PEG-Intron is a covalent conjugate of recombinant alpha-2b interferon with monomethoxy polyethylene glycol (PEG). Compared to standard interferon-alpha injections, this preparation has a longer half-life allowing for once-weekly injections and superior antiviral efficacy in the treatment of hepatitis C when used in combination with ribavirin. We report the first case of a local blistering reaction developing in a patient receiving pegylated interferon-alpha-2b. Previous reports of local cutaneous reactions to standard and pegylated interferon-alpha are reviewed and the pathophysiological mechanisms are discussed.
A plethora of cutaneous reactions have been reported at sites of interferon injection. These include pyoderma gangrenosum, leukocytoclastic vasculitis, suppurative and granulomatous dermatitis, interface dermatitis, dermal hypersensitivity, and most commonly, cutaneous ulcerations (1). We report a case of local blistering at the site of injection of pegylated interferon-alpha-2b in a patient with chronic hepatitis C. This patient received PEG-Intron (pegylated interferon-alpha-2b; Schering-Plough, Kenilworth, NJ), a derivative of recombinant interferon-alpha-2b designed to reduce protein immunogenicity and delay clearance. By prolonging the duration of pharmacological activity patient compliance is improved, as the frequency of injections is reduced to once-weekly (2,3). Two cases of PEG-modified interferon-alpha-2b injection reactions have recently been reported, each demonstrating cutaneous reactions with ulcerations similar to those reported with standard interferon injections (4,5). To the best of our knowledge, this is the first reported case of blistering at a site of a PEG-interferon injection.
Report of a Case
A 50-year-old white male with hepatitis C presented with a blistering rash on his left anterior thigh. He contracted hepatitis C from a blood transfusion during an orthopedic surgery. Treatment consisted of weekly subcutaneous self-injections with PEG-Intron (120 micrograms per 0.5 ml) and ribavirin 1000 mg daily. During the first 4 injections, the patient noted an erythematous, slightly scaled patch at the injection site that lasted only a few days. The fifth injection caused a slightly more exuberant reaction on the right anterior thigh, and the sixth injection, also on the right anterior thigh, produced an even more vigorous reaction that did not completely resolve in a week. With the seventh injection on the left anterior thigh, tender erythematous rash with blistering developed within hours. The patient used an alcohol swab to prepare the skin for the injections. There was no history of using betadine, polysporin, or any other topical agents.
Physical examination revealed erythema and scaling, and mild lichenification in an 8 cm diameter area on the right anterior thigh (location of fifth and sixth injection sites). At the site of the seventh injection on the left anterior thigh, vesicles and bulla 1-20 mm were present over a 5 cm diameter area surrounded by a flare of erythema and slight scale (see Figure 1). A 6 mm punch biopsy at the edge of a blister area on the left anterior thigh was obtained.
[FIGURE 1 OMITTED]
Histologic examination revealed a mildly acanthotic epidermis with intercellular spongiosis and marked papillary dermal edema leading to dermal-epidermal separation. Lymphocytes and histiocytes were present within the superficial and deep dermis in perivascular, periadnexal, and interstitial locations. Focal red blood cell extravasation was also noted. There was no leukocytoclastic vasculitis. No eosinophils were present. No evidence of epidermal necrosis or dyskeratosis was found.
A diagnosis of localized hypersensitivity reaction to injectable pegylated interferon was made. Halobetasol propionate cream .05% followed by mupirocin calcium cream 2% was applied tid to the involved areas on the thighs. The ribavirin and PEG-Intron injections were discontinued, and the patient was seen again 9 days after initial presentation. Examination revealed a marked reduction in inflammation and the halobetasol propionate cream was tapered off over one month.
The patient underwent testing with two simultaneous subcutaneous injections, one injection containing PEG-Intron and the other injection containing Infergen (Interferon alfacon-1, a non-pegylated interferon). The patient received twenty percent of a normal dose of PEG-Intron to his right anterior thigh and twenty percent of a normal dose of Infergen to his left anterior thigh. The patient reacted at 30 hours to the Infergen and at 36 hours to the PEG-Intron. The PEG-Intron injection site demonstrated more severe erythema and induration than the Infergen site.
Interferons are a group of proteins with antiviral, antiproliferative, and immunoregulatory actions. Interferon-alpha has demonstrated effectiveness in treating many diseases, including hepatitis C, Kaposi's sarcoma, hairy cell leukemia, malignant melanoma, renal cell carcinoma, and chronic myelogenous leukemia (5-7). Until recently, the standard of care in the treatment of chronic hepatitis C was interferon alpha-2b combination therapy with ribavirin (3). One drawback of this therapy, however, was the need for thrice-weekly injections because of the rapid clearance and short serum half-life of interferon-alpha protein. Through pegylation of interferon-alpha-2b by attaching a 12-kDa single straight-chain molecule of monomethoxy polyethylene glycol to the protein, a decreased clearance and a 10-fold increased plasma half-life (from approximately 4 to 40 hours) is achieved allowing once-weekly dosing (2). In addition, pegylation is known to reduce antigenicity and immunogenicity of the protein, although the reservoir effect of the drug could induce a more vigorous reaction in patients who do become sensitized (3). Both forms of interferon have been found to have comparable safety and pharmacodynamic profiles (8). Most importantly, the greatest efficacy in treating hepatitis C has been achieved with once-weekly dosing of PEG-Intron in combination with ribavirin, making this combination therapy the new standard of care for the treatment of hepatitis C (3). The most common side effects of PEG-Intron are similar to those found in its respective native interferon alpha protein, including mild reversible bone marrow suppression and flu-like symptoms (fevers, chills, myalgias, and arthralgias) that improve with subsequent doses and can be alleviated with pretreatment acetaminophen (2).
In our patient, inflammatory reactions occurred at the site of pegylated-interferon injections. Cytokine therapies, including interferons, have been reported to cause a wide variety of skin reactions, ranging from injection site reactions, pruritus, alopecia, eosinophilic fasciitis, paraneoplastic pemphigus, and worsening of autoimmune diseases such as psoriasis, sarcoidosis, and lichen planus (6,8-12). Injection site reactions reported to occur as a result of interferon alpha therapy include pyoderma gangrenosum, leukocytoclastic vasculitis, interface dermatitis, dermal hypersensitivity, suppurative and granulomatous dermatitis, and most commonly, necrotizing ulcerations (1). These injection site reactions occurred in 5% of 938 patients treated with interferon-alpha therapy for various chronic conditions (13). Since Cnudde's first case report in 1991 (14), cutaneous ulceration at the injection sites of recombinant and natural interferon alpha have been reported many times (13,15-22). In two of these cases, cutaneous ulceration followed pegylated interferon (4,5). Unlike in our patient, however, these reactions did not occur immediately following interferon-alpha injections, but had highly variable onsets, ranging from months to years after injections began. Erythematous and often painful patches or indurated nodules became violaceous and necrotic with minimally purulent bases. Histological findings consisted of nonspecific superficial and deep lymphohistiocytic infiltrate mixed with polymorphonuclear leukocytes. Thrombosis of venules and capillaries was also reported (22). The pathogenesis of these interferon-alpha induced injection site reactions remains elusive. Allergic sensitization to interferon products appeared unlikely in these previously reported cases since there was an absence of anti-interferon antibodies, and negative patch and prick tests (5,13,14,16). Furthermore, the lesions occurred intermittently. It has been suggested that injection site reactions, including skin necrosis, are more likely if the interferon powder is not reconstituted with the appropriate volume of diluent, resulting in an inappropriately high concentration of interferon (13). This explains the intermittent nature of these reactions in patients who prepared the injections themselves. Rotation of injection sites has been recommended to decrease the additive inflammatory effects of repeated injections in one location.
Only two case reports demonstrated blistering reactions following injections of interferon-alpha. One of these articles described five patients developing local painful nodules with central vesiculation induced by subcutaneous interleukin-2 and interferon alpha-2a immunotherapy following an acute bone marrow transplant (23). Histologic examination revealed lesions consistent with a fixed drug eruption. The other report described a widespread bullous eruption with low-titer (1:40) pemphigus-like antibodies on indirect immunofluorescence testing during interferon-alpha treatment (24). Delayed hypersensitivity reactions have also been reported via positive patch tests and a positive ELISA test to interferon-alpha-2c in a patient with indurated erythema at the site of injection (25).
Reactions to pegylated injections of interferon have been less commonly reported. In clinical trials of HIV-infected patients receiving injections of peglylated interferon, mild inflammation at the site of injections was noticed in approximately 40-45% patients (4). In another similar study of HIV-infected patients, 67% (38/58) of PEG-interleukin-2 subjects developed injection site reactions not otherwise specified (26). A phase III study conducted to access safety and efficacy of PEG-Intron for treatment of chronic hepatitis C found that injection site disorders appeared with greater frequency in PEG-Intron treated patients than those with the non-pegylated form of interferon alpha-2b, Intron A (27). These cases were classified as mild to moderate in severity. Most consisted of inflammation at the injection site, bruising, itchiness, and irritation. Injection site disorders were most common during the first few injections with intermittent recurrences later in therapy. Product information for PEG-Intron reports PEG-Intron (1.0 microgram/kg) and PEG-Intron (1.5 microgram/kg) in combination with Rebetol (ribavirin) caused injection site inflammation/reaction "not otherwise specified" in 47% (n=297) and 75% (n=511) of patients respectively (28). This was compared to patients who received Intron A 3 MIU (non-pegylated IFN-alpha) and Intron A 3 MIU plus Rebetol who had reaction rates of 20% and 49% respectively. Injection site disorders were typically characterized by local erythema and sometimes pruritus, but no blistering reactions.
Our patient displayed positive subcutaneous injection reactions to twenty percent of a normal dose of both PEG-Intron and non-pegylated interferon, possibly implicating a protein allergy to interferon as a cause of his reaction. The PEG-Intron site showed a more severe reaction, as would be expected in view of its longer half-life and delayed clearance. The patient might have also developed a protein allergy if too superficial an injection, such as into the dermis rather than subcutaneous tissue, might have increased the risk of sensitization by allowing more exposure to the dendritic cells that present antigen. Diluents used to dissolve the interferons such as polyethylene glycol could also be responsible for a local reaction (29-35). This is unlikely in this case since there were no common ingredients in the vehicles of the pegylated and non-pegylated interferon products. Thus, the timing of the onset of the lesions and the patient's positive reactions to both pegylated and non-pegylated formulations all suggest a protein allergy to interferon as a cause of his local blistering reaction.
This case is a unique local reaction to pegylated interferon that further expands the broad spectrum of cutaneous reaction patterns already described. The dermatologist should be aware of these side effects, since treatment with subcutaneous pegylated interferon can be expected to increase as its indications are further delineated.
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