MILAN – in a joint presentation at the 9th Joint ECTRIMS-ACTRIMS meeting.
Armed with the findings of his own landmark 2022 study into EBV and MS, Harvard Medical School, Boston, professor of medicine Alberto Ascherio, MD, DrPH, argued that they’re tightly connected. But rheumatologist William H. Robinson, MD, PhD, of Stanford (Calif.) University, said that while he also believes EBV plays a significant role in MS, “there’s likely a role for a second hit” – some other factor. “Why are 95% of us EBV-infected, but only a small subset ultimately develop MS or ... other autoimmune diseases?”
As a 2023 review noted, researchers have puzzled over the connection between EBV and MS since the early 1980s. “Until that point, EBV was primarily viewed as a cancer-causing agent, but the culmination of evidence now shows that EBV has a pivotal role in development of MS.” But it’s not clear how EBV – which strikes more than an estimated 95% of humans and causes mononucleosis – manages to trigger MS.
A rare complication of EBV infection
In the 2022 study, Dr. Ascherio aimed to understand exactly how deeply EBV and MS are connected by analyzing serum data gathered from more than 10 million active-duty members of the U.S. military. Of those, 955 were diagnosed with MS.
The researchers focused on 801 subjects with MS and matched them to 1,566 controls. Only 1 of the 801 subjects with MS had a negative EBV test prior to diagnosis, a fact that researchers believe could be due to a factor such as a failure to seroconvert during infection. “At baseline, 35 MS cases and 107 controls were EBV-negative,” the study reported. “All but one of these 35 EBV-negative MS cases became infected with EBV during the follow-up.”
Overall, subjects who were positive for EBV were 32.4 times to develop MS than those who weren’t (95% confidence interval, 4.3-245.3; P < 0.001).
Is it possible that immune dysregulation from MS precedes EBV infection? The researchers analyzed viruses in 30 subjects with MS – before and after MS onset – and in 30 controls. The findings suggested that EBV was the major player, Dr. Ascherio said.
Researchers also focused on cytomegalovirus (CMV) infection, which is closely related to EBV and to the chicken pox virus. “CMV seroconversion is not associated with MS, and positivity for CMV at baseline was associated with a modestly lower risk of MS,” Dr. Ascherio said.
In the big picture, “this data establishes beyond reasonable doubt that MS is a rare complication of EBV infection,” Dr. Ascherio said. “The main question now is whether the virus triggers an immune process that then is self-maintained, or whether the presence of the infection keeps feeding the immune process.”
Inadequate evidence for causation
In his presentation, Dr. Robinson asked: “Does EBV cause MS? Really? All of MS? In humans [with MS], yes, we found monoclonal antibodies expressed by the B cells that bound to EBV. But we also found spinal fluid B cells and coding antibodies that bound to multiple other viruses, including rubella, VZV [varicella-zoster virus/chickenpox], CMV, and HSV [herpes simplex virus]. And there’s even a measles reactive antibody there.”