Injection Site Bullous Eruption and Generalized Rash Induced by Pegylated Interferon Treatment for Hepatitis C

Hepatitis C is a blood-borne infection of global epidemic concern. Its biggest risk factor is intravenous drug use, but it is also prevalent among healthcare workers and individuals with high-risk sexual behaviors. Chronic hepatitis C virus (HCV) infection is associated with significant morbidity and mortality; of the estimated 169.7 million people in the world infected with hepatitis C,1 3.2 million are in the United States, and it is the leading indication for liver transplantation.2,3 Pegylated interferon with ribavirin is the current standard of care for chronic hepatitis C treatment, but only 50–60% of patients will achieve sustained virologic response,4 with better outcomes associated with factors such as genotype 2/3 disease, race, advanced fibrosis, lack of co-infection with HIV, and a viral load of less than 600,000 IU/mL.5 Interferons exert their antiproliferative and antiviral activities by blocking HCV RNA translation and replication through protein kinase R and p56, along with the activation of innate immune systems through natural killer cells, B cells, and T cells.6 Standard interferon has a short half-life of 6–20 hours, but when covalently conjugated with polyethylene glycol, it has the advantage of improved pharmacokinetics with dosing changes to once-weekly dosing and greater therapeutic efficacy. The trade-offs include a reduction in biologic activity due to less robust binding to the interferon receptor and a change in side effect profile, in particular, greater hematologic abnormalities.7,8 Combination pegylated interferon and ribavirin also has a higher rate of injection site reactions compared to standard interferon and ribavirin.9 Cutaneous side effects of pegylated interferon are most common at the injection site and include necrotizing ulcerations10 and leukocytoclastic vasculitis,11 though generalized skin rash (eg, exfoliative dermatitis, epidermal necrolysis, alopecia) is also noted.12,13 Ribavirin exerts its antiviral activity by acting as an inosine 5'-monophosphatase inhibitor through its metabolite ribavirin monophosphate. Although generally well tolerated, ribavirin's most common side effect is hemolytic anemia. Dermatologic adverse effects, including photoallergic reactions, occur in approximately 14% of patients.14 No clear underlying mechanism has been elucidated to explain the etiology of the cutaneous adverse reaction in patients receiving combination pegylated interferon and ribavirin; however, many different theories have been proposed, including cutaneous deposition of immune complex.15 The patient in the case report by Toney and Agrawal16 developed erythematous edematous vesiculobullous patches following subcutaneous injection of pegylated interferon alfa-2b (Pegintron Redipen, Schering) on both thighs and eventually developed generalized rash. Punch biopsy of the persistent urticarial plaque was suggestive of perniotic reactions. As the authors noted in their report, perniotic reaction is not specific and may be found in a variety of disease conditions, including viral hepatitis, cryoglobulinemia, and rheumatoid arthritis, or even as an abnormal reaction to cold or damp environments. The initial approach is to determine whether the above reaction was possibly caused by pegylated interferon alfa-2b. In this case, it is possible, and quite likely, that it was, in fact, due to the pegylated interferon alfa-2b and/or ribavirin. However, pegylated interferon alfa-2b, while containing no preservatives, contains additional additives, including dibasic sodium phosphate anhydrous, monobasic sodium phosphate dehydrate, sucrose, and polysorbate 80, apart from its active ingredients. This is similar to peginterferon alfa-2a, which also contains additional additives, namely sodium chloride, polysorbate 80, benzyl alcohol, sodium acetate trihydrate, and acetic acid. It is possible that the additives in the pegylated interferon alfa-2b preparation may have contributed toward the development of the cutaneous manifestations reported in this case, as some of the additives have been reported to cause hypersensitivity reactions with other preparations. Steele and coworkers reported on two patients who developed hypersensitivity reactions while receiving darbepoetin and erythropoietin. Skin testing demonstrated that polysorbate 80 (Tween 80) used an excipient as the cause.15 Polysorbate 80 is a water-soluble polymer composed of fatty acid esters of polyoxyethylene sorbitan monooleate and is used as a solubilizing agent in biopharmaceuticals. It has also been shown to cause both respiratory and dermatologic side effects when used as an emulsifier in inhalation suspensions. Isaksson and colleagues reported a case of severe recurrent asthma in a patient with a negative prick test and no other signs of atopy. The patient was on budesonide-pressurized metered-dose inhaler as prophylaxis, along with different combinations of beta-2 agonists, and did not become symptom-free until budesonide was changed to a fluticasone propionate metered-dose inhaler, along with the same beta-2 agonist. The patient underwent skin patch testing for various types of allergens, including environmental and past exposed medications. The test was only positive for polysorbate 80, which was contained in the budesonide preparation.17 Grims and associates also showed that drug allergy could be due to “hidden” additives. One patient was falsely diagnosed with penicillin allergy. Due to inconsistent laboratory results, further skin testing was performed for both the additives and active ingredients, and the patient was later found to be sensitized to polysorbate 80, which was contained in the penicillin preparations.18 The case report by Toney and Agrawal16 adds to the list of possible cutaneous manifestations of peginterferon side effects and raises awareness of uncommon presentations of cutaneous manifestations of peginterferon and ribavirin. Although there is no standard algorithm with respect to adverse drug reaction, this patient may benefit from further diagnostic testings, including patch, prick, enzyme-linked immunosorbent assay, and, possibly, lymphocyte proliferation assay, not only to the active ingredients but also the additives associated with peginterferon alfa-2b. This may be particularly significant if repeat therapy is considered for this patient.