Early Intensive Treatment Better in MS?

February 21, 2019

For patients with relapsing remitting multiple sclerosis (MS), long-term outcomes were more favorable following early intensive therapy rather than using first-line, moderate-efficacy drugs and escalating treatment as the disease progressed, according to a new "real life" study. 

"Our study shows that in our patient cohort those patients started on the most aggressive therapies did the best even though they had more active disease at baseline," coauthor Neil Robertson, MD, University Hospital of Wales, Cardiff, United Kingdom, told Medscape Medical News. "This makes us think we should be using these more intensive therapies earlier in more patients."

The researchers conclude: "Our study undermines the prevalent belief that an escalation approach represents a lower-risk strategy to MS treatment and suggests that, in the real world, an escalation approach to disease-modifying therapy may be inadequate to prevent unfavorable long-term outcomes. These data should prompt a more detailed study of whether refined selection and escalation criteria could negate the long-term risk of disability accumulation observed in this escalation cohort."

Commenting on the study for Medscape Medical News, Jeffrey Cohen, MD, of the Cleveland Clinic's Mellen Center for Multiple Sclerosis in Ohio, said the issue of whether the traditional escalation approach is better than the early high-efficacy therapeutic approach is "actively debated." 

"This observational study supports the latter but clinicians tend to put different patients on these two therapies, making interpretation not straightforward," said Cohen, who was not involved with the current study. "There are two randomized clinical trials of this question currently underway which will provide a more definitive answer."

The current study was published online February 18 in JAMA Neurology.

The researchers explain that disease-modifying therapies in MS can be broadly divided according to the efficacy with which they prevent MS relapses. The licensed drugs with the highest efficacy are associated with more complex safety profiles, monitoring requirements, and the need for hospital or day-unit admission, which tend to lead clinicians (or treatment guidelines) to recommend that they be reserved for use in individuals with the most aggressive or resistant forms of MS.

In those with moderately active MS, clinicians often adopt an escalation approach whereby a drug that is considered to be most safe is selected, subsequently escalating to more efficacious therapies, with more complex safety profiles, in the event of continued disease activity.

However, the researchers add, "in light of current knowledge, it is possible that the inevitable delay imposed by escalation strategies may result in a lost therapeutic opportunity."

To look at this issue, they analyzed data from a cohort of 592 MS patients in southeast Wales, United Kingdom, who were prescribed a disease modifying therapy between 1998 and 2016 and had at least 5 years of follow-up.

Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment group) or moderate-efficacy therapy (escalation group).

Intensive therapy was defined as use of the monoclonal antibodies alemtuzumab or natalizumab. All other disease-modifying therapies were categorized as moderate efficacy, including interferons, glatiramer acetate, dimethyl fumarate, fingolimod, and teriflunomide.

The primary outcome was 5-year change in Expanded Disability Status Scale (EDSS) score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting therapy, and escalation to high-efficacy treatment in the escalation group.

Of the 592 patients included, 104 (17.6%) had been prescribed a high-efficacy therapy as first-line, whereas 488 patients (82.4%) had started treatment with a moderate-efficacy agent.

Of the 488 patients who initially embarked on moderate-efficacy treatment, 58 patients (11.9%) subsequently went on to receive a high-efficacy therapy.

Individuals who received early intensive therapy were more likely to receive alemtuzumab (67%) than natalizumab (33%), while individuals who received high-efficacy therapy second line as part of an escalation algorithm were more likely to receive natalizumab (74%) than alemtuzumab (26%).

Results showed that the mean 5-year change in EDSS score was lower in the early intensive treatment group than in the escalation group (0.3 vs 1.2). This remained significant after adjustment for relevant covariates.

The median time to SAD was 6.0 years for the intensive group and 3.14 years for the escalating group. For those within the escalating group who escalated to high-efficacy therapy as second-line treatment, the median time to SAD was 3.3 years. 

After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy therapy were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.

As expected, the pretreatment annualized relapse rate (ARR) was higher in the early intensive group (1.7) than in the escalation group (0.7).

In retrospect, those who commenced a moderate-efficacy therapy but subsequently escalated to a high-efficacy agent had a pretreatment ARR of 1.2 compared with 0.7 in those who continued with moderate-efficacy treatment.

The ARR fell in all groups following the introduction of therapy, reducing to 0.16 in the escalating group and 0 in the early intensive group.

Within the escalating group — those patients who later escalated to high-efficacy treatment — the ARR following initial treatment with moderate efficacy therapy was 0.9 but fell to 0 following escalation to high-efficacy therapy. The ARR was 0.11 in the group who continued with moderate-efficacy therapy.

In terms of safety, 87% of patients receiving alemtuzumab developed infusion-related adverse events, and 47% developed autoimmunity (35 thyroid, 3 immune thrombocytopenic purpura, and 13 other), but there were no serious infections and no treatment-related deaths.

In patients receiving natalizumab, there were no serious adverse events, no cases of progressive multifocal leukoencephalopathy, and no treatment-related deaths.

In patients receiving moderate-efficacy therapy, there were seven serious adverse events (1.4%) – 3 cases of necrotic skin reactions, 1 case of anaphylaxis while receiving injectable drugs, and 3 severe infections while receiving fingolimod.         

Robertson outlined two possibilities that may explain why earlier intensive treatment may be better.

"One involves the thinking that if we stamp on the disease hard at the start this gives a biological advantage going forward," he said. "The second is that the systems we have in place at present are not adequate to identify patients who need more intensive treatment. Patients need to be seen more regularly to detect disease activity that would trigger earlier escalation of therapy."

Robertson said there is a general shift happening in MS: more efficacious therapies are being used from the start, whereas original drugs like interferon and glatiramer acetate are being used less now.

"But whether we should start the much more intensive agents right from the start is not known," he added. "Our results suggest this may be the way forward, but our study was retrospective and we need confirmation in randomized controlled trials."

One such trial — DELIVER MS — a joint UK/US initiative, is starting shortly.

Robertson reports honoraria from Biogen and Merck & Co and grants from Novartis, Genzyme, Roche, and Teva outside the submitted work. Cohen has disclosed no relevant financial relationships.

JAMA Neurol. Published online February 18, 2019. Abstract.

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