The Brave New World of Early Treatment of Multiple Sclerosis: Using the Molecular Biomarkers CXCL13 and Neurofilament Light to Optimize Immunotherapy

Abstract

Multiple sclerosis (MS) is a highly heterogeneous disease involving a combination of inflammation, demyelination, and CNS injury. It is the leading cause of non-traumatic neurological disability in younger people. There is no cure, but treatments in the form of immunomodulatory drugs (IMDs) are available. Experience over the last 30 years has shown that IMDs, also sometimes called disease-modifying therapies, are effective in downregulating neuroinflammatory activity. However, there are a number of negatives in IMD therapy, including potential for significant side-effects and adverse events, uncertainty about long-term benefits regarding disability outcomes, and very high and increasing financial costs. The two dozen currently available FDA-approved IMDs also are heterogeneous with respect to efficacy and safety, especially long-term safety, and determining an IMD treatment strategy is therefore challenging for the clinician. Decisions about optimal therapy have been particularly difficult in early MS, at the time of the initial clinical demyelinating event (ICDE), at a time when early, aggressive treatment would best be initiated on patients destined to have a highly inflammatory course. However, given the fact that the majority of ICDE patients have a more benign course, aggressive immunosuppression, with its attendant risks, should not be administered to this group, and should only be reserved for patients with a more neuroinflammatory course, a decision that can only be made in retrospect, months to years after the ICDE. This quandary of moderate vs. aggressive therapy facing clinicians would best be resolved by the use of biomarkers that are predictive of future neuroinflammation. Unfortunately, biomarkers, especially molecular biomarkers, have not thus far been particularly useful in assisting clinicians in predicting the likelihood of future neuroinflammation, and thus guiding therapy. However, the last decade has seen the emergence of two highly promising molecular biomarkers to guide therapy in early MS: the CXCL13 index and neurofilament light. This paper will review the immunological and neuroscientific underpinnings of these biomarkers and the data supporting their use in early MS and will propose how they will likely be used to maximize benefit and minimize risk of IMDs in MS patients.

Exploring the immune‐modulating properties of boswellic acid in experimental autoimmune encephalomyelitis

“…Our study aimed to examine the therapeutic potential of boswellic acid in EAE mice, as a widely accepted animal model for MS [31]. MS has no cure, and current medicines are only partially effective and have side effects [32]. Hence consequently, there is an urgent need to discover innovative and safe medicines capable of modulating the immune system, protecting the CNS, and promoting remyelination.…”

Decision trees to evaluate the risk of developing multiple sclerosis

“…Early diagnosis and treatment are crucial, and immunotherapy using immunomodulatory drugs (IMDs) is currently the primary approach to slow its progression ( Frau et al, 2018 ; Pachner, 2022 ). In recent years, the application of artificial intelligence (AI) in healthcare ( Davenport and Kalakota, 2019 ) has shown significant potential, particularly in the analysis of medical images created by MRI.…”

Neurodegeneration and its potential markers in the diagnosing of secondary progressive multiple sclerosis. A review

“…It was also found that by combining the CXCL13 index with the CSF NfL score, predictive values can be further maximized ( Pachner, 2022 ). Among the 67 patients with MS, 41 demonstrated an initial clinical demyelinating event (ICDE), which is an early signal to apply immunomodulatory therapy.…”

“…Otherwise, CXCL13 has been found to increase significantly in MS patients compared to a CIS group ( Khademi et al, 2011 ). Such inconsistencies may be due to some studies not employing optimal analytical techniques; while most studies have been based on ELISA, more accurate results have been achieved using Luminex, SIMOA or immuno-PCR have been proven to provide more sensitive results in CXCL13 detection ( Pachner, 2022 ).…”