MS ECHO: Stopping Disease Modifying

Therapies Gary Stobbe, MD

Medical Director, MS Project ECHO Clinical Assistant Professor, UW

Neurology

Conflicts of Interest

• Dr. Stobbe has no conflicts of interest to disclose

Objectives

• Consider situations that may arise for stopping disease modifying therapies (DMTs)

• Review available data on risk of stopping DMTs and benefits of long term DMT use

Case Study

• 49 yo female, RRMS x 20 yrs – asks when can she stop her therapy? • 1994 – probable optic neuritis, recovered • 2001 – left ON; brain MRI c/w MS • 2005 – numb perineum; MRI progressed

– started Rebif • 2007 – clinical/radiologic progression

– switched to Tysabri • 2010 – L hand and B leg tingling – steroids • 2011 – L hand/foot tingling – no steroids • 2013 – JCV positive

– switched to Tecfidera • Current exam – WNL; T25FW – 4.3 sec

Case Study (cont.)

Minimal change from 2006-2014; no T1 lesions; no cord abnormalities

Case Study (cont.)

• Questions – – What you recommend stopping DMTs? – What would influence you in this decision? – How would you have the discussion with the

patient?

Evidence supporting long-term use of DMTs

• Observational study of 3060 patients (Cocco, 2015)

– DMTs delayed disability progression measured by EDSS in patients treated early (and to a lesser extent later) in disease

• Swedish MS Registry (Kavaliunas, 2015) – Newly diagnosed patients between 2001-05, followed

prospectively – Early treatment corresponded with a delay to reach EDSS

of 4 or greater • Pivotal trial extension studies

NMSS Consensus Paper, updated March 2015 – see Resources

Evidence supporting the need to continue DMTs

• Non-adherence and gaps in treatment are associated with an increase in relapses and progression of disability (Cohen, 2013; Burks, 2012)

• Increase in ED utilization by patients who stopped DMTs (Menzin, 2013)

• Relapse rate and MRI activity returns to pre-treatment baseline after stopping interferon (Richert, 2000; Siger, 2011), natalizumab (O’Connor, 2011; Fox, 2014), and fingolimod (Ghezzi, 2013; Hakiki, 2012)

NMSS Consensus Paper, updated March 2015 – see Resources

Evidence supporting the need to continue DMTs (cont.)

• Review of MSBase Registry – datebase, 42 sites across 15

countries • Identified 182 patients – criteria of confirmed MS, over age

40, stable > 5 yrs (EDSS & no exacerbations), on DMT > 3 yrs prior to baseline, followed for > 3 yrs after d/c DMT

• Results – followed for median 4.2 yrs; 24.2% relapsed; 31.9% progressed on EDSS

• Of the 182 pts, 42% were restarted on DMT (after being off at least 3 months; median 22 months) – those restarted had 59% reduction in rate of confirmed EDSS progression

Kister, 2015

What are reasons to stop DMTs? - Sub-optimal treatment response as determined by the

individual and his or her treating clinician - Intolerable side effects - Inadequate adherence to the treatment regimen - Availability of a more appropriate treatment option

(Note: in these situations, an alternative DMT should be considered)

Absence of relapses while on treatment should not be considered a justification for discontinuation of treatment.

NMSS Consensus Paper, updated March 2015 – see Resources

Why do patients stop DMTs?

• Perceived “lack of improvement” (9%) • Perceived disease progression (10%) • Intolerance (8%) • Inconvenience (8%) • Adverse event (6%) Kister, 2015.

How to discuss stopping DMTs

• Understand what is “driving” the discussion • Be aware of how your view of risk and

tolerability may differ from your patient • “Legitimize” concern • Encourage switch to alternative agent rather

than stopping altogether

Resources • The Use of Disease Modifying Therapies in

Multiple Sclerosis: Principles and Current Evidence. A consensus paper by the Multiple Sclerosis Coalition, updated March 2015.

• Kister, I, et al. “Doctor, can I stop my medicine?” analysis of disease course after stopping disease-modifying therapy in stable MS patients. Poster P5.192, AAN Annual Meeting, Washington, DC, April 22, 2015.

Dr. Orr’s case

• 43 yr old Caucasian female with a history of MS since age 27

• Symptoms: constipation, leg weakness, urinary incontinence

• Referred for presumed dysbiotic IBS by her PCP (neurologist managing her MS)

Dr. Orr’s case (cont.)

• Bowel sxs upon initial presentation included: – Post-prandial dyspepsia – Foul flatus 20-30x QD – LLQ abdominal discomfort – Alternating constipation and diarrhea – Inconsistent BM frequency ranging from 1-2x/wk

to 4x daily – Rectal cramping relieved by BM

Dr. Orr’s case (cont.) • Previous failed txs included:

– Gluten-free diet – Anti-inflammatory elimination diet – low FODMAPs diet – Supplemental psyllium fiber – Loperamide (immodium) – Imipramine (Tofranil) – Fluoxetine (Prozac) – Lubiprostone (Amitiza) – Currently on vancomycin (vancocin) and sertraline

(zoloft)

Dr. Orr’s case (cont.) • Neurological symptoms included:

– Episodic vertigo – Poor concentration and “brain fog” – Severe leg weakness (typically required a wheelchair but

occasionally used a walker) – Poor coordination – urinary incontinence (uses indwelling catheter)

• Disease modifying therapies included: – Glatiramer (Copaxone) and interferon beta-1a (Avonex) in

past – Currently on interferon beta-1b (Extavia) and

teriflunomide (Aubagio)

Dr. Orr’s case (cont.)

• Other notable history: – Mixed anxiety and depression – Significant food avoidance behavior – Lack of support network – Feels socially isolated d/t bowel complaints (flatus

especially) and restricted mobility

Dr. Orr’s case (cont.) • PE revealed:

– Hyperreflexive DTRs in LEs – Unsteady/inaccurate finger-to-nose – diminished borborygmi – Fully tympanic abdomen upon percussion – Tenderness to light palpation of LLQ – Tenderness to deep palpation of LLQ and RLQ – Dysthymic affect with diminished range of

expression in office

Dr. Orr’s case (cont.) • Lab testing –

– Hydrogen/Methane breath analysis revealed significant methanogenic bacteria in terminal ileum (59ppm, RR <20ppm)

– PCR microbiome analysis (Genova 2200 GI Effects Profile) revealed low microbial diversity, skewed Bacteroidies/Firmicutes ratio, high Odoribacter ssp., high Prevotella ssp., low Butyrivibrio crossotus, low Akkermansi muciniphilia, and high Klebsiella pnumoniae

Dr. Orr’s case (cont.) • Impression –

– Perturbed intestinal microbiota - very poor diversity, small intestinal bacterial overgrowth, and pathogenic bacteria (associated with autoimmune disease)

• Tx - “Weed & Feed” protocol – D/c’d vancomycin – 1 round of rifaximin (xifaxan) antibiotics combined

with a botanical antimicrobial formula (Para-Gard by Integrative Therapeutics)

– a biofilm disruptor (NAC), and a narrow-spectrum multi-strain pharmaceutical probiotic (VSL#3 DS by Sigma-Tau) for 14 days

Dr. Orr’s case (cont.) • Progress –

– Patient had complete resolution of bowel sxs after 3 weeks

– Switched probiotic to a wide-spectrum multi-strain probiotic (HLC Multi-Strain by Pharmax) and made diet recommendations to increase fermented foods, restrict simple carbohydrates (modified FODMAPs/SCD diet), and increase soluble fiber

– Referred patient to a psychiatrist active in the CCFA (Crohn’s & Colitis Foundation of America) community

– 4 months later, I get a call from the patient’s neurologist: “What did you do to my patient!” (Uh-oh)

Dr. Orr’s case (cont.) • Progress (cont.)

– Patient’s neurologist says the patient’s MS has been progressively improving the past 3 months despite no other changes in treatment protocol (interferon beta-1b, aubagio, and sertraline)

– Patient has regained the ability to walk assisted with cane, no longer uses indwelling catheter, has had no episodes of vertigo, and now performs the daily crossword puzzle

– Social interactions, self-esteem, and general wellness measures have also improved. Neurologist says “It’s better than remission. I don’t know what to call it.”

Dr. Orr’s case (cont.)

• Long-term follow-up – At 1 year follow-up phone consultation with

neurologist, patient reportedly remains well without relapse.

– Patient has d/c’d sertralineand continues on interferon beta-1b and teriflunomide (at lower dosages than previously used)

Dr. Jean Thomas Case • 32 yo female with headaches • Has felt related to hysterectomy • No visual complaints • Topiramate/gabapentin – “some relief” • PMHx – depression, FMS, IBS, asthma

Dr. Thomas’ Case (cont.) • Exam (2/2015)

– BMI – 47 (259 lbs, 5’2”)

• Imaging (1/2015) – Normal brain MRI

• Plan – increase meds, weight loss • Follow-up (3/2015)

– 60% improved – topiramate increased further

Dr. Thomas’ Case (cont.)

• Follow-up (5/2015) – Headaches worsened, now with blurry vision – LP performed – CSF – opening pressure 120 mm water; positive OCBs (3) – Ophtho consult sent

• Follow-up (6/2015) – “downhill since spinal tap – feels like my FMS are mixing with

my headaches” – c/o urinary incontinence, severe fatigue, hand tingling, muscle

spasms in legs, mild post-LP HA – Labs sent for CSF mimickers, C/T spine MRI, EMG/NCS – Oral methylprednisolone taper (Dosepak) ordered