Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan

Keywords: myasthenia gravis; retinopathy; interferon

Interferons (IFNs) have antiviral and antimitogenic effects and are often used in the treatment of viral hepatitis or some neoplasms. However, they have various side effects including fever, nausea, depression, retinopathy, and autoimmune diseases. Although myasthenia gravis (MG) is rarely associated with IFN therapy, some cases developing MG after IFN or IFN/ribavirin combined therapy for chronic active hepatitis C have been reported.1–5 We report such a case by reviewing the clinical data.

Case report

A 69 year old man with chronic hepatitis C for 11 years had been treated with IFN- monotherapy (IFN 6x106 IU three times a week after 2 weeks of daily injections). The first treatment started in April 2002. There was no complication noted in that treatment. After the therapy hepatitis C virus activity settled for a while, but during the observation his clinical data showed a rise in hepatitis C virus RNA and aminotransferases. He underwent IFN- therapy conjugated with ribavirin (IFN 6x106 IU three times a week after 2 weeks of daily injections, ribavirin 800 mg twice a day) again on 6 December 2002. During the course his condition was checked periodically, mainly in terms of retinopathy. He had finished 7 months of treatment without significant side effects.

Around December 2003 he began to notice fluctuating diplopia. Examination revealed his reduced right adduction, exotropia and left/right hypertropia. Since his condition drifted and there was no significant disorder on magnetic resonance imaging, MG was suspected and edrophonium chloride was tested. With the medication, his diplopia prominently improved and MG was diagnosed; however, there was no elevation in his anti-acetylcholine receptor antibody titre or other auto-antibodies, and thymoma was not detected.

Comment

It is well known that IFN therapy induces autoimmunity. Thyroid auto-antibodies are the most frequent findings; autoimmune hepatitis, rheumatoid symptoms, induction of insulin dependent diabetes, etc, are also seen. In relation to this autoimmune effect, several cases concerning MG associated with IFN therapy have been reported. Some cases developed myasthenia newly or others exacerbated pre-existing symptoms.1–5 It is reported that cases with pre-existing MG have a tendency to present more severe symptoms including myasthenic crisis.4 The pathogenesis is not completely understood because of the complex immunological effects of IFNs, including enhanced lymphocyte cytotoxicity, inhibition of T suppressor cell function, increased expression of major histocompatibility complex (MHC) class I antigens, production of proinflammatory cytokines, and differentiation of antigen presenting cell activation of T helper lymphocytes by autoantigens. Some or all of them might contribute to the development of autoimmune disease.6

In this case the patient had no sign of MG or other autoimmune disease before the IFN treatment. His symptom is limited only to extraocular muscles: the condition is relatively mild. That is consistent with the previous report referring to the relation between the severity and the presence of a history of autoimmune disease; but the fact that anti-acetylcholine receptor antibody titre was not elevated is contradictory.4 We could not establish the causality.

These days many patients with chronic active hepatitis C virus receive IFN or IFN/ribavirin combined therapy. We usually examine these patients only in terms of retinopathy. Although this case could be a coincidental sporadic autoimmune disorder, we should take MG into consideration. We should recognise the risk of development or worsening of MG and be careful in managing patients undergoing therapy, especially when they already have MG or compatible symptoms. It can be a serious complication although it is very rare.

References

Gurtubay IG, Morales G, Arechaga O, et al. Development of myasthenia gravis after interferon alpha therapy. Electromyogr Clin Neurophysiol 1999;39:75–8.

Borgia G, Reynaud L, Gentile I, et al. Myasthenia gravis during low-dose IFN-alpha therapy for chronic hepatitis C. J Interferon Cytokine Res 2001;21:469–70.

Weegink CJ, Chamuleau RA, Reesink HW, et al. Development of myasthenia gravis during treatment of chronic hepatitis C with interferon-alpha and ribavirin. J Gastroenterol 2001;36:723–4.

Konishi T. A case of myasthenia gravis which developed myasthenic crisis after alpha-interferon therapy for chronic hepatitis C. Rinsho Shinkeigaku 1996;36:980–5.

Harada H, Tamaoka A, Kohno Y, et al. Exacerbation of myasthenia gravis in a patient after interferon ? treatment for chronic active hepatitis C. J Neurol Sci 1999;165:182–3.

Dumoulin FL, Leifeld L, Sauerbruch T, et al. Autoimmunity induced by interferon- therapy for chronic viral hepatitis. Biomed Pharmacother 1999;53:242–54.

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《英国眼科学杂志》2005年11月第89卷第11期