DR [Dermatology Reports 2013; 5:e1] [page 1] Erythema annulare centrifugum-like eruption associated with pegylated interferon treatment for hepatitis C Mark Naccarato,1 Deborah Yoong,1 Robert Solomon,2 Mario Ostrowski1,3 1Department of Infectious Diseases and HIV, St. Michael’s Hospital, Toronto, Ontario; 2Department of Dermatology, St. Michael’s Hospital, Toronto, Ontario; 3Faculty of Medicine, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada Abstract Current standard of treatment for chronic hepatitis C virus infection requires the use of pegylated interferon plus ribavirin. Treatment with these two agents has been associated with numerous side effects, which frequently include dermatologic eruptions. We report a cutaneous eruption associated with interferon having clinical presentation of erythema annu- lare centrifugum. The eruption occurred with- in days of the first interferon injection and repeatedly flared following subsequent injec- tions. Our patient was able to continue therapy without interruption, while managing the reaction with topical corticosteroid and oral antihistamine. We conclude that this is a benign cutaneous eruption associated with interferon which can be managed without dis- continuing treatment for hepatitis C. Case Report A 48-year-old male was referred to our clinic for assessment of hepatitis C (HCV). His past medical history included mild chronic obstruc- tive pulmonary disease, spinal surgery, remote eczema, and past alcohol, cigarette and intra- venous drug use. He reported an allergy to penicillin and was taking naproxen daily for back pain. Treatment for HCV, genotype 1, was initiated with pegylated interferon alfa-2a 180 mcg subcutaneously once per week and oral ribavirin 1000 mg per day. On the fourth day of treatment he experienced an intermittently pruritic and enlarging rash localized to his arms and legs. He described these painless lesions as migrating cloud-like rings, which eventually became confluent with nearby lesions. Dermatologic exam one week after starting therapy showed multiple large annular erythematous lesions, each with a non-scaly peripheral red border (Figure 1). The patient denied any fevers or chills, the eruption was not localized to the injection site, there was no presence of bullae, erosions, or mucous mem- brane involvement. Punch biopsy was obtained; however, due to the absence of alarming symptoms we elected to continue treatment at the same dosages and manage the reaction with betamethasone valerate 0.1% cream applied twice daily along with oral hydroxyzine 25 mg as needed for pruritus. Histopathology of the skin biopsy (Figure 2) revealed a sparse superficial perivascular infil- trate of lymphocytes and eosinophils. The epi- dermis was unremarkable, there was no evi- dence of vasculitis, and the periodic acid- Schiff (PAS) stain was negative for fungi. As well, labs at this time did not show any eosinophilia. Following the second interferon injection, the eruption flared at the same sites and had the same migratory nature as observed the prior week. The rash again improved over the next several days with topi- cal steroids while continuing on ribavirin, yet re-emerged following the third interferon injection. The rash then completely resolved by the fourth week of interferon with no further dermatologic reactions. Diagnosis based on clinicopathology was an annular erythematous drug reaction, however the patient successful- ly completed 48 weeks of uninterrupted thera- py and achieved cure of his hepatitis C. As well, investigations for internal malignancy have thus far been negative. Discussion Various cutaneous conditions have been associated with HCV infection and its treat- ment (Table 1).1,2 Interferon and ribavirin ther- apy have been reported to cause dermatologic reactions in approximately 13-23% of HCV patients.2 However annular erythematous eruptions associated with interferon appear rare as only one case of granuloma annulare and two cases of erythema gyratum repens have been reported in literature.3,4 The admin- istration of exogenous interferon alfa is thought to up-regulate hundreds of genes involved in inflammatory cell responses, along with having immunomodulating effects.5 Therefore a cutaneous eruption following ini- tiation of interferon is consistent with its pro- inflammatory properties. The term erythema annulare centrifugum (EAC) was first introduced by Darier in 1916 to describe an eruption of annular lesions that enlarged rapidly then disappeared in 1 to 2 weeks while new lesions continued to develop.6 EAC lesions usually present as ery- thematous macules or urticarial papules, which enlarge centrifugally and clear centrally, thereby creating an annular appearance.7 As the edges of lesions advance, they may become confluent with adjacent lesions developing arciform segments.7 Darier described the clas- sical histopathologic feature as a dense perivascular sleeve-like lymphocytic infiltrate throughout the thickness of the dermis.6 However since that time, the term EAC has grown to include similar presentations which have an entirely superficial histology lacking the classic sleeve-like arrangement.6 Lesions of superficial EAC, unlike the deep-type, often include scaling along with nonspecific histo- logic findings of mild spongiosis and peraker- atosis.6 The etiology of EAC is not known, how- ever it has been associated with a variety of etiologic factors including neoplasms, infec- tious agents, and several different medica- tions.6 Given the myriad of histologic findings and association to a variety of etiologic agents, EAC likely represents a clinical reaction pat- tern whose diagnosis cannot be made on pathology alone. Our patient experienced a new migratory annular dermatologic eruption within four days of starting pegylated interferon, which was clinically indistinguishable from EAC. The lesions initially waned over the next few days while he continued taking twice daily rib- avirin; however, again flared following each of the next two weekly doses of interferon. Based on the clinical presentation of his migrating lesions following interferon, distribution limit- ed to his extremities, lack of scaling or eosinophilia, non-specific histopathology, and the resolution of symptoms without any target- Dermatology Reports 2013; volume 5:e1 Correspondence: Mark Naccarato, Department of Infectious Diseases and HIV, St. Michael’s Hospital, 30 Bond Street, 4CCN, 4-177, Toronto, Ontario, M5B 1W8, Canada. E-mail: naccaratom@smh.ca Key words: interferon, ribavirin, hepatitis C, ery- thema annulare centrifugum, drug eruption. Contributions: the authors contributed equally. Conflict of interests: the authors declare no potential conflict of interests. Received for publication: 11 June 2013. Revision received: 5 July 2013. Accepted for publication: 8 July 2013. This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY- NC 3.0). ©Copyright M. Naccarato et al., 2013 Licensee PAGEPress, Italy Dermatology Reports 2013; 5:e1 doi:10.4081/dr.2013.e1 No n- co mm er cia l u se on ly [page 2] [Dermatology Reports 2013; 5:e1] ed therapy; other causes of annular lesions or migrating erythemas were excluded.7 A pri- mary differential diagnosis of this eruption includes a similar reactive erythema, erythe- ma gyratum repens (EGR), which has been previously reported in association with inter- feron.4 Histopathologically both EGR and superficial EAC have nonspecific perivascular lymphocytic or eosinophilic infiltrates as shown in our case. Clinically however, EGR is characterized by its wood-grain appearance, presents with multiple or a generalized pattern of lesions, and is associated with intense pru- ritus and scaling which was absent,8 making EAC the most likely diagnosis. Therefore, we propose that interferon caused an EAC-like eruption in our patient given the clinical pres- entation. Although, the classical sleeve-like finding of deep-EAC was absent, the lympho- cytic infiltrate involving eosinophils was con- sistent with a drug etiology. It is unclear why despite continued treat- ment with interferon, the lesions did not return after resolution. Interferon is noted to promote memory T-cell proliferation, stimulate natural-killer-cell activation and dendritic-cell maturation,5 thus it is possible the EAC-like eruption represents an up-regulated immune response to an unknown skin pathogen in our case. As well, it is possible that the etiologic agent or stimulus that induced EAC may have been eliminated. Given that the etiology of EAC has not been fully elucidated, it is difficult to speculate why continued interferon therapy did not incite more lesions, however the obser- vations highlight that development of EAC is not a contraindication to continuing interferon treatment. Noteworthy to the clinician is that psoriatic, eczematoid and lichenoid eruptions associated with interferon therapy can also be successfully managed using corticosteroids without discontinuation of interferon.2 As well, some reactive annular erythemas are associat- ed with an underlying malignancy,9 however all screening tests in our patient have remained negative. Using the Naranjo probability scale to evaluate a potential adverse drug reaction,10 our proposed causal relationship of interferon producing this dermatologic eruption was cal- culated as probable. Conclusions Annular erythematous drug eruptions asso- ciated with interferon appear to be rare, how- ever this report adds to the literature on this subject. In this case, recognizing the benign nature of the reaction and continuing with HCV therapy were factors enabling the patient to complete treatment and achieve cure of his hepatitis C. We conclude that in the treatment of HCV, clinicians need to distinguish benign from life-threatening dermatologic conditions in order to avoid unnecessary treatment inter- ruption risking therapeutic failure. References 1. Crowson AN, Nuovo G, Ferri C, Magro C. The dermatopathologic manifestations of hepatitis C infection: A clinical, histologi- cal, and molecular assessment of 35 cases. Human Pathol 2003;34:573-9. 2. Mistry N, Shapero J, Crawford RI. A review of adverse cutaneous drug reactions resulting from the use of interferon and ribavirin. Can J Gastroenterol 2009;23: 677-83. 3. Kluger N, Moguelet P, Chaslin-Ferbus D, et al. Generalized interstitial granuloma annulare induced by pegylated interferon- alpha. Dermatology 2006;213:248-9. 4. Rongioletti F, Fausti V, Parodi A. Erythema gyratum repens induced by pegylated interferon alfa for chronic hepatitis C. Arch Dermatol 2012;148:1213-4. 5. Feld J, Hoofnagle J. Mechanism of action of interferon and ribavirin in treatment of Hepatitis C. Nature 2005;436:967-72. 6. Weyers W, Diaz-Cascajo C, Weyers I. Erythema annulare centrifugum: results of a clinicopathologic study of 73 patients. Am J Dermatopathol 2003;25:451-62. 7. Burgdorf W. Erythema annulare cen- trifugum and other figurate erythemas. In: Fitzpatrick’s dermatology in general medi- cine. 7th ed. Wolff K, Goldsmith L, Katz S, et al, eds. New York: McGraw-Hill; 2008. pp 366-9. 8. Tyring SK. Reactive erythemas: erythema annulare centrifugum and erythema gyra- tum repens. Clin Dermatol 1993;11:135-9 9. Abreu Velez AM, Howard M. Diagnosis and treatment of cutaneous paraneoplastic disorders. Dermatol Ther 2010;23:662-75. 10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45. Case Report Table 1. Dermatologic manifestations of hepatitis C virus and cutaneous reactions to interferon and ribavirin. Dermatologic manifestations of HCV Cutaneous reactions to interferon and ribavirin Pruritus, vasculitis, urticaria, lichen planus, cryoglubulinemia, Injection-site reactions, pruritus, psoriasis, alopecia, sarcoidosis, eczematoid, porphyria cutanea tarda, pityriasis rubra pilaris, lichenoid, lupus, fixed-drug eruptions, pigmentation disorders, skin necrosis, graft-versus-host disease, polyarteritis nodosa, Meyerson nevi erythema nodosum, erythema multiforme, pyoderma gangrenosum, granuloma annulare, perniosis-like lesions, lichenoid, follicular-based purpura HCV, hepatitis C virus Figure 2. Histopathology showing a der- mal infiltrate in superficial dermis; at 50× magnification. Figure 1. Patient presenting with erythe- matous, annular, maculo-papular lesions. No n- co mm er cia l u se on ly