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Three Distinct Endophenotypes Identified in Patients With MS
abstract
This abstract is available on the publisher's site.
Access this abstract nowOne of the biggest challenges in managing multiple sclerosis is the heterogeneity of clinical manifestations and progression trajectories. It still remains to be elucidated whether this heterogeneity is reflected by discrete immune signatures in the blood as a surrogate of disease pathophysiology. Accordingly, individualized treatment selection based on immunobiological principles is still not feasible. Using two independent multicentric longitudinal cohorts of patients with early multiple sclerosis (n = 309 discovery and n = 232 validation), we were able to identify three distinct peripheral blood immunological endophenotypes by a combination of high-dimensional flow cytometry and serum proteomics, followed by unsupervised clustering. Longitudinal clinical and paraclinical follow-up data collected for the cohorts revealed that these endophenotypes were associated with disease trajectories of inflammation versus early structural damage. Investigating the capacity of immunotherapies to normalize endophenotype-specific immune signatures revealed discrete effect sizes as illustrated by the limited effect of interferon-β on endophenotype 3-related immune signatures. Accordingly, patients who fell into endophenotype 3 subsequently treated with interferon-β exhibited higher disease progression and MRI activity over a 4-year follow-up compared with treatment with other therapies. We therefore propose that ascertaining a patient's blood immune signature before immunomodulatory treatment initiation may facilitate prediction of clinical disease trajectories and enable personalized treatment decisions based on pathobiological principles.
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Multiple sclerosis endophenotypes identified by high-dimensional blood signatures are associated with distinct disease trajectories
Sci Transl Med 2024 Mar 27;16(740)eade8560, CC Gross, A Schulte-Mecklenbeck, OV Steinberg, T Wirth, S Lauks, S Bittner, P Schindler, SE Baranzini, S Groppa, J Bellmann-Strobl, N Bünger, C Chien, E Dawin, M Eveslage, V Fleischer, G Gonzalez-Escamilla, B Gisevius, J Haas, M Kerschensteiner, L Kirstein, C Korsukewitz, L Lohmann, JD Lünemann, F Luessi, G Meyer Zu Hörste, J Motte, T Ruck, K Ruprecht, N Schwab, F Steffen, SG Meuth, F Paul, B Wildemann, T Kümpfel, R Gold, T Hahn, F Zipp, L Klotz, H WiendlFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Despite tremendous progress in the treatment of MS over the last 2 decades, one of the greatest challenges that remains is the ability to provide personalized medicine. MS is a highly heterogenous disease, and predicting an individual's response to treatment and the risk of future disability remains difficult. Immune heterogeneity among patients may drive variability in both disease pathophysiology and response to immunological therapy.
In this study, the investigators combined high-dimensional flow cytometry of peripheral blood mononuclear cells and serum proteomics with unsupervised clustering. Blood samples from 309 treatment-naive patients with early (<2 years from disease onset) MS were analyzed in a discovery cohort, and the results were replicated in an independent validation cohort comprising 232 patients.
Overall, three immunological endophenotypes were identified: E1, E2, and E3. These distinct endophenotypes were primarily driven by cellular, not soluble, parameters. Alterations in the CD4 T-cell compartment characterized E1, alterations in the CD8 T-cell compartment characterized E3, and E2 displayed greater changes in the natural killer cell compartment. Importantly, the endophenotypes demonstrated clear differences in clinical and paraclinical measures of disease activity over a 2-year period. Patients with the E3 phenotype demonstrated an inflammatory phenotype, whereas patients with the E1 phenotype had markers of early neurodegeneration. Moreover, there were different responses among endophenotypes to three platform disease-modifying treatments (DMTs): interferon-β (IFN- β), glatiramer acetate (GA), and dimethyl fumarate (DMF).
In E1 and E2, immune signatures were normalized to a comparable extent to healthy donors by all DMTs, whereas, in E3, IFN-β exhibited limited effects compared with GA and DMF, corresponding to the observation that patients with the E3 phenotype on IFN- β had greater radiological disease progression and more rapid increase in disability compared with those treated with GA and DMF. Such differences in the effects of IFN- β were not observed in E1 or E2, suggesting that treatment response may be influenced by endophenotype.
In conclusion, this is a landmark study demonstrating the potential of blood immunophenotyping as a first step toward personalized medicine in MS — the ultimate treatment goal that will maximize outcomes in people with MS. Future directions will include validation in external cohorts with greater geographic and ethnic diversity, utilization of additional paraclinical measures (imaging and biological) to better characterize MS endophenotypes, a longitudinal follow-up of this cohort, and evaluation of differences in treatment responses to a wider range of DMTs, including high-efficacy therapies.