Granular C3 dermatosis-A report of two cases and a mini-review of literature.

Granular C3 dermatosis (GCD) is characterized by bullous, erythematous, and eczematous skin lesions similar to dermatitis herpetiformis, and granular deposition of complement C3 and C5b-9 along the epidermal basement membrane zone (BMZ) by direct immunofluorescence (IF). Here, we present two cases of GCD with different clinical features. Case 1, a 49-year-old man, showed pruritic blisters and erythema of the extremities. Case 2, a 53-year-old woman, showed severely pruritic papules, erythema, and erosions on the entire body with scattered blisters, mainly on the lower extremities. Both patients showed mild eosinophilia on blood tests, subepidermal blisters and prominent eosinophilic infiltration in the upper dermis on histopathological examination, and granular BMZ deposition of C3, but not of immunoglobulins or other complement components, on direct IF. No circulating autoantibodies were detected on enzyme-linked immunosorbent assays, chemiluminescent enzyme immunoassays, indirect IF using 1 mol/L NaCl-split normal human skin, or immunoblotting. Diagnosis of GCD was made in both cases. Case 1 was successfully treated with topical steroids, oral minocycline, and nicotinamide without any recurrence of symptoms. Case 2 was treated with oral steroids and showed remarkable improvement, although mild pruritic papules remained. We reviewed 30 reported GCD cases, including the two cases presented here, since Hashimoto et al. first described GCD in 2016. GCD should be more widely recognized, and further accumulation and validation of cases are required.

Prevalence and clinical markers of herpes simplex virus infection in oral lesions of bullous pemphigoid.

Background: The 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. Objective: To identify the prevalence and clinical markers of HSV infection in oral lesions of BP. Methods: This 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. Results: A 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). Conclusion: HSV 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.

Single-cell sequencing reveals distinct immune cell features in cutaneous lesions of pemphigus vulgaris and bullous pemphigoid.

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two common subtypes of autoimmune bullous disease (AIBD). The key role of circulating autoreactive immune cells contributing to skin damage of AIBD has been widely recognized. Nevertheless, the immune characteristics in cutaneous lesions remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ sequencing (scRNA-seq) to generate transcriptional profiles for cells and T/B cell clonetype in skin lesions of BP and PV. We found that the proportions of NK&T, macrophages/ dendritic cells, B cells, and mast cells increased in BP and PV lesions. Then, BP and PV cells constituted over 75% of all myeloid cell subtypes, CD4+ T cell subtypes and CD8+ T cell subtypes. Strikingly, CD8+ Trm was identified to be expanded in PV, and located in the intermediate state of the pseudotime trajectory from CD8+ Tm to CD8+ Tem. Interestingly, CD8+ Tem and CD4+ Treg highly expressed exhaustion-related genes, especially in BP lesions. Moreover, the enhanced cell communication between stromal cells and immune cells like B cells and macrophages/ dendritic cells was also identified in BP and PV lesions. Finally, clone expansion was observed in T cells of BP and PV compared with HC, while CD8+ Trm represented the highest ratio of hyperexpanded TCR clones among all T cell subtypes. Our study generally depicts a large and comprehensive single-cell landscape of cutaneous lesions and highlights immune cell features in BP and PV. This offers potential research targets for further investigation.

Understanding patient perspectives on vaccine decision making in adults with autoimmune bullous diseases: a qualitative study.

Patients with autoimmune bullous diseases are at an increased risk of infection, both from the underlying skin disease and from immunosuppressive treatments. Limited information is available on vaccine beliefs and behaviors in dermatology patients and adults with autoimmune bullous diseases in particular. To understand vaccine decision making, identify perceived risks and benefits of vaccinations, and discuss individual experiences in patients with autoimmune bullous diseases in the United States. A qualitative study was performed utilizing semi-structured interviews, and analysis was conducted on NVivo. Patterns were identified in the coded data, and representative quotations were recorded for each major theme. Interviews were conducted between February 15, 2022 and September 15, 2022. Twenty patients with a diagnosis of bullous pemphigoid, mucous membrane pemphigoid, pemphigus vulgaris, or pemphigus foliaceous were interviewed. Of the 20 participants, 14 (70%) were female, with a mean (SD, range) age of 64.8 (13.2, 34-83) years. Key themes that emerged from qualitative analysis of the interviews included patient concerns regarding their increased susceptibility to infection, potential exacerbation of skin disease following vaccination, and the effect of immunosuppressive medications on humoral response to vaccines. Lack of appointment availability, difficulty accessing vaccines, and cost were commonly identified barriers to vaccination. These findings provide valuable knowledge for dermatologists in regard to providing counseling specific to patient concerns and to improve communication surrounding vaccination in the dermatology setting.

The Prevalence of Clinically Undiagnosed Depression in Patients With Autoimmune Bullous Diseases Seen at Inkosi Albert Luthuli Central Hospital, Durban, South Africa.

Background Chronic autoimmune bullous diseases have been associated with major depression in previous studies. This has been attributed to inflammatory cytokines, chronic pain, and the chronicity and debilitating nature of the disease. As no similar studies have been conducted in our setting, we aimed to determine the prevalence and severity of clinically undiagnosed depression in patients with autoimmune bullous diseases. Methodology We performed a cross-sectional study among outpatients managed in a bullous disease clinic at Inkosi Albert Luthuli Central Hospital, a quaternary provincial hospital in Durban, South Africa. Results A total of 44 participants were recruited and included in this study. The majority of the participants were females (29, 65.9%). The most common autoimmune bullous diseases were pemphigus vulgaris (19, 43.2%), bullous pemphigoid (18, 40.9%), and pemphigus foliaceus (5, 11.4%). The overall prevalence of at least mild and at least moderate depression in patients with autoimmune bullous diseases in our clinic was 52.3% and 20.5%, respectively. Pemphigus vulgaris showed the highest median Patient Health Questionnaire-9 score compared to other bullous dermatoses. Statistically significant differences were observed between females and males for the duration with the bullous disease (p = 0.014) and between intraepidermal and subepidermal disease for both the mean age (p = 0.038) and age at onset (p = 0.015). Conclusions Clinically undiagnosed depression is common in patients with autoimmune bullous disease. Its frequency and severity may differ depending on the underlying autoimmune bullous disease and possibly other factors. Dermatologists should always be alert to this fact and prompt psychiatric consultation as required to comprehensively manage these patients.

Maintenance treatment of pemphigus with rituximab in real life: A single-center study of 50 patients.

BACKGROUND: Following the RITUX 3 therapeutic trial, the French national diagnosis and care protocol (NDCP) for the treatment of pemphigus was updated in 2018. The updated protocol recommends initial treatment with rituximab (RTX) followed by maintenance therapy at 12 and 18 months, and potentially at 6 months where there are risk factors for early relapse. We evaluated these recommendations regarding the management of our own patients. PATIENTS AND METHODS: Our single-center retrospective study included all patients with pemphigus diagnosed between 01/2015 and 10/2020 and receiving at least one initial infusion of RTX. We collected the following data: type of pemphigus, severity, levels of anti-desmoglein 1 and 3 antibodies at diagnosis and between 2 and 6 months after initial RTX, presence or absence of maintenance therapy and modalities, time to first relapse and duration of associated systemic corticosteroid therapy ≥5 mg/day. Maintenance treatment modalities were as follows: no maintenance treatment, maintenance "on demand" (MT1) i.e. not performed at the rate imposed by the NDCP, and maintenance "according to NDCP" (MT2). RESULTS: Fifty patients were included (women 54%, median age 58 years, pemphigus vulgaris 68%, moderate to severe 68%). Initial RTX was combined with systemic corticosteroid therapy at 0.5 to 1 mg/kg in 74% of cases. Twenty-seven patients (54%) received no maintenance therapy, 13 were on an MT1 regimen (26%), and 10 were on an MT2 regimen (20%). Median follow-up was 42 months. At the last follow-up, 39 patients (78%) were in complete remission. A total of 25 patients (50%) relapsed: 18/27 (67%) patients without maintenance, 5/13 (38%) with MT1, and 2/10 (20%) with MT2 (p = 0.026). The probability of relapse over time was significantly lower in patients receiving maintenance therapy compared to those who receiving none (p = 0.022). The median time to relapse was 15 months in patients without maintenance, and 30 and 28 in those with maintenance (p = 0.27). The median duration of systemic corticosteroid therapy ≥ 5 mg/day in the no-maintenance group was 10 months, compared to 7 and 9 months respectively in MT1 and MT2 (p = 0.91). CONCLUSION: Our study confirms the value of RTX maintenance therapy in pemphigus in real life.

Eye and lid involvement as an uncommon feature of pemphigus foliaceus in a pediatric patient.

Pemphigus foliaceus (PF) is an autoimmune blistering disorder which affects the superficial layers of the epidermis with rare mucosal involvement. We present the case of a 12-year-old girl with PF involving the eyes and eyelids. A literature review of pediatric nonendemic PF revealed another two cases with ocular manifestations. Eyelid involvement is an uncommon feature of PF that should be properly identified and treated.

Linear IgA bullous dermatosis of childhood: Retrospective single-center cohort.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder impacting children and adults. In this single-center retrospective chart review of pediatric patients with LABD at a large tertiary referral center, we report the unifying and unique clinical features of 10 pediatric patients. Patients typically presented with the "cluster of jewels" sign (n = 6; 60%), mucous membrane involvement (n = 5; 50%) and had a mean disease duration of 38 months; six patients (60%) required inpatient admission for management of their skin disease, including all five patients who had mucous membrane involvement. Our findings suggest that pediatric LABD may be a disease with high morbidity and may be associated with severe complications when mucous membranes are involved.

New-onset of pemphigus following COVID-19 infection: A case report.

COVID-19 has been implicated in various cutaneous autoimmune diseases. Pemphigus is a group of autoimmune blistering diseases that target the desmosomal complexes. Pemphigus triggered by COVID-19 has been seldom reported in the literature and remains both a diagnostic and therapeutic challenge. We report a case of COVID-19-induced pemphigus that responded well to prednisone and mycophenolate mofetil after 9 months from initial presentation. On histologic examination, both intercellular and basement membrane staining were noted. Indirect immunofluorescence staining was positive against the intercellular cement of the stratified epithelium from monkey esophagus. We hypothesize that COVID-19 stimulated the release of multiple pemphigus antigens, which resulted in the unusual histologic pattern reported in the present case. Although malignancy should be suspected when features of paraneoplastic pemphigus, such as basement membrane staining on direct immunofluorescence, are noted, it may also be a histologic pattern of pemphigus secondary to COVID-19 that clinicians may consider.

Comparison of gut microbiota dysbiosis between pemphigus vulgaris and bullous pemphigoid.

OBJECTIVE: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are two prevalent bullous diseases. Previous studies found that the antibodies of BP could be expressed in the intestinal epithelium and BP was tightly related to inflammatory bowel disease. Therefore, gut microbiota might also play an important role in bullous disease. However, the specific relationship between gut microbiota and bullous diseases remains unknown. Our study aimed to investigate the potential role of gut microbiota in the development and progression of different bullous diseases. METHODS: We conducted a prospective and observational cohort study at Peking Union Medical College Hospital. Untreated BP and PV patients were recruited, along with healthy controls (HC) who were spouses or caregivers of these patients. Fecal samples were collected, followed by 16S rRNA gene sequencing. Bioinformatics analyses were performed to assess the composition and function of gut microbiota. RESULTS: A total of 38 HC, 32 BP, and 19 PV patients were enrolled in this study. Compared to HC, BP, and PV exhibited a distinct gut microbiota composition, especially BP. The gut microbiota changes were mainly observed in the phylum Bacteroidetes, Firmicutes, and Proteobacteria. The ratio of Faecalibacterium to Escherichia-Shigella (F/E ratio) had a considerable predictive value (AUC: 0.705) for recognizing BP from PV. The levels of Faecalibacterium and Enterobacter were correlated to the anti-BP 180 and anti-desmoglein 3. Microbial functional prediction revealed elevated activity in pathways related to gut microbiota translocation significantly increased in BP patients, indicating a potential pathogenetic role in BP. CONCLUSIONS: Our study suggests that the composition of gut microbiota is specific in different bullous diseases and the role of gut microbiota differs. Gut microbiota could help distinguish BP and PV, and might play a role in the pathogenesis of different bullous diseases.

Immunogenicity of Intradermal Versus Intramuscular BNT162b2 COVID-19 Booster Vaccine in Patients with Immune-Mediated Dermatologic Diseases: A Non-Inferiority Randomized Controlled Trial.

The intradermal route has emerged as a dose-sparing alternative during the coronavirus disease 2019 (COVID-19) pandemic. Despite its efficacy in healthy populations, its immunogenicity has not been tested in immune-mediated dermatologic disease (IMDD) patients. This assessor-blinded, randomized-controlled, non-inferiority trial recruited patients with two representative IMDDs (i.e., psoriasis and autoimmune bullous diseases) to vaccinate with fractionated-dose intradermal (fID) or standard intramuscular (sIM) BNT162b2 vaccines as a fourth booster dose under block randomization stratified by age, sex, and their skin diseases. Post-vaccination SARS-CoV-2-specific IgG and interferon-γ responses measured 4 and 12 weeks post-intervention were serological surrogates used for demonstrating treatment effects. Mean differences in log-normalized outcome estimates were calculated with multivariable linear regression adjusting for their baseline values, systemic immunosuppressants used, and prior COVID-19 vaccination history. The non-inferiority margin was set for fID to retain >80% immunogenicity of sIM. With 109 participants included, 53 received fID (all entered an intention-to-treat analysis). The fID demonstrated non-inferiority to sIM in humoral (mean outcome estimates of sIM: 3.3, ΔfID-sIM [mean, 95%CI]: -0.1, -0.3 to 0.0) and cellular (mean outcome estimates of sIM: 3.2, ΔfID-sIM [mean, 95%CI]: 0.1, -0.2 to 0.3) immunogenicity outcomes. Two psoriasis patients from the fID arm (3.8%) developed injection-site Koebner's phenomenon. Fewer fID recipients experienced post-vaccination fever (fID vs. sIM: 1.9% vs. 12.5%, p = 0.027). The overall incidence of disease flare-ups was low without a statistically significant difference between groups. The intradermal BNT162b2 vaccine is a viable booster option for IMDD patients troubled by post-vaccination fever; its role in mitigating the risk of flare-ups remains unclear.

Risk factors of rituximab-induced thrombocytopenia in patients with autoimmune bullous diseases.

Rituximab has been the mainstay treatment for autoimmune bullous diseases (AIBDs). Among the side effects of rituximab, rituximab-induced thrombocytopenia (RIT) is a rare but critical complication. However, there have been no reports or identification of risk factors for RIT in patients with AIBD. In our retrospective study, we compared rituximab-treated AIBD in patients with and without thrombocytopenia to explore the risk factors. In addition, we compared two different rituximab protocols (rheumatoid arthritis [RA] and lymphoma) in terms of the incidence and severity of thrombocytopenia. A total of 222 patients were enrolled, and 46 patients (20.7%) developed RIT. Multivariate logistic regression analysis identified age and chronic kidney disease (CKD) as significant factors for RIT. We also found that patients treated with the lymphoma protocol demonstrated a significantly higher mean post-rituximab platelet count compared with those on the RA protocol. This was the first analysis, to our knowledge, of risk factors for RIT in patients with AIBD. Individuals aged 70 or older and those with multiple comorbidities, particularly CKD, should be closely monitored for thrombocytopenia. For patients with CKD, it may be safer to use the lymphoma protocol for rituximab administration as it results in a lesser reduction in post-rituximab platelet count.

Potential Indications of Dupilumab in Th-2 Inflammatory Disease.

Dupilumab is a fully humanized IgG4 monoclonal antibody, inhibiting IL-4 and IL-13 signaling, which are the main cytokines involved in type 2 inflammatory diseases. Its introduction was a breakthrough in the treatment of moderate-to-severe atopic dermatitis, but it is also used in other inflammatory diseases, including asthma, eosinophilic esophagitis and chronic rhinosinusitis with nasal polyposis. Recent advances in the understanding of inflammatory pathways have revealed that Th2-type inflammation is involved in a wider range of diseases than previously thought. The aim of our review is to examine off-label therapeutic indications of dupilumab, including bullous dermatoses (pemphigus, bullous pemphigoid) and alopecia areata, and to investigate its potential applications in cancer patients on anti-PD1 therapy.

Do We Need to Monitor for Graves' Disease After a Diagnosis of Pemphigoid Gestationis?

Pemphigoid gestationis (PG) is a rare autoimmune bullous disease that occurs during pregnancy or the postpartum period. PG has been associated with an increased risk of Graves' disease possibly due to shared genetic factors and immune system fluctuations during pregnancy. However, the evidence supporting the association between PG and Graves' disease is mixed. Although dermatologists are cautioned to watch for Graves' disease in patients with a history of PG, this guidance is based on a single cohort where most patients were diagnosed with Graves' disease prior to PG onset. Recent data failed to find an association between Graves' disease and PG but did not capture the lifetime risk of Graves' disease in these patients. Future studies could focus on long-term follow-up of females with PG, shedding light on the lifetime risk profiles of these patients.

Oral Pemphigus Vulgaris: A Case Report With Review of Literature.

Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease that is characterized by mucocutaneous blister formation resulting in painful erosions. The autoantibody immunoglobulin (Ig) G directed toward glycoproteins desmoglein (Dsg) 3 and desmoglein 1 is the main underlying mechanism behind PV leading to intraepithelial clefting and bulla formation. Patients usually present with oral ulcers causing severe pain and dysphagia that can be misdiagnosed as erythema multiforme (EM) or viral infections. The diagnostic process requires the correlation between clinical, histopathological, and immunopathological findings. Systemic and/or local corticosteroids are considered the cornerstone therapy of PV cases. This article describes a case of a 42-year-old male patient who presented in the Department of Oral Medicine and Radiology with chronic oral ulcers that were diagnosed with PV and treated using systemic corticosteroids.

A case of radiotherapy-induced bullous pemphigoid with unusually delayed onset: A case report.

Bullous pemphigoid is an auto-immune blistering disease that generally affects older patients. Radiotherapy is one of the many triggering factors that have been described. Time to disease onset is variable; cases have been described during the course of radiotherapy while others have occurred up to 9 years later. We report a case of localized bullous pemphigoid on an irradiated site with unusual late presentation, 25 years after radiotherapy for left breast cancer. The pathophysiology of radiation-induced bullous pemphigoid is not clear, but the concept of an immunocompromised district seems to be a plausible explanation for the delayed onset of the disease.

Role of Human Leukocyte Antigen Class II in Antibody-Mediated Skin Disorders.

HLA class II molecules are key factors determining susceptibility to autoimmune disorders, and their role in immune-mediated skin conditions such as psoriasis has been extensively investigated. However, there is currently little understanding of their role in antibody-mediated skin diseases such as autoimmune blistering disorders. We researched the available literature using PubMed to narratively review the current knowledge on HLA associations in antibody-mediated blistering skin pathologies. Our results summarized the risk alleles that are identified in the literature, together with certain known protective alleles: in the pemphigus group, alleles HLA-DQB1*0503 and HLA-DRB1*0402 are most commonly associated with disease; in the pemphigoid group, the most studied allele is HLA-DQB1*0301; in epidermolysis bullosa acquisita, few genetic studies are available; in dermatitis herpetiformis, the association with haplotypes HLA-DQ2 and HLA-DQ8 is strongly established; finally, in linear IgA bullous disease, specific HLA alleles may be responsible for pediatric presentations. Our current pathogenic understanding of this group of disorders assigns a key role to predisposing HLA class II alleles that are able to bind disease autoantigens and therefore stimulate antigen-specific autoreactive T cells. The latter engage B lymphocytes that will produce pathogenic autoantibodies. The distribution of HLA alleles and their disease associations are variable across demographics, and an in-depth pathogenetic understanding is needed to support associations between HLA alleles and disease phenotypes. Additionally, in a personalized medicine approach, the identification of HLA alleles associated with the risk of disease may become clinically relevant in identifying susceptible subjects that should avoid exposure to known triggers, such as medication, when possible.