From Molecular Insights to Clinical Perspectives in Drug-Associated Bullous Pemphigoid.

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is characterized by the presence of autoantibodies targeting BP180 and BP230 in the basement membrane zone. This leads to the activation of complement-dependent and independent pathways, resulting in proteolytic cleavage at the dermoepidermal junction and an eosinophilic inflammatory response. While numerous drugs have been associated with BP in the literature, causality and pathogenic mechanisms remain elusive in most cases. Dipeptidyl peptidase 4 inhibitors (DPP4i), in particular, are the most frequently reported drugs related to BP and, therefore, have been extensively investigated. They can potentially trigger BP through the impaired proteolytic degradation of BP180, combined with immune dysregulation. DPP4i-associated BP can be categorized into true drug-induced BP and drug-triggered BP, with the latter resembling classic BP. Antineoplastic immunotherapy is increasingly associated with BP, with both B and T cells involved. Other drugs, including biologics, diuretics and cardiovascular and neuropsychiatric agents, present weaker evidence and poorly understood pathogenic mechanisms. Further research is needed due to the growing incidence of BP and the increasing identification of new potential triggers.

Precision in treatment evaluation: importance of minimal clinically important differences (MCIDs) of outcome measures for autoimmune blistering diseases.

Autoimmune blistering diseases (AIBDs) comprise a group of rare conditions marked by autoantibodies that specifically target intercellular adhesion molecules. Despite the progress made in comprehending the disease and the increasing number of treatment options available, there is still no definitive cure for AIBDs such as pemphigus, and it continues to have a devastating impact on those affected. The challenges in achieving new approved therapies for AIBDs are complex and multifaceted. One significant obstacle was the prior lack of validated and standardized outcome measures, which are crucial for ensuring precise comparisons between new and traditional therapies. This gap in knowledge has prompted the development of minimal clinically important differences (MCIDs), which enable efficient and reliable comparison of therapeutic outcomes between trials. MCID is defined as the minimum difference in an outcome measure that indicates a clinically significant improvement/deterioration in disease severity. Additionally, MCIDs provide a patient-centered approach to evaluating treatment efficacy, by considering whether patients experience a subjective improvement in their symptoms. Therefore, this literature review will examine the derivation and significance of MCIDs for various scoring systems in AIBDs.

Accuracy of serration pattern analysis by direct immunofluorescence in subepidermal autoimmune blistering diseases.

Background Direct immunofluorescence (DIF) is essential for the diagnosis of sub-epidermal immunobullous diseases (SIBD). Bullous pemphigoid (BP), a sub-epidermal immunobullous disease, shows linear IgG and C3 deposition along the dermo-epidermal junction by DIF. However, similar histological and DIF findings are also seen in epidermolysis bullosa acquisita (EBA). High-power examination of antibody deposition by DIF in a "u" or "n" serrated pattern can help differentiate these two entities. Aims/Objectives The aim of this study was to determine the diagnostic accuracy of serration patterns in IgG-mediated sub-epidermal immunobullous disease. Methods All cases of IgG-mediated sub-epidermal immunobullous disease diagnosed over the past 2 years and 9 months period and confirmed serologically, were included. Examination of the serration pattern in DIF was assessed on oil emersion. Salt split skin indirect immunofluorescence (SSS IIF), BP180 enzyme-linked immunosorbent assay (ELISA), profile ELISA and BIOCHIP mosaic were performed, wherever available. Results This study included 74 cases of bullous pemphigoid, eight cases of mucus membrane pemphigoid (MMP) and one case of epidermolysis bullosa acquisita. The characteristic zigzag "n" pattern was visualised in 66 out of 82 cases (80.5%) of the pemphigoid group (BP + MMP); the single epidermolysis bullosa acquisita case showed the "u" serrated pattern. No statistical correlation was seen between serration pattern and BP180 positivity by ELISA (P = 0.05). Limitations The study is limited by the single case of epidermolysis bullosa acquisita (which could be due to rarity of this disease in north Indian population due to genetic variation), lack of detailed serological investigations and immunoblot in all cases. Conclusion Serration pattern analysis is an easy-to-interpret and highly useful technique for characterisation of sub-epidermal immunobullous diseases.

Rituximab for linear immunoglobulin A bullous dermatosis.

Linear immunoglobulin A bullous dermatosis (LABD) is an idiopathic or drug-induced vesiculobullous disease typically managed with dapsone or colchicine. We report a case of LABD successfully treated with rituximab in a patient who was intolerant to first-line therapies and recalcitrant to typical immunosuppressants. The patient was initially started on prednisone and mycophenolate mofetil which resulted in minimal response and disease progression. Improvement was seen after two infusions of rituximab 1000 mg at 2 weeks apart with planned maintenance therapy.

Case report: A case of epidermolysis bullosa acquisita with IgG and IgM anti-basement membrane zone antibodies relapsed after COVID-19 mRNA vaccination.

We report a case of autoimmune bullous disease (AIBD) with IgG and IgM autoantibodies against epidermal basement membrane zone (BMZ), which showed recurrence of mucocutaneous lesions after coronavirus disease 2019 (COVID-19) mRNA vaccination. A 20-year-old Japanese woman with a 4-year history of epidermolysis bullosa acquisita (EBA) presented to our clinic. She noticed fever and rash on the same day and visited at our hospital 2 days later. Physical examination revealed blisters, erosions and erythema on the face, shoulder, back, upper arms, and lower lip. A skin biopsy from the forehead showed subepidermal blister. Direct immunofluorescence showed linear depositions of IgG, IgM, and C3c in the epidermal BMZ. By indirect immunofluorescence of 1M NaCl-split normal human skin, circulating IgG autoantibodies were bound to the dermal side of the split at 1:40 serum dilution, and circulating IgM antibodies were bound to the epidermal side of the spilt. After the increase of prednisolone dose to 15 mg/day, the mucocutaneous lesions resolved in a week. The present case is the first case of possible EBA with IgG and IgM anti-BMZ antibodies, in which the mucocutaneous lesions were recurred after COVID-19 mRNA vaccination. Clinicians should be aware that bullous pemphigoid-like AIBDs, including EBA and IgM pemphigoid, might be developed after COVID-19 mRNA vaccination.

The Essential Role of microRNAs in Inflammatory and Autoimmune Skin Diseases-A Review.

The etiopathogenesis of autoimmune skin diseases is complex and still not fully understood. The role of epigenetic factors is emphasized in the development of such diseases. MicroRNAs (miRNAs), a group of non-coding RNAs (ncRNAs-non-coding RNAs), are one of the important post-transcriptional epigenetic factors. miRNAs have a significant role in the regulation of the immune response by participating in the process of the differentiation and activation of B and T lymphocytes, macrophages, and dendritic cells. Recent advances in research on epigenetic factors have provided new insights into the pathogenesis and potential diagnostic and therapeutic targets of many pathologies. Numerous studies revealed a change in the expression of some microRNAs in inflammatory skin disorders, and the regulation of miRNA expression is a promising therapeutic goal. This review presents the state of the art regarding changes in the expression and role of miRNAs in inflammatory and autoimmune skin diseases, including psoriasis, atopic dermatitis, vitiligo, lichen planus, hidradenitis suppurativa, and autoimmune blistering diseases.

Clinical manifestations of alopecia in autoimmune blistering diseases: A cross-sectional study.

Background: Alopecia is a complication of autoimmune blistering diseases (AIBDs) that affects patients' quality of life; however, it has generally been overlooked in patients with severe disease because it is regarded as a cosmetic issue. Objective: To study the epidemiologic data and clinical presentations of alopecia in our cohort of patients with AIBDs. Methods: Forty-one patients with AIBDs were assessed in this cross-sectional study. An assessment tool to collate patient information, including AIBD scalp involvement, trichoscopic findings, and Severity of Alopecia Tool II scores, was used. Results: More than 70% of patients in our cohort had at least 1 type of alopecia, with 10% presenting with a nonspecific (end-stage) scarring alopecia. Elevated Dsg1 ratios were predictive of hair loss in pemphigus vulgaris (P < .001) and increased alopecia was associated with worse disease severity in bullous pemphigoid (P = .001). Limitations: The small sample size and lack of severe cases. Conclusion: There is a likelihood that 1 in 10 patients with AIBDs have a scarring alopecia related to their disease. To our knowledge, this is the first study including alopecia prevalence in patients with bullous pemphigoid, which was not significantly increased despite providing clues to disease severity.

The Successful Treatment of COVID-19-Induced Bullous Pemphigoid With Dupilumab.

Bullous pemphigoid (BP) is a rare autoimmune blistering condition that predominantly affects the elderly population. Typical treatment regimens target the immune system and inflammatory response. We present a case of BP in a 78-year-old male patient that occurred following the coronavirus disease 2019 (COVID-19) vaccination. This case was refractory to topical steroids and immunosuppressants. However, it responded to treatment with dupilumab, a monoclonal antibody therapy. Dupilumab is classically indicated for the treatment of asthma, eosinophilic esophagitis, atopic dermatitis, and chronic rhinosinusitis with nasal polyposis. We highlight the importance of considering the off-label use of dupilumab and its success in treating BP.

Applicability of glucocorticoid toxicity index in pemphigus: Comparison between two groups of rituximab-treated and rituximab-naïve patients.

Rituximab (RTX) combined with short-term glucocorticoids (GC) is an effective therapeutic option for pemphigus. The newly developed Glucocorticoid Toxicity Index (GTI) tool provides the possibility to measure GC toxicities over time. To compare 1-year GTI between two groups of RTX-treated and RTX-naïve patients with pemphigus. The responsiveness of the GTI was also investigated. A prospective cohort of 129 adults with newly diagnosed pemphigus was conducted. GC-related toxicities were assessed at 3-month intervals according to Composite and Specific lists of the GTI. Of the patients, 76.7% (n = 99) received RTX. Throughout the time intervals, RTX-treated patients had lower GTI compared to RTX-naïve ones (p = 0.036). The mean GTI at 1-year was 34.3 in the RTX-treated group and 50.8 in the RTX-naïve group (p = 0.04). The most commonly observed GC-related toxicity was neuropsychiatric manifestations for 34% (224 events). The relapse rate of RTX-treated patients (1%) was significantly lower than RTX-naïve patients (10%) (p = 0.037). The GTI showed no correlation with cumulative GC consumption in both groups (p > 0.05, both). Patients treated with GC alone had remarkably higher GTI than patients treated with GC plus RTX. The GTI is an applicable tool to quantitatively capture GC toxicities at the patient level in pemphigus.

Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. METHODS: Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. RESULTS: Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. CONCLUSIONS: Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379.

Side effects of steroid-sparing agents in patients with bullous pemphigoid and pemphigus: A systematic review.

Background: Systemic glucocorticoids are first-line treatment options for autoimmune blistering diseases; however, their long-term use is associated with significant toxicities. Objective: To evaluate the side effects of steroid-sparing agents and compare them with those of steroids. Methods: We searched Cochrane Reviews, Embase, MEDLINE, and Scopus between October 1978 and May 2020 using the keywords "bullous pemphigoid," "pemphigus," "autoimmune blistering diseases," and "side effects." A total of 31 randomized controlled trials and retrospective case series were critically appraised. Results: This review includes a total of 1685 patients with autoimmune blistering diseases, of whom 781 had bullous pemphigoid and 904 had either pemphigus vulgaris or pemphigus foliaceous. Limitations: A major limitation is that because adjuvants are generally used in combination with steroids, only 12 of the studies reviewed included a "steroid-only" arm to allow for a direct comparison of side effects. Additionally, there is inadequate literature and lack of standardized grade reporting of specific side effects of each steroid-sparing agent. Conclusion: In the future, researchers should consider implementing the Common Terminology Criteria for Adverse Events, version 5.0, for reporting of all side effects to allow for consistency and standardization. It would be useful to have an index similar to the Glucocorticoid Toxicity Index to quantify these side effects.

Ocular Involvement in Pemphigus Vulgaris Without Skin Lesions: A Case Report.

Pemphigus vulgaris (PV) is an autoimmune disorder affecting the skin and mucous membranes. The condition may be confused with a number of disorders, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme (EM), all of which are life-threatening. Immunohistological and histochemical analyses remain the optimal methods for differentiating these diseases. There is still insufficient evidence regarding the true incidence rate of ocular disease in PV as well as its distinct clinical types. This report sets to review the case of a 62-year-old male with atypical ocular pemphigus vulgaris and review the literature.

Insights Into the Pathogenesis of Bullous Pemphigoid: The Role of Complement-Independent Mechanisms.

Bullous pemphigoid is an autoimmune blistering disease caused by autoantibodies targeting BP180 and BP230. While deposits of IgG and/or complement along the epidermal basement membrane are typically seen suggesting complement -mediated pathogenesis, several recent lines of evidence point towards complement-independent pathways contributing to tissue damage and subepidermal blister formation. Notable pathways include macropinocytosis of IgG-BP180 complexes resulting in depletion of cellular BP180, direct induction of pro-inflammatory cytokines from keratinocytes, as well as IgE autoantibody- and eosinophil-mediated effects. We review these mechanisms which open new perspectives on novel targeted treatment modalities.

Use of Dupilumab in Bullous Pemphigoid: Where Are We Now?

Bullous pemphigoid (BP) is the most frequent autoimmune subepidermal bullous disease. At present, the main treatment options are represented by corticosteroids and immunosuppressant drugs. Steroids often need to be administered in high doses, with subsequent adverse events and safety issues, as BP mainly affects elderly people. As dupilumab, a recombinant fully human IgG4 monoclonal antibody with binding specificity to human interleukin-4 receptor IL-4Rα has become paramount in the treatment of atopic dermatitis, its use in autoimmune bullous diseases has been theorized and it has been used to treat patients with BP. Dupilumab seems to be an effective and safe option to treat recalcitrant BP. Here, we report the results of a literature review on the use of dupilumab in BP, including a total of 30 treated patients in 9 papers.

Annular bullous pemphigoid: A case report and review of literature.

Bullous pemphigoid is an autoimmune blistering disease that primarily affects the geriatric population. It often presents as urticarial erythematous plaques, which evolve into subepidermal blisters accompanied by pruritus. Although rare, clinical variants of bullous pemphigoid have been documented. We present a rare case of annular bullous pemphigoid in a 50-year-old male and offer a brief review of the literature. Only five other case reports, including three in adults, have described this unusual presentation, which can mimic other autoimmune blistering diseases, including linear IgA bullous dermatosis and pemphigus herpetiformis. Therefore, histopathology and immunologic studies were essential in properly diagnosing this patient. Our case supports that annular blistering lesions can be a clinical variant of bullous pemphigoid.

Antibody-Negative Paraneoplastic Autoimmune Multiorgan Syndrome (PAMS) in a Patient with Follicular Lymphoma Accompanied by an Excess of Peripheral Blood CD8+ Lymphocytes.

Paraneoplastic autoimmune multiorgan syndrome (PAMS) is a life-threatening autoimmune disease associated with malignancies. Here, we present a patient initially misdiagnosed with "chronic" Stevens-Johnson syndrome. Over a year later, the patient was diagnosed with stage IV follicular lymphoma and treated with an anti-CD20 antibody. At this time, his skin condition had significantly worsened, with erythroderma and massive mucosal involvement, including in the mouth, nose, eyes, and genital region. Histopathology revealed lichenoid infiltrates with interface dermatitis, dyskeratoses, necrotic keratinocytes, and a dense CD8+ infiltrate with strong epidermotropism. Direct and indirect immunofluorescence tests for autoantibodies were negative. Remarkably, we retrospectively discovered a chronic increase in peripheral CD8+ lymphocytes, persisting for over a year. Consequently, the patient was diagnosed with antibody-negative PAMS. Three weeks later, he succumbed to respiratory failure. This dramatic case highlights the challenges in diagnosing PAMS, particularly in cases where immunofluorescence assays are negative. Importantly, we observed, for the first time, a chronic excess of CD8+ peripheral blood lymphocytes, associated with PAMS, consistent with the systemic, autoreactive T-cell-driven processes that characterize this condition.

Anti-laminin 332 antibody detection using biochip immunofluorescence microscopy in a real-life cohort of Italian patients with mucous membrane pemphigoid

Background: Mucous membrane pemphigoid (MMP) with anti-laminin 332 autoantibodies may be associated with malignancies, however, current serological assays have considerable limitations. At present, no commercial test for anti-laminin 332 antibodies is available, restricting the diagnosis to specialized laboratories worldwide. Biochip immunofluorescence microscopy has shown promising results in selected cohorts of laminin 332-MMP patients. Objectives: To detect anti-laminin 332 antibodies by biochip immunofluorescence microscopy in a real-life cohort of MMP patients and compare the results with those from traditional immunoblotting. Materials & Methods: Sera were obtained from 31 patients with MMP, 28 with bullous pemphigoid, five with pemphigus vulgaris, five with paraneoplastic pemphigus, five with linear IgA bullous dermatosis, and 10 controls, and analysed by biochip immunofluorescence using human cells expressing laminin 332. Immunoblotting was performed using purified laminin 332. Results: MMP involved the oral mucosa in 65%, ocular mucosa in 9%, oral and ocular mucosae extensively in 13% as well as other mucosae in 13% of patients. Concomitant cutaneous involvement was reported in 35% of patients. Three MMP patients had an underlying malignancy. Anti-laminin 332 antibodies were detected in 2/31 (6%) cases by both methods. Based on immunoblotting, both laminin 332-positive sera reacted with α3 chain (in one case also with ß3 chain). Both patients with anti-laminin 332 antibodies had extensive mucosal involvement and only one had cancer. Anti-laminin 332 antibodies were not detected in control groups. Conclusion: Biochip immunofluorescence is an appropriate technique to detect anti-laminin 332 antibodies which should be tested in patients with MMP.