Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3⁺ cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions. ScRNA expression profiles and ex vivo blocking studies further identify TNF signaling as a pathway responsible for macrophage-derived CXCL10 and CTL activation. Based on the trajectory analysis, ICI-activated T cells from whole blood are proposed to serve as the initial cells involved in inflammation, that lead to monocytes differentiating into macrophages and increasing their susceptibility to migrate to the lesion sites. Compared with systemic corticosteroids treatment, ICI-induced SJS/TEN patients treated with biologic TNF blockade showed a significantly rapid recovery and no recurrence of SCAR with continuous ICI therapy. Our findings identify that macrophage-eliciting CTL contribute to the pathogenesis of ICI-induced epidermal necrolysis and provide potential therapeutic targets for the management and prevention of SCAR induced by ICI therapy.

The efficacy and the safety of psoriasis medications have been proved in trials, but unideal responses and side effects are noted in clinical practice. Genetic predisposition is known to contribute to the pathogenesis of psoriasis. Hence, pharmacogenomics gives the hint of predictive treatment response individually. This review highlights the current pharmacogenetic and pharmacogenomic studies of medical therapy in psoriasis. HLA-Cw*06 status remains the most promising predictive treatment response in certain drugs. Numerous genetic variants (such as ABC transporter, DNMT3b, MTHFR, ANKLE1, IL-12B, IL-23R, MALT1, CDKAL1, IL17RA, IL1B, LY96, TLR2, etc.) are also found to be associated with treatment response for methotrexate, cyclosporin, acitretin, anti-TNF, anti-IL-12/23, anti-IL-17, anti-PDE4 agents, and topical therapy. Due to the high throughput sequencing technologies and the dramatic increase in sequencing cost, pharmacogenomic tests prior to treatment by whole exome sequencing or whole genome sequencing may be applied in clinical in the future. Further investigations are necessary to manifest potential genetic markers for psoriasis treatments.

Aims: Antithyroid drug (ATD)‐induced agranulocytosis is a life‐threatening adverse drug reaction. Previous studies suggested that HLA genotypes may play an important role in ATD‐induced agranulocytosis. To examine the associations between HLA genotypes and ATD‐induced agranulocytosis, we conducted a systematic review and meta‐analysis of pharmacogenomics studies.Methods: We searched the MEDLINE, Embase and CENTRAL databases on 16 June 2018 for case–control studies on the associations between HLA genotypes with ATD‐induced agranulocytosis. The Newcastle–Ottawa scale was used to evaluate the risk of bias of included studies. We conducted random‐effects model meta‐analysis to obtain pooled odds ratios (ORs) with 95% confidence intervals (CIs) to determine the associations between HLA genotypes and ATD‐induced agranulocytosis.Results: We included 5 studies with 142 ATD‐induced agranulocytosis cases, 1529 matched ATD‐tolerant controls and 5945 healthy controls. The risk of bias of included studies was generally low. ATD‐induced agranulocytosis was associated with HLA‐B*27:05 (OR 10.97; 95% CI 0.75–159.99), HLA‐B*38:02 (OR 19.85; 95% CI 7.94–49.57) and HLA‐DRB1*08:03 (OR 5.29; 95% CI 3.44–8.14). After excluding propylthiouracil, the associations of ATD‐induced agranulocytosis with HLA‐B*27:05 and HLA‐B*38:02 were strengthened (OR being 20.61 (95% CI 5.21–81.58) and 40.59 (95% CI 13.24–124.47), respectively). The associations of ATD‐induced agranulocytosis with HLA‐B*27:05, HLA‐B*38:02 and HLA‐DRB1*08:03 remained significant when compared to population controls (OR being 7.37 (95% CI 3.86–14.07), 36.43 (95% CI 12.80–103.70) and 5.42 (95% CI 2.36–12.47), respectively). HLA‐B*27:05, HLA‐B*38:02, and HLA‐DRB1*08:03 alleles were associated with ATD‐induced agranulocytosis, especially in carbimazole/methimazole‐induced agranulocytosis.Conclusions: HLA‐B*27:05, HLA‐B*38:02 and HLA‐DRB1*08:03 alleles were associated with ATD‐induced agranulocytosis, especially in carbimazole/methimazole‐induced agranulocytosis.

Background: Bullous pemphigoid (BP) is a common immunobullous disease that mainly affects older people; however, the molecular pathogenesis of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in BP is not fully understood. Objectives: To characterize the immune profiles of and the key JAK/STAT pathway in patients with BP. The clinical efficacy of JAK inhibition in patients with BP was also assessed. Methods: Skin transcriptome profiling, measurement of plasma cytokine/chemokine levels, and an in vitro T-cell activation and JAK inhibitor (JAKi) blocking assay were performed for patients with BP. The clinical improvement in steroid-resistant patients with BP treated with JAKi was evaluated. Results: Fifty patients with BP and 31 healthy donor individuals were enrolled in this study. JAK3 and STAT3 mRNA levels were increased in skin lesions from patients with BP. BP-related inflammatory-mediated cytokines/chemokines, including interleukin 5, CCL22, CCL17, CCL18, matrix metalloproteinase 9 and granzyme B, were significantly elevated in patients with BP compared with the healthy donors (all P < 0.001). An in vitro T-cell activation and JAKi blocking assay revealed that tofacitinib (JAK1/3i) and ritlecitinib (JAK3i) had better inhibitory effects than upadacitinib on granzyme B and CCL17 in patients with BP. Eight patients with steroid-resistant BP were treated with oral tofacitinib. Of these patients, five had a rapid reduction in their Bullous Pemphigoid Disease Area Index (from 104.2 to 34.8) within 5 weeks. Conclusions: JAK3i can attenuate JAK3/STAT3-mediated inflammatory factors, providing an alternative treatment strategy for patients with refractory BP in combination with low-dose steroids.