Gary Birnbaum, MD
One DMT may not be enough
Paper #1: Silent Progression in Disease Activity–Free Relapsing Multiple Sclerosis
University of California, San Francisco MS-EPIC Team, Bruce A. C. Cree, MD, PhD, MAS, Jill A. Hollenbach, PhD, MPH et al.
Paper #2: Contribution of Relapse-Independent Progression vs
Relapse-Associated Worsening to Overall Confirmed Disability Accumulation in Typical Relapsing Multiple Sclerosis in a Pooled Analysis of 2 Randomized Clinical Trials
Ludwig Kappos, MD; Jerry S. Wolinsky, MD; Gavin Giovannoni, PhD et al.
JAMA Neurol. 2020;77(9):1132-1140
Clinical attacks (relapses) of MS can result in increased disability. However, data described in the above two papers indicate that even in persons newly diagnosed with relapsing forms of multiple sclerosis another disease process is occurring, one that results in a gradually increasing accumulation of disability in the absence of relapses. Indeed, in one study, most of the accumulated disability, up to 80-90%, was the result of non-relapse associated progression.
Such progressive disability is felt to result from low-grade, chronic inflammation, very different from the acute inflammation associated with MS relapses, and is present even in the very early phases of relapsing MS. Unfortunately, such tissue “degenerative” processes have been resistant to treatment with almost all current disease-modifying therapies.
It is not clear is how these two disease processes interact. What is clear is that even with almost complete control of acute inflammation, as described in Paper #2 with the high-potency disease-modifying therapy ocrelizumab, significant, accumulation of disability still occurred, albeit less than noted with a less potent disease-modifying therapy.
Two main points can be made from the above results. One is that even in persons diagnosed with relapsing forms of multiple sclerosis, processes related to progressive forms of multiple sclerosis occur, even early in the disease. Secondly, while several of the newer disease-modifying therapies are approved for treatment of persons with progressive MS who also have evidence of acute inflammation, and such while effects are statistically significant, only very modest clinical benefit is noted. Thus, while control of acute MS relapses has been achieved with many of the current disease-modifying therapies, future treatments of MS may require a “cocktail” of therapies, not only to reduce acute inflammation, but to arrest the degenerative phase of the disease that appears responsible for most of the gradually accumulating disability and loss of brain tissue described in the above studies.
1. The above two papers studied well-defined populations of persons with relapsing forms of multiple sclerosis. Their aims were to determine whether the gradual accumulation of disability in many of these individuals was the result of clinical relapses or due to more indolent, chronic, “degenerative” inflammation, the hallmark of secondary progressive and primary progressive multiple sclerosis.
2. Progression of disability was measured using several scales. One was the EDSS (expanded disability status scale. Other measurements were the timed 25-foot walk, measures of cognitive function, and the 9-hole peg test.
3. Paper #1 describes results from a well-characterized population of persons at a single center. Individuals had either a clinically isolated syndrome (the first attack of an illness likely to become clinically definite multiple sclerosis) and those with relapsing forms of multiple sclerosis. Individuals were evaluated at least annually for five to ten years. Relapses were determined on the basis of both the clinical history and exam as well as with central nervous system MRIs, looking for subclinical evidence of both ongoing acute inflammation and loss of brain tissue (atrophy).
4. Three hundred seventy-two persons with relapsing forms of multiple sclerosis, from an initial population of 480 individuals with MS, completed ten years of follow-up. Disease-modifying therapies were continued, with individuals grouped into those receiving either “platform” therapies(e.g. interferons, glatiramer acetate) or “high-potency therapy” (e.g. natalizumab, mitoxantrone, rituximab, cyclophosphamide).
5. Half of the study population showed progression of disability over the course of the ten years of the study. Worsening mainly involved motor function and cerebellar function.
6. There was short-term worsening of disability during relapses, but numbers of persons accumulating long term disability over the ten years of the study were no different for those with, and those without, clinical relapses. This was also the case for persons with or without new lesions on central nervous system MRIs.
7. Progression of disability was associated with a loss of central nervous system tissue (atrophy) and was noted even very early in the course of their illness, regardless of their treatment with disease-modifying therapies, and whether or not they had relapses.
8. In other words, progression of disability in persons with relapsing forms of multiple sclerosis occurred via processes not related to acute central nervous system inflammation, a process the authors felt was related to what occurs in persons with progressive forms of multiple sclerosis. They called such worsening disability “silent disease progression.”
9. Paper #2 describes an analysis of 1,656 persons with active relapsing forms of multiple sclerosis who participated in one of two clinical trials involving the disease-modifying therapy ocrelizumab compared to high dose interferon-beta (OPERA Trials).
10. Participants were reevaluated retrospectively (after the study was completed) for the development of disease progression using the EDSS, 25-foot timed walk and the 9-hole peg test. Progression was then related to the presence or absence of clinical relapses. Central nervous system MRIs were not used to indicate sub-clinical “relapses.”
11. Between 80-90% of the disease progression noted in persons on either ocrelizumab or interferon-beta was not related to clinical relapses. Thus, even in a population of persons with MS selected for active relapsing forms of multiple sclerosis insidious disease progression occurred, suggestive of disease processes seen predominantly in persons with progressive forms of multiple sclerosis.
12. Since the greatest effect of current disease-modifying therapies is on reducing active brain inflammation, the above two studies further indicate the urgent need to find treatments that address the chronic, low-grade, degenerative disease processes that occur from onset in relapsing forms of multiple sclerosis.
13. Future therapies of MS will thus most likely require a cocktail of drugs to address issues of acute inflammation, chronic tissue destruction, and myelin repair (remyelination).
Controlling relapses of multiple sclerosis has been a primary outcome measure in almost all clinical trials of current disease-modifying therapies. While relapses can contribute to disability, recovery can occur, either partially or completely. What has become clear in the past several years is that even with almost complete control of relapses many persons with MS continue to gradually accumulate disability. This phenomenon is usually noted later in the course of the illness as persons with relapsing forms of multiple sclerosis transition to secondary progressive MS or as occurs in persons with primary progressive multiple sclerosis.
The immune mechanisms associated with relapses are very different from those seen in persons with progressive disease. Relapses are associated with acute inflammation, resulting in tissue destruction by activated lymphocytes. Progressive disease is associated with low grade, chronic inflammation, also involving lymphocytes but involving other cells as well, such as macrophages, microglia, and glial cells. While current disease-modifying therapies do an excellent job controlling the inflammation associated with relapses, their ability to control the more indolent, chronic, degenerative tissue processes of progressive disease are modest at best.
The above noted papers are important for at least two reasons. They convincingly demonstrate that chronic, gradual accumulation of disability can occur in persons diagnosed with relapsing forms of multiple sclerosis, even very early in the disease. They also convincingly show that up to 90% of accumulated disability results from non-relapse related mechanisms. That does not mean an absence of interaction between the acute and chronic inflammatory mechanisms. Indeed, a recent paper noted that the risks for developing secondary progressive MS were decreased in persons treated with high-efficacy disease-modifying therapies. Nevertheless, more potent treatments of progressive disease are urgently needed to control this phase of the illness. Research is being done in this area and as the complexities of this phase of the disease are understood, possible therapies are being tested, such as Bruton thymidine kinase inhibitors (BTK inhibitors).