ity10 might render MS trials comparing new vs pres-
`ently available treatments more easily feasible.
`
`Acknowledgment
`The authors thank TEVA Pharmaceutical Industries Ltd. and
`Schering AG for providing the MR data of the treated arms of
`previous MS trials. They also thank all the investigators who
`contributed to data collection of these treatment trials and Prof. L.
`Kappos for his critical review of the manuscript.
`
`References
`1. Nauta JJP, Thompson AJ, Barkhof F, Miller DH. Magnetic
`resonance imaging in monitoring the treatment of multiple
`sclerosis patients: statistical power of parallel-groups and
`crossover designs. J Neurol Sci 1994;122:6–14.
`2. Truyen N, Barkhof F, Tas M, et al. Specific power calculations
`for magnetic resonance imaging (MRI) in monitoring active
`relapsing–remitting multiple sclerosis (MS): implications for
`phase II therapeutic trials. Multiple Sclerosis 1997;2:283–290.
`3. Tubridy N, Ader HJ, Barkhof F, Thompson AJ, Miller DH.
`Exploratory treatment trials in multiple sclerosis using MRI:
`sample size calculations for relapsing remitting and secondary
`progressive subgroups using placebo controlled parallel
`groups. J Neurol Neurosurg Psychiatry 1998;64:50–55.
`4. Sormani MP, Molyneux PD, Gasperini C, et al. Statistical
`power of MRI monitored trials in multiple sclerosis: new data
`
`and comparison with previous results. J Neurol Neurosurg
`Psychiatry 1999;66:465–469.
`5. Pozzilli C, Bastianello S, Koudriatseva T, et al. Magnetic res-
`onance imaging changes with recombinant human interferon
`b-1a: a short term study in relapsing–remitting multiple scle-
`rosis. J Neurol Neurosurg Psychiatry 1996;61:251–258.
`6. European Study Group on Interferon Beta-1b in Secondary
`Progressive MS. Placebo-controlled multicentre randomised
`trial of interferon beta-1b in treatment of secondary progres-
`sive multiple sclerosis. Lancet 1998;352:1491–1497.
`7. Comi G, Filippi M, Wolinsky JS, and European/Canadian
`Glatiramer Acetate Study Group. European/Canadian multi-
`center, double-blind, randomized, placebo-controlled study of
`the effects of glatiramer acetate on magnetic resonance
`imaging-measured disease activity and burden in patients
`with relapsing multiple sclerosis. Ann Neurol 2001;49:290–
`297.
`8. Sormani MP, Bruzzi P, Miller DH, Gasperini C, Barkhof F,
`Filippi M. Modelling MRI enhancing lesion counts in multiple
`sclerosis using a negative binomial model: implications for
`clinical trials. J Neurol Sci 1999;163:74–80.
`9. Kappos L, Moeri D, Radue EW, et al. Predictive value of
`gadolinium-enhanced MRI for relapse rate and changes in
`disability/impairment in multiple sclerosis: a meta-analysis.
`Lancet 1999;353:964–969.
`10. Rovaris M, Filippi M. Magnetic resonance techniques to mon-
`itor disease evolution and treatment trial outcomes in multi-
`ple sclerosis. Curr Opin Neurol 1999;12:337–344.
`
`Onset of multiple
`sclerosis associated
`with anti-TNF therapy
`
`Article abstract—Therapies aimed at inhibiting tumor necrosis factor
`(TNF), a proinflammatory cytokine implicated in autoimmune disease are
`effective, especially for rheumatoid arthritis. We report a patient with new
`onset MS closely associated with the initiation of anti-TNF therapy for juve-
`nile rheumatoid arthritis. It is possible that the inhibition of TNF triggered
`MS in this individual.
`NEUROLOGY 2001;57:1885–1888
`
`Nancy L. Sicotte, MD; and Rhonda R. Voskuhl, MD
`
`Tumor necrosis factor (TNF) is a proinflammatory
`cytokine that is involved in lymphocyte signaling
`and plays an important role in cell-mediated immu-
`nity. TNF has multiple effects including the induc-
`tion of adhesion molecules on endothelial cells and
`the enhanced production of reactive oxygen species.1
`In contrast to its proinflammatory properties, TNF
`can also mediate T cell receptor–induced apoptosis.2
`Therefore, TNF and its receptors are involved not
`only in inflammation, but also in the regulation of
`
`From the Division of Brain Mapping (Dr. Sicotte), Department of Neurology
`(Drs. Sicotte and Voskuhl), UCLA School of Medicine, Los Angeles, CA.
`N.L.S.
`is supported by a Clinical Investigator Award (NINDS K08/
`NS02044) and the Leonard and Dorothy Strauss Scholars in Neuroscience
`Program and is a Harry Weaver Neuroscience Scholar of the National
`Multiple Sclerosis Society (JF2107). R.R.V. is supported by NINDS/NIH
`RO1 NS36680 and is a Harry Weaver Neuroscience Scholar of the National
`Multiple Sclerosis Society (JF2094).
`Received June 20, 2001. Accepted in final form August 8, 2001.
`Address correspondence and reprint requests to Dr. Nancy L. Sicotte, 710
`Westwood Boulevard, Rm. A135, Los Angeles, CA 90095; e-mail:
`nsicotte@ucla.edu
`
`immune activity through the elimination of autore-
`active inflammatory cells.3
`TNF is thought to be an important mediator in
`several autoimmune diseases including rheumatoid
`arthritis, ulcerative colitis, and MS.4 Anti-TNF ther-
`apy was initially considered for the treatment of MS
`based on studies of experimental autoimmune en-
`cephalomyelitis (EAE) as well as human data. In-
`creased TNF production from T lymphocytes has
`been associated with their ability to transfer more
`severe disease in an adoptive transfer model of
`EAE.5 Blocking TNF with antibodies or soluble TNF
`receptors decreased EAE severity.6 In humans, high
`levels of TNF␣ have been found in MS plaques and
`CSF.7
`Despite these findings, anti-TNF treatments for
`MS worsen disease. In a trial of anti-TNF targeted
`therapy using a recombinant protein consisting of
`the TNF receptor fused to a human IgG heavy chain
`(lerencept), treated patients had significantly more
`exacerbations than placebo-treated patients.8 Treat-
`
`Copyright © 2001 by AAN Enterprises, Inc. 1885
`
`Page 1 of 4
`
`Biogen Exhibit 2117
`Mylan v. Biogen
`IPR 2018-01403
`
`

`

`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.
`
`ment with anti-TNF antibody in two patients with
`rapidly progressive MS led to a transient increase in
`gadolinium-enhancing lesions and no improvement
`in disease severity.9 These studies suggest that anti-
`TNF therapy worsens MS.
`Etanercept (Enbrel) is a fusion protein consisting
`of the extracellular portion of the human TNF recep-
`tor linked to the Fc portion of human IgG. It has
`become widely used in the treatment of refractory
`rheumatoid arthritis.10 Several unpublished observa-
`tions of presumed isolated demyelinating events and
`worsening of established MS disease activity in indi-
`viduals treated with etanercept led to a drug warn-
`ing by Immunex in October 2000. We report a
`patient with new-onset MS that coincided with the
`initiation of etanercept treatment for juvenile rheu-
`matoid arthritis.
`
`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 ar-
`thritis at age 8. Oral and IM gold, methotrexate, and sul-
`fasalazine were only partially effective. Nine months of
`treatment with etanercept markedly improved her arthri-
`tis. She was also on celecoxib (Celebrex) and lansoprazole
`1886 NEUROLOGY 57 November (2 of 2) 2001
`
`Figure 2. MRI scans obtained 2 months after presenta-
`tion. 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 gad-
`olinium demonstrates enhancement of these same areas
`consistent with active inflammation.
`
`(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 fin-
`
`Page 2 of 4
`
`

`

`was normal. An MRI of the brain revealed two large en-
`hancing lesions (figure 2). Etanercept was discontinued,
`and another course of high-dose steroids was initiated. She
`began treatment
`for her arthritis with leflunomide
`(Arava).
`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 ␤-1a.
`
`Discussion. Shortly after this patient presented,
`Immunex issued a drug warning citing observations
`of rare cases of demyelinating episodes including op-
`tic neuritis and transverse myelitis in patients with
`rheumatoid arthritis treated with etanercept. At the
`time of this writing, 20 to 25 cases of CNS demyeli-
`nation associated with the use of etanercept have
`been reported to Immunex (Donald Goodkin, unpub-
`lished data, 2001).
`Optic neuritis developed in this individual after
`using etanercept for 9 months. Cerebral MRI per-
`formed 2 months later revealed new disease activity
`in the absence of new symptoms. Despite discontinu-
`ing etanercept, new enhancing lesions and neuro-
`logic 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 et-
`anercept 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 etaner-
`cept 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 at-
`tack. 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 indi-
`viduals with new-onset demyelinating events on
`anti-TNF therapy appears to be small, but these ep-
`isodes 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 expo-
`sure. 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 ap-
`pears warranted.
`Patients who develop new neurologic symptoms
`while on any anti-TNF medication should be moni-
`November (2 of 2) 2001 NEUROLOGY 57 1887
`
`Figure 3. MRI scans performed 3.5 months after presenta-
`tion 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 enhance-
`ment of these areas (bottom row).
`
`gers 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 hyperintensi-
`ties 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. Brain-
`stem auditory evoked responses and somatosensory evoked
`responses were normal.
`After a 5-day course of high-dose IV methylpred-
`nisolone, the right eye pain resolved and vision was nor-
`mal. 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 reluc-
`tant to stop therapy with etanercept because of the im-
`provement 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
`
`Page 3 of 4
`
`

`

`tored closely with frequent MRI regardless of their
`clinical status. Finally, all cases of new-onset demy-
`elination should be identified and studied to deter-
`mine what, if any, risk factors they share. Thorough
`investigations of these cases may lead to insights
`into the pathogenesis of MS.
`
`References
`1. Hohlfeld R. Inhibitors of tumor necrosis factor-alpha: promis-
`ing agents for the treatment of multiple sclerosis? Mult Scler
`1996;1:376–378.
`2. Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo
`MJ. Induction of apoptosis in mature T cells by tumour necro-
`sis factor. Nature 1995;377:348–351.
`3. Segal BM, Cross AH. Fas(t) track to apoptosis in MS: TNF
`receptors may suppress or potentiate CNS demyelination.
`Neurology 2000;55:906–907.
`4. Raza A. Anti-TNF therapies in rheumatoid arthritis, Crohn’s
`disease, sepsis, and myelodysplastic syndromes. Microsc Res
`Tech 2000;50:229–235.
`
`5. Powell MB, Mitchell D, Lederman J, et al. Lymphotoxin and
`tumor necrosis factor-alpha production by myelin basic
`protein-specific T cell clones correlates with encephalitogenic-
`ity. Int Immunol 1990;2:539–544.
`6. Selmaj KW, Raine CS. Experimental autoimmune encephalo-
`myelitis: immunotherapy with anti-tumor necrosis factor anti-
`bodies and soluble tumor necrosis factor receptors. Neurology
`1995;45(6 suppl 6):S44–S49.
`7. Selmaj K, Raine CS, Cannella B, Brosnan CF. Identification of
`lymphotoxin and tumor necrosis factor in multiple sclerosis
`lesions. J Clin Invest 1991;87:949–954.
`8. The Lerencept Multiple Sclerosis Study Group. TNF neutral-
`ization in MS: results of a randomized, placebo-controlled
`multicenter study. The Lenercept Multiple Sclerosis Study
`Group and The University of British Columbia MS/MRI Anal-
`ysis Group. Neurology 1999;53:457–465.
`9. van Oosten BW, Barkhof F, Truyen L, et al. Increased MRI
`activity and immune activation in two multiple sclerosis pa-
`tients treated with the monoclonal anti-tumor necrosis factor
`antibody cA2. Neurology 1996;47:1531–1534.
`10. Fernandez-Botran R. Soluble cytokine receptors: novel immuno-
`therapeutic agents. Expert Opin Invest Drugs 2000;9:497–514.
`
`Transcallosal bands: A
`sign of neuronal tract
`degeneration in
`early MS?
`
`Article abstract—A pattern of injury observed in patients at high risk for
`MS described as transcallosal bands (TCB) is hypothesized to be the result of
`neuronal tract degeneration in earliest MS, extending from typical acute,
`focal demyelinating lesions located along the lateral borders of the corpus
`callosum. The TCB, a T2-hyperintense lesion traversing the corpus callosum
`is recognized on 3-mm thick, T2-weighted imaging, develops over months and
`persists over years.
`NEUROLOGY 2001;57:1888–1890
`
`Jack H. Simon, MD, PhD; Lawrence Jacobs, MD; and R. Philip Kinkel, MD
`
`Although the principal pathology of acute MS lesions
`in the CNS is an inflammatory-demyelinating pro-
`cess, there is evidence from biochemical and micro-
`scopic analyses of brain specimens that the acute
`inflammatory MS lesion is also the site of early ax-
`onal injury.1 In vivo MRS studies of early and acute
`lesions show reduced N-acetylaspartate and support
`the concept of early axonal injury in focal MS le-
`sions.2,3 Beyond the earliest stages of disease, for
`example, once a patient can be classified as in the
`stage of relapsing MS, the disease is characterized
`by diffuse and global injuries, as indicated by abnor-
`malities of the normal-appearing white matter
`(NAWM),4 and by brain and/or spinal cord atrophy.5
`Although some abnormalities in the NAWM are
`
`From the Department of Radiology–Neuroradiology (Dr. Simon), University
`of Colorado Health Sciences Center, Denver; Department of Neurology (Dr.
`Jacobs), Buffalo General Hospital, NY; and Cleveland Clinic Foundation
`(Dr. Kinkel), OH.
`The CHAMPS Trial was supported by Biogen, Inc., Cambridge, MA.
`Presented in part at the annual meeting of the Academy of Neurology; San
`Diego, CA; May 2, 2000.
`Received May 18, 2001. Accepted in final form August 1, 2001.
`Address correspondence and reprint requests to Dr. Jack H. Simon, Depart-
`ment of Radiology/MRI, University of Colorado Health Sciences Center, Box
`A-034, 4200 E. Ninth Avenue, Denver, CO 80262; e-mail: jack.simon@uchsc.edu
`
`1888 Copyright © 2001 by AAN Enterprises, Inc.
`
`likely the result of microscopic or other primary focal
`pathology to which conventional MRI is insensitive,
`an alternative explanation is that these abnormali-
`ties may be the consequence of multiple focal inju-
`ries, with extension of these injury to distant sites,
`such as through tract degeneration.6 Although tract
`degeneration is well recognized in the late stages of
`MS, as seen at autopsy, it has not been considered a
`major feature of early MS. Here we present direct
`imaging evidence for an injury pattern in the corpus
`callosum suggestive of tract degeneration emanating
`from focal demyelinating-like lesions at the earliest
`stages of MS, which we call transcallosal bands (TCB).
`
`Methods. The TCB pattern is demonstrated based on
`MRI of patients enrolled in the Controlled High-Risk Sub-
`jects Avonex Multiple Sclerosis Prevention Study
`(CHAMPS) trial.7 Inclusion in the trial was based on the
`first occurrence of an acute, isolated neurologic syndrome
`consistent with demyelination, and an MRI study with a
`minimum of two lesions 3 mm or greater in diameter, one
`of which was periventricular or ovoid. The baseline and
`follow-up MRI protocol at 1.5 T included 1) axial interme-
`diate and more T2-weighted classic spin-echo series with
`3-mm nongapped slices, 2) a pre– and post–contrast en-
`hanced T1-weighted classic spin-echo series with 5-mm
`
`Page 4 of 4
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`