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 1-2% of all pemphigus . It is often difficult to diagnose and clinically misleading due to the variable presentation and presence of verrucous vegetations. 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. The most common cause of pemphigus vegetans is autoantibodies against desmoglein 3 (DSG3) and desmoglein 1 (DSG1). The mainstay of treatment for pemphigus vegetans is similar to that of pemphigus vulgaris, consisting of systemic corticosteroids and immunosuppressants.
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. 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.
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.
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.
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. 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.
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. 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.
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.
The majority of patients initially present to their provider with stomatitis. 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. 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. 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.
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.
Immunoblot or ELISA analysis of serum:
Direct Immunofluorescence (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:
Additional methods for evaluation:
Wound Care: Daily cleansing and dressing. Medicated gauzes and chemical cautery.
Surgical options: Surgical excision of vegetative lesions.
Treatment for Oral Involvement: Magic mouthwash comprised of liquid dexamethasone; 5 cc rinse, 2x per day or clobetasol ointment.
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.
If standard steroids and immunosuppressants are not sufficient, second-line treatments include:
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.
Emerging Therapies: The goal is to offer long-term therapy with fewer side effects and less systemic immunosuppression.
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.
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.
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.
Pemphigus vulgaris has a known association with myasthenia gravis and thymoma, and patients diagnosed with these conditions are more likely to develop pemphigus.
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%.
There is a known association between intranasal heroin use and pemphigus vegetans.
Special care should be taken not to pop the blisters; no scrubbing or high-pressure water, as this increases the risk of infection.
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]
Unfortunately, despite optimal treatment, the disorder still carries a mortality rate of nearly 10% a year.
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