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Competing Interests: Conflicts of interest None disclosed.

Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies against components of the cutaneous basement membrane zone. Autoantibodies lead to complement-dependent and -independent inflammation and blistering. Blister fluid is a valuable biologic resource, as it provides insight into both systemic and local microenvironment responses. Here, we utilized liquid chromatography with tandem mass spectrometry to characterize the bullous pemphigoid blister fluid proteome. We then depleted exosomes to better understand the exosomal versus non-exosomal proteome. We identified 339 proteins in the blister fluid of bullous pemphigoid patients. Gene ontology demonstrated enrichment of several key biologic processes including innate immune response, neutrophil degranulation, platelet degranulation, and complement activation. Exosome depletion resulted in a significant decrease in normalized reporter intensities of 192 proteins, consistent with our observation of a large number of exosomal proteins found in the blister fluid. We then compared the bullous pemphigoid blister fluid proteome to prior proteomic datasets in suction blister fluid, snake bites, and thermal burns, identifying 76 proteins unique to bullous pemphigoid. These include major basic protein, eosinophil peroxidase, galectin-10, and the immunoglobulin epsilon heavy constant region, consistent with tissue eosinophilia. We lastly validated several previously reported blister fluid exosomal components. Blister fluid in bullous pemphigoid contains a mixture of numerous biologic processes. While many of these processes are shared with blistering from alternative causes, we have identified several notable features unique to bullous pemphigoid., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The association of autoimmune bullous diseases (AIBDs) with thyroid disorders remains to be profoundly investigated., Objective: To evaluate the epidemiological association between six AIBDs and thyroid disorders., Methods: A population-based cross-sectional study enrolled patients with bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), pemphigoid gestationis (PG), pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Patients with these six AIBDs were compared with six age- and sex-matched control groups regarding the prevalence of thyroiditis and hyperthyroidism. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for thyroid disorders., Results: The study population included 1,743, 251, 106, 126, 860 and 103 patients with BP, MMP, EBA, PG, PV and PF respectively. The corresponding control groups consisted of 10,141, 1,386, 606, 933, 5,142 and 588 matched controls respectively. A significant association was found between thyroiditis and BP (OR, 1.98; 95% CI, 1.18-3.35; P = 0.010), MMP (OR, 7.02; 95% CI, 1.87-26.33; P = 0.004) and PV (OR, 2.73; 95% CI, 1.45-5.15; P = 0.002). With regards to hyperthyroidism, PF was the only AIBD to demonstrate significant comorbidity (OR, 2.42; 95% CI, 1.13-5.21; P = 0.024). EBA and PG were not found to cluster with any of the investigated thyroid conditions., Conclusion: Patients with BP, MMP, PV and PF experience an elevated burden of thyroid disorders. Patients with these AIBDs presenting with suggestive symptoms may be carefully screened for comorbid thyroid disorders., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: While the coexistence of vitiligo and Crohn's disease (CD) has been reported in individual patients, the epidemiological association between these autoimmune conditions remains inconclusive., Objective: To assess the bidirectional association between vitiligo and CD., Methods: A population-based study was performed to compare vitiligo patients ( n  = 20,851) with age-, sex- and ethnicity-matched control subjects ( n  = 102,475) regarding the incidence of new-onset and the prevalence of preexisting CD. Adjusted hazard ratios (HRs) and adjusted odds ratios (ORs) were calculated by multivariable Cox regression and logistic regression, respectively., Results: The incidence rate of new-onset CD was evaluated at 3.6 (95% CI, 2.7-4.9) cases per 10,000 person-years (PY) in patients with vitiligo and 2.4 (95% CI, 2.0-2.9) cases per 10,000 PY in controls. Patients with vitiligo experienced an elevated risk of CD (fully adjusted HR, 1.60; 95% CI, 1.10-2.34; p  = 0.015). Congruently, a history of preexisting CD predicted elevated odds of having subsequent vitiligo (fully adjusted OR, 1.49; 95% CI, 1.15-1.93; p  = 0.002). Compared to other patients with vitiligo, those with vitiligo and comorbid CD were older and had a higher prevalence of diabetes mellitus, hyperlipidemia, and hypertension but a comparable all-cause mortality rate., Conclusions: The current study depicts a robust bidirectional association between vitiligo and CD. This knowledge is of clinical implication for physicians managing patients with both conditions. The diagnostic threshold for CD should be lowered in vitiligo patients with compatible symptoms.

Autoimmune bullous skin diseases (AIBDs), such as bullous pemphigoid (BP) and pemphigus, are characterized and caused by autoantibodies targeting structural proteins. In BP, clinical experience and recent systematic evaluation identified pruritus to be common and an important cause of impaired quality of life. Furthermore, chronic pruritus may be the sole clinical symptom of BP. In pemphigus, a retrospective study recently documented a high prevalence of pruritus. The temporal relation between pruritus and BP/pemphigus are, however, unknown. Likewise, the presence of pruritus in AIBDs other than BP and pemphigus is unknown. To address this, we performed propensity-matched retrospective cohort studies using TriNetX, providing real-world patient data to (i) assess the risk to develop AIBDs following the diagnosis of pruritus and (ii) vice versa. We assessed this in eight AIBDs: BP, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita, dermatitis herpetiformis, lichen planus pemphigoides (LPP), pemphigus vulgaris, pemphigus foliaceous, and paraneoplastic pemphigus (PNP). For all AIBDs, pruritus was associated with an increased risk for the subsequent diagnosis of each of the eight investigated AIBDs in 1,717,744 cases (pruritus) compared with 1,717,744 controls. The observed hazard ratios ranged from 4.2 (CI 3.2-5.5; p < 0.0001) in MMP to 28.7 (CI 3.9-211.3; p < 0.0001) in LPP. Results were confirmed in two subgroup analyses. When restricting the observation time to 6 months after pruritus onset, most HRs noticeably increased, e.g., from 6.9 (CI 6.2-7.9; p < 0.0001) to 23.3 (CI 17.0-31.8; p < 0.0001) in BP. Moreover, pruritus frequently developed following the diagnosis of any of the eight AIBDs, except for PNP. Thus, all AIBDs should be considered as differential diagnosis in patients with chronic pruritus.

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease., Competing Interests: Declaration of Competing Interest Christian M. Karsten has received honoraria for speaking from Alexion, and Vifor Pharma during the last 3 years. Peter Lamprecht has received honoraria for speaking or consulting or has obtained research grants from BMBF, BMS, DFG, DGRh, GSK, Janssen, Roche, UCB, and Vifor Pharma during the last 3 years. Gabriela Riemekasten has received honoraria for speaking or consulting or has obtained research grants from Abbvie, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Galapagos, Janssen Cilag, Novartis, Pfizer during the last 3 years. Enno Schmidt receives grant funding from Euroimmun, Incyte, Dompe, Admirx, Synthon/biondis, Bayer, Pharmix, Alpine Immune, AstraZeneca, Sanofi, ArgenX, UCB, Novartis, Biotest, Fresenius Medical Care, and is consulting for Roche, Imevax, Thermo Fisher, Janssen, Topas, Bristol-Myers Squibb, Almirall, and Chugai. Ralf J. Ludwig has received honoraria for speaking or consulting or has obtained research grants from Novartis, Lilly, Bayer, Dompe, Synthon, Argen-X, and Incyte during the last 3 years. All other authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Importance: Mucous membrane pemphigoid (MMP) is a rare and heterogeneous subepithelial autoimmune bullous disease with predominant mucosal involvement. Characteristics associated with the disease course and complications are yet to be delineated., Objectives: To evaluate characteristics associated with refractory disease course and blindness among patients with MMP and to estimate the association of different treatment strategies with the prognostic outcome., Design, Setting, and Participants: A retrospective cohort study of consecutive patients diagnosed with MMP and followed up for more than 1 year from 2007 to 2020 in 2 tertiary referral centers. Data were analyzed from January 1, 2009, to June 30, 2020., Main Outcomes and Measures: Characteristics associated with refractory disease course and blindness were evaluated using multivariable logistic regression model., Results: The study encompassed 121 patients with MMP (mean [SD] age, 66.0 [14.0] years; 78 (64.5%) were women), of whom 56 (46.3%) followed a refractory course and 13 (10.7%) developed blindness. Anti-LAD-1 IgA (odds ratio [OR], 3.42; 95% CI, 1.11-10.52; P = .03) and anti-dermal-epidermal/epithelial junction (DEJ) IgG (by indirect immunofluorescence on human salt-split skin; OR, 2.92; 95% CI, 1.26-6.78; P = .01) were significantly associated with refractory course. Development of blindness was associated with older age (≥68 years; OR, 6.38; 95% CI, 1.35-30.16; P = .009), initial presentation with bilateral ocular involvement (OR, 7.92; 95% CI, 2.04-30.68; P = .001), and scarring ocular lesions (OR, 5.11; 95% CI, 1.47-17.79; P = .006). However, 4 (30.8%) and 2 (15.4%) of those experiencing blindness had no ocular scarring lesions and unilateral ocular involvement at the onset of their disease, respectively. Patients progressing to blindness were more likely to be treated by 3 or more immunosuppressive/immunomodulatory drugs (OR, 4.07; 95% CI, 1.17-14.14; P = .02) and by cyclophosphamide (OR, 7.64; 95% CI, 2.24-26.09; P < .001). Patients developing blindness and refractory course were more frequently managed by intravenous immunoglobulin (OR, 7.64; 95% CI, 2.24-26.09; P < .001 and OR, 3.47; 95% CI, 1.42-8.45; P = .005, respectively)., Conclusions and Relevance: Findings of this cohort study support that patients with MMP with anti-LAD-1 IgA and anti-DEJ IgG reactivity should be carefully monitored. While initial bilateral ocular disease and scarring ocular lesions were associated with blindness, patients initially presenting with unilateral and nonscarring ocular disease may still develop severe vision impairment.

Background: Apart from bullous pemphigoid (BP), the association of other autoimmune bullous diseases (AIBDs) with neurological conditions is poorly understood., Objective: To estimate the association between a wide array of AIBDs and neurological conditions., Methods: A retrospective cross-sectional study recruited patients with BP, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), pemphigoid gestationis (PG), pemphigus vulgaris (PV) and pemphigus foliaceus (PF). These patients were compared with their age- and sex-matched control subjects with regard to the lifetime prevalence of Parkinson's disease (PD), Alzheimer's disease (AD), stroke, epilepsy and multiple sclerosis (MS). Logistic regression was used to calculate OR for specified neurological disorders., Results: The current study included 1743, 251, 106, 126, 860 and 103 patients diagnosed with BP, MMP, EBA, PG, PV and PF, respectively. These patients were compared with 10 141, 1386, 606, 933, 5142 and 588 matched controls, respectively. Out of the investigated neurological conditions, PD associated with BP (OR, 2.71; 95% CI, 2.19-3.35); AD with BP (OR, 2.11; 95% CI, 1.73-2.57), MMP (OR, 2.37; 95% CI, 1.03-5.47), EBA (OR, 6.00; 95% CI, 1.90-18.97) and PV (OR, 2.24; 95% CI, 1.40-3.60); stroke with BP (OR, 1.84; 95% CI, 1.55-2.19) and EBA (OR, 2.79; 95% CI, 1.11-7.01); and epilepsy with BP (OR, 2.18; 95% CI, 1.72-2.77) and PV (OR, 1.80; 95% CI, 1.19-2.73). MS did not significantly cluster with any of the six AIBDs., Conclusion: In addition to BP, EBA and PV were found to cluster with neurological comorbidities. Patients with these AIBDs with compatible symptoms may be carefully assessed for comorbid neurological disorders., (© 2021 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Limited data exist on the factors associated with hospitalization and mortality in Asian inpatients with autoimmune bullous dermatoses (AIBDs). This study aimed to elucidate the risk factors affecting hospitalization and mortality rates in Asian patients with AIBDs. A retrospective analysis of patients with AIBDs treated at Siriraj Hospital during a 17-year period was performed using the International Classification of Diseases 10th revision codes. The characteristics of inpatients and outpatients were compared, and mortality rates and associated factors were identified. The study included 360 AIBD patients (180 inpatients, 180 outpatients). Inpatients were significantly younger than outpatients. The identified risk factors for hospitalization were malignancy (odds ratio [OR] 2.83, 95% confidence interval [CI] 1.13-8.04; p = 0.034), moderate to severe disease (OR 2.52, 95% CI 1.49-4.34; p < 0.001), systemic corticosteroid use ≥15 mg/day (OR 2.27, 95% CI 1.21-4.41; p = 0.013) and oral cyclophosphamide treatment (OR 9.88, 95% CI 3.82-33.7; p < 0.001). Kaplan-Meier analysis revealed mortality rates of 26%, 36% and 39% for inpatients with pemphigus at 1, 3 and 5 years, respectively. For inpatients with pemphigoid, the corresponding rates were 28%, 38% and 47%. Infections, particularly pneumonia, were the predominant cause of death in both conditions. This study confirmed that both Asian ethnicity and healthcare disparities may be correlated with adverse outcomes in patients with AIBDs. Pemphigus mortality rates were substantially greater in Asian patients than in Caucasian patients. Continuous monitoring of factors contributing to hospitalization and mortality is imperative to improve treatment outcomes., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Autoimmune blistering diseases comprise a group of heterogenous conditions characterized by the loss of tolerance and subsequent development of autoantibodies targeting epidermal and subepidermal adhesion proteins. Blisters and erosions form on the skin and mucous membranes leading to significant morbidity and mortality. Traditional therapies rely on systemic immunosuppression. Advancements in our understanding of the pathophysiology of pemphigus and pemphigoid have led to the development of molecules which target specific pathways involved in induction and perpetuation of disease. In this review, we outline the novel therapeutic strategies including B-cell depletion, T-regulatory cell repletion, cell signalling inhibitors and small molecular inhibitors, inhibitory monoclonal antibodies, as well as complement inhibition. We additionally review their current level of clinical evidence. We lastly review therapeutics targets gleaned from the experimental epidermolysis bullosa acquisita mouse model. These emerging treatments offer an exciting progression from basic science discoveries that have the potential to transform the treatment paradigm in autoimmune blistering diseases., (© 2019 European Academy of Dermatology and Venereology.)

Pemphigus, an autoimmune intraepidermal bullous disease group with roughly eight distinct forms, includes pemphigus vulgaris (PV) and pemphigus foliaceus (PF) as its predominant global forms. Despite the increased utilization of global health records and reporting systems, epidemiological data remain limited and poorly categorized. Therefore, this study aimed to conduct a review to track, identify, and characterize cases of PV and PF published and categorized worldwide. A research question was formulated; studies were selected based on the inclusion criteria; and data from these publications were systematically collected, summarized, and presented using narrative descriptions. The search strategy yielded 3,212 articles, of which 95 underwent critical analysis and data extraction. Studies from 52 countries contributed to the dataset, covering various pemphigus variants. Notably, only two countries, Iran (18.87%) and South Korea (11.43%), accounted for approximately a third of the reported PV cases, while Brazil contributed 40.25% of the foliaceus variants cases documented in the literature. These findings offer valuable insights into the global distribution of pemphigus and inform future research and healthcare efforts., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Bullous pemphigoid is one of the most common autoimmune bullous diseases occurring primarily in the elderly. Pathogenic autoantibodies against BP180 and BP230 at the dermal-epidermal junction cause subepidermal blisters, erosions, and intense pruritus, all of which adversely affect the patients' quality of life and may increase their morbidity and mortality. Current systemic treatment options for bullous pemphigoid are limited to corticosteroids and immunosuppressants, which can have substantial side effects on these vulnerable patients that even exceed their therapeutic benefits. Therefore, more precisely, targeting therapies to the pathogenic cells and molecules in bullous pemphigoid is an urgent issue. In this review, we describe the pathophysiology of bullous pemphigoid, focusing on autoantibodies, complements, eosinophils, neutrophils, proteases, and the T helper 2 and 17 axes since they are crucial in promoting proinflammatory environments. We also highlight the emerging therapeutic targets for bullous pemphigoid and their latest discoveries in clinical trials or experimental studies. Further well-designed studies are required to establish the efficacy and safety of these prospective therapeutic options., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: MS has received honoraria from AbbVie, Biogen, Almirall, Leo, Novartis, UCB, Janssen, Leo. RL has received honoraria and/or research grants from the following companies: Admirx, Almirall, Amryth, ArgenX, Biotest, Biogen, Euroimmun, Incyte, Immungenetics, Lilly, Novartis, UCB Pharma, Topadur, True North Therapeutics and Tx Cell. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Alopecia areata (AA) is a complex autoimmune condition resulting in nonscarring hair loss. In recent years, many studies have provided new evidence on comorbid diseases present in patients with AA. However, some studies have conflicting results, and analyses conducting a comprehensive approach are lacking., Objective: The aim of our study was to provide an updated systematic review and meta-analysis of medical comorbidities associated with AA., Methods: We searched PubMed, Embase, and Web of Science for case-control, cross-sectional, and cohort studies investigating medical comorbidities in AA published from inception through 1 February 2023., Results: We screened 3428 abstracts and titles and reviewed 345 full text articles for eligibility. Ultimately, 102 studies were analyzed, comprising 680,823 patients with AA and 72,011,041 healthy controls. Almost all included studies (100 of 102 studies) were of satisfactory to high quality (Newcastle-Ottawa scale score ≥ 4). Among patients with AA, comorbidities with the highest odds ratios (OR) compared with healthy controls and data available from more than one study included vitamin D deficiency (OR 10.13, 95% CI 4.24-24.20), systemic lupus erythematous (OR 5.53, 95% CI 3.31-9.23), vitiligo (OR 5.30, 95% CI 1.86-15.10), metabolic syndrome (OR 5.03, 95% CI 4.18-6.06), and Hashimoto's thyroiditis (OR 4.31, 95% CI 2.51-7.40). AA may be a protective factor for certain disorders, for which the AA group had lower odds compared with healthy controls, such as irritable bowel syndrome (OR 0.38, 95% CI 0.14-0.99) and colorectal cancer (OR 0.61, 95% CI 0.42-0.89)., Conclusion: These findings corroborate and contextualize the risks across comorbidities for patients with AA. Further work should be done to identify the underlying pathophysiology and understand appropriate screening criteria., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Due to the long disease duration, impact on appearance, social stigmatization, and numerous side effects of treatment, pemphigus, an autoimmune bullous disease, often has a significant psychological impact on patients. On the other hand, mood disorders may exacerbate the disease by affecting the patient's self-management, forming a vicious circle. To investigate anxiety and depressive disorders in patients with pemphigus, a total of 140 patients with pemphigus were recruited for this cross-sectional retrospective study between March 2020 and January 2022. A control group of 118 patients with psoriasis, a commonly known psychosomatic dermatosis, was established. Patients were evaluated at the visiting day with the Beck Anxiety Inventory and Beck Depression Inventory second edition for mood disorders, the Dermatology Life Quality Index and the EuroQol Five Dimensions Questionnaire for disease-related life quality, and the Visual Analogue Scale for pain and itching symptoms. In our cohort, 30.7% of patients with pemphigus suffered from either anxiety disorder (25%) or depressive disorders (14.3%). Propensity score matching was implemented to create a comparable cohort of pemphigus and psoriasis groups considering the baseline discrepancy. Thirty-four comparable pairs of pemphigus and psoriasis patients were extracted. The prevalence and severity of depressive disorder in pemphigus patients were significantly higher than in psoriasis patients, while anxiety disorder levels appeared to be similar in two groups. Multivariate logistic regression analysis further revealed that disease-related hospitalization history, active mucosal damage, and concomitant thyroid disease are independent risk factors for mood disorders in pemphigus patients. Our results showed that pemphigus patients had a high prevalence and severity of mood disorders. Relevant clinicodemographic indicators may be valuable for prediction and early identification of mood disorders in pemphigus. Better disease education from physicians may be important for these patients to achieve overall disease management., (© 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Pemphigus vulgaris (PV) is a rare autoimmune intraepidermal bullous disease. PV has a major effect on morbidity as well as quality of life. There is sparse literature regarding the association between pemphigus vulgaris (PV) and comorbid malignancies. In this study we aimed to assess the risk of malignancy in a cohort of patients with PV and characterize PV-associated malignancies. Data were collected from two tertiary referral centers between the years 2008 and 2019 and compared with the national cancer registry. Of 164 patients with PV, 19 were diagnosed with malignancy: seven prior to PV diagnosis and 12 after. All cancers, solid and hematological, displayed higher incidences compared to the general population (p <0.001). In conclusion, we demonstrated higher rates of malignancies among patients with PV than in the general population. These observations suggest the need for careful assessment and follow up of patients with PV, given the possibility of associated malignancies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Pemphigoid diseases are a group of bullous autoimmune diseases characterized by autoantibodies against structural proteins of the dermal-epidermal junction. With a steadily growing aging population, pemphigoid diseases are emerging as a significant medical challenge, because they occur primarily in older individuals. The by far most common disease is bullous pemphigoid, which is clinically characterized by tense blisters, erosions, erythema or urticarial plaques, while severe pruritus is the leading subjective symptom. Mucous membrane pemphigoid predominantly affects surface-close mucous membranes with painful erosions and blisters as well as frequently scarring usually in the mouth, nose, and eyes. Anti-p200 pemphigoid clinically resembles bullous pemphigoid but is much less common. Diagnosis of these diseases involves the combination of clinical evaluation, lesional histopathology, direct immunofluorescence microscopy of a perilesional biopsy and serology. Topical and systemic corticosteroids are the mainstay of pemphigoid diseases treatment. Depending on the severity of the disease, various potentially corticosteroid-sparing therapies, such as dapsone, doxycycline, methotrexate, azathioprine and mycophenolate may be used. In severe courses, treatment with rituximab, cyclophosphamide, intravenous immunoglobulins or immunoadsorption are second- or third-line treatment options. Patients are best managed in centers experience with the management of pemphigoid diseases. Updated national and international guidelines for the diagnosis and treatment of bullous pemphigoid and mucous membrane pemphigoid have recently been published., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two major autoimmune blistering skin diseases. Unlike PV, BP is accompanied by intense pruritus, suggesting possible involvement of the pruritogenic cytokine IL-31. However, the underlying mechanisms of the clinical difference between BP and PV in terms of pruritus are not fully understood. To compare the expression levels of IL-31 and its receptor IL-31RA in the lesional skin, including peripheral nerves in BP and PV patients, immunohistochemical staining for IL-31 and IL-31RA was performed in skin samples of BP and PV patients and healthy controls (HC). The IL-31RA-expressing area in epidermis and peripheral nerves was analysed using ImageJ and the percentage of positive cells for IL-31/IL-31RA in dermal infiltrating cells was manually quantified. Quantitative analyses revealed that IL-31/IL-31RA expressions in the epidermis and dermal infiltrate were significantly increased in BP compared to PV and HC. The difference between BP and PV became more obvious when advanced bullous lesions were compared. Peripheral nerves in BP lesions presented significantly higher IL-31RA expression compared to PV lesions. In conclusion, we found significantly augmented expressions of IL-31/IL-31RA in BP lesions, including peripheral nerves, in comparison to PV. These results suggest a possible contribution of IL-31/IL-31RA signalling to the difference between BP and PV in the facilitation of pruritus and local skin inflammation, raising the possibility of therapeutic targeting of the IL-31/IL-31RA pathway in BP patients., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

Objectives: To investigate predictors of hypogammaglobulinemia (HGG) and severe infection event (SIE) in patients with autoimmune disease (AID) receiving rituximab (RTX) therapy., Methods: This was a retrospective study conducted in a tertiary medical center in China. Predictors of HGG or SIE were assessed using Cox analysis. Restricted cubic spline (RCS) analysis was applied to examine the correlation between glucocorticoid (GC) maintenance dose and SIE., Results: A total of 219 patients were included in this study, with a cumulative follow-up time of 698.28 person-years. Within the study population, 117 patients were diagnosed with connective tissue disease, 75 patients presented with ANCA-associated vasculitis, and 27 patients exhibited IgG4-related disease. HGG was reported in 63.3% of the patients, where an obvious decline in IgG and IgM was shown three months after RTX initiation. The rate of SIE was 7.2 per 100 person-years. An increase in the GC maintenance dose was an independent risk factor for both hypo-IgG (HR 1.07, 95% CI 1.02-1.12, p = 0.003) and SIE (HR 1.06, 95% CI 1.02-1.1, p = 0.004). Further RCS analysis identified 7.48 mg/d prednisone as a safe threshold dose for patients who underwent RTX treatment to avoid a significantly increased risk for SIE., Conclusion: HGG was relatively common in RTX-treated AID patients. Patients with chronic lung disease or who were taking ≥ 7.5 mg/d prednisone during RTX treatment were at increased risk for SIE and warrant attention from physicians., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background Information on bullous pemphigoid in an Indian context is scarce. Aim To report clinico-demographic profile, associated comorbidities and prescription pattern of bullous pemphigoid patients in India. Methods This was a retrospective study, where past records of all bullous pemphigoid patients diagnosed and treated between November 2013 and October 2019 were accessed and analysed. Patients having a compatible clinical presentation with either histopathological and/or direct immunofluorescence evidence of bullous pemphigoid were included. Results There were 96 bullous pemphigoid patients, with a male: female ratio of 1.6:1. The mean age at diagnosis was 62.5 ± 2.2 years, with mean duration of illness 27.5 ± 4.5 months before presentation. Comorbidities were present in 80 (83%) patients, with type 2 diabetes mellitus (38.5%), hypertension (36.4%) and neurological illness (16.7%) being the commonest ones. Clinically, blisters were the predominant presentation in 81 (84.4%) patients. The majority (87.5%) of patients showed a predominant eosinophilic infiltrate on histopathology. Direct immunofluorescence revealed immunoglobulin G deposits with complement C3 in 77 (80.2%) cases. The majority of patients (77.1%) were treated with oral prednisolone, either alone (11.5%) or in combination (65.6%) with other topical and systemic agents. Topical steroids were used in 29.1%, azathioprine in 28%, dapsone in 16.7% and omalizumab in 6.2% of patients. Limitations The study is retrospective. Immunofluorescence on salt split skin, direct immunofluorescence serration pattern analysis, and immunoblotting were not performed. Hence, there is a possibility that a few included cases were suffering from other subepidermal autoimmune bullous diseases like epidermolysis bullosa acquisita or anti-p200 pemphigoid. Conclusion Bullous pemphigoid patients in this study had a younger age of onset and showed male preponderance. Comorbidities like type 2 diabetes, hypertension and neurological disorders were frequent. Cutaneous blisters were the most frequent clinical presentation. Systemic corticosteroids comprised the mainstay of therapy.

Autoimmune bullous diseases (AIBDs) are a group of rare blistering dermatoses of the mucous membrane and/or skin. The efficacy, safety and treatment durability of intravenous immunoglobulin (IVIg) as an alternative treatment should be explored to systematically review the available literature regarding treatment outcomes with IVIg in AIBD patients. The predefined search strategy was incorporated into the following database, MEDLINE/PubMed, Embase, Scopus and Web of Science on 18 July 2022. Sixty studies were enrolled using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The use of IVIg alone or combined with rituximab was reported in 500 patients with pemphigus, 82 patients with bullous pemphigoid, 146 patients with mucous membranes pemphigoid and 19 patients with epidermolysis bullosa acquisita. Disease remission with IVIg therapy and RTX + IVIg combination therapy were recorded as 82.8% and 86.7% in pemphigus, 88.0% and 100% in bullous pemphigoid and 91.3% and 75.0% in mucous membrane pemphigoid, respectively. In epidermolysis bullosa acquisita, treatment with IVIg led to 78.6% disease remission; no data were available regarding the treatment with RTX + IVIg in this group of patients. Among all the included patients, 37.5% experienced at least one IVIg-related side effect; the most common ones were headaches, fever/chills and nausea/vomiting. The use of IVIg with or without rituximab had a favourable clinical response in patients with AIBDs. IVIg has no major influence on the normal immune system, which makes its utilization for patients with AIBDs reasonable., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Dermoscopy is a noninvasive technique for the evaluation of different pigments and microstructures of the epidermis, dermoepidermal junction, and papillary dermis that are not apparent to the naked eye, which therefore improves diagnostic accuracy., Aim of the Study: This study aims to describe the characteristic dermoscopic features of bullous diseases and analyze the characteristic dermoscopic features of bullous diseases of the skin and hair., Patients and Methods: A descriptive study was conducted to describe and analyze the characteristic dermoscopic features of bullous diseases in the Zagazig University Hospitals., Results: This study enrolled 22 patients. Dermoscopy revealed yellow hemorrhagic crusts in all patients and white yellow structure with red halo in 90.9% of patients. Pemphigus vulgaris patients were identified by the presence of dermoscopic clues such as bluish deep discoloration, tubular scaling, black dots, hair casts, hair tufts, yellow dots with whitish halos (fried egg sign) and yellow follicular pustules that are not seen in pemphigus foliaceus and IgA pemphigus., Discussion: Dermoscopy is an important tool that serves as a link between clinical and histopathological diagnoses, and it can easily be used in daily practice. Several suggestive dermoscopic features can help in the differential diagnosis of autoimmune bullous disease but only after making a provisional clinical diagnosis. Dermoscopy is a very useful tool in the differentiation of pemphigus subtypes., (© 2023 the International Society of Dermatology.)

Autoimmune bullous dermatoses (AIBD) are a heterogeneous group of about a dozen diseases characterized clinically by erosions and blisters and immunopathologically by autoantibodies against structural proteins of the skin or transglutaminase 2/3. The diagnosis of AIBD has made tremendous progress in the last decade due to the availability of standardized serological assays that, knowing the clinical picture, allow the diagnosis in the vast majority of patients. The development of various in vitro and in vivo models of the most common AIBD, namely, bullous pemphigoid, pemphigus vulgaris, mucous membrane pemphigoid, and the rare epidermolysis bullosa acquisita, allows identification of key molecules and inflammatory pathways as well as preclinical evaluation of the effect of new anti-inflammatory agents. The approval of rituximab for moderate and severe pemphigus vulgaris and the development of national and international guidelines for the most common AIBD have considerably advanced the care of these patients. Nevertheless, the limited therapeutic armamentarium is the main challenge for the management of AIBD. Several phase II and III randomized controlled clinical trials provide hope for new, effective, and safe therapeutic options in the coming years. This review summarizes the epidemiology, clinic, diagnosis, pathophysiology, and therapy of AIBD and gives an outlook on both current diagnostic and therapeutic needs as well as future developments., (© 2023 The Authors. Journal der Deutschen Dermatologischen Gesellschaft published by John Wiley & Sons Ltd on behalf of Deutsche Dermatologische Gesellschaft.)

The treatment of refractory autoimmune blistering diseases (AIBDs) has always been a challenge. Because randomized controlled trials are lacking, treatment has been based on analysis of anecdotal data. The last 2 decades has seen the use of rituximab become a conventional treatment in the therapeutic armamentarium of AIBDs, leading to its Food and Drug Administration indication for pemphigus vulgaris in 2018. We review the current updated data on the use of rituximab including dosing, protocols, and its role in the algorithm of AIBDs. In addition, we discuss several promising novel emerging therapeutic agents for AIBDs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Abstract: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of hematological malignancies. Based on the immunomodulatory capability of CAR-T cells, efforts have turned toward exploring their potential in treating autoimmune diseases. Bibliometric analysis of 210 records from 128 academic journals published by 372 institutions in 40 countries/regions indicates a growing number of publications on CAR-T therapy for autoimmune diseases, covering a range of subtypes such as systemic lupus erythematosus, multiple sclerosis, among others. CAR-T therapy holds promise in mitigating several shortcomings, including the indiscriminate suppression of the immune system by traditional immunosuppressants, and non-sustaining therapeutic levels of monoclonal antibodies due to inherent pharmacokinetic constraints. By persisting and proliferating in vivo , CAR-T cells can offer a tailored and precise therapeutics. This paper reviewed preclinical experiments and clinical trials involving CAR-T and CAR-related therapies in various autoimmune diseases, incorporating innovations well-studied in the field of hematological tumors, aiming to explore a safe and effective therapeutic option for relapsed/refractory autoimmune diseases., (Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.)

It has been rediscovered in the last fifteen years that B-cells play an active role in autoimmune etiology rather than just being spectators. The clinical success of B-cell depletion therapies (BCDTs) has contributed to this. BCDTs, including those that target CD20, CD19, and BAFF, were first developed to eradicate malignant B-cells. These days, they treat autoimmune conditions like multiple sclerosis and systemic lupus erythematosus. Particular surprises have resulted from the use of BCDTs in autoimmune diseases. For example, even in cases where BCDT is used to treat the condition, its effects on antibody-secreting plasma cells and antibody levels are restricted, even though these cells are regarded to play a detrimental pathogenic role in autoimmune diseases. In this Review, we provide an update on our knowledge of the biology of B-cells, examine the outcomes of clinical studies employing BCDT for autoimmune reasons, talk about potential explanations for the drug's mode of action, and make predictions about future approaches to targeting B-cells other than depletion., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Pemphigus, an autoimmune blistering disease that affects the skin and mucous membranes, significantly impairs the quality of life (QoL) of affected individuals. While there are a variety of QoL measurement tools available for assessing this disease, there is a lack of studies that specifically evaluate the sexual QoL of patients with pemphigus., Objectives: This case-control study aims to investigate the impact of the disease on sexual activity as well as its overall effect on QoL., Materials and Methods: Fifty pemphigus patients, who were referred to the Dermatology Department at the University Hospital of Brescia in the period March 2019-September 2021, completed several QoL surveys, including the 36-item Short Form Health survey (SF-36), the 12-Item General Health Questionnaire (GHQ-12), the Autoimmune Bullous Disease Quality of Life (ABQOL) and either the International Index of Erectile Function (IIEF) or the Female Sexual Function Index (FSFI). The severity of the disease was assessed using the Pemphigus Disease Area Index (PDAI). Differences in QoL surveys between the case and control groups were analysed using either the t-test or the Wilcoxon-Mann-Whitney test. The correlation between QoL surveys in pemphigus patients and disease severity were analysed using Spearman's coefficient (r)., Results: The results revealed a marked impairment in overall QoL among patients with pemphigus compared to the healthy control subjects. Significant differences were observed in various domains of QoL, including physical health, mental well-being, social functioning and, notably, sexual health. Furthermore, disease severity as evaluated by the PDAI showed correlations with specific aspects of health status, and disease-specific QoL demonstrated associations with nearly all domains of health status. No significant correlations were found between sexual activity, mucosal involvement or steroid therapy and PDAI scores or disease-specific QoL measures., Conclusion: These findings emphasize the significant impact of pemphigus on patients' well-being, with particular attention to the impaired sexual activity., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Various mechanisms contributing to the activity of chronic spontaneous urticaria (CU) have been postulated. Associated comorbidities are increasingly leading to the discovery of further signaling pathways which may support the activity of chronic urticaria or contribute to low-grade systemic inflammation. Moreover psychoimmunological factors may also be involved. The aim of this work is to improve the clinical care of patients with CU by increasing knowledge regarding optional influencing factors due to comorbidities and to possibly influence disease activity. Chronic urticaria due to autoimmune mechanisms may dispose to other autoimmune diseases, especially autoimmune thyroiditis, which can trigger chronic disease. Association of CU with metabolic syndrome has received little attention to date. Obesity may contribute to low-grade systemic inflammation by cytokine-secreting adipose tissue and hence to mediator-release of mast cells. Furthermore, neuroimmunological pathways, especially increased release of substance P, an activating ligand of Mas-related G protein-coupled receptor X2 (MRGPX2) on mast cells, should be addressed when optimizing therapy., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Blistering autoimmune dermatoses are a heterogeneous group of rare diseases. Pemphigus diseases are distinguished from pemphigoid diseases as well as dermatitis herpetiformis. In pemphigus diseases, cutaneous blistering is caused by an intraepidermal loss of adhesion between keratinocytes. In pemphigoid diseases, blister formation is due to a subepidermal loss of adhesion of keratinocytes from the basement membrane., Objectives: This article reviews the most important trigger factors associated with bullous autoimmune dermatoses and discusses their role in their initial manifestation as well as exacerbation., Materials and Methods: A focused review of the literature including original articles, guidelines, reference works and previously published review articles was performed., Results: Vaccinations, viral infections, ultraviolet light (UV) exposure and radiation therapies are possible triggers of pemphigus vulgaris in predisposed patients. For the much rarer pemphigus foliaceus, UV exposure is of particular importance. Thiols and phenols are drugs that can induce pemphigus usually resembling pemphigus foliaceus clinically. Age is the most important risk factor of bullous pemphigoid. In addition, in bullous pemphigoid associations with dipeptidyl peptidase 4 inhibitors, programmed cell death protein‑1 or programmed death-ligand‑1 inhibitors as well as neurological diseases are particularly relevant. Severe mucosal damage, certain drugs and in particular cases neoplasms might play a role in mucous membrane pemphigoid., Conclusion: Knowing possible trigger factors facilitates a timely diagnosis upon initial manifestation and supports the prevention of relapse of bullous autoimmune dermatoses., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Subepidermal autoimmune bullous diseases of the skin and mucosae comprise a large group of chronic diseases, including bullous pemphigoid, pemphigoid gestationis, mucous membrane pemphigoid, linear IgA bullous dermatosis, epidermolysis bullosa acquisita, and anti-p200 pemphigoid. These diseases are characterized by an antibody response toward structural components of the basement membrane zone, resulting in subepidermal blistering. The epidemiological features of these diseases vary substantially in different regions of the world. Observational studies investigating comorbidities and associations among patients with these diseases are inconsistent and sometimes inconclusive. This review provides a brief overview regarding each one of the subepidermal autoimmune bullous diseases. In addition, it summarizes the most recent understanding of the epidemiological features and associations of this group of organ-specific autoimmune diseases.

In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Background: Bullous pemphigoid is a common autoimmune blistering skin disease that is significantly associated with a high rate of morbidity and mortality., Objective: Our aim was to determine the 1-, 2- and 3-year mortality rate and standardized mortality ratio of BP in Moroccan patients, as well as to identify risk factors that influence survival both in the 1st and 3rd year of follow-up., Methods: All patients with BP diagnosed between January 2008 and December 2017 in a tertiary referral centre at the Mohammed V Military Hospital in Morocco were included retrospectively., Results: The 1-year, 2-year and 3-year mortality rates of the cases were 25.8%, 32.3% and 43%, respectively. The median age of onset was 72 years (range, 64 ∼ 80 years), and 51 (54.8%) patients were men. The standardized mortality ratio of patients with BP was 2.6 times higher than that of age- and sex-matched members of the general Moroccan population. Besides advanced age, the presence of diabetes mellitus at the time of diagnosis was associated with increased 3-year mortality in multivariate analysis., Conclusion: This is the first study analysing the mortality rate of bullous pemphigoid in Morocco. Our findings confirm a high mortality rate for BP patients compared with the expected mortality rate for age- and sex-adjusted general Moroccan population. Risk factors for increased 3-year mortality include advanced age at the time of diagnosis and diabetes mellitus., (© 2022 Australasian College of Dermatologists.)

Background/objectives: Bullous pemphigoid (BP) is an uncommon autoimmune bullous disorder, with significant morbidity and mortality. Mortality may be as high as 23.5% in the first year after diagnosis. Clear epidemiologic data across Australasia are lacking., Methods: A retrospective, multi-centred cohort study was designed to determine the incidence and mortality of bullous pemphigoid in New Zealand. Data from all histopathologically diagnosed patients with bullous pemphigoid between 2009 and 2015 from the Auckland region were obtained. Demographics, clinical characteristics and outcome 3 years from diagnosis (until 31 December 2018) were collected. Demographic data were compared against a denominator year-matched New Zealand Census population., Results: One hundred sixty-one patients had confirmed bullous pemphigoid, with an incidence rate of 3.03/100 000 person-years [95% CI 2.58-3.54]; 70% were of European ethnicity; 12.4% were Pacific peoples; 11.2% were Asian; and 6.8% were Māori. 45.3% had associated cognitive impairment and/or stroke. In the 3-year follow-up, 25% had treatment complications mostly from prednisone therapy. The mortality rate was 40%, highest in the first year of diagnosis, with age at diagnosis a predictor., Conclusion: The incidence and mortality rates are comparable to the UK/Northern Europe. Knowledge of the epidemiology of bullous pemphigoid in New Zealand and within an international settling informs the provision of future care and treatments., (© 2022 Australasian College of Dermatologists.)

Dermatological conditions constituting the group of autoimmune blistering diseases (AIBD) are characterized by loss of immunotolerance and humoral, as well as cellular, autoimmune responses that result in the development of bullae and erosions on the skin and mucous membranes. AIBDs are broadly categorized into pemphigus and pemphigoid classes with several distinct subtypes amongst them. Advances in genetics have allowed for the study and identification of alleles, and even single nucleotide polymorphisms, that harbor increased susceptibility or confer protection for the development of these conditions. The focus of this chapter pertains to a comprehensive review of the known genetic associations with AIBDs, including HLA class I-III, as well as non-HLA genes and non-coding sequences that influence cellular processes and signaling pathways., (© 2022. Springer Nature Switzerland AG.)

Patients with autoimmune bullous diseases (AIBDs) are considered to be immunocompromised and, consequently, they may be more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and have poorer outcomes. However, the risk and repercussions of SARS-CoV-2 infection in patients with AIBDs have not been fully understood. Therefore, we aimed to investigate the risk factors of SARS-CoV-2 infection and the impact of SARS-CoV-2 on patients with AIBDs. From December 2022 to January 2023, all patients with AIBDs who visited our clinic were enrolled in this study. Meanwhile, web-based questionnaires and telesurveys were used as supplements. Information about patients' demographics, comorbidities, SARS-CoV-2 infection, and vaccination, as well as AIBD status and treatments were collected and analyzed. The diagnosis of SARS-CoV-2 infection was based on a positive polymerase chain reaction test, and/or an antigen test, or the presence of typical symptoms in conjunction with an epidemiological history. Finally, 95 patients with AIBDs were enrolled, including 47 cases of pemphigus and 48 cases of pemphigoid cases, and 73 had symptoms consistent with coronavirus disease 2019. Common symptoms after SARS-CoV-2 infection were fever (80.8%), fatigue (75.0%), cough (71.2%), muscle/joint pain (49.3%), and sore throat (45.2%). No significant differences were found between SARS-CoV-2-infected and asymptomatic patients. Patients who had hypertension (p = 0.034), hyperlipidemia (p = 0.017), or more than two comorbidities (p = 0.011) were more likely to develop pneumonia after infection. Patients with pemphigus who did not achieve disease control (p = 0.045) or had an oral corticosteroid dose ≥15 mg/day (p = 0.024) and patients with pemphigoid with a disease duration ≥2 years (p = 0.037) were more prone to AIBDs aggravation. In conclusion, patients with AIBDs are generally susceptible to SARS-CoV-2 infection. Individuals with newly diagnosed AIBDs, uncontrolled disease, and a higher corticosteroid dose are more susceptible to disease exacerbation., (© 2023 Japanese Dermatological Association.)

Objectives: The existence of standard methods for diagnosis and measuring the severity of diseases leads to a more accurate severity assessment, the possibility of following up, and the possibility of comparing the results of studies. This study aimed to compare different pemphigus vulgaris (PV) assessment methods regarding inter-observer reliability and testing times-focusing on oral parts., Materials and Methods: Two dermatologists evaluated orally involved PV patients by oral parts of Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), Pemphigus Disease Area Index (PDAI), and Oral Disease Severity Score (ODSS)., Results: Seventy patients completed the study. The intraclass correlation coefficient showed the evaluators' agreements on ABSIS, PDAI, and ODSS with 0.98, 0.94, and 0.95, respectively. Reliability analyses showed near-perfect relationships between each scoring methods pairs. There was no association between lesion sites and disease severity. The PDAI scoring duration was significantly shorter, and the ABSIS scoring duration was significantly longer., Conclusion: ODSS is valid for evaluating oral involvement in patients with PV and relates to ABSIS and PDAI almost perfectly. Besides, it was shown that the evaluation of patients' oral involvement based on PDAI and ODSS is done in about 1 min, which seems clinically reasonable., (© 2022 Wiley Periodicals LLC.)

The predilection for women in systemic autoimmune diseases is well established. However, this sex bias in oral autoimmune diseases has been classically reported from an epidemiological perspective without any elaborate attempts to unveil the underlying mechanisms. The unique nature of the oral environment is likely to impose a combination of systemic and local factors that ultimately result in the sex bias in autoimmune diseases of the oral cavity. Variations of immune responses, target organ vulnerability, endocrine and genetic factors, sex chromosomes and modes of parental inheritance are potential systemic factors, while the oral microbiome, oral tolerance, saliva, and oral epithelial stem cells may account for local contributing factors. This review will discuss the preponderance of women in oral immune-mediated diseases, the potential systemic and local mechanisms underlying this predominance and highlight the crucial need for further research in this area., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Objectives: Pemphigus has been associated with physical and psychiatric comorbid diseases. This study aims to further investigate these associations in patients with pemphigus, and to analyze the relationships of comorbid conditions with sex and age, pemphigus disease area index score, diagnostic delay and cutaneous/mucous involvement., Patients and Methods: Patients with pemphigus were matched by age, gender and area of residence with eight controls each. The odds of comorbid conditions in patients vs. matched controls was determined using univariate conditional logistic regression models. Comorbid diseases significantly associated with the diagnosis of pemphigus at P < 0.05 in univariate models were subsequently included in a multivariable conditional logistic regression model with a forward procedure., Results: The study sample included 163 patients with pemphigus. Cardiovascular diseases, hyperlipidemia, autoimmune thyroid disorders, dermatological autoimmune/inflammatory conditions and cancer were the most prominent conditions at the time of diagnosis. In the multiple conditional regression analysis, the two diagnoses independently associated with patients with pemphigus were cancer and dermatological autoimmune/inflammatory conditions. In sensitivity analyses excluding four patients with paraneoplastic pemphigus, these associations were still significant., Conclusions: Cancer and dermatological autoimmune/inflammatory conditions may represent possible triggering conditions for pemphigus and should be considered as early warning signs for the disease., (© 2021 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)

Autoimmune bullous diseases are a heterogeneous group of diseases characterized by the development of cutaneous and mucosal vesicles, blisters, and finally erosions. The common pathogenetic mechanism is the presence of autoantibodies targeting structural proteins of the skin and mucous membranes (demosomes and hemidesmosomes): in the case of pemphigus, the antigens are intraepidermal, whereas in the case of pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita they are subepidermal. Mucosal involvement typically affects the oral and ocular mucosa, but in some cases, the upper airways or the upper digestive tract are affected. The burden on patients' lives could be severe due to the impairment of normal feeding or breathing. In other cases, they may represent paraneoplastic syndromes. Since autoimmune bullous diseases may result in significant morbidity and mortality, depending on the grade of cutaneous and mucosal involvement, a prompt therapeutic approach is mandatory and, in recalcitrant cases, may be challenging. The first line therapy consists of corticosteroids, both topical and systemic. Once remission or control of the acute phase is obtained, adjuvant therapies need to be introduced in order to spare the corticosteroid load and minimize side effects such as iatrogenic diabetes or osteoporosis. Herein, we describe all current therapeutic approaches to autoimmune bullous diseases, also including emerging therapies., (© 2021 Wiley Periodicals LLC.)

Autoimmune bullous diseases can be intraepidermal (pemphigus group of disorders) or subepidermal (pemphigoid group of disorders). The treatment of these disorders chiefly comprises corticosteroids and immunosuppressant adjuvants like azathioprine and mycophenolate mofetil. Autoantibodies are the main mediators of these diseases. Rituximab, a chimeric anti-CD20 monoclonal antibody targeting B-cells, has emerged as an excellent treatment option for refractory pemphigus vulgaris in the last decade. Since then, many new biologics have been proposed/explored for managing autoimmune bullous diseases. These hold potential for greater efficacy and lesser adverse effects than conventional immunosuppressants. In this review, we discuss the role of various biologics in the treatment of autoimmune bullous diseases, followed by a brief discussion on the drawbacks to their use and new developments in this area.

Background Bullous pemphigoid is the most common subepidermal autoimmune blistering disease. Till now, the reported prognostic factors in bullous pemphigoid vary considerably. Aims The purpose of this study was to determine the overall survival rate and prognostic factors in bullous pemphigoid. Methods We conducted a retrospective cohort study on newly diagnosed bullous pemphigoid patients between July 2001 and November 2019 in a referral unit for autoimmune blistering skin diseases in Romania. Results One hundred forty-eight patients were included in the study. The Kaplan-Meier overall survival rates at 1, 3, 5 and 10 years were respectively 74.2% (95% confidence interval, 67.5-81.6%), 53.4% (45.7-62.2%), 43.6% (35.9-53%) and 31.3% (23.5-41.7%). The median follow-up among survivors was 48 months (interquartile range: 11-150). Ninety (60.8%) patients died during the follow-up period; of them, 38 (42.2%) had active disease at the time of death. Advanced age, neurological diseases, valvular heart disease, malignancies, use of statins, skin infections and extensive cutaneous involvement were linked to poorer outcomes, while the use of topical corticosteroids was associated with increased overall survival. Limitations This study lacks a control cohort to validate the obtained results. It was conducted in a retrospective manner in a single centre. In addition, indirect immunofluorescence microscopy was not performed in all patients. Conclusion Beyond ageing and neurological comorbidities, the prognosis of bullous pemphigoid patients was significantly influenced by the presence of skin infections, valvular heart disease, use of statins and extensive cutaneous involvement. Topical corticosteroid treatment was associated with increased survival in these patients.

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

Previous studies have found conflicting results about the association of autoimmune blistering disease (AIBD) with cardiovascular disease (CVD) risk. The objective of the study was to systematically review the relationship of AIBD, including pemphigus vulgaris (PV), and its treatment with CVD and CVD risk factors. MEDLINE, EMBASE, Cochrane, LILACS, SCOPUS, and Web of Science were searched. We included all studies of CVD and CVD risk factors in AIBD patients. Two reviewers performed title and/or abstract review and data extraction. Pooled random-effects meta-analysis was performed. Forty papers met inclusion criteria. AIBD was associated with higher odds of diabetes (DM) (odds ratio [95% confidence interval]: 1.809 [1.258-2.601]), hypertension (HTN) (1.393 [1.088-1.784]), dyslipidemia (2.177 [1.163-4.073]) and heart failure (1.919 [1.603-2.298]), but was not associated with obesity, stroke, angina, heart attack, or arrhythmia. The pooled random-effects prevalence for treatment-related adverse events (AEs) in AIBD was 13.7% for DM, 10.7% for HTN, and 17.1% for CVD. Sensitivity analysis of high-quality studies revealed similar results. AIBD patients have increased CVD risk factors and heart failure. Systemic corticosteroid treatment results in CVD-related AEs in AIBD. Increased CVD screening and prevention strategies are warranted in AIBD., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: To investigate the clinical course of autoimmune blistering diseases (AIBDs) following treatment with biologic agents (BAs) for chronic inflammatory diseases., Methods: A comprehensive review of available, published literature was performed using PubMed and CINAHL search engines. Diagnostic criteria of AIBD included positive direct immunofluorescence studies and/or positive serology with clinically suggestive features., Results: A total of 22 cases of AIBDs provoked by the use of BAs were found. The most commonly implicated agents were tumor necrosis factor-alpha inhibitors (n = 14). The mean age of onset of AIBD was 59.4 years (median 61.5 years, range 31-82). Average time to onset of AIBD following initiation of the suspected BA was 33.7 ± 43.8 weeks (range 3 days to 152 weeks). Psoriasis was the most common associated condition for which the BA was prescribed (n = 11), followed by rheumatoid arthritis (n = 6) and ulcerative colitis (n = 5). Of the 21 cases reporting AIBD outcome, 17 reported remission or complete resolution upon stopping treatment with the involved BA. Four cases reported continued bullae formation without worsening of disease following cessation of the BA or systemic corticosteroids used to treat the AIBD. Five cases rechallenged the patient with the involved BA and four of the five reported recurrence, often with quicker onset and more severe symptoms., Conclusions: BAs may be suspected in patients developing AIBD while being treated for chronic inflammatory diseases. A majority of cases resolve upon cessation of the offending agent., (© 2019 The International Society of Dermatology.)

Immunoglobulin A (IgA) pemphigus, also known as intercellular IgA dermatosis, is a rare autoimmune bullous disease presenting with IgA anti-keratinocyte cell surface autoantibodies. Concomitant lymphoproliferative disorders have been reported in IgA pemphigus, including IgA monoclonal gammopathy of undetermined significance and IgA type multiple myeloma (MM). A 35-year-old Japanese woman with a 3-year history of pruritic papulovesicles on her lower legs and trunk was referred to our department. Histopathological examination revealed acantholytic blisters, and results of both direct and indirect immunofluorescence were negative. Direct and indirect immunofluorescence were still negative 3 years and 7 months later. Approximately 7 years after her first visit, the patient was re-referred to us because of disease exacerbation. Histopathological findings revealed subcorneal blistering with acantholysis, in which neutrophil-dominant inflammatory cells were present. Indirect immunofluorescence was positive for IgA on the epidermal cell surface and both desmoglein (Dsg) 1/3 and (Dsc) desmocollin 1-3 enzyme-linked immunosorbent assays (ELISAs) for IgA were positive. The histological findings and positive Dsc1 IgA ELISA led to the diagnosis of subcorneal pustular dermatosis (SPD)-type IgA pemphigus. Further examination revealed hyper-IgA globulinemia, increased serum IgA-κ protein, and increased plasma cells in the bone marrow, enabling the diagnosis of IgA type MM. Daratumumab, lenalidomide, and dexamethasone (DLd) therapy was effective for both the MM and the skin lesions, resulting in negative results on Dsg1/3 and Dsc1-3 IgA ELISAs. The association between IgA pemphigus and IgA type multiple myeloma remains unclear, and only seven cases including the present case have been reported. Literature review revealed associations between SPD-type and IgA κ chain in IgA pemphigus and MM, and that in most cases the onset or diagnosis of MM was simultaneous or occurred after the diagnosis of IgA pemphigus. Therefore, clinicians should be aware of the development of multiple myeloma during the clinical course of patients with SPD-type IgA pemphigus., (© 2022 Japanese Dermatological Association.)

Background: Lichen planus (LP) is a relatively frequent mucocutaneous inflammatory disease affecting the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx., Objectives: To estimate the association of LP, with emphasis on dermatological and gastrointestinal conditions, in two large independent population cohorts., Materials and Methods: We performed a phenome-wide association study (PheWAS) and examined conditions associated with LP in two unrelated cohorts, i.e. the multicentre, community-based UK Biobank (UKB: 501 381 controls; 1130 LP subjects) and the healthcare-associated Penn Medicine BioBank (PMBB; 42 702 controls; 764 LP subjects). The data were analysed in 2021. The 'PheWAS' R package was used to perform the PheWAS analyses and Bonferroni correction was used to adjust for multiple testing. Odds ratios (ORs) were adjusted for age, sex and body mass index., Results: In the UKB, PheWAS revealed 133 phenome codes (PheCodes) significantly associated with LP and most of them were confirmed in PMBB. Dermatological and digestive PheCodes were the most abundant: 29 and 34 of these disorders, respectively, were significantly overrepresented in LP individuals from both cohorts. The 29 dermatological and 12 oral disorders were often highly enriched, whereas hepatic, gastric, oesophageal and intestinal PheCodes displayed ORs in the range of 1·6-4·5. Several autoimmune disorders also exhibited OR > 5 in both cohorts., Conclusions: PheWAS in two large unrelated cohorts identified previously unknown comorbidities and may support clinical counselling of patients with LP. What is already known about this topic? Lichen planus (LP) is known to affect the skin, skin appendages and mucosae, including oral mucosae, and less frequently the anogenital area, conjunctivae, oesophagus or larynx. What does this study add? Our data provide the most comprehensive collection of associated dermatological, digestive and autoimmune disorders to date. Our findings are expected to be useful for the evaluation and management of patients with LP., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)