Intrathecal B-cell accumulation and axonal
damage distinguish MRI-based benign from
aggressive onset in MS
Sinah Engel,* Michaela Friedrich,* Muthuraman Muthuraman, PhD, Falk Steffen,
Alicia Poplawski, PhD, Sergiu Groppa, MD, Stefan Bittner, MD, Frauke Zipp, MD,
and Felix Luessi, MD
Neurol Neuroimmunol Neuroinflamm 2019;6:e595. doi:10.1212/NXI.0000000000000595
The Bottom Line:
Indicators of disease activity in the spinal fluid and blood of persons in the very early stages of their MS may allow neurologists to predict whether their course of disease will be aggressive or relatively mild. With this knowledge two major aspects of care could be determined. Disease-modifying therapies could be chosen that have the best ratios of risk and benefit for an individual. Second, the person with MS and his/her neurologist could decide whether induction therapy is warranted, that is initial treatment with a very powerful, but potentially more toxic disease-modifying therapy followed by treatment with a possibly less effective but also less potentially toxic drug, or whether an incremental approach to treatment is better, one involving initial treatment with a “milder” and less potentially toxic disease-modifying therapy, with changes to a more powerful disease-modifying therapy only if the “milder” drug is insufficient to control their disease.
Key Points:
1. There is no single test or finding on exam that is unique to MS. As a result, making a diagnosis of MS depends on multiple factors such as clinical history, findings on neurologic exam, on changes seen in central nervous system MRIs, and on excluding other diseases that can mimic MS.
2. Scientists have looked for unique findings in MS, so called disease-specific “biomarkers” for decades without success. This paper used multiple biomarkers to try to predict the severity of disease in person’s MS.
3. These scientists evaluated 93 patients, 17 with clinically isolated syndrome (the first attack of a disease that has a high probability of progressing to definite MS) and 76 persons with very early definite MS . They compared results from these individuals to 97 other persons with non-inflammatory central nervous system disease and 48 persons with inflammatory central nervous system disease other than MS.
4. They studied blood and spinal fluids. First they counted numbers of immune cells called B-cells in the spinal fluid. In particular they looked at the ratio of B-cells to other cells called macrophages. B- cells are powerful immune cells that stimulate other immune cells, such as T-cells, to respond to proteins. B-cells also make antibodies. B-cells play an important role in MS and several of the current disease-modifying therapies for MS exert their beneficial effects by removing B-cells from the circulation. Macrophages are “clean-up” cells that remove tissue debris but can also participate in the immune response.
5. The researchers also measured levels of proteins called neurofilament light chains (NfL). These are proteins present in nerve cells. When a nerve cells dies neurofilament light chains are released into the blood and spinal fluid.
6. The investigators judged the severity of a person’s MS by the changes present on their central nervous system MRIs. In particular they evaluated numbers of lesions and the numbers of lesions that showed active inflammation. Based on these findings individuals were classified as having either aggressive disease, moderate disease, or “benign” (mild) disease.
7. Results of their studies showed that persons with “aggressive” MS, that is those individuals with large numbers of lesions on their central nervous system MRIs, had increased numbers of B-cells (high B-cell to macrophage ratios) and high levels of NfL in both their spinal fluid and their blood. Patients with mild changes on their central nervous system MRIs had significantly lower levels of both B-cells and NfL.
8. Using a combination of markers, i.e. both numbers of B-cells and levels of NfL in blood and spinal fluid, was much more accurate in identifying persons with more aggressive disease from those with milder MRI changes.
9. While these observations are important, work still needs to be done. Persons in the study need to be followed clinically, as well as with MRIs, to truly determine that changes noted on their initial MRIs truly correlated with more severe or milder MS clinical course.
No-one can predict with certainty the clinical course of MS. That said, there are clues that can suggest either a more aggressive course of disease or a mild one. One of the clues is changes seen on central nervous system MRIs. Such changes include numbers of lesions, numbers of lesions with active inflammation, numbers of lesions that show a loss of tissue (so called “black holes”), the presence of lesions in the back of the brain (posterior fossa) and in the spinal cord, and shrinkage of the brain (called “atrophy”).
The above paper looked at changes in blood and spinal fluids of persons with either clinically isolated syndrome or very early MS. They divided persons into three groups based on changes noted on their central nervous system MRIs. Those with many of the changes noted above were felt to be a greater risk for developing a more severe clinical course, Those with moderate changes on MRIs, and those with very few lesions were felt to be more likely to have a milder clinical course. Ninety-three persons with MS were studied. Seventeen had a clinically isolated syndrome (first attack of a disease that had a high probability of developing into clinically definite MS) and 76 persons with very early relapsing forms of multiple sclerosis. Results were compared to 97 persons with non-inflammatory central nervous system disease and 48 persons with central nervous system inflammations other than MS.
As noted for many years, more than 90% of persons with MS had proteins in their spinal fluid called oligoclonal bands. Such bands are useful in separating persons with MS from those without MS, and the presence of oligoclonal bands may increase the risks of severe disease in persons with MS compared to those persons with MS that do not have bands. However, the presence of bands alone cannot predict disease severity. The investigators thus looked at other biomarkers of central nervous system inflammation and tissue damage, namely numbers of immune cells called B-cells and macrophages in spinal fluid and blood and spinal fluid levels of proteins called neurofilament light chains.
B-cells play a very important role in MS. They can stimulate other immune cells such as T-cells that then can attack the brain. They also produce antibodies. Several of the newer disease-modifying therapies exert their beneficial effects on MS by depleting B-cells in the blood.
Macrophages are also important cells in MS. They can have a dual role. They can participate in an immune response by stimulating T cells. They also are important in removing damaged tissue from sites of tissue inflammation and destruction.
Much recent work has been done studying levels of proteins called neurofilament light chains (NfL) in the blood and spinal fluid of persons with MS and other neurologic diseases. NfL are present in nerve cells and the protein is released when nerve cells are injured or die. Elevated levels of NfL are found in many different neurologic illnesses and are not specific for MS. Nevertheless, recent data indicate that elevated levels of NfL in persons with MS are associated with active disease.
The above paper is important because it utilized two biomarkers to identify persons with greater or lesser risk of developing disabling MS. Elevated levels of B-cells and macrophages in the spinal fluid and elevated levels of NfL in the blood and spinal fluid of persons with CIS or early MS correlated with more severe changes on central nervous system MRIs. Being able to identify persons at high risk for having more disabling disease early in their course will allow those individuals to choose disease-modifying therapies that are more potent but also may have a higher risk of drug toxicity. Similarly, by identifying persons with a low risk of developing disabling MS, such individuals may elect to choose a less powerful disease-modifying therapy, with less toxicity, but one that may still be sufficient to control their disease.
There are several caveats to be noted with this paper. First is the assumption that changes noted on central nervous system MRIs are accurate predictors of a person’s clinical course. This may not be true for all individuals. Persons may present with very active disease on MRIs initially, only to have a subsequent course that is very mild. Second, there are no data presented on the clinical picture of those persons with many abnormalities on their MRIs compared to those with very few lesions. Was there an initial correlation between a person’s clinical presentation and their changes on MRIs? Finally, the study was cross-sectional, meaning individuals were studied at only one time point. Long-term follow-up is needed to fully assess whether the changes in B-cell/macrophage ratios and in levels of NfL truly were accurate in predicting clinical course.