Cutaneous sarcoidosis during interferon alfa and ribavirin treatment of hepatitis C virus infection: two cases

Interferon-induced sarcoidosis is well documented. We report two new cases of sarcoidosis in two patients with hepatitis C virus infection treated with interferon alfa and ribavirin. These patients developed cutaneous sarcoidosis about 3 months after the beginning of the combination therapy. Spontaneous regression of the lesions was noted after discontinuation of the treatment. There have been more than 20 observations of the appearance or aggravation of this granulomatosis with interferon alfa and more recently with the combination of interferon alfa plus ribavirin. Dermatological signs are found in 50% of cases, and are often diagnostic. Other clinical symptoms of sarcoidosis resemble side-effects of interferon. The evolution is fairly stereotypical and is marked by a regression of the lesions following a dose reduction or curtailment of interferon. Interferon alfa acts by stimulating the T-helper (Th) 1 immune response. In addition to its antiviral action, ribavirin also enhances the Th1 response. Indeed, the superiority of the combination of interferon alfa and ribavirin in terms of antiviral action is corroborated by the enhancement of a Th1-type immune reaction by this combination. At the same time, this immune cell reaction triggers a greater granulomatous reaction.     

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.     

Diffuse inflammatory lesions in patients treated with interferon alfa and ribavirin for hepatitis C: a series of 20 patients

BACKGROUND: Cutaneous side-effects of treatment with interferon alfa or interferon alfa plus ribavirin in patients with hepatitis C have already been reported but they are mostly local with inflammation and, much less frequently, necrosis at the injection points. By contrast, very few data are available with regard to distant skin reactions, particularly inflammatory lesions on other parts of the body. OBJECTIVES: To assess the clinical and histological pattern of inflammatory skin lesions outside the injection points in patients treated with interferon alfa and ribavirin for chronic hepatitis C. METHODS: Twenty patients attending a University Hospital in Southern France (secondary referral centre) were evaluated regard to clinical history, type and localization of lesions, progression and histology. Skin testing was performed in some patients and the relevance of the results was evaluated. RESULTS: Eczema-like skin lesions were mainly distributed on the extremities, sometimes associated with photosensitivity. They usually occurred between 2 and 4 months of treatment. Histology was nonspecific, with a dermal, mainly perivascular, mononuclear infiltrate. Skin testing was poorly informative and was not predictive of relapse. Treatment had to be interrupted in half the patients, of whom two of three relapsed on resuming therapy. CONCLUSIONS: The incidence of inflammatory skin lesions at a distance from injection sites in patients treated with interferon alfa and ribavirin for chronic hepatitis C is currently unknown, but this adverse event must be taken into consideration as it may lead to the transient or definitive interruption of treatment.     

Reacción granulomatosa a cuerpo extraño a sílice,silicona y ácido hialurónico,en paciente con sarcoidosis inducida por interferón

We report the case of a patient who developed sarcoid granulomas 11 months after starting treatment with pegylated interferon alfa and ribavirin for chronic hepatitis C. The sites of the lesions were related to 3 different foreign bodies: silica in old scars on the skin, hyaluronic acid that had been injected into facial tissues, and silicone in an axillary lymph node draining the area of a breast implant. Systemic sarcoidosis was diagnosed on the basis of a history of dry cough and fever and blood tests that revealed elevated angiotensin converting enzyme and liver enzymes. Interruption of the antiviral therapy led to normalization of liver function tests and disappearance of the skin lesions and lymphadenopathies. Dermatologists and cosmetic surgeons should be aware of the risk of sarcoid lesions related to cosmetic implants in patients who may require treatment with interferon in the future.     

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.     

Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient.

Pegylated interferon alfa is a pegylated formulation of recombinant human interferon (IFN) conjugated with polyethylene-glycol (PEG). The major advantages of this formulation, compared to standard IFN, is a prolonged half-life which allows for once-weekly injection. Its antiviral efficacy in association with ribavirin as a new standard treatment of chronic hepatitis C has been recently documented. Efficacy of PEG-IFN in the therapy of HIV infection is currently being evaluated in prospective pilot studies. We describe herein the first observation of cutaneous necrosis at the sites of PEG-IFN injection in an HIV-infected patient. A 50-year-old man, HIV infected, was treated with antiretroviral bitherapy combining zidovudine and didanosine for 30 months. Weekly subcutaneous injections of PEG-IFN-alpha-2b were started at a dose of 1.5 microg/kg. Nine months later, two successive necrotizing cutaneous lesions developed at the site of injection. The cutaneous ulcerations slowly healed under local therapy without interruption or dose modification of the PEG-IFN. We review the literature on previously reported cases of cutaneous necrosis following standard or pegylated IFN-alpha injection and discuss the different pathophysiological mechanisms that might be involved.     

Pulmonary and cutaneous sarcoidosis associated with interferon therapy for melanoma

Interferon alfa is widely used as adjuvant therapy for melanoma. Numerous side effects have been attributed to interferon alfa. Interferon alfa-induced sarcoidosis is an uncommon event. We report the third case of pulmonary and cutaneous sarcoidosis in the course of interferon alfa treatment for melanoma. Most cases of sarcoidosis have been reported during treatment of chronic hepatitis C. The prognosis is good with discontinuation of treatment. Other than interferon therapy, sarcoidosis or granulomatosis reactions rarely have been reported in malignant melanoma. We discuss and review the literature on the physiopathology of sarcoidosis brought on by interferon therapy.     

Photodynamic therapy as an alternative treatment for cutaneous sarcoidosis

Sarcoidosis is a systemic granulomatous disease. In more than 90% of the cases, sarcoidosis affects the lung with bilateral hilar adenopathy, while skin involvement occurs in about 25% of the cases. Whereas sarcoidosis of the lung is often successfully treated with oral corticosteroids, therapy of cutaneous sarcoidosis is frequently frustrating because some of the lesions may be refractory to treatment or recur quickly after resolution. We report two cases of cutaneous sarcoidosis successfully treated with photodynamic therapy, which represents an effective alternative therapy with fewer side effects.     

Cutaneous sarcoid with varied morphology associated with hypercalcaemia and renal impairment

Sarcoidosis is a multisystem disorder of unknown aetiology, which presents with hilar lymphadenopathy, pulmonary infiltration, and ocular and cutaneous involvement. Cutaneous lesions often present as erythema nodosum, maculopapular, plaque, scar, subcutaneous nodule or lupus pernio. Most patients with cutaneous involvement have a single type of skin lesion, but some cases may have ≥ 2 types. We report a case of sarcoidosis presenting with various types of skin lesions. The case was also complicated by hypercalcaemia and renal dysfunction, and was successfully treated with oral corticosteroids. Presentation of various skin lesions may indicate systemic organ involvement requiring treatment with systemic corticosteroid.     

Severe, generalized nummular eczema secondary to interferon alfa-2b plus ribavirin combination therapy in a patient with chronic hepatitis C virus infection

BACKGROUND: With increasing rates of hepatitis C virus infection and diagnosis, more patients are being treated with interferon alfa-2b plus ribavirin therapy. Cutaneous side effects to combination therapy are common and may limit treatment. There are few previous case reports of generalized eczematous dermatoses occurring after combination therapy for hepatitis C virus, none in a North American patient, and none of this severity or recalcitrance. OBSERVATIONS: A man with chronic hepatitis C virus infection and no history of atopy developed severe, recalcitrant nummular eczema secondary to interferon alfa-2b plus ribavirin combination therapy. The cutaneous side effect was more severe than in previously reported cases and did not remit on discontinuation of therapy. CONCLUSIONS: Greater awareness of the range of dermatologic responses to interferon alfa-2b plus ribavirin therapy may lead to improved surveillance for and treatment of these side effects. Investigating the underlying pathologic mechanisms may ultimately allow for a greater understanding of the immunomodulatory effects of this therapy in the setting of chronic hepatitis C virus infection.     

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.     

Splenic lymphoma with villous lymphocytes revealed by purpura pigmentosa progressiva associated with cryoglobulinemia and chronic hepatitis C infection

BACKGROUND: Splenic lymphoma with villous lymphocytes is occasionally associated with chronic hepatitis C infection. Antiviral hepatitis C therapy has been recently reported to be efficacious against splenic lymphoma with villous lymphocytes. We report a new case revealed by cutaneous symptoms. CASE REPORT: A 53-year-old patient with arthritis and neuropathy of the lower limbs consulted for vascular purpura on both legs. The blood picture showed an increase in villous lymphocytes leading to a diagnosis of splenic lymphoma with villous lymphocytes. Histologic examination of a cutaneous biopsy specimen showed thrombosis of the superficial dermal vessels, associated with cryoglobulinemia with renal and neurologic failure, a satellite of hepatitis C virus infection. The patient was treated with interferon, ribavirin and plasmapheresis. DISCUSSION: Vascular purpura, often associated with cryoglobulinemia, may reveal chronic hepatitis C infection. The efficacy of interferon and ribavirin treatment for splenic lymphoma with villous lymphocytes associated with hepatitis C infection has already been documented, and results in remission of cryoglobulinemia and lymphoma as well a eradication of viral load in 78% patients.     

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-alpha Induced Sarcoidosis with Cutaneous Involvement along the Lines of Venous Drainage

Sarcoidosis is a systemic inflammatory disease of an unknown origin and it is characterized by the presence of noncaseating epitheloid cell granulomas in multiple organs. Herein we report on a case of cutaneous and pulmonary sarcoidosis that was associated with interferon alpha treatment for hepatitis C. A 39-year-old man, a former intravenous drug user, presented with several erythematous papules on both antecubital areas. The histopathologic finding of a skin biopsy showed noncaseating granuloma. The mediastinal and axillary lymph nodes were enlarged on chest X-ray and computed tomography. To the best of our knowledge, this is the first report of cutaneous and pulmonary sarcoidosis that was associated with interferon treatment in the Korean dermatologic literature.     

Cutaneous sarcoidosis: Prognosis and treatment

The physician who has made a diagnosis of cutaneous sarcoidosis is faced with three basic questions: (1) Are there lesions in organs other than the skin? (2) Should the patient be given treatment? (3) What will the final outcome of the disease be?

Cutaneous sarcoidosis can be a great imitator of other skin diseases with a wide spectrum of clinical manifestations ranging from small asymptomatic cutaneous lesions that fade spontaneously without scarring, to widespread skin lesions and disease in many organ systems. The latter may be associated with severe symptoms such as pulmonary insufficiency or life-threatening biochemical abnormalities. Approximately two thirds of all patients recover completely or with a minimum of residual changes, while 2–5% of sarcoidosis patients die from the disease.^1,2

It is therefore of interest to review the literature that deals with the course and prognosis of sarcoidosis. It is also important to deal with the association of cutaneous sarcoidosis and other types of sarcoidosis in order to provide the dermatologist with a basis for his or her decision about whether treatment should, in fact, be instituted.     

Drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy

Pegylated interferon-alpha in combination with ribavirin currently represents the therapeutic standard for the hepatitis C virus infection. Interferon based therapy may be responsible for many cutaneous side effects. We report a case of drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy. To our knowledge, this is the first reported case of Sweet's syndrome in association with pegylated interferon-alpha therapy.     

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.     

Necrolytic acral erythema associated with hepatitis C: effective treatment with interferon alfa and zinc

BACKGROUND: Necrolytic acral erythema is a recently described necrolytic erythema that is unique in its exclusive acral location and strong association with hepatitis C. OBSERVATION: We report the first case of necrolytic acral erythema in the United States. The patient is a 43-year-old black woman who presented with a 4-year history of tender, flaccid blisters localized to the dorsal aspect of her feet. Serum zinc and glucagon levels were normal. Serum antibodies were positive for hepatitis C, and a liver biopsy specimen showed chronic hepatitis. She was successfully treated with interferon alfa-2b and zinc. We review all previously reported cases. CONCLUSIONS: Necrolytic acral erythema is a distinct entity. In a review of the literature, most patients were between 35 and 55 years of age, although 1 patient was 12 years old. Five of 8 patients were female. Four of 7 patients described previously were treated with variable success using oral zinc sulfate and amino acids, whereas 2 were successfully treated with interferon alfa. All patients were infected with hepatitis C. Necrolytic acral erythema appears to be a skin disorder linked to infection with hepatitis C virus that responds to treatment with interferon alfa and oral zinc.     

Specific cutaneous lesions in patients with systemic sarcoidosis: relationship to severity and chronicity of disease

Background. Specific (granulomatous) cutaneous lesions are seen in 9–37% of cases of systemic sarcoidosis, and are usually classified into maculopapules, plaques, lupus pernio (LP), scar sarcoidosis, and subcutaneous sarcoidosis. Their prognostic significance has not been fully established. Aim. To analyse the relationship between the clinical type of granulomatous cutaneous lesions and the systemic features and prognosis of systemic sarcoidosis. Methods. The clinical charts of 86 patients (19 men, 67 women, mean age 46.82 years) with systemic sarcoidosis and granulomatous cutaneous involvement followed up for > 2 years at Bellvitge University Hospital were reviewed. Results. Cutaneous lesions developed before or at the time of diagnosis of systemic sarcoidosis in 80.23% of patients. The main cutaneous lesions were classified as maculopapules (28 patients), plaques (31), LP (6), scar sarcoidosis (7) and subcutaneous sarcoidosis (14). Erythema nodosum (EN) was seen in 30 patients. Radiological stage was 0 for 8 patients, I for 48, II for 24, III for 5 and IV for 1. Systemic sarcoidosis activity persisted for > 2 years in 47 patients, and 42 received systemic corticosteroid treatment for their disease. Maculopapular and subcutaneous sarcoidosis were mainly seen in patients with EN and radiological stage I. Plaques and LP were associated with chronic disease and requirement for systemic corticosteroids. Conclusions. Cutaneous granulomatous lesions are usually present at the diagnosis of systemic sarcoidosis, and the type of cutaneous involvement may have prognostic significance.     

Cutaneous sarcoidosis: an intriguing model of immune dysregulation

Sarcoidosis is a systemic granulomatous disease characterized by the presence of non‐caseating granulomas. Its etiology remains obscure. A plausible hypothesis suggests that a complex interplay of host factors, infectious processes, and non‐infectious environmental factors, matched with a susceptible genetic background, results in a pathway that leads to systemic granulomatous inflammation. Although presentations of sarcoidosis vary enormously, multi‐organ involvement is a common feature. Cutaneous involvement occurs in about 25% of patients with protean manifestations and variable prognoses. Skin manifestations are divided into specific lesions with histopathologically evident non‐caseating granulomas and nonspecific lesions arising from a reactive process that does not form granulomas. A peculiar form of cutaneous sarcoidosis is represented by sarcoidal lesions at sites of trauma that has caused scarring. The pathogenesis of scar sarcoidosis remains unknown. Scar sarcoidosis is also associated with herpes zoster infection, surgery, and tattooing. Such heterogeneous events, along with those at the sites of chronic lymphedema, thermal burns, radiation dermatitis, and vaccinations, occur on areas of vulnerable skin labeled “immunocompromised districts”. Numerous options are available for the treatment of cutaneous sarcoidosis. Although corticosteroids remain the treatment of choice for initial systemic therapy, other nonsteroidal agents have proven effective and therefore useful for long‐term management. Tumor necrosis factor‐α antagonists such as infliximab may have a role in the treatment of cutaneous sarcoidosis, especially in refractory cases that are resistant to standard regimens. Elucidation of the relationship of sarcoidal granulomas with malignancy and immunity may facilitate a better understanding of some pathomechanisms operating in neoplastic and immunity‐related disorders.