Cutaneous necrosis after injection of polyethylene glycol-modified interferon alfa

Pegylated interferon alfa-2b is a formulation of recombinant human interferon conjugated with polyethylene glycol. Compared with standard interferon alfa 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. Cutaneous side effects caused by interferon are well known. Cutaneous necrosis as a result of interferon alfa is an infrequent complication with unknown pathogenesis, in which a cutaneous local immune-mediated inflammatory process might be involved. We report 5 patients (3 patients with chronic hepatitis C treated with pegylated interferon alfa-2b in association with oral ribavirin and two patients with chronic myelocytic leukemia) who developed local cutaneous reactions at sites of injection after the administration of weekly subcutaneous injections of pegylated interferon alfa-2b at different doses. The ulcers slowly healed with local therapy, but two patients required dose modification of the pegylated interferon alfa-2b and one patient required treatment withdrawal. We review the literature on previously reported cases of cutaneous necrosis after injection of standard interferon alfa or pegylated interferon alfa-2b and discuss the different pathophysiologic mechanisms that might be involved.     

Cutaneous necrosis complicating the injection of pegylated interferon alpha-2b in a patient with chronic hepatitis C

Pegylated interferon alpha (PEG-IFN-alpha) is a formulation of recombinant human interferon conjugated with polyethylene-glycol. This preparation has a long half-life (compared with conventional IFN), which allows for once-weekly injection. Elimination half-life of PEG-IFN-alpha 2b is 22-60 hours (average, 35-40 hours). We report the development of a local necrotizing reaction complicating subcutaneous injection of PEG-IFN in a patient with hepatitis C. This case enhances the need of careful training in drug reconstitution and self injection, with as much variation as possible of the injection site.     

Cutaneous necrosis due to interferon alpha in a patient with melanoma

We present the case of a 55-year-old male with melanoma in the right retroauricular region who had cutaneous necrosis only in one of the injection sites after adjuvant treatment with interferon (IFN alpha 2b) according to the Kirkwood proposed regime. Appearance of cutaneous necrosis is a rare condition that has been described in patients treated with different types of IFN.     

Adverse skin reactions due to pegylated interferon alpha 2b plus ribavirin combination therapy in a patient with chronic hepatitis C virus

Pegylated interferon (IFN)-alpha-2b with ribavirin has recently replaced "standard" IFN-alpha for the treatment of chronic hepatitis C. The most common side-effect of pegylated IFN-alpha-2b plus ribavirin combination therapy is localized inflammatory skin lesions at the site of injection. A 66-year-old female treated with once-weekly pegylated IFN-alpha-2b plus ribavirin for active chronic hepatitis C developed inflammatory skin lesions 2 months after starting antiviral treatment. The type of skin reactions observed were vesicle erythematous eruptions at the injection sites, and pruritic papular erythematous eruptions located on the face, neck, distal limbs, dorsa of the hands, trunk and buttocks away from the injection sites. Histological examination was performed on the pruritic papular erythematous eruption located on the left forearm, away from the injection sites. It showed epidermal spongiosis, a spongiotic microvesicle, and perivascular infiltration of the upper dermis with lymphocytes. The treatment was interrupted subsequently and the patient was rechallenged with pegylated IFN-alpha-2b plus ribavirin combination therapy, oral prednisolone with olopatadine hydrochloride and topical 0.1% diflucortolone valerate, which led to a significant improvement of skin lesions. Erythema with infiltration can occur at the injection sites of pegylated IFN-alpha-2b. However, the occurrence of vesicle erythematous eruptions away from the injection sites and autosensitization dermatitis apart from injection sites have not yet been frequently reported.     

Generalized eczema secondary to combined treatment with peginterferon alfa-2a and ribavirin in a patient with chronic hepatitis from the hepatitis C virus

Adverse skin effects from interferon (IFN) plus ribavirin combined therapy are relatively frequent, but they are usually local and related to the IFN injection site. However, distant or generalized eczematous reactions secondary to this treatment are rare. The introduction of pegylated interferons may increase the frequency of these skin lesions.     

Repeated episodes of fixed eruption 3 months after discontinuing pegylated interferon‐α‐2b plus ribavirin combination therapy in a patient with chronic hepatitis C virus infection

We report a 73‐year‐old man who developed repeated episodes of erythematous, bullous plaques beginning 3 months after discontinuation of combination treatment with pegylated interferon (IFN)‐α‐2b and ribavirin for hepatitis C virus infection. The first episode resolved within a week without treatment, but the lesions recurred about once a month and were associated with high fever. Physical examination found darkly reddish, pigeon‐egg‐sized erythematous plaques with occasional flaccid blisters, predominantly on the trunk and proximal limbs, lip and penis. Histological examination showed well‐demarcated foci of full‐thickness epidermal necrosis and exocytosis of lymphoid cells. Pegylated IFN‐α2b and ribavirin produced no response in lymphocyte stimulation tests. Systemic prednisolone led to rapid healing of skin lesions at the time of the fifth episode, leaving pigmented macules, but lesions recurred at the same sites within weeks of discontinuation of this treatment. It is uncertain whether this case represented a prolonged drug rash provoked by pegylated IFN‐α2b or a fixed eruption in response to another antigen.     

Cutaneous ulcerations following subcutaneous interferon beta injection to a patient with multiple sclerosis

We report a case treated with interferon beta-1b for multiple sclerosis (MS), who developed severe cutaneous ulcers after six months of therapy. Interferon beta-1b had been used in a regimen of 8 million IU administered subcutaneously through oblique direction of the needle, twice a week. The cutaneous ulcers developed at inoculation sites, as a result of penetration of interferon beta into dermis. Other underlying diseases of coagulative or bleeding disorders or secondary infection were excluded. Histological features of non-specific inflammatory reactions including hyperplastic changes of blood vessels without any evidence of vasculitis were the prominent features in this case. Corticosteroid and interferon beta-1b therapy was continued on restricted sites on the extremities with care not to repeat injections at the same sites previously used. The administration of interferon beta into subcutaneous fatty tissues vertically reduced the incidence of dermal penetration of drug and occurrence of ulcerations in this patient. We review other case reports of severe cutaneous reactions associated with interferon beta-1b therapy in MS patients and conclude that local cytokine-mediated, adverse, immune reaction or non-specific cutaneous inflammatory reaction to interferon beta-1b initiated the skin ulceration long after institution of therapy at the injection sites, and the reaction might be related to the depth of injection.     

Cutaneous ulceration after injection of polyethylene-glycol-modified interferon alpha associated with visual disturbances in a melanoma patient

Interferons are used in the therapy of multiple sclerosis, Kaposi's sarcoma, hepatitis and melanoma. Their short half-life that requires frequent injections can be increased by polyethylene glycol (PEG) modification. A 50-year-old patient was diagnosed as having an acrolentiginous melanoma (Breslow >5 mm, Clark level IV) and inguinal lymph node metastases. After surgical excision and lymphadenectomy, immune therapy with 6.0 microg pegylated interferon alpha(2b)/kg body weight, s.c., was started. Cutaneous ulcerations at the injection sites developed 9 months after treatment initiation. The patient also developed blurred vision and presented with binasal scotomas and pathological visually evoked potentials and electroretinogram. The cutaneous ulcerations slowly healed under local therapy and reduction of the concentration of the PEG-modified interferon from 0.86 to 0.43 mg/ml. The dosage was maintained. Two months later, the therapy was stopped due to disease progression. Vision subsequently recovered. Cutaneous reactions evolved at the sites of subcutaneous injections of PEG-modified interferon alpha(2b). Changes in vision can probably be attributed to immunotherapy.     

Comparison of pegylated interferon α-2b plus psoralen PUVA versus standard interferon α-2a plus PUVA in patients with cutaneous T-cell lymphoma

Objective The aim of this study was to evaluate the safety and efficacy profile of pegylated interferon α‐2b (PEG‐IFN α‐2b) in combination with photochemotherapy (PUVA) in the treatment of cutaneous T‐cell lymphoma (CTCL) in comparison with standard IFN α plus PUVA. Design Retrospective cohort study over a period of 7 years. Patients and interventions A total of 17 consecutive CTCL patients (stage IA–IV) were retrospectively analysed for toxicity and response rates associated with PEG‐IFN α‐2b (1.5 μg/kg weekly) plus PUVA (n = 9) or standard IFN α‐2a (9 MIU 3×/week) plus PUVA (n = 8). Main outcome measures Differences of response rates (complete/partial remission), progression‐free survival, discontinuation of therapy, safety and toxicity profiles according to World Health Organization – Common Terminology Criteria of Adverse Events (WHO‐CTCAE). Results Myelosuppression and liver toxicity occured more frequently during PEG‐IFN α‐2b plus PUVA treatment than during standard IFN α‐2a plus PUVA therapy [77.8 vs. 50% (odds ratio 1.477) and 77.8 vs. 50% (odds ratio 1.692), respectively]. By contrast, the occurence of constitutional side‐effects (mainly fatigue) [100 vs.77.8% (odds ratio 0.889)] and more adverse events leading to study discontinuation was considerably higher in the standard IFN α‐2a plus PUVA group. The overall response rate in the PEG‐IFN α‐2b plus PUVA group (89%) was significantly superior. Conclusions In patients with cutaneous T‐cell lymphoma PEG‐IFN α‐2b plus PUVA might become a promising treatment alternative as its higher rate of myelosuppression and liver toxicity is outweighed by its lower percentage of constitutional side‐effects, and its significantly higher overall response. Due to the small number of participants at this retrospective study, a larger prospective study is essential to verify our results.     

Development of cutaneous sarcoidosis in a patient with chronic hepatitis C treated with interferon alpha 2b

BACKGROUND: Sarcoidosis is a multisystemic granulomatous disorder of unknown etiology that most commonly affects young adults. A probable induction of sarcoidosis by interferons (IFN) has been published. To this date, few cases of cutaneous sarcoidosis inpatients with chronic hepatitis C under interferon treatment have been reported. OBJECTIVE: We describe a 50-year-old woman with chronic hepatitis C who developed lesions of cutaneous sarcoidosis three months after IFN treatment. CONCLUSIONS: The possible role of INF therapy in the development of cutaneous sarcoidosis in a patient with chronic hepatitis C should be considered.     

Interferon-induced cutaneous necrosis

BACKGROUND: Due to advances in recombinant DNA technology, interferons are now readily available and are frequently used in all branches of medicine. These potent biologic response modifiers carry a number of systemic and local side effects. These cytokines are usually administered subcutaneously, and recent studies have described the occurrence of inflammation or necrosis at the site of injection. OBJECTIVE: We report a case of cutaneous necrosis at the sites of interferon injections in a 35-year-old man treated for chronic myeloid leukemia with high, daily doses of interferon alfa. In addition, we review the existing literature on interferon-induced cutaneous necrosis and discuss preventive strategies. CONCLUSION: Cutaneous inflammation or necrosis at interferon injection sites is not uncommon. Although interferon beta-1b is most commonly responsible for this complication, it is now increasingly reported with interferon alfa. It appears to be secondary to the proinflammatory effects of these cytokines or to their unmasking of a subtle hypercoagulable state.     

Sarcoidosis associated with pegylated interferon alfa and ribavirin treatment for chronic hepatitis C: a case report and review of the literature

BACKGROUND: At least 2.7 million Americans are infected with chronic hepatitis C. An increasing number are treated with interferon alfa plus ribavirin regimens. Not surprisingly, this immune stimulation is associated with the development of autoimmune and cutaneous diseases. Several cases of sarcoidosis have been reported with hepatitis C treatment, most recently in association with pegylated interferon alfa plus ribavirin. Systemic manifestations of sarcoidosis are usually treated with oral steroids, which unfortunately often increase the hepatitis C viral load. Thus, it is important to ascertain whether systemic corticosteroids are required to treat interferon alfa-associated sarcoidosis. OBSERVATIONS: We report the third case of cutaneous sarcoidosis in association with pegylated interferon alfa plus ribavirin treatment. Our patient had both cutaneous and pulmonary involvement, which has been spontaneously resolving since his treatment regimen was completed. In addition, we review the 12 previously reported cases of cutaneous sarcoidosis that occurred in patients undergoing hepatitis C treatment with interferon alfa. CONCLUSIONS: As the number of patients being treated with interferon alfa and ribavirin for hepatitis C increases, it is essential that dermatologists recognize the association of this treatment with sarcoidosis, because skin lesions may provide the first clue to diagnosis. Development of sarcoidosis may relate to hepatitis C as a possible antigenic trigger in the presence of an enhanced helper T cells type 1 response from treatment. Sarcoidosis with skin lesions in patients undergoing hepatitis C treatment often follows a benign course, and interferon alfa therapy may sometimes be continued with resolution of sarcoidosis occurring spontaneously or within a few months of completing treatment. Cautious use of systemic corticosteroids is warranted given their adverse effects on hepatitis C viral loads.     

Cutaneous sarcoidosis developing after treatment with pegylated interferon and ribavirin: a new case and review of the literature

Sarcoidosis is a multisystem granulomatous disease that affects multiple organs in adults between 20 and 50 years old. Interferon alpha (IFN-α) is an immunomodulator that has been used in a wide range of diseases, including hepatitis C virus infection, multiple sclerosis, and other types of neoplasias, including leukemia, lymphoma, Kaposi's sarcoma, and melanoma. Standard IFN-α-induced sarcoidosis has been reported, but there are few reports of cutaneous sarcoidosis with pegylated IFN-α therapy. We present a new case of cutaneous sarcoidosis after treatment with pegylated IFN, and a review of the literature.     

Lupus-like reaction to interferon at the injection site: report of five cases

Background:  Interferon therapy at the injection sites has been related to different cutaneous lesions including erythema and induration as the most frequent ones. While the glycoprotein induces fatigue, fever and is even believed to precipitate autoimmune disorders such as type I diabetes, thyroid disease and systemic lupus erythematosus, a lupus erythematosus-like histologic reaction at the interferon injection site has never been reported. To our knowledge, a microscopic self-resolving lesion mimicking lupus erythematosus at the injection site of interferon has not been described.
Results:  We report five cases of cutaneous lesions at the inoculation site of interferon with a histopathologic lupus erythematosus-like pattern. Three of them were receiving interferon alfa therapy because of a malignant melanoma and the other two patients were receiving interferon beta-1b for multiple sclerosis. Biopsy specimens taken from different lesions showed similar microscopic findings consisting of dermal mucin deposits and dense lymphocytic infiltrates along hair follicles with hydropic degeneration of follicular basal layer.
Conclusions:  Multiple cutaneous lesions related to interferon at the injection site have been reported, but none of them with a histologic lupus-like presentation. In this study we describe five cases in which interferon therapy has induced a resolutive cutaneous lesion mimicking lupus erythematous. This peculiar microscopic pattern has been previously described once before, but interpreted as cutaneous mucinosis.     

The effects of human herpesvirus 8 infection and interferon-gamma response in cutaneous lesions of Kaposi sarcoma differ among human immunodeficiency virus-infected and uninfected individuals

Background Kaposi sarcoma (KS) is associated with human herpesvirus 8 (HHV‐8). The cutaneous immune response in this tumour is not well established and a better understanding is necessary. Objectives To evaluate the HHV‐8 expression and immune response in cutaneous lesions of classic KS (CKS) and AIDS‐associated KS (AIDS‐KS). Methods We performed a quantitative immunohistochemical study of cells expressing HHV‐8 latency‐associated nuclear antigen (LANA), CD4, CD8 and interferon (IFN)‐γ in skin lesions from patients with CKS and AIDS‐KS (with or without highly active antiretroviral therapy, HAART). Results CKS showed higher LANA expression compared with AIDS‐KS, regardless of HAART. We also found higher LANA expression in nodules compared with patch/plaque lesions. The tissue CD4+ cell proportion was lower in AIDS‐KS patients without HAART than in patients with CKS. In CKS lesions, CD4+ and CD8+ cells expressed IFN‐γ, as shown by double immunostaining. AIDS‐KS presented low numbers of IFN‐γ‐expressing cells. CD8+ cell numbers were similar in all groups, which appeared unrelated to the clinical or epidemiological type of KS. Conclusions Our quantitative data on the pattern of KS lesions in selected groups of patients, as shown by in situ immune response, demonstrated a CD4+ T‐cell involvement associated with IFN‐γ, an environment of immune response‐modified human immunodeficiency virus (HIV) infection. In our sample, the promotion of KS in patients without HIV appears to be related to higher HHV‐8 load or virulence than in those with AIDS. This higher resistance may be explained by a sustained immune response against this herpesvirus, that is only partially restored but effective after HAART.     

Postoperative DAV‐IFN‐β therapy does not improve survival rates of stage II and stage III melanoma patients significantly

Background DAV‐interferon (IFN)‐β therapy is a combination chemotherapy of dacarbazine (D TIC), nimustine (A CNU) and vincristine (V CR) with local subcutaneous injection of IFN‐β that is widely employed as postoperative adjuvant chemotherapy to treat malignant melanoma in Japan. However, the efficacy of DAV‐IFN‐β therapy has not been confirmed by randomized controlled trials and the benefit of DAV‐IFN‐β therapy has not been established yet. This study evaluated the contribution of DAV‐IFN‐β therapy to improve survival of postoperative patients with cutaneous melanoma. Methods Patients with stage II or III cutaneous melanoma seen at Nagoya University Hospital from January 1998 to December 2009 were eligible for this study. Disease‐free survival rates and melanoma‐specific survival rates were evaluated. A propensity score was calculated to control for the effects of variables related to decisions regarding the application of DAV‐IFN‐β therapy. Results Eighty‐two stage II and 60 stage III melanoma patients were included. In the post‐matched stage II patients (17 matched pairs), the mean (±SE) disease‐free survival rates were 39.9±13.7% for DAV‐IFN‐β therapy and 73.1±11.7% for non‐use (hazard ratio for recurrence, 2.06; 95% CI, 0.63–6.69; P = 0.23), and the melanoma‐specific survival rates were 66.2±20.0% for DAV‐IFN‐β therapy and 86.2±9.1% for non‐use (hazard ratio for death, 1.09; 95% CI, 0.17–6.82; P = 0.93). In the post‐matched stage III patients (nine matched pairs), the disease‐free survival rates were 29.6±16.4% for DAV‐IFN‐β therapy and 33.3±15.7% for non‐use (0.69; 95% CI, 0.22–2.17; P = 0.53), and the melanoma‐specific survival rates were 55.6±16.6% for DAV‐IFN‐β therapy and 44.4±16.6% for non‐use (0.67; 95% CI, 0.18–2.50; P = 0.55). Conclusions DAV‐IFN‐β therapy brought no significant improvement in either disease‐free survival rates or melanoma‐specific survival rates of patients with stage II or III cutaneous melanoma. A randomized controlled trial would be required to further evaluate the efficacy of DAV‐IFN‐β therapy as an adjuvant chemotherapy.     

Non-human immunodeficiency virus Kaposi's sarcoma can be effectively treated with low-dose interferon-α despite the persistence of herpesvirus-8

Three patients, negative for human immunodeficiency virus (HIV), with histologically and polymerase chain reaction-proven non-HIV Kaposi's sarcoma who received low-dose interferon (IFN) as first-line treatment because of disseminated symptomatic disease are reported. Applying 3–18 million IU of IFN-α2a per day, 3 days a week, subcutaneously for 8–20 months, major responses were achieved in all three cases. Tumour regression was observed within 4 months and has continued for 57 and 18 months to date (cases 1 and 2, respectively). Influenza-like symptoms, including fever, headaches and fatigue, were mild side-effects. However, in the third patient interferon injections had to be stopped because of hepatic enzyme elevation. Including this case report, 27 non-HIV Kaposi's sarcoma patients subcutaneously treated with IFN-α have been reported in literature. Most therapy regimens included 3–18 million IU IFN-α per day for 3 days a week. Twenty of 27 patients, or 74%, responded to therapy, whereas seven patients or 26% had stable or progressive disease. Relapse after IFN withdrawal can occur but is frequently delayed and limited, as in case 1. Following the response to IFN treatment, human herpesvirus-8 DNA was detected in the blood mononuclear cells of all three patients, possibly contributing to future relapses.     

Concomitant vitiligo and psoriasis in a patient treated with interferon alfa-2a for chronic hepatitis B infection

Well-known cutaneous side effects of interferon (IFN)-alfa therapy include dry skin, pruritus, hair loss, and psoriasis. Presumably because of its potent immunomodulatory activity, the use of IFN-alfa has also led to the development of autoimmune diseases in susceptible individuals. Vitiligo, an autoimmune cutaneous disease, has been reported to occur during IFN-alfa therapy. We report a 10-year-old girl with chronic hepatitis B infection in whom IFN-alfa treatment induced de novo development of vitiligo and psoriasis. Neither skin condition improved after withdrawal of interferon treatment. Concomitant occurrence of vitiligo and psoriasis due to IFN-alfa has not been reported previously.     

Synergistic effects of interferon‐beta and nivolumab in oral mucosal melanoma

Mucosal melanoma is a rare aggressive cancer with a very poor prognosis. Clinical and pathological characteristics of mucosal melanoma differ from those of cutaneous melanoma and there are no established management guidelines for mucosal melanoma. Complete surgical excision is one of the most effective treatments for localized lesions, while targeted therapies and immunotherapies, such as monoclonal antibodies that target cytotoxic T‐lymphocyte‐associated molecule‐4, and the programmed death (PD)‐1/PD‐ligand 1 pathway inhibitors, are treatment options for unresectable or metastatic lesions. Here, we describe the case of a patient with oral mucosal melanoma with multiple metastases. In our case, local injection of interferon (IFN)‐β with dacarbazine–nimustine–vincristine therapy provided antitumor effects on an invasive tumor on the upper gingiva. Nivolumab therapy produced complete remission of lymph node and bone metastases. In contrast, the remaining in situ portion of oral mucosal melanoma on the hard palate was refractory to IFN‐β monotherapy and nivolumab therapy. However, after administration of nivolumab, peritumoral injection of IFN‐β showed rapid therapeutic effects. Our case suggested that nivolumab upregulated the antitumor effects of IFN‐β, which induced the recruitment of CD8⁺ T cells into the tumor microenvironment contributing to the deletion of tumor cells. Combination therapy of IFN‐β and nivolumab may be a potential treatment option for patients with oral mucosal melanoma.     

Cutaneous lesions as initial signs of interferon α-induced sarcoidosis: report of three new cases and review of the literature

Sarcoid reactions are well-recognized adverse events during interferon (IFN) therapy. They are frequently underdiagnosed because misinterpreted as IFN-induced side effects. Sarcoid cutaneous lesions may therefore represent useful hints to an early diagnosis, but their incidence is unknown. We report three new cases of mono-localized, purely cutaneous IFNα-induced sarcoidosis. In addition, an extensive review of the literature, with special attention to skin involvement, was performed through a PubMed search. The analysis of the retrieved articles showed that cutaneous lesions are frequent signs of IFN-induced sarcoidosis. Skin involvement is documented in 56% of the reports and it appears among the presenting and diagnostic signs of a sarcoid reaction in 51%. Special attention to dermatologic signs is imperative in the course of IFN therapy because even minimal skin involvement may offer a clue to an early diagnosis of IFN-induced sarcoidosis.