Cutaneous necrosis associated with recombinant interferon injection

CORRESPONDENCE Cutaneous necrosis associated with recombinant interferon injection To the Editor: I read with interest the article by Elgart et al entitled "Cutaneous Reactions to Recombinant Human Interferon beta-l b: The Clinical and Histologic Spectrum" (J Am Acad Dermatol 1997;37:553-8). We recently reviewed all cases of cutaneous necrosis associated with recombinant interferon (IFN) injection.! It is important to clarify that ulceration and findings of vascular thrombosis with interferon use are not restricted to IFN-~lb and patients with multiple sclerosis. Cnudde et al 2 first reported recombinant IFN-a-induced cutaneous necrosis at injection sites in a patient with AIDSrelated Kaposi's sarcoma (KS). Two months after treatment, this patient developed localized erythema, induration, and finally necrosis at the injection sites. A skin biopsy specimen revealed thrombotic occlusion of venules. The patient had a history of congenital type II antithrombin III deficiency but normal protein C and S levels. The authors theorized that local necrosis resulted from a procoagulant activity of IFN, possibly provoked or potentiated by the antithrombin III deficiency. Orlow and Friedman-Kien3 subsequently described a similar case of cutaneous ulcerations at sites of repeated injections of IFN-a2b in a patient with KS. In an additional case involving IFN-a therapy,4 a patient with AIDSrelated KS developed atrophic plaques on the lower abdomen at the sites of IFN injection. Histologic examination showed that these lesions had necrotic changes within large venules deep in the dermis. In addition to the cases reported by Elgart et aI, Berard et al 5 described a 56-year-old man in whom cutaneous necrosis developed at injection sites in the abdominal area after 6 months of treatment with IFN-~. A biopsy specimen revealed fibrin thrombosis of deep dermal vessels. There was no evidence of a coagulation abnormality in this patient. We also described 3 cases of ulceration caused by IFN-~ injections in patients with multiple sclerosis.! Biopsy was performed in only one case; there was no evidence of vascular thrombosis. In two of our cases, the patients were able to continue use of the IFN injections without further cutaneous ulceration. These cases of cutaneous ulceration in patients receiving interferon therapy suggest possible pathologic mechanisms. Most of the cases with documented histologic findings suggest that thrombosis and necrosis of dermal vessels are important etiologic factors. Such a local procoagulant effect may be caused by a toxic effect of the drug on the endothelium or a localized deficiency of an anticoagulant such as protein c. 4 Orlow and Friedman-Kien3 attributed cutaneous ulceration to repeated injections in the same area. As in our Journal of the American Academy of Dennatology

first and second cases, this patient was able to continue injections in other skin sites without further complications. Most recently, Webster et al 6 hypothesized that production of endogenous mediators or coadministered medications may create situations promoting ulceration or that there may be a vasospastic effect of the drug. They reported 1 patient who continued to use the IFN in whom the ulcerations ceased. Therefore they stated that the conditions favoring ulceration may be transitory. Additional cases will provide more information on the pathogenesis of cutaneous necrosis occurring after IFN therapy. Biopsy data will be helpful in elucidating mechanisms and may help to define subsets of cutaneous necrosis. In particular, it may be possible to define groups of patients in whom the therapy must be discontinued. This latter group may include those who are predisposed to local thrombosis of dermal vessels as a result of an inherited or acquired coagulopathy and therefore will not be able to tolerate treatment. Jeffrey M. Weinberg, MD Department of Dermatology New York Medical College-Metropolitan Hospital Center 1901 First Ave New York, NY 10029

REFERENCES 1. Weinberg JM, Wolfe JT, Sood S, Saruk M, Rook AH, Spiers EM. Cutaneous necrosis associated with recombinant interferon injection: report of three cases with interferon beta-1 b and review of the literature. Acta Derm Venereol (Stockh) 1997;77: 146-8. 2. Cnudde F, Gharakhanian S, Luboinski J, Dry J, Rozenbaum W. Cutaneous local necrosis following interferon injections [letter]. Int J DennatoI1991;30:147. 3. Orlow SJ, Friedman-Kien AB. Cutaneous ulceration secondary to interferon alfa~therapy of Kaposi's sarcoma [letter]. Arch DennatoI1992;128:566. 4. Oeda E, Shinohara :k. Cutaneous necrosis caused by injection of alpha-interferon in a patient with chronic myelogenous leukemia [letter]. Am J Hematol 1993;44: 213-4. 5. Berard F, Canillot S, Balme B, Perrot H. Cutaneous local necrosis following interferon-beta injections. Ann Dennatol VenereoI1995;122:105-7. 6. Webster GF, Knobler RL, Lublin FD, Kramer EM, Hochman LR. Cutaneous ulcerations and pustular psoriasis caused by recombinant interferon beta injections. J Am Acad DennatoI1996;34:365-7.

Reply To the Editor: Dr. Weinberg makes several excellent points in his letter regarding our publication (J Am Acad Dermatol 1997;37:553-8). We focused our comments November. Part 1, 1998 807