Diagnosis and Treatment of Pemphigus
Diagnosis and Treatment of Pemphigus
Issues to be addressed when evaluating a patient for pemphigus include the age of onset, previous clinical symtoms, initial presentation, presence of mucous membrane symptoms and the presence of Nikolsky's phenomenon.
Pemphigus Vulgaris At the initial stage, most patients only show oral mucosal lesions. Thus, a diagnosis of pemphigus vulgaris should be strongly considered in patients presenting with stubborn oral mucosal lesions. In addition to oral mucosal symptoms, patients with the mucocutaneous type of pemphigus vulgaris show skin symptoms including flaccid bullae and erosions. The involvement of the esophagus, conjunctiva, nasal mucosa, vagina, labia, penis and anus is also observed in the mucocutaneous type of pemphigus vulgaris. In the mucosal-dominant type of pemphigus vulgaris, there is only oral mucosal erosion, while in mucocutaneous type of pemphigus vulgaris, flaccid blisters and erosions involve both the skin and oral mucosa (Figure 2A).
Pemphigus Foliaceus The clinical symptom of pemphigus foliaceus is fingernail-sized erythemas with scales and crusts associated with relatively superficial bullae and erosion, particularly on the sebaceous areas. Normally, there are no mucosal lesions (Figure 2B).
(Enlarge Image)
Figure 2.
Characteristics of pemphigus vulgaris and pemphigus foliaceus.
(A) Clinical appearance of pemphigus vulgaris. (B) Clinical appearance of pemphigus foliaceus. (C) Histopathological feature of pemphigus vulgaris. (D) Histopathological feature of pemphigus foliaceus. (E) Direct immunofluorescence staining of pemphigus vulgaris. (F) Direct immunofluorescence staining of pemphigus foliaceus.
Pemphigus Vegetans Pemphigus vegetans is a rare variant of pemphigus vulgaris. It occurs on the skin folds, including the axillary, inguinal, perianal, mammary, umbilical and scalp areas. There are two subtypes for pemphigus vegetans. Neumann-type pemphigus vegetans initially presents with bullae and erosions, which then become proliferative. Hallopeau-type pemphigus vegetans starts with pustules on the intertriginous regions, and after that it develops proliferative lesions. Neumann-type pemphigus vegetans is more proliferative and intractable than Hallopeau-type pemphigus vegetans.
Pemphigus Erythematosus Pemphigus erythematosus is a limited type of pemphigus foliaceus, which is clinically characterized by a butterfly rash on the face.
Pemphigus Herpetiformis Pemphigus herpetiformis is considered to be a distinct entity. The clinical characteristics are annularly arranged small vesicles with pruritic erythemas, which clinically mimic dermatitis herpetiformis or bullous pemphigoid. Immunohistochemically, it shows a pemphigus-like IgG deposition pattern.
IgA Pemphigus Clinically, IgA pemphigus presents annular erythemas with minimal blisters or vesicles arranged at the periphery, mimicking pemphigus herpetiformis or dermatitis herpetiformis. IgA pemphigus is subdivided into subcorneal pustular dermatosis (SPD)-type and intraepidermal neutrophilic IgA dermatosis (IEN)-type. The antigen of SPD-type IgA pemphigus is desmocollin-1, while the antigen of IEN-type IgA pemphigus is still unknown.
Paraneoplastic Pemphigus Paraneoplastic pemphigus classically presents intractable oral mucosal lesions and pseudomembranous conjunctivitis. The skin lesions of paraneoplastic pemphigus are variable, including erythemas, flaccid bullae, tense bullae, erosions, erythema multiforme-like skin lesions and lichen planus-like skin lesions. The associated internal tumors are mostly hematological, particularly Castleman's disease and lymphomas, but are sometimes gastrointestinal, lung or breast cancers. Bronchiolitis obliterans is frequently associated with paraneoplastic pemphigus and is a poor prognostic factor.
Diagnosis is made by clinical appearance, histopathology, direct and indirect immunofluorescence, and serological tests including ELISA or immunoblotting. Severity is assessed by the pemphigus disease activity index (PDAI). In the PDAI, the areas affected are categorized as the skin, scalp and mucous membranes, and these are further divided them into 12 skin sites, one scalp site and 12 mucous membrane sites. Next, 1, 2, 3, 5 or 10 points are allocated to each site. The PDAI is notable for its detailed division of body sites with higher score signifying more severe disease. The PDAI has a score range of 0–250, allowing sensitive assessment of disease activity. The PDAI is an objective scoring system for pemphigus, just as Psoriasis Area and Severity Index for psoriasis. Therefore, it does not include analysis of Nikolsky's phenomenon, direct or indirect immunofluorescence or ELISA.
Histopathologic findings of pemphigus lesions are acantholysis and cleft formation in the epidermis. In pemphigus vulgaris, cleft formation is observed at the suprabasal layer of the epidermis; whereas, in pemphigus foliaceus, cleft formation is observed at the granular layer (Figure 2C & 2D). In pemphigus vulgaris, cell–cell adhesion is disrupted at the basal layer while the basement membrane zone is intact, resulting in the 'row of tombstones' appearance. Pemphigus vegetans shows epidermal hyperplasia and eosinophilic/neutrophilic pustules in addition to cleft formation. Pemphigus herpetiformis shows faint acantholysis and eosinophilic spongiosis. The histopathology of paraneoplastic pemphigus is variable, including acantholysis, intraepidermal blisters, lichenoid change and vacuolar change.
Direct immunofluorescence for all types of IgG class pemphigus shows IgG deposition at the cell surface of epidermal keratinocytes (Figure 2E & 2F). In IgA pemphigus, IgA is deposited at the cell surface of epidermal keratinocytes. Indirect immunofluorescence of patient sera shows circulating IgG anti-keratinocyte cell surface antibodies.
ELISA of recombinant proteins of Dsg1 and Dsg3 for IgG antibodies shows that mucosal-dominant type of pemphigus vulgaris reacts only with Dsg3; mucocutaneous type of pemphigus vulgaris reacts with both Dsg1 and Dsg3; and pemphigus foliaceus and pemphigus erythematosus react with Dsg1. The ELISA titer usually parallels clinical severity; therefore, ELISA titer can be used to evaluate treatment efficacy.
The role of anti-Dsg1 or anti-Dsg3 antibodies in the pathogenesis of paraneoplastic pemphigus, pemphigus vegetans or pemphigus herpetiformis is not yet known. Reportedly, 80% of pemphigus herpetiformis patients react with Dsg1 and 20% react with Dsg3. Autoantibodies to non-Dsg antigens, including desmocollins and various plakin proteins, are detected by immunoblotting or immunoprecipitation using epidermal extracts or recombinant proteins. Antidesmocollin antibodies are detected by indirect immunofluorescence using desmocollin-encoding vector-transfected COS-7 cells. With these techniques, paraneoplastic pemphigus or pemphigus herpetiformis can be diagnosed.
Diagnosis of Pemphigus
Patient History
Issues to be addressed when evaluating a patient for pemphigus include the age of onset, previous clinical symtoms, initial presentation, presence of mucous membrane symptoms and the presence of Nikolsky's phenomenon.
Clinical Diagnosis
Pemphigus Vulgaris At the initial stage, most patients only show oral mucosal lesions. Thus, a diagnosis of pemphigus vulgaris should be strongly considered in patients presenting with stubborn oral mucosal lesions. In addition to oral mucosal symptoms, patients with the mucocutaneous type of pemphigus vulgaris show skin symptoms including flaccid bullae and erosions. The involvement of the esophagus, conjunctiva, nasal mucosa, vagina, labia, penis and anus is also observed in the mucocutaneous type of pemphigus vulgaris. In the mucosal-dominant type of pemphigus vulgaris, there is only oral mucosal erosion, while in mucocutaneous type of pemphigus vulgaris, flaccid blisters and erosions involve both the skin and oral mucosa (Figure 2A).
Pemphigus Foliaceus The clinical symptom of pemphigus foliaceus is fingernail-sized erythemas with scales and crusts associated with relatively superficial bullae and erosion, particularly on the sebaceous areas. Normally, there are no mucosal lesions (Figure 2B).
(Enlarge Image)
Figure 2.
Characteristics of pemphigus vulgaris and pemphigus foliaceus.
(A) Clinical appearance of pemphigus vulgaris. (B) Clinical appearance of pemphigus foliaceus. (C) Histopathological feature of pemphigus vulgaris. (D) Histopathological feature of pemphigus foliaceus. (E) Direct immunofluorescence staining of pemphigus vulgaris. (F) Direct immunofluorescence staining of pemphigus foliaceus.
Pemphigus Vegetans Pemphigus vegetans is a rare variant of pemphigus vulgaris. It occurs on the skin folds, including the axillary, inguinal, perianal, mammary, umbilical and scalp areas. There are two subtypes for pemphigus vegetans. Neumann-type pemphigus vegetans initially presents with bullae and erosions, which then become proliferative. Hallopeau-type pemphigus vegetans starts with pustules on the intertriginous regions, and after that it develops proliferative lesions. Neumann-type pemphigus vegetans is more proliferative and intractable than Hallopeau-type pemphigus vegetans.
Pemphigus Erythematosus Pemphigus erythematosus is a limited type of pemphigus foliaceus, which is clinically characterized by a butterfly rash on the face.
Pemphigus Herpetiformis Pemphigus herpetiformis is considered to be a distinct entity. The clinical characteristics are annularly arranged small vesicles with pruritic erythemas, which clinically mimic dermatitis herpetiformis or bullous pemphigoid. Immunohistochemically, it shows a pemphigus-like IgG deposition pattern.
IgA Pemphigus Clinically, IgA pemphigus presents annular erythemas with minimal blisters or vesicles arranged at the periphery, mimicking pemphigus herpetiformis or dermatitis herpetiformis. IgA pemphigus is subdivided into subcorneal pustular dermatosis (SPD)-type and intraepidermal neutrophilic IgA dermatosis (IEN)-type. The antigen of SPD-type IgA pemphigus is desmocollin-1, while the antigen of IEN-type IgA pemphigus is still unknown.
Paraneoplastic Pemphigus Paraneoplastic pemphigus classically presents intractable oral mucosal lesions and pseudomembranous conjunctivitis. The skin lesions of paraneoplastic pemphigus are variable, including erythemas, flaccid bullae, tense bullae, erosions, erythema multiforme-like skin lesions and lichen planus-like skin lesions. The associated internal tumors are mostly hematological, particularly Castleman's disease and lymphomas, but are sometimes gastrointestinal, lung or breast cancers. Bronchiolitis obliterans is frequently associated with paraneoplastic pemphigus and is a poor prognostic factor.
Clinical Score
Diagnosis is made by clinical appearance, histopathology, direct and indirect immunofluorescence, and serological tests including ELISA or immunoblotting. Severity is assessed by the pemphigus disease activity index (PDAI). In the PDAI, the areas affected are categorized as the skin, scalp and mucous membranes, and these are further divided them into 12 skin sites, one scalp site and 12 mucous membrane sites. Next, 1, 2, 3, 5 or 10 points are allocated to each site. The PDAI is notable for its detailed division of body sites with higher score signifying more severe disease. The PDAI has a score range of 0–250, allowing sensitive assessment of disease activity. The PDAI is an objective scoring system for pemphigus, just as Psoriasis Area and Severity Index for psoriasis. Therefore, it does not include analysis of Nikolsky's phenomenon, direct or indirect immunofluorescence or ELISA.
Histopathology
Histopathologic findings of pemphigus lesions are acantholysis and cleft formation in the epidermis. In pemphigus vulgaris, cleft formation is observed at the suprabasal layer of the epidermis; whereas, in pemphigus foliaceus, cleft formation is observed at the granular layer (Figure 2C & 2D). In pemphigus vulgaris, cell–cell adhesion is disrupted at the basal layer while the basement membrane zone is intact, resulting in the 'row of tombstones' appearance. Pemphigus vegetans shows epidermal hyperplasia and eosinophilic/neutrophilic pustules in addition to cleft formation. Pemphigus herpetiformis shows faint acantholysis and eosinophilic spongiosis. The histopathology of paraneoplastic pemphigus is variable, including acantholysis, intraepidermal blisters, lichenoid change and vacuolar change.
Immunological Findings
Direct immunofluorescence for all types of IgG class pemphigus shows IgG deposition at the cell surface of epidermal keratinocytes (Figure 2E & 2F). In IgA pemphigus, IgA is deposited at the cell surface of epidermal keratinocytes. Indirect immunofluorescence of patient sera shows circulating IgG anti-keratinocyte cell surface antibodies.
ELISA of recombinant proteins of Dsg1 and Dsg3 for IgG antibodies shows that mucosal-dominant type of pemphigus vulgaris reacts only with Dsg3; mucocutaneous type of pemphigus vulgaris reacts with both Dsg1 and Dsg3; and pemphigus foliaceus and pemphigus erythematosus react with Dsg1. The ELISA titer usually parallels clinical severity; therefore, ELISA titer can be used to evaluate treatment efficacy.
The role of anti-Dsg1 or anti-Dsg3 antibodies in the pathogenesis of paraneoplastic pemphigus, pemphigus vegetans or pemphigus herpetiformis is not yet known. Reportedly, 80% of pemphigus herpetiformis patients react with Dsg1 and 20% react with Dsg3. Autoantibodies to non-Dsg antigens, including desmocollins and various plakin proteins, are detected by immunoblotting or immunoprecipitation using epidermal extracts or recombinant proteins. Antidesmocollin antibodies are detected by indirect immunofluorescence using desmocollin-encoding vector-transfected COS-7 cells. With these techniques, paraneoplastic pemphigus or pemphigus herpetiformis can be diagnosed.
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