Novel strategy of starting high and early to treat RRMS

25 Oct 2021

Multiple sclerosis (MS) is a disease of the central nervous system (CNS), where the immune system attacks the CNS, disrupting the transmission of information within the brain and between the brain and body.1 The proposed pathology is that an abnormal immune response leads to the inflammation and damage of the CNS.1 Preventing the occurrence of exacerbation is of utmost importance as it often leads to the progression of disease into higher grades.2 A novel strategy of starting high and early has been proposed to avoid exacerbation and achieve a good prognosis based on the longitudinal data in comparison of the treatment strategies in different countries.2

Based on the progression of disease, MS is classified into 4 types, namely clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS).3 The goal of MS treatment is to preserve brain tissue while minimizing disease progression, and to maximize neurologic reserve and long-term brain health. Therefore, lifestyle interventions and disease modifying treatment (DMT) are recommended to be initiated as early as possible.2 Currently, the primary approach to treatment is the escalation approach, where moderately effective and low-cost medications are initiated first; switches are made when the adverse effects are no longer tolerable or when the patient relapses with new magnetic resonance imaging lesions.2

Until the late 20th century, the staple of MS treatment was mainly corticosteroids and some wide spectrum immunosuppressants.4 The new era was then accompanied with other more specific DMT drugs like interferon beta and glatiramer acetate, which have remained as the first-line treatment in most places due to their relative safety.4 However, with the advent of new drugs with different mechanisms of action (MOA) like fingolimod, natalizumab and alemtuzumab, the pitfalls of traditional medications, including the less-than-ideal efficacy and injection related adverse events can be avoided, facilitating the novel strategy of starting high and early.2 Fingolimod is a  sphingosine-1-phosphate (S1P) receptor modulator which blocks lymphocytes from emerging from lymph nodes and reduces the number of lymphocytes available to the CNS.5 Natalizumab is a monoclonal antibody targeting the alpha-4 subunit of integrin molecules which affect the adhesion and immigration of leukocytes to the CNS.6 Lastly, alemtuzumab binds to CD52, an antigen on the surface of immunomodulatory cells including B cells, T lymphocytes, monocytes, macrophages, natural killer cells, and granulocytes, allowing for antibody-dependent lysis of the malignant cells.7

In a cohort study, published in August 2020, involving patients from Denmark and Sweden, the effectiveness of the novel approach of starting high and early has been observed by comparing their different national strategies towards MS.8 The primary outcome was the confirmed disability worsening over a time span of 24 weeks, while the 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching were the secondary outcomes.8 About 2,700 patients from Sweden and 2,161 patients from Denmark were included in the study between the years of 2013-2016, with a mean observational period of 4.1 years.8 The percentage of patients initiated with highly effective DMT (as opposed to low or moderately effective DMT) was 7.6% in Denmark and 34.5% in Sweden.8 According to Dr. Tim Spelman, the lead researcher on the team, “MS clinicians in Sweden have much more flexibility when it comes to prescribing DMT, as evidenced by the popularity of off-label rituximab use in Sweden,”9 contrasting to Danish clinicians who were limited to the strategy of dose escalation. As a result, there was an associated 29% reduction (HR=0.71; 95% CI: 0.57-0.90; p=0.004) in the rate of post-baseline 24-week confirmed disability worsening in the Swedish population relative to the Danish population.8 There was also a notable 24% and 25% reduction in the rate of reaching an EDSS of 3 (HR=0.76; 95% CI: 0.60-0.97; p=0.03) and 4 (HR=0.75; 95% CI: 0.61-0.96; p= 0.01) respectively, among the Swedish patients as compared with the Danish counterparts.8

Despite the promising results, there are still barriers to use high efficacy agents as the initial treatment due to the lack of guideline support and sufficient justification for an insurance claim.2 Dr. Spelman added that “This serves as a reminder for authorities that cost-based policies based on the perceived needs of the average patient may have consequences for some patients who are not average.”9

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