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- systemic lupus erythematosus
- progressive multifocal leucoencephalopathy
Progressive multifocal leucoencephalopathy (PML) is an opportunistic infection caused by human polyomaviruses such as the JC virus. It usually occurs as a severe complication of immunosuppression in patients with primary disorders of the immune system or secondary impairment of immune function, for example, after iatrogenic states of immunosuppression. PML usually takes a rapidly progressive course and advances to death within 1 to 18 months. Today, PML is mainly seen in AIDS, while previously it was typically found in patients with granulomatous, neoplastic, or infectious diseases. In granulomatous diseases particularly, PML is thought to occur as a result of iatrogenic states of immunosuppression, but it is also seen in patients aggressively treated with immunosuppressive agents for systemic lupus erythematosus (SLE).1,2 PML progresses to death in most of these patients even after withdrawing immunosuppressive therapy.2 Therefore additional therapy, aimed at supporting a more rapid restoration of immune function his warranted.
We report a 40 year old woman diagnosed with SLE at the age of 20 years, based on four American College of Rheumatology criteria (erythema, arthritis, elevated antinuclear antibodies, and anti-dsDNA antibodies). Owing to neuropsychiatric lupus (the patient had experienced several psychotic episodes) with suspected vasculitic changes on cerebral magnetic resonance imaging (MRI), the patient had undergone 12 cycles of cyclophosphamide pulse therapy in 1995/96 followed by immunosuppressive treatment with mycophenolate mofetil in 1998, and azathioprine in 1999. Follow up cerebral MRI scans at that time were normal.
In January 2001, she again developed psychotic episodes and an initially mild ataxia. She had repeatedly been put on low doses of corticoids but on no other immunosuppressive therapy during the previous 2 years. MRI revealed a lesion in the left cerebellum, which was hyperintense on T2 and hypointense on T1 weighted images. No lesions were seen in the cerebral hemispheres. Central nervous system manifestation of SLE was suspected, although the patient revealed only moderate signs of SLE activity (elevated anti-dsDNA antibodies, slightly decreased complement levels C3c and C4, increased erythrocyte sedimentation rate, but normal C reactive protein). There were no signs of severe immunosuppression; laboratory data showed normal levels of immunoglobulins and only slightly decreased lymphocytes, especially CD8+ T lymphocytes. The patient received two pulses of cyclophosphamide and high doses of corticosteroids to reduce the presumed cerebral SLE activity. In addition, she received antipsychotic medication.
While the psychosis was readily controlled by this treatment, the patient deteriorated neurologically. She developed a severe, disabling, rapidly progressive, left sided hemiataxia. and was unable to walk. A control MRI of the brain in February 2001 revealed a progression of the lesion in the left cerebellum and a new lesion in the middle cerebellar peduncle. The lesions again presented as hyperintense on T2 and hypointense on T1-weighted images (fig 1A). Owing to the neurological deterioration after initiation of immunosuppression and the presentation of the lesions on MRI, PML was considered as a differential diagnosis. PCR revealed JC virus DNA in the cerebrospinal fluid (CSF). As cerebral SLE and PML require an intense but divergent therapy, a brain biopsy was obtained from the cerebellar lesion. Histopathology confirmed the diagnosis of PML. HIV tests were negative, T cell counts were normal, and signs of malignancy were lacking. Immunosuppression was discontinued. Because PML is usually lethal in patients with SLE even after omission of immunosuppression,1,2 we considered options for an active antiviral therapy. There was evidence from several reports in AIDS patients that cidofovir, an inhibitor of viral DNA polymerase, may reduce the size of PML lesions and thus prolong survival.3,4 Lacking therapeutic alternatives we therefore administered intravenous cidofovir (5 mg/kg body weight) at initially bi-weekly intervals, after obtaining informed consent. After the third and fourth cycle, the patient improved dramatically. She was able to walk again and only showed a mild residual ataxia. MRI revealed reduction of the lesions in the cerebellum and middle cerebellar peduncle with no new sites of active disease (fig 1B). PCR for JC virus DNA in the CSF was now negative. The treatment with cidofovir was continued with longer intervals (8–12 weeks). The therapy was generally well tolerated. After the fifth cycle, mildly increased creatinine levels were found. After one cycle with 4 mg cidofovir/kg body weight, kidney function was quickly normalised and the following cycles could be administered at the initial dosage. Fourteen months after initiation of the treatment, the patient had completed the 10th cycle of therapy with no signs of disease activity. MRI scans of the brain showed further regression of the lesion with no signs of active inflammation (not shown), and cidofovir treatment was discontinued. At present, (4 years follow up after the first treatment and 2.5 years after the last cycle of cidofovir), the patient still shows no signs of disease activity. CSF PCR for JC virus DNA remains negative, and a recent MRI scan of the brain was unchanged (fig 1C). As of March 2005, the patient lives at home, is able to walk, and is independent.
We report a patient with SLE who survived PML after treatment with cidofovir and discontinuation of immunosuppression. First evidence for possible efficacy of cidofovir in the treatment of PML in a patient with SLE was presented in a case report.5 Discontinuation of immunosuppression and treatment with cidofovir resulted in reversal of JC virus positivity and stabilisation of MRI lesions. However, the patient died due to serious kidney failure.
It remains unclear whether the improvement in both patients was induced or supported by cidofovir or whether it could have been acquired by discontinuation of immunosuppression alone. However, patients with PML in SLE usually die after discontinuation of immunosuppression alone.1,2 Interestingly, our patient did not show signs of severe immunosuppression at the point of manifestation of PML. These observations may suggest a predisposition of patients with SLE to PML that may not be explained by their immunosuppression alone.
We conclude that cidofovir should be offered to SLE patients developing PML due to immunosuppression in addition to withdrawal of immunosuppressive therapy, as death is likely without antiviral therapy. Cidofovir may be effective against PML caused by non-AIDS related states of immunosuppression.
Competing interests: none
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