MS Society-funded study identifies a biomarker in primary progressive MS for targeting with immune-directed treatments
An estimated 10 to 15% of people with MS suffer from the primary progressive MS (PPMS) subtype; unlike the more common relapsing-remitting (RRMS) subtype, those with PPMS experience steady progressive deterioration in neurological function without remissions (periods of recovery) and a poorer prognosis. Additionally, the immune-directed therapies that are the mainstay of RRMS treatment appear to offer little, if any, benefit to people with PPMS, and there are currently no approved therapies for treating this serious form of the illness.
In a ground-breaking study funded, in part, by a collaborative grant from the MS Scientific Research Foundation, a research team led by Dr. Amit Bar-Or identified a biomarker that can distinguish certain PPMS patients who may be able to benefit from immune-directed therapies. This work, published recently in Annals of Neurology, investigated immunoglobulin (Ig) M, an antibody that can be detected using a method called oligoclonal band (OCB) testing. Screening for this antibody shows great promise as a potential tool to detect active inflammatory disease in people with PPMS, which could aid in determining the appropriate treatment for these individuals.
Dr. Bar-Or and colleagues examined clinical, demographic and laboratory data from a large group of people with PPMS from centres in Spain, Turkey, and Russia. Cerebral spinal fluid (CSF) samples collected from the patients were tested for the presence of the IgM OCB (OCMB) biomarker. Additionally, the researchers followed a subset of patients participating in a clinical trial to test the effectiveness of the immunotherapy drug rituximab, which targets immune B cells that are thought to damage the myelin sheath in MS. The purpose of this additional study was to establish whether PPMS patients with the OCMB biomarker would show improvements from taking the drug.
Samples from the patients were classified based on whether they tested positive for OCMB, or OCMB(+). Within each classification group, the researchers analyzed and compared demographic and neurologic exam features, the quantities of B cells in the CSF, and the presence of active inflammatory lesions in the brain based on magnetic resonance imaging (MRI) scans. Finally, the researchers looked to see whether OCMB(+) patients receiving rituximab experienced diminished inflammatory brain lesions compared to those receiving mock drugs (placebo).
Comparison of the clinical and demographic data revealed that PPMS patients who were OCMB(+) had more severe disease symptoms overall than the OCMB(-) group, based on standardized clinical measures. Furthermore, OCMB(+) patients exhibited more B cells in the CSF, and the majority of these patients had characteristic inflammatory lesions in their brain. In contrast, OCMB(-) patients had significantly fewer CSF B cells, and only a small fraction of them exhibited inflammatory lesions.
Most strikingly, the immunotherapy drug rituximab eliminated the presence of inflammatory brain lesions in OCMB(+) patients upon follow-up, while patients who did not receive the drug continued to have these lesions. These important findings show that: a) there is a strong association between PPMS patients exhibiting the OCMB biomarker and inflammatory disease activity, and; b) OCMB(+) PPMS patients responded positively to a promising immune-targeting drug.
Since effective therapies for people with PPMS have thus far proved to be elusive, this study is a critical first step in identifying a potential biomarker in the CSF of people with PPMS who may benefit from immune-directed therapies. Such a biomarker, in turn, represents a powerful tool for guiding effective treatment decisions in this subset of people with MS, offering them hope for the future. This research also demonstrated differences among people with PPMS, and provides detailed clues about the biological mechanisms that give rise to these differences. Specifically, those individuals with the OCMB biomarker had elevated B cell counts in the CSF, suggesting that B cells may be to blame for the damaging inflammation experienced by some people with PPMS, but not others. The evidence demonstrating that drugs which target immune cells, such as rituximab, can treat people with PPMS who have the OCMB biomarker supports this hypothesis, although the results are still preliminary and have only been shown in a small group of people. Nevertheless, this work provides an important step towards larger studies that will further test these observations and probe the disease mechanisms underlying this and other biomarkers.
Villar LM et al. Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis. Ann Neurol. 2014 Aug; 76:231-240