Expert Consensus on Disease-Modifying Therapies in MS

Pauline Anderson

August 20, 2014

A growing body of evidence suggests that early control of disease activity in patients with multiple sclerosis (MS) plays a key role in preventing disability, prolonging the period of being active and engaged, and protecting quality of life.

For that reason, MS experts are calling for early and full access to all disease-modifying therapies (DMTs) for patients with MS.

The experts recommend initiation of these therapies as soon as possible following a diagnosis of relapsing MS. They also advise these agents for patients with a first clinical event and MRI features consistent with MS in whom other possible causes have been excluded, and for those with secondary progressive MS who continue to demonstrate clinical relapses and/or demonstrate inflammatory changes on MRI.

These recommendations, based on a comprehensive review of current evidence, appear in the paper,"The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence," produced by the Multiple Sclerosis Coalition, a group of MS organizations including the Accelerated Cure Project for Multiple Sclerosis, Can Do Multiple Sclerosis, the Consortium of Multiple Sclerosis Centers, the International Organization of Multiple Sclerosis Nurses, the Multiple Sclerosis Association of America, the Multiple Sclerosis Foundation, the National Multiple Sclerosis Society, and the United Spinal Association.

The document, written by a 5-member team and vetted by more than 50 experts in the field, has been endorsed by Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Not Carved In Stone

There's currently no algorithm for the order in which DMTs should be prescribed, said Kathleen Costello, MS, associate vice president clinical care, National Multiple Sclerosis Society, and one of the paper's authors. "It's not carved in stone which one you should start with, which one should be the next treatment or the 3rd treatment."

Because of this, said Costello, experts believe that "access needs to be available for all the therapies so decision-making on which therapy to use can be made on an individual basis." Factors to consider include patients' MRI findings, their clinical presentation, their risk tolerance, and their ability to adhere to a therapy.

Access to all the DMTs is all the more important as MS is a such a variable disease, added Rosalind Kalb, PhD, vice president, clinical care, advocacy, services and research department, also at the National Multiple Sclerosis Society. "Not only does the disease present and progress differently in different people, but individuals respond very differently for a variety of reasons to the available medications."

At the time of writing the document, 10 DMTs had been approved by the US Food and Drug Administration (FDA), all of which primarily target inflammation; however, none are fully effective in stopping MS disease activity or disease progression, the authors noted. An 11th agent (Plegridy, Biogen Idec Inc), a long-acting interferon β-1a, was just approved last week.

Although there are a growing number of approved treatment choices, patients sometimes have difficulty accessing them. In the past, it wasn't uncommon for providers to tell patients, "you don't need to be on that (β interferon); you're not 'bad enough' yet," said Costello. "But over the years, evidence has mounted showing that the better outcomes occur when treatment is initiated as early in the disease process as possible."

Early treatment can affect a range of disease factors, including delayed conversion to clinically definite MS, the document notes. The authors cited 4 phase 3 studies showing that in patients with clinically isolated syndrome, defined as the first episode of neurologic symptoms lasting at least 24 hours and caused by inflammation and demyelination in 1 or more sites in the central nervous system, conversion was delayed by about 45% at 2 to 3 years in patients taking glatiramer acetate or interferon compared with placebo.

As well, said the authors, early treatment may result in reduced relapse rates and slowed progression of disability. Reduced loss of mobility may improve the ability to carry out important activities of daily living.

No Catch-Up?

Such benefits, they added, "may not be equaled in those who start treatment later in the disease course," who may never "catch up" with those who start treatments immediately. However, a 10-year follow-up found no difference in disability outcomes between the early and delayed groups treated with intramuscular interferon β-1a, possibly indicating the delayed treatment group did catch up in this case.

"It remains to be determined the extent to which the older medications — and the newer medications for which we do not yet have any long-term data — impact longer-term disability outcomes for people with MS," the authors write.

The course of MS varies, with 85% to 90% of patients demonstrating a relapsing-remitting pattern at onset, which transitions over time in most untreated patients to a pattern of progressive worsening with few or no relapses (secondary progressive MS). The authors stressed that the optimal window for reducing long-term disability is during the early relapsing phase of the disease, with the goal being to slow the accumulation of lesion volume, decrease the number of relapses and prevent disability from both unresolved relapse and disease progression.

Patients without this relapsing pattern might demonstrate a steady progression of symptoms over time. This primary progressive disease presentation is generally diagnosed at an older age.

The paper includes an informative table listing the proposed mechanisms of action, adverse effects, and warnings/precautions of each MS agent. Another table shows the effect of self-injected, oral and intravenous agents on annualized relapse rate compared to placebo, and their effects on disability progression compared to placebo. A third table illustrates the effect of the various drugs on gadolinium-enhancing lesions and on new and enlarging T2 lesions.

An MS diagnosis often comes with other comorbidities. Some 60% of patients with MS will experience cognitive impairment, 36% to 54% will have a major depressive disorder, and up to 92% will endure substantial fatigue, which contributes to increased disability and reduction in quality of life.

There are an estimated 450,000 people with MS in the United States. Women are affected at least 2 to 3 times more than men, except for primary progressive MS, which is equally distributed between the sexes, and whites are affected more than other racial groups. Although some research shows a high incidence of MS farther away from the equator, recent studies have not demonstrated such a North-South gradient.

The Coalition will distribute the paper to delegates attending the upcoming joint ACTRIMS-ECTRIMS meeting in Boston, Massachusetts (September 10-13), and will post it on the Web sites of the participating MS groups. It will be updated at least every 6 months, something that is necessary because the MS treatment landscape changes so frequently, said Dr. Kalb.

Limited Therapy Options?

Asked for comment, Lily Jung Henson, MD, an MS neurologist, Swedish Medical Center, Seattle, Washington, said that the new paper nicely "summarizes the current level of evidence and knowledge around the management of MS."

"The fact that this is created by a coalition of MS groups stresses the consensus amongst MS specialists," she told Medscape Medical News.

The coalition's call for full access to DMTs is likely in response to some insurers trying to limit therapy options based on pricing, commented Dr. Jung Henson.

"A lot of the payers will, for example, insist that you use several of the interferons and glatiramer before you can use a more expensive pill. Or, patients have to fail several drugs before they can use the one that their neurologist thinks may be the best for them."

Although most MS neurologists do initiate treatment as soon as a diagnosis is made, "a lot of general neurologists are amazingly passive in their use of DMTs and their willingness to tolerate breakthrough disease without making a change," said Dr. Jung Henson.

Funding for the document was provided by member societies of the MS Coalition with no external support. Ms. Costello and Dr. Kalb have disclosed no relevant financial relationships. Dr. Jung Henson reports receiving honoraria from Biogen, Teva, EMD Serono, Pfizer, Novartis, and Genzyme and research funding from Biogen, Novartis, Genzyme, and Opexa.


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