Treating Early Relapsing Multiple Sclerosis: Induction & Escalation Approaches

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. Traditional natural history studies showed that patients with the relapsing-remitting form of MS (RRMS) often convert to a secondary progressive form in a median time of 10 to 20 years.¹ Progressive MS can severely affect the quality of life of patients and their families. Moreover, it has been shown that society as a whole can be negatively affected owing to the resulting disability of working-age individuals.² The development of disease modifying therapies (DMTs) over the past 2 decades, with the goal of preventing the accumulation of lesions and the secondary progression of disability, has significantly improved the prognosis of MS.²

A characterization of MS phenotypes based on disease activity and progression, both defined over a specific time frame, has been created in recent years.³ Active MS refers to occurrence of new inflammatory disease, including clinical relapses (ie, neurologic symptoms that can eventually fully or partially recover) or new or enhancing lesions on brain or spinal cord MRI. Progressive MS refers to a steady, objective, neurologic deterioration without recovery.³ Most DMTs target the inflammatory component of MS, which is most prominent in RRMS and present to a lesser extent, if at all, in progressive MS.⁴ DMTs have little to no direct effect on neurodegeneration, the main driver of progressive MS.⁴ As such, most available DMTs are only approved for treating active forms of MS, and adequate treatments for inactive, progressive MS are lacking.

DMTs can be classified according to their efficacies based on results from clinical trials. Interferons, glatiramer acetate, teriflunomide, and fumarates are considered moderate-efficacy DMTs, and the monoclonal antibodies natalizumab, ocrelizumab, rituximab (off-label), ofatumumab, and alemtuzumab, as well as mitoxantrone and cladribine are considered higher efficacy. Opinions vary regarding the categorization of sphingosine-1-phosphate receptor (S1PR) modulators, which likely have intermediate efficacy. However, it is important to keep in mind that efficacy, which is determined under the ideal conditions of a clinical trial, is different from the effectiveness of an intervention, which speaks more to the effect of the medication in real-world clinical practice.

Treatment Strategies

Although multiple treatment options are available from which physicians and patients may choose, there are no clear class I evidence-based guidelines that dictate the ideal approach for treatment. There is general consensus that most people with relapsing MS should be treated soon after diagnosis, as data suggest that the earlier start of treatment after diagnosis, the better the prognosis.² This notion is supported by both the American Academy of Neurology (AAN) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) guidelines.^5,6 The 2017 McDonald criteria⁷ allow for an earlier time of diagnosis of RRMS after a first consistent demyelinating attack compared with previous criteria,⁸ which facilitates an even earlier start of treatment. Despite this progress in the diagnosis of MS, it remains difficult to determine which treatment is best to use initially. The lack of definite recommendations allows for greater flexibility in clinical practice, with physicians relying mostly on the efficacy and risk profiles of available DMTs, disease phenotypes, their own clinical expertise, and patient characteristics. There are 2 general approaches for the initial treatment of relapsing MS: the escalation approach and the induction approach (Figure).

Escalation Approach

The escalation approach emphasizes initiation of a moderate-efficacy DMT, with careful monitoring for ongoing disease activity and change in therapy if it does occur. This treatment approach is justified by the fact that not everyone with MS requires higher efficacy therapy to stop the formation of new lesions or the occurrence of relapses, such that the generally higher risks associated with higher efficacy therapeutics are not justified. This approach relies on adequate follow-up to detect possible breakthrough disease in a timely manner. Early detection of treatment failure is needed to act on and prevent the accumulation of additional inflammatory disease activity. The precise threshold, however, that distinguishes acceptable disease activity from that requiring a change in therapy is not well understood, with most data coming from small centers evaluating breakthrough disease activity after interferon therapy,⁹ limiting generalizability across the population in the modern treatment era.

There is no uniformly appropriate approach after breakthrough disease occurs when a person has been receiving treatment with first-line therapy. Switching to a higher efficacy DMT is a reasonable approach for many individuals. Alternatively, switching to a DMT with a similar level of efficacy but a different mechanism of action can be attempted before escalation to a more aggressive treatment. This decision, in part, may be influenced by a number of factors, including the degree of breakthrough disease; degree of adherence to DMT, follow-ups, and safety monitoring; patient factors, such as age, MS severity features, future pregnancy goals, comorbidities, contraindications to specific treatments, or concerns about risk; and many others.

The escalation approach is successful for many with MS. When considering DMT efficacy in clinical trials, the reduction in disease activity reported represents an average across those individuals assigned to a given therapy; in reality, a proportion of the participants have no further disease activity, while others may experience a good deal of disease activity despite use of a treatment with efficacy in the trial. The main drawback of escalation is the risk of accumulating further lesions if initial treatment with moderate-efficacy DMTs is unsuccessful, which may be associated with increased risk of disability accumulation, although the literature surrounding whether this is true in the context of systematic and vigilant escalation is not robust (Table). Another challenge to the escalation strategy is the lack of a universal method to identify nonresponders in the assessment of treatment response. Several composite outcome measures, including the Rio score, the modified Rio score, the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) score, and no evidence of disease activity (NEDA), have been developed to monitor for treatment response. Nonetheless, all these assessment measures face challenges in clinical practice,¹⁰ including concerns that ongoing disease activity might be undetectable using these metrics and that more sensitive biomarkers may be needed to identify suboptimal treatment.^11,12

Induction Approach

Induction refers to the initial use of strong immunosuppressive agents to control or eliminate disease activity. The term induction is commonly used in the treatment of hematologic malignancies; some in the MS field prefer other terminology. Induction, or early aggressive therapy, in MS relies on using higher efficacy therapies to decrease inflammatory activity early in the disease course, when the bulk of injury is due to inflammation. Later in the disease course, when inflammatory activity is lessened because of age and, for some, neurodegeneration becomes the main driver of clinical disability progression, the therapeutic effects of DMTs appear to be much lower. Some experts argue that since there is a lack of regenerative therapies, the early use of higher efficacy therapies to prevent destruction and irreversible injury is warranted.¹³ They postulate that there is a short therapeutic window early in the disease process during which DMTs can significantly alter long-term disease outcome.¹⁴ A meta-analysis supporting this notion showed that the higher efficacy DMTs appear to be associated with more disability prevention than moderate-efficacy DMTs only among patients younger than 40.5 years.¹⁵

The main disadvantage of this approach is that the higher efficacy DMTs may be associated with increased risk. Serious infections and potentially, increased risk of malignancy, are some of the major adverse events associated with these therapies. Long-term risks, particularly in real-world populations, remain to be fully established for many of the higher efficacy therapies. Some experts argue that younger people are less prone to serious side effects,¹⁰ and therefore starting with higher efficacy DMTs is less dangerous than exposing patients to these risks when they are older. It is unclear, however, whether an attentive escalation approach (rigorous monitoring with early switch for breakthrough disease) leads to a dramatically older age for starting a higher efficacy DMT; rather, it just eliminates the need to use the more efficacious class at all in those who do well on moderate-efficacy therapy. Other issues with the induction approach include the unknown duration of treatment needed to definitively control disease activity before de-escalation can be safely attempted. In addition, it can be challenging to de-escalate some medications that, when stopped, may be associated with risk of MS rebound.^16,17

Escalation vs Induction

The escalation approach has been more commonly used because of the longer experience with and greater availability of traditional, moderate-efficacy therapies compared with relatively new higher efficacy therapies. However, some have argued for using higher efficacy therapies as initial MS treatment. There are no published randomized controlled studies that compare the 2 approaches head-to-head, but several studies attempted to compare the 2 approaches using longitudinal datasets (Table). Brown et al. showed that initial treatment of RRMS with higher efficacy therapies was associated with less risk of conversion to secondary progressive MS.¹⁸ A retrospective, observational cohort study by He et al. showed that treatment with higher efficacy therapies within 2 years of disease onset was associated with lower risk of disability progression compared with starting those medications 4 to 6 years after onset.¹⁹ Harding et al. showed that the mean Expanded Disability Status Scale (EDSS) score increased by 1.2 over 5 years in persons treated with the escalation approach vs 0.3 in those treated with an early intensive treatment.¹² A study by Buron et al. showed that initial treatment with higher efficacy vs moderate-efficacy DMTs was associated with reduced risk of confirmed disability worsening and occurrence of a first on-treatment relapse.²⁰ Iaffaldano et al. also showed that initiating higher efficacy DMTs was associated with lower risk of disability progression.²¹ Spelman et al. compared disability progression between patients from the Danish and Swedish national MS registries. They found reduced rates of disability progression in the Swedish population, where a bigger proportion of patients were started on higher efficacy DMTs.²²

Although such observational studies have the advantage of evaluating effectiveness, potentially in more representative populations, the studies described have several weaknesses that limit certainty about the results. Unlike randomized controlled trials that lead to an even distribution of factors across treatment groups, observational studies are unable to fully account for confounding by potentially relevant covariates, such as ethnicity, race, genetics, environmental influences, and socioeconomic status as well as, and perhaps more importantly, indication for therapy. Observational studies do not have control over treatment allocation. As a result, there is a very high likelihood that individuals included in the studies who started higher efficacy therapies differed from those who were started on moderate-efficacy therapies, and that these differences relate to the disability outcome, a concept known as confounding by indication. Although advanced statistical methods attempt to account for such confounding, there is a strong likelihood that these methods do not fully do so, reducing confidence in the results. The small sample size of many studies and the lack of representation of traditionally underrepresented and underserved groups decrease the generalizability of the results. Moreover, imaging data, which are usually used in clinical practice to monitor treatment response and the need for switching therapy, are lacking in most of these studies. Finally, the cohorts lacked a systematic, clear treatment strategy, taking into account changes in practice over the years owing to the increasing understanding and availability of DMTs and regional or even clinician-level differences in prescribing. In particular, the published studies do not report on clear, defined thresholds for escalation consistent across centers and over time.

To overcome the weaknesses inherent to the currently available data, there are 2 ongoing, pragmatic randomized controlled trials, TREAT-MS^a and DELIVER-MS,^b which are comparing treatment strategies. Participants with RRMS who are treatment naïve are randomly assigned to escalation vs higher efficacy therapy. Disability progression is the primary endpoint in 1 of these trials and the other uses MRI-determined brain atrophy as the primary outcome. These trials promise to provide the higher quality evidence that patients and clinicians need to make treatment decisions after a new MS diagnosis.

Multidimensional Approach for Treatment and Current Recommendations

Reaching an evidence-based consensus regarding the best approach for initiating treatment in newly diagnosed MS is essential. It is important to keep in mind, however, that choosing a treatment is a multidimensional process in which patients should be significantly involved in decision-making with their clinician. In the absence of class I evidence for a specific treatment strategy, many factors may influence the discussion neurologists have with their patients regarding treatment options (Figure). Many physicians consider the severity and prognostic factors of a given patient when counseling about therapeutic approach. Proposed negative prognostic markers include male sex, high severity and frequency of relapses, rapid disability accumulation, high lesion burden on MRI, infratentorial and spinal cord lesions, and brain atrophy.²³ The presence of some of these factors prompts some clinicians to recommend higher efficacy medication as a first DMT. It is important to recall that at the time of diagnosis, it is unclear how much prognostic modification the medications will confer—it is possible that these negative markers at onset mean that the burden of damage has already set up a pathway to longer term disability before the opportunity to intervene with DMTs, at least for some. Further, the studies of prognostic factors in MS often emerge from small cohorts of unclear generalizability and do not fully account for confounding by indication and other factors. The use of prognosis to stratify patients into those 2 approaches is difficult without a unified system to predict unfavorable prognosis and aggressive disease course.²⁴

Aside from the risk-benefit profiles of DMTs and disease burden and prognosis, patient characteristics and preferences often guide the choice of treatment. Certain medical conditions, pregnancy plans, route and frequency of administration of therapies, intensity of monitoring, and risk tolerance are examples of factors that can influence treatment decision.¹⁰ The cost of DMTs and insurance coverage may also be major determinants of treatment choice.¹⁰ A shared decision-making process, personally tailored for each patient, likely ensures patient satisfaction with treatment.²⁵

Conclusion

The treatment of MS over the past couple of decades witnessed a tremendous leap in decreasing disease burden and improving quality of life. The development of several different classes of DMTs without definitive evidence to guide clinical practice, however, renders the choice of treatment approach challenging. As such, developing evidence-based recommendations that guide this difficult decision-making process is more important than ever; the TREAT-MS and DELIVER-MS trials promise to provide some of the higher quality data surrounding this topic. In addition to determining optimal treatment strategies, other unmet needs include the development of unified prognostication methods and monitoring strategies for detection of suboptimal treatment. Only then will we be able to utilize the full potential of DMTs in MS treatment.