Practical Controversies in MS

Lucas McCarthy, MD, MSc Neurologist, Director MS Center Practical Controversies

How to approach common questions in the gray-zone of evidence- based practice?

© 2016 Virginia Mason Medical Center The Evidence Free Zone

© 2016 Virginia Mason Medical Center Practical Controversies in MS

• Misdiagnosis of MS

• Vitamin D testing / supplementation

• Use of complimentary / experimental treatments

• Treatment of Progressive MS

© 2016 Virginia Mason Medical Center Poll Everywhere – Audience Participation

Open cell phone or laptop to following link to participate in live questions

https://pollev.com/MSsummit

© 2016 Virginia Mason Medical Center Misdiagnosis of Misdiagnosis of MS

Updated 2017 McDonald MS Diagnostic Criteria

Easier to diagnosis = Easier to misdiagnose?

© 2016 Virginia Mason Medical Center MS Diagnosis – 2017 Updated Criteria

Lesions: ≥ 2 characteristic lesions (>3mm) in ≥ 2 different locations

Symptoms: objective clinical evidence of at least 1 lesion

Relapse: ≥ 1 characteristic clinical attack

Changes over Time: ≥2 CSF Oligoclonal bands or >1 attack over time or new lesions over time (including enhancing and non-enhancing)

*No other reasonable diagnosis

© 2016 Virginia Mason Medical Center MS Diagnosis – Evolving Diagnostic Criteria

MS Diagnostic Criteria Comments

1965 - 2 attacks of neurologic symptoms > 24 hours in duration, separated by at least one month. No MRI yet 1983 - Added (CSF) markers and Evoked Potentials to diagnostic criteria. No MRI yet 2001 - McDonald Criteria Added MRI (commonly use since early 1990’s) Classifications: "MS", "possible MS", or "not MS“ 2005 –McDonald Criteria updated Added more MRI considerations; attention to enhancing lesions and primary progressive MS (PPMS) 2010 – McDonald Criteria updated Added - Asymptomatic contrast enhancing lesion and non- enhancing lesion = DIT Earlier diagnosis possible 2017 - McDonald Criteria updated Added - +CSF and non-enhancing lesions = DIT; Enhancing lesions do not have to be asymptomatic (except ) Even earlier diagnosis possible © 2016 Virginia Mason Medical Center MS Diagnosis – 2017 Updated Criteria

Using 2017 Criteria compared with 2010 MS Criteria:

23-27% more patients diagnosed with MS at first attack

Previously needed to wait until MRI change or second attack Can make MS diagnosis easier now with 1st Attack and 1st MRI Earlier Diagnosis, Earlier Treatment, Lower Future Disability

© 2016 Virginia Mason Medical Center ECTRIMS 2018. Abstracts 139-142, presented October 11, 2018. Multiple Sclerosis Differential Diagnosis ExcludeAutoimmune Others:Infectious DiseasesGenetic that Mimic OtherMS Neurologic: HIV CADASIL Neoplasm (Glioma, Lymphoma) - Multiple Sclerosis Lyme MELAS Vitamin B12 or Copper deficiency - Neuromyelitis Optica Syphilis Neurofibromatosis Thiamine (B1) Deficiency - Autoimmune PML Porphyria Vascular Malformations - ADEM Tuberculosis Friedrich’s Medication Effects (TNF-alpha) - Susac’s Syndrome Neuro-cysticercosis SCA - Hashimoto’s Encephalitis Coccidiomycosis ALS / - CLIPPERS Cryptococcus Adult Onset Leukodystrophy: Compressive Myelopathy - CRION Brucellosis - Adreno-Leukodystrophy SSPE - Metachromatic Vascular: Systemic: HHV6 - Alexander’s Disease - - SLE () Whipple’s Disease - Krabbe’s Disease - Amyloid Angiopathy - APS - Granulomatous Vasculitis - Sjogren’s - Primary CNS Angiitis - Sarcoidosis - Moya-Moya Disease - Behcet disease - Celiac disease Infiltrative: - Paraneoplastic - Langerhan’s Cell Histiocytosis - Lymphomatoid Granulomatosis - Erdheim-Chester Disease - HLH

© 2016 Virginia Mason Medical Center © 2016 Virginia Mason Medical Center Haselink. Top Mag Reson Imaging. 2006 © 2016 Virginia Mason Medical Center Haselink. Top Mag Reson Imaging. 2006 MS Mis-diagnosis

Caution on Overdiagnosis for the sake of naming

“My radiologist said it could be MS”

“My symptoms fit perfectly with MS”

”I just want an answer…”

© 2016 Virginia Mason Medical Center Alternative Diagnosis in an MS Specialty Clinic

754 consecutive patients referred to an MS Center in the Netherlands:

67 % - MS or Probable MS (52% Definite, 15% Probable MS) 23 % - No Certain Diagnosis 7.7 % - Other Neurologic Disease • 2.2 % Ischemic • 0.5 % Vasculitis • 0.4 % Multi-System Atrophy 1.3% - Other

© 2016 Virginia Mason Medical Center Nielsen et al. Ann Neurol 2005 MS Misdiagnosis

18% Misdiagnosed with MS on second opinion

Previously diagnosed MS patients did not fit criteria for MS when seen for second opinion at an MS specialty center (UCLA / Cedars- Sinai) Other Diagnosis: 1. Migraine headache (most common) 2. Radiologically Isolated Syndrome (RIS) 3. Cervical spinal stenosis 4. Peripheral Neuropathy 5. Optic Neuropathy © 2016 Virginia Mason Medical Center Kaisey et al. ECTRIMS 2018 MS Conference Experimental Diagnostic Testing

Iquity RNA testing

Machine Learning Discrimination Analysis of serum RNA

© 2016 Virginia Mason Medical Center Experimental Diagnostic Testing

Iquity RNA testing

RNA expression levels of 30 genes in blood 199 subjects with MS, 203 subjects with other neurologic disorders, 114 healthy control subjects Used to train machine learning algorithms.

© 2016 Virginia Mason Medical Center Journal of Clinical Bioinformatics 2013 Experimental Diagnostic Testing

Iquity RNA testing

© 2016 Virginia Mason Medical Center Vitamin D and Multiple Sclerosis Vitamin D and MS

Cohort Evidence Low Vitamin D serum levels associates with increased prevalence of MS, MRI lesions and relapses in RRMS

“Correlation does not equal Causation”

Just because something is associated, does not make it causal.

Low Vitamin D levels also correlate with risk for: • Colon cancer, Breast cancer, Prostate cancer, Type 1+2 Diabetes; Cardiovascular Disease; ; Osteoperosis; Depression; Schizophrenia;

© 2016 Virginia Mason Medical Center Vitamin D

© 2016 Virginia Mason Medical Center Ascherio A, Munger KL, Simon KC. “Vitamin D and Multiple Sclerosis”. Lancet Neurol. 2010 Vitamin D

(25 – 60 ng/mL)

© 2016 Virginia Mason Medical Center Ascherio A, Munger KL, Simon KC. “Vitamin D and Multiple Sclerosis”. Lancet Neurol. 2010 Low Vit D associated with New MRI Lesions

Each 10 ng/mL higher vitamin D level was associated ~32% reduced risk of a subsequent contrast-enhancing lesion (IRR=0.68, 95% CI [0.54, 0.86], p=0.001)

© 2016 Virginia Mason Medical Center Vitamin D and MS

Vitamin D has anti-inflammatory actions in vitro1 - enhanced Th2 and decreased Th1 cytokine production - dendritic cell effects - enhanced macrophage phagocytosis

In experimental autoimmune encephalitis (EAE)2 • pre-induction treatment prevents disease development • Post-induction treatment ameliorates disease activity

Genetic association of SNPs with Vitamin D and MS

1Smolders et al. Neuroimmunol 2008 2Vieth R. Am J Clin Nutr 1999

© 2016 Virginia Mason Medical Center Institute of Medicine (IOM) Recommendations

"a considerable overestimation of the levels of vitamin D deficiency" exists in North America

© 2016 Virginia Mason Medical Center High Dose Vitamin D Supplements in MS

Prior lower dose trials did not show significant benefits

Larger trials have been and are being done

Lets look at some – trend toward benefit, low risk for harm

© 2016 Virginia Mason Medical Center High Dose Vitamin D Supplements

Seemingly safe at high doses (~10,000IU D3 daily) in RCTs

Burten, JM et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010. 25 treated patients (49 total) spent 36+ weeks on doses of 10,000 IU/day D3 or greater. No significant side effects.

Sotirchos et al. Safety and immunologic effects of high vs low dose cholecalciferol in multiple sclerosis. Neurology 2016 20 treated patients (40 total) - 10,400IU vs. 800IU D3 in with RRMS x 6 months. No significant safety concerns. 1 Relapse in each group. Reductions in IL17 seen in treated group.

© 2016 Virginia Mason Medical Center High Dose Vitamin D Supplements

Largest high dose Vitamin D trial to date: SOLAR trial: Smolders et al. “Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon β-1a”. ECTRIMS 2016

229 MS patients Taking Interferon β-1a sc already Age 18 - 55 Vitamin D levels < 150nmol/ml (60ng/ml) Randomized to 14,000IU D3 (VigantOL Oil) vs. placebo 48 Weeks duration *reported but unpublished

© 2016 Virginia Mason Medical Center data SOLAR Trial Results

Poor recruitment – reduced study duration from 96 to 48 week *Primary Endpoint: % Disease Activity Free (NEDA) No relapses, no EDSS progression, no new or enhancing lesions

Vitamin D3 Placebo Endpoint 14,000 Difference P Value (n = 116) (n = 113) *Disease 37.2 35.3 1.9% 0.912 Activity Free (%) Relapse Free (%) 78.8 75.0 3.8% Annualized 0.28 0.41 31.7% 0.165 Relapse Rate New/Active MRI 1.09 1.49 32% 0.0005 Lesions (mean) Results Reported : https://clinicaltrials.gov/ct2/show/results/NCT01285401

© 2016 Virginia Mason Medical Center Presented: Ectrims 2016 Vitamin D Supplementation Trials

Camu et al. Cholecalciferol supplementation in relapsing multiple sclerosis patients treated with subcutaneous interferon beta-1a: a randomized, controlled trial. ECTRIMS 2016. Abstract P750

129 pts, randomized placebo controlled trial; 2 year duration 100,000IU D3 q2 weeks (7,143IU / day) + IFNB-1a

Results: No benefit for MS relapse (ARR 0.34 vs. 0.45, p = 0.38)

Subgroup analysis: per protocol, completers (90 out of 129): - ARR reduction – RR 0.40, p = 0.011 - New T2 lesions – RR 0.23, p < 0.001 *reported but unpublished - New T1 lesions – RR 0.22, p = 0.001 © 2016 Virginia Mason Medical Center data Vitamin D Supplementation Trials

Koduah et al. Vitamin D supplementation in multiple sclerosis: primary efficacy endpoint and safety of a randomized, controlled, double-blind phase II trial (EVIDIMS). ECTRIMS 2018.

EVIDIMS trial - German multicenter RCT

Patients: 53 pts with CIS or MS on IFNB-1b

Intervention: equivalent to 10,200 IU vs. 200 IU D3 Daily x 18mo

Primary Outcome: New T2 lesions – no significant difference

*reported but unpublished

© 2016 Virginia Mason Medical Center data Evidence

© 2016 Virginia Mason Medical Center Systematic Review – Vit D and MS

Jagannath VA et al. Vitamin D for the management of multiple sclerosis. Cochrane Database Syst Rev. 2018 Sep 24

12 RCTs including 933 subjects in years 2010 – 2017

464 in vitamin D group, 469 in comparison groups

© 2016 Virginia Mason Medical Center Systematic Review – Vit D and MS

No Significant Differences:

Annualized Relapse Rate (ARR) - difference = -0.05 (-0.17 to 0.07) from five trials; 417 participants

EDSS – mean difference = -0.25, (-0.61 to 0.10) from five trials; 221 participants

MRI Gad enhancing lesions – difference = 0.02, (-0.45 to 0.48) two trials; 256 participants

© 2016 Virginia Mason Medical Center Systematic Reviews – Vit D and MS

Jagannath VA et al. Cochrane Database Syst Rev. 2018 Sep 24 “evidence suggests no benefit of vitamin D for patient‐important outcomes among people with MS”

McLaughlin et al. J Neurol. 2018 “No statistically significant difference was seen for any of the outcome measures. There were non-significant trends in favour of vitamin D for all outcome measures”

Zheng et al. Mult Scler Relat Disord. 2018 Jul “Our findings suggest that vitamin D appeared to have no therapeutic effect on EDSS score or ARR in the patients with MS.”

© 2016 Virginia Mason Medical Center Vitamin D Supplementation – Risks

Meta-analysis Serious Adverse Events – difference = 1%, (-3% to 4%) Minor Adverse Effects – difference = 2%, (-2% to 6%)

Cost of Testing: Vit D-25(OH)- $96 (range $33 – $231)1

IOM Report 2011: • >4000IU D3 daily supplement not recommended • levels >50–60 ng/mL should be avoided • “are associated with increases in all-cause mortality, greater risk of cancer at some sites like the pancreas, greater risk of cardiovascular events, and more falls and fractures among the elderly”

1Healthcarebluebook.com; Accessed 3/2019; 2NIH Office of Dietary Supplements © 2016 Virginia Mason Medical Center https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ Vitamin D Status Institute of medicine Endocrine society Vitamin D status “Deficient” – ≤ 20 ng/mL (≤ 50 nmol/L) “Insufficient” – 21–29 ng/mL (51–74 nmol/L) “Sufficient” 20 ng/mL (50 nmol/L) ≥ 30 ng/mL (≥ 75 nmol/L) “Ideal” – 40–60 ng/mL (100–150 nmol/L) Considered “safe” – ≤ 100 ng/mL (≤ 250 nmol/L) Daily vitamin D intake recommendations (upper limit recommendation) Infants 400 IU/day 400–1000 IU/day Children 600 IU/day (2500–3000 IU/day) 600–1000 IU/day (4000 IU/day) Adults 600 IU/day (4000 IU/day), 1500–2000 IU/day (10,000 IU/day) 800 IU/day for seniors

© 2016 Virginia Mason Medical Center Ongoing Clinical Trials

VIDAMS trial: Vitamin D to Ameliorate MS Ellen Mowry, MD at Johns Hopkins; Recruiting 2012 – 2019

Patients: 172 pts with RRMS; age 18 – 50, EDSS ≤ 4

Intervention: 600 IU vs. 5,000 IU D3 +

Primary outcome: Relapses

Secondary outcomes: MRI lesions, EDSS, brain volume, OCT, LCVA

© 2016 Virginia Mason Medical Center Options for MS Providers

Do not recommend supplements until more evidence - pros: saves costs and unnecessary supplementation - cons: risk ‘missing out’ on treatment if beneficial

’Blindly’ recommend supplements to all e.g. 2,000IU D3 daily (200% RDA for adults) - pros: saves costs of testing, possible benefits for multiple diseases - cons: unnecessary for those not deficient?, cost of supplements

Test Vitamin D levels and Supplement if lower than ’goal’ - pros: avoids unnecessary supplementation - cons: costs of labs (not covered) and supplements, unclear if

© 2016beneficial, Virginia Mason Medical Center no goal levels established Off Label Use of Experimental Complimentary MS Disease Modifying Therapy Repairing / Preventing MS Damage?

Current MS Drugs prevent but do not likely help with repair

Many off-label medications and supplements have been studied

Some may recommend these therapies to their patients

© 2016 Virginia Mason Medical Center Repairing / Preventing MS Damage?

Off label medications or Supplements Under Investigation for MS Repair / Slowing Degeneration:

• Biotin • Clemastine • Simvastatin • Alpha Lipoic Acid • Phenytoin • Minocycline

© 2016 Virginia Mason Medical Center Updates – Biotin for progressive MS?

High dose Biotin (MD1003) for improvements in Progressive MS

First trial in France in 154 patients, progressive MS, 12 month trial 12.6% had improvements in disability at 1 year

© 2016 Virginia Mason Medical Center MS Journal 9/2016 MD1003 (Biotin) Reduced MS Progression

High dose Biotin (MD1003) for improvements in Progressive MS In extension trial for 1 more year, all groups given Biotin Initially given Placebo, patients given Biotin had improvements 11.9% disability improvement at 1 year extension

© 2016 Virginia Mason Medical Center MS Journal 9/2016 MD1003 (Biotin) Reduced MS Progression

Other Progressive MS Trials

Switched to MD1003 (Biotin) Worse Disability

Placebo group

MD1003 (Biotin) Group

© 2016 Virginia Mason Medical Center Tourbah et al. MS Journal 2016 Ongoing Phase III Trial - High Dose Biotin

100,000mcg Biotin (proprietary) TID vs. Placebo

Patients with primary or secondary progressive MS

Add on therapy to current stable Disease Modifying MS Medication

Typical dosing OTC – 5,000mcg Biotin Daily

Safety is good compared to placebo, can cause Blood Test Abnormalities (e.g. Thyroid studies, Troponin)

© 2016 Virginia Mason Medical Center Clemastine Fumarate for MS Repair?

A repurposed non-prescription sedating anti-histamine (similar to Benadryl in mechanism of action)

Clemastine studied for repair of Optic Nerve damage in MS

© 2016 Virginia Mason Medical Center Clemastine Fumarate for MS Repair?

A repurposed non-prescription anti-histamine for MS?

Clemastine studied for remyelination of Optic Neuritis in MS

Small Pilot Trial – 50 patients (25 on drug, 25 on placebo)

Small significant improvement in VEP electrical response (1.7ms speed improvement, average speed ~105ms)

Ongoing Larger trial - NCT02521311 ReCOVER Trial, 90 pts, Acute Optic Neuritis, Clemastine vs. Placebo 3 months of treatment, then monitoring for 9 months © 2016 Virginia Mason Medical Center Green et al. Lancet, 10/2017 Simvastatin for MS

© 2016 Virginia Mason Medical Center Simvastatin for MS

MS STAT 1 Trial

N=140 18-65 yrs old EDSS 4.0 – 6.5 no relapses or steroid use in 3 months No DMT use in last 6 months

© 2016 Virginia Mason Medical Center Simvastatin for MS

• Relative Brain Atrophy reduced by 43% vs. Placebo

• Absolute Brain Atrophy Rate reduced by 0.25%/year • 0.28% in Simvastatin vs. 0.58% in Placebo per year, p = 0.003

Perspective: FREEDOMS 2010 study Brain Volume Changes 12-24mo: 0.37% in Fingolimod 0.5mg vs. 0.67% in Placebo, p = 0.002

MS STAT2 Trial – ongoing (NCT03387670) 1180 patients, 40 vs. 80mg vs. Placebo x 35 months; no DMT use

© 2016 Virginia Mason Medical Center Alpha Lipoic Acid for MS

SPMS aged 40–70 years

Enrolled in a single center, (OHSU)

2-year, double-blind, randomized trial

1,200 mg LA daily vs placebo

© 2016 Virginia Mason Medical Center Spain et al. Neurol Neuroimmunol Neuroinflamm 2017 Alpha Lipoic Acid for MS

Annualized Brain Volume Loss

LA -0.21% Placebo -0.65%

COMPARISONS:

MS STAT Trial -0.28 % vs. -0.58%

FREEDOMS Trial -0.37% vs. -0.67% 68% reduction in annualized percent change in brain volume (slowed decline) © 2016 Virginia Mason Medical Center Spain et al. Neurol Neuroimmunol Neuroinflamm 2017 Use of Experimental Therapy

Ongoing placebo controlled clinical trials: • Biotin • Simvastatin • Alpha Lipoic Acid • Clemastine

Equipoise – uncertainty of differences, null hypothesis

Use of off-label therapies outside of clinical trials

© 2016 Virginia Mason Medical Center Thank you