Practical Controversies in MS...© 2016 Virginia Mason Medical Center Practical Controversies How to approach common questions in the gray-zone of evidence-based practice?

Practical Controversies in MS

Lucas McCarthy, MD, MSc

Neurologist, Director MS Center

© 2016 Virginia Mason Medical Center

Practical Controversies

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


The Evidence Free Zone


Practical Controversies in MS

• Misdiagnosis of MS

• Vitamin D testing / supplementation

• Use of complimentary / experimental treatments

• Treatment of Progressive MS


Poll Everywhere – Audience Participation

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

https://pollev.com/MSsummit

Misdiagnosis of Multiple Sclerosis


Misdiagnosis of MS

Updated 2017 McDonald MS Diagnostic Criteria

Easier to diagnosis = Easier to misdiagnose?


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


MS Diagnosis – Evolving Diagnostic Criteria

MS Diagnostic Criteria Comments

1965 - Schumacher Criteria 2 attacks of neurologic symptoms > 24 hours in duration,

separated by at least one month. No MRI yet

1983 - Poser Criteria Added cerebrospinal fluid (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 optic neuritis)

Even earlier diagnosis possible


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

ECTRIMS 2018. Abstracts 139-142, presented October 11, 2018.


Exclude Others: Diseases that Mimic MSMultiple Sclerosis Differential Diagnosis

Autoimmune Infectious Genetic Other

Neurologic:

- Multiple Sclerosis

- Neuromyelitis Optica

- Autoimmune Encephalitis

- ADEM

- Susac’s Syndrome

- Hashimoto’s Encephalitis

- CLIPPERS

- CRION

Systemic:

- SLE (Lupus)

- APS

- Sjogren’s

- Sarcoidosis

- Behcet disease

- Celiac disease

- Paraneoplastic

HIV

Lyme

Syphilis

PML

Tuberculosis

Neuro-cysticercosis

Coccidiomycosis

Cryptococcus

Brucellosis

SSPE

HHV6

Whipple’s Disease

CADASIL

MELAS

Neurofibromatosis

Porphyria

Friedrich’s Ataxia

SCA

Adult Onset Leukodystrophy:

- Adreno-Leukodystrophy

- Metachromatic

- Alexander’s Disease

- Krabbe’s Disease

Neoplasm (Glioma, Lymphoma)

Vitamin B12 or Copper deficiency

Thiamine (B1) Deficiency

Vascular Malformations

Medication Effects (TNF-alpha)

Migraine Headache

ALS / Motor Neuron Disease

Compressive Myelopathy

Vascular:

- Stroke

- Amyloid Angiopathy

- Granulomatous Vasculitis

- Primary CNS Angiitis

- Moya-Moya Disease

Infiltrative:

- Langerhan’s Cell Histiocytosis

- Lymphomatoid Granulomatosis

- Erdheim-Chester Disease

- HLH


Haselink. Top Mag Reson Imaging. 2006


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…”


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 Cerebrovascular Disease

• 0.5 % Vasculitis

• 0.4 % Multi-System Atrophy

1.3% - Other Demyelinating Disease

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 NeuropathyKaisey et al. ECTRIMS 2018 MS Conference


Experimental Diagnostic Testing

Iquity RNA testing

Machine Learning Discrimination

Analysis of serum RNA



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.

Journal of Clinical Bioinformatics 2013



Iquity RNA testing

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; Dementia; Osteoperosis; Depression; Schizophrenia; Rheumatoid Arthritis


Vitamin D

Ascherio A, Munger KL, Simon KC. “Vitamin D and Multiple Sclerosis”. Lancet Neurol. 2010


Vitamin D

Ascherio A, Munger KL, Simon KC. “Vitamin D and Multiple Sclerosis”. Lancet Neurol. 2010

(25 – 60 ng/mL)


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)


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


Institute of Medicine (IOM) Recommendations

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


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


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.


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 alreadyAge 18 - 55

Vitamin D levels < 150nmol/ml (60ng/ml)

Randomized to 14,000IU D3 (VigantOL Oil) vs. placebo

48 Weeks duration*reported but unpublished

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

Results Reported : https://clinicaltrials.gov/ct2/show/results/NCT01285401

Presented: Ectrims 2016

Endpoint

Vitamin D3

14,000

(n = 113)

Placebo

(n = 116)Difference P Value

*Disease

Activity Free (%)37.2 35.3 1.9% 0.912

Relapse Free (%) 78.8 75.0 3.8%

Annualized

Relapse Rate0.28 0.41 31.7% 0.165

New/Active MRI

Lesions (mean)1.09 1.49 32% 0.0005

https://clinicaltrials.gov/ct2/show/results/NCT01285401


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

- New T1 lesions – RR 0.22, p = 0.001*reported but unpublished

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

data


Evidence


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

https://www.ncbi.nlm.nih.gov/pubmed/30246874


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


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.”




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

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),

800 IU/day for seniors

1500–2000 IU/day (10,000 IU/day)


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 + Glatiramer Acetate

Primary outcome: Relapses

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


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 beneficial, 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


Repairing / Preventing MS Damage?

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

• Biotin

• Clemastine

• Simvastatin

• Alpha Lipoic Acid

• Phenytoin

• Minocycline


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

MS Journal 9/2016


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

MS Journal 9/2016

MD1003 (Biotin) Reduced MS Progression


MD1003 (Biotin) Reduced MS Progression

Tourbah et al. MS Journal 2016

Other Progressive MS Trials

Placebo group

MD1003 (Biotin) Group

Switched to MD1003 (Biotin)

Worse

Disability


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)


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


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 monthsGreen et al. Lancet, 10/2017


Simvastatin for MS


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


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 Fingolimod 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


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

Spain et al. Neurol Neuroimmunol Neuroinflamm 2017


Alpha Lipoic Acid for MS

68% reduction in annualized percent change in brain volume (slowed decline)

Spain et al. Neurol Neuroimmunol Neuroinflamm 2017

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%


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

Thank you

Documents

Practical Controversies in MS...© 2016 Virginia Mason Medical Center Practical Controversies How to approach common questions in the gray-zone of evidence-based practice?