High-Efficacy Therapies for Treatment-Naïve Patients With Relapsing–Remitting MS

A research overview of disease-modifying therapy (DMT) options and multiple sclerosis (MS) treatment strategies suggests that minimizing the accumulation of neurological damage early in the disease course and early treatment with high-efficacy therapies (HETs) may enhance long-term clinical outcomes over the lifetime of the patient. 

The use of DMT for newly diagnosed patients with MS is a debated topic due to the multitude of available treatment options and differing recommendations. While historically an escalation approach was used, there is emerging evidence for early HET, which we discuss in this review for patients with relapsing-remitting MS (RRMS). 

Neurological damage in MS begins before clinical symptoms appear, as shown by elevated levels of neurofilament light proteins detected years in advance. Additionally, brain atrophy is accelerated in asymptomatic individuals with radiologically isolated syndrome and in patients with clinically isolated syndrome. 

Effective treatment and close monitoring are essential in slowing or stopping the progression of MS, with the current focus on monitoring both clinical and neuroimaging disease activity. Patient-centered care in MS involves understanding individual patient goals and values, including prioritizing brain health, and considering treatment efficacy and potential side effects when choosing a DMT. 

There are over 18 immunomodulatory DMTs available for the treatment of MS in the US and Europe, including anti-CD20 monoclonal antibodies, natalizumab, S1P receptor modulators, fumarates, interferons, teriflunomide, and glatiramer acetate. Some DMTs are approved for all types of MS, while others are specifically approved for certain types, such as primary progressive MS. The classification of some treatments as HET vs moderate- or low-efficacy therapies remain variable and lacks consensus across studies. 

There are 2 treatment strategies for MS medications: the escalation approach, which starts with low/moderate-efficacy therapies and escalates to high-efficacy therapies if needed, and the early HET approach, which advocates for using HETs from the start. The early HET approach includes induction therapy, which resets the immune system, and continuous treatment with high-efficacy DMTs. 

Early intervention with HETs has shown to improve short-term and long-term clinical outcomes in patients with RMS. Data from phase III trials comparing HETs to lower-efficacy therapies have demonstrated reductions in annualized relapse rates, disability worsening, new MRI lesions, and brain volume loss. Additionally, a higher proportion of patients achieved no evidence of disease activity (NEDA-3) with HETs compared to their respective comparators. Long-term open-label extension studies have further emphasized the benefits of early HET use, as patients who switched from lower-efficacy therapies to HETs had similar treatment responses but higher disability levels and more whole-brain volume loss. 

Real-world studies have also supported the use of HETs as first-line therapy in treatment-naïve patients, showing better outcomes compared to lower-efficacy therapies. Studies have shown that initiating HETs early in the disease course is associated with less disability and a lower risk of conversion to secondary progressive MS. However, further research is needed to directly compare early HET use with treatment escalation strategies. 

Hemologic abnormalities can occur from MS DMTs usage, specifically with anti-CD20 monoclonal antibodies, which can lead to a decline in serum immunoglobulin levels and lymphopenia. Alemtuzumab and cladribine treatments have also been associated with reductions in lymphocyte counts. While anti-CD20 therapies do not completely deplete tissue-resident B cells, there is no consistent increase in disease activity following discontinuation of these therapies. The risk of infections, particularly PML, is highest with natalizumab, but the risk can be managed through anti-JCV antibody testing and monitoring. PML cases have been rare with other HETs such as rituximab and ocrelizumab, but there have been some cases of PML reported in patients treated with ocrelizumab alone. 

“Based on the need for efficacious treatment in the early stages of MS disease, we believe HETs are appropriate for most patients with RMS as a first-line treatment option,” said researchers. “However, a shared decision-making approach should occur between the patient and their care teams, including comprehensive discussions on available treatment options as well as the benefits and risks of early HET use, to ensure that an informed decision is made as a team on the appropriate treatment.” 

Reference  

Freeman L, Longbrake EE, Coyle PK, et al. High-efficacy therapies for treatment-naïve individuals with relapsing-remitting multiple sclerosis. CNS Drugs. 2022;36(12):1285–1299. doi:10.1007/s40263-022-00965-7