How Do You Select the Appropriate Disease-modifying Therapy?
It is not appropriate to let patients choose their DMT in isolation. Multiple factors must be considered, and the treating neurologist should provide an informed perspective and guide the optimal choice (Table 12).

Table 12. Factors in Choosing an Immunomodulator DMT
MS Factors


- Clinical subtype

- Disease duration

- Prognostic profile

- Clinical disease severity (relapse rate, type of relapse, extent of
recovery, disability)

- MRI disease severity

Patient Factors


- Comorbidity

- Lifestyle preferences

- History of drug tolerance

- Ability to inject

- Compliance

Drug Factors


- Efficacy

- Side-effect profile

- Convenience

- Expense

- Route of delivery



Disease/Patient Factors
Disease considerations involved in the choice of treatment include clinical subtype, duration of MS, prognostic profile, and a variety of disease severity measures. Although the formal trials in first-attack patients were carried out with IFN beta-1a, it is reasonable to conclude that any immunomodulator that works for patients with relapsing MS will work for first-attack patients.

Clinical disease severity is measured by relapse criteria, including number, severity (motor, cerebellar, and sphincter involvement indicate a more severe attack), and degree of recovery, and by development of disability/progression. More severe clinical disease clearly warrants more effective DMT. When seen early in relapsing MS, certain factors suggest a more rapid onset of progressive disease and disability (Table 13). The patient's prognostic profile is also an important factor when choosing therapy. Patient-specific factors include comorbidity (psychiatric disorders, hepatic disease, psoriasis), which may influence choice of drug, as well as practical issues such as ability to self-inject or availability of a partner to do so (Table 13).

Table 13. Factors Indicating Worse Prognosis in Relapsing MS
Early high relapse rate


- > 2 in yr 1

Late in relapse rate


Poor relapse recovery


- EDSS >/= 3 by yr 3

- moderate pyramidal involvement

IgG index (> 1.0) at diagnosis


Late age at onset


EDSS > 3.5


Polyregional onset


- especially sphincter, motor involvement

Sphincter, motor relapses



Drug Factors
Among drug factors, efficacy and side-effect profile are probably the 2 most important considerations. Good data now exist to show that the 3 IFN beta DMTs are not equally effective. Two randomized, prospective, multicenter phase 3 trials have compared the different IFN betas head-to-head. The Independent Comparison of Interferon (INCOMIN) study was funded by the Italian government and the Italian MS Society.[38] The 2-year study enrolled 188 patients with mild (EDSS 1.0-3.5) active relapsing disease. Patients were randomized to receive IFN beta-1a 30 mcg IM once weekly or IFN beta-1b 8 MIU SC every other day. At the end of 2 years, the group receiving IFN beta-1b included a higher proportion of relapse-free patients (51% vs 36%, P = .035), fewer patients with sustained EDSS worsening (14% vs 30%, P = .04), and a greater proportion of patients with no new T2 lesion activity on brain MRI (55% vs 26%, P = .0003) compared with the IFN beta-1a group. Although treating physicians and patients were not blinded, MRIs were read blinded at a central site.

The European-North American Comparative Efficacy (EVIDENCE) study was funded by Serono, the makers of the SC formulation of IFN beta-1a.[39]This 48-week study entered 677 patients with active relapsing MS. Patients were randomized to receive IFN beta-1a 30 mcg IM weekly or IFN beta-1a 44 mcg SC 3 times weekly. Participants underwent monthly MRI scans for 24 weeks, then a final scan at 48 weeks. The critical primary and secondary outcomes, judged at 24 weeks, were proportion of relapse-free patients and combined unique MRI lesions (Gd+ plus T2 lesions, not double counted). Although patients and treating physicians were aware of their therapy, evaluating physicians (who judged relapses) were blinded, and MRIs were read blinded at a central site.

At 24 weeks, the proportion of relapse-free patients was higher in the SC IFN beta-1a compared with the IM regimen arm (75% vs 63%, P = .0005), and combined unique MRI lesions were fewer compared with the IM arm (0.8 vs 1.2, P < .0001). In addition, the group receiving the higher, more frequent IFN beta-1a dose experienced a lower relapse rate (P = .022), fewer treated relapses (P = .004), longer time to relapse (P = .001), lower rate of active MRI scans (P < .0001), and included more patients without any MRI activity (P < .0001).

The 48-week data continued to show a statistically significant difference in favor of the higher, more frequent dose regimen of IFN beta-1a. The proportion of relapse-free patients was 62% vs 52% (P = .009) in the SC vs IM dose regimen, and the number of mean T2 active lesions was lower (0.9 vs 1.4, P < .001), as were proportions of active scans per patient (27% vs 43%, P < .001). The higher, more frequent regimen group was also more likely to have shown no MRI activity (63% vs 45%, P < .001).

In summary, these randomized, prospective comparison trials indicate that, for a broad spectrum of patients with MS, IFN beta has greater efficacy when it is given several times a week (vs once a week) and at higher doses. This is consistent with data showing that a sustained level of IFN beta (with a greater area under the curve drug concentration) is better than brief periods of IFN beta exposure. Dosing frequency may be more important than dosing amount, since a recent study of IM IFN beta-1a given at 30 vs 60 mcg once a week showed similar clinical and MRI effects for both dosing schedules.[40]

Side effects are another important factor in drug selection. Among the DMTs, GA has the best side-effect profile. Since this DMT also has good long-term efficacy data, it is an attractive choice when overall tolerability is a major issue.