New Genes Confirm Immune System 'Intimately' Involved in MS

Megan Brooks

August 12, 2011

August 12, 2011 — A large genome-wide association study (GWAS) has confirmed 23 previously reported genetic variants associated with multiple sclerosis (MS) and implicated 29 new genetic variants in susceptibility to the neurologic disorder.

Eighty percent of the new genetic variants linked to MS are "intimately involved in the workings of the immune response," Alastair Compston, PhD, FMedSci, FRCP, from University of Cambridge, United Kingdom, reported at a press briefing in London Wednesday.

These genes "tell a very, very coherent story and the story is immunological," said Dr. Compston. He co-led the research with Peter Donnelly, FRS, FMedSci, from University of Oxford Wellcome Trust Centre for Human Genetics in the United Kingdom.

This research, published online August 10 in the journal Nature, would appear to cast doubt on the controversial theory of chronic cerebrospinal venous insufficiency (CCSVI) as an etiologic player in MS.

International Collaborative Effort Pays Off

An international team made up of more than 250 scientists participated in what is believed to be the largest GWAS in MS to date. They evaluated genetic data from 9772 MS patients from 15 countries and 17,376 control subjects, analyzing a total of 465,434 autosomal single-nucleotide polymorphisms (SNPs).

The researchers say they replicated nearly all of the previously identified susceptibility loci and identified at least 29 novel susceptibility loci.

They performed a replication analysis with 102 SNPs in 4218 MS cases and 7296 controls. For 98 of these SNPs, the same allele was overrepresented in cases compared with controls, including 23 of the 26 known MS-associated loci and the other 29 novel loci.

Of note, "[i]mmunologically relevant genes," the study authors report, "are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis."

This knowledge, Dr. Compston said, "can drive a new research agenda," as well as inform immunologic strategies for treatment. He pointed out that some of the implicated genes "are highly relevant to the actions" of several immunologic drugs available or in development, including natalizumab, rituximab, alemtuzumab, and daclizumab.

The researchers say it's also worth noting that just more than one-third of the identified loci overlap with regions already known to be associated with other autoimmune disorders.

Vascular Theory Takes a Hit

On the basis of this new research, it is clear that MS is "primarily an immunological disease. This is the way to nail this disease and get on top of it," Dr. Compston said. There is also evidence of "an interplay between genes and the environment," he noted.

Their work also points to inflammation as the first step toward the disease, with neurodegeneration, "so it does resolve a very live and a very real debate," he said.

There is little sound evidence, on the other hand, for the "completely rival theory" that MS is a vascular problem caused by CCSVI, he said. "The general point I'm making is that I think our work really puts some of these, what you might call maverick or eccentric, ideas on one side, and it is not in the interests of patients to go on pursuing those ideas when we have such a clear narrative going across the nature of the disease."

The controversial vein-narrowing theory, put forth in 2009 by Paolo Zamboni, MD, and colleagues from Italy, holds that MS could be caused by abnormal venous drainage from the brain due to outflow obstruction in the draining jugular vein and/or azygos veins and that addressing the obstructions with angioplasty might help alleviate MS symptoms.

The first in a series of studies into the relationship between MS and CCSVI in the brain conducted by Dr. Zamboni's team involved 109 patients with MS and 177 control subjects. Using transcranial and extracranial color Doppler imaging, they found that MS patients were more likely than controls to have predefined abnormal venous outflow hemodynamic parameters.

In a follow-up study, they performed selective venography in 65 patients with MS and several control groups and found severe extracranial stenoses only in the patients with MS.

Dr. Zamboni's team subsequently reported a successful initial treatment trial using percutaneous transluminal angioplasty (PTA) on the stenotic veins in the 65 patients with MS who underwent venography.

They found that PTA of venous strictures in patients with evidence of CCSVI was safe and significantly improved MS clinical outcomes, particularly in the 35 patients with relapsing-remitting MS. The rate of relapse-free patients improved from 27% before surgery to 50% after, and the rate of gadolinium-enhancing lesions on magnetic resonance imaging decreased from 50% to 12%.

Replication Proves Difficult

Yet, in the 2 years since the original series of articles on CCSVI in MS, there have been several independent investigations into whether CCSVI exists in MS, and "none of these studies have replicated Dr. Zamboni's findings," Bridget A. Bagert, MD, MPH, chief of the Division of Neuroimmunology, Ochsner Foundation Clinic in New Orleans, Louisiana, told Medscape Medical News.

Dr. Bagert is first author of a review on CCSVI in MS published online July 11 in Archives of Neurology.

More recently, in the August 8 online issue of Archives of Neurology, Dr. Bagert and colleagues report results of a study that also failed to support a role for CCSVI in MS.

In that study, they didn't see any significant difference in the number or type of venous outflow abnormalities in 18 patients with MS fulfilling revised McDonald criteria compared with controls.

"I'd advise that clinicians tell patients with MS that the most recent scientific evidence has not supported a strong link between CCSVI and MS and that there is now some doubt among many in the scientific community that CCSVI in MS exists at all," Dr. Bagert told Medscape Medical News.

'Countess' Editorials and Opinions

Asked to comment on the review by Dr. Bagert and colleagues, Dr. Zamboni expressed some exasperation that the review again does not represent actual new evidence, but is a review, including opinion pieces.

"Until a few years ago, the Archives of Neurology had a section of great interest [called] Controversies, where the reader had the opportunity to consider different visions," said Dr. Zamboni, who is director of the Vascular Diseases Center at the University of Ferrara, Italy.

"Nowadays, countless editorials and opinion articles about CCSVI have been invited in journals of clinical neurology with no chance to reply. This habit, certainly not academic, helps to make me a defendant in science, just to get reported in 30 peer-review articles an underdeveloped aspect of MS research," he told Medscape Medical News.

In their review article, Dr. Bagert and colleagues refer to the Bradford Hill Criteria that are used to assess scientific evidence of causation in biological systems and suggest that in this case, "there is very little validated scientific evidence to support the theory that CCSVI is the cause of MS, especially among the criteria of biological plausibility, coherence, and analogy."

To this point, Dr. Zamboni responds that he would like to see the authors apply the Bradford Hill Criteria, citing exclusively original articles and not editorials and opinions. If his own work is scientifically inaccurate by these criteria, then so is much of the epidemiologic data in other aspects of MS, he says, where studies are equally inconsistent in sample sizes and methods of data collection.

Of the studies published to date on CCSVI, despite the high variability, MS is associated with CCSVI in an average of 80% of cases vs 10% of the healthy population, Dr. Zamboni asserts.

"Furthermore, with respect to the biological plausibility and the coherence of Bradford Hill Criteria, the autoimmune theory cannot in turn explain several vascular aspects well detailed in the MS literature," he told Medscape Medical News.

In their article, Dr. Bagert and colleagues argue that a critical look at the scientific methods used in the original studies of CCSVI in MS "reveals several methodological problems with regard to potential bias and confounding."

For example, the MS patients who underwent PTA of stenotic veins had recently initiated disease-modifying therapy, which could have been responsible for the clinical improvement seen.

"In our opinion, this potential confounder is one of the most egregious methodological problems with the initial treatment trial," they write. Another problem, in their opinion, is the lack of a control group and therefore no blinding of neurologists.

Invasive Treatments for CCSVI 'Premature'

Since 2009, invasive procedures, such as angioplasty and stenting of the cerebrospinal veins, have been performed on eager patients with MS, despite a lack of convincing evidence that CCSVI even exists in MS, Dr. Bagert and colleagues note in their article.

To date, 2 deaths in MS patients have been linked to these procedures.

"It is our opinion that until the existence of CCSVI in MS can be independently verified by other investigators, research into invasive treatments of CCSVI should not be pursued," Dr. Bagert told Medscape Medical News.

But Dr. Zamboni disagrees. "As for the use of venous angioplasty in this setting, it is a safe intervention that can provide insight into the pathophysiological underpinnings of this disease," he said.

The conclusion of the authors is to prohibit studies on this treatment, even when the studies are "well designed and ethically approved," Dr. Zamboni points out.

On the contrary, he thinks "a lot of research, conducted with greater humility and a better interdisciplinary attitude, is still needed to find the exact location of venous function in the complex and mysterious context of MS."

Robert Zivadinov, MD, PhD, from the Buffalo Neuroimaging Analysis Center and the Jacobs Neurological Institute at the University of Buffalo, New York, is also performing research into the relationship, if any, between CCSVI and MS.

He recently published an article in Neurology showing some relationship between CCSVI and MS, but suggesting that MS may cause CCSVI and not the other way around.

Dr. Zivadinov declined to comment on the report by Bagert and colleagues but noted they have several articles looking further into the relationship soon to be published.

Funding for More Study Earmarked

The Canadian government and the US National MS Society have earmarked funds to research CCSVI as it relates to MS.

"The issue of CCSVI is getting a lot of attention," Timothy Coetzee, PhD, chief research officer for the National MS Society, noted in an interview with Medscape Medical News.

"Our sense is that there are a lot of questions about it, and that's exactly why you need to invest in research for these kinds of new leads. When a new concept is advanced in medicine, you need to deploy resources to understand it and get some clarity," he said.

Principal funding for the GWAS was provided by the Wellcome Trust. An extensive and complete list of funding agencies is listed with the original article. The study authors have disclosed no relevant financial relationships. Dr. Bagert has disclosed no relevant financial relationships on her 2 articles. Dr. Coetzee has disclosed no relevant financial relationships.

Nature. 2011;476:214-219. Text

Arch Neurol. Published online July 11, 2011. Abstract

Arch Neurol. Published online August 8, 2011. Abstract

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