Lehigh Valley Health Network - National Multiple Sclerosis

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					Progressive MS Research

              David E. Jones, MD
                Director, MS Center
 Comprehensive Care of MS
MS Specialists
                                 Symptom Mgmt

                   MS Center

      History of Multiple Sclerosis
■   Saint Lidwina of Schiedam
    – A Dutch nun from 1400’s with
      intermittent pain, leg weakness,
      vision loss
■   Augustus Frederick d’Este
    – Grandson of King George III
      whose diary (1822-1846)
      describes episodes of LE
      weakness, dizziness, bladder
      dysfunction, clumsiness
■   Jean-Martin Charcot
    – Clinicopathological treatise of
      patient with dysarthria, ataxia,
      and tremor in 1868

                    Multiple Sclerosis
■   Likely, a chronic, inflammatory condition of the
    CNS likely induced by an environmental trigger in
    a genetically susceptible patient
■   “Neurological lesions disseminated in time and
    space” without an alternative explanation for
            Clinical MRI Paradox

36yo woman                           42yo woman
Avid hiker, recently completed PhD   Cane and bilateral MAFO
EDSS 2.0                             EDSS 6.0

                     Immunopathogenesis of
            Regeneration                                                                               Degeneration
  n of
   Onset                                                              Time
                           A                             B                               C
Compston A, et al. Lancet. 2008;372:1502-1517; Kuhlmann T, et al. Brain. 2002;125:2202-2212; Paolilo A, et al. J Neurol. 2004;251:432-439.

                                     Subtypes of MS
                        1. Relapsing-remitting                                 2. Primary-progressive

                                                       Increasing disability
Increasing disability

                                     Time                                                   Time
                        3. Secondary-progressive                               4. Progressive-relapsing

                                                       Increasing disability
Increasing disability

                                     Time                                                   Time
                                                   Lublin FD, Reingold SC. Neurology. 1996;46:907-911.
       Relapsing Remitting MS
■   RRMS
    – 85% of patients with MS start with a relapsing remitting
        • Exacerbations / Flares / Relapses
           – Rapid onset of new symptoms
           – Association with gadolineum enhancement on MRI
           – May improve resolve over weeks to months (remission)
              » Steroids (iv) speed up the improvement and likely delay future
        • Pseudo-exacerbation
           – Previous symptoms can reoccur / worsen in setting of infection,
             heat, stress
    – Inflammation plays a big role, but there is evidence of
      degeneration / atrophy in RRMS
    – Treatment delays progression into SPMS
                    Progressive MS
■   Degeneration plays more of a role in progressive MS
■   Secondary Progressive Multiple Sclerosis (SPMS)
     – Currently felt to be about 30% of MS patients
     – Always follows relapsing-remitting MS (RRMS)
     – Transition from episodic flares to slow, gradual worsening of symptoms
       independent of flares
     – Often occurs 10-20 years after beginning of MS (highly variable)
■   Primary Progressive Multiple Sclerosis (PPMS)
     – ~10% of multiple sclerosis patients
     – Gradual worsening of symptoms without preceding flares
         • Can have mild fluctuations in symptoms
         • Rare cases of PPMS will have occasional relapse (PRMS)
     – 85% predominance of spinal cord symptoms (myelopathy)
         • Slow worsening of gait is the most common presentation
     – Sex ratio 1:1
     – Later onset of symptoms (~45yo)

    Treatment of Progressive MS
■   All of our therapies work on the inflammatory component
    of the disease; however, progressive MS is felt to be
    more degenerative.
■   None of the currently approved medications have been
    proven to alter the course of progressive MS
    – Failed trials in PPMS
        • Rituxan (OLYMPUS) – possible response if <50yo, have relapses,
          or enhancing lesions
        • Copaxone
        • Mitoxantrone
    – Trials suggesting effects in disease transitioning to SPMS
        • Betaseron (European trial)
        • Mitoxantrone
    – Failed trials in SPMS
        • Betaseron (North American trial)
        • Dirucotide (MBP 8298)
    Treatment of Progressive MS
■   My approach
     – Assess for amount of inflammation
        • Gad-enhancing lesions, positive spinal fluid, response to
          iv corticosteroids
     – If evidence of inflammation, consider off-label
       immunosuppressive drugs (Rituxan, Cellcept)
■   Occasional pulses of steroids is another
     – Steroids come with risks

         Natalizumab (Tysabri)
■ Monoclonal    Ab to VLA
– Disrupts interaction with
– Reduces ability of WBCs
 to cross the BBB
■ Efficacy (vs placebo)
– Reduces relapses by 67%
– Reduces disability progression by 42-54%
– Reduces enhancing lesions by 92%
– Reduces black holes by 76%
                                       Polman NEJM 354; 2006.
        Natalizumab (Tysabri)
■   Improvement in Disability (EDSS)
     – 29.6% of patients had sustained improvement in
       physical disability (vs 18.7% placebo)
■   Improvement in Disability (MSFC)
     – Improvement in 25 foot walk speed
     – Improvement in 9 hole PEG test
     – Improvement in cognitive function (PASAT)
■   Improvement in quality of life (QOL)
     – Both physical and mental components
           Progressive Multifocal
        Leukoencephalopathy (PML)
■   Rare, opportunistic infection of brain myelin caused by JC virus
      – Dysarthria, ataxia, cognitive impairment, cortical blindness
      – Symptoms progress over 1-3 months
■   JC virus is latent in many people (kidneys, bone marrow)
      – 50% in recent studies (old studies suggesting 80% included BKV)
      – Can reactivate in AIDS, CLL, organ transplant patients
■   No proven treatment, can be fatal
      – AIDS patients can reverse infection if immune system restore
PML with natalizumab

             PML with natalizumab
■   As of December, 2011
     – 95,300 patients exposed, 55% of which in the US
■   As of March, 2012
     – 212 reported cases of PML with natalizumab, 38% in US
         • 46 deaths; others with varying degrees of disability
             – 10% mild, 50% moderate, 40% severe disability
     – 42% of cases were previously treated with immunosuppressant
          • Per TYGRIS, 14% of US patients and 24% of EU patients previously on IS
             – Novantrone          17
             – Imuran               5
             – Methotrexate         5
             – Cellcept    5

■   JC virus antibody assay
     – 59/59 patients with serum collected before PML (or even starting
       natalizumab) were JCV positive

PML with Natalizumab

       Natalizumab (Tysabri)
    – Ongoing clinical trial of Tysabri in SPMS
    – Rationale - CXCL13
       • May be a marker for SPMS
       • May be involved in SPMS
       • Is reduced by natalizumab

                  Fingolimod (Gilenya)
 ■    First approved oral DMT disease for MS
         – MOA – traps ~70% of circulating immune cells in LN
Activation     Proliferation and                                   Lymphatic sinus
  Afferent lymphatic vessel                                                  Sinus-lining endothelium
                                            Activated T cells

       Naïve T cell                      S1P1 receptor                         Efferent lymphatic vessel

                      Lymph node

                                                      S1P1                   Sinus-lining endothelial cell
                                                  downregulation                barrier enhancement

                                                                               Reduced T cell egress

                                                                      Horga Expert Rev Neurother 8;2008.
            Fingolimod (Gilenya)
■   TRANSFORMS – fingolimod vs. IM interferon-beta
     – 52% reduction in ARR; 80-83% of patients relapse free
     – No difference in disability (only 12 month trial)
     – 2 deaths (herpetic infection), 15 cardiac conduction
       abnormalities, 8 macular edema, 3 melanoma
■   FREEDOMS 1 – EU fingolimod vs placebo
     – 54-60% reduction in relapses
     – 30-32% reduction in sustained disability (24 month trial)
     – No significant difference in infection or malignancy, 3 cases
       macular edema, few asymptomatic cardiac conduction abnl
■   FREEDOMS 2 – US fingolimod vs. placebo
     – 48% reduction in ARR
     – 17-28% reduction in SAD (NS)
     – 74% reduction in new T2; 70% reduction in Gd+
                                            Cohen NEJM 2010; Kappos NEJM 2010.
                            Fingolimod (Gilenya)
 • Airways                                                    • Angiogenesis (S1P1)
   hyperactivity                                              • Vasodilation (S1P1, 3)
                                 Bronchial                    • Barrier decrease (S1P2–
                                  smooth                        3)
                                  muscle                      • Barrier enhancement
                   Retina                S1
• Swelling
  (S1P2)                                                                • Heart-rate reduction
                                                                          and regulation
                              Vascular         Atrial                     (S1P1, 3)
   • Vasoconstriction,        smooth          myocytes
     blood pressure            muscle

                                                    Brinkmann Pharmacol Ther 115;2007.
    Recent changes with fingolimod
■   Defined patient selection:
     – Appropriate - no pre-existing CV conditions, baseline EKG
       OK, no meds to lower HR
     – Caution – h/o CAD/CHF, CVD, HR-lowering drugs, recurrent
       syncope, severe OSA, mild dysryhthmias
     – Avoid – recent CAD/CHF, CVD, Class 1a or III
       antiarrhythymics, QTc > 500, Mobitz II or greater AV block
■   Monitoring:
     – Hourly 6 hours; ECG before and after
     – Overnight with caution or with symptoms during monitoring
          Fingolimod (Gilenya)
■   INFORMS clinical trial in PPMS
      – Potential role in repair of myelin
         • S1P receptors in oligodendrocyte progenitor
           cells (OPCs)
         • In vitro studies suggest can stimulate OPCs,
           inducing production of myelin

Dimethyl fumarate (BG00012)
■   Presented to FDA 2/12
■   MOA
     – Cytokine shift to more anti-inflammatory, Th2 cytokine milieu
     – May be neuroprotective (activation of nrf2/keap1 antioxidant
■   Phase II data
     – 69% reduction in Gad lesions
■   DEFINE study
     – 2 year, placebo-controlled, Phase 3 study of BG12 240mg
       bid and tid in patients with RRMS (n=1,011)
         • 54% reduction in relapses in bid group
         • 38% reduction in disability progression
         • 85% reduction in new MRI lesions; 90% reduction in gad
Dimethyl fumarate (BG00012)
■   CONFIRM trial
     – 2 yr Phase 3 study of BG12 bid and tid vs Copaxone vs
         • 44% reduction in ARR in bid dose, 51% reduction in tid dose, 29%
           reduction in Copaxone group (vs placebo)
         • 65-7( % reduction in Gd+; 71-73% reduction in new T2
         • Disability chg NS (very little progression in placebo group)
■   Safety
     – Seemingly few issues; available for psoriasis
       (Fumaderm) in Germany since 1994
         • Flushing, especially first month (aspirin may reduce)
         • GI side effects, including diarrhea initially
■   Given potential “neuroprotection”, may be reasonable
    to study in progressive MS
■   MOA
      – Unclear; suspect shift in cytokine milieu to Th2; may be neuro-protective
■   ALLEGRO: 2 year, placebo-controlled, Phase 3 study of laquinimod
    0.6mg in pts with RRMS (n=1,106)
      – Efficacy
           • 23% reduction in relapses; 36% reduction in disability progression
           • Reasonable MRI data
      – Safety data appears promising
           • Reversible LFT elevations; back & abdominal pain
■   BRAVO: 2 year, comparator (placebo or Avonex), Phase 3 study of
    laquinimod 0.6mg in pts with RRMS (n=1,331)
      – Efficacy
           • 21% reduction in ARR (after correcting for randomization “dissimilarity”) - NS
           • 34% reduction in SAD; 28% reduction in brain atrophy
■   Pooled analysis
     – 21% reduction in ARR; 34% reduction disability; 30% reduction in atrophy
■   Would be reasonable to study in progressive forms of MS
         Rituximab / Ocrelizumab
■   MOA
     – Humanized anti-CD20 monoclonal antibody; depletes B cells
■   Efficacy
     – HERMES Phase 2trial of rituximab in RRMS showed >50%
       reduction in relapses; 91% reduction in Gd+
     – 96 week trial of OCR (600 and 2000mg) vs placebo or Avonex in
       220 patients with RRMS; 73-80% reduction in ARR; 89-96%
       reduction in T2 lesions at 24 weeks
          • No gad or new T2 lesions weeks 24-96
          • 67.3% of patients free of clinical activity at 96 week
          • 78-80% of patients relapse free
     – Ofatumumab (human) forms of rituximab
         • 99% reduction in Gad lesions
     – Trial in PPMS

■   Myelin-producing cells (oligodendrocytes) are dying in
    evolving MS lesions
     – One of the key causes of axon loss is myelin damage
■   Is it possible to make more oligodendrocytes?
     – Oligodendrocyte Precursor Cells (OPCs) are not rare in
       MS lesions, are sitting at the periphery
     – LINGO is a molecule that keeps OPCs quiet
         • Anti-LINGO molecule is under development
         • Entering Phase II
                          Stem Cells
■   Autologous hematopoietic stem cell transplantation (AHSCT)
     – “Treat MS by resetting the immune system”
         • Remove immune stem cells from bone marrow
         • Obliterate immune cells with high dose chemotherapy / radiation
         • Replace stem cells to reset immune system
            – This is treatment for RRMS
■   Replacement of oligodendrocytes (myelin)
     – Potential problem – tumor formation
■   Replacement of neurons
     – Problem – creation of neural networks
■   Adult human mesenchymal stem cells
     – International MSCT Study Group
     – Cells may be anti-inflammatory, promote repair, and potentially
       secrete substances that help protect axons / neurons
    Low Dose Naltrexone (LDN)
■   Excitement at “grass roots” level
     – Opioid agonist, increased β-endorphins
     – ? Placebo effect
     – Compounding pharmacy
■   Studies
     – 17 patients with MS
         • Self-reported decreased disease activity
     – 35 patients with PPMS (open-label)
         • Improved fatigue and depression
     – 80 patients with MS (randomized)
         • Improved QOL, pain, cognition
■   My take – probably safe, may offer symptomatic benefit
                                     Cree, B. et al. Ann Neurol 2010,
              And The Bizarre …
■   Chronic Cerebrospinal Venous Insufficiency (CCSVI)
     – Reports from Italy suggested abnormalities in venous
       drainage of the brain in patients with MS
        • Zivadinov - >500 ultrasounds
           – Approx. 55% of MS patients with CCSVI, 45% of pts with OND
           – 22% of healthy controls with CCSVI
        • Most recent papers - no CCSVI
        • No data to suggest CCSVI causes MS
     – Studies of interventions correcting these narrowings
       have been initiated
        • “Liberation therapy”
        • Thus far, no positive data to support this practice
        • Recent FDA warnings
    Treatment of Progressive MS
■   There is even more hope …
     – In NY database of MS patients, up to 25% of
       patients with PPMS do not require a cane at 20
     – There are significant benefits of attainable with
       appropriate multidisciplinary management of
       symptoms in a comprehensive MS center

    Physical Therapy / Exercise
■   Randomized trial of efficacy of
    resistance training in RRMS
     – Exercise group
        • 15% improvement in strength
        • 21% improvement in functional status
        • Mild improvements in mood, fatigue, QOL
        • Biopsy – increase in size of muscle fibers
■   Obvious benefits of physical therapy in
    MS in other trials
■   Most common (and frequently most disabling) symptom of MS
      – Physical lassitude that hits “like a Mack truck” and feels like “carrying weights”
      – Compounded by increased energy expenditure needed to compensate for motor
■   Potential confounders, especially if “sleepiness”
      – Obstructive sleep apnea
      – Physical deconditioning
      – Drug side effects
      – Frequent nocturia
      – Depression
■   Treatment
      – Non-pharmacological
            • Maintain appropriate sleep
            • Energy conservation – pacing, planning activities
            • Mild exercise to prevent physical de-conditioning
      –   Pharmacologic
            • Amantadine, Provigil, stimulants, l-carnitine?
              Abnormal Mobility
■   Goal - safely maximize independence
    – Ambulatory patients
        • Strengthening
        • Treat spasticity
        • Treat foot drop
           – Modified ankle-foot orthosis (MAFO)
           – Peroneal stimulators - WalkAide, Bioness
        • Assistive devices
        • Ampyra
    – Non-ambulatory patients
        • Scooter, wheelchair to maintain independence
        • Augment ability to transfer
           – Transfer boards, Hoyer lift, grab bars
        • Meticulous skin care

■   “Velocity-dependent resistance to muscle stretch”
      – Complications of spasticity
           •   Limitations in ability to walk / transfer
           •   Pain, muscle spasms
           •   Increased fatigue
           •   Joint changes
           •   Pressure sores
      – Benefits
           • Compensation for weakness
      – Exacerbating factors
           • Stress, infection, pain, temperature changes
      – Treatment is multifactorial
           • PT / OT - ROM / stretching, strengthening
           • Meds - baclofen, Zanaflex, BOTOX
              – Baclofen pump
              Neurogenic Bladder
■   2 basic problems
     – Failure to store – spastic bladder
         • Urgency, frequency, incontinence
         • Treatment
            – Timed void, pelvic floor therapy
            – Avoid bladder irritants (caffeine, alcohol)
            – Anticholinergics - Detrol, Ditropan, etc.
     – Failure to empty – atonic bladder or spastic
         • Hesitancy, retention, UTIs, incontinence
         • Treatment
            – Double voids, pelvic-floor therapy
            – Clean intermittent catheterization
            – Flomax?
■   Combination –> detrusor-sphincter dyssynergia
                   Sexual dysfunction
■   Lack of desire (Libido)
      – Psychological issues, including altered identity roles
      – Physical factors, including fatigue, bowel/bladder dysfunction, pain
■   Lack of arousal
      – Women
           • Diminished sensation in pelvic floor may cause decreased arousal
               – Vibrators, EROS device, “bag of frozen peas”
           • Lack of lubrication
               – Lubricants
      – Men
           • Erectile dysfunction
               – Phosphodiesterase inhibitors – Viagra, Cialis, Levitra
               – Caverject, prostheses
■   Anorgasmia
      – Psychological factors
      – Fatigue
      – Can respond to stimulants, alpha agonists
          Neuropsychiatric Issues
■   Depression in MS
     – Situational stressors AND neurotransmitter deficiencies
     – More common in MS than in other neurological diseases
     – Requires multi-disciplinary care
          • Psychologist
          • Psychiatrist
             – Activating antidepressants (Effexor, Prozac, Wellbutrin)
■   Memory issues
     – Difficulty with processing speed, multi-tasking, rapid word retrieval,
       problem solving, and maintaining attention
     – Fatigue, depression, medications can worsen
■   Pseudobulbar affect
     – Spontaneous, inappropriate expression of emotion (laughter, crying)
     – Can respond to TCAs, SSRI
     – Neudexta
                        Pain in MS
■   Common causes of primary MS pain
     – Parathesias, including Lhermitte’s symptom
         • Most common type of pain in MS
         • Ephatic transmission between denuded axons
            – Often, responds to anticonvulsants
            – Often, lack of response to typical analgesics (i.e., narcotics)
     – Trigeminal neuralgia
     – Spasticity is painful!
■   Secondary MS pain
     – Osteoarthritis / joint pain can be attributed to abnormalities of gait
     – Musculoskeletal pain, skin breakdown, compression fractures
■   Psychiatric / emotional component to pain, especially chronic
     – Duloxetine (Cymbalta) is approved for depression and neuropathic pain
■   Role for PT / OT, acupuncture, massage, exercise (yoga, aqua)
■ Relapsing multiple sclerosis has an
  inflammatory component which has been
  amenable to anti-inflammatory therapies
■ Progressive MS may be more degenerative, a
  process that we do not understand as much
■ Some of the drugs in development offer hope of
■ Care of the MS should be multidisciplinary with
  some focus on symptomatic management


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