Abstract
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.
Clinicaltrials.gov listing
INTRODUCTION
Rosacea is a prevalent and chronic inflammatory skin disorder that is typically characterized by flushing, persistent centrofacial erythema, papules and pustules, phymatous changes and ocular manifestations. 1 It affects about 5% of the global population and despite the widespread prevalence, its neurobiological underpinnings remain poorly understood. 2 , 3
Capsaicin, a well‐known trigger of rosacea flushing, 4 , 5 , 6 , 7 has been shown to increase dermal skin blood flow in the forearm 8 , 9 by activating transient receptor potential vanilloid (TRPV) channels and promoting the release of calcitonin gene‐related peptide (CGRP). 10 In healthy individuals, the small molecule CGRP receptor antagonist telcagepant has been demonstrated to inhibit capsaicin‐induced increase in dermal blood flow in the forearm. 9 Preclinical models have also shown that CGRP receptor antagonists can inhibit increased blood flow and plasma extravasation induced by capsaicin in the mouse ear. 11 , 12 CGRP plays an important role in the pathogenesis of migraine, 13 a prevalent neurologic disorder characterized by recurrent headache attacks. 14 Interestingly, rosacea and migraine share several triggers, such as emotional stress, UV exposure and certain foods and beverages, suggesting a possible overlap in their pathophysiology. 15 In a recent cross‐sectional study, the prevalence of migraine was reported to be 54% in individuals with rosacea, while the prevalence of rosacea was 65% in individuals with migraine. 16 Elevated plasma levels of CGRP have been reported in individuals with migraine 17 , 18 but this has never been examined in rosacea. Given the similarities in triggers and epidemiology, it is possible that CGRP plasma levels might also have a role in rosacea. However, to date, no studies have examined plasma levels of CGRP in individuals with rosacea. Additional research in this area might provide insights into the pathogenesis of rosacea and identify potential therapeutic targets for this chronic and debilitating disease.
In the present study we investigated plasma levels of CGRP in individuals with rosacea and healthy controls. Furthermore, we explored the potential impact of comorbid migraine on our findings.
PATIENTS AND METHODS
Study population
Participants were recruited from outpatient clinics in three different hospitals in Copenhagen (the Department of Dermatology and Allergy at Herlev‐Gentofte Hospital; the Department of skin and wound healing at Frederiksberg‐Bispebjerg hospital and the Danish Headache Center, Rigshospitalet Glostrup) as well as from online interest groups for rosacea. Individuals with a physician diagnosis of rosacea with or without concomitant migraine were eligible. Furthermore, we recruited 68 healthy controls through posters placed publicly at various institutions in Copenhagen or a Danish website for research subject recruitment (https://www.forsoegsperson.dk).
This study was conducted as part of a larger parental study that was approved by the Health Research Ethics Committee of the Capital Region of Denmark (H‐17023750) and the Danish Data Protection Agency (I‐suite: 05694). All participants provided written consent after receiving detailed oral and written information. Study visits and procedures were performed at two different outpatient clinics in the Capital Region of Denmark in accordance with the principles of the Declaration of Helsinki. The STrengthering the Reporting of Observational studies in Epidemiology (STROBE) guidelines were adopted for reporting.
Rosacea
The study included adults between the ages 18 and 65 years who met criteria for rosacea according to the updated 2017 guidelines. 1 Participants had rosacea features for at least 1 year before the examination (diagnosed by either the general practitioner or a dermatologist) and had to exhibit current rosacea features at the time of the blood sampling. All phenotypes and severities of rosacea were allowed. Diagnosis and phenotype were verified by three rosacea specialists (authors NKFW, AE and JPT), two of whom are full professors of dermatology, and disagreements were resolved by discussion. Considering the high prevalence of migraine in individuals with rosacea and the potential influence on our data, we recorded migraine history and divided participants into two groups: one with rosacea without comorbid migraine for primary analysis, and another with rosacea and comorbid migraine for secondary analyses. This was done to investigate the possible influence of migraine on CGRP plasma levels. Migraine was diagnosed according to the third edition of International Classification of Headache Disorders. 2
Healthy controls
Healthy controls between the ages of 18 and 65 were eligible for the study if they had no history of rosacea and no history of any primary headache disorder, except for infrequent tension‐type headache. They could not have daily medication intake except for oral contraceptives, and no history of neurological, psychological or structural heart disease.
Study design and procedures
In this cross‐sectional case–control study, patients came for a single study visit where all procedures were performed. Study visits were performed at either the Danish Headache Center, Rigshospitalet Glostrup, Denmark, at the department of Dermatology and Allergy, Gentofte, Denmark, or at a place of the patient's choice (usually either at their home or work). For details, see our previous paper on the study design. 3 Demographics and diagnoses were collected via a semi‐structured interview. 3 Blood samples were collected from the cubital fossa into EDTA tubes which were centrifuged within 60 min from collection at 2000 g for 10 min. The plasma was subsequently transferred to cryo vials (2 mL) and stored at −80°C until analysis. Analysis of plasma concentrations of CGRP was performed in‐house using a previously validated radioimmunoassay 4 which has previously been described in detail. 5 , 6 Protease inhibitors were not utilized as the validation of the assay showed no effect of enzymatic degradation on CGRP plasma levels. 4 To ensure that analyses were performed in a blinded manner without knowledge of participant characteristics, the samples were randomly arranged before analyses. The analyses were conducted by a board‐certified laboratory technician who was blinded to all clinical information regarding the subjects.
Severity of rosacea
Rosacea severity was assessed by two different assessment tools: the Rosacea Area and Severity Index (RASI) 7 and Clinician's Erythema Assessment (CEA). 8 The RASI is a composite index for evaluating severity of rosacea by evaluating four rosacea features (erythema, papules/pustules, telangiectasia and rhinophyma) in four facial areas (cheeks, forehead, nose and chin) resulting in a score from 0 to 72. The CEA is a 5‐point scale for evaluating severity of erythema from 0 (clear) to 4 (severe erythema). Both tools were evaluated by the same physician (author NKFW).
Statistical analysis
Categorical data presented as frequencies with percentages, and continuous data are presented as means with standard deviations (SD) or medians with interquartile ranges (IQR). Linear regressions were used for testing differences in mean plasma CRRP levels between healthy controls and individuals with rosacea as well as for testing for different co‐factors. All data were adjusted for age and sex. Statistical analyses were performed in R version 3.5.2 with stats and lme4 packages. p‐Values were two‐tailed and were considered statistically significant at p‐values <0.05.
RESULTS
Study population
A total of 123 individuals with rosacea without comorbid migraine were included. The mean age (SD) was 54.6 (11.9) years, and 61 participants (49%) were women. The mean (SD) body mass index was 26.0 kg/m2 (3.9 kg/m2), and the median (IQR) duration of disease was 10 years (5–14 years). All four subtypes of rosacea were represented: 74 participants (60%) with erythematotelangiectatic rosacea (ETR); 40 participants (33%) with papulopustular rosacea (PPR); 9 participants (7%) with phymatous rosacea (PR) and 53 participants (43%) with ocular rosacea (OR) (overlapping with other subtypes). Some participants used medication for their rosacea: 50 participants (41%) used topical treatments (metronidazole, ivermectin, calcineurin inhibitors, corticosteroids, azelaic acid, laser treatment or over the counter treatments); 36 participants (29%) used systemic treatments (doxycycline, tetracycline, isotretinoin and beta blockers). None of the participants had currently or previously received antibodies against CGRP or its receptors. We included 68 healthy controls. Furthermore, we included 300 participants with rosacea with coexisting migraine. Characteristics of the study population and controls are shown in Table 1.
TABLE 1.
Characteristics of individuals with rosacea and healthy controls.
| Characteristics | Rosacea n = 123 | Rosacea with migraine n = 300 | Healthy controls n = 68 |
|---|---|---|---|
| Age, years, mean (SD) | 54.6 (11.9) | 44.1 (12.8) | 35.2 (11.5) |
| Female, % (n) | 49 (61) | 87 (260) | 82 (56) |
| Height, mean (SD), cm | 173.9 (9.9) | 170.0 (7.8) | 171.3 (8.2) |
| Weight, mean (SD), kg | 79.0 (14.9) | 75.8 (16.8) | 72.4 (14.0) |
| Body mass index, mean (SD), kg/m2 | 26.0 (3.9) | 26.2 (5.6) | 24.5 (3.8) |
| Disease duration, median (IQR), years | 9 (5) | 10 (5) | – |
| Subtype, % (n) | |||
| Erythematotelangiectatic | 60 (74) | 78 (234) | – |
| Papulopustular | 33 (40) | 19 (57) | – |
| Phymatous | 7 (9) | 3 (9) | – |
| Ocular | 43 (53) | 54 (161) | – |
| Current medication, % (n) | 33 (55) | 23 (69) | – |
| Local | 41 (50) | 20 (59) | – |
| Azelaic acid | 5 (6) | 3 (10) | – |
| Brimonidine | 4 (5) | 1.7 (5) | |
| Calcineurin inhibitors | 5 (6) | 2 (7) | |
| Ivermectin | 11 (13) | 6 (18) | – |
| Metronidazole | 17 (21) | 7 (21) | – |
| Over the counter creams/regimens | 2 (3) | 3 (10) | – |
| Steroid cream | 6 (7) | 4 (11) | – |
| Laser treatment | 27 (33) | 25 (76) | – |
| Systemic | 29 (36) | 13 (40) | – |
| Doxycycline | 5 (6) | 2 (6) | – |
| Tetracycline | 10 (12) | 5 (16) | – |
| Isotretinoin | 3 (4) | 4 (11) | – |
| Beta blockers | 0 (0) | 1 (3) | – |
| Comorbidities, % (n) | – | ||
| Migraine | 0 (0) | 100 (300) | – |
Plasma CGRP
Plasma levels of CGRP were significantly higher in individuals with rosacea (n = 123) (mean = 140.21 pmol/L; 95% CI = 128.50–151.92 pmol/L) compared with controls (mean = 110.77 pmol/L, 95% CI = 99.91–120.14 pmol/L, p = 0.002) after adjusting for age and sex (Figure 1). We did not find any difference between individuals with rosacea with (n = 300) and without (n = 123) coexisting migraine (p = 0.59). We found a slightly negative association between rosacea duration (years) and plasma CGRP levels (CGRP levels decreased with 0.73 per year with rosacea, 95% CI = −1.31 to −0.15, p = 0.014).
FIGURE 1.
Plasma levels of calcitonin gene‐related peptide (CGRP) (pmol/L) in healthy controls versus individuals with rosacea adjusted for age and sex. X‐axis represents group of individuals and y‐axis represents mean CGRP‐levels. *** signifies p‐value <0.001 when comparing mean difference in mean CGRP levels between the two groups.
We did not find any significant associations between any rosacea features or subtypes and CGRP levels (Table 2, Figures 2 and 3). There was no difference between severity of rosacea (mean difference in CGRP with change in RASI = −0.59, 95% CI = −2.27 to 1.08, p = 0.49; mean change in CGRP with change in CEA = 0.49, 95% CI = −4.49 to 5.47, p = 0.36). Current rosacea treatment did not affect CGRP plasma levels (p = 0.89).
TABLE 2.
Difference in plasma CGRP levels according to rosacea pheno‐ and subtype. Calculated by linear regression.
| Mean difference, pmol/L (95% CI), p‐value | |
|---|---|
| Rosacea phenotype | |
| Persistent centrofacial redness | −72.44, 95% CI [−125.86 to −19.02], p = 0.0084 |
| Phymatous changes | −6.72, 95% CI [−51.06 to 37.62], p = 0.76 |
| Flushing | 0.44, 95% CI [−24.91 to 25.79], p = 0.97 |
| Inflammatory papules/pustules | −9.02, 95% CI [−32.58 to 14.54], p = 0.45 |
| Burning/stinging | −1.50, 95% CI [−25.04 to 22.05], p = 0.9 |
| Oedema | 0.52, 95% CI [−36.47 to 37.51], p = 0.98 |
| Xerosis | −14.82, 95% CI [−38.49 to 8.86], p = 0.22 |
| Rosacea subtype | |
| Erythematotelangiectatic rosacea (= reference) | Mean = 134.88, 95% CI [121.68 to 148.07] |
| Papulopustular rosacea | 17.72, 95% CI [−5.26 to 40.69], p = 0.13 |
| Phymatous rosacea | −0.88, 95% CI [−40.74 to 38.98], p = 0.97 |
| Ocular rosacea | −2.77, 95% CI [−14.50–8.96], p = 0.64 |
FIGURE 2.
Plasma levels of calcitonin gene‐related peptide (CGRP) (pmol/L) in individuals with different subtypes of rosacea adjusted for age and sex. X‐axis represents rosacea subtype and y‐axis represents mean CGRP‐levels. ETR, erythematotelangiectatic rosacea; PPR, papulopustular rosacea; PR, phymatous rosacea.
FIGURE 3.
Plasma levels of calcitonin gene‐related peptide (CGRP) (pmol/L) in individuals with/without ocular rosacea adjusted for age and sex. X‐axis represents ocular rosacea and y‐axis represents mean CGRP‐levels.
We did not observe any correlation between CGRP and age, sex or body mass index (BMI) in neither healthy individuals (p = 0.63 for age; p = 0.61 for sex; p = 0.23 for BMI) nor in individuals with rosacea (p = 0.39 for age; p = 0.69 for sex; p = 0.35 for BMI).
DISCUSSION
The present study revealed a novel finding that plasma levels of CGRP were elevated in individuals with rosacea. Intriguingly, there was a negative correlation between CGRP levels and the duration of rosacea symptoms. However, we did not find any significant associations between CGRP levels and rosacea severity (neither with overall rosacea nor with erythema severity), any specific rosacea subtypes/phenotypes or other rosacea features.
CGRP is a proinflammatory neuropeptide primarily expressed in unmyelinated sensory nerve fibres colocalized with melanocytes, keratinocytes and Langerhans cells in both the dermis and epidermis of humans and rodents. There are two isoforms of CGRP, α‐ and β‐, with similar activity; however, the αCGRP isoform is commonly found in human skin colocalized with substance P. CGRP interacts with several structurally related receptors, including the CGRP receptor, adrenomedullin receptors, the amylin receptor and the calcitonin receptor, which are all present in both the peripheral and central nervous systems, as well as in vascular structures. 9 Most skin cells express receptors for CGRP, 31 , 32 and mechanical and psychological stress can induce release of CGRP from cutaneous sensory nerves, specifically C‐type or Aδ type fibres. 33 , 34 , 35 , 36 Moreover, CGRP is also released from sensory nerves during inflammation. 37 In rodent skin, UVB radiation, which is a known trigger for rosacea, can increase both CGRP and epidermal thickness. 38
The pathophysiology of rosacea involves neurogenic vasodilation induced and sustained by inflammatory mediators such as CGRP as well as modulation of both the innate and adaptive immune system. 10 CGRP release leads to inflammation, resulting in increased microvascular permeability, 11 vasodilation, 12 , 13 oedema, blood flow increase and recruitment of inflammatory cells. 14 , 15 , 16 In mice, local administration of capsaicin in the ear induces CGRP‐dependent blood flow increase and plasma extravasation with subsequent oedema. 17 , 18 In humans, topical application of capsaicin can induce release of CGRP, 19 possibly through activation of TRPV1. 20 Interestingly, capsaicin‐induced vasodilation in both monkeys 21 and humans 22 is inhibited by CGRP‐receptor antagonism, and an oral CGRP‐antagonist has been shown to inhibit capsaicin‐induced skin vasodilation in humans. 22 CGRP has been linked to several features that govern the cell biology of rosacea, including toll‐like receptors (TLR) 2 and 4, nuclear factor Kappa‐B (NF‐κB) and myeloid differentiation factor 88. 10 , 23 In vitro and in vivo studies in rodents show that CGRP is colocalized in neurons 24 and can modulate TLR4 to enhance expression of interleukin (IL)‐10 in bone marrow‐derived macrophages from rodents. 25 Interestingly, blocking TLR4 can downregulate nuclear factor Kappa‐B (NF‐κB) and myeloid differentiation factor 88, 24 which have both been found upregulated in biopsies from patients with ocular rosacea. 26 , 27 In vitro studies in rodents show that macrophage depletion can ameliorate rosacea‐like skin inflammation, possibly via the NF‐κB‐signalling pathway 28 Interestingly, NF‐κB seems to be involved in the IL18 pathway which also seems to be relevant in rosacea inflammation pathway with increased mast cells in rosacea. 29 Interestingly, dietary supplement with an omega‐3 fatty acid may ameliorate skin inflammation via the TLR2/MyD88/NF‐κB pathway. 30
A study compared facial skin biopsies from 26 individuals with the rosacea subtype ETR, 20 individuals with normal photoaging as well as 11 healthy controls, and found significantly higher levels of CGRP in ETR skin compared with normal photoaging and healthy controls. 31 Notably, we did not find any impact of current rosacea treatment on CGRP levels. While somewhat unsurprising for topical treatments, due to limited systemic absorption over a small area (face), the apparent lack of impact of oral therapies (e.g. tetracycline‐class agents) on CGRP levels could, at least in theory, suggest that CGRP levels in rosacea patients are unaffected by this type of therapy (which typically targets inflammatory lesions rather that erythema). However, although speculative, it is also possible that rosacea‐therapeutic dosages of these drugs are simply too small to exert a measurable change in CGRP levels.
In our study, we observed elevated levels of CGRP in the plasma in individuals with all subtypes of rosacea. However, we found no difference between subtypes/phenotypes or severity of rosacea. Interestingly, local administration of CGRP has been shown to induce reddening of the human skin 32 and even low doses of intravenously administered CGRP can cause flushing. 32 While CGRP is primarily known for its vasodilatory effects, recent studies suggest that it may also exhibit nociceptive effects in the trigeminovascular system. 32 This raises the possibility that CGRP might be involved in the painful attacks of flushing associated with burning and stinging in individuals with rosacea, although further research is needed to confirm this. Our study revealed increased CGRP plasma levels in all subtypes of rosacea, with no difference between subtypes or severities of the disease. However, as CGRP is also increased in other diseases, such as migraine, 33 it might not be a viable biomarker in rosacea, and we cannot rule out the possibility that CGRP may be acting as an innocent bystander to another target. Nevertheless, our findings suggest that CGRP plays an important role in rosacea pathophysiology, and future treatments targeting CGRP or its receptors could prove to be beneficial in rosacea. Interestingly, CGRP plasma levels have been shown to negatively correlate with treatment response in individuals with migraine treated with CGRP antibodies 34 and it would be interesting to investigate whether this holds true for individuals with rosacea. The finding of a negative association between levels of CGRP and rosacea duration in years suggests that early intervention might be important for controlling the disease. However, future studies involving larger populations of rosacea are needed to determine the significance of CGRP in rosacea.
Our study groups significantly differed in age and sex, although there were no significant differences in BMI between groups. In the groups with rosacea (with and without migraine), participants were significantly older than in the healthy group (approximately 10 years difference between each group). Data on age‐related CGRP level changes in healthy group are incomplete. One study comparing plasma CGRP in healthy people and patients with posttraumatic headache shows no signal in CGRP changes with age in healthy individuals. 35 In vitro studies in rodents show that CGRP concentration in multiple tissues including areas of the brain, bladder, kidney and testes declines with age. 36 , 37 , 38 Another study found plasma levels of CGRP in rodents to be unaffected by age, 39 whereas one study found plasma levels of CGRP to be increased in older rodents. 38 In our data set we failed to find any age‐dependent difference in plasma CGRP levels in neither patients with rosacea nor in healthy controls.
Strengths and limitations
Our study has several strengths including a large sample size and extensive phenotyping into severities and subgroups of rosacea. However, we also acknowledge some limitations including individuals with rosacea often having coexisting migraine which is a possible confounder. Nevertheless, we demonstrated that rosacea independently correlates with increased levels of CGRP. Participants were not age‐, sex‐ or BMI‐matched; however, previous studies have not shown a correlation between CGRP levels and age or sex in healthy controls 33 , 35 and we found no correlation between CGRP levels and BMI in neither healthy controls nor individuals with rosacea in our study.
CONCLUSIONS
Our study provides evidence that plasma levels of CGRP are elevated in individuals with rosacea compared with healthy controls. However, we did not find a correlation between CGRP levels and rosacea severity or subtype, indicating that CGRP might not be a reliable biomarker for diagnosis or assessing the severity of rosacea. Nevertheless, our findings suggest that CGRP might be involved in the pathophysiology of rosacea. Further research is thus needed to investigate the potential of medications targeting CGRP signalling in managing rosacea.
AUTHOR CONTRIBUTIONS
Nita K. F. Wienholtz: Study concept and design, acquisition of data, data curation, analysis (including statistical analyses) and interpretation, drafting of the manuscript. Casper E. Christensen: Study concept and design, analysis (including statistical analyses) and interpretation, critical revision of the manuscript for important intellectual content. Håkan Ashina: Acquisition of data, critical revision of the manuscript for important intellectual content. Niklas R. Jørgensen: Blood sample analyses, critical revision of the manuscript for important intellectual content. Alexander Egeberg: Study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content. Jacob P. Thyssen: Study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content. Messoud Ashina: Study concept and design, funding acquisition, interpretation of data, critical revision of the manuscript for important intellectual content.
FUNDING INFORMATION
This study was supported by grants from Novo Nordisk Foundation (NNF170C0029698). MA was supported by the Lundbeck Foundation professor grant (R310‐2018‐3711).
CONFLICT OF INTEREST STATEMENT
Nita K. F. Wienholtz reports no conflicts of interest. Casper E. Christensen reports personal fees as consultant and speaker from Teva pharmaceuticals. Håkan Ashina reports personal fees from Teva, outside of the submitted work. Niklas R. Jørgensen reports no conflict of interest. Alexander Egeberg has received honoraria as consultant and/or speaker from AbbVie, Almirall, Bristol‐Meyers Squibb, Leo Pharma, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals and being an employee of LEO pharma outside the submitted work. Jacob P. Thyssen is an advisor for AbbVie, Almirall, Arena Pharmaceuticals, Coloplast, OM Pharma, ASLAN Pharmaceuticals, Union Therapeutics, Eli Lilly and Company, LEO Pharma, Pfizer, Regeneron and Sanofi Genzyme; a speaker for AbbVie, Almirall, Eli Lilly and Company, LEO Pharma, Pfizer, Regeneron and Sanofi Genzyme; has received research grants from Pfizer, Regeneron and Sanofi Genzyme and being an employee of LEO pharma outside the submitted work. Messoud Ashina reports receiving personal fees from AbbVie, Amgen, Eli Lilly, Lundbeck, Novartis, Pfizer and Teva Pharmaceuticals during the conduct of the study. MA reports serving as associate editor of Cephalalgia, associate editor of The Journal of Headache and Pain and associate editor of Brain.
ETHICAL APPROVAL
This study was approved by the Health Research Ethics Committee of the Capital Region of Denmark (H‐17023750) and the Danish Data Protection Agency (I‐suite: 05694).
ACKNOWLEDGEMENTS
We thank all participants for their time and contribution to this study. We would also like to thank clinical project coordinator Britt Corfixen for her contribution to analysis of the data as well the staff members at Danish Headache Center, Rigshospitalet Glostrup, Department of Dermatology and Allergy at Gentofte hospital and Department of Dermatology and Wound Healing at Bispebjerg hospital.
Wienholtz NKF, Christensen CE, Ashina H, Jørgensen N, Egeberg A, Thyssen JP, et al. Elevated plasma levels of calcitonin gene‐related peptide in individuals with rosacea: A cross‐sectional case–control study. J Eur Acad Dermatol Venereol. 2025;39:181–188. 10.1111/jdv.19954
DATA AVAILABILITY STATEMENT
Data are available upon reasonable request from the corresponding author.
REFERENCES
- 1. Gallo RL, Granstein RD, Kang S, Mannis M, Steinhoff M, Tan J, et al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee. J Am Acad Dermatol. 2018;78(1):148–155. [DOI] [PubMed] [Google Scholar]
- 2. Headache Classification Committee of the International Headache Society (IHS) . Headache classification Committee of the International Headache Society (IHS) the international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. [DOI] [PubMed] [Google Scholar]
- 3. Wienholtz NKF, Christensen CE, Haugaard JH, Zhang DG, Ashina M, Thyssen JP, et al. Cohort profile : COpenhagen ROsacea COhort (COROCO) and COpenhagen MIgraine COhort (COMICO). BMJ Open. 2020;10(8):e039445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Schifter S. Circulating concentrations of calcitonin gene‐related peptide (CGRP) in Normal man determined with a new, highly sensitive radioimmunoassay. Peptides. 1991;12:365–369. [DOI] [PubMed] [Google Scholar]
- 5. Guo S, Vollesen ALH, Hansen YBL, Frandsen E, Andersen MR, Amin FM, et al. Part II: biochemical changes after pituitary adenylate cyclase‐activating polypeptide‐38 infusion in migraine patients. Cephalalgia. 2017;37(2):136–147. [DOI] [PubMed] [Google Scholar]
- 6. Snoer A, Vollesen A, Beske R, Guo S, Hoffmann J, Fahrenkrug J, et al. Calcitonin‐gene related peptide and disease activity in cluster headache. Cephalalgia. 2019;39(5):575–584. [DOI] [PubMed] [Google Scholar]
- 7. Wienholtz N, Thyssen J, Christensen C, Thomsen S, Karmisholt K, Jemec G, et al. Validity and reliability of the rosacea area and severity index (RASI): a scoring system for clinical assessment of rosacea severity. J Eur Acad Dermatol Venereol. 2023;37(3):573–580. [DOI] [PubMed] [Google Scholar]
- 8. Tan J, Liu H, Leyden JJ, Leoni MJ. Reliability of clinician erythema assessment grading scale. J Am Acad Dermatol. 2014;71:760–763. [DOI] [PubMed] [Google Scholar]
- 9. Scholzen T, Armstrong CA, Bunnett NW, Luger TA, Olerud JC, Ansel JE. Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems. Exp Dermatol. 1998;7(2–3):81–96. [DOI] [PubMed] [Google Scholar]
- 10. Steinhoff M, Urgen Schauber J, Leyden JJ, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013;69(6 SUPPL.1):15–26. [DOI] [PubMed] [Google Scholar]
- 11. Cao T, Pintér E, Al‐rashed S, Gerard N, Hoult JR, Brain SD. Neurokinin‐1 receptor agonists are involved in mediating neutrophil accumulation in the inflamed, but not normal, cutaneous microvasculature: an in vivo study using Neurokinin‐1 receptor knockout mice. J Immunol. 2000;164:5425–5429. [DOI] [PubMed] [Google Scholar]
- 12. Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I. Calcitonin gene‐related peptide is a potent vasodilator. Nature. 1985;313(5997):54–56. [DOI] [PubMed] [Google Scholar]
- 13. Akaishi S, Ogawa R, Hyakusoku H. Keloid and hypertrophic scar : neurogenic inflammation hypotheses. Med Hypotheses. 2008;71:32–38. [DOI] [PubMed] [Google Scholar]
- 14. Kawasaki H, Takasaki K, Saito A, Goto K. Calcitonin gene‐related peptide acts as a novel vasodilator neurotransmitter in mesenteric resistance vessels of the rat. Nature. 1988;335:164–167. [DOI] [PubMed] [Google Scholar]
- 15. Fujimori A, Saito A, Kimura S, Watanabe T, Uchiyama Y, Kawasaki H, et al. Neurogenic vasodilation and release of calcitonin gene‐related peptide (CGRP) from perivascular nerves in the rat mesenteric artery. Biochem Biophys Res Commun. 1989;165(3):1391–1398. [DOI] [PubMed] [Google Scholar]
- 16. Han S‐P, Naes L, Westfall TC. Inhibition of periarterial nerve stimulation‐induced vasodilation of the mesenteric arterial bed by CGRP (8‐37) and CGRP receptor desensitization. Biochem Biophys Res Commun. 1990;168(2):786–791. [DOI] [PubMed] [Google Scholar]
- 17. Starr A, Graepel R, Keeble J, Schmidhuber S, Clark N, Grant A, et al. A reactive oxygen species‐mediated component in neurogenic vasodilatation. Cardiovasc Res. 2008;78(1):139–147. [DOI] [PubMed] [Google Scholar]
- 18. Grant AD, Gerard NP, Brain SD. Evidence of a role for NK1and CGRP receptors in mediating neurogenic vasodilatation in the mouse ear. Br J Pharmacol. 2002;135(2):356–362. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Anand U, Otto WR, Casula MA, Day NC, Davis JB, Bountra C, et al. The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons. Neurosci Lett. 2006;399(1–2):51–56. [DOI] [PubMed] [Google Scholar]
- 20. Aubdool AA, Brain SD. Neurovascular aspects of skin neurogenic inflammation. J Investig Dermatol Symp Proc. 2011;15(1):33–39. [DOI] [PubMed] [Google Scholar]
- 21. Hershey JC, Corcoran HA, Baskin EP, Salvatore CA, Mosser S, Williams TM, et al. Investigation of the species selectivity of a nonpeptide CGRP receptor antagonist using a novel pharmacodynamic assay. Regul Pept. 2005;127:71–77. [DOI] [PubMed] [Google Scholar]
- 22. Sinclair SR, Kane SA, Van Der Schueren BJ, Xiao A, Willson KJ, Boyle J, et al. Inhibition of capsaicin‐induced increase in dermal blood flow by the oral CGRP receptor antagonist, telcagepant (MK‐0974). Br J Clin Pharmacol. 2009;69(1):15–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Moura A, Karina A, Guedes F, Rivitti‐Machado MC, Sotto MN. Inate immunity in rosacea. Langerhans cells, plasmacytoid dentritic cells, toll‐like receptors and inducible oxide nitric synthase (iNOS) expression in skin specimens: case‐control study. Arch Dermatol Res. 2018;310(2):139–146. [DOI] [PubMed] [Google Scholar]
- 24. Lin J‐J, Du Y, Cai W‐K, Kuang R, Chang T, Zhang Z, et al. Toll‐like receptor 4 signaling in neurons of trigeminal ganglion contributes to nociception induced by acute pulpitis in rats. Sci Rep. 2015;5:12549. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Baliu‐Piqué M, Jusek G, Holzmann B. Neuroimmunological communication via CGRP promotes the development of a regulatory phenotype in TLR4‐stimulated macrophages. Eur J Immunol. 2014;44(12):3708–3716. [DOI] [PubMed] [Google Scholar]
- 26. Wladis EJ, Arunachalam T, LaJoie J, Lau KW, Adam AP. Myeloid differentiation factor 88 expression in eyelid specimens of rosacea. Orbit. 2022;41(3):329–334. [DOI] [PubMed] [Google Scholar]
- 27. Wladis EJ, Lau KW, Adam AP. Nuclear factor kappa‐B is enriched in eyelid specimens of rosacea: implications for pathogenesis and therapy. Am J Ophthalmol. 2019;201:72–81. [DOI] [PubMed] [Google Scholar]
- 28. Zhou L, Zhao H, Zhao H, Meng X, Zhao Z, Xie H, et al. GBP5 exacerbates rosacea‐like skin inflammation by skewing macrophage polarization towards M1 phenotype through the NF‐κB signalling pathway. J Eur Acad Dermatol Venereol. 2023;37(4):796–809. [DOI] [PubMed] [Google Scholar]
- 29. Wang X, Wang L, Wen X, Zhang L, Jiang X, He G. Interleukin‐18 and IL‐18BP in inflammatory dermatological diseases. Front Immunol. 2023;14. 10.3389/fimmu.2023.955369 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Shen S, Yan G, Cao Y, Zeng Q, Zhao J, Wang X, et al. Dietary supplementation of n‐3 PUFAs ameliorates LL37‐induced rosacea‐like skin inflammation via inhibition of TLR2/MyD88/NF‐κB pathway. Biomed Pharcother. 2023;157:114091. [DOI] [PubMed] [Google Scholar]
- 31. Helfrich YR, Maier LE, Cui Y, Fisher GJ, Chubb H, Fligiel S, et al. Clinical, histologic, and molecular analysis of differences between erythematotelangiectatic rosacea and telangiectatic photoaging. JAMA Dermatol. 2015;151(8):825–836. [DOI] [PubMed] [Google Scholar]
- 32. Brain SD, Cox HM. Neuropeptides and their receptors: innovative science providing novel therapeutic targets. Br J Pharmacol. 2006;147:202–211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Cernuda‐Morollón E, Larrosa D, Ramón C, Vega J, Martínez‐Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013;81(14):1191–1196. [DOI] [PubMed] [Google Scholar]
- 34. Lentsch SDV, Garrelds IM, Danser AHJ, Terwindt GM, Maassenvandenbrink A. Serum CGRP in migraine patients using erenumab as preventive treatment. J Headache Pain. 2022;23(120):1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Ashina H, Al‐Khazali HM, Iljazi A, Ashina S, Jørgensen NR, Amin FM, et al. Low plasma levels of calcitonin gene‐related peptide in persistent post‐traumatic headache attributed to mild traumatic brain injury. Cephalalgia. 2020;40(12):1276–1282. [DOI] [PubMed] [Google Scholar]
- 36. Rubino A, Burnstock G. Capsaicin‐sensitive sensory‐motor neurotransmission in the peripheral control of cardiovascular function. Cardiovasc Res. 1996;31(4):467–479. [PubMed] [Google Scholar]
- 37. Kawasaki H, Saito A, Takasaki K. Age‐related decrease of calcitonin gene‐related peptide‐containing vasodilator innervation in the mesenteric resistance vessel of the spontaneously hypertensive rat. Circ Res. 1990;67(3):733–743. [DOI] [PubMed] [Google Scholar]
- 38. Wimalawansa S. Age‐related changes in tissue contents of immunoreactive calcitonin gene‐related peptide. Aging. 1992;4(3):211–217. [DOI] [PubMed] [Google Scholar]
- 39. Lu R, Zhu H‐Q, Peng J, Li N‐S, Li Y‐J. Endothelium‐dependent vasorelaxation and the expression of calcitonin gene‐related peptide in aged rats. Neuropeptides. 2002;36(6):407–412. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data are available upon reasonable request from the corresponding author.