CAMEO
PYODERMA GANGRENOSUM ASSOCIATED WITH ANTIPHOSPHOLIPID ANTIBODIES KENNETH S. BABE JR, ALEXANDER S. GROSS, M.D., WILLIAM H. LEYVA, M.D., ANn LLOYD E. KING Ju, M.D., PH.D.
An otberwise healthy 67-year-old man was seen for evaluation and treatment of painful right ankle skin ulcers. Physical examination revealed two closely situated cutaneous ulcerations measuring 2.0 by 3.0 cm^ and 1.7 by 2.0 cm^ in tbe region of tbe right medial malleolus (Fig. 1). Tbe border of the lesions appeared undermined, and tbe skin between and surrounding them was violaceous in color and infiltrated in texture. Abnormal laboratory values included tbe following: WBC 1780/mm^ Hgb 9.6 g/dL, platelets 81,000/mm^ PTT 40.8 s, Westergren ESR 102 mm/b, C-reactive protein 3.7 mg/dL (NV, 0-0.8), weakly positive RPR, and ANA 1:320 dilutions witb a homogeneous pattern. Anticardiolipin IgG antibodies were detected by ELISA and were quantitated at 33 g/L (0-15). The following were negative or normal: serum chemistries, urinalysis, PT, direct and indirect Coombs test, serum protein electrophoresis, and rheumatoid factor. Biopsy of perilesional skin revealed thrombosis of small and medium sized dermal blood vessels witbout accompanying inflammation or vasculitis {Fig. 2). The patient was treated with oral prednisone 15 mg twice daily, dapsone 100 mg daily, and cephradine 500 mg four times daily. Topical tberapy consisted of normal saline rinses followed by application of silver sulfadiazine cream and a telfa dressing. Over the course of several montbs, tbe skin lesions resolved slowly and completely, wbile tbe patients wbite blood cell counts returned to normal. Tbe patient continues to do well on a maintenance dose of oral aspirin 325 mg daily.
DISCUSSION
Figure 1. Cutaneous ulcerations consistent with pyoderma gangrenosum overlying the right internal malleolus. The edge of tbe lesions have a heaped-up, undermined appearance. Tbe surrounding skin has a violaceous discoloration and infiltrated texture.
Antiphospholipid antibodies (AI'LA) are immunoglobulins directed against a diverse group of phospholipid antigens.' Originally described in a subset of patients with systemic lupus erythematosus (SLE) and recurrent vascular thrombosis,^'-' APLAs include the lupus anticoagulant and anticardiolipin antibodies. Pathogetiically, APLAs produce disease by decreasing prostacyclin forma-
'' interfering with protein C activation/' or inhibiting prekallilkrein activity.^ In addition to thromboocclusive disorders, APLAs are associated with a variety of other laboratory and clinical abnormalities including thrombocytopenia,**'' false positive VDRL,^''" and recttrrent fetal death in utero.^^'^^ Due to the strength of the association of APLAs with these disorders, the concept of the APLA syndrome was proposed.'•'''"' This syndrome occurs both in patients with SLE and as a separate entity.
From tbe Department of Veterans Affairs, Medical Center, Nashville, Tennessee, and the Division of Dermatology, Department of Medicine, Vanderbilt University Medical Cetiter, Nashville, Tennessee. Address for correspondence: Alexander S. Gross, M.D., 2675 North Decatur Road, Suite 601, Decatur, GA 30033. 588
Pyoderma Grangrenosum B.ibe et al.
frequent histologic abnormalities may include capillary proliferation, endarteritis obliterans, hemosiderin deposition, and derma! hemorrhage.'^ The finding of antiphospholipid antibodies in a patient with pyoderma gangrenosum suggests that the role of these antibodies in "idiopathic" and autoimmune disease-related PG requires further investigation. As the interest in APLAs increases, the association of these antibodies with a variety of other cutaneous and systemic disorders is anticipated.
REFERENCES
Figure 2. A fibrin thrombus occludes a superficial dermal blood vessel. There is no significant inflammation present, (hematoxylin and eosin, original magnification x400)
1.
2.
Recently, the role of APLAs in the pathogenesis of skin disease has been described. Livedo reticularis'-''''^' and lower extremity ulcers'^ are the two most commonly observed lesions with gangrene, thrombophlebitis, hemorrhage (ecchymosis and hematoma), and cutaneous necrosis occurring less frequently.''''"* Pyoderma gangrenosum (PG) is a chronic, ulcerative lesion usually found on the lower extremities. The diagnosis is made clinically based on the characteristic appearance of the lesional border, which is described as being heaped up, rolled, or undermined, and the color of the surrounding skin, which is often red-purple or violaceous."'^" Although 40 to 50% of lesions are classified as idiopathic,-^''^^ PG has been associated with a variety of other disorders including ulcerative colitis,^''-'' diabetes mellitus,^^ Wegener's granulomatosis,^'' and leukemia.'^'^* In addition, PG may occur as a sequela of autoimmune diseases including rheumatoid arthritis^''^" and lupus erythematosis.^'''' To our knowledge, the association of antiphospholipid antibodies and pyoderma gangrenosum is previously unreported. A similar case of skin ulceration associated with APLAs has been described,^^ but the authors themselves indicated that classic features of pyoderma gangrenosum were lacking iti their patient's lesion. Although our patient does not meet the American Rheumatologic Association (ARA) criteria for the diagnosis of SLE, he does demonstrate features of the APLA syndrome and cutaneous pathology consistent with APLA-related skin disease. The laboratory findings of thrombocytopenia and elevated PTT are both frequently encountered in patients with APLAs.^'' Although frequently absent, ANAs may also be detected.^''""''' False positive RPR or VDRL occurs in approximately 30% of patients with the APLA syndrome.^''" The pathologic finding of nonvasculitic thrombosis in the biopsy specimen obtained from our patient has also been reported to occur in a high frequency of patients with gangrenous or ulcerative lesions related to APLAs.''' Other
3.
4. 5.
6.
7.
Tripplett DA, Brandt JT, Maas RL. The laboratory heterogeneity of lupus anticoagulant. Arch Pathol Lab 1985; 109:946-951. Mueh JR, Herbst KD, Papaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980; 92:156-159. Boey ML, Colaco CB, Gharavi AE, et al. Thrombosis in systemic lupus erytbetnatosus: striking association with the presence of circulating lupus anticoagulant. BMJ 1983; 287:1021-1023. Alarcon-Segovia D. Pathogenetic potential of antiphospholipid antibodies. J Rbeumatol 1988; 15:890-893. Carreras LO, Defreyn J, Machin SJ, et al. Arterial thrombosis, intrauterine death and lupus anticoagulant: detection of itrtmunoglobulin ititerfering with prostacyclin formation. Lancet 1981; i:244-246. Cariou R, Tobeletn G, Soria C, Caen J. Inhibition of protein C coactivation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314: 1193-1194. Sanfelippo MJ, Drayna CJ. Prekallikrein inhibition associated with the lupus anticoagulant: a mechanistn of thrombosis. Am J Clin Patb 1982; 77:275-279.
8.
Harris EN, Asherson RA, Gharavi AE, et al. Thrombocytopenia in SLE and related autoimmune disorders: as' sociation with anticardiolipin antibodies. Br J Haematol 1985; 59:227-230. 9. Harris EN, Boey ML, Mackworth-Young CG, et al. Anticardiolipin antibodies detectioti by radioimmunoassay and association with thrombosis in systemic lupus erythetnatosus. Lancet 1983; ii:12ri-1214. 10. Elias M, Eldor A. Thrornboembolism in patients with circulatitig anticoagulant. Arch Intern Med 1984; 1 14: 510-515. 11. Nilsson IM, Astedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant ("antithrotnboplastin"). Acta Med Scand 1975; 197:153-159. 12. Loizou S, Byron MA, Englert HJ, et al. Association of quantitative anticardiolipin antibody levels witb fetal loss and time of loss in systemic lupus erytbematosus. Q J Med 1988; 68:525-531. 13. 14.
589
Hughes GRV, Harris EN, Gharavi AE. Tbe anticardiolipin syndrome. J Rheutniatol 1986; 13:486-489. Hughes GRV. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. BMJ 1983; 287:10881089.
International Journal of Dermatology Vol. 31, No. 8, August 1992
15.
16.
17.
18.
19. 20.
21. 22.
23. 24. 25.
sum, rheumatoid arthritis and diabetes mellitus. Arch Dermatol 1966; 94:732-736. 26. Thomas RH, Payne CM, Black MM. Wegener's granulomatosis presenting as pyoderma gangrenosum. Clin Exp Dermatol 1982; 7:523-528. 27. Romano J, Safai B. Pyoderma gangrenosum and myeloproliferative disorders. Arch Intern Med 1979; 139: 932-934. 28. Newell LM, Malkinson FD. Pyoderma gangrenosum. Arch Dermatol 1982; 118:769-773. 29. Powell FC, Schroeter AL, Su WPD, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985; 55:173-186. 30. Stolman LP, Rosenthal D, Yaworsky R, Horan F. Pyoderma gangrenosum and rheumatoid arthritis. Arch Dermatol 1975; 111:1020-1023. 31. Olson K. Pyoderma gangrenosum witb systemic lupus erytbematosis. Acta Derm Venereol (Stockh) 1979; 51: 233-234. 32. Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 1986; 15:211-219. 33. Peterson LL. Hydralazine-induced systemic lupus erythematosus presenting as pyoderma grangrenosum-like ulcers. J Am Acad Dermatol 1984; 10:379-384. 34. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erytbematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112:682-698.
Englert HJ, Loizou S, Derue GGM, et al. Clinical and immunologic features of livedo reticularis in lupus: a case-control study. Am J Med 1989; 87:408-410. Asherson RA, Mayou SC, Merry P, et al. The spectrum of livedo reticularis and anticardiolipin antibodies. Br J Dermatol 1989; 120:215-221. Alegre VA, Winkelmann RK. Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatoi 1988; 19:117-124. O'Neill A, Gatenby PA, McGaw B. Widespread cutaneous necrosis associated with cardioliptn antibodies. J Am Acad Dermatol 1990; 22:356-359. Lever WF, Shaumberg-Lever G. Histopathology of the Skin. 7th Ed. Pbiladelpbia: JB Lippincott, 1990:214. Wolff K, Stingl G. Pyoderma gangrenosum. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in general medicine. 3rd Ed. New York: McGraw-Hill, 1987:1329. Newell LM, Malkinson FD. Pyoderma gangrenosum. Arch Dermatol 1982; 118:769-773. Hickman JG, Lazarus GS. Pyoderma gangrenosum: a reappraisal of associated systemic disease. Br J Dermatol 1980; 102:235-232. Perry HO. Pyoderma gangrenosum. South Med J 1969; 62:899-908. Callen JP, Taylor WB. Pyoderma gangrenosum - a literature review. Cutis 1978; 21:61-64. Philpott JA, Goltz RW, Park RK. Pyoderma gangreno-
Total body tattoo depicting scenes from Richard Wagner's "Ring of the Niebelungen" operas on a Texas physician. Tattoo art by Ed Hardy of San Francisco (late 1980s). From the collection of Norman Goldstein, M.D., Tbe World of Tattoos, Honolulu, Hawaii. 590
PYODERMA GANGRENOSUM ASSOCIATED WITH ANTIPHOSPHOLIPID ANTIBODIES KENNETH S. BABE JR, ALEXANDER S. GROSS, M.D., WILLIAM H. LEYVA, M.D., ANn LLOYD E. KING Ju, M.D., PH.D.
An otberwise healthy 67-year-old man was seen for evaluation and treatment of painful right ankle skin ulcers. Physical examination revealed two closely situated cutaneous ulcerations measuring 2.0 by 3.0 cm^ and 1.7 by 2.0 cm^ in tbe region of tbe right medial malleolus (Fig. 1). Tbe border of the lesions appeared undermined, and tbe skin between and surrounding them was violaceous in color and infiltrated in texture. Abnormal laboratory values included tbe following: WBC 1780/mm^ Hgb 9.6 g/dL, platelets 81,000/mm^ PTT 40.8 s, Westergren ESR 102 mm/b, C-reactive protein 3.7 mg/dL (NV, 0-0.8), weakly positive RPR, and ANA 1:320 dilutions witb a homogeneous pattern. Anticardiolipin IgG antibodies were detected by ELISA and were quantitated at 33 g/L (0-15). The following were negative or normal: serum chemistries, urinalysis, PT, direct and indirect Coombs test, serum protein electrophoresis, and rheumatoid factor. Biopsy of perilesional skin revealed thrombosis of small and medium sized dermal blood vessels witbout accompanying inflammation or vasculitis {Fig. 2). The patient was treated with oral prednisone 15 mg twice daily, dapsone 100 mg daily, and cephradine 500 mg four times daily. Topical tberapy consisted of normal saline rinses followed by application of silver sulfadiazine cream and a telfa dressing. Over the course of several montbs, tbe skin lesions resolved slowly and completely, wbile tbe patients wbite blood cell counts returned to normal. Tbe patient continues to do well on a maintenance dose of oral aspirin 325 mg daily.
DISCUSSION
Figure 1. Cutaneous ulcerations consistent with pyoderma gangrenosum overlying the right internal malleolus. The edge of tbe lesions have a heaped-up, undermined appearance. Tbe surrounding skin has a violaceous discoloration and infiltrated texture.
Antiphospholipid antibodies (AI'LA) are immunoglobulins directed against a diverse group of phospholipid antigens.' Originally described in a subset of patients with systemic lupus erythematosus (SLE) and recurrent vascular thrombosis,^'-' APLAs include the lupus anticoagulant and anticardiolipin antibodies. Pathogetiically, APLAs produce disease by decreasing prostacyclin forma-
'' interfering with protein C activation/' or inhibiting prekallilkrein activity.^ In addition to thromboocclusive disorders, APLAs are associated with a variety of other laboratory and clinical abnormalities including thrombocytopenia,**'' false positive VDRL,^''" and recttrrent fetal death in utero.^^'^^ Due to the strength of the association of APLAs with these disorders, the concept of the APLA syndrome was proposed.'•'''"' This syndrome occurs both in patients with SLE and as a separate entity.
From tbe Department of Veterans Affairs, Medical Center, Nashville, Tennessee, and the Division of Dermatology, Department of Medicine, Vanderbilt University Medical Cetiter, Nashville, Tennessee. Address for correspondence: Alexander S. Gross, M.D., 2675 North Decatur Road, Suite 601, Decatur, GA 30033. 588
Pyoderma Grangrenosum B.ibe et al.
frequent histologic abnormalities may include capillary proliferation, endarteritis obliterans, hemosiderin deposition, and derma! hemorrhage.'^ The finding of antiphospholipid antibodies in a patient with pyoderma gangrenosum suggests that the role of these antibodies in "idiopathic" and autoimmune disease-related PG requires further investigation. As the interest in APLAs increases, the association of these antibodies with a variety of other cutaneous and systemic disorders is anticipated.
REFERENCES
Figure 2. A fibrin thrombus occludes a superficial dermal blood vessel. There is no significant inflammation present, (hematoxylin and eosin, original magnification x400)
1.
2.
Recently, the role of APLAs in the pathogenesis of skin disease has been described. Livedo reticularis'-''''^' and lower extremity ulcers'^ are the two most commonly observed lesions with gangrene, thrombophlebitis, hemorrhage (ecchymosis and hematoma), and cutaneous necrosis occurring less frequently.''''"* Pyoderma gangrenosum (PG) is a chronic, ulcerative lesion usually found on the lower extremities. The diagnosis is made clinically based on the characteristic appearance of the lesional border, which is described as being heaped up, rolled, or undermined, and the color of the surrounding skin, which is often red-purple or violaceous."'^" Although 40 to 50% of lesions are classified as idiopathic,-^''^^ PG has been associated with a variety of other disorders including ulcerative colitis,^''-'' diabetes mellitus,^^ Wegener's granulomatosis,^'' and leukemia.'^'^* In addition, PG may occur as a sequela of autoimmune diseases including rheumatoid arthritis^''^" and lupus erythematosis.^'''' To our knowledge, the association of antiphospholipid antibodies and pyoderma gangrenosum is previously unreported. A similar case of skin ulceration associated with APLAs has been described,^^ but the authors themselves indicated that classic features of pyoderma gangrenosum were lacking iti their patient's lesion. Although our patient does not meet the American Rheumatologic Association (ARA) criteria for the diagnosis of SLE, he does demonstrate features of the APLA syndrome and cutaneous pathology consistent with APLA-related skin disease. The laboratory findings of thrombocytopenia and elevated PTT are both frequently encountered in patients with APLAs.^'' Although frequently absent, ANAs may also be detected.^''""''' False positive RPR or VDRL occurs in approximately 30% of patients with the APLA syndrome.^''" The pathologic finding of nonvasculitic thrombosis in the biopsy specimen obtained from our patient has also been reported to occur in a high frequency of patients with gangrenous or ulcerative lesions related to APLAs.''' Other
3.
4. 5.
6.
7.
Tripplett DA, Brandt JT, Maas RL. The laboratory heterogeneity of lupus anticoagulant. Arch Pathol Lab 1985; 109:946-951. Mueh JR, Herbst KD, Papaport SI. Thrombosis in patients with the lupus anticoagulant. Ann Intern Med 1980; 92:156-159. Boey ML, Colaco CB, Gharavi AE, et al. Thrombosis in systemic lupus erytbetnatosus: striking association with the presence of circulating lupus anticoagulant. BMJ 1983; 287:1021-1023. Alarcon-Segovia D. Pathogenetic potential of antiphospholipid antibodies. J Rbeumatol 1988; 15:890-893. Carreras LO, Defreyn J, Machin SJ, et al. Arterial thrombosis, intrauterine death and lupus anticoagulant: detection of itrtmunoglobulin ititerfering with prostacyclin formation. Lancet 1981; i:244-246. Cariou R, Tobeletn G, Soria C, Caen J. Inhibition of protein C coactivation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314: 1193-1194. Sanfelippo MJ, Drayna CJ. Prekallikrein inhibition associated with the lupus anticoagulant: a mechanistn of thrombosis. Am J Clin Patb 1982; 77:275-279.
8.
Harris EN, Asherson RA, Gharavi AE, et al. Thrombocytopenia in SLE and related autoimmune disorders: as' sociation with anticardiolipin antibodies. Br J Haematol 1985; 59:227-230. 9. Harris EN, Boey ML, Mackworth-Young CG, et al. Anticardiolipin antibodies detectioti by radioimmunoassay and association with thrombosis in systemic lupus erythetnatosus. Lancet 1983; ii:12ri-1214. 10. Elias M, Eldor A. Thrornboembolism in patients with circulatitig anticoagulant. Arch Intern Med 1984; 1 14: 510-515. 11. Nilsson IM, Astedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant ("antithrotnboplastin"). Acta Med Scand 1975; 197:153-159. 12. Loizou S, Byron MA, Englert HJ, et al. Association of quantitative anticardiolipin antibody levels witb fetal loss and time of loss in systemic lupus erytbematosus. Q J Med 1988; 68:525-531. 13. 14.
589
Hughes GRV, Harris EN, Gharavi AE. Tbe anticardiolipin syndrome. J Rheutniatol 1986; 13:486-489. Hughes GRV. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. BMJ 1983; 287:10881089.
International Journal of Dermatology Vol. 31, No. 8, August 1992
15.
16.
17.
18.
19. 20.
21. 22.
23. 24. 25.
sum, rheumatoid arthritis and diabetes mellitus. Arch Dermatol 1966; 94:732-736. 26. Thomas RH, Payne CM, Black MM. Wegener's granulomatosis presenting as pyoderma gangrenosum. Clin Exp Dermatol 1982; 7:523-528. 27. Romano J, Safai B. Pyoderma gangrenosum and myeloproliferative disorders. Arch Intern Med 1979; 139: 932-934. 28. Newell LM, Malkinson FD. Pyoderma gangrenosum. Arch Dermatol 1982; 118:769-773. 29. Powell FC, Schroeter AL, Su WPD, Perry HO. Pyoderma gangrenosum: a review of 86 patients. Q J Med 1985; 55:173-186. 30. Stolman LP, Rosenthal D, Yaworsky R, Horan F. Pyoderma gangrenosum and rheumatoid arthritis. Arch Dermatol 1975; 111:1020-1023. 31. Olson K. Pyoderma gangrenosum witb systemic lupus erytbematosis. Acta Derm Venereol (Stockh) 1979; 51: 233-234. 32. Grob JJ, Bonerandi JJ. Cutaneous manifestations associated with the presence of the lupus anticoagulant. J Am Acad Dermatol 1986; 15:211-219. 33. Peterson LL. Hydralazine-induced systemic lupus erythematosus presenting as pyoderma grangrenosum-like ulcers. J Am Acad Dermatol 1984; 10:379-384. 34. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erytbematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112:682-698.
Englert HJ, Loizou S, Derue GGM, et al. Clinical and immunologic features of livedo reticularis in lupus: a case-control study. Am J Med 1989; 87:408-410. Asherson RA, Mayou SC, Merry P, et al. The spectrum of livedo reticularis and anticardiolipin antibodies. Br J Dermatol 1989; 120:215-221. Alegre VA, Winkelmann RK. Histopathologic and immunofluorescence study of skin lesions associated with circulating lupus anticoagulant. J Am Acad Dermatoi 1988; 19:117-124. O'Neill A, Gatenby PA, McGaw B. Widespread cutaneous necrosis associated with cardioliptn antibodies. J Am Acad Dermatol 1990; 22:356-359. Lever WF, Shaumberg-Lever G. Histopathology of the Skin. 7th Ed. Pbiladelpbia: JB Lippincott, 1990:214. Wolff K, Stingl G. Pyoderma gangrenosum. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al., eds. Dermatology in general medicine. 3rd Ed. New York: McGraw-Hill, 1987:1329. Newell LM, Malkinson FD. Pyoderma gangrenosum. Arch Dermatol 1982; 118:769-773. Hickman JG, Lazarus GS. Pyoderma gangrenosum: a reappraisal of associated systemic disease. Br J Dermatol 1980; 102:235-232. Perry HO. Pyoderma gangrenosum. South Med J 1969; 62:899-908. Callen JP, Taylor WB. Pyoderma gangrenosum - a literature review. Cutis 1978; 21:61-64. Philpott JA, Goltz RW, Park RK. Pyoderma gangreno-
Total body tattoo depicting scenes from Richard Wagner's "Ring of the Niebelungen" operas on a Texas physician. Tattoo art by Ed Hardy of San Francisco (late 1980s). From the collection of Norman Goldstein, M.D., Tbe World of Tattoos, Honolulu, Hawaii. 590
