No association of multiple sclerosis activity and progression with EBV or tobacco use in BENEFIT

Abstract

Objective: To evaluate whether Epstein-Barr virus (EBV) immunoglobulin G (IgG) antibody levels or tobacco use were associated with conversion to multiple sclerosis (MS) or MS progression/activity in patients presenting with clinically isolated syndrome (CIS). Methods:In this prospective, longitudinal study, we measured EBV IgG antibody and cotinine (biomarker of tobacco use) levels at up to 4 time points (baseline, months 6, 12, and 24) among 468 participants with CIS enrolled in the BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) clinical trial. Outcomes included time to conversion to clinically definite or McDonald MS, number of relapses, Expanded Disability Status Scale (EDSS) changes, brain and T2 lesion volume changes, and number of new active lesions over 5 years. Analyses were adjusted for age, sex, treatment allocation, baseline serum 25-hydroxyvitamin D level, number of T2 lesions, body mass index, EDSS, steroid treatment, and CIS onset type. Results:We found no associations between any EBV IgG antibody or cotinine levels with conversion from CIS to MS or MS progression as measured by EDSS or activity clinically or on MRI. The relative risk of conversion from CIS to clinically definite MS was 1.14 (95% confidence interval 0.76-1.72) for the highest vs the lowest quintile of EBNA-1 IgG levels, and 0.96 (95% confidence interval 0.71-1.31) for cotinine levels .25 ng/mL vs ,10.Conclusions: Neither increased levels of EBV IgG antibodies, including against EBNA-1, nor elevated cotinine levels indicative of tobacco use, were associated with an increased risk of CIS conversion to MS, or MS activity or progression over a 5-year follow-up. Elevated immunoglobulin G (IgG) antibodies against Epstein-Barr virus nuclear antigen-1 (EBNA-1) and cigarette smoking are established risk factors for multiple sclerosis (MS).1 However, there is less understanding of whether and how they are involved in MS disease activity and progression.Results of previous studies on Epstein-Barr virus (EBV) IgG antibody titers, cigarette smoking, and MS activity and progression have been mixed. Three prior studies examining EBV and MS activity and/or progression among patients with clinically isolated syndrome (CIS) (first neurologic event suggestive of MS) suggest there is no association with conversion to MS, but have shown mixed results regarding activity and progression.2-4 Two studies on the effects of smoking and CIS report conflicting results regarding the association between smoking and conversion to clinically definite MS. 2,5 In this study, we examined whether serum levels of anti-EBV IgG antibodies or cotinine, a marker of tobacco use, are associated with early MS disease activity and progression among †Deceased.

Epstein-Barr virus antibodies in serum and DNA load in saliva are not associated with radiological or clinical disease activity in patients with early multiple sclerosis

“…While previous reports described associations of EBV antibodies in serum with certain radiological and clinical markers of MS disease activity, results were not always consistent across those studies [15, 19–26]. Furthermore, a recent large prospective study did not identify an association of EBV IgG antibodies in serum with risk of CIS conversion to MS, or MS activity or progression [27]. …”

Disease modifying therapies for relapsing multiple sclerosis

“…Although more data are needed, some RCTs or observational studies suggest that vitamin D 3 supplementation, cessation of tobacco smoking, and modifying dietary salt are some potential opportunities. [192][193][194][195][196] Furthermore, certain cardiovascular (ischemic heart disease, congestive heart failure), oncologic (meningiomas, urinary tract cancers), autoimmune (thyroid disease, inflammatory bowel disease, uveitis), and musculoskeletal (arthritis, fibromyalgia) disorders are more common than expected in multiple sclerosis cohorts. 197 These comorbidities reduce quality of life and life expectancy, influence DMT selection, and increase disability.…”

Effect of high-dose vitamin D3 supplementation on antibody responses against Epstein–Barr virus in relapsing-remitting multiple sclerosis

“…11,13 Furthermore, observational studies have found both factors to be associated with increased disease activity, 14,15 although these results are subject to controversy. [16][17][18] Vitamin D inhibits both maturation and proliferation of activated B cells and limits antibody production in vitro, 19,20 but oral vitamin D 3 supplementation has shown an inconsistent effect on these parameters in clinical trials. 21,22 We previously examined the effect of high-dose oral vitamin D 3 supplementation (20,000 IU/ week) on clinical activity and systemic inflammation in 68 patients with relapsing-remitting multiple sclerosis (RRMS) included in a randomised 2-year doubleblinded placebo-controlled clinical trial and did not detect any effect of the intervention.…”