Immune interplay from circulation to local lesion in pemphigus pathogenesis.

Pemphigus, a potentially lethal autoimmune skin disease, is mediated by desmoglein-specific antibodies, manifesting cutaneous and mucosal blisters and erosions. The interaction between multiple immune counterparts contributes to the progress of pemphigus. Currently, the emergence of bioinformatic analysis enables investigators to gain a global picture of the pemphigus immune network, based on the exhaustive pedigree annotation of multiple subsets. T helper subsets dominate the landscape as mentioned previously, and innate immune cells have been involved as well. Of particular interests is which phenotype of T cells orchestrates the autoimmune process and chronic inflammation in a certain condition. In this review, the circulatory and peripheral immune cells and cytokine components constituting the immune microenvironment are separately discussed to provide a perspective on pemphigus pathogenesis, with particular reference to insights provided by the bioinformation technique.

Paraneoplastic pemphigus uncovers distinct clinical and biological phenotypes of western unicentric Castleman disease.

Unicentric Castleman disease (UCD) is a lymphoproliferative disease of unknown cause. Paraneoplastic pemphigus (PNP) is a major complication shown to be associated with a poor prognosis, with particular severity in patients with bronchiolitis obliterans (BO). This study describes the clinical and biological characteristics of UCD-PNP patients in a large Western cohort. A total of 148 patients diagnosed with UCD were identified, including 14 patients with a defined PNP. PNP was significantly associated with myasthenia gravis (MG) and FDC sarcoma during follow-up (FDCS). PNP was also significantly associated with reduced survival. These data, together with a multivariate analysis by principal components, led to the identification of UCD-PNP as a group at risk of MG, FDCS and death. PDGFRB sequencing performed on UCD lesions from six patients found the gain-of-function p.N666S variant in two. Interestingly, both patients had hyaline-vascular UCD subtype, were in the UCD-PNP subgroup and had FDCS. Sera from 25 UCD-PNP patients and 6 PNP patients without UCD were tested for PNP-associated autoantibodies. Sera from UCD-PNP patients had a strong reactivity against the N-terminal domain of recombinant periplakin (rPPL, 82%) and showed reactivity against at least two domains of rPPL. These features were not found in patients with UCD alone or in the PNP group without UCD. These data indicate that UCD-PNP patients belong to a subgroup sharing strong clinical and biological identity that might help to decipher the different dynamics of UCD natural history.

Apoptolysis: a less understood concept in the pathogenesis of Pemphigus Vulgaris.

Pemphigus Vulgaris (PV) is a severe autoimmune disease characterized by supra-basal blisters in the skin and mucous membranes of a wide range of mammals, including humans. It not only affects the skin but also has severe oral manifestations. It has been stated that auto-antibodies are produced, for unknown reasons, which are directed against desmogleins present on the epithelium and thus leads to acantholysis and intraepithelial blistering. But the exact mechanism is still not completely understood. Here we would like to shed light on a new pathologic mechanism i.e., apoptolysis, which emphasizes that apoptotic enzymes contribute to acantholysis development both in terms of molecular events and chronologic sequence. A possible role of apoptolysis has been discussed in purview of PV.

Pemphigus vulgaris after SARS-CoV-2 vaccination: A case with new-onset and two cases with severe aggravation.

Pemphigus may be induced or aggravated by certain drugs and vaccines. People worldwide are currently vaccinated with several SARS-CoV-2 vaccines which may be associated with increased number of aggravated or triggered autoimmune bullous diseases in subjects with an underlying genetic predisposition. Herein, a case of new-onset pemphigus vulgaris (PV) and two cases with aggravation of PV after vaccinations for SARS-CoV-2 are reported.

[A Case of Pemphigus Vulgaris Showing a Local Nose Erosion as the First Clinical Manifestation].

A 73-year-old male noticed a localized nose erosion that we thought was possibly an exacerbation of skin erosion due to the direct influence of friction from wearing a mask. Blood examination revealed a remarkable increase in serum anti-desmoglein-1 and anti-desmoglein-3 antibodies. A skin biopsy showed acantholysis in the epidermal granular layer. Based on the clinical manifestation and laboratory examination, we diagnosed his eruption as anti-desmoglein-1 and anti-desmoglein-3 antibody - positive pemphigus vulgaris. His skin eruption responded well to oral prednisolone and azathioprine and gradually improved. Pemphigus was a candidate as a differential diagnosis in this case, in which the direct mechanical friction from wearing a mask was thought to be an exacerbating factor of skin eruption.

Therapy of paraneoplastic pemphigus with Rituximab: A case report.

We report a case of 39-year-old female patient with paraneoplastic pemphigus (PNP) associated with thymoma treated with rituximab plus corticosteroids and methotrexate. After rituximab therapy for 8 weeks, oral ulcerations had cured, lesions on the trunk and limbs improved. Rituximab may be useful for PNP therapy, but further studies are necessary to confirm this hypothesis.

Peristomal Punctate Pemphigus.

ABSTRACT: Cutaneous reactions surrounding abdominal stoma sites are typically irritant, allergic, infectious, traumatic or pathergic in etiology. Pemphigus, which encompasses a group of vesiculobullous autoimmune skin disorders, is seldom encountered as a peristomal dermatosis. Direct immunofluorescence (DIF) studies of pemphigus generally show continuous intercellular net-like depositions of IgG. However, punctate or dot-like intercellular deposition of IgG can also be seen in cases of pemphigus. The punctuate pattern is underreported in the literature and little is known about its implication. We describe a case of a 58-year-old Caucasian man with a history of bowel obstruction, status postcolostomy, who presented with a sharply demarcated, erythematous, crusted plaque surrounding his abdominal stoma. The patient endorsed persistent pruritus. A punch biopsy of the lesion was performed for clinical suspicion of fungal infection versus irritant dermatitis. Histopathology revealed a predominantly subcorneal acantholytic dermatitis. Periodic acid-Schiff with diastase and Grocott methenamine silver histochemical stains were negative for fungi. DIF was positive for IgG and C3 detected in a punctate intercellular pattern. In conjunction with the patient's clinical presentation and DIF, a diagnosis of peristomal pemphigus foliaceous was rendered. Herein, we describe a case of punctate pemphigus presenting as a peristomal dermatosis and include a review of the literature to raise awareness of this phenomenon.

Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: A 9-year experience in a tertiary care paediatric hospital setting.

BACKGROUND: Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children. OBJECTIVE: The aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence. METHODS: From 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases. RESULTS: Incidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred. CONCLUSIONS: In this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.

Paraneoplastic pemphigus associated with a pericardial ectopic thymoma.

Paraneoplastic Pemphigus (PNP), a rare autoimmune blistering disease, can be accompanied by both benign and malignant neoplasms. The most frequently reported associated malignancies include lymphomatoid and hematologic malignancies, Castleman's disease, carcinoma, thymoma. In a patient suspected of PNP, with no known history of malignancy, an extensive workup is suggested to look for underlying malignancy, which has to be treated to induce PNP remission. In this clinical case report, cross sectional imaging of a young female diagnosed with PNP, unveiled a pericardial mass lesion extending into transverse pericardial sinus. Excisional biopsy was performed. Histopathology revealed pericardial ectopic thymoma.

Paraneoplastic pemphigus and myasthenia gravis as the first manifestations of a rare case of pancreatic follicular dendritic cell sarcoma: CT findings and review of literature.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from follicular dendritic cells in lymphoid tissue while paraneoplastic pemphigus (PNP) is an autoimmune blistering disease associated with neoplasms. Pancreatic FDCS associated with PNP and myasthenia gravis (MG) is even rarer and highly malignant. We present the clinical data, pathological materials and computed tomography (CT) features of a rare case of this disease. CASE PRESENTATION: A 49-year-old woman presented with repeated ptosis of both eyelids, oral ulcers and erosions. Her laboratory results showed a slight elevation of CA125 and positivity of some autoimmune antibodies. CT revealed a round solid mass with central necrosis in the pancreatic tail. The solid component of the mass showed slight enhancement and serpentine feeding arteries in the arterial phase, moderate enhancement with a draining vein around the tumor in the portal venous phase and persistent enhancement in the delayed phase. Surgical resection was performed, and the pathological diagnosis was FDCS. However, the patient died of inability to excrete sputum and occlusion of the respiratory tract. CONCLUSIONS: Pancreatic FDCS manifested as PNP and MG is very rare. Its CT features are not specific, and the disease should be differentiated from neuroendocrine tumors, solid pseudopapillary neoplasms and acinar cell carcinoma.

Risk factors for death and survival in paraneoplastic pemphigus associated with hematologic malignancies in adults.

BACKGROUND: Paraneoplastic pemphigus (PNP) occurs more often in patients with hematologic malignancies (HMs) than in patients with solid cancer. Lung bronchiolitis obliterans (BO) is a severe complication of PNP. OBJECTIVE: To determine the precise clinical and biologic features of HM-associated PNP and identify factors associated with mortality and survival. METHODS: Systematic review of previously described cases of PNP associated with HMs. RESULTS: A total of 144 patients were included. The HMs were non-Hodgkin lymphoma (52.78%), chronic lymphocytic leukemia (22.92%), Castleman disease (18.60%), and other underlying hematologic malignancy (5.70%). The mortality rate was 57%, and most deaths occurred within the first year after the diagnosis of PNP. Multivariate analysis showed that (1) the presence of antienvoplakin antibodies and BO were significantly associated with death, and (2) a toxic epidermal necrolysis-like clinical pattern, bullous pemphigoid-like clinical pattern, and BO were significantly associated with decreased survival. LIMITATION: Only case reports with sufficient mortality data were included. CONCLUSION: PNP associated with HM has a high mortality rate. The toxic epidermal necrolysis-like and BO-associated forms are independent survival factors in PNP associated with HMs.

Expression of human endogenous retroviruses in pemphigus vulgaris patients.

Pemphigus is a severe, potentially life-threatening autoimmune blistering mucocutaneous disease which establishes with autoreactive IgG antibodies that target cellular adhesions, precisely extracellular domains of keratinocyte proteins. Several genetic and environmental elements are believed to contribute to the pathogenesis of the disease. The extent to which the initiation and progress of this autoimmune blistering disease may be influenced by the expression of human endogenous retroviruses (HERVs) remains to be elucidated. In this study, we evaluated the expression of HERV groups (K, W, and H) in pemphigus vulgaris (PV) patients in comparison to controls. Peripheral blood samples were collected from 24 PV patients and the corresponding age- and sex-matched healthy controls to extract total RNA for evaluation of HERV-K (HML-2), HERV-W, and HERV-H, env gene expression profile by qPCR. The mRNA expression level of HERV-K, HERV-W, and HERV-H were significantly upregulated in PV patients in comparison to healthy controls (P < 0.0001). The difference in expression of studied HERVs groups between men and women was no significant (P > 0.05). Although rituximab taking patients had a decreased expression level of studied HERVs, the results were not significant (P > 0.05). According to our obtained data, HERVs expression could be measured as a possible diagnostic tool for detection of PV and monitoring of the treatment.

Association between climate, pollution and hospitalization for pemphigus in the USA.

BACKGROUND: Little is known about the impact of ultraviolet exposure, climate factors and pollutants on pemphigus. AIM: To determine whether these factors are associated with pemphigus exacerbation resulting in hospitalization. METHODS: The analysis used data from the 2002-2012 National Inpatient Sample in the USA, including 68 476 920 children and adults, and measurements of relative humidity (%), ultraviolet (UV) index, outdoor air temperature and particulate matter of ≤ 2.5 or ≤ 10 µm (PM2.5 and PM10). RESULTS: Higher rates of admission primarily for pemphigus occurred during the summer and autumn months (June-November), with the highest admission rates in July and October (both 19.7 per million). There was significant statewide variation of the prevalence of hospitalization for pemphigus, with apparent hotspots located in the southwest and northeast states. Hospitalization for a primary diagnosis of pemphigus vs. other diagnosis was associated with significantly lower humidity [mean (95% confidence interval): 64.8% (63.2-66.4%) vs. 66.4% (65.6-67.3%); analysis of variance, P < 0.01) and higher temperature [58.7 (57.1-60.2) vs. 56.3 (55.8-56.7)°F, P = 0.001], UV index [6.0 (5.7-6.2) vs. 5.7 (5.6-5.7), P = 0.02], PM2.5 [12.9 (12.0-13.7) vs. 11.8 (11.5-12.0) mg/m3 , P < 0.001] and PM10 [26.2 (24.5-27.9) vs. 23.1 (22.6-23.6) mg/m3 , P < 0.001]. All associations remained significant in multilevel regression models that controlled for age, sex and race/ethnicity, except for ultraviolet index, which was associated with pemphigus hospitalization only for Hispanic patients [odds ratio (95% CI) for quartile 4: 2.07 (1.02-4.21)]. CONCLUSION: Increasing temperature, UV exposure and small particle air pollution are associated with increased hospitalization for pemphigus. Patients with pemphigus may benefit from avoidance of these potential environmental triggers.

Immortalized Human hTert/KER-CT Keratinocytes a Model System for Research on Desmosomal Adhesion and Pathogenesis of Pemphigus Vulgaris.

Pemphigus Vulgaris is an autoimmune disease that results in blister formation in the epidermis and in mucosal tissues due to antibodies recognizing desmosomal cadherins, mainly desmoglein-3 and -1. Studies on the molecular mechanisms of Pemphigus have mainly been carried out using the spontaneously immortalized human keratinocyte cell line HaCaT or in primary keratinocytes. However, both cell systems have suboptimal features, with HaCaT cells exhibiting a large number of chromosomal aberrations and mutated p53 tumor suppressor, whereas primary keratinocytes are short-lived, heterogeneous and not susceptible to genetic modifications due to their restricted life-span. We have here tested the suitability of the commercially available human keratinocyte cell line hTert/KER-CT as a model system for research on epidermal cell adhesion and Pemphigus pathomechanisms. We here show that hTert cells exhibit a calcium dependent expression of desmosomal cadherins and are well suitable for typical assays used for studies on Pemphigus, such as sequential detergent extraction and Dispase-based dissociation assay. Treatment with Pemphigus auto-antibodies results in loss of monolayer integrity and altered localization of desmoglein-3, as well as loss of colocalization with flotillin-2. Our findings demonstrate that hTert cells are well suitable for studies on epidermal cell adhesion and Pemphigus pathomechanisms.

T helper type 1 polarizing γδ T cells and Scavenger receptors contribute to the pathogenesis of Pemphigus vulgaris.

γδ T cells and Scavenger receptors are key parts of the innate immune machinery, playing significant roles in regulating immune homeostasis at the epithelial surface. The roles of these immune components are not yet characterized for the autoimmune skin disorder Pemphigus vulgaris (PV). Phenotyping and frequency of γδ T cells estimated by flow cytometry have shown increased frequency of γδ T cells (6·7% versus 4·4%) producing interferon- γ (IFN-γ; 35·2% versus 26·68%) in the circulation of patients compared with controls. Dual cytokine-secreting (IFN-γ and interleukin-4) γδ T cells indicate the plasticity of these cells. The γδ T cells of patients with PV have shown higher cytotoxic potential and the higher frequency of γδ T cells producing IFN-γ shows T helper type 1 polarization. The increased expression of Scavenger receptors expression (CD36 and CD163) could be contributing to the elevated inflammatory environment and immune imbalance in this disease. Targeting the inflammatory γδ T cells and Scavenger receptors may pave the way for novel therapeutics.

Antioxidant status of serum bilirubin, uric acid and albumin in pemphigus vulgaris.

BACKGROUND: Oxidative stress and low antioxidant status are implicated in the pathogenesis of inflammatory and autoimmune diseases. Pemphigus vulgaris (PV) is an extremely severe autoimmune bullous dermatosis characterized by intraepithelial bullae on the skin and mucosa, and its antioxidant status is not fully understood. AIM: To assess correlations between PV and serum antioxidant levels of bilirubin, uric acid (UA) and albumin. METHODS: We enrolled 116 patients newly diagnosed with PV who were admitted to the First Affiliated Hospital of Guangxi Medical University (Guangxi, China), and 108 healthy controls (HCs). Clinical characteristics and laboratory parameters of patients were retrospectively analysed. RESULTS: Our survey shows that compared with the HC groups, serum levels of bilirubin [total bilirubin (Tbil), direct bilirubin (Dbil) and indirect bilirubin (Ibil)], UA and albumin were significantly lower in patients with PV, regardless of sex. In all groups, serum Tbil, Dbil, Ibil, UA and albumin levels were lower for women than for men. Severity of pemphigus was slightly negatively associated with Tbil, Dbil and Ibil, but was not associated with UA or albumin. Moreover, when the data were adjusted for the covariances of age and sex separately, Tbil, Dbil, Ibil, UA and albumin were all relevant to PV. CONCLUSIONS: Our findings demonstrate that serum levels of bilirubin (Tbil, Dbil and Ibil), UA and albumin are reduced in patients with PV supporting the hypothesis that oxidative stress and antioxidant status are important in the pathogenic mechanism of PV.

A rare presentation of congenital syphilis: Pemphigus syphiliticus in a newborn infant with extensive desquamation of the extremities.

Congenital syphilis is an infection transmitted from mother to fetus and can present with early but variable cutaneous manifestations. In rare situations, a bullous eruption known as pemphigus syphiliticus may develop. We present an unusual case of broad desquamation of the extremities in a newborn infant who was found to have congenital syphilis. Pemphigus syphiliticus should be considered in the differential diagnosis of neonatal bullous eruptions and erosions.

Paraneoplastic pemphigus without antibodies to desmoglein 1 and 3.

Paraneoplastic pemphigus is a severe autoimmune blistering disease presenting in the setting of underlying malignancy. Paraneoplastic pemphigus is associated with diffuse painful stomatitis throughout the oral cavity with extension to the lips. The cutaneous findings are varied and have been described as lichenoid, pemphigoid, and targetoid lesions. Herein, we report a patient with paraneoplastic pemphigus whose routine testing led to a diagnosis of pemphigus vulgaris. However, further testing was pursued revealing an antibody profile consistent with paraneoplastic pemphigus. Subsequent neoplastic workup revealed an intra-abdominal mass. Our case represents a subtle, non-classic presentation of paraneoplastic pemphigus and suggests the importance of a comprehensive investigative work-up in atypical cases of pemphigus.