Predicting RRMS Treatment Response with ELISPOT: A New Frontier in Personalized MS Therapy

Relapsing-Remitting Multiple Sclerosis (RRMS) treatment still faces the critical challenge of individual variability in response to disease-modifying therapies (DMTs). Two of the most widely prescribed first-line therapies—glatiramer acetate (GA) and interferon-beta (IFN-β)—exhibit highly variable efficacy between patients. But what if we could predict which drug would work best before beginning treatment?

A study by Braune et al. (2020), published in Neurology, proposes just that, using an ELISPOT-based assay to measure in-vivo brain-reactive B-cell activity. This work suggests a personalized approach to RRMS therapy selection by assessing a patient’s immunological profile.

Study Design: Assessing Treatment Response Through Immune Profiling
The study analyzed peripheral blood mononuclear cells (PBMCs) from patients with RRMS, grouped according to their response to GA or IFN-β (defined as remaining relapse-free for at least 12 months).

For GA, 68 responders and 35 treatment failures were analyzed.

For IFN-β, 55 responders and 37 failures were evaluated.

Patients had no previous or concurrent therapies that could interfere with B-cell function, making the immunological readouts more specific to the treatment effect.

PBMCs were polyclonally stimulated in vitro with IL-2 and R848, cultured for 96 hours, and then exposed to whole human brain tissue lysate on ELISPOT plates. After incubation, B-cell spot formation was detected using the Vector Blue AP-kit. A cut-off of 4.5 spots per well was established to define a positive ELISPOT response, indicating the presence of brain-reactive B cells.

Key Findings: Positive ELISPOT Linked to GA Response, Negative Linked to IFN-β Success
The ELISPOT assay results revealed a clear distinction between treatment responders and non-responders:

Among patients who responded to glatiramer acetate (GA), 50 out of 68 (approximately 74%) had a positive ELISPOT result, indicating strong brain-reactive B-cell activity. In contrast, only 7 out of 35 GA treatment failures (just 20%) showed a positive result.

For patients treated with interferon-beta (IFN-β), only 15 of the 55 responders (about 27%) had a positive ELISPOT result. However, 73% of the IFN-β treatment failures (27 of 37 patients) were ELISPOT-positive—suggesting that these individuals might have responded better to GA instead.

This pattern suggests that a positive ELISPOT result (i.e., presence of brain-reactive B cells) is strongly associated with a favorable response to GA and a poor response to IFN-β—and conversely, a negative ELISPOT response predicts better outcomes with IFN-β.

Diagnostic Performance: Sensitivity, Specificity, and Predictive Values
The study also assessed the test’s diagnostic accuracy. For GA-treated patients, the ELISPOT test had a sensitivity of 0.74, meaning it correctly identified 74% of true responders, and a specificity of 0.80, correctly identifying 80% of non-responders. The positive predictive value (PPV)—the likelihood that a patient with a positive ELISPOT actually responds to GA—was 0.88, while the negative predictive value (NPV) was 0.39.

In the IFN-β group, the sensitivity and specificity were both 0.73, but the PPV dropped to 0.64, and the NPV increased to 0.80. This means a negative ELISPOT test is more predictive of IFN-β treatment success.

Clinical Relevance: A Path Toward Individualized MS Therapy
These findings support a biologically-informed treatment strategy in MS care. Rather than trial-and-error prescribing, clinicians could use the ELISPOT assay to match a patient’s immune profile to the most effective therapy. For instance, a newly diagnosed RRMS patient with a positive ELISPOT result might be guided toward glatiramer acetate, while a negative result could support starting interferon-beta.

This approach may also be valuable for:

Switching therapies in patients who experience early relapses

Selecting participants for clinical trials based on immune response phenotype

Improving overall outcomes by reducing time to effective treatment

Limitations and Next Steps
While this study presents compelling evidence, it is still retrospective and observational. Future prospective trials are needed to validate the ELISPOT assay in clinical workflows. Standardization of the brain lysate antigen, assay conditions, and interpretation criteria will be essential before widespread clinical adoption.

Moreover, given the increasing use of newer DMTs like anti-CD20 monoclonal antibodies and S1P receptor modulators, the relevance of ELISPOT in guiding second-line or high-efficacy treatment decisions should also be explored.

Conclusion: Toward Immune-Guided Precision Medicine in MS
This research offers a transformative vision for RRMS management. By identifying brain-reactive B-cell activity through a relatively straightforward ex-vivo assay, clinicians could make more informed, personalized treatment decisions. The ELISPOT test, while still in the validation phase, may represent a key piece in the evolving toolkit for precision neurology.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Braune S, Tacke S, Ziemssen T, Lehmann P, Bergmann A, Kuerten S. In-vivo B-cell activity predicts response to treatment with glatiramer acetate and interferons in patients with RRMS. Neurology. 2020;94(15 Supplement):1764.