Pemphigus Foliaceus Research Articles

Anti-desmoglein 1 antibody-positive mother and antibody-negative child with Darier's disease.

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.

Development of pemphigus vegetans and exacerbation of pemphigus foliaceus after secukinumab loading in a patient with complicated generalized pustular psoriasis and pyoderma gangrenosum.

In dermatology, biologics that block signaling pathways of TNF-α, IL-4/IL13, IL-17s, and IL-23 are widely used for the treatment of several inflammatory skin diseases, such as atopic dermatitis and psoriasis. They have shown excellent efficacy with an acceptable safety profile. However, these biologics targeting pathogenic cytokines and their receptors could modulate immunological balance, leading to the development of other inflammatory or autoimmune skin diseases in some cases. In this study, we present a patient who suffered pemphigus vegetans and showed an exacerbation of pemphigus foliaceus after secukinumab loading for the treatment of complicated generalized pustular psoriasis and pyoderma gangrenosum.

34374 Three North American cases of cutaneous pemphigus vulgaris in patients without history of mucosal disease

Pemphigus is a group of autoimmune blistering diseases including pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Lesion morphology has been explained by the desmoglein compensation hypothesis (DCH), which uses the epidermal distribution of desmoglein (Dsg) proteins and autoantibody profile. The DCH theorizes 3 types of lesion morphology: mucosal PV, mucocutaneous PV, and cutaneous PF. While the DCH has been supported in the literature, logical inconsistencies have been identified and published in multiple small-scale studies.

PEMPHIGUS VULGARIS AFFECTING GENGIVAL MUCOSA IN A PEDIATRIC PATIENT: CLINICAL CASE REPORT

A 7-year-old female patient reporting burning and pain in the gingiva for 1 year was seen in the clinic. Medical history was without relevance. The person responsible for the child reported that her father was diagnosed with pemphigus foliaceus. Intraoral examination showed atrophy in the upper and lower gingival mucosa associated with vesicles and ulcerations. The diagnostic hypotheses were pemphigoid mucous membranes and pemphigus vulgaris (PV). Incisional biopsy was performed and the histopathology was inconclusive but suggestive of PV. Topical application of clobetasol propionate (0.05%) was prescribed for the patient, with partial resolution. The patient was referred to a specialized medical center, and direct immunofluorescence testing was performed, which was positive for PV. After the evaluation of G6PD test, the patient started dapsone (50 mg/day) treatment. There is difficulty in the diagnosis of immune-mediated diseases, especially in children, so direct immunofluorescence may be necessary for a conclusive diagnosis.

Distinct impact of IgG subclass on autoantibody pathogenicity in different IgG4-mediated diseases.

IgG4 is the least potent human IgG subclass for the FcγR-mediated antibody effector function. Paradoxically, IgG4 is also the dominant IgG subclass of pathogenic autoantibodies in IgG4-mediated diseases. Here, we show that the IgG subclass and Fc-FcγR interaction have a distinct impact on the pathogenic function of autoantibodies in different IgG4-mediated diseases in mouse models. While IgG4 and its weak Fc-FcγR interaction have an ameliorative role in the pathogenicity of anti-ADAMTS13 autoantibodies isolated from thrombotic thrombocytopenic purpura (TTP) patients, they have an unexpected exacerbating effect on anti-Dsg1 autoantibody pathogenicity in pemphigus foliaceus (PF) models. Strikingly, a non-pathogenic anti-Dsg1 antibody variant optimized for FcγR-mediated effector function can attenuate the skin lesions induced by pathogenic anti-Dsg1 antibodies by promoting the clearance of dead keratinocytes. These studies suggest that IgG effector function contributes to the clearance of autoantibody-Ag complexes, which is harmful in TTP, but beneficial in PF and may provide new therapeutic opportunity.

Patterns of Antinuclear Antibodies in a New Variant of Endemic Pemphigus in El Bagre, Colombia, Colocalizing with Antigens against MIZAP, ARVCF, p0071, and Desmoplakins I and II.

A new variant of endemic pemphigus foliaceus (EPF) has been documented, El Bagre-EPF. We aimed to study antinuclear antibodies (ANAs) in these patients. We performed a case-control study, testing 57 patients affected by this disease and 57 controls from the endemic area matched by work activity and demographics. The participants were evaluated clinically as well as by detection of ANAs utilizing HEp-2 cells. We utilized Triton-induced partial permeabilization of the cell membranes, allowing for the visualization of intracellular and intranuclear antigens. We also immunoadsorbed the ANAs using synthetic peptides to elucidate the nature of the ANA. We detected the presence of a new pattern of ANAs. The new pattern of ANAs was seen in 24% of the El Bagre-EPF patients, compared to our controls (P < 0.001). The new ANA pattern consisted of a thin nuclear and nucleolar rim, finely speckled nucleolar, nuclear membrane pores stains, and a positive intranuclear stain directed against small nuclear components, as well as cytoplasmic deposits of autoantibodies were also observed. The new ANAs pattern perfectly colocalized with commercial antibodies to miocardium-enriched zonula occlusans-1 associated protein (MIZAP), armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF), p0071 and desmoplakins I-II (all from Progen Biotechnik). Additionally in 14% of patients with El Bagre-EPF forme fruste and hyperpigmented clinical presentations, a classic homogeneous ANA pattern was observed with autoantibodies specific for Ro, La, Sm, and double-stranded DNA antigens. Immunoadsorption with peptide-based sequences from MIZAP, ARVCF, p0071 and desmoplakins I-II removed the new ANA pattern. We describe a new pattern of ANAs in El Bagre-EPF, colocalizing with autoantibodies directed against MIZAP, ARVCF, p0071, and desmoplakins I-II.

Pediatric autoimmune blistering disorders - a five-year demographic profile and therapy experience.

There is a paucity of literature on pediatric autoimmune bullous disorders (AIBD) in the Indian population. We aimed to retrospectively evaluate the clinico-demographic profile of pediatric AIBDs in our patients and their response to various therapeutic modalities. This was a retrospective chart review of patients enrolled in our immunobullous disease clinic from November 2013 to August 2019. The clinical records of all the patients aged less than 18 years old with a definitive diagnosis of AIBD were reviewed based on clinical, histopathological, and immunological features. Forty out of 1209 patients with AIBD (3.3%) belonged to the pediatric age group. Pemphigus vulgaris (PV) was the most common AIBD (24, 60%) followed by chronic bullous disease of childhood (CBDC) at 15% (6) and pemphigus foliaceus (PV) at 12.5% (5). Subepidermal blistering disorders had a significantly younger age of onset (P = 0.04) compared to intraepidermal blistering disorders but higher frequency of achieving complete remission off therapy (P = 0.02). The mean time to achieve remission was significantly shorter in PV patients treated with a combination of rituximab and corticosteroids compared to those treated with oral prednisolone and oral immunosuppressive adjuvants (P = 0.001). Rituximab was tolerated well in all 12 pemphigus patients. Oral lesions in PV patients took significantly longer time to achieve remission compared to the cutaneous lesions (P = 0.001). PV was the most common pediatric AIBD in Indian patients. Rituximab was a safe and effective modality of treatment in moderate to severe pediatric pemphigus.

Rituximab‐induced new onset palmo‐plantar pustulosis in patients with pemphigus foliaceus: A rare adverse effect

Rituximab‐induced new onset palmo‐plantar pustulosis in patients with pemphigus foliaceus: A rare adverse effect

Clinical Patterns, Survival, Comorbidities, and Treatment Regimens in 149 Patients With Pemphigus in Tuscany (Italy): A 12-Year Hospital-Based Study.

IntroductionPemphigus encompasses a group of muco-cutaneous autoimmune bullous diseases characterized by the loss of adhesion between keratinocytes. The disease is associated with increased morbidity and mortality.Materials and MethodsWe characterized clinical patterns, survival, comorbidities, and drug prescriptions in patients with pemphigus referred to the Section of Dermatology of the University of Florence from January 2010 to December 2021.ResultsA total of 149 patients were identified (female/male sex ratio = 2.0). Median age at diagnosis was 57.7 ± 17.2 years; 108 patients were diagnosed with pemphigus vulgaris (PV) (72.5%) and 35 (23.5%) with pemphigus foliaceus (PF). Paraneoplastic pemphigus (PNP) and IgA-pemphigus accounted for three patients each. The overall survival rate was 86.9%. Accordingly, 14 (9%) patients died during the study period. The average age at death was 77.8 ± 9.3. Age at diagnosis was a risk factor for death in patients with pemphigus. Average concentration of Dsg3-IgG and Dsg1-IgG was 85.6 ± 68.8 and 75.9 ± 68.4, respectively. The most serious comorbid diseases included cerebro- and cardiovascular accidents and malignancies. Regarding the treatment regimen, we found a substantially stable use of systemic steroids in the 2010–2018 period; the prevalence of use of mycophenolic acid increased, whereas that of azathioprine decreased. The use of rituximab showed the highest increase in the 2013–2018 period. Proton-pump inhibitors and antibiotics were the most frequently prescribed non-immunomodulating drugs.ConclusionsIn this large series of the patients, patients with pemphigus showed a high incidence of serious comorbid diseases, highlighting the importance of a multidisciplinary approach for a proper management of the patients. Rituximab was the immunomodulating drug showing the highest increase in use over time, reflecting the growing evidence of its efficacy as a first-line treatment in pemphigus.

Pemphigus Vulgaris and Pemphigus Foliaceus: A Single-Centre Comparative Study in Rabat, Morocco

Background: Pemphigus is a group of rare autoimmune blistering diseases affecting the skin and mucous membranes. Pemphigus foliaceus (PF) is known to be relatively benign than the other forms of pemphigus. Methods: The authors carried out a single-centre retrospective study of 40 patients with PF and 125 patients with pemphigus vulgaris (PV) over a 30-year period. The aim was to compare the course of these two major variants. Results: Both populations shared similar age, sex ratio, and treatment received. This investigation showed that relapses were more frequent in the group of PF, whereas the PV group needed a higher dose of corticosteroids to control the disease, a higher mortality rate, and complications were documented in this group. Severity, remissions, and mean duration of the disease were the same in both groups. Conclusion: This investigation arises some doubts concerning the relative mildness of PF. Despite the improvement of the prognosis of pemphigus through the use of immunosuppressive therapy, few studies have been interested in comparing the clinical course of treated PF and PV. In the authors’ experience, PF should be treated as PV, as they may share a mutual evolutive profile. Further investigations are needed to define if the prognosis of PF depends on epidemiological, environmental, and genetic factors, including the optimal therapeutic management of this disease.

Clinical manifestations and comorbidities of pemphigus: a retrospective case-control study in southern Finland

Pemphigus is associated with several autoimmune, dermatological, and psychiatric diseases. Previous studies have reported an increasing incidence of pemphigus in Finland, particularly pemphigus foliaceus and erythematosus. The aim of this study was to determine the clinical presentation and associated comorbidities in pemphigus patients. We retrospectively assessed 66 pemphigus patients in Helsinki University Hospital and, with an age-standardised control group, performed a comparison of the studied comorbidities. The patients displayed a 0.8 female:male distribution and a mean age of 57.4 years. Pemphigus vulgaris (41%), foliaceus (30%), and erythematosus (15%) were the most common subtypes. Hypertension (30%) and dyslipidaemia (21%) were the most prevalent comorbidities. We found a statistically significant association between pemphigus and a past history of, or concurrent malignancies and atopic dermatitis (p = 0.002 and p = 0.028, respectively). No significant difference was observed in the prevalence of cardiovascular disease, asthma, chronic obstructive lung disease, type I or II diabetes mellitus, inflammatory bowel disease, depression, or anxiety. Erosions (65%), bullae (59%), and crusted lesions (55%) were observed in most patients. Half of the patients experienced pruritus before or at diagnosis. Pruritus was associated with pemphigus without mucosal involvement (p = 0.01). We found a significant association between pemphigus and atopic dermatitis and a history of malignancy. The clinical picture frequently included pruritus. These results support the findings of some recent studies of pruritus occurring more frequently in patients with pemphigus foliaceus and cutaneous pemphigus vulgaris.

The coincidence of psoriasis vulgaris and pemphigus foliaceous in geriatric after COVID-19 vaccination

Background: Psoriasis is a chronic autoimmune disease characterized by well-demarcated, erythematous, scaly plaques, such as mica. Psoriasis occurs as a damaging result of Th17, TNF-α, and IFN-γ cells. The coincidence of psoriasis with pemphigus foliaceous is rare. Several studies have shown that Th17, TNF-α, and IFN-γ cells induced by COVID-19 vaccination can play a role in this mechanism although it remains unclear. Case series: A 60-year-old woman without comorbidities with a 6-year history of controlled psoriasis, since 2016, with the administration of methotrexate and phototherapy. The diagnosis of psoriasis is clinically based on the form of erythematous, scaly plaques scattered throughout the body. The patient got the COVID-19 vaccination twice during the pandemic, followed by the exacerbation of psoriasis and coincidence with pemphigus foliaceus. The biopsy showed epidermal acantholysis with perivascular infiltration of PMN inflammatory cells and lymphocytes. The patient did not improve with the administration of methotrexate and phototherapy but showed improvement with methylprednisolone injections with tapering. Psoriasis relapsed again, but the patient improved after being given 4 times injections of secukinumab. Conclusion: COVID-19 vaccination is necessary during a pandemic, but can lead to post-vaccination autoimmune exacerbations, such as the coincidence of psoriasis and pemphigus foliaceus. More research is needed to understand the potential of COVID-19 vaccination which is the first mRNA vaccine in humans.

Successful Treatment of Recalcitrant Juvenile Pemphigus Foliaceus with Intravenous Immunoglobulin and Rituximab

Pemphigus foliaceus (PF) is uncommon among children. The usage of rituximab in childhood PF is even less documented. We reported a case of a 16-year-old boy with juvenile PF who failed conventional treatments and was started on combination therapy of intravenous immunoglobulin (IVIG) and rituximab followed by six-monthly rituximab maintenance therapy. He achieved full remission and no adverse effects. Therefore, in cases of recalcitrant juvenile PF, combination therapy of IVIG and rituximab can be considered.

Assessing the use of methotrexate as an alternate therapy for pemphigus vulgaris and pemphigus foliaceus.

Methotrexate is historically recognized as an effective treatment of pemphigus but its utility as a single or alternate steroid-sparing agent was not recognized in recent consensus recommendations in pemphigus management. We aimed to evaluate the efficacy and safety of a treatment course for pemphigus that involves methotrexate as a single or steroid-sparing agent. In a retrospective cohort study, we examined patients with pemphigus vulgaris or pemphigus foliaceus who were on ≥3 months of methotrexate therapy. Efficacy and safety were evaluated by established pemphigus disease endpoints. Of the 34 patients who met inclusion criteria, 25 (73.5%) were on glucocorticoids at time of methotrexate initiation (median follow-up: 5.4 years; median time on methotrexate: 3.7 years). An appreciable proportion achieved disease control (91.2%), with some achieving clinical remission off all systemic therapies (23.5%). For patients on glucocorticoids, median time to control was 42 days, median time to minimal steroid dose tapering (5mg prednisone) was 161 days, and median time to complete steroid tapering was 308 days. For patients on methotrexate as a single agent, median time to control was 119 days. Among all patients, relapse commonly occurred (88.2%). At last follow-up, 26.5% were managed on topical therapies alone and 11.8% required systemic steroid therapy. Methotrexate was largely tolerated with a low incidence of adverse events leading to treatment discontinuation (2.9%). Methotrexate has the potential to be an effective and well-tolerated option for patients and may be considered for use as an alternate single or steroid-sparing agent for pemphigus.

In Vitro, Ex Vivo, and In Vivo Models for the Study of Pemphigus.

Pemphigus is a life-threatening autoimmune disease. Several phenotypic variants are part of this family of bullous disorders. The disease is mainly mediated by pathogenic autoantibodies, but is also directed against two desmosomal adhesion proteins, desmoglein 1 (DSG1) and 3 (DSG3), which are expressed in the skin and mucosae. By binding to their antigens, autoantibodies induce the separation of keratinocytes, in a process known as acantholysis. The two main Pemphigus variants are Pemphigus vulgaris and foliaceus. Several models of Pemphigus have been described: in vitro, ex vivo and in vivo, passive or active mouse models. Although no model is ideal, different models display specific characteristics that are useful for testing different hypotheses regarding the initiation of Pemphigus, or to evaluate the efficacy of experimental therapies. Different disease models also allow us to evaluate the pathogenicity of specific Pemphigus autoantibodies, or to investigate the role of previously not described autoantigens. The aim of this review is to provide an overview of Pemphigus disease models, with the main focus being on active models and their potential to reproduce different disease subgroups, based on the involvement of different autoantigens.

The association of six autoimmune bullous diseases with thyroid disorders: a population-based study.

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

Trunk-dominant and classic facial pemphigus foliaceus in dogs - comparison of anti-desmocollin-1 and anti-desmoglein-1 autoantibodies and clinical presentations.

Canine trunk-dominant pemphigus foliaceus (PF) is mentioned rarely in the literature. The goal of this study was to provide clinical description of trunk-dominant PF and to demonstrate the prevalence of serum antikeratinocyte, anti-desmocollin-1 (DSC1) and anti-desmoglein-1 (DSG1) antibodies, and determine their diagnostic value in this particular PF phenotype. Clinically relevant information was collected from 31, 25 and 34 dogs with trunk-dominant and facial PF and superficial pyoderma (SP), respectively. Sera from these dogs were tested for antikeratinocyte, anti-DSC1 and anti-DSG1 antibodies using indirect immunofluorescence on canine tissues and DSC1- and DSG1-transfected cells. Sera from healthy dogs and dogs with clinically irrelevant diseases served as controls. Footpad involvement and grouped/polycyclic lesion organisation were identified as features of both PF phenotypes, and not of SP. Antikeratinocyte immunoglobulin (Ig)G was not specific for canine PF. By contrast, antigen-specific IgG was detected only in PF sera; anti-DSC1 IgG in 100% and 58% of dogs with facial and trunk-dominant PF, respectively, and anti-DSG1 IgG in 7% of dogs with trunk-dominant PF only. Trunk-dominant PF shares DSC1 as a major autoantigen with facial PF. The ability to detect anti-DSC1 IgG is lower in trunk-dominant PF, yet despite the lower sensitivity, the positive predictive value and accuracy of this particular anti-DSC1 IgG test are high. A negative test result, however, cannot exclude the diagnosis, and characteristic clinical features such as footpad involvement and/or grouped/polycyclic lesions must be considered when distinguishing trunk-dominant PF from its most relevant differential diagnosis: SP.

Pemphigus foliaceus in cats

Pemphigus foliaceus is the most common autoimmune skin disease in cats. Autoantibodies attack and destroy desmosomes, the structures connecting one keratinocyte to the other, causing what is clinically recognised as a pustular dermatitis. The target autoantigen within the desmosome is unknown in cats. The disease occurs more frequently in middle-aged cats and involves predominantly the pinnae, head and feet, including the claw folds. Clinical lesions include superficial erosions and honey-coloured crusts, alopecia, scaling and caseous material that can be expressed out of the claw folds, while pustules are rarely appreciated. Cats may be systemically ill. Diagnosis requires cytology and histopathology, as well as ruling out dermatophytosis and bacterial infections. Treatment is based on glucocorticoid monotherapy. Other immunomodulatory drugs, such as ciclosporin or chlorambucil, may be added to reduce the glucocorticoid requirement. The prognosis is good, but regular checks-ups are mandatory because of potential relapse and possible adverse effects of the drugs used.

From Insect Bites to a Skin Autoimmune Disease: A Conceivable Pathway to Endemic Pemphigus Foliaceus.

In the endemic variants of pemphigus foliaceus (PF), in Brazil and Tunisia, patients generate pathogenic IgG4 anti-desmoglein 1 autoantibodies. Additionally, these patients possess antibodies against salivary proteins from sand flies that react with Dsg1, which may lead to skin disease in susceptible individuals living in endemic areas. This minireview focuses on recent studies highlighting the possible role of salivary proteins from Lutzomyia longipalpis (L. longipalpis) in EPF from Brazil and Phlebotomus papatasi (P. papatasi) in EPF from Tunisia. We will briefly discuss the potential mechanisms of molecular mimicry and epitope spreading in the initiation and development of endemic PF (EPF) in Brazil and Tunisia.

Clinical, Histopathologic, and Immunohistochemical Features of Patients with IgG/IgA Pemphigus.

Pemphigus is an autoantibody-mediated blistering disease. In addition to conventional pemphigus vulgaris and pemphigus foliaceus, several other types have been reported. Among them, IgG/IgA pemphigus is less well defined and seldom reported. To characterize the clinical, histopathologic, and immunohistochemical presentation of IgG/IgA pemphigus, we retrospectively identified 22 patients with the disease at a referral center in Taiwan. These patients showed two types of skin lesion: annular or arciform erythemas with blisters or erosions (45.5%) and discrete erosions or blisters such as those in conventional pemphigus (54.5%). Mucosal involvement was found in 40.9%. Histopathologic analysis identified acantholysis (77.3%) and intra-epidermal aggregates of neutrophils (40.9%) and eosinophils (31.8%). Direct immunofluorescence studies showed IgG/IgA (100%) and C3 (81.8%) depositions in the intercellular space of the epidermis. In immunohistochemical staining, patients with IgG/IgA pemphigus demonstrated significantly higher levels of epidermal expression of interleukin-8 and matrix metalloproteinase-9 than those with conventional pemphigus (p < 0.05). In conclusion, although IgG/IgA pemphigus is heterogeneous in presentation, it shows characteristic features that are different from other forms of pemphigus and should be considered a distinct type of pemphigus.