Onset of multiple sclerosis associated with anti-TNF therapy

Case presentation.

A 21-year-old woman with juvenile rheumatoid arthritis presented with a 1-week history of pain and decreased vision in her right eye. She had no previous visual symptoms or other neurologic dysfunction. She had no recent illness or travel.

She had been diagnosed with juvenile rheumatoid arthritis at age 8. Oral and IM gold, methotrexate, and sulfasalazine were only partially effective. Nine months of treatment with etanercept markedly improved her arthritis. She was also on celecoxib (Celebrex) and lansoprazole (Prevacid). Family history was significant for RA in her maternal grandmother. There was no family history of MS.

On physical examination, joint deformities of the fingers and toes were noted. Visual acuity in the right eye was 20/20−2 and 20/20−1 in the left. There was a 1+ relative afferent papillary defect on the right. Disks were edematous, right greater than left. Visual fields were full to confrontation. The rest of the neurologic examination was normal.

An MRI of the brain revealed several T2 hyperintensities within the white matter including the right middle cerebellar peduncle, posterior temporal lobe, and right frontal lobe (figure 1). After contrast, two small areas of enhancement were noted high in the right frontal lobe. Spinal fluid analysis showed six white blood cells, normal protein and glucose, an elevated IgG index at 1.1 (normal range, 0.0 to 0.6) with two oligoclonal bands. Visual evoked responses showed significant slowing on the right. Brainstem auditory evoked responses and somatosensory evoked responses were normal.

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Figure 1. Axial T2-weighted MRI obtained at the time of initial presentation with optic neuritis. Arrows indicate areas of white matter hyperintensity consistent with demyelination.

After a 5-day course of high-dose IV methylprednisolone, the right eye pain resolved and vision was normal. At the time of this patient’s presentation, no official warnings regarding the use of etanercept and the risk of demyelination had been reported. The patient was reluctant to stop therapy with etanercept because of the improvement in her arthritis symptoms. She continued her usual medications plus a prednisone taper.

The patient was evaluated 2 months later. There were no new symptoms. Visual acuity was 20/20 in both eyes, the disk edema had resolved. The neurologic examination was normal. An MRI of the brain revealed two large enhancing lesions (figure 2). Etanercept was discontinued, and another course of high-dose steroids was initiated. She began treatment for her arthritis with leflunomide (Arava).

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Figure 2. MRI scans obtained 2 months after presentation. There were no new complaints and the neurologic examination was normal. (A) Axial T2-weighted images reveal two new large areas of hyperintensity. (B) Axial T1-weighted images obtained after the administration of gadolinium demonstrates enhancement of these same areas consistent with active inflammation.

Six weeks later, the patient was evaluated again. She had worsening arthritis symptoms, numbness in her right foot, and dysequilibrium. Her examination revealed a new up-going toe on the right. Another brain MRI showed two new enhancing lesions (figure 3). At this time, a diagnosis of MS was made and the patient began treatment with interferon β-1a.

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Figure 3. MRI scans performed 3.5 months after presentation and 6 weeks after discontinuing etanercept. Axial T2-weighted images show new lesions in the left temporal lobe and right frontal lobe (top row). Axial T1-weighted images obtained after contrast was given shows enhancement of these areas (bottom row).

Discussion.

Shortly after this patient presented, Immunex issued a drug warning citing observations of rare cases of demyelinating episodes including optic neuritis and transverse myelitis in patients with rheumatoid arthritis treated with etanercept. At the time of this writing, 20 to 25 cases of CNS demyelination associated with the use of etanercept have been reported to Immunex (Donald Goodkin, unpublished data, 2001).

Optic neuritis developed in this individual after using etanercept for 9 months. Cerebral MRI performed 2 months later revealed new disease activity in the absence of new symptoms. Despite discontinuing etanercept, new enhancing lesions and neurologic symptoms developed, fulfilling the criteria for clinically definite relapsing remitting MS. What role, if any, did the use of etanercept play in the onset of MS in this individual? Three possibilities exist. First, the development of MS and the use of etanercept could have been coincidental. Second, the use of etanercept could have triggered latent MS, uncovering the disease that the patient was destined to develop at some point in the future. Third, the use of etanercept could have caused MS to develop in this patient who otherwise would never have had the disease.

When patients with established MS were treated with lerencept, relapse rates increased in the first few weeks of treatment. In contrast, our patient was on therapy for 9 months before the first clinical attack. The latency period difference suggests that this patient did not have undiagnosed MS at the time etanercept treatment began.

Current guidelines are to avoid the use of anti-TNF drugs in individuals with a history of MS or demyelinating disease. The overall numbers of individuals with new-onset demyelinating events on anti-TNF therapy appears to be small, but these episodes can be clinically silent, making it difficult to assess the actual numbers of affected individuals. The risk may be higher at the initiation of therapy or alternatively could increase with cumulative exposure. In light of the case reported here, a serial MRI study designed to systematically assess the risk of developing demyelinating lesions at specific time points after the initiation of etanercept therapy appears warranted.

Patients who develop new neurologic symptoms while on any anti-TNF medication should be monitored closely with frequent MRI regardless of their clinical status. Finally, all cases of new-onset demyelination should be identified and studied to determine what, if any, risk factors they share. Thorough investigations of these cases may lead to insights into the pathogenesis of MS.