Correlation of autoantibodies against BP180/BP230 in response to topical corticosteroids in patients with bullous pemphigoid

Topical steroids are effective in treating bullous pemphigoid (BP). Autoantibodies against BP180 are related to disease activity, but correlation of these autoantibodies with response to topical steroid therapy has not yet been clearly evaluated. We investigate the usefulness of close and early monitoring of autoantibodies against BP180 and BP230 for assessment of response to therapy and early detection of therapeutic failure in BP patients treated topically. In eight BP patients under treatment with topical or systemic steroid therapy we retrospectively evaluated clinical course and autoantibodies against BP180 and BP230 as well as indirect immunofluorescence titres (IIF). Data were included at diagnosis, during hospitalization and follow‐ups. Autoantibodies against BP180 parallel disease activity in all topically and as well as systemically treated patients. Autoantibodies against BP230 correlated in five out of eight patients. Autoantibodies directed against BP180 and, to a lesser degree, against BP230 correlate with the clinical course of topically treated BP patients. Monitoring autoantibodies against BP180 is a useful tool to evaluate the efficacy of topical therapy in BP.     

10例寻常型银屑病合并大疱性类天疱疮临床分析

目的：总结寻常型银屑病合并大疱性类天疱疮患者的临床特征及治疗方法。方法：回顾性分析2016年1月至2018年12月我院住院患者中诊断为寻常型银屑病合并大疱性类天疱疮的临床资料。结果：共发现10例寻常型银屑病合并大疱性类天疱疮患者,其中男9例,女1例,平均年龄为（59.90±10.18）岁,银屑病均先于大疱性类天疱疮发病。8例患者水疱发生于银屑病斑块上,2例水疱发生于外观正常的皮肤上。9例患者采用糖皮质激素和/或免疫抑制剂治疗,1例患者应用口服四环素、烟酰胺配合光疗治疗。出院后随访150~1065天,7例患者无新发水疱,银屑病皮损病情稳定;2例失访,1例死亡。结论：寻常型银屑病合并大疱性类天疱疮临床相对少见,中老年患者居多,糖皮质激素联合免疫抑制剂治疗有效。     

CCL18 is expressed in patients with bullous pemphigoid and parallels disease course

Background The autoimmune skin disease bullous pemphigoid (BP) is characterized by subepidermal blister formation and a strong dermal infiltrate of mononuclear cells and eosinophils as well as a T‐helper (Th) 2‐dominated cytokine milieu. CCL18 is a chemokine, with unknown receptor counterpart, frequently associated with inflammatory Th2‐type responses. Objectives The study was performed to investigate an association of CCL18 with BP. Methods CCL18 was determined by enzyme‐linked immunosorbent assay in serum and blister fluid of patients with BP, pemphigus vulgaris and healthy individuals. In vitro chemotaxis assays were performed to demonstrate migration of peripheral blood mononuclear cells to BP blister fluid. Immunohistology and immunofluorescence staining were used to evaluate CCL18 expression in skin. Results We have found that the levels of CCL18 in sera from patients with BP are 84% higher than those normally observed in healthy individuals. In addition, blister fluid of patients with BP is extremely rich in CCL18, reaching concentrations which are fivefold and sevenfold higher than those found in the sera of patients with BP and healthy individuals, respectively. Using immunofluorescence techniques we identified Langerhans cells, antigen‐presenting cells of the dermis and eosinophils as producers of CCL18 in BP skin. We studied the possibility of using CCL18 expression as a biomarker linked to BP by monitoring the serum levels of CCL18 and the disease course of nine patients with BP over a maximum period of 54 months. In this study, CCL18 levels correlated with the disease course in most of the patients. Conclusions Our data implicate CCL18 as a functionally relevant chemokine in BP, mediating recruitment of blood mononuclear cells into the hallmark infiltrated skin lesion. The high correlation of CCL18 expression and BP disease suggests that blood levels of this chemokine can be used as an easy method to monitor disease progression and/or efficacy of therapeutic interventions.     

大疱性类天疱疮患者发根毛囊中抗体的检测

目的：通过检测大疱性类天疱疮患者拔出的头发上残留毛囊中大疱性类天疱疮抗体的沉积情况,建立一种快捷、损伤小的检测大疱性类天疱疮的方法。方法：直接免疫荧光方法测定35例大疱性类天疱疮患者拔出的头发上残留毛囊中类天疱疮抗体的沉积,10例健康人及20例天疱疮病人头发作为对照。结果：35例大疱性类天疱疮患者的毛发,其中阳性28例,阴性7例,阳性率80%;类天疱疮IgG和C3在毛囊表皮下的外毛根鞘外层与结缔组织鞘之间呈明显的线状沉积。10例正常人及20例天疱疮患者均无线状沉积。结论：本实验方法简单、快速、敏感,且具有较高特异性,有可能成为诊断和鉴别诊断大疱性类天疱疮的一种有效的方法。     

Assessment of hydro-saline retention in bullous pemphigoid patients treated with super-potent topical corticosteroids

IntroductionSuper-potent topical corticosteroids (CS) are the mainstay of treatment for bullous pemphigoid. Since super-potent topical CS have systemic effects due to their transcutaneous absorption, we assessed whether super-potent CS were responsible for hydro-saline retention (HSR) in bullous pemphigoid patients.Patients and MethodsFrom 2015 to 2017, patients with newly-diagnosed bullous pemphigoid treated using clobetasol propionate cream at a starting daily dose of 20 to 40 g were subsequently included in a prospective study. HSR was assessed by longitudinally measuring extracellular water (ECW) volume using bioimpedance analysis (BodyStat QuadScan 4000®) from Day 0 to Day 30 after the initiation of topical CS. Other parameters related to HSR such as weight, blood pressure, natriuresis and proteinuria, were also recorded.ResultsTwenty-nine patients (14 men and 15 women) of mean age 81.8 ± 9.3 years were included and analysed. The mean ECW volume decreased from Day 0 to Day 7 (18.1 ± 4.2 vs 16.7 ± 2.7, p = 0.0094) and was maintained from Day 7 to Day 30 (16.8 ± 2.8 vs 17.0 ± 3.4 L; p = 0.8040). Patient weight loss at Day 30 (69.9 ± 13.6 vs 72.5 ± 14.2 kg, p = 0.0085) was closely correlated with the decrease in ECW volume (r = 0.6740, p < 0.0001). No significant changes in natriuresis, 24-hour proteinuria or blood pressure were observed from Day 0 to Day 30.ConclusionWe found no evidence of HSR in bullous pemphigoid patients treated with super-potent topical CS. Conversely, ECW volume decreased from Day 0 to Day 30, which was correlated with patient weight loss.     

米诺环素联合烟酰胺治疗121例大疱性类天疱疮

目的:了解米诺环素联合烟酰胺治疗大疱性类天疱疮的疗效。方法:121例大疱性类天疱疮患者初诊时给予米诺环素200mg/d;烟酰胺600-1500mg/d,服用2周。2周后复查,根据病情或继续口服米诺环素及烟酰胺;或米诺环素及烟酰胺加服少量泼尼松;或停服米诺环素及烟酰胺,改为单独服用泼尼松或用其他方法治疗,总共随访观察24周。结果:使用米诺环素联合烟酰胺治疗2周后达到完全控制40例(33.1%),基本控制48例(39.7%),无效33例(27.3%)。有效者合计88例(72.7%),最终完成24周米诺环素联合烟酰胺治疗的有29例(24.0%)。严重程度与2周后疗效,经Spearman相关分析,r=0.264,P=0.003,有显著相关性。结论:轻中度的大疱性类天疱疮患者,可以考虑首选米诺环素联合烟酰胺治疗。     

Polymorphisms of HLA-DR and -DQ genes in Japanese patients with bullous pemphigoid

Bullous pemphigoid (BP), an autoimmune skin disease of the elderly, is mediated by autoantibodies that bind to hemidesmosomes of epidermal basal cells. This study investigated BP-associated HLA-DR and -DQ genes among Japanese patients. We analyzed HLA-DR and -DQ genes among 23 Japanese BP patients based on the polymerase chain reaction-restriction fragment length polymorphism. Eighteen of these 23 patients (78%) carried at least one allele of HLA-DRB1*04 or DRB1*1101, with significant increases in HLA-DRB1*04 (*0403, *0406)/DQA1*0301/DQB1*0302 and DRB1*1101/DQA1*0505/DQB1*0302 haplotypes as well as the individual alleles DRB1*1101 and DQB1*0302 (corrected p < 0.05 for each comparison), when compared to control subjects. These data differ from the accepted DQB1*0301 (DQ7) association with the same disease among Caucasians. These findings indicate that different HLA class II haplotypes genetically influence susceptibility to BP among different ethnic groups. Our findings, together with previous reports on Caucasian patients with the pemphigoid group of bullous diseases, suggest that HLA-DRB1 molecules might participate in the regulation of autoimmune responses to BP antigens.     

A retrospective review of the therapeutic response with remission in patients with newly diagnosed bullous pemphigoid

We reviewed the clinical characteristics and therapeutic response in cases of newly diagnosed bullous pemphigoid at the National Skin Centre between June 2009 and December 2010. Most (76%, n = 68/90) achieved clinical remission within 6 months of commencement of therapy. Oral mucosal involvement was identified as a risk factor associated with a prolonged duration of treatment beyond 6 months.     

Association between bullous pemphigoid and psoriasis: Systematic review and meta-analysis of case-control studies

Several case reports and cohort studies have recently investigated the potential association between bullous pemphigoid (BP) and psoriasis. It has been speculated that chronic inflammation in the dermo-epidermal junction can trigger exposure to antigens to autoreactive T cells, resulting in autoimmune blistering disease. However, the association described has been inconsistently reported amongst studies. We performed a systematic review and meta-analysis to investigation this potential association. We identified four case–control studies for inclusion in the present meta-analysis, with a total of 4035 bullous pemphigoid cases and 19 215 control cases. There was a significantly higher prevalence of psoriasis in BP compared to controls (2.6% vs 1.1%, OR 2.5, 95% CI 1.4–4.6). Subgroup analysis showed that this association remained significant in both males (3.0% vs 1.3%, OR 2.4, 95% CI 1.6–3.6) as well as females (1.9% vs 0.7%, OR 2.9, 95% CI 1.4–5.9). A significantly higher proportion of cases were reported in males (3.0% vs 1.9%, OR 1.75, 95% CI 1.1–2.7). This pooled analysis of existing case–control studies to date demonstrates a significant association between BP and psoriasis. We also showed that in contrast with the majority of autoimmune diseases which are predisposed in females, that the coexistence of BP and psoriasis appears to be predisposed in male patients.     

Case of localized bullous pemphigoid with unique clinical manifestations in the lower legs

We report the case of a 71-year-old Japanese woman who presented with persistent band-like erosions in the lower legs. Histological examination suggested subepidermal blister formation. Direct and indirect immunofluorescence studies revealed tissue-deposited and circulating immunoglobulin G autoantibodies against the basement membrane. Western blotting revealed autoantibodies to BP230, but not to BP180. Based on these findings, the patient was diagnosed as having a localized type of bullous pemphigoid. We suggest that the unique clinical manifestations in this patient could be attributable to bacterial or fungal infection, and/or mechanical trauma, such as the pressure of her socks.     

大疱性类天疱疮患者血清及疱液中SOCS-1和SOCS-3的水平检测

目的：检测大疱性类天疱疮（BP）患者血清及疱液中细胞因子信号传导抑制蛋白1（SOCS-1）、细胞因子信号传导抑制蛋白3（SOCS-3）的表达水平。方法：收集我院2017年1月至2018年12月的大疱性类天疱疮患者，同时选取II度烫伤患者为对照组，ELISA法检测患者与对照血清及疱液中SOCS-1、SOCS-3表达水平，自身免疫性疱病严重程度评分（ABSIS）判定患者疾病严重程度。采用Pearson相关性分析法分析BP患者血清与疱液中SOCS-1、SOCS-3表达的关系及SOCS-1、SOCS-3水平与ABSIS的关系。结果：共收集42例BP患者和30例对照。BP患者血清SOCS-1和SOCS-3水平为62.14±12.45和47.23±10.72，高于对照组的31.25±9.85和20.62±9.06，差异具有统计学意义（均P＜0.05）；BP患者疱液中SOCS-1和SOCS-3水平为106.45±30.27和91.42±24.58，高于对照组的67.26±21.33和51.07±15.16，差异具有统计学意义（均P＜0.05）；BP患者SOCS-1与SOCS-3水平呈正相关（P＜0.05），SOCS-1和SOCS-3水平分别与ABSIS评分呈正相关（P＜0.05）。结论：大疱性类天疱疮患者血清及疱液中SOCS-1和SOCS-3表达水平升高，其表达水平与ABSIS评分呈正相关，可能与大疱性类天疱疮疾病的发病机制有关。     

Mortality in bullous pemphigoid: A systematic review and meta‐analysis of standardized mortality ratios

There are inconsistent data on mortality rates in patients with bullous pemphigoid (BP). Trends in mortality in BP throughout the years are yet to be established. The aim of the present study was to study the mortality in BP patients relative to the general population and to estimate trends in standardized mortality over the past 30 years. We performed a systematic review and meta‐analysis of observational studies in Medline, Embase and Scopus (1823–2017). Reference lists of included studies were also searched for eligible studies. Quality of evidence was assessed using the Newcastle–Ottawa Scale (NOS). A meta‐analysis was performed using random‐effects models to estimate pooled standardized mortality ratios (SMR) with 95% confidence intervals (CI). Meta‐regression models were used to investigate the secular trends in SMR. Ten studies were included covering the period 1960–2015 (1736 patients, 746 deaths). Pooled all‐cause SMR was 3.6 (95% CI, 2.6–5.0). There was no trend in all‐cause SMR across the last three decades (regression coefficient 0.02 [change in logSMR/year]; 95% CI, 0.04–0.08; P = 0.545). In conclusion, there is a 3.6‐fold increased mortality among patients with BP as compared with the age‐matched general population. The excess mortality in BP has not changed significantly over the past 30 years.     

Omalizumab as an alternative therapeutic tool in the treatment of bullous pemphigoid: A case report

Bullous pemphigoid (BP) is an acquired autoimmune bullous disease characterized by autoantibodies against the hemidesmosomal proteins found in the basal keratinocytes of the basement membrane zone (BMZ): a 180 kDa protein (type XVII collagen) mainly and the 230 kDa antigen. There is such evidence that the antibodies against the BMZ components are not only of IgG type, but also this bullous disease may have IgE antibodies directed to the BMZ that contribute to the pathogenesis of the disorder. IgE is not only thought to contribute to the pathogenesis of BP, it has also been suggested that eosinophils play a role in the development of the first signs associated with BP. A humanized monoclonal antibody directed to IgE, omalizumab, is approved for the treatment of severe asthma and chronic spontaneous urticaria, and it may be useful in the treatment of BP in the first stages of the disease.     

Bullous pemphigoid antigen II (BP180) and its soluble extracellular domains are major autoantigens in mucous membrane pemphigoid: the pathogenic relevance to HLA class II alleles and disease severity

BACKGROUND: Mucous membrane pemphigoid (MMP), a chronic autoimmune subepithelial blistering disease, is associated with circulating IgG and/or IgA autoantibodies against several basement membrane zone antigens. The heterogeneity of clinical presentation and diversity of target autoantigens have contributed to difficulties in characterizing this condition immunologically. OBJECTIVES: To analyse serum autoantibody profile and HLA class II alleles in MMP patients and to correlate this with the clinical presentation of disease. METHODS: Well-defined subgroups consisting of 124 patients with MMP were examined for IgG and IgA reactivity with immunoblotting using human epidermal, dermal and placental amnion proteins. The results were further analysed on the basis of detailed clinical (sites of involvement and disease severity) and immunopathological criteria (immunofluorescence study and HLA class II alleles). RESULTS: Immunoblot assay revealed that the majority of MMP patients had IgG (93 of 124, 75%) and/or IgA autoantibodies (63 of 124, 51%) to BP180 (including its soluble ectodomains, 120-kDa LAD-1 and 97-kDa LABD97 antigens). Other antigens targeted predominantly by IgG autoantibodies included: BP230 in 34 (27%), beta4 integrin in 26 (21%), and laminin 5 in three (2%). All the BP230+ sera and 23 (88%) beta4 integrin+ sera also reacted with at least one of the BP180 antigens. Over 85% of patients with reactivity to beta4 integrin had ocular involvement. In most cases of MMP, more severe clinical features were associated with antibody reactivity to multiple basement membrane zone antigens, as well as reactivity to multiple BP180 component antigens. Dual BP180/LAD-1 reactivity with IgG and IgA was associated with a more severe phenotype. In addition, the subset-dependent autoantibody reactivity correlated well with specific HLA class II alleles, DQB1*0301, DRB1*04 and DRB1*11. CONCLUSIONS: Our results confirmed that BP180 is a major autoantigen targeted by the sera of patients with MMP. The disease-prevalent HLA class II alleles and humoral autoimmune response against the particular subsets of antigenic epitope(s) within BP180 ectodomain may contribute to the clinicopathological significance and disease severity of MMP.     

大疱性类天疱疮患者血清与疱液中巨噬细胞游走抑制因子的检测

目前认为大疱性类天疱疮(BP)的发病不仅与自身抗体的产生有关,而且与细胞因子网络的紊乱密切相关.巨噬细胞游走抑制因子(macrophage migration inhibitory factor,MIF)作为一种前炎症因子,在细胞因子网络平衡中发挥一定作用.本研究采用ELISA方法检测BP患者活动期血清、疱液中MIF的含量和缓解期血清中MIF的含量,以探讨MIF在BP发病机制中的作用及其临床意义.     

Treatment of bullous pemphigoid in Chinese patients with Tripterygium wilfordii Hook F

Tripterygium wilfordii Hook F (TwHF) is a traditional Chinese herb used in many medicinal applications, but the treatment of bullous pemphigoid (BP) with TwHF has never been reported. The aim of this study was to evaluate the efficacy and safety of TwHF in BP patients. A retrospective study was performed from January 2015 to September 2019 in the Department of Dermatology, Peking Union Medical College Hospital. A total of 10 patients with mild to moderate BP and treated with TwHF were enrolled in the study with 10 mild or moderate BP patients treated with systemic glucocorticoid randomly selected as controls. In the TwHF group, a major response was seen in seven patients, a minor response in one and no response was seen in two patients. In the glucocorticoid group, a major response was seen in nine patients and a minor response in one patient. Two patients experienced treatment failure. The time to disease control in the TwHF group (34 ± 11 days) was longer as compared to the glucocorticoid group (18 ± 8 days, P < .05). Ten patients relapsed during the follow‐up period. The adverse events in the TwHF group were lower than those in the glucocorticoid group (13 vs 19). Low‐dose TwHF may be effective and safe for treating mild and moderate BP.     

类天疱疮与HLA-DRB1基因的相关性研究

为探讨HLA-DRE1基因与类天疱疮（BP）的相关性，采用聚合酶链反应序列特异性寡核苷酸探针PCR-SSOP方法对上海地区汉族56个BP患者和150名健康对照进行了HLA-DRB1基因分型。结果与健康对照组比较，BP患者HLA-DRBI*10（DRB1*1001）基因频率明显增高(Pc=0.022，RR=6.466)。结果提示HLA-DRB1*10(DRB1*1001)可能是我国上海地区汉族BP患者的易感基因。