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In the Clinic-Migraine

Migraine Biomarkers Offer Clues to Response to Onabotulinumtoxin A

May Lead to More Personalized Treatment

Tarkan, Laurie

doi: 10.1097/01.NT.0000530036.10553.72
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In an observational study, Spanish researchers found that higher plasma levels of calcitonin gene-related peptide and pentraxin 3 in chronic migraineurs were associated with better response to onabotulinumtoxin type A.

Plasma levels of calcitonin gene-related peptide (CGRP) and pentraxin 3 (PTX3) were elevated in chronic migraineurs and associated with a good response to onabotulinumtoxin A (Botox) compared to non-responders, according to a study published in the November 13 online issue of Headache.

The observational study compared baseline levels of a broad range of molecular biomarkers in chronic migraineurs with good outcomes after treatment with botulinum toxin, chronic migraineurs who didn't respond well to treatment, and healthy controls. The researchers found that plasma basal levels of CGRP greater than 50 ng/mL and PTX3 greater than 1,000 pg/mL were associated with good response to onabotulinumtoxin A.

“A new era is beginning for migraine treatment with anti-CGRP antibodies, and these biomarkers could be helpful in the future to tailor a personal treatment for each patient,” said the lead study author Clara Domínguez, MD, of the Universidade de Santiago de Compostela in Santiago de Compostela, Spain.

CGRP, which has been found to be elevated during migraine attacks, is thought to induce neural inflammation and vasodilation of blood vessels, and plays a role in central sensitization. Prior studies have also found that botulinum toxin blocks the release of CGRP.

This study was the first to report a relationship between PTX3 levels and treatment response to onabotulinum toxin A, the study authors said. PTX3, an inflammatory protein, has been associated with endothelial dysfunction in coronary artery disease and atherosclerosis. The identification of PTX3 as a marker for responders is important as it points to the role of the vascular endothelium in migraine pathophysiology and in botulinum toxin's mechanism of action, Dr. Domínguez explained.

“PTX3 constitutes a very specific biomarker of endothelial dysfunction, which is one of the main mechanisms in the pathophysiology of migraine,” Dr. Domínguez said.

Botulinum toxin appears to reduce headaches by acting on meningeal fibers, inhibiting mechanical nociception, and by blocking the release of neurotransmitters such as glutamate, CGRP, and substance P. Botulinum toxin is a safe and effective treatment to prevent pain and frequency of migraines in chronic migraineurs, Dr. Dominguez noted, but it is not effective in all migraineurs. Studies have tried to find factors that predict response to botulinum toxin, including molecular markers and clinical factors, but results have been inconsistent. Therefore, choosing candidates for botulinum toxin has been based on poor response to oral medications or adverse effects.

The study authors disclosed no financial interests related to the therapy. The study was funded by grants from various governmental agencies in Spain.

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For the observational study, the researchers measured serum levels of several biomarkers of inflammation, endothelial dysfunction, blood-brain barrier disruption, brain damage, and trigeminovascular activation. They included 62 patients with chronic migraine who were candidates for treatment with botulinum toxin and 24 healthy controls. Patients were included whether they were taking any other preventative drugs or not.

Blood samples were obtained before initiating treatment. Other treatments were not interrupted. Patients received a second treatment after 12 weeks.

After 24 weeks, patients were classified into two groups based on their headache frequency: nonresponders (no improvement or improvement less than 50 percent) and responders (improvement greater than 50 percent). The authors compared baseline levels of biomarkers between these groups.

Forty-seven patients (75.8 percent) treated with botulinum toxin responded and 15 did not (24.2 percent). PTX3 and CGRP showed significantly higher levels in responders than nonresponders. In a secondary analysis, researchers found significantly higher levels of CGRP in excellent responders compared to moderate responders.

Compared with healthy controls, the researchers did find that migraineurs had higher levels of certain molecule markers for endothelial dysfunction, inflammation, blood-brain disruption, and brain damage, but the differences between responders and nonresponders to botulinum toxin were not significant.

The only significant difference in clinical characteristics between responders and nonresponders was age. Responders tended to be younger, with a median age of 39.4, compared to nonresponders, whose median age was 51.6. The authors expressed surprise that there was no significant difference in response based on other characteristics such as frequency or intensity of migraine, sex, weight, or medications.

The authors calculated predictive values for CGRP and PTX3 and concluded that the optimal threshold for CGRP would be 50 ng/mL and 1,000 pg/mL for PTX3. The authors noted that the CGRP level of 50 ng/mL is lower than other studies have reported, which might be due to the relatively small size of the sample.

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“The study is important because it focuses on personalized medicine, looking at biomarkers for migraines,” said Matthew Robbins, MD, associate professor of neurology at Albert Einstein College of Medicine, who was not involved with the study. “We're faced with choosing treatments based on their side effect profile rather than their individual merits. Before you go down the road of getting a series of injections or before you take a medication, it would be great to have more scientific information,” he said.

The study was also helpful in narrowing in on important biomarkers, he said. “What's new in this study is that they used a broad panel of different potential biomarkers.” But he added that it's too preliminary to consider testing for these biomarkers. “It's probably quite an expensive thing to do,” he said.

The study results are limited by the small sample size of patients, however, and they came from a selected clinical population, Dr. Robbins continued. The study was not a randomized controlled trial, so the results could have been an association. “It could be that people who got better had higher levels in the first place and maybe they were more likely to improve with any therapy,” said Dr. Robbins, adding that the placebo response is high in botulinum toxin therapy.

“It seems to me a population effect, not necessarily a direct measure of the pathophysiological process,” added Peter Goadsby, MD, PhD, professor of neurology at the University of California, San Francisco School of Medicine. He said the most pressing question in botulinum toxin is how it works and this study did not fully answer this question.

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•. Dominguez C, Vietes-Prado A, Perez-Mato M, et al CGRP and PTX3 as predictors of efficacy of onabotulinumtoxin type A in chronic migraine: An observational study Headache 2017; Epub 2017 Nov 13.
    © 2018 American Academy of Neurology