) Retrospective Study: AEs and efficacy were retrospectively investigated based on physician’s reports and medical records for 102 RA patients (male/female; 29/73, mean age; 60.2±14.6 years), whose mean DAS28-CRP (DAS28) was 4.26±1.08 at baseline.

2.) Prospective Study: Forty three RA patients who initiated SASP between Jan 2010 and Mar 2012 (male/female; 15/28, mean age; 64.4±12.4 years, mean DAS28 at baseline; 4.11±0.99) were followed for 12 month (M). DAS28 and response according to EULAR response criteria were recorded at 3^rd M, 6^th M, and 12^th M. In principal, NAT2 typing was done at 6^th M The change of DAS28 (DDAS28) from baseline was used as primary endpoint for evaluation of the efficacy. The EULAR response was used as secondly endpoint.

Results:

1.) Retrospective Study: There was a significant association between AEs (total of hepatic, hematological, and dermatological AEs) and NAT2 genotype (FA+IA vs SA; p=0.0046, IA vs SA; p=0.024). Efficacy was difficult to evaluate in this retrospective study because of incomplete medical records and irregular timings of evaluation.

2.) Prospective Study: Thirty-one patients have reached to 6^th M of the following period (FA; 15, IA; 15, SA; 1). At 6^th M, mean DDAS28 was significantly greater in IA than that of FA (FA; -1.03±0.86, IA; -1.88±0.67, p=0.013)(Fig.). In addition, the EULAR response was significantly better in IA than FA at 6^th M (p=0.013)(Fig.). Mean SASP dosages at 6^th M were not significantly different in FA and IA (FA; 1016.7±148.4 mg/Day, IA; 966.7±228.9 mg/Day, p=0.61). For SA group, analysis was unable to perform because 4 of 6 patients dropped off due to AEs (n=3) or changing hospital (n=1) before 6^th M, and 60% of SA had experienced AEs before 6^th M.

Conclusion:

Response to SASP was significantly better in IA than FA, and three-fifths of SA experienced AEs. SASP treatment outcome may be improved by advance examination of NAT2 genotype, which will be contributory to apply personalized medicine to RA treatment.