Risk factors for cutaneous reactions to allopurinol in Kinh Vietnamese: results from a case-control study

Abstract

Objective: The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. Methods: All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Results: On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8-40.1], P < 0.0001), female sex (OR 333 [40-43,453], P < 0.0001), allopurinol for asymptomatic hyperuricemia (OR 955 [120-125,847], P < 0.0001), allopurinol starting dose > 150 mg (OR 316 [101-122], P < 0.0001), diuretics intake (OR 304 [35-40,018], P < 0.0001), eGFR < 60 ml/min/1.73 m 2 (OR 100 [32-353], P < 0.0001), history of allopurinolinduced skin reaction (OR 78 [6-10,808], P = 0.004), and HLA-B*58:01 carriage (OR 147 [45-746], P < 0.0001). HLA-B*58:01 allele frequency in controls was 7.3%. For MCARs (n = 74), risk factors were eGFR < 60 ml/min/1.73 m 2 (OR 4.9 [1.61-14.6], P = 0.006), history of allopurinol-induced skin reaction (OR 27 [2-3777], P = 0.01), and asymptomatic hyperuricemia (OR 27 [2-3777], P = 0.01). Conclusion: This study confirmed 8 risk factors, including HLA-B*58:01, for SCARs and identified 3 risk factors for MCARs in Kinh Vietnamese. HLA-B*58:01 genotyping could guide the indication for allopurinol in Kinh Vietnamese patients with gout.

Predominant HLA Alleles and Haplotypes in Mild Adverse Drug Reactions Caused by Allopurinol in Vietnamese Patients with Gout

“…It is well known that the presence of HLA-B * 58:01 is closely related to the occurrence of severe adverse drug reactions (SJS, SJS/TEN, TEN, and DRESS) in the skin of patients (SCARs) when ALP is used for gout treatment, especially for Black and Asian people rather than white people [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 29 ]. Previous studies have found that the frequency of the HLA-B * 58:01 allele in patients with ALP-induced SCARs in Han Chinese, Taiwanese, Thai, Korean, Japanese and Vietnamese populations varies between 90% and 100%, while the frequency of the HLA-B * 58:01 allele in healthy people is 6–10%, depending on the ethnic population [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Therefore, the HLA-B * 58:01 allele has been approved as a diagnostic marker for ALP-induced SCARs, and its screening is recommended before using ALP for gout treatment [ 3 , 4 ].…”

“…A previous study in a Han Chinese population showed that 100% of ALP-treated patients with gout and MCARs carry the HLA-B * 58:01 allele [ 12 ]. However, another study on Kinh Vietnamese reported that only approximately 6.8% of a total of 75 patients with gout and MCARs were positive for the HLA-B * 58:01 allele [ 20 ], a frequency that is almost equal to that observed in healthy Kinh Vietnamese individuals (6.5%). In this study, we found that the frequency of the HLA-B * 58:01 allele in Vietnamese patients with ALP-induced MCARs was 38.1%.…”

“…The frequency of the HLA-B * 58:01 allele varies among ethnic subpopulations. In particular, the frequencies of the HLA-B * 58:01 allele in Han Chinese, Taiwanese, Korean, Vietnamese, and European populations is 10–15%, 12%, 6–8%, 7–8%, and 1–2%, respectively [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. Previous studies have revealed that the HLA-B * 58:01 allele is strongly associated with SCARs caused by ALP.…”

“…Previous studies have revealed that the HLA-B * 58:01 allele is strongly associated with SCARs caused by ALP. The frequency of the HLA-B * 58:01 allele in patients with ALP-induced SCARs, ALP-tolerant patients, and healthy individuals is approximately 90–100%, 10–15%, and 8–10%, respectively [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

“…However, there are a significant number of HLA-B * 58:01-negative patients with ALP-induced SCARs, which implies that the presence of the HLA-B * 58:01 allele is not the only requirement, indicating that other variants of HLA or other genetic risk factors may also contribute to the etiology [ 1 , 6 , 19 , 20 , 23 , 24 , 25 ]. Furthermore, previous studies have shown a strong relationship between the presence of HLA-B * 58:01 and severe symptoms such as SJS and TEN in patients with ALP-induced SCARs; however, the relationship between HLA-B * 58:01 and mild symptoms in patients with gout treated with ALP is unclear [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”