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.