Multiple Sclerosis: Autoimmune or Neurodegenerative?
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ORLANDO, Florida — Despite all the evidence to the contrary — and maybe even common sense — there's some indication that multiple sclerosis (MS) is not primarily an autoimmune disease but instead is due to a neurodegenerative process that sparks an inflammatory response.
That point was argued by Peter Stys, MD, professor, neurology, University of Calgary, Alberta, Canada, during a debate here at the 5th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS).
"MS is an autoimmune disease, but the question is, is MS primarily an autoimmune disease?" said Dr. Stys.
He squared off with Richard Ransohoff, MD, director, Neuroinflammation Research Center, Cleveland, Ohio, who argued the more "orthodox" view of MS.
While he conceded there is "overwhelming evidence" that MS is an immunologic disorder, Dr. Stys pointed out several factors that raise doubts that the condition is primarily autoimmune. For one thing, in the earliest lesions, where there is profound myelination, there’s little evidence of any inflammatory response.
Dr. Stys pointed out that anti-inflammatory treatments don't have much effect on the progressive phase of the disease and that some nonautoimmune diseases share pathologic and immunologic characteristics with MS.
The argument that because some patients with MS benefit from bone marrow transplants, MS must be an autoimmune disease doesn't hold up, said Dr. Stys. He noted some "clearly genetically mediated neurometabolic disorders" that are "absolutely not primarily autoimmune" disorders are also helped by bone marrow transplants.
One example he used was adrenoleukodystrophy (ALD), a genetically inherited disorder in which patients lack a protein necessary to sustain myelin.
Dr. Stys believes that MS has 2 key contributing factors: dysimmunity and an underlying cytodegeneration. "In my mind, the underlying degeneration may well be primary," he said.
He pointed out that the overwhelming majority of patients in MS studies have relapsing-remitting MS (RRMS). This research, he said, has taught scientists little about the progressive phase of the disease.
"Despite common sense, despite what’s obvious, maybe the real MS is primary progressive disease, and relapsing-remitting MS, which curiously represents the vast majority of our patients, is actually a reaction, a distraction if you will, to the primary root cause," said Dr. Stys. "I don’t know the reason for that reaction, but I suspect it has to do with myelin being so antigenic."
I would … call for experts to repeat over the next decade much of what we've done in MS research but focusing on the minority of patients with primary progressive MS.
Dr. Peter Stys
It's time, said Dr. Stys, to refocus attention on primary progressive MS. "I would argue, and call for, experts to repeat over the next decade much of what we’ve done in MS research but focusing on the minority of patients with primary progressive MS. What kind of genetics will come out of that? What kind of biology, what kind of biochemistry?"
The key question, said Dr. Stys, is not whether dysimmunity or cytodegeneration is more important but rather which comes first. It’s impossible to say how long it will take to answer that, but Dr. Stys said he "worries" that the MS research community is already "40 years behind" colleagues in the field of Alzheimer's and Parkinson's disease.
Taking the more accepted side of the debate, Dr. Ransohoff said he doesn't rule out the possibility of an underlying cytodegenerative process, but he insisted that indisputable and mounting data support the theory that MS is primarily an inflammatory disease. He outlined elements of a "coherent" scheme of MS that is supported by genetic, environmental, immunologic, and treatment response evidence.
To illustrate how the pathology of MS differs from that of similar but non–immune system-related disorders, he compared MS with ALD at the cellular level. Concentrations of macrophages behave differently with respect to lesions in the 2 diseases, he said.
Genome-wide association studies also show that the genetic variants that are significant for MS are related to the function of the immune system, said Dr. Ransohoff. "Some play a role in neurobiology as well, but their main function is inside the immune system."
Dr. Ransohoff also pointed to the "impressive sharing" of allelic variants from the immune system between MS and other autoimmune inflammatory diseases, including psoriasis, rheumatoid arthritis, lupus, Crohn’s disease, type 1 diabetes, and celiac disease.
In contrast, he added, genes harboring variance for risks for conditions such as autism live in the nervous system, not the immune system. And a newly identified gene defect has been associated with frontal temporal dementia, Alzheimer's disease, and Huntington's disease, but not MS. "So MS does not seem to track genetically with the primary neurodegenerative diseases."
Dr. Ransohoff reminded the audience of the environmental factors linked to MS, including sun exposure and vitamin D, which decrease risk, and smoking, which increases risk. But perhaps the "most impressive" factor linked to MS is infectious mononucleosis, he said. "It seems as if it’s almost impossible to get MS unless a person has been infected with the Epstein-Barr virus."
Dr. Ransohoff also noted that treatments that are immune modulators appear effective in patients with MS. If MS were caused by a virus or another pathogen, "there should be a drastic worsening during treatment, and we don't see that," he said.
As well, he added, if MS was an inflammatory result of primary neurodegeneration, "there should be no lasting benefit of early immunological treatment," although he conceded that "the jury is still out on that."
Dr. Ransohoff agreed that the pathogenesis of progressive MS is not well understood. What is also not well understood about the immune process in MS is what T cells say to macrophages to get them to target myelin so selectively, he said.
Both Dr. Ransohoff and his friendly opponent broached the issue of why in some people, the relapsing phase of MS is "silent." In these cases of radiographically isolated syndrome, MRI turns up evidence of lesions, but patients have no symptoms until much later, when they develop primary progressive MS.
Another attendee at the debate, Robert Herndon, MD, professor, neurology, University of Mississippi Medical Center, Jackson, commented that that there has been a "dramatic" decrease over the years in the proportion of patients with relapsing-remitting disease who go on to secondary progressive MS.
"It used to be, before we had treatments, that you could anticipate that after 20 years or so, close to 90% of relapsing-remitting patients would develop secondary progression, but long-term follow-up on patients taking Copaxone [glatiramer acetate; Teva Pharmaceuticals] showed that rate is now about 49%," Dr. Herdon pointed out. "This is very evident in clinics."
The discussants have disclosed no relevant financial relationships.
5th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) and the Americas Committee for Treatment and Research In Multiple Sclerosis (ACTRIMS). Debate. Presented June 1, 2013.