Continuing Education Activity

Pemphigus is a potentially life-threatening, autoimmune blistering disease characterized by the presence of circulating antibodies against desmogleins, key components of epidermal intercellular adhesion. In contrast to pemphigus vulgaris, in which mucosal lesions are classically present, pemphigus foliaceus does not involve mucosal lesions and only involves skin involvement. Pemphigus foliaceus involves immunoglobulin G (IgG) antibodies directed against desmoglein-1 (Dsg1) found in the granular layer of the epidermis. This activity describes the evaluation and management of pemphigus foliaceus and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

• Review the pathophysiology of pemphigus foliaceus.
• Describe the typical presentation of pemphigus foliaceus.
• Outline the treatment options for pemphigus foliaceus.
• Explain the importance of improving care coordination amongst interprofessional team members to optimize outcomes for patients affected by pemphigus foliaceus.

Introduction

Pemphigus is a potentially life-threatening, autoimmune blistering disease characterized by the presence of circulating antibodies against desmogleins, key components of the integrity of epidermal intercellular adhesion. However, in contrast to pemphigus vulgaris (PV) where mucosal lesions are classically present, pemphigus foliaceus (PF) there is only skin involvement without mucosal lesions.  As an acquired form of pemphigus, pemphigus foliaceus is caused by immunoglobulin G (IgG) antibodies directed against desmoglein-1 (Dsg1) found in the granular layer of the epidermis.[1][2]

Etiology

Susceptibility to pemphigus foliaceus has been correlated with the presence of HLA-DR4, DR-14, and DR-1, but unlike pemphigus vulgaris, no single allele has been associated with the disease.[3][4]

Epidemiology

Pemphigus foliaceous is less common worldwide than pemphigus vulgaris. Pemphigus foliaceous affects men and women equally, and the mean age of onset is usually 50 to 60 years. However, PF has been reported in children.

Endemic pemphigus foliaceus is common in Tunisia and Brazil, where it is also commonly known as fogo selvagem. This endemic form frequently occurs in genetically related family members, although it is not contagious, and to date, spread by blood products or body fluids has not been documented. [5][6]

Pathophysiology

Experimental evidence suggests that autoantibodies in all forms of pemphigus foliaceus are pathogenic. Those autoantibodies recognize desmoglein-1 (Dsg1), a 160-KDa desmosomal cadherin, which is expressed more strongly in the skin from the upper torso. Dsg1 is present but only weakly in mucosae, accounting for the lack of mucosal involvement in pemphigus foliaceous. Some patients have also desmoglein-3 antibodies in the absence of clinical evolution.[7]

Patients with both sporadic and endemic forms of pemphigus foliaceus have antibodies anti- Dsg1, the titer correlating both with the extent and activity of the disease.[8]

Some cases have been associated with the use of certain drugs. In patients receiving penicillamine, pemphigus foliaceus is seen more commonly than pemphigus vulgaris, with a ratio of 4:1. Penicillamine and captopril contain sulfhydryl groups that are speculated to interact with the sulfhydryl groups in Dsg1 and Dsg3. Most patients with drug-induced pemphigus go into remission after the offending drug is discontinued.[9]

Histopathology

The histopathology of early blisters in pemphigus foliaceus demonstrates acantholysis just below de stratum corneum and in the granular layer. The stratum corneum is often lost from the surface. The deeper epidermis remains intact. Histological features may not be diagnostic in the early stages, and eosinophilic spongiosis is an early manifestation.

In early lesions, vacuoles form in the intercellular spaces in the upper levels of the epidermis. These coalesce to form clefts and superficial bullae high in the granular layer or immediately below the stratum corneum. Bullae contain fibrin, neutrophils, and scattered acantholytic keratinocytes. These superficial blisters are histologically indistinguishable from those seen in staphylococcal scalded skin syndrome or bullous impetigo because Dsg1 is targeted in both of these diseases.

Older lesions are acanthotic, papillomatous, and hyperkeratotic with focal parakeratosis. Dyskeratotic cells in the granular layer of older lesions distinguish pemphigus foliaceus from pemphigus vulgaris. The dermis may show an inflammatory infiltrate of eosinophils and neutrophils.[1][10]

History and Physical

It should be noted that most patients with PF are not severely ill. Patients may complain of burning, pruritis, and pain. The onset is usually subtle with a few scattered, crusted lesions involving the seborrheic areas: scalp, face, chest, and upper back. Blisters are typically not found or clinically evident because they are superficial and rupture easily, often only the resultant crust and scale are seen. The Nikolsky sign is present. The disease may stay localized for years, or it may rapidly progress to generalized involvement, resulting in exfoliative erythroderma. Mucous membrane involvement is uncommon, even with widespread disease.

Variants of pemphigus foliaceus have been described, including pemphigus resembling dermatitis herpetiformis, especially in its early phase (pemphigus herpetiformis). Widespread clusters of pruritic papules and vesicles develop on an erythematous background. The condition usually evolves into classical pemphigus foliaceus but has also been described as preceding pemphigus vulgaris. In general, the clinical course is benign.

Pemphigus erythematosus (Senear-Usher syndrome) is a variant, in which patients have immunological features of both lupus erythematosus and pemphigus: IgG and C3 deposition at the basement membrane zone and on the cell surfaces of keratinocytes, in addition to circulating antinuclear antibodies. Progression to lupus erythematosus is rare. Clinically it manifests as scaly, erythematous lesions over the nose and malar region of the face, in a butterfly distribution. Sunlight may exacerbate the disease. Oral mucosa is rarely involved.

Myasthenia gravis, thymoma, or both have been associated with pemphigus vulgaris and pemphigus foliaceus.[11]

Evaluation

A complete review of medications should be done to exclude the possibility of drug-induced pemphigus foliaceus.

Diagnosis of pemphigus relies on skin biopsy of a fresh lesion for histology to determine the site of blister formation, a well as a confirmatory immunochemical study to document the presence of skin autoantibodies, either by direct immunofluorescence of perilesional skin or direct immunofluorescence (DIF) of ELISA.

The hallmark of pemphigus is the finding of IgG autoantibodies against the cell surface of keratinocytes with DIF. The diagnosis of pemphigus should be seriously questioned if the test result of direct immunofluorescence is negative. It is important that the biopsy for direct immunofluorescence be performed on the normal-appearing perilesional skin, as immune reactants can be difficult to detect in the blistered epidermis

Direct and indirect immunofluorescent findings are usually indistinguishable from pemphigus vulgaris, with intercellular IgG and C3 throughout the epidermis. Occasionally intercellular staining is restricted to the upper layers of the epidermis, both on direct and indirect immunofluorescence.

Indirect immunofluorescence is positive in over 85% of pemphigus foliaceus, ELISA detects anti-desmoglein-1 antibodies in up to 71% of patients, but immunoblotting is less sensitive.[12]

Recently, trichoscopy has been evaluated as a useful tool in the differential diagnosis of scalp pemphigus. Extravasations and yellow hemorrhagic crusts were the most frequent findings. The “fried egg sign” (yellow dots with a whitish halo) was identified as a new trichoscopic feature of pemphigus.[13][1]

Treatment / Management

Before the advent of steroid therapy, pemphigus foliaceus was fatal in approximately 60% of patients, and almost always fatal in elderly patients with concurrent medical problems. With steroid and immunosuppressive therapy, the mortality has been dramatically reduced.

Corticosteroids represent the first-line treatment in all forms of pemphigus. Prednisone at 0.5 to 1.5 mg/kg per day or prednisolone 20 to 40 mg per day may be used. If initial control is not reached within 2 weeks, a higher prednisone dose is advised.

Azathioprine 1 to 3 mg/kg per day and mycophenolate mofetil 2 g per day are effective adjuvants to oral steroids but the best time for its introduction remains unclear (early versus treatment-resistant cases). It should be noted that the onset of action with mycophenolate mofetil is slow and evidence of response occurs between 2 and 12 months of continued use.

Other treatment options for refractory disease, or in case of contraindications to immunosuppressive agents include hydroxychloroquine 200 mg twice daily, dapsone 100 mg per day or up to 1.5 mg/kg per day, methotrexate 10 to 20 mg/week, intravenous immunoglobulin 2 g/kg per month or rituximab, given as either 4 weekly infusions of 375 mg/m2 or as 2 1-g infusions, separated by 2 weeks.

Due to the potential side effects of therapy, patients should be monitored closely. After discontinuation of systemic corticosteroids in patients with complete remission, adjuvant immunosuppression can also be reduced over 6 to 12 months. The discontinuation of therapy is based on the clinical presentation with a complete absence of active cutaneous lesions over several months. Negative or low ELISA-Dsg1 values or negative immunofluorescence are useful to support the discontinuation of therapy.[1][14][15]

Differential Diagnosis

The differential diagnosis includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, subacute cutaneous lupus erythematosus, and seborrheic dermatitis. The demonstration of IgG autoantibodies against epidermal surfaces is essential to determine if the disorder accounts for a form of pemphigus.

Prognosis

Pemphigus foliaceus is regarded as a benign disease that responds well to treatment and may remit. Pemphigus erythematosus may persist as a localized disease for years. The clinical course is often similar to pemphigus foliaceous.

Enhancing Healthcare Team Outcomes

Pemphigus foliaceus is best managed by an interprofessional team including pharmacists. Patients respond to corticosteroids but some may require more potent immunosuppressives. The pharmacist should educate the patient about compliance and potential adverse effects. For those who remain compliant, the outlook is good. Without treatment, the condition can lead to poor quality of life.