Approaching Multiple Sclerosis With a Global Perspective

Fred Lublin, MD

Avoiding siloed thinking also applies to medical decisions. Much of the information in treatment guidelines and medical textbooks is based on varied experiences and reports, brought together to help form a collective opinion. Knowledge to be gained from the experience of others is especially meaningful in a disease where treatment optimization is a work in progress. Although many treatments exist for multiple sclerosis (MS), the decision to pursue one treatment over another can often be enhanced based on the experiences of our peers and their patients.

Differences in treatment, from drug availability to strategy, are especially apparent across inter- national borders, where usage and clinical guidelines may vary. In MS, there are clear departures in diagnostic and treatment guidelines between those set forth by various clinical governing bodies; these are exacerbated by differences in drug approval patterns by the US FDA and the European Medicines Agency (EMA), as well.

In an effort to capture these differences and learn from them in a leveled environment, NeurologyLive^® recently brought together a panel of international MS experts for a Peer Exchange titled “Global Approaches to the Management of Relapsing Multiple Sclerosis.” Led by Fred Lublin, MD, the Saunders Family Professor of Neurology and director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York, New York, the panelists discussed their experiences managing MS across the spectrum, beginning in a logical place: differentiation.

Clinically Isolated Syndrome Versus Multiple Sclerosis

In 2017, the latest update to the McDonald diagnostic criteria made for more clear and concise decision-making, especially between patients who should be treated with disease-modifying therapies (DMTs) and those who should not—particularly in the instance of patients with clinically isolated syndrome (CIS) compared with those with a confirmed MS diagnosis.

“In Germany, we had an ongoing discussion when we still worked with the concept of CIS and early relapsing-remitting MS, and since we have the new criteria, my idea is that the group of patients with CIS is now much smaller,” Sven Meuth, MD, PhD, of the University of Münster in Germany, said. “This is also why we don’t have to discuss any more that some of the platform therapies are only approved for relapsing-remitting MS, but not for CIS.”

Meuth explained that when the updated criteria were published and adopted, ongoing discussion surrounding CIS and early stage MS was halted because of the criteria’s allowance for a better opportunity to diagnosis these patients with relapsing-remitting MS earlier, and thus begin treatment earlier in instances where previously they may have hesitated. Wallace Brownlee, MBChB, PhD, of the National Hospital for Neurology and Neurosurgery in London, United Kingdom, echoed Meuth’s sentiments about the update to the McDonald criteria as helpful for earlier diagnosis, which he said “open up new therapeutic opportunities for patients with relapsing MS.”

This has not necessarily been the case across the globe. Patricia K. Coyle, MD, of Stony Brook Neurosciences Institute in Stony Brook, New York, noted that in the United States there is an important distinction that had allowed for high-risk CIS patients to be treated.

“Granted, greater than 50% of first-attack patients will meet the 2017 criteria,” Coyle noted. “But if you have a first attack and you fit for high risk for MS, and you’ve ruled out other things, you basically have relapsing MS. That’s your first attack, whether you met the criteria or not. We can treat those patients in the United States.”

Lublin concurred that in his experience, CIS has been treated without difficulty in the US even prior to the official recognition of CIS as a condition. Aside from those with particularly aggressive cases, these patients are often given the CIS label. Lublin noted that physicians often do not distinguish a difference between the first and subsequent attacks, but with regulatory agencies and authori- ties, that was not always the case.

Following an earlier update to the criteria in 2010, a rather large change to how physicians viewed dissemination in time was made, thereby allowing a single MRI to identify the dissemination. This, Lublin said, dropped the prevalence of CIS by about 50% because patients were now meeting criteria for MS and could be treated as such. Whether a similar difference was brought on by this latest update or not, remains to be seen.

“Some very early data that have come out of the Netherlands have shown that perhaps up to 70% of patients can now be diagnosed confidently with MS at the time of the first clinical attack that is highly suggestive of relapsing MS, like optic neuritis or partial myelitis,” Brownlee said.

The First-, Second-, Third-Line Concept

Once a patient has been properly identified and diagnosed with MS, the process is not clear-cut and simple. With a large armamentarium of DMTs to choose from, deciding which therapy is best for an individual patient can be a daunting task. As such, the community built out a designation system for a number of agents, denoting them as first-line, second-line, and third-line agents.

This system was developed to help physicians pick the best treatment for their patients as more are diagnosed earlier in the disease process. However, the concept has its flaws. “I don’t like the concept of first line, second line, third line. We should be able to use any agent that we feel is the best choice in our patient initially,” Coyle said.

First-line treatments often consist of injectable agents—varieties of glatiramer acetate and interferon-beta—and Coyle noted that she considers a number of oral agents to be first line, save for cladribine (Mavenclad; EMD Serono), a recently approved immune reconstitution therapy that is not recommended for patients’ first attack on its FDA label.

“I think it could be, but that’s bending the curve a little,” Coyle noted. “Then, when we go to the infusible agents—the mono- clonal antibodies—I think they’re all first line with the exception of mitoxantrone, which we basically never use in the United States, and alemtuzumab, which has been recommended on the US label as a third-line agent. I feel very comfortable using the orals, using several of the monoclonals and infusibles, and certainly the injectables as first-line agents.”

Meuth agreed with Coyle, adding that physicians need freedom to decide which agent is best for a given patient. He noted that at his institution, the University of Münster, the MS center does have the freedom to operate outside of the first-, second-, and third-line concept. But it is complicated because of several factors outside the physician’s control.

“When it comes to reimbursement, the office-based neurologists are not allowed to go on these treatments, and this is why we are a little bit limited, based on this reimbursement situation,” Meuth said. “From the pathophysiology behind it, I cannot agree more. If we have a given patient with a highly active disease, we should not play around with something like platform therapies, but we should be able to start with a monoclonal, for instance.”

Meuth explained that community clinicians in these instances are allowed to start with a high-efficacy agent only when the patient is highly active themselves. They are required to have 9 or more T2 lesions on magnetic resonance imaging (MRI) and more than 2 relapses coinciding with progression on the Expanded Disability Status Scale (EDSS).

“I think you will agree that this is far too late to quantify these patients as highly active,” he posed to the group.

Additionally, the designation of a therapy as a first-, second-, or third-line agent can differ globally. Meuth mentioned fingolimod (Gilenya; Novartis), which in the United State is considered a first-line agent, but in Europe has been approved for use only in those highly active patients. “This is a difference, and this brings me to the approval of new sphingosine 1-phosphate (S1P) modulators. But in the majority of patients, we have to start with platform therapy or first-line therapy, and then we can have this escalation concept, and this is, in my opinion, not the way to go,” he said.

In the United Kingdom, Brownlee added, neurologists are increasingly initiating intensive therapies early on in those with newly diagnosed relapsing MS. He explained that alemtuzumab (Lemtrada; Sanofi) was used extensively as a first-line agent prior to the recent suspension and investigation from the EMA. Now, it is mainly used as a later therapy in those who have continued to experience relapses and/or MRI activity on a first-line treatment.

Those first-line treatments include the oral agents dimethyl fumarate (Tecfidera; Biogen) and teriflunomide (Aubagio; Sanofi), and increasingly ocrelizumab (Ocrevus; Genentech) or cladribine—though not fingolimod.

“Fingolimod, like in Germany, is reserved for patients who are second line or very highly active, and that’s really on the basis of concerns around the time it was licensed over cardiac safety,” Brownlee said. “I must say with long-term clinical experience with this drug, that has become less of an issue, and it’s become clear that really that is a problem only with the first dose.”

"Some very early data that have come out of the Netherlands have shown that perhaps up to 70% of patients can now be diagnosed confidently with MS at the time of the first clinical attack that is highly suggestive of relapsing MS, like optic neuritis or partial myelitis," Browlee added.

Global Use of Interferon in MS

Historically, interferon-beta has played a pivotal role in the treatment of MS. Now considered a first-line therapy, it was among the first agents approved to treat the disease in the US and throughout the world.

Meuth explained that 2 decades ago when it first entered the market, it was the go-to therapy in Germany. Now, its use has become generally limited to those who have remained stable on an interferon over the years. “Never change a winning team,” he said. But for those who are newly diagnosed, interferon has lost its go-to status as a first-line agent.

“Since the approval of the oral agents, electromagnetic fields, and teriflunomide, we don’t find too many patients starting with interferons anymore,” he said. “There’s a significant decrease in the usage of interferons. For newly diagnosed patients, they are looking, at least in our country, more for the oral agents, so there is a development in this injectable market, I have to say.”

Lublin asked about the role mechanism of action has played in that shift at his institution, and Meuth noted that it has to some extent, and that he and his colleagues seek to keep things simple for patients. With interferons, that includes talking about a shift from type 1 helper T-cell responses toward type 2 helper T-cell responses, but he acknowledged that the effects contributing to the mechanism of action of interferons are various.

“If we have the pathophysiology of MS in mind, we can nearly say that each and every step in this whole cascade is somehow impacted by interferon. It alters the cellular recognition by a modulation of major histocompatibility complex class 2 and the T-cell receptor,” Meuth said. “It reduces, thereby, lymphocyte activation and proliferation, but it has also an impact on the transmigration over the blood-brain barrier from the periphery to the central nervous system.”

Some data suggest that in the central nervous system, this process leads to a downregulation of pro-inflammatory cytokines, and it shifts—though not in a fashion entirely understood—the differentiation toward the type 2 helper T cells, giving it a “very broad mechanism of action,” Meuth said.

Brownlee explained that, similar to other countries, the use of interferon as a first-line DMT in the United Kingdom is on the downward slope. In recent years, the regulatory agency has taken action on updating the label for interferon with regard to pregnancy in Europe, which has allowed the therapy to find its place in the landscape.

Now, physicians in Europe have the option to treating women who are planning to become pregnant, or are pregnant and breast- feeding, on the basis of observational studies suggesting the safety of those approaches. Additionally, interferons and the other injectable therapies also have a role to play for those with certain comorbidities that complicate treatment with other DMTs.

“I recently saw a patient who’d had a renal transplant, so they were immunosuppressed on 2 immunosuppressive medications and low dose steroids, and they developed relapsing-remitting MS on top of that,” Brownlee said. “One of the injectable agents, the patient in this case went for interferon, is a good option because you don’t need to worry about drug interactions or immunosuppressive effects.”

The case has been similar in the US, with the usage of interferons being much lower than when they entered the market. Coyle explained that in her experience, their use has been compa- rable to that of Germany—those who are on it and doing well remain unless a significant adverse event (AE) arises.

“I haven’t started many patients with interferon, but I have individuals who I’ve been treating since November 1993 when we first got interferon beta-1b, and they’ve done spectacularly well. As we know with all of these agents, there are some people who have responded to all of them, and I think ‘don’t change a winning team’ was pretty much the logic,” Lublin said.

To watch the full Peer Exchange, "Global Approaches to the Management of Relapsing Multiple Sclerosis," click here.