Serum neurofilament light (NfL) levels were not associated with disease progression in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab (Tysabri), an observational study found.
“In our cohort of natalizumab-treated patients with RRMS, NfL fails to capture or predict progression that occurs largely independently of clinical or radiological signs of acute focal inflammatory disease activity,” wrote Claire Bridel, MD, PhD, of Amsterdam University Medical College in the Netherlands, and co-authors in Neurology. “Additional biomarkers may thus be needed to monitor progression in these patients.”
Natalizumab effectively suppresses focal inflammation in MS. By restricting the study to people with very little inflammation, the researchers focused on whether serum NfL could be used as a marker to develop and guide treatment preventing disability that can accrue in the absence of inflammation in both relapsing and progressive forms of MS.
This study has two main messages, Bridel noted in an email to BreakingMED. “First, progression occurs in a significant proportion of people with RRMS, and additional disease-modifying treatments targeting this process are needed,” she wrote. “Second, neurofilament light, which is an excellent biomarker reflecting neuroaxonal damage in the context of a relapse or MRI acute inflammatory disease activity, fails to capture progression in these RRMS patients.”
“Additional biomarkers are needed, and in a way this is not surprising, given the complexity of the disease,” she continued. “Many mechanisms probably contribute to progression, and it is unlikely a single biomarker will be able to capture them all.”
Bridel’s group included 89 patients with RRMS from a prospective observational cohort study begun in 2006. Participants were 18 or older with minimum 3 years followup after beginning natalizumab, a humanized monoclonal antibody that suppresses leukocyte migration across the blood-brain barrier into the central nervous system. The cohort was 74% women, had mean age of about 37 when beginning natalizumab, and had median disease duration of 7.4 years.
A serum NfL baseline value was obtained when patients began natalizumab and at 3 months, 1 year, 2 years, and on the final followup visit. Serum NfL was compared for those with and without confirmed Expanded Disability Severity Score (EDSS) between the 1-year assessment and the final followup visit.
EDSS was obtained at yearly followup for a median followup of 5.2 years after beginning natalizumab. Disability progression was defined by sustained EDSS worsening of 1.5 points from a baseline score of 0; 1 from a baseline score of 1-5.5; or 0.5 from a baseline of ≥ 6.0.
Between year 1 and the last follow-up, confirmed EDSS progression was seen in 31.5% of the cohort. In addition, 47.9% met a combined endpoint called EDSS+ progression that added assessments of upper extremity function and short-distance walking ability to the EDSS score. No patient fulfilled the criteria for transition to secondary progressive MS during the study.
The median EDSS score for EDSS-defined non-progressors and progressors, respectively, at 12 months was 3.0 and 3.8. At last followup, the scores were 3.5 and 5.8.
Analysis showed:
- Serum NfL was significantly reduced by 3 months and reached its minimum, near 50% of baseline levels, 1 year after beginning treatment.
- There was no difference in NfL levels in progressors versus non-progressors for EDSS or EDSS+ defined progression between the 1-year assessment and the final followup.
- Neither baseline nor 1 year NfL levels predicted progression.
“Our data do not support a prognostic value for baseline or year 1 NfL in terms of EDSS or EDSS+ progression prediction at last follow-up, when focal acute inflammatory disease activity is largely suppressed,” the researchers concluded. “This finding suggests the prognostic value of NfL reported in other studies may rather be related to its ability to reflect acute neuroaxonal damage due to focal inflammatory disease activity than progression.”
In an accompanying editorial, Carolyn Goldschmidt, DO, and Robert Fox, MD, both of the Cleveland Clinic in Ohio, wrote that the study “surprisingly, found no association between serum NfL levels at baseline or longitudinally with disability progression over time.”
“The story of serum NfL in MS parallels the complexities of the disease: inflammatory disease activity is easily identifiable, has a well-established pathophysiology, and is clearly associated with temporal increases in serum NfL, while progressive disease is more elusive in its pathophysiology, quantification, and relationship to biomarkers such as serum NfL,” they observed.
“This story also tracks with the dichotomous history of disease modifying therapy in MS, with massive advances in relapsing MS therapies but little success in progressive MS,” Goldschmidt and Fox added.
Irreversible disability, once thought of as accompanying progressive forms of MS and beginning 10-15 years after disease onset, may also occur as relapse-independent progression from the earliest stages of the disease. Disability appears to occur to a significant degree through pathways independent of focal inflammation. A 2019 review proposed the term “silent progression” to capture the idea of long-term worsening in relapsing MS patients that is relatively independent of relapse activity.
Inflammation-related MS findings include radiologic signs (new T2 or enhancing MRI lesions) and clinical relapse. Both these inflammatory findings are reflected in increases in serum NfL, a neuron-specific cytoskeletal protein elevated by multiple causes of axonal injury. Whether serum NfL levels relate to disability progression that occurs independent of inflammatory activity has remained unclear.
Bridel and colleagues also reported that the percentage of those with relapses or new inflammatory lesions on MRI (an enhancing or new T2 lesion) did not significantly differ between progressors and non-progressors.
“This supports the hypothesis that the mechanisms driving progression are distinct from those underlying acute focal inflammatory disease activity,” they wrote. “We find that individuals who progressed either according to the confirmed EDSS or the confirmed EDSS+ outcome were slightly older and their disease duration at baseline was slightly longer compared to those who did not, suggesting an age and disease duration threshold before progression becomes clinically manifest.”
“Currently, serum NfL appears well suited to predict inflammatory activity in MS and treatment response to anti-inflammatory disease modifying therapy,” the editorialists said. “Its role in relation to disability progression in the absence of inflammation remains less clear, and we need more analyses of natural history and clinical trial datasets, particularly those focusing on patients treated with anti-inflammatory therapies.”
Limitations of the study included those inherent to the EDSS as an outcome measure, including high intra- and inter-rater variability.
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Serum neurofilament light (NfL) levels were not associated with disease progression in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab, an observational study found.
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Additional biomarkers may be needed to monitor progression in these patients.
Paul Smyth, MD, Contributing Writer, BreakingMED™
The researchers reported no targeted funding.
Bridel is is supported by a Swiss MS Society Grant.
Goldschmidt has received consultant fees for serving on an advisory committee for EMD Serono/ Fox has received personal consulting fees from AB Science, Biogen, Celgene, EMD Serono, Genentech, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; has served on advisory committees for AB Science, Biogen, Genzyme, Immunic, Janssen, Novartis, Sanofi, and TG Therapeutics; and has received clinical trial contract and research grant funding from Biogen, Novartis, and Sanofi.
Cat ID: 36
Topic ID: 82,36,730,36,192,925
