Despite the recognized association between bullous pemphigoid (BP) and psoriasis, the clinical and immunological profiles, and inflammation patterns of coexistence remain undefined. We therefore conducted a retrospective cohort study of 140 BP patients without psoriasis (BP alone group) and 24 BP patients with comorbid psoriasis (BP-PsO group) to characterise these features. Average age of BP onset was significantly lower in the BP-PsO group, compared with the BP alone group (median [IQR]: 67.00 [58.00-75.75] years vs. 75.00 [64.00-82.00] years) (p = 0.021). In the BP-PsO group, 21 patients (87.5%) had coexisting active psoriatic plaques and BP lesions. The overall disease activity of BP was comparable between the BP-PsO and BP alone groups, both showing typical BP immunological features. Serum IL-17A level was significantly elevated in the BP-PsO group (median [IQR]: 18.29 [10.39-43.50] pg/mL), compared with the BP alone group (median [IQR]: 10.36 [9.16-12.11] pg/mL) and psoriasis alone groups (median [IQR]: 11.65 [10.10-12.78] pg/mL), and correlated with disease activity. Flow cytometry confirmed enhanced IL-17A response in peripheral blood mononuclear cells from the BP-PsO group, with an elevated proportion of CD4+ IL-17A+ cells and IL-17A+ T follicular helper cells versus corresponding controls. IL-13 was comparably elevated in both the BP-PsO and BP alone groups, relative to psoriasis alone group and healthy controls. In a representative case, inhibition of IL-17A led to concurrent remission of both diseases. BP with psoriasis shares foundational features with idiopathic BP, but represents a distinct clinical entity characterised by a predominant IL-17A signature, highlighting its potential as a therapeutic target.

Bullous pemphigoid (BP) triggers profound functional changes in both immune and non-immune cells in the skin and circulation, though the underlying mechanisms remain unclear. In this study, we conduct single-cell transcriptome analysis of lesional and non-lesional skin, as well as blood samples from BP patients. In lesional skin, non-immune cells upregulate pathways related to metabolism, wound healing, immune activation, and cell migration. LAMP3+DCs from cDC2 show stronger pro-inflammatory signatures than those from cDC1, and VEGFA+ mast cells, crucial for BP progression, are predominantly in lesional skin. As BP patients transition from active to remission stages, blood B cell function shifts from differentiation and memory formation to increased type 1 interferon signaling and reduced IL-4 response. Blood CX3CR1+ ZNF683+ and LAG3+ exhausted T cells exhibit the highest TCR expansion among clones shared with skin CD8+T cells, suggesting their role in fueling skin CD8+T cell clonal expansion. Clinical BP severity correlates positively with blood NK cell IFN-γ production and negatively with amphiregulin (AREG) production. NK cell-derived AREG mitigates IFN-γ-induced keratinocyte apoptosis, suggesting a crucial balance between AREG and IFN-γ in BP progression. These findings highlight functional shifts in BP pathology and suggest potential therapeutic targets. Single-cell analysis reveals bullous pemphigoid alters the function of skin non-immune and immune cells as well as blood lymphocytes, links progression to NK cell IFN-γ/AREG balance, and suggests potential therapeutic targets.

Natural killer (NK) cells are potent mediators of anti-tumor immunity, yet their functions are frequently subverted by tumor microenvironment-driven immunosuppression. Here, it dissects the molecular mechanisms underlying NK cell dysfunction in cutaneous malignancies and identifies a paradoxical cytokine shift in tumor-associated NK cells-reduced production of IFN-γ and TNF-α alongside elevated amphiregulin (AREG), an EGFR ligand linked to tumor progression. Single-cell transcriptomic analysis indicates that this reprogramming correlates with elevated glucocorticoid receptor (GR/NR3C1) pathway activity in tumor-infiltrating NK cells. Functional validation demonstrated that glucocorticoids specifically induce AREG production in NK cells, with tumor-associated prostaglandin E2 (PGE2) augmenting this response. Genetic ablation or pharmacological inhibition of NR3C1 abolished glucocorticoid-driven AREG induction. Moreover, primary GR activation established persistent chromatin accessibility at the AREG locus, sensitizing NK cells to enhanced AREG production upon secondary glucocorticoid exposure. Functionally, AREG counteracts NK cell-mediated tumor apoptosis, while the adoptive transfer of AREG-deficient human NK cells significantly suppressed melanoma, cutaneous squamous cell carcinoma (cSCC), and hepatocellular carcinoma growth in NCG mice. These findings establish the GR-AREG axis as a multi-layered therapeutic target for restoring NK cell anti-tumor function.

BACKGROUND:Anti-p200 pemphigoid is a rare autoimmune blistering disorder with limited data from China. This retrospective study aimed to investigate the clinical and serological characteristics of anti-p200 pemphigoid to enhance disease understanding. METHODS:We analysed 86 confirmed anti-p200 pemphigoid patients, evaluating their clinical manifestations, histopathological findings, and immunoserological profiles. RESULTS:The patients had a mean onset age of 56.92 ± 18.59 years and a male-to-female ratio of 2.31:1. The clinical presentation is highly heterogeneous, mimicking classic BP (57/86, 66.28%), and four cases (4/52, 7.69%) had concurrent psoriasis. Subepidermal blistering with variable dermal infiltrates was observed in 68 cases (68/70, 97.14%): neutrophil-predominant (24.89%), mixed neutrophilic/eosinophilic (31.43%), or eosinophil-predominant (27.14%). The positive rates of DIF, ss-IIF, IB with dermal extract, and IB with laminin γ1 C-terminal domain (LNγ1C) were 94.29% (66/70), 80.23% (69/86), 100% (86/86), and 64.29% (45/70), respectively. CONCLUSIONS:Anti-p200 pemphigoid closely resembles BP clinically but exhibits distinct immunopathological features. The partial reactivity to laminin γ1 (LNγ1) implies antigenic heterogeneity, warranting further investigation.

Background: Conventional systemic corticosteroid therapy for bullous pemphigoid (BP) has been challenged due to severe adverse events. Dupilumab has emerged as an alternative therapeutical option of BP patients. Objectives: To evaluate the efficacy of dupilumab monotherapy and the combination with medium/low-dose corticosteroids for BP treatment. Methods: Thirteen, twenty-four and thirty-two BP patients treated with Dupilumab monotherapy (Dupi group), dupilumab combined with corticosteroids (Dupi + CS group), and corticosteroid monotherapy (CS group), respectively, were retrospectively analyzed for various clinical and laboratory parameters. Results: In the Dupi group, the total Bullous Pemphigoid Disease Area Index (BPDAI) Total, Erosion/Blister, Urticaria/Erythema and Itching NRS scores were all reduced significantly after 2--4 weeks of treatment, but the BPDAI Mucosal Score was not changed significantly at the end of the overextended time of treatment. All the above clinical parameters and many laboratory parameters (including the serum anti-BP180 autoantibodies [IgG] level, blood eosinophil count, and percentage) were significantly reduced in both Dupi + CS and CS groups after treatment, but no statistical differences were found in the reduction rates of these parameters between the two groups. However, the Dupi + CS group had less baseline dose and cumulative dosage of prednisone at the time of disease control, and fewer adverse effects were reported than the CS group. Study limitations: The retrospective design and small clinical sample size of the Dupi group. Conclusions: For BP patients, dupilumab monotherapy based on the treatment of atopic dermatitis can significantly improve skin lesions and pruritus symptoms but may be ineffective for oral mucosal lesions. The combination of dupilumab and medium/low-dose corticosteroids can achieve the same effect of corticosteroid therapy with superior safety. (c) 2024 Sociedade Brasileira de Dermatologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND:Anti-p200 pemphigoid is a rare autoimmune subepidermal blistering disease. Although the phenomenon of epitope spreading has been reported to be common in anti-p200 pemphigoid, the association between its clinical and immunoserological features has yet to be elucidated. OBJECTIVES:Our aim was to compare the clinical and immunoserological characteristics of anti-p200 pemphigoid patients with and without epitope spreading. METHODS:We performed a retrospective cohort study encompassing 30 patients with anti-p200 pemphigoid between January 2015 and December 2022. The clinical and immunoserological characteristics of anti-p200 pemphigoid were analyzed using combined immunoserological assays. RESULTS:Epitope spreading was observed in 11 of 30 patients (36.7%) with anti-p200 pemphigoid. Compared with patients in the non-epitope spreading group, patients in the epitope spreading group showed more heterogeneous clinical presentations (P = 0.018), a higher proportion of mucosal involvement (P = 0.003), higher Bullous Pemphigoid Disease Area Index (BPDAI) scores for skin erosions/blisters (P = 0.018), mucosal erosions/blisters (P = 0.001), activity (P = 0.017) and total scores (P = 0.022), and required a higher initial dose of prednisone for disease control (P = 0.040). CONCLUSIONS:This study supported the idea that anti-p200 pemphigoid was prone to epitope spreading. Anti-p200 pemphigoid patients with epitope spreading are more likely to present heterogeneous clinical phenotypes, frequent mucosal involvement, and a more severe and recalcitrant disease course.

Bullous pemphigoid (BP) is an autoimmune blistering disorder occurring mostly in the elderly. The standard treatment of BP patients with systemic corticosteroid have some potential serious side effects. Up till now, there is still lack of novel treatment for BP patients. Baricitinib, a selective Janus kinase (JAK) 1 and 2 inhibitor, has been used to treat rheumatoid arthritis, alopecia areata, and COVID-19. Successful treatment of refractory BP by JAK inhibitors has been reported in sporadic cases. In this study, we reported 8 BP patients treated with baricitinib. The patients after treatment were followed up for 3-24 months, with an average of 9.1 months. All 8 cases achieved disease control and the mean disease control period was 3 weeks (1-6 weeks). The bullous pemphigoid disease area index total (21.2 ± 13.0 to 2.5 ± 4.3, p<0.01), erosion/blister (6.0 ± 7.7 to 0.2 ± 0.5, p<0.05), urticaria/erythema (10.2 ± 11.9 to 0.0 ± 0.0, p=0.06), mucosal erosion/blister (10.0 ± 6.4 to 4.5 ± 5.1, n=4, p=0.25) and itching NRS (3.6 ± 3.5 to 0.0 ± 0.0, p=0.06) scores were all reduced after 2 months’ treatment. Seven of 8 patients achieved complete remission during tapering at month 3 and did not experience relapse during the follow-up period. The serum levels of anti-BP180 autoantibodies (IgG) were reduced significantly (77.1 ± 47.8U/mL to 40.1 ± 37.1U/mL, n=6, p<0.05) after 3 months’ treatment. During the follow-up period, only one patient experienced mild elevation of serum creatinine level after 3 months’ treatment of baricitinib, which returned to normal through discontinuation of the medication. In conclusion, this study demonstrated that low-dose, short-term administration of baricitinib is effective and safe for treating BP patients.

BackgroundThe manifestations of bullous pemphigoid (BP) and herpes simplex virus (HSV) infection are similar in oral mucosa, and the laboratory detection of HSV has some limitations, making it difficult to identify the HSV infection in oral lesions of BP. In addition, the treatments for BP and HSV infection have contradictory aspects. Thus, it is important to identify the HSV infection in BP patients in time.ObjectiveTo identify the prevalence and clinical markers of HSV infection in oral lesions of BP.MethodsThis prospective cross-sectional descriptive analytical study was conducted on 42 BP patients with oral lesions. A total of 32 BP patients without oral lesions and 41 healthy individuals were enrolled as control groups. Polymerase chain reaction was used to detect HSV. Clinical and laboratory characteristics of patients with HSV infection were compared with those without infection.ResultsA total of 19 (45.2%) BP patients with oral lesions, none (0.0%) BP patients without oral lesions, and four (9.8%) healthy individuals were positive for HSV on oral mucosa. Among BP patients with oral lesions, the inconsistent activity between oral and skin lesions (p=0.001), absence of blister/blood blister in oral lesions (p=0.020), and pain for oral lesions (p=0.014) were more often seen in HSV-positive than HSV-negative BP patients; the dosage of glucocorticoid (p=0.023) and the accumulated glucocorticoid dosage in the last 2 weeks (2-week AGC dosage) (p=0.018) were higher in HSV-positive BP patients. Combining the above five variables as test variable, the AUC was 0.898 (p<0.001) with HSV infection as state variable in ROC analysis. The absence of blister/blood blister in oral lesions (p=0.030) and pain for oral lesions (p=0.038) were found to be independent predictors of HSV infection in multivariable analysis. A total of 14 (73.7%) HSV-positive BP patients were treated with 2-week famciclovir and the oral mucosa BPDAI scores significantly decreased (p<0.001).ConclusionHSV infection is common in BP oral lesions. The inconsistent activity between oral and skin lesions, absence of blister in oral lesions, pain for oral lesions, higher currently used glucocorticoid dosage, and higher 2-week AGC dosage in BP patients should alert physicians to HSV infection in oral lesions and treat them with 2-week famciclovir in time.

Importance Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study. Objective To assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes. Design, Setting, and Participants A retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded. Main Outcomes and Measures The primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed. Results Among 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02). Conclusions and Relevance In this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.

The interplay between natural killer (NK) cells and tumor microenvironment (TME) is closely associated with tumor progression. We showed NK cells are common constituents in the tissue of skin cancers including basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), extramammary paget disease (EMPD) and acral melanoma (aMM). scRNA-Seq revealed an inter and intra-tumor transcriptional heterogeneity of NK cells dependent on different skin TMEs. Unexpectedly, compared to peri-tumor, skin tumor NK cells down regulated the production of anti-tumor cytokines, IFN-γ and TNF-α, and up regulated the production of amphiregulin (AREG), a ligand of epidermal growth factor receptor (EGFR), which functions in promoting skin tumor growth and mediating immune tolerance. Mechanistically, skin TME upregulated NK cell glucocorticoid receptor (GR, NR3C1) activity, which specifically induced NK cell AREG production, and switched the anti-tumor characteristics of NK cells to a homeostatic feature. NR3C1 knockout or GR inhibitor abolished NK cell AREG production. Finally, we showed primary GR activation induced a memory response of AREG production by NK cells upon secondary stimuli, however pro-inflammatory cytokine induced memory response of IFN-γ production was inhibited by GR activation. These findings highlight the glucocorticoid receptor-NK cell-AREG axis may serve as a potential target for anti-cancer therapies.### Competing Interest StatementThe authors have declared no competing interest.

Bullous pemphigoid (BP) is a complex inflammatory process with elevated levels of autoantibodies, eosinophils, neutrophils, and various cytokines. Hematological inflammatory biomarkers can reflect inflammatory state in various diseases. Up to now, the correlations of hematological inflammatory biomarkers and disease activity of BP remain unknown. The purpose of this study was to clarify the associations between hematological inflammatory biomarkers and disease activity of BP. The levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), platelet-to-neutrophil ratio (PNR) and mean platelet volume (MPV) of 36 untreated BP patients and 45 age and gender matched healthy controls were detected by routine blood tests. The correlations between hematological inflammatory markers and clinical characteristics of BP were statistically analyzed. The Bullous Pemphigoid Disease Area Index (BPDAI) was used to measure disease activity of BP. The mean levels of NLR, PLR, PNR and MPV in 36 untreated BP patients were 3.9, 157.9, 45.7 and 9.4 fl, respectively. Increased NLR (p < 0.001), PLR (p < 0.01), and MPV (p < 0.001) but decreased PNR (p < 0.001) were observed in BP patients when compared with healthy controls. In BP patients, the levels of NLR were positively correlated to BPDAI Erosion/Blister Scores (p < 0.01); and the levels of NLR and PLR were both positively correlated to BPDAI without Damage Score (both p < 0.05) and BPDAI Total Score (both p < 0.05). No correlation was found in other statistical analyses between hematological inflammatory markers and clinical characteristics in BP patients involved in the present study. Therefore, NLR and PLR are positively correlated with disease activity of BP.

The correlation between IgE anti-BP180 NC16A autoantibody and disease activity of bullous pemphigoid (BP) remains disputable. To determine the levels of IgE anti-BP180 NC16A autoantibody and its clinical significance in untreated BP patients. IgG and IgE anti-BP180 NC16A autoantibody in serum and blister fluid samples of 34 untreated BP patients was detected by enzyme-linked immunosorbent assay (ELISA), and correlation with clinical and pathological features of BP were statistically analysed. The Bullous Pemphigoid Disease Area Index (BPDAI) was used to measure disease activity of BP. The mean baseline level of IgG anti-BP180 NC16A autoantibody in serum and blister fluid samples of untreated BP patients was 75.3 U/mL and 1.54 U/mL, respectively (A450, cutoff: 0.126). IgE anti-BP180 NC16A autoantibody was positive in 21.9% serum and 14.7% blister fluid samples of untreated BP patients. IgE anti-BP180 NC16A autoantibody levels in serum samples positively correlated with those from blister fluid samples (r = 0.983, p < 0.05). However, IgE anti-BP180 NC16A autoantibody level in both serum and blister fluid samples of untreated BP patients did not correlate with IgG anti-BP180 NC16A autoantibody, age, extent of elevated peripheral blood eosinophils, BPDAI erosion/blister score, BPDAI urticaria/erythema score, BPDAI pruritus score, BPDAI without damage score, or BPDAI total score (all p > 0.05). No significant correlation was identified between disease activity and positive or negative anti-BP180 NC16A IgE autoantibody. Conclusion: IgE anti-BP180 NC16A autoantibody in both serum and blister fluid samples does not appear to correlate with disease activity of BP.

Objective:To analyze clinical and immunoserological features of patients with anti-p200 pemphigoid.Methods:Clinical data were collected from patients with confirmed anti-p200 pemphigoid in Hospital of Dermatology, Chinese Academy of Medical Sciences from January 2015 to October 2021, and their clinical and immunoserological characteristics were retrospectively analyzed.Results:Seven patients with anti-p200 pemphigoid were included. Indirect immunofluorescence on salt-split skin (IIF-SSS) showed that serum IgG antibodies of the 7 patients were located in the dermis of the salt-split skin, and Western blot analysis with dermal extracts as substrates revealed a protein band with a relative molecular mass of 200 000. Four patients presented with classic bullous pemphigoid-like skin lesions, 2 initially presented with eczematous lesions, and 1 presented with linear IgA bullous dermatosis-like skin lesions. Circulating IgG antibodies could recognize the recombinant laminin γ1 C-terminal region in 6 cases. Four patients received different doses of systemic glucocorticoids, 1 of whom was resistant to high-dose systemic glucocorticoids (equivalent to 1.4 mg·kg -1·d -1 prednisone) ; 2 responded well to minocycline and dapsone; 1 was lost to follow-up. Four patients achieved complete remission and discontinued the treatment at a mean follow-up of 22.5 months; 2 received complete remissiona on minimal therapy at a mean follow-up of 8 months. Conclusion:Patients with anti-p200 pemphigoid presented with heterogeneous clinical manifestations, and the recombinant C-terminal fragment of laminin γ1 can serve as a reliable antigen substrate for the detection of autoantibodies in patients with anti-p200 pemphigoid; some patients can eventually achieve complete remission off treatment.

在特定基因背景下由药物诱发的自身免疫性水疱病(autoimmune bul-lous dermatoses,AIBD),称为药物相关AIBD.临床上最常见的药物相关AIBD包括天疱疮、大疱性类天疱疮和线状IgA大疱性皮病.本文对三种最常见的药物相关AIBD进行综述,主要阐述了引起发病的相关药物、临床表现和治疗方面的进展,旨在为临床医师在药物相关AIBD方面的临床诊断、治疗提供参考.

To investigate the associations of alopecia areata (AA) with serum vitamin D and calcium levels. A systematic review of all relevant articles published up to February 2020 in PubMed, Embase, and Cochrane Library databases was conducted. Primary endpoints were serum 25-hydroxyvitamin D [25(OH)D] levels and vitamin D deficiency, and the secondary endpoint was serum calcium level. Odds ratio (OR) and standardized mean difference (SMD) with 95% CI across studies were analyzed. Data on 1585 patients with AA and 1114 controls from 16 case–control studies and three cross-sectional studies were included in this meta-analysis. A pooled meta-analysis was conducted using the random-effects model because of inter-study heterogeneity (vitamin D level, I2 = 87.90%; vitamin D deficiency, I2 = 81.10%; serum calcium level, I2 = 83.80%). A combined analysis revealed that patients with AA had significantly lower mean serum 25(OH)D level compared with control (WMD − 9.08, 95% CI − 11.65, − 6.50, p < 0.001), and were more likely to have vitamin D deficiency (OR 4.14, 95% CI 2.34, 7.35, p < 0.001). However, the pooled analysis revealed that patients with AA did not have significantly lower serum calcium levels compared with control (WMD − 0.17, 95% CI − 0.40, 0.06, p = 0.143). Subgroup analysis suggested that matched control, mean age, and country might contribute to the heterogeneity of serum vitamin D level, while study design, matched control, and country might contribute to the heterogeneity of vitamin D deficiency. Deficiency of serum 25(OH)D level, rather than calcium level, was present in patients with AA. Screening for vitamin D deficiency and vitamin D supplementation may be beneficial in the treatment of patients with AA.