1. Multiple Sclerosis GP update Martin Duddy Consultant Neurologist Royal Victoria Infirmary Newcastle upon Tyne

2. epidemiology and nomenclature

3. risk factors for MS smoking (HR 1.48) –duration and intensity –also risk factor for progression vitamin D status –>100nmol/L HR 0.5 vs <75nmol/L EBV –100% MS seropositivity vs 95% controls –IM HR 2.17

4. normal clinically isolated syndrome radiologically isolated syndrome McDonald criteria 2005 McDonald criteria 2010 secondary progressive MS clinically definite MS active RRMS shifting the definition

5. diagnostic criteria (McDonald 2010) Polman et al. Ann Neurol 2011;69:292–302

6. PPMS

7. relapsing/ remitting patterns of MS (1996) primary progressive (benign) secondary progressive 85%13% 5% 2% PRMS

8. Lublin et al. Neurology 2014;83:278 defining phenotypes “The Group recommended at least annual assessment of disease activity by clinical and brain imaging criteria for relapsing MS”

9. referral for diagnosis

10. progression of MS

11. treating MS

12. treatment of acute relapse disease modification –disease modifying treatments (DMTs) management of symptoms and disability

13. treatment of acute relapse disease modification –disease modifying treatments (DMTs) management of symptoms and disability

14. case a 34-year-old woman with MS 2d history of worsening intense pain in a band, right side, roughly T7 distribution. generally fatigued and her right leg feels heavier worsening hesitancy feels similar to a previous relapse successfully treated with oral steroids in primary care on oral fingolimod for 6 months fully ambulant with no new signs on examination

15. would you? 1.prescribe oral steroids 2.prescribe oral steroids only after checking for a UTI 3.acknowledge episode as relapse but withhold treatment awaiting natural history 4.ask her to contact her MS team if symptoms don’t settle 5.refer as emergency to MS team

16. management of acute relapse increasingly rare: usually in consultation with local MS team methylprednisolone –oral 500mg x 5d (PPI cover if symptomatic) –IV 1000mg x 3d always specialist centre if on natalizumab, fingolimod or alemtuzumab

17. treatment of acute relapse disease modification –disease modifying treatments (DMTs) management of symptoms and disability

18. where are we leaving? NI population study 1996 1, n=281 –fully independent for all ADLs 29% –unable to manage flight of stairs 23% –in full time employment 25% –institutionalised 5% –unable to use public transport or drive a car33% half leave work force within 3 years of diagnosis 2 employment at 10yr 25% 1.McDonnell & Hawkins Mult Scler 2001;7:111 2. Doogan & Playford. Mult Scler 2014;14:646

19. RRMS interferon-  (Betaferon/Extavia Avonex Rebif) glatiramer acetate (Copaxone) natalizumab (Tysabri) fingolimod (Gilenya) teriflunomide (Aubagio) dimethyl fumarate (BG12, Tecfidera) alemtuzumab (Campath, Lemtrada) pegylated interferon (Plegridy)

20. how good are current treatments?

21. reducing relapses transient disability can leave persistent disability –(> 1point EDSS in >15%) impact on patients –work –finances marker of disease activity predictor of later disability

22. drugreduction in annualised relapse rate against placebo ARR on drug in RCT interferon-  / glatiramer acetate 1 sc im 30-35%0.3-0.7 pegylated IFN 9 sc Q2W 36%0.29 teriflunomide 2 po33.7%0.35 dimethyl fumarate 3 po49%0.19 fingolimod 4,5 po48-54%0.18-0.21 natalizumab 6 iv68% (81% active disease)0.26 alemtuzumab 7,8 iv 49% (vs interferon-  ) 0.26 reducing relapse rates 1.Galetta et al. Arch Intern Med 2002;19:2161 2.Kappos et al. P618 ECTRIMS 2013 3.Fox et al. P07.097 AAN 2013 4.Kappos et al. N Engl J Med 2010;362:387 5.Calabresi et al. Lancet Neurol 2014;13:545 6.Polman et al. N Engl J Med 2006;354: 899 7.Coles et al. Lancet 2012;380:1829 8.Cohen et al. Lancet 2012;380:1819 9.Kieseier et al. Mult Scler 2014 Nov 28. pii: 1352458514557986

23. drugreduction in sustained progression in disability rate of progression in placebo interferon-  / glatiramer acetate sc im 12-37%c.30% pegylated interferon sc Q2W 38% (1 yr)10.5% (1 yr) teriflunomidepo30.5%24% dimethyl fumarate po29% (combined analysis: NS CONFIRM)15% finglimodpo37% (F1) NS (F2)19% (F1) natalizumabiv54% (-64% active disease)28% alemtuzumabivNS (CARE-MS 1) -42% (CARE MS2) 20% (IFN-  ) reducing short term disability Calabresi et al. Lancet Neurol 2014;13:657 refs as slide 18 unless stated

24. reducing MRI measures of inflammation drugreduction in number of new/enlarging T2 lesions reduction in number of Gd+ve lesions interferon-  / glatiramer acetate sc im -78%- pegylated interferon sc Q2W -67%-86% teriflunomidepo -69.4% (T2 and Gd combined) dimethyl fumarate po-78%-82% finglimodpo-74% (F1)-70% (F1) natalizumabiv-83%-84% (active disease) alemtuzumabiv-32% (no. pts vs IFN C-MS2) -60% (no. pts vs IFN C-MS2) Arnold et al BMC Neurol 2014; doi:10.1186/s12883-014-0240-x refs as slide 18 unless stated

25. TherapyReduction in PBVC IFN β/glatiramer acetate Avonex: positive effect Year 2 pegylated interferonnot presented teriflunomidenot significant dimethyl fumarateno peer reviewed data presented fingolimod–35% (FREEDOMS); –33% (FREEDOMS II); –32% (TRANSFORMS) natalizumab-55% yr 2 alemtuzumab–42% (naive vs. IFN); –24% (previously treated vs. IFN) reducing brain atrophy refs as slide 18 unless stated

26. NEDA 3 relapses EDSS progression MRI activity NEDA 4 relapses EDSS progression MRI activity brain volume loss definable? achievable? useful?

27. quoted rates for NEDA3 23% OR 2.56 vs placebo combined analysis logistic regression placebo teriflunomide 23% x 1.6 vs placebo TEMSO crude placebo natalizumab 27% x 13.5 vs placebo AFFIRM RES subgroup Rebif alemtuzumab 39% x 1.75 vs Rebif CARE-MS1 all 2year Havrdova et al Lancet Neurol 2009;8:254 Hardova et al P521 ECTRIMS 2013Freedman et al. Neurology PD5.007 AAN 2012 Giovannoni et al. 2012 ENS

28. quoted rates for NEDA3 39.8% 1 year OR 3.06 vs placebo placebo fingolimod 24% OR 4.0 vs placebo combined analysis logistic model Arnold et al BMC Neurol 2014; doi:10.1186/s12883-014-0240-x Bergvall et al P112 ECTRIMS Boston 2014 placebo pegylated interferon

29. NEDA 4 Freedoms 1 and 2 1. relapse protocol defined 2. EDSS confirmed at 3 months 1.5 from 0; 0.5 over 5; otherwise 1 3. MR: NET2 only: m6, 12, 24 (Gd did not add anything) 4. atrophy: >0.4% Kappos 2014 platform ECTRIMS Boston placebofingolimod OR 4.41 p<0.0001

30. tolerability and safety interferons (injectables) fingolimod (tablet) natalizumab (infusion) teriflunomide (tablet) DMF (tablet) alemtuzumab (infusion) flu-like symptoms first dose bradycardia (1%) 1 0 AVB(0.5%) PML 0.5% JC+ve >2yr hair thinning (8%) flushing (34%)thyroid disease (30%) LFTs (can be late) LFTs GI upsetTTP (1.3%) site reactionsmacular oedema (0.4%) infections (HZV)hypertensionleucopenianephropathy thyroid disorders infections: LRTI HZV 1/100 pt yr accelerated washout infusion reactions capillary leak syndrome hypertensioncytotoxicinfections HZV microangiopathic haemolytic anaemia potentially teratogenic teratogenic in animals bloods 0, 1, 3, 6, 9, 12 bloods 0, 3, 6, 9, 12 2wkly testing x 6m bloods 0, 1, 3, 6, 9, 12 monthly blood/urine 48m

31. Sept 27 th 2011 risk management with natalizumab

32. PML risk estimates by index threshold in anti-JCV Ab+ patients with no prior IS use PML risk estimates for anti-JCV antibody index thresholds were calculated based on the current PML risk stratification algorithm (from September 2012) and predicted probabilities shown in the previous slide (8) for the population at or below that particular index (0.9−1.5) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates. Index threshold PML risk estimates (95% CI) per 1000 patients (no prior IS use) 1−24 months25−48 months49−72 months ≤0.9 0.1 (0–0.41) 0.3 (0.04–1.13) 0.4 (0.01–2.15) ≤1.1 0.1 (0–0.34) 0.7 (0.21–1.53) 0.7 (0.08–2.34) ≤1.3 0.1 (0.01–0.39) 1.0 (0.48–1.98) 1.2 (0.31–2.94) ≤1.5 0.1 (0.03–0.42) 1.2 (0.64–2.15) 1.3 (0.41–2.96) >1.5 1.0 (0.64–1.41) 8.1 (6.64–9.8) 8.5 (6.22–11.38) Plavina et al. Ann Neurol; 76:802

33. presentation of PML asymptomatic (MR screening) cognitive/behavioural ataxia hemiplegia

34. alemtuzumab NICE approval for “relapsing MS” dosing schedule: –year 1: 5d 12mg infusion –year 2: 3d 12mg infusion –subsequent years: 3d infusions if indicated

35. risk management strategy predose: VZV, cervical screening, HIV, HBV, HCV, TB aciclovir for first month monthly for 4 years after last infusion –CBC (platelets) –U&E and urine for microscopy –TFTs 3 monthly annual MRI (for efficacy)

36. long term study 87 patients 1999-2007 median 7 year follow up (33-144 months) 48% (41 patients) had secondary autoimmunity –3 ITP –1 neutropenia –1 haemolytic anaemia –1 Goodpasture’s (transplant required) –35 thyroid (22 Graves, 1 transient thyroiditis, 12 1 o hypothyroidism) relapses triggered reinfusion 45% –(38% 3; 4% 4; 1% 5) 60% stabilisation of improvement in disability Tuohy et al 2014 JNNP 10.1136/jnnp-2014-307721

37. DMT cases in primary care

38. case 34-year-old woman presented for advice following a positive home pregnancy test, 7 weeks after her last menstrual period teriflunomide 14mg daily for 9 months for relapsing remitting multiple sclerosis relapse free for 5 years. relying on condoms for contraception conception was unplanned but wishes to continue with the pregnancy

39. options (nurses all on study day) 1.teriflunomide should be cleared by cholestyramine 2.teriflunomide should be cleared rapidly by plasmaphoresis 3.teriflunomide should be continued throughout the pregnancy 4.teriflunomide should be discontinued and allowed to clear gradually 5.termination is advisable due to an unacceptable risk of teratogenicity

40. pregnancy & conception interferon-  (Betaferon/Extavia Avonex Rebif) glatiramer acetate (Copaxone) natalizumab (Tysabri) fingolimod (Gilenya) teriflunomide (Aubagio) dimethyl fumarate (BG12, Tecfidera) alemtuzumab (Campath, Lemtrada) pegylated interferon (Plegridy)

41. case 42-year-old man 18 month review on fingolimod 0.5mg no attacks on the drug which was well tolerated felt well, had no history of infection and remained at work routine bloods

42. would you (neurology team on team bonding away day)? 1.admit immediately to unit equipped to manage severely immunocompromised patients 2.check JC antibody status to stratify risk of progressive multifocal leucoencephalopathy 3.continue at current dose while lymphocytes remain >0.2 x 10 9 /l 4.discontinue drug and monitor lymphocyte count to ensure recovery 5.reduce dose to alternate days and monitor lymphocyte count to ensure recovery

43. case 42-year-old man 18 month review on dimethyl fumarate 240mg bd no attacks on the drug which was well tolerated felt well, had no history of infection and remained at work routine bloods

44. would you (neurology team all abroad at conference)? 1.admit immediately to unit equipped to manage severely immunocompromised patients 2.check JC antibody status to stratify risk of progressive multifocal leucoencephalopathy 3.continue at current dose while lymphocytes remain >0.2 x 10 9 /l 4.discontinue drug and monitor lymphocyte count to ensure recovery 5.reduce dose to 120mg bd and monitor lymphocyte count to ensure recovery

45. case 36-year-old man with multiple sclerosis 15 months after his completing his second year of alemtuzumab (3 x 12mg infusions) clinically well with no relapses or progression. no evidence of infection, rash or bruising.

46. plan? 1.monitor 2.admit as emergency 3.refer back to centre

47. case 37-year-old woman MS presents late afternoon following an episode of transient loss of consciousness lasting about one minute. returned from two weeks abroad that morning and recommenced her medication which she had omitted while on holiday. HR 38 beats BP90/64

48. what’s going on?

49. cost effectiveness of disease modification?

50. UK risk-sharing scheme 6 year cohort RSS n=4137 age at eligibility (mean)38.4 age at onset (mean)30.5 female (%)75.5 disease duration (baseline) 7.7 relapses last 2 years (median [quartiles]) 3 [2-3]

51. time (years) EDSS UK risk-sharing scheme: modelled natural history of cohort

52. time (years) EDSS UK risk-sharing scheme: EDSS results against -38% target

53. UK risk-sharing scheme: utility results against -38% target time (years) change in utility 0.02 0.04 0.06 0.08 0.10 0.12

54. who is eligible? interferonsfingolimodnatalizumabteriflunomideDMFalemtuzumab first line (ABN guidelines 2009) failed interferon or copaxone 2 relapses in 1 year and active MRI (rapidly evolving severe) first line (unless rapidly evolving severe) first line (unless rapidly evolving severe) any relapsing MS step down from natalizumab (if JC +ve plus prior IS plus 2 years natalizumab treatment) either newly diagnosed or failed first line

55. phase III clinical trials in SPMS – cladribine – cyclophosphamide – dirucotide – dronabinol – interferon-beta1a i.m. – interferon-beta1a s/c – interferon-beta-1b s/c – intravenous immunoglobulin – lamotrigine – mitoxantrone – alemtuzumab (phase 2 only)

56. first choices? standard newly diagnosed –DMF –IFN/GA –teriflunomide –alemtuzumab RES newly diagnosed –natalizumab –alemtuzumab

57. failing first line tolerability –determine issue –switch within licensed drugs efficacy –consider concordance –escalate suboptimal response? rapidly evolving severe? DMF IFN/GA teriflunomide alemtuzumab fingolimod alemtuzumab natalizumab alemtuzumab

58. after second line fingolimod –concordance? –tolerability –efficacy natalizumab –efficacy (Nabs) –hypersensitivity –JC concerns alemtuzumab –efficacy –adverse event escalation: natalizumab/alemtuzumab switch: ?DMFalemtuzumab alemtuzumab fingolimod repeat course; consider ASCT ? natalizumab

59. treatment of acute relapse disease modification –disease modifying treatments (DMTs) management of symptoms and disability

60. NICE: 2014 comprehensive review and symptom check –site not specified general health social activity and participation targeted systems review

61. arms ADL swallow & speech bowels memory & concentration bladder ambulation spasticity sexual dysfunction mood fatigue vision numbness/tingling/pain systematic enquiry of impairment/symptoms

62. continence in MS 1.assessment urinary tract symptoms bowel symptoms sexual function comorbidities use of prescription and other medication and therapies 2.if the dipstick test result and person's symptoms suggest an infection, arrange a urine bacterial culture and antibiotic sensitivity test before starting antibiotic treatment treatment need not be delayed but may be adapted when results are available

63. continence in MS 3.be aware that bacterial colonisation will be present in people using a catheter and so urine dipstick testing and bacterial culture may be unreliable for diagnosing active infection 4.red flags for referral haematuria recurrent UTI (≥3 in 6m) loin pain recurrent catheter blockages (<6 wk of change) hydronephrosis or kidney stones on imaging (rare in MS) biochemical evidence of renal deterioration.

64. continence in MS 4.if catheters, appliances or pads: training access to suitable products review of products, at least every 2 years 5.offer botulinum toxin to improve bladder storage if OAB and anti-muscarinics failed or not tolerated 5.do not routinely offer antibiotic prophylaxis but consider if recent history of frequent or severe UTI

65. intractable constipation: what’s new prucalopride (women only, specialist centre) Peristeen (continence service)

66. last one: vitamin D and MS role in susceptibility secure role in disease modification unsure advice on high dose replacement

67. thank you reflections or questions?