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Sequencing of Disease Modifying Treatments in Multiple Sclerosis - Belinda Weller
1) There are two broad categories of disease modifying treatments (DMTs) for multiple sclerosis - drugs of moderate efficacy including beta interferons, glatiramer acetate, teriflunomide, and dimethyl fumarate, and drugs of high efficacy including alemtuzumab and natalizumab. 2) The prevailing practice is treatment escalation, starting with a first-line drug and changing treatments based on tolerability, safety, and efficacy. No relapses, disability progression, or MRI activity (NEDA) indicates treatment success. 3) There is no accepted treatment algorithm in the UK. Involving patients in decision making is important as the treatment landscape becomes more complex
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Sequencing of Disease Modifying Treatments in Multiple Sclerosis - Belinda Weller
- 1. Sequencing of Disease ModifyingTreatments in Multiple Sclerosis MS TRUST CONFERENCE Beaumont Estate 06/11/2016
- 2. Benefit of EarlyTreatment
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- 10. ABN Guidelines • Eligiblepatients will normally be ambulant. • All patients with active RRMS should be considered expeditiously for treatment. • The currently licensed DMTs divide broadly into two categories. • Drugs of moderate efficacy ( category 1) • beta interferons ( Including pegylated) • Glatiramer acetate • Teriflunomide • Dimethyl fumarate • fingolimod
- 11. The currently licensedDMTs divide broadly into two categories. Drugs of moderate efficacy ( category 1) • Beta-interferons ( Including pegylated) • Glatiramer acetate • Teriflunomide • Dimethyl fumarate • Fingolimod Drugs of high efficacy • Alemtuzemab • Natalizumab
- 12. Induction versus Escalation(Maintenance) Prevailing practice escalation.(Maintenance) Treatment starts with a “first line”agent. Changes are made based upon • Tolerability • Safety • Efficacy
- 13. • 32 yearold woman, single mother of daughter three. • Nursery manager. • PMHx asthma, hyperhidrosis. • Presentation Sept 2015 ascending numbness both legs up to waist. • April 2016 Right facial numbness tingling lips and dropping right eye. • June 2016 admission with spasticity of legs.
- 17. • JCV positive. •Given information about treatment options while IP. • 5 days oral methylprednisolone. • OP clinic August 2016. • Had developed new left facial sensory changes over previous 3 weeks with feeling of pressure in her spine. • Treatment choice??
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- 19. Tolerability changes • Limitedby license. • If no evidence of poor efficacy ( clinical / MRI) No problem to change between platform therapies. • Changes between Avonex/ Plegridy, Dimethyl fumarate to Teriflunomide. • Dependent on preference. Oral/ Injectable, plans for pregnancy etc.
- 21. What constitutes efficacyfailure? NEDA (no evidence of disease activity) • (i) no relapses; • (ii) no disability progression and • (iii) no MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions).
- 22. How do weassess this? • Patient report of relapses. • Rebaselining with MRI scan after commencement of treatment. • Annual MRI monitoring. • NEDA4 • NEDA5
- 25. Efficacy Failure • DMF •Fingolimod • Natalizumab • Clinical trials ie Ocrelizumab • Potentially Daclizumab/Cladribine/Rituximab
- 26. PwMS and Clinicianpreferences • Level of MS activity. • Oral versus Infusion (versus Injectable). • Life style. • Reliability of PwMS to attend for required monitoring. • Adherence. • Level of MS activity. • JCV status. • PwMS understanding of risk/benefit. • Pregnancy. • Cost.
- 30. JB male aged41,Financial adviser married one child 6 months. Initial presentation 06/11/2011 with confusion, visual blurring and unsteadiness, sensory changes in feet. OE ACE 71/100 CSF 40 WC paired OCBs.
- 31. Diagnosis on basisof Clinical and MRI – ADEM Treated with 3 days IVMP. Improvement discharged 30/11/2011
- 32. Represents 06/12/2011 withslurred speech, poor balance bilateral ptosis.
- 33. • 3 daysIVIg no improvement. • Worsening with increased confusion, ataxia, L UMN facial weakness and weak left arm and leg. • 16/12/2011 Admitted ITU. • Further deterioration –improved left sided weakness but now right arm and leg weakness and aphasia. • Develops bilateral PEs, treated with IVIg. • Further deterioration with complex opthalmoplegia. • PLEX. • First treatment with Natalizumab Jan 2012.
- 34. • JCV negative. Commencedon natalizumab Jan 2012. • Complete resolution of signs and symptoms. • Returned to work. • Monitored with annual MRI scans and 6 monthly JCV. • Late 2014 first time JCV Positive –no titre • March 2015 JCV positive titre 2.49 • Repeated May2015 JCV positive titre 3.19. • Expressed extreme anxiety regarding risk of PML. • Wishing to consider stopping or changing to another treatment.
- 35. What is hisrisk of PML?
- 36. • Some persistingdoubt as to whether this was MS given aggressive presentation. • • ? Multiphasic ADEM. • Tysabri stopped after stable MRI June 2015. • Represented August 2015 with new symptoms. • “Visual Snow”. Vague description of visual disurbances. • No focal signs.
- 38. • Given timescale decided this was MS reactivation. • Restarted on Natalizumab. • MRI stabilised but increasing concern about PML. • Discussion about changing treatment. • Decision to change to alemtuzemab with fingolimod as bridging agent.
- 40. • Option 3 •Further MRI with contrast. • LP. CSF negative for JCV PCR • Admitted for first dose monitoring fingolimod 20/08/2016. • Represented 29/09/2016, confused agititated, word finding difficulty and worsening of visual disturbance. • Admitted.
- 42. Options now? • IVmethyl prednisolone. • Further LP and csf testing for JCV negative at several institutions. • Brain Biopsy? • Urgent switch to Alemtuzemab? • Rituximab off label? • Decision back onto Natalizumab but with very close surveillance.
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- 45. RESTORE ( Natalizumab treatmentinterruption)
- 48. • Disease recurredin large proportion of patients who discontinued Natalizumab treatment. • Radiologic disease recurrence was more frequent in patients with high disease activity (relapses) prior to Natalizumab treatment than those with lower disease activity. • MRI evidence notable from 12 weeks. • Clinical activity reported from 4-8 weeks
- 49. Fingolimod after Natalizumaband the risk of short-term relapse. • 533 patients from MS base registry. • 10 months follow up. • 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. • Jokubatis et al, Neurology 2014:82:1204-1211
- 53. Natalizumab-Fingolimod • Timing remainsan important issue. • Currently no guidelines for the optimal period between natalizumab cessation and fingolimod start. • Data suggest that a treatment gap of 2–4 months is an independent predictor of increased relapse risk on fingolimod vs no treatment gap, whereas a treatment gap of 1 day to 2 months was not. • This study suggests that a treatment gap of less than 2 months between prior treatment (including natalizumab) cessation and fingolimod commencement reduces the risk of disease reactivation. Jokubatis et al, Neurology 2014:82:1204- 1211
- 55. Other potential reasonsto consider a switch. • Neutralizing antibody. • Pregnancy.
- 57. • Case: • 42year old man • Smoker 15-20 day. • Previous IV drug use. • Living with partner and young daughter. • Father has epilepsy. • Presented 02/04/2010 with numbness left arm and hand. Couldn’t do up buttons.
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- 59. • MRI ScanOctober 2013 after presented with sensory symptoms in legs.
- 63. • KB 28years old. • Feb 2016 2 weeks numbness R arm and right foot. Numb right side of tongue. Poor balance and falls. • OE reduced sensation Right arm, leg and face. Power normal. Plantars flexor. • GP--- Possible SOL • Urgent referral MAU 19/02/2016. • CT brain. Normal
- 64. • Further history •Previously well, no regular medication. • 2 children aged 10 and 3. • No family history. • OE variable convergence spasm. • Positive Hoovers sign. • Sensory loss ( Midline) affecting right face, arm and leg,variable right sided weakness. • Dx ? Functional. ? MS • MRI
- 67. • Diagnosis RRMSconfirmed. • Treatment with dimethyl fumarate. • September 2016 new symptoms. • Repeat MRI three enhancing lesions.
- 70. • JCV negative. •What would you do next?
- 72. Conclusions. • The diseasemodifying landscape is becoming more complex as new treatment options become available. • We need to involve pwMS in decision making . • No accepted treatment algorithm in UK. • Currently no large evidence base to inform switching between higher efficacy treatments. • Unmet need for treatment registry. • Treat aggressively early. NEDA.
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