310 Letters to the Editor Cutaneous Necrosis after Subcutaneous Injection of Polyethylene-Glycol-modi ed Interferon alpha Hjalmar Kurzen, Detlef Petzoldt, Wolfgang Hartschuh and Uta Jappe Department of Dermatology, University of Heidelberg, Voss-str.2, DE-69115 Heidelberg, Germany. E-mail: [email protected] e Accepted April 19, 2002. Sir, Laboratory examinations revealed leukopenia and anemia, Interferon-a-2b has been shown to be eVective in the although thrombocytes, electrolytes, liver enzymes, urea and creatinine were within normal range. treatment of hepatitis C and malignant melanoma A skin biopsy was taken from the in ammatory margin of (1, 2). In order to improve treatment comfort and the rst lesion. Microscopic examination revealed dilatation eYcacy, polyethylene glycol (PEG) modi cation of of the vessels with extravasation of erythrocytes, but no signs interferon-a-2b has recently been introduced. Injection of vasculitis. The epidermis showed an almost complete frequency can thus be reduced from 3 times a week to necrosis of the basal layer (Fig. 2a). The second site was removed surgically before complete once a week. We report the development of a cutaneous necrosis had occurred. The epidermis and upper parts of the necrosis (embolia cutis medicamentosa) at the injection dermis were necrotic in a wedge-shaped central part sur- site after subcutaneous injection of PEG-modi ed rounded by vasodilatation. Some of the periadnexial small interferon-a-2b in 2 patients with hepatitis C. vessels were partly occluded due to endothelial swelling. Lymphocytes were found perivascularly and around the sweat glands. Occlusion of arterial vessels or larger veins was not CASE REPORT observed. Patient 1 Patient 2 A 44-year-old man with hepatitis C had been receiving treat- A 35-year-old man with hepatitis C developed a painful ment with PEG-modi ed interferon-a 2b (PegIntron 100 mg) 2 ´ 3 cm red in ltrate, surrounded by typical ‘‘blitz gures’’ at subcutaneously once a week since September 2000. The treat- the injection site of PEG-modi ed interferon-a 2b. Prior ment was well tolerated and without any major side eVects. injections had been well tolerated. The in ltration was removed In June 2001, the patient developed a painful reddish-brown surgically, followed by normal healing. The treatment with deep in ltrate, measuring 1.5 ´ 1 cm in diameter, at the injec- tion site on the left abdominal wall, with irregular, but well- marked demarcation like a spark or ‘‘blitz’’ (Fig. 1). One week later the skin overlying the in ltrate had turned dark brown and was painful. The necrosis was surgically removed and the ulcer left to heal using hydrocolloid dressings. The ulcer healed after 4 weeks. Interferon treatment could be continued without modi ca- tion and was well tolerated. However 2 months later, the patient again developed a painful lesion, this time on the right abdominal wall shortly after a PegIntron injection. Topical heparin ointment and oral NSAIDs were ineVective and the lesion was therefore removed surgically, sutured and healed without complications. a b Fig. 2. (a) Almost complete necrosis of the epidermal basal layer Fig. 1. One week after injection of pegylated interferon-a-2b, the (patient 1). The super cial vessels are dilated and lled with erythro- injection site shows a well-demarcated brownish-red surface, 1.5 ´ 1 cm cytes ( ´ 50). (b) Small arterioles in the deeper dermis are occluded in size, overlying a deep, tender in ltrate. Typical ‘‘blitz gures’’ while accompanying veins are widely dilated (patient 2) ( ´ 325); surround the injection site. H&E staining. Acta Derm Venereol 82 Letters to the Editor 311 PEG-modi ed interferon-a-2b could be continued without ocytic in ltrates and karyorhexis has been described. further complications. Laboratory examinations were within Vessel walls showed brinoid necrosis and thrombotic normal range. Histological examination showed a super cial erosion of the occlusion of the vessel lumina with progression of vascu- epidermis and a subepidermal necrosis of the collagenous soft lar and perivascular necrosis (6). In our patients, we tissue. The blood vessels were dilated and lled with erythro- did not detect any signs of vasculitis. In patient 2, we cytes. The adnexal structures were surrounded by a few were able to examine deeper dermal and subcutaneous lymphocytes, histiocytes and neutrophils. In the deeper dermis, vessels because the aVected skin tissue had been small arterioles were completely occluded, while accompanying venoles were widely dilated (Fig. 2b). A major vein in the removed. Occlusion of bigger veins and small arterioles deep dermis showed an almost complete occlusion by throm- by thrombotic material could be demonstrated. In botic material. There were no signs of vasculitis. animal studies, embolia cutis medicamentosa could only be reproduced by direct intra-arterial injection of diVer- DISCUSSION ent drugs, but not via periarterial or intramuscular injections (14). Cutaneous necroses after accidental intra-arterial injec- While polyethylene glycol might lead to unspeci c tions were rst described 80 years ago and seen as side in ammatory reactions, the most likely mechanism for eVects in treating syphilis with bismuth (3, 4). Later, the development of the reported skin necrosis is the the term ‘‘embolia cutis medicamentosa’’ or Nicolau occlusion of an artery, i.e. ischemia. This is in conc- syndrome (5) became widely accepted, referring to pain- ordance with the pain that was observed during the ful erythematous, irregular but well-marked swellings development of the necrosis. after intramuscular injection of drugs into the gluteal In treating embolia cutis medicamentosa, we were area. Apart from bismuth, drugs such as benzathine able to compare three diVerent modalities. In patient 1 penicillin, other antibiotics, anti-rheumatic drugs, phe- the rst necrosis was removed and the wound was left nobarbital, lidocaine, steroids, chlorpromazine and to secondary healing. This resulted in prolonged morbid- mercury can cause this syndrome (6). ity. The second necrosis in patient 1 was treated topically So far, embolia cutis medicamentosa after subcutane- with heparin ointment and oral NSAIDs, which did not ous injection has only been described for heparin and prevent further demarcation and the cutaneous necrosis interferon-a. While in the case of heparin a true immuno- had to be removed surgically. In patient 2, the painful logic or allergic reaction can be found (7), interferon-a in ltrate was removed before complete necrosis had apparently did not lead to an allergic reaction. The cases occurred, resulting in immediate pain relief and primary of embolia cutis medicamentosa after interferon-a injec- wound healing, without complications. We conclude, tion reported elsewhere (8–10) and our cases are charac- therefore, that surgical treatment with primary wound terized by pain as the main symptom and development healing is the treatment of rst choice in embolia cutis of cutaneous ulcerating necrosis after subcutaneous medicamentosa. injection of interferon-a. A watery solution of the pep- tide interferon-a induced the changes. In our patients we utilized the newly developed polyethylene-glycol REFERENCES modi ed (‘‘pegylated’’) interferon-a-2b (PegIntron ). 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