Treatment strategies for multiple sclerosis: When to start, when to change, when to stop?

Table 1 Main characteristics of available disease-modifying therapies for multiple sclerosis

Agent	Indication and line of therapy	Dosage, route and frequency	Clinical efficacy in placebo-controlled phase III trials	Tolerability issues	Safety issues
Interferon beta 1b	RR MS; SP MS with relapses; CIS First line	250 mcg s.c. every other day	34% reduction of ARR over two years (RR MS) 50% risk reduction of conversion to CD MS at two years (CIS) No statistically significant effect on disability progression	Flu-like syndrome; injection site reactions	Hepatotoxicity; myelotoxicity; autoimmune thyroiditis; microangiopathy; epileptic seizures (rare)
Interferon beta 1a	RR MS; CIS First line	30 mcg i.m. once a week	18% reduction of ARR over two years (RR MS) 44% risk reduction of conversion to CD MS at two years (CIS) No statistically significant effect on disability progression	Same as above	Same as above
Interferon beta 1a	RR MS; CIS First line	44 mcg s.c. three times a week	32% reduction of ARR over two years (RR MS) 45% risk reduction of conversion to CD MS at two years (CIS) 30% reduction of progression of disability at two years (RR MS)	Same as above	Same as above
Peginterferon beta 1a	RR MS First line	125 mcg s.c. every two weeks	36% reduction of ARR over one year	Same as above	Same as above
Glatiramer acetate	RR MS; CIS First line	20 mg s.c. every day	29% reduction of ARR over two years (RRMS) 45% risk reduction of conversion to CDMS at three years (CIS) No statistically significant effect on disability progression	Injection site reactions; post-injection reaction (chest pain, flushing and dyspnea)	Cutaneous necrosis; anaphylaxis (rare)
Mitoxantrone	RR MS; SP MS; PR MS Second or third line	12 mg/m2i.v. every three months or 8 mg/m2i.v. every month	65% reduction of relapse risk over two years (mostly in RR MS)[98] 66% reduction of risk of disability progression at two years (mostly in RR MS)[98]	Nausea/vomiting; amenorrhea/infertility; alopecia; blue discoloration of sclera and urine	Infusion site tissue necrosis; myelotoxicity; infections; cardiotoxicity; acute leukemia
Natalizumab	RR MS Second line	300 mg i.v. every four weeks	68% reduction of ARR over two years 42% reduction of progression of disability at two years	Headache	Infusion associated reactions; anaphylaxis; infections; hepatotoxicity; progressive multifocal leukoencephalopathy
Fingolimod	RR MS Second line (first line in the United States)	0.5 mg per os every day	48%-54% reduction of ARR over two years 30% reduction of progression of disability at two years	Fatigue; headache	Bradyarrhythmias after first dose; lymphopenia; viral infections (VZV); macular edema; hepatotoxicity; hypertension
Teriflunomide	RR MS First line	14 mg per os every day	31%-36% reduction of ARR over one year or more 26%-32% reduction of progression of disability at one year or more	Nausea; diarrhea; alopecia	Myelotoxicity; hepatotoxicity; infections; peripheral neuropathy; pancreatic fibrosis; teratogenicity (requires accelerated elimination procedure)
Dimethyl fumarate	RR MS First line	240 mg per os twice a day	44%-53% reduction of ARR over two years 38% reduction of progression of disability at two years	Flushing; gastrointestinal symptoms; pruritus	Lymphopenia; progressive multifocal leukoencephalopathy
Alemtuzumab	RR MS Second or third line	12 mg/d i.v. for five days followed by 12 mg/d i.v. for three days one year after the first course	49%-55% reduction of ARR over two years compared to s.c. interferon beta 1a 42% reduction of progression of disability at two years compared to s.c. interferon beta 1a	Infusion associated reactions; myalgia; arthralgia; irregular menstruation	Infusion associated reactions; cytokine release syndrome; lymphopenia; infections; autoimmune thyroiditis; thrombocytopenic purpura; glomerulonephritis
Azathioprine1	MS of all types First or second line	2.5 mg/kg per os every day	23% relative risk reduction of the frequency of relapses over two years No statistically significant effect on disability progression at two and three years[98]	Gastrointestinal symptoms; photosensitivity; irregular menstruation/reduced fertility	Myelotoxicity; hepatotoxicity; lymphopenia; infections; acute pancreatitis; increased toxicity in subjects with thiopurine methyltransferase deficiency; malignancies (cumulative dose > 600 g)
Cyclophos- phamide1	SP MS; PP MS Third line	1 g i.v. over three days or 500 mg i.v. over five days	No statistically significant effect on disability progression at two and three years[98]	Nausea/vomiting; amenorrhea/infertility; alopecia	Myelotoxicity; hepatotoxicity; infections; hemorrhagic cystitis; bladder cancer

¹The use of these drugs for the treatment of multiple sclerosis is off-label in most countries. ARR: Annualized relapse rate; CD: Clinically definite; CIS: Clinically isolated syndrome; PP: Primary progressive; PR: Progressive-relapsing; RR: Relapsing-remitting; SP: Secondary progressive.

Table 2 Critical factors affecting the decision of starting disease-modifying therapies for multiple sclerosis

Factors suggesting not to start a DMT	CIS with favourable prognostic factors
	RR MS with no relapses in previous two years, no disability, and no evidence of MRI activity (potential “benign” case)
	Progressive forms of MS with no relapses or evidence of MRI activity
	Pregnancy planning
	High risk of low adherence to treatment
Factors suggesting to start a first line DMT	CIS with unfavourable prognostic factors
	RR MS with at least one relapse in previous two years but less than two relapses in the last year, low residual disability, and/or active MRI
Factors suggesting to start a second line DMT	RR MS with at least 2 disabling relapses in the last year
	Progressive forms of MS with relapses and/or active MRI

DMT: Disease-modifying therapy; CIS: Clinically isolated syndrome; MS: Multiple sclerosis.

Table 3 Critical factors affecting the decision of changing current disease-modifying therapy for multiple sclerosis

Factors suggesting to switch from a first line DMT to another	Tolerability/safety issues
	Suboptimal efficacy with disease activity not suitable for escalation to a second line DMT
	Persistent high-titre neutralizing antibodies in patients treated with interferon beta
Factors suggesting to switch from a first line to a second line DMT	RR MS patients experiencing at least one relapse and with an active MRI during the previous year on treatment
	RR MS patients transitioning to the secondary progressive phase with evidence of relapses or MRI activity
Factors suggesting to switch from a second line DMT to another or to a third line DMT	RR MS patients continuing to experience relapses
	Progressive forms of MS with relapses and/or active MRI despite treatment
	Safety issues (e.g., patients on natalizumab at high risk of developing progressive multifocal leukoencephalopathy)
Factors suggesting to switch from a second line to a first line DMT	Tolerability/safety issues
	Risk perception of patient

DMT: Disease-modifying therapy; RR: Relapsing-remitting; MS: Multiple sclerosis.