Escalation vs Early Aggressive Treatment in Multiple Sclerosis

The treatment of patients with MS has historically involved escalating therapies from a moderate-efficacy DMT to a higher-efficacy DMT when treatment failure is observed. With the introduction of increasingly effective DMTs in recent years, accumulating evidence supports the benefits of initiating high-efficacy DMTs early in the disease course for patients with RRMS.¹
 
Yinan Zhang, MD, is an assistant professor of neurology at the Ohio State University Wexner Medical Center in Columbus. Clinically, Dr Zhang’s specialties include MS and related neuroimmunological disorders, and his focus is on identifying the optimal individualized treatment approach for each patient. In his research, Dr Zhang studies the effects of age-related clinical and molecular changes on MS disease progression. In this article, Dr Zhang discusses the benefits and risks associated with escalation vs early aggressive treatment approaches and key considerations that may inform treatment selection among the range of DMTs for MS.

According to the available literature on the topic, what are the key benefits and risks associated with the incorporation of early aggressive treatment with DMTs as a broader strategy, compared to the escalation approach for patients with MS?

The early aggressive treatment approach in MS uses high-efficacy DMTs at the start of treatment of RRMS as opposed to starting with a lower-efficacy DMT with a low side-effect profile.^1,2 Data indicate that progression of disability in MS has 2 stages, with the first being dependent on focal and acute inflammatory activity, causing relapses and new lesion formation on MRI. With early aggressive treatment, the goal is to suppress disease activity early on to prevent the accumulation of disability and the conversion of RRMS to SPMS, since DMTs are generally ineffective in the treatment of people with progressive forms of MS.¹
 
The main risk for starting with high-efficacy DMTs is that they also generally have a high side-effect profile, such as an increased risk for infections.² In contrast, the escalation strategy starts with moderate-efficacy, lower-risk DMTs; monitors for ongoing disease activity; and changes therapy when it occurs. Historical evidence from observational studies have fueled support for early aggressive treatment, but these studies have limitations. Current randomized controlled trials such as DELIVER-MS (ClinicalTrials.gov identifier: NCT03535298) and TREAT-MS (ClinicalTrials.gov identifier: NCT03500328) are in the process of comparing the 2 treatment strategies.³

Could you elaborate on the nuanced role of patient age in deciding whether to pursue an escalation or early aggressive treatment approach in MS? Furthermore, what additional patient-specific factors should clinicians take into account when choosing between these distinct MS treatment strategies?

Age has a major impact on disease pathophysiology in MS. Young people with MS are at higher risk of having relapses and forming new lesions seen on MRI, whereas with increasing age, the relapse rate decreases and MRI results are more often stable.⁴ Young patients with RRMS with active disease, numerous T2 lesions on the brain and spine, and no irreversible disability likely stand to benefit the most from early aggressive treatment.¹ However, older adults with MS are at higher risk of developing progressive forms of MS. In older adults with MS, you also must consider the potential for increased side effects with age, including a higher risk of infections, greater potential for drug interactions, and contributions to polypharmacy.⁵
 
In addition to age, a main factor driving how I make the decision for DMT selection is disease activity. For instance, in a newly diagnosed patient with RRMS who has had multiple relapses in the past year and corresponding new and enhancing lesions in the brain and spine, I would say that this type of patient is a better candidate for early aggressive therapy — rather than starting with a modest-efficacy DMT in the setting of a high likelihood of breakthrough disease activity. On the other hand, in another patient with multiple comorbidities and frequent infections, such as urinary tract infections, I may rather start them on safer but lower-efficacy DMTs.

What do research findings suggest about the comparative effectiveness and safety of the 2 approaches to early aggressive treatment in MS: using high-efficacy DMTs such as natalizumab to achieve sustained immunosuppression vs the use of induction drugs such as mitoxantrone?

The approach to using high-efficacy drugs involves continuing treatment for years to, potentially, decades while maintaining immunosuppression. Induction therapies are used for a short time to control disease activity before the patient is switched to maintenance therapy or taken off treatment with plans for careful monitoring of disease reactivation. DMTs in the high-efficacy treatment category, such as anti-CD20 agents, natalizumab, and S1P receptor modulators, have all been shown in multiple phase 3 trials to have a marked reduction in the annualized relapse rate compared to placebo or an active comparator drug, with real-world data confirming low relapse rates.¹
 
Induction therapies include mitoxantrone, alemtuzumab, cladribine, and autologous hematopoietic stem cell transplant. While these drugs also show significant reductions in the annualized relapse rate, concern about safety risks have relegated these agents to second-line or third-line treatment at many institutions.¹
 
When comparing the efficacy of MS DMTs, it should be noted that because trial populations have inherent differences, you cannot simply compare outcomes across clinical trials. For instance, placebo groups in historical trials tended to have higher relapse rates than placebo groups in more recent trials.⁶ Only a head-to-head trial of a DMT vs an active comparator DMT would allow conclusions to be drawn on the basis of comparisons of the 2 drugs.

Between these 2 early aggressive treatment approaches for MS, what key factors should be considered in selecting a specific DMT for a patient?

In most patients who receive early aggressive treatment, the initial approach is to use 1 of the high-efficacy drugs, such as anti-CD20 agents, natalizumab, or a S1P receptor modulator. Natalizumab should not be considered for patients who are positive for John Cunningham (JC) virus due to the risk for progressive multifocal leukoencephalopathy (PML), liver failure, and other major adverse reactions.³
 
Ocrelizumab is often preferred in patients who desire infrequent treatment limited to every 6 months yet high treatment efficacy, and those who do not wish to travel may consider the self-injectable anti-CD20 agent ofatumumab, which is administered monthly. In other cases, preexisting comorbidities or the preference to avoid certain side effects may direct the selection of DMTs.³
 
Patients who continue to have breakthrough disease on a high-efficacy drug may be advised to consider induction therapy. Among these therapies, many patients prefer cladribine due to a lower treatment burden and ease of use in pregnancy planning.^1,7 Stem cell transplant was not often used due to higher mortality risks, but growing experience in transplant centers and better selection of patients in recent years have helped bolster this therapy’s safety.⁸

For MS patients receiving early aggressive treatment with DMTs, can you describe the importance of monitoring — and which types of monitoring are indicated — for adverse effects, disease progression, and treatment response?

Safety monitoring includes liver function tests, urinalysis, and routine checks of complete blood count to watch for lymphopenia.⁹ With natalizumab, it is important to check JC virus antibodies every 3 to 6 months to monitor for seroconversion to positive JC status.³
 
For the anti-CD20 therapies, periodic checks of immunoglobulins can identify individuals who have developed hypogammaglobulinemia, and assessment of B cell counts can provide assurance that the medication is appropriately depleting B cells and check for early B cell reconstitution.^3,10 S1P receptor modulators require additional monitoring, with annual exams for macular edema and periodic skin exams to look for potentially cancerous lesions.¹¹
 
MRI of the brain and spinal cord, with and without contrast, should be performed within 6 months of treatment initiation to establish baseline MRI findings on the new therapy and can be repeated annually for disease monitoring. In the real world, it may not be feasible to obtain annual brain and spine MRI on all patients for a variety of reasons, in which case priority should be given to performing brain MRI due to the higher likelihood of lesions, in particular asymptomatic lesions, forming in the brain.^8,12 The induction agents have similar monitoring parameters, but MRI monitoring should be more stringent in patients who have stopped treatment after induction therapy.

What are some important factors that may inform the decision to switch treatment classes for MS patients receiving early aggressive treatment, and what drug selection considerations exist in this setting?

These days, most patients receiving early aggressive treatment achieve good control of MS disease activity and rarely switch treatment due to breakthrough disease. Instead, safety-related concerns are common reasons for switching. For example, patients receiving natalizumab who seroconvert to positive JC status should come off the treatment due to increased risk of developing PML.³ For my patients receiving anti-CD20 therapies, I may advise them to switch if they experience frequent infections, symptomatic hypogammaglobulinemia, and/or infusion intolerance, although infusion intolerance is rare in my experience. A common reason I have seen for switching among recipients of S1P receptor modulators is persistent high-grade lymphopenia.
 
In these situations, a relatively quick transition to another DMT in the setting of disease rebound typically seen after discontinuation of natalizumab or the S1P receptor modulators should be ensured.¹ It is common to see providers switch between the 3 rather than favor induction therapy when the reason for switch is not treatment failure.

What research is needed to increase our understanding and further elucidate optimal strategies for early aggressive treatment in patients with MS?

Numerous areas would benefit from additional research to advance the clinical practice of selecting the best treatment plan for these patients:

• As mentioned, randomized controlled trials are underway to determine whether early aggressive therapy is more beneficial than escalation therapy.³
• Real-world data on safety and long-term side effects of DMTs would continue to inform providers of the risks of starting and remaining on treatment.
• Studies on patient characteristics that affect disease pathophysiology may help guide the selection of DMTs for individuals at risk for a more aggressive disease course.
• The development and validation of new biomarkers for disease monitoring, such as serum neurofilament light chain, can provide additional dimensions of monitoring for treatment effectiveness.
• More data on the safety and efficacy of DMT discontinuation with age will help inform providers and patients about the optimal duration of treatment.
• There is also a role for behavioral and social research on issues such as disparities in DMT access and prescription patterns.

This list is by no means comprehensive. On a smaller scale, institutional research and quality-improvement projects can shed additional light on understanding DMT strategies within the institution as well as barriers to and challenges in their use. This may have immediate potential to improve clinical practice.
 
This Q&A was edited for clarity and length.

References

1. Edan G, Le Page E. Escalation versus induction/high-efficacy treatment strategies for relapsing multiple sclerosis: which is best for patients? Drugs. 2023;83:1351-1363. doi:10.1007/s40265-023-01942-0
 
2. Filippi M, Amato MP, Centonze D, et al. Early use of high-efficacy disease‑modifying therapies makes the difference in people with multiple sclerosis: an expert opinion. J Neurol. 2022;269:5382-5394. doi:10.1007/s00415-022-11193-w
 
3. Simpson A, Mowry EM, Newsome SD. Early aggressive treatment approaches for multiple sclerosis. Curr Treat Options Neurol. 2021;23(19). doi:10.1007/s11940-021-00677-1
 
4. Zhang Y, Cofield S, Cutter G, Krieger S, Wolinsky JS, Lublin F. Predictors of disease activity and worsening in relapsing-remitting multiple sclerosis. Neurol Clin Pract. 2022;12(4):e58-e65. doi:10.1212/CPJ.0000000000001177
 
5. Macaron G, Larochelle C, Arbour N, et al. Impact of aging on treatment considerations for multiple sclerosis patients. Front Neurol. 2023;14:1197212. doi:10.3389/fneur.2023.1197212
 
6. Zhang Y, Salter A, Wallström E, Cutter G, Stüve O. Evolution of clinical trials in multiple sclerosis. Ther Adv Neurol Disord. 2019;12:1756286419826547. doi:10.1177/1756286419826547
 
7. Krysko KM, Bove R, Dobson R, Jokubaitis V, Hellwig K. Treatment of women with multiple sclerosis planning pregnancy. Curr Treat Options Neurol. 2021;23(11). doi:10.1007/s11940-021-00666-4
 
8. Patti F, Chisari CG, Toscano S, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis patients: monocentric case series and systematic review of the literature. J Clin Med. 2022;11(4):942. doi:10.3390/jcm11040942
 
9. Olek MJ, Mowry E. Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults. UpToDate. Last updated November 20, 2023. Accessed January 17, 2023.
 
10. Fischer T, Ni A, Bantilan KS, et al. The impact of anti-CD20-based therapy on hypogammaglobulinemia in patients with follicular lymphoma. Leuk Lymphoma. 2022;63(3):573-582. doi:10.1080/10428194.2021.2010058
 
11. Dumitrescu L, Papathanasiou A, Coclitu C, et al. An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis. Expert Opin Pharmacother. 2023;24(4):495-509. doi:10.1080/14656566.2023.2178898
 
12. Marrodan M, Gaitán MI, Correale J. Spinal cord involvement in MS and other demyelinating diseases. Biomedicines. 2020;8(5):130. doi:10.3390/biomedicines8050130
 
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