Erenumab for Treatment of Persistent Erythema and Flushing in Rosacea

Silberstein S.D., Reshef S., Cohen J.M., Gandhi S., Seminerio M., Ramirez Campos V., Kessler Y., Thompson S.F., Blumenfeld A.

Through 2018, three calcitonin gene-related peptide pathway–targeted monoclonal antibodies (CGRP mAbs) had received US Food and Drug Administration (FDA) approval for migraine prevention: erenumab, fremanezumab, and galcanezumab. This retrospective analysis evaluated adverse events (AEs) spontaneously reported to the FDA Adverse Event Reporting System (FAERS) safety surveillance database during the first 6 months post-approval of erenumab (May 2018 to November 2018), fremanezumab (September 2018 to March 2019), and galcanezumab (September 2018 to March 2019). Reporting rates (RR) per 1000 exposed patients were calculated from number of reported events (when product classified as “primary suspect”) in each AE category and estimated number of treated patients based on de-identified prescription data (IQVIA database) and were ranked on the basis of frequency for each product. RR per 1000 exposed patients for “migraine” (erenumab, 4.89; fremanezumab, 1.01; galcanezumab, 2.99), “headache” (3.32, 1.27, 3.07), and “drug ineffective” (3.68, 1.14, 1.69) were commonly reported for all three products, as were migraine-associated symptoms (“nausea”: 2.94, 0.91, 1.09) and “injection-site” reactions (“pain”: 2.94, 0.8, 4.9; “swelling”: 0.56, 0.53, 1.25; “pruritus”: 0.26, 0.63, 1.14; “erythema”: 0.58, 0.71, 1.58). “Constipation” ranked second for erenumab (4.90) but did not make the top ten events for fremanezumab (0.46) or galcanezumab (0.76); cardiovascular events did not rank in the top ten AEs for any product. The frequency of serious outcomes was low, with ≤ 2% of AEs categorized as serious across the CGRP mAbs. These results aid in supporting the safety profile of CGRP mAbs in the real-world setting and may provide clinicians and patients with additional insight when considering migraine preventive treatments.

Wienholtz N.K., Christensen C.E., Zhang D.G., Rechnagel A.A., Byrnel H.V., Haugaard J.H., Ashina M., Thyssen J.P., Egeberg A.

BackgroundAn 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.ObjectiveThe 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.MethodsIn 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.ResultsWe 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.ConclusionThis 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.

Cullum C.K., Do T.P., Ashina M., Bendtsen L., Hugger S.S., Iljazi A., Gusatovic J., Snellman J., Lopez-Lopez C., Ashina H., Amin F.M.

Clinical trials have shown that erenumab is effective and well-tolerated for the preventive treatment of chronic migraine. To extend the results from clinical trials, we assessed the real-world efficacy and safety of erenumab in patients with chronic migraine from the outpatient clinic at the Danish Headache Center. A 52-week, single-center, prospective, observation study of erenumab in adults with chronic migraine who are eligible for treatment with monoclonal antibodies against CGRP or its receptor in Denmark. The primary outcome was defined as proportion of patients who achieved ≥ 30% reduction in monthly migraine days (MMDs) from baseline to weeks 9–12. A total of 300 adult patients with chronic migraine were enrolled and received at least one dose of erenumab. At baseline, the mean (SD) number of monthly headache days was 23 ± 4.9 and mean number of MMDs was 16.8 ± 6.4. Of 300 enrolled patients, 273 (91.0%) patients completed 12 weeks of treatment, and 119 (39.7%) completed 52 weeks of treatment. The number of patients who achieved ≥ 30% reduction in MMDs from baseline to weeks 9–12 was 195 (71.4%) of 273 patients. Sustained ≥ 30% reduction in MMDs at all assessment periods throughout the 52-week treatment period was achieved by 102 (34%) of 300 patients. Adverse events occurred in 220 (73.3%) out of 300 patients. The most common adverse event was constipation. Treatment discontinuation due to lack of tolerability occurred in 41 (13.7%) patients. Among adult patients with chronic migraine and previous failure of medications for migraine prevention, erenumab was found to be effective and well-tolerated.

Chang H., Huang Y., Lien Y., Chang Y.

Rosacea is associated with several comorbidities, but its relationship with psychiatric disorders remains controversial. We aimed to investigate the association of rosacea with depression and anxiety.

Ashina M., Buse D.C., Ashina H., Pozo-Rosich P., Peres M.F., Lee M.J., Terwindt G.M., Halker Singh R., Tassorelli C., Do T.P., Mitsikostas D.D., Dodick D.W.

Summary Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.

van Zuuren E.J., Arents B.W., van der Linden M.M., Vermeulen S., Fedorowicz Z., Tan J.

Rosacea is a chronic inflammatory dermatosis mainly affecting the cheeks, nose, chin, and forehead. Rosacea is characterized by recurrent episodes of flushing or transient erythema, persistent erythema, phymatous changes, papules, pustules, and telangiectasia. The eyes may also be involved. Due to rosacea affecting the face, it has a profound negative impact on quality of life, self-esteem, and well-being. In addition to general skin care, there are several approved treatment options available for addressing these features, both topical and systemic. For some features, intense pulse light, laser, and surgery are of value. Recent advances in fundamental scientific research have underscored the roles of the innate and adaptive immune systems as well as neurovascular dysregulation underlying the spectrum of clinical features of rosacea. Endogenous and exogenous stimuli may initiate and aggravate several pathways in patients with rosacea. This review covers the new phenotype-based diagnosis and classification system reflecting pathophysiology, and new and emerging treatment options and approaches. We address new topical and systemic formulations, as well as recent evidence on treatment combinations. In addition, ongoing studies investigating novel therapeutic interventions will be summarized.

Wienholtz N.K., Christensen C.E., Zhang D.G., Coskun H., Ghanizada H., Al-Karagholi M.A., Hannibal J., Egeberg A., Thyssen J.P., Ashina M.

Objective To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. Methods A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. Results Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( p < 0.001). Conclusions and relevance: Early treatment with intravenously administered sumatriptan prevented PACAP38-induced migraine. Prevention of migraine attacks was associated with vasoconstriction by sumatriptan in the earliest phases of PACAP provocation. These results suggest that sumatriptan prevents PACAP38-induced migraine by modulation of nociceptive transmission within the trigeminovascular system. Trial Registration: ClinicalTrials.gov (NCT03881644).

Thiboutot D., Anderson R., Cook-Bolden F., Draelos Z., Gallo R.L., Granstein R.D., Kang S., Macsai M., Gold L.S., Tan J.

In 2017, a National Rosacea Society Expert Committee developed and published an updated classification of rosacea to reflect current insights into rosacea pathogenesis, pathophysiology, and management. These developments suggest that a multivariate disease process underlies the various clinical manifestations of the disorder. The new system is consequently based on phenotypes that link to this process, providing clear parameters for research and diagnosis as well as encouraging clinicians to assess and treat the disorder as it may occur in each individual. Meanwhile, a range of therapies has become available for rosacea, and their roles have been increasingly defined in clinical practice as the disorder has become more widely recognized. This update is intended to provide a comprehensive summary of management options, including expert evaluations, to serve as a guide for tailoring treatment and care on an individual basis to achieve optimal patient outcomes.

Scala J., Vojvodic A., Vojvodic P., Vlaskovic-Jovicevic T., Peric-Hajzler Z., Matovic D., Dimitrijevic S., Vojvodic J., Sijan G., Stepic N., Wollina U., Tirant M., Nguyen V.T., Fioranelli M., Lotti T.

Botulinum toxin (BTX) is a neurotoxin derived from the Clostridium botulinum bacterium that inhibits the release of acetylcholine at the neuromuscular junction level whose effects has been used for many years to treat a variety of muscular/neuromuscular conditions and more recently also for cosmetic use. BTX has experimented in some dermatological conditions, which include Rosacea and facial flushing treatment with good results. The complex mechanism underlying those results is not completely understood but was proposed a release inhibition of acetylcholine from peripheral autonomic nerves of the cutaneous vasodilatory system combined with the blockade substance P and calcitonin gene-related peptide (CGRP) thus modulating blood vessel dilatation. We analysed the published data on BTX off label applications rosacea and flushing retrieved from PubMed.

Ashina M., Goadsby P.J., Reuter U., Silberstein S., Dodick D., Rippon G.A., Klatt J., Xue F., Chia V., Zhang F., Cheng S., Mikol D.D.

Background Previously published three-month placebo-controlled and one-year open-label clinical trial data have provided information on the efficacy and safety of erenumab. Methods Interim analysis was undertaken from an ongoing five-year open-label treatment phase after all patients completed three years in the open-label treatment phase or discontinued the study. Adult patients with episodic migraine enrolled in the open-label treatment phase initially received 70 mg erenumab monthly. A protocol amendment increased the dosage to 140 mg monthly to assess long-term safety of the higher dose. Safety and tolerability were assessed by monitoring adverse events, electrocardiograms, laboratory assessments, and vital signs. Results Of 383 patients enrolled in the open-label treatment phase, at data cutoff 235 (61.3%) remained in the study, all received 140 mg for ≥1 year. Median (Q1, Q3) exposure (70 or 140 mg) for all patients enrolled was 3.2 (1.3, 3.4) years. The most frequent adverse events (≥4.0/100 patient-years) were reported as viral upper respiratory tract infection, sinusitis, influenza, and back pain. Exposure-adjusted serious adverse event rates were 4.2/100 patient-years. There was no increase in cardiovascular events over time. Conclusions In this long-term study of a CGRP-receptor antibody, erenumab was found to be safe and well-tolerated with a spectrum and rate of adverse events consistent with shorter-term placebo-controlled studies. Trial registration ClinicalTrials.gov NCT01952574

Gether L., Overgaard L.K., Egeberg A., Thyssen J.P.

The exact prevalence and incidence of rosacea remain unknown, although it is a common condition associated with severe noncutaneous diseases.To perform a systematic review of the published literature to examine the global incidence and prevalence of rosacea.A systematic review of population-based and dermatological outpatient studies reporting the incidence and/or prevalence of rosacea was performed using three electronic medical databases: PubMed, Embase and Web of Science. Data were extracted and a proportion meta-analysis was performed to obtain pooled proportions.In total 32 studies were included examining a total of 41 populations with 26 519 836 individuals. Twenty-two populations were from Europe, three from Africa, four from Asia, nine from North America and three from South America. The pooled proportion of individuals with rosacea was 5·46% [95% confidence interval (CI) 4·91-6·04] in the general population and 2·39% (95% CI 1·56-3·39) among dermatological outpatients. Self-reported rosacea gave higher prevalence estimates than rosacea diagnosed by clinical examination, suggesting a low specificity of questionnaires based on symptoms. Rosacea affected both women (5·41%, 95% CI 3·85-7·23) and men (3·90%, 95% CI 3·04-4·87), and mostly those aged 45-60 years.We estimated the global prevalence of rosacea based on published data and found that 5·46% of the adult population is affected. However, the prevalence of rosacea depended on the diagnostic method, with higher estimates in questionnaire studies of rosacea symptoms and lower estimates in health registries with International Classification of Diseases codes.

Vera N., Patel N.U., Seminario-Vidal L.

Rosacea is a chronic inflammatory cutaneous disorder with an unclear pathogenesis. It has been associated with multiple comorbidities, including cardiovascular diseases, malignancies, depression, migraines, dementia, Parkinson disease, gastrointestinal disorders, and autoimmune conditions. The extent, clinical significance, and implications of these associations remain a topic of discussion. Further evaluation of these comorbidities may offer valuable insight for future screening practices and treatment recommendations.

Haber R., El Gemayel M.

Rosacea is linked to abnormalities of cutaneous vasculature and dysregulation of the inflammatory response. Recent reports on rosacea have shown a significant association with cardiovascular, gastrointestinal, and psychiatric diseases, all of which may affect morbidity and mortality among these patients.To review available data regarding comorbidities associated with rosacea, discuss their pathogenesis, and highlight the evaluation of affected patients.We performed a complete and systematic literature review in PubMed/Medline, Embase, and the Cochrane Collaboration databases, searching for all articles on possible associated diseases that have been reported with rosacea, with no limits on publication date, participant age, sex, or nationality.A total of 29 studies were included in this systematic review, including 14 case-control, 8 cross-sectional, and 7 cohort studies. Statistically significant association with rosacea has been mostly demonstrated with depression (n = 117,848 patients), hypertension (n = 18,176), cardiovascular diseases (n = 9739), anxiety disorder (n = 9079), dyslipidemia (n = 7004), diabetes mellitus (n = 6306), migraine (n = 6136), rheumatoid arthritis (n = 4192), Helicobacter pylori infection (n = 1722), ulcerative colitis (n = 1424), and dementia (n = 1194).Limitations included the accuracy of the published data, potential patient selection, and possible confounding factors. The true nature of the drawn correlations is uncertain, and causality cannot be established.Rosacea is associated with a number of systemic disorders. Recognition of these conditions is critical to providing appropriate screening and management of affected patients.

Shinkai K.

Kotlyar J., Granstein R.D.

Moran S.K., Wong S.C., Taylor S.L., Feldman S.R.

Chen S., Hu H., Wu J., Dong M., Zhang Y., Zhu Q., Wang Z., Sun Y., Gao X.

Barbieri J.S.