Disease modifying therapy: What is it and will it work for me?

What is disease modifying therapy?

A symptomatic therapy is a therapy designed to reduce the symptoms of a disease. Aspirin to lower the fever from an infection is an example of a symptomatic therapy. A disease-modifying therapy (DMT) is a category of medications used to slow down disease progression.

How do we determine if a medication is useful to improve the outcome of someone with MS?

A randomized clinical trial (RCT) is a study that is done to show whether a new medication or treatment is effective in preventing or improving the outcome of a disease. In a randomized clinical trial, volunteers with MS are given an active medication or an inactive substance called a placebo and followed over time to see if the medication improves their outcome. The study is called randomized because whether or not a person receives the active medication or placebo is determined at random (by chance). Most randomized clinical trials are also double blinded which mean that neither the patient nor the investigator involved in the trial know who is getting the active medication.  Randomized clinical trials can be used to test a medication to see whether it works better than no treatment or to compare one medication against another to see which works better. They are also important to determine the side effects of a medication.

 The outcome of a randomized clinical trial is usually expressed in terms of the difference between the rate of an outcome in the treated versus untreated group. Outcome measures used in randomized clinical trials for MS depend upon the aim of the study (Uitdehaag, 2017). The earliest used and most traditional outcome measures are relapses and 3 or 6 month confirmed disability or improvement on the expanded disability status scale (EDSS). Relapses are characterized as an annualized relapse rate or time to second relapse. More recent clinical outcome measures include time to secondary progression in patients with relapsing-remitting MS, the Multiple Sclerosis Functional Composite Score, patient reported outcomes, and paraclinical measures such as MRI findings, optical coherence tomography (a technique that images the nerve layers in the back of the eye which may be affected by MS), and biomarkers. Biomarkers are laboratory studies of body fluids which can be abnormal in people with MS[ix].

Older MRI outcomes that have been studied are the number and volume of MS lesions on T2 weighted images, black holes seen on T1 weighted images which represent small areas of prior intense inflammation which have led to destruction of brain tissue, and gadolinium enhancing lesions. Newer MRI outcome measures include brain atrophy and rim lesions. Future studies may use newer MRI techniques such as diffusion tensor imaging (DTI), functional MRI, and magnetization transfer imaging (MTR) to examine brain tissue integrity, functional connectivity, and brain myelin respectively.

Although randomized clinical trials are the best way to determine if a medication helps to improve the outcome in people with MS, in practice, there are some problems using the results of these trials to treat individuals. First, the costs for randomized clinical trials performed to determine if a medication is effective are usually borne by a pharmaceutical company. The aim of the pharmaceutical company is to show that the medication is safe and effective enough to pass the U.S. Food and Drug Administration (FDA) Federal agency

FDA requirements to be marketed in the United States. The FDA is a federal agency that ensures that medications marketed in the United States are safe and effective. Since these studies are costly and because the pharmaceutical companies patent rights to exclusively market the drug are limited to a certain number of years, the studies are as short as possible.. The randomized clinical trials sponsored by pharmaceutical companies are thus helpful mainly to show short term outcomes which may or may not translate into true long-term outcome benefit.

Second, enrolling patients with certain characteristics into a randomized clinical trial maximizes the chance of the trial having a positive result. A positive result is necessary for the pharmaceutical company to show benefit of the medication to the FDA to allow it to market the medication. Usually, MS patients with special characteristics are chosen for randomized clinical trials of MS medications[x]. Although the medication may show benefits in those patients specifically chosen for the study, it does not necessarily benefit other unselected MS patients. Thus, if you do not have the same characteristics as the patients chosen for the study, the medication may not benefit you. For example, most MS clinical trials include patients who have had one or two exacerbations in the previous two years, and are within a specific age range or severity of disease. A person who presents with an initial exacerbation, or who has not had an exacerbation for the prior three years is different from the patient studied in the clinical trial. We can’t tell from the trial whether or not this person will benefit from the medication.

Third, randomized clinical trials study groups of patients of various sizes made up of people with MS. Although individuals with MS are examined over time in these trials, the results of these studies describe what happened to the group or average of these patients and it remains difficult to extrapolate from the group study what to expect in an individual patient placed on the medication studied.

One needs to keep in mind that these studies showed these medications improved these outcomes in groups of MS patients treated with the medication but did not show that each medication will be effective for each individual patient. The results of these studies showed that groups of MS patients who took these medications did better, on average, than groups of patients who did not take these medications. The group result was an average result made up of individual scores from the participants in the trials. To make up the average score, results from people who may have had no improvement with the medication or even got worse with the medication are summed with those who got better on the medication and then divided by the number of people in the trial. If more people did better on the medication than those who got worse or had no improvement, the average score will be elevated and, when compared to the average scores of those people in the trial who did not get the medication, will show that the medication works “better” than getting no medication.

Finally, randomized clinical trials are performed in a very controlled environment. Their results may not always be valid in a real-world setting. Although the trial may determine the overall efficacy of a medication, what may be efficacious in the setting of a randomized clinical trial where the participants are closely monitored by the investigator and study staff, may not be effective when placed into a routine health care delivery system. In practice, the people treated and their compliance with the medication may be different.

Winston Churchill once commented that “democracy is the worst form of government, except for all the others”. While randomized clinical trials have some flaws, they remain the best way we have to determine the effectiveness and potential side effects of a medication.

Active and inactive relapsing-remitting MS

Before proceeding to a discussion of disease modifying therapy, it is important for the reader to be aware of the different uses of the adjective active when describing relapsing-remitting and progressive forms of MS. The adjective active, when used in the context of relapsing-remitting MS, refers to patients with relapsing-remitting MS who have had relapses within the past 2 years and have new MS lesions on recent MRI scans. The term active when referring to either secondary progressive or primary progressive MS patients indicates the person has attacks or relapses in addition to having a progressive course.

With regard to treatment of relapsing-remitting MS, the benefit of starting  disease modifying therapy in patients with active relapsing-remitting MS has been studied extensively, but has not been studied in untreated patients with clinically isolated syndrome or relapsing forms of MS who have not had a relapse in 2 or more years and do not have new MRI lesion activity on recent imaging (Rae-Grant A, et al. 2018). We can refer to these patients as having inactive relapsing-remitting MS.

The problem for the neurologist is that active inflammation may continue in MS patients without relapses or new symptoms and may occur on a level that is not easily seen on MRI scans. Without clinical trials of inactive relapsing-remitting MS, it is a judgment call on the part of the neurologist whether or not to start a disease modifying therapy. In inactive relapsing-remitting MS patients, we do not know the risk of harm from disease modifying therapy compared to the potential benefit of treatment, The American Academy of Neurology guidelines for inactive relapsing-remitting MS patients are that neurologists “may recommend” serial imaging annually and “close follow-up” rather than initiating disease modifying therapy (Rae-Grant A, et al. 2018).

Multiple randomized clinical trials have been done which show disease modifying therapy helps MS patients with active relapsing-remitting MS in the short run (Chaflin SB 2018). Most of these trials lasted 2 -3 years. They proved that these medications decrease the average relapse rate in groups of MS patients over the 2-3-year course of these trials. These trials also showed that some of the medications can decrease the development of short-term disability and the number of new lesions on MRI scans of the brain.

Even though these studies do not tell your neurologist definitively which medication will be effective for you, they are helpful to tell how likely each of these medications is to be effective and establish the possible side effects of each of these medications.

When thinking about treatment for MS, one also needs to keep in mind that disease modifying therapy reduces but does not eliminate the risk of relapse or progression of MS. The job of your neurologist is to use his experience and data from the randomized clinical trials to choose which disease modifying therapy is most likely to help you while minimizing the risk of side effects. However, there is no way for your neurologist to predict with 100% certainty that a specific disease modifying therapy will benefit you and that you won’t suffer side effects from the chosen medication.

References

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