Vitamin D Deficiency, Smoking Tied to a Worse Prognosis of Multiple Sclerosis

Healthy neurons and nerve damage in multiple sclerosis. Illustration of damage (inset, right) to nerve cells caused by the degenerative disease multiple sclerosis. Healthy neurons are shown at left. Immune system cells (microglia, red) have attacked the nerve cell sheaths (myelin), resulting in damaged myelin and disturbed signalling function between the nerves cells (neurons, blue). Multiple sclerosis is a progressive disorder that can cause tingling, speech disorders, lack of coordination, paralysis and death. The microglia cells attack the oligodendrocytes that form the insulating myelin sheath around neuron axons, leading to the destruction of the myelin sheath.
Compromise of long-term cognitive function and neuronal integrity are associated with vitamin D deficiency and smoking in patients with MS.

In patients with multiple sclerosis (MS), low vitamin D levels and smoking are associated with worse long-term cognitive function and neuronal integrity, according to study results published in Neurology.

Previous studies reported that low vitamin D, cigarette smoking, and elevated antibodies against Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA-1) are risk factors for MS. However, it is not clear whether these factors can predict long-term cognitive status. The researchers previously reported on an association between higher vitamin D levels and fewer active lesions and less brain atrophy during 5 years of follow-up.  In the current study, they extended the follow-up to 11 years and assessed the importance of vitamin D, smoking, and anti-EBNA-1 antibodies as predictors of long-term cognitive function and neuroaxonal integrity.

BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment; Identifier: NCT00185211) was a multicenter, double-blind, phase 3 clinical trial of early vs delayed treatment with interferon beta-1b in patients with clinically isolated syndrome (CIS).

The current study included 278 patients who completed the 11-year examination (BENEFIT-11; Identifier: NCT01795872). Serum biomarkers of vitamin D (25-hydroxyvitamin-D [25(OH)D]), smoking (cotinine), and EBV infection (EBNA-1 IgG) were measured at baseline and at 6, 12, and 24 months, and vitamin D was also assessed at 54 and 60 months. Cognitive function was assessed during neurologic examinations at baseline and repeatedly throughout the follow-up via the Paced Auditory Serial Addition Test (PASAT)-3 and neurofilament light chain (NfL) concentrations at 11 years.

Individuals with higher 25(OH)D during the first years following a CIS were less likely to score below the median in the PASAT performed at year 11. A 50-nmol/L higher mean level within the first 24 months after CIS was associated with 65% lower odds of obtaining a below median PASAT score at year 11 (adjusted odds ratio, 0.35; 95% CI, 0.14-0.89; P =.027).

Overall, smoking tended to predict worse long-term cognitive function, although the associations did not reach statistical significance in all analyses. Smokers tended to have worse long-term cognitive performance corresponding to clinically meaningful 5.4 points on the PASAT, most pronounced among patients considered heavy smokers (cotinine consistently >193 ng/mL).

There was no association between baseline anti-EBNA-1 IgG antibodies and PASAT scores.

The associations with long-term neuronal integrity corroborated the main findings regarding long-term cognitive performance: higher vitamin D levels were protective against neuroaxonal loss, as a 50 nmol/L higher mean 25(OH)D level in the first 2 to5 years was associated with a 20% lower serum NfL. Smoking within the first 24 months from onset was associated with a 20% higher NfL at year 11. Once more, there was no association between quartiles of anti-EBNA-1 IgG indices and 11-year NfL concentrations.

The researchers acknowledged several study limitations, including the population being limited to White patients, inability to assess the effects of even higher vitamin D levels (~100 nmol/L), and the limitations of the PASAT. In addition, the researchers noted the potential underestimation of the effect of smoking as ever-smokers were misclassified as nonsmokers if the patients quit smoking at or before CIS.

“These results suggest that correcting vitamin D insufficiency and abstaining from cigarette smoking after clinical MS onset might protect long-term cognitive function and CNS integrity,” concluded the researchers.

Disclosure: This clinical trial was supported by Bayer. Please see the original reference for a full list of authors’ disclosures.


Cortese M, Munger KL, Martínez-Lapiscina EH, et al; on behalf of the BENEFIT Study Group. Vitamin D, smoking, EBV, and long-term cognitive performance in MS: 11-year follow-up of BENEFIT. Neurology. 2020;94(18):e1950‐e1960. doi:10.1212/WNL.0000000000009371