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We have reported the successful induction of remission with interferon α (IFNα) in severe Churg-Strauss syndrome (CSS) refractory to treatment with corticosteroid and cyclophosphamide.1 The effectiveness and safety of short term administration of IFNα was confirmed by a subsequent case series.2 Now, we report a potentially hazardous adverse event seen in two of 12 patients with CSS during long term IFNα treatment.
The first patient was a 48 year old woman with biopsy proven CSS, fulfilling the American College of Rheumatology criteria and Chapel Hill Consensus Conference definition, with blood eosinophilia, involvement of the respiratory tract, skin, peripheral nervous system, musculoskeletal system, and heart. Remission was induced with cyclophosphamide and corticosteroid for 10 months and maintained with methotrexate for 12 months, but she then relapsed with eosinophilic pleural effusion and pulmonary infiltrates. To avoid prolonged administration of cytotoxic drugs she received 3×3–3×7.5 million units IFNα/week subcutaneously. Remission with IFNα lasted for 61 months when a pulmonary relapse occurred. Surprisingly, magnetic resonance imaging (MRI) of the head, performed for staging of ear, nose, and throat activity, disclosed multifocal leucoencephalopathy (fig 1) in the absence of neurological signs and in contrast with previous images obtained 74 and 47 months previously. The cerebrospinal fluid (CSF) was normal. Infectious and other causes were excluded. Treatment was switched to methotrexate. During 24 months of follow up she was free of neurological symptoms, but the MRI findings persisted.
The second patient with CSS, a 59 year old women with multiorgan involvement, had been treated with 3×5 million units IFNα/week subcutaneously since 1997. A cardiac relapse of her CSS and a transient psychotic episode, possibly related to the increased intake of prednisolone for the treatment of the cardiac relapse, occurred in January 2001. MRI of the head disclosed leucoencephalopathy. The CSF was normal. Infections and other causes were excluded. Psychotic symptoms subsided after withdrawal of IFNα and reduction of prednisolone. During follow up (October 2001, January 2003) the MRI findings remained unchanged, but remission was successfully re-induced with cyclophosphamide.
Leucoencephalopathy has been reported in a number of diseases necessitating immunosuppressive treatment such as autoimmune disorders—for example, systemic lupus erythematosus; neoplastic diseases—for example, leukaemias; and in organ transplant recipients. Several immunosuppressive or cytotoxic agents such as methotrexate, ciclosporin, flutarabine, and l-asparaginase, can cause leucoencephalopathy.3 Leucoencephalopathy can either be a result of the direct toxic effect of the drug or may be caused by infections during immunosuppressive treatment (for example, papovavirus infections like JC and BK or human immunodeficiency virus (HIV)). Further differential diagnoses include severe central nervous system manifestations of systemic vasculitides and diffuse cerebral neoplasms. A family history may give clues to the diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL).
Infectious causes were excluded in both of our patients. The disease course with the detection of leucoencephalopathy by MRI during a relapse in the presence of previously successful IFNα treatment suggested either a cerebral manifestation of CSS or that IFNα was the cause of the leucoencephalopathy. Because cerebral lesions caused by vasculitides usually have a less diffuse and widespread character and CSF analysis showed no signs of inflammation, central nervous involvement of CSS appeared unlikely. In addition, multiple ischaemic lesions are extremely rare in CSS and were found in only one of 96 patients in a recent study.4
Leucoencephalopathy has been described in patients treated with IFNα for melanoma, leukaemia, lymphoma, or hepatitis C, usually presenting with somnolence, headache, disorientation, or short term memory loss, and resolving after IFNα is stopped.3,5–7 The causal relation between IFNα treatment and leucoencephalopathy is unclear. However, leucoencephalopathic lesions have been seen both in Aicardi-Goutieres syndrome, a human autosomal recessive progressive encephalopathy with raised CSF IFNα levels, and in transgenic mice overexpressing IFNα predominantly in astrocytes, suggesting that IFNα may induce leucoencephalopathy.8
These two cases suggest that IFNα may cause cerebral cytotoxicity also in CSS. Thus, long term treatment of CSS with IFNα should be restricted to patients who are unresponsive to other forms of treatment. Close monitoring of patients is mandatory and should include cerebral MRI in order to detect asymptomatic leucoencephalopathy at an early stage.
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