Pemphigus Herpetiformis

Etiology

Pemphigus herpetiformis appears to be mediated by an immunoglobulin G (IgG) autoantibody that primarily targets desmoglein (Dsg) proteins in the epidermis. The mechanism by which these autoantibodies produce characteristic skin lesions remains debated.[5] Some cases of drug-induced pemphigus herpetiformis have also been reported.[6][7][8][9] Recent case studies have revealed a possible association between pemphigus herpetiformis and gastric cancer.[10]

Epidemiology

Pemphigus herpetiformis accounts for 6% to 7.3% of pemphigus cases. Since the condition was initially described by Jablonska and colleagues in 1975, approximately 100 cases have been documented in the literature. Both sexes are affected equally. Reported ages of onset range from 5 to 92 years, with only 4 pediatric cases identified. No ethnic predilection has been observed. Cases have been reported across multiple continents, including North and South America, Europe, Asia, and Africa.

Pathophysiology

The primary target antigens in pemphigus herpetiformis are Dsg1 and, less frequently, Dsg3. However, recent reports have described cases lacking detectable anti-Dsg1 or -Dsg3 autoantibodies, with some patients exhibiting reactivity against alternative antigens such as desmocollins (Dsc).

Unlike pemphigus vulgaris and pemphigus foliaceus, pemphigus herpetiformis is characterized by marked inflammation, often without evident acantholysis. Autoantibodies in pemphigus herpetiformis may recognize functionally nonpathogenic epitopes on Dsg1 or Dsg3, which may explain the absence of acantholysis. A recent study supports this hypothesis, demonstrating a broader epitope distribution than that observed in pemphigus vulgaris or pemphigus foliaceus. Autoantibody-mediated stimulation of keratinocytes appears to trigger interleukin-8 release, promoting eosinophil and neutrophil recruitment. The resulting eosinophilic or neutrophilic spongiosis and focal intercellular edema contribute to blister formation.[11][12] Additionally, recent case reports have described pemphigus foliaceus transitioning to pemphigus herpetiformis.[13]

Histopathology

Histopathological features of pemphigus herpetiformis differ from those of pemphigus vulgaris and pemphigus foliaceus due to prominent spongiosis, typically without acantholysis. Histological patterns may vary among patients, and a single patient can exhibit different histologic findings over time. Multiple biopsies may therefore be required to establish the diagnosis.

The hallmark histopathologic feature is eosinophilic spongiosis. Additional findings may include neutrophilic spongiosis, mixed eosinophilic-neutrophilic spongiosis, subcorneal pustules, and intraepidermal vesicles containing eosinophils or neutrophils.[14]

Acantholysis is generally absent in early stages but may develop later in the disease course. Dermal papillary neutrophilic microabscesses may also be observed. The inflammatory cell profile varies, with mixed eosinophil and neutrophil infiltrates in 60% of cases, eosinophil-dominant infiltrates in approximately 20%, and neutrophil-dominant infiltrates in 20%.

History and Physical

Pemphigus herpetiformis typically has a subacute onset. Diagnosis is rarely established at the initial consultation due to atypical clinical features. Common differential considerations include dermatitis herpetiformis, bullous pemphigoid, and linear immunoglobulin A (IgA) bullous dermatosis.

Cutaneous findings may include erythematous, vesicular, bullous, pustular, or papular lesions arranged in a herpetiform pattern, often accompanied by intense pruritus. An annular distribution is frequently observed, likely reflecting centrifugal spread of the inflammatory process (see Image. Pemphigus Herpetiformis). In some cases, urticarial pruritic papules and plaques predominate—features uncommon in pemphigus vulgaris and pemphigus foliaceus.

Lesions typically involve the trunk and proximal extremities. Although widespread involvement is common, reports exist of localized or atypical presentations. Mucosal involvement is infrequent.

During the disease course, pemphigus herpetiformis may transition into pemphigus vulgaris or pemphigus foliaceus. Reverse transformation from other pemphigus variants to pemphigus herpetiformis has also been observed.

Evaluation

Peripheral blood eosinophilia may be present in some patients with pemphigus herpetiformis. Direct immunofluorescence of perilesional skin biopsy specimens typically reveals intercellular IgG and C3 deposition in the superficial layers of the epidermis, consistent with other pemphigus variants. Deposits may also appear in the lower epidermis in individuals with circulating autoantibodies against Dsg3.

Indirect immunofluorescence using substrates such as healthy human skin, monkey or guinea pig esophagus, or rat bladder may demonstrate intercellular IgG antibody binding. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting often detect circulating antibodies targeting Dsg1 and, less frequently, Dsg3. Additional target antigens reported in recent studies include Dsc1, Dsc3, a 178-kDa antigen, the C-terminus of BP180, and the γ2 subunit of laminin 332.[15][16]

Treatment / Management

Pemphigus herpetiformis generally follows an indolent clinical course and poses less risk to life than pemphigus vulgaris or pemphigus foliaceus. Progression to these classical forms has been reported in some cases. Limited case numbers constrain the available evidence on optimal management strategies. Dapsone and corticosteroids remain the primary agents used, based on the literature review. Dapsone is widely considered the first-line treatment due to its inhibitory effects on neutrophil chemotaxis.

Corticosteroids are also effective, with lower daily doses typically sufficient to induce remission compared to other pemphigus subtypes. Dapsone and corticosteroids may be administered either as monotherapy or in combination.

Patients with refractory disease or transformation to pemphigus vulgaris or pemphigus foliaceus may require escalation to more intensive immunosuppressive regimens. Reported treatments in such cases include cyclophosphamide, mycophenolate mofetil, sulfapyridine, azathioprine, methotrexate, intravenous immunoglobulin, rituximab, and plasmapheresis.[17][18][19][20](B3)

Differential Diagnosis

Accurate diagnosis of pemphigus herpetiformis requires distinction from a wide range of primary and secondary bullous disorders. Clinical, histologic, and immunologic overlap may complicate differentiation, especially with the following disorders that share similar pruritic or vesiculobullous features:

• Bullous pemphigoid
• Erythema multiforme
• Excoriation disorder
• Familial benign pemphigus (Hailey-Hailey disease)
• IgA pemphigus
• Linear IgA bullous dermatosis
• Papular urticaria
• Paraneoplastic pemphigus
• Pemphigus erythematosus
• Pemphigus foliaceus
• Scabies

Overlapping features can obscure the diagnosis without thorough assessment. A structured approach to the differential diagnosis is essential for early and effective intervention.

Prognosis

The prognosis of pemphigus herpetiformis is generally favorable compared to classic pemphigus variants. Most studies report a high rate of therapeutic response, with 70% to 80% of patients achieving partial or complete remission, often with dapsone monotherapy or low-dose systemic corticosteroids. The clinical course is typically chronic but less aggressive, and long-term control is achievable in most cases. Mucosal involvement is rare, and extensive erosive disease is uncommon, contributing to the lower burden of morbidity.

Mortality directly attributable to pemphigus herpetiformis is exceedingly rare. Estimated death rates range from 0% to 2%, with fatalities primarily resulting from treatment complications or misdiagnosis leading to inappropriate management. In contrast to pemphigus vulgaris, where historical mortality exceeded 75% prior to the introduction of corticosteroids, pemphigus herpetiformis follows a markedly more indolent course.

Approximately 10% to 15% of cases may evolve into pemphigus foliaceus or pemphigus vulgaris, likely reflecting an immunologic shift rather than true disease transformation. Relapses may occur, particularly during tapering of therapy, but are typically milder than in other pemphigus forms. The long-term prognosis is excellent with early recognition and appropriate treatment. Many patients maintain stable remission with minimal or no systemic immunosuppression.

Complications

The most frequent complications of pemphigus herpetiformis are iatrogenic, arising from prolonged immunosuppressive therapy rather than from the disease itself. Chronic corticosteroid use may result in systemic effects such as osteoporosis, hyperglycaemia, hypertension, and increased susceptibility to infections. Secondary bacterial infections of excoriated or vesiculated skin, particularly with Staphylococcus aureus or Streptococcus pyogenes, can occur in inadequately treated or severely pruritic lesions. Although mucosal involvement is uncommon, its presence may lead to diagnostic confusion and inappropriate therapy, delaying effective disease control.

Dapsone-related adverse effects may complicate treatment. Manifestations include methemoglobinemia, hemolytic anaemia (especially in individuals with glucose-6-phosphate dehydrogenase deficiency), and dapsone hypersensitivity syndrome. Such reactions may necessitate discontinuation of an otherwise highly effective therapy.

In rare cases, pemphigus herpetiformis may immunologically transition into other pemphigus variants, such as pemphigus foliaceus. This shift may require escalation of therapy and closer clinical monitoring.

Persistent pruritus and postinflammatory dyspigmentation may affect quality of life. However, unlike pemphigus vulgaris, systemic complications such as fluid-electrolyte imbalance, protein loss, or sepsis are uncommon. With early diagnosis and careful therapeutic monitoring, the risk of serious complications remains low and primarily treatment-related.