AJNR Am J Neuroradiol 26:1548–1550, June/July 2005
`Case Report
`
`Anti-Tumor Necrosis Factor Alpha-Associated
`Multiple Sclerosis
`
`David S. Titelbaum, Alexandra Degenhardt, and R. Philip Kinkel
`
`Summary: A case of multiple sclerosis presenting during
`anti–tumor necrosis factor treatment for rheumatoid ar-
`thritis is discussed. This association has been reported in
`the nonradiological literature, but is an important associ-
`ation for radiologists to be aware of, as they may be in a
`position to first suggest the diagnosis.
`
`Tumor necrosis factor (TNF) alpha is an immuno-
`modulatory cytokine that has been implicated in cer-
`tain inflammatory diseases, including multiple sclero-
`sis (MS), rheumatoid arthritis (RA), and Crohn
`disease (1). TNF alpha-blockers include the TNF-
`receptor fusion proteins etanercept (Enbrel) and le-
`nercept, and infliximab (Remicade), an anti-TNF al-
`pha monoclonal antibody. Etanercept and infliximab
`are effective treatments in RA and Crohn disease (2,
`3). Anti-TNF therapy for RA has been associated
`with monophasic CNS demyelination (4, 5) and wors-
`ening of known MS (6, 7). There is only one prior
`case report of a first demyelinating episode and new
`onset of MS following treatment with anti-TNF ther-
`apy (8). Here we report a second case.
`
`Case Report
`A 33-year-old woman with a 10-year history of RA pre-
`sented with right-hand numbness, which gradually spread to
`her arm, chest, and thighs over 6 months, and L’Hermitte
`sign. She had been treated with etanercept for almost 2
`years. Several months before, she complained of ankle pain,
`shown on MR imaging to be due to inflammatory peroneal
`tenosynovitis (Fig 1A). There was no prior history of neu-
`rologic disease and no family history of MS. The physical
`examination was remarkable for decreased position sense in
`her feet and hands. Etanercept was discontinued after MR
`imaging of the brain (Fig 1B and 1C) and cervical spine (Fig
`1D) revealed multifocal cerebral white matter disease and
`cervical cord lesions, with some lesions enhancing following
`administration of gadolinium. Within 4 months, lesion en-
`hancement resolved. Six months after stopping etanercept, a
`repeat MR imaging showed a new cervical cord lesion.
`Thereafter, she experienced exacerbation of her joint pains
`from her RA. Several months later and 1 year after stopping
`
`Received July 26, 2004; accepted after revision September 16.
`From the Department of Radiology, Shields Health Care
`(D.S.T.), Brockton, MA; and the Department of Neurology, Mul-
`tiple Sclerosis Clinic (A.D., R.P.K.), Beth Israel Deaconess Medi-
`cal Center, Boston, MA.
`Address correspondence to David S. Titelbaum, MD, c/o Lor-
`raine Abbene, Department of Radiology, Shields Health Care, 265
`Westgate Drive, Brockton, MA 02301.
`
`© American Society of Neuroradiology
`
`anti-TNF therapy, she developed diplopia and bilateral pto-
`sis from supranuclear gaze and left cranial nerve III palsies.
`An MR imaging of the cervical cord showed significant
`regression of prior cord lesions, whereas the brain MR
`imaging showed a new nonenhancing lesion in the periaq-
`ueductal region of the midbrain (Fig 2) and a new enhancing
`lesion in the corpus callosum. She was treated with intrave-
`nous methylprednisolone with partial resolution of her
`symptoms.
`
`Discussion
`Anti-TNF associated demyelinating disease has
`been described in the neurologic and rheumatologic
`literature, but we are unaware of similar descriptions
`in the radiologic literature. Mohan et al in 2001 (4)
`reviewed cases of neurologic symptoms in patients
`receiving anti-TNF therapy for inflammatory arthritis
`reported to the U.S. Food and Drug Administration
`from 1998 to 2000. Of a total of 20 patients, 18
`received etanercept and two received infliximab. Ages
`ranged between 21 and 56 years, similar to that seen
`in MS. Sixteen of 19 patients who had MR imaging
`examinations had findings considered compatible
`with demyelination, and one patient had clinical optic
`neuritis with normal MR imaging. Four of these pa-
`tients had a prior history of either MS or symptoms
`suggestive of MS (9). The duration of therapy before
`development of neurologic symptoms ranged from 1
`week to 15 months, with a mean duration of 5 months.
`The most common presentation was paresthesias, fol-
`lowed by optic neuritis. Other symptoms included gait
`disturbance, weakness, and bladder dysfunction. All
`patients showed complete or partial resolution of
`their neurologic symptoms after discontinuing anti-
`TNF therapy. One patient was rechallenged and ex-
`perienced recurrent symptoms. Follow-up on these
`patients, however, is limited, and therefore it is not
`clear whether these cases were etanercept-induced
`demyelination or the unmasking of definitive MS.
`Sicotte and Voskuhl (8) describe a definitive case
`of new-onset MS in a 21-year-old woman with a his-
`tory of RA. The patient developed optic neuritis after
`9 months of etanercept therapy. MR imaging of the
`brain showed several T2 hyperintensities in the white
`matter and two enhancing lesions. Therapy was con-
`tinued, and 2 months later there were two new en-
`hancing lesions. At this point, etanercept was discon-
`tinued. Six weeks later, she had new neurologic
`symptoms and the MR imaging showed two addi-
`tional enhancing lesions.
`In this case, the diagnosis of MS was made on the
`basis of polyphasic occurrence of neurologic events
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`1548
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`Biogen Exhibit 2116
`Mylan v. Biogen
`IPR 2018-01403
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`AJNR: 26, June/July 2005
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`ANTI-TNF ALPHA-ASSOCIATED MULTIPLE SCLEROSIS
`
`1549
`
`A 33-year-old woman with long-
`FIG 1.
`standing RA on etanercept treatment, pre-
`senting with neurologic symptoms includ-
`ing body numbness and L’Hermitte sign.
`A, Sagittal T2-weighted fat suppressed
`image of the left ankle shows severe per-
`oneal
`tenosynovitis from the patient’s
`known RA.
`B and C, Axial brain images from fluid-
`attenuated inversion recovery sequence
`reveal multifocal white matter lesions.
`D, Midline sagittal proton attenuation
`weighted image of the cervical spine re-
`veals large demyelinating lesions at the C2
`and C5 levels.
`
`location of lesions in this case, however, were typical
`of white matter disease and not of infarcts. Moreover,
`in a study assessing the extent of white matter disease
`in RA on MR images, Bekkelund et al (10) found no
`white matter difference in RA patients versus control
`subjects, even when accounting for pharmacologically
`treated RA (none treated with etanercept) or long-
`standing RA. In addition, no RA patients studied
`revealed lesions in the brain stem, corpus callosum, or
`cerebellum.
`The incidence of MS onset associated with anti-
`TNF therapy is rare but may be underreported be-
`cause of insufficient follow-up in most cases. It is also
`unclear how many patients with known MS have been
`exposed to anti-TNF therapy. Although a causal re-
`lationship is not conclusive, the apparent temporal
`association has raised enough concern that caution is
`warranted in the treatment of patients with anti-TNF
`therapy if there is any history of MS or neurologic
`symptoms suspicious of MS. In these cases, if anti-
`TNF therapy is initiated, close neurologic surveillance
`with MR imaging of the brain is recommended (6, 8).
`It is interesting that anti-TNF therapy reduces in-
`flammation in RA but may promote CNS demyeli-
`nating disease. Indeed, TNF-alpha is implicated in
`oligodendroctye cell death, active MS lesions are
`found to contain elevated TNF alpha, and there may
`be correlation between CSF TNF alpha level and
`
`FIG 2. One year after discontinuation of etanercept, the patient
`developed new diplopia, gaze deficit, and left cranial nerve III
`palsy. Shown is an axial T2-weighted image at level of the
`midbrain, revealing a demyelinating lesion centered in the left
`periaqueductal region, in proximity to the oculomotor nucleus.
`
`and MR findings, independent of etanercept cessa-
`tion. Polyphasic disease argues against acute dissem-
`inated encephalomyelitis. Cerebral vasculitic isch-
`emic disease can occur in RA. The appearance and
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`1550
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`TITELBAUM
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`AJNR: 26, June/July 2005
`
`demyelinating disease activity (1, 7, 11). Anti-TNF
`alpha antibodies and TNF-receptor fusion proteins
`block experimental autoimmune encephalomyelitis
`(EAE) mouse model of autoimmune demyelination
`(11). Trials of an anti-TNF antibody and lenercept in
`humans affected with MS, however, showed probable
`disease worsening (6, 7). Proposed theories to explain
`the apparent discordant response to anti-TNF include
`the inability of peripherally administered anti-TNF
`agents to act directly on the CNS, enhanced periph-
`eral autoreactive T-cell activity that then enter the
`CNS, up-regulation of CNS TNF receptors, elevated
`interferon gamma, and latent infection (1, 6). It is
`unclear whether the effectiveness of anti-TNF in
`EAE is related to greater blood-brain barrier disrup-
`tion inherent in most cases of EAE or due to a
`difference in pathophysiology (1).
`It is important that radiologists be aware of the rare
`association of anti-TNF therapy and demyelinating
`disease, because they may be uniquely able to suggest
`it as an etiology of white matter changes on imaging
`and thus may aid clinicians in deciding to discontinue
`anti-TNF therapy. Furthermore, elucidating the exact
`mechanism of the apparently paradoxical response to
`anti-TNF therapy in MS may yield significant ad-
`vancement in our understanding of the pathophysiol-
`ogy of MS.
`
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