This study demonstrated an association between HLA-B*13:01 and dapsone-induced SCARs including Stevens-Johnson syndrome/toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms in nonleprosy patients. Moreover, these results suggest that the HLA-B*13:01 allele may be a useful genetic marker for prediction of dapsone-induced SCARs in Thai and Han-Chinese populations.

Background: Most Thai patients with systemic sclerosis (SSc) have diffuse cutaneous SSc (dcSSc) unlike most Caucasians and some Asians. A longitudinal cohort study among Thai dcSSc is needed. Objectives: We aimed to determine the overall clinical characteristics, define the clinical difference between limited cutaneous SSc (lcSSc) and dcSSc, and ascertain the mortality rate and the factors associated with mortality. Method: We conducted a cohort study including 566 Thai adult SSc patients between January 2013 and June 2019. Clinical difference between lcSSc and dcSSc was investigated using generalized estimating equations (GEE). Results: Females presented more than males (356 vs 210 cases). The majority of cases were dcSSc (411; 72.6%). The median duration of disease at the time of pulmonary fibrosis (PF) detection was 2.5 years, pulmonary arterial hypertension 8.1 years, and renal crisis 4.1 years. By GEE analysis, dcSSc was significantly associated with salt-and-pepper skin, hand deformity, and every 1-point increase in modified Rodnan skin score (mRSS). A greater mortality risk was associated with age at onset >60 years (hazards ratio [HR] 5.5), a World Health Organization functional class (FC) III (HR 5.1), FC IV (HR 34.8), edematous skin (HR 11.4), early onset of PF (HR 1.7), each 5-point increase in the mRSS (HR 4.5), and ≥2 internal organ involvements (HR 10.1). Conclusion: dcSSc is a common SSc subset among Thais. PF was an early complication in SSc and earlier PF detection was associated with a poorer prognosis. Elderly onset, high FC, severe skin tightness, and multiple organ involvements were associated with a greater mortality risk.

https://clinicaltrials.gov (NCT01878526).

These recommendations will help Thai rheumatologists prescribe bDMARDs and tsDMARD more appropriately when treating RA patients.

HLA-B*13:01 allele has been identified as the genetic determinant of dapsone hypersensitivity syndrome (DHS) among leprosy and non-leprosy patients in several studies. Dapsone hydroxylamine (DDS-NHOH), an active metabolite of dapsone, has been believed to be responsible for DHS. However, studies have not highlighted the importance of other genetic polymorphisms in dapsone-induced severe cutaneous adverse reactions (SCAR). We investigated the association of HLA alleles and cytochrome P450 (CYP) alleles with dapsone-induced SCAR in Thai non-leprosy patients. A prospective cohort study, 16 Thai patients of dapsone-induced SCARs (5 SJS-TEN and 11 DRESS) and 9 Taiwanese patients of dapsone-induced SCARs (2 SJS-TEN and 7 DRESS), 40 dapsone-tolerant controls, and 470 general Thai population were enrolled. HLA class I and II alleles were genotyped using polymerase chain reaction-sequence specific oligonucleotides (PCR-SSOs). CYP2C9, CYP2C19, and CYP3A4 genotypes were determined by the TaqMan real-time PCR assay. We performed computational analyses of dapsone and DDS-NHOH interacting with HLA-B*13:01 and HLA-B*13:02 alleles by the molecular docking approach. Among all the HLA alleles, only HLA-B*13:01 allele was found to be significantly associated with dapsone-induced SCARs (OR = 39.00, 95% CI = 7.67–198.21, p = 5.3447 × 10−7), SJS-TEN (OR = 36.00, 95% CI = 3.19–405.89, p = 2.1657 × 10−3), and DRESS (OR = 40.50, 95% CI = 6.38–257.03, p = 1.0784 × 10−5) as compared to dapsone-tolerant controls. Also, HLA-B*13:01 allele was strongly associated with dapsone-induced SCARs in Asians (OR = 36.00, 95% CI = 8.67–149.52, p = 2.8068 × 10−7) and Taiwanese (OR = 31.50, 95% CI = 4.80–206.56, p = 2.5519 × 10−3). Furthermore, dapsone and DDS-NHOH fit within the extra-deep sub pocket of the antigen-binding site of the HLA-B*13:01 allele and change the antigen-recognition site. However, there was no significant association between genetic polymorphism of cytochrome P450 (CYP2C9, CYP2C19, and CYP3A4) and dapsone-induced SCARs (SJS-TEN and DRESS). The results of this study support the specific genotyping of the HLA-B*13:01 allele to avoid dapsone-induced SCARs including SJS-TEN and DRESS before initiating dapsone therapy in the Asian population.