Therapy of MS
The DMTs are expensive, and when trying to optimize cost-effective management of MS, several controversial issues must be confronted (Table 8). The remainder of this clinical update will address these topics and review the rationale for specific recommended approaches.

Table 8. Current Controversial Topics in the Management of MS
Should DMT be recommended for all patients with MS?


How early should DMT be started?


How do you select which DMT to use?


How do you determine suboptimal response/treatment failure?


How do you deal with suboptimal response/treatment failure?


What future treatment approaches look promising?


What is the role of steroids for patients with MS?



Should DMT Be Recommended for All Patients With MS?
The National MS Society has recently updated its consensus guidelines for use of MS DMT (Table 9).[26] It endorses the use of immunomodulators for all relapsing forms of MS and for consideration of treatment for selected first-attack/high-risk patients. Thus, unless a specific contraindication exists, therapy is appropriate in all relapsing patients, secondary progressive patients with superimposed relapses, progressive relapsing patients, and many first-attack patients. The single exception is benign relapsing MS, which does not need to be treated. However, because benign MS is a strictly retrospective diagnosis, most patients and physicians will choose not to gamble on a benign course and risk missing the benefits of treatment. This approach is predicated on the fact that the immunomodulator DMTs are safe and well tolerated. Contraindications to therapy include pregnancy, attempts to become pregnant, breastfeeding, inability to tolerate DMT, allergy to the drugs or their carriers, and severe comorbidity (such as significant psychiatric disease that makes compliance impossible or risky).

Table 9. NMSS Disease Management Consensus Statement (NMSS, 2002)[26]
Initiate immunomodulator treatment as soon as possible following diagnosis of MS with a relapsing course; consider for selected first-attack/high-risk patients.


Access to therapy should not be limited by relapse frequency, age, level of disability, or most medical conditions.


There should be access to/coverage for all FDA-approved agents; it is permissible to change drugs.


Immunosuppressant (mitoxantrone) therapy may be considered for selected worsening and/or relapsing patients.


None of the DMTs are approved for use in women who are pregnant, nursing, or trying to become pregnant.


Treatment should not be stopped while insurers evaluate for continuing coverage.


Therapy continues indefinitely except in the event of


- clear lack of benefit;

- intolerable side effects;

- new data; or

- better therapy.



Treatment of Secondary Progressive MS Without Relapse
Data to support treatment of patients with secondary progressive MS without relapses are mixed. The European study of IFN beta-1b found treatment to be quite effective in patients with secondary progressive MS, with or without relapses.[27] No other study has been as convincingly positive. The International MS Secondary Progressive Avonex Controlled Trial (IMPACT), using double-dose IM IFN beta-1a, documented a treatment effect on progression as measured by the MS functional composite (MSFC) (25-foot timed walk, 9-hole peg test, Paced Auditory Serial Addition Test [PASAT]), but not on the EDSS.[28] However, the only significant effect on the MSFC was in the 9-hole peg test component. Neither the North American IFN beta-1b study nor the SC IFN beta-1a Secondary Progressive Efficacy Clinical Trial of Recombinant IFN beta-1a in MS (SPECTRIMS) trial showed an effect on progression based on EDSS.[29,30]

Despite the discrepancies in the effect of treatment on EDSS progression, all the trials of treatments for secondary progressive MS have shown benefits in suppressing superimposed relapses, and on MRI (T2 lesion burden, Gd+ lesions) parameters. The only DMT approved for secondary progressive MS in the United States is the immunosuppressor mitoxantrone. Because of concerns about cardiotoxicity, this drug can only be used up to a lifetime maximum of 140 mg/m2 (about 11 doses). The pivotal mitoxantrone in MS (MIMS) trial entered 194 patients who had relapsing and secondary progressive MS with or without relapses, but participants were randomized to 1 of 3 treatment arms,[31] and thus, no statement about statistical significance of treatment is possible with regard to the group of patients with secondary progressive MS without relapses.

Treatment of Primary Progressive MS
There is no proven treatment for primary progressive MS. The recent phase 3 trial of glatiramer acetate (GA), the PROMISE trial, did not find a treatment benefit on progression. Although the drug was well tolerated, neither placebo- nor GA-treated patients deteriorated at the rate predicted from natural history studies. Two phase 2 trials of IFN beta in primary progressive MS have proved disappointing; 1 suggested modest benefits on secondary outcomes, the other was almost uniformly negative.[32,33] An ongoing phase 2 trial of mitoxantrone has not yet reported any results.

Thus, based on available evidence, use of DMT cannot be endorsed for patients with either secondary progressive MS without relapses or those with primary progressive MS, who together may account for 25% of all patients with MS. At the same time, a case can be made for treatment benefit in patients who have secondary progressive MS with Gd+ activity on MRI, who have worsened by greater than 1 EDSS point in the previous 2 years, or who are temporally close to their relapsing phase. In addition, a benefit of DMT, especially over the long term, has not been disproven for primary progressive MS.