AAN Final Roundup
Noteworthy talks summarized
NEW ORLEANS—As we continue to digest all we learned in the whirlwind of AAN, we thought we’d share notes from talks that we found especially worth mentioning.
Three of the presentations given Thursday afternoon shed new light on the role of vitamin D and related molecules in MS. Ellen Mowry, now at Johns Hopkins University in Baltimore, Maryland, noted that low vitamin D concentrations are associated not only with susceptibility to MS but also with relapse and lesion activity; therefore, lack of this micronutrient might also correlate with disability progression and brain atrophy. Mowry conducted the study when she was at the University of California, San Francisco; she and her colleagues culled data from the EPIC cohort, a group of 469 white Relapsing-Remitting MS (RRMS)/Clinically Isolated Syndrome (CIS) subjects who were followed for 5 years with annual blood samples, clinical evaluations, and MRIs. At the study’s start, 9% of the subjects took supplemental vitamin D (this percentage increased over time), approximately half took a multivitamin, and two-thirds were on a disease-modifying therapy. Blood samples were analyzed for vitamin D concentrations. By combining these results with Expanded Disability Status Scale (EDSS) and MRI data, the researchers discovered that each 10 ng/ml increase in vitamin D correlated with lower EDSS scores (0.05 points), higher Multiple Sclerosis Functional Composite (MSFC) scores (0.014 points), and higher brain parenchymal volumes, which were driven by higher gray matter volumes (7 cc). As these subjects had relapsing disease, the connection between higher vitamin D levels and lower EDSS scores might have resulted from fewer or less severe relapses or more complete recovery from relapses, as opposed to slower progression or delay in onset of progression. It would be useful to repeat this study in a progressive MS cohort to check whether the results were similar.
The next presentation suggested that low vitamin D levels might affect men and women with MS in different ways, both undesirable. John Rose of the Veterans Administration Medical Center in Salt Lake City shared the results of a cross-sectional study of vitamin D concentrations, MRI measures, and ambulation scores. Although vitamin D concentrations were generally comparable between men and women, men with low levels of the vitamin fared worse than women with similar levels in terms of ambulation, brain atrophy, and likelihood of having progressive MS. Meanwhile, women who were deficient in vitamin D and positive for the DR2 genotype were more likely to have contrast-enhancing lesions than their DR2-negative counterparts.
Finally, Jorge Correale of the Raúl Carrea Institute for Neurological Research, FLENI, in Buenos Aires, Argentina, reminded us that vitamin D precursors are not the only UV-absorbing chromophores in the skin that modulate the immune system. He’s been studying another such molecule called cis-urocanic acid (cis-UCA). Plasma levels of cis-UCA were lower on average in 90 MS subjects than in 40 healthy controls. In vitro studies of immune cells stimulated with cis-UCA resulted in more IL-10 and less IFN-γ production by T cells, more prostaglandin E2 secretion by monocytes and dendritic cells, larger numbers of FoxP3+ regulatory T cells, reduced NK cell activity, and reduced antigen-presentation capability in dendritic cells. Dr. Correale noted that there is still a lot we don’t know about cis-UCA, including the identity of its receptor.
Although reducing relapse rates is usually the primary goal for experimental therapies that target relapsing forms of MS, reducing the severity of relapses is also a worthy outcome—albeit one that clinical trials don’t usually focus on. Aaron Miller of Mount Sinai Hospital in New York City presented a retrospective analysis of results from the TEMSO trial of teriflunomide that addressed this issue: In addition to reducing the number of relapses, this drug dampens relapse severity. Compared with subjects in the placebo arm, those assigned to teriflunomide had fewer relapses leading to hospitalization as well as fewer relapses with sequelae; these effects were stronger with the 14-mg dose than the 7-mg dose. Dr. Miller suggested that teriflunomide could therefore cut health-care costs by keeping people with MS out of the hospital. I think the benefits could extend further than that, given that a single severe relapse could have a profound impact on a person’s quality of life, employment status, etc. I would be interested to see how other drugs perform using this type of measure.
I saw two presentations on the use of helminths (parasitic worms) to treat relapsing MS. My hat is off to the investigators, who not only have an open mind about trying new and unusual types of therapies, but have also managed to recruit people to a study in which they’ll be asked to ingest worm eggs with potentially no benefit. Both studies involved biweekly administration of ova from Trichuris suis (a porcine whipworm) for 3 months. When given to humans, this organism doesn’t multiply, can’t spread to contacts, and isn’t pathogenic. John Fleming of the University of Wisconsin School of Medicine and Public Health in Madison reported that a preliminary study in five treatment-negative subjects uncovered no safety concerns and suggested a possible reduction in Gd-enhancing lesions, along with higher IL-10 production and a modified Th2 response. He is now leading a larger study in 18 subjects who are being treated for 10 months. The other study, reported by Ana Voldsgaard of Copenhagen University Hospital in Denmark and now completed, found no apparent effect toward reduction of lesion or relapse activity in 10 participants, 6 of whom were also taking IFN-β at the time. According to clinicaltrials.gov, helminth trials are also under way in England and Germany, so someday we’ll have more evidence about whether this is a good (if somewhat creepy) way to treat the disease.
The drug natalizumab appears to owe its effectiveness in MS to its ability to prevent circulating immune cells from adhering to and then crossing the blood-brain barrier. However, the cases of progressive multifocal leukoencephalopathy (PML) that have developed in patients who are taking natalizumab indicate that perhaps a little immunosurveillance would be a good thing. In her talk, Catherine Larochelle of Montreal University Hospital Center in Canada asked whether it’s possible to identify and then block only those adhesion molecules that are specific for cells that are likely to cause trouble and let everything else in. The candidate that she and her team are focusing on is called melanoma cell adhesion molecule (MCAM); this protein appears on the surface of endothelial cells of the blood-brain barrier as well as on lymphocytes that express Th17 markers. Unusually high proportions of MCAM+ CD4+ cells have been found in the blood and cerebrospinal fluid of people with MS, especially during relapse, and MCAM-expressing cells have been detected in MS lesions. Cells that produce MCAM migrate more readily across an in vitro endothelial cell layer than their MCAM-negative counterparts. MCAM might turn out to be a biomarker of MS activity and a therapeutic target. The research team is generating MCAM blockers as well as a knockout mouse for future study.
A few research teams presented posters on treatment studies in progressive MS. For example, James Stark and colleagues from the MS Research Center of New York have been conducting an uncontrolled trial of intrathecal methotrexate in patients with progressive forms of MS. They reported results from 33 subjects [27 Secondary Progressive MS (SPMS) and 6 Primary Progressive MS (PPMS)] who have been dosed with 12.5 mg every 8 to 11 weeks for 3 to 6 years (18 to 40 treatments in all). Few adverse events, no serious adverse events, no hospitalizations, and no deaths have been associated with the treatment. The mean EDSS score was 6.4 at baseline and increased over the course of the study to only 6.6, suggesting a stabilizing effect. EDSS scores were improved or unchanged in 48% of the subjects, and the scores of the rest increased by an average of 0.68 points.
In another study presented by Sarah Bernsen of Cologne City Hospital Germany, researchers administered rituximab to 11 SPMS, 1 PPMS, and 3 neuromyelitis optica subjects, with redosing performed after 4 to 12 months—as soon as B cell counts began to rebound. Subjects entered the study with EDSS scores that ranged from 2.5 to 8.0 and had two to six courses of treatment. The subjects were observed for 24 to 224 weeks, during which time the annualized relapse rate fell from 1.67 to 0.73, and the mean EDSS score increased by only 0.1 point (5.6 to 5.7). No serious adverse events were reported.
A number of other progressive MS trials are currently under way, including several multicenter, large-scale controlled trials of drugs approved or under investigation for RRMS. We’ll have to wait until a future meeting to find out how effective the treatments are, but in the meantime these results provide some degree of hope that progressive MS has a vulnerable side.
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