Allopurinol is widely used for hyperuricemia and gouty arthritis, but is associated with cutaneous adverse drug reactions (CADRs). Recently, HLA-B*58:01 allele was identified as a strong genetic marker for allopurinol-induced CADRs in Han Chinese. However, the magnitude of association and diagnosis value of HLA-B*58:01 in allopurinol-induced CADRs remain inconclusive. To investigate this inconsistency, we conducted a meta-analysis of 21 pharmacogenetic studies, including 551 patients with allopurinol-induced CADRs, and 2,370 allopurinol-tolerant controls as well as 9,592 healthy volunteers. The summary OR for allopurinol-induced CADRs among HLA-B*58:01 carriers was 82.77 (95% CI: 41.63 – 164.58, P < 10−5) and 100.87 (95% CI: 63.91 – 159.21, P < 10−5) in matched and population based studies, respectively. Significant results were also observed when stratified by outcomes and ethnicity. Furthermore, the summary estimates for quantitative analysis of HLA-B*58:01 allele carriers in allopurinol-induced CADRs screening were as follows: sensitivity, 0.93 (95% CI: 0.85 – 0.97); specificity, 0.89 (95% CI: 0.87 – 0.91); positive likelihood ratio, 8.24 (95% CI: 6.92 – 9.81); negative likelihood ratio, 0.084 (95% CI: 0.039 – 0.179); and diagnostic odds ratio, 98.59 (95% CI: 43.31 – 224.41). The AUSROC was 0.92 (95% CI: 0.89–0.94), indicating the high diagnostic performance. Our results indicated that allopurinol–SCAR is strongly associated with HLA-B*58:01, and HLA-B*58:01 is a highly specific and effective genetic marker for the detection allopurinol-induced CADRs, especially for Asian descents.
The interleukin‐23 (IL‐23)/IL‐17 immune axis has been linked to the pathology of psoriasis, but how this axis contributes to skin inflammation in this disease remains unclear. We measured inflammatory cytokines associated with the IL‐23/IL‐17 immune axis in the serum of patients with psoriasis using enzyme‐linked immunosorbent assays. Psoriasis was induced in male C57BL/6J mice using imiquimod (IMQ) cream, and animals received intraperitoneal injections of recombinant mouse anti‐IL‐23A or anti‐IL‐17A antibodies for 7 days. The potential effects of the IL‐23/IL‐17 immune axis on skin inflammation were assessed based on pathology scoring, hematoxylin–eosin staining of skin samples, and quantitation of inflammatory cytokines. Western blotting was used to evaluate levels of the following factors in skin: ACT1, TRAF6, TAK1, NF‐κB, and pNF‐κB. The serum of psoriasis patients showed elevated levels of several cytokines involved in the IL‐23/IL‐17 immune axis: IL‐2, IL‐4, IL‐8, IL‐12, IL‐17, IL‐22, IL‐23, and interferon‐γ. Levels of IL‐23p19 and IL‐17 were increased in serum and skin of IMQ‐treated mice, while ACT1, TRAF6, TAK1, NF‐κB, and pNF‐κB were upregulated in the skin. A large proportion of NF‐κB p65 localized in nucleus of involucrin+ cells in the epidermis and in F4/80+ cells of the dermis of psoriatic lesional skin. Treating these animals with anti‐IL‐23 or anti‐IL‐17 antibodies improved pathological score and immune imbalance, mitigated skin inflammation and downregulated ACT1, TRAF6, TAK1, NF‐κB, and pNF‐κB in skin. Our results suggest that skin inflammation mediated by the IL‐23/IL‐17 immune axis in psoriasis involves activation of the ACT1/TRAF6/TAK1/NF‐κB pathway in keratinocytes and macrophage.
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