`
`A PATHOPHYSIOL
`
`OGIC APPROACH
`
`Joseph T. DiPiro, PharmD, FCCP
`Executive Dean and Professor. South Carolina College of Pharmacy, University of
`South Carolina and Medical University of South Carolina, Charleston and Columbia.
`South Carolina
`
`Robert L.Ta|bert, PharmD, FCCP, BCPS, FAHA
`
`Professor, Pharmacotherapy Division, College of Pharmacy, University of Texas at
`Austin, Professor, Department of Medicine, School of Medicine, University ofTexas
`Health Science Center at San Antonio, San Antonio, Texas
`
`Gary C. Yee, PharmD, FCCP, BCOP
`Professor and Associate Dean, Department of Pharmacy Practice, College of Pharmacy,
`University of Nebraska Medical Center, Omaha, Nebraska
`
`Gary R. Matzke, PharmD, FCP, FCCP, FASN, FNAP
`Professor and Director, Pharmacy Practice TransformationInitiatives and Founding
`Director, ACCP/ASHPNCU Congressional Health Care Policy Fellow Program,
`Department of Pharmacotherapy and Outcome Sciences, School of Pharmacy,
`Virginia Commonwealth University, Richmond,Virginia
`
`Barbara G. Wells, PharmD, FCCP, FASHP
`
`Dean Emeritus and Professor Emeritus, Department of Pharmacy Practice,
`University of Mississippi, School of Pharmacy, Oxford, Mississippi
`
`L. Michael Posey, BSPharm, MA
`Associate Vice President, Periodicals Department. American Pharmacists Association.
`Washington, District of Columbia
`
`.
`Mc
`Graw ,
`HillEducation
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`Page 1 of 22
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`adrid
`89385“ EXhibit 2053
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`IPR 2018-01403
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`

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`Pharmaeothcrapy: A Pathophysiologic Approach, Ninth Edition
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`Pharmacotherapy : a pathophysiologic approach / [edited] by Joseph T. DiPiro.
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`Robert L. Talbert. Gary C. Yee. Gary R. Matzke. Barbara G. Wells, L. Michael
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`

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`
`
`r
`li
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`this material may be protected by Cow-[tit law [title I? U.S (one)
`
`] Multiple Sclerosis
`
`: Jacquelyn L. Bainbridge,Augusto Miravalle, andJohn R. Corboy
`
`,.
`
`'¢
`
`
`
`
`
`The etiology of multiple sclerosis (MS)ts unknown. but
`it appears to be autoimmune in nature. Currently thereis
`no cure.
`
`o The definition of treatment inadequacy for RRMS remains
`unclear, and therapy changes after "treatment failure" should
`be individualized.
`
`MS is characterized by CNS demyelination and axonal
`damage.
`
`MS is classified by the nature of progression over time
`into several categories, which have different clinical
`presentations and responses to therapy.
`
`Although studies do not support the general use of any of
`the FDA-approved disease~modifying therapies (DMTs) in
`patients with progressive forms of the illness. information
`derived from multiple studies suggests younger patients
`with progressive illness and those with either superimposed
`acute relapses or enhancing lesions on magnetic resonance
`imaging (MRl) scans may benefit from some of the presently
`used DMTs.
`
`Diagnosis of MS reguires evidence of dissemination
`of lesions overtime and in multiple parts of the CNS
`and/or optic nerve. and is made primarily on the basis
`of clinical symptoms and examination. Diagnostic criteria
`also allow for the use of MRI, spinal fluid evaluation, optical
`coherence tomography. and evoked potentials to aid in
`the diagnosis.
`
`Exacerbations 0r relapses of MS can be disabling.
`When this is the case exacerbations and relapses
`are treated with high-dose glucocorticoids, such as
`methylprednisolone IV, with onset of clinical response
`typically within 3 to 5 days.
`
`Treatment of relapsing—remitting multiple sclerosis (RRMS)
`with the DMTs interferon-litlFN-IJ‘) (Avonex, Betaseron,
`Rebil, Extavia). glatiramer acetate (Copaxone), natalizumab
`(Tysabri), mitoxantrone (Novantrone), fingolimod (Gilenya).
`teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera)
`can reduce annual relapse rate, lessen severity of relapses,
`slow progression of changes on MRI scans, slow progression
`of disability, and slow cognitive decline. In addition, they
`have been shown to reduce the likelihood of developing a
`second attack alter a first clinically isolated syndrome (05)
`consistent with MS.
`
`In most cases, treatment with OMTs should begin
`promptly after the diagnosis of relapsing-remitting MS.
`or alter a CIS if the brain MRI is Suggestive of high risk
`of further attacks. Natalizumab and other choices that
`
`have been associated with problematic adverse events
`should be reserved for those patients who have failed
`one or more standard therapies and those with peer
`prognostic signs.
`Page 3 of 22
`
`® Patients suffering with MS frequently have symptoms such
`asspasticity, bladder dysfunction, fatigue. neuropathic pain,
`cognitive dysfunction, and depression that can require
`treatment. Patients must be counseled that therapies such as
`lFN-Iiand glatira‘mer acetate will not relieve these symptoms.
`Depression is common in MS and can pose the risk of suicide.
`
`
`Multiplc sclerosis (MS) is an inflammatory disease of the CNS that
`al‘l‘ccts approximately I
`in 200 women and fewer men in the Unitcd
`States.’ The term “multiple sclerosis" rcl'crs to two characteristics
`of thc tliscasc: numerous affected areas ol' the brain and spinal cord
`(CNS) producing multiplc neurologic symptoms that accrue over
`time. and the characteristic plaques or sclcroscd areas that are the
`hallmark of thc (liscasc.
`
`0 Although MS was lirst described almost I40 years ago. the
`cause rcmains a mystery. and a cure is still unavailable. chcrthe-
`. less. many advances ltavc bccn made in treating antl managing the
`disease complications and improving the quality-of—lil'c of affected
`individuals.
`
`EPIDEMIOLOGY
`Epitlcmiologic aspects of MS have been reviewed in many publi-
`cations.” MS affects approximately 400.000 people in the Unilcd
`States and 2.5 million pcoplc worldwide." MS is usually diagnosed
`hctwccn tht: ages ol’ l5 and 45 ycars: peak incidence occurs in tlic
`l‘ourth dccadc’. Approximately l0.00l) ncw cascs arc diagnosed per
`year in the United States. Women are at'flictcd more than men by
`:t ratio of '1
`I. Men usually dcvclop the lirst signs of MS at a later
`age than wurttcn. and arc more likely to dcvclop a progressive form
`of thc discasc. The most important factors in determination of risk
`for dcvcloping thc discasc arc geography. :tgc. environmental influ-
`cnccs. and gcnclics. In gcncral. tliscasc prevalence is higher thc
`grcatcr tlic distance truth the cutiator: within the United States the
`prcvalcncc ol. MS is higher in stalcs above the 37th parallel. Rcccnl
`stutlics. howcvcr, suggest a waning latitude gradient as demon-
`stratcd by a substantial incrcasc itt MS incidence in h'lctlitcrrancan
`rcgions, Rising incidcttcc ol' MS itt I'cmalcs appcars to be associatcd
`with tulianiration. As art csantplc. rcccnt rcports suggest that MS
`incidcncc markedly rose on Crctc among female subjects residing
`in urban settings or relocating at a young age from rural areas: this
`suggests that an environmental factor yet to be identified might play
`a role in changing discasc sttsccptihility.’
`
`835
`
`"‘.
`
`
`

`

`MS occurs tttorc frequently in whites of Scandinavian ances-
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`try than in other ethnic groups.
`In addition. an inverse relation-
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`ship between MS risk and ZS-liytlrtisyvitattiin I) levels has been
`proposed."'
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`Etiology
`
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`is thought that genetically susceptible individuals S15 years of
`It
`age who have lived ill a high-risk area for at least 3 years and were
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`exposed to a crucial environmental agent are at risk for develop~
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`ing MS. Interestingly. an indi\idua| who migrates from a low- to
`high-risk area prior to the age of 15 years acquires the satne chance
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`of developing MS as those who live in a high-risk area all their
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`lives
`‘ If the move is made from a high- to a low—risk area. the
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`individttal retains the high risk if the move is made after the age
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`of 15 years. httt acquires the lower risk if the move is made prior
`to this age." Smoking cigarettes has been associated with both an
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`increased risk of developing MS and with more severe progression
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`of tlisabilityf”
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`Viral or bacterial inlcctions may he an importattt environmen-
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`tal cause of MS. Although no clear association has been identilied.
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`certain infections might participate in the pathogenesis of MS by ini-
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`tiating or activating autorcactiye immune cells in genetically suscep—
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`tible individuals. leading to subsequent demyclittation. Evidence to
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`support a viral etiology includes increased immunoglobttlin Ci tlgLi]
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`synthesis in the CNS. increased antibody titers to certain viruses.
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`and epidemiologic studies that indicate a childhood exposure factor.
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`suggesting that "viral" infections may precipitate exacerbations. In
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`addition. vimses have been shown to cause diseases with prolonged
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`incubation periods. myelitt destruction. and a relapsing-remitting
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`course in botlt htttnans and experimental animal models.'-"'
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`Although numerous viruses have. a proposed association with
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`MS. the greatest evidence supports l‘ipstein—Barr virus ('EBV). Links
`of EBV ittfection to MS pathology are yet
`largely hypothetical.
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`Autoreactive T—eells cottld be activated by EBV through molecular
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`tttimicry. wltereby sequence similarities between EBV and self-pep-
`tides are sufficient to result
`iii the cross—activation of atttoreaetive
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`T- or B-cclls. Other potential mechanisms of detnyclination include
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`enhanced breakdown and presentation of self-antigens. expre 'sion
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`to
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`of viral superantigcns. or bystander activation.” Antibody titv;
`s‘
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`Epstein—Barr nuclear antigen tliliNA) complex are higher in MS
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`patients versus controls. especially if blood is collected 25 years
`before onset. These titers increase over little in MS patients (controls
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`are unchanged). and a fourfold increase in EBNA titers over time
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`results in a threefold increased risk of developing MS (almost an
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`lS—fold increase itt those with lirst samples before age Elli.” lttter—
`estingly. one paper notes individuals positive for [11.4 DREW/50]
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`have a 24-fold increased risk of developing MS when tltey also have
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`antibodies to certain epitopes within liBNA-l compared with oth-
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`ers.” This is consistent witlt a genetic-environmental
`interactit'in.
`In addition. anti‘ljl'lNA titers have been associated with relaps-
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`ing-remitting multiple sclerosis (RRMS). conversion of clinically
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`isolated syndrottte tClS) to clinically delittite multiple sclerosis
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`(CDMS. conlirmed diagnosis of MS). and with tnagnctic resonance
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`imaging (MRII measures such as gadtiliniunt-cnhancing lesions.
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`change in 'l'. lesion volume (r : (L27: l' = (Hi-14). and Expanded
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`Disability Status Scale (liDSS) score (120.3: I" = 0,035 ). 7.ivadinov
`et al. also found anti—IZBNA attd anti»vascttlar cell adhesion (VCA)
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`titers associated with gray matter atrophy in MS.” While Seraftni
`et al. have claimed to identify evidence of abortive infection in a
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`signilicant number of MS patients.” others have not been able to
`replicate these lindings.” The majority ofdata would lead to a cott-
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`clusiott that exposure to lEBV is somehow associated with develop-
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`ing MS. bttt does not support the concept of an active or aborting
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`liHV infection directly causing MS.
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`The familial recurrence rate of MS is approximately 5' S. \tith
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`siblings being the most cotntnottly reported relationship.2 attd a cott-
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`cordancc ratc among motioxygotic twins of approximately 35“}.
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`This is consistent with the idea that an environtm'ntal agent is impor»
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`tant iii the etiology of MS. bttt also suggests a role for one or more
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`genes. Genes that
`lie within the major histtIcompatibility complex
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`lMl‘lC). which is located on the sixth chromosome in humans. have
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`been linked to MS.” Recent data show a signilicant association of
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`risk with mutations in the interleukin-2ft(IL-“m and interleukin-
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`7r’1 l ll--7(1l receptor genes." "‘ African Americans are significantly
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`less likely to be diagnosed with MS compared with whites. although
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`there is emerging evidence that they are more likely to have a “were
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`disease course-m and respond less well to interferon (II:
`it therapy.”
`A locus on‘chromosotne I may be associated with increased .stlst'cp-
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`tibility in African Americans}:
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`PATHOPHYSIOLOGY
`
`22W_H—~A—
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`-4-“23.-.“;-
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`..a.
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`o The basic physiologic derangement in MS is stripping of the
`tnyelitt sheath surrounding CNS axons. This activity is associated
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`with an inllamtttatory. perivcnular inliltratc consisting of T and B
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`lymphocytes. macrophages. antibodies. attd complementf" Deniy
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`renders a.\ons sttsceptihle to damage. which becomes
`clittatiott
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`irreversible \\ hen they are severed. Irreversible axonal damage cot-
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`relates with disability and can be visttali/cd as hypointcnse lesions.
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`or "black holes." on TI-neighted M Rl.
`It is well accepted that MS lesions are heterogeneous. uhieh
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`may be due in part to differences in the stage of evolution of the
`lesions over tinte. differences in underlying immum\pathogcnesb.
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`or a combination. Brielly stated. acute lesions show demyelination
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`and axonal destruction with lymphocytie activity consistent with an
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`inflammatory state.
`In contrast. more chronic lesions display less
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`inllatmnatory lymphocytes with active remyelination."' Although
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`traditional descriptions have focused on white matter as the sole
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`location of MS lesions. more recent studies have clearly identitied
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`cortical and sttbcortical gray matter lesions both pathologically”
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`and radiiigraphicallyi" In addition. a subset of patiettts with pr0~
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`grcssiVe MS are noted to have abnormalities consistent with ll-cell
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`follicles in the meningcsr"
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`Just as the fttll dimensions of the neurttpathology are uncer-
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`tain. so is the pathogenesis of the MS lesion. Substantial evi»
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`dence suggests it
`is an autoimmune process directed against
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`tnyelin and oligodendrocyaes.
`the cells
`that make tny'elin'0
`(Fir; 3° 1). A new concept of T—cell entry into the CNS suggests
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`that the initial lymphocyte invasion in MS may proceed through
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`the ventricles. toward the choroid plext
`‘ along a (Cl. 20 gradi-
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`that attracts activated Thl7 cells.” The actual
`ttiediatot of
`ent
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`myelin and axonal destruction has ttot been established. bttt may
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`retlect a combination of macrophages. antibodies. destructive
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`cytokines.
`rind reactive oxygen intermediates. The exact
`trig-
`ger for activation of T—cclls in the periphery remains unclear.
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`the 'lleells in MS patients recogtti/_e myelin basic protein
`bttt
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`(MBP). protcolipid protein. myclin oligodendrocytc glycopro-
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`teitt. and myeliii—associated glyeoprotein. T—helpcr subtypes can
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`be either pathogenic or protective in MS. Furthermore.
`theory
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`holds that certain T-cell subsets are not terminally differentiated.
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`instead engender a level of plasticity that allows for their
`but
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`conversion from pathogenic to protective and vice versa under
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`certain conditions (fm ”7 7).” In patients with stable or mild
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`disease. increased numbers of cells are found that express mes-
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`senger RNA ttnRNA) for transforming growth factor-1! (TGF-fi)
`and interleukin-Ill (ll->l(l) compared with patients with severe
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`disease. Conversely. a reductiott
`iii the ttutnber of 'l‘-regu|atory
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`fTreg) cells. which exhibit suppressor activity. is associated with
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`Page 4 of 22
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` ; ti
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`1 g
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`.r
`1
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`u.
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`".
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`Page 4 of 22
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`3C
`E.
`E0
`U5
`2ID-1
`9.VI
`
`O‘
`
`Blood-brailn
`barrier
`
`lL-d. 5. 10
`
`LlNGO-l (-)
`
`(DC. mo Bcell)
`mi ti Illa
`
`Ventricle
`
`
`
`Demyelinated
`Na” channels
`
`“01“” i'?
`
`Autoimmune theory of the pathogenesis of multiple sclerosis (MS). In M5, the immunogenic cells tend to be more
`myelin-reactive, and these T-cells produce cytokines mimicking a Thl-mediated proinflammatory reaction. T-helper cells (CD4+) appear
`to be key initiators of myelin destruction in MS. These autoreactive CD4+ cells. especially of the T-helper cell type 1 (Th l) subtype,
`are activated in the periphery, perhaps following a viral infection. The activation of T- and B-cells requires two signals. The first signal
`is the interaction between MHC and APC (macrophage. dendritic cell. B-cell).The second signal consists of the binding between 87
`on the APC and C028 on the T-cell for T-cell activation. Similarly, CD40 expressed on APCs and CD4OL expressed on T-cells interact
`to signal the proliferation of B-cells within the blood—brain barrier following the entry to T-cells. The T-cells in the periphery express
`adhesion moleCUles on their surfaces that allow them to attach and roll along the endothelial cells that constitute the blood—brain
`barrier. The activated T-cells also produce MMP that help to create openings in the blood-brain barrier, allowing entry of'the activated
`T-cells past the blood-brain barrier and into the CNS. Once inside the CNS, the T-cells produce proinflammatory cytokines, especially
`interleukins (ILs) 1,2, 12, I7. and 23, tumor necrosis factor-atTNF-a). and interferon-ytINF-yl, which further create openings in the
`blood-brain barrier, allowing entry of B—cells, complement, macrophages, and antibodies. The T-cells also interact within the CNS with
`the resident microglia, astrocytes, and macrophages, further enhancing production of proinflammatory cytokines and other porential
`mediators of CNS damage, including reactive Oxygen intermediates and nitric oxide. The role of modulating, or downregulating,
`cytokines such as IL-4, IL~S. IL- 10. and transforming growth factor-[3(TGF-[ii also has been described. These cytokines are the products
`olCD4+, CD8+, and Thl ~ce|ls.‘° New pathogenic mechanisms involve, but are not limited to, receptor-ligand mediated T-cell entry via
`choroid plexus (CCR6-CCL20 axisi.” coupling of key receptor-ligands for inhibition of myelination/demyelination (LINGO-l/NOGOGé/
`p75 or TROY complex, Jagged-Notch signaling).(Ag, antigens; APC, antigen presenting cell; DC, dendrite cell: lgG, immunoglobulin G;
`Md). macrophage; Na+, sodium ion; MMP, matrix metalloproteinases; MHC. major histocompatibility complex; OPC, oligodendrocyte
`precursor cell; VLA, very late antigen; VCAM. vascular cell adhesion molecule.)
`
`active MS and can he found in patients with progressive dis-
`ease.
`It should be noted. however. that Treg ratios do not always
`correlate with disease activity. Ol~ note. experimental evidence
`assuriates high 2S-hydroxyvitamin D levels with improved Treg
`function. favoring the Th) phenotype in the ThllTltl balances“
`Finally. the significance of one ol‘ the immunological hallmarks
`
`of MS. the imrathccal synthesis of multiple clones ol‘ immuno-
`globulins. remains unclear. The antigcnts) against which these
`immunoglobulins are directed remain unknown. bttt do not
`appear to include common CNS myelin antigens." The complex
`interplay of a Variety of cells. antibodies. and cytokines remains
`to be elucidated.
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`Page 5 of 22
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`2‘
`.
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`'J: c
`J"—
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` ts‘JL
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`c
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`-. MI.“
`3. "t ‘~.‘ ti
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`General
`- Most patients with MS present with nonspecific
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`complaints. Many have problems with their vision
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`or paresthesias
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`gle‘is'c'lérosis -'
`, «mgr-y -
`
`Laboratory Tests
`- MS is a diagnosis of exclusion
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`
`
`- MRI
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`- CSF studies
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`
`- Evoked potentials
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`Primary Symptoms/Signs
`- Visual complaints/optic neuritis
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`- Gait problems and falls
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`- Paresthesias
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`- Pain
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`- Spasticity
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`- Weakness
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`- Ataxia
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`- Speech difficulty
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`
`- Psychological changes
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`- Cognitive changes
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`- Fatigue
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`- Bowel/bladder dysfunction
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`~ Sexual dysfunction
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`- Tremor
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`Secondary Symptoms
`- Recurrent UTls
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`- Urinary calculi
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`- DeCubiti and osteomyelitis
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`- OsteopOrosis
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`- Respiratory infections
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`
`- Poornutrition
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`
`- Depression
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`Tertiary Symptoms
`- Financial problems
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`- Personal/social problems
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`- Vocational problems
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`- Emotional problems
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`
` 2mCR C
`
`.’
`O
`‘9.n
`
`9.Vi
`O1
`‘D1
`Vi
`
`QI
`
`CLINICAL PRESENTATION
`
`
`AND COURSE OF ILLNESS
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`e 'I'hc clinical prcscntation ol‘ MS is cstt‘ctncly yariahlc among
`paticnts :qu typically yat‘it-s orcr titnc itt a giycn paticutt 'I‘Itc signs
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` 'v
`attd sytnplonts ol' MS can hc dividcd into tItt'cc calcgot'ics. I’t'itn:
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`s) tnptotns arc- a direct consctlucncc ol’conduction disturlutnccs pro-
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`duccd hy dcmyclination and asonal datnagc. attd t'cllcct thc at'ca ol‘
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`thc (INS that is damagcd. Sccondat'y symptoms arc complications
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`rcsulting from primary symptoms. For csatnplc. urinary rctcntion.
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`a primary symptom. catt Icad to t't'cnucnt urinary tract
`inl'cctions
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`Mills). a sccondary syntptotn. 'I'crtiar} symptoms rclatc to thc cl‘lcct
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`ol' lltc discasc on thc paticnt's cycryda} IiI'c.“
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`'I‘hc clinical cottrsc of (HMS is classilicd into four cat-
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`cgorics.“ Al
`the onset of symptoms. about 350; ml paticnts Itayc
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`csaccrlxttitins—«new symptoms
`lasting at
`Icas‘t
`Z—I hours and
`scparatcd l'rotn othcr new symptoms by at
`least Jll days—lidltm‘cd
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`hy rcntissions tcontplctc or incotuplctc).
`lisaccrhations arc l'rc-
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`qucntly rclcrrcd to as rclapscs or attack» This course is callcd
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`RRMS: thc tirst clinical prcs‘cntation is typically (‘ISI During thc
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`RRMS pltasc. tltcrc is a corrclatiou Itctwcctt ttc\\ brain MRI Icsions
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`and clinical attacks. but
`typically thcrc arc tnauy ntot'c llc“ MRI
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`Icsions than ncw clinical symptoms. In RRMS palicttts. attack l't'c-
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`nucncy tcnds to dccrcasc ovcr titnc and hccomcs indcpcndcnt ol
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`thc dcyclopmcnt nl' progrcssiyc disahilitics.” t\'curo|ogic rccoycry
`following an cxaccrhation is oi'tcn quitc good cat'ly in tltc discasc
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`cout'sct hut I'ollowing rcpcatcd rclapscs. rccmcry tcnds' to hc Icss
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`complctc.
`In addition.
`lltcrc is a |lL‘\\' conccpt ot' a t':tdio|ogicall_\'
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`isolatcd syndrome IRIS]. rcl'crring to individuals \\Ittt hayc clinical
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`sccnarios not typical ol‘ MS. yet ohtaitt MRI scans tor othcr rcasous
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`(cg. Itcadachci and ham: radiological signs suggcs’tirc ol‘MS. Sonic
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`pcrccntagc oli thcsc paticnts cottvcrt to RRMS mcr titnc.“ although
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`whcn to start lrcatmcnt rcntains unclcat and \arics hy practicc.
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`Up to |()’./;
`to 20']: ot' RRMS paticnts Itat‘c a benign coursc.
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`charactcri/cd by few t‘clapscs. ol'tcn scttsor). with tttittitttal dis
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`ability accruing o\'cr tintc.
`;\Io-.t RRMS paticnts c-Jctttually cntct
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`“—5-.i--
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`W...»
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`Page 6 of 22
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`a progressive phase in which attacks and remissions arc tlil'ticult to
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`identify. This is referred to as sectindary—progrcssive multiplc sclc-
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`rosis ('SI’MS). Disability tends to accumulate morc signilicantly
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`during this phasc ol' lItc illncss. chx brain MRI Icsions. c-spccially
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`Ihosc scctt only :il'tcr tltc iujcction ot'contrast ntatcrial. arc lcss corti-
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`tuna. and brain atrophy and TI IlttIc\ ittct‘cascl"
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`o (\pprosimatcly li'ri
`ot‘ paticnts nct'cr ltayc attacks and
`rctnissions hut hayc progrcssirc tliscasc from Ihc outsct. known as
`
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`primary-prttgt'cssiyc ntultiplc sclcrosis tI’I’MSL iI'hcsc patients will
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`have symptoms. cspccially spastic paraparcsis that may “ors‘cn rap-
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`idly or rclativcly slowly over tintc. and accrnc progrcssivcl)’ tttorc
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`disability. Patients with l’l’MS arc diagttoscd at a latcr agc. \s'itIt tltc
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`nunthcr ol' tnalcs roughly canal to that ol‘ I'cmalcs. 1n gcncral. I’I'MS'
`paticnts tcnd to Itatc a \t'otsc prognosis than thosc \\Iu- prcscttt itti-
`
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`tiaIIy \\'IlIl RRMS, although tnot‘c rcccttt data sag cst progrcssion
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`is variahlc." Many clinical trials It:t\'c suggcstcd that a signiticant
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`portion of paticnts \vtth I’I’MS do not rcccitc hcnctit
`l'runt slttdicd
`thcrapics. I-Iowcycr. a rcccttt at‘ticlc using ritusiinah suggcsts a sub-
`
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`gt'oup ol‘ I’I’MS paticttts \\ho arc <5| _\cars ol‘ :tgc and Inn c at Icast
`
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`ouc gadtiliniuttt»cnltancing Icsion may hcnctit from this thi.‘rap_\-.:~
`
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`l"inal|_\. a small pcrccntagc ol' paticttts ma} haw a tnistnrc ol hotlt
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`progrcsstou and rclapscs. t'cl‘crrcd to as progr
`ssitc-rclapsing multi-
`
`
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`
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`
`
`plc sclcrosis l I’RMS I. ‘I'hcsc paticnts arc gcncrall) trcalcd as rclaps-
`
`
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`
`
`
`
`
`
`ittg paticnts.
`
`Progression of thc iIIncss throughout thc Iilictintc can bc Inca-
`
`
`
`
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`
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`sttrcd in litany \t-‘ays‘.
`'I‘ltc n'tost \t'idcly ttscd clinical rating scalc is
`
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`thc EDSS. which uscs a numcrical
`\';t|ttc ranging from I) (no dis-
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`ability) to H) (dcatht to cvalnatc ncttt'ologic l'tutctionsi'” 'I‘hc limita-
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`tions ol' this scalc :u‘c lhc t‘cIati\'c ittscnsitiyit} to clinical cItattgcs
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`not involving intpairmcnt ot'anthnlatiotr such as changcs in cogtti»
`
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`lion. Iatigttc. and all‘cct. ()thcr tools. such as thc mulltplc sclct'osis
`
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`
`
`I'ttnctinttal compositc tMSH't. arc hcittg csahtatcd t'ot'
`ittct'cascd
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`scnsttivity and utility to dcscrihing cha gcs‘ in h‘IS—rclatcd disability
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`ovcr time.“ Incrcasing|_\'. MRI is hciug used as an iudcy of both
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`discasc actiyity and progrcssion.” Spccitically thc appcarancc ot
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`ttc\\ Ics‘ions or changcs itt Icsion nunthct: st/c, and \oItttnc arc hcing
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`us‘cd .ts outcoutc tncasutcs itt
`t‘cs;.uc|t stutlics Upttcal tullctcncc
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`Page 6 of 22
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`

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`
`
`3C
`E
`'2m
`
`mQmHO‘
`
`2.0‘
`
`T-Cell dillerentiation and plasticity in multiple sclerosis
`
`I
`
`T helper
`
`cell subtypes
`
`Clinical
`significance in MS
`
`Prainllammatory
`
`Th1 pathogenic
`
`IL-12I23.
`lFN-y
`
`Mutual suppression
`
`
`
`
`Th2
`
`-lL-4. IL-S
`
`-lL-lO. lL-l3
`
`Th2 protective
`
`Antiinllammatory
`
`
`
`Dillerenliation:
`
`Plasticity:
`
`Thl? pathogenic
`Proinllammatory
`
`autoimmunity
`
`Tteg protective
`Preventive ol
`
`Upon interaction with an antigen—laden APC and specific cytokines, the innate TAcells undergo differentiation into
`Ftc
`afew lineages (subtypes). Four subtypes significant for MS pathophysiology are illustrated here (Th 1 , Th2. Th] 7, and Treg). Th1
`and TM? are proinllammatory, Th2 is anti-inflammatory. and Treg is regulatory. Thl and Th2 are mutually suppressive and are
`relatively stable differentiated subtypes. In contrast, Th 1 7 and Treg subtypes are recently found to exhibit "plasticity." In other words,
`they can undergo phenotypic conversion to another T-cell subtype (Thl or Th2) in the presence of Specific cytokine conditions.
`This plasticity of Th 1 7 and Treg is the immunologic basis.lor development of therapeutic agents to favor the production of
`suitable Th subtypes for combating microbial invasion and also concurrently achieving neurocellular recovery after an infection.”
`(AFC, antigen presenting cell.)
`
`lmnograplty measures the retinal neural lihcr layer thickness, and
`may also he a ittcasttrahle sign of pathological progression over
`time.”
`
`The unpredictable nature ol‘ MS makes it impossible to antici-
`pate when an exacerbation will occur. However. certain factors.
`includingI
`infections. heat
`(including l'et'cr). sleep deprivation.
`stress. malnutrition. anemia. concurrent organ dysfunction. escr-
`lion. and childhinh. may aggravate symptoms or lead to an attack.
`Interestingly. many patients experience a significant reduction in
`relapses during tltc third trimester of pregnancy. followed by a rela-
`tive increase postpartum.” Between 60% and 80% of individuals
`diagnosed with the MS have been reported to he sensitive to envi—
`ronmental heat.
`
`in “'IHIS‘
`Clinically. increased body temperature might result
`rating of previous neurological delicits.
`including fatigue and
`decreased muscular endurance. Blurred vision. known as lllhol'l"s
`Page 7 of 22
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`is caused by increased hotly temperature due to
`phenomenon.
`physical exercise or physical restraint. Body temperature influences
`nerve impulses. which are hlockcd or slowed down in a damaged
`nerve. Alter normalization of the temperature. signs and symptoms
`improve or