Interleukin-37 inhibits desmoglein-3 endocytosis and keratinocyte dissociation via upregulation of Caveolin-1 and inhibition of the STAT3 pathway.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease primarily caused by acantholysis of keratinocytes attributed to pathogenic desmoglein-3 (Dsg3) autoantibodies. Interleukin-37 (IL-37) reportedly plays important roles in a variety of autoimmune diseases, but its role in PV is not clear. OBJECTIVES: To investigate whether IL-37 plays a role in the occurrence and progression of PV. METHODS: HaCaT keratinocytes were stimulated with anti-Dsg3 antibody to establish an in vitro PV model, which was defined as anti-Dsg3 group. Cells incubated with medium without anti-Dsg3 treatment were used as control. IL-37 was cultured with these cells infected with or without lentiviral vector shRNA-Caveolin-1 (sh-Cav-1-LV). Cell dissociation assay and immunocytofluorescence were performed to assess keratinocyte dissociation, keratin retraction and Dsg3 endocytosis. Real-time PCR was used to detect the mRNA level of Cav-1, and western blot was used to determine the protein expression of Cav-1, Dsg3, STAT3 and phosphorylated-STAT3 (p-STAT3). RESULTS: The anti-Dsg3 group showed more cell debris, increased keratin retraction, increased Dsg3 endocytosis, reduced Cav-1 expression and co-localization than the control group, while IL-37 treatment neutralized all of these changes. Interestingly, Cav-1 knockdown supressed the inhibitory effect of IL-37 on keratinocyte dissociation and Dsg3 internalization. The protein expression of p-STAT3 was increased in keratinocytes of the PV model but decreased by IL-37. Re-activation of the STAT3 pathway by colivelin supressed the inhibitory effect of IL-37 on keratinocyte dissociation and Dsg3 internalization, along with upregulation of Cav-1 and Dsg3. CONCLUSIONS: IL-37 inhibited keratinocyte dissociation and Dsg3 endocytosis in an in vitro PV model through the upregulating Cav-1 and inhibiting STAT3 pathway.

Targeting therapy in pemphigus: Where are we now and where are we going?

Pemphigus is a heterogeneous group of autoimmune skin disorders characterized by blistering of the skin and mucosal membranes, potentially affecting the quality of life if left unchecked. The current mainstay of treatment is systemic corticosteroids and immunosuppressive agents. Nevertheless, long-term use of these drugs can easily cause infections and other life-threatening adverse reactions. Thus, currently, researchers are trying to develop new and safer therapeutic approaches. Specifically, targeted therapies to pathogenic immune pathways have been gradually introduced and used for the treatment of pemphigus or in clinical trials, such as monoclonal anti-CD20 antibody, BAFF inhibitor, BTK inhibitor, CAAR-T therapy, FcRn antagonist, and TNF-α inhibitor. In addition, IL-4Rα antibody, IL-17 blockade, mTOR pathway inhibitor, CTLA-4Ig, and p38 MAPK inhibitors are theoretically promising treatment for pemphigus. Here, we review the research progress on the mechanism of targeted therapies for pemphigus.

Nine cases of refractory bullous pemphigoid treated with dupilumab and literature review.

BACKGROUND AND AIMS: Bullous pemphigoid is an autoimmune blistering disease that affects the elderly mostly. First-line treatment of systemic corticosteroids may cause significant adverse effects, especially in patients with multiple co-morbidities. Dupilumab shows certain effectiveness in treating BP. We aim to profile our experience with dupilumab in a series of patients with BP and review the articles published to date. METHODS: Medical records of 9 patients with moderate-to-severe BP were retrospectively reviewed. All patients were administered dupilumab. Response to dupilumab was evaluated by NRS scores, number of lesions, and the systemic corticosteroids' dosage. The PubMed, Embase, and Web of Science databases were searched to identify eligible studies. RESULTS: The 9 patients were identified in this case series with a median age of 68 years (range 42-89) and the median duration of disease before being treated with dupilumab was 6 months (range 1-144). Complete remission was achieved in 6 patients while partial response was achieved in one patient. The NRS score had decreased to varying degrees at week 2 in all patients, and skin lesions improved within 2 to 6 weeks. Fifteen publications were included: 3 retrospective studies and 12 case series or reports, with a total of 63 patients. The overall complete response and partial response rates were 74.6 % and 11.1 %, respectively. CONCLUSION: Dupilumab appears to be a safe alternative for the treatment of patients with refractory BP.

Safety and Efficacy of Nemolizumab for Atopic Dermatitis With Pruritus: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials.

Background: Nemolizumab is deemed as a promising drug for atopic dermatitis (AD) patients with pruritus. Objective: This study aimed to evaluate the efficacy of nemolizumab in treating patients with AD and the association between the dosage or regimen of nemolizumab with the improvement in clinical indices. Methods and Materials: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) published from inception to August 2021. Results: A total of 14 cohorts of participants from six randomized controlled studies were included in the meta-analysis. Nemolizumab significantly reduced the pruritus VAS (WMD = -18.86, 95% CI: -27.57 to -10.15, p < 0.001; I2 = 56.2%, pheterogeneity = 0.005) and EASI (WMD = -11.76, 95% CI: -20.55 to -2.96, p = 0.009; I2 = 0%, pheterogeneity = 0.978) scores compared with placebo. No significant difference was observed in the occurrence of any AEs (RR = 1.03, 95% CI: 0.93 to 1.13, p = 0.593; I2 = 0%, pheterogeneity = 0.980) between the two groups. The univariate meta-regression showed that both the dosage and study duration had no association with the change of pruritus VAS score. Conclusion: Nemolizumab presented a promising effect based on the difference in the average change in pruritus VAS and EASI scores compared with placebo. The results indicated its efficacy in relieving pruritus and the severity of AD and improving patients' quality of life.

Mechanisms of pruritus in bullous pemphigoid / 中华皮肤科杂志

Pruritus is one of the typical clinical manifestations of bullous pemphigoid (BP) . In recent years, researchers have gradually recognized that the histamine-independent itch pathway plays an important role in BP. Eosinophils, basophils, interleukin (IL) -31, IL-4, IL-13, thymic stromal lymphopoietin, periostin and substance P are all closely related to the occurrence of pruritus in BP. This review mainly elaborates research progress in mechanisms related to pruritus in BP.