Ehrsam E

Sarcoidosis initially was described by Sir Jonathan Hutchinson in 1875, and cutaneous sarcoidosis (lupus pernio) was described by Besnier 1 in 1899. Sarcoidosis is a multisystem disease that may involve almost any organ system and, therefore, may present with various clinical manifestations.2 Cutaneous sarcoidosis occurs in up to one third of patients with systemic sarcoidosis. Recognition of cutaneous lesions is important because the lesions provide a visible clue to the diagnosis and are an easily accessible source of tissue for histologic examination.3 Because lesions can exhibit many different morphologies, cutaneous sarcoidosis is known as one of the "great imitators" in dermatology.4 Lesions of cutaneous sarcoidosis also can appear in preexisting scars, a condition known as scar sarcoidosis.5 The latter condition may be caused by mechanical trauma such as venipuncture, scars caused by infection such as herpes zoster,6 and tattoos.7 Treatment of cutaneous lesions can be frustrating. For patients with widespread disease, the most effective treatment is systemic glucocorticoids. The prognosis of sarcoidosis usually is good, in particular, if the condition predominantly or solely affects the skin.8 

Case Report
A 34-year-old man presented with a progressively enlarging lesion on his left calf. He reported that about 3 months prior he had developed a small ulceration at this location following a fall. With local wound care, the ulceration healed with a scar. The scar, however, continued to grow beyond the borders of the previous ulceration and became raised with violaceous discoloration. The patient denied any history of excessive scarring or keloid formation after skin surgeries or trauma. There were no personal or family histories of granulomatous diseases. Results of a physical examination showed an erythematous-to-dusky plaque measuring approximately 4X3 cm (Figure 1) on the left calf with well-defined irregular borders and discrete papules on the internal aspect of the knee. No tender nodules on the shins were noticed, and no lymphadenopathy was present. Results from a review of systems and a routine chest x-ray were unremarkable. Results of a punch biopsy revealed changes consistent with sarcoid naked granulomas (Figure 2). The patient was started on topical potent corticosteroid tapes and experienced marked improvement.

Comment

Sarcoidosis occurs more frequently in females than in males, with reported ratios as high as 5:1. In the United States, black individuals are affected 3 to 4 times more often than white individuals.9 Sarcoidosis is found worldwide and in every race, though the incidence varies dramatically. In Europe, the disease affects white individuals more commonly than other races, and it affects Western Europeans more than Eastern Europeans. People from Scandinavia have one of the highest incidence rates at 64 cases per 100,000 population; in Poland, the incidence is 3 cases per 100,000 population. The disease is rare in Eskimos, Southeast Asians, New Zealand Maoris, and native Canadian populations.10,11 The difference in prevalence among certain populations in varying geographic locations suggests that ethnic susceptibility factors, as well as environmental factors, contribute to the etiology of sarcoidosis.11 Sarcoidosis is a multisystem disorder characterized by noncaseating, naked, epithelioid granulomas and commonly involves the hilar lymph nodes, lungs, skin, and eyes. The frequency of skin involvement in sarcoidosis is 10% to 30% of all cases, but the prevalence of particular types of cutaneous lesions varies among races, as well as among individual cases.12 Clinically, there is spontaneous development of livid or reddish-brown plaques on scars that were previously and mostly atrophic; this phenomenon occurs at varying intervals. Therefore, sarcoidosis should be considered in the differential diagnosis of an enlarging previously inactive scar. Lesions can develop in scars caused by mechanical trauma, such as in Kveim test sites, tuberculin test sites,5 sites that have received hyaluronic acid injection for wrinkles,13 sites of cosmetic tattoos,¹⁴ sites of previous laser surgery,15 and sites used for desensitization injections.16 Scar sarcoidosis has been reported following herpes zoster infection.17 Correctly diagnosing sarcoidosis may be a challenge. Unfortunately, no single test can lead to diagnosis of the condition. Patients are diagnosed with sarcoidosis when a compatible clinical or radiologic picture is present, along with histologic evidence of noncaseating granulomas, and when other potential causes, such as infections, are excluded. Cutaneous sarcoidosis varies greatly in its clinical presentation and has been labeled as one of the great dermatologic masqueraders.4,18 Maculopapular lesions can appear as xanthelasma, acne rosea, lupus erythematosus, or adenoma sebaceum. The differential diagnoses of plaques include lupus vulgaris, necrobiosis lipoidica, leprosy, leishmaniasis, psoriasis, and discoid lupus.4,18 The etiology of sarcoidosis is unknown, but several immune aberrations have been noted and are thought to play a role in its pathogenesis.19 Immune dysregulation has been theorized to result from a persistent antigen of low virulence that is poorly cleared by the immune system, leading to a chronic T cell of the TH1 subtype response and causing granuloma formation. Proposed antigens fall into 3 categories that include infectious, environmental, and autoantigens.20 The most common infectious agents implicated are Mycobacterium tuberculosis, Mycoplasma species, Corynebacterium species, spirochetes, atypical mycobacteria, Propionibacterium acnes, Borrelia burgdorferi, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, coxsackievirus, rubella virus, Histoplasma species, Cryptococcus species, coccidioidomycosis, and sporotrichosis.21 Environmental antigens implicated include metals (eg, zirconium, aluminum, beryllium), organic dusts (eg, pine, pollen), inorganic dusts (eg, clay, soil, talc), and autoantigens (AV 2S3+ and HLA-DR17+).22 Genetic factors also are thought to play a role in the disease process.23 Familial clustering of cases has been reported. Monozygotic twins are 2 to 4 times more likely to have the disease than dizygotic twins.23 Certain HLA associations have been demonstrated; the most common allele found in sarcoidosis is HLA-B8. Other associated alleles include HLA-A1 and HLA-DR3.24 Most authors divide cutaneous lesions into specific and nonspecific categories.25 Specific skin lesions display noncaseating granulomas on biopsy. Nonspecific skin lesions display no granulomas on biopsy. Scar sarcoidosis is a specific form of cutaneous sarcoidosis in which old scars become infiltrated with noncaseating epithelioid cell granulomas. Typical sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no necrosis. Granulomas usually are in the superficial dermis but may involve the full thickness of the dermis and extend to the subcutaneous tissue. Islands of epithelioid cells may have a few Langerhans giant cells.25 Giant cells may contain asteroid or Schaumann bodies; asteroid bodies are star-shaped eosinophilic structures; and Schaumann bodies are round or oval laminated structures that usually are calcified at the periphery.26 Granulomas are referred to as naked because they have only a sparse lymphocytic infiltrate at the margins of the granulomas. Fibrosis, if present, usually starts at the periphery and advances toward the center.26 The treatment of cutaneous sarcoidosis often is frustrating, and the condition often is refractory to therapy or recurs following successful treatment. Therapeutic approaches range from topical, intralesional, and systemic use of corticosteroids to systemic medications such as cytostatic drugs, chloroquine,27 allopurinol (300 mg/d),28 and thalidomide.29 For localized involvement of cutaneous sarcoidosis, topical or intralesional steroids are used. Physicians frequently use superpotent topical corticosteroids because the drugs occasionally are effective.30-32 However, the corticosteroid often does not adequately penetrate the skin lesion. Intralesional corticosteroids (eg, triamcinolone acetonide in a dose of 5 mg/mL) typically are more effective, with injections repeated at 2- to 3-week intervals.30,31 Alternative therapies include oral psoralen plus UVA, surgical excision, and laser treatment.32 The Q-switched ruby laser appears to be a rapid and effective means of treating scar sarcoidosis in traumatic tattoos without adverse effects.33 Surgical excision of small lesions or excision of larger lesions with skin grafting can be attempted but may cause the recurrence of hypertrophic and keloidal scarring.34 Systemic agents are reserved for widespread progressive lesions or for lesions that impair function. Systemic glucocorticoids are the most effective agents and are commonly used at slow tapering dosages, starting at 20 to 60 mg/d of oral prednisone for 4 to 5 weeks. However, there are many drawbacks to this therapy. Aside from the well-known complications of chronic steroid use, not all patients respond to systemic steroids.35 Patients who do respond frequently experience disease flare-ups after cessation of therapy. Many other medications may be used in refractory cases, including agents such as hydroxychloroquine sulfate,36 methotrexate,37 and thalidomide.29 Although randomized controlled trials are lacking, multiple anecdotal reports suggest the efficacy of these agents. The course and prognosis of sarcoidosis correlates with the mode of onset of the disease, the patient's race, and the presenting stage. In general, the prognosis of cutaneous sarcoidosis depends on systemic involvement. The course is variable, ranging from self-limited acute episodes to a chronic debilitating disease that may result in death.³⁸ Spontaneous remissions occur in nearly two thirds of patients, but 10% to 30% of patients have a more chronic or progressive course. The mortality rate is 1% to 6%. Sarcoidosis can lead to death either from severe involvement of lung parenchyma, which leads to pulmonary fibrosis and respiratory failure,38,39 or from myocardial involvement, which leads to arrhythmias and cardiac failure.39 Other causes of significant morbidity and mortality include central nervous system involvement, blindness, pulmonary hemorrhage, renal insufficiency, hypopituitarism, and liver disease.35 Cutaneous sarcoidosis usually has a prolonged course. Papules and nodules tend to resolve over months or years, though plaques may be more resistant.19 As treatment is withdrawn, relapses are frequent, especially in black patients who tend to have more severe and prolonged symptoms.11 

Sarcoidosis initially was described by Sir Jonathan Hutchinson in 1875, and cutaneous sarcoidosis (lupus pernio) was described by Besnier 1 in 1899. Sarcoidosis is a multisystem disease that may involve almost any organ system and, therefore, may present with various clinical manifestations.2 Cutaneous sarcoidosis occurs in up to one third of patients with systemic sarcoidosis. Recognition of cutaneous lesions is important because the lesions provide a visible clue to the diagnosis and are an easily accessible source of tissue for histologic examination.3 Because lesions can exhibit many different morphologies, cutaneous sarcoidosis is known as one of the "great imitators" in dermatology.4 Lesions of cutaneous sarcoidosis also can appear in preexisting scars, a condition known as scar sarcoidosis.5 The latter condition may be caused by mechanical trauma such as venipuncture, scars caused by infection such as herpes zoster,6 and tattoos.7 Treatment of cutaneous lesions can be frustrating. For patients with widespread disease, the most effective treatment is systemic glucocorticoids. The prognosis of sarcoidosis usually is good, in particular, if the condition predominantly or solely affects the skin.8 

Case Report
A 34-year-old man presented with a progressively enlarging lesion on his left calf. He reported that about 3 months prior he had developed a small ulceration at this location following a fall. With local wound care, the ulceration healed with a scar. The scar, however, continued to grow beyond the borders of the previous ulceration and became raised with violaceous discoloration. The patient denied any history of excessive scarring or keloid formation after skin surgeries or trauma. There were no personal or family histories of granulomatous diseases. Results of a physical examination showed an erythematous-to-dusky plaque measuring approximately 4X3 cm (Figure 1) on the left calf with well-defined irregular borders and discrete papules on the internal aspect of the knee. No tender nodules on the shins were noticed, and no lymphadenopathy was present. Results from a review of systems and a routine chest x-ray were unremarkable. Results of a punch biopsy revealed changes consistent with sarcoid naked granulomas (Figure 2). The patient was started on topical potent corticosteroid tapes and experienced marked improvement.

Comment

Sarcoidosis occurs more frequently in females than in males, with reported ratios as high as 5:1. In the United States, black individuals are affected 3 to 4 times more often than white individuals.9 Sarcoidosis is found worldwide and in every race, though the incidence varies dramatically. In Europe, the disease affects white individuals more commonly than other races, and it affects Western Europeans more than Eastern Europeans. People from Scandinavia have one of the highest incidence rates at 64 cases per 100,000 population; in Poland, the incidence is 3 cases per 100,000 population. The disease is rare in Eskimos, Southeast Asians, New Zealand Maoris, and native Canadian populations.10,11 The difference in prevalence among certain populations in varying geographic locations suggests that ethnic susceptibility factors, as well as environmental factors, contribute to the etiology of sarcoidosis.11 Sarcoidosis is a multisystem disorder characterized by noncaseating, naked, epithelioid granulomas and commonly involves the hilar lymph nodes, lungs, skin, and eyes. The frequency of skin involvement in sarcoidosis is 10% to 30% of all cases, but the prevalence of particular types of cutaneous lesions varies among races, as well as among individual cases.12 Clinically, there is spontaneous development of livid or reddish-brown plaques on scars that were previously and mostly atrophic; this phenomenon occurs at varying intervals. Therefore, sarcoidosis should be considered in the differential diagnosis of an enlarging previously inactive scar. Lesions can develop in scars caused by mechanical trauma, such as in Kveim test sites, tuberculin test sites,5 sites that have received hyaluronic acid injection for wrinkles,13 sites of cosmetic tattoos,¹⁴ sites of previous laser surgery,15 and sites used for desensitization injections.16 Scar sarcoidosis has been reported following herpes zoster infection.17 Correctly diagnosing sarcoidosis may be a challenge. Unfortunately, no single test can lead to diagnosis of the condition. Patients are diagnosed with sarcoidosis when a compatible clinical or radiologic picture is present, along with histologic evidence of noncaseating granulomas, and when other potential causes, such as infections, are excluded. Cutaneous sarcoidosis varies greatly in its clinical presentation and has been labeled as one of the great dermatologic masqueraders.4,18 Maculopapular lesions can appear as xanthelasma, acne rosea, lupus erythematosus, or adenoma sebaceum. The differential diagnoses of plaques include lupus vulgaris, necrobiosis lipoidica, leprosy, leishmaniasis, psoriasis, and discoid lupus.4,18 The etiology of sarcoidosis is unknown, but several immune aberrations have been noted and are thought to play a role in its pathogenesis.19 Immune dysregulation has been theorized to result from a persistent antigen of low virulence that is poorly cleared by the immune system, leading to a chronic T cell of the TH1 subtype response and causing granuloma formation. Proposed antigens fall into 3 categories that include infectious, environmental, and autoantigens.20 The most common infectious agents implicated are Mycobacterium tuberculosis, Mycoplasma species, Corynebacterium species, spirochetes, atypical mycobacteria, Propionibacterium acnes, Borrelia burgdorferi, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, coxsackievirus, rubella virus, Histoplasma species, Cryptococcus species, coccidioidomycosis, and sporotrichosis.21 Environmental antigens implicated include metals (eg, zirconium, aluminum, beryllium), organic dusts (eg, pine, pollen), inorganic dusts (eg, clay, soil, talc), and autoantigens (AV 2S3+ and HLA-DR17+).22 Genetic factors also are thought to play a role in the disease process.23 Familial clustering of cases has been reported. Monozygotic twins are 2 to 4 times more likely to have the disease than dizygotic twins.23 Certain HLA associations have been demonstrated; the most common allele found in sarcoidosis is HLA-B8. Other associated alleles include HLA-A1 and HLA-DR3.24 Most authors divide cutaneous lesions into specific and nonspecific categories.25 Specific skin lesions display noncaseating granulomas on biopsy. Nonspecific skin lesions display no granulomas on biopsy. Scar sarcoidosis is a specific form of cutaneous sarcoidosis in which old scars become infiltrated with noncaseating epithelioid cell granulomas. Typical sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no necrosis. Granulomas usually are in the superficial dermis but may involve the full thickness of the dermis and extend to the subcutaneous tissue. Islands of epithelioid cells may have a few Langerhans giant cells.25 Giant cells may contain asteroid or Schaumann bodies; asteroid bodies are star-shaped eosinophilic structures; and Schaumann bodies are round or oval laminated structures that usually are calcified at the periphery.26 Granulomas are referred to as naked because they have only a sparse lymphocytic infiltrate at the margins of the granulomas. Fibrosis, if present, usually starts at the periphery and advances toward the center.26 The treatment of cutaneous sarcoidosis often is frustrating, and the condition often is refractory to therapy or recurs following successful treatment. Therapeutic approaches range from topical, intralesional, and systemic use of corticosteroids to systemic medications such as cytostatic drugs, chloroquine,27 allopurinol (300 mg/d),28 and thalidomide.29 For localized involvement of cutaneous sarcoidosis, topical or intralesional steroids are used. Physicians frequently use superpotent topical corticosteroids because the drugs occasionally are effective.30-32 However, the corticosteroid often does not adequately penetrate the skin lesion. Intralesional corticosteroids (eg, triamcinolone acetonide in a dose of 5 mg/mL) typically are more effective, with injections repeated at 2- to 3-week intervals.30,31 Alternative therapies include oral psoralen plus UVA, surgical excision, and laser treatment.32 The Q-switched ruby laser appears to be a rapid and effective means of treating scar sarcoidosis in traumatic tattoos without adverse effects.33 Surgical excision of small lesions or excision of larger lesions with skin grafting can be attempted but may cause the recurrence of hypertrophic and keloidal scarring.34 Systemic agents are reserved for widespread progressive lesions or for lesions that impair function. Systemic glucocorticoids are the most effective agents and are commonly used at slow tapering dosages, starting at 20 to 60 mg/d of oral prednisone for 4 to 5 weeks. However, there are many drawbacks to this therapy. Aside from the well-known complications of chronic steroid use, not all patients respond to systemic steroids.35 Patients who do respond frequently experience disease flare-ups after cessation of therapy. Many other medications may be used in refractory cases, including agents such as hydroxychloroquine sulfate,36 methotrexate,37 and thalidomide.29 Although randomized controlled trials are lacking, multiple anecdotal reports suggest the efficacy of these agents. The course and prognosis of sarcoidosis correlates with the mode of onset of the disease, the patient's race, and the presenting stage. In general, the prognosis of cutaneous sarcoidosis depends on systemic involvement. The course is variable, ranging from self-limited acute episodes to a chronic debilitating disease that may result in death.³⁸ Spontaneous remissions occur in nearly two thirds of patients, but 10% to 30% of patients have a more chronic or progressive course. The mortality rate is 1% to 6%. Sarcoidosis can lead to death either from severe involvement of lung parenchyma, which leads to pulmonary fibrosis and respiratory failure,38,39 or from myocardial involvement, which leads to arrhythmias and cardiac failure.39 Other causes of significant morbidity and mortality include central nervous system involvement, blindness, pulmonary hemorrhage, renal insufficiency, hypopituitarism, and liver disease.35 Cutaneous sarcoidosis usually has a prolonged course. Papules and nodules tend to resolve over months or years, though plaques may be more resistant.19 As treatment is withdrawn, relapses are frequent, especially in black patients who tend to have more severe and prolonged symptoms.11 

Sarcoidosis initially was described by Sir Jonathan Hutchinson in 1875, and cutaneous sarcoidosis (lupus pernio) was described by Besnier 1 in 1899. Sarcoidosis is a multisystem disease that may involve almost any organ system and, therefore, may present with various clinical manifestations.2 Cutaneous sarcoidosis occurs in up to one third of patients with systemic sarcoidosis. Recognition of cutaneous lesions is important because the lesions provide a visible clue to the diagnosis and are an easily accessible source of tissue for histologic examination.3 Because lesions can exhibit many different morphologies, cutaneous sarcoidosis is known as one of the "great imitators" in dermatology.4 Lesions of cutaneous sarcoidosis also can appear in preexisting scars, a condition known as scar sarcoidosis.5 The latter condition may be caused by mechanical trauma such as venipuncture, scars caused by infection such as herpes zoster,6 and tattoos.7 Treatment of cutaneous lesions can be frustrating. For patients with widespread disease, the most effective treatment is systemic glucocorticoids. The prognosis of sarcoidosis usually is good, in particular, if the condition predominantly or solely affects the skin.8 

Case Report
A 34-year-old man presented with a progressively enlarging lesion on his left calf. He reported that about 3 months prior he had developed a small ulceration at this location following a fall. With local wound care, the ulceration healed with a scar. The scar, however, continued to grow beyond the borders of the previous ulceration and became raised with violaceous discoloration. The patient denied any history of excessive scarring or keloid formation after skin surgeries or trauma. There were no personal or family histories of granulomatous diseases. Results of a physical examination showed an erythematous-to-dusky plaque measuring approximately 4X3 cm (Figure 1) on the left calf with well-defined irregular borders and discrete papules on the internal aspect of the knee. No tender nodules on the shins were noticed, and no lymphadenopathy was present. Results from a review of systems and a routine chest x-ray were unremarkable. Results of a punch biopsy revealed changes consistent with sarcoid naked granulomas (Figure 2). The patient was started on topical potent corticosteroid tapes and experienced marked improvement.

Comment

Sarcoidosis occurs more frequently in females than in males, with reported ratios as high as 5:1. In the United States, black individuals are affected 3 to 4 times more often than white individuals.9 Sarcoidosis is found worldwide and in every race, though the incidence varies dramatically. In Europe, the disease affects white individuals more commonly than other races, and it affects Western Europeans more than Eastern Europeans. People from Scandinavia have one of the highest incidence rates at 64 cases per 100,000 population; in Poland, the incidence is 3 cases per 100,000 population. The disease is rare in Eskimos, Southeast Asians, New Zealand Maoris, and native Canadian populations.10,11 The difference in prevalence among certain populations in varying geographic locations suggests that ethnic susceptibility factors, as well as environmental factors, contribute to the etiology of sarcoidosis.11 Sarcoidosis is a multisystem disorder characterized by noncaseating, naked, epithelioid granulomas and commonly involves the hilar lymph nodes, lungs, skin, and eyes. The frequency of skin involvement in sarcoidosis is 10% to 30% of all cases, but the prevalence of particular types of cutaneous lesions varies among races, as well as among individual cases.12 Clinically, there is spontaneous development of livid or reddish-brown plaques on scars that were previously and mostly atrophic; this phenomenon occurs at varying intervals. Therefore, sarcoidosis should be considered in the differential diagnosis of an enlarging previously inactive scar. Lesions can develop in scars caused by mechanical trauma, such as in Kveim test sites, tuberculin test sites,5 sites that have received hyaluronic acid injection for wrinkles,13 sites of cosmetic tattoos,¹⁴ sites of previous laser surgery,15 and sites used for desensitization injections.16 Scar sarcoidosis has been reported following herpes zoster infection.17 Correctly diagnosing sarcoidosis may be a challenge. Unfortunately, no single test can lead to diagnosis of the condition. Patients are diagnosed with sarcoidosis when a compatible clinical or radiologic picture is present, along with histologic evidence of noncaseating granulomas, and when other potential causes, such as infections, are excluded. Cutaneous sarcoidosis varies greatly in its clinical presentation and has been labeled as one of the great dermatologic masqueraders.4,18 Maculopapular lesions can appear as xanthelasma, acne rosea, lupus erythematosus, or adenoma sebaceum. The differential diagnoses of plaques include lupus vulgaris, necrobiosis lipoidica, leprosy, leishmaniasis, psoriasis, and discoid lupus.4,18 The etiology of sarcoidosis is unknown, but several immune aberrations have been noted and are thought to play a role in its pathogenesis.19 Immune dysregulation has been theorized to result from a persistent antigen of low virulence that is poorly cleared by the immune system, leading to a chronic T cell of the TH1 subtype response and causing granuloma formation. Proposed antigens fall into 3 categories that include infectious, environmental, and autoantigens.20 The most common infectious agents implicated are Mycobacterium tuberculosis, Mycoplasma species, Corynebacterium species, spirochetes, atypical mycobacteria, Propionibacterium acnes, Borrelia burgdorferi, herpes simplex virus, Epstein-Barr virus, cytomegalovirus, coxsackievirus, rubella virus, Histoplasma species, Cryptococcus species, coccidioidomycosis, and sporotrichosis.21 Environmental antigens implicated include metals (eg, zirconium, aluminum, beryllium), organic dusts (eg, pine, pollen), inorganic dusts (eg, clay, soil, talc), and autoantigens (AV 2S3+ and HLA-DR17+).22 Genetic factors also are thought to play a role in the disease process.23 Familial clustering of cases has been reported. Monozygotic twins are 2 to 4 times more likely to have the disease than dizygotic twins.23 Certain HLA associations have been demonstrated; the most common allele found in sarcoidosis is HLA-B8. Other associated alleles include HLA-A1 and HLA-DR3.24 Most authors divide cutaneous lesions into specific and nonspecific categories.25 Specific skin lesions display noncaseating granulomas on biopsy. Nonspecific skin lesions display no granulomas on biopsy. Scar sarcoidosis is a specific form of cutaneous sarcoidosis in which old scars become infiltrated with noncaseating epithelioid cell granulomas. Typical sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no necrosis. Granulomas usually are in the superficial dermis but may involve the full thickness of the dermis and extend to the subcutaneous tissue. Islands of epithelioid cells may have a few Langerhans giant cells.25 Giant cells may contain asteroid or Schaumann bodies; asteroid bodies are star-shaped eosinophilic structures; and Schaumann bodies are round or oval laminated structures that usually are calcified at the periphery.26 Granulomas are referred to as naked because they have only a sparse lymphocytic infiltrate at the margins of the granulomas. Fibrosis, if present, usually starts at the periphery and advances toward the center.26 The treatment of cutaneous sarcoidosis often is frustrating, and the condition often is refractory to therapy or recurs following successful treatment. Therapeutic approaches range from topical, intralesional, and systemic use of corticosteroids to systemic medications such as cytostatic drugs, chloroquine,27 allopurinol (300 mg/d),28 and thalidomide.29 For localized involvement of cutaneous sarcoidosis, topical or intralesional steroids are used. Physicians frequently use superpotent topical corticosteroids because the drugs occasionally are effective.30-32 However, the corticosteroid often does not adequately penetrate the skin lesion. Intralesional corticosteroids (eg, triamcinolone acetonide in a dose of 5 mg/mL) typically are more effective, with injections repeated at 2- to 3-week intervals.30,31 Alternative therapies include oral psoralen plus UVA, surgical excision, and laser treatment.32 The Q-switched ruby laser appears to be a rapid and effective means of treating scar sarcoidosis in traumatic tattoos without adverse effects.33 Surgical excision of small lesions or excision of larger lesions with skin grafting can be attempted but may cause the recurrence of hypertrophic and keloidal scarring.34 Systemic agents are reserved for widespread progressive lesions or for lesions that impair function. Systemic glucocorticoids are the most effective agents and are commonly used at slow tapering dosages, starting at 20 to 60 mg/d of oral prednisone for 4 to 5 weeks. However, there are many drawbacks to this therapy. Aside from the well-known complications of chronic steroid use, not all patients respond to systemic steroids.35 Patients who do respond frequently experience disease flare-ups after cessation of therapy. Many other medications may be used in refractory cases, including agents such as hydroxychloroquine sulfate,36 methotrexate,37 and thalidomide.29 Although randomized controlled trials are lacking, multiple anecdotal reports suggest the efficacy of these agents. The course and prognosis of sarcoidosis correlates with the mode of onset of the disease, the patient's race, and the presenting stage. In general, the prognosis of cutaneous sarcoidosis depends on systemic involvement. The course is variable, ranging from self-limited acute episodes to a chronic debilitating disease that may result in death.³⁸ Spontaneous remissions occur in nearly two thirds of patients, but 10% to 30% of patients have a more chronic or progressive course. The mortality rate is 1% to 6%. Sarcoidosis can lead to death either from severe involvement of lung parenchyma, which leads to pulmonary fibrosis and respiratory failure,38,39 or from myocardial involvement, which leads to arrhythmias and cardiac failure.39 Other causes of significant morbidity and mortality include central nervous system involvement, blindness, pulmonary hemorrhage, renal insufficiency, hypopituitarism, and liver disease.35 Cutaneous sarcoidosis usually has a prolonged course. Papules and nodules tend to resolve over months or years, though plaques may be more resistant.19 As treatment is withdrawn, relapses are frequent, especially in black patients who tend to have more severe and prolonged symptoms.11 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49