Continuing Education Activity

Pemphigus is a group of vesiculobullous autoimmune diseases. The most common type of pemphigus is pemphigus vulgaris, characterized by mucocutaneous bullae. Among the many types of pemphigus, the rarest clinical variant is pemphigus vegetans. It distinguishes itself from pemphigus vulgaris by the formation of vegetative plaques in intertriginous areas and oral mucosa. Thought to be a subtype of pemphigus vulgaris, pemphigus vegetans represents 1 to 2% of all pemphigus. This activity highlights the presentation and diagnosis of pemphigus vegetans, a rare variant of autoimmune pemphigus and emphasizes the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of pemphigus vegetans.
• Explain the history and physical exam of a patient with pemphigus vegetans.
• Outline the treatment and management options available for pemphigus vegetans.
• Review interprofessional team strategies for improving care coordination and communication to advance pemphigus vegetans and improve outcomes.

Introduction

Pemphigus is a group of vesiculobullous autoimmune diseases. The most common type of pemphigus is pemphigus vulgaris, characterized by mucocutaneous bullae.[1] Among the many types of pemphigus, the rarest clinical variant is pemphigus vegetans. It distinguishes itself from pemphigus vulgaris by the formation of vegetative plaques in intertriginous areas and oral mucosa. Thought to be a subtype of pemphigus vulgaris, pemphigus vegetans represents 1-2% of all pemphigus [2]. It is often difficult to diagnose and clinically misleading due to the variable presentation and presence of verrucous vegetations.[3] There are two clinically recognized forms of pemphigus vegetans, the Hallopeau type, and Neumann type. The Hallopeau type has an indolent course and characteristically demonstrates pustules that heal as vegetative plaques. The oral mucosa is frequently uninvolved. The Neumann type is more severe and refractory to treatment, with vegetations that develop during an eruption of vesiculobullous lesions. The oral mucosa is usually involved.[4] The most common cause of pemphigus vegetans is autoantibodies against desmoglein 3 (DSG3) and desmoglein 1 (DSG1).[5] The mainstay of treatment for pemphigus vegetans is similar to that of pemphigus vulgaris, consisting of systemic corticosteroids and immunosuppressants.[2]

Etiology

Pemphigus vegetans results from autoantibodies against the transmembrane proteins that comprise desmosomes, which are responsible for keratinocyte cell to cell adhesion. Specifically, pemphigus vegetans is most commonly caused by autoantibodies against desmoglein 3 and often desmoglein 1.[5] Mucosal dominant disease is more frequently associated with desmoglein 3, and mucocutaneous disease associated with autoantibodies against both desmoglein 3 and desmoglein 1. Additionally, IgG and IgA antibodies against desmocollins are also present in patients with pemphigus vegetans.[6]

Epidemiology

The epidemiology of pemphigus vegetans has not been a topic of research. Reports are that it represents 1 to 2% of all pemphigus cases, and worldwide, the incidence of pemphigus vulgaris is approximately 0.7 per 100000. Given the limited cases, the epidemiology is thought to be similar to pemphigus vulgaris, which occurs more frequently in women, with a female to male ratio of between 1.3 and 2.3 to 1. Age at diagnosis is typically 50 to 70 years in the United States and European countries, and 30 to 50 years, in the remaining countries. Pemphigus vulgaris is reportedly more common among the Ashkenazi Jewish, Mediterranean, and Middle Eastern populations.[7][8]

Pathophysiology

The pathophysiology of pemphigus is characterized by IgG autoantibodies against the components of desmosomes that are responsible for keratinocyte adhesion, specifically desmoglein 3 and desmoglein 1. Autoantibody binding to desmogleins has been shown to cause blistering through several mechanisms- including steric hinderance, interruption of desmosome assembly and/or increased breakdown, and secondary activation of signal transduction events involving keratinocyte adhesion.  Structural studies suggest steric hinderance from the molecular structure of the desmoglein-antibody complex creates the intraepidermal spaces that result in spongiosis and blister formation. These studies also show anti-desmoglein 3 antibodies present deep in the epidermis with concentrations of anti-desmoglein 1 antibodies in the upper epidermis.[9][5] 

Autoantibody deposition against desmogleins within the epidermal space and on the outer surface of keratinocytes leads to acute inflammation and blister formation. In pemphigus vegetans, in addition to desmogleins 1 and 3, there are frequently antibodies to desmocollins 1 and 2. The addition of these antibodies has been suggested as an etiology for the difference in clinical appearance between pemphigus vulgaris and pemphigus vegetans, and have been known to synergize with anti-desmoglein 3 antibodies to induce acantholysis.[10] It is still unknown how the characteristic vegetative lesions form following blister formation. Associated factors are thought to include semi-occlusion or maceration due to intertriginous location. Other theories suggest vegetative plaques form after serial bacterial or fungal infections as a protective response.

Genetics

There is a known component of genetic susceptibility to pemphigus. Studies have shown that certain human leukocyte antigen (HLA) alleles may be responsible for increased autoantibody formation against desmogleins. Mapping of the major histocompatibility complex region of chromosome 11 has shown an association between pemphigus vulgaris and HLA-DRB1, and HLA-DQB1, with the strongest association between HLA-DQB1*05:03.[11] In addition to increased genetic susceptibility, there is a hypothesis that B cells with VH1-46 heavy chain gene usage may be hypersensitive to desmoglein 3, increasing cellular damage.[12][13][14]

Histopathology

Classical histologic findings in pemphigus vegetans include hyperkeratosis, pseudoepitheliomatous hyperplasia, and papillomatosis, with acantholysis that creates a suprabasal cleft. The basal cells maintain their attachment to the basement membrane by intact hemidesmosomes, creating the characteristic appearance of “tombstones.” Follicular involvement is a frequent occurrence. Especially in the Hallopeau type, there is a strong eosinophilic response, with eosinophilic spongiosis, intraepidermal eosinophilic microabscesses, and dense eosinophilic dermal infiltrate. Neutrophils and lymphocytes usually accompany the eosinophilic response and are more likely to be the primary inflammatory component in the Neumann type. There may be papillary dermis edema to the heavy inflammatory infiltrate.[4]

History and Physical

The majority of patients initially present to their provider with stomatitis.[15] A few weeks to months after the mucosal blisters, cutaneous pustules and/or flaccid bullae form, typically affecting the trunk, arms, legs, and flexural areas. The Hallopeau subtype characteristically demonstrates initial pustular lesions and has a more indolent course. The Neumann subtype has characteristic large vesiculobullous, erosive lesions, and is more severe.  The cutaneous lesions rupture and ulcerate and verrucous, crusting vegetative plaques form over the erosions. These hyperkeratotic lesions characteristically present in the intertriginous areas- including the groin/inguinal folds, armpits, thighs, and flexural surfaces.[5] Less common areas affected include the scalp, soles of the feet, and skin graft sites. There are also reports of nasal, vaginal, and conjunctival involvement.[16][17] In the oral cavity, the hyperkeratotic plaques appear on the tongue in a cerebriform pattern.

Although most patients present with pertinent physical exam findings, it is important to take a detailed history- including a family and personal history of autoimmune disease and skin problems. Other relevant details include stressors, history of radiation, recent illness, changes in medications, or if there is pain associated with activities such as eating, swallowing, sexual activity, or if the symptoms flare with menstruation.[18]

Evaluation

The diagnosis of pemphigus vegetans is made based on clinical features, histologic examination, and identification of autoantibodies.  There are several methods to evaluate and identify autoantibodies.[19] 

Immunoblot or ELISA analysis of serum: 

• Blood tests can identify patients with desmoglein 3 autoantibodies in their serum with a specificity and sensitivity of 98 to 100%, so nearly all patients with pemphigus will have detectable desmoglein 3 reactivity, and unaffected individuals will not.[10]

Direct Immunofluorescence (DIF):

• Similar to pemphigus vulgaris, the direct immunofluorescence findings in pemphigus vegetans show intercellular deposition of IgG and C3 within the intraepidermal space and on the surface of keratinocytes. IgG4 and IgG1 are the predominant types of IgG involved. This deposition creates a characteristic “fishnet” or “chicken wire” pattern.[9]
• For optimal DIF evaluation, a punch biopsy or deep shave from normal-appearing peri-lesional skin should be submitted in Michel’s solution (or fixative appropriate for DIF).

Serum immunoglobulins: IgG and IgA titers are often correlated with disease activity and can be used to follow therapeutic response.

Less commonly used methods of evaluation include:

• Indirect immunofluorescence (IIF), a semi-quantitative method for identifying autoantibodies.
• Electron microscopy: Keratinocytes show a reduction of tonofilaments. Only rarely are there desmosomes identified. The basement membrane often appears damaged as a result of inflammatory infiltrate.[20]

Additional methods for evaluation:

• Nikolsky Sign: Side pressure on blister leads to blister extension. Often positive; however, this test is non-specific and seen in several blistering skin diseases.
• Tzanck Test: Cutaneous cytology is useful to rule out pemphigus; however, the diagnosis should be by clinical exam, histopathology, and antibody identification. The reported sensitivity and specificity of a Tzanck smear is 85.0% and 83.33% for pemphigus.[21]
• Complete Blood Count with Differential: May show peripheral eosinophilia. 

Treatment / Management

Wound Care: Daily cleansing and dressing. Medicated gauzes and chemical cautery.[22]

Surgical options: Surgical excision of vegetative lesions.[22]

Treatment for Oral Involvement: Magic mouthwash comprised of liquid dexamethasone; 5 cc rinse, 2x per day or clobetasol ointment.

Topical Options[23]:

• Class I steroids applied twice daily
• Topical tacrolimus for facial involvement or if sensitive to chronic steroid therapy
• Minocycline/nicotinamide at onset and relapse has been used with success and avoids systemic steroids

Intralesional Therapy:

• Triamcinolone is injected directly into refractory vegetative lesions

Systemic Therapy: The gold standard for treatment is systemic corticosteroids. Corticosteroids are thought to upregulate desmoglein expression in keratinocytes, resulting in rapid therapeutic effect. Corticosteroids and immunosuppressants are the most effective in managing patients with pemphigus.[24]

• Prednisone: 0.5 to 2 mg/kg/day for 2 to 4 weeks.
• Azathioprine: 50 mg daily, and upwards titrate to 2.5 mg/kg/day.
• Dapsone: 100 to 200mg daily. Ideal for mucosal involvement. May combine with mycophenolate or azathioprine.[25]
• Mycophenolate mofetil: 30 to 40 mg/kg/day. Risk of side effects, lymphoma, and JC virus.
• Methotrexate: 15 mg/week. Safe and beneficial steroid-sparing agent.[26]
• Cyclophosphamide: Works well for oral mucosa, but has extensive side effect profile.
• First-line combination therapies:
  • Corticosteroid plus one of the following agents: rituximab, mycophenolate mofetil, azathioprine, methotrexate, cyclophosphamide, or IVIG.

If standard steroids and immunosuppressants are not sufficient, second-line treatments include:

• Rituximab, an anti-CD20 monoclonal antibody, with or without IVIG dosed at 2 mg/kg over 3 to 5 days every 4 weeks. Rituximab has shown to elucidate short-term remission in 95% to 100% of pemphigus patients and correlates with a decrease in anti-DSG3 titers.[10]

• Pulse Therapy:  Intermittent high dose IV corticosteroids and immunosuppressive agents, to achieve faster results and minimize side effects of long-term steroid therapy.[27]

The recommendation is to maintain remission for 1 year and then slowly taper therapy over another year, tailored to the individual patient and their co-morbidities.

Less common treatment options include plasmapheresis, immunoadsorption, and hematopoietic stem cell transplant.[24]

Emerging Therapies: The goal is to offer long-term therapy with fewer side effects and less systemic immunosuppression.

• B cell-activating factor (BAFF): B-cell-activating factor co-stimulates B-cell responses. Patients with B-cell mediated autoimmune diseases often have increased BAFF, which makes it a novel therapeutic target.[28]
• Proliferation-inducing ligand (APRIL) inhibitors: Proliferation-inducing ligand is a key biomarker in the regulation of B-cells, humoral immunity, and pathogenicity of autoimmune disease. Inhibitors are a therapeutic option.[29]
• Anti-cytokine therapy, anti- interleukin (IL)-4 and anti-interleukin (IL)-6): Interleukins, particularly IL-4 and IL-6, have been implicated in pemphigus by exacerbating Th2 overexpression and isotype switching to IgG1 and IgG4, which have been shown to play a role in the loss of desmoglein.  Direct inhibition of IL-4 and IL-6 is a potential treatment for patients with pemphigus.[30]
• Co-stimulatory and co-inhibitors- manipulators and inhibitors of pathogenic signaling pathways (p38MAPK, c-Myc, and EGFR) are currently being studied and may be targets for novel therapies.[31]

Differential Diagnosis

• Pyodermatitis pyostomatitis vegetans: Clinically and histologically look similar to pemphigus vegetans, but is often associated with inflammatory bowel disease and should have a negative DIF.[32]
• Bullous pemphigoid: Typically presents with tense blisters, urticarial plaques, and pruritus. Mucosal involvement is rare. The histopathological evaluation shows a subepidermal cleft, and DIF shows IgG and/or C3 deposition at the basement membrane. Circulating IgG and IgE autoantibodies are detected against hemidesmosomal proteins.[33][34] 
• IgA pemphigus: A subacute autoimmune intraepidermal blistering diseases associated with circulating IgA antibodies. DIF shows intracellular IgA deposits within the epidermis.[35]
• Hailey-Hailey Disease: Hailey-Hailey disease is an autosomal dominant genodermatosis that often forms chronic inflammatory plaques in intertriginous areas. The plaques appear as crusted macerated erosions with dry, velvety fissures. Histologic evaluation of the epidermis demonstrates the characteristic “dilapidated brick wall” appearance, which consists of suprabasal clefting and acantholysis.[36][37]
• Pyoderma vegetans: Rare vesiculopustular disease, characterized by vegetative plaques with exudate, classically located in the inguinal and axillary folds. It is generally found in immunocompromised patients and is associated with bacterial infections. Histologically, there is pseudoepitheliomatous hyperplasia with sub and intraepidermal microabscesses.[38]
• Paraneoplastic pemphigus: Similar findings to pemphigus vulgaris, often with severe mucosal involvement. It is always associated with underlying malignancy, most commonly a hematopoietic malignancy such as chronic lymphocytic leukemia, or other B-cell lymphomas.[39] Anti-periplakin is also associated with paraneoplastic pemphigus.[5][40] 
• Epidermolysis bullosa acquisita (EBA): EBA is an autoimmune blistering disease, with mucosal involvement. It is caused by circulating autoantibodies against type VII collagen, which is responsible for maintaining the dermal-epidermal junction.  The clinical picture is variable, and linear deposits of IgG, IgA, and/or C3 along the dermal-epidermal junction and identification of serum autoantibodies against type VII collagen confirm the diagnosis.[41]
• Porphyria: Porphyrias are genetic diseases of the heme biosynthesis pathway.  Porphyria cutanea tarda (PCT) is the commonest, characterized by defective uroporphyrinogen III decarboxylase enzyme. Dermatological manifestations include erosions, vesicles, and bullae in areas exposed to sunlight.[42][43]
• Pemphigus foliaceus (PF): PF is similar to pemphigus vulgaris, but autoantibodies direct their activity against desmoglein (DSG) 1, and it does not involve the mucosal membranes.  The blister is often more superficially located in the epidermis.[44]
• Disseminated Herpes infection: May cause vesiculobullous eruptions, but due to viral infection. Histopathological evaluation, viral studies, and culture are key for diagnosis.[4]
• Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN): Spectrum of desquamative disorders characterized by prodromal upper respiratory symptoms, followed by a rash that progresses to full or partial thickness epidermal loss. Most often caused by medication, but has also been associated with infectious etiologies.[45][46] 
• Desquamative gingivitis- may be seen in herpes, oral lichen planus, erythema multiforme, and SJS/TEN.[4]

Prognosis

Autoimmunity is not curable, but rather only treated, and managed. If untreated, pemphigus, including pemphigus vegetans, can be fatal within 5 years due to severe blistering, secondary infection, and malnutrition. Mortality is approximately 5 to 15% per year.[10]

Complications

Secondary infection of lesions: Staphylococcus aureus, MRSA, herpes, and fungal organisms are most common.

There can be increased susceptibility to systemic infection due to chronic use of immunosuppressive therapies.

Malnutrition due to oral mucosa involvement causing pain, decreased oral intake, and weight loss.

Pap smears may present as dysplastic due to the appearance of acantholytic cells from the cervical and vaginal mucosa.[47]

Consultations

Consultation with a dermatologist is the recommended course for diagnosis and management. Patients on long term corticosteroids may need endocrinology consultation to manage metabolic side effects.

Deterrence and Patient Education

Pemphigus vulgaris has a known association with myasthenia gravis and thymoma, and patients diagnosed with these conditions are more likely to develop pemphigus.[48]

Patients taking penicillamine or ACE inhibitors (particularly captopril and enalapril) are at increased risk of developing pemphigus. The reported prevalence of pemphigus among patients taking penicillamine is around 7%.[49]

There is a known association between intranasal heroin use and pemphigus vegetans.[50]

Special care should be taken not to pop the blisters; no scrubbing or high-pressure water, as this increases the risk of infection.

Enhancing Healthcare Team Outcomes

All autoimmune diseases require an interprofessional approach for appropriate diagnosis and life-long management. Pemphigus vegetans is a unique variant of pemphigus that is often underrecognized and frequently misdiagnosed. Although it is the rarest form of pemphigus, it is potentially fatal if untreated. Healthcare teams need to work together to recognize and treat patients with this rare form of vesiculobullous autoimmune disease. Because management of these patients is with a variety of immunosuppressive agents, they not only need to be educated about the adverse effects but need life long monitoring. Because of the constant state of suppressed immunity, they also develop bacterial and viral infections. Thus, an infectious disease nurse should follow the patient and monitor for signs of an infection. Pharmacists should verify all dosing and perform medication reconciliation, reporting any concerns to the rest of the healthcare team. Corticosteroids may induce diabetes, so an endocrine consult is necessary. Also, these agents may cause bone thinning, and hence, osteoporosis should be screened to prevent fractures. Many patients develop chronic wounds that fail to heal. Therefore, a wound care nurse should educate the patient on wound care. Only through open communication between the team members can the morbidity and mortality of this severe disorder be reduced.

In summary, pemphigus vulgaris requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]

Outcomes

Unfortunately, despite optimal treatment, the disorder still carries a mortality rate of nearly 10% a year.