Identifying the Role of Disease-Modifying Drugs in the Treatment of Patients With Multiple Sclerosis
Disease-modifying drugs (DMDs) are indicated to reduce relapse rates and slow disease progression in patients with relapsing-remitting multiple sclerosis (MS). The healthcare provider and the patient often jointly decide which DMD is most appropriate to treat the patient’s MS. Results of a recent survey showed that neurologists and nurses viewed DMD safety as the most important attribute in their treatment decision, closely followed by effect on disability progression, quality of life, and relapse rate. Patients with MS agreed with the importance of the latter 3 attributes; however, they valued safety significantly lower (P<.001). Results from clinical trials and observational studies indicate that treatment with DMDs is associated with the improvement of, or the prevention of worsening of health-related quality of life (HRQoL), and, in general, second-line DMDs may have a greater impact on HRQoL than first-line DMDs. However, an assessment of data from clinical trials and observational studies showed that the chances of relapse were lower with early treatment than with delayed treatment, and that early treatment reduced the hazard of conversion to clinically definite MS, compared with no treatment, placebo, or delayed treatment. Early treatment may lead to more discontinuations due to adverse events (although evidence was of low quality). Side effects and risk of relapse may be important predictors of patient adherence to DMDs. Results of a recent real-world study derived from a pharmacy claims database demonstrated better adherence to fingolimod than to dimethyl fumarate and teriflunomide over a 12-month period. Treatment discontinuation was approximately twice as high for dimethyl fumarate (hazard ratio [HR] = 1.93; P<.001) and teriflunomide (HR = 2.27; P< .001) than for fingolimod. Our featured experts in the field discuss identifying the role of DMDs in the treatment of patients with MS.
Q: What is the role of DMDs in the treatment of MS?
Professor and Chair
“Information from clinical trials indicates that all DMDs are efficacious in reducing relapse rate to some degree. Many of them, in addition to that outcome, also improve disability measures, compared with placebo or another medication.”
The purpose of DMDs is to reduce relapse rates and measurable disease progression in people with relapsing MS, and now in patients with primary progressive MS. Information from clinical trials indicates that all DMDs are efficacious in reducing relapse rate to some degree. Many of them, in addition to that outcome, also improve disability measures, compared with placebo or another medication. We hope that by accomplishing those outcomes in a 2- to 3-year period, which is typical for most phase 3 clinical trials, patients who successfully take those medications will sustain good outcome, which will be translated into meaningful benefit for them over many years.
Professor of Neurology
“Approximately half of the disability that is acquired is due to relapses, so decreasing relapses is important, but reducing disability is the key issue so that people can continue to work and raise their families.”
We have been circling around this, about decreasing magnetic resonance imaging (MRI) activity, about decreasing relapses. Approximately half of the disability that is acquired is due to relapses, so decreasing relapses is important, but reducing disability is the key issue so that people can continue to work and raise their families. So, although we may disagree about how to approach that, the bottom line is that we want to use the best drug for the patient—it may be a more aggressive approach or it may be more of a step-wise approach, but quality of life is paramount. The rheumatology literature has showed that an initial double dosing of rituximab, compared with an initial single dose, had a greater effect on reducing—even stopping—joint erosion, which rationalized the use of the double dosing of rituximab in rheumatoid arthritis. If we can treat patients with MS early, using an agent that the patient can tolerate and that is effective for him or her, then we have won the initial skirmish. Nevertheless, we have to surveil the patient all the time with frequent MRIs, particularly at the beginning when he or she has active disease or when we change therapy.
Chairman, Department of Neurology
“The eventual treatment of MS may be early diagnosis, identifying individuals genetically at risk (eg, first-degree relatives), frequent monitoring, and then resetting the immune thermostat by either B-cell depletion (currently with either alemtuzumab or ocrelizumab) and monitoring patients to see if they need to be re-treated.”
We are having a really good discussion about 1 of the major issues in MS, which is whether or not to use step therapy. The problem is that we do not have good data on how to resolve that issue. In my opinion, the issue facing us is that we are all hesitant to start treating a young patient (eg, a woman who is 18 years old or in her 20s) because once you start, the treatment—if successful in stopping exacerbations—becomes a self-fulfilling prophecy. That is, if the patient does well, we attribute that to the therapy, but those of us who were practicing before there were any treatments realize that some patients have very benign courses of disease without treatment. However, every well-conducted study to date has shown that early treatment is better than delayed treatment. In addition, the results of the rheumatoid arthritis data showing that early treatment in the first year allows one to stop treatment suggest that we should offer patients the most effective treatment at disease initiation. I am concerned with the use of autologous bone marrow transplant because pulse cyclophosphamide likely works as well and alemtuzumab also seems highly effective with fewer side effects than bone marrow transplant. So this bone marrow transplant approach does not make a lot of sense to me. But the point is whether we can create a method of treating aggressively early on, then stopping treatment and looking for possible disease reactivation by frequent MRIs and by immune monitoring. To me, that is the real issue, because even in very benign MS—maybe Dr Brod is right—just start treatment with alemtuzumab, stop after 2 rounds, and then follow the patient. Perhaps that is all we need to do to reset the immune thermostat. We have identified 233 genetic variants associated with risk of MS; we know that it is a genetic disease and, so, patients at risk probably have approximately a 10% to 20% chance of developing the disease in terms of interacting with various environmental factors. However, if you can reset the immune thermostat and then decrease the likelihood of redeveloping the disease by a factor of 80%, then we may have avoided disability. The big efforts on disability, neuroprotection, and remyelination are interesting and should definitely be pursued, but the eventual treatment of MS may be early diagnosis, identifying individuals genetically at risk (eg, first-degree relatives), frequent monitoring, and then resetting the immune thermostat by either B-cell depletion (currently with either alemtuzumab or ocrelizumab) and monitoring patients to see if they need to be re-treated. That, to me, is going to be the future of MS.
Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234.
Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209-220.
Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: disease-modifying therapies for adults with multiple sclerosis: report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):789-800.
Rocca MA, Sormani MP, Rovaris M, et al. Long-term disability progression in primary progressive multiple sclerosis: a 15-year study. Brain. 2017;140(11):2814-2819.
Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.