Monday, January 22, 2018

CGRP and PTX3 as predictors of efficacy of onabotulinumtoxin type A in chronic migraine

Domínguez C, Vieites-Prado A, Pérez-Mato M, Sobrino T, Rodríguez-Osorio X, López A, Campos F, Martínez F, Castillo J, Leira R. CGRP and PTX3 as Predictors of Efficacy of Onabotulinumtoxin Type A in Chronic Migraine: An Observational Study. Headache. 2018 Jan;58(1):78-87.

The aim of this study is to find a relation between several biomarkers in peripheral blood and outcome after treatment with onabotulinumtoxin A (OnabotA).

OnabotA is an effective treatment in chronic migraine (CM). Different studies have tried to find predictors of response to treatment, either with clinical characteristics, neuroimaging features, or molecular biomarkers; however, it is still not possible to predict the individual outcome.

We measured serum levels of biomarkers of inflammation (IL-6, IL-10, TNF-α, and hs-CRP), endothelial dysfunction (PTX3 and sTWEAK), blood-brain barrier disruption (cFN), brain damage (S100b, NSE), and trigemino-vascular activation (CGRP) by ELISA in a group of CM patients treated with OnabotA and healthy controls. After 24 weeks, patients were classified in two groups according to their outcome considering variations in headache frequency: nonresponders (nonimprovement or improvement <50%) and responders (improvement >50%). We compared baseline levels of biomarkers between these groups.

Sixty-two patients diagnosed with CM (IHS 2013 criteria) who fulfilled criteria for treatment with OnabotA and 24 healthy controls were included. Fifteen patients did not respond to treatment (24.2%) and 47 were responders (75.8%). Pentraxin 3 (PTX3) serum levels (1455.4 ± 487.5 pg/mL versus 720.3 ± 334.1 pg/mL, P < .0001) and calcitonin gene-related peptide (CGRP) serum levels (133.1 ± 86.6 ng/mL versus 58.2 ± 91.7 ng/mL, P = .004) were significantly higher in responders than nonresponders. Serum basal levels of PTX3 >1000 pg/mL (AUC 0.908; 95% CI: 0.827-0.990) and CGRP >50 ng/mL (AUC 0.800; 95% CI: 0.652-0.947) were associated with good response to OnabotA treatment.

These results show that molecular markers of trigeminovascular activation (CGRP) and endothelial dysfunction (PTX3) are associated with response to OnabotA and may act as new biomarkers for the selection of treatment in chronic migraineurs.

“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 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 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.

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