Expert consensus from the Arabian Gulf on selecting disease-modifying treatment for people with multiple sclerosis according to disease activity

Figures & data

Table 1. Overview of key properties of currently available DMDs for use in patients with MS.

	Efficacy	Overview of typical side-effects^a	Administration
Beta interferons See note b	Risk reductions for relapses vs. placebo of 27–33% (21 to 44) Reduced accumulation of long-term disability vs. placebo in some studies (based on EDSS progression)	Psychological disturbances, hepatic disturbances, influenza-like symptoms. Caution where there is history of seizures or CV disease.	Injection: IFNβ1a: 30 μg i.m. QW IFNβ1b: 44 μg TIW by s.c. injection (22 mg TIW if higher dose is not tolerated)
Glatiramer acetate (GA) [17,18]	29–34% reduction in risk of relapses for GA vs. placebo Improved EDSS category in one study	Flushing and CV disturbances occur on administration (usually resolves). Convulsions, anaphylaxis and serious hypersensitive reactions are rare.	Injection: 20 mg s.c. QD
Dimethyl fumarate (DMF) [19,20]	Relative risk reductions vs. placebo of 44–53% vs. placebo (different dosing regimens) and 29% vs. GA Significant reduction in likelihood of 1-step EDSS progression Greater likelihood of NEDA on DMF vs. placebo	Typically flushing, gastrointestinal side-effects. Severe, prolonged lymphopenia may occur. PML has been reported associated with prolonged lymphopenia.	Oral: 120 mg BID titrated to recommended maintenance dose of 240 mg BID
Teriflunomide [21,22]	Lower relapse (by 31–36%), disability accumulation and MRI progression vs. placebo	Abnormal LFTs, alopecia, gastrointestinal disturbances, elevated BP, skin reactions (possibly severe).	Oral: 14 mg QD
Alemtuzumab [23,24]	50–78% reduction in relapses vs. interferon-beta1a; more relapse free at 2 y vs. interferon in one study in patients with breakthrough disease despite treatment (p < 0.0001) Similar sustained disability accumulation, but more NEDA vs. interferon	Infusion-associated reactions in >90%. Autoimmune conditions are common (now contraindicated in autoimmune conditions other than MS). Risk of serious cardiovascular side-effects.^c Risk of Infections (mainly herpes simplex, varicella zoster and listeriosis)	Infusion: 1st course: 12 mg/day on 5 consecutive days 2nd treatment course: 12 mg/day on 3 consecutive days 12 months after the first treatment course. Up to two more courses can be given
Cladribine tablets [25,26]	58% reduction in relapse rates and 2.53-fold chance of being disease free vs. placebo at up to 4 y More with no change in 3-month EDSS and more with NEDA vs. placebo	Mainly lymphopenia/leukopenia, and opportunistic infections (mainly varicella zoster). Screen carefully for latent TB. Label has warning on malignancy (see text). PML has been noted on other cladribine regimens.^d	Oral: 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days or QD treatment, depending on body weight.
Fingolimod [27,28]	Reduced annualized relapse rates (p < 0.001)^e and more relapse free, vs. placebo or i.m. interferon Greater likelihood of no disability progression or NEDA vs. placebo only	Bradycardia and transient intracardiac conduction delays are the principal side-effect. Also potential for opportunistic infections, macular edema, raised liver function tests. Possible increased risk of malignancy, especially of the skin	Oral: 0.5 mg QD (0.25 mg QD for children ≤40 kg body weight)
Natalizumab [29,30]	Reduction in relapses (by 68%) over 1 y and reduction in sustained disability progression over 2 y vs. placebo	Risk of PML, especially in JCV+ patients and after long-term administration; also risk of other, potentially serious opportunistic infections. Also hepatic disturbance. Risk of Immune Reconstitution Inflammatory Syndrome on withdrawal.	Infusion: 300 mg infused every 4 weeks
Ocrelizumab [31,32]	46% reduction in annualized relapses over 1 y (vs. s.c. interferon-beta1a)	Infusion reactions may be severe or even life-threatening. PML has been observed with another drug of similar mechanism (rituximab)	Infusion: Initial 600 mg dose followed by 300 mg 2 weeks later, then 600 mg 6-monthly. Premedicate to reduce severity of infusion reactions.^f

Statements on efficacy are from randomized, Phase 3 clinical trials cited, statements on side-effects are abstracted and pooled from US and European labeling. ^aBrief overview only – consult your local labeling for a full account of side effects, contraindications, and warnings/precautions over use. ^bIncludes interferon-beta_1a, interferon-beta_1b. ^cNew European CV contraindications include uncontrolled hypertension, angina pectoris, myocardial infarction, stroke or dissection of the cervicocephalic arteries, coagulopathy, use of antiplatelet, or anticoagulant therapy. ^dRefers to higher dose, parenterally administered regimens used in the management of leukemias. ^eAnnual relapse rates 0.16–0.18 vs. 0.40 on placebo, and 0.16–0.20 vs. 0.33 on i.m. interferon-beta_1a. ^fGive 100 mg i.v. methylprednisolone (or an equivalent) 30 min before infusion and antihistamine 30–60 min prior to infusion; consider antipyretic 30–60 min prior to infusion (EU label). BP: blood pressure; BID: twice daily; CV: cardiovascular; JCV+: John Cunningham virus positive; PML: Progressive multifocal leukoencephalopathy; QD: once daily; QW: once weekly; TB: tuberculosis; TIW: three times weekly.

Table 2. Therapeutic indications for DMDs used in the management of MS.

DMD	US Food and Drug Administration	European Medicines Agency
Interferon-beta1a and interferon-beta1b	Relapsing forms of MS^a	CIS^c and active relapsing MS (≥2 attacks in previous 2 years)
Glatiramer acetate	Relapsing forms of MS^a in adults	Relapsing forms of MS (excludes secondary forms of MS)
Dimethyl fumarate	Relapsing forms of MS^a	RRMS
Teriflunomide	Relapsing forms of MS^a	RRMS
Alemtuzumab^e	Relapsing forms of MS^b in adults (generally for patients with inadequate response to ≥2 other DMDs)	Highly active RRMS^d (despite ≥1 prior DMD) or if disease is worsening rapidly^d
Cladribine tablets	Relapsing forms of MS^b in adults (generally for patients uncontrolled by/intolerant to another DMD)	Adults with highly active RRMS defined by clinical or imaging features
Fingolimod	Relapsing forms of MS^a (≥10 y)	Highly active RRMS^c (≥10 y)^d
Natalizumab	Relapsing forms of MS^a (generally after inadequate response to ≥2 other DMDs)	Highly active RRMS^d
Ocrelizumab	Relapsing forms of MS^a Primary progressive forms of MS	Relapsing forms of MS with active disease Early PPMS with MRI evidence of inflammation

^aSpecifically includes clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS) and active secondary progressi e MS (SPMS). ^bRRMS and active SPMS. ^cDefined in EU label as ‘single demyelinating event with an active inflammatory process, if alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis’. ^dDefined as highly active disease despite a full and adequate course of treatment with at least one DMD or rapidly evolving severe RRMS (≥2 disabling relapses in 1 year, and with 1 or more gadolinium-enhancing lesions or a significant increase in T2 lesion load as compared to a previous recent MRI). ^eRestriction applied by European regulator in November 2019 (see text). Abstracted from US and European labeling. Indications are paraphrased for brevity, see labels for full wording.

Table 3. Consensus recommendations on the use of DMDs in people with RRMS according to disease activity and previous treatment status.

	Treatment recommendation
Disease activity at first presentation	No prior DMD (1st-line)	1 prior DMD (2nd-line)	2 prior DMD (3nd-line)
Active MS without indicators of poor Prognosis	Beta Interferon Glatiramer acetate Teriflunomide Dimethyl fumarate	Cladribine tablets Dimethyl fumarate Fingolimod Natalizumab^b	Cladribine tablets Natalizumab Fingolimod Ocrelizumab Alemtuzumab^b
Highly active MS	Cladribine tablets Natalizumab Fingolimod Ocrelizumab Dimethyl fumarate^a	Cladribine tablets Natalizumab Ocrelizumab Alemtuzumab^a,c Fingolimod^a	Cladribine tablets Natalizumab Ocrelizumab Alemtuzumab^c
Rapidly evolving severe MS	Cladribine tablets Natalizumab Ocrelizumab Fingolimod^a	Natalizumab Ocrelizumab Alemtuzumab^a,c Cladribine tablets^a	Natalizumab Fingolimod Ocrelizumab

All recommendations were achieved via a high level of expert consensus (at least seven out of 10 experts agreed), except where indicated as ^amoderate consensus (between four and six experts agreed) or ^blow consensus (three experts or fewer agreed). DMD: disease-modifying drug. ^cNew restrictions on the prescribing of alemtuzumab were applied in Europe in November 2019 (see text).

Table 4. Actions recommended for specific manifestations of suboptimal treatment response.

Suboptimal response after 1 year of 1st line treatment:	Action recommended
A single MRI lesion in a strategic location (spinal cord, cerebellum, brain stem) or ≥3 MRI lesions in non-strategic locations. Single relapse (non-disabling), without EDSS progression^a or MRI activity.	This may prompt scheduling further follow-up MRI at 6 months or Lateral switching to other DMD (with different mechanism of action) but this depends on the overall presentation (consider a higher efficacy DMD)
MRI progression + relapse EDSS progression + relapse	Switching DMD treatment

^aUsually defined as progression by 1 point for EDSS <5, or 0.5 points if EDSS ≥5.

Box 1. NHS England definition of a disabling MS relapse [44].

Affects the patient’s social life or occupation, or is otherwise considered disabling by the patient. Affects the patient’s activities of daily living as assessed by an appropriate method. Affects motor or sensory function sufficiently to impair the capacity or reserve to care for themselves or others. Needs treatment/hospital admission.

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