Multiple sclerosis (MS) has three distinct subtypes based on immune markers in patient's blood, each with slightly different disease trajectories and responses to therapy, a new study suggested.
With further validation, determining a patient's blood "immune signature," or endophenotype, before starting immunomodulatory therapy may help predict clinical disease trajectories and lead to more personalized treatment decisions, investigators said.
"The characterization of an endophenotype at timepoints of diagnosis will help to determine likely trajectory of the disease course but also will help to refine the chosen immune therapy," Heinz Wiendl, MD, professor and chair, Department of Neurology, University of Münster, Münster, Germany, told Medscape Medical News. "This is a rationale way of precision medicine for the future."
The study was published online on March 27 in Science Translational Medicine.
Degenerative and Inflammatory Subtypes
MS is a highly heterogeneous disorder with different clinical manifestations and disease trajectories, making it a challenge to manage. Whether this heterogeneity is reflected by discrete immune signatures in the blood has been unclear.
To investigate, Wiendl and a multicenter team comprehensively analyzed the immunological properties of blood samples collected from 309 patients with early MS and an independent validation cohort of 232 patients with early MS.
In both cohorts, they found that cellular immune signatures split into three distinct immunological endophenotypes, dubbed E1, E2, and E3.
E1 is characterized by alterations in the CD4 T-cell compartment, with increases in inflammatory cytokines, namely interleukin-17A (IL-17A), IL-22, and granulocyte-macrophage colony-stimulating factor, as well as earlier structural brain damage, more severe disease, and higher disability.
Alterations in natural killer cells are a hallmark of the E2 subtype, while alterations in the CD8 T cells dominate the E3 subtype.
The different subtypes were associated with distinct clinical disease trajectories. E3 patients displayed a pattern reflecting higher inflammatory disease activity, as illustrated by a higher relapse rate (≥ 2) within the first year from baseline and more frequent use of highly active disease-modifying therapies as first immunomodulatory treatment.
E3 patients also had higher numbers of gadolinium-enhancing lesions at baseline, a higher conversion rate from clinically isolated syndrome to relapsing-remitting MS, and rapid disability accrual within 2 years after baseline.
This endophenotype was also associated with an increase in total cell numbers within the cerebrospinal fluid and intrathecal immunoglobulin (Ig) G synthesis at baseline.
E1 patients had a higher degree of early structural brain damage and disease severity, including disability and impaired evident at baseline, and increased serum neurofilament light and increased intrathecal IgM synthesis at baseline.
"According to these different patterns of disease trajectories, we therefore termed these subsets degenerative E1 and inflammatory E3. Overall, although some of the clinical and paraclinical parameters partially overlapped, our analysis reveals that distinct immunological endophenotypes might have predictive value with regard to clinically relevant disease trajectories," the researchers wrote.
Toward Personalized Care
In addition, during up to 4-year follow-up of some patients, they observed that patients with the inflammatory E3 endophenotype treated with interferon-β exhibited higher disease progression and MRI activity relative to E3 patients receiving other therapies. These differential effects of interferon-β were not observed in the other endophenotypes.
With further study and refinement, the hope is to make this test a "clinical reality," Wiendl said.
Commenting on the findings for Medscape Medical News, Kimberly O'Neill, MD, clinical instructor, Department of Neurology, NYU Grossman School of Medicine, New York City, noted that people with MS can have "a broad variety of disease course and outcomes ranging from mild to a very severe and life-altering disease course. At this point, we are not great at predicting who is going to be on which path and also which medication is right for each patient."
"Research like this gives us hope for a more personalized precision medicine in MS," said O'Neill, who was not part of the study. "The ideal world would be to have a blood test that could tell their disease course and which treatments will work for an individual patient, but we are certainly not there yet."
Also providing an outside perspective, Mary Rensel, MD, director of wellness and pediatric MS at the Cleveland Clinic Mellen Center for MS, Cleveland, Ohio, said, "Precision medicine is our goal and dream in MS care — to be able to do a blood test and know what medicine a patient may or may not respond to and save them years of ongoing symptoms or the risk of disability. This study is a great start."
Support for this research was provided by grants from the Federal Ministry of Education and Research, the German Research Council, and the Hermann and Lilly Schilling Foundation. Disclosures for study authors are listed with the original article. O'Neill and Rensel had no relevant disclosures.