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Cutaneous reactions to recombinant human interferon beta-1b: The clinical and histologic spectrum
CLINICAL AND LABORATORY STUDIES Cutaneous reactions to recombinant human interferon beta- lb: The clinical and histologic spectrum George W. Elgart, MD, William Sheremata, MD, and Yeon S. Ahn, MD Miami, Florida
Background: Recombinant human interferon beta-lb has been recently approved for the treatment of multiple sclerosis. A significant proportion of patients treated with this medication experienced cutaneous reactions. Objective: We describe the clinical and histologic features of cutaneous reactions to recombinant human interferon beta- lb. Methods: Consecutive patients with cutaneous reactions to recombinant interferon betalb were evaluated clinically and by biopsy. Results: Clinical lesions varied from subtle uninflamed sclerotic dermal plaques to erythematous plaques to cutaneous ulcers at injection sites. The nonsclerotic lesions were frequently painful. The firm plaques showed fibrosis histologically, whereas nonsclerotic inflammatory lesions demonstrated a consistent pattern of vascular thrombosis. Hematologic evaluation demonstrated platelet activation in most patients with inflammatory lesions, a feature also noted before interferon treatment in some patients. Conclusion: Therapy with recombinant interferon beta-lb is associated with a spectrum of cutaneous reactions and vascular thrombosis. (J Am Acad Dermatol 1997;37:553-8.)
The cause and pathogenesis of multiple sclerosis are unknown. However, the demonstration of numerous immunologic abnormalities has led to the belief that immunologic mechanisms are important in its pathogenesis.1 Despite controversy in some quarters over the certainty of an immune cause, 2 this has been responsible for many trials of immunomodulatory medications including the only one with demonstrated value, interferon beta. 3,4 Recombinant human interferon beta-lb (Betaseron, Berlex, Wayne, N.J.) was approved by the Food and Drug Administration in 1993 for the treatment of multiple sclerosis. It differs from natural human interferon beta at a single amino acid residue. 5 A serine residue is substituted for cysteine at position 17 enhancing the stability of the From the Departments of Dermatology and Cutaneous Surgery, Neurology, and Hematology/Oncology, University of Miami School of Medicine. Accepted for publication May 2, 1997. Reprint requests: George W. Elgart, MD, Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, 1444 N.W. 9th Ave., Miami, FL 33136. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/82927
Fig. 1. Clinical appearance of index patient. Deep cutaneous ulcer with necrotic base and irregular border.
recombinant molecule. 6 Subcutaneous injections are given at least two to three times weekly. Studies have demonstrated an approximately 30% decrease in the frequency of multiple sclerosis exacerbations in human interferon beta-lb-treated patients. 3,4 We have observed 10 patients treated with this medication who had a spectrum of cutaneous clinical and histologic findings. 553
554 Elgart, Sheremata, and Ahn
Journal of the American Academy of Dermatology October 1997
Fig. 2. Erythematous plaque lesion. Orange-red minimally raised plaque from patient 4. Lesion partially blanches with pressure.
Fig. 3. Intermediate lesion from patient 5 with epidermal necrosis centrally and underlying orange erythema.
METHODS Multiple sclerosis patients receiving recombinant human interferon beta-lb and referred for cutaneous reactions were evaluated. Skin biopsies were performed on all patients. Two specimens were obtained on separate visits from patient 4. Formalin-fixed tissue was routinely processed, and hematoxylin-andeosin-stained sections were reviewed. Stains for fibrin (phosphotungstic acid-hematoxylin), fungi (periodic acid-Schiff), elastic tissue (Verhoeff-Van Gieson), and mucin (Alcian blue, pH 2.5) were performed. RESULTS
Clinical findings Ten patients of nearly 100 under therapy with
human interferon beta-lb seen in a 9-month period were examined. The index patient was reported previously. 7 She experienced extensive deep skin ulcers and a livedo pattern of the nonulcerated skin (Fig. 1). Subsequent patients have shown less severe cutaneous features of three main lesion types: ulcers, erythematous plaques, and deep farm dermal plaques. Ulcers were present in six patients receiving human interferon beta-lb. These occurred weeks to months after therapy at the injection sites. Because most patients rotated their injection sites, many could recall precisely when the specific affected site had last been injected. The period varied from a week to more than a month.
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Elgart, Sheremata, and Ahn 555
Fig. 4. Histology from patient 2. Thrombosed dermal vein. (Hematoxylin-eosin stain; original magnification xl0.)
Fig. 5. Histology from patient 5. Epidermal ulcer with adherent crust. (Hematoxylin-eosin stain; original magnification x4.)
In the severe reactions observed, an initial erythema (Fig. 2) in the injection site cleared and was replaced by a gray discoloration (Fig. 3) that subsequently degenerated and formed an ulcer. Several lesions were exquisitely tender. The ulcer extended in several days to replace the site of the cutaneous discoloration. Two patients had livedo reticularis in the skin surrounding the injection-
site lesions. Lesions were slow to heal as were biopsy sites. Erythematous plaques were seen in four patients including two of the patients with ulcers. The plaques were slightly raised and had a poorly defined border. They were not warmer than the surrounding skin. In several patients, the plaques had an orange color rather than the violaceous
556
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Elgart, Sheremata, and Ahn
Fig. 6. Histology from patient 3. Necrotic epidermis with superficial dermal inflammation. (Hematoxylin-eosin stain; original magnification x40.)
Table I. Case No.
1 2 3 4A 4B 5 6 7 8 9
S u m m a r y o f the histologic findings in our cases Inflammation
+/+ + +/+ + +
Neutrophils
Lymphocytes
Thrombi
Necrosis
Mucin
+ +/+ -
++ + +/++ + + + + ++ +
+ +/+ + +/+ +
+ Ulcer +++ Superficial necrosis + Ulcer -
+ + + +
e r y t h e m a s u r r o u n d i n g ulcers. T h e o r a n g e - c o l o r e d e r y t h e m a t o u s l e s i o n s w e r e t e n d e r and also a p p e a r e d at injection sites. Their time o f o c c u r rence was similar to the ulcers. A striking feature was the t e n d e n c y to persist for w e e k s to months. Additionally, b i o p s y sites w e r e often slow to heal and several required in excess o f 2 m o n t h s for c o m p l e t e epithelialization. Sclerotic firm d e r m a l plaques w e r e present in t w o patients. T h e s e w e r e not raised. In o n e patient, the lesions w e r e a p p r o x i m a t e l y 3 c m in d i a m e t e r and tender. T h e other patient had lesions a p p r o x i m a t e l y 8 m m in diameter. A s with the i n f l a m m a t o r y l e s i o n s , the s c l e r o t i c p l a q u e s a p p e a r e d at sites patients used for injections.
Histopathologic findings T h e h i s t o p a t h o l o g i c features o f the i n f l a m m a tory nonsclerotic lesions w e r e similar despite the variable clinical appearance. T h e m o s t frequent features w e r e a superficial mild perivascular infiltrate, w h e r e a s d e e p e r vessels, m a i n l y venules, d e m o n s t r a t e d t h r o m b o s i s (Table I). In the original case p r e v i o u s l y reported, 7 the b i o p s y s p e c i m e n w a s s u p e r f i c i a l a n d d e m o n s t r a t e d o n l y the perivascular inflammation. S u b s e q u e n t m o r e generous specimens consistently demonstrated t h r o m b i in the l o w e r p o r t i o n o f the dermis or subc u t a n e o u s tissue (Fig. 4). L e u k o c y t o c l a s t i c vasculitis was absent, even in s p e c i m e n s f r o m acute cases.
Journal of the American Academy of Dermatology Volume 37, Number 4
The ulcerated lesions initially demonstrated necrosis of the most superficial layers of the epidermis (Fig. 5) that progressed to ulceration (Fig. 6). Many of the ulcers demonstrated features of partial thickness wound repair with some epithelialization, superficial dermal fibrosis, and inflammation. A bed of granulation tissue was not detected in any of our cases. It is unclear whether evidence of repair is merely evidence of the relatively late stage at which many of the patients presented. The sclerotic lesions lacked significant inflammation. The main feature was a poorly circumscribed increase in reticular dermal collagen.
Laboratory findings The presence of thrombi in the deep portion of the dermal vessels raised the possibility that this finding could be related to a clotting abnormality. Hematologic evaluation revealed abnormalities of platelet aggregation in all interferon-treated patients and in occasional multiple sclerosis patients before interferon treatment. The patients demonstrated a consistent activation of platelets as determined by a platelet microparticle assay and by expression of CD62 on the platelet surface.
DISCUSSION The cutaneous findings in these patients are a spectrum that progress from an erythematous plaque to surface necrosis and eventually to ulceration with slow healing. Two patients had a livedo pattern surrounding the ulcers. Thrombosis of dermal venules was often present on histologic examination. 8 Evaluation of our patients has demonstrated that several had abnormalities of platelet activation. Some multiple sclerosis patients demonstrated these abnormalities before interferon therapy, suggesting that the underlying disease m a y cause platelet activation which, in some manner, was enhanced by recombinant human interferon betalb therapy. There is some evidence that multiple sclerosis patients have enhanced platelet aggregation. 9 Additionally, a study in cancer patients has shown an increase of in vitro platelet aggregation during interferon beta administration, l° These findings support platelet-dependent thrombosis as the cause of recombinant human interferon betaIb-related skin abnormalities. Studies of skin reactions to recombinant human
Elgart, Sheremata, and Ahn 557 interferon beta- lb suggest necrotizing vasculitis I 1 as the m e c h a n i s m or did not comment. 12 Vasculitis other than a mild pefivascular lymphocytic infiltrate was absent in our patients. Skin ulcerations may be caused by other thrombotic disorders such as warfarin necrosis, 13,!4 cryofibrinogenemia, 15,16 purpura fulminans, 17,18 and the antiphospholipid s y n d r o m e ) 9,2° In each of these, a form of consumptive coagulopathy incites vascular thrombosis 21 and m a y proceed to localized cutaneous necrosis. These conditions were not present in our patients and the skin lesions observed were localized to the sites of the injections rather than the symmetric and widespread necrosis observed in the these coagulopathies. All of the patients recovered with scarring after cessation of therapy.
REFERENCES 1. Williams KC, Ulvestad E, Hickey WE Immunology of multiple sclerosis. Clin Neurosci 1994;2:229-45. 2. Gulcher JR, Vartanian T, Stefansson K. Is multiple sclerosis an autoimmune disease? Clin Neurosci 1994;2:24652. 3. Panitch HS, Bever CT Jr. Clinical trials of interferons in multiple sclerosis: What have we learned? Neuroimmunology 1993;46:155-64. 4. Panitch HS. Interferons in multiple sclerosis: a review of the evidence. Drugs 1992;44:946-62. 5. Betaseron (interferon beta-lb) product information. Physician's Desk Reference. Montvale (NJ): Medical Economics Company; 1996. p. 658-63. 6. Khosrovi B. The production, characterization, and testing of a modified recombinant human interferon beta. In: Zoon K, Noguchi P, Liu T-Y, editors. Interferon: research, clinical application, and regulatory consideration. Amsterdam: Elsevier; 1984. p. 89-99. 7, Sheremata WA, Taylor JR, Elgart GW. Severe necrotizing cutaneous lesions complicating treatment with interferon beta-lb [letter]. N Engl J Med 1995;332:1584. 8. Sheremata WA, Taylor JR, Elgart GW. More on interferon-induced cutaneous necrosis (reply to letter). N Engl J Med 1995;333:1223-4. 9. Prosiegel M, Neu I, Mehlber L. Encephalitogenic peptide and platelet aggregation in multiple sclerosis. Acta Neurol Scand 1986;73:141-4. 10. Ferroni R Roselli M, Diodatti A, et al. Effects on platelet function by human interferon-beta in carcinoma patients. Anticancer Res 1994;14:2779-84. 11. Rest EB, Yokel BK, Bart BJ. Local reactions to injection to recombinant human beta interferon [abstract]. J Cutan Pathol 1995;22:81. 12. Webster GE Knobler RL, Lubin FD, et al. Cutaneous ulcerations and pustular psoriasis flare caused by recombinant interferon beta injections in patients with multiple sclerosis. J Am Acad Dermatol 1996;34:365-7. 13. Eby CS. Warfarin-inducedskin necrosis. Hematol Oncol Clin North Am 1993;7:1291-300. 14. Kirby JD, Marriott PJ. Skin necrosis following warfarin therapy. Br J Dermatol 1976;94:97-9.
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15. Beightler E, Diven DG, Sanchez RL, et al. Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol 1991;24:342-5. 16. Klein AD, Kerdel FA. Purpura and recurrent ulcers on the lower extremities. Essential cryofibrinogenemia. Arch Dermatol 1991;127:115, 118. 17. Phillips WG, Marsden JR, Hill FG. Purpura fulminans due to protein S deficiency following chickenpox. Br J Dermatol 1992;127:30-2. 18. Benson PM, Lupton GP, James WD. Purpura and gangrene in a septic patient: purpura fulminans secondary to
Journal of the American Academy of Dermatology October 1997
pneumococcal sepsis. Arch Dermatol 1988; 124:1851, 1854. 19. Abernethy ML, McGuinn JL, Callen JP. Widespread cutaneous necrosis as the initial manifestation of the antiphospholipid antibody syndrome. J Rheumatol 1995 ;22:1380-3. 20. Lockshin MD. Answers to the antiphospholipid antibody syndrome? N Engl J Med 1995;332:993-7. 21. Rubin RN, Colman RW. Disseminated intravascular coagulation. Drags 1992;44:963-97.
Background: Recombinant human interferon beta-lb has been recently approved for the treatment of multiple sclerosis. A significant proportion of patients treated with this medication experienced cutaneous reactions. Objective: We describe the clinical and histologic features of cutaneous reactions to recombinant human interferon beta- lb. Methods: Consecutive patients with cutaneous reactions to recombinant interferon betalb were evaluated clinically and by biopsy. Results: Clinical lesions varied from subtle uninflamed sclerotic dermal plaques to erythematous plaques to cutaneous ulcers at injection sites. The nonsclerotic lesions were frequently painful. The firm plaques showed fibrosis histologically, whereas nonsclerotic inflammatory lesions demonstrated a consistent pattern of vascular thrombosis. Hematologic evaluation demonstrated platelet activation in most patients with inflammatory lesions, a feature also noted before interferon treatment in some patients. Conclusion: Therapy with recombinant interferon beta-lb is associated with a spectrum of cutaneous reactions and vascular thrombosis. (J Am Acad Dermatol 1997;37:553-8.)
The cause and pathogenesis of multiple sclerosis are unknown. However, the demonstration of numerous immunologic abnormalities has led to the belief that immunologic mechanisms are important in its pathogenesis.1 Despite controversy in some quarters over the certainty of an immune cause, 2 this has been responsible for many trials of immunomodulatory medications including the only one with demonstrated value, interferon beta. 3,4 Recombinant human interferon beta-lb (Betaseron, Berlex, Wayne, N.J.) was approved by the Food and Drug Administration in 1993 for the treatment of multiple sclerosis. It differs from natural human interferon beta at a single amino acid residue. 5 A serine residue is substituted for cysteine at position 17 enhancing the stability of the From the Departments of Dermatology and Cutaneous Surgery, Neurology, and Hematology/Oncology, University of Miami School of Medicine. Accepted for publication May 2, 1997. Reprint requests: George W. Elgart, MD, Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, 1444 N.W. 9th Ave., Miami, FL 33136. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97/$5.00 + 0 16/1/82927
Fig. 1. Clinical appearance of index patient. Deep cutaneous ulcer with necrotic base and irregular border.
recombinant molecule. 6 Subcutaneous injections are given at least two to three times weekly. Studies have demonstrated an approximately 30% decrease in the frequency of multiple sclerosis exacerbations in human interferon beta-lb-treated patients. 3,4 We have observed 10 patients treated with this medication who had a spectrum of cutaneous clinical and histologic findings. 553
554 Elgart, Sheremata, and Ahn
Journal of the American Academy of Dermatology October 1997
Fig. 2. Erythematous plaque lesion. Orange-red minimally raised plaque from patient 4. Lesion partially blanches with pressure.
Fig. 3. Intermediate lesion from patient 5 with epidermal necrosis centrally and underlying orange erythema.
METHODS Multiple sclerosis patients receiving recombinant human interferon beta-lb and referred for cutaneous reactions were evaluated. Skin biopsies were performed on all patients. Two specimens were obtained on separate visits from patient 4. Formalin-fixed tissue was routinely processed, and hematoxylin-andeosin-stained sections were reviewed. Stains for fibrin (phosphotungstic acid-hematoxylin), fungi (periodic acid-Schiff), elastic tissue (Verhoeff-Van Gieson), and mucin (Alcian blue, pH 2.5) were performed. RESULTS
Clinical findings Ten patients of nearly 100 under therapy with
human interferon beta-lb seen in a 9-month period were examined. The index patient was reported previously. 7 She experienced extensive deep skin ulcers and a livedo pattern of the nonulcerated skin (Fig. 1). Subsequent patients have shown less severe cutaneous features of three main lesion types: ulcers, erythematous plaques, and deep farm dermal plaques. Ulcers were present in six patients receiving human interferon beta-lb. These occurred weeks to months after therapy at the injection sites. Because most patients rotated their injection sites, many could recall precisely when the specific affected site had last been injected. The period varied from a week to more than a month.
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Elgart, Sheremata, and Ahn 555
Fig. 4. Histology from patient 2. Thrombosed dermal vein. (Hematoxylin-eosin stain; original magnification xl0.)
Fig. 5. Histology from patient 5. Epidermal ulcer with adherent crust. (Hematoxylin-eosin stain; original magnification x4.)
In the severe reactions observed, an initial erythema (Fig. 2) in the injection site cleared and was replaced by a gray discoloration (Fig. 3) that subsequently degenerated and formed an ulcer. Several lesions were exquisitely tender. The ulcer extended in several days to replace the site of the cutaneous discoloration. Two patients had livedo reticularis in the skin surrounding the injection-
site lesions. Lesions were slow to heal as were biopsy sites. Erythematous plaques were seen in four patients including two of the patients with ulcers. The plaques were slightly raised and had a poorly defined border. They were not warmer than the surrounding skin. In several patients, the plaques had an orange color rather than the violaceous
556
Journal of the American Academy of Dermatology October 1997
Elgart, Sheremata, and Ahn
Fig. 6. Histology from patient 3. Necrotic epidermis with superficial dermal inflammation. (Hematoxylin-eosin stain; original magnification x40.)
Table I. Case No.
1 2 3 4A 4B 5 6 7 8 9
S u m m a r y o f the histologic findings in our cases Inflammation
+/+ + +/+ + +
Neutrophils
Lymphocytes
Thrombi
Necrosis
Mucin
+ +/+ -
++ + +/++ + + + + ++ +
+ +/+ + +/+ +
+ Ulcer +++ Superficial necrosis + Ulcer -
+ + + +
e r y t h e m a s u r r o u n d i n g ulcers. T h e o r a n g e - c o l o r e d e r y t h e m a t o u s l e s i o n s w e r e t e n d e r and also a p p e a r e d at injection sites. Their time o f o c c u r rence was similar to the ulcers. A striking feature was the t e n d e n c y to persist for w e e k s to months. Additionally, b i o p s y sites w e r e often slow to heal and several required in excess o f 2 m o n t h s for c o m p l e t e epithelialization. Sclerotic firm d e r m a l plaques w e r e present in t w o patients. T h e s e w e r e not raised. In o n e patient, the lesions w e r e a p p r o x i m a t e l y 3 c m in d i a m e t e r and tender. T h e other patient had lesions a p p r o x i m a t e l y 8 m m in diameter. A s with the i n f l a m m a t o r y l e s i o n s , the s c l e r o t i c p l a q u e s a p p e a r e d at sites patients used for injections.
Histopathologic findings T h e h i s t o p a t h o l o g i c features o f the i n f l a m m a tory nonsclerotic lesions w e r e similar despite the variable clinical appearance. T h e m o s t frequent features w e r e a superficial mild perivascular infiltrate, w h e r e a s d e e p e r vessels, m a i n l y venules, d e m o n s t r a t e d t h r o m b o s i s (Table I). In the original case p r e v i o u s l y reported, 7 the b i o p s y s p e c i m e n w a s s u p e r f i c i a l a n d d e m o n s t r a t e d o n l y the perivascular inflammation. S u b s e q u e n t m o r e generous specimens consistently demonstrated t h r o m b i in the l o w e r p o r t i o n o f the dermis or subc u t a n e o u s tissue (Fig. 4). L e u k o c y t o c l a s t i c vasculitis was absent, even in s p e c i m e n s f r o m acute cases.
Journal of the American Academy of Dermatology Volume 37, Number 4
The ulcerated lesions initially demonstrated necrosis of the most superficial layers of the epidermis (Fig. 5) that progressed to ulceration (Fig. 6). Many of the ulcers demonstrated features of partial thickness wound repair with some epithelialization, superficial dermal fibrosis, and inflammation. A bed of granulation tissue was not detected in any of our cases. It is unclear whether evidence of repair is merely evidence of the relatively late stage at which many of the patients presented. The sclerotic lesions lacked significant inflammation. The main feature was a poorly circumscribed increase in reticular dermal collagen.
Laboratory findings The presence of thrombi in the deep portion of the dermal vessels raised the possibility that this finding could be related to a clotting abnormality. Hematologic evaluation revealed abnormalities of platelet aggregation in all interferon-treated patients and in occasional multiple sclerosis patients before interferon treatment. The patients demonstrated a consistent activation of platelets as determined by a platelet microparticle assay and by expression of CD62 on the platelet surface.
DISCUSSION The cutaneous findings in these patients are a spectrum that progress from an erythematous plaque to surface necrosis and eventually to ulceration with slow healing. Two patients had a livedo pattern surrounding the ulcers. Thrombosis of dermal venules was often present on histologic examination. 8 Evaluation of our patients has demonstrated that several had abnormalities of platelet activation. Some multiple sclerosis patients demonstrated these abnormalities before interferon therapy, suggesting that the underlying disease m a y cause platelet activation which, in some manner, was enhanced by recombinant human interferon betalb therapy. There is some evidence that multiple sclerosis patients have enhanced platelet aggregation. 9 Additionally, a study in cancer patients has shown an increase of in vitro platelet aggregation during interferon beta administration, l° These findings support platelet-dependent thrombosis as the cause of recombinant human interferon betaIb-related skin abnormalities. Studies of skin reactions to recombinant human
Elgart, Sheremata, and Ahn 557 interferon beta- lb suggest necrotizing vasculitis I 1 as the m e c h a n i s m or did not comment. 12 Vasculitis other than a mild pefivascular lymphocytic infiltrate was absent in our patients. Skin ulcerations may be caused by other thrombotic disorders such as warfarin necrosis, 13,!4 cryofibrinogenemia, 15,16 purpura fulminans, 17,18 and the antiphospholipid s y n d r o m e ) 9,2° In each of these, a form of consumptive coagulopathy incites vascular thrombosis 21 and m a y proceed to localized cutaneous necrosis. These conditions were not present in our patients and the skin lesions observed were localized to the sites of the injections rather than the symmetric and widespread necrosis observed in the these coagulopathies. All of the patients recovered with scarring after cessation of therapy.
REFERENCES 1. Williams KC, Ulvestad E, Hickey WE Immunology of multiple sclerosis. Clin Neurosci 1994;2:229-45. 2. Gulcher JR, Vartanian T, Stefansson K. Is multiple sclerosis an autoimmune disease? Clin Neurosci 1994;2:24652. 3. Panitch HS, Bever CT Jr. Clinical trials of interferons in multiple sclerosis: What have we learned? Neuroimmunology 1993;46:155-64. 4. Panitch HS. Interferons in multiple sclerosis: a review of the evidence. Drugs 1992;44:946-62. 5. Betaseron (interferon beta-lb) product information. Physician's Desk Reference. Montvale (NJ): Medical Economics Company; 1996. p. 658-63. 6. Khosrovi B. The production, characterization, and testing of a modified recombinant human interferon beta. In: Zoon K, Noguchi P, Liu T-Y, editors. Interferon: research, clinical application, and regulatory consideration. Amsterdam: Elsevier; 1984. p. 89-99. 7, Sheremata WA, Taylor JR, Elgart GW. Severe necrotizing cutaneous lesions complicating treatment with interferon beta-lb [letter]. N Engl J Med 1995;332:1584. 8. Sheremata WA, Taylor JR, Elgart GW. More on interferon-induced cutaneous necrosis (reply to letter). N Engl J Med 1995;333:1223-4. 9. Prosiegel M, Neu I, Mehlber L. Encephalitogenic peptide and platelet aggregation in multiple sclerosis. Acta Neurol Scand 1986;73:141-4. 10. Ferroni R Roselli M, Diodatti A, et al. Effects on platelet function by human interferon-beta in carcinoma patients. Anticancer Res 1994;14:2779-84. 11. Rest EB, Yokel BK, Bart BJ. Local reactions to injection to recombinant human beta interferon [abstract]. J Cutan Pathol 1995;22:81. 12. Webster GE Knobler RL, Lubin FD, et al. Cutaneous ulcerations and pustular psoriasis flare caused by recombinant interferon beta injections in patients with multiple sclerosis. J Am Acad Dermatol 1996;34:365-7. 13. Eby CS. Warfarin-inducedskin necrosis. Hematol Oncol Clin North Am 1993;7:1291-300. 14. Kirby JD, Marriott PJ. Skin necrosis following warfarin therapy. Br J Dermatol 1976;94:97-9.
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15. Beightler E, Diven DG, Sanchez RL, et al. Thrombotic vasculopathy associated with cryofibrinogenemia. J Am Acad Dermatol 1991;24:342-5. 16. Klein AD, Kerdel FA. Purpura and recurrent ulcers on the lower extremities. Essential cryofibrinogenemia. Arch Dermatol 1991;127:115, 118. 17. Phillips WG, Marsden JR, Hill FG. Purpura fulminans due to protein S deficiency following chickenpox. Br J Dermatol 1992;127:30-2. 18. Benson PM, Lupton GP, James WD. Purpura and gangrene in a septic patient: purpura fulminans secondary to
Journal of the American Academy of Dermatology October 1997
pneumococcal sepsis. Arch Dermatol 1988; 124:1851, 1854. 19. Abernethy ML, McGuinn JL, Callen JP. Widespread cutaneous necrosis as the initial manifestation of the antiphospholipid antibody syndrome. J Rheumatol 1995 ;22:1380-3. 20. Lockshin MD. Answers to the antiphospholipid antibody syndrome? N Engl J Med 1995;332:993-7. 21. Rubin RN, Colman RW. Disseminated intravascular coagulation. Drags 1992;44:963-97.