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There is a critical need for a prognostic biomarker at the time of the first symptoms of MS that predicts subsequent disability accumulation and thus can guide therapeutic interventions
To date, no biomarker has allowed clinicians to answer the question of what the future holds for their patients with clinically isolated syndrome (CIS) with any degree of certainty. In the journal, Rathbone et al 1 provide further evidence to support the utility of the ratio of cerebrospinal fluid (CSF) immunoglobulin kappa to lambda free light chains (FLC κ:λ ratio), measured at diagnostic lumbar puncture (LP) at the time of CIS, in predicting multiple sclerosis (MS) disease progression out to 5 years post-CIS.
Previously, MRI, clinical features, oligoclonal bands (OCBs) in CSF and serum/CSF neurofilament components have all been advanced as potential prognostic biomarkers, but all have significant shortcomings, and none provide any clear certainty for the patient with CIS or the clinician. A recent assessment of the utility of MRI in predicting MS progression has outlined the limitations of this modality and has emphasised the need for more work.2
The FLC κ:λ ratio predicted expanded disability status scores (EDSS) progression at 5 years, with a lower median EDSS in the group with high (>10) CSF κ:λ FLC ratio (0.0; 95% CI 0 to 2.5 vs 2.5; 95% CI 0 to 4, high vs low; p=0.049). They also found a tendency for those with high κ:λ ratios to remain CIS for longer. CSF κ:λ FLC correlated with CSF IgG1 κ:λ (r=0.776; p<0.0001) and was intrinsic to CSF plasmablasts (r=0.65; p=0.026) providing support for the importance of B cells in MS progression and a mechanism for the success of B cell therapies in MS.
These findings, although not providing the definitive biomarker for MS progression, are a step in the right direction. They emphasise the importance of markers of intrathecal inflammatory cell activation in MS severity and in particular, the role of B cells as either producers of pathogenic antibodies or presenters of antigens to T cells. With the recent changes to the McDonald criteria3 allowing positive OCBs to contribute to making a diagnosis of MS at the time of CIS, the number of CIS cases undergoing LP will increase and therefore the ability to validate this finding in larger cohorts of CIS will become easier.
A significant problem with all studies of MS progression, and thus validation of biomarkers is that we can only define progression once it has occurred and therefore long-term studies are required to separate those who will progress from those who will not, hence the 5-year duration of the study by Rathbone et al. However, in their study only 29 of their 321 recruited cases of CIS contributed to the final disability and annualised relapse rates (ARR) outcomes for this analysis resulting in significantly reduced power. Large prospective studies of MS outcomes with CSF collected at CIS are uncommon and therefore as their cohort matures Rathbone et al will be able to provide further information from this highly informative cohort.
Contributors BVT is the sole author.
Funding The author is supported by A MS Research Australia Senior Clinical Research Fellowship.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Commissioned; internally peer reviewed.
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