Disease-modifying therapies in relapsing–remitting multiple sclerosis

Figures & data

Table 1 Randomized controlled trials and other studies of the effects of IFNβ1a

Study	Duration/follow-up	Type of study and subtype of MS	Drug and route	n	Main results
Jacobs et al^Citation8	3 years	-RCT - RRMS	IM IFNβ1a 30 μg versus placebo	301	Reduced activity, volume, and number of lesions on MRI in 71% of cases (0 lesions), showed moderate side effects and short-term effect, less than 2 years; it reduced the accumulation of permanent physical disability, exacerbation frequency, and disease activity as measured by gadolinium-enhanced lesions on brain MRI
Bermel et al^Citation33	15 years (follow-up of MSCRG study)^Citation8	Multicenter, single timepoint	At follow-up, 46% (56 of 122) of patients were receiving IM IFNβ1a and 54% (66 of 122) were not	122	For some patients with MS, long-term use of IM IFNβ1a is associated with significantly less disability progression, better quality of life, and greater independence with self-care; IM IFNb-1a is well tolerated, and no new safety concerns were identified over 15 years of use; long-term effect (more than 10 years)
Jacobs et al^Citation4	3 years	RCT CIS	IV and oral steroids, followed by placebo versus IFNβ1a IM 30 μg weekly	383	Delay in disability progression was significantly lower on IM IFNβ1a than on placebo; compared with placebo, patients on IFNβ1a had a relative reduction in volume of brain lesions, fewer new or enlarging lesions, and fewer gadolinium-enhancing lesions at 18 months; moderate side effects and short-term effect (less than 2 years)
Kinkel et al^Citation47	5 years (follow-up of CHAMPS) study^Citation4	RCT CIS	IM, IV, and oral steroids, followed by placebo versus IFNβ1a IM 30 μg weekly	203	Delayed disability progression, delay of conversion to CDMS, reduction in activity, volume, and number of lesions on MRI in 71% of cases (0 lesions), moderate side effects, short-term effect (less than 2 years); modest beneficial effects of immediate treatment compared with delayed initiation of treatment
PRISMS^Citation48	2 years	RCT RRMS	SC IFNβ1a 22 μg versus placebo or SC IFNβ1a 44 μg SC versus placebo	560	Significantly lower relapse rates at 1 and 2 years with both doses of SC IFNβ1a than with placebo; time to first relapse was prolonged by 3 and 5 months in the 22 μg and 44 μg groups, respectively, and the proportion of relapse-free patients was significantly increased; SC IFNβ1a delayed progression in disability, and decreased accumulated disability during the study; the accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group; short-term effect (less than 2 years)
Schwid et al^Citation49	2 years	RCT RRMS	IM IFNβ1a 30 μg versus SC IFNβ1a 44 μg	439	SC IFNβ1a 44 μg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFNβ1a 30 μg QW treatment; the SC group also had a decreased number of relapses, and reduced activity, volume, and number of lesions on MRI with SC IFNβ1a, moderate side effects, short-term effects (of less than 2 years)
Durelli et al^Citation50	2 years	RCT RRMS	IM IFNβ1a 30 μg weekly versus SC IFNβ1b SC QOD	188	High-dose IFNβ1b administered every other day was more effective than interferon IFNβ1a given once a week; delayed disability progression and a significant reduction in activity, volume, and number of lesions on MRI; short-term effects (less than 2 years)
Koch-Henriksen et al^Citation51	2 years	Multicenter, controlled, open-label, randomized, head-to-head	IFNβ1a SC 22 μg weekly versus IFNβ1b 250 μg QOD	278	250 μg of IFNβ1b administered every other day did not prove clinically superior to once-a-week administration of 22 μg of IFNβ1a; relapse rates, sustained progression, and time to first relapse were eqivalent; short-term effect, less than 2 years
Mikol et al^Citation52	2 years	Multicenter, randomized, comparative parallel-group, open-label study RRMS	IFNβ1a 44 μg SC TIW, Glatiramer 20 mg SC weekly	764	There was no significant difference between IFNβ1a and glatiramer acetate in the primary outcome; relapse rates were equal between groups, fewer gadolinium-enhancing lesions in IFN β1a group; lesions per patient, similar side effects in number and type, both showed similar delay disability progression and moderate side effects; short-term effect (less than 2 years)
Comi et al^Citation53	2 years	RCT CIS	IFNβ1a 22 μg SC TIW versus placebo	308	Delayed conversion to CDMS in IFN β1a group versus placebo; significant effect on MRI measures and reduced activity, volume, and number of lesions in MRI; short-term effect (less than 2 years)
Sorensen et al^Citation30	2 years	Multicenter RCT RRMS	MP 100 mg PO, daily for 5 days every 4 weeks + IFNβ1a 44 μg SC TIW	130	Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to SC-IFNβ-1a in patients with RRMS led to a significant reduction in relapse rate
Cohen et al^Citation54	2 years	RCT Phase IV	IM IFNβ1a 30 mg + placebo + IV MP 1000 mg/day for 3 days or IM IFNβ1a 30 mg + MTX 20 mg PO + IV MP 1000 g/day for 3 days	313	This trial did not demonstrate a benefit of adding low-dose oral methotrexate or IV MP every other month to IFNβ1a in RRMS patients; all of the drug combinations showed a reduction in number and size of previous T2-hyperintense lesions; IV MP decreased the formation of anti-IFN NABs

Abbreviations: QOD, every other day; TIW, 3 times per week; RCT, randomized control trial; R, randomized; NR, nonrandomized; IM, intramuscular; SC, subcutaneous; CDMS clinically definite multiple sclerosis (Kaplan-Meier ± 95% CI); CIS, clinically isolated symptom; RRMS, relapsing–remitting multiple sclerosis; MRI, magnetic resonance imaging; IV, intravenous; PO, orally; MP, methylprednisolone; MTX, methotrexate; NABs, neutralizing antibodies.

Table 2 Current drugs used in relapsing–remitting multiple sclerosis.

Drug	Brand name	Delivery systems	Dosage	Side effects	Monitoring
IFNβ-1a (IM)	Avonex^®	Reconstitution needed/prefilled syringe	30 μg IM once weekly	Influenza-like symptoms	CBC, LFTs
IFNβ-1a (SC)	Rebif^®	Ready to use prefilled syringe	22–44 μg SC three times weekly	Influenza-like symptoms and injection site reactions	CBC, LFTs
IFNβ-1b (SC)	Betaseron^®	Reconstitution needed	0.25 mg SC every other day	Influenza-like symptoms and injection site reactions;	CBC, LFTs
Glatiramer acetate	Copoxone^®	Ready to use prefilled syringe	20 mg SC once daily	injection site reactions and a benign systemic reaction (flushing, chest tightness with racing or pounding heartbeat, anxiety, and difficulty in breathing)	Local site of injection
Mitoxantrone (immunosuppressive)	Novantrone^®	Injection concentrate supplied, dilution required	5 to 12 mg per m^2 IV every 3 months	Mild chemotherapy-related side effects, cumulative cardiotoxicity, small increased risk of leukemia	CBC, cardiological assessment

Abbreviations: IFN, interferon; IM, intramuscular; SC, subcutaneous; IV, intravenous; CBC, complete blood count; LFTs, liver function tests.

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