Vitamin D, Smoking in MS Predict Long-Term Cognition, Axonal Injury

Low vitamin D (25[OH]D) and smoking after clinical onset of multiple sclerosis (MS) predicted worse long-term cognitive function and neuronal integrity in MS patients, a secondary analysis of BENEFIT study data showed.

A 50-nmol/L higher mean 25(OH)D in the first 2 years after clinical onset was related to both 65% lower odds of poorer cognitive performance at year 11 (95% CI 0.14-0.89) and a 20% lower level of the axonal injury marker neurofilament light chain (NfL; 95% CI -36% to 0%), reported Marianna Cortese, MD, PhD, of Harvard University and coauthors in Neurology.

Smoking was associated with a significant change in cognitive performance in some but not all models, and smoking within the first 2 years was associated with a 20% higher NfL level at year 11 (95% CI 2%-40%).

However, markers of Epstein-Barr virus (EBV), a third MS risk factor that might presage more aggressive disease, were not associated with either NfL levels or cognitive scores.

“These results are consistent with the suggestion that vitamin D supplementation and smoking cessation early after MS onset might protect long-term cognitive function and central neuroaxonal integrity, independent of disease-modifying treatment,” Cortese and colleagues wrote.

BENEFIT was a randomized, 2-year phase III trial that examined whether early versus delayed treatment with interferon beta-1b in patients with clinically isolated syndrome (CIS) delayed progression to clinically definite MS. It enrolled 468 patients with CIS and 2-year analysis showed a benefit for immediate treatment, with persistent benefit seen at 11 years. A secondary analysis of 5-year BENEFIT data reported that higher vitamin D levels at 1 or 2 years after recruitment was associated with fewer active lesions and less brain atrophy on imaging.

Established risk factors for MS include low levels of vitamin D, smoking, and Epstein-Barr virus infection. Whether these predict or modify disease course is unknown. Cognitive impairment in MS is common, and associated with both white and gray matter pathology.

NfL is an indicator of axonal injury that is elevated in many neurologic conditions. “The CSF concentration of NfL is 3- to 10-fold higher during acute relapses” in MS, observed Oluf Andersen, MD, PhD, of the University of Gothenburg in Sweden and Massimo Filippi, MD, of San Raffaele University in Milan, Italy, in an accompanying editorial. “It peaks 2 weeks after a relapse, and its level increases with MRI measures of disease activity (enhancing lesions and new T2 lesions),” they wrote.

“The important take-home message of the study by Cortese et al. is that the serum NfL seems to be useful not only for assessing the current status of patients, but also as a long-term outcome,” they added.

In their study, Cortese and her team analyzed data from 278 patients who completed the 11-year BENEFIT assessment. These participants comprised 71.3% of all patients at the sites eligible to participate in BENEFIT-11 and were comparable at baseline to the originally randomized trial population.

Median age was 30, median Expanded Disability Status Scale (EDSS) score was 1.50 (indicating no disability; minimal signs in more than one functional system) and about 70% of participants were female. The group had a median of 18 T2 lesions.

At year 11 assessment, 62% of the 278 enrolled patients were on disease-modifying treatment. Of these, about half were on INF β-1b, 23% on other injectables, 15% on oral drugs, 9% on monoclonal antibodies, 5% on immunosuppressants, and <1% on immunoglobulins. About 14% reported intake of vitamin D supplements from baseline to year 11.

Data for vitamin D, cotinine (a smoking biomarker), and anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibodies were studied for associations with 11-year serum NfL levels and scores on the Paced Auditory Serial Addition Test (PASAT), a measure of processing speed, attention, and working memory. Standardized PASAT scores were lower in smokers than nonsmokers (P trend = 0.026), and smokers had 20% higher NfL levels than nonsmokers (95% CI 2%–40%).

Limitations of the study include attrition; only 60% of the original BENEFIT patients were available for the current analysis. The study’s population consisted of white Caucasians, limiting its generalizability. Analyses were not adjusted for education or physical activity; these or other factors may have confounded associations with cognitive decline in this study. In addition, cognitive function could not be fully assessed with the PASAT.

“In future studies, it would be important to include additional cognitive tests (with the addition of an evaluation of fatigue) and integrate complete pharmacologic and epidemiologic factors as predictors in a common regression model,” the editorialists noted. “This was difficult in the BENEFIT follow-up in which half of the patients on treatment remained on interferon beta-1b therapy, whereas half received several other MS disease-modifying drugs.”

1. Low vitamin D (25[OH]D) and smoking after clinical onset of multiple sclerosis (MS) predicted worse long-term cognitive function and neuronal integrity in MS patients, a secondary analysis of BENEFIT study data showed.

2. However, markers of Epstein-Barr virus (EBV), a third MS risk factor that might presage more aggressive disease, were not associated with either neurofilament light levels or cognitive scores at 11 years.

Paul Smyth, MD, Contributing Writer, BreakingMED™