Table 1.
Reported associations between HLA-B*58:01 and risk of allopurinol-induced SCARs
| Study Type | Cases | Controls | OR (95% C.I.) |
P value | Patient Population |
Race/ethnicity | Typing and genotyping method |
Reference |
|---|---|---|---|---|---|---|---|---|
| Case/control study | n=7 (SJS, SJS ocular type, erythema exudativum multiforme (EEM) minor). | n=25 (no ADRs). | 65.6 (2.9–1497) | 9.733×10−4 | Hyperuricemia. | Japanese. | PCR-rSSO and PCR-SBT. | PMID: 23669020 [99] |
| Case/control study | n=25 (SJS, SJS/TEN, DRESS). | n=23 allopurinol- tolerant. | 39.11 (4.49–340.51) | 5.9×10−4 | Asymptomatic hyperuricemia, gouty arthritis or nephropathy. | Portuguese. | PCR-rSSO and SSO-HR typing kit. | PMID: 23600531 [100] |
| Observational study in family members | n=1 male who developed SJS. | n=1 the brother of the case, allopurinol-tolerant. | NA | NA | Gout and essential hypertension. | Self-described Han Chinese. | 4-digit, high resolution DNA sequencing. | PMID: 23280169 [101] |
| Case/control study | n=20 (SJS, DRESS, TEN, EMM). | n=30 allopurinol-tolerant, treated for at least 1 year (not matched to cases). | 123.5 (12.8–1195.1) (OR was higher when EMM case was excluded). | <1×10−4 | NA | Han Chinese (Hong Kong). | Sequence-based typing. | PMID: 22348415 [102] |
| Case-control study | n= 51 patients with allopurinol-induced SCAR (SJS, TEN or HSS). | n= 135 allopurinol-tolerant (at least 6 months of treatment). | 580.3 (34.4–9780.9) | 4.7×10−24 | Hyperuricemia. Chronic renal insufficiency was significantly higher in cases vs controls, and gouty arthritis was the converse. | Han Chinese residing in Taiwan. | Sequence-specific oligonucleotide reverse lineblot. | PMID: 15743917 [24] |
| Comparison of allele frequencies in a population. | n=31 patients with allopurinol-induced SJC or TEN. | NA | 61 (32–118) for the allele frequency of cases compared to the allele frequency found in the general European population. | <10−8 | Mostly hyperuricemia. | Mixed population, mostly European. | OLERSUP SSP HLA-B kit, sequencing in three cases. | PMID: 18192896 [103] |
| Comparison of allele frequencies in a population. | n=10 patients with allopurinol-induced SJS, TEN (one also treated with carbamazepine, another also treated with phenytoin). | NA | 40.83 (10.53–158.9) allele frequency compared to the frequency in n=493 healthy Japanese subjects. | <0.0001 | NA | Japanese. | Sequencing. | PMID: 19018717 [104] |
| Case-control | n= 27 patients with allopurinol-induced SJS or TEN (within 3 months of treatment). | n=54 allopurinol-tolerant patients (>6 months treatment) from the same hospitals. | 348.3 (19.2–6336.9) | 1.6×10−13 | Hyperuricemia, some patients with gouty arthritis. | Self-identified Thai or Thai-Chinese. | PCR with sequence specific primers, and sequence-based typing. | PMID: 19696695 [105] |
| Case/control | n=25 patients with allopurinol-induced SCARs (20 with DIHS, 5 with SJS/TEN). | n=57 allopurinol-tolerant patients. | 97.8 (18.3–521.5) (cases verses tolerant control). | 2.45×10−11 | Cases = patients with gouty arthritis or hyperuricemia related to chronic renal failure. Controls = patients with chronic renal failure. | Korean. | Direct DNA sequencing analysis. | PMID: 21301380 [28] |
| Comparison of allele frequency in healthy individuals. | n=7 allopurinol-induced SJS/TEN patients. | n=115 healthy individuals. | 13.625 (2.774–69.448) | 0.248 after correction for multiple comparisons. | NA | Caucasian, Northern Italy. | 4-digit allele level within the antigen binding domain. PCR-SSP. | PMID: 21545408 [29] |
| Case/control | n=16 patients with an allopurinol hypersensitivity reaction (9 had SCARs, 7 had simple rashes). | n=432 allopurinol-tolerant patients (≥60 days). | 179.24 (10.19–3151.74) SCARs patients vs tolerant. | <0.001 | Patients with chronic renal insufficiency who took allopurinol. | Korean. | Serologic HLA typing by microlymphoctotocity method for HLA-B*58. | PMID: 21393610 [106] |
| Case/ control | n=38 allopurinol- induced MPE, DRESS, SJS/TEN (within first 2 months of exposure). | n=63 allopurinol- tolerant (treated for >3 months with no cuteanous manifestations). | 580.07 (32.18–10456.80) | 7.01×10−18 | Hyperuricemia and gouty arthritis. (A higher frequency of chronic renal insufficiency was seen in cases). | Cases = from the Southern region of China, control = all Han Chinese. | Direct DNA sequencing. | PMID: 22909208 [107] |
| Case report | n=1, an 8-year old girl who developed TEN. | NA | NA. A test revealed she had HLA-B*5801. |
NA | Developed asymptomatic hyperuricemia due to anti-TB treatment and was treated with allopurinol. | German, Kenyan parents. | Not described. | PMID: 19483528 [108] |
| Case report | n=1, a 65-year old male who developed DRESS 1 month after allopurinol treatment initiation. | NA | NA. A test revealed he had a HLA-B*5801 positive genotype. |
NA | Hyperuricemia. | Han Chinese. | Method not described. | PMID: 22901319 [109] |
| Study identified patients across Australia with allopurinol hypersensitivity and carried out genotyping. | N=11 patients with allopurinol hypersensitivity including SJS/TEN and DRESS/DIHS, n=12 patients with MPE. | NA | NA. HLA-B*5801 was found in 6/5 cases with SJS/Ten, 1/5 cases with DRESS/DIHS and none of the patients with MPE. |
NA | Not described. | Australian, mixed population: Caucasian and South-East Asian. | Four-digit high resolution DNA sequence-based HLA typing. | PMID: 21790926 [110] |
| Case report | n=1, a 57-year old male who was diagnosed with SJS 10 days after allopurinol treatment. | NA | NA. Typing showed he had HLA-A31, A33, B51 and B58. |
NA | Not described. | Not described. | Reverse sequence-specific oligonucleotide with PCR for serological HLA typing. | PMID: 17587850 [111] |
| Case report | n=1, a 77 year-old male who was diagnosed with allopurinol-induced DIHS. | NA | NA. Typing showed he had HLA-A31, A33, B39 and B58. |
NA | Not described. | Not described. | Not described. | PMID: 17587850 [111] |
| Case report | n=1, a 93-year old male diagnosed with Allopurinol-induced SJS/TEN (a year earlier he had previously experienced maculopapular-type eruption and fever within 1 month of allopurionol treatment). | NA | NA. He had HLA-A24, A33, B52 and B58. |
NA | Not described. | Not described. | Not described. | PMID: 17587850 [111] |
| Drug-surveillance programme assessing Allopurinol cutaneous ADRs | n=84 cases, including maculopapular eruptions, SJS, TEN and DRESS. Testing for HLA-B*5801 was only done in a subgroup of patients with SJS/TEN. | Allele frequency in a general European population of 0.015 was compared. | 18/18 cases of SJS/TEN in whom the assay was performed carried HLA-B*5801. OR=65.07 (30.66–138.09) compared to the general European population allele frequency. | <0.0000. | Asymptomatic hyperuricemia, gout or secondary hyperuricemia (many also with hypertensive heart disease and renal failure). | Southern Sardinia, Italian, European. | PCR-SSO/PCR-SSP. | PMID: 22017528 [112] |
Abbreviations
ADRs = adverse drug reactions
DIHS= drug-induced hypersensitivity syndrome
DRESS = drug reaction with eosinophilia and systemic symptoms
EMM = erythema multiforme major
HSHSS= hypersensitivity syndrome
NA = not applicable
MPE = maculopapular exanthema
PCR = polymerase chain reaction
PCR-rSSO = PCR- reverse sequence-specific oligonucleotide
PCR-SBT = PCR-sequence based typing
SJS = Steven’s Johnson Syndrome
SSP = sequence-specific primers
TEN = toxic epidermal necrolysis
OR = odds ratio
CI = confidence interval
HLA = human leukocyte antigen