Debate: Do subtypes of multiple sclerosis exist?
Key takeaways:
- One expert said there are three immunological subtypes of multiple sclerosis.
- Another argued that MS should be defined as a disease spectrum, rather than by subtypes.
WEST PALM BEACH, Fla. — Two experts debated the issue of whether subtypes of multiple sclerosis exist, one from Europe and the other from the United States, during the final day of ACTRIMS.
Arguing for the existence of subtypes was Heinz Wiendl, MD, director of the department of neurology and neurophysiology at the University of Freiburg in Germany, while arguing for the negative was Kathryn C. Fitzgerald, ScD, associate professor in the departments of neurology and epidemiology at Johns Hopkins University.
The case for MS subtypes
In his opening argument, Wiendl questioned why this is a debate at all, stating “it’s pretty clear that subtypes exist.”
Wiendl asserted that MS is “a whole brain disease” and that imaging alone cannot find all traces of the condition, hence the need for alternate models to distinguish subtypes.
His first piece of evidence arose from current clinical definitions of MS having at least two dimensions relating to relapsing or primary-progressive phases of disease, along with at least two diagnostic modalities of clinical evaluation and MRI analysis.
Next, he asserted that peripheral blood analysis via a sequential matrix could be one of these methods. Wiendl and colleagues analyzed a multicenter cohort of homogeneous individuals with early MS from Germany. The study attempted to answer if a diagnosis could be made from peripheral blood, and if that were possible, if it could yield different subtypes.
This method yielded three immunological subtypes, called endothelial subtypes, which were associated with three separate disease-related trajectories.
Then, he asserted that classification of disease types and disease course can become more unified if approached through data-driven methods.
Wiendl and colleagues gathered clinical and MRI data from 35,000 individuals involved in clinical trials and fed the information through a machine model, where it produced four dimensions and eight states of disease progression related to physical disability.
States 1 through 3 deal with early or evolving disease states, states 4 and 5 are a nexus point where inflammation drives disease worsening, and in states 6 through 8, advanced disease occurs with significant physical and mental disability.
“This is work that is, in my opinion, relevant because it can then be applied to questions like: ‘would a more homogeneous state accumulation or subtype have a better likelihood to select patients for clinical trials?’” Wiendl concluded.
The case against MS subtypes
Fitzgerald countered by asserting “clinical subtypes create constructs that aren’t fully reflective of the underlying pathology and ongoing biological processes.”
As there are no “clear” biological boundaries that define MS subtypes, Fitzgerald said the question that needs to be answered is, when, exactly does a person transition from relapsing into secondary progressive MS?
The answer is complicated by a number of factors, Fitzgerald continued, chief among them determining the stages of disease course within the four main disease types (relapsing, progressive, radiologically and clinically isolated syndromes). Environmental risk factors such as diet, exercise and substance use also muddy the waters, with one study showing the link between smoking and MS did not significantly differ for those with relapsing and progressive forms of the disease.
Genetic factors also play a part, she added, with research uncovering specific features of disease course which overlap with clinical subgroups with approximately 50% concordance in certain studies. Additionally, Fitzgerald noted, some immunologic and metabolic research can infer differences between relapsing and progressive MS but fail to do so between primary and secondary stages of the disease.
More likely, MS should be defined as a disease spectrum, which focuses on quantitative rather than qualitative differences in disease types. Evidence of certain characteristics such as acute axonal damage as well as compensatory or repair mechanisms can overlap in both early stages and progressive stages of MS, she said.
“It’s likely that many of these subgroups themselves exist on a spectrum and have a continuous, rather than distinct percentage of being in disease clusters,” Fitzgerald said. “A spectrum model is likely to be a better fit.”