Cutis

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 

Case Report

A 41-year-old man was referred to our dermatology clinic because of a 3-day history of a widespread painful eruption. The patient had no significant past medical history and denied fevers, chills, nausea, vomiting, abdominal pain, chest pain, and shortness of breath. The patient's vital signs were stable. A full skin examination revealed multiple reticulate, purpuric, and necrotic plaques on all 4 extremities (Figure 1). The affected areas varied in size from 1 cm to greater than 10 cm in length, and some had overlying vesiculation. The trunk was relatively spared.

PLEASE VIEW THE PDF FOR THE FIGURES

Two punch biopsies from the left thigh showed fibrin thrombi in the dermal vessels, ischemic necrosis of the overlying epidermis, dermal hemorrhage, and no evidence of vasculitis (Figure 2). The patient's anticardiolipin antibody titer (immunoglogulin [Ig] G >150 anticardiolipin units; reference, high >80 anticardiolipin units) and anti-β₂-glycoprotein I antibody titer (IgG 53 U/mL; reference, normal <10 U/mL) were both very elevated and remained significantly elevated when tested 6 weeks later. A complete blood count with differential, comprehensive metabolic profile, urinalysis, blood cultures, coagulation studies, dilute Russell viper venom test, protein C and S activity levels, cryoglobulin levels, serum protein electrophoresis, rheumatoid factor, and antinuclear antibody screen were all within reference range or negative.

PLEASE VIEW THE PDF FOR THE FIGURES

The patient was diagnosed with primary antiphospholipid syndrome (APS) and referred to rheumatology for treatment. He was subsequently placed on enoxaparin sodium (a low molecular weight heparin) and has not developed any skin lesions or other symptoms of APS for more than 1 year after beginning treatment. His skin lesions were treated with local wound care (mupirocin and nonadhesive dressing) and healed with minimal scarring over 2 to 3 months.

Comment

APS is a relatively new disease entity. The first antiphospholipid antibody was described in patients with syphilis in 1906,¹ while the first lupus anticoagulant was described in 1952 by Conley and Hartmann.² However, it was not until the 1980s that APS was described by Hughes³ and Hughes et al,⁴ the first to note the association between antiphospholipid antibodies and hypercoagulability.

APS is divided into primary and secondary categories. Primary APS occurs in the absence of any other disease, whereas secondary APS is associated with autoimmune disease or another condition. Systemic lupus erythematosus is by far the most common condition seen with secondary APS.⁵ Antiphospholipid antibodies also can be seen in association with infections, medications, and cancers; these antibodies usually are IgM antibodies, present at low levels, often only transiently elevated, and usually do not lead to APS.⁵ However, it has been shown that patients with infection-related antiphospholipid antibodies may be at increased risk for developing catastrophic APS.⁶

Dermatologic symptoms are common in APS and often can be the first or only signs of the disease. In a study of 200 patients with APS, Francès et al⁷ reported that 49% of the patients had dermatologic findings and more than 30% of the patients presented with skin complaints. In a study of 39 patients with APS, Diógenes et al⁸ reported that 16 patients (41%) had a dermatologic symptom as the main complaint. In a study of 295 patients with circulating lupus anticoagulant, Alegre et al⁹ reported that nearly one quarter of the patients displayed cutaneous manifestations. Finally, in a study of 100 patients with infection-related APS, 36% of patients developed skin findings.⁶

Livedo reticularis is the most common skin finding in APS. In the study by Francès et al,⁷ livedo reticularis was the most frequent dermatologic symptom occurring in slightly more than one quarter of cases. In a study of 1000 patients with APS, Cervera et al¹⁰ reported that livedo reticularis was found in just more than 24% of patients and was the presenting sign in 20.4% of patients. In the study of 100 patients with infection-related APS, 16% of patients developed livedo reticularis.⁶ Furthermore, a large percentage of cases of Sneddon syndrome (livedo reticularis and cerebrovascular accidents) have been shown to be manifestations of APS.^11-13

Cutaneous necrosis is another common manifestation of APS and, after livedo reticularis, is likely the most common dermatologic finding.^14-18 Cervera et al¹⁰ reported that necrotic skin ulcerations were seen in 5.5% of 1000 patients with APS and was the presenting manifestation in 3.9% of patients. It is important that patients be tested for APS whenever they display unexplained necrotic and ulcerative lesions that appear secondary to thrombosis and vascular occlusion.

In addition to livedo reticularis and cutaneous necrosis, other cutaneous manifestations of APS have been reported, including pyoderma gangrenosum,^19,20 gangrene,⁹ purpura fulminans,⁶ acrocyanosis,⁸ Raynaud phenomenon,⁸ livedoid vasculitis,²¹ subungual splinter hemorrhages,²² venous leg ulcerations,²³ Degos disease-type lesions,^24,25 thrombophlebitis,⁹ cutaneous papules and nodules,²⁶ erythema nodosum,²⁷ anetoderma,^28,29 and multiple sterile abscesses.³⁰

The nondermatologic features of APS are numerous and depend on the size and location of the vessels involved. The most common manifestation of APS is venous thrombosis, particularly lower extremity deep venous thrombosis. Up to one half of patients with venous thrombosis will develop pulmonary emboli.5 Arterial thromboses occur less often than venous thromboses and can present as strokes and transient ischemic attacks (most common), myocardial infarctions, blindness, and acute renal failure.³¹ The search for APS is suggested in any young patient who develops a stroke.³¹ Catastrophic APS occurs when numerous thromboses develop in multiple organs, frequently resulting in death.⁵

Cardiac valvular vegetations with resultant emboli are not uncommon in patients with APS.³² Hematologic findings include thrombocytopenia, hemolytic anemia, and thrombotic microangiopathies (eg, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura).⁵ Obstetric complications are common and are among the diagnostic criteria for APS (Table 1).³³ Although the exact incidence of pregnancy loss in women with antiphospholipid antibodies currently is unknown, rates as high as 90% have been reported in untreated patients.³⁷ However, this rate drops to between 15% and 35% with appropriate therapy (ie, low dose aspirin and low molecular weight heparin).³⁸ In addition, antiphospholipid antibodies have been shown to be responsible for 15% of patients with 3 or more consecutive fetal losses.³⁹

PLEASE VIEW THE PDF FOR THE TABLES

According to the proposed criteria, the diagnosis of APS requires at least 1 clinical and 1 laboratory criterion (Table 1).³⁴ The clinical criteria include a documented episode of vascular thrombosis (arterial, venous, or small vessel) and complications of pregnancy (eg, recurrent spontaneous abortions at <10 weeks of gestation). The laboratory criteria include the presence of anticardiolipin antibodies and a positive lupus anticoagulant test on 2 or more occasions at least 6 weeks apart.³⁴ Anticardiolipin antibodies are a more sensitive test for APS, while positive tests for lupus anticoagulant are more specific.⁵ In addition, although not included in the official criteria, it also is important to obtain anti-β₂-glycoprotein I antibodies, as these are felt to be very important in the pathophysiology of APS.^34-36

Although the histopathologic findings of APS are nondiagnostic and do not differ from the findings caused by other thrombotic conditions (eg, monoclonal cryoglobulinemia), histologic confirmation of thrombosis sometimes is helpful. Biopsy of early skin lesions can show dermal edema, hemorrhage, noninflammatory thrombosis of small- and medium-sized vessels, and occasional epidermal necrosis.⁴⁰ Later findings include organization and recanalization of thrombi, vascular proliferation, and hemosiderin deposition. Although a perivascular lymphocytic infiltrate may be seen, vasculitis is absent.⁴⁰

For the unfamiliar, the laboratory evaluation of APS can be confusing, raising questions on what tests to order and how to interpret them. A practical approach to the laboratory evaluation of the patient with suspected APS is presented in Table 2. This approach can be divided into tests specific for APS, tests to investigate other potential causes of a hypercoagulable state, and tests to identify associated conditions. Laboratory investigations related specifically to APS include the lupus anticoagulant test, anticardiolipin antibody titers, and anti-β₂-glycoprotein I antibody titers.

PLEASE VIEW THE PDF FOR THE TABLES

Phospholipid-dependent coagulation tests, including the activated partial-thromboplastin time, kaolin clotting time, and dilute Russell viper venom, are used to detect the presence of lupus anticoagulant antibodies. In APS, these coagulation tests are prolonged and fail to correct with the addition of normal plasma, but they do correct with the addition of excess phospholipid or platelets.⁴¹ At least 2 coagulation tests should be conducted and need to be negative in order to rule out the presence of lupus anticoagulant antibodies.⁴² The physician only needs to order "lupus anticoagulant," as most hematology laboratories will then automatically conduct 2 anticoagulant tests.

Enzyme-linked immunosorbent assays (ELISAs) are used to detect and quantify IgM and IgG levels of anticardiolipin and anti-β₂-glycoprotein I antibodies.^43,44 Results often are expressed in terms of low, moderate, and high titers. Moderate or high levels of these antibodies are considered clinically significant and suggestive of APS.⁵ Low levels are less specific and can be associated with postinfectious sequelae or can be seen in clinically healthy patients. ELISAs for antibodies against prothrombin, annexin V, and other phospholipids (eg, phosphatidylserine, phosphatidylethanolamine) are still under development and not routinely obtained.^45,46

It should be stressed that the presence of antiphospholipid antibodies alone does not necessarily indicate disease. Up to 5% of healthy control subjects will have antiphospholipid antibodies, and this prevalence increases with age.⁴⁷ Also, anticardiolipin and lupus anticoagulant antibodies have been found in 5% and 8% of healthy blood donors, respectively.^48,49

The exact mechanism of how antiphospholipid antibodies produce thrombosis is unknown. Theories include activation of endothelial cells, oxidative damage to endothelial cells, and interference with the coagulation cascade. The latter theory seems most plausible given that β₂-glycoprotein I is felt to be a natural anticoagulant.⁵

Long-term anticoagulation with coumadin is the treatment of choice for patients with thrombosis secondary to APS.⁵⁰ Patients with venous thrombosis should have an International Normalized Ratio (INR) of 2 to 3; patients with arterial thrombosis require more aggressive therapy with an INR of 2.5 to 3.5. Low molecular weight heparin is an alternative to coumadin. Any risk factors for thrombosis (eg, smoking) should be reduced or eliminated. Symptomatic pregnant patients normally are treated with low molecular weight heparin and possibly low dose aspirin.⁵⁰ Hydroxychloroquine and steroids have no role in APS, unless it is secondary to an underlying systemic disease (eg, systemic lupus erythematosus).⁵¹ Finally, intravenous immunoglobulin may have a role in severe recalcitrant APS, APS associated with severe thrombocytopenia, and cases of catastrophic APS.^52-54

Conclusion

Given that many patients with APS present initially or only with dermatologic manifestations, it is crucial that the dermatologist has a sound working knowledge of this important condition. With timely diagnosis and treatment, patients may be spared significant morbidity and even occasional mortality caused by this serious disease.

Case Report

A 41-year-old man was referred to our dermatology clinic because of a 3-day history of a widespread painful eruption. The patient had no significant past medical history and denied fevers, chills, nausea, vomiting, abdominal pain, chest pain, and shortness of breath. The patient's vital signs were stable. A full skin examination revealed multiple reticulate, purpuric, and necrotic plaques on all 4 extremities (Figure 1). The affected areas varied in size from 1 cm to greater than 10 cm in length, and some had overlying vesiculation. The trunk was relatively spared.

PLEASE VIEW THE PDF FOR THE FIGURES

Two punch biopsies from the left thigh showed fibrin thrombi in the dermal vessels, ischemic necrosis of the overlying epidermis, dermal hemorrhage, and no evidence of vasculitis (Figure 2). The patient's anticardiolipin antibody titer (immunoglogulin [Ig] G >150 anticardiolipin units; reference, high >80 anticardiolipin units) and anti-β₂-glycoprotein I antibody titer (IgG 53 U/mL; reference, normal <10 U/mL) were both very elevated and remained significantly elevated when tested 6 weeks later. A complete blood count with differential, comprehensive metabolic profile, urinalysis, blood cultures, coagulation studies, dilute Russell viper venom test, protein C and S activity levels, cryoglobulin levels, serum protein electrophoresis, rheumatoid factor, and antinuclear antibody screen were all within reference range or negative.

PLEASE VIEW THE PDF FOR THE FIGURES

The patient was diagnosed with primary antiphospholipid syndrome (APS) and referred to rheumatology for treatment. He was subsequently placed on enoxaparin sodium (a low molecular weight heparin) and has not developed any skin lesions or other symptoms of APS for more than 1 year after beginning treatment. His skin lesions were treated with local wound care (mupirocin and nonadhesive dressing) and healed with minimal scarring over 2 to 3 months.

Comment

APS is a relatively new disease entity. The first antiphospholipid antibody was described in patients with syphilis in 1906,¹ while the first lupus anticoagulant was described in 1952 by Conley and Hartmann.² However, it was not until the 1980s that APS was described by Hughes³ and Hughes et al,⁴ the first to note the association between antiphospholipid antibodies and hypercoagulability.

APS is divided into primary and secondary categories. Primary APS occurs in the absence of any other disease, whereas secondary APS is associated with autoimmune disease or another condition. Systemic lupus erythematosus is by far the most common condition seen with secondary APS.⁵ Antiphospholipid antibodies also can be seen in association with infections, medications, and cancers; these antibodies usually are IgM antibodies, present at low levels, often only transiently elevated, and usually do not lead to APS.⁵ However, it has been shown that patients with infection-related antiphospholipid antibodies may be at increased risk for developing catastrophic APS.⁶

Dermatologic symptoms are common in APS and often can be the first or only signs of the disease. In a study of 200 patients with APS, Francès et al⁷ reported that 49% of the patients had dermatologic findings and more than 30% of the patients presented with skin complaints. In a study of 39 patients with APS, Diógenes et al⁸ reported that 16 patients (41%) had a dermatologic symptom as the main complaint. In a study of 295 patients with circulating lupus anticoagulant, Alegre et al⁹ reported that nearly one quarter of the patients displayed cutaneous manifestations. Finally, in a study of 100 patients with infection-related APS, 36% of patients developed skin findings.⁶

Livedo reticularis is the most common skin finding in APS. In the study by Francès et al,⁷ livedo reticularis was the most frequent dermatologic symptom occurring in slightly more than one quarter of cases. In a study of 1000 patients with APS, Cervera et al¹⁰ reported that livedo reticularis was found in just more than 24% of patients and was the presenting sign in 20.4% of patients. In the study of 100 patients with infection-related APS, 16% of patients developed livedo reticularis.⁶ Furthermore, a large percentage of cases of Sneddon syndrome (livedo reticularis and cerebrovascular accidents) have been shown to be manifestations of APS.^11-13

Cutaneous necrosis is another common manifestation of APS and, after livedo reticularis, is likely the most common dermatologic finding.^14-18 Cervera et al¹⁰ reported that necrotic skin ulcerations were seen in 5.5% of 1000 patients with APS and was the presenting manifestation in 3.9% of patients. It is important that patients be tested for APS whenever they display unexplained necrotic and ulcerative lesions that appear secondary to thrombosis and vascular occlusion.

In addition to livedo reticularis and cutaneous necrosis, other cutaneous manifestations of APS have been reported, including pyoderma gangrenosum,^19,20 gangrene,⁹ purpura fulminans,⁶ acrocyanosis,⁸ Raynaud phenomenon,⁸ livedoid vasculitis,²¹ subungual splinter hemorrhages,²² venous leg ulcerations,²³ Degos disease-type lesions,^24,25 thrombophlebitis,⁹ cutaneous papules and nodules,²⁶ erythema nodosum,²⁷ anetoderma,^28,29 and multiple sterile abscesses.³⁰

The nondermatologic features of APS are numerous and depend on the size and location of the vessels involved. The most common manifestation of APS is venous thrombosis, particularly lower extremity deep venous thrombosis. Up to one half of patients with venous thrombosis will develop pulmonary emboli.5 Arterial thromboses occur less often than venous thromboses and can present as strokes and transient ischemic attacks (most common), myocardial infarctions, blindness, and acute renal failure.³¹ The search for APS is suggested in any young patient who develops a stroke.³¹ Catastrophic APS occurs when numerous thromboses develop in multiple organs, frequently resulting in death.⁵

Cardiac valvular vegetations with resultant emboli are not uncommon in patients with APS.³² Hematologic findings include thrombocytopenia, hemolytic anemia, and thrombotic microangiopathies (eg, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura).⁵ Obstetric complications are common and are among the diagnostic criteria for APS (Table 1).³³ Although the exact incidence of pregnancy loss in women with antiphospholipid antibodies currently is unknown, rates as high as 90% have been reported in untreated patients.³⁷ However, this rate drops to between 15% and 35% with appropriate therapy (ie, low dose aspirin and low molecular weight heparin).³⁸ In addition, antiphospholipid antibodies have been shown to be responsible for 15% of patients with 3 or more consecutive fetal losses.³⁹

PLEASE VIEW THE PDF FOR THE TABLES

According to the proposed criteria, the diagnosis of APS requires at least 1 clinical and 1 laboratory criterion (Table 1).³⁴ The clinical criteria include a documented episode of vascular thrombosis (arterial, venous, or small vessel) and complications of pregnancy (eg, recurrent spontaneous abortions at <10 weeks of gestation). The laboratory criteria include the presence of anticardiolipin antibodies and a positive lupus anticoagulant test on 2 or more occasions at least 6 weeks apart.³⁴ Anticardiolipin antibodies are a more sensitive test for APS, while positive tests for lupus anticoagulant are more specific.⁵ In addition, although not included in the official criteria, it also is important to obtain anti-β₂-glycoprotein I antibodies, as these are felt to be very important in the pathophysiology of APS.^34-36

Although the histopathologic findings of APS are nondiagnostic and do not differ from the findings caused by other thrombotic conditions (eg, monoclonal cryoglobulinemia), histologic confirmation of thrombosis sometimes is helpful. Biopsy of early skin lesions can show dermal edema, hemorrhage, noninflammatory thrombosis of small- and medium-sized vessels, and occasional epidermal necrosis.⁴⁰ Later findings include organization and recanalization of thrombi, vascular proliferation, and hemosiderin deposition. Although a perivascular lymphocytic infiltrate may be seen, vasculitis is absent.⁴⁰

For the unfamiliar, the laboratory evaluation of APS can be confusing, raising questions on what tests to order and how to interpret them. A practical approach to the laboratory evaluation of the patient with suspected APS is presented in Table 2. This approach can be divided into tests specific for APS, tests to investigate other potential causes of a hypercoagulable state, and tests to identify associated conditions. Laboratory investigations related specifically to APS include the lupus anticoagulant test, anticardiolipin antibody titers, and anti-β₂-glycoprotein I antibody titers.

PLEASE VIEW THE PDF FOR THE TABLES

Phospholipid-dependent coagulation tests, including the activated partial-thromboplastin time, kaolin clotting time, and dilute Russell viper venom, are used to detect the presence of lupus anticoagulant antibodies. In APS, these coagulation tests are prolonged and fail to correct with the addition of normal plasma, but they do correct with the addition of excess phospholipid or platelets.⁴¹ At least 2 coagulation tests should be conducted and need to be negative in order to rule out the presence of lupus anticoagulant antibodies.⁴² The physician only needs to order "lupus anticoagulant," as most hematology laboratories will then automatically conduct 2 anticoagulant tests.

Enzyme-linked immunosorbent assays (ELISAs) are used to detect and quantify IgM and IgG levels of anticardiolipin and anti-β₂-glycoprotein I antibodies.^43,44 Results often are expressed in terms of low, moderate, and high titers. Moderate or high levels of these antibodies are considered clinically significant and suggestive of APS.⁵ Low levels are less specific and can be associated with postinfectious sequelae or can be seen in clinically healthy patients. ELISAs for antibodies against prothrombin, annexin V, and other phospholipids (eg, phosphatidylserine, phosphatidylethanolamine) are still under development and not routinely obtained.^45,46

It should be stressed that the presence of antiphospholipid antibodies alone does not necessarily indicate disease. Up to 5% of healthy control subjects will have antiphospholipid antibodies, and this prevalence increases with age.⁴⁷ Also, anticardiolipin and lupus anticoagulant antibodies have been found in 5% and 8% of healthy blood donors, respectively.^48,49

The exact mechanism of how antiphospholipid antibodies produce thrombosis is unknown. Theories include activation of endothelial cells, oxidative damage to endothelial cells, and interference with the coagulation cascade. The latter theory seems most plausible given that β₂-glycoprotein I is felt to be a natural anticoagulant.⁵

Long-term anticoagulation with coumadin is the treatment of choice for patients with thrombosis secondary to APS.⁵⁰ Patients with venous thrombosis should have an International Normalized Ratio (INR) of 2 to 3; patients with arterial thrombosis require more aggressive therapy with an INR of 2.5 to 3.5. Low molecular weight heparin is an alternative to coumadin. Any risk factors for thrombosis (eg, smoking) should be reduced or eliminated. Symptomatic pregnant patients normally are treated with low molecular weight heparin and possibly low dose aspirin.⁵⁰ Hydroxychloroquine and steroids have no role in APS, unless it is secondary to an underlying systemic disease (eg, systemic lupus erythematosus).⁵¹ Finally, intravenous immunoglobulin may have a role in severe recalcitrant APS, APS associated with severe thrombocytopenia, and cases of catastrophic APS.^52-54

Conclusion

Given that many patients with APS present initially or only with dermatologic manifestations, it is crucial that the dermatologist has a sound working knowledge of this important condition. With timely diagnosis and treatment, patients may be spared significant morbidity and even occasional mortality caused by this serious disease.

Case Report

A 41-year-old man was referred to our dermatology clinic because of a 3-day history of a widespread painful eruption. The patient had no significant past medical history and denied fevers, chills, nausea, vomiting, abdominal pain, chest pain, and shortness of breath. The patient's vital signs were stable. A full skin examination revealed multiple reticulate, purpuric, and necrotic plaques on all 4 extremities (Figure 1). The affected areas varied in size from 1 cm to greater than 10 cm in length, and some had overlying vesiculation. The trunk was relatively spared.

PLEASE VIEW THE PDF FOR THE FIGURES

Two punch biopsies from the left thigh showed fibrin thrombi in the dermal vessels, ischemic necrosis of the overlying epidermis, dermal hemorrhage, and no evidence of vasculitis (Figure 2). The patient's anticardiolipin antibody titer (immunoglogulin [Ig] G >150 anticardiolipin units; reference, high >80 anticardiolipin units) and anti-β₂-glycoprotein I antibody titer (IgG 53 U/mL; reference, normal <10 U/mL) were both very elevated and remained significantly elevated when tested 6 weeks later. A complete blood count with differential, comprehensive metabolic profile, urinalysis, blood cultures, coagulation studies, dilute Russell viper venom test, protein C and S activity levels, cryoglobulin levels, serum protein electrophoresis, rheumatoid factor, and antinuclear antibody screen were all within reference range or negative.

PLEASE VIEW THE PDF FOR THE FIGURES

The patient was diagnosed with primary antiphospholipid syndrome (APS) and referred to rheumatology for treatment. He was subsequently placed on enoxaparin sodium (a low molecular weight heparin) and has not developed any skin lesions or other symptoms of APS for more than 1 year after beginning treatment. His skin lesions were treated with local wound care (mupirocin and nonadhesive dressing) and healed with minimal scarring over 2 to 3 months.

Comment

APS is a relatively new disease entity. The first antiphospholipid antibody was described in patients with syphilis in 1906,¹ while the first lupus anticoagulant was described in 1952 by Conley and Hartmann.² However, it was not until the 1980s that APS was described by Hughes³ and Hughes et al,⁴ the first to note the association between antiphospholipid antibodies and hypercoagulability.

APS is divided into primary and secondary categories. Primary APS occurs in the absence of any other disease, whereas secondary APS is associated with autoimmune disease or another condition. Systemic lupus erythematosus is by far the most common condition seen with secondary APS.⁵ Antiphospholipid antibodies also can be seen in association with infections, medications, and cancers; these antibodies usually are IgM antibodies, present at low levels, often only transiently elevated, and usually do not lead to APS.⁵ However, it has been shown that patients with infection-related antiphospholipid antibodies may be at increased risk for developing catastrophic APS.⁶

Dermatologic symptoms are common in APS and often can be the first or only signs of the disease. In a study of 200 patients with APS, Francès et al⁷ reported that 49% of the patients had dermatologic findings and more than 30% of the patients presented with skin complaints. In a study of 39 patients with APS, Diógenes et al⁸ reported that 16 patients (41%) had a dermatologic symptom as the main complaint. In a study of 295 patients with circulating lupus anticoagulant, Alegre et al⁹ reported that nearly one quarter of the patients displayed cutaneous manifestations. Finally, in a study of 100 patients with infection-related APS, 36% of patients developed skin findings.⁶

Livedo reticularis is the most common skin finding in APS. In the study by Francès et al,⁷ livedo reticularis was the most frequent dermatologic symptom occurring in slightly more than one quarter of cases. In a study of 1000 patients with APS, Cervera et al¹⁰ reported that livedo reticularis was found in just more than 24% of patients and was the presenting sign in 20.4% of patients. In the study of 100 patients with infection-related APS, 16% of patients developed livedo reticularis.⁶ Furthermore, a large percentage of cases of Sneddon syndrome (livedo reticularis and cerebrovascular accidents) have been shown to be manifestations of APS.^11-13

Cutaneous necrosis is another common manifestation of APS and, after livedo reticularis, is likely the most common dermatologic finding.^14-18 Cervera et al¹⁰ reported that necrotic skin ulcerations were seen in 5.5% of 1000 patients with APS and was the presenting manifestation in 3.9% of patients. It is important that patients be tested for APS whenever they display unexplained necrotic and ulcerative lesions that appear secondary to thrombosis and vascular occlusion.

In addition to livedo reticularis and cutaneous necrosis, other cutaneous manifestations of APS have been reported, including pyoderma gangrenosum,^19,20 gangrene,⁹ purpura fulminans,⁶ acrocyanosis,⁸ Raynaud phenomenon,⁸ livedoid vasculitis,²¹ subungual splinter hemorrhages,²² venous leg ulcerations,²³ Degos disease-type lesions,^24,25 thrombophlebitis,⁹ cutaneous papules and nodules,²⁶ erythema nodosum,²⁷ anetoderma,^28,29 and multiple sterile abscesses.³⁰

The nondermatologic features of APS are numerous and depend on the size and location of the vessels involved. The most common manifestation of APS is venous thrombosis, particularly lower extremity deep venous thrombosis. Up to one half of patients with venous thrombosis will develop pulmonary emboli.5 Arterial thromboses occur less often than venous thromboses and can present as strokes and transient ischemic attacks (most common), myocardial infarctions, blindness, and acute renal failure.³¹ The search for APS is suggested in any young patient who develops a stroke.³¹ Catastrophic APS occurs when numerous thromboses develop in multiple organs, frequently resulting in death.⁵

Cardiac valvular vegetations with resultant emboli are not uncommon in patients with APS.³² Hematologic findings include thrombocytopenia, hemolytic anemia, and thrombotic microangiopathies (eg, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura).⁵ Obstetric complications are common and are among the diagnostic criteria for APS (Table 1).³³ Although the exact incidence of pregnancy loss in women with antiphospholipid antibodies currently is unknown, rates as high as 90% have been reported in untreated patients.³⁷ However, this rate drops to between 15% and 35% with appropriate therapy (ie, low dose aspirin and low molecular weight heparin).³⁸ In addition, antiphospholipid antibodies have been shown to be responsible for 15% of patients with 3 or more consecutive fetal losses.³⁹

PLEASE VIEW THE PDF FOR THE TABLES

According to the proposed criteria, the diagnosis of APS requires at least 1 clinical and 1 laboratory criterion (Table 1).³⁴ The clinical criteria include a documented episode of vascular thrombosis (arterial, venous, or small vessel) and complications of pregnancy (eg, recurrent spontaneous abortions at <10 weeks of gestation). The laboratory criteria include the presence of anticardiolipin antibodies and a positive lupus anticoagulant test on 2 or more occasions at least 6 weeks apart.³⁴ Anticardiolipin antibodies are a more sensitive test for APS, while positive tests for lupus anticoagulant are more specific.⁵ In addition, although not included in the official criteria, it also is important to obtain anti-β₂-glycoprotein I antibodies, as these are felt to be very important in the pathophysiology of APS.^34-36

Although the histopathologic findings of APS are nondiagnostic and do not differ from the findings caused by other thrombotic conditions (eg, monoclonal cryoglobulinemia), histologic confirmation of thrombosis sometimes is helpful. Biopsy of early skin lesions can show dermal edema, hemorrhage, noninflammatory thrombosis of small- and medium-sized vessels, and occasional epidermal necrosis.⁴⁰ Later findings include organization and recanalization of thrombi, vascular proliferation, and hemosiderin deposition. Although a perivascular lymphocytic infiltrate may be seen, vasculitis is absent.⁴⁰

For the unfamiliar, the laboratory evaluation of APS can be confusing, raising questions on what tests to order and how to interpret them. A practical approach to the laboratory evaluation of the patient with suspected APS is presented in Table 2. This approach can be divided into tests specific for APS, tests to investigate other potential causes of a hypercoagulable state, and tests to identify associated conditions. Laboratory investigations related specifically to APS include the lupus anticoagulant test, anticardiolipin antibody titers, and anti-β₂-glycoprotein I antibody titers.

PLEASE VIEW THE PDF FOR THE TABLES

Phospholipid-dependent coagulation tests, including the activated partial-thromboplastin time, kaolin clotting time, and dilute Russell viper venom, are used to detect the presence of lupus anticoagulant antibodies. In APS, these coagulation tests are prolonged and fail to correct with the addition of normal plasma, but they do correct with the addition of excess phospholipid or platelets.⁴¹ At least 2 coagulation tests should be conducted and need to be negative in order to rule out the presence of lupus anticoagulant antibodies.⁴² The physician only needs to order "lupus anticoagulant," as most hematology laboratories will then automatically conduct 2 anticoagulant tests.

Enzyme-linked immunosorbent assays (ELISAs) are used to detect and quantify IgM and IgG levels of anticardiolipin and anti-β₂-glycoprotein I antibodies.^43,44 Results often are expressed in terms of low, moderate, and high titers. Moderate or high levels of these antibodies are considered clinically significant and suggestive of APS.⁵ Low levels are less specific and can be associated with postinfectious sequelae or can be seen in clinically healthy patients. ELISAs for antibodies against prothrombin, annexin V, and other phospholipids (eg, phosphatidylserine, phosphatidylethanolamine) are still under development and not routinely obtained.^45,46

It should be stressed that the presence of antiphospholipid antibodies alone does not necessarily indicate disease. Up to 5% of healthy control subjects will have antiphospholipid antibodies, and this prevalence increases with age.⁴⁷ Also, anticardiolipin and lupus anticoagulant antibodies have been found in 5% and 8% of healthy blood donors, respectively.^48,49

The exact mechanism of how antiphospholipid antibodies produce thrombosis is unknown. Theories include activation of endothelial cells, oxidative damage to endothelial cells, and interference with the coagulation cascade. The latter theory seems most plausible given that β₂-glycoprotein I is felt to be a natural anticoagulant.⁵

Long-term anticoagulation with coumadin is the treatment of choice for patients with thrombosis secondary to APS.⁵⁰ Patients with venous thrombosis should have an International Normalized Ratio (INR) of 2 to 3; patients with arterial thrombosis require more aggressive therapy with an INR of 2.5 to 3.5. Low molecular weight heparin is an alternative to coumadin. Any risk factors for thrombosis (eg, smoking) should be reduced or eliminated. Symptomatic pregnant patients normally are treated with low molecular weight heparin and possibly low dose aspirin.⁵⁰ Hydroxychloroquine and steroids have no role in APS, unless it is secondary to an underlying systemic disease (eg, systemic lupus erythematosus).⁵¹ Finally, intravenous immunoglobulin may have a role in severe recalcitrant APS, APS associated with severe thrombocytopenia, and cases of catastrophic APS.^52-54

Conclusion

Given that many patients with APS present initially or only with dermatologic manifestations, it is crucial that the dermatologist has a sound working knowledge of this important condition. With timely diagnosis and treatment, patients may be spared significant morbidity and even occasional mortality caused by this serious disease.