Last literature review version 17.2: May 2009 | This topic last updated: June 17, 2009 (More)
INTRODUCTION - Pemphigus and bullous pemphigoid are autoimmune blistering diseases. The autoantibodies in these disorders are directed against different epitopes (antigenic specificity to binding sites), resulting in intraepidermal blistering in pemphigus, and subepidermal blistering in pemphigoid.
Pemphigus is a group of rare, chronic, autoimmune, potentially fatal vesiculobullous diseases of the mucous membranes and skin. The term pemphigus (from the Greek pemphix, bubble) was used to describe most bullous diseases until the 20th century. Blister formation occurs in the epidermis by a process known as acantholysis, which refers to a loss of cohesion between epidermal cells.
Three major types of pemphigus have been described, each of which has distinct clinical and pathological features:
- Pemphigus vulgaris
- Pemphigus foliaceus
- Paraneoplastic pemphigus.
Pemphigus is reviewed here; bullous pemphigoid is discussed separately. (See "Bullous pemphigoid"). Also discussed separately are other blistering diseases, including porphyria cutanea tarda, dermatitis herpetiformis, erythema multiforme, and toxic epidermal necrolysis. (See "Porphyria cutanea tarda; hepatoerythropoietic porphyria; and toxic porphyria" and see "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults" and see "Drug eruptions").
PEMPHIGUS VULGARIS - Pemphigus vulgaris ("vulgar" referring to the "common" form of the disease) is the most common form of pemphigus in the United States and Europe, although it is a rare disease . It usually occurs in middle-aged and older persons.
Epidemiology - Most studies of pemphigus vulgaris have been hospital-based. A population-based study from the United Kingdom found the following for pemphigus vulgaris :
- Incidence of 0.7 per 100,000 person-years
- Incidence increasing over time (from 1996 to 2006) by 11 percent per year
- Increasing incidence with increasing age; median age at presentation was 71 years
- More cases occurred in women than men (66 versus 34 percent)
- Higher risk of death compared with control patients (hazard ratio 3.3, 95% CI 2.2-5.2)
Pathogenesis - Pathogenic autoantibodies in patients with pemphigus vulgaris, usually immunoglobulin G (IgG), are directed against desmoglein (Dsg), an adhesion molecule [3,4]. This interferes with the intercellular cement that holds epidermal cells together and results in intraepidermal blister formation. The pathogenic nature of these antibodies has been confirmed by the following observations:
- Transfer of antibody containing serum into newborn mice induces a similar bullous skin disease [5,6]
- An active model of pemphigus can be induced by immunization of transgenic mice lacking Dsg 3 with Dsg 3; adoptive transfer of splenocytes from the immunized transgenic mice to mice that express Dsg 3 leads to anti-Dsg 3 antibody formation and disease mimicking pemphigus vulgaris .
Pemphigus vulgaris may be associated with both mucosal and cutaneous lesions. Patients with limited mucosal disease primarily have autoantibodies directed against Dsg 3, while those with more extensive cutaneous disease (or, as described below, paraneoplastic pemphigus) may have both anti-Dsg 3 and anti-Dsg 1 [8-10]. In comparison, patients with pemphigus foliaceus, in which the lesions are limited to the skin, only have anti-Dsg 1 antibodies (see "Pemphigus foliaceus" below) [11,12]. In an animal model, blisters could be induced in areas of epidermis and mucous membrane that express both Dsg 1 and Dsg 3 only by antibodies directed against both antigens, not by either one alone . Non-desmoglein autoantibodies may also play a role .
The stimulus that leads to autoantibody formation is unknown. There is an increased incidence in Ashkenazi Jews, in whom it is associated with the HLA-DR4 phenotype; more than 90 percent of Ashkenazi Jews who have pemphigus vulgaris carry the DRB1*0402 haplotype . Pemphigus vulgaris is particularly associated with the rare DRB1*0402 subtype [15,16]. The prevalence of human herpesvirus 8 (HHV8) infection appears to be higher in patients with pemphigus than in controls, but it is unclear if this association is causal .
Clinical features - Pemphigus vulgaris is characterized by flaccid bullae that typically begin in the oropharynx and then may spread to involve the skin, with a predilection for the scalp, face, chest, axillae, and groin (show picture 1). The bullae rupture easily, so that the patient often presents with only erosions and no intact bullae (show picture 2). Virtually all patients have oropharyngeal disease at some point in the course of disease. Other mucous membranes may also be involved . A Nikolsky sign may be present (see "Nikolsky sign" below).
Lesions typically are painful, particularly after the blisters rupture. Open denuded areas can become secondarily infected. Severe oral involvement may impair oral intake. Lesions do not resolve without therapy and often heal with postinflammatory hyperpigmentation. The pigmentary changes generally resolve within one to two years and do not leave scarring.
Diagnosis - The diagnosis of pemphigus requires biopsy of skin lesions. A deep shave or 4-mm punch biopsy should be performed for routine light microscopy from an early, small bulla or from the edge of a new erosion; histologically there is evidence of intraepithelial acantholysis without disruption of the basement membrane (show histology 1). Biopsy of a section of normal skin a few millimeters from an involved area should also be obtained for direct immunofluorescence, looking for deposits of IgG between epidermal cells. This second biopsy requires specimen placement in a special media (not formalin).
Enzyme-linked immunosorbent assay (ELISA) - Enzyme-linked immunosorbent assay (ELISA) is also useful for the diagnosis of pemphigus, and can assist with the identification of the pemphigus subtypes [19,20]. Patients with pemphigus foliaceus will exhibit serum positivity for antibodies against Dsg 1, but not Dsg 3. Individuals with pemphigus vulgaris with both mucosal and cutaneous features are typically positive for both Dsg 1 and Dsg 3 antibodies. Patients with mucosal-predominant pemphigus vulgaris often have an assay that is positive for only Dsg 3.
Measurements of circulating autoantibodies against Dsg in serum specimens correlate loosely with clinical activity and can be useful for gauging disease activity in some patients [21-24]. In one retrospective study assessing the predictive value of pemphigus antibodies, anti-Dsg 1 antibodies were more closely correlated with disease course than anti-Dsg 3 antibodies . Anti-Dsg 3 levels remained high during disease remissions in some patients with mucosal pemphigus vulgaris, suggesting that other confounding factors may be involved .
The differential diagnosis of pemphigus vulgaris includes:
- If mouth erosions predominate, consider herpes simplex virus, aphthae, lichen planus, or erythema multiforme.
- If widespread erosions predominate, consider pyoderma, impetigo, or other bullous diseases (eg, bullous pemphigoid, bullous drug eruptions).
Treatment - Before the introduction of systemic glucocorticoids, pemphigus vulgaris was associated with a high mortality rate . The current mortality rate with combination therapy including glucocorticoids and immunosuppressive drugs is approximately 5 percent, with most deaths due to drug-induced complications, including sepsis [28,29].
Patients should be referred to a dermatologist for initial consultation and management of the disease. Long-term follow-up is the rule; some patients require years to life-long suppressive therapy. A minority of patients (approximately 10 percent) achieve complete remission after initial treatment and do not need continued drug therapy; the majority require maintenance therapy to stay in remission .
Systemic glucocorticoids (eg, prednisone 1 mg/kg/day) are the mainstay of initial therapy in most patients with pemphigus vulgaris . Glucocorticoids diminish autoantibody production. The duration of treatment is variable; the drugs are tapered as soon as allowed depending upon patient response. Patients with very limited disease may respond to sublesional glucocorticoids (triamcinolone acetonide 5 to 10 mg/cc), while those with mild to moderate disease may derive benefit from lower doses of systemic glucocorticoids .
A number of "adjuvant" immunosuppressive agents have been studied in combination with glucocorticoid therapy in an effort to reduce the dose of the latter and thereby decrease complications . Combination therapy with a glucocorticoid-sparing agent is indicated if patients cannot be controlled within six months on relatively low doses of prednisone (eg, 5 to 10 mg daily to every other day).
Azathioprine (4 mg/kg/day) and cyclophosphamide (2 to 3 mg/kg/day) are commonly used as glucocorticoid-sparing agents [34-36]. Mycophenolate mofetil (2 g/day) has also been used successfully [37,38].
In one study, 13 of 29 patients (45 percent) with pemphigus vulgaris achieved complete remission with the combination of prednisone plus azathioprine and required no maintenance therapy, while 11 patients (38 percent) were clinically free of disease but still had circulating antibodies and required low-dose maintenance therapy . Side effects were rare and predominantly related to glucocorticoids. Only one death occurred due to disease with up to 16 years of follow-up.
A small randomized trial found similar efficacy and sparing when either azathioprine (2 mg/kg/day) or mycophenolate mofetil (1000 mg twice daily) was combined with methylprednisolone .
Dapsone has also been investigated as a glucocorticoid-sparing agent in a small trial showing possible benefit ; further investigation is indicated.
Refractory disease - Rituximab, alone or in combination with intravenous immunoglobulin (IVIG), appears to be an effective therapy for patients with refractory pemphigus vulgaris and pemphigus foliaceus [40-45]. Illustrative case series include:
- Combination therapy with rituximab and IVIG was given to 11 patients with pemphigus refractory to high dose prednisone tried in combination with at least three immunosuppressive agents; the patients also had at most a minimal or brief response to IVIG alone or in combination with other immunosuppressive medications . Four months of combination therapy with IVIG and rituximab led to sustained remissions in nine patients, and repeated courses of rituximab led to sustained remissions in the other two patients.
- A single cycle of rituximab alone appears to have similar efficacy to that seen with combination therapy. A multicenter study in 21 patients with refractory pemphigus vulgaris and pemphigus foliaceus administered four weekly treatments of rituximab 375 mg/m2 . At three months, 18 patients (86 percent) had a complete remission; two more patients achieved remission later (at 6 months and at one year). One patient failed therapy. Nine patients had relapses, of which seven were managed with topical or oral glucocorticoids and two which responded to a second cycle of rituximab.
Based on these case series, rituximab therapy appears to be the treatment of choice for patients with severe pemphigus vulgaris or foliaceus that is refractory to conventional therapy with systemic glucocorticoids and immunosuppressives .
Other potential options include methotrexate, dapsone, hydroxychloroquine, gold, and cyclosporine. Removal of circulating autoantibodies with plasmapheresis has been used in particularly aggressive cases . Intravenous immunoglobulin (IVIG) may be useful as monotherapy in patients who do not respond to glucocorticoids or who have contraindications to glucocorticoid use [48,49]. A randomized controlled trial with the primary endpoint measured as the duration of time patients could be maintained on the therapy protocol until symptoms required alternative treatment (time to escape treatment protocol) found that high dose IVIG (400 mg/kg/day) was an effective treatment for patients with glucocorticoid resistant pemphigus vulgaris and pemphigus foliaceus .
PEMPHIGUS FOLIACEUS - Pemphigus foliaceus occurs less commonly than pemphigus vulgaris in the United States and Europe, but is more prevalent in Africa . It is characterized by erythema, scaling, and crusting that first appears on the face and scalp (show picture 3), and later involves the chest and back (show picture 4). An endemic form, occurring in certain areas of Brazil, is called fogo selvagem; other endemic forms have been described as well . Histologically the lesions are more superficial so that erosions, rather than blisters, are typically observed. Unlike pemphigus vulgaris, mucous membrane involvement does not occur.
Pemphigus foliaceus is characterized predominantly by the presence of anti-Dsg 1 antibodies without anti-Dsg 3 [11,12]. This may explain the more superficial location of blistering histologically, since the most differentiated area of the epidermis is the only area in which Dsg 1 is critical for cell adhesion . The disease can be reproduced by injection of the pathogenic antibodies to mice [11,12]. Similar tissue specificity and histologic lesions are seen in bullous impetigo and scalded skin syndrome in which exfoliative toxin A, produced by Staphylococcus aureus, produces a proteolytic attack on desmoglein 1 .
Foliaceus may be drug-induced or drug-triggered. The latter term refers to unmasking of latent disease by a particular drug. The drugs most often implicated are penicillamine and other thiol (SH) compounds, including captopril, or drugs such as piroxicam that are metabolized to thiols . Penicillin and its derivatives, but not cephalosporins, also have been implicated . Treatment with topical imiquimod also appears able to induce pemphigus foliaceus [55,56].
Thiol-induced pemphigus can occur up to one year after beginning therapy. It presents as a superficial pemphigus with no mucosal involvement (pemphigus foliaceus) in 65 percent of cases, and is associated with antinuclear antibodies (ANA) in 25 percent . Spontaneous remission is common (35 percent of cases).
The diagnosis and treatment of pemphigus foliaceus are similar to that of pemphigus vulgaris (see "Treatment" above). Some mild cases of pemphigus foliaceus respond to topical glucocorticoids [57,58]. Most cases, however, require systemic glucocorticoids with or without immunosuppressive therapy, although often treatment can be less aggressive since overall morbidity and mortality are lower in this disease than in pemphigus vulgaris.
PARANEOPLASTIC PEMPHIGUS - Paraneoplastic pemphigus occurs in patients with a known or occult neoplasm . It is typically associated with lymphoreticular malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, Castleman's disease, thymoma, and Waldenstrom's macroglobulinemia [60,61]. A blistering disorder characterized as a paraneoplastic pemphigus-like phenomenon has also been described with the antineoplastic drug fludarabine .
Paraneoplastic pemphigus is associated with autoantibodies directed against both basement membrane and epithelial cell surface membranes . Patients form anti-Dsg 1 and anti-Dsg 3 antibodies, and also have pathogenic autoantibodies against plakin proteins .
Patients with paraneoplastic pemphigus often have severe mucocutaneous disease with ocular and oral blisters and skin lesions that resemble erythema multiforme, bullous pemphigoid, or lichen planus (show picture 5). This can be the initial presentation of malignancy or may occur in individuals with a known neoplastic process. A clue to the presence of paraneoplastic pemphigus in the former case is the presence of apparently severe oral pemphigus with atypical cutaneous findings.
The disease tends to be progressive and is often fatal within two years when associated with a malignant neoplasm . Treatment of the underlying malignancy does not influence the skin disease, although treatment of associated benign neoplasms (eg, thymoma, Castleman's disease [61,64]) does lead to resolution of paraneoplastic pemphigus.
Treatment of paraneoplastic pemphigus is similar to that for pemphigus vulgaris. Systemic glucocorticoids are the mainstay of therapy; combination therapy with cyclosporine or cyclophosphamide has also been used.
NIKOLSKY SIGN - The Nikolsky sign is a mechanical sign that involves the clinician applying pressure to skin causing an intraepidermal cleavage that allows the superficial skin to slip free from the deeper layers . There is some disagreement about the exact definition and method of eliciting a Nikolsky sign, and the term is often also applied to a subepidermal cleavage. We will use the term to refer to the presence of either depth of cleavage (a positive Nikolsky sign); this can be seen in various bullous diseases including pemphigus, bullous pemphigoid, toxic epidermal necrolysis, and staphylococcal scalded skin syndrome .
The clinician can attempt to elicit a Nikolsky sign either on normal skin or at the margin of a blister (show picture 6). A study involving 123 patients with blisters and erosions (26 of whom had pemphigus, including 21 with pemphigus vulgaris and 3 with pemphigus foliaceus) found that these two methods had differing sensitivity and specificity for pemphigus. A positive Nikolsky sign on normal skin had a sensitivity of 38 percent and specificity of 100 percent for pemphigus, while a positive Nikolsky sign at the margin of a blister had a sensitivity of 69 percent and a specificity of 94 percent . Four of 10 patients with bullous pemphigoid had a positive Nikolsky sign at the margin of a blister, but none had a positive Nikolsky sign on normal skin.
However, in typical clinical practice where the Nikolsky sign is both being elicited and interpreted by a provider with little or no experience with the sign, it is unlikely that it will have similar sensitivity and specificity to that seen in the above study .