SAN DIEGO – , rather than a mixture of conditions with different genetic or other causes, according to a new analysis. The work suggests that personalized therapy based on clinical characteristics is likely to be the best approach, rather than precision medicine based on molecular or other subtypes.
Think MS is heterogeneous? Think again
The work drew upon data from 22,000 individuals, 32,000 attacks, 156,000 EDSS scores, 250,000 observation years, and 110,000 treatment years recorded in the Swedish MS registry. The researchers examined distributions in age of onset, severity, and distribution of relapses. Among patients treated with one of 12 disease-modifying therapies, they examined patterns of EDSS progression, appearance of new lesions, and relapses.
Regardless of which clinical characteristic of the MS syndrome that I study, I find a uniform distribution with very few if any outliers. That argues that MS is likely to be a homogeneous condition with some variation, but it’s highly unlikely that MS is a mixture of different conditions masquerading as the same thing,” said Jan Hillert, MD, PhD, who presented the study during a poster session at the annual meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis.
“There are big efforts out there trying to decipher the molecular basis of the MS syndrome, thinking that it’s a mixture of different things. And I would argue that our data very strongly argue against that,” said Dr. Hillert, who is a professor of neurology at Karolinska Institutet in Solna, Sweden.
Specific subtypes should produce individual groupings rather than a broad distribution. “If you have a multitude of factors, then this (finding of a broad distribution) is what you have. If you have a small number of strongly acting factors, like if there were genetic subgroups, then you would have a different distribution. So this is in line with the polygenic, complex nature of MS that we have been thinking about for many, many years, and which the genetics also support,” said Dr. Hillert.
The findings suggest that physicians should be emphasizing personalized treatment of MS based on factors like age, weight, disease activity and severity, disability, side effects, and other factors. “Personalized medicine I embrace, but the concept of precision medicine is naive. It’s not founded on any sound scientific evidence,” said Dr. Hillert.
An evolving definition
The conclusion is compelling, according to Patricia Coyle, MD, who was asked to comment on the study. “I have not seen this sort of analysis before. I think it doesn’t absolutely prove the case in talking about very small numbers, but it does make a very logical argument. This is not showing any meaningful large subgroups that you can call out,” said Dr. Coyle, who is a professor of neurology and director of the MS Comprehensive Care Center at Stonybrook Neurosciences Institute in New York.
“I think that it’s interesting, because we have routinely said we think this is heterogeneous, because no two patients are alike. But this is speaking against meaningful heterogeneity in MS. When you look at these sorts of statistical results, this is what you’d expect in a normal population, not in a disease where you might say, genetically, or molecularly, you could define significant subsets of individuals,” said Dr. Coyle.
The study isn’t the last word. “You would probably like to see some follow-up data, perhaps in other very large databases to make it more convincing, but I think you’re not hearing as many people talk about MS heterogeneity anymore. We know there’s a focal inflammatory component, we know there’s a neurodegenerative component. Both are present in all MS. People are even arguing that maybe it’s not meaningful to call out progressive and relapsing MS. I don’t agree with that, but I think the concept that there are meaningful subsets of patients is probably incorrect. [The idea that] one set is due to perhaps an infection, another might be molecular mimicry. ... Maybe that’s not the case at all,” said Dr. Coyle.
For example, some companies are looking into whether B cell depletion treatments might be more effective for one set of patients versus another. “The issue is, can you dissect out subsets where hitting B cells is really good and others where it doesn’t seem to matter? That really hasn’t [been successful],” said Dr. Coyle.
Dr. Hillert has served on scientific advisor boards for or received speaker’s fees from Biogen, Bristol Myers Squibb/Celgene, Janssen, Novartis, Teva, Merck KGaA, Sandoz, and Sanofi Genzyme. He has received research support from Biogen, Bristol Myers Squibb/Celgene, Merck, Janssen, Novartis, Roche, and Sanofi-Genzyme. Dr. Coyle has consulted for or received speaker fees from Accordant, Biogen, Bristol Myers Squibb, GlaxoSmithKline, Horizon Therapeutics, LabCorp, Eli Lilly and Company, Mylan, Novartis, Sanofi Genzyme, TG Therapeutics. She has received research support from Actelion, Alkermes, Celgene, CorEvitas, Genentech/Roche, Janssen, MedDay, NINDS, Novartis, and Sanofi Genzyme.