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 antagonism is effective in treating migraine and monoclonal antibodies targeting CGRP (MAbs) are currently one of the available anti-CGRP therapies,2 but the only one available in Spain. However, CGRP has several other functions in the human body.3 For example, by producing vasodilation and modifying vascular permeability, potentially allows the recruitment of inflammatory cells to the local area,4 being involved in tissue inflammation and sepsis. However, CGRP, depending on the situation, may promote inflammation or protect from it, through its ability to increase cAMP.5 Another function of CGRP is the regulation of the peripheral resistance of the cardiovascular and pulmonary systems during infection, and in this context CGRP antagonism may alter the ability to cope with acute lung injury.6

At present the world is facing the Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe-Acute-Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) that is able to produce a respiratory infection associated with a severe inflammatory response.7 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 real-time 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

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 (Table 2). Headache was the most frequent symptom in 82.9% of patients (34/41) (Table 2). 47.1% (16/34) of patients with headache associated with COVID-19 reported that it had worsened compared to their usual migraine.

Comparing patients with and without MAbs, no differences were found in terms of baseline characteristics or proportion of COVID-19 cases, with the exception of adherence to migraine preventive treatment: patients with MAbs presented a statistically significant higher adherence than patients without MAbs (97.6% vs. 84.1%; P=0.008) (Table 1). Discontinuation was due to lack of efficacy, impossibility in administering or collecting the medication.

In the subgroup of COVID-19 cases, there were no differences in COVID-19 symptoms except for diarrhea (without MAbs: 68.8% vs. with MAbs: 28.0%; P=0.022). The proportions of patients with headache as a COVID-19 symptom as well as with worsening with respect to the usual migraine (47.1%, 16/34) were not different between the group with and without MAb. Healthcare resource utilization related to COVID-19 and adherence to other preventive medications was similar between the two groups (Table 2). 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 13.69–18.6%.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.

Third, patients with confirmed or suspected COVID-19 under MAb treatment do not seem to have a worse course of the disease compared with migraine patients under other preventive treatments.

Yet, what are the implications, in particular, of these latter findings?

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 COVID-19.

PPR and EC made substantial contributions to conception and study design. EC, VJG, AA, MTF, NMSM, JVR, ACLV, ALB, MFR, MDGB, SMGS, MMB, MPA, CS, CV, BCC, CVE, PPJ, CTP, LGV, AGV, PIS, JPE, SSL, PPR 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.

All patients consented to publication of anonymous individual data.

All data are available and any anonymized data will be shared by request from any qualified investigator.

No funding was received for this study.

Dr. Caronna reports no disclosures relevant to the manuscript.

Mr. Gallardo reports no disclosures relevant to the manuscript.

Dr. Alpuente has received honoraria from Allergan plc, Novartis, Chiesi.

Dr. Torres-Ferrus has received honoraria from Allergan plc, Novartis, Chiesi.

Dr. Morollón Sánchez-Mateo reports no disclosures relevant to the manuscript.

Dr. Viguera-Romero has received honoraria from Allergan plc, Novartis, Chiesi.

Dr. López-Veloso reports no disclosures relevant to the manuscript.

Dr. López-Bravo reports no disclosures relevant to the manuscript.

Dr. Gago-Veiga has received honoraria from Allergan plc, Novartis, Chiesi.

Dr. Irimia Sieira has received honoraria from Allergan, Novartis and Teva Pharmaceuticals.

Dr. Porta-Etessam has received honoraria from Allergan, Chiesi, Eli Lilly, Novartis and Teva.

Dr. Santos-Lasaosa has received honoraria from Allergan, Chiesi, Eli Lilly, Novartis and Teva.

Dr. Pozo-Rosich has received honoraria as a consultant and speaker for: Allergan, Almirall, Biohaven, Chiesi, Eli Lilly, Novartis and Teva. Her research group has received research grants from Allergan and Novartis, and has received funding for clinical trials from Alder, Electrocore, Eli Lilly, Novartis, Teva. She is in the editorial board of Revista de Neurologia. She is an associate editor for Cephalalgia, Headache, Neurologia and Frontiers of Neurology. She is the founder of www.midolordecabeza.org. PP-R does not own stocks from any pharmaceutical company.