Sirs: Tumor Necrosis Factor alpha (TNFalpha) is a cytokine released by activated monocytes, macrophages, and T-lymphocytes. It is involved in several processes, but plays an important role particularly in inflammation [1]. Its overproduction is implicated in a wide range of pathological conditions, including rheumatoid arthritis (RA) [2] and multiple sclerosis (MS) [3]. High concentrations of TNFalpha are present in synovial fluid of RA patients [4] and in cerebro-spinal fluid (CSF) of MS patients [5]. Considering its role in inflammatory disease, numerous drugs have been developed to modulate its action on inflammation in recent years [6, 7]. Some are characterized by monoclonal antibodies against TNFalpha (Infliximab, Adalimumab), while others are soluble TNF-receptor fusionproteins (Etanercept, Lenercept), but all inhibit the TNFalpha effect [6, 7]. In the literature the effectiveness of TNFalpha therapy in experimental models and in studies of RA in humans is well known [8]. In addition several studies have shown its preventive role in experimental autoimmune encephalomyelitis (EAE), a well established experimental model of MS [9]. Despite these findings, antiTNFalpha treatment for MS worsens the disease. In a trial of antiTNFalpha-targeted therapy using Lenercept, treated patients had significantly more exacerbations than placebo-treated patients [7]. Moreover, other studies have demonstrated that Etanercept and Infliximab may also worsen preexisting MS and trigger de-novo CNS demyelination [10, 11]. The patient we report experienced CNS demyelination using Adalimumab, a new TNFalpha-blocker. A 40-year old woman with RA on methotrexate (10 mg i. m. once a week) treatment for several months started a therapy with Adalimumab (40 mg s. c. once 15 days), a TNFalpha-blocker. After two months she experienced diplopia, headache, nausea and dizziness with subacute onset. She had no family history of neurological disturbances and there was no evidence of a previous febrile episode or other previous neurological dysfunction. Neurological examination showed VI and VII right cranial nerve palsy, a tetrapyramidal syndrome, bladder voiding disorder, mild leg extremity sensory deficit. Immunological and infection investigations were normal, whereas CSF analysis showed barrier damage and several oligoclonal bands. VEPs, SEPs and BAEPs were abnormal. Brain and spinal cord MRI revealed several T2-hyperintensities in the hemispheric white matter, in the brainstem and in the spinal cord. Following gadolinium-DTPA (Gd) administration, some areas of enhancement were present in both hemispheres and in cervical spinal cord (Fig. 1A, B). Anti-TNFalpha therapy was stopped and methylprednisolone 1 g/day i. v. for five days was administered with a progressive improvement of the clinical picture. After six months brain and spinal MRI showed the persistence of T2-weighted hyperintensities (Fig. 1C), but there was no evidence of enhancement after Gd administration (Fig. 1D). After 6 and 14 months the clinical picture was normal except for mild hyperreflexia in all four limbs. Exacerbation of previously quiescent MS and new-onset demyelinating disease have been reported during Infliximab and Etenarcept therapy for RA. Moreover it has been well documented that another TNF-antagonist, Lenercept, increased the number of attacks of pre-existing MS [7, 10, 11]. The present data – in particular the temporal correlation of neurological symptoms onset with TNFalpha-blocker administration and the monophasic course – suggest that even Adalimumab, like other TNFalpha blockers, may trigger denovo CNS demyelination. Therefore, although a causal relationship between anti-TNFalpha therapy and CNS demyelination has not been well established, all reports make this association more plausible, indicating a possible protective role of TNFalpha in demyelinating diseases. Until further long-term safety data are available, we suggest that anti-TNFalpha therapy should not be administered to patients with MS or to patients with neurological signs or symptoms possibly arising from previous demyelinating episodes. Moreover it would be useful to look for MRI signs of leukoencephalopathy, possibly due to silent CNS demyelination, before starting a therapy with TNF-blockers.
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Open Access
Mar 1, 2024
Arnaud Kwiatkowski + 23
