Introduction

Polymyositis (PM) and dermatomyositis (DM) are autoimmune muscle disorders that symmetrically affect primarily the proximal limbs, neck, and pharyngeal muscles. DM is accompanied by a characteristic rash such as Gottron’s papules and heliotrope rash of the eyelids. CD4+ T cells, CD8+ T cells, macrophages, and dendritic cells infiltrate around muscular tissue and blood vessels with degeneration and regeneration of muscular fibers. Inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-15, and IL-18 are thought to play a crucial role in the pathogenesis of PM/DM [1].

Type I interferon (IFN) is a giant cytokine family including IFN-α, IFN-β, IFN-ω, IFN-λ, and IFN-τ. These cytokines have antiviral and antitumor activities. IFN-α and IFN-β are used to treat viral hepatitis or malignant melanoma. Furthermore, the efficacy of IFN-β for multiple sclerosis was also demonstrated [2]. However, several studies reported that autoimmune diseases such as systemic lupus erythematosus and PM/DM can develop during treatment with IFN-α or IFN-β [3–14]. We report a patient who developed DM as a complication of IFN-α therapy for hepatitis C. In this patient, dermatomyositis was rapidly progressive and successfully treated with glucocorticoid therapy in addition to intravenous immunoglobulin (IVIG) and tacrolimus without reactivation of the hepatitis C virus.

Case report

A 52-year-old man was diagnosed as being a hepatitis C virus (HCV, Genotype 1) carrier in 1997, but he was not treated. He sought medical advice in regard to hepatitis at a hospital. Combination therapy with weekly subcutaneous injection of pegylated IFN-α-2b (PEG-IFN-α-2b) 100 mg/body and oral administration of ribavirin 800 mg/day were initiated in June 2011. Erythema involving the cervical and dorsal regions appeared, and weight loss was noted 3 months after the initiation of therapy. In January 2012, exacerbation of the erythema, general malaise, muscular pain, and a severe increase in the level of creatine kinase (CK) 23–36,500 U/l were observed. Therefore, PEG-IFN-α-2b and ribavirin were discontinued, and the patient was admitted to our hospital. Heliotrope rash on the eyelids, shawl sign, and protruding and purple-red erythema (Fig. 1) were present on the posterior cervical to dorsal and anterior cervical to thoracic regions. Proximal upper limb-dominant muscular weakness of the cervical flexors and deltoid muscle and decreased grip strength were also observed. The blood examination showed increased levels of CK (29,333 U/l), aldolase (288.8 U/l), C-reactive protein (3.94 mg/dl), aspartate aminotransferase (1,106 U/l), alanine aminotransferase (1,171 U/l), and lactate dehydrogenase (1,709 U/l). The thyroid function was normal. Positive levels of antinuclear antibody (1:640, speckled pattern) were detected. Anti-aminoacyl tRNA synthetase (ARS), anti-signal recognition particle, anti-Mi-2 antibody, anti-PM/SCL antibody, anti-MDA5 antibody, anti-ribonucleoprotein antibody, anti-double stranded DNA antibody, and other disease-specific autoantibodies were negative. Complement level was normal. Electromyography showed proximal muscle-predominant myogenic changes. Magnetic resonance imaging of upper limbs showed diffuse myopathy. A skin biopsy showed infiltration of monocytes and CD4+-dominant lymphocytes around blood vessels in the superficial corium layer and in the middle to deep layers of the corium (Fig. 1). Although a muscle biopsy was not performed because of the patient’s non-consent, based on these findings, a diagnosis of DM was made [3, 4], and prednisolone 80 mg/day and IVIG (400 mg/kg/day × 5 days) were initiated. Because a sufficient decrease in the levels of muscle enzymes was not achieved, administration of tacrolimus (3 mg/day) was initiated 13 days after admission, and IVIG was performed twice more. The serum levels of muscle enzymes decreased to the reference range without the reactivation of HCV.

Fig. 1
figure 1

a Erythema on the posterior cervical region. b, c Monocytes and lymphocytes infiltrate around blood vessels in the superficial corium layer and in the middle to deep layers of the corium. (b H&E, ×40) (c H&E, ×400) d and e Lymphocytes stained with CD4 infiltrate into the perivascular region more than those with CD8. (d immunostaining for CD4, ×400) (e immunostaining for CD8, ×400)

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Discussion

We experienced a patient who developed DM during IFN-α therapy for hepatitis C. Eleven patients with PM/DM (8 with PM and 3 with DM) related to IFN-α therapy, including our patient, have been reported (Table 1) [5–14]. PM/DM related to IFN-α therapy is more frequent in males. The diseases for which IFN-α therapy was indicated in these patients included hepatitis C in 6 patients, malignant melanoma in 2, hepatitis B in 1, essential thrombocytosis in 1, and chronic myelocytic leukemia in 1. Most patients, including our patient, developed PM/DM within 3 months after the start of IFN-α therapy that ranged from 2 weeks to 7 months in duration. Two previously reported patients with DM were positive for anti-ARS antibodies, such as anti-Jo-1 and anti-PL-7 antibodies, and interstitial pneumonia was concomitantly present [5, 6]. However, these findings were absent in our patient. The PM/DM related to IFN-α in these patients responded to treatment well with a favorable prognosis. In one patient, the discontinuation of IFN-α improved DM spontaneously without immunosuppressive treatment.

Table 1 DM and PM associated with IFN alpha therapy
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Re-administration of IFN-α should be considered cautiously. It was reported that re-administration of IFN-α caused rapid recurrence of myositis in a patient with inclusion body myositis related to IFN-α [17]. However, the discontinuation of IFN therapy in HCV carriers or the use of steroids in HCV-infected patients may increase the RNA levels of HCV, causing hepatitis [18]. We could find no reports of reactivation of HCV or onset of hepatitis caused by discontinuation of IFN-α or start of immunosuppressive therapy in IFN-α-related DM/PM patients with HCV infection. Reactivation of HCV in our patient was not observed despite strong immunosuppressive therapy with high-dose glucocorticoid and tacrolimus. However, therapeutic strategies for the reactivation of HCV or progression of hepatitis are not established, and care must be taken to avoid these risks.

Type I IFN is involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus and PM/DM [19–21]. A large number of plasmacytoid dendritic cells infiltrate into the muscle tissue of patients with PM/DM, and mRNAs of the type I IFN-associated gene (IFN signature) are highly expressed [22]. Myxovirus-resistant protein A, a gene that is induced by type I IFN, is highly expressed in the muscle fibers and blood vessels of these patients [22, 23]. PM/DM as a complication of IFN-α, including that in the present patient, indicates that type I IFN may be involved in the onset of PM/DM, although the exact relation between type I IFN and the development of PM/DM as well as the potential mechanism of disease development remain unclear. These issues must be examined more thoroughly in the future.

We presented a patient who developed DM during the administration of IFN-α for treatment of hepatitis C. He was successfully treated with IVIG and tacrolimus in addition to glucocorticoid despite serious muscular symptoms. Several similar cases of PM/DM as a complication related to IFN-α have been reported. These cases suggest that IFN-α may contribute to the pathogenesis of PM/DM.