The HLA-B*58:01 allele is strongly associated with allopurinol-induced severe cutaneous adverse reactions (SCARs), which include hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [Article:23232549][Roujeau et al.]. Allopurinol is mainly used for conditions associated with hyperuricemia, such as gout and tumor lysis syndrome [Article:16507884]. The drug works by inhibiting the enzyme xanthine oxidase, which is responsible for the conversion of hypoxanthine and xanthine into uric acid. In this manner, the drug lowers the amount of uric acid created in the body [Article:23232549]. Most side effects from allopurinol are mild, with the most common complaint being gastrointestinal upset [Articles:23232549, 23381951]. However, allopurinol has also been associated with severe adverse reactions. SJS and TEN (or SJS/TEN when referencing both) are two forms of the same condition. Both involve severe mucocutaneous blistering and epidermal detachment, and usually present one to three weeks after treatment begins. SJS and TEN are distinguished by the amount of skin detachment: SJS is classified as 1-10% detachment of body surface area (BSA), SJS and TEN overlap as 10-30% of BSA, and TEN as greater than 30% of BSA. Though the occurrence of these symptoms is rare (only two patients per million per year), SJS and TEN can be permanently disabling or even fatal. The mortality rate correlates with the level of skin detachment, ranging from a 1-5% mortality rate for SJS, to a 25-35% mortality rate for TEN [Articles:20536296, 19933789]. In contrast to SJS/TEN, HSS (also known as drug-induced hypersensitivity syndrome (DIHS) or drug reaction with eosinophilia and systemic symptoms (DRESS)) typically has organ involvement, such as hepatitis or nephritis, in addition to fever and a severe rash [Articles:7794310, 15743917][Rademaker and Maling]. The risk of developing SCARs during allopurinol treatment is 0.1-0.4% [Article:23232549]. In some association studies with allopurinol-induced SCARs, only the relationship with SJS/TEN is discussed, and HSS is not used as an associated phenotype.
The first association between HLA-B*58:01 and SCARs came from a 2005 Taiwanese study on Han Chinese patients, which found that 100% of the 51 patients that developed allopurinol-induced SCARs had the HLA-B*58:01 allele, while only 15% of the 135 allopurinol-tolerant patients carried the allele. This gave an odds ratio of 580 for development of SCARs with this particular allele [Article:15743917]. Follow-up studies in Thai, Korean, Japanese, Han Chinese and European populations also found significant results [Articles:19696695, 21301380, 21393610, 19018717, 21912425, 22348415, 18192896, 23600531, 22909208, 23669020], though one study in a European population found no significant association [Article:21545408]. However, differences exist between these ethnicities when considering the magnitude of risk for developing SCARs. While Han Chinese and Thai patients show exceptionally high odds ratios for developing SCARs, European and Japanese *58:01 carriers show comparatively much lower risks for SCAR development (see Table 1 below). This disparity in odds ratios is likely due to variations in *58:01 frequencies between ethnicities, rather than a differing effect of the *58:01 allele depending on ethnicity. While the Han Chinese and Thais tend to have *58:01 allele frequencies of around 8%, Europeans and Japanese have allele frequencies of approximately 1.4% and 0.5%, respectively (http://www.allelefrequencies.net) [Articles:18192896, 19696695, 21301380]. The *58:01 allele may also be associated with a more mild cutaneous adverse drug reaction (cADR), maculopapular eruption (MPE), which presents as a rash consisting of macules and papules. Cao et al. found that 100% of their Han Chinese patients who developed a MPE while receiving allopurinol carried the *58:01 allele [Article:22909208]. In contrast, Lee et al. found that none of their 12 patients who presented with MPE carried the *58:01 allele, while 6 out of 11 of their patients who developed SCARs did. However, this may be due to the large presence of Caucasians in their study, a population with a low *58:01 frequency. Eleven of the patients with MPE were Caucasian, as were the 5 patients who developed SCARs but did not carry *58:01 [Article:21790926]. Table 1 below provides an overview of allopurinol and *58:01 pharmacogenetic studies, and indicates whether a study has analyzed SCARs, SJS/TEN, DRESS or MPE; this table is updated as new findings come to our attention.
Since there is no difference in phenotype depending on whether one or two HLA-B alleles are present, most pharmacogenetic studies only consider whether an individual has the allele or not. Therefore, in this table, "prevalence" of an HLA-B allele refers to how many patients carry that allele, and not the frequency of the allele in the population. Some studies do use allele frequencies in their statistical analyses, and these cases are noted within the table.
| Table 1: Summary of allopurinol and *58:01 pharmacogenetic studies. p-values and odds ratios (ORs) listed pertain to the risk for allopurinol-induced adverse reactions patients carrying the *58:01 allele as compared to non-carriers. p-values and ORs were calculated by comparing the frequency of *58:01 in patients who developed adverse reactions to the frequency of *58:01 in allopurinol-tolerant controls or in healthy population controls. Prevalence of *58:01 is listed for patients who developed adverse reactions (case) and in those who were allopurinol-tolerant (tolerant control) or from a healthy population (population control). |
| Reference | Population | *58:01 prevalence | p-value | Odds ratio (95% CI) |
|---|
| [Article:21790926] | Australian | Case (SCARs) 1: 6/11 (55%) | | |
| | Case (MPE) 2: 0/12 (0%) | | |
| | | | |
| [Article:18192896] | European | Case (SJS/TEN; Caucasians only): 15/27 (55%) | | |
| | Case (SJS/TEN; Mixed ethnicities) 3: 19/31 (61%) | | |
| | Population control 4: 28/1822 (1.5%) | | |
| | vs Caucasians only | < 1 x 10 -6 | 80 (34 - 187) |
| | vs Mixed ethnicities | < 1 x 10 -8 | 61 (32 - 118) |
| [Article:23600531] | European | Case (SCARs) 5: 16/25 (64%) | | |
| | Tolerant control 6: 1/23 (4.3%) | 5.9 x 10 -4 | 39.1 (4.5 - 340) |
| | Population controls 6: 63/3200 (2%) | | 88.5 (38 - 208) |
| | | | |
| [Article:21545408] | European 7 | Case (SCARs): 3/7 (43%) | | |
| | Population controls: 6/115 (5.2%) | 0.248 | |
| | | | |
| [Article:15743917] | Han Chinese | Case (SCARs): 51/51 (100%) | | |
| | Tolerant control: 20/135 (15%) | 4.7 x 10 -24 | 580 (34 - 9781) |
| | Population control: 19/93 (20%) | 8.1 x 10 -18 | 393 (23 - 6625) |
| | | | |
| [Article:22348415] | Han Chinese | Case (SCARs): 19/19 (100%) | | |
| | Tolerant control: 4/30 (13%) | | 230 (11.7 - 4520) |
| | | | |
| [Article:22909208] | Han Chinese | Case (SCARs): 16/16 (100%) | | |
| | Case (MPE): 22/22 (100%) | | |
| | Case (All cADRs 8): 38/38 (100%) | | |
| | Tolerant control: 7/63 (11%) | | |
| | vs SCAR cases | 7.4 x 10 -12 | 248 (13.5 - 4585) |
| | vs MPE cases | 9.2 x 10 -14 | 339 (18.6 - 6186) |
| | vs cADR cases | 7.0 x 10 -18 | 580 (32.1 - 10457) |
| | Population control: 80/572 (14%) | | |
| | vs SCAR cases | 1.8 x 10 -18 | 202 (12 - 3398) |
| | vs MPE cases | 3.7 x 10 -24 | 275 (16.5 - 4584) |
| | vs cADR cases | 3.2 x 10 -38 | 471 (28.7 - 7744) |
| | | | |
| [Article:22901319] | Han Chinese | Case (DRESS): 1/1 (100%) | | |
| | | | |
| [Article:23280169] | Han Chinese | Case (SJS): 1/1 (100%) | | |
| | Tolerant control: 0/1 (0%) | | |
| | | | |
| [Article:19018717] | Japanese | Case (SJS/TEN): 4/20 9 (20%) | | |
| | Population control: 6/986 9 (0.6%) | <0.0001 | 40.8 (10.5 - 159) |
| | | | |
| [Article:21912425] | Japanese | Case (SJS/TEN): 10/36 9 (28%) | | |
| | Population control: 6/986 9 (0.6%) | 5.4 x 10 -12 | 62.8 (21.2 - 185.8) |
| | | | |
| [Article:17587850] | Japanese | Case (SCARs): 3/3 (100%) | | |
| | | | |
| [Article:23669020] | Japanese | Case (SJS + EEM minor) 10: 4/7 (57%) | | |
| | Tolerant control: 0/25 (0%) | 9.73 x 10 -4 | 65.6 (2.9 - 1497) |
| | | | |
| [Article:19483529] | Kenyan 11 | Case (TEN): 1/1 (100%) | | |
| | | | |
| [Article:21301380] | Korean | Case (SCARs): 24/26 (92%) | | |
| | Tolerant control: 6/57 (11%) | 2.45 x 10 -11 | 97.8 (18.3 - 522) |
| | Population control: 59/485 (12%) | 2.47 x 10 -16 | 83.0 (19.0 - 361) |
| | | | |
| [Article:21393610] | Korean | Case (SCARs): 9/9 (100%) | | |
| | Tolerant control: 41/432 (9.5%) | < 0.001 | 179 (10.2 - 3152) |
| | Population control: 59/485 (12%) | < 0.001 | 136 (7.8 - 2381) |
| | | | |
| [Article:25115449] | Taiwanese | Case (SCARs): 46/48 (96%) | | |
| | Tolerant control: 24/138 (17.4%) | <0.001 | 109 (24.8 - 481) |
| | | | |
| [Article:19696695] | Thai | Case (SJS/TEN): 27/27 (100%) | | |
| | Tolerant control: 7/54 (13%) | 1.6 x 10 -13 | 348 (19.2 - 6337) |
| | | | |
Table last updated 01/22/2015
SCAR, severe cutaneous adverse reactions; SJS/TEN, Stevens-Johnson Syndrome/toxic epidermal necrolysis; MPE, maculopapular eruption; cADR, cutaneous adverse drug reactions; DRESS, drug reaction with eosinophilia and systemic symptoms; EEM, erythema exudativum multiforme
1 - 4 of the 6 patients with *58:01 were of Southeast Asian origin; 2 were Caucasian. All patients with SCARs but without *58:01 (i.e. the 5 remaining patients) were Caucasian
2 - One patient was of Southeast Asian origin, the remaining patients were Caucasian
3 - Includes 27 Caucasian patients, and four non-Caucasian patients of Pakistani, Cuban, Indian and Senegalese background; all four non-Caucasian patients carried the *58:01 allele
4 - Controls came from Western Europe but specific ethnic information was not provided; the majority of these controls are assumed to be Caucasian
5 - Cases were exclusively Caucasian
6 - Ethnicity of the controls was not specified
7 - Caucasian, Northern Italy
8 - MPE and SCAR
9 - Allele frequencies
10 - 2 SJS, 1 SJS ocular type, 4 EEM minor
11 - Born in Germany, Kenyan parents
Due to the strong associations seen between *58:01 and allopurinol, the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends genotyping prior to treatment with allopurinol, and suggests that the drug should be contraindicated in patients with one or more *58:01 alleles [Article:23232549]. The American College of Rheumatology also recommends that *58:01 screening be considered when assessing the risks of the drug, especially in populations with high frequencies of the allele, such as the Han Chinese or Thais [Article:23024028]. Unlike abacavir, no clinical trials have been published that test whether genotyping for the presence of HLA-B*58:01 can reduce the number of SCAR or SJS/TEN cases in patients treated with allopurinol. Based on data from Han Chinese and Thai populations, the negative predictive value of this allele for SJS/TEN development is 100%, but the positive predictive value is only about 1.5% [Article:23232549]. This indicates that most patients who carry the allele will not develop SCARs. Discovery of new genetic, or non-genetic, factors that lead to SCAR development may help increase the positive predictive value. Studies on the mechanism of SCAR development in HLA-B*58:01 carriers have been limited. A recent study suggested that it is a metabolite of allopurinol, oxypurinol, that causes the hypersensitivity reaction in individuals with the HLA-B*58:01 allele. Oxypurinol was found to bind to the F pocket of HLA-B*58:01 through the pharmacological interactions with immune receptors (p-i) mechanism [Article:24591375], a mechanism which states that drugs can bind directly and reversibly to immune receptors and stimulate an immune reaction [Article:17075282]. Oxypurinol bound to the pocket with a higher affinity compared to allopurinol [Article:24591375].
