A case of IgA pemphigus, with a poor response to dapsone, successfully treated with adalimumab.

Key Clinical Message: IgA pemphigus is usually treated by Dapsone. Recalcitrant cases may be treated by Colchicine, Sulfapyridine, or Acitretin. Some patients with recurrent severe disease may not respond to the aforementioned medications. Our study highlights the role of TNFa inhibitor as an alternative modality in the treatment of recalcitrant IgA pemphigus. Abstract: IgA pemphigus is a rare autoimmune blistering disease characterized by a pruritic, annular, vesiculopustular eruption. In IgA pemphigus, there are IgA autoantibodies targeting the keratinocyte cell surface adhesion molecules, causing cell-to-cell dehiscence and a flaccid vesiculopustular eruption, mainly in the axilla and groin. Dapsone, despite being the drug of choice for treating IgA pemphigus, is not effective in clearing lesions in a minority of patients and such rare cases of recalcitrant IgA pemphigus need alternative modalities of treatment. Here, we report the successful treatment of a 50-year-old male patient with an adalimumab injection who had a poor response to dapsone.

Superficial and Bullous Neutrophilic Dermatoses: Sneddon-Wilkinson, IgA Pemphigus, and Bullous Lupus.

Sneddon-Wilkinson disease (SWD), IgA pemphigus, and bullous systemic lupus erythematosus (BSLE) are superficial and bullous neutrophilic dermatoses. They are all characterized by sterile neutrophilic infiltrate but differ in the level of skin affected and presence of autoantibodies. Both SWD and IgA pemphigus present with grouped flaccid pustules and have epidermal involvement; it is unclear whether they are distinct or exist on a spectrum of the same disease. IgA pemphigus is distinguished from SWD by positive direct immunofluorescence showing intercellular IgA deposition. BSLE presents with tense bullae, dermal neutrophilic infiltrate, and direct immunofluorescence showing linear IgG deposition along the dermal-epidermal junction.

IgA pemphigus following COVID-19 vaccination: A case report.

A patient presented with pruritic lesions on their back and leg after COVID-19 vaccination. Biopsy and direct immunofluorescence were consistent with IgA pemphigus-likely caused by the COVID-19 vaccine.

Subcorneal pustular dermatosis-type IgA pemphigus associated with multiple myeloma: A case report and literature review.

Immunoglobulin A (IgA) pemphigus, also known as intercellular IgA dermatosis, is a rare autoimmune bullous disease presenting with IgA anti-keratinocyte cell surface autoantibodies. Concomitant lymphoproliferative disorders have been reported in IgA pemphigus, including IgA monoclonal gammopathy of undetermined significance and IgA type multiple myeloma (MM). A 35-year-old Japanese woman with a 3-year history of pruritic papulovesicles on her lower legs and trunk was referred to our department. Histopathological examination revealed acantholytic blisters, and results of both direct and indirect immunofluorescence were negative. Direct and indirect immunofluorescence were still negative 3 years and 7 months later. Approximately 7 years after her first visit, the patient was re-referred to us because of disease exacerbation. Histopathological findings revealed subcorneal blistering with acantholysis, in which neutrophil-dominant inflammatory cells were present. Indirect immunofluorescence was positive for IgA on the epidermal cell surface and both desmoglein (Dsg) 1/3 and (Dsc) desmocollin 1-3 enzyme-linked immunosorbent assays (ELISAs) for IgA were positive. The histological findings and positive Dsc1 IgA ELISA led to the diagnosis of subcorneal pustular dermatosis (SPD)-type IgA pemphigus. Further examination revealed hyper-IgA globulinemia, increased serum IgA-κ protein, and increased plasma cells in the bone marrow, enabling the diagnosis of IgA type MM. Daratumumab, lenalidomide, and dexamethasone (DLd) therapy was effective for both the MM and the skin lesions, resulting in negative results on Dsg1/3 and Dsc1-3 IgA ELISAs. The association between IgA pemphigus and IgA type multiple myeloma remains unclear, and only seven cases including the present case have been reported. Literature review revealed associations between SPD-type and IgA κ chain in IgA pemphigus and MM, and that in most cases the onset or diagnosis of MM was simultaneous or occurred after the diagnosis of IgA pemphigus. Therefore, clinicians should be aware of the development of multiple myeloma during the clinical course of patients with SPD-type IgA pemphigus.

Subcorneal pustular dermatosis type of IgA Pemphigus in a 35-year-old female: A case report

Introduction@#IgA pemphigus is a rare, distinct variant of Pemphigus characterized by vesiculopustular eruptions mediated by IgA autoantibodies targeting keratinocyte cell surface antigens, desmocollins 1-3 and sometimes desmogleins 1 and 3. Its classical features have been described in literature but atypical cases have also been documented. This report presents such case posing a diagnostic dilemma.@*Case Report@#A 35-year-old female presented with a 16-year history of intermittent eruptions of multiple hyperpigmented, annular and circinate, desquamating plaques and coalescing flaccid pustules on erythematous bases on the scalp, neck, trunk, and extremities. Histopathologic examination revealed subcorneal pustular dermatitis, and direct immunofluorescence was positive for granular intercellular IgG and IgA deposits in the epidermis. Antinuclear antibody test was negative and C3 level was normal. Antibody tests against desmogleins 1 and 3 were both negative. Topical potent corticosteroid therapy resulted in complete resolution of all lesions in three weeks.@*Conclusion@#Diagnostic dilemmas arise when laboratory results do not correlate with clinical findings. Findings of IgA autoantibodies in patients with pemphigus-like skin eruptions led to the diagnosis of subcorneal pustular dermatosis type of IgA pemphigus. Dapsone is the treatment of choice although topical potent corticosteroid alone may provide complete remission in some cases, avoiding the potential adverse effects of systemic therapy

Current and Innovated Managements for Autoimmune Bullous Skin Disorders: An Overview.

Autoimmune bullous skin disorders are a group of disorders characterized by the formation of numerous blisters and erosions on the skin and/or the mucosal membrane, arising from autoantibodies against the intercellular adhesion molecules and the structural proteins. They can be classified into intraepithelial or subepithelial autoimmune bullous dermatoses based on the location of the targeted antigens. These dermatoses are extremely debilitating and fatal in certain cases, depending on the degree of cutaneous and mucosal involvement. Effective treatments should be implemented promptly. Glucocorticoids serve as the first-line approach due to their rapid onset of therapeutic effects and remission of the acute phase. Nonetheless, long-term applications may lead to major adverse effects that outweigh the benefits. Hence, other adjuvant therapies are mandatory to minimize the potential harm and ameliorate the quality of life. Herein, we summarize the current therapeutic strategies and introduce promising therapies for intractable autoimmune bullous diseases.

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.

Comprehensive review on the pathophysiology, clinical variants and management of pemphigus (Review).

Pemphigus represents a group of chronic inflammatory disorders characterized by autoantibodies that target components of desmosomes, leading to the loss of intercellular adhesion between keratinocytes and causing intraepithelial blistering. The pemphigus group consists of four main clinical types with several variants: pemphigus vulgaris (with pemphigus vegetans and pemphigus herpetiformis as variants), pemphigus foliaceus, paraneoplastic pemphigus and IgA pemphigus (with two clinical variants: intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis). Genetic factors are involved in the pathogenesis, with HLA-DR4 (DRB1*0402) and HLA-DRw6 (DQB1*0503) allele more common in patients with pemphigus vulgaris, HLA class II DRB1*0344 and HLA Cw*1445 correlated with paraneoplastic pemphigus, and HLA-DRB1*04:01, HLA-DRB1*04:06, HLA-DRB1*01:01, HLA-DRB1*14, associated with a higher risk of developing pemphigus foliaceus. Autoantibodies are conducted against structural desmosomal proteins in the skin and mucous membranes, mainly desmogleins, desmocollins and plakins. Cell-mediated immunity may also play a role, especially in paraneoplastic pemphigus. Patients may present erythema, blisters, erosions, and ulcers that may affect the skin, as well as mucosal surfaces of the oral cavity, eyes, nose, leading to severe complaints including pain, dysphagia, and fetor. Oral mucosal postbullous erosive lesions are frequently the first sign of disease in pemphigus vulgaris and in paraneoplastic pemphigus, without skin involvement, making the diagnosis difficult. Treatment options classically include immunosuppressive agents, such as corticosteroids and corticosteroid-sparing agents such as azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate or dapsone. Newer therapies focus on blocking cell signaling events induced by pathogenic autoantibodies and/or targeting specific autoantibodies. The disease evolution is conditioned by the treatment with maximum doses of corticosteroids and the side effects associated with long-term immunosuppressive therapy, which is why patients need a multidisciplinary approach in following the treatment. In this review, we provide a comprehensive overview of the epidemiology, pathophysiology, clinical aspect, diagnosis and management of the main intraepidermal blistering diseases from the pemphigus group.

An Updated Review of Pemphigus Diseases.

Clinicians may encounter a variety of skin conditions that present with vesiculobullous lesions in their everyday practice. Pemphigus vulgaris, pemphigus foliaceus, IgA pemphigus, and paraneoplastic pemphigus represent the spectrum of autoimmune bullous dermatoses of the pemphigus family. The pemphigus family of diseases is characterized by significant morbidity and mortality. Considering the risks associated with a delayed diagnosis or misdiagnosis and the potential for overlap in clinical features and treatment, evaluation for suspected pemphigus disease often requires thorough clinical assessment and laboratory testing. Diagnosis is focused on individual biopsies for histopathology and direct immunofluorescence. Additional laboratory methods used for diagnosis include indirect immunofluorescence and enzyme-linked immunosorbent assay. Recent advancements, including anti-CD20 therapy, have improved the efficacy and reduced the morbidity of pemphigus treatment. This contribution presents updates on the pathophysiology, clinical features, diagnostic work-up, and medical management of pemphigus. Improved strategies for diagnosis and clinical assessment are reviewed, and newer treatment options are discussed.

Intraepithelial autoimmune blistering dermatoses: Clinical features and diagnosis.

Intraepithelial autoimmune blistering dermatoses are a rare group of skin disorders characterized by the intraepithelial disruption of intercellular connections through the action of autoantibodies. The first article in this continuing medical education series explores the background, epidemiology, clinical features, and diagnostic criteria of each of the major intraepithelial autoimmune blistering dermatoses, including pemphigus foliaceus, pemphigus erythematosus, pemphigus herpetiformis, fogo selvagem, pemphigus vulgaris, pemphigus vegetans, drug-induced pemphigus, IgA pemphigus, IgG/IgA pemphigus, and paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome.

IgA pemphigus: A systematic review.

BACKGROUND: The clinical, histologic, and immunopathologic features of IgA pemphigus have not been studied on a large scale. OBJECTIVE: To synthesize existing data on the epidemiologic, clinical, histologic, and immunologic features of IgA pemphigus. METHODS: We performed a systematic review using MEDLINE, Embase, and Web of Science databases. Case reports and series of patients with IgA pemphigus were included. RESULTS: A total of 119 eligible studies, comprising 137 patients with IgA pemphigus with a mean age of 51.5 ± 21.0 years, were included. Most patients presented with vesicles (80.8%), pustules (75.0%), and circinate plaques (63.6%). Pruritus was present in 65.6% of reported patients. Intercellular deposition of IgA was noted in almost all patients (97.0%), and the remaining 3.0% of patients had IgA positivity on indirect immunofluorescence or enzyme-linked immunosorbent assay confirming the diagnosis. IgA circulating intercellular antibodies were detected in only 66.7% patients. IgA gammopathy and ulcerative colitis were associated with IgA pemphigus in 9.5% and 6.6% patients, respectively. Oral dapsone and corticosteroids were the mostly commonly used treatments. LIMITATIONS: Results are mainly based on case reports and small case series. CONCLUSIONS: The diagnosis of IgA pemphigus may be considered in patients presenting with vesiculopustular eruption and circinate plaques with truncal and extremity involvement.

IgG/IgA pemphigus in a patient with a history of pemphigus vulgaris: An example of epitope spreading?

We report a case of IgG/IgA pemphigus presenting as pemphigus foliaceus following diagnosis and treatment of classic IgG-mediated pemphigus vulgaris. The dual presentation of IgG and IgA positivity on direct immunofluorescence (DIF) constitutes a rare form of pemphigus with a wide variety of clinicopathologic manifestations. The progression of pemphigus vulgaris is commonly because of epitope spreading. However, the patient's disease was partially refractory to rituximab and showed a change in the DIF with dual staining for IgG and IgA. This indicates that class-switching may have occurred with epitope spreading or that there was autoreactive IgA at the onset of disease below the threshold of detection by DIF. Our case indicates that in progressive autoimmune disease refractory to treatment, re-evaluation of the patient for antibody isotypes absent on initial diagnosis may offer key information in better identifying the cause of progression as well as in directing the necessary treatment.

A Case of Immunoglobulin A Pemphigus: Intraepidermal Neutrophilic Dermatosis Type / 대한피부과학회지

Immunoglobulin A (IgA) pemphigus is a rare variant of an autoimmune bullous disease with IgA antibodies. IgA pemphigus is divided into 2 major subtypes: the subcorneal pustular dermatosis (SPD) type and intraepidermal neutrophilic (IEN) dermatosis type. We documented a case of an 18-year-old woman with recurrent generalized blisters and pustules that were especially severe in the intertriginous areas. Some half-and-half blisters and coalesced pustules in an annular pattern with crusts were simultaneously observed. A biopsy specimen from one of the half-and-half blister lesions showed intraepidermal separation with multiple neutrophils. Direct immunofluorescence staining revealed lace-like intercellular deposition of IgA in the entire epidermis. IgA antibody deposits were also observed in the patient's serum. The eruptions cleared with systemic steroids and colchicine 0.6 mg for 1 week, and the patient remained in partial remission at the 8-month follow-up. Herein, we report a case of IEN-type IgA pemphigus, clinically mimicking SPD with half-and-half blisters.

Pemphigus group: overview, epidemiology, mortality, and comorbidities.

Pemphigus forms a group of rare autoimmune bullous diseases that affect the skin and mucous membranes. This group has a chronic course leading to high morbidity and mortality. It is characterized by the production of pathogenic autoantibodies directed against different proteins of the desmosome, leading histologically to intraepidermal cleavage, and clinically to vesicles and erosions on the epithelium of the mucous membranes and/or the skin. The diagnosis of the subtype of pemphigus is based on clinical features, the level of histologic cleavage, and the identification of the antigens recognized by circulating autoantibodies by immunoserological analyses. The epidemiological features of pemphigus vary considerably in different regions of the world. Observational studies examining comorbidities and associations among patients with pemphigus are scarce and sometimes inconclusive. The prognosis, mortality, and clinical outcomes in pemphigus have undergone dramatic change throughout the years. This review provides a brief overview about the different subtypes of pemphigus: pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, pemphigus herpetiformis, and IgA pemphigus. In addition, it summarizes the most recent understanding of the epidemiology, mortality data, and comorbidities of this group of organ-specific autoimmune diseases.

IgA pemphigus showing IgA antibodies to desmoglein 1 and 3.

BACKGROUND: IgA pemphigus is a rare autoimmune vesiculo-pustular skin disease. Only approximately 70 cases have been reported to date. We report a case of IgA pemphigus with IgA antibodies to desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3). CASE REPORT: We report the case of an 60-year-old man with intraepidermal neutrophilic IgA pemphigus with IgA antibodies to Dsg1 and Dsg3. Histologic examination revealed subcorneal neutrophilic pustules with few acantholytic cells. The disease was not effectively controlled by conventional therapeutic regimens (colchicine, dapsone). Systemic treatment with isotretinoin 25 mg/d and prednisone 20 mg/d achieved only a slight effect after six months. CONCLUSIONS: Our case confirmed the recalcitrant nature of IgA pemphigus in response to distinct therapies, indicating that further research focusing on therapeutic approaches for this type of pemphigus is needed. Physicians should keep IgA pemphigus in mind when approaching patients with bullous eruption.

Epidermal polymeric immunoglobulin receptors: leads from intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus.

In this study, we attempted to identify unknown autoantigen for intraepidermal neutrophilic IgA dermatosis-type IgA pemphigus by novel IgA-specific immunoprecipitation. Mass-spectrometry study identified polymeric immunoglobulin receptor (PIGR) as the candidate protein, and we confirmed that PIGR expressed in both epidermis and cultured keratinocytes. Eukaryotic recombinant protein of PIGR expressed in COS7 cells was reacted with both patient and normal sera, indicating that PIGR binds physiologically to IgA. To detect antigen-specific binding by IgA autoantibodies, we performed several experiments using deglycosylated PIGR and F(ab)2 fragments from patient sera. However, these analyses suggested that patient IgA bound physiologically, but not immunologically, to PIGR. Nevertheless, our study provided two important insights. Newly developed IgA-immunoprecipitation system should be a useful tool in the future study of identification of antigens for IgA autoantibodies. Detection of epidermal PIGR in this study confirmed previous results and indicated possible immunological role of PIGR in epidermis.

[Efficacy of acitretin in IgA pemphigus]. / Pemphigus à IgA: efficacité de l'acitrétine.

BACKGROUND: IgA pemphigus is a particular entity among autoimmune blistering intraepidermal diseases. IgA pemphigus is subdivided into two types: intraepidermal neutrophilic IgA dermatosis and subcorneal pustular dermatosis. PATIENTS AND METHODS: We report the case of an 82-year-old woman with intraepidermal neutrophilic IgA pemphigus associated with IgA gammopathy. The histopathological findings were unusual, with numerous large subcorneal pustules, a few pustules in the stratum spinosum, and basal IgA deposition. A favourable outcome was achieved with acitretin. DISCUSSION: This observation is significant in that it highlights the difficulty of classification of IgA pemphigus, which is currently based on clinical and histopathological findings. There is currently no therapeutic consensus attitude but simply a set of empirical data.

IgA pemphigus with non-pustular erythematous lesions and IgA antibodies to desmocollins 1 and 2.

IgA pemphigus is a rare variant of pemphigus. IgA pemphigus is subdivided into intraepidermal neutrophilic IgA dermatosis-type (IEN-type), whose target antigen is still an enigma, and subcorneal pustular dermatosis-type, whose target antigen is desmocollin 1 (Dsc1). We report a 56-year-old Japanese male with IgA pemphigus showing atypical erythema. One month after erythema developed, the patient visited his private physician, and was tentatively diagnosed as having erythema multiforme. The patient had been intermittently treated with a low dose of oral prednisolone for a year without benefit before visiting our hospital. Clinical examination revealed irregularly-shaped and partially edematous erythema over the trunk and extremities without mucosal involvement. Neither bullae nor pustules were seen during the course. Direct immunofluorescence showed IgA deposition on cell surfaces of keratinocytes in the upper two thirds of the epidermis. Indirect immunofluorescence of monkey esophagus sections revealed IgA and IgG anti-cell surface antibodies. Our new enzyme-linked immunosorbent assays using eukaryotic recombinant proteins of human Dsc 1-3 detected IgA antibodies to Dsc1 and Dsc2. Although no apparent bullae were observed, the diagnosis of IgA pemphigus was made. Prednisolone 30 mg daily was required to control erythematous lesions. Although the pathomechanism for the unique skin lesion is unknown, the possibility that IgA pemphigus has a prodromal phase and that early administration of low dose prednisolone suppressed the development of pustules or bullae were considered.