B-Cell Activity Predicts Response to Glatiramer Acetate and Interferon in Relapsing-Remitting Multiple Sclerosis

Abstract

Objective: We investigated the predictive value of the enzyme-linked immunospot technique (ELISPOT) in identifying patients with relapsing-remitting multiple sclerosis (RRMS) who will respond to treatment with glatiramer acetate (GA) or interferon-β (IFN-β), based on the brain-reactive B-cell activity of peripheral blood cells.

Methods: In this retrospective, cross-sectional, real-world multicenter study, we identified patients with RRMS in the NeuroTransData MS registry and stratified them based on their documented treatment response (relapse-free in the first 12 months of treatment) to GA or IFN-β. The GA group comprised 73 patients who responded to GA and 35 nonresponders. The IFN-β group comprised 62 responders to IFN-β and 37 nonresponders. Patients with previous or current therapy affecting B-cell activity were excluded. We polyclonally stimulated mononuclear cells from peripheral blood samples (collected after participant selection) and investigated brain-reactive B-cell activity after incubation on brain tissue lysate-coated ELISPOT plates. Validity metrics of the ELISPOT testing results were calculated (Python 3.6.8) in relation to the clinical responsiveness in the 2 treatment groups.

Results: The ELISPOT B-cell activity assay showed a sensitivity of 0.74, a specificity of 0.76, a positive predictive value of 0.78, a negative predictive value of 0.28, and a diagnostic OR of 8.99 in predicting clinical response to GA vs IFN-β therapy in patients with RRMS.

Conclusion: Measurement of brain-reactive B-cell activity by ELISPOT provides clinically meaningful predictive probabilities of individual patients' treatment response to GA or IFN-β. The assay has the potential to improve the selection of optimal first-line treatment for individual patients with RRMS.

Classification of evidence: This study provides Class II evidence that in patients with RRMS, the brain reactivity of their peripheral-blood B cells predicts clinical response to GA and IFN-β.

Figure 1. Time to (A) Relapse and (B) 3-Month EDSS CDP for Patients Defined by Treatment Response

Kaplan-Meier curves for patient strata defined by treatment response: responders defined by freedom from relapse within first 12 months of treatment with GA or IFN-β; nonresponders/failure defined as treatment failure on GA or IFN-β therapy (see text). Patient numbers indicate the number of patients within 3 months before and after the time indicated. CDP = confirmed disability progression; EDSS = Expanded Disability Status Scale; GA = glatiramer acetate; IFN-β = interferon-β.

Figure 2. Receiver Operating Characteristic Curves for Enzyme-Linked Immunospot Technique Test Results in (A) GA-Treated Patients, (B) IFN-β–Treated Patients, and (C) Combined for GA- and IFN-β–Treated Patients

The tables are the confusion matrices for a positive-outcome threshold of 4.5 spots. The study expected positive evidence of brain-related B-cell activity in GA responders and IFN-β nonresponders, and no evidence of B-cell activity in GA nonresponders or IFN-β responders. Responder: freedom from relapse activity within the first 12 months of GA or IFN-β treatment; nonresponder: treatment failure on GA or IFN-β therapy (see text). GA = glatiramer acetate; IFN-β = interferon-β; ROC = receiver operating characteristic curve.

Figure 3. Time to (A) Relapse and (B) 3-Month EDSS CDP for Patients Defined by ELISPOT Result

Kaplan-Meier curves for patient strata defined by positive or negative ELISPOT results indicating presence or absence of in vivo brain-specific B-cell activity in patients on GA or IFN-β therapy. Patient numbers indicate the number of patients within 3 months before and after the time indicated. It was hypothesized that positive B-cell activity in patients treated with GA and negative B-cell activity in patients treated with IFN-β would be associated with better clinical outcome. CDP = confirmed disability progression; EDSS = Expanded Disability Status Scale; ELISPOT = enzyme-linked immunospot technique; GA = glatiramer acetate; IFN-β = interferon-β.