Management of relapsing–remitting multiple sclerosis in Qatar: an expert consensus

Figures & data

Table 1. Overview of principal randomized phase 3 evaluations of disease-modifying therapies (DMTs) for multiple sclerosis.

DMT/trial	Overview of efficacy outcomes
	Relapses	Disability	NEDA
Interferons (IFN)
PRISMS (sc IFNβ-1a vs. placebo)^16	Risk reductions for relapses vs. placebo of 27% (14 to 39) and for IFN 22 mg tid 33% (21–44) for INF 44 mg tid	Reduced accumulation of long-term disability for INF vs. placebo	See studies below that employed IFN-β1a as a comparator
MSCRG (im IFNβ-1a vs. placebo)^17	Over 2 y, annual exacerbation rate was 0.90 on placebo and 0.61 on INF	EDSS score progressed ≥1 point in 34.9% on placebo and 21.9% on IFN (p=.02)	–
MSSG (sc IFNβ-1b vs. placebo)^18	Annual “exacerbation rate” at 2 y was 1.27 for placebo, 1.17 for 1.6 million IU dose (p=.01) and IFNB, and 0.848 million IU (p = .0001) after 2 y	No differences between groups for effects on EDSS scores	See studies below that employed IFNβ-1a as a comparator
ADVANCE (pegylated INFβ-1a vs. placebo)^19	Rate ratios 0.644 (0.500–0.831, p = .0007) for 2-weekly treatment, 0.725 (0.565–0.930, p = .0114) for monthly treatment	–	–
Glatiramer acetate (GA)
CMSSG (vs. placebo)^20	34.0% reduction in risk of relapses for GA vs. placebo (p < .0001)	–	–
ECGASG (vs. placebo)^21	29% reduction in relapse rate for GA vs. placebo (p = .007)	More on GA vs. placebo improved EDSS score and more on placebo vs. GA worsened (p = .037 for the difference)	–
Dimethyl fumarate (DMF)
DEFINE (vs. placebo)^22	Relative risk reductions vs. placebo of 53% (bid dosing) and 48% (tid dosing), p < .001 for each	Relative risk reductions vs. placebo for 1-step EDSS progression of 38% (bid, p = .005) and 34% (tid, p = .01)	More NEDA on DMF (39% vs. 27%), p < .05
CONFIRM (vs. glatiramer acetate)^23	Risk reductions vs. placebo: bid DMF 44%, p < .001; tid DMF 51%, p < .001; GA 29%, p = 0.01	No significant changes in EDSS progression between groups	–
Alemtuzumab
CARE-MS I (vs. IFNβ-1a)^24	54.9% reduction in relapses^a (p < .0001) 78% relapse free at 2 y, vs. 59% on IFN (p < .0001)	Similar sustained disability accumulation^a (HR 0.70 [0.40–1.23]); p = .22	More NEDA on alemtuzumab (39% vs. 27%), p < .05
CARE-MS II (vs. IFNβ-1a)^25	49.4% reduction in relapses^a (p < .0001) 65% relapse free at 2 y, vs. 47% on IFN (p < .001)	42% improvement^a in sustained disability (p = .008)	More NEDA on alemtuzumab (32% vs. 14%), p < .0001
Cladribine tablets
CLARITY (vs. placebo)^26^,^27	57.6% reduction in relapse rates^b (p < .001) Higher proportion relapse free^b (OR 2.53 [1.87–3.43]) (p < .001)	More with no change in 3 month EDSS^b (OR 1.55 [1.09–2.22]) (p = .02)	More with NEDA at 96 weeks (47% vs. 17% on placebo)
Fingolimod
FREEDOMS (vs. placebo)^28^,^29	Annualized relapse rate 0.16–0.18 over 2 y vs. 0.40% on placebo (p < .001) 52–62% increase in relapse free over 2 y^b for two fingolimod regimens (p < .001)	No disability progression in 82–83% vs. 75% on placebo (p = .01–.03)	More NEDA on fingolimod^b (33% vs. 13%), p < .001
TRANSFORMS^28 (vs. intramuscular interferon)	Annualized relapse rates 0.20 for fingolimod 1.25 mg and 0.16 for fingolimod 0.5 mg vs. 0.33 for interferon (p < .001 for each)	No difference between groups for progression of disability	–
Natalizumab
AFFIRM (vs. IFNβ-1a)^30^,^31	68% reduction in relapses over 1 y^b	42% reduction in sustained disability progression over 2 y (p < .001)^a	More NEDA on natalizumab^a (37% vs. 7%), p < .0001
Ocrelizumab
OPERA I (vs. IFNβ-1a)^32^,^33	46% reduction in annualized relapses over 1 y^b	40% reduction in risk of 24 week disability progression (p < .001; prespecified pooled analysis for OPERA I and II)	More NEDA on ocrelizumab^a (48% vs. 29%), p < .0001
OPERA II (vs. IFNβ-1a)^32^,^33	47% reduction in annualized relapses over 1 y^b		More NEDA on ocrelizumab^a (48% vs. 25%), p < .0001

A cladribine tablet 5.25 mg/kg arm was included in the CLARITY trial, but this dosage strength is not used clinically and so is not included here.

Abbreviations. bid, Twice daily administration; im, intramuscular; NEDA, no evidence of disease activity; sc, subcutaneous; tid, Three times daily administration.

^a Compared with interferon β-1a (IFN).

^bCompared with placebo. IFN was given subcutaneously as per label, except for the DECIDE trial where IFN was given via the intramuscular route (30 μg once weekly).

Table 2. Most common side-effects and monitoring burden associated with DMTs, according to their European summaries of product characteristics.

DMT	Administration	Principal side-effects	Monitoring requirements
Alemtuzumab	Five daily infusions followed by a course of 3 daily infusions 1 year later (all infusions contain 12 mg of alemtuzumab) One or two additional treatment courses can be given if required (each involving infusions on three consecutive days)	Infusion-associated reactions (>90% of patients) Autoimmune conditions, mainly thyroid disorders and also thrombocytopenic purpura, nephropathies, and cytopenias Infections (mainly herpes simplex and zoster)	Before initiation and thereafter: Monthly complete differential blood count Monthly serum creatinine measurement Thyroid testing
Dimethyl fumarate (DMF)	Twice daily oral administration	Flushing Gastrointestinal effects Possibility of severe, prolonged lymphopenia (one case of progressive multifocal leukoencephalopathy [PML] has been reported in a patient taking DMF who had prolonged lymphopenia)	Complete blood counts, including lymphocytes, every 3 months (consider withdrawal if lymphocytes <500/mm^3 for 6 months) Check renal status at 3 and 6 months, every 6–12 months during long-term treatment (more often if indicated clinically)
Cladribine tablets	Two treatment weeks at the beginning of year 1 and year 2 of treatment, to a total dose of 3.5 mg/kg Each treatment week consists of 4 or 5 days in which patients receive 1 or 2 cladribine 10 mg tablets, depending on body weight	Lymphopenia/leukopenia Opportunistic infections (mainly herpes zoster)	Ensure lymphocyte counts are “normal” before initiation, and at least 800/mm^3 before the second course in year 2 Measure lymphocyte count at months 2 and 6 of each treatment year; monitor for signs of infection where lymphocyte count is <500/mm^3 and follow lymphocyte count until it is increased Monitor patients taking treatments that may affect blood counts or exposure to cladribine
Fingolimod	Single oral dose of 0.5 mg daily	Bradycardia and transient atrioventricular conduction delays Opportunistic infections Macular oedema Raised liver function tests Possible increased risk of malignancy, especially of the skin	ECG and blood pressure before and 6 hours after the first dose Complete blood count 3 months after initiation and at least annually thereafter
Natalizumab	300 mg by intravenous infusion every 4 weeks	PML and other potentially serious opportunistic infections Hepatic disturbance Immune reconstitution inflammatory syndrome (on withdrawal)	JC virus test and MRI scan to check for PML before initiation Re-counsel patients receiving natalizumab for more than 2 years on risk of PML
Ocrelizumab	Two 300 mg infusions, 2 weeks apart, followed by single 600 mg infusions every 6 months Corticosteroid and antihistamine treatment (and optionally, an antipyretic) is required before infusion to limit the potential for infusion reactions	Infusion reactions, which may be severe or even life threatening Risk of PML or other serious infections cannot be ruled out, based on observations with other treatments with a similar mechanism	Screen for hepatitis B, as per local guidelines
Teriflunomide	14 mg orally once daily	Alopecia, nausea, increased liver enzymes Increased blood pressure	Measure complete blood count, blood pressure, liver enzymes, before treatment Monitor liver enzymes every 2 weeks during the first 6 months and every 8 weeks thereafter Conduct complete blood count when prompted by symptoms on treatment, e.g. infection

Information in this table is from European Summaries of Product Characteristics as of 11 March 2019, available for each therapy at www.medicines.org.uk. Descriptions of side-effects are abbreviated, always consult full labelling.

Table 3. Consensus recommendations on the pharmacologic management of RRMS according to disease activity.

First-line treatment	Following sub-optimal response	Following further sub-optimal response
Mild RRMS disease activity^a
Glatiramer acetate (A)	Dimethyl fumarate (A)	Alemtuzumab (A)^b
High-dose interferon β (A)	Fingolimod (A)	Cladribine tablets (A)
Low-dose interferon β (C)	Cladribine tablets (A)	Natalizumab (A)
Teriflunomide (C)	Natalizumab (B)	Ocrelizumab (A)
	High-dose interferon β (C)
	Ocrelizumab (C)
Moderate RRMS disease activity^a
Cladribine tablets (A)	Alemtuzumab (A)^b	Alemtuzumab (A)^b
Dimethyl fumarate (A)	Cladribine tablets (A)	Cladribine tablets (A)
Fingolimod (A)	Natalizumab (A)	Natalizumab (A)
High-dose interferon β (A)	Ocrelizumab (A)	Ocrelizumab (A)
Natalizumab (C)
High RRMS disease activity^a
Alemtuzumab (A)^b	Alemtuzumab (A)^b	Alemtuzumab (A)^b
Cladribine tablets (A)	Cladribine tablets (A)	Cladribine tablets (A)
Natalizumab (A)	Natalizumab (A)	Natalizumab (A)
Ocrelizumab (A)	Ocrelizumab (A)	Ocrelizumab (A)
Fingolimod (C)

Letters in parentheses show the level of expert consensus, defined according to the number of votes of independent clinical experts (representatives of the company that sponsored this meeting did not take part in this exercise): A = supported by at least 5/8 consensus panel members, B = 3–4/8, C = 1–2/8. Treatments are listed alphabetically within each level of consensus and order of listing does not imply preference over other drugs supported by the same level of consensus.

^aSee text for definitions of RRMS disease activity.

^bThe consensus meeting was held before the European Medicines Agency applied new restrictions to the use of alemtuzumab as follows: “Lemtrada should only be started in adults with relapsing–remitting multiple sclerosis that is highly active despite treatment with at least two disease-modifying therapies…or where other disease-modifying therapies cannot be used”.

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