key: cord-0832223-643nxhoh authors: Caronna, Edoardo; Gallardo, Victor José; Alpuente, Alicia; Torres-Ferrus, Marta; Sánchez-Mateo, Noemi Morollón; Viguera-Romero, Javier; López-Veloso, Ana Carolina; López-Bravo, Alba; Gago-Veiga, Ana Beatriz; Sieira, Pablo Irimia; Porta-Etessam, Jesús; Santos-Lasaosa, Sonia; Pozo-Rosich, Patricia title: Safety of anti-CGRP monoclonal antibodies in patients with migraine during the COVID-19 pandemic: present and future implications date: 2021-03-19 journal: Neurologia DOI: 10.1016/j.nrl.2021.03.003 sha: f673d1ec86d0f39d0d6b9e282b2890ca96900503 doc_id: 832223 cord_uid: 643nxhoh Background and objective: CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in such immunological conditions as sepsis. We analysed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus. Methods: This is a multicentre cross-sectional study. From May to November 2020, through a national survey distributed by the Spanish Society of Neurology, we collected data about the presence of COVID-19 symptoms including headache and their characteristics and severity in patients with migraine treated with anti-CGRP monoclonal antibodies (mAb), and compared them against patients with migraine not receiving this treatment. We also conducted a subanalysis of patients with COVID-19 symptoms. Results: We recruited 300 patients with migraine: 51.7% (155/300) were taking anti-CGRP mAbs; 87.3% were women (262/300). Mean age (standard deviation) was 47.1 years (11.6). Forty-one patients (13.7%) met diagnostic criteria for COVID-19, with no statistically significant difference between patients with and without anti-CGRP mAb treatment (16.1% vs 11.0%, respectively; P = .320). Of the patients with COVID-19, 48.8% (20/41) visited the emergency department and 12.2% (5/41) were hospitalised. Likewise, no clinical differences were found between the groups of patients with and without anti-CGRP mAb treatment. Conclusion: Anti-CGRP mAbs may be safe in clinical practice, presenting no association with increased risk of COVID-19. J o u r n a l P r e -p r o o f 3 worked for acquisition of data. VJG and EC contributed to analysis and interpretation of data. EC and VJG wrote first draft. PPR, MTF, AA critically revised and finally approved the version to be published. All authors fully comply with and approve the version to be published. Dr Caronna reports no disclosures relevant to the manuscript. Frontiers of Neurology. She is the founder of www.midolordecabeza.org. PP-R does not own stocks from any pharmaceutical company. Background and objective: CGRP, a neuropeptide involved in migraine pathophysiology, is also known to play a role in the respiratory system and in such immunological conditions as sepsis. We analysed the impact of the use of CGRP antagonists in patients with migraine during the COVID-19 pandemic, caused by the SARS-CoV-2 coronavirus. Methods: This is a multicentre cross-sectional study. From May to November 2020, through a national survey distributed by the Spanish Society of Neurology, we collected data about the presence of COVID-19 symptoms including headache and their characteristics and severity in patients with migraine treated with anti-CGRP monoclonal antibodies (mAb), and compared them against patients with migraine not receiving this treatment. We also conducted a subanalysis of patients with COVID-19 symptoms. We recruited 300 patients with migraine: 51.7% (155/300) were taking anti-CGRP mAbs; 87.3% were women (262/300). Mean age (standard deviation) was 47.1 years (11.6). Forty-one patients (13.7%) met diagnostic criteria for COVID-19, with no statistically significant difference between patients with and without anti-CGRP mAb treatment (16.1% vs 11.0%, respectively; P = .320). Of the patients with COVID-19, 48.8% (20/41) visited the emergency department and 12.2% (5/41) were hospitalised. Likewise, no clinical differences were found between the groups of patients with and without anti-CGRP mAb treatment. Anti-CGRP mAbs may be safe in clinical practice, presenting no association with increased risk of COVID-19. Key words: Migraine; CGRP; COVID-19; monoclonal antibodies; SARS-CoV-2 Seguridad de los anticuerpos monoclonales anti-CGRP en pacientes con migraña durante la pandemia de COVID-19: implicaciones actuales y futuras RESUMEN Antecedentes y objetivo: El péptido relacionado con el gen de la calcitonina (CGRP, por sus siglas en inglés), es un neuropéptido involucrado en la fisiopatología de la migraña que también es conocido por participar en la función del sistema respiratorio y en algunas enfermedades inmunológicas como la sepsis. Hemos analizado el impacto del uso de los antagonistas de CGRP en pacientes con migraña durante la pandemia de COVID-19, causada por el coronavirus SARS-CoV-2. Métodos: Estudio transversal multicéntrico desarrollado entre mayo y noviembre de 2020, en el que la Sociedad Española de Neurología distribuyó a nivel nacional una encuesta de la que recogimos datos sobre la presencia, características y gravedad de síntomas de COVID-19, entre los que se encontraba la cefalea, en pacientes con migraña tratados con anticuerpos monoclonales (AcM) anti-CGRP, y los comparamos con los de pacientes con migraña que no recibían dicho tratamiento. También realizamos un subanálisis de los pacientes con síntomas de COVID-19. Resultados: Identificamos 300 pacientes con migraña: 51,7% (155/300) recibían AcM anti-CGRP; 87,3% eran mujeres (262/300) y la edad media (desviación estándar) de la muestra fue de 47,1 (11,6) años. Un total de 41 pacientes (13,7%) cumplían los criterios diagnósticos de COVID-19, sin diferencias estadísticamente significativas entre los pacientes que recibían tratamiento con AcM anti-CGRP y los que no (16,1% y 11,0%, respectivamente, p = 0,320). De los pacientes con COVID-19, 48,8% (20/41) acudieron a urgencias y 12,2% (5/41) fueron hospitalizados. Igualmente, no se detectaron diferencias clínicas entre los pacientes que recibían dicho tratamiento y los que no. Calcitonin Gene-Related Peptide (CGRP) is a 37-amino acid peptide with strong vasodilating properties, that has a fundamental role in migraine pathophysiology 1 . Its Under the hypothesis that CGRP may play a role in the evolution of COVID-19, it was necessary to assess the impact of drugs promoting its antagonism. Therefore, we decided to investigate the impact of the use of anti-CGRP MAbs in migraine patients during the COVID-19 pandemic, specifically analyzing their safety profile since new waves of the disease may be approaching. This is a Spanish multicenter cross-sectional study, conducted between May and November 2020. The following represents the primary analysis of these data. Outpatients with migraine, who were under treatment with anti-CGRP MAbs, were invited to fill in an online survey available on the website of the Spanish Neurological Society. The same questionnaire was filled in, at the same time, to age-and sex-matched random outpatients with migraine but without anti-CGRP treatment. Demographic data, presence of symptoms suggestive of COVID-19 and headache, including its characteristics, acute medication intake, type of anti-CGRP MAb and other preventive treatment were collected through the survey. COVID-19 symptoms were selected according to the list of symptoms reported by the World Health Organization (WHO) 8 . We also collected data about healthcare resource utilization (outpatient visits, ER admission, hospitalization) in relation to COVID-19 as indicators of disease severity. Then, we compared participants with and without anti-CGRP MAbs and conducted a subanalysis in those patients that had a confirmed diagnosis of COVID-19 or represented suspected cases of COVID-19. We defined confirmed cases as those participants who reported a SARS-CoV-2 positive realtime reverse transcriptase polymerase-chain reaction (RT-PCR) assay by nasopharyngeal swabs. We defined suspected cases as those with three or more of the COVID-19 symptoms reported by WHO either with negative RT-PCR assay or if no confirmatory test had been performed, following the definition used in a national epidemiological study 9 . We obtained descriptive and frequency statistics and made comparisons using the SPSS, version 21.0 for Windows. We reported nominal (categorical) variables as frequencies (percentages) and continuous variables as mean ± standard deviation (age). We checked normality assumption of quantitative variables through visual methods (Q-Q plots) and normality tests (Kolmogorov-Smirnov test). For our preplanned analyses, we assessed statistical significance for intergroup variables by Pearson's chi-square when comparing categorical variables. In the case of having an expected count less than 5 in more than 20% of cells in the contingency table, we used Fisher's exact test. We used linear trend chi-square for ordinal variables and the independent t-test for the continuous variable that We did not conduct a statistical power calculation prior to the study because the sample size was based on the available data. All patients recruited completed the survey and there were no missing data. P values presented are for a two-tailed test and we considered P values <0.05 statistically significant. The study was approved by the Vall d'Hebron Ethics Committee (PR(AG)317/2020). All patients gave informed consent for the analysis of patients' data which was collected according to Spanish regulation on clinical trials. All patients consented to publication of anonymous individual data. Of the 300 participants with migraine who answered the survey, 51.7% (155/300) were treated with MAbs. 87.3% were women and mean age was 47.1±11.6 years old (Table 1) . In our cohort, 13.7% (41/300) met the criteria for either confirmed or suspected case of COVID-19, 5 of them required hospital admission ( Two patients in this group discontinued MAbs, reporting that it was for fear of possible interactions with the concomitant COVID-19 infection. We finally performed a sensitivity analysis of confirmed COVID-19 patients (12/41) and we also found no statistically significant differences between patients with MAbs vs. without MAbs. In our study we decided to evaluate de potential impact of CGRP antagonism through MAbs in patients with migraine during COVID-19 pandemic, considering that, at present, there are no clear data assessing the effects of this treatment during a viral infection. Our findings are relevant for three main reasons: First, we observed that prevalence of COVID-19 in people with migraine is similar to the general population, suggesting that they have not an increased risk on the basis of their migraine history. In our cohort, 13.7% of participants had confirmed or suspected COVID-19 in line with national epidemiological study in Spain conducted in the same period on the general population, showing COVID-19 prevalence around 13.6% 9 -18.6% 10 . Second, prevalence of COVID-19 is similar in migraine patients with and without MAbs, suggesting that anti-CGRP MAbs may be safe, not predisposing to COVID-19. Yet, what are the implications, in particular, of these latter findings? From the migraine standpoint, since new waves of the pandemic may be approaching, neurologists can keep prescribing anti-CGRP MAbs, reassuring migraine patients on their use in order to avoid unnecessary discontinuation, as it does not seem to be associated with an increased susceptibility to SARS-CoV-2 infection. Extremely interesting could be the COVID-19 perspective. In this context, new studies are hypothesizing that a neuro-immunological cross-talk within the lungs takes place through the activation of the vagus nerve during infections. CGRP may be involved in this pathway and could alter inflammatory responses 11 . In support to this concept, a study on animal models of Staphylococcus Aureus pneumonia, for example, has observed that antagonizing CGRP improves survival in infected mice 12 . So far, the role of CGRP had not been studied in viral infections, but recently a clinical trial has started to investigate intranasal vazegepant, a new anti-CGRP molecule for migraine therapy, specifically to treat COVID-19 13 . In our study, we have observed that anti-CGRP MAbs have no major negative effects during COVID-19, however according to this neuro-immunological hypothesis, they could even represent a new option to treat infectious diseases such as COVID-19. Therefore, further studies must be designed to specifically address this relevant question, while the results of the previously mentioned clinical trial are awaited. As for the main limitations of our study, we are aware of the potential selection bias related to patient self-reported symptoms without possibility of a laboratory confirmation for SARS-CoV-2 in most of the cases. However, we have to consider that at the time of the peak of the pandemic, almost exclusively patients admitted at the hospital were tested to confirm COVID-19, being such bias inevitable in many online-based questionnaires. In addition, our findings should be examined carefully since the size of the COVID-19 group in our cohort is limited and participants had a mild-moderate course of the disease, being more severe patients unlikely to answer an online survey. Nevertheless, our work represents a useful exploratory study on the impact of anti-CGRP in patients with migraine. Our real-life data should be confirmed by further and ampler population-based studies with the objective of clarifying not only the absence of negative effects but also the potential therapeutic activity of these drugs in COVID-19. The prevalence of COVID-19 cases in people with migraine is similar to the one of the general population. The use of monoclonal antibodies against CGRP may be safe in clinical practice, not being associated with an increased risk or worse prognosis of Consent to publish: All patients consented to publication of anonymous individual data Funding statement: No funding was received for this study Data availability statement: All data are available and any anonymized data will The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats Targeting calcitonin gene-related peptide: a new era in migraine therapy Calcitonin gene-related peptide: physiology and pathophysiology Sensory neuropeptides: Their role in inflammation and wound healing COVID-19: consider cytokine storm syndromes and immunosuppression Primera Ronda Estudio Nacional de Sero-Epidemiología de la Infección por SARS-CoV-2 en España Cuarta Ronda Estudio Nacional de Sero-Epidemiología de la Infección por SARS-CoV-2 en España Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19 Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia Biohaven achieves positive topline results in pivotal phase 2/3 study of & vazegepant, the first and only intranasal CGRP receptor antagonist in clinical development for the acute treatment of migraine Migraine treatment Concomitant preventive treatment