Continuing Education Activity

IgA pemphigus is a rare autoimmune blistering disease characterized by painful and pruritic vesiculopustular eruptions. These eruptions form as a result of circulating IgA antibodies against keratinocyte cell surface components responsible for cell to cell adherence. While the disease has been associated with several malignancies and chronic conditions, the exact etiology is unclear. This activity reviews the presentation of IgA pemphigus and highlights the role of the interprofessional team in its management.

Objectives:

• Review the presentation of IgA pemphigus.
• Summarize the treatment of IgA pemphigus.
• Describe the workup of a patient with IgA pemphigus.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by IgA pemphigus.

Introduction

IgA pemphigus is a rare autoimmune blistering disease characterized by painful and pruritic vesiculopustular eruptions. These eruptions form as a result of circulating IgA antibodies against keratinocyte cell surface components responsible for cell to cell adherence. While the disease has been associated with several malignancies and chronic conditions, the exact etiology is unclear. The two distinct subtypes of IgA pemphigus are subcorneal pustular dermatosis (SPD) and intraepidermal neutrophilic dermatosis (IND). The subcorneal pustular dermatosis subtype demonstrates intercellular IgA deposition against the glycoprotein desmocollin-1, predominantly in the upper epidermis.[1][2] In contrast, the intraepidermal neutrophilic dermatosis shows autoantibodies against desmoglein members of the cadherin superfamily, primarily in the lower epidermis. IgA pemphigus shows a milder course of disease than that of IgG-driven pemphigus, but careful diagnosis and aggressive treatment with steroids and dapsone are still required to prevent recurrence.

Etiology

The etiology behind IgA pemphigus is not clearly understood. Based on previously studied cases, IgA pemphigus has been associated with monoclonal IgA gammopathy and multiple myeloma. In a 1992 paper describing IgA pustulosis, Wallach et al. described six out of 29 cases of IgA pemphigus that were found positive for monoclonal IgA gammopathy.[3] It is unclear whether or not monoclonal gammopathy precedes or follows IgA pemphigus, but most cases were detected at the time of presentation. Other associated diseases include human immunodeficiency virus (HIV) infection, Sjogren disease, rheumatoid arthritis, and Crohn's disease. While the direct relationship between the various diseases and IgA pemphigus is still unclear, a thorough survey of hematologic and infectious disorders is advised for patients presenting with IgA pemphigus.

Epidemiology

IgA pemphigus is one of the rarest forms of the autoimmune blistering disease. Not much is known about the epidemiology of the disease, including age and race distribution. Cases have been reported in all age groups, and no particular sex distribution has been reported.[4]

Pathophysiology

The pathogenesis of IgA pemphigus is related to IgA autoantibodies that target desmosomal and non-desmosomal keratinocyte cell surface components. These components are cell-to-cell-adhering molecules, including desmoglein-1, desmoglein-3, and desmocollin-1. Desmogleins and desmocollin are glycoproteins that belong to a superfamily of cadherin molecules. The antigen of the subcorneal pustular dermatosis subtype was identified as desmocollin-1,[5] while the antigen of the intraepidermal neutrophilic dermatosis has been found to interact with both desmoglein-1 and 3.[6] The binding of IgA antibodies to the Fc receptor CD89 on cell surfaces causes a massive inflammatory reaction, resulting in a neutrophilic infiltration of the epidermis which clinically presents as blistering and pustule formation. Although the targets of IgA antibodies have been identified, the exact step-by-step mechanism behind the resulting clinical picture of IgA pemphigus is not well known and requires further investigation.[1]

Histopathology

Histologic examination of IgA pemphigus demonstrates subcorneal blisters with massive neutrophilic infiltration and with a mild loss of cohesion between keratinocytes. Histopathology is useful in differentiating the two major subtypes of IgA pemphigus discussed earlier. In the subcorneal pustular dermatosis subtype, there is an increased intensity of IgA autoantibodies in the upper surface of the epidermis. In contrast, the intraepidermal neutrophilic type is histologically characterized by inflammatory infiltrates, primarily in either the entire or lower part of the dermis.[7][8]

History and Physical

The initial presentation of IgA pemphigus is a subacute onset of flaccid pustules on an erythematous base that quickly rupture to form annular crusts over the plaque. Patients often describe the plaques as painful and pruritic. The most common areas of presentation include flexural areas such as the axilla and groin. It is not uncommon, however, for the whole body and trunk to be affected. One key feature that differentiates IgA pemphigus from other blistering diseases is the absence of mucosal involvement. Patient symptoms are usually limited to skin manifestations, and systemic symptoms such as fever, malaise, headache, and weight loss are absent.[9][10]

Evaluation

The workup of suspected IgA pemphigus includes a skin biopsy to detect positive histologic and immunologic findings on direct and indirect immunofluorescence mentioned earlier.

Direct immunofluorescence is considered an early screening tool for the diagnosis of IgA pemphigus. With the use of direct immunofluorescence, one can detect the absence or presence of IgA autoantibodies on epidermal cell surfaces. Moreover, direct immunofluorescence can be used to differentiate IgA pemphigus from classic pemphigus by demonstrating minimal to no acantholysis. Indirect immunofluorescence can be a useful tool in detecting circulating IgA autoantibodies in a patient’s serum.[1]

Histology of IgA pemphigus is useful in demonstrating the hallmark finding of intraepidermal neutrophilic infiltration. Specimens of blistering skin will show little to no acantholysis, with a mixed inflammatory infiltrate located either in the upper epidermis, mid, or lower epidermis based on the subtype of IgA pemphigus (SPD versus IND).[11][12]

Treatment / Management

Due to the inflammatory nature of the disease, the mainstays for the treatment of IgA pemphigus are oral and topical corticosteroids with a suggested daily dose of 0.5 to 1 mg/kg.[13] Patients should be aware of the complications associated with long-term use of steroids, including osteoporosis, diabetes, cataracts, and infection. However, unlike IgG pemphigus, IgA pemphigus is often not controlled by steroids alone. Many studies have found the addition of dapsone to the treatment regimen to be far superior to just steroids.[14] The main effect of dapsone in the treatment of IgA pemphigus is thought to be related to the suppression of neutrophilic infiltration found in the disease. Long-term treatment with dapsone should be observed for potential adverse effects, including hemolysis and methemoglobinemia.

Other drugs that have been reported to be successful in the treatment of IgA pemphigus include colchicine, retinoids, mycophenolate mofetil, and adalimumab.[15] Many of these drugs were tested due to their success in the treatment of other forms of neutrophilic dermatoses and classic pemphigus. For example, adalimumab, a recombinant human immunoglobulin antibody, is thought to be therapeutic due to its inhibition of tumor necrosis factor (TNF-alpha). TNF-alpha is involved in the activation of neutrophilic infiltration of the epidermis, and thus its inhibition is believed to hinder the further progression of IgA pemphigus.[16]

Differential Diagnosis

Due to the rarity of IgA pemphigus, various differential diagnoses should be considered when approaching the management and treatment of the condition.

Classic subcorneal pustular dermatosis, also known as Sneddon-Wilkinson disease, is a chronic dermatosis characterized by sterile pustular lesions that erupt in cyclical patterns. Similar to the subcorneal pustular subtype of IgA pemphigus, the pustular lesions found in Sneddon-Wilkinson disease coalesce in an annular pattern and eventually burst to form crusted plaques. The two conditions even have the same area of distribution, favoring the groin, trunk, and axillae, and avoiding mucosal surfaces. Histological examination of Sneddon-Wilkinson disease demonstrates perivascular infiltration of neutrophils and mild spongiosis. However, in contrast to IgA pemphigus, direct immunofluorescence of Sneddon-Wilkinson disease will be negative for IgA deposits against adhesion molecules like desmocollin-1 that are key in the diagnosis of the SPD subtype of IgA pemphigus.[17]

Another differential diagnosis to consider when managing a patient with suspected IgA pemphigus is pemphigus foliaceus. Pemphigus foliaceus is a condition characterized by flaccid bullae usually found on the trunk that eventually crust over much like the lesions in IgA pemphigus. It is usually considered a benign disease that responds well to topical and oral corticosteroids. Clinical differentiation between IgA pemphigus and pemphigus foliaceus is nearly impossible. Thus immunofluorescence is key in diagnosis. Direct immunofluorescence of pemphigus foliaceus demonstrates IgG autoantibodies against desmoglein-1 in contrast to the IgA deposits against desmocollin-1 found in IgA pemphigus. Thus, proper diagnosis using histology and immunofluorescence is essential in the differentiation of the two conditions.[18]

Other differential diagnoses to consider when a patient presents with a blistering disease include pemphigus herpetiformis, linear IgA bullous dermatosis, and bacterial skin infections. It is important to take into account the patients’ age, sex, and the course of the disease. Other important features to take note of include the distribution and involvement of the blisters, in particular, whether or not there is mucosal involvement. Regardless of the presentation, careful investigation of the symptoms using histology and immunofluorescence is essential in every case.[9]

Prognosis

Unlike classic pemphigus, IgA pemphigus presents as a milder and more limited disease. With the use of appropriate treatment and follow-up, IgA pemphigus usually heals without scarring. Studies have shown recurrence of lesions with abrupt cessation of oral prednisone, thus a gradual reduction in dosage and weaning off is recommended. When IgA pemphigus is associated with other diagnoses, including malignancies, gastrointestinal disease, and monoclonal gammopathy, the prognosis is based on the progression of these particular conditions.[1]

Complications

While considered a milder form of pemphigus, patients should still be aware of the possible complications related to IgA pemphigus. Patients placed on corticosteroid therapy should be counseled on the adverse effects of long-term steroid therapy, including osteoporosis and adrenal insufficiency. Care should be administered to open wounds that result from the blistering process of IgA pemphigus to avoid infection and scarring. As mentioned previously, patients diagnosed with IgA pemphigus are advised to undergo screening for hematologic diseases, especially patients who are elderly and those presenting with systemic symptoms.[1]

Deterrence and Patient Education

Patients should be made aware of the complications associated with long-term use of steroids, including osteoporosis, diabetes, cataracts, and infection. The importance of medication adherence and the consequence of recurrence of lesions with abrupt cessation of oral prednisone should be stressed. Patients should also be educated that long-term treatment with dapsone may cause hemolysis and methemoglobinemia. Patients diagnosed with IgA pemphigus are advised to undergo screening for hematologic diseases, especially patients who are elderly and those presenting with systemic symptoms. Patients should be advised that with the use of appropriate treatment and follow-up, IgA pemphigus usually heals without scarring, although recurrence is common.

Enhancing Healthcare Team Outcomes

The dermatologist primarily manages IgA pemphigus. However, the disorder may be initially encountered by the primary care clinician. Hence, an appropriate referral is necessary. Because these patients are treated with corticosteroids, healthcare workers, including the pharmacist, must observe the patient for adverse effects likes osteoporosis, diabetes, cataracts, and infection. However, unlike IgG pemphigus, IgA pemphigus is often not controlled by steroids alone. Many studies have found the addition of dapsone to the treatment regimen to be far superior to just steroids.[14] Pharmacists should review medication selection, check for interactions, and provide patient and family education. The main effect of dapsone in the treatment of IgA pemphigus is thought to be related to the suppression of neutrophilic infiltration found in the disease. Long-term treatment with dapsone should be observed for potential adverse effects, including hemolysis and methemoglobinemia. Relapses and remissions mark the long term outcome of IgA pemphigus. Overall the quality of life is poor, and some patients may develop other malignancies. [Level 5]