Clinical, Histologic, and Molecular Analysis of Differences Between Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

Helfrich, Yolanda; Maier, Lisa E.; Cui, Yaqiong; Fisher, Gary J.; Chubb, Heather; Fligiel, Suzanne E. G.; Sachs, Dana L.; Varani, James; Voorhees, John J.

doi:10.1001/jamadermatol.2014.4728

Cited by 73 publications

(73 citation statements)

References 34 publications

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“…1 Moreover, photodistributed, mostly vasodilator drug-related telangiectasia underscores the potential role for actinic exposure in the pathogenesis of telangiectasia. 6 Yano et al 7 and Kajiya et al, 8 in exploring the mechanisms of acute UV-B-induced angiogenesis and photodamage in human skin, demonstrated the consequent epidermal hyperplasia, infiltration of elastin-producing neutrophils, and elastin fiber damage, along with a significant increase in both vascular density and vessel size, features consistent with the proposed pathogenesis of ETR 1 as well as the cutaneous signs of telangiectatic photoaging (TP), as described by Helfrich et al 9 There are now plausible molecular links for clinically well-recognized rosacea triggers, including actinic damage, with the proposed inflammatory vascular pathogenesis of rosacea, beginning with ETR. 1 However, not everyone agrees that rosacea begins with ETR or that ETR is even a subtype of rosacea.…”

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confidence: 62%

“…1 However, not everyone agrees that rosacea begins with ETR or that ETR is even a subtype of rosacea. Helfrich et al 9 remind us that ETR is probably the most disputed subtype of rosacea, with some authors arguing that it is merely photodamage or, at least, difficult to distinguish from photodamage. This is a curious twist given that rosacea was first recognized as a distinct facial dermatosis separate from common acne (acne vulgaris) by virtue of its rosy hue (acne rosacea).…”

mentioning

confidence: 99%

“…The cheek is then examined for the sum of all 3 factors, and the contribution attributable to rosacea is often pink, actually rosy, with or without fine wispy telangiectases. This calculus of rough apportionment of erythema might now be reconsidered, and possibly simplified, in light of the observation by Helfrich et al 9 that ETR is more centrally facial, and telangiectatic photoaging more laterally facial. Such an apportionment of erythema and finer definition of ETR, if confirmed, may favorably affect regulatory criteria for approval of drug products for rosacea or its subgroup(s) by providing a more rational basis for the clinical descriptions within the investigator's global assessment (IGA) for efficacy end points and also for inclusion and exclusion criteria for pivotal clinical trials.…”

mentioning

confidence: 99%

“…The potential for this article by Helfrich et al 9 to provide an improved understanding and clinical recognition of ETR depends on how well ETR and TP were distinguished from each other. Excluding subjects with both photodamage and flushing was a necessity.…”

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Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

Wilkin

2015

JAMA Dermatol

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confidence: 99%

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Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

Wilkin

2015

JAMA Dermatol

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“…In this study, treatment with a brimonidine gel was as- and matrix metalloproteinase-9 (MMP-9), which are important in the pathogenesis of rosacea. [7,8] Furthermore, the number of MCs is increased in skin lesions of patients with rosacea, and inhibition of this increased MC activity has been suggested as a potential treatment for rosacea. [9] Interestingly, we found an increase in mRnA levels of chymase and tryptase in the MCs in mouse skin injected with LL-37, which was consistent with previous study by Muto et al [4] In addition, Muto et al suggested that MCs play an important role in the development of rosacea by demonstrating that MC stabilizers improve rosacea phenotype by decreasing MMP activity and MC proteases (chymase and tryptase) in both rosacea-induced mouse model and patients with rosacea.…”

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Inhibition of mast cell infiltration in an LL‐37‐induced rosacea mouse model using topical brimonidine tartrate 0.33% gel

Kim

Jeong

et al. 2017

Experimental Dermatology

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Brimonidine is a highly selective α2-adrenergic receptor agonist approved by the FDA for the treatment of rosacea. Rosacea is a major clinical disease with vasodilatation and rash on the centre of the face, and that brimonidine as a vasoconstrictor can act as a remedy for rosacea. However, there is no study of how brimonidine has an effect on rosacea-related immune cells or mechanisms in the skin to improve rosacea. In this study, we observed that clinical features of rosacea induced by LL-37 in Balb/c mice were improved after the application of brimonidine gel, and we also showed a marked decrease in the number of inflammatory cells, especially mast cells (MCs) histologically. Furthermore, we confirmed that mRnA levels of MC enzymes increased by LL-37 were reduced by brimonidine gel. To our knowledge, we first found that brimonidine has a mechanism of treating rosacea by reducing the number and mRnA levels of MC-specific enzymes, an important immune cell in the pathogenesis of rosacea. | BACKGROUNDRosacea is a common chronic inflammatory skin disease characterized by telangiectasia and flushing.[1] The erythema of rosacea is thought to result from abnormal cutaneous vasomotor activity in the central part of the face. Brimonidine tartrate 0.33% gel (Mirvaso gel; Galderma, Lausanne, Switzerland), a highly selective α2-adrenergic receptor agonist, was recently recommended for the treatment of persistent facial erythema in patients with rosacea due to its potent vasoconstrictive effects. [2] Several clinical studies have demonstrated that brimonidine rapidly improves facial flushing and erythema. [2,3] However, the molecular and histological effects of brimonidine on rosacea remain largely unknown. Although the vasoconstrictive property of brimonidine gel has been suggested to contribute to the therapeutic effect, it was assumed that not only contracting the expanded blood vessels would act on the therapeutic mechanism. | QUESTION ADDRESSEDThe aims of this study were to investigate the histological changes and gene expression levels in rosacea-like skin lesions when applied with brimonidine and to identify the role of brimonidine gel in the pathogenesis of rosacea. In this study, we investigated whether brimonidine gel could influence the number of mast cells (MCs) and mRnA levels of tryptase and chymase by evaluating the response of topical application of brimonidine gel to rosacea-like skin lesions in mice. | EXPERIMENTAL DESIGNThirty-five 7-week-old female Balb/c mice were used in this study (Dooyeol Biotech, Seoul, Korea). The experimental protocol was approved by the Animal Care Committee of Catholic University of Korea. The mice were divided into three groups: control (n=11), LL-37 (n=12), and LL-37 plus brimonidine (LL-37+ brimonidine; n=12). The mice in the LL-37 and LL-37+ brimonidine groups had LL-37 injected intradermally into shaved back skin to induce rosacea-like skin lesions.Immediately after the injection of LL-37 (40 μL), the mice in the LL-37+ brimonidine group had brimonidine tartrate 0.3...

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Erenumab for Treatment of Persistent Erythema and Flushing in Rosacea

Wienholtz,

Christensen,

et al. 2024

JAMA Dermatol

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ImportanceTreatment 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.ObjectiveTo 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 ParticipantsThis 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.Intervention140 mg of erenumab every 4 weeks for 12 weeks.Main Outcomes and MeasuresThe 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.ResultsA 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 &lt; .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 &lt; .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 RelevanceThese 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 RegistrationClinicalTrials.gov Identifier: NCT04419259

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Clinical, Histologic, and Molecular Analysis of Differences Between Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

Cited by 73 publications

References 34 publications

Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

Erythematotelangiectatic Rosacea and Telangiectatic Photoaging

Inhibition of mast cell infiltration in an LL‐37‐induced rosacea mouse model using topical brimonidine tartrate 0.33% gel

Erenumab for Treatment of Persistent Erythema and Flushing in Rosacea

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