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Demyelinating disease and cutaneous lymphocitic vasculitis after etanercept therapy in a patient with rheumatoid arthritis

Inhibition of tumour necrosis factor alpha (TNFa) has emerged as an effective therapy for treating inflammatory diseases (1, 2). As TNFa plays a crucial role in immune system responses and T-cell-mediated tissue injury, antagonism of TNFa should be of benefit in T-cell-mediated autoimmune conditions. Nevertheless, there is evidence that inhibiting TNFa does not provide clinical benefit in multiple sclerosis (MS), and may in fact exacerbate this disease (3). Moreover, demyelinating events have been reported recently during etanercept treatment in patients with inflammatory arthropathies (4–8). We report the case of a patient with rheumatoid arthritis (RA) who developed a demyelinating syndrome during etanercept therapy. At the same time, she developed an injection-site reaction (ISR) that revealed a cutaneous lymphocytic vasculitis. A possible link between these side-effects is discussed. A 59-year-old woman with a 5-year history of seropositive erosive RA (9) had been previously treated with five different disease-modifying antirheumatic drugs (DMARDs), alone or in combination. All treatments were ineffective or discontinued because of side-effects. Her disease was still active [disease activity score (DAS28) of 6.48] and etanercept was started. Twenty-four hours after the third dose, she developed a large annular and erythematous cutaneous reaction over the injection sites on both thighs. At the same time, she reported an intense headache, paresthesias on the left side of the inferior lip and legs, as well as intermittent diplopia and a short episode of lateropulsion towards the left. At the time of admission etanercept was discontinued. General and neurological examinations were within the normal limits. A magnetic resonance imaging (MRI) examination of the brain was performed on a 1.0-Tesla superconductive unit. T1-weighted images were unremarkable. Fluid attenuated inversion-recovery (FLAIR) and T2-weighted MR images revealed small punctate nonspecific hyperintense lesions in the periventricular and subcortical white matter. Following intravenous administration of gadolinium, no enhancement was evident. Two months later, an MRI control study showed slight progression of the periventricular lesions and also revealed three new small punctuate lesions in the subcortical white matter (Figure 1). These lesions were considered to be due to unspecific demyelinating lesions. A skin biopsy from the cutaneous lesion was taken 24 h after the last injection, and revealed a lymphocytic vasculitis. The immunohistochemical cell marker study showed that the infiltrate was composed of mature CD3+ T-lymphocytes, with a clear predominance of CD4+ T-cells. Five days later she was discharged with partial resolution of the symptoms, although with paresthesias persisting on the distal part of both legs for an additional 7 months. As TNFa antagonists are being used increasingly, there have been several reports of neurological events in patients receiving these therapies (4–7). It remains to be clarified whether these cases represent a sideeffect of the new therapies or coincidental events. Although certain autoimmune diseases are associated with a secondary autoimmune process, to date no reports exist definitely supporting an increased incidence or prevalence of MS in RA patients (8). As the incidence of MS and RA are relatively high and both diseases can affect similar populations, it has been suggested that most of the neurological events associated with anti-TNF therapy represent an exacerbation of a pre-existing state of subclinical or established MS (7). There is evidence that inhibiting TNFa may exacerbate MS, based on two trials of infliximab and lenercept in MS (3, 10). In both trials, the use of TNFa antagonists was associated with an increase in disease activity and worsening of the MRI lesions. A possible explanation for the worsening of MS under treatment with TNFa antagonists could be that these treatments enhance disease activity in MS through an increase in peripheral T-cell autoreactivity (8). The administration of TNFa antagonists enhances antigen-presenting cell function, increases T-cell signalling, and decreases apoptosis of potentially 322 Scand J Rheumatol 2006;35:322–331