Practical Controversies in MS - nationalmssociety.org · Siponimod is a selective S1P1 and S1P5...

Practical Controversies in MS

Lucas McCarthy, MD, MSc

Neurologist, MS Specialist

© 2016 Virginia Mason Medical Center

Practical Controversies

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


Practical Controversies

• Treatment of CIS or Benign MS

• Treatment of inactive primary progressive MS

• Treatment of secondary progressive MS

• DMT Discontinuation

• Use of Oral Steroids for MS relapses


Poll Everywhere – Audience Participation

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

https://pollev.com/MSsummit

Treatment of Clinically Isolated Syndrome


Treatment of CIS

Clinically Isolated Syndrome (CIS)

- Single inflammatory demyelinating clinical event

Limited as of 2017 McDonald MS Diagnostic Criteria

– DIT = enhancing (except optic nerve) and non-enhancing typical MS lesion (>3mm in size)

- DIT = +OCB in CSF

- DIS = 2 or more lesions in 2 or more territories (periventricular, juxtacortical / cortical, infratentorial, spinal cord)

DIT = Dissemination in Time DIS = Dissemination in Space


McDonald 2017 MRI Criteria

MS Lesion >3 mm in size

4 Locations

- Periventricular (has to touch ventricles) – NOT subcortical

- Juxtacortical / Cortical

- Infratentorial

- Spinal Cord

Subcortical Lesions+Periventricular Subcortical Lesions


CIS Examples

Optic Neuritis isolated, no brain lesions

Optic Neuritis, 1+ non-enhancing lesions

Transverse Myelitis, isolated, no brain lesions

Transverse Myelitis, 2+ subcortical (non-periventricular) lesions

Transverse Myelitis, 2+ cord lesions

Transverse Myelitis, 1+ simultaneously enhancing brain lesion

Brain demyelinating lesion, isolated, no other lesions

Brain demyelinating lesion, 1+ subcortical lesions

Brain demyelinating lesion, simultaneous enhancing lesions (e.g. ADEM)


Treatment of CIS

Prior CIS (now different based on updated criteria)

- 60-80% Risk of MS conversion if other brain lesions

- 20% Risk for MS conversion in 10 years if no brain lesions

Multiple Trials for treatment of CIS - Interferons (BENEFIT, ETOMS, CHAMPS), Glatiramer (PreCISe), Teriflunomide (TOPIC)

CIS DMT Treatment reduced MS conversion by ~30% in 2 years


Treatment of CIS

AAN DMT Guideline

Clinicians should prescribe DMT to people with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy (Level B)

Clinicians may recommend serial imaging at least annually for the first 5 years and close follow-up rather than initiating DMT in people with CIS or relapsing forms of MS who are not on DMT, have not had relapses in the preceding 2 years, and do not have active new MRI lesion activity on recent imaging (Level C).


Treatment of CIS

Does Isolated CIS require treatment without risk factors?

- Isolated Unilateral Optic Neuritis?

- Isolated Transverse Myelitis?

Risk Factors:

- CSF Oligoclonal bands (satisfies DIT but not DIS)

- Other brain / cord lesions that do not make diagnostic criteria

- Associated factors (age, peri-infectious onset, gender, family history)

- Presence of auto-antibodies (AQP-4, MOG)


Treatment of CIS

Risk factors for Optic Neuritis conversion to MS in 15 years1

Lesions on MRI

Brain

Probability of MS, % Probability of MS

None 25 Reference

1 60 2.8x higher

2 68 2.7x higher

≥3 78 4.5x higher

The Optic Neuritis Study Group. “Multiple Sclerosis Risk After Optic Neuritis:

Final Optic Neuritis Treatment Trial Follow-up”. Arch Neurol. 2008.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440583/



Treatment of CIS

Risk factors for Optic Neuritis conversion to MS in 15 years1

The Optic Neuritis Study Group. “Multiple Sclerosis Risk After Optic Neuritis:

Final Optic Neuritis Treatment Trial Follow-up”. Arch Neurol. 2008.


Risk Factor Probability of MS

Female Gender 3.6x higher

White Race 0.6x higher

Preceding “Viral Symptoms” 2.4x higher

No Optic Disc Swelling on Exam 2.4x higher

CSF with antibodies (Oligoclonal

Bands)

Higher risk

Older Age Higher risk



Treatment of CIS

Would you recommend serial monitoring or early treatment for low/moderate risk patients?

Example:

- Young female with isolated classic unilateral moderately severe Optic Neuritis, no OCB, but 1 suspect >3mm periventricular brain lesion

Treatment of (inactive) Primary Progressive MS


Treatment of Primary Progressive MS

Miller DH, Leary SM. Primary-progressive multiple sclerosis. Lancet

Neurol 2007; 6: 903-12.

10-15% of all MS

Older age of onset

Higher proportion male

Axonal loss more predominant than active inflammation



Dis

ab

ility

Relapsing-Remitting

Time

Dis

ab

ility

Secondary Progressive

Time

Dis

ab

ility

Time

Primary Progressive

Dis

ab

ility

Time

Progressive Relapsing

Lublin FD et al. Neurology. 1996;46:907-911.



Primary Progressive MS

- ORATORIO Trial – Ocrelizumab

• 732 PPMS, randomized, placebo controlled

• 18 – 55yrs old, EDSS 3.0 – 6.5, < 10-15yrs of MS, +OCB

• 26% with Gad+ Lesions on baseline MRI

• 88% not on DMT prior




- ORATORIO Trial – Ocrelizumab

• 732 PPMS, randomized, placebo controlled

• 18 – 55yrs old, EDSS 3.0 – 6.5, < 10-15yrs of MS, +OCB

• 26% with Gad+ Lesions on baseline MRI

• 88% not on DMT prior

• 2x higher Gad+ lesions on baseline MRI than Fingolimod PPMS trial (INFORMIS, Lublin et al. Lancet, 2016)



Primary Progressive MS - ORATORIO Trial – Ocrelizumab- 24% Disability Progression Relative Reduction- Significantly reduced T2 lesion volume compared with increase in placebo



ORATORIO Subgroup Analysis – Disability Progression

Younger patients (< 45yrs) and those with +Gad enhancing lesions have greater benefit.

Subgroup HR 95% CI

< 45 years 0.64 0.45 – 0.92

> 45 years 0.88 0.62 – 1.26

WITH Gad+ Lesions 0.65 0.40 – 1.06

WITHOUT Gad+ Lesions 0.84 0.62 – 1.13

BOTH < 45 and WITH Gad+ Lesions 0.52 0.27 – 1.00




FDA Indication for Ocrevus – 3/2017:

“OCREVUS is indicated for the treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis.”

EMA Indication for Ocrevus – 10/2017:

“Ocrevus is indicated for the treatment of adult patients with early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, AND with imaging features characteristic of inflammatory activity”



AAN MS DMT Guideline 2018

The [AAN] committee recommends that ambulatory patients [with primary progressive

MS] should be prescribed ocrelizumab barring any contraindication or situation

whereby risk outweighs benefit. (Level B)



Should patients with INACTIVE primary progressive MS be placed on DMTs?

Are there benefits of Ocrelizumab for inactive progressive MS?

Are there benefits of other DMTs for inactive progressive MS?

Do risks / burdens outweigh benefits for patients with longstanding inactive primary progressive disease?

Treatment of (inactive) Secondary Progressive MS


Treatment of Secondary Progressive MS

Secondary Progressive MS

Progression of clinical disability from MS unrelated to clinical relapses after an initially relapsing course

Differentiate progressive MS in two groups:

ACTIVE MS – with relapses and new lesions

vs.

INACTIVE MS – without relapses or new lesions

Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course

of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–86.



Should we consider starting or changing a DMT in patients with INACTIVE secondary progression of clinical disability?

Inflammation

Regeneration

TimeRelapsing Remitting MS

Compston A, et al. Lancet. Kuhlmann T, et al. Brain. 2002;125:2202-2212; Paolilo A, et al J Neurol. 2004;251:432-439.




Dis

ab

ility

Relapsing-Remitting

Time

Dis

ab

ility

Secondary Progressive

Time

Dis

ab

ility

Time

Primary Progressive

Dis

ab

ility

Time

Progressive Relapsing

Lublin FD et al. Neurology. 1996;46:907-911.



Should we consider starting or changing a DMT in patients with INACTIVE secondary progression of clinical disability?

Some SPMS Trials- ASCEND – Natalizumab in SPMS – Lancet 2018

- Betaseron in SPMS – Lancet 1998, Neurology 2004

- Mitoxantrone in SPMS – Lancet 2002

- Avonex in SPMS – Neurology 2001



EXPAND Trial 2017

Siponimod is a selective S1P1 and S1P5 receptor modulator

Similar to Gilenya (Fingolimod), a non-specific sphingosine 1-phosphate receptor modulator

Inclusion:

• 18-60yrs old with SPMS (progression in >=2yrs in-between relapses or without relapses, no relapse within 3 months)

• Moderately disabled (EDSS 3.0 – 6.5, ambulate with walker >20m)

• 1651 patients - randomized 2:1 Siponimod to placebo

Kappos et al. Lancet 2018



Siponimod for Secondary Progressive MS

Very active patients included, many untreated

• 21% of patients with Gad+ enhancing lesions at baseline

• 36% of patients with clinical relapses in last 2 years

• 22% did not ever have DMT use

• 33% in Placebo vs. 11% in Siponimod group had new gad+ lesions

on follow-up



EXPAND - Siponimod Trial – Clinical Disability Progression

Subgroup HR (95% CI)

No Relapses in prior 2 yrs 0.87 (0.68 - 1.11)

Relapses in prior 2yrs 0.67 (0.49 - 0.91)

No Gad+ lesions at baseline 0.87 (0.68 - 1.11)

Gad+ lesions at baseline 0.64 (0.42 - 0.95)

MS Duration since first symptoms

< 10 yrs 0.77 (0.61 - 0.97)

10-20yrs 0.82 (0.66 - 1.02)

20-30yrs 0.88 (0.59 - 1.31)

This benefit seems most prevalent in those with ACTIVE MS, early in disease course



AAN DMT Guideline

Clinicians should assess the likelihood of future relapse in individuals with SPMS by assessing patient age, disease duration, relapse history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gad+ lesion) (Level B).

Clinicians may advise discontinuation of DMT in people with SPMS who do not have ongoing relapses (or gad+ lesions on MRI activity) and have not been ambulatory (EDSS 7 or greater) for at least 2 years (Level C).



For a patient with inactive secondary progressive MS, do you initiate DMT?

Do you change DMT based on inactive secondary progression?

Do you stop DMT if secondary progression occurs with longstanding inactivity (no relapses or new lesions in 5-10+ years)?

DMT Discontinuation


DMT Discontinuation

Is it reasonable to recommend DMT discontinuation in a patient with longstanding disease stability with a long disease duration in older age?

Inflammation

Regeneration

TimeRelapsing Remitting MS

Compston A, et al. Lancet. Kuhlmann T, et al. Brain. 2002;125:2202-2212; Paolilo A, et al J Neurol. 2004;251:432-439.



DMT Discontinuation

Hua et al. Mult Scler 2018

Clevaland Clinic Group

Large observational trial on DMT discontinuation

600 patients, >60yrs old, DMT > 2 years

178 (30%) discontinued DMT, mostly by provider recommendation

10.7% re-initiated DMT

1 clinical relapse in discontinuers (1 in 178 pts)


DMT Discontinuation – Upcoming Trial

Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) (DISCOMS)

NCT 03073603 – University of Colorado, PI – John Carboy, MD

Randomized Controlled Trial of DMT discontinuation

Funded by the Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society

DMT discontinuation in those >= 55 years with no evidence of relapse or MRI activity for >= 5 years

Goal – 300 patients

Start – 4/2017

Trial Duration – 2 years

Estimated End – 2/2021

Measures – EDSS, MSIS, MRI, Relapses – every 6 months


DMT Discontinuation

AAN DMT Guideline

In people with RRMS who are stable on DMT and want to

discontinue therapy, clinicians should counsel people regarding

the need for ongoing follow-up and periodic reevaluation

of the decision to discontinue DMT (Level B).

Clinicians should advocate that people with MS who are

stable (that is, no relapses, no disability progression, stable

imaging) on DMT should continue their current DMT unless

the patient and physician decide a trial off therapy is warranted

(Level B).


DMT Discontinuation

Is it reasonable (risks / burdens / costs vs. benefits) to discontinue a DMT in patients with longstanding stable and inactive MS?

What about DMTs with possible rebound effects - Natalizumab and possibly Fingolimod?

What age, disease duration, activity free duration should be used?

- ongoing trial for age >55, >5 years stable

Oral Steroids for MS Relapse


Oral Steroids for MS Relapse?

Is it reasonable to routinely use high dose oral steroids for MS relapse in place of IV steroids?



Is is equally effective? Is it well tolerated?

Is is cost effective? Is it more convenient?

1,250mg PO Prednisone = 1,000mg IV Methylprednisolone1

USA Doses - Prednisone 50mg pill size max = 25 pills per day

UK Doses – Methylprednisolone 100mg pills (USA 32mg max)

Drug Costs:

- Methylprednisolone = $150 (3gm IV) + infusion costs

- Prednisone = $25 (3.75gm PO)1 Morrow et al. Neurology 2004



Largest PO vs. IV Steroid trial in any MS Relapse

COPOUSEP Trial – Le Page et al. Lancet 2015

• 199 pts, RRMS, 18-55yrs age, relapse within 15 days (avg 7 days)

• 1000mg IV vs 1000mg PO Methylprednisolone

• Endpoint – improvement of 1 point EDSS FSS after 28 days

81% in PO and 80% in IV group had clinical improvements

Similar adverse events

- except slight increase in Insomnia (77% in PO vs. 64% in IV)



Systematic Reviews comparing IV vs. Oral Steroids:

• Burton et al. Cochrane Database, 2012

• Lattanzi et al. Journal of Neurology 2017; Lui et al. PLoS One 2017

No differences in 6 trials -

- similar rates of improvement of EDSS at 1 and 4 weeks

- similar adverse effects

- no differences in relapse rates on 6 month follow-up

“Based on the evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy in the treatment of MS relapses.”



What about Optic Neuritis?

Optic Neuritis Treatment Trial (ONTT)

- 457 patients, ON, <= 8 days since onset

- IV Steroids 250mg Solumedrol q6 hours x 3 days with oral taper vs. Prednisone 1mg/kg (~70mg x 14 days) vs. Placebo

LOW DOSE PO steroid group

– increased risk for short term recurrent optic neuritis

- no difference in outcomes compared to placebo

HIGH DOSE IV steroid group

- slight improvement in visual outcomes at 6 months

- shorter time to recovery

Beck et al. NEJM, 1992



Optic Neuritis Treatment Trial

Beck et al. NEJM, 1992



High dose oral steroids for Optic Neuritis

Morrow et al JAMA Neurol. 2018

- 55 patients, ON with visual acuity < 20/40

- 1000mg IV Methylprednisolone vs. 1250mg PO Prednisone

Results:

- no difference in VEP at 6 months

- no difference in relapses

High dose oral steroids may be just as good for Optic Neuritis as high dose IV Steroids



Are oral steroids as effective for MS relapses than IV?

Do they have equal tolerability and risks?

Would you prefer to give a patient with a severe MS relapse IV or Oral Steroids?

Thank you

Practical Controversies in MS - nationalmssociety.org · Siponimod is a selective S1P1 and S1P5...

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