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10/25/2018

MS by the numbers

• Age: 20-50 y.o Overview of MS Management: – 5% < 19 y.o – 5% > 60 y.o Practical Points To Family Physicians • Gender 3:1 F:M ratio • Prevalence: – 1 million total in the US; 402.8/100,000 (Wattlin et al., ECTRIMS 2017) https://multiplesclerosisnewstoday.com/2017/11/20/nearly-1-million- Rana K. Zabad, MD americans-have-multiple-sclerosis-nmss-prevalence-study-finds/ – US distribution, in order, highest to lowest Associate Professor • NE: 459.3/100,000 • Midwest: 434.9/100,000 Director MS Program • West: 352.3/100,000 • South: 334.7/100,000 University of Nebraska Medical Center • Natural history of untreated individuals: & Nebraska Medicine – SPMS by 8-10 years – Unilateral assistance by 15-20 years

Disclosure RK Zabad, • Was a grant reviewer for PCORI within the last 2 years. • Served as a consultant for Bayer, Celgene, Genzyme, TEVA Neuroscience and TG therapeutics in the last 2 years. • Is Member of the Adjudication Committee for a of biotin in primary and secondary progressive multiple sclerosis sponsored by PAREXEL and MedDay pharmaceutical. • Main site PI or Sub-I for clinical trials funded by Adamas, Biogen, , Novartis, Sunpharma. • Speaker for unbranded lectures sponsored by Novarties and TEVA Neuroscience.

Objectives Courses of MS • Introduction – MS by the numbers – Immunopathogenesis of MS Relapsing Non-Relapsing – Courses of MS • Treatments of MS • Radiologically isolated • Radiologically isolated – Relapse Management syndrome syndrome – Symptom Management • High dose CS • Clinically isolated syndrome • Primary progressive MS • Plasma Exchange (PLEX) – Disease Modifying Therapies • RRMS • Disease Modifying Therapies in MS • SPMS – Injectable – Oral – Infusions • Issues of particular importance to the Family Practitioner – DMT and infections – DMT and neoplasia – DMT and vaccination – Vitamin D level Optimization

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Putative Mechanism Of High dose Corticosteroids IV/oral Pseudorelapse Due To Infection Relapse management Plasma Exchange (PLEX)

Injectable MS Symptom management beta Comorbidities Management Non-interferon

Orals Aubagio Disease Modifying Therapies BG-12

Infusions

Khanna et al., Immunome Research, 2014

Putative Mechanisms Of Relapse Due To Infection

MS Relapse Management

1. Relapse Definition 2. High dose Corticosteroids 3. PLEX

MS relapse versus Pseudorelapse

Relapse Definition On Relapse and Infection • A clinical episode with patient- • Relationship between MS reported symptoms and exacerbation and infection has objective findings reflecting a been known for long time focal or multifocal inflammatory demyelinating • 1985, Sibley et al, Berkovich R. Translational Neuroimmunology event in the CNS, developing demonstrated an increase in in MS, 2016 acutely or subacutely, with a MS relapse by 2.8 in the at-risk duration of at least 24 h, with versus control group. or without recovery, and in the • However the relationship of absence of fever or infection infection and MS relapse should be looked at it as a Thompson A et al., Lancet Neurology, 2018 continuum

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Relapse Management Symptom Management

High Dose Steroids Comments Bladder issues Refer men> 40 y.o • 1 g IVSM daily x 3-5 days Bowel issues Diarrhea is not common • Or Prednisone 1250 mg (50 md x 25 tabs) EOD Sexual dysfunction Commonly associated with bowel and bladder dysfunction • In am and on full stomach Fatigue Check for secondary causes: Thyroid, anemia, OSA, RLS, pain, maladaptive sleep behavior

Temperature sensitivity • Heat Worsens fatigue, nerve pain • Cold Worsens spasticity

Spasticity PT/stretching; Oral meds; Mg; ITBP; botox Neuropathic pain Avoid narcotics; refer for pain management Depression Avoid paroxetine SSRI might occasionally worsen spasticity Cognitive impairment Avoid memantine No evidence for donepezil effectiveness

Plasma Exchange (PLEX) Report of the Therapeutics and Technology Assessment Symptom Management: Subcommittee of the AAN Tips and Tricks (Cortese I et al., Neurology, 2011) • Avoid polypharmacy whenever possible and do frequent • Plasmapheresis as adjunctive therapy is probably med checks; prioritize symptom management effective for management of exacerbations in • Beware of interactions relapsing forms of MS, based on a single Class I • Use combination judiciously study. – Fatigue and depression: fluoxetine, bupropion in am – Pain, HA, depression, and bladder frequency: amitriptyline and • Based on a single Class II study, plasmapheresis is nortriptyline possibly effective for acute fulminant CNS • For some , use weekend drug holiday: demyelinating diseases (including MS, ADEM, NMO, stimulants and TM) that fail to respond to high-dose • Treat comorbidities: thyroid disease, sleep apnea, RLS, DM corticosteroid treatment.

Symptom Management in MS Comorbidities and MS

• Comorbidities have been associated with – Delay in MS diagnosis – Delay in DMT initiation – Increased hospitalizations • Meta-analysis reported the following in the MS population: – 18.6% HTN – 10% HLP – 10% chronic lung diseases – Higher prevalence of IHD, seizures

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Comorbidities and MS progression Comorbidities and Relapse Risk in MS (Zhang T et al., Neurology, 2018) Kowalee K. et al., Neurology, 2018 • Using health administrative and clinical databases in 2 Canadian provinces, the presence of physical comorbidities was associated with disability

• With each additional comorbidity, there was an increase in disability score by 0.18

• IHD and seizures were associated with the highest disability score, 0.31 and 0.68 respectively similar to other neurological diseases such as AD

• Vascular comorbidities at diagnosis had an increased risk of ambulatory disability, and risk increased with the number of vascular conditions reported (hazard ratio [HR]/condition for early gait disability 1.51; 95% confidence interval [CI] 1.41– 1.61)

• Natural history data from Rochester MN, showed a yearly increase in disability by 0.09 – 1 disability confers an increase of disability equal to 2 years of progression

MS, Vascular Comorbidities and Epilepsy: Why?

• Vascular comorbidities and Disability – HTN, HLD, BM are associated with cognitive decline and brain atrophy independent of overt clinical CVA – Increased peripheral inflammation associated with these Injectable comorbidities results in brain atrophy – Diabetes may increase susceptibility to oxidative stress; alter Disease Modifying Therapies blood vessel structure and function; and increase inflammatory responses in the brain.

• Epilepsy increases inflammatory cortical lesions, due to BBB breach, as observed on MRI brain; frequent seizures are associated with cortical atrophy and neurodegeneration.

Comorbidities and Relapse Risk in MS Interferon Beta Glatiramer Acetate (Avonex®, Betaseron®, Extavia®, Rebif®, (Copaxone®; 2 generics: Glatopa® and Kowalee K. et al., Neurology, 2018 Plegridy®) Glatiramer Acetate)

SC injections except Avonex® SC • 885 patients with different comorbidities were prospectively followed for 2 years for relapses from 4 Canadian sites. Injection site reactions Injection site reactions Lipoatrophy Lipoatrophy • Relapse rate (RR) in year prior to study & RR for next 2 years was determined.

• Comorbidities included HTN, HLP, DM, heart diseases, anxiety & depression. Flu-like symptoms None

• 178 relapses counted: Unmask thyroid disease None – 67% had one relapse – 27% had 2 relapses Monitor CBC, LFT, TSH None – 6% had 3 or more relapse Fulminant Hepatic Failure None • Those who relapsed where younger, had a relapse in the year before and had lower EDSS RARE Neutralizing Non-neutralizing antibodies • Patients with ≥ 3 comorbidities experienced higher RR (adjusted RR 1.45) Worsening depression None reported literature • Migraine and hyperlipidemia were associated with higher RR (adjusted RR 1.38) Post-injection reaction SOB, tachycardia, chest pain

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Natalizumab Alemtuzumab Ocrelizumab Tysabri® Lemtrada® Ocrevus®

FDA Approval 2004-2005 2014 2017 MOA inhibitor Mini bone marrow transplant B cell inhibitor Frequency of administration Every 4 weeks 5 days on year 1 Day 1& 15 3 days on year 2 Then 6 months Administration side effects Infusion and allergic reactions Infusion and allergic reactions Infusion and allergic reactions Mild Severe Mild Side Effects Mitigation Benadryl Benadryl Benadryl Tylenol Tylenol Tylenol Corticosteroids High-dose Corticosteroids Corticosteroids Risks Infections Infections Infections Oral PML No PML PML possible Malignancy: does not seem to be an Malignancy: Thyroid, Skin Malignancy issue Lymphoma/Leukemia Disease Modifying Therapies 2ndary Autoimmune Diseases ITP Kidney Disease Thyroid disease

Risk Mitigation Screening and infectious workup Screening and infectious workup Screening and infectious workup TOUCH Lemtrada REMS Program Questionnaire Monthly CBC, Cr, UA, CD4 count CBC, CD19 count CBC, LFT, JCV tests every 3 months Quarterly TSH Yearly dermatology, OB-GYN Other Data Rebound inflammation possible Acute coronary syndrome No rebound inflammation after stopping Acalculous cholecystitis Hemophagocytic lymphohistiocytosis No rebound inflammation

Fingolimod Dimethylfumarate Gilenya® Aubagio ® Tecfidera ® Progressive Multifocal Leukoencephalopathy Background Transplant FDA Approval 2010 2012 2013 (PML) Frequency QD QD BID MOA Traps lymphocytes Slows down lymphocytic Apoptosis T cells • Caused by John Cunningham Virus (JCV) that within the lymph nodes proliferation infects oligodendrocytes Side Effects Headaches Diarrhea Skin: Flushing, rash (Tolerance) Hair thinning GI+++ • PML reported in Safety Bradyarrhythmias Infections (PML) Infections (PML) (Risks) Macular edema TB reactivation – Pre-HIV era: Leukemia, lymphoma, solid organ Infections (PML) Hepatotoxicity Malignancy Pregnancy category X transplant PRES Mitigation Strategies First dose observation TB test CBC – HIV: Eye exam 0 & 3 months LFT monthly x 6 then Q 6 Varicella serology months – Non-biologic and biologic drugs such as: Others Possible rebound Accelerated clearance Long term mycophenolate mofetil (Cellcept®), , inflammation (cholestyramine, Medication Interaction charcoal) efalizumab & Natalizumab (Beta Blockers, CCB, SSRI)

JCV Distribution • JCV is present in 10% of 5 year old and 80% of elderly. • In the MS population it is present in about 55% cases • Portal of entry is unknown but may be Infusible – Oral as virus is present in the tonsils and GI epithelial cells Disease Modifying Therapies – Respiratory • The virus is typically transmitted from parent to child Mitoxantrone • The virus is typically present and quiescent in the Natalizumab tonsillar stroma, BM, B cells and the renal tubular Alemtuzumab epithelial cells and is excreted in the urine in particular > Ocrelizumab Non-FDA approved: Cyclophosphamide and Rituximab 40 y.o • There are about 1000 viral particles/ml in sewage water but none was reported in public swimming pools.

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Natalizumab Risk Stratification Clinical Pictures of PML Ho PR. Et al., Lancet Neurology, 2017

• There is an overlap in clinical presentation between the 2 conditions: walking instability, weakness, memory problems, confusion, dysarthria, visual hallucinations, cognitive impairment, speech disturbances, concentration deficits, and visual impairment. * • Cortical signs such as aphasia and apraxia in MS should prompt for an alternative explanation

* Index refers to level

PML diagnosis Immunosuppression and Infection

• Listeria • HSV1 & 2 • VZV • Cryptococcal • Histoplasmosis

Definitive Test: Ultrasensitive JCV DNA in the CSF

PML and MS Disease Modifying Therapies Preliminary Workup Prior to DMT Frequency Comments in MS Immunosuppressants Natalizumab Variable JCV status • CBC with diff (NTZ) 1/100- 1/10,000 Duration of therapy Prior immunosuppressant use • CD4, CD8, CD19, count Fingolimod 15 cases/ 0.7 per 10,000 patients • Ig M, A, G levels 217,000 1 case after NTZ discontinuation • EKG (prior to fingolimod; ? Alemtuzumab) 1 case following a switch to NTZ • Ophthalmological evaluation (prior to fingolimod) Teriflunomide 1 case 8 months > NTZ discontinuation • TB quantiferon (Teriflunomide) Dimethylfumarate 5 cases in MS/ 14 additional cases with fumarate esters • HIV 224,542 13/19 cases had grade 3 lymphopenia • HCV total antibodies 1 reported after NTZ discontinuation • HBs Ag and Ab; HB core antibody (Rituximab) Alemtuzumab Not yet reported Reported in the cancer literature in MS • CXR (PA/lat) Ocrelizumab 3 ALL reported after NTZ and fingolimod • Other consults depending on the need discontinuation • Vaccination (Influenza, if season); pneumovax; Shingrix Rituximab None yet 1/25,000 in other diseases • CSF reported

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Recommended Vaccination

• Similar to all adults unless on medications that preclude vaccination MS, Vaccination and DMTs • https://www.cdc.gov/vaccines/schedules/dow nloads/adult/adult-pocket-size.pdf (2018)

Do Vaccinations Cause MS? Should Any Specific Vaccination Be No Link • No association between Avoided? – Hep B vaccination – HPV vaccination • Inactivated vaccines , whether the vaccine is a killed – Any vaccination and the risk of MS and other CNS disease in the next three whole-organism or a recombinant, subunit, split-virus, years toxoid, polysaccharide, or polysaccharide protein- conjugate vaccine, are generally considered safe for • A systematic review found no increased risk of MS after vaccination: BCG, Hepatitis B, Influenza, Measles-Mumps-Rubella. people with MS including those taking a disease modifying therapy • Risk of MS appeared reduced after tetanus or diphtheria vaccination. • Live attenuated vaccines are generally not recommended because their ability to cause disease is • A single retrospective case control study in 47 MS patients receiving VZV vaccination showed improvement in 29.8%, deterioration in 8.5%, weakened but not totally inactivated. This is a and no change in 61.7%. Four patients developed a mild vaccine- theoretical risk; there is no high quality evidence associated chickenpox. The significance of this study is unclear at the showing an increased risk in the MS population of live present time. attenuated vaccines at this time.

Recommendations for use of standard vaccines in the general population and in MS Do Vaccinations Cause or Precipitate MS Relapse? Disease or pathogen USA Use in patients with MS* No Link Diphtheria All individuals Inactivated vaccine; vaccine possibly associated with decreased risk of MS Influenza All individuals Inactivated vaccine; no restrictions; recommended in patients with risk of influenza

• A practice advisory from the AAN (Rutschmann et al Human papilloma Females 11–12 years old Inactivated vaccine; inadequately investigated in MS virus 2002) found strong evidence against an increased risk of Measles, mumps Individuals <50 years old with lack of Live attenuated vaccine; MS relapse risk not and rubella immunity, and at-risk individuals >50 increased by vaccination; not recommended in MS exacerbation after influenza immunization years old immunosuppressed patients • Meningococcal At-risk individuals Inactivated vaccine; inadequately investigated in MS; Injectable flu vaccine is recommended by NMSS and CDC meningitis consider vaccination before immunomodulatory – https://www.nationalmssociety.org/Living-Well-With-MS/Diet- therapy Pertussis All adults: one dose combined with Inactivated vaccine; insufficient data in MS; Exercise-Healthy-Behaviors/Vaccinations tetanus and diphtheria combination vaccines only Pneumococcus At-risk individuals and those >65 years Inactivated vaccine; insufficient data in MS; consider – https://www.cdc.gov/flu/protect/keyfacts.htm old vaccination before immunomodulatory therapy • Limited data related to other vaccinations increasing Tetanus Allindividuals Inactivated vaccine; no restrictions;vaccine possibly associated with decreased risk of MS relapse rate Varicella Individuals lacking evidence of Live attenuated vaccine; risk of MS relapse not immunity increased by vaccination; possible positive effect on MS; not recommended in immunosuppressive therapy Zoster reactivation Individuals >60 years old Live attenuated vaccine; not studied in MS

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Recommendations for use of supplementary vaccines in the general population and in MS Vaccine Recommended in Vaccine type Use in patients with MS* On Cancer Risk and MS Cholera Country-specific entry regulations may apply Inactivated vaccine Insufficiently investigated in MS Tick-borne Endemic areas and tick exposure Inactivated vaccine No influence of vaccine on disease Sun LM et a., European J of Neurol., 2014) encephalitis activity Yellow fever Endemic areas; country-specific entry Live attenuated May cause worsening of MS regulations may apply vaccine Haemophilus Underlying medical condition or at-risk individuals Inactivated vaccine Insufficiently investigated in MS • A study from Taiwan (N= 1292 MS patients each influenzae with asplenia; may only be available in combination with tetanus/diphtheria matched to 4 healthy controls) demonstrated an

Hepatitis A At-risk individuals including those with chronic Inactivated vaccine Insufficiently investigated in MS overall increase in cancer risk (HR= 1.85) and hepatic disease or other underlying medical condition specifically breast cancer (HR= 2.23) Hepatitis B Endemic areas; at-risk individuals including those Inactivated vaccine Extensive studies without evidence of with chronic hepatic disease or other underlying increased risk of MS induction or relapse • This is clearly a different trend from the western medical condition Japanese B Endemic areas Inactivated vaccine Insufficiently investigated in MS world, however: encephalitis Rabies Endemic areas and for post-exposure Inactivated vaccine No studies in MS – Contrary to the US, the incidence of cancer has been prophylaxis in combination with hyperimmunoglobulin raising in Taiwan and Ca is the leading cause of death. Poliomyelitis Booster before travel to endemic areas Inactivated vaccine Insufficient data in MS for risk evaluation – A number of autoimmune diseases are associated with Ca: Tuberculosis Children at risk Live vaccine Protective effect questionable; not recommended; meta-analysis showed no MG, LEMS, UC, SLE, SS, SCL, dermatomyositis, etc. increased risk of MS induction or relapse Typhoid fever Endemic areas Inactivated vaccine Insufficiently investigated in MS; avoid live (intramuscular) or vaccine and use inactivated vaccine live vaccine (oral)

Immunosuppression and Vaccination https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.pdf Malignancy and MS: Why?

• Altered immunocompetence is an indication to vaccinate • Chronic Inflammation peripherally and outside of routinely recommended age groups centrally • Persons with altered immunocompetence generally are recommended to receive polysaccharide-based vaccines • Heightened autoimmunity against self is (PCV13, PPSV23, and Hib), on the basis of increased risk for associated with heightened autoimmunity in disease if the vaccine is withheld. general including tumor • Shingrix and Zostavax might be given in contemplation of immunosuppressant use • For certain specific categories of altered immunocompetence (asplenia, complement deficiency, ) patients are also recommended to receive polysaccharide based vaccines (MenACWY, Hib-MenCY, and MPSV4)

On Cancer Risk and MS (Bahmanyar S. et al., Neurology, 2009) Immunosuppression and Malignancy Nielsen NM, et al., Int J Cancer, 2006 Handel AE et al., JNNP, 2010 Kingwell E. et al., Brain, 2012) • Studies showed decreased risk for GI, respiratory, ovarian and • Sicilian study: 581 patients with MS who received IS prostate cancer • A study from Sweden (N= 20,276) showed vs 581 patients with MS who did not received IS – Overall decreased cancer risk by ≈ 10% (HR 0.91; 0.87-0.95); effect • more pronounced in women IS used were AZA (5 yrs), mitoxanthrone (MTX) and – Increased risk for brain tumors (HR 1.44; 1.21-1.72) and GU organs (HR cyclophosphamide ( each for 1 yr) 1.27; 1.05-1.53) – No increased or decreased cancer risk in parents • There was a strong association between IS use and • Kingwell et al. used a large Canadian MS cohort (N= 6820) to cancer risk; standardized incidence ratio (SIR) was 4, investigate a population-based study and found that the standardized incidence ratio (SIR) for overall cancer was 0.86 similar to both AZA and MTX. (95% CI 0.78–0.94.) • Cancer risk was related to the duration of exposure • A meta-analysis conducted by Handel and Ramagopalan also found a significantly lower risk of developing all cancer types in and cumulative dose the MS cohort relative to the control (P = 0.004).

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DMT Cancer Incidence Comments Mitoxantrone Acute Leukemia 0.07-0.81% Variability in function of geography, duration Real-world risk (APL) of FU, cumulative dose, other genotoxic drugs, genetic risk factors, infusion protocols Natalizumab Melanoma Several reported but no difference between NTZ treated and non-NTZ treated PCNSL 1 case T cell Lymphoma 1 case Fingolimod Melanoma < 1% Examine all patients for skin lesions before Skin T cell Lymphoma < 1/10,000 Re-examine skinQ 6-12 months or more if Squamous cell Ca < 1/1000 indicated after Questions? Kaposi’s sarcoma < 1/10,000 Merkell cell Unknown Teriflunomide None yet N/A None with leflunomide either [email protected] Dimethyl- None yet N/A N/A MS Clinic fumarate Alemtuzumab Thyroid; Basal cell; 2% No cervical cancer observed Phone: 402-559-7857 Phase 2 and 3 Breast; Melanoma Rate of cancer was not different than Fax: 402-559-3545 clinical trials with Burkitt’s Lymphoma interferon beta; therefore the importance of extension studies Castleman disease post-marketing surveillance Ocrelizumab Breast cancer risk still within epidemiological OPERA I & II Breast and others 0.7 vs 0.2% range OROTARIO 2.3 vs 0.8%

Vitamin D and MS Sintzel M. et al., Neurol Ther., 2018

• Evidence available to date suggests that low level of serum vitamin D is associated with – Increased risk of MS – Greater disease activity • However the impact of vitamin D supplementation on MS is not appropriately investigated • In aggregate, studies suggest that vitamin D supplementation may be beneficial for patients with MS and others • There is no consensus between IOM (20 ng/ml is sufficient) and Endocrine society (30 ng/ml at least) on the optimal range of vitamin D • However numerous studies showed a minimal level of 40 ng/ml is required to control clinical and MRI disease activity • Based on the plethora of indirect data, vitamin D correction is a sensible objective even from a public health perspective

Conclusions

• MS care is complex • MS care requires coordinated, continuous, comprehensive, collaborative care by the Family Practitioner and the Neurologist • Aggressive management of comorbidities likely impacts MS course and prognosis • Orals and infusions therapies of MS require hypervigilance for infections and malignancy. Time will tell about the real risk associated with newer DMTs • Vaccination is indicated for these patients who are going on long-term immunosuppression • Vitamin D optimization is an integral part of a comprehensive care for MS

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