Corey C. Ford, MD, PhD
Professor of Neurology
University of New Mexico Medical Center, Albuquerque
Director, University of New Mexico Multiple Sclerosis Specialty Clinic

 

Long-term data have recently been reported for various MS disease-modifying drugs, but without having a placebo group or other comparator, how can we show that the treatments make a difference versus no therapy?

This is an excellent question with important implications for chronic illnesses like MS. Some people with MS will live with the disease for 40 to 50 years or more. In this context, a two- or three-year clinical trial does not provide much information about long-term benefits and risks of treatments. On the other hand, natural history studies show MS to be a disabling disorder and provide some idea of what happens to untreated patients. The problem is that natural history studies were done at a different time and enrolled MS patients with different characteristics than a current group of MS patients (typically diagnosed earlier in the disease process) might display. For ethical reasons it is not possible to conduct a long-term placebo-controlled trial when effective disease-modifying treatments exist.

I think long-term studies provide useful safety information. If the follow-up methods in these trials consist of regular examinations and/or MRI scans, objective data can be generated about the clinical stability or change in disability status of the treatment groups. These data may be compromised by subjects who discontinue the trial. In general, dropouts tend to be those who are not responding as well to therapy or have other complications. This has the potential to bias the data toward those who do respond to the therapy and therefore choose to remain on the drug. Notwithstanding these problems, long-term studies involving 10 or 15 years of follow up have shown that patients staying on MS disease-modifying therapies do better, as a group, compared with those who do not stay on therapy and compared with existing natural history data.

I served as an investigator for the US Glatiramer Acetate Trial, which was unique in that it followed patients who remained on glatiramer acetate as their sole immunomodulating agent—without switching to other drugs or going off therapy—for as long as 15 years. Despite a mean disease duration of 22 years (mean age 50 years), two-thirds of the treated group did not transition to secondary-progressive MS during the 15-year period, 57% had stable or improved EDSS scores, and 82% remained ambulatory without the need for mobility aids.

The ongoing long-term study for interferon beta-1b followed the original pivotal trial participants for up to 16 years after randomization, stratifying patients according to their exposure to the study drug over the 16 years (< 10%, 10% to 80%, or >80% of the time since the start of the trial). Those with greater exposure had the lowest annualized relapse rates and the longest time from diagnosis to a confirmed EDSS score of 6.0 (13 years in the >80% group).

Because the designs of the various long-term trials in MS vary so widely, it is impossible to make any head-to-head comparisons of the data.

Suggested reading:

Ford C, Goodman AD, Johnson K, et al. Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis: Results from the 15-year analysis of the US prospective open-label study of glatiramer acetate. Mult Scler. 2010;16:342-350.

Ebers G, Rice G, Konieczny A, et al. The interferon beta-1b 16-year long-term follow-up study: The final results. Neurology. 2006;66(Suppl 2):A32.

Goodin D, Ebers G, Traboulsee A, et al for the Betaseron LTF Study Group. The interferon beta-1b 16-year long-term follow-up study: Clinical outcomes.Ann Neurol. 006;60:S1-S160(abstract M-3).

Bermel RA, Weinstock-Guttman B, Bourdette D, et al. Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: A 15-year follow-up study.>Mult Scler. 2010;16:588-596.

Carroll WM. Clinical trials of multiple sclerosis therapies: Improvements to demonstrate long-term patient benefit.>Mult Scler. 2009;15:951-958.

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The effects of pregnancy hormones on MS have been long discussed—is there any new information about whether these hormones can be used clinically for MS management?

It has been noted for many years that women with MS who are pregnant tend to do well with fewer relapses and less progression of disability, especially during their third trimester. In addition, during the three- to six-month period after delivery women with MS may be more likely to have a relapse. For these reasons, determining the biologic changes in pregnancy that confer this protective effect has been an important research goal.

There is an ongoing study to determine whether the pregnancy hormone estriol, added to treatment with glatiramer acetate, provides additive benefit. This study is still seeking to enroll women with MS who are starting or have recently started glatiramer acetate treatment for their MS. Estriol seems to induce some of the immune shifts that occur in pregnancy and might be important in reducing MS disease activity. Estriol is an inexpensive treatment and a relatively safe estrogen-like hormone that can be taken orally. If the study results are positive, estriol tablets plus glatiramer acetate could be a combination therapy with an evidence-based rationale for use in MS.

Another ongoing study is looking at whether post-partum treatment with the hormones progestin and estradiol could help prevent the post-partum relapse commonly seen in women with MS.

Suggested reading:

Gold SM, Voskuhl RR. Estrogen and testosterone therapies in multiple sclerosis. Prog Brain Res. 2009;175:239-251.

ClinicalTrials.gov. A combination trial of Copaxone plus estriol in relapsing remitting multiple sclerosis (RRMS) (Estriol in MS).

Vukusic S, Ionescu I, El Etr M, et al. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: rationale, objectives and state of advancement.J Neurol Sci. 2009;286:114-118.

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Would you use polysomnography to explore the possibility of an underlying sleep disorder contributing to MS patient complaints of fatigue?

MS and its complications may affect sleep in many ways. In addition, people with MS are not immune to the range of sleep disorders that might affect any person. It has been shown that quality of life and sense of well being in people with MS improve with adequate sleep. Fatigue, as the most common symptom of MS, is often multifactorial. It can arise from combinations of injured axons struggling to conduct impulses, cytokines and other immune mediators released in the disease, weakness, depression, heat sensitivity, and poor sleep. If a person with MS has persistent sleep complaints, it can be difficult to characterize the etiology and significance of the problem without a formal sleep study. In some cases, physicians should use their clinical judgment to determine when to obtain a more detailed workup of sleep complaints. This can definitely involve polysomnography (a sleep study), which analyzes how long and how well a person sleeps and what happens to the body during sleep.

In a study reported at the most recent Consortium of Multiple Sclerosis Centers meeting in San Antonio, investigators from Baylor College of Medicine in Houston examined 100 people with MS (81% women; mean age 40) to identify sleep disorder prevalence and related factors. A high percentage (40%) were shown to have some sleep disturbance (score of 9 or above on the Epworth Sleepiness Scale), while over 87% of the patients said they experienced significant fatigue. The take-home point of these findings should be to look at MS-related fatigue as multifactorial and determine any possible sources of fatigue that might be treatable.

Suggested reading:

Elkins LE, Krupp LB, Scheri W. The measurement of fatigue and contributing neuropsychiatric factors. Semin Clin Neuropsychiatry. 2000;5:58-61.

Kos D, Kerckhofs E, Nagels G, et al. Origin of fatigue in multiple sclerosis: review of the literature. Neurorehabil Neural Repair. 2008;22:91-100.

Avila ML, Prieto PG, Avila J, et al.Sleep disorders in multiple sclerosis. Poster presented at: Consortium of Multiple Sclerosis Centers, 24th Annual Conference. San Antonio, TX: June 4, 2010, Abstract S07.

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