Case report: Managing pemphigus foliaceus using apremilast without systemic glucocorticosteroids or immunosuppressive agents.

Pemphigus foliaceus (PF) is a superficial form of pemphigus. Treatment options for PF resemble pemphigus vulgaris, including glucocorticosteroids, immunosuppressive agents and rituximab et al. These treatment approaches can effectively improve the condition but may also be accompanied by high risks of side effects. Therefore, it is crucial to find a safe and effective treatment options for patients with PF. It will not only benefit/be necessary for patients who refuse glucocorticosteroids or immunosuppressive agents treatments, but also for patients who cannot be treated with glucocorticosteroids or immunosuppressive agents. Herein, we reported a case of PF that was treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. A 54-year-old woman presented with itchy erythema and erosions on the trunk for more than 1 month. The patient applied mometasonefuroate cream without improvement for a duration of two weeks. The past history of diabetes mellitus and atrophic gastritis was reported. Physical examination revealed scattered erythematous macules and erosions on the trunk. No mucosal involvement was observed. The condition was assessed by the pemphigus disease area index and numerical rating scale, with baseline scores of 7 and 8, respectively. Histopathological examination showed acantholysis and intraepithelial blister. Direct immunofluorescence revealed the presence of IgG and Complement 3 deposition between the acanthocytes with the reticular distribution. Based on enzyme-linked immunosorbent assay results, the levels of Dsg1 and Dsg3 antibodies were 28.18 and 0.26 kU/L respectively. The diagnosis of PF was made. This patient was successfully treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. The patient has continued with apremilast 30mg once daily for maintenance and no adverse events related to apremilast such as gastrointestinal side effects were observed during the 9-month follow-up period. In conclusion, apremilast therapy without systemic glucocorticosteroids nor immunosuppressive agents might provide an effective alternative to management of mild PF without obvious side effect.

[Hailey-Hailey disease: A case report]. / Enfermedad de Hailey-Hailey: reporte de un caso.

Background: Hailey-Hailey disease is a rare autosomal dominant genodermatosis whose cause is the ATP2C1 gene mutation. A prevalence of 1 in 50,000 cases is estimated and it manifests as grouped flaccid vesicles that break easily. The diagnosis is confirmed with the histopathological study creating an appearance called "dilapidated brick wall", identifying dyskeratosis in the form of round bodies and pimples. Treatment ranges from general measures to multiple pharmacological options, with topical corticosteroids being the most commonly used. Clinical case: Male patient diagnosed with Hailey-Hailey disease. On physical examination we observed a dermatosis disseminated to the neck, trunk, axillary and inguinal folds, and intergluteal region, unilateral, asymmetric with a polymorphous appearance, constitution due to exulceration, erythema, some pustules and flaccid vesicles that coalesced to form eczematous and hypertrophic plaques with the presence of fine scales on their surface, with a chronic evolution accompanied by pruritus. We also took the opportunity to review the most relevant information in the literature regarding Hailey-Hailey disease, especially focused on the therapeutic aspect. Conclusions: It is important to take into account that Hailey-Hailey disease is a rare pathology, in order to make a differential diagnosis in daily clinical practice.

Introducción: la enfermedad de Hailey-Hailey es una rara genodermatosis autosómica dominante cuya causa es la mutación del gen ATP2C1. Se estima una prevalencia de 1 por cada 50,000 casos y se manifiesta como vesículas flácidas agrupadas que se rompen con facilidad. El diagnóstico se confirma con el estudio histopatológico que crea una apariencia denominada "pared de ladrillo dilapidada" y se identifica disqueratosis en forma de cuerpos redondos y granos. El tratamiento comprende desde medidas generales hasta múltiples opciones farmacológicas y los corticoesteroides tópicos son los más utilizados. Caso clínico: paciente del sexo masculino con diagnóstico de enfermedad de Hailey-Hailey. A la exploración física observamos una dermatosis diseminada a cuello, tronco, pliegues axilares, inguinales y región interglútea, de manera unilateral, asimétrica, de aspecto polimorfo, constituida por exulceración, eritema, algunas pústulas y vesículas flácidas que confluían para formar placas eccematosas e hipertróficas con escama fina, de evolución crónica, acompañada de prurito. Además, aprovechamos la oportunidad para revisar la informacion más relevante en la literatura con respecto a la enfermedad de Hailey-Hailey, especialmente enfocados en el aspecto terapéutico.es importante tener en cuenta que la enfermedad de Hailey-Hailey es una patología rara, a fin de hacer un diagnóstico diferencial en la práctica clínica rutinaria.

Co-occurrence of oral pemphigus vulgaris and herpes simplex virus infection in a young patient with Crohn's disease: report of a rare case of oral lesions during anti-TFN alpha and immunomodulator therapy.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially life-threatening mucocutaneous autoimmune disease that affects desmoglein-1 and desmoglein-3, leading to intraepithelial vesiculobullous lesions. In the oral mucosa, PV lesions can mimic other diseases such as mucous membrane pemphigoid, other forms of pemphigus, recurrent aphthous stomatitis, erythema multiforme, Stevens-Johnson syndrome, and virus-induced ulcers like herpes simplex virus (HSV), making diagnosis challenging. The co-occurrence of PV with Crohn's disease is rare and predominantly seen in younger patients. The therapeutic mainstay for both PV and Crohn's disease usually involves systemic corticosteroids combined with immunosuppressants and immunobiological drugs. Literature indicates that the use of these drugs, particularly TNF-alpha inhibitors, for managing autoimmune diseases like Crohn's can potentially induce other autoimmune diseases known as autoimmune-like syndromes, which include episodes of lupus-like syndrome and inflammatory neuropathies. There are few cases in the literature reporting the development of PV in individuals with CD undergoing infliximab therapy. CASE REPORT: A young female with severe Crohn's disease, treated with the TNF-alpha inhibitor infliximab, developed friable pseudomembranous oral ulcerations. Histopathological and immunofluorescence analyses confirmed these as PV. The treatment included clobetasol propionate and low-level photobiomodulation, which resulted in partial improvement. The patient later experienced severe intestinal bleeding, requiring intravenous hydrocortisone therapy, which improved both her systemic condition and oral lesions. Weeks later, new ulcerations caused by herpes virus and candidiasis were identified, leading to treatment with oral acyclovir, a 21-day regimen of oral nystatin rinse, and photodynamic therapy, ultimately healing the oral infections. To manage her condition, the gastroenterologists included methotrexate (25 mg) in her regimen to reduce the immunogenicity of infliximab and minimize corticosteroid use, as the patient was in remission for Crohn's disease, and the oral PV lesions were under control. CONCLUSION: Young patients with Crohn's disease should be referred to an oral medicine specialist for comorbidity investigation, as oral PV and opportunistic infections can arise during immunosuppressive therapy. The use of TNF-alpha inhibitors in patients treated for inflammatory bowel disease, such as Crohn's, should be carefully evaluated for potential side effects, including oral PV.

Solitary verrucous plaque on a leg.

We present the case of a female in her 70s who presented with a solitary verrucous plaque on her left leg accompanied by painful oral erosions. Various differential diagnoses were considered, like lichen simplex chronicus, hypertrophic lichen planus, and chromoblastomycosis. We diagnosed pemphigus vegetans (PVeg) on a nonintertriginous site through comprehensive clinical examination and histopathological and immunopathological evaluations. This case highlights the importance of considering PVeg in the differential diagnosis of solitary verrucous plaques, even in atypical extra-flexural anatomical locations.

The potential of Bruton's tyrosine kinase (BTK) inhibitors in the pharmacotherapeutic management of immune and dermatological disease.

INTRODUCTION: The review article explores the evolving role of Bruton's tyrosine kinase (BTK) inhibitors in immune-mediated dermatological conditions, addressing significant gaps in current treatment approaches. AREAS COVERED: The review comprehensively discusses the mechanisms of action of BTK inhibitors, including irreversible and reversible inhibitors. Clinical applications of BTK inhibitors in dermatological diseases such as pemphigus, chronic spontaneous urticaria (CSU), hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), and atopic dermatitis are explored, highlighting recent advancements and ongoing clinical trials. Potential advantages of BTK inhibitors over existing therapies and challenges in translating preclinical findings to clinical outcomes are discussed. EXPERT OPINION/COMMENTARY: BTK inhibitors represent a promising therapeutic avenue for immune-mediated dermatological conditions, offering oral administration, targeted pathway inhibition, and a favorable safety profile compared to biologic therapies. Ongoing research and clinical trials hold the potential to address unmet needs and reshape the therapeutic landscape in dermatology.

Our manuscript explores how a new class of medications called Bruton tyrosine kinase (BTK) inhibitors could revolutionize the treatment of skin conditions caused by the immune system. These conditions, like chronic spontaneous urticaria (CSU), pemphigus, and systemic lupus erythematosus (SLE), often lack effective treatments. BTK inhibitors work by targeting specific pathways in the immune system, offering hope for patients with these challenging conditions.We reviewed clinical trials and research studies to understand how BTK inhibitors could benefit patients. One significant advantage of BTK inhibitors is their ability to provide targeted therapy, meaning they can specifically block the faulty immune responses driving these conditions without affecting the entire immune system. This targeted approach could lead to fewer side effects compared to current treatments, such as corticosteroids or immunosuppressants, which can have widespread effects on the body.Overall, BTK inhibitors represent a promising new approach to treating immune-mediated skin conditions. With further research and development, they could offer safer and more effective alternatives to current treatments, improving the lives of patients worldwide.

Direct immunofluorescence on plucked hair outer root sheath can predict relapse in pemphigus vulgaris.

BACKGROUND: Prospective research is lacking on the utility of plucked hair outer root sheath direct immunofluorescence (ORS DIF) in the prediction of relapse in pemphigus vulgaris (PV) and the correlation of ORS DIF positivity with serum desmoglein antibody titers. METHODS: We performed a prospective cohort study enrolling 80 PV patients in complete clinical remission at a tertiary care center in North India. Study participants underwent ORS DIF at baseline, which was repeated every 3 months. Skin biopsy DIF was done at study inclusion, repeated at 3 months, and upon clinical relapse. An antidesmoglein antibody titer was assessed concurrently with ORS DIF in a subset of patients. Patients on adjuvant therapy had their adjuvant therapy withdrawn either at the initial visit, at 3 months, or at a 6-month follow-up. Our objectives were to determine the association between positive ORS DIF and clinical relapse, the correlation between positive ORS DIF and skin biopsy DIF, and between positive ORS DIF and positive antidesmoglein antibody titers (when concurrently done). RESULTS: Twenty-two patients (27.5%) had a clinical relapse. Baseline immunological markers significantly associated with relapse are ORS DIF positivity with IgG (16/36 [45.44%] P = 0.005) and C3 (12/29 [41.37%] P = 0.047) and greater intensity of baseline IgG and C3 positivity in ORS DIF (IgG, P = 0.002; C3, P = 0.033). Notably, a significant correlation was observed between baseline positive ORS DIF and skin biopsy DIF (IgG, ρ = 0.695; C3, ρ = 0.498). Positive ORS DIF strongly correlated with positive anti-Dsg3 antibody titers (φs = 0.815; P < 0.01). Early withdrawal of adjuvant immunosuppressant (within 3 months) (P = 0.007) and positive ORS DIF were also associated with relapse (P = 0.017). CONCLUSION AND RELEVANCE: ORS DIF is a reliable predictor of PV clinical relapse and demonstrated robust correlations with skin biopsy DIF and antidesmoglein antibody titers. Periodic assessment of ORS DIF aids in determining new-onset positivity that heralds clinical relapse.

Alteration of reactive oxygen species master transcription factor Nrf2 in keratinocytes exposed to monoclonal pathogenic antibody AK23 against desmoglein-3 in pemphigus vulgaris.

Keratinocytes in mucosal and skin tissues maintain tissue integrity via desmosomes and desmoglein-3 (Dsg3). Pemphigus Vulgaris (PV) is a life-threatening autoimmune blistering disease characterized by autoantibodies against Dsg3, disrupting desmosomes. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates oxidative stress responses crucial for skin tissue protection. Although the pathogenesis of PV is known, the detailed molecular events remain unclear. This study investigates changes in Nrf2 expression in keratinocytes following pathogenic anti-Dsg3 antibody AK23 exposure, using dose- and time-dependent studies employing immunofluorescence analysis. N/TERT keratinocytes were cultured in keratinocytes serum-free medium and treated with AK23 at varying doses (5 µg/mL,40µg/mL,75µg/mL) and durations (2, 6, 24 h). Immunofluorescence staining was performed to assess the expression of Nrf2 and Dsg3. All fluorescent images were analyzed using ImageJ software. A dose-dependent increase in Dsg3 was noted following AK23 treatment, while Nrf2 expression and subcellular localization varied. Time-course analyses showed decreased Nrf2 at 24 h and increased Dsg3 levels. Early time-point (2 and 6 h) variations were evident in Nrf2 levels. This study highlights the impact of AK23 on Nrf2 expression, potentially disrupting Nrf2-mediated cytoprotection and implicating oxidative stress (ROS generation) in PV pathogenesis. Further investigation is necessary to validate the findings.

Immunostimulatory effects of Toll-like receptor ligands as adjuvants in establishing a novel mouse model for pemphigus vulgaris.

BACKGROUND: The meticulous selection of appropriate vaccine adjuvants is crucial for optimizing immune responses. Traditionally, pemphigus vulgaris (PV), an autoimmune disorder, has been modelled using complete Freund's adjuvant (CFA). In this study, we aimed to discern potential variations in immune responses elicited by Toll-like receptor (TLR) ligands as compared to CFA. METHODS: A comprehensive investigation was conducted, comparing the effects of these adjuvants in conjunction with ovalbumin or desmoglein-3. Flow cytometry was employed to analyse distinct cell subsets, while enzyme-linked immunosorbent assay quantified antigen-specific antibodies and cytokine levels. Histological examination of harvested skin tissues and transcriptome analysis of skin lesions were performed to identify differentially expressed genes. RESULTS: TLR ligands demonstrated efficacy in inducing PV-like symptoms in wild-type mice, in contrast to CFA. This underscored the substantial impact of the adjuvant on self-antigen tolerance. Furthermore, we proposed an enhanced method for establishing a PV model through adoptive transfer, substituting CFA with TLR ligands. Our results revealed that in contrast to the perception that CFA being the most potent immunopotentiator reported, CFA promoted regulatory T cells (Treg), follicular regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10. This suggested potential implications for the recruitment and activation of Treg subsets. While B cell and CD8+ T cell responses exhibited similarity, CFA induced less activation in dendritic cell subsets. A novel mouse model of PV and systemic comparison of immunostimulatory effects of adjuvants were provided by this study. CONCLUSIONS: The systematic comparison of CFA and TLR ligands shed light on the distinctive properties of these adjuvants, presenting innovative mouse models for the investigation of pemphigus. This study significantly contributes to adjuvant research and advances our understanding of PV pathogenesis. KEY POINTS/HIGHLIGHTS: Immunization with desmoglein 3 and Toll-like receptor (TLR) ligands effectively induces pemphigus symptoms in wild-type mice, whereas complete Freund's adjuvant (CFA) fails. TLR ligands heightened the autoreactivity of donor cells in the adoptive transfer pemphigus model. CFA promoted regulatory T cells and IL-10-producing neutrophils, whereas TLR ligands downregulated CCL17 and IL-10, leading to more effective immune responses.

Utility of C4d Immunohistochemistry in the Diagnosis of Esophageal Pemphigus Vulgaris.

Aims. To assess the utility of C4d immunohistochemistry for esophageal pemphigus vulgaris. Methods and results. We searched for patients with a history of esophageal pemphigus vulgaris who had esophageal biopsies for routine hematoxylin and eosin (H&E) staining. A total of 8 biopsies from 7 patients were available. We also identified 18 non-pemphigus esophageal biopsies for controls. C4d immunohistochemistry was performed on each biopsy. Five of 6 (83%) biopsies with classic pemphigus vulgaris histologic findings were positive for intercellular staining at the basal layer. The negative biopsy was in a patient that had recently received high-dose corticosteroid treatment for a flare. Two biopsies with atypical histologic features for pemphigus vulgaris had negative C4d staining but positive direct immunofluorescence (DIF) studies. Various nonspecific C4d staining patterns were observed in the controls, but none showed the intercellular staining pattern that was observed in pemphigus vulgaris. Conclusions. Suprabasal clefting with acantholysis and "tombstone effect" are described histologic features of pemphigus vulgaris on H&E. However, procedural artifact may mimic these findings. Currently, the gold standard for pemphigus vulgaris is DIF, which is not always available because it cannot routinely be performed on formalin-fixed paraffin embedded tissue. Our study shows that C4d immunohistochemistry may be a useful adjunct in evaluating esophageal pemphigus vulgaris.

Epidemiological Insights into Autoimmune Bullous Diseases in China: A Comprehensive Analysis.

OBJECTIVE: This study aims to conduct an extensive analysis of autoimmune bullous diseases, particularly pemphigus vulgaris and bullous pemphigoid, in Shanghai, China, from 2016 to 2023. It seeks to understand the demographic profiles, comorbidities, mortality rates, risk factors, and socioeconomic impacts associated with autoimmune bullous disease. METHODS: A cross-sectional study design was employed, enrolling 1,072 patients. Diagnostic measures included clinical manifestations, histopathology, direct immunofluorescence, and serologic tests. The study also involved a detailed socioeconomic analysis and evaluation of occupational risks. RESULTS: The findings highlight a significant occupational risk in industries requiring enhanced safety measures, with a notable prevalence of autoimmune bullous disease among workers in these sectors. A considerable portion of the patients were from low-income backgrounds with limited literacy, indicating the economic burden of autoimmune bullous disease. A key discovery of the study is the potential pathological link between autoimmune bullous disease and interstitial lung disease. CONCLUSION: This research, one of the first comprehensive studies on autoimmune bullous disease in China, underscores the need for targeted healthcare strategies and further investigation into autoimmune bullous disease, particularly its relationship with interstitial lung disease.

Distorted frequency and functionality of natural killer cells in pemphigus vulgaris: A potential therapeutic target.

Pemphigus vulgaris (PV) is a rare autoimmune disorder where autoantibodies target the desmosomal proteins resulting in blistering of oral mucosa and skin. While the pathogenesis of PV is mainly mediated by the adaptive immune system, key players of innate immunity are also emerging. This study outlines the phenotypic as well as functional attributes of NK cells in PV. Through in-depth analysis using flow cytometry we identified an increase in the frequency of CD56+ CD3- NK cells and their subtypes in periphery. Along with this there is an increased frequency of IFNγ+ CD56bright CD16dim NK cells. mRNA expression of sorted NK cells for differentially expressed genes, particularly key transcription factors such as T-bet and EOMES, as well as surface receptors like NKG2D and KIR2D, and the cytokine IFNγ, displayed significant upregulation. A significant activation of NK cells was seen in the disease state. The levels of perforin and IFNγ were significantly elevated in the culture supernatants of patients. Additionally, a significantly higher cytotoxicity of NK cells in PV was observed. In lesioned tissues of PV, NK related markers were significantly increased. Lastly, we observed NK cells using confocal microscopy in the tissue biopsies of patients which showed significant infiltration of CD56+ CD3- NK cells at the lesional sites. This study aimed to shed light on the pivotal role of NK cells in the immunopathology of PV, offering a thorough understanding of their behaviour and changes in expression which might help in contributing to the development of novel therapeutics.

Biomarkers in Pemphigus Vulgaris: A Systematic Review.

INTRODUCTION: Pemphigus vulgaris (PV) is a rare intraepidermal blistering disease that is potentially life-threatening due to risk of infection and failure of skin barrier function. The identification of biomarkers has the potential to provide diagnostic utility and identify new therapeutic targets. The objective of this systematic review is to identify all potentially relevant PV biomarkers, categorize them, and identify trends to determine the involvement of T-cell-mediated, B-cell-1mediated, and innate immune-mediated pathways in PV pathogenesis. METHODS/RESULTS: Medline and Embase databases were searched according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, resulting in the inclusion of 66 studies that reported on a total of 2463 patients and 146 unique biomarkers. Biomarkers were categorized into T-cell-mediated, B-cell-mediated, and innate immune system pathways. The most notable biomarkers trends include elevations in IL-4, IL-6, IL-17A, anti-Dsg1/3 autoantibodies, and a reduction in Treg cells and FOXP3. CONCLUSION: The results of this review support current theories of PV pathogenesis, with increased Th2 activity, increased Th17 activity, decreased Treg activity, and production of anti-Dsg1/3 autoantibodies being observed. Targeting of IL-4 and IL-6 may provide therapeutic benefit. However, more research is required to validate biomarkers for clinical utility and assess viability as therapeutic targets.

Immunohistopathological analyses of a case of pemphigus vegetans with antibodies against desmoglein 1 and desmocollins 1-3.

Pemphigus vegetans is a rare type of pemphigus characterized by vegetative lesions primarily localized to the intertriginous area. Despite its unique clinical presentation, the underlying pathomechanism remains unclear owing to the rarity of the disease. We report a case of pemphigus vegetans with antibodies against desmoglein 1 and desmocollins 1-3. Furthermore, immunohistochemical analyses were performed to address the pathogenesis of this disease. A 73-year-old man presented with multiple vegetative plaques with erythema on the trunk, groins, and extremities. Mucosal lesions were not observed. Laboratory examinations revealed mild leukocytosis with eosinophilia. A histopathological examination of the skin lesion showed epidermal hyperplasia and intraepidermal abscesses with marked infiltration of neutrophils and eosinophils, and infiltration of lymphocytes and eosinophils into the upper derms. Bacterial culture of the skin tissue was positive for Staphylococcus aureus. Direct immunofluorescence showed deposits of IgG and C3 on keratinocyte surfaces in the epidermis. Autoantibodies against desmoglein 1 and autoantibodies against desmocollin 1, desmocollin 2, and desmocollin 3 were detected by enzyme-linked immunosorbent assays. The diagnosis of pemphigus vegetans was made. Initiation of prednisolone (1.0 mg/kg/day) gradually improved his skin symptoms. We performed immunohistochemical analyses of the lesional skin, which revealed infiltration of CD3-positive, CD4-positive, and CD68-positive cells in the upper dermis, but CD20- or CD56-positive cells were negative. In addition, the present case showed more prominent infiltration of IL-17A- and IL-22-positive cells in the upper dermis than in pemphigus foliaceus, a type of pemphigus with autoantibodies against desmoglein 1. Furthermore, these cells co-expressed CD3 and CD68. We hypothesized that IL-22 and IL-17A produced by T cells and macrophages and their dysregulation might be involved in the pathogenesis of pemphigus vegetans. Additionally, skin colonization and/or infection with Staphylococcus aureus could potentially contribute to the pathogenesis of the disease.

Pemphigus vulgaris in association with human immunodeficiency virus infection: A management dilemma.

The association of immunobullous disorders with human immunodeficiency virus (HIV) infection is rare. Concurrence of these two conditions poses a therapeutic challenge as both cause immune dysregulation. We report pemphigus vulgaris in association with HIV infection in a 50-year-old woman who died of sepsis after receiving high-dose corticosteroids for the treatment of pemphigus vulgaris.