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Necrosing livedo reticularis in a patient with recurrent pulmonary hemorrhage
Necrosing livedo reticularis in a patient with recurrent pulmonary hemorrhage David M. Aronoff, MD, and Jeffrey R Callen, MD Louisville, Kentucky
The antiphospholipid antibody (APS) syndrome is characterized by antiphospholipid antibodies (lupus anticoagulant [LA] or anticardiolipin [aCL], a recurrent arterial and venous thrombosis, recurrent fetal loss, and thrombocytopenia. Pulmonary hemorrhage is an unusual complication. We describe a 32-year-old woman with a history of recurrent pulmonary hemorrhage and transient renal dysfunction. Her original diagnosis was Goodpasture's syndrome, and she was treated with imrnunosuppressive drugs. Necrosing livedo reticularis of the legs subsequently developed. The presence of aCL and LA in the patient's serum, the finding of noninflammatory microthrombi in the dermal capillaries, and the lack of laboratory or pathologic features of Goodpasture's syndrome, confirmed a diagnosis of APS in this patient. (J Am Acad Dermatol 1997;37:300-2.)
The antiphospholipid antibody syndrome (APS) is characterized by circulating antiphospholipid immunoglobins, thrombocytopenia, and intravascular thrombi. 1 Pulmonary arteritis and renal failure from microvascular thrombosis may also occur. 26 We describe a patient with APS with recurrent pulmonary hemorrhage and transient hematuria and proteinuria. CASE REPORT A 32-year-old woman had a sudden massive pulmonary hemorrhage. This was preceded 3 months earlier by myalgia, arthralgia, fever, chills, sweats, and a productive cough with blood-tinged sputum. Examination revealed an obese, febrile (99.8 ° F), mildly hypertensive (140/95 mm Hg) woman. Chest examination was abnormal and revealed diffusely coarse breath sounds bilaterally. Laboratory findings included the following: hematocrit 33% (normal, 35% to 45%), Westergren erythrocyte sedimentation rate 78 mm/hr (normal, 0 to 20 mm/hr), and activated partial thomboplastin time 56 seconds (normal, 22 to 32 seconds). Urinalysis revealed microscopic hematuria and 1+ proteinuria, but no casts.
From the Division of Dermatology, Department of Medicine,Universityof Louisville,School of Medicine. Reprint requests: Jeffrey P. Callen,MD, 310 E. Broadway, #200, Louisville,KY 40202. Copyright © 1997 by the AmericanAcademyof Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/80005 OFITHO
~
300
Fig. 1. Biopsy specimen showing noninflammatory, bland thrombi filling multiple small vessels in dermis. (Hematoxylin-eosin stain; original magnification xlO0.) Her blood urea nitrogen and creatinine levels were normal. Antinuclear antibody was positive 1:150 homogeneous, and an anticardiolipin IgG antibody was highly positive at 115.1 GPL units (normal, <20). A chest x-ray examination and computed tomography scan showed bilateral, diffuse, fluffy alveolar infiltrates. Anti-nDNA, anti-Sin, anti-UiRNP, and anti-Ro (SS-A) antibodies were absent. The patient received parenteral antibiotics for a possible pneumonia, and her symptoms abated. During the next several months she continued to have intermittent hemoptysis. A slightly elevated antiglomerular basement membrane antibody was noted and a working diagnosis of Goodpasture's syndrome was made
Journal of the American Academy of Dermatology Volume 37, Number 2, Part 2
despite nonspecific histologic and immunopathologic findings in lung and kidney biopsy specimens. She was treated with prednisone, 60 mg/day, and cyclophosphamide, 100 mg/day. She had another episode of massive pulmonary hemorrhage accompanied by acute respiratory failure. Livedo reticularis was noted on her palms and sotes. Her cyclophosphamide and prednisone therapy was continued in varying doses for the next 2 years. Her condition gradually improved but was complicated by hemorrhagic cystitis. Oral chlorambucil, 6 mg/day, was substituted for the cyclophosphamide. Her prednisone dosage was slowly reduced and eventually stopped, as was the chlorambucil. Thereafter, the patient noted painful skin lesions on her legs and feet. Examination revealed a reticulated pattern of purpura on the dorsum of the feet that extended onto her toes bilaterally. She also had some areas of erythema and small ulcerations on the medial aspect of both lower extremities just above the ankles. Two-plus pitting edema was also noted on both lower extremities. A biopsy specimen demonstrated bland thrombi within numerous capillary-sized vessels within the dermis (Fig. 1). Extravasated red blood cells and hemosiderin-laden macrophages were also noted. There was no inflammation or fibrinous degeneration of the vessel walls. Immunofluorescence microscopy was nonspecific. Laboratory studies for cryoglobulins and cryofibrinogen were negative, but the anticardiolipin IgG level was elevated. These findings led to a diagnosis of primary APS. The patient was treated with oral enteric coated aspirin, 325 mg daily. One year later she noted progressive small ulcerations of the skin on her ankles. Examination revealed slightly palpable, purpuric reticulated areas bilaterally on the legs, with more prominent erosions and crusts over the fight medial malleolus (Fig. 2). She was again given oral chlorambucil, 4 mg daily, with oral hydroxychloroquine, 200 mg twice a day. Six months later, her cutaneous lesions were inactive. The chlorambucil was stopped, and aspirin and hydroxychloroquine were continued. She has had no further episodes of pulmonary hemorrhage or evidence of respiratory, renal, or cardiac dysfunction, but her skin lesions reactivated 6 months later. DISCUSSION
APS is characterized by antiphospholipid antibodies (lupus anticoagulant or anticardiolipin), arterial and venous thrombosis, recurrent fetal loss, and thrombocytopenia. 1 A variety of cutaneous manifestations occur in this syndrome. 7 Livedo reticularis and leg ulcerations are both common. 7 Pulmonary hemorrhage has been uncommonly associated with APS.2-6
Aronoffand Callen 301
Fig. 2. Purpuric livedo reticularis with small areas of necrosis and ulceration.
Conditions that can manifest as livedo reticularis have in common an impairment of the cutaneous circulation. The differential diagnosis of necrosing livedo reticularis includes APS, cryoglobulinemia, polyarteritis nodosa, cryofibrinogenemia, and Wegener's granulomatosis. Sneddon's syndrome, a triad of livedo reticularis, hypertension, and neurologic thrombotic events, can also present with necrosing livedo reticularis. 8 Emboli resulting from cholesterol crystals, atrial myxoma, or bacterial endocarditis may produce similar lesions. The differential diagnosis of pulmonary hemorrhage includes focal diseases of the lung panenchyma and airways, as well as diffuse processes involving the pulmonary microvasculature and alveoli. Autoimmune diseases such as Goodpasture's syndrome, Wegener's granulomatosis, and systemic lupus erythematosus can involve multiple systems, including the lungs and kidneys. The combination of lung hemorrhage and nephritis is commonly presumed to be Goodpasture's syndrome. However in a recent report by Niles et al., 9 the majority of patients were found to have antineutrophil cytoplasmic antibodies rather than antiglomerular basement membrane antibodies. In a minority of patients, including those with an antineutrophil cytoplasmic antibody, Wegener's granulomatosis was not found to be the cause of the pulmonary-renal syndrom. Within this report there were two patients with APS, one of whom had pulmonary emboli. Other causes of lung hemorrhage with nephritis include microscopic polyarteritis, Henoch-Sch6nlein purpura, and mixed cryoglobulinemia. Pulmonary hemorrhage in APS may be multi-
302 Aronoffand Callen factorial. In a recent review, Asherson and Cervera 1° identified eight reported pulmonary processes that complicate APS. We were unable to demonstrate evidence of pulmonary emboli or coagulopathy (other than APS) in our patient, and because her pulmonary, cardiac, and renal functions were not permanently impaired, we postulate that intraalveolar pulmonary hemorrhage was the cause. The optimal treatment for patients with APS is unclear. The major manifestations of the illness result from recurrent arterial and venous thromboses. The cause of the thrombosis is not well understood. 11 Evidence exists that the antiphospholipid antibodies themselves are directly harmful, but other studies suggest that the antibodies are merely markers for an underlying abnormality of a coagulation protein or platelets or endothelial cells. Given the lack of understanding of its pathogenesis, APS is often treated with an empiric regimen of immunosuppressive, antiplatelet, and anticoagulant drugs. 12 The treatment of the leg ulcers in patients with APS is also varied. The successful use of intralesional corticosteroid injections has been reported. 13 Heparin, in combination with intravenous thrombolytics such as urokinase and tissue plasminogen activator, has also been reported as effective. 14 Our patient was treated with hydroxychloroquine and chlorambucil. Hydroxychloroquine has been reported to decrease the risk of thromboembolism in patients with systemic lupus erythematosus. 15 Although there have been no studies on the use of chlorambucil, our patient seemed to respond to that drug on two occasions. REFERENCES 1. Petri M. Antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibody. Curr Prob Dermatol 1992;4:173-5.
Journal of the American Academy of Dermatology August 1997
2. Howe HS, Boey ML, Fong KY, et al. Pulmonary hemorrhage, pulmonary infarction, and the lupus anticoagulant. Ann Rheum Dis 1988;47:869-72. 3. Craussman RS, Achenbach GA, Pluss WT, et al. Pulmonary capillaritis and alveolar hemorrhage associated with the antiphospholipid antibody syndrome. J Rheumatol 1995;22:554-6. 4. Gertner E, Lie JT. Pulmonary capillaritis, alveolar hemorrhage, and recurrent microvascular thrombosis in primary antiphospholipid antibody syndrome. J Rheumatol 1993;20:1224-8. 5. Hillerdal G, Hagg A, Licke G, et al. Intra-alveolar hemorrhage in the anticardiolipin antibody syndrome. Scand J Rheumatol 1991;20:58-62. 6. Piette JC, Cacoub P, Wechsler B. Renal manifestations of the antiphospholipid antibody syndrome. Semin Arthritis Rheum 1994;23:357-66. 7. Asherson RA, Cervera R. Antiphospholipid antibody syndrome. J Invest Dermatol 1993;100:21S-7S. 8. Sneddon lB. Cardiovascular lesions and livedo reticularis. Br J Dermatol 1965;77:180-5. 9. Niles JL, Bottinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCAassociated condition. Arch Intern Med 1996;156:440-5. 10. Asherson RA, Cervera R. Review: antiphospholipid antibodies and the lung. J Rheumatol 1995;22:62-6. 11. Lockshin MD. Answers to the antiphospholipid antibody syndrome? (Editorial.) N Engl J Med 1995;332:1025-7. 12. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid antibody syndrome. N Engl J Med 1995;332:993-7. 13. Falanga V, Kirsner RS, Eaglstein WH, et al. Stanozolol in the treatment of leg ulcer due to cryofibrinogenemia. Lancet 1991;1:347-8. 14. Gertner E, Lie J. Systemic therapy with fibrinolytic agents and heparin for recalcitrant nonhealing cutaneous ulcer in the antiphospholipid syndrome. J Rheumatol 1994;21:2159-61. 15. Petri M, Hellman D, Hochberg M, et al. Arterial thrombotic events (TE) in SLE: the Baltimore Lupus Cohort Study (Abstract). Arthritis Rheum 1994;37:$297.
The antiphospholipid antibody (APS) syndrome is characterized by antiphospholipid antibodies (lupus anticoagulant [LA] or anticardiolipin [aCL], a recurrent arterial and venous thrombosis, recurrent fetal loss, and thrombocytopenia. Pulmonary hemorrhage is an unusual complication. We describe a 32-year-old woman with a history of recurrent pulmonary hemorrhage and transient renal dysfunction. Her original diagnosis was Goodpasture's syndrome, and she was treated with imrnunosuppressive drugs. Necrosing livedo reticularis of the legs subsequently developed. The presence of aCL and LA in the patient's serum, the finding of noninflammatory microthrombi in the dermal capillaries, and the lack of laboratory or pathologic features of Goodpasture's syndrome, confirmed a diagnosis of APS in this patient. (J Am Acad Dermatol 1997;37:300-2.)
The antiphospholipid antibody syndrome (APS) is characterized by circulating antiphospholipid immunoglobins, thrombocytopenia, and intravascular thrombi. 1 Pulmonary arteritis and renal failure from microvascular thrombosis may also occur. 26 We describe a patient with APS with recurrent pulmonary hemorrhage and transient hematuria and proteinuria. CASE REPORT A 32-year-old woman had a sudden massive pulmonary hemorrhage. This was preceded 3 months earlier by myalgia, arthralgia, fever, chills, sweats, and a productive cough with blood-tinged sputum. Examination revealed an obese, febrile (99.8 ° F), mildly hypertensive (140/95 mm Hg) woman. Chest examination was abnormal and revealed diffusely coarse breath sounds bilaterally. Laboratory findings included the following: hematocrit 33% (normal, 35% to 45%), Westergren erythrocyte sedimentation rate 78 mm/hr (normal, 0 to 20 mm/hr), and activated partial thomboplastin time 56 seconds (normal, 22 to 32 seconds). Urinalysis revealed microscopic hematuria and 1+ proteinuria, but no casts.
From the Division of Dermatology, Department of Medicine,Universityof Louisville,School of Medicine. Reprint requests: Jeffrey P. Callen,MD, 310 E. Broadway, #200, Louisville,KY 40202. Copyright © 1997 by the AmericanAcademyof Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/4/80005 OFITHO
~
300
Fig. 1. Biopsy specimen showing noninflammatory, bland thrombi filling multiple small vessels in dermis. (Hematoxylin-eosin stain; original magnification xlO0.) Her blood urea nitrogen and creatinine levels were normal. Antinuclear antibody was positive 1:150 homogeneous, and an anticardiolipin IgG antibody was highly positive at 115.1 GPL units (normal, <20). A chest x-ray examination and computed tomography scan showed bilateral, diffuse, fluffy alveolar infiltrates. Anti-nDNA, anti-Sin, anti-UiRNP, and anti-Ro (SS-A) antibodies were absent. The patient received parenteral antibiotics for a possible pneumonia, and her symptoms abated. During the next several months she continued to have intermittent hemoptysis. A slightly elevated antiglomerular basement membrane antibody was noted and a working diagnosis of Goodpasture's syndrome was made
Journal of the American Academy of Dermatology Volume 37, Number 2, Part 2
despite nonspecific histologic and immunopathologic findings in lung and kidney biopsy specimens. She was treated with prednisone, 60 mg/day, and cyclophosphamide, 100 mg/day. She had another episode of massive pulmonary hemorrhage accompanied by acute respiratory failure. Livedo reticularis was noted on her palms and sotes. Her cyclophosphamide and prednisone therapy was continued in varying doses for the next 2 years. Her condition gradually improved but was complicated by hemorrhagic cystitis. Oral chlorambucil, 6 mg/day, was substituted for the cyclophosphamide. Her prednisone dosage was slowly reduced and eventually stopped, as was the chlorambucil. Thereafter, the patient noted painful skin lesions on her legs and feet. Examination revealed a reticulated pattern of purpura on the dorsum of the feet that extended onto her toes bilaterally. She also had some areas of erythema and small ulcerations on the medial aspect of both lower extremities just above the ankles. Two-plus pitting edema was also noted on both lower extremities. A biopsy specimen demonstrated bland thrombi within numerous capillary-sized vessels within the dermis (Fig. 1). Extravasated red blood cells and hemosiderin-laden macrophages were also noted. There was no inflammation or fibrinous degeneration of the vessel walls. Immunofluorescence microscopy was nonspecific. Laboratory studies for cryoglobulins and cryofibrinogen were negative, but the anticardiolipin IgG level was elevated. These findings led to a diagnosis of primary APS. The patient was treated with oral enteric coated aspirin, 325 mg daily. One year later she noted progressive small ulcerations of the skin on her ankles. Examination revealed slightly palpable, purpuric reticulated areas bilaterally on the legs, with more prominent erosions and crusts over the fight medial malleolus (Fig. 2). She was again given oral chlorambucil, 4 mg daily, with oral hydroxychloroquine, 200 mg twice a day. Six months later, her cutaneous lesions were inactive. The chlorambucil was stopped, and aspirin and hydroxychloroquine were continued. She has had no further episodes of pulmonary hemorrhage or evidence of respiratory, renal, or cardiac dysfunction, but her skin lesions reactivated 6 months later. DISCUSSION
APS is characterized by antiphospholipid antibodies (lupus anticoagulant or anticardiolipin), arterial and venous thrombosis, recurrent fetal loss, and thrombocytopenia. 1 A variety of cutaneous manifestations occur in this syndrome. 7 Livedo reticularis and leg ulcerations are both common. 7 Pulmonary hemorrhage has been uncommonly associated with APS.2-6
Aronoffand Callen 301
Fig. 2. Purpuric livedo reticularis with small areas of necrosis and ulceration.
Conditions that can manifest as livedo reticularis have in common an impairment of the cutaneous circulation. The differential diagnosis of necrosing livedo reticularis includes APS, cryoglobulinemia, polyarteritis nodosa, cryofibrinogenemia, and Wegener's granulomatosis. Sneddon's syndrome, a triad of livedo reticularis, hypertension, and neurologic thrombotic events, can also present with necrosing livedo reticularis. 8 Emboli resulting from cholesterol crystals, atrial myxoma, or bacterial endocarditis may produce similar lesions. The differential diagnosis of pulmonary hemorrhage includes focal diseases of the lung panenchyma and airways, as well as diffuse processes involving the pulmonary microvasculature and alveoli. Autoimmune diseases such as Goodpasture's syndrome, Wegener's granulomatosis, and systemic lupus erythematosus can involve multiple systems, including the lungs and kidneys. The combination of lung hemorrhage and nephritis is commonly presumed to be Goodpasture's syndrome. However in a recent report by Niles et al., 9 the majority of patients were found to have antineutrophil cytoplasmic antibodies rather than antiglomerular basement membrane antibodies. In a minority of patients, including those with an antineutrophil cytoplasmic antibody, Wegener's granulomatosis was not found to be the cause of the pulmonary-renal syndrom. Within this report there were two patients with APS, one of whom had pulmonary emboli. Other causes of lung hemorrhage with nephritis include microscopic polyarteritis, Henoch-Sch6nlein purpura, and mixed cryoglobulinemia. Pulmonary hemorrhage in APS may be multi-
302 Aronoffand Callen factorial. In a recent review, Asherson and Cervera 1° identified eight reported pulmonary processes that complicate APS. We were unable to demonstrate evidence of pulmonary emboli or coagulopathy (other than APS) in our patient, and because her pulmonary, cardiac, and renal functions were not permanently impaired, we postulate that intraalveolar pulmonary hemorrhage was the cause. The optimal treatment for patients with APS is unclear. The major manifestations of the illness result from recurrent arterial and venous thromboses. The cause of the thrombosis is not well understood. 11 Evidence exists that the antiphospholipid antibodies themselves are directly harmful, but other studies suggest that the antibodies are merely markers for an underlying abnormality of a coagulation protein or platelets or endothelial cells. Given the lack of understanding of its pathogenesis, APS is often treated with an empiric regimen of immunosuppressive, antiplatelet, and anticoagulant drugs. 12 The treatment of the leg ulcers in patients with APS is also varied. The successful use of intralesional corticosteroid injections has been reported. 13 Heparin, in combination with intravenous thrombolytics such as urokinase and tissue plasminogen activator, has also been reported as effective. 14 Our patient was treated with hydroxychloroquine and chlorambucil. Hydroxychloroquine has been reported to decrease the risk of thromboembolism in patients with systemic lupus erythematosus. 15 Although there have been no studies on the use of chlorambucil, our patient seemed to respond to that drug on two occasions. REFERENCES 1. Petri M. Antiphospholipid antibodies: lupus anticoagulant and anticardiolipin antibody. Curr Prob Dermatol 1992;4:173-5.
Journal of the American Academy of Dermatology August 1997
2. Howe HS, Boey ML, Fong KY, et al. Pulmonary hemorrhage, pulmonary infarction, and the lupus anticoagulant. Ann Rheum Dis 1988;47:869-72. 3. Craussman RS, Achenbach GA, Pluss WT, et al. Pulmonary capillaritis and alveolar hemorrhage associated with the antiphospholipid antibody syndrome. J Rheumatol 1995;22:554-6. 4. Gertner E, Lie JT. Pulmonary capillaritis, alveolar hemorrhage, and recurrent microvascular thrombosis in primary antiphospholipid antibody syndrome. J Rheumatol 1993;20:1224-8. 5. Hillerdal G, Hagg A, Licke G, et al. Intra-alveolar hemorrhage in the anticardiolipin antibody syndrome. Scand J Rheumatol 1991;20:58-62. 6. Piette JC, Cacoub P, Wechsler B. Renal manifestations of the antiphospholipid antibody syndrome. Semin Arthritis Rheum 1994;23:357-66. 7. Asherson RA, Cervera R. Antiphospholipid antibody syndrome. J Invest Dermatol 1993;100:21S-7S. 8. Sneddon lB. Cardiovascular lesions and livedo reticularis. Br J Dermatol 1965;77:180-5. 9. Niles JL, Bottinger EP, Saurina GR, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCAassociated condition. Arch Intern Med 1996;156:440-5. 10. Asherson RA, Cervera R. Review: antiphospholipid antibodies and the lung. J Rheumatol 1995;22:62-6. 11. Lockshin MD. Answers to the antiphospholipid antibody syndrome? (Editorial.) N Engl J Med 1995;332:1025-7. 12. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid antibody syndrome. N Engl J Med 1995;332:993-7. 13. Falanga V, Kirsner RS, Eaglstein WH, et al. Stanozolol in the treatment of leg ulcer due to cryofibrinogenemia. Lancet 1991;1:347-8. 14. Gertner E, Lie J. Systemic therapy with fibrinolytic agents and heparin for recalcitrant nonhealing cutaneous ulcer in the antiphospholipid syndrome. J Rheumatol 1994;21:2159-61. 15. Petri M, Hellman D, Hochberg M, et al. Arterial thrombotic events (TE) in SLE: the Baltimore Lupus Cohort Study (Abstract). Arthritis Rheum 1994;37:$297.