Erenumab for Treatment of Persistent Erythema and Flushing in Rosacea: A Nonrandomized Controlled Trial.

Importance: Treatment of erythema and flushing in rosacea is challenging. Calcitonin gene-related peptide (CGRP) has been associated with the pathogenesis of rosacea, raising the possibility that inhibition of the CGRP pathway might improve certain features of the disease. Objective: To examine the effectiveness, tolerability, and safety of erenumab, an anti-CGRP-receptor monoclonal antibody, for the treatment of rosacea-associated erythema and flushing. Design, Setting, and Participants: This single-center, open-label, single-group, nonrandomized controlled trial was conducted between June 9, 2020, and May 11, 2021. Eligible participants included adults with rosacea with at least 15 days of either moderate to severe erythema and/or moderate to extreme flushing. No concomitant rosacea treatment was allowed throughout the study period. Visits took place at the Danish Headache Center, Copenhagen University Hospital, Rigshospitalet in Copenhagen, Denmark. Participants received 140 mg of erenumab subcutaneously every 4 weeks for 12 weeks. A safety follow-up visit was performed at week 20. Data analysis occurred from January 2023 to January 2024. Intervention: 140 mg of erenumab every 4 weeks for 12 weeks. Main Outcomes and Measures: The primary outcome was mean change in the number of days with moderate to extreme flushing during weeks 9 through 12, compared with the 4-week run-in period (baseline). The mean change in number of days with moderate to severe erythema was a secondary outcome. Adverse events were recorded for participants who received at least 1 dose of erenumab. Differences in means were calculated with a paired t test. Results: A total of 30 participants (mean [SD] age, 38.8 [13.1] years; 23 female [77%]; 7 male [23%]) were included, of whom 27 completed the 12-week study. The mean (SD) number of days with moderate to extreme flushing was reduced by -6.9 days (95% CI, -10.4 to -3.4 days; P < .001) from 23.6 (5.8) days at baseline. The mean (SD) number of days with moderate to severe erythema was reduced by -8.1 days (95% CI, -12.5 to -3.7 days; P < .001) from 15.2 (9.1) days at baseline. Adverse events included transient mild to moderate constipation (10 participants [33%]), transient worsening of flushing (4 participants [13%]), bloating (3 participants [10%]), and upper respiratory tract infections (3 participants [10%]), consistent with previous data. One participant discontinued the study due to a serious adverse event (hospital admission due to gallstones deemed unrelated to the study), and 2 participants withdrew consent due to lack of time. Conclusions and Relevance: These findings suggest that erenumab might be effective in reducing rosacea-associated flushing and chronic erythema (participants generally tolerated the treatment well, which was consistent with previous data), and that CGRP-receptor inhibition holds potential in the treatment of erythema and flushing associated with rosacea. Larger randomized clinical trials are needed to confirm this finding. Trial Registration: ClinicalTrials.gov Identifier: NCT04419259.

Elevated plasma levels of calcitonin gene-related peptide in individuals with rosacea: A cross-sectional case-control study.

BACKGROUND: Understanding the role of calcitonin gene-related peptide (CGRP) in the pathogenesis of rosacea might provide new therapeutic avenues for individuals with this disease. OBJECTIVE: To compare plasma levels of CGRP between individuals with rosacea and healthy controls. METHODS: In this cross-sectional case-control study conducted in Copenhagen, Denmark, we collected blood samples from the antecubital vein from adults with rosacea and from healthy controls. RESULTS: We enrolled 123 individuals with rosacea and 68 healthy controls. After adjusting for age and sex, plasma levels of CGRP were significantly higher in individuals with rosacea (mean, 95% confidence interval: 140.21 pmol/L, 128.50-151.92 pmol/L), compared with controls (110.77 pmol/L, 99.91-120.14 pmol/L, p = 0.002). Plasma levels of CGRP were not affected by age, sex, BMI, concomitant migraine, rosacea sub- or phenotype, concomitant disease or current treatment. LIMITATIONS: Participants were not age-, sex- and BMI-matched. CONCLUSIONS AND RELEVANCE: Elevated plasma levels of CGRP in individuals with rosacea suggest a role of CGRP in the pathogenesis of rosacea. Targeting CGRP signalling might hold therapeutic promise in people affected by this disease. GOV LISTING: NCT03872050.

Clinical characteristics of combined rosacea and migraine.

Background: An overlap between the skin disease rosacea and the headache disease migraine has been established; however, the magnitude of this overlap and the distribution between subtypes/phenotypes remains unclear. Objective: The aim was to determine the magnitude of the overlap between rosacea and migraine, and to determine which subtypes/phenotypes were present in patients with concomitant rosacea and migraine. Methods: In this cross-sectional study, 604 patients with a diagnosis of either rosacea or migraine were phenotyped through a face-to-face interview with clinical examination, to determine prevalence and phenotype of rosacea, and prevalence and subtype of migraine. Results: We found a prevalence of migraine of 54% in patients with rosacea, and a prevalence of rosacea of 65% in patients with migraine. Concomitant migraine was significantly associated with the rosacea features flushing (odds ratio = 2.6, 95% confidence interval = 1.4-4.7, p = 0.002), ocular symptoms (odds ratio = 2.4, 95% confidence interval = 1.5-3.9, p < 0.001), and burning (odds ratio = 2.1, 95% confidence interval = 1.3-3.4, p = 0.002), whereas papules/pustules were inversely related with concomitant migraine (odds ratio = 0.5, 95% confidence interval = 0.3-0.8, p = 0.006). No association was found between concomitant migraine and centrofacial erythema, rhinophyma, telangiectasia, edema, or dryness. Concomitant rosacea was not associated with any specific migraine subtype in patients with migraine. Conclusion: This study highlights a substantial overlap between rosacea and migraine, particularly in patients with certain rosacea features. Individuals with rosacea should be asked about concomitant migraine, and comorbidities should be considered when choosing between treatments.

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine. METHODS: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period. RESULTS: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale. CONCLUSION: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache.

Interictal pontine metabolism in migraine without aura patients: A 3 Tesla proton magnetic resonance spectroscopy study.

In the pons, glutamatergic mechanisms are involved in regulating inhibitory descending pain modulation, serotoninergic neurotransmission as well as modulating the sensory transmission of the trigeminovascular system. Migraine involves altered pontine activation and structural changes, while biochemical, genetic and clinical evidence suggests that altered interictal pontine glutamate levels may be an important pathophysiological feature of migraine abetting to attack initiation. Migraine without aura patients were scanned outside attacks using a proton magnetic resonance spectroscopy protocol optimized for the pons at 3 Tesla. The measurements were performed on two separate days to increase accuracy and compared to similar repeated measurements in healthy controls. We found that interictal glutamate (i.e. Glx) levels in the pons of migraine patients (n = 33) were not different from healthy controls (n = 16) (p = 0.098), while total creatine levels were markedly increased in patients (9%, p = 0.009). There was no correlation of glutamate or total creatine levels to migraine frequency, days since the last attack, usual pain intensity of attacks or disease duration. In conclusion, migraine is not associated with altered interictal pontine glutamate levels. However, the novel finding of increased total creatine levels suggests that disequilibrium in the pontine energy metabolism could be an important feature of migraine pathophysiology.

Glutamate levels and perfusion in pons during migraine attacks: A 3T MRI study using proton spectroscopy and arterial spin labeling.

Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.

Intradural artery dilation during experimentally induced migraine attacks.

The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% [95% CI: 1.4%-5.7%]. Middle cerebral artery dilated by 9.4% [95% CI: 7.1%-11.7%] and superficial temporal artery by 2.3% [95% CI: 0.2%-4.4%]. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.

Feasibility of Glutamate and GABA Detection in Pons and Thalamus at 3T and 7T by Proton Magnetic Resonance Spectroscopy.

Glutamate detection in pons and thalamus using proton magnetic resonance spectroscopy (1H-MRS) after an intervention is of interest for studying various brain disorders. However, 1H-MRS in these brain regions is challenging and time-consuming, especially in longitudinal study designs. 1H-MRS of more cortical structures at the ultrahigh magnetic field strength of 7T yields an improved spectral output, including separation of the glutamate signal from the glutamine signal, in a shorter and more feasible scan time, as compared to conventional clinical field strengths. For this purpose, we compared the feasibility of 1H-MRS at 3T and 7T in pons and thalamus by applying a longitudinal study design of repeated measures on same day and three separate days at both field strength in five healthy participants. Total 1H-MRS acquisition time was reduced by a factor 3.75 for pons and by a factor 3 for thalamus at 7T as compared to 3T. We found higher spectral signal-to-noise ratio (SNR) (p < 0.001), lower linewidth (p = 0.001) and lower Cramér-Rao lower bounds (CRLB) (p < 0.001) for the combined glutamate and glutamine signal (Glx) in thalamus at 7T as compared to 3T. In pons, CRLB of Glx and SNR were lower at 7T (p = 0.002 and p = 0.006), with no differences in linewidth compared to 3T. Mean within-subject variability of Glx concentration estimates was lower at 7T compared to 3T for both pons and thalamus. At 7T, it was possible to assess glutamate and γ-aminobutyric acid (GABA) simultaneously in pons and thalamus. In conclusion, 1H-MRS at 7T resulted in improved spectral quality while allowing shorter scan times than at 3T as well as estimation of the pure glutamate signal in pons and thalamus. This opens up the opportunity for multimodal study designs and multiregional subcortical 1H-MRS research. Glutamate and GABA measurement at 7T in pons and thalamus is advantageous for future investigations of excitatory-inhibitory mechanisms in brain disorders.

Hypersensitivity to Calcitonin Gene-Related Peptide in Post-Traumatic Headache.

OBJECTIVE: To demonstrate that calcitonin gene-related peptide (CGRP) induces headache exacerbation with migraine-like features in patients with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). METHODS: A randomized, double-blind, placebo-controlled, two-way crossover study was conducted. Analyses were intention-to-treat. Eligible patients were aged 18 to 65 years and had a history of persistent PTH after mild TBI for at least 12 months. Patients were randomized to receive an intravenous infusion of 1.5µg/min of CGRP or placebo (isotonic saline) over 20 minutes on two separate experimental days. A 12-hour observational period was used to evaluate the following outcomes: (1) difference in incidence of headache exacerbation with migraine-like features and (2) difference in area under the curve for headache intensity scores. RESULTS: Thirty patients (mean age = 37 years, 25 women [83%]) were randomized and completed the study. During the 12-hour observational period, 21 of 30 patients (70%) developed headache exacerbation with migraine-like features after CGRP, compared with 6 patients (20%) after placebo (p < 0.001). The baseline-corrected area under the curve for headache intensity scores was significantly larger after CGRP, compared with placebo (p < 0.001). INTERPRETATION: Patients with persistent PTH are hypersensitive to CGRP, which underscores its pathophysiological importance. Furthermore, CGRP-targeted therapies might provide a novel mechanism-based treatment option for patients with persistent PTH. ANN NEUROL 2020;88:1220-1228.

Risk of COVID-19 in health-care workers in Denmark: an observational cohort study.

BACKGROUND: Health-care workers are thought to be highly exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to investigate the prevalence of antibodies against SARS-CoV-2 in health-care workers and the proportion of seroconverted health-care workers with previous symptoms of COVID-19. METHODS: In this observational cohort study, screening was offered to health-care workers in the Capital Region of Denmark, including medical, nursing, and other students who were associated with hospitals in the region. Screening included point-of-care tests for IgM and IgG antibodies against SARS-CoV-2. Test results and participant characteristics were recorded. Results were compared with findings in blood donors in the Capital Region in the study period. FINDINGS: Between April 15 and April 23, 2020, we screened 29 295 health-care workers, of whom 28 792 (98·28%) provided their test results. We identified 1163 (4·04% [95% CI 3·82-4·27]) seropositive health-care workers. Seroprevalence was higher in health-care workers than in blood donors (142 [3·04%] of 4672; risk ratio [RR] 1·33 [95% CI 1·12-1·58]; p<0·001). Seroprevalence was higher in male health-care workers (331 [5·45%] of 6077) than in female health-care workers (832 [3·66%] of 22 715; RR 1·49 [1·31-1·68]; p<0·001). Frontline health-care workers working in hospitals had a significantly higher seroprevalence (779 [4·55%] of 16 356) than health-care workers in other settings (384 [3·29%] of 11 657; RR 1·38 [1·22-1·56]; p<0·001). Health-care workers working on dedicated COVID-19 wards (95 [7·19%] of 1321) had a significantly higher seroprevalence than other frontline health-care workers working in hospitals (696 [4·35%] of 15 983; RR 1·65 [1·34-2·03]; p<0·001). 622 [53·5%] of 1163 seropositive participants reported symptoms attributable to SARS-CoV-2. Loss of taste or smell was the symptom that was most strongly associated with seropositivity (377 [32·39%] of 1164 participants with this symptom were seropositive vs 786 [2·84%] of 27 628 without this symptom; RR 11·38 [10·22-12·68]). The study is registered at ClinicalTrials.gov, NCT04346186. INTERPRETATION: The prevalence of health-care workers with antibodies against SARS-CoV-2 was low but higher than in blood donors. The risk of SARS-CoV-2 infection in health-care workers was related to exposure to infected patients. More than half of seropositive health-care workers reported symptoms attributable to COVID-19. FUNDING: Lundbeck Foundation.

Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil.

OBJECTIVE: Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. METHODS: Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. RESULTS: Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42-81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. CONCLUSION: A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.

Measurement of Blood Flow Velocity in the Middle Cerebral Artery During Spontaneous Migraine Attacks: A Systematic Review.

OBJECTIVE: To assess the evidence for blood flow velocity changes in the middle cerebral artery during and outside of spontaneous migraine attacks. METHODS: A systematic literature search on PubMed was performed and reference lists of assessed articles to identify studies on spontaneous migraine attacks that used transcranial Doppler on the middle cerebral artery with comparisons to interictal measurements were reviewed. Studies on non-spontaneous attacks and intervention studies were excluded. RESULTS: A total of 17 original articles reporting blood flow velocity values in the middle cerebral artery using transcranial Doppler in migraine patients both with and without aura were identified. A total of 24 subgroups (ie, migraine patients without aura = 11, migraine patients with aura = 9, and mixed = 4) of migraine patients were investigated during and outside spontaneous migraine attacks in the 17 studies. No change was reported in 15 subgroups (63%), while decreased blood flow velocity was found in 8 subgroups (33%) and increased blood flow velocity was found in one study (4%). Exploratory analysis revealed that studies showing decreased blood flow velocity were carried out earlier after onset of attack (mean time, 4.1 h) compared with those showing no change (mean time, 6.0 h). CONCLUSIONS: Overall, spontaneous migraine attacks are not accompanied by blood flow velocity changes in the middle cerebral artery. However, explorative analyses on the time from attack onset to examination revealed side-specific attack-related decrease in blood flow velocity in the early, but not late phases. This is the first systematic review focusing on the flow changes in the middle cerebral artery of spontaneous migraine attacks. Future studies should focus on the early blood flow velocity changes in migraine attacks.

Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura.

See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier disruption as a possible mechanism linking aura and headache.awx089media15422686892001.