What Caused This Patient’s Intense Pruritus?

Patient Presentation

An 80-year-old nursing home resident woman presented with a 6-month history of intermittent intense pruritus involving the trunk and extremities followed by an eruption of blisters on the palms and soles. The patient’s medical history was significant for coronary artery disease but no previous skin diseases. Her family history was non-contributory. No other residents at the nursing home had similar symptoms. A review of her list of medications did not suggest a potential role in the blistering process. On examination, multiple tense bullae ranging from 1 cm to 3 cm in size were noted on her palms, soles and shins, on an erythematous base, with a few crusted lesions, without signs of scarring. Examination of other systems was unremarkable. Scabies preparations were negative, and laboratory results revealed an elevated eosinophil count of 1200 cells/mm3. A skin biopsy was taken from a representative lesion.

What is Your Diagnosis?

Diagnosis: Bullous Pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune sub-epidermal blistering disease of the skin.¹ It was first described as a distinct disorder by Lever.² BP is primarily a disease of the elderly, usually occurring after the age of 60. It has an incidence of at least six to seven new cases per million in the general population, with an apparent predominance in men.³ A Look at BP

Antigens and HLA Subtypes

BP is an autoantibody-mediated disease, where the antibodies bind to the basement membrane zone and activate complement. The same immunopathological mechanisms are implicated in both localized and generalized BP.⁴ The antibodies target two key hemidesmosomal proteins, the NC16A domain of BP180 (BPAG2) and BP230 (BPAG1).⁵ It has been established that rabbit polyclonal antibodies directed against BP 180 fusion protein can reproduce the clinical, histologic and immunopathologic features of BP when injected into neonatal mice.⁶ Very recently, this has also been demonstrated for antibodies against BP230.⁷ The NC16A domain harbors key epitopes of autoantibodies on T cells, indicating that it plays an essential pathogenic role.⁵ Serum levels of autoantibodies to BP180 NC16A have been shown to parallel the disease activity in BP patients.⁸ Studies sequencing specific genotype polymorphism in HLA-DR and DQ have identified DRB1*0301 in Caucasian patients, and DRB1*04, DRB1*1101 and DQB1*0302 in Japanese patients. Ethnic differences in the polymorphic composition of the HLA-DR and DQ genes may influence genetic susceptibility to BP.⁹

Clinical Features and Variants of BP

The cutaneous manifestations of BP are variable. The French study group for bullous disease^10,11 proposed a set of four clinical criteria for the diagnosis of BP. These criteria are:

• age greater than 70 years
• absence of atrophic scars
• absence of mucosal involvement
• absence of predominant bullous lesions on the head and neck.

According to the authors, if three of these four characteristics were present, a diagnosis of BP could be made with a sensitivity of 90% and a specificity of 83%. These predictive values were calculated on a sample of 70 new cases. A minority of patients may present with only localized lesions, usually on the lower legs.¹² The disease may become generalized or may remain localized.¹³ Mucous membranes are involved in up to 50% of patients, with the oral mucosa most frequently affected.¹ Oral lesions consist of small blisters or erosions and are found mainly on the palatal mucosa. BP may begin with a prodromal non-bullous phase in which pruritus, excoriations, eczematous change and urticarial lesions may be the only signs of the disease.¹⁴ The characteristic clinical picture is the development of tense blisters on healthy skin or on an erythematous base, typically found on the flexural surfaces of the arms and legs, axillae, groin and abdomen.¹⁵ Vegetating plaques may occasionally be found in the intertriginous zones.¹⁴ Blisters are usually 1 cm to 4 cm in size, contain clear fluid, and may be accompanied by urticarial and infiltrated papules and plaques that occasionally assume an annular or figurate pattern. The degree of itch varies from none to intense and may precede the appearance of blisters by weeks, months or occasionally years.¹ Several clinical variants of BP have been described. These variants include pretibial pemphigoid, dyshidrosiform pemphigoid with isolated palmoplantar involvement, vesicular pemphigoid mimicking dermatitis herpetiformis, and pemphigoid nodularis mimicking prurigo nodularis. Other variants include gestational pemphigoid, which usually occurs in late pregnancy, childhood BP, vulvar childhood pemphigoid and erythrodermic BP.¹⁴

Histology, Immunofluorescence and More for Diagnosis

The diagnosis of BP is made on the basis of the clinical presentation, histology and immunofluorescence microscopy (IF). IF is the most reliable investigation for making the diagnosis.¹⁶ Histology shows subepidermal blistering with many infiltrating polymorphonuclear cells along the basement membrane and within the blister cavity. Eosinophils are prominent in the infiltrate, and early urticarial lesions may show only intracellular edema of the epidermis with diffuse eosinophilic infiltration, a finding called eosinophilic spongiosis.¹⁷ Direct IF of perilesional skin reveals linear deposits of IgG and C3 at the basement membrane. Indirect IF shows circulating autoantibodies in the sera of 60% to 80% of patients. These antibodies typically bind to the epidermal side of the salt-split skin.¹⁸ More sensitive ELISA techniques increase the frequency of detection.¹⁹ BP may also be associated with a peripheral eosinophilia.²⁰

Differential Diagnosis

Clinical diagnosis of BP can sometimes be difficult. The non-bullous phase of BP has no clear distinguishing feature, and may be mistaken for contact dermatitis, drug reaction, vasculitis, prurigo and scabies. The bullous phase may be mistaken for several blistering diseases such as epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, bullous drug eruption, linear IgA bullous dermatosis, dermatitis herpetiformis and cicatricial pemphigoid.¹³ As opposed to BP, cicatricial pemphigoid usually manifests clinical activity predominantly on mucous membranes.

Management

The goals of treatment in BP are to prevent the appearance of new lesions and to heal existing lesions. Before a therapeutic choice is made, it is important to consider the extent of involvement, patient age and other co-morbid factors.²¹ In a recent study, superpotent topical glucocorticoid (clobetasol propionate) therapy was effective for moderate and severe BP and was superior to oral corticosteroid therapy for extensive disease.²² A total of 341 patients with BP were enrolled in a randomized, multicenter trial and stratified according to the severity of their disease. Patients were randomly assigned to receive either topical clobetasol propionate cream (Cormax, Temovate) (40 g per day) or oral prednisone (0.5-1mg/kg/day). The primary endpoint was overall survival, and the mean duration of follow-up was 360 days in the oral-prednisone group and 359 days in the topical corticosteroid group.²² Patients with more than 40% involvement of their body surface will probably need systemic corticosteroids.²³ The most commonly used systemic agent is prednisone at a dose of 0.5 mg/kg/day to 1 mg/kg/day, which in most cases is sufficient as monotherapy. The clinical response, indicated by healing of existing lesions and cessation of new blister formation, is usually obtained within 1 to 4 weeks. The dose can then be gradually tapered off.²¹ Patients who require high doses of steroids, or develop side effects are considered for immunosuppressive therapy. The most commonly used agents include azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan, Neosar) and mycophenolate mofetil (CellCept); azathioprine is the best established agent, followed by methotrexate.¹⁶ Mycophe-nolate mofetil has also been used successfully as adjuvant corticosteroid-sparing therapy and monotherapy, and is generally well tolerated.²⁴ The dose of these drugs is decreased after remission, and ultimately discontinued.²¹ Plasmapheresis has been employed in some severe cases,²⁵ but should be used in conjunction with immunosuppressive therapy, as a rebound rise in autoantibody titer frequently occurs. Intravenous immunoglobulin appears to be a promising agent, especially for patients who are not responding to conventional therapy. In a recent review, 12 of 17 patients had a clinical benefit.²⁶ Other agents that have been shown effective include dapsone,²⁷ erythromycin²⁸ and tetracyclines.²⁹ Tetracyclines with or without niacinamide can be used as a steroid-sparing drug; they can also be used in combination with prednisone. Colchicine, cyclosporine, chlorambucil, and extracorporeal photochemotherapy have also been used.²¹ A recent case report demonstrated a potential therapeutic role of etanercept, a TNF antagonist, in BP.³⁰

Prognosis

The natural history of both treated and untreated BP shows a long-term course within which relapses and exacerbations may occur. The estimated death rate during the first year varies between 10% and 40%, depending on the series.^15,31 Mortality may also reflect side effects related to treatment. However, in most patients, the disease was in remission within 5 years.¹⁶ Our patient was initially treated with topical steroids, but was lost to follow-up.

Patient Presentation

An 80-year-old nursing home resident woman presented with a 6-month history of intermittent intense pruritus involving the trunk and extremities followed by an eruption of blisters on the palms and soles. The patient’s medical history was significant for coronary artery disease but no previous skin diseases. Her family history was non-contributory. No other residents at the nursing home had similar symptoms. A review of her list of medications did not suggest a potential role in the blistering process. On examination, multiple tense bullae ranging from 1 cm to 3 cm in size were noted on her palms, soles and shins, on an erythematous base, with a few crusted lesions, without signs of scarring. Examination of other systems was unremarkable. Scabies preparations were negative, and laboratory results revealed an elevated eosinophil count of 1200 cells/mm3. A skin biopsy was taken from a representative lesion.

What is Your Diagnosis?

Diagnosis: Bullous Pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune sub-epidermal blistering disease of the skin.¹ It was first described as a distinct disorder by Lever.² BP is primarily a disease of the elderly, usually occurring after the age of 60. It has an incidence of at least six to seven new cases per million in the general population, with an apparent predominance in men.³ A Look at BP

Antigens and HLA Subtypes

BP is an autoantibody-mediated disease, where the antibodies bind to the basement membrane zone and activate complement. The same immunopathological mechanisms are implicated in both localized and generalized BP.⁴ The antibodies target two key hemidesmosomal proteins, the NC16A domain of BP180 (BPAG2) and BP230 (BPAG1).⁵ It has been established that rabbit polyclonal antibodies directed against BP 180 fusion protein can reproduce the clinical, histologic and immunopathologic features of BP when injected into neonatal mice.⁶ Very recently, this has also been demonstrated for antibodies against BP230.⁷ The NC16A domain harbors key epitopes of autoantibodies on T cells, indicating that it plays an essential pathogenic role.⁵ Serum levels of autoantibodies to BP180 NC16A have been shown to parallel the disease activity in BP patients.⁸ Studies sequencing specific genotype polymorphism in HLA-DR and DQ have identified DRB1*0301 in Caucasian patients, and DRB1*04, DRB1*1101 and DQB1*0302 in Japanese patients. Ethnic differences in the polymorphic composition of the HLA-DR and DQ genes may influence genetic susceptibility to BP.⁹

Clinical Features and Variants of BP

The cutaneous manifestations of BP are variable. The French study group for bullous disease^10,11 proposed a set of four clinical criteria for the diagnosis of BP. These criteria are:

• age greater than 70 years
• absence of atrophic scars
• absence of mucosal involvement
• absence of predominant bullous lesions on the head and neck.

According to the authors, if three of these four characteristics were present, a diagnosis of BP could be made with a sensitivity of 90% and a specificity of 83%. These predictive values were calculated on a sample of 70 new cases. A minority of patients may present with only localized lesions, usually on the lower legs.¹² The disease may become generalized or may remain localized.¹³ Mucous membranes are involved in up to 50% of patients, with the oral mucosa most frequently affected.¹ Oral lesions consist of small blisters or erosions and are found mainly on the palatal mucosa. BP may begin with a prodromal non-bullous phase in which pruritus, excoriations, eczematous change and urticarial lesions may be the only signs of the disease.¹⁴ The characteristic clinical picture is the development of tense blisters on healthy skin or on an erythematous base, typically found on the flexural surfaces of the arms and legs, axillae, groin and abdomen.¹⁵ Vegetating plaques may occasionally be found in the intertriginous zones.¹⁴ Blisters are usually 1 cm to 4 cm in size, contain clear fluid, and may be accompanied by urticarial and infiltrated papules and plaques that occasionally assume an annular or figurate pattern. The degree of itch varies from none to intense and may precede the appearance of blisters by weeks, months or occasionally years.¹ Several clinical variants of BP have been described. These variants include pretibial pemphigoid, dyshidrosiform pemphigoid with isolated palmoplantar involvement, vesicular pemphigoid mimicking dermatitis herpetiformis, and pemphigoid nodularis mimicking prurigo nodularis. Other variants include gestational pemphigoid, which usually occurs in late pregnancy, childhood BP, vulvar childhood pemphigoid and erythrodermic BP.¹⁴

Histology, Immunofluorescence and More for Diagnosis

The diagnosis of BP is made on the basis of the clinical presentation, histology and immunofluorescence microscopy (IF). IF is the most reliable investigation for making the diagnosis.¹⁶ Histology shows subepidermal blistering with many infiltrating polymorphonuclear cells along the basement membrane and within the blister cavity. Eosinophils are prominent in the infiltrate, and early urticarial lesions may show only intracellular edema of the epidermis with diffuse eosinophilic infiltration, a finding called eosinophilic spongiosis.¹⁷ Direct IF of perilesional skin reveals linear deposits of IgG and C3 at the basement membrane. Indirect IF shows circulating autoantibodies in the sera of 60% to 80% of patients. These antibodies typically bind to the epidermal side of the salt-split skin.¹⁸ More sensitive ELISA techniques increase the frequency of detection.¹⁹ BP may also be associated with a peripheral eosinophilia.²⁰

Differential Diagnosis

Clinical diagnosis of BP can sometimes be difficult. The non-bullous phase of BP has no clear distinguishing feature, and may be mistaken for contact dermatitis, drug reaction, vasculitis, prurigo and scabies. The bullous phase may be mistaken for several blistering diseases such as epidermolysis bullosa acquisita, bullous systemic lupus erythematosus, bullous drug eruption, linear IgA bullous dermatosis, dermatitis herpetiformis and cicatricial pemphigoid.¹³ As opposed to BP, cicatricial pemphigoid usually manifests clinical activity predominantly on mucous membranes.

Management

The goals of treatment in BP are to prevent the appearance of new lesions and to heal existing lesions. Before a therapeutic choice is made, it is important to consider the extent of involvement, patient age and other co-morbid factors.²¹ In a recent study, superpotent topical glucocorticoid (clobetasol propionate) therapy was effective for moderate and severe BP and was superior to oral corticosteroid therapy for extensive disease.²² A total of 341 patients with BP were enrolled in a randomized, multicenter trial and stratified according to the severity of their disease. Patients were randomly assigned to receive either topical clobetasol propionate cream (Cormax, Temovate) (40 g per day) or oral prednisone (0.5-1mg/kg/day). The primary endpoint was overall survival, and the mean duration of follow-up was 360 days in the oral-prednisone group and 359 days in the topical corticosteroid group.²² Patients with more than 40% involvement of their body surface will probably need systemic corticosteroids.²³ The most commonly used systemic agent is prednisone at a dose of 0.5 mg/kg/day to 1 mg/kg/day, which in most cases is sufficient as monotherapy. The clinical response, indicated by healing of existing lesions and cessation of new blister formation, is usually obtained within 1 to 4 weeks. The dose can then be gradually tapered off.²¹ Patients who require high doses of steroids, or develop side effects are considered for immunosuppressive therapy. The most commonly used agents include azathioprine (Imuran), methotrexate, cyclophosphamide (Cytoxan, Neosar) and mycophenolate mofetil (CellCept); azathioprine is the best established agent, followed by methotrexate.¹⁶ Mycophe-nolate mofetil has also been used successfully as adjuvant corticosteroid-sparing therapy and monotherapy, and is generally well tolerated.²⁴ The dose of these drugs is decreased after remission, and ultimately discontinued.²¹ Plasmapheresis has been employed in some severe cases,²⁵ but should be used in conjunction with immunosuppressive therapy, as a rebound rise in autoantibody titer frequently occurs. Intravenous immunoglobulin appears to be a promising agent, especially for patients who are not responding to conventional therapy. In a recent review, 12 of 17 patients had a clinical benefit.²⁶ Other agents that have been shown effective include dapsone,²⁷ erythromycin²⁸ and tetracyclines.²⁹ Tetracyclines with or without niacinamide can be used as a steroid-sparing drug; they can also be used in combination with prednisone. Colchicine, cyclosporine, chlorambucil, and extracorporeal photochemotherapy have also been used.²¹ A recent case report demonstrated a potential therapeutic role of etanercept, a TNF antagonist, in BP.³⁰

Prognosis

The natural history of both treated and untreated BP shows a long-term course within which relapses and exacerbations may occur. The estimated death rate during the first year varies between 10% and 40%, depending on the series.^15,31 Mortality may also reflect side effects related to treatment. However, in most patients, the disease was in remission within 5 years.¹⁶ Our patient was initially treated with topical steroids, but was lost to follow-up.