Expert Perspectives on Disease Burden of Relapsing-Remitting Multiple Sclerosis: A Q&A With Jonathan C. Calkwood, MD

This publication was sponsored and written in partnership with Bristol-Myers Squibb.



The American Journal of Managed Care^®: What are some specific patient characteristics associated with relapsing-remitting multiple sclerosis (MS)?

Jonathan C. Calkwood, MD: In general, female predominance of the disease, at least in the relapsing forms, and onset in early to mid-adulthood is the well-known demographic of MS. The prognosis for an individual with MS can be highly variable and can be hard to predict. The disease is characterized by intermittent neurological attacks and recoveries which progress to permanent physical and cognitive disability. The patient characteristics associated with relapsing-remitting MS that interest me most are those characteristics that help me understand where a patient is currently in their disease course as well as those that help me predict a patient’s risk of disability. To me, the important characteristics are those that are predictive of long-term accumulation of disability. How do I predict where that patient might be? If I have someone with aggressive disease, I want to match that disease aggressiveness with an appropriately efficacious treatment. Now, that might beg the question, “If highly officious treatments preserve neurons and prevent more disability, when should we use a less efficacious treatment?” The question I often ask other neurologists who might be reluctant to make a treatment change is, “How many brain cells is it ok to lose on a lesser efficacious treatment that we might have prevented?” The answer should be zero and current research strongly supports early intervention with highly efficacious therapies to limit development of disability.

There are three patient characteristics that I am most concerned with: relapses, magnetic resonance imaging (MRI) lesions, and the level of disability based on neurological exams. I focus on those characteristics that are predictive of a more aggressive disease including: race, frequency of exacerbations, incomplete recovery from a relapse, or more severe relapses. The character of the patient’s neurologic symptoms, be it relapses or their day-to-day symptoms, can help us. Patients who have symptoms or relapses with predominantly involved symptoms that are coming from their brainstem or their spinal cord may have more disabling issues. It’s the same for MRI characteristics. If lesions are accumulating in the brainstem and the spinal cord, that patient is at higher risk for physical disability. We also use a patient’s neurologic exam abnormalities in a similar way. There are many risk factors that may exist in an individual that may influence risk assessment so it is important to form a type of a “matrix” of what those characteristics are to try to identify a higher-risk patient.

AJMC^®: What do you see as existing gaps in care for patients with relapsing-remitting MS?

Jonathan C. Calkwood, MD: There are many gaps in our healthcare system that may influence a patient’s ultimate accumulation of disability. I think there is a huge gap that readers of AJMC© could, and should, influence. The healthcare insurance industry attempts to apply utilization management practices that work well in many other disease states but are fundamentally flawed when applied to MS. Individual patient variability in a disease state like diabetes or hypertension is relatively uniform compared to MS. These diseases have easily measured and inexpensive biomarkers that tightly correlate with outcome. In these diseases, you can identify a treatment failure before there is permanent end organ damage. Selectively limiting access to treatments is less likely to have permanent consequence for the patient with diabetes or hypertension when end organ damage can be predicted by biomarkers. Treatment escalation based on efficacy, cost, or treatment risk has little if any long-term consequences for the patient and makes sense in these diseases where treating to those biomarkers prevents end organ damage in the future.

In MS, the measure of treatment failure is end organ damage. We grow all the brain cells we have by the age of 19 to 21 years of age. Neurons, unlike other tissues in our body, do not have the capacity to regenerate. In MS, a new lesion on the MRI, a relapse, worsening on neurological exam, cognitive decline, or other changes indicate that the patient has already lost brain cells.

Even as an expert in MS, it is difficult to predict how an individual patient is going to progress, but I can put them in a higher risk group. As such, we should treat patients proactively to prevent disability accumulation.

I believe the single biggest clinical gap in care is the limited access to classes of therapy or individual medications that may be medically determined by the physician as appropriate for an individual patient. Since more efficacious treatments have demonstrated better outcomes, we want to use the most efficacious treatment early in the course of disease that is appropriate for that individual patient.

Other important gaps in care are access to MRIs and medications because of the financial burden it puts on them. A patient with MS is usually on multiple symptomatic medications, so they’re paying copays on those medications, too.

Another gap in care is the support of insurance companies of nonpharmacological measures, which have been proven to reduce disability. Some structure is needed that encourages patients with disabilities to participate in wellness programs (eg, physical therapy, exercise programs focused for patients with MS and disabilities, etc).

AJMC^®: If left untreated, what is the course of disease for patients with relapsing-remitting MS?

Jonathan C. Calkwood, MD: If left untreated or undertreated, the data have been very clear that patients do worse and accumulate disability. Our earliest studies on disease-modifying therapies involved a placebo control group. With the very earliest studies on platform therapies, we saw the same thing when there was a placebo-controlled trial. Even if that study is only a year long, we will see on the Kaplan-Meier curve a separation between the 2 groups of patients in terms of their disability, MRI, or relapse rates that shows the difference between a patient who’s on treatment versus not on treatment. Typically, in those studies, the patients in the placebo group rolled into a treatment trial or the treatment group for an extension study. When we put the patients taking placebo on treatment, they paralleled the other group, but at a significantly higher rate of disability. Even a delay in treatment of 1 or 2 years makes a difference in the disability progression of a patient with MS.

AJMC^®: How quickly will symptoms develop in these patients if they’re left untreated?

Jonathan C. Calkwood, MD: It’s really unpredictable but virtually every patient will worsen more than they would have to if they weren’t on a treatment or if incomplete efficacy is not addressed.

We have an older MS disability scale that attempts to predict progression—the MS severity scale. This is a “natural history scale” of the disease untreated. It is a tool to gauge the risk of progression by essentially gauging the length of time they had MS against their disability score. If we don’t treat those people early, the data have been very clear that they will do worse and accumulate disability. The disability score is the Expanded Disability Status Scale, which is used in most clinical trials and can be used to gauge the risk of the individual patient. I think the best indication would be if I’m able to gauge that individual’s overall MS risk and disability based on the MS severity scale. It is important to monitor the patients to see how quickly disability is evolving while they are on treatment. These scales can be helpful but have significant limitations to predict an individual patient’s future disability, and to help determine a treatment approach to match the aggressiveness of the disease.

MS can be more inflammatory in adolescents and young adults—their symptoms may change very quickly. I have a tendency to use more efficacious therapies in these patient types as I am more concerned about the risk of disease progression. Postpartum mothers are another high-risk group. Then there are those patients who aren’t necessarily relapsing but they’re neurologically worsening, seemingly relentlessly, despite our most effacious treatments. The progressive patients with MS that are incompletely responsive to our current treatments represent a challenging group of patients to treat. We are sometimes left with supportive care measures alone.

While we commonly talk about physical symptoms, we also have to consider cognitive symptoms which develop from the onset of disease, but may not be visible until later in life. Early and effective treatment is necessary to preserve the brain cells and neurologic function. The brain of a patient with MS can atrophy at a faster rate than non-MS patients and have a greater risk for losing neurologic function sooner. If you have patients on a less efficacious therapy, their disease may not be controlled. Time equals brain cells, and we can’t grow those neurons back. While it’s hard to predict how quickly symptoms will develop when a patient is untreated, it doesn’t matter if they’re developing symptoms or not because they’re losing brain cells faster. If they’re not on the appropriate treatment, this results in more brain loss and greater levels of disability.

AJMC^®: Could you provide a couple of examples of how relapsing-remitting MS affects patients’ quality of life?

Jonathan C. Calkwood, MD: I think the two most underappreciated areas that affect quality of life of patients with MS are fatigue and cognitive dysfunction.

The most profound, universal impact is fatigue. A symptomatic issue with MS that we really don’t understand very well but profoundly affects the ability of many patients to fully participate in work, life and relationships. Fatigue is commonly cited as a reason that a person with MS chooses to leave the work force.

The cognitive decline that I alluded to scares me the most because it’s silent, and it really creeps up. We’ve got very crude tools for assessing cognitive functioning. We don’t have a very good clinical metric, and by the time the person with MS has cognitive symptoms, they already lost many brain cells. We may not have good biological markers. Brain atrophy is a trailing indicator of disease severity but is linked with fatigue and cognitive dysfunction. By the time we can measure brain atrophy, we’re well behind the curve. That’s one of the bigger, more worrisome quality-of-life issues, because cognitive dysfunction is pervasive in patients with MS, as early as clinically isolated syndrome.

A third aspect of MS on quality of life is physical disability. Some people with MS can be cognitively functioning but physically disabled or, on the flip side, they could look fine but be cognitively disabled. I have plenty of patients who have significant gait limitations, yet they’re still fully functioning in the workforce. They’re cognitively intact and are able to do highly cognitive jobs, yet physically they need to ride a scooter to get from the parking lot to their desks. MS manifests very differently in different people.

AJMC^®: What utility do biomarkers have for patients with relapsing-remitting MS?

Jonathan C. Calkwood, MD: At this point in time, immune system biomarkers measured by laboratory tests are of limited usefulness in MS because we just don’t understand the immune system abnormalities in MS well enough. That’s where MRI, relapse rates, disabilities, and monitoring response to treatment come into place as biomarkers. I think one of the problems in MS is we’re managing the patient with a reactive approach. From a neurologist’s perspective, treating a patient with MS is like driving a bus while looking through the rearview mirror. We are always responding to what has already injured the patient’s brain. We don’t have good, predictive biomarkers so we’re often responding after a patient has developed more disability. That’s why we’re often left using scales like the MS severity scale, the risk factor assessment, and a patient’s individual risk factors. If someone had a relapse, the biomarker could be a change on MRI. That’s probably our biggest, most useful biomarker because the brain MRI scans will show us lesions in the absence of new symptoms. The MRI is an effective biomarker, to help us define and identify an inadequate response to treatment, so we can then escalate therapy. But even an asymptomatic lesion can cause permanent loss of precious neurons.

The ideal biomarker would identify an inadequate response to therapy and warn us that a patient was headed for trouble before they lost brain cells. The biomarker of interest recently has been neurofilament light chains, which are proteins normally only found inside of nerve cells. These proteins are increased in the spinal fluid and blood of people with MS. The FDA has recently granted fast track review of a commercial lab test for neurofilament light. There is still a lot to learn, changes in neurofilament light chain correlates with disease activity and may be predictive for an individual or as a biomarker to distinguish relapses. Obviously, the neurofilament lights are going up in the blood or in the spinal fluid because brain cells are dying; those neurofilament light chains belong inside nerve cells. We can at least use that as a general biomarker now, but it is yet another example of a biomarker indicating that the end organ has already been irreversibly damaged.

AJMC^®: What nonpharmacologic approaches do you think are helpful in your patients?

Jonathan C. Calkwood, MD: It takes a village to care for a person with MS. They require so much support. The care provider and support partners of persons with MS deserve enormous credit. Education, social and psychological support provided by MS nonprofits and MS nurses are an important source of support. A neurologist trying to take care of people with MS can’t just be a neurologist. We already talked about how you have to be an immunologist. Sadly, our patients, despite our best efforts, become disabled, and we have to understand physical medicine and rehabilitation. I would say probably one of the single biggest positives coming out of the neurologic literature in the past decade, but especially the last 5 years, has been a broadening of our approach to focus on biological and immunologic systems. Now we postulate, “What’s the impact of general health and wellness on persons with MS?” As we have learned, the data on smoking have trickled out in MS. It’s not just the other health issues associated with combustion products of tobacco. Smoking tobacco makes the immune system more aggressive.

Recently, we have identified obesity to be an immunological issue for patients with MS. The immune system becomes more aggressive. Managing the patient’s general medical issues, managing their quality of life, and managing exercise is absolutely one of the most important things. We’ve known about that for quite a long time. People with MS will go into a slow downward spiral just from inactivity, so regular exercise is important.

Here’s an example. When I joined Randall T. Schapiro, MD, FAAN at the Schapiro Center for MS, we had a program called the “Back to Fitness” program. That program took patients who had wrapped up physical therapy, but they still weren’t back to where they were prior to their MS relapse, or, in some cases, they just became deconditioned. Here in Minnesota the winters are long and hard and people with MS may lose function quickly if they are not able to exercise and be active. Every spring, we get calls from our patients. They’d say, “I need steroids.” I’d say, “Well, why do you need steroids?” “I can’t walk to the mailbox anymore,” they’d say. I’d ask, “Well, when was the last time you walked to the mailbox?” “Last September,” they’d answer, and it was April. The patient hadn’t been active, so we got them into physical therapy. That Back to Fitness program was hugely cost-effective. We had an exercise physiologist who would spend 3 days a week for a couple of weeks taking that patient into the gym and showing them how to exercise. Then patients could use a community health club to do their own therapy. The program reduced steroid use and side effects, reduced fall risk, gave patients a transition from physical therapy, and kept me from having to order physical therapy. It was cost-effective and benefitted patient overall well-being.

In addition to access for pharmacological therapies, a comprehensive approach to the disease should include support for health and wellness, access to primary care and internal medicine services for comanagement of medical conditions, smoking cessation, diet, and exercise. These interventions could help these patients more by helping them learn how to do those things that are going to maintain their health better, prevent disability, and lower cost to the healthcare system and society.

AJMC^®: How do you decide on the appropriate pharmacologic treatment for your patients?

Jonathan C. Calkwood, MD: It starts from having an accurate diagnosis. Once we have made a diagnosis, I try and assess a patient’s risk of future disability. If the risk is high, we definitely want to use a stronger treatment, even if the treatment comes with some risk. The majority of what I do, day in day out, is risk management for my patients. I can’t really predict what’s going to happen to them, and I can only put them in a higher or lower risk group based on the factors I mentioned earlier.

When I meet a patient with MS for the first time, the first thought process I go through is, “Do they have MS?” And then, “Are they on the right disease-modifying therapy?” By that, I mean the right efficacy. I think selecting the treatment for the patient starts from that—matching the treatment, the risk of the disease, and the risk of the treatment at some level.

The risk of treatment is not just adverse effects and lab abnormalities. The risk of a less efficacious treatment, may be disability for the patient with MS. If we can’t truly predict how an individual is going to do, should we plan and treat for the best or worst potential outcome? If it is my brain we are talking about, I am going to want to err on the side of prophylaxis against the worst possible outcome. If I have a game plan that they have mild disease, and I’m wrong, they get more disabled. If I have a game plan for the worst-case scenario, and I’m not putting the patient at inordinate risk from the therapy and then it doesn’t happen, is the patient any worse off? No, as long as you pay attention to risk, tolerability, adverse effects, and cost.

Based on research data and my experience, I prefer to use the higher-efficacy therapies early in the course of disease. It does not make sense to me to let a patient lose brain cells that we could otherwise prevent. The neurology community is in the process of making a 180-degree turn away from a treatment approach that starts with less efficacious therapies and escalates treatment as disease progresses to starting with higher-efficacy therapies. Among the MS specialists, we are making a change, but it’s slow going.

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