Salvador Arias-Santiago, MD, PhD

A 64-year-old man with diabetes and hypertension presented with a 2-day history of sudden onset of acute pain and cyanosis on the sole of his right foot 4 days after undergoing cardiac catheterization and coronary angiography.

The physical examination revealed macular, violaceous, connecting rings in a net-like pattern that blanched with pressure and disappeared when the foot was elevated, a presentation compatible with livedo reticularis (Figure 1). Laboratory testing (complete blood cell count, biochemistry panel, coagulation test, and C-reactive protein test) was notable only for eosinophilia.

A few days later, the patient returned with abdominal pain, diarrhea, and acute renal injury with urinary eosinophils (7% of the white blood cells in the urine) and proteinuria.

Q: Which is the most likely diagnosis?

• Infective endocarditis
• Pernio (chilblain)
• Cholesterol crystal embolism
• Cutaneous small-vessel vasculitis

A: Cholesterol crystal embolism is the correct diagnosis.

Infective endocarditis is an infection of the endocardium, but systemic signs may be present, including cutaneous lesions such as Osler nodes (painful papules on the tips of the fingers and toes) and Janeway lesions (painless macules on the palms and soles). Histologic staining of skin biopsy specimens often shows vasculitis, occasionally with a positive Gram stain. Severe renal injury is not common, and the timing of the acute illness and skin lesion fits better with an acute embolic phenomenon.

Pernio is a form of cold injury, localized in peripheral parts of the body and occurring after exposure to cold temperatures in damp conditions. It usually manifests bilaterally as painful erythematous or purple lesions on the acral areas of the hands and feet, nose, ears, and, rarely, the thighs and buttocks. Pernio most commonly affects women between 20 and 40 years of age. It can be idiopathic or associated with a systemic disease such as systemic lupus erythematosus or Sjögren syndrome.

Cutaneous small-vessel vasculitis is a heterogeneous group of disorders with inflammation and damage of the blood vessels; it may be limited to the skin or it may involve multiple systems. Palpable or nonpalpable purpura and ulceration are common clinical findings, and histologic study shows an inflammatory infiltrate of vessel walls, fibrinoid necrosis, thrombosis, and extravasation of red blood cells.

While this patient’s problems are not consistent with small-vessel vasculitis, the single skin lesion, the timing after the catheterization, and the urinary eosinophils are best explained by cholesterol embolization.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol crystal embolism is commonly iatrogenic, a complication of mechanical damage to the arterial walls from vascular surgery or invasive percutaneous procedures. Material dislodged from atheromatous arterial plaques can occlude the small vessels of the feet, producing this syndrome.

The onset of the clinical disease is often delayed for days to weeks after an angiographic procedure.¹ Spontaneous hemorrhage, disruption of plaque, or drug therapy with an anticoagulant or a fibrinolytic can precipitate embolization of cholesterol crystals. The source of the emboli is atheromatous plaque in major blood vessels, particularly the abdominal aorta.

 

 

Many organs and systems can be affected

These emboli can affect many organs and systems: eg, the kidneys (causing hypertension and acute renal failure), the muscles (causing myalgias), gastrointestinal organs (causing bleeding, abdominal pain, and bowel infarction), the lungs (causing acute respiratory distress syndrome), the eyes (causing Hollenhorst plaques in retinal arteries), and the central nervous system (causing stroke, confusion, and delirium). Cardiac or central nervous system involvement is associated with a high risk of death.

After angiography, clinical manifestations of cholesterol embolization have been reported in 0.06% to 1.4% of patients,^2,3 although the finding of cholesterol emboli is more common in autopsy studies.⁴

Recognizing skin signs is the key

Cutaneous abnormalities are usually the earliest and often the only clinical manifestation of this syndrome. Findings on the lower limbs include blue toes, cutaneous nodules, and livedo reticularis, affecting the feet and legs and sometimes extending upward to the trunk. Other findings include digital infarcts, ulceration, gangrene, purpura, cyanosis, and splinter hemorrhages in the nail bed.

In our patient, microscopic study of skin biopsy specimens showed needle-shaped clefts within the lumen of blood vessels—ie, dissolved cholesterol crystals obstructing small arteries (Figure 2).

Biopsy studies of skin lesions are positive in a high percentage of cases, showing dissolved cholesterol crystals within the lumen of blood vessels, especially in the small to large arteries and arterioles of the deep dermis or subcutaneous fat. Deep biopsies and carefully examination are necessary, as emboli tend to be patchily distributed. Early recognition of cutaneous clinical findings is essential to establish the proper diagnosis and treatment.

The diagnostic triad of this disease includes blue toe syndrome, acute or subacute renal failure, and a temporal relation with an inciting event (particularly angiography). But despite these diagnostic criteria,² the diagnosis is often based on a combination of signs and symptoms specific to end-organ damage and a systemic inflammatory response.³

Histologic confirmation is considered essential to the diagnosis of cholesterol crystal embolism, and as the skin is the most accessible site, skin biopsy provides the best sample for histologic diagnosis.⁵

Postprocedural embolism of a blood clot, vasculitis, and infective endocarditis are the most important differential diagnoses.^6,7

Treatment is supportive, preventive

Treatment is mainly supportive with hemodynamic monitoring, nutritional and metabolic support, mechanical ventilation, and dialysis if necessary. The underlying atherosclerotic disease should be treated aggressively. Prevention of another episode involves modification of traditional risk factors such as serum cholesterol, diabetes, hypertension, and smoking. Additional vascular surgery procedures should be avoided, as they can induce new episodes.

A 64-year-old man with diabetes and hypertension presented with a 2-day history of sudden onset of acute pain and cyanosis on the sole of his right foot 4 days after undergoing cardiac catheterization and coronary angiography.

The physical examination revealed macular, violaceous, connecting rings in a net-like pattern that blanched with pressure and disappeared when the foot was elevated, a presentation compatible with livedo reticularis (Figure 1). Laboratory testing (complete blood cell count, biochemistry panel, coagulation test, and C-reactive protein test) was notable only for eosinophilia.

A few days later, the patient returned with abdominal pain, diarrhea, and acute renal injury with urinary eosinophils (7% of the white blood cells in the urine) and proteinuria.

Q: Which is the most likely diagnosis?

• Infective endocarditis
• Pernio (chilblain)
• Cholesterol crystal embolism
• Cutaneous small-vessel vasculitis

A: Cholesterol crystal embolism is the correct diagnosis.

Infective endocarditis is an infection of the endocardium, but systemic signs may be present, including cutaneous lesions such as Osler nodes (painful papules on the tips of the fingers and toes) and Janeway lesions (painless macules on the palms and soles). Histologic staining of skin biopsy specimens often shows vasculitis, occasionally with a positive Gram stain. Severe renal injury is not common, and the timing of the acute illness and skin lesion fits better with an acute embolic phenomenon.

Pernio is a form of cold injury, localized in peripheral parts of the body and occurring after exposure to cold temperatures in damp conditions. It usually manifests bilaterally as painful erythematous or purple lesions on the acral areas of the hands and feet, nose, ears, and, rarely, the thighs and buttocks. Pernio most commonly affects women between 20 and 40 years of age. It can be idiopathic or associated with a systemic disease such as systemic lupus erythematosus or Sjögren syndrome.

Cutaneous small-vessel vasculitis is a heterogeneous group of disorders with inflammation and damage of the blood vessels; it may be limited to the skin or it may involve multiple systems. Palpable or nonpalpable purpura and ulceration are common clinical findings, and histologic study shows an inflammatory infiltrate of vessel walls, fibrinoid necrosis, thrombosis, and extravasation of red blood cells.

While this patient’s problems are not consistent with small-vessel vasculitis, the single skin lesion, the timing after the catheterization, and the urinary eosinophils are best explained by cholesterol embolization.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol crystal embolism is commonly iatrogenic, a complication of mechanical damage to the arterial walls from vascular surgery or invasive percutaneous procedures. Material dislodged from atheromatous arterial plaques can occlude the small vessels of the feet, producing this syndrome.

The onset of the clinical disease is often delayed for days to weeks after an angiographic procedure.¹ Spontaneous hemorrhage, disruption of plaque, or drug therapy with an anticoagulant or a fibrinolytic can precipitate embolization of cholesterol crystals. The source of the emboli is atheromatous plaque in major blood vessels, particularly the abdominal aorta.

 

 

Many organs and systems can be affected

These emboli can affect many organs and systems: eg, the kidneys (causing hypertension and acute renal failure), the muscles (causing myalgias), gastrointestinal organs (causing bleeding, abdominal pain, and bowel infarction), the lungs (causing acute respiratory distress syndrome), the eyes (causing Hollenhorst plaques in retinal arteries), and the central nervous system (causing stroke, confusion, and delirium). Cardiac or central nervous system involvement is associated with a high risk of death.

After angiography, clinical manifestations of cholesterol embolization have been reported in 0.06% to 1.4% of patients,^2,3 although the finding of cholesterol emboli is more common in autopsy studies.⁴

Recognizing skin signs is the key

Cutaneous abnormalities are usually the earliest and often the only clinical manifestation of this syndrome. Findings on the lower limbs include blue toes, cutaneous nodules, and livedo reticularis, affecting the feet and legs and sometimes extending upward to the trunk. Other findings include digital infarcts, ulceration, gangrene, purpura, cyanosis, and splinter hemorrhages in the nail bed.

In our patient, microscopic study of skin biopsy specimens showed needle-shaped clefts within the lumen of blood vessels—ie, dissolved cholesterol crystals obstructing small arteries (Figure 2).

Biopsy studies of skin lesions are positive in a high percentage of cases, showing dissolved cholesterol crystals within the lumen of blood vessels, especially in the small to large arteries and arterioles of the deep dermis or subcutaneous fat. Deep biopsies and carefully examination are necessary, as emboli tend to be patchily distributed. Early recognition of cutaneous clinical findings is essential to establish the proper diagnosis and treatment.

The diagnostic triad of this disease includes blue toe syndrome, acute or subacute renal failure, and a temporal relation with an inciting event (particularly angiography). But despite these diagnostic criteria,² the diagnosis is often based on a combination of signs and symptoms specific to end-organ damage and a systemic inflammatory response.³

Histologic confirmation is considered essential to the diagnosis of cholesterol crystal embolism, and as the skin is the most accessible site, skin biopsy provides the best sample for histologic diagnosis.⁵

Postprocedural embolism of a blood clot, vasculitis, and infective endocarditis are the most important differential diagnoses.^6,7

Treatment is supportive, preventive

Treatment is mainly supportive with hemodynamic monitoring, nutritional and metabolic support, mechanical ventilation, and dialysis if necessary. The underlying atherosclerotic disease should be treated aggressively. Prevention of another episode involves modification of traditional risk factors such as serum cholesterol, diabetes, hypertension, and smoking. Additional vascular surgery procedures should be avoided, as they can induce new episodes.

A 64-year-old man with diabetes and hypertension presented with a 2-day history of sudden onset of acute pain and cyanosis on the sole of his right foot 4 days after undergoing cardiac catheterization and coronary angiography.

The physical examination revealed macular, violaceous, connecting rings in a net-like pattern that blanched with pressure and disappeared when the foot was elevated, a presentation compatible with livedo reticularis (Figure 1). Laboratory testing (complete blood cell count, biochemistry panel, coagulation test, and C-reactive protein test) was notable only for eosinophilia.

A few days later, the patient returned with abdominal pain, diarrhea, and acute renal injury with urinary eosinophils (7% of the white blood cells in the urine) and proteinuria.

Q: Which is the most likely diagnosis?

• Infective endocarditis
• Pernio (chilblain)
• Cholesterol crystal embolism
• Cutaneous small-vessel vasculitis

A: Cholesterol crystal embolism is the correct diagnosis.

Infective endocarditis is an infection of the endocardium, but systemic signs may be present, including cutaneous lesions such as Osler nodes (painful papules on the tips of the fingers and toes) and Janeway lesions (painless macules on the palms and soles). Histologic staining of skin biopsy specimens often shows vasculitis, occasionally with a positive Gram stain. Severe renal injury is not common, and the timing of the acute illness and skin lesion fits better with an acute embolic phenomenon.

Pernio is a form of cold injury, localized in peripheral parts of the body and occurring after exposure to cold temperatures in damp conditions. It usually manifests bilaterally as painful erythematous or purple lesions on the acral areas of the hands and feet, nose, ears, and, rarely, the thighs and buttocks. Pernio most commonly affects women between 20 and 40 years of age. It can be idiopathic or associated with a systemic disease such as systemic lupus erythematosus or Sjögren syndrome.

Cutaneous small-vessel vasculitis is a heterogeneous group of disorders with inflammation and damage of the blood vessels; it may be limited to the skin or it may involve multiple systems. Palpable or nonpalpable purpura and ulceration are common clinical findings, and histologic study shows an inflammatory infiltrate of vessel walls, fibrinoid necrosis, thrombosis, and extravasation of red blood cells.

While this patient’s problems are not consistent with small-vessel vasculitis, the single skin lesion, the timing after the catheterization, and the urinary eosinophils are best explained by cholesterol embolization.

CHOLESTEROL CRYSTAL EMBOLISM

Cholesterol crystal embolism is commonly iatrogenic, a complication of mechanical damage to the arterial walls from vascular surgery or invasive percutaneous procedures. Material dislodged from atheromatous arterial plaques can occlude the small vessels of the feet, producing this syndrome.

The onset of the clinical disease is often delayed for days to weeks after an angiographic procedure.¹ Spontaneous hemorrhage, disruption of plaque, or drug therapy with an anticoagulant or a fibrinolytic can precipitate embolization of cholesterol crystals. The source of the emboli is atheromatous plaque in major blood vessels, particularly the abdominal aorta.

 

 

Many organs and systems can be affected

These emboli can affect many organs and systems: eg, the kidneys (causing hypertension and acute renal failure), the muscles (causing myalgias), gastrointestinal organs (causing bleeding, abdominal pain, and bowel infarction), the lungs (causing acute respiratory distress syndrome), the eyes (causing Hollenhorst plaques in retinal arteries), and the central nervous system (causing stroke, confusion, and delirium). Cardiac or central nervous system involvement is associated with a high risk of death.

After angiography, clinical manifestations of cholesterol embolization have been reported in 0.06% to 1.4% of patients,^2,3 although the finding of cholesterol emboli is more common in autopsy studies.⁴

Recognizing skin signs is the key

Cutaneous abnormalities are usually the earliest and often the only clinical manifestation of this syndrome. Findings on the lower limbs include blue toes, cutaneous nodules, and livedo reticularis, affecting the feet and legs and sometimes extending upward to the trunk. Other findings include digital infarcts, ulceration, gangrene, purpura, cyanosis, and splinter hemorrhages in the nail bed.

In our patient, microscopic study of skin biopsy specimens showed needle-shaped clefts within the lumen of blood vessels—ie, dissolved cholesterol crystals obstructing small arteries (Figure 2).

Biopsy studies of skin lesions are positive in a high percentage of cases, showing dissolved cholesterol crystals within the lumen of blood vessels, especially in the small to large arteries and arterioles of the deep dermis or subcutaneous fat. Deep biopsies and carefully examination are necessary, as emboli tend to be patchily distributed. Early recognition of cutaneous clinical findings is essential to establish the proper diagnosis and treatment.

The diagnostic triad of this disease includes blue toe syndrome, acute or subacute renal failure, and a temporal relation with an inciting event (particularly angiography). But despite these diagnostic criteria,² the diagnosis is often based on a combination of signs and symptoms specific to end-organ damage and a systemic inflammatory response.³

Histologic confirmation is considered essential to the diagnosis of cholesterol crystal embolism, and as the skin is the most accessible site, skin biopsy provides the best sample for histologic diagnosis.⁵

Postprocedural embolism of a blood clot, vasculitis, and infective endocarditis are the most important differential diagnoses.^6,7

Treatment is supportive, preventive

Treatment is mainly supportive with hemodynamic monitoring, nutritional and metabolic support, mechanical ventilation, and dialysis if necessary. The underlying atherosclerotic disease should be treated aggressively. Prevention of another episode involves modification of traditional risk factors such as serum cholesterol, diabetes, hypertension, and smoking. Additional vascular surgery procedures should be avoided, as they can induce new episodes.

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

A physical examination revealed acrocyanotic lesions on the nose that were covered with scales (Figure 1). Laboratory testing showed increased cholesterol levels, a positive antinuclear antibody titer (1:160 or higher is positive), and a positive anti-Ro/SS-A antibody titer (1:80 or higher is positive). Tests for cryoglobulin, cold agglutinins, anti-double-stranded DNA antibody, anti-extractable nuclear antigens, C3 and C4 complement proteins, and anticardiolipin antibody were normal or negative.

Histologic examination revealed degeneration of the basal layer of the dermis, with periadnexal and perivascular inflammatory infiltrates (Figure 2). On immunofluorescence testing, linear deposits of immunoglobulin M were noted at the dermoepidermal junction.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

A physical examination revealed acrocyanotic lesions on the nose that were covered with scales (Figure 1). Laboratory testing showed increased cholesterol levels, a positive antinuclear antibody titer (1:160 or higher is positive), and a positive anti-Ro/SS-A antibody titer (1:80 or higher is positive). Tests for cryoglobulin, cold agglutinins, anti-double-stranded DNA antibody, anti-extractable nuclear antigens, C3 and C4 complement proteins, and anticardiolipin antibody were normal or negative.

Histologic examination revealed degeneration of the basal layer of the dermis, with periadnexal and perivascular inflammatory infiltrates (Figure 2). On immunofluorescence testing, linear deposits of immunoglobulin M were noted at the dermoepidermal junction.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

A physical examination revealed acrocyanotic lesions on the nose that were covered with scales (Figure 1). Laboratory testing showed increased cholesterol levels, a positive antinuclear antibody titer (1:160 or higher is positive), and a positive anti-Ro/SS-A antibody titer (1:80 or higher is positive). Tests for cryoglobulin, cold agglutinins, anti-double-stranded DNA antibody, anti-extractable nuclear antigens, C3 and C4 complement proteins, and anticardiolipin antibody were normal or negative.

Histologic examination revealed degeneration of the basal layer of the dermis, with periadnexal and perivascular inflammatory infiltrates (Figure 2). On immunofluorescence testing, linear deposits of immunoglobulin M were noted at the dermoepidermal junction.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 78-year-old man with hyperuricemia treated with allopurinol (Zyloprim) presented with asymptomatic nodules on both hands (Figure 1), with progressive growth for 2 years.

Q: Which is the most likely diagnosis?

• Rheumatoid arthritis
• Nodular osteoarthritis
• Tophaceous gout
• Pseudogout
• Xanthoma tuberosum

A: Tophaceous gout is the diagnosis. This patient’s serum urate level was 9 mg/dL (normal range 4.0–8.0) despite allopurinol therapy, with normal levels of lipids, urea, and creatinine. Polarized light microscopy of aspirated synovial fluid showed monosodium urate crystals, thus confirming the diagnosis.

Rheumatoid arthritis is typically polyarticular and symmetrical and spares the distal interphalangeal joints. Subcutaneous rheumatoid nodules may mimic gouty tophi.

Pseudogout shares some of the features of gout. It results from deposits of calcium pyrophosphate crystals in and around the joints. The diagnosis is made by identifying the crystals on microscopy when calcinosis is seen on x-ray. Tophaceous nodules almost never occur.

Xanthoma tuberosum is associated with hypercholesterolemia, particularly with elevated levels of low-density lipoprotein cholesterol. Lesions occur on pressure areas such as the knees or elbows and vary in size and shape from small papules to firm, lobulated tumors. They are yellow or orange, often with an erythematous halo. They are not associated with chronic proliferative arthritis.

CLINICAL PRESENTATION OF GOUT

Gout is a common metabolic disease characterized by an intermittent course of acute inflammatory arthritis initially affecting one or a few joints. Almost all patients have hyperuricemia, but serum urate levels can be normal or low during an acute attack. On the other hand, many hyperuricemic patients never have a clinical event.

If the hyperuricemia is untreated, some patients develop chronic polyarthritis and nephrolithiasis.¹ Inadequate treatment of hyperuricemia may result in chronic tophaceous gout. Although tophaceous gout usually is a sign of long-standing hyperuricemia, tophi can in rare cases be a first symptom of the disorder.²

Even though our patient had been on allopurinol therapy, the dose was not high enough to achieve a serum urate level significantly below the saturation point of urate (about 6.7 mg/dL).

A 78-year-old man with hyperuricemia treated with allopurinol (Zyloprim) presented with asymptomatic nodules on both hands (Figure 1), with progressive growth for 2 years.

Q: Which is the most likely diagnosis?

• Rheumatoid arthritis
• Nodular osteoarthritis
• Tophaceous gout
• Pseudogout
• Xanthoma tuberosum

A: Tophaceous gout is the diagnosis. This patient’s serum urate level was 9 mg/dL (normal range 4.0–8.0) despite allopurinol therapy, with normal levels of lipids, urea, and creatinine. Polarized light microscopy of aspirated synovial fluid showed monosodium urate crystals, thus confirming the diagnosis.

Rheumatoid arthritis is typically polyarticular and symmetrical and spares the distal interphalangeal joints. Subcutaneous rheumatoid nodules may mimic gouty tophi.

Pseudogout shares some of the features of gout. It results from deposits of calcium pyrophosphate crystals in and around the joints. The diagnosis is made by identifying the crystals on microscopy when calcinosis is seen on x-ray. Tophaceous nodules almost never occur.

Xanthoma tuberosum is associated with hypercholesterolemia, particularly with elevated levels of low-density lipoprotein cholesterol. Lesions occur on pressure areas such as the knees or elbows and vary in size and shape from small papules to firm, lobulated tumors. They are yellow or orange, often with an erythematous halo. They are not associated with chronic proliferative arthritis.

CLINICAL PRESENTATION OF GOUT

Gout is a common metabolic disease characterized by an intermittent course of acute inflammatory arthritis initially affecting one or a few joints. Almost all patients have hyperuricemia, but serum urate levels can be normal or low during an acute attack. On the other hand, many hyperuricemic patients never have a clinical event.

If the hyperuricemia is untreated, some patients develop chronic polyarthritis and nephrolithiasis.¹ Inadequate treatment of hyperuricemia may result in chronic tophaceous gout. Although tophaceous gout usually is a sign of long-standing hyperuricemia, tophi can in rare cases be a first symptom of the disorder.²

Even though our patient had been on allopurinol therapy, the dose was not high enough to achieve a serum urate level significantly below the saturation point of urate (about 6.7 mg/dL).

A 78-year-old man with hyperuricemia treated with allopurinol (Zyloprim) presented with asymptomatic nodules on both hands (Figure 1), with progressive growth for 2 years.

Q: Which is the most likely diagnosis?

• Rheumatoid arthritis
• Nodular osteoarthritis
• Tophaceous gout
• Pseudogout
• Xanthoma tuberosum

A: Tophaceous gout is the diagnosis. This patient’s serum urate level was 9 mg/dL (normal range 4.0–8.0) despite allopurinol therapy, with normal levels of lipids, urea, and creatinine. Polarized light microscopy of aspirated synovial fluid showed monosodium urate crystals, thus confirming the diagnosis.

Rheumatoid arthritis is typically polyarticular and symmetrical and spares the distal interphalangeal joints. Subcutaneous rheumatoid nodules may mimic gouty tophi.

Pseudogout shares some of the features of gout. It results from deposits of calcium pyrophosphate crystals in and around the joints. The diagnosis is made by identifying the crystals on microscopy when calcinosis is seen on x-ray. Tophaceous nodules almost never occur.

Xanthoma tuberosum is associated with hypercholesterolemia, particularly with elevated levels of low-density lipoprotein cholesterol. Lesions occur on pressure areas such as the knees or elbows and vary in size and shape from small papules to firm, lobulated tumors. They are yellow or orange, often with an erythematous halo. They are not associated with chronic proliferative arthritis.

CLINICAL PRESENTATION OF GOUT

Gout is a common metabolic disease characterized by an intermittent course of acute inflammatory arthritis initially affecting one or a few joints. Almost all patients have hyperuricemia, but serum urate levels can be normal or low during an acute attack. On the other hand, many hyperuricemic patients never have a clinical event.

If the hyperuricemia is untreated, some patients develop chronic polyarthritis and nephrolithiasis.¹ Inadequate treatment of hyperuricemia may result in chronic tophaceous gout. Although tophaceous gout usually is a sign of long-standing hyperuricemia, tophi can in rare cases be a first symptom of the disorder.²

Even though our patient had been on allopurinol therapy, the dose was not high enough to achieve a serum urate level significantly below the saturation point of urate (about 6.7 mg/dL).

A healthy 47-year-old woman presents with a 3-day history of widespread asymptomatic lesions in the extremities, fever, arthralgias, and mild abdominal pain. A physical examination reveals a symmetric rash in the lower legs with erythematous purple papules. These papules do not blanch when pressure is applied and so are clinically compatible with palpable purpura (Figure 1). Skin biopsy shows leukocytoclastic vasculitis with immunoglobulin A (IgA) deposits in the vascular wall.

Q: Which is the most likely diagnosis?

• Idiopathic thrombocytopenic purpura
• Vitamin C deficiency (scurvy)
• Kaposi sarcoma not related to human immunodeficiency virus (HIV) infection
• Henoch-Schönlein purpura
• Polyarteritis nodosa

A: The correct answer is Henoch-Schönlein purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease caused by specific antibodies against platelet-membrane glycoproteins. It is characterized by thrombocytopenia not explainable by contact with toxic substances or by other causes. Along with nonpalpable purpura, other common signs are epistaxis, gingival bleeding, menorrhagia, and retinal hemorrhage.

Scurvy is an uncommon deficiency of ascorbic acid (vitamin C). The elderly and alcoholics are at higher risk, as they do not take in enough vitamin C in the diet. Patients usually show perifollicular hemorrhages of the skin and mucous membranes, typically petechial hemorrhage or ecchymosis of the gums around the upper incisors. Other cutaneous signs are follicular hyperkeratosis on the forearms, small corkscrew hairs, and sicca syndrome, which is more common in adults.

Non-HIV Kaposi sarcoma usually affects elderly patients, with pink, red, or brown papules or nodules on the legs and, less commonly, on the head and neck. Histopathologic examination shows newly formed irregular blood vessels with an inflammatory infiltrate of plasma cells and lymphocytes; immunohistochemical human herpes virus staining is usually positive.

Polyarteritis nodosa is a systemic vasculitis that affects medium or small arteries with necrotizing inflammation; renal glomeruli and arterioles, capillaries, and venules are unaffected. Skin manifestations include palpable purpura, livedo reticularis, ulcers, and distal gangrene. The condition also usually affects the kidneys, the heart, and the musculoskeletal and nervous systems.

 

A SYSTEMIC VASCULITIS

Henoch-Schönlein purpura is a systemic vasculitis affecting the skin, gastrointestinal tract, kidneys, and joints. Palpable purpura and joint pain are the most common and consistent presenting symptoms. The kidneys are affected in about one-third of children and in 60% of adults, and this is the major factor determining the long-term outcome.¹

In our patient, laboratory testing that included a complete blood cell count, biochemical testing (including IgA levels), urinary sediment, and coagulation studies showed no abnormalities except elevations of the erythrocyte sedimentation rate and the concentration of C-reactive protein (an acute-phase reactant). These can be normal in some patients. Renal involvement was also not present.

DIAGNOSIS

The diagnosis relies on clinical manifestations. Because Henoch-Schönlein purpura is less common in adults, biopsy plays a more important role in establishing the diagnosis in this age group, and it does this by demonstrating leukocytoclastic vasculitis with a predominance of IgA deposition under immunofluorescence. Recent studies in children showed that an elevated IgA concentration along with reduced IgM levels was associated with a higher rate of severe complications.² However, depending on the age of the biopsied lesion, IgA may not be detected.

TREATMENT DIRECTED AT SYMPTOMS

Our patient received oral corticosteroids 0.5 mg/kg per day for 20 days, and the lesions resolved by 4 weeks.

Management of Henoch-Schönlein purpura is mainly directed at the symptoms, with oral hydration and nonsteroidal anti-inflammatory drugs. For severe cases, a short course of corticosteroids (0.5–1 mg/kg) may be used.

Although no controlled clinical trial has proven that Henoch-Schönlein purpura responds to corticosteroids, colchicine, or other drugs, corticosteroids are used most often, especially in patients with renal disease. Patients with severe renal insufficiency, abdominal pain, joint involvement, or bleeding should be hospitalized. Plasmapheresis³ has been used in severe cases.

HENOCH-SCHÖNLEIN PURPURA AND MALIGNANCY

During a follow-up evaluation 1 month later, our patient was diagnosed with adenocarcinoma of the breast. This highlights the value of a workup for cancer in adults with cutaneous vasculitis.

Cutaneous vasculitis can represent a paraneoplastic syndrome associated with a malignant tumor. The pathophysiology of this association is unclear, but one proposed mechanism is the exaggerated production of antibodies that react against tumor neoantigens, leading to the formation of immune complexes, or that occasionally recognize endothelial cells because of similarities with tumor antigens. Another theory is that abnormally high levels of inflammatory cytokines are produced by neoplastic cells or in response to decreased immune complex clearance.

Yet another theory is that hyperviscosity of the blood, seen in some cancers, increases the contact time for deposition of immune complexes and causes endothelial damage. Drugs used to treat cancer have also been reported to produce Henoch-Schönlein purpura.⁴

Although hematologic malignancy is three to five times more common than solid tumors in patients with small-vessel vasculitis, the disease has been associated with solid tumors of the liver, skin, colon, and breast in adults over age 40.⁵ An evaluation for neoplasm is therefore reasonable in adults with Henoch-Schönlein purpura, as is an evaluation for tumor recurrence or metastasis if the patient has been previously treated for a malignant tumor.

A healthy 47-year-old woman presents with a 3-day history of widespread asymptomatic lesions in the extremities, fever, arthralgias, and mild abdominal pain. A physical examination reveals a symmetric rash in the lower legs with erythematous purple papules. These papules do not blanch when pressure is applied and so are clinically compatible with palpable purpura (Figure 1). Skin biopsy shows leukocytoclastic vasculitis with immunoglobulin A (IgA) deposits in the vascular wall.

Q: Which is the most likely diagnosis?

• Idiopathic thrombocytopenic purpura
• Vitamin C deficiency (scurvy)
• Kaposi sarcoma not related to human immunodeficiency virus (HIV) infection
• Henoch-Schönlein purpura
• Polyarteritis nodosa

A: The correct answer is Henoch-Schönlein purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease caused by specific antibodies against platelet-membrane glycoproteins. It is characterized by thrombocytopenia not explainable by contact with toxic substances or by other causes. Along with nonpalpable purpura, other common signs are epistaxis, gingival bleeding, menorrhagia, and retinal hemorrhage.

Scurvy is an uncommon deficiency of ascorbic acid (vitamin C). The elderly and alcoholics are at higher risk, as they do not take in enough vitamin C in the diet. Patients usually show perifollicular hemorrhages of the skin and mucous membranes, typically petechial hemorrhage or ecchymosis of the gums around the upper incisors. Other cutaneous signs are follicular hyperkeratosis on the forearms, small corkscrew hairs, and sicca syndrome, which is more common in adults.

Non-HIV Kaposi sarcoma usually affects elderly patients, with pink, red, or brown papules or nodules on the legs and, less commonly, on the head and neck. Histopathologic examination shows newly formed irregular blood vessels with an inflammatory infiltrate of plasma cells and lymphocytes; immunohistochemical human herpes virus staining is usually positive.

Polyarteritis nodosa is a systemic vasculitis that affects medium or small arteries with necrotizing inflammation; renal glomeruli and arterioles, capillaries, and venules are unaffected. Skin manifestations include palpable purpura, livedo reticularis, ulcers, and distal gangrene. The condition also usually affects the kidneys, the heart, and the musculoskeletal and nervous systems.

 

A SYSTEMIC VASCULITIS

Henoch-Schönlein purpura is a systemic vasculitis affecting the skin, gastrointestinal tract, kidneys, and joints. Palpable purpura and joint pain are the most common and consistent presenting symptoms. The kidneys are affected in about one-third of children and in 60% of adults, and this is the major factor determining the long-term outcome.¹

In our patient, laboratory testing that included a complete blood cell count, biochemical testing (including IgA levels), urinary sediment, and coagulation studies showed no abnormalities except elevations of the erythrocyte sedimentation rate and the concentration of C-reactive protein (an acute-phase reactant). These can be normal in some patients. Renal involvement was also not present.

DIAGNOSIS

The diagnosis relies on clinical manifestations. Because Henoch-Schönlein purpura is less common in adults, biopsy plays a more important role in establishing the diagnosis in this age group, and it does this by demonstrating leukocytoclastic vasculitis with a predominance of IgA deposition under immunofluorescence. Recent studies in children showed that an elevated IgA concentration along with reduced IgM levels was associated with a higher rate of severe complications.² However, depending on the age of the biopsied lesion, IgA may not be detected.

TREATMENT DIRECTED AT SYMPTOMS

Our patient received oral corticosteroids 0.5 mg/kg per day for 20 days, and the lesions resolved by 4 weeks.

Management of Henoch-Schönlein purpura is mainly directed at the symptoms, with oral hydration and nonsteroidal anti-inflammatory drugs. For severe cases, a short course of corticosteroids (0.5–1 mg/kg) may be used.

Although no controlled clinical trial has proven that Henoch-Schönlein purpura responds to corticosteroids, colchicine, or other drugs, corticosteroids are used most often, especially in patients with renal disease. Patients with severe renal insufficiency, abdominal pain, joint involvement, or bleeding should be hospitalized. Plasmapheresis³ has been used in severe cases.

HENOCH-SCHÖNLEIN PURPURA AND MALIGNANCY

During a follow-up evaluation 1 month later, our patient was diagnosed with adenocarcinoma of the breast. This highlights the value of a workup for cancer in adults with cutaneous vasculitis.

Cutaneous vasculitis can represent a paraneoplastic syndrome associated with a malignant tumor. The pathophysiology of this association is unclear, but one proposed mechanism is the exaggerated production of antibodies that react against tumor neoantigens, leading to the formation of immune complexes, or that occasionally recognize endothelial cells because of similarities with tumor antigens. Another theory is that abnormally high levels of inflammatory cytokines are produced by neoplastic cells or in response to decreased immune complex clearance.

Yet another theory is that hyperviscosity of the blood, seen in some cancers, increases the contact time for deposition of immune complexes and causes endothelial damage. Drugs used to treat cancer have also been reported to produce Henoch-Schönlein purpura.⁴

Although hematologic malignancy is three to five times more common than solid tumors in patients with small-vessel vasculitis, the disease has been associated with solid tumors of the liver, skin, colon, and breast in adults over age 40.⁵ An evaluation for neoplasm is therefore reasonable in adults with Henoch-Schönlein purpura, as is an evaluation for tumor recurrence or metastasis if the patient has been previously treated for a malignant tumor.

A healthy 47-year-old woman presents with a 3-day history of widespread asymptomatic lesions in the extremities, fever, arthralgias, and mild abdominal pain. A physical examination reveals a symmetric rash in the lower legs with erythematous purple papules. These papules do not blanch when pressure is applied and so are clinically compatible with palpable purpura (Figure 1). Skin biopsy shows leukocytoclastic vasculitis with immunoglobulin A (IgA) deposits in the vascular wall.

Q: Which is the most likely diagnosis?

• Idiopathic thrombocytopenic purpura
• Vitamin C deficiency (scurvy)
• Kaposi sarcoma not related to human immunodeficiency virus (HIV) infection
• Henoch-Schönlein purpura
• Polyarteritis nodosa

A: The correct answer is Henoch-Schönlein purpura.

Idiopathic thrombocytopenic purpura is an autoimmune disease caused by specific antibodies against platelet-membrane glycoproteins. It is characterized by thrombocytopenia not explainable by contact with toxic substances or by other causes. Along with nonpalpable purpura, other common signs are epistaxis, gingival bleeding, menorrhagia, and retinal hemorrhage.

Scurvy is an uncommon deficiency of ascorbic acid (vitamin C). The elderly and alcoholics are at higher risk, as they do not take in enough vitamin C in the diet. Patients usually show perifollicular hemorrhages of the skin and mucous membranes, typically petechial hemorrhage or ecchymosis of the gums around the upper incisors. Other cutaneous signs are follicular hyperkeratosis on the forearms, small corkscrew hairs, and sicca syndrome, which is more common in adults.

Non-HIV Kaposi sarcoma usually affects elderly patients, with pink, red, or brown papules or nodules on the legs and, less commonly, on the head and neck. Histopathologic examination shows newly formed irregular blood vessels with an inflammatory infiltrate of plasma cells and lymphocytes; immunohistochemical human herpes virus staining is usually positive.

Polyarteritis nodosa is a systemic vasculitis that affects medium or small arteries with necrotizing inflammation; renal glomeruli and arterioles, capillaries, and venules are unaffected. Skin manifestations include palpable purpura, livedo reticularis, ulcers, and distal gangrene. The condition also usually affects the kidneys, the heart, and the musculoskeletal and nervous systems.

 

A SYSTEMIC VASCULITIS

Henoch-Schönlein purpura is a systemic vasculitis affecting the skin, gastrointestinal tract, kidneys, and joints. Palpable purpura and joint pain are the most common and consistent presenting symptoms. The kidneys are affected in about one-third of children and in 60% of adults, and this is the major factor determining the long-term outcome.¹

In our patient, laboratory testing that included a complete blood cell count, biochemical testing (including IgA levels), urinary sediment, and coagulation studies showed no abnormalities except elevations of the erythrocyte sedimentation rate and the concentration of C-reactive protein (an acute-phase reactant). These can be normal in some patients. Renal involvement was also not present.

DIAGNOSIS

The diagnosis relies on clinical manifestations. Because Henoch-Schönlein purpura is less common in adults, biopsy plays a more important role in establishing the diagnosis in this age group, and it does this by demonstrating leukocytoclastic vasculitis with a predominance of IgA deposition under immunofluorescence. Recent studies in children showed that an elevated IgA concentration along with reduced IgM levels was associated with a higher rate of severe complications.² However, depending on the age of the biopsied lesion, IgA may not be detected.

TREATMENT DIRECTED AT SYMPTOMS

Our patient received oral corticosteroids 0.5 mg/kg per day for 20 days, and the lesions resolved by 4 weeks.

Management of Henoch-Schönlein purpura is mainly directed at the symptoms, with oral hydration and nonsteroidal anti-inflammatory drugs. For severe cases, a short course of corticosteroids (0.5–1 mg/kg) may be used.

Although no controlled clinical trial has proven that Henoch-Schönlein purpura responds to corticosteroids, colchicine, or other drugs, corticosteroids are used most often, especially in patients with renal disease. Patients with severe renal insufficiency, abdominal pain, joint involvement, or bleeding should be hospitalized. Plasmapheresis³ has been used in severe cases.

HENOCH-SCHÖNLEIN PURPURA AND MALIGNANCY

During a follow-up evaluation 1 month later, our patient was diagnosed with adenocarcinoma of the breast. This highlights the value of a workup for cancer in adults with cutaneous vasculitis.

Cutaneous vasculitis can represent a paraneoplastic syndrome associated with a malignant tumor. The pathophysiology of this association is unclear, but one proposed mechanism is the exaggerated production of antibodies that react against tumor neoantigens, leading to the formation of immune complexes, or that occasionally recognize endothelial cells because of similarities with tumor antigens. Another theory is that abnormally high levels of inflammatory cytokines are produced by neoplastic cells or in response to decreased immune complex clearance.

Yet another theory is that hyperviscosity of the blood, seen in some cancers, increases the contact time for deposition of immune complexes and causes endothelial damage. Drugs used to treat cancer have also been reported to produce Henoch-Schönlein purpura.⁴

Although hematologic malignancy is three to five times more common than solid tumors in patients with small-vessel vasculitis, the disease has been associated with solid tumors of the liver, skin, colon, and breast in adults over age 40.⁵ An evaluation for neoplasm is therefore reasonable in adults with Henoch-Schönlein purpura, as is an evaluation for tumor recurrence or metastasis if the patient has been previously treated for a malignant tumor.