Rosacea

Complex MONDO:0006604 Pathograph 29 Dermatological Disease Inflammatory Skin Disease

Rosacea is a chronic relapsing inflammatory facial dermatosis centered on persistent or episodic centrofacial erythema, flushing, telangiectasia, and papulopustular lesions, with phymatous and ocular involvement in a subset of patients. Current mechanistic models emphasize dysregulated innate immunity, neurovascular hyperreactivity, skin barrier impairment, and trigger-dependent disease amplification.

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Mappings
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Definitions
0
Inheritance
18
Pathophysiology
6
Histopathology
9
Phenotypes
29
Pathograph
8
Genes
8
Treatments
4
Subtypes
6
Differentials
4
Datasets
4
Trials
0
Models
1
Literature
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Subtypes

4
Erythematotelangiectatic Rosacea
Predominantly vascular rosacea phenotype characterized by persistent centrofacial erythema, flushing, and telangiectasia without dominant papulopustular or phymatous change.
Show evidence (2 references)
PMID:28150107 SUPPORT Human Clinical
"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
This review explicitly recognizes erythematotelangiectatic rosacea as one of the four canonical clinical subtypes.
PMID:27718519 SUPPORT Human Clinical
"The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
This phenotype-led consensus supports the core vascular features that anchor erythematotelangiectatic rosacea.
Papulopustular Rosacea
Inflammatory rosacea subtype with persistent facial erythema accompanied by papules and pustules in the central face.
Show evidence (2 references)
PMID:28150107 SUPPORT Human Clinical
"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
This review explicitly recognizes papulopustular rosacea as a major clinical subtype.
PMID:28150107 SUPPORT Human Clinical
"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
This supports the inflammatory papule-pustule phenotype that defines papulopustular rosacea.
Phymatous Rosacea
Tissue-remodeling subtype marked by thickening and hypertrophy of facial skin and sebaceous structures, most commonly affecting the nose as rhinophyma.
Show evidence (2 references)
PMID:28150107 SUPPORT Human Clinical
"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
This review explicitly recognizes phymatous rosacea as one of the canonical clinical subtypes.
PMID:41918801 SUPPORT Human Clinical
"Phymatous rosacea (PhR), also known as "rhinophyma", refers to a benign condition characterized by the excessive proliferation of sebaceous glands and fibrosis in the facial skin due to rosacea"
This supports the hypertrophic and fibrotic tissue-remodeling pattern characteristic of phymatous rosacea.
Ocular Rosacea
Ocular subtype involving chronic inflammatory disease of the eyelids and ocular surface, often with blepharitis, meibomian dysfunction, dryness, and photophobia.
Show evidence (2 references)
PMID:28150107 SUPPORT Human Clinical
"Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
This review explicitly recognizes ocular rosacea as a canonical rosacea subtype.
PMID:40522449 SUPPORT Human Clinical
"Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."
This supports ocular rosacea as a distinct subtype centered on eyelid and ocular surface inflammation.
📚

References

30
PMID:41918801
CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report.
No top-level findings curated for this source.
PMID:41695827
Rosacea overlapping the malar rash: A diagnostic challenge in early systemic lupus erythematosus.
No top-level findings curated for this source.
PMID:41694889
Facial Swelling in a Young Adult With Type 1 Diabetes: Morbihan Disease as a Scleroderma Mimic.
No top-level findings curated for this source.
PMID:41426892
Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case.
No top-level findings curated for this source.
PMID:41222206
Unilateral presentation of Morbihan's disease: a comprehensive case report and review.
No top-level findings curated for this source.
PMID:41058755
Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea.
No top-level findings curated for this source.
PMID:41017054
Cutaneous Coccidioidomycosis Mimicking Rosacea in Immunosuppressed Patient, Arizona, USA, 2024.
No top-level findings curated for this source.
PMID:40860281
Rhinophyma treated by skin graft: a case report.
No top-level findings curated for this source.
PMID:40827152
Recurrent Periocular Nodules: Lymphomatoid Papulosis in an Uncommon Anatomic Site.
No top-level findings curated for this source.
PMID:40791837
Rhinophyma Treatment with Blue Laser.
No top-level findings curated for this source.
PMID:41909715
Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq.
No top-level findings curated for this source.
PMID:41800255
Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea.
No top-level findings curated for this source.
PMID:41562711
Increased Expression of Angiopoietin 2 and Tie2 in Rosacea.
No top-level findings curated for this source.
PMID:41203722
Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea.
No top-level findings curated for this source.
PMID:41139274
Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy.
No top-level findings curated for this source.
PMID:41087666
LAPTM5 exacerbates STING-mediated inflammation induced by LL-37 through stabilizing STING in rosacea.
No top-level findings curated for this source.
PMID:40890957
Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation.
No top-level findings curated for this source.
PMID:40835085
Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway.
No top-level findings curated for this source.
PMID:40635520
Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea.
No top-level findings curated for this source.
PMID:40567003
Novel Molecular Subtyping Revealed Molecular Pathways That Contribute to the Pathogenesis of Rosacea.
No top-level findings curated for this source.
PMID:11582639
[Rosacea in the year 2001].
No top-level findings curated for this source.
PMID:27718519
Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel.
No top-level findings curated for this source.
PMID:28150107
Acne and Rosacea.
No top-level findings curated for this source.
PMID:34035646
Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models.
No top-level findings curated for this source.
PMID:35392024
Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea.
No top-level findings curated for this source.
PMID:37626650
Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates.
No top-level findings curated for this source.
PMID:39823143
Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments.
No top-level findings curated for this source.
PMID:40522449
[Ocular rosacea : Clinical aspects, diagnostics, management and treatment].
No top-level findings curated for this source.
PMID:25151931
[Physiopathology of rosacea].
No top-level findings curated for this source.
PMID:19428039
[Rhinophyma in a black African male patient].
No top-level findings curated for this source.
⚙

Pathophysiology

18
Skin barrier dysfunction
Epidermal barrier disruption amplifies inflammatory signaling in rosacea and serves as an early permissive event for downstream innate immune activation.
keratinocyte link
establishment of skin barrier link
Show evidence (1 reference)
PMID:35392024 SUPPORT Human Clinical
"our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
This study establishes barrier dysfunction as a disease-amplifying mechanism in rosacea.
Pro-cathelicidin transcription
Keratinocytes in rosacea upregulate pro-cathelicidin transcription, creating substrate for downstream proteolytic generation of inflammatory peptides.
keratinocyte link
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"The sequence of innate immune activation in rosacea starts with factors increasing keratinocyte transcription of pro-cathelicidin"
This review explicitly places pro-cathelicidin transcription near the start of rosacea innate immune activation.
TLR2 upregulation
Keratinocyte TLR2 expression is increased in rosacea and sensitizes skin to environmental and microbial stimuli.
keratinocyte link
Show evidence (1 reference)
PMID:39823143 SUPPORT In Vitro
"Specifically, Toll-like receptor 2 (TLR2) and S100A9 proteins were upregulated, potentially promoting these processes."
This study supports increased TLR2 expression as part of rosacea inflammatory activation.
KLK5/KLK7 activation
Kallikrein-family serine proteases are activated downstream of TLR2 and participate in cathelicidin processing.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"the serine proteases of the KLK family, KLK5 and KLK7 (activation mediated by TLR-2, which is upregulated by environmental and microbial stimuli)"
This review identifies KLK5/KLK7 as activated proteases in rosacea innate immune signaling.
LL-37 generation
Proteolytic cathelicidin processing yields LL-37 and related peptides with inflammatory and angiogenic activity.
inflammatory response link angiogenesis link
Show evidence (3 references)
PMID:28150107 SUPPORT Human Clinical
"This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
This review identifies LL-37 generation as a key inflammatory and angiogenic step in rosacea.
PMID:40835085 SUPPORT In Vitro
"Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea."
This study reinforces LL-37 overexpression as a central proximal mechanism in rosacea biology.
PMID:41087666 SUPPORT Model Organism
"Both STING antagonist H-151 and LAPTM5 knockdown alleviate LL-37-induced rosacea-like phenotypes."
This model-organism evidence supports LL-37 as a proximal inducer of rosacea-like inflammatory disease programs.
Mast cell-mediated amplification
Mast cells amplify cathelicidin-initiated inflammation and increase local vasodilation within rosacea lesions.
mast cell link
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation—amplifying inflammation, vasodilation, and generation of LL-37"
This review places mast cells in an amplification loop that increases inflammatory and vascular disease activity.
STAT3-mediated cytokine signaling
Keratinocyte STAT3-centered cytokine signaling links barrier injury to inflammatory persistence and immune-cell recruitment.
keratinocyte link
cytokine-mediated signaling pathway link
Show evidence (1 reference)
PMID:35392024 SUPPORT Human Clinical
"our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
This study identifies STAT3-mediated cytokine signaling as a key inflammatory amplifier in rosacea.
Immune cell infiltration
Rosacea lesions show increased immune-cell infiltration that reinforces inflammatory lesion formation.
Show evidence (1 reference)
PMID:35392024 SUPPORT Human Clinical
"The XCell immune cell assays showed that the increased immune infiltration with SBD."
This transcriptomic analysis supports increased immune-cell infiltration in rosacea with barrier dysfunction.
Th1/Th17 adaptive inflammation
Chemokine and cytokine networks in rosacea polarize adaptive immunity toward Th1/Th17 inflammatory programs.
inflammatory response link
Show evidence (2 references)
PMID:28150107 SUPPORT Human Clinical
"Chemokine and cytokine signals interact to generate a Th1/Th17-polarized adaptive immune response in rosacea"
This review supports a Th1/Th17-polarized adaptive inflammatory response in rosacea.
PMID:40835085 SUPPORT In Vitro
"T-cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure."
This supports a chemokine-driven adaptive immune arm linking keratinocyte activation to pathogenic T-cell recruitment.
TRP and neuropeptide signaling
TRP-channel activation and neuropeptide signaling form a neurocutaneous branch of rosacea pathophysiology that increases vascular reactivity.
neuropeptide signaling pathway link
Show evidence (1 reference)
PMID:34035646 SUPPORT Human Clinical
"Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides"
This review identifies TRP and neuropeptides as part of the neurovascular arm of rosacea pathophysiology.
Neurovascular vasodilation
Exaggerated vasodilation is a proximal vascular event that drives flushing and contributes to persistent background erythema.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"while the multifactorial pathology of rosacea is thought to involve both vasoactive and neurocutaneous mechanisms."
This overview supports a vasoreactive proximal mechanism in rosacea.
Angiogenic vascular remodeling
Angiogenic signaling contributes to persistent vascular remodeling and visible superficial telangiectatic change.
angiogenesis link
Show evidence (2 references)
PMID:28150107 SUPPORT Human Clinical
"This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
This supports angiogenic signaling as a discrete downstream consequence of cathelicidin pathway activation.
PMID:40567003 SUPPORT Computational
"angiogenesis and neutrophil activation may contribute to persistent erythema and a large number of papules and pustules in the severe stage of rosacea."
This molecular subtyping study supports angiogenesis as a driver of persistent erythema and lesion-rich severe rosacea.
Papulopustular inflammation
Convergent innate, adaptive, and keratinocyte inflammatory programs produce inflammatory papules and pustules in papulopustular rosacea.
inflammatory response link
Show evidence (1 reference)
PMID:39823143 SUPPORT Human Clinical
"Transcriptomic analysis revealed significantly elevated expression of inflammatory-related genes in rosacea patients."
This study supports a lesion-forming inflammatory state in rosacea skin.
Sebaceous gland dysfunction
Dysfunction of cutaneous sebaceous glands is recognized as part of the multifactorial tissue biology of rosacea.
Show evidence (1 reference)
PMID:34035646 SUPPORT Human Clinical
"Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of..."
This review identifies sebaceous gland dysfunction as a discrete component of rosacea pathophysiology.
Meibomian gland dysfunction
Ocular rosacea includes meibomian gland dysfunction as part of its site-specific pathophysiology.
Show evidence (1 reference)
PMID:34035646 SUPPORT Human Clinical
"Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of..."
This review identifies meibomian gland dysfunction as part of ocular rosacea biology.
Ocular surface and eyelid inflammation
Ocular rosacea produces chronic inflammatory involvement of the eyelids and ocular surface, with posterior blepharitis as a characteristic clinical expression.
inflammatory response link
Show evidence (1 reference)
PMID:40522449 SUPPORT Human Clinical
"Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."
This review supports ocular rosacea as an inflammatory disease of the eyelids and ocular surface.
Fibrotic dermal remodeling
Advanced rosacea can shift toward a fibrotic remodeling program in which vascular changes are coupled to connective-tissue fibrosis.
Show evidence (2 references)
PMID:25151931 SUPPORT Human Clinical
"Finaly, rhinophyma is linked to both vascular changes and activation of fibrosis, involving TGF beta."
This review supports fibrosis as a specific mechanism underlying rhinophyma development.
PMID:41139274 SUPPORT In Vitro
"GZMK also promoted cell proliferation and inflammatory factors (including IL-1β, IL-6, and TNFα) production in fibroblasts through activating the NF-κB pathway in vitro."
This directly supports fibroblast proliferative and inflammatory programs that can feed fibrotic remodeling in advanced rosacea.
Sebaceous gland and soft tissue hyperplasia/fibrosis
Rhinophyma reflects progressive hypertrophic remodeling of sebaceous glands and adjacent soft tissue in the nose.
Show evidence (1 reference)
PMID:19428039 SUPPORT Human Clinical
"Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
This abstract defines rhinophyma in terms of sebaceous-gland and soft tissue hyperplasia/fibrosis.
✶

Histopathology

6
Dermal vascular endothelial Angiopoietin 2 and Tie2 overexpression
Lesional erythematotelangiectatic and papulopustular rosacea skin shows increased Angiopoietin 2 and Tie2 staining in endothelial cells of dermal vessels compared with non-lesional skin, supporting a vascular remodeling-associated histopathology pattern.
Show evidence (1 reference)
PMID:41562711 SUPPORT Human Clinical
"Significantly increased expression of Tie2 and Angiopoietin 2 in the endothelial cells of the dermal vessels in rosacea skin vs. non-lesional skin (100% and 33.3% for Tie2, and 100% and 50% for Angiopoietin 2) was observed."
This provides direct biopsy-level immunohistochemical evidence for altered dermal vascular endothelium in rosacea lesions.
Early dermal fibrotic remodeling
Fibrotic remodeling is detectable in rosacea skin biopsies even at inflammation-dominant stages, indicating that tissue-remodeling changes begin before fully developed phymatous disease.
Show evidence (1 reference)
PMID:41800255 SUPPORT Human Clinical
"single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages"
This study directly supports fibrosis as an observable tissue-level change in rosacea biopsies, not only in late rhinophyma.
Sebaceous gland and surrounding soft tissue hyperplasia with fibrosis
Rhinophyma shows hypertrophic remodeling of sebaceous glands and adjacent soft tissue accompanied by fibrosis, forming the core microscopic pattern of phymatous rosacea.
Show evidence (1 reference)
PMID:19428039 SUPPORT Human Clinical
"Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
This abstract directly supports sebaceous gland hyperplasia with fibrosis as a defining microscopic tissue-remodeling feature of rhinophyma.
Leaky vascular architecture in rhinophyma tissue
Rhinophyma tissue shows an abnormal vascular architecture with leaky vessel profiles rather than the stromal-enveloped vascular pattern seen in hypertrophic scars.
Show evidence (1 reference)
PMID:41909715 SUPPORT Human Clinical
"Vascular structures in hypertrophic scar tissues are enveloped by a significant number of stromal cells, in contrast to the leaky vascular profiles observed in rhinophyma tissues."
This study supports a distinctive vascular tissue architecture in rhinophyma that fits the disease's vascular-remodeling phenotype.
Immune-cell-rich rhinophyma tissue
Rhinophyma tissue contains a relatively expanded immune-cell compartment, consistent with persistent inflammatory remodeling in phymatous disease.
Show evidence (1 reference)
PMID:41909715 SUPPORT Human Clinical
"the number of immune cells in rhinophyma is significantly higher than in hypertrophic scar tissues."
This supports immune-cell enrichment as a tissue-level feature of rhinophyma.
Eyelid tissue lymphoedema in ocular rosacea
In rare ocular rosacea with persistent peri-orbital swelling, eyelid debulking biopsy can show rosacea-associated inflammatory change with superimposed lymphoedematous tissue remodeling.
Show evidence (1 reference)
PMID:41058755 SUPPORT Human Clinical
"Histopathological analysis of the debulking biopsy confirmed the diagnosis of rosacea, with additional features indicative of lymphoedema."
This provides direct biopsy-level support for lymphoedematous tissue change in a rare ocular rosacea presentation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Rosacea Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

9
Cardiovascular 2
Persistent centrofacial erythema VERY_FREQUENT Facial erythema (HP:0001041)
Persistent background erythema of the central face is a core diagnostic phenotype in modern phenotype-led rosacea classification.
Show evidence (1 reference)
PMID:27718519 SUPPORT Human Clinical
"The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
ROSCO identifies persistent centrofacial erythema as one of the two diagnostic phenotypes for rosacea.
Facial telangiectasia FREQUENT Facial telangiectasia (HP:0007380)
Show evidence (1 reference)
PMID:37626650 SUPPORT Human Clinical
"Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face."
This review includes telangiectasia among the central defining manifestations of rosacea.
Eye 1
Blepharitis OCCASIONAL Blepharitis (HP:0000498)
Ocular rosacea often presents with eyelid margin inflammation.
Show evidence (1 reference)
PMID:40522449 SUPPORT Human Clinical
"It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
This directly supports chronic posterior blepharitis as a hallmark ocular phenotype of ocular rosacea.
Head and Neck 3
Phymatous change of the nose OCCASIONAL Bulbous nose (HP:0000414)
Phymatous rosacea is most often expressed as progressive tissue thickening of the nose (rhinophyma).
Show evidence (1 reference)
PMID:27718519 SUPPORT Human Clinical
"The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
ROSCO identifies phymatous change as the second independently diagnostic phenotype of rosacea.
Facial edema RARE Facial edema (HP:0000282)
A rare rosacea-associated lymphedematous presentation, often termed Morbihan disease, causes chronic persistent facial swelling.
Show evidence (1 reference)
PMID:41426892 SUPPORT Human Clinical
"Morbihan disease, also known as rosacea-associated solid facial edema, is a rare and chronic condition that presents with persistent facial swelling and often proves difficult to treat."
This directly supports persistent facial edema as a rare rosacea- associated phenotype.
Upper eyelid edema RARE Upper eyelid edema (HP:0012724)
Ocular rosacea can rarely present with persistent peri-orbital swelling, sometimes accompanied by secondary ptosis.
Show evidence (1 reference)
PMID:41058755 SUPPORT Human Clinical
"A 64-year-old Caucasian man presented with a 9-month history of persistent painless swelling of the right upper eyelid and secondary ptosis."
This case report supports persistent upper-eyelid edema as a rare ocular manifestation of rosacea.
Immune 1
Pustules FREQUENT Pustule (HP:0200039)
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
This overview identifies papulopustular lesions as part of the core clinical spectrum of rosacea.
Integument 2
Flushing FREQUENT Flushing (HP:0031284)
Episodic flushing commonly accompanies the vascular phenotype.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
This overview identifies flushing as a characteristic clinical manifestation of rosacea.
Papules FREQUENT Erythematous papule (HP:0030350)
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
This overview identifies inflammatory papules as a characteristic lesion type in rosacea.
🧬

Genetic Associations

8
IRF1 (MR-supported druggable gene)
Show evidence (1 reference)
PMID:40635520 SUPPORT Computational
"MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."
This directly supports IRF1 as a genetically prioritized therapeutic target in rosacea.
SLC22A5 (MR-supported druggable gene)
Show evidence (1 reference)
PMID:40635520 SUPPORT Computational
"MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."
This directly supports SLC22A5 as a genetically prioritized therapeutic target in rosacea.
GZMK (MR-supported drug target)
Show evidence (1 reference)
PMID:41139274 SUPPORT Computational
"MR and colocalization identified Granzyme K (GZMK) as a drug target, whose expression increased in the affected samples."
This supports GZMK as a genetically prioritized rosacea target with increased expression in disease-associated samples.
MSR1 (MR-supported risk-promoting biomarker)
Show evidence (1 reference)
PMID:40890957 SUPPORT Computational
"Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
This directly supports MSR1 as the risk-promoting protein among the final MR-prioritized rosacea biomarkers.
ABHD14B (MR-supported protective biomarker)
Show evidence (1 reference)
PMID:40890957 SUPPORT Computational
"Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
This supports ABHD14B as one of the final MR-prioritized proteins associated with lower rosacea risk.
CHMP6 (MR-supported protective biomarker)
Show evidence (1 reference)
PMID:40890957 SUPPORT Computational
"Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
This supports CHMP6 as one of the final MR-prioritized proteins associated with lower rosacea risk.
DBNL (MR-supported protective biomarker)
Show evidence (1 reference)
PMID:40890957 SUPPORT Computational
"Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
This supports DBNL as one of the final MR-prioritized proteins associated with lower rosacea risk.
MCFD2 (MR-supported protective biomarker)
Show evidence (1 reference)
PMID:40890957 SUPPORT Computational
"Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
This supports MCFD2 as one of the final MR-prioritized proteins associated with lower rosacea risk.
💊

Treatments

8
Trigger avoidance and photoprotection
Baseline management includes avoidance of provoking exposures, gentle skin care, moisturization, and sun protection to reduce flares.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"While standard measures, including avoidance of triggers, gentle cleansers, and moisturizers in combination with sun protection, may mitigate flares, control signs and symptoms in some patients"
This review supports trigger avoidance, gentle skin care, and photoprotection as foundational rosacea management.
Papulopustular-directed pharmacotherapy
Action: pharmacotherapy MAXO:0000058
Agent: metronidazole ↗ azelaic acid ↗ ivermectin ↗ doxycycline ↗ isotretinoin ↗
Papulopustular rosacea is commonly treated with topical metronidazole, azelaic acid, or ivermectin, and in more inflammatory disease with oral doxycycline or isotretinoin.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"topical metronidazole, azelaic acid, ivermectin, or oral doxycycline and isotretinoin for papulopustules of rosacea"
This review summarizes standard pharmacologic options used for papulopustular rosacea.
Topical brimonidine therapy
Action: pharmacotherapy MAXO:0000058
Agent: brimonidine ↗
Persistent background erythema can be treated with topical brimonidine to reduce visible vasodilatory erythema.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"topical brimonidine or intense pulsed light (IPL) for background persistent erythema"
This review identifies brimonidine as a targeted therapy for persistent background erythema.
Vascular light-based therapy
Persistent vascular erythema may also be treated with light-based therapy such as intense pulsed light.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"topical brimonidine or intense pulsed light (IPL) for background persistent erythema"
This review identifies light-based vascular therapy as another targeted approach for persistent erythema.
Cyclosporine eye drops
Action: pharmacotherapy MAXO:0000058
Agent: cyclosporine ↗
Ocular rosacea may require targeted ophthalmic anti-inflammatory therapy such as cyclosporine eye drops.
Show evidence (1 reference)
PMID:28150107 SUPPORT Human Clinical
"cyclosporine eye drops for ocular rosacea"
This review identifies cyclosporine eye drops as a treatment option for ocular rosacea.
Morbihan disease-directed pharmacotherapy
Action: pharmacotherapy MAXO:0000058
Agent: isotretinoin ↗ triamcinolone ↗ ketotifen ↗
Rosacea-associated solid facial edema may require individualized combination pharmacotherapy centered on isotretinoin and intralesional corticosteroid treatment, with ketotifen used in selected refractory cases.
Target Phenotypes: facial edema ↗
Show evidence (2 references)
PMID:41426892 SUPPORT Human Clinical
"The patient reported partial improvement, most notably with higher isotretinoin dosing and intralesional corticosteroid injections, though intermittent flares persisted."
This supports isotretinoin and intralesional corticosteroid treatment as active components of Morbihan disease management.
PMID:41222206 SUPPORT Human Clinical
"Successful treatment with a series of triamcinolone injections to the upper and lower eyelids was achieved after several unsuccessful therapies."
This independently supports intralesional triamcinolone as a useful treatment option for rosacea-associated solid facial edema.
Laser surgical debulking for rhinophyma
Action: laser surgical procedure MAXO:0001578
CO2 laser or blue-laser debulking can remove phymatous nasal tissue and improve function and cosmesis in selected rhinophyma.
Target Phenotypes: rhinophyma ↗
Show evidence (2 references)
PMID:41918801 SUPPORT Human Clinical
"we emphasize the surgical value of local anesthesia with CO2 laser for rhinophyma, reducing blood loss, operation time, and the need for secondary surgery."
This case report supports CO2 laser debulking as an effective rhinophyma procedure with practical operative advantages.
PMID:40791837 SUPPORT Human Clinical
"The use of blue laser to treat rhinophyma has shown to be an effective and safe procedure with very promising results."
This provides additional support for laser-based debulking in rhinophyma.
Excisional reconstruction for advanced rhinophyma
Action: surgical procedure MAXO:0000004
Severe rhinophyma may require excision with reconstructive approaches such as graft-based resurfacing when tissue overgrowth is extensive.
Target Phenotypes: rhinophyma ↗
Show evidence (1 reference)
PMID:40860281 SUPPORT Human Clinical
"Surgical excision is the primary treatment, and various techniques are available."
This supports excisional surgery as the primary treatment framework for advanced rhinophyma, including graft-based reconstruction.
🌍

Environmental Factors

2
Ultraviolet B radiation
Ultraviolet B exposure is a recognized favoring factor that can worsen rosacea activity and amplify inflammatory and vascular responses.
Show evidence (1 reference)
PMID:34035646 SUPPORT Human Clinical
"Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
This review explicitly identifies UVB radiation as an important rosacea-promoting exposure.
Corticosteroid treatment
Corticosteroid exposure can favor rosacea expression and is a recognized exacerbating factor in susceptible patients.
Show evidence (1 reference)
PMID:34035646 SUPPORT Human Clinical
"Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
This review explicitly identifies corticosteroid treatment as a favoring factor for rosacea.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Rosacea:

Acne MONDO:0011438
Overlapping Features Acne can overlap clinically with papulopustular rosacea because both produce inflammatory papules and pustules on the face.
Distinguishing Features
  • Acne more often shows open or closed comedones and broader sebaceous facial or truncal involvement.
  • Rosacea more often centers on persistent centrofacial erythema, flushing, and telangiectasia without comedones.
Show evidence (1 reference)
PMID:11582639 SUPPORT Human Clinical
"It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
This review explicitly lists acne vulgaris among the core differential diagnoses for rosacea.
Seborrheic dermatitis MONDO:0006608
Overlapping Features Facial seborrheic dermatitis can mimic rosacea when patients present with chronic erythema in sebaceous facial regions.
Distinguishing Features
  • Seborrheic dermatitis more often has greasy yellow-white scale involving the eyebrows, nasolabial folds, and scalp.
  • Rosacea more often has flushing, telangiectasia, and papulopustular lesions without prominent greasy scale.
Show evidence (1 reference)
PMID:11582639 SUPPORT Human Clinical
"It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
This review explicitly identifies seborrheic eczema as a major rosacea mimic; the corresponding MONDO disease term used here is seborrheic dermatitis.
Lupus erythematosus Not Yet Curated MONDO:0004670
Overlapping Features Lupus erythematosus can resemble rosacea when facial erythema or a butterfly-pattern eruption predominates.
Distinguishing Features
  • Lupus erythematosus more often has photosensitivity, scale, dyspigmentation, scarring plaques, or systemic autoimmune features.
  • Rosacea more often has trigger-provoked flushing, telangiectasia, and papulopustular centrofacial inflammation.
Show evidence (2 references)
PMID:11582639 SUPPORT Human Clinical
"It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
This review explicitly lists lupus erythematosus among disorders that can be difficult to distinguish from rosacea.
PMID:41695827 SUPPORT Human Clinical
"The coexistence of rosacea and lupus-like lesions delayed diagnosis, highlighting the need for clinicopathological correlation."
This case report reinforces lupus erythematosus as a real-world rosacea mimic and overlap diagnosis.
Systemic sclerosis MONDO:0005100
Overlapping Features Rosacea-associated solid facial edema can mimic systemic sclerosis when facial induration or swelling dominates the presentation.
Distinguishing Features
  • Systemic sclerosis more often has Raynaud phenomenon, acral involvement, and broader connective-tissue disease manifestations.
  • Morbihan-type rosacea edema may remain centered on the face with sparing of the hands and feet.
Show evidence (1 reference)
PMID:41694889 SUPPORT Human Clinical
"Scleredema diabeticorum and Morbihan disease (solid facial edema) can mimic scleroderma, creating diagnostic challenges for rheumatologists."
This directly supports systemic sclerosis-spectrum disease as a differential diagnosis for edematous rosacea presentations.
Coccidioidomycosis MONDO:0005706
Overlapping Features Cutaneous coccidioidomycosis can mimic rosacea-like dermatitis, particularly in immunocompromised patients living in endemic regions.
Distinguishing Features
  • Coccidioidomycosis is favored by endemic exposure, immunosuppression, and biopsy evidence of fungal infection.
  • Rosacea lacks an infectious tissue diagnosis and more typically follows a chronic trigger-responsive vascular-inflammatory course.
Show evidence (1 reference)
PMID:41017054 SUPPORT Human Clinical
"An immunocompromised patient in Arizona, USA, experienced cutaneous coccidioidomycosis mimicking rosacea-like dermatitis"
This directly documents cutaneous coccidioidomycosis as a rosacea mimic in the appropriate epidemiologic context.
Lymphomatoid papulosis Not Yet Curated MONDO:0020326
Overlapping Features Recurrent periocular nodules can be misclassified as papulopustular rosacea before biopsy reveals a CD30-positive lymphoproliferative lesion.
Distinguishing Features
  • Lymphomatoid papulosis shows recurrent papulonodules with diagnostic CD30-positive atypical lymphoid infiltrates on histopathology.
  • Rosacea more typically produces diffuse erythema, papules, pustules, and telangiectasia rather than isolated recurrent nodules.
Show evidence (1 reference)
PMID:40827152 SUPPORT Human Clinical
"he was subsequently diagnosed with papulopustular rosacea and impetigo. However, despite multiple treatment trials, he still experienced recurrent flares with nodules"
This case report documents an initial rosacea diagnosis later revised to lymphomatoid papulosis after biopsy.
📊

Related Datasets

4
Th1/Th17 Immune Response in Rosacea geo:GSE65914
Human facial biopsy transcriptomic dataset spanning rosacea subtypes and healthy controls, used to define adaptive immune and inflammatory cell programs across erythematotelangiectatic, papulopustular, and phymatous disease.
human MICROARRAY n=58
Conditions: erythematotelangiectatic rosacea papulopustular rosacea phymatous rosacea healthy control facial skin
Show evidence (1 reference)
GEO:GSE65914 SUPPORT Human Clinical
"The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example."
This GEO series directly supports subtype-spanning adaptive immune polarization in human rosacea tissue.
Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq] geo:GSE155141
Human RNA-seq dataset from paired non-lesional and lesional papulopustular rosacea explants, linked to paired proteomic profiling and inflammatory pathway analysis.
human BULK RNA SEQ n=15
Conditions: non-lesional papulopustular rosacea skin lesional papulopustular rosacea skin IL-1beta-treated non-lesional rosacea skin
Show evidence (1 reference)
GEO:GSE155141 SUPPORT Human Clinical
"Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator."
This dataset captures lesion-associated inflammatory pathway activity in papulopustular rosacea.
Cathelicidin LL-37-induced transcriptome of human keratinocyte identifies chemokine CXCL10 link to T cell-mediated rosacea pathogenesis via JAK-1/STAT-1 pathway geo:GSE303282
Human keratinocyte microarray dataset modeling LL-37-driven rosacea-like inflammation in vitro to resolve chemokine and JAK-STAT signaling outputs downstream of cathelicidin exposure.
human MICROARRAY n=6
Conditions: LL-37-treated primary keratinocytes untreated primary keratinocytes
Show evidence (1 reference)
GEO:GSE303282 SUPPORT In Vitro
"Mechanistically, LL-37 induced CXCL10 production relied on JAK-1/STAT-1 signaling pathway."
This in vitro transcriptomic dataset is directly relevant to the cathelicidin and STAT-linked mechanism nodes in rosacea.
Effect of eyelid UVB irradiation on gene expression of rat meibomian gland geo:GSE277020
Rat bulk RNA-seq dataset from a UVB-induced ocular rosacea model focused on meibomian gland dysfunction, ocular surface injury, and downstream inflammatory and keratinization pathways.
Rattus norvegicus BULK RNA SEQ n=7
Conditions: UVB-irradiated rat eyelids and meibomian glands non-irradiated rat controls
Show evidence (1 reference)
GEO:GSE277020 SUPPORT Model Organism
"We have developed a rat model of UVB-induced ocular surface and eyelid damages mimicking ocular rosacea, a common chronic inflammatory and neurovascular ocular surface disease associated with meibomian gland dysfunction."
This dataset provides an ocular/meibomian model aligned to the ocular rosacea subgraph in this entry.
🔬

Clinical Trials

4
NCT01493947 PHASE_III COMPLETED
Phase III comparative topical trial of ivermectin 1% cream versus metronidazole 0.75% cream in papulopustular rosacea, with an extension period assessing relapse-related outcomes.
Target Phenotypes: erythematous papule ↗ pustule ↗
Show evidence (1 reference)
clinicaltrials:NCT01493947 SUPPORT Human Clinical
"To compare efficacy and safety of Ivermectin 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea after 16-week topical treatment."
This registry summary supports a pivotal interventional trial focused on papulopustular rosacea lesion control.
NCT00126399 PHASE_III COMPLETED
Phase III placebo-controlled trial of once-daily 40 mg doxycycline controlled-release capsules for rosacea.
Target Phenotypes: erythematous papule ↗ pustule ↗
Show evidence (1 reference)
clinicaltrials:NCT00126399 SUPPORT Human Clinical
"The objective of this study is to evaluate the safety and efficacy of 40 mg doxycycline controlled-release capsules administered once daily for the treatment of rosacea compared with a placebo."
This registry entry supports controlled clinical evaluation of subantimicrobial-dose doxycycline for rosacea.
NCT03380390 PHASE_IV COMPLETED
Phase IV open-label study of oxymetazoline 1.0% cream used adjunctively with energy-based therapy for persistent facial erythema in rosacea.
Target Phenotypes: persistent centrofacial erythema ↗
Show evidence (1 reference)
clinicaltrials:NCT03380390 SUPPORT Human Clinical
"This study will evaluate the safety and tolerability of oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for participants with moderate to severe persistent facial erythema associated with rosacea."
This trial directly targets the persistent erythema phenotype that anchors erythematotelangiectatic rosacea.
NCT05616923 PHASE_I COMPLETED
Early-phase vehicle-controlled trial evaluating topical MEK inhibition in erythematotelangiectatic rosacea.
Target Phenotypes: persistent centrofacial erythema ↗ flushing ↗
Show evidence (1 reference)
clinicaltrials:NCT05616923 SUPPORT Human Clinical
"This is a prospective, vehicle controlled, double blinded study to evaluate the safety and potential efficacy of a topical formulation of a MEK inhibitor in patients with erythematotelangiectatic rosacea"
This registry entry supports a mechanism-oriented interventional study in the vascular erythematotelangiectatic phenotype.
📚

Literature Summaries

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Rosacea. Core disease mechanisms, molecular and cellular pathways, involve...
Asta Scientific Corpus Retrieval 17 citations 2026-04-05T13:10:23.887177

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Rosacea. Core disease mechanisms, molecular and cellular pathways, involve...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 17
  • Snippets retrieved: 20

Relevant Papers

[1] Cutaneous lesions of the nose

  • Authors: M. Sand, D. Sand, Christina Thrandorf, V. Paech, P. Altmeyer et al.
  • Year: 2010
  • Venue: Head & Face Medicine
  • URL: https://www.semanticscholar.org/paper/225d599a8fe838041291aab676cb50ef2394f711
  • DOI: 10.1186/1746-160X-6-7
  • PMID: 20525327
  • PMCID: 2903548
  • Citations: 30
  • Influential citations: 2
  • Summary: This article is the second part of a review series dealing with cutaneous lesions on the head and face, which are frequently seen in daily practice by a dermatologic surgeon.
  • Evidence snippets:
  • Snippet 1 (score: 0.497) > Rosacea is a multiphasic inflammatory condition that typically affects the skin of the face and nose. Clinically, rosacea has been classified in four different stages. Stage I, also called rosacea erythematosa telangiectasia (prerosacea), shows facial flushing and telangiectasia. Stage II, rosacea papulopustulosa (vascular rosacea), is characterized by persistent facial erythema, telangiectasia, thickened skin, papules and pustules (Fig 9). Stage III, glandular-hypertrophic or inflammatory rosacea, shows erythematous papules and pustules, telangiectasias, edema, connective tissue and sebaceous gland hyperplasia. Stage IV, or rhinophyma, shows dermal and sebaceous gland hyperplasia, and dilated and cystic sebaceous glands. Most individuals affected by rosacea are of northern European origin, and up to one-third have a family history of the disorder [91]. Clinical signs include facial flushing, erythema, telangiectasia and papulopustular efflorescence similar to acne as described previously. Women are three times more likely to be affected than men, with the reported prevalence between 0.5 and 10% [92,93]. The pathophysiology has been poorly understood, and there have been only limited descriptions of factors that exacerbate or improve this disease [94]. Recent molecular studies suggest that an altered innate immune response is involved in the pathogenesis of vascular and inflammatory disease and is responsible for the observed clinical findings in patients with rosacea [95]. > A variety of topical, systemic and physical treatment options are available that have been adjusted to the stage and severity of the disease [96]. Standard topical therapy includes metronidazole 0.75% or 1% gel. Alternatively, azelaic acid 15% gel or 20% cream has also been successfully used in five randomized and controlled studies with good results [97].

[2] Elucidating the potential pharmaceutical mechanism of Gyejibokryeong-hwan on rosacea using network analysis

  • Authors: Jundong Kim, Kyuseok Kim
  • Year: 2023
  • Venue: Medicine
  • URL: https://www.semanticscholar.org/paper/11e9f13d08ccf6bfa9dd044db6b1e054bc8d88c1
  • DOI: 10.1097/MD.0000000000033023
  • PMID: 36862896
  • PMCID: 9981404
  • Citations: 3
  • Summary: Gyejibokryeong-hwan has the potential to act on IL-17 signaling pathway, neuroinflammatory response and vascular wound healing pathway, and further studies are needed to determine the potential mechanism of GBH in rosacea.
  • Evidence snippets:
  • Snippet 1 (score: 0.496) > Rosacea is a chronic erythematous disease with telangiectasia that affects the central area of the face. However, because of the ambiguity in the pathophysiology of rosacea, its treatment has not been clearly elucidated; therefore, new therapeutic options need to be developed. Gyejibokryeong-hwan (GBH) is widely used in clinical practice for various blood circulation disorders, including hot flushes. Therefore, we explored the potential pharmaceutical mechanism of GBH on rosacea and investigated the therapeutic points exclusive to GBH through comparative analysis with chemical drugs recommended in 4 guidelines for rosacea based on network analysis. The active compounds in GBH were identified, and the proteins targeted by these compounds and the genes related to rosacea were searched. Additionally, the proteins targeted by the guideline drugs were also searched to compare their effects. And the pathway/term analysis of common genes was conducted. Ten active compounds were obtained for rosacea. There were 14 rosacea-related genes targeted by GBH, with VEGFA, TNF, and IL-4, which were suggested as core genes. The pathway/term analysis of the 14 common genes revealed that GBH could potentially act on rosacea via 2 pathways: the “interleukin 17 signaling pathway” and the “neuroinflammatory response.” Comparison and analysis of the protein targets between GBH and guideline drugs revealed that only GBH separately acts on the “vascular wound healing pathway.” GBH has the potential to act on IL-17 signaling pathway, neuroinflammatory response and vascular wound healing pathway. Further studies are needed to determine the potential mechanism of GBH in rosacea.

[3] Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments

  • Authors: Luxi Chen, Juan Wang
  • Year: 2025
  • Venue: Journal of Cosmetic Dermatology
  • URL: https://www.semanticscholar.org/paper/29caec1e8ca2ad4852ea656bfc9ea8c22c8ae2e1
  • DOI: 10.1111/jocd.16753
  • PMID: 39823143
  • PMCID: 11739675
  • Summary: Rosacea is a prevalent inflammatory skin condition, but its molecular mechanisms and treatment responses remain poorly understood.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > Rosacea is a common chronic skin disease characterized by facial skin erythema, papules, and pustules, severely impacting the patient's appearance and quality of life [1][2][3]. However, the pathogenesis of rosacea remains poorly understood at present [4][5][6]. Although some studies have identified potential influences of inflammatory reactions and genetic factors, there is still a lack of in-depth understanding regarding its molecular mechanisms and individualized treatment strategies [7][8][9]. > Transcriptomics, a high-throughput technology for studying gene expression, has been widely applied to investigate the pathogenesis and treatment response of various diseases [10][11][12]. Therefore, in this study, we conducted a systematic analysis of gene expression patterns in rosacea patients using high-throughput RNA sequencing technology. Through this approach, we can identify key genes and signaling pathways related to rosacea development and treatment response, providing important insights for a deeper understanding of the pathogenesis of this disease [13][14][15]. > To investigate the molecular mechanisms and drug response of rosacea further, a series of in vitro experiments were performed. First, techniques such as RT-qPCR, Western blot, and ELISA were used to assess the expression levels of rosacea-related cytokines and key genes [16]. Additionally, scratch assays and Transwell experiments were employed to study cell migration and proliferation [17]. These experimental results provide important clues for a comprehensive understanding of the roles of inflammatory reactions and cellular functions in rosacea development. > The aim of this study is to reveal the pathogenesis and individualized treatment possibilities of rosacea by investigating its molecular mechanisms and drug response in depth. By utilizing a comprehensive research approach combining transcriptomics technology and in vitro experiments, we hope to gain a more comprehensive understanding of the development process of rosacea and explore new treatment strategies. The research findings may provide scientific evidence for individualized treatment and clinical practice, offering important information and directions to improve the quality of life of patients.
  • Snippet 2 (score: 0.482) > In summary, this study employed transcriptomics and in vitro experiments to investigate the molecular pathological features of rosacea and identified potential therapeutic approaches. It was found that rosacea is closely associated with a chronic inflammatory state, particularly with significantly elevated expression of genes such as IL6, OSM, and TNF-α. Rosacea also displayed a close relationship with genes involved in cell proliferation and migration, as evidenced by increased expression of TLR2 and S100A9 (Figure 6). These findings not only enhance our understanding of the pathophysiology of rosacea but also provide a scientific basis for developing treatment strategies targeting specific types of rosacea. > The scientific significance of this study lies in its comprehensive exploration of the molecular mechanisms and drug responses in rosacea through transcriptomics analysis and in vitro experiments. Analysis of the gene expression patterns in rosacea patients revealed elevated levels of genes related to inflammatory reactions, leading to new insights into the pathogenesis of rosacea. In in vitro experiments, the study found that TLR2 and S100A9 protein levels increased in HaCaT cells under conditions simulating rosacea, and the cytokines IL6, OSM, and TNF-α were significantly elevated, implying their potential promoting roles in the progression of rosacea. Therefore, this study provides important scientific evidence for a deeper understanding and treatment of rosacea. > However, there are still some limitations to this study. First, the study only involved a cell line model, which limits the generalizability of the results, and it is possible that the results may differ from other animal models. In addition, more clinical data and human studies are needed to validate the reliability and applicability of these results. > Future research can further explore the molecular mechanisms and drug responses in rosacea. More key molecules can be studied at the genomic and proteomic levels to reveal the pathological mechanisms of rosacea. Additionally, in vivo experiments and clinical research can further validate the reliability of the research results and further optimize and improve existing treatment strategies. Personalized therapy can also be a future research direction, with the development of treatment strategies targeting specific molecular targets based on a deeper understanding of the pathogenesis of rosacea, providing more precise, safe, and effective treatment options.
  • Snippet 3 (score: 0.441) > Rosacea is a common chronic skin disease with unclear pathogenic mechanisms [8,31,32]. The objective of this study is to explore the molecular mechanisms of rosacea and the effects of drug response through the application of transcriptomics and in vitro experiments. We analyzed the gene expression patterns of rosacea patients using high-throughput RNA sequencing and further validated them in vitro experiments [33]. Through these experiments, we aim to better understand the pathogenic mechanisms of rosacea and provide important information for the development of therapeutic strategies. > Compared to previous studies, our findings suggest a significant increase in the expression levels of genes associated with inflammatory reactions in rosacea patients [7][8][9]. Specifically, the expression of FLT1 and TLR2 genes is significantly elevated in rosacea patients [34]. These results are consistent with previous research and further support the crucial role of inflammatory reactions in the pathogenesis of rosacea [35]. The sustained activation of inflammatory reactions may contribute to the development of skin lesions and further exacerbate the expression of genes related to inflammatory reactions [36,37]. > Our study demonstrates that HaCaT cells exhibit enhanced proliferation and migration abilities under conditions simulating a rosacea environment. This finding is consistent with previous observations of behavioral changes in HaCaT cells in previous studies. The increased proliferation and migration of HaCaT cells may be associated with the upregulation of genes related to inflammatory reactions [38,39]. These results further support the crucial role of inflammatory reactions in the pathological progression of rosacea [40]. > Our findings also reveal a significant upregulation of TLR2 and S100A9 expression in rosacea patients, which is consistent with previous research on TLR2 and S100A9 [41][42][43]. The upregulation of TLR2 and S100A9 may promote the pathogenesis of rosacea and inflammatory reaction [44,45]. TLR2 is involved in the regulation of inflammatory reactions through the activation of the inflammatory pathway, while S100A9 serves as an inflammatory mediator involved in the spread and maintenance of inflammation [45]. > In summary, this study employed transcriptomics and in vitro experiments to investigate the molecular pathological features of rosacea and identified potential therapeutic approaches.

[4] Acne and Rosacea

  • Authors: M. Picardo, L. Eichenfield, Jerry Tan
  • Year: 2017
  • Venue: Dermatology and Therapy
  • URL: https://www.semanticscholar.org/paper/eafcdab44124661cdeba5997d4e2ca3cf5a7627e
  • DOI: 10.1007/s13555-016-0168-8
  • PMID: 28150107
  • PMCID: 5289119
  • Citations: 149
  • Influential citations: 4
  • Summary: An overview of current perspectives on the pathogenesis and treatment of acne and rosacea is provided, including a summary of findings from recent landmark pathophysiology studies considered to have important implications for future clinical practice.
  • Evidence snippets:
  • Snippet 1 (score: 0.470) > Rosacea has a multifactorial pathology involving vasoactive and neurocutaneous mechanisms, as well as innate and adaptive immunity. Each of these factors contributes to the disease to a different extent in each individual (Fig. 3). Over the past decade, the management of rosacea has evolved from empiricism to rational selection based on disease pathogenesis. While standard measures, including avoidance of triggers, gentle cleansers, and moisturizers in combination with sun protection, may mitigate flares, control signs and symptoms in some patients, others will require more specific therapy. > In the past, treatments for rosacea have primarily been confined to therapies indicated for other conditions (e.g., beta-blockers for flushing, antibiotics for acne vulgaris). However, more recently, treatments have been specifically developed based on our evolving understanding of the pathogenesis of rosacea (Fig. 4). Currently available treatment options based on positive outcomes from randomized controlled trials include topical brimonidine or intense pulsed light (IPL) for background persistent erythema; topical metronidazole, azelaic acid, ivermectin, or oral doxycycline and isotretinoin for papulopustules of rosacea; and cyclosporine eye drops for ocular rosacea [47]. Consensus on the optimal treatment for phymatous rosacea has yet to be reached because of a lack of robust clinical trial data. A useful summary of findings for all evidence-based interventions for treating different manifestations of rosacea is provided in a recently published Cochrane review [48]. > Although the past decade has witnessed important advances in our understanding and management of rosacea, it is anticipated that the findings from recent landmark pathophysiology studies will have important implications for future clinical practice. For example, gene array analyses indicate that each rosacea subtype can be differentiated by a selective gene profile, suggesting that the pathomechanisms of the different subtypes may vary with respect to the molecular pathways involved [49]. Other promising avenues of research include the role of cathelicidin antimicrobial peptides in aberrant innate immune responses [44,50], the role of mast cells as key mediators of cathelicidin-initiated inflammation in

[5] Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates

  • Authors: Cheng Chen, Peiru Wang, Linglin Zhang, Xiaojing Liu, Haiyan Zhang et al.
  • Year: 2023
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/79a2e71639c81efae823ea0b5f4b691d9fbd7e38
  • DOI: 10.3390/biomedicines11082153
  • PMID: 37626650
  • PMCID: 10452301
  • Citations: 57
  • Influential citations: 2
  • Summary: This comprehensive review investigates the pathogenesis of rosacea in depth, with a focus on emerging and novel mechanisms, and provides an up-to-date overview of therapeutic strategies that target the diverse pathogenic mechanisms.
  • Evidence snippets:
  • Snippet 1 (score: 0.453) > Given the multifaceted pathogenic mechanisms involved in rosacea, investigating these emerging areas may offer novel therapeutic avenues for the condition. Our future goal is to pinpoint the key molecules or mechanisms that drive inflammation in rosacea, akin to the role of IL-17 in psoriasis, and to develop therapeutic agents based on these findings. > Recent advances in our understanding of the pathogenesis of rosacea have led to the emergence of various new therapies. In this paper, we have dedicated comprehensive chapters to elaborate on the current understanding and recent advancements in therapeutic strategies that specifically address (1) immune dysregulation, (2) neurovascular dysregulation, (3) neurological and psychological factors, and (4) microbial dysbiosis. Additionally, we have meticulously explored the latest developments in (5) physical treatment methods, encompassing photodynamic therapy and other innovative approaches. Moreover, we have delved into (6) miscellaneous therapeutic avenues, including the promising utilization of traditional herbal medicines, small-molecule inhibitors, and RNA medicines. These promising therapies have enriched the range of available treatment options, providing new avenues for managing the complex pathophysiology of rosacea. Nonetheless, the efficacy of many of these novel therapies necessitates further validation through rigorous clinical trials. Some physical therapies have also emerged as potential avenues for future development. These therapies target specific symptoms with minimal systemic adverse effects, making them suitable for combination with other therapeutic modalities or post-pharmacological intervention. Tailored combinations of physical therapies present advantages in optimizing treatment regimens for rosacea patients and may contribute to improved aesthetic outcomes. Given that rosacea may extend beyond the skin, personalized therapies that target the comorbidities associated with rosacea, such as β-adrenergic receptor antagonists for patients with anxiety and rifaximin for those with SIBO, could be another promising direction for the future of rosacea treatment. By addressing the individual needs of patients with specific comorbidities, these therapies have the potential to provide more effective and tailored treatment options. With the emergence of monoclonal antibodies, small-molecule drugs, and RNA medicines, we now have more precise drugs that target the disease development process.
  • Snippet 2 (score: 0.415) > Rosacea is a common chronic inflammatory cutaneous disorder that affects about 5.46% of the global adult population [1]. It primarily affects the central facial skin and presents with symptoms such as recurrent episodes of flushing, persistent erythema, telangiectasia, papules, pustules, edema, phymatous changes, or a combination of these symptoms. Rosacea can be classified into four subtypes based on these symptoms: erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR), phymatous rosacea (PhR), and ocular rosacea (OR) [2,3]. Although the pathophysiological mechanisms of rosacea remain unclear, the prevailing consensus is that the condition primarily stems from immune dysregulation and/or neurovascular dysfunction, as well as an impaired skin barrier. Triggers such as ultraviolet radiation, temperature changes, diet, and stress can exacerbate the underlying innate immune response and/or neurovascular dysfunction [4]. Recent studies have also highlighted the role of microbial dysbiosis, neuroimmune interactions, metabolic dysfunction, and sebaceous gland dysregulation in the development of rosacea. Other factors such as genetic predisposition and oxidative stress are also thought to play a role (Figure 1). > Regarding treatment, various guidelines and expert consensus offer a range of therapeutic options tailored to different phenotypes [2,[5][6][7]. In terms of addressing the pathogenesis of rosacea, the most traditional and commonly employed approach is through the use of anti-inflammatory treatments. Novel drugs targeting neurological and psychological factors have recently gained attention. Several other therapeutic options have emerged targeting other specific pathways, including vascular dysregulation, and microbial dysbiosis. New formulations or routes of administration for some drugs are also being explored. Physical therapies, such as laser and photodynamic therapy, have also shown promising outcomes in the treatment of rosacea. > In this article, we provide a detailed and comprehensive investigation o pathogenesis of rosacea, with a particular focus on the emerging and novel mechan that may contribute to its development.

[6] Advances in the pathogenesis of rosacea

  • Authors: Hui Wang, Chen-Han Zhou
  • Year: 2026
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/624cb421fe66bdc40aba068d85f82deb30776da2
  • DOI: 10.3389/fimmu.2025.1705588
  • PMID: 41646975
  • PMCID: 12868226
  • Citations: 1
  • Summary: The latest significant advances in the pathogenesis of rosacea in recent years are summarized and the dysbiosis of skin and gut microbiota, together with the impairment of skin barrier function, is also closely associated with the onset and progression of this disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.444) > Rosacea is a complex chronic inflammatory skin disease driven by the interaction of genetics, neurovascular function, immunity, skin barrier and microorganisms, with each factor amplifying the others to maintain the disease. In recent years, with the advancement of basic scientific research and the application of emerging technologies, the pathological mechanism of rosacea has gradually been revealed. Advances in genomics, immunology, and microbiology have helped to uncover more information about the susceptibility and inducing factors of the disease. However, the specific pathophysiological mechanism of rosacea has not been fully elucidated. Future research should further explore its molecular and cellular mechanisms, which will provide a theoretical basis for the establishment of personalized treatment strategies and the development of new treatment methods, thereby improving the clinical prognosis of patients.

[7] ACSL5 mediates macrophage infiltration and lipid metabolism in erythrotelangiectasia rosacea via potential pathogenic mechanisms and therapeutic targets

  • Authors: Xiaoxia Ding, Youxia Xi, Y. Sheng, Yibin Fan, Yong Yu
  • Year: 2025
  • Venue: Scientific Reports
  • URL: https://www.semanticscholar.org/paper/a303581a3610c61b54ad91d0bbb427dab34ee9bd
  • DOI: 10.1038/s41598-025-96756-3
  • PMID: 40195491
  • PMCID: 11976930
  • Summary: New insights into ETR pathogenesis are provided and the co-localization of ACSL5 with M1 macrophage markers suggests a mechanistic link between lipid metabolism and inflammatory responses.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Rosacea is a chronic inflammatory skin disease characterized by centro-facial erythema, telangiectasia, papules, and pustules. Oral medication or light-based therapies for persistent erythema and flushing in rosacea may be ineffective in some cases. However, the efficacy of erythema rosacea is still not satisfactory, so more in-depth mechanism research and therapeutic target mining are still necessary. > In this study, a total of 304 differentially expressed genes associated with erythematotelangiectatic rosacea (ETR) were identified through differential gene analysis and weighted gene co-expression network analysis (WGCNA). Enrichment analysis revealed that these genes were primarily involved in metabolic pathways, PPAR signaling pathway, fatty acid metabolism, and lipid metabolic processes. While comprehensive lipidomic studies on rosacea skin lesions remain limited, one previous small-scale analysis reported no significant differences in major lipid components, including cholesterol, triglycerides, and squalene, between patients with rosacea and healthy controls 13 . This discrepancy may reflect limitations in the resolution and sensitivity of conventional lipidomic analyses. In contrast, our transcriptomic data revealed marked alterations in genes associated with lipid metabolism, particularly those involved in fatty acid pathways such as ACSL5 and ACADVL. These transcriptional changes indicate potential metabolic dysregulation that may not be reflected at the bulk lipid level. Such molecular alterations could influence enzyme function, lipid signaling, or metabolic fluxes, which may escape detection by untargeted lipid profiling. To address this gap, advanced approaches-such as targeted or spatial lipidomics-could complement transcriptomic findings and offer deeper insight into lipid pathway disturbances in rosacea. This integrative strategy may help uncover subtle metabolic shifts relevant to disease pathogenesis and expand the current understanding of rosacea at the molecular level. Previous research has indicated that inflammatory processes, triggered by oxidative stress and lipid oxidation, contribute to the development and progression of rosacea 14 .

[8] Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel

  • Authors: Jerry Tan, L. Almeida, A. Bewley, B. Cribier, N. Dlova et al.
  • Year: 2017
  • Venue: British Journal of Dermatology
  • URL: https://www.semanticscholar.org/paper/cc6ada668802c4547f0cb2246bdb471109c85dae
  • DOI: 10.1111/bjd.15122
  • PMID: 27718519
  • Citations: 259
  • Influential citations: 12
  • Summary: Rosacea is currently diagnosed by consensus‐defined primary and secondary features and managed by subtype, however, individual features can span multiple subtypes, which has implications for clinical practice and research.
  • Evidence snippets:
  • Snippet 1 (score: 0.436) > • This study re-evaluates the primary and secondary features of rosacea in order to rationalize diagnosis and classification based on a phenotype approach. > • This study provides a global perspective on rosacea diagnosis and classification with representation from Africa, Asia, Europe, North America and South America. > Rosacea is a chronic inflammatory disease of the skin predominantly affecting the centrofacial region. Although several potential pathways are under investigation, its pathophysiology has yet to be fully determined. So far, dysregulation of the innate (keratinocytes, endothelial cells, macrophages, mast cells, dendritic cells) and adaptive [T helper (Th)1 cells, Th17 cells, plasma cells] immune system has been found. In this dysregulated network, increased levels of antimicrobial peptides, neuropeptides, nitric oxide radical species, proteases, cytokines, chemokines, vascular growth factor (VEGF) along with receptors for cytokines, chemokines, neurotransmitters, VEGF or transient receptor potential ion channels have been detected. [1][2][3][4][5][6][7][8][9][10][11] Trigger factors including Demodex and ultraviolet radiation exposure may activate some of these pathways, although the molecular mechanisms are poorly understood thus far. For this reason, no diagnostic laboratory test is available. Therefore, rosacea diagnosis and classification are based on the patient's presenting features. > Current diagnostic practice largely follows the recommendations of the National Rosacea Society (NRS) expert panel, which is composed of North American and European dermatologists. According to the NRS system, any one of the following is a primary diagnostic criterion for rosacea: transient erythema, persistent erythema, inflammatory papules/pustules and telangiectasia. 12 Secondary features, which may be present with primary features or appear independently, include phymatous changes, burning or stinging sensations, erythematous plaques, facial dryness and scaling, oedema, peripheral location and ocular manifestations. 12 As multiple features tend to present simultaneously, a subtype classification system was also proposed, grouping the most

[9] Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea

  • Authors: Yaling Wang, Ben Wang, Yingxue Huang, Yangfan Li, Sha Yan et al.
  • Year: 2022
  • Venue: Journal of Inflammation Research
  • URL: https://www.semanticscholar.org/paper/87618144363399c0147ca2fad7eea0772561cac1
  • DOI: 10.2147/JIR.S356551
  • PMID: 35392024
  • PMCID: 8980297
  • Citations: 28
  • Influential citations: 2
  • Summary: The results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > Rosacea is a chronic inflammatory skin disease characterized by flushing, persistent erythema, papules and pustules, telangiectasia and phyma, especially on the cheek, nose, chin, forehead and eyes. 1 The incidence of rosacea varies in different areas of the world and a cross-sectional study showed that about 3.48% of individuals are affected in China. 2 According to the National Rosacea Society Expert Committee in 2017, the updated classification of rosacea is based on phonotypes linked to clinical manifestations and provides criterion of diagnosis and severity assessment of the disease. 3 Although the pathophysiology of rosacea remains unclear, genetic factors, dysregulation of the innate and adaptive immune system, vascular and neuronal dysfunction, and microorganisms such as Demodex folliculorum appear to be involved. 4 Above these, Zuo et al found overcleaning were positively associated with rosacea, 5 indicating that rosacea is also associated with impairment of the skin barrier. > Skin barrier plays a critical role in skin homeostasis. Various skin barrier-related genes (SBRGs) have been reported to be involved in the progression of skin disease via regulating the skin barrier. The tight junction protein and Filaggrin (FLG) are important SBRGs, 6 playing a central role for the physical integrity of the skin barrier. The biological and chemical stimulations from the external environment disrupted the skin barrier by reducing tight junctions, triggering epithelial alarmin, including barrier alarms (KRT6A, KRT16), AMPs (DEFB4B, CAMP, LCN2, S100A7, S100A8, S100A9) and KLK enzyme. 7 Previous investigations have shown that patients with rosacea have impaired facial skin barrier, characterized by increased PH, abnormal fatty acid composition and increased trans epidermal water Loss (TEWL). 8,9 Previous research demonstrated the dysregulated SBRGs in rosacea patients 10,11 and barrier repair could be of therapeutic benefit in rosacea, revealing the potential role of skin barrier dysfunction (SBD) in the pathogenesis of rosacea. However, the underlying mechanism is still unknown. > STAT3 is a crucial signal transducer factor in the pathogenesis

[10] Major Pathophysiological Correlations of Rosacea: A Complete Clinical Appraisal

  • Authors: R. Vemuri, R. Gundamaraju, S. Sekaran, R. Manikam
  • Year: 2015
  • Venue: International Journal of Medical Sciences
  • URL: https://www.semanticscholar.org/paper/51b4e4217168b6531c70567d1884ae3fbd379a3c
  • DOI: 10.7150/ijms.10608
  • PMID: 26005373
  • PMCID: 4441063
  • Citations: 32
  • Influential citations: 3
  • Summary: Vasculature, chronic inflammatory responses, environmental triggers, food and chemicals ingested and microorganisms either alone or in combination are responsible for rosacea.
  • Evidence snippets:
  • Snippet 1 (score: 0.415) > Background: Rosacea is a characteristic cutaneous disorder with a diverse clinical manifestations ranging from facial vascular hyper-reactivity to sebaceous gland hyperplasia. Many theories on pathophysiology of rosacea were proposed over the past decade, however the pathogenicity is poorly understood. Aim: To review the evidence on different pathophysiological correlations of rosacea. Methods: A literature search was conducted for studies published between 1990 to March 2014. The inclusion criteria was pathophysiology, randomized controlled trials, controlled trials on rosacea. Results: Out of 5141 articles, 14 high quality studies met all the selection criteria. Of 14 articles, 5 are randomized control trials (RCTs), 2 are controlled trial, 3 comparative trials, 2 observational trials, 1 prospective and 1 diagnostic trial. The studies were categorized into two groups: the trigger factors and sub-types & symptoms. Of 7 high quality studies, 4 provided strong evidence that immune responses causing disease triggered by external/internal factors such as sunlight, food and chemical agents, 3 trials provided significant evidence of microorganisms as causative agents. The remaining trials did not provide significant evidences on pathophysiology. Conclusion: Vasculature, chronic inflammatory responses, environmental triggers, food and chemicals ingested and microorganisms either alone or in combination are responsible for rosacea. Many promising drugs are under various phases of clinical trials and interestingly, probiotics could also possibly be used as one of the treatment option.

[11] Mechanisms and Recent Advances of Small-Molecule Therapeutics in Rosacea Treatment

  • Authors: M. Ye, P. Hao, Nana Luo, Tianhao Li
  • Year: 2025
  • Venue: Clinical, Cosmetic and Investigational Dermatology
  • URL: https://www.semanticscholar.org/paper/d26e50b88d294744bc3e3985fe208bd4e62b021e
  • DOI: 10.2147/CCID.S525787
  • PMID: 40529547
  • PMCID: 12170860
  • Summary: This review summarizes the latest advances in small molecules targeting key inflammatory pathways in rosacea, provides new ideas for the treatment of rosacea and new directions for the clinical management of rosacea.
  • Evidence snippets:
  • Snippet 1 (score: 0.409) > Therefore, there is a need for effective new therapies. > Currently, small molecule inhibitors are at the vanguard of medical research endeavors. 28 In recent times, with the ongoing and profound exploration of inflammatory mediators and signaling cascades implicated in the pathophysiology of rosacea, more and more targeted therapies have emerged, including biologics and small-molecule drugs. 29,30 ompared with biologics, small-molecule drugs with a molecular weight <1 kDa have unique properties: they can act by targeting intracellular targets that biologics cannot act on through cell membranes; Reduce the loss of response caused by immunogenicity of macromolecular proteins; The adjustment of its chemical structure and dosage is conducive to achieving the balance of clinical pharmacokinetics and pharmacodynamics. Convenient oral or topical administration and relatively low cost are more acceptable to patients. 31,32 For patients with rosacea who are tolerated or even unable to respond to conventional treatment regimens, small-molecule drugs are a new alternative to treatment. This paper provides an overview of the mechanisms of action and advancements in clinical research concerning small-molecule drugs utilized for rosacea treatment in recent years.

[12] Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models

  • Authors: Daniela Rodrigues-Braz, Min Zhao, N. Yesilirmak, S. Aractingi, F. Behar-Cohen et al.
  • Year: 2021
  • Venue: Molecular Vision
  • URL: https://www.semanticscholar.org/paper/f6a633d5daa6cb8227a8f05de54fe713a1b48ff0
  • PMID: 34035646
  • PMCID: 8131178
  • Citations: 67
  • Influential citations: 3
  • Summary: The common and specific molecular mechanisms involved in the pathogenesis of cutaneous and ocular rosacea are reviewed and laboratory and clinical studies, as well as experimental models are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.406) > Finally, the molecular steps involved in the pathogenesis of ocular rosacea are not fully known. Meibomian gland dysfunction has been recognized as a major component [13,26]. Like in the skin, activation of the innate and adaptive immune response and abnormal vascular regulations have been identified. In the tears and in the ocular surface tissues of ocular rosacea patients, high levels of TLR-4 and LL-37 were measured together with cell infiltration and the release of proinflammatory factors [13,27,28]. A link between Demodex infestation and ocular rosacea has also been advocated [29,30]. Overall, all these phenomena in the skin and eye act in synergy to maintain chronic inflammation at the cutaneous, epidermal, conjunctival, and perivascular interface, eventually leading to secondary fibrosis [31]. In this paper, we aim to review the common and specific pathogenic mechanisms of cutaneous and ocular rosacea and focus on the few models used to study this disease. > Deregulation of the immune system: Activation of immunemediated inflammatory pathways appears to be at the center of the pathogenesis of rosacea and involves the coordinated activity of several cell types, such as mast cells and macrophages, and the release of proinflammatory mediators, such as IL-6, IL-1β, IL-18, or TNF-α [32,33]. Inhibition of these inflammatory pathways is correlated with clinical improvement.

[13] Probiotics and Diet in Rosacea: Current Evidence and Future Perspectives

  • Authors: M. Manfredini, Michele Barbieri, Margherita Milandri, C. Longo
  • Year: 2025
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/c662166e77008a0248667360e90bce45205ade0a
  • DOI: 10.3390/biom15030411
  • PMID: 40149947
  • PMCID: 11940470
  • Citations: 10
  • Influential citations: 1
  • Summary: Improved understanding of the gut–skin axis in rosacea is improved, focusing on how probiotic supplementation and diet could improve the clinical management of patients affected by this common and debilitating disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.403) > Studies and reports over the past several decades have analyzed the association between common dietary triggers and rosacea pathogenesis. The avoidance of common triggers can reduce rosacea flares and improve the management of the disease. Probiotics, such as certain strains of Lactobacillus, Bifidobacteria and Saccharomyces, can positively influence several immune mechanisms that are implicated in rosacea pathogenesis by increasing IL10 and reducing TNF-a, IL-17A. Prebiotics, which supports gut colonization by beneficial gut bacteria, could favorably influence the gut-skin axis mechanisms involved in rosacea pathogenesis. To the best of our knowledge, the paucity of clinical studies and the lack of randomized trials and standardization of the use of probiotics are major limitations to the current adoption of probiotics as part of standard rosacea care and management. Diet and nutritional counseling may enhance rosacea management through the direct effects of food metabolites and the modulation of the gut microbiota. Highfiber diets, particularly those rich in vitamin A, may exhibit potent anti-inflammatory and sebum-regulating properties that help to manage the factors contributing to the progression of rosacea. Therefore, modulating the skin and gut microbiota through diet, prebiotics, probiotics, and postbiotics could represent an effective and innovative strategy for the therapeutic control and management of rosacea. However, few studies are available, and more rigorous clinical trials are needed.

[14] Rosacea pathogenesis and therapeutics: current treatments and a look at future targets

  • Authors: Garrett W Fisher, J. B. Travers, C. Rohan
  • Year: 2023
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/0acb3a9da9d339fdd67f5ed8c60b39fb03fc7ef5
  • DOI: 10.3389/fmed.2023.1292722
  • PMID: 38193038
  • PMCID: 10773789
  • Citations: 29
  • Influential citations: 2
  • Summary: Current concepts of rosacea pathogenesis will be addressed which involve skin barrier and permeability dysfunction, the innate and adaptive immune systems, and the neurovascular system.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > Research into the pathogenesis of rosacea is trending upward owing to rapid discoveries in the field, which indicates pathophysiology has attracted attention for future research (86). Novel discoveries increase our understanding of intrinsic and extrinsic pathways contributing to rosacea and allow for new opportunities of therapeutics. Descriptions of future therapies are broken down into subsections of implicated pathogenesis such as skin barrier dysfunction, cathelicidin pathway, mast cell targets, and microvesicle particles. Each pathogenic target then discusses proposed medications, and hypothetical targets based upon pathogenic insight. For reference, Figure 2 depicts the future treatment targets in relation to pathophysiology and Table 2 provides a summary of each target, proposed mechanism of action, and example medications.

[15] Cutaneous rosacea: a thorough overview of pathogenesis, clinical presentations, and current recommendations on management

  • Authors: J. Rosso, Дел Россо Джим
  • Year: 2016
  • Venue: Vestnik dermatologii i venerologii
  • URL: https://www.semanticscholar.org/paper/bfc788c245291c6dc7ace98ddb6c58f51e6c977a
  • DOI: 10.25208/0042-4609-2016-92-2-21-31
  • Citations: 4
  • Summary: В обзоре обобщены и систематизированы имеющиеся международные данные по патогенезу, клиническим проявлениям и текущим рекомендациям по тактике ведения пациентов с розацеа.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > Publications devoted primarily to pathophysiology of rosacea appear elsewhere in the medical literature; nev ertheless, explanations of rosaceaprone skin and the basic pathophysiologic mechanisms that seem to be op erative in rosacea are necessary in order to better un derstand the direct correlations with specific signs and symptoms of rosacea and allow for more rational selec tion of individual therapies in each case that address spe cific clinical manifestations of rosacea [5, 6, 13, 22, 26 32]. Rosaceaprone skin is characterized by three major

[16] Molecular Mechanisms in the Etiopathology of Rosacea—Systematic Review

  • Authors: Anastazja Andrusiewicz, Sofiia Khimuk, Daniel Mijas, Bohdan Shmorhun, D. Nowicka
  • Year: 2025
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/46211301b204c0f77bf013d73f281a9dc16b296e
  • DOI: 10.3390/ijms262311292
  • PMID: 41373451
  • PMCID: 12692705
  • Citations: 3
  • Summary: Results highlight that rosacea involves both cutaneous and systemic molecular alterations, and the evidence identifies multiple biomarkers with diagnostic potential and provides mechanistic insights into immune, vascular, and metabolic dysregulation.
  • Evidence snippets:
  • Snippet 1 (score: 0.391) > In analyzing the molecular mechanisms of rosacea, we categorized them into four main groups: (1) oxidative stress, (2) cytokine-driven signaling pathways, (3) immune cell signaling and skin barrier dysfunction, and (4) metabolic molecular markers. The schematic overview of these molecular mechanisms and their contribution to rosacea pathogenesis is presented in Figure 2.

[17] Exploring the molecular mechanisms of huperzine a in the treatment of rosacea through network pharmacology, machine learning, and molecular dynamics simulations

  • Authors: Xin Luo, S. Yang, Lian Zhong, Peng Zhang
  • Year: 2025
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/9ee98971fad0d5953c1934ff6437920464526139
  • DOI: 10.3389/fphar.2025.1586829
  • PMID: 40474977
  • PMCID: 12137240
  • Citations: 3
  • Summary: This study systematically elucidates the potential mechanisms of Hup A in the treatment of rosacea and provides a theoretical basis for its application in rosacea therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Rosacea is a recurrent inflammatory skin condition, with a worldwide prevalence exceeding 5% (Gether et al., 2018). Although there are many treatments including topical therapies, systemic treatments, as well as light-based therapy, rosacea cannot be completely cured (Sharma et al., 2022;Hua et al., 2025). Therefore, more effective, and safe therapeutic strategy for rosacea is urgently required. This study integrated network pharmacology, molecular docking, and computational modeling to systematically investigate the potential mechanisms and core targets of Hup A in treating rosacea. > The precise mechanisms underlying rosacea remain elusive, but it is well known that dysregulation of the immune and neurovascular systems has been recognized as playing crucial roles in its pathogenesis (Schwab et al., 2011). Patients with rosacea have an increased risk of depression and anxiety, which may exacerbate flushing and disease progression (Yang et al., 2024;Sinikumpu et al., 2024), underscoring the interplay between neuropsychiatric factors and cutaneous pathophysiology. Hup A was initially identified as an inhibitor of acetylcholinesterase (AChE) based on Chinese databases, and it has been utilized in the treatment of cognitive disorders related to memory deficits, including Alzheimer's disease and other types of dementia (Damar et al., 2016). By network pharmacology and pathway enrichment analysis, we identified 21 overlapping targets between Hup A and rosacea. KEGG pathway analysis revealed multiple signaling pathways including the MAPK, NF-κB, TNF-a, and PI3K-AKT pathways between Hup A and rosacea (Figure 2). In rosacea, activation of the MAPK signaling cascade drives inflammatory responses via regulation of IL-1β release (Harden et al., 2021). Notably, Isosilybin A has been shown to attenuate rosacea symptoms through MAPK pathway inhibition (Wu et al., 2024), suggesting conserved therapeutic utility of this axis. Similarly, the NF-κB pathway plays a central role in disease progression.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.
{ }

Source YAML

click to show 
name: Rosacea
creation_date: "2026-04-05T12:00:00Z"
updated_date: "2026-04-07T21:21:12Z"
category: Complex
description: >-
  Rosacea is a chronic relapsing inflammatory facial dermatosis centered on
  persistent or episodic centrofacial erythema, flushing, telangiectasia, and
  papulopustular lesions, with phymatous and ocular involvement in a subset of
  patients. Current mechanistic models emphasize dysregulated innate immunity,
  neurovascular hyperreactivity, skin barrier impairment, and trigger-dependent
  disease amplification.
disease_term:
  preferred_term: rosacea
  term:
    id: MONDO:0006604
    label: rosacea
parents:
  - Dermatological Disease
  - Inflammatory Skin Disease
has_subtypes:
  - name: Erythematotelangiectatic Rosacea
    description: >-
      Predominantly vascular rosacea phenotype characterized by persistent
      centrofacial erythema, flushing, and telangiectasia without dominant
      papulopustular or phymatous change.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
        explanation: >-
          This review explicitly recognizes erythematotelangiectatic rosacea as
          one of the four canonical clinical subtypes.
      - reference: PMID:27718519
        reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
        explanation: >-
          This phenotype-led consensus supports the core vascular features that
          anchor erythematotelangiectatic rosacea.
  - name: Papulopustular Rosacea
    description: >-
      Inflammatory rosacea subtype with persistent facial erythema accompanied
      by papules and pustules in the central face.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
        explanation: >-
          This review explicitly recognizes papulopustular rosacea as a major
          clinical subtype.
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
        explanation: >-
          This supports the inflammatory papule-pustule phenotype that defines
          papulopustular rosacea.
  - name: Phymatous Rosacea
    description: >-
      Tissue-remodeling subtype marked by thickening and hypertrophy of facial
      skin and sebaceous structures, most commonly affecting the nose as
      rhinophyma.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
        explanation: >-
          This review explicitly recognizes phymatous rosacea as one of the
          canonical clinical subtypes.
      - reference: PMID:41918801
        reference_title: "CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Phymatous rosacea (PhR), also known as \"rhinophyma\", refers to a benign condition characterized by the excessive proliferation of sebaceous glands and fibrosis in the facial skin due to rosacea"
        explanation: >-
          This supports the hypertrophic and fibrotic tissue-remodeling pattern
          characteristic of phymatous rosacea.
  - name: Ocular Rosacea
    description: >-
      Ocular subtype involving chronic inflammatory disease of the eyelids and
      ocular surface, often with blepharitis, meibomian dysfunction, dryness,
      and photophobia.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea can be divided into four subtypes (erythemato-telangiectatic, papulopustular, phymatous, and ocular), with erythemato-telangiectatic rosacea being the most common"
        explanation: >-
          This review explicitly recognizes ocular rosacea as a canonical
          rosacea subtype.
      - reference: PMID:40522449
        reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."
        explanation: >-
          This supports ocular rosacea as a distinct subtype centered on eyelid
          and ocular surface inflammation.
pathophysiology:
  - name: Skin barrier dysfunction
    description: >-
      Epidermal barrier disruption amplifies inflammatory signaling in rosacea
      and serves as an early permissive event for downstream innate immune
      activation.
    biological_processes:
      - preferred_term: establishment of skin barrier
        term:
          id: GO:0061436
          label: establishment of skin barrier
    cell_types:
      - preferred_term: keratinocyte
        term:
          id: CL:0000312
          label: keratinocyte
    downstream:
      - target: Pro-cathelicidin transcription
        description: >-
          Barrier-disrupting triggers increase keratinocyte pro-cathelicidin
          transcription.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "The sequence of innate immune activation in rosacea starts with factors increasing keratinocyte transcription of pro-cathelicidin (including vitamin D activated by UV, UV itself, infection, injury, and other triggers to barrier disruption)"
            explanation: >-
              This directly links barrier-disrupting triggers to increased
              pro-cathelicidin transcription in rosacea keratinocytes.
      - target: STAT3-mediated cytokine signaling
        description: >-
          Barrier injury activates a keratinocyte cytokine-signaling program
          centered on STAT3.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:35392024
            reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
            explanation: >-
              This directly supports barrier dysfunction as an upstream driver
              of STAT3-mediated cytokine signaling.
    evidence:
      - reference: PMID:35392024
        reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
        explanation: >-
          This study establishes barrier dysfunction as a disease-amplifying
          mechanism in rosacea.
  - name: Pro-cathelicidin transcription
    description: >-
      Keratinocytes in rosacea upregulate pro-cathelicidin transcription,
      creating substrate for downstream proteolytic generation of inflammatory
      peptides.
    cell_types:
      - preferred_term: keratinocyte
        term:
          id: CL:0000312
          label: keratinocyte
    downstream:
      - target: LL-37 generation
        description: >-
          Increased pro-cathelicidin availability supports downstream formation
          of LL-37 after proteolytic processing.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - kallikrein-mediated cathelicidin cleavage
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
            explanation: >-
              This supports cathelicidin-processing output to LL-37 downstream
              of increased pro-cathelicidin availability.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The sequence of innate immune activation in rosacea starts with factors increasing keratinocyte transcription of pro-cathelicidin"
        explanation: >-
          This review explicitly places pro-cathelicidin transcription near the
          start of rosacea innate immune activation.
  - name: TLR2 upregulation
    description: >-
      Keratinocyte TLR2 expression is increased in rosacea and sensitizes skin
      to environmental and microbial stimuli.
    cell_types:
      - preferred_term: keratinocyte
        term:
          id: CL:0000312
          label: keratinocyte
    downstream:
      - target: KLK5/KLK7 activation
        description: >-
          Increased TLR2 signaling promotes activation of kallikrein-family
          serine proteases.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "the serine proteases of the KLK family, KLK5 and KLK7 (activation mediated by TLR-2, which is upregulated by environmental and microbial stimuli)"
            explanation: >-
              This directly supports TLR2 as an upstream driver of KLK5/KLK7
              activation in rosacea.
    evidence:
      - reference: PMID:39823143
        reference_title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Specifically, Toll-like receptor 2 (TLR2) and S100A9 proteins were upregulated, potentially promoting these processes."
        explanation: >-
          This study supports increased TLR2 expression as part of rosacea
          inflammatory activation.
  - name: KLK5/KLK7 activation
    description: >-
      Kallikrein-family serine proteases are activated downstream of TLR2 and
      participate in cathelicidin processing.
    downstream:
      - target: LL-37 generation
        description: >-
          Activated KLK5/KLK7 cleave pro-cathelicidin to generate LL-37 and
          related peptides.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
            explanation: >-
              This supports KLK-mediated proteolytic generation of LL-37.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "the serine proteases of the KLK family, KLK5 and KLK7 (activation mediated by TLR-2, which is upregulated by environmental and microbial stimuli)"
        explanation: >-
          This review identifies KLK5/KLK7 as activated proteases in rosacea
          innate immune signaling.
  - name: LL-37 generation
    description: >-
      Proteolytic cathelicidin processing yields LL-37 and related peptides
      with inflammatory and angiogenic activity.
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
      - preferred_term: angiogenesis
        term:
          id: GO:0001525
          label: angiogenesis
    downstream:
      - target: Mast cell-mediated amplification
        description: >-
          Cathelicidin signaling recruits mast-cell-dependent amplification of
          inflammation and vascular reactivity.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation"
            explanation: >-
              This directly supports mast cells as downstream mediators of
              cathelicidin signaling.
      - target: Angiogenic vascular remodeling
        description: >-
          LL-37 and related peptides promote angiogenic changes in cutaneous
          vasculature.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
            explanation: >-
              This directly supports an angiogenic vascular effect downstream of
              LL-37 generation.
      - target: Th1/Th17 adaptive inflammation
        description: >-
          LL-37-exposed keratinocytes induce chemokine programs that recruit
          pathogenic T cells and strengthen adaptive inflammatory polarization.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - CXCL10 induction
          - Jak1/STAT1 signaling
        evidence:
          - reference: PMID:40835085
            reference_title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
            supports: SUPPORT
            evidence_source: IN_VITRO
            snippet: "Mechanistically, LL-37-induced CXCL10 production relied on the Jak1/signal transducer and activator of transcription 1 signaling pathway."
            explanation: >-
              This supports a mechanistic bridge from LL-37 exposure to
              chemokine-driven adaptive inflammatory recruitment.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
        explanation: >-
          This review identifies LL-37 generation as a key inflammatory and
          angiogenic step in rosacea.
      - reference: PMID:40835085
        reference_title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Abnormal overexpression of human antimicrobial peptide LL-37 is a hallmark of rosacea."
        explanation: >-
          This study reinforces LL-37 overexpression as a central proximal
          mechanism in rosacea biology.
      - reference: PMID:41087666
        reference_title: "LAPTM5 exacerbates STING-mediated inflammation induced by LL-37 through stabilizing STING in rosacea."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Both STING antagonist H-151 and LAPTM5 knockdown alleviate LL-37-induced rosacea-like phenotypes."
        explanation: >-
          This model-organism evidence supports LL-37 as a proximal inducer of
          rosacea-like inflammatory disease programs.
  - name: Mast cell-mediated amplification
    description: >-
      Mast cells amplify cathelicidin-initiated inflammation and increase local
      vasodilation within rosacea lesions.
    cell_types:
      - preferred_term: mast cell
        term:
          id: CL:0000097
          label: mast cell
    downstream:
      - target: Neurovascular vasodilation
        description: >-
          Mast-cell activation promotes vasodilatory responses in affected skin.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation—amplifying inflammation, vasodilation, and generation of LL-37"
            explanation: >-
              This directly supports mast cells as mediators of vasodilation in
              rosacea lesions.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Mast cells are pivotal mediators of cathelicidin-initiated skin inflammation—amplifying inflammation, vasodilation, and generation of LL-37"
        explanation: >-
          This review places mast cells in an amplification loop that increases
          inflammatory and vascular disease activity.
  - name: STAT3-mediated cytokine signaling
    description: >-
      Keratinocyte STAT3-centered cytokine signaling links barrier injury to
      inflammatory persistence and immune-cell recruitment.
    biological_processes:
      - preferred_term: cytokine-mediated signaling pathway
        term:
          id: GO:0019221
          label: cytokine-mediated signaling pathway
    cell_types:
      - preferred_term: keratinocyte
        term:
          id: CL:0000312
          label: keratinocyte
    downstream:
      - target: Immune cell infiltration
        description: >-
          STAT3 activation promotes immune-cell accumulation within rosacea
          lesions.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:35392024
            reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "STAT3 could contribute to the progression of rosacea partly by dysregulating immune infiltration via activating the cytokine/chemokines signal."
            explanation: >-
              This directly links STAT3-mediated cytokine signaling to increased
              immune infiltration in rosacea.
    evidence:
      - reference: PMID:35392024
        reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes."
        explanation: >-
          This study identifies STAT3-mediated cytokine signaling as a key
          inflammatory amplifier in rosacea.
  - name: Immune cell infiltration
    description: >-
      Rosacea lesions show increased immune-cell infiltration that reinforces
      inflammatory lesion formation.
    downstream:
      - target: Papulopustular inflammation
        description: >-
          Increased lesional immune infiltration supports development of
          inflammatory papules and pustules.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:35392024
            reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea"
            explanation: >-
              This supports immune infiltration as part of the inflammatory
              lesion-forming program in rosacea.
    evidence:
      - reference: PMID:35392024
        reference_title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The XCell immune cell assays showed that the increased immune infiltration with SBD."
        explanation: >-
          This transcriptomic analysis supports increased immune-cell
          infiltration in rosacea with barrier dysfunction.
  - name: Th1/Th17 adaptive inflammation
    description: >-
      Chemokine and cytokine networks in rosacea polarize adaptive immunity
      toward Th1/Th17 inflammatory programs.
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
    downstream:
      - target: Papulopustular inflammation
        description: >-
          Th1/Th17-skewed adaptive inflammation contributes to inflammatory
          papulopustular lesions.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Chemokine and cytokine signals interact to generate a Th1/Th17-polarized adaptive immune response in rosacea"
            explanation: >-
              This supports an adaptive inflammatory branch converging on
              papulopustular disease activity.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Chemokine and cytokine signals interact to generate a Th1/Th17-polarized adaptive immune response in rosacea"
        explanation: >-
          This review supports a Th1/Th17-polarized adaptive inflammatory
          response in rosacea.
      - reference: PMID:40835085
        reference_title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "T-cell recruiting chemokine CXCL10 turns out to be the most abundant inflammatory mediator overexpressed upon LL-37 exposure."
        explanation: >-
          This supports a chemokine-driven adaptive immune arm linking
          keratinocyte activation to pathogenic T-cell recruitment.
  - name: TRP and neuropeptide signaling
    description: >-
      TRP-channel activation and neuropeptide signaling form a neurocutaneous
      branch of rosacea pathophysiology that increases vascular reactivity.
    biological_processes:
      - preferred_term: neuropeptide signaling pathway
        term:
          id: GO:0007218
          label: neuropeptide signaling pathway
    downstream:
      - target: Neurovascular vasodilation
        description: >-
          TRP and neuropeptide signaling promote exaggerated vasodilatory
          responses in rosacea skin.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:34035646
            reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides"
            explanation: >-
              This directly supports TRP and neuropeptides as upstream drivers
              of rosacea neurovascular dysregulation.
    evidence:
      - reference: PMID:34035646
        reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides"
        explanation: >-
          This review identifies TRP and neuropeptides as part of the
          neurovascular arm of rosacea pathophysiology.
  - name: Neurovascular vasodilation
    description: >-
      Exaggerated vasodilation is a proximal vascular event that drives flushing
      and contributes to persistent background erythema.
    downstream:
      - target: Flushing
        description: Vasodilatory surges produce episodic flushing.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema)"
            explanation: >-
              This supports flushing as a direct clinical output of vascular
              hyperreactivity in rosacea.
      - target: Persistent centrofacial erythema
        description: >-
          Recurrent vasodilatory instability contributes to chronic background
          centrofacial erythema.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - recurrent vascular hyperreactivity
          - persistent superficial vasodilation
        evidence:
          - reference: PMID:27718519
            reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "persistent, centrofacial erythema associated with periodic intensification"
            explanation: >-
              This supports persistent erythema as a chronic vascular phenotype
              that periodically intensifies.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "while the multifactorial pathology of rosacea is thought to involve both vasoactive and neurocutaneous mechanisms."
        explanation: >-
          This overview supports a vasoreactive proximal mechanism in rosacea.
  - name: Angiogenic vascular remodeling
    description: >-
      Angiogenic signaling contributes to persistent vascular remodeling and
      visible superficial telangiectatic change.
    biological_processes:
      - preferred_term: angiogenesis
        term:
          id: GO:0001525
          label: angiogenesis
    downstream:
      - target: Facial telangiectasia
        description: >-
          Persistent angiogenic remodeling contributes to telangiectatic
          centrofacial vessels.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:37626650
            reference_title: "Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face."
            explanation: >-
              This supports telangiectasia as a major downstream vascular
              manifestation of rosacea.
      - target: Persistent centrofacial erythema
        description: >-
          Remodeling of superficial vasculature helps sustain background facial
          erythema.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - superficial vascular enlargement
          - persistent cutaneous hyperemia
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
            explanation: >-
              This supports an angiogenic component in the pathway that sustains
              persistent erythematous change.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This leads to the formation of LL-37 and other peptides that are inflammatory and angiogenic"
        explanation: >-
          This supports angiogenic signaling as a discrete downstream consequence
          of cathelicidin pathway activation.
      - reference: PMID:40567003
        reference_title: "Novel Molecular Subtyping Revealed Molecular Pathways That Contribute to the Pathogenesis of Rosacea."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "angiogenesis and neutrophil activation may contribute to persistent erythema and a large number of papules and pustules in the severe stage of rosacea."
        explanation: >-
          This molecular subtyping study supports angiogenesis as a driver of
          persistent erythema and lesion-rich severe rosacea.
  - name: Papulopustular inflammation
    description: >-
      Convergent innate, adaptive, and keratinocyte inflammatory programs
      produce inflammatory papules and pustules in papulopustular rosacea.
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
    downstream:
      - target: Papules
        description: Inflammatory lesion formation produces papular eruptions.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
            explanation: >-
              This directly supports papules as a downstream inflammatory lesion
              type in rosacea.
      - target: Pustules
        description: Ongoing inflammatory lesion formation produces pustules.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:28150107
            reference_title: "Acne and Rosacea."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
            explanation: >-
              This directly supports pustules as a downstream inflammatory lesion
              type in rosacea.
    evidence:
      - reference: PMID:39823143
        reference_title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Transcriptomic analysis revealed significantly elevated expression of inflammatory-related genes in rosacea patients."
        explanation: >-
          This study supports a lesion-forming inflammatory state in rosacea
          skin.
  - name: Sebaceous gland dysfunction
    description: >-
      Dysfunction of cutaneous sebaceous glands is recognized as part of the
      multifactorial tissue biology of rosacea.
    downstream:
      - target: Sebaceous gland and soft tissue hyperplasia/fibrosis
        description: >-
          In advanced disease, altered sebaceous-unit biology can progress to
          hyperplastic and fibrotic phymatous tissue remodeling.
        causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
        intermediate_mechanisms:
          - chronic inflammation
          - connective tissue remodeling
        evidence:
          - reference: PMID:19428039
            reference_title: "[Rhinophyma in a black African male patient]."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
            explanation: >-
              This supports progression from abnormal sebaceous-unit biology to
              sebaceous and soft-tissue hyperplasia/fibrosis in phymatous
              rosacea.
    evidence:
      - reference: PMID:34035646
        reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands."
        explanation: >-
          This review identifies sebaceous gland dysfunction as a discrete
          component of rosacea pathophysiology.
  - name: Meibomian gland dysfunction
    description: >-
      Ocular rosacea includes meibomian gland dysfunction as part of its
      site-specific pathophysiology.
    downstream:
      - target: Ocular surface and eyelid inflammation
        description: >-
          Meibomian-gland disease contributes to chronic inflammatory
          involvement of the eyelids and ocular surface.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:40522449
            reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
            explanation: >-
              This directly links meibomian disease to chronic inflammatory
              involvement of the eyelids and ocular surface in ocular rosacea.
    evidence:
      - reference: PMID:34035646
        reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Recognized mechanisms include the innate immune system, with the implication of Toll-like receptors (TLRs) and cathelicidins; neurovascular deregulation involving vascular endothelial growth factor (VEGF), transient receptor potential (TRP) ion channels, and neuropeptides; and dysfunction of skin sebaceous glands and ocular meibomian glands."
        explanation: >-
          This review identifies meibomian gland dysfunction as part of ocular
          rosacea biology.
  - name: Ocular surface and eyelid inflammation
    description: >-
      Ocular rosacea produces chronic inflammatory involvement of the eyelids
      and ocular surface, with posterior blepharitis as a characteristic
      clinical expression.
    biological_processes:
      - preferred_term: inflammatory response
        term:
          id: GO:0006954
          label: inflammatory response
    downstream:
      - target: Blepharitis
        description: >-
          Chronic eyelid inflammation manifests clinically as posterior
          blepharitis.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:40522449
            reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
            explanation: >-
              This directly supports blepharitis as a downstream phenotype of
              ocular rosacea inflammatory eyelid disease.
    evidence:
      - reference: PMID:40522449
        reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Ocular rosacea is a chronic inflammatory disease that affects the surface of the eye and the eyelids."
        explanation: >-
          This review supports ocular rosacea as an inflammatory disease of the
          eyelids and ocular surface.
  - name: Fibrotic dermal remodeling
    description: >-
      Advanced rosacea can shift toward a fibrotic remodeling program in which
      vascular changes are coupled to connective-tissue fibrosis.
    downstream:
      - target: Sebaceous gland and soft tissue hyperplasia/fibrosis
        description: >-
          Fibrotic remodeling progresses to phymatous tissue overgrowth
          involving sebaceous units and surrounding soft tissue.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:25151931
            reference_title: "[Physiopathology of rosacea]."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Finaly, rhinophyma is linked to both vascular changes and activation of fibrosis, involving TGF beta."
            explanation: >-
              This supports a fibrotic remodeling step in advanced phymatous
              rosacea.
    evidence:
      - reference: PMID:25151931
        reference_title: "[Physiopathology of rosacea]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Finaly, rhinophyma is linked to both vascular changes and activation of fibrosis, involving TGF beta."
        explanation: >-
          This review supports fibrosis as a specific mechanism underlying
          rhinophyma development.
      - reference: PMID:41139274
        reference_title: "Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "GZMK also promoted cell proliferation and inflammatory factors (including IL-1β, IL-6, and TNFα) production in fibroblasts through activating the NF-κB pathway in vitro."
        explanation: >-
          This directly supports fibroblast proliferative and inflammatory
          programs that can feed fibrotic remodeling in advanced rosacea.
  - name: Sebaceous gland and soft tissue hyperplasia/fibrosis
    description: >-
      Rhinophyma reflects progressive hypertrophic remodeling of sebaceous
      glands and adjacent soft tissue in the nose.
    downstream:
      - target: Phymatous change of the nose
        description: >-
          Hyperplastic and fibrotic tissue overgrowth produces the bulbous,
          progressively deformed nasal phenotype of rhinophyma.
        causal_link_type: DIRECT
        evidence:
          - reference: PMID:19428039
            reference_title: "[Rhinophyma in a black African male patient]."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
            explanation: >-
              This directly supports phymatous nasal change as the clinical
              result of sebaceous-gland and soft-tissue hyperplasia/fibrosis.
    evidence:
      - reference: PMID:19428039
        reference_title: "[Rhinophyma in a black African male patient]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
        explanation: >-
          This abstract defines rhinophyma in terms of sebaceous-gland and soft
          tissue hyperplasia/fibrosis.
phenotypes:
  - name: Persistent centrofacial erythema
    category: Dermatological
    frequency: VERY_FREQUENT
    diagnostic: true
    subtype: Erythematotelangiectatic Rosacea
    notes: >-
      Persistent background erythema of the central face is a core diagnostic
      phenotype in modern phenotype-led rosacea classification.
    phenotype_term:
      preferred_term: persistent centrofacial erythema
      term:
        id: HP:0001041
        label: Facial erythema
    evidence:
      - reference: PMID:27718519
        reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
        explanation: >-
          ROSCO identifies persistent centrofacial erythema as one of the two
          diagnostic phenotypes for rosacea.
  - name: Flushing
    category: Dermatological
    frequency: FREQUENT
    subtype: Erythematotelangiectatic Rosacea
    notes: Episodic flushing commonly accompanies the vascular phenotype.
    phenotype_term:
      preferred_term: flushing
      term:
        id: HP:0031284
        label: Flushing
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
        explanation: >-
          This overview identifies flushing as a characteristic clinical
          manifestation of rosacea.
  - name: Facial telangiectasia
    category: Dermatological
    frequency: FREQUENT
    subtype: Erythematotelangiectatic Rosacea
    phenotype_term:
      preferred_term: facial telangiectasia
      term:
        id: HP:0007380
        label: Facial telangiectasia
    evidence:
      - reference: PMID:37626650
        reference_title: "Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face."
        explanation: >-
          This review includes telangiectasia among the central defining
          manifestations of rosacea.
  - name: Papules
    category: Dermatological
    frequency: FREQUENT
    subtype: Papulopustular Rosacea
    phenotype_term:
      preferred_term: erythematous papule
      term:
        id: HP:0030350
        label: Erythematous papule
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
        explanation: >-
          This overview identifies inflammatory papules as a characteristic
          lesion type in rosacea.
  - name: Pustules
    category: Dermatological
    frequency: FREQUENT
    subtype: Papulopustular Rosacea
    phenotype_term:
      preferred_term: pustule
      term:
        id: HP:0200039
        label: Pustule
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rosacea is a chronic facial inflammatory dermatosis characterized by flushing (or transient facial erythema), persistent central facial erythema, inflammatory papules/pustules, and telangiectasia."
        explanation: >-
          This overview identifies papulopustular lesions as part of the core
          clinical spectrum of rosacea.
  - name: Phymatous change of the nose
    category: Dermatological
    frequency: OCCASIONAL
    diagnostic: true
    subtype: Phymatous Rosacea
    notes: >-
      Phymatous rosacea is most often expressed as progressive tissue
      thickening of the nose (rhinophyma).
    phenotype_term:
      preferred_term: rhinophyma
      term:
        id: HP:0000414
        label: Bulbous nose
    evidence:
      - reference: PMID:27718519
        reference_title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The following two features were independently considered diagnostic for rosacea: (i) persistent, centrofacial erythema associated with periodic intensification; and (ii) phymatous changes."
        explanation: >-
          ROSCO identifies phymatous change as the second independently
          diagnostic phenotype of rosacea.
  - name: Blepharitis
    category: Ophthalmological
    frequency: OCCASIONAL
    subtype: Ocular Rosacea
    notes: Ocular rosacea often presents with eyelid margin inflammation.
    phenotype_term:
      preferred_term: blepharitis
      term:
        id: HP:0000498
        label: Blepharitis
    evidence:
      - reference: PMID:40522449
        reference_title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "It is characterized by bilateral chronic posterior blepharitis and meibomitis, which can involve the entire surface of the eye, including the cornea, during the course of the disease."
        explanation: >-
          This directly supports chronic posterior blepharitis as a hallmark
          ocular phenotype of ocular rosacea.
  - name: Facial edema
    category: Dermatological
    frequency: RARE
    notes: >-
      A rare rosacea-associated lymphedematous presentation, often termed
      Morbihan disease, causes chronic persistent facial swelling.
    phenotype_term:
      preferred_term: facial edema
      term:
        id: HP:0000282
        label: Facial edema
    evidence:
      - reference: PMID:41426892
        reference_title: "Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Morbihan disease, also known as rosacea-associated solid facial edema, is a rare and chronic condition that presents with persistent facial swelling and often proves difficult to treat."
        explanation: >-
          This directly supports persistent facial edema as a rare rosacea-
          associated phenotype.
  - name: Upper eyelid edema
    category: Ophthalmological
    frequency: RARE
    subtype: Ocular Rosacea
    notes: >-
      Ocular rosacea can rarely present with persistent peri-orbital swelling,
      sometimes accompanied by secondary ptosis.
    phenotype_term:
      preferred_term: upper eyelid edema
      term:
        id: HP:0012724
        label: Upper eyelid edema
    evidence:
      - reference: PMID:41058755
        reference_title: "Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "A 64-year-old Caucasian man presented with a 9-month history of persistent painless swelling of the right upper eyelid and secondary ptosis."
        explanation: >-
          This case report supports persistent upper-eyelid edema as a rare
          ocular manifestation of rosacea.
histopathology:
  - name: Dermal vascular endothelial Angiopoietin 2 and Tie2 overexpression
    description: >-
      Lesional erythematotelangiectatic and papulopustular rosacea skin shows
      increased Angiopoietin 2 and Tie2 staining in endothelial cells of dermal
      vessels compared with non-lesional skin, supporting a vascular
      remodeling-associated histopathology pattern.
    context: Erythematotelangiectatic and papulopustular rosacea skin biopsies
    evidence:
      - reference: PMID:41562711
        reference_title: "Increased Expression of Angiopoietin 2 and Tie2 in Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Significantly increased expression of Tie2 and Angiopoietin 2 in the endothelial cells of the dermal vessels in rosacea skin vs. non-lesional skin (100% and 33.3% for Tie2, and 100% and 50% for Angiopoietin 2) was observed."
        explanation: >-
          This provides direct biopsy-level immunohistochemical evidence for
          altered dermal vascular endothelium in rosacea lesions.
  - name: Early dermal fibrotic remodeling
    finding_term:
      preferred_term: fibrosis
      term:
        id: NCIT:C3044
        label: Fibrosis
    description: >-
      Fibrotic remodeling is detectable in rosacea skin biopsies even at
      inflammation-dominant stages, indicating that tissue-remodeling changes
      begin before fully developed phymatous disease.
    context: Inflammation-dominant rosacea skin biopsies
    evidence:
      - reference: PMID:41800255
        reference_title: "Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages"
        explanation: >-
          This study directly supports fibrosis as an observable tissue-level
          change in rosacea biopsies, not only in late rhinophyma.
  - name: Sebaceous gland and surrounding soft tissue hyperplasia with fibrosis
    subtype: Phymatous Rosacea
    description: >-
      Rhinophyma shows hypertrophic remodeling of sebaceous glands and adjacent
      soft tissue accompanied by fibrosis, forming the core microscopic pattern
      of phymatous rosacea.
    context: Rhinophyma / phymatous rosacea
    evidence:
      - reference: PMID:19428039
        reference_title: "[Rhinophyma in a black African male patient]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Rhinophyma is an irregular and progressive nasal hypertrophy, due to hyperplasia and fibrosis of the sebaceous glands and surrounding soft tissues."
        explanation: >-
          This abstract directly supports sebaceous gland hyperplasia with
          fibrosis as a defining microscopic tissue-remodeling feature of
          rhinophyma.
  - name: Leaky vascular architecture in rhinophyma tissue
    subtype: Phymatous Rosacea
    description: >-
      Rhinophyma tissue shows an abnormal vascular architecture with leaky
      vessel profiles rather than the stromal-enveloped vascular pattern seen
      in hypertrophic scars.
    context: Rhinophyma tissue
    evidence:
      - reference: PMID:41909715
        reference_title: "Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Vascular structures in hypertrophic scar tissues are enveloped by a significant number of stromal cells, in contrast to the leaky vascular profiles observed in rhinophyma tissues."
        explanation: >-
          This study supports a distinctive vascular tissue architecture in
          rhinophyma that fits the disease's vascular-remodeling phenotype.
  - name: Immune-cell-rich rhinophyma tissue
    subtype: Phymatous Rosacea
    description: >-
      Rhinophyma tissue contains a relatively expanded immune-cell compartment,
      consistent with persistent inflammatory remodeling in phymatous disease.
    context: Rhinophyma tissue
    evidence:
      - reference: PMID:41909715
        reference_title: "Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "the number of immune cells in rhinophyma is significantly higher than in hypertrophic scar tissues."
        explanation: >-
          This supports immune-cell enrichment as a tissue-level feature of
          rhinophyma.
  - name: Eyelid tissue lymphoedema in ocular rosacea
    subtype: Ocular Rosacea
    description: >-
      In rare ocular rosacea with persistent peri-orbital swelling, eyelid
      debulking biopsy can show rosacea-associated inflammatory change with
      superimposed lymphoedematous tissue remodeling.
    context: Ocular rosacea with persistent peri-orbital edema
    evidence:
      - reference: PMID:41058755
        reference_title: "Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Histopathological analysis of the debulking biopsy confirmed the diagnosis of rosacea, with additional features indicative of lymphoedema."
        explanation: >-
          This provides direct biopsy-level support for lymphoedematous tissue
          change in a rare ocular rosacea presentation.
genetic:
  - name: IRF1
    gene_term:
      preferred_term: IRF1
      term:
        id: hgnc:6116
        label: IRF1
    association: MR-supported druggable gene
    notes: >-
      Integrative MR/SMR analysis prioritized IRF1 as a rosacea-linked
      druggable gene and connected it to immune-cell activation and interferon
      signaling.
    evidence:
      - reference: PMID:40635520
        reference_title: "Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."
        explanation: >-
          This directly supports IRF1 as a genetically prioritized therapeutic
          target in rosacea.
  - name: SLC22A5
    gene_term:
      preferred_term: SLC22A5
      term:
        id: hgnc:10969
        label: SLC22A5
    association: MR-supported druggable gene
    notes: >-
      SLC22A5 emerged from integrative MR/SMR analysis as a rosacea-linked
      druggable gene, with proposed relevance to transport and lipid
      homeostasis.
    evidence:
      - reference: PMID:40635520
        reference_title: "Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "MR and SMR analyses identified IRF1 and SLC22A5 as druggable genes for rosacea, with Bayesian colocalization strongly supporting shared causal variants."
        explanation: >-
          This directly supports SLC22A5 as a genetically prioritized
          therapeutic target in rosacea.
  - name: GZMK
    gene_term:
      preferred_term: GZMK
      term:
        id: hgnc:4711
        label: GZMK
    association: MR-supported drug target
    notes: >-
      Multi-omics prioritization identified GZMK as a rosacea-linked target and
      functionally connected it to inflammatory fibroblast activation.
    evidence:
      - reference: PMID:41139274
        reference_title: "Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "MR and colocalization identified Granzyme K (GZMK) as a drug target, whose expression increased in the affected samples."
        explanation: >-
          This supports GZMK as a genetically prioritized rosacea target with
          increased expression in disease-associated samples.
  - name: MSR1
    gene_term:
      preferred_term: MSR1
      term:
        id: hgnc:7376
        label: MSR1
    association: MR-supported risk-promoting biomarker
    notes: >-
      Integrative proteomic and Mendelian-randomization analysis identified
      MSR1 as a rosacea-promoting protein target.
    evidence:
      - reference: PMID:40890957
        reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
        explanation: >-
          This directly supports MSR1 as the risk-promoting protein among the
          final MR-prioritized rosacea biomarkers.
  - name: ABHD14B
    gene_term:
      preferred_term: ABHD14B
      term:
        id: hgnc:28235
        label: ABHD14B
    association: MR-supported protective biomarker
    notes: >-
      ABHD14B was among the final proteins whose genetically informed analyses
      suggested an inhibitory relationship with rosacea onset.
    evidence:
      - reference: PMID:40890957
        reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
        explanation: >-
          This supports ABHD14B as one of the final MR-prioritized proteins
          associated with lower rosacea risk.
  - name: CHMP6
    gene_term:
      preferred_term: CHMP6
      term:
        id: hgnc:25675
        label: CHMP6
    association: MR-supported protective biomarker
    notes: >-
      CHMP6 was among the final proteins whose genetically informed analyses
      suggested an inhibitory relationship with rosacea onset.
    evidence:
      - reference: PMID:40890957
        reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
        explanation: >-
          This supports CHMP6 as one of the final MR-prioritized proteins
          associated with lower rosacea risk.
  - name: DBNL
    gene_term:
      preferred_term: DBNL
      term:
        id: hgnc:2696
        label: DBNL
    association: MR-supported protective biomarker
    notes: >-
      DBNL was among the final proteins whose genetically informed analyses
      suggested an inhibitory relationship with rosacea onset.
    evidence:
      - reference: PMID:40890957
        reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
        explanation: >-
          This supports DBNL as one of the final MR-prioritized proteins
          associated with lower rosacea risk.
  - name: MCFD2
    gene_term:
      preferred_term: MCFD2
      term:
        id: hgnc:18451
        label: MCFD2
    association: MR-supported protective biomarker
    notes: >-
      MCFD2 was among the final proteins whose genetically informed analyses
      suggested an inhibitory relationship with rosacea onset.
    evidence:
      - reference: PMID:40890957
        reference_title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
        supports: SUPPORT
        evidence_source: COMPUTATIONAL
        snippet: "Further refinement through SMR and differential expression analysis reduced this to five key proteins, including four (ABHD14B, CHMP6, DBNL and MCFD2) that inhibit rosacea onset and one (MSR1) that promotes it."
        explanation: >-
          This supports MCFD2 as one of the final MR-prioritized proteins
          associated with lower rosacea risk.
environmental:
  - name: Ultraviolet B radiation
    description: >-
      Ultraviolet B exposure is a recognized favoring factor that can worsen
      rosacea activity and amplify inflammatory and vascular responses.
    effect: TRIGGERS
    evidence:
      - reference: PMID:34035646
        reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
        explanation: >-
          This review explicitly identifies UVB radiation as an important
          rosacea-promoting exposure.
  - name: Corticosteroid treatment
    description: >-
      Corticosteroid exposure can favor rosacea expression and is a recognized
      exacerbating factor in susceptible patients.
    effect: TRIGGERS
    evidence:
      - reference: PMID:34035646
        reference_title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Microorganisms, genetic predisposition, corticosteroid treatment, and ultraviolet B (UVB) radiation are favoring factors."
        explanation: >-
          This review explicitly identifies corticosteroid treatment as a
          favoring factor for rosacea.
treatments:
  - name: Trigger avoidance and photoprotection
    description: >-
      Baseline management includes avoidance of provoking exposures, gentle skin
      care, moisturization, and sun protection to reduce flares.
    role: Foundational nonpharmacologic management
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "While standard measures, including avoidance of triggers, gentle cleansers, and moisturizers in combination with sun protection, may mitigate flares, control signs and symptoms in some patients"
        explanation: >-
          This review supports trigger avoidance, gentle skin care, and
          photoprotection as foundational rosacea management.
  - name: Papulopustular-directed pharmacotherapy
    description: >-
      Papulopustular rosacea is commonly treated with topical metronidazole,
      azelaic acid, or ivermectin, and in more inflammatory disease with oral
      doxycycline or isotretinoin.
    role: Mainstay treatment for papulopustular disease
    treatment_term:
      preferred_term: pharmacotherapy
      term:
        id: MAXO:0000058
        label: pharmacotherapy
      therapeutic_agent:
        - preferred_term: metronidazole
          term:
            id: CHEBI:6909
            label: metronidazole
        - preferred_term: azelaic acid
          term:
            id: NCIT:C47407
            label: Azelaic Acid
        - preferred_term: ivermectin
          term:
            id: CHEBI:6078
            label: ivermectin
        - preferred_term: doxycycline
          term:
            id: CHEBI:50845
            label: doxycycline
        - preferred_term: isotretinoin
          term:
            id: NCIT:C603
            label: Isotretinoin
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "topical metronidazole, azelaic acid, ivermectin, or oral doxycycline and isotretinoin for papulopustules of rosacea"
        explanation: >-
          This review summarizes standard pharmacologic options used for
          papulopustular rosacea.
  - name: Topical brimonidine therapy
    description: >-
      Persistent background erythema can be treated with topical brimonidine to
      reduce visible vasodilatory erythema.
    role: Pharmacologic treatment for the vascular erythema phenotype
    treatment_term:
      preferred_term: pharmacotherapy
      term:
        id: MAXO:0000058
        label: pharmacotherapy
      therapeutic_agent:
        - preferred_term: brimonidine
          term:
            id: CHEBI:3175
            label: brimonidine
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "topical brimonidine or intense pulsed light (IPL) for background persistent erythema"
        explanation: >-
          This review identifies brimonidine as a targeted therapy for
          persistent background erythema.
  - name: Vascular light-based therapy
    description: >-
      Persistent vascular erythema may also be treated with light-based therapy
      such as intense pulsed light.
    role: Procedural treatment for the vascular erythema phenotype
    treatment_term:
      preferred_term: vascular light-based therapy
      qualifiers:
        - predicate:
            preferred_term: therapeutic procedure
            term:
              id: NCIT:C49236
              label: Therapeutic Procedure
          value:
            preferred_term: phototherapy
            term:
              id: NCIT:C15301
              label: Phototherapy
    notes: >-
      Local OAK searches in MAXO for phototherapy, light therapy, laser
      therapy, and intense pulsed light did not return a suitable non-ionizing
      light-treatment term. This remains an NTR candidate, so the entry is
      represented with a free-text preferred term and an NCIT phototherapy
      qualifier rather than the incorrect radiotherapy term.
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "topical brimonidine or intense pulsed light (IPL) for background persistent erythema"
        explanation: >-
          This review identifies light-based vascular therapy as another
          targeted approach for persistent erythema.
  - name: Cyclosporine eye drops
    description: >-
      Ocular rosacea may require targeted ophthalmic anti-inflammatory therapy
      such as cyclosporine eye drops.
    role: Pharmacologic treatment for ocular rosacea
    treatment_term:
      preferred_term: pharmacotherapy
      term:
        id: MAXO:0000058
        label: pharmacotherapy
      therapeutic_agent:
        - preferred_term: cyclosporine
          term:
            id: CHEBI:4031
            label: cyclosporin A
    evidence:
      - reference: PMID:28150107
        reference_title: "Acne and Rosacea."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "cyclosporine eye drops for ocular rosacea"
        explanation: >-
          This review identifies cyclosporine eye drops as a treatment option
          for ocular rosacea.
  - name: Morbihan disease-directed pharmacotherapy
    description: >-
      Rosacea-associated solid facial edema may require individualized
      combination pharmacotherapy centered on isotretinoin and intralesional
      corticosteroid treatment, with ketotifen used in selected refractory
      cases.
    role: Targeted treatment for rosacea-associated solid facial edema
    target_phenotypes:
      - preferred_term: facial edema
        term:
          id: HP:0000282
          label: Facial edema
    treatment_term:
      preferred_term: pharmacotherapy
      term:
        id: MAXO:0000058
        label: pharmacotherapy
      therapeutic_agent:
        - preferred_term: isotretinoin
          term:
            id: NCIT:C603
            label: Isotretinoin
        - preferred_term: triamcinolone
          term:
            id: NCIT:C901
            label: Triamcinolone
        - preferred_term: ketotifen
          term:
            id: CHEBI:92511
            label: ketotifen
    evidence:
      - reference: PMID:41426892
        reference_title: "Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The patient reported partial improvement, most notably with higher isotretinoin dosing and intralesional corticosteroid injections, though intermittent flares persisted."
        explanation: >-
          This supports isotretinoin and intralesional corticosteroid treatment
          as active components of Morbihan disease management.
      - reference: PMID:41222206
        reference_title: "Unilateral presentation of Morbihan's disease: a comprehensive case report and review."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Successful treatment with a series of triamcinolone injections to the upper and lower eyelids was achieved after several unsuccessful therapies."
        explanation: >-
          This independently supports intralesional triamcinolone as a useful
          treatment option for rosacea-associated solid facial edema.
  - name: Laser surgical debulking for rhinophyma
    description: >-
      CO2 laser or blue-laser debulking can remove phymatous nasal tissue and
      improve function and cosmesis in selected rhinophyma.
    role: Procedural treatment for phymatous rosacea
    target_phenotypes:
      - preferred_term: rhinophyma
        term:
          id: HP:0000414
          label: Bulbous nose
    treatment_term:
      preferred_term: laser surgical procedure
      term:
        id: MAXO:0001578
        label: laser surgical procedure
    evidence:
      - reference: PMID:41918801
        reference_title: "CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "we emphasize the surgical value of local anesthesia with CO2 laser for rhinophyma, reducing blood loss, operation time, and the need for secondary surgery."
        explanation: >-
          This case report supports CO2 laser debulking as an effective
          rhinophyma procedure with practical operative advantages.
      - reference: PMID:40791837
        reference_title: "Rhinophyma Treatment with Blue Laser."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The use of blue laser to treat rhinophyma has shown to be an effective and safe procedure with very promising results."
        explanation: >-
          This provides additional support for laser-based debulking in
          rhinophyma.
  - name: Excisional reconstruction for advanced rhinophyma
    description: >-
      Severe rhinophyma may require excision with reconstructive approaches
      such as graft-based resurfacing when tissue overgrowth is extensive.
    role: Reconstructive procedural treatment for advanced phymatous rosacea
    target_phenotypes:
      - preferred_term: rhinophyma
        term:
          id: HP:0000414
          label: Bulbous nose
    treatment_term:
      preferred_term: surgical procedure
      term:
        id: MAXO:0000004
        label: surgical procedure
      qualifiers:
        - predicate:
            preferred_term: therapeutic procedure
            term:
              id: NCIT:C49236
              label: Therapeutic Procedure
          value:
            preferred_term: skin graft
            term:
              id: NCIT:C12842
              label: Skin Graft
        - predicate:
            preferred_term: therapeutic procedure
            term:
              id: NCIT:C49236
              label: Therapeutic Procedure
          value:
            preferred_term: reconstructive surgery
            term:
              id: NCIT:C25351
              label: Reconstructive Surgery
    evidence:
      - reference: PMID:40860281
        reference_title: "Rhinophyma treated by skin graft: a case report."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Surgical excision is the primary treatment, and various techniques are available."
        explanation: >-
          This supports excisional surgery as the primary treatment framework
          for advanced rhinophyma, including graft-based reconstruction.
clinical_trials:
  - name: NCT01493947
    phase: PHASE_III
    status: COMPLETED
    description: >-
      Phase III comparative topical trial of ivermectin 1% cream versus
      metronidazole 0.75% cream in papulopustular rosacea, with an extension
      period assessing relapse-related outcomes.
    target_phenotypes:
      - preferred_term: erythematous papule
        term:
          id: HP:0030350
          label: Erythematous papule
      - preferred_term: pustule
        term:
          id: HP:0200039
          label: Pustule
    evidence:
      - reference: clinicaltrials:NCT01493947
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "To compare efficacy and safety of Ivermectin 1% cream versus metronidazole 0.75% cream in subjects with papulopustular rosacea after 16-week topical treatment."
        explanation: >-
          This registry summary supports a pivotal interventional trial focused
          on papulopustular rosacea lesion control.
  - name: NCT00126399
    phase: PHASE_III
    status: COMPLETED
    description: >-
      Phase III placebo-controlled trial of once-daily 40 mg doxycycline
      controlled-release capsules for rosacea.
    target_phenotypes:
      - preferred_term: erythematous papule
        term:
          id: HP:0030350
          label: Erythematous papule
      - preferred_term: pustule
        term:
          id: HP:0200039
          label: Pustule
    evidence:
      - reference: clinicaltrials:NCT00126399
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The objective of this study is to evaluate the safety and efficacy of 40 mg doxycycline controlled-release capsules administered once daily for the treatment of rosacea compared with a placebo."
        explanation: >-
          This registry entry supports controlled clinical evaluation of
          subantimicrobial-dose doxycycline for rosacea.
  - name: NCT03380390
    phase: PHASE_IV
    status: COMPLETED
    description: >-
      Phase IV open-label study of oxymetazoline 1.0% cream used adjunctively
      with energy-based therapy for persistent facial erythema in rosacea.
    target_phenotypes:
      - preferred_term: persistent centrofacial erythema
        term:
          id: HP:0001041
          label: Facial erythema
    evidence:
      - reference: clinicaltrials:NCT03380390
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This study will evaluate the safety and tolerability of oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for participants with moderate to severe persistent facial erythema associated with rosacea."
        explanation: >-
          This trial directly targets the persistent erythema phenotype that
          anchors erythematotelangiectatic rosacea.
  - name: NCT05616923
    phase: PHASE_I
    status: COMPLETED
    description: >-
      Early-phase vehicle-controlled trial evaluating topical MEK inhibition in
      erythematotelangiectatic rosacea.
    target_phenotypes:
      - preferred_term: persistent centrofacial erythema
        term:
          id: HP:0001041
          label: Facial erythema
      - preferred_term: flushing
        term:
          id: HP:0031284
          label: Flushing
    evidence:
      - reference: clinicaltrials:NCT05616923
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This is a prospective, vehicle controlled, double blinded study to evaluate the safety and potential efficacy of a topical formulation of a MEK inhibitor in patients with erythematotelangiectatic rosacea"
        explanation: >-
          This registry entry supports a mechanism-oriented interventional study
          in the vascular erythematotelangiectatic phenotype.
datasets:
  - accession: geo:GSE65914
    title: Th1/Th17 Immune Response in Rosacea
    description: >-
      Human facial biopsy transcriptomic dataset spanning rosacea subtypes and
      healthy controls, used to define adaptive immune and inflammatory cell
      programs across erythematotelangiectatic, papulopustular, and phymatous
      disease.
    organism:
      preferred_term: human
      term:
        id: NCBITaxon:9606
        label: Homo sapiens
    data_type: MICROARRAY
    sample_count: 58
    conditions:
      - erythematotelangiectatic rosacea
      - papulopustular rosacea
      - phymatous rosacea
      - healthy control facial skin
    evidence:
      - reference: GEO:GSE65914
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The T cell response is dominated by Th1/Th17-polarized immune cells, as demonstrated by significant upregulation of IFNγ or IL-17, for example."
        explanation: >-
          This GEO series directly supports subtype-spanning adaptive immune
          polarization in human rosacea tissue.
  - accession: geo:GSE155141
    title: Paired transcriptomic and proteomic analysis implicates IL-1β in the pathogenesis of papulopustular rosacea explants [RNA-seq]
    description: >-
      Human RNA-seq dataset from paired non-lesional and lesional
      papulopustular rosacea explants, linked to paired proteomic profiling and
      inflammatory pathway analysis.
    organism:
      preferred_term: human
      term:
        id: NCBITaxon:9606
        label: Homo sapiens
    data_type: BULK_RNA_SEQ
    sample_count: 15
    conditions:
      - non-lesional papulopustular rosacea skin
      - lesional papulopustular rosacea skin
      - IL-1beta-treated non-lesional rosacea skin
    evidence:
      - reference: GEO:GSE155141
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Our study suggests that MAPK and TNF signaling pathways are the most significantly upregulated pathways in lesional papulopustular rosacea human skins, highlighting IL-1β as a potential central mediator."
        explanation: >-
          This dataset captures lesion-associated inflammatory pathway activity
          in papulopustular rosacea.
  - accession: geo:GSE303282
    title: Cathelicidin LL-37-induced transcriptome of human keratinocyte identifies chemokine CXCL10 link to T cell-mediated rosacea pathogenesis via JAK-1/STAT-1 pathway
    description: >-
      Human keratinocyte microarray dataset modeling LL-37-driven rosacea-like
      inflammation in vitro to resolve chemokine and JAK-STAT signaling outputs
      downstream of cathelicidin exposure.
    organism:
      preferred_term: human
      term:
        id: NCBITaxon:9606
        label: Homo sapiens
    data_type: MICROARRAY
    sample_count: 6
    conditions:
      - LL-37-treated primary keratinocytes
      - untreated primary keratinocytes
    evidence:
      - reference: GEO:GSE303282
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Mechanistically, LL-37 induced CXCL10 production relied on JAK-1/STAT-1 signaling pathway."
        explanation: >-
          This in vitro transcriptomic dataset is directly relevant to the
          cathelicidin and STAT-linked mechanism nodes in rosacea.
  - accession: geo:GSE277020
    title: Effect of eyelid UVB irradiation on gene expression of rat meibomian gland
    description: >-
      Rat bulk RNA-seq dataset from a UVB-induced ocular rosacea model focused
      on meibomian gland dysfunction, ocular surface injury, and downstream
      inflammatory and keratinization pathways.
    organism:
      preferred_term: Rattus norvegicus
      term:
        id: NCBITaxon:10116
        label: Rattus norvegicus
    data_type: BULK_RNA_SEQ
    sample_count: 7
    conditions:
      - UVB-irradiated rat eyelids and meibomian glands
      - non-irradiated rat controls
    evidence:
      - reference: GEO:GSE277020
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We have developed a rat model of UVB-induced ocular surface and eyelid damages mimicking ocular rosacea, a common chronic inflammatory and neurovascular ocular surface disease associated with meibomian gland dysfunction."
        explanation: >-
          This dataset provides an ocular/meibomian model aligned to the ocular
          rosacea subgraph in this entry.
differential_diagnoses:
  - name: Acne
    disease_term:
      preferred_term: acne
      term:
        id: MONDO:0011438
        label: acne
    description: >-
      Acne can overlap clinically with papulopustular rosacea because both
      produce inflammatory papules and pustules on the face.
    distinguishing_features:
      - Acne more often shows open or closed comedones and broader sebaceous facial or truncal involvement.
      - Rosacea more often centers on persistent centrofacial erythema, flushing, and telangiectasia without comedones.
    evidence:
      - reference: PMID:11582639
        reference_title: "[Rosacea in the year 2001]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
        explanation: >-
          This review explicitly lists acne vulgaris among the core differential
          diagnoses for rosacea.
  - name: Seborrheic dermatitis
    disease_term:
      preferred_term: seborrheic dermatitis
      term:
        id: MONDO:0006608
        label: seborrheic dermatitis
    description: >-
      Facial seborrheic dermatitis can mimic rosacea when patients present with
      chronic erythema in sebaceous facial regions.
    distinguishing_features:
      - Seborrheic dermatitis more often has greasy yellow-white scale involving the eyebrows, nasolabial folds, and scalp.
      - Rosacea more often has flushing, telangiectasia, and papulopustular lesions without prominent greasy scale.
    evidence:
      - reference: PMID:11582639
        reference_title: "[Rosacea in the year 2001]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
        explanation: >-
          This review explicitly identifies seborrheic eczema as a major
          rosacea mimic; the corresponding MONDO disease term used here is
          seborrheic dermatitis.
  - name: Lupus erythematosus
    disease_term:
      preferred_term: lupus erythematosus
      term:
        id: MONDO:0004670
        label: lupus erythematosus
    description: >-
      Lupus erythematosus can resemble rosacea when facial erythema or a
      butterfly-pattern eruption predominates.
    distinguishing_features:
      - Lupus erythematosus more often has photosensitivity, scale, dyspigmentation, scarring plaques, or systemic autoimmune features.
      - Rosacea more often has trigger-provoked flushing, telangiectasia, and papulopustular centrofacial inflammation.
    evidence:
      - reference: PMID:11582639
        reference_title: "[Rosacea in the year 2001]."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "It can be difficult to distinguish acne vulgaris, seborrheic eczema, perioral dermatitis and lupus erythematosus from rosacea."
        explanation: >-
          This review explicitly lists lupus erythematosus among disorders that
          can be difficult to distinguish from rosacea.
      - reference: PMID:41695827
        reference_title: "Rosacea overlapping the malar rash: A diagnostic challenge in early systemic lupus erythematosus."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The coexistence of rosacea and lupus-like lesions delayed diagnosis, highlighting the need for clinicopathological correlation."
        explanation: >-
          This case report reinforces lupus erythematosus as a real-world
          rosacea mimic and overlap diagnosis.
  - name: Systemic sclerosis
    disease_term:
      preferred_term: systemic sclerosis
      term:
        id: MONDO:0005100
        label: systemic sclerosis
    description: >-
      Rosacea-associated solid facial edema can mimic systemic sclerosis when
      facial induration or swelling dominates the presentation.
    distinguishing_features:
      - Systemic sclerosis more often has Raynaud phenomenon, acral involvement, and broader connective-tissue disease manifestations.
      - Morbihan-type rosacea edema may remain centered on the face with sparing of the hands and feet.
    evidence:
      - reference: PMID:41694889
        reference_title: "Facial Swelling in a Young Adult With Type 1 Diabetes: Morbihan Disease as a Scleroderma Mimic."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Scleredema diabeticorum and Morbihan disease (solid facial edema) can mimic scleroderma, creating diagnostic challenges for rheumatologists."
        explanation: >-
          This directly supports systemic sclerosis-spectrum disease as a
          differential diagnosis for edematous rosacea presentations.
  - name: Coccidioidomycosis
    disease_term:
      preferred_term: coccidioidomycosis
      term:
        id: MONDO:0005706
        label: coccidioidomycosis
    description: >-
      Cutaneous coccidioidomycosis can mimic rosacea-like dermatitis,
      particularly in immunocompromised patients living in endemic regions.
    distinguishing_features:
      - Coccidioidomycosis is favored by endemic exposure, immunosuppression, and biopsy evidence of fungal infection.
      - Rosacea lacks an infectious tissue diagnosis and more typically follows a chronic trigger-responsive vascular-inflammatory course.
    evidence:
      - reference: PMID:41017054
        reference_title: "Cutaneous Coccidioidomycosis Mimicking Rosacea in Immunosuppressed Patient, Arizona, USA, 2024."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "An immunocompromised patient in Arizona, USA, experienced cutaneous coccidioidomycosis mimicking rosacea-like dermatitis"
        explanation: >-
          This directly documents cutaneous coccidioidomycosis as a rosacea
          mimic in the appropriate epidemiologic context.
  - name: Lymphomatoid papulosis
    disease_term:
      preferred_term: lymphomatoid papulosis
      term:
        id: MONDO:0020326
        label: lymphomatoid papulosis
    description: >-
      Recurrent periocular nodules can be misclassified as papulopustular
      rosacea before biopsy reveals a CD30-positive lymphoproliferative lesion.
    distinguishing_features:
      - Lymphomatoid papulosis shows recurrent papulonodules with diagnostic CD30-positive atypical lymphoid infiltrates on histopathology.
      - Rosacea more typically produces diffuse erythema, papules, pustules, and telangiectasia rather than isolated recurrent nodules.
    evidence:
      - reference: PMID:40827152
        reference_title: "Recurrent Periocular Nodules: Lymphomatoid Papulosis in an Uncommon Anatomic Site."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "he was subsequently diagnosed with papulopustular rosacea and impetigo. However, despite multiple treatment trials, he still experienced recurrent flares with nodules"
        explanation: >-
          This case report documents an initial rosacea diagnosis later revised
          to lymphomatoid papulosis after biopsy.
references:
  - reference: PMID:41918801
    title: "CO(2) Laser Resection of Giant Rhinophyma Under Local Anesthesia: A Case Report."
    findings: []
  - reference: PMID:41695827
    title: "Rosacea overlapping the malar rash: A diagnostic challenge in early systemic lupus erythematosus."
    findings: []
  - reference: PMID:41694889
    title: "Facial Swelling in a Young Adult With Type 1 Diabetes: Morbihan Disease as a Scleroderma Mimic."
    findings: []
  - reference: PMID:41426892
    title: "Multimodal Management of Morbihan Disease: Isotretinoin, Intralesional Triamcinolone, and Ketotifen in a Recalcitrant Case."
    findings: []
  - reference: PMID:41222206
    title: "Unilateral presentation of Morbihan's disease: a comprehensive case report and review."
    findings: []
  - reference: PMID:41058755
    title: "Unilateral Peri-Orbital Oedema and Mechanical Ptosis: An Unusual Case Presentation of Rosacea."
    findings: []
  - reference: PMID:41017054
    title: "Cutaneous Coccidioidomycosis Mimicking Rosacea in Immunosuppressed Patient, Arizona, USA, 2024."
    findings: []
  - reference: PMID:40860281
    title: "Rhinophyma treated by skin graft: a case report."
    findings: []
  - reference: PMID:40827152
    title: "Recurrent Periocular Nodules: Lymphomatoid Papulosis in an Uncommon Anatomic Site."
    findings: []
  - reference: PMID:40791837
    title: "Rhinophyma Treatment with Blue Laser."
    findings: []
  - reference: PMID:41909715
    title: "Distinct diversity of skin cell populations of rhinophyma and hypertrophic scar illustrated by scRNA-seq."
    findings: []
  - reference: PMID:41800255
    title: "Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea."
    findings: []
  - reference: PMID:41562711
    title: "Increased Expression of Angiopoietin 2 and Tie2 in Rosacea."
    findings: []
  - reference: PMID:41203722
    title: "Lipidomic profiling of skin surface lipids in a cohort of Chinese patients with rosacea."
    findings: []
  - reference: PMID:41139274
    title: "Integrated Multi-Omics and Experimental Validation Unveil the GZMK/NF-κB Axis Driving Inflammation and Fibroblast Proliferation in Rosacea: A Novel Drug Target Selection Strategy."
    findings: []
  - reference: PMID:41087666
    title: "LAPTM5 exacerbates STING-mediated inflammation induced by LL-37 through stabilizing STING in rosacea."
    findings: []
  - reference: PMID:40890957
    title: "Exploring Novel Biomarkers for Rosacea Through Cohort Study and Mendelian Randomisation."
    findings: []
  - reference: PMID:40835085
    title: "Cathelicidin LL-37-Induced Transcriptome of Human Keratinocyte Identifies Chemokine CXCL10 Link to T-Cell-Mediated Rosacea Pathogenesis through Jak1/STAT1 Pathway."
    findings: []
  - reference: PMID:40635520
    title: "Integrated Genomic and GEO Data Analysis Reveals Therapeutic Targets for Rosacea."
    findings: []
  - reference: PMID:40567003
    title: "Novel Molecular Subtyping Revealed Molecular Pathways That Contribute to the Pathogenesis of Rosacea."
    findings: []
  - reference: PMID:11582639
    title: "[Rosacea in the year 2001]."
    findings: []
  - reference: PMID:27718519
    title: "Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea COnsensus (ROSCO) panel."
    findings: []
  - reference: PMID:28150107
    title: "Acne and Rosacea."
    findings: []
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    title: "Cutaneous and ocular rosacea: Common and specific physiopathogenic mechanisms and study models."
    findings: []
  - reference: PMID:35392024
    title: "Multi-Transcriptomic Analysis and Experimental Validation Implicate a Central Role of STAT3 in Skin Barrier Dysfunction Induced Aggravation of Rosacea."
    findings: []
  - reference: PMID:37626650
    title: "Exploring the Pathogenesis and Mechanism-Targeted Treatments of Rosacea: Previous Understanding and Updates."
    findings: []
  - reference: PMID:39823143
    title: "Unveiling the Molecular Mechanisms of Rosacea: Insights From Transcriptomics and In Vitro Experiments."
    findings: []
  - reference: PMID:40522449
    title: "[Ocular rosacea : Clinical aspects, diagnostics, management and treatment]."
    findings: []
  - reference: PMID:25151931
    title: "[Physiopathology of rosacea]."
    findings: []
  - reference: PMID:19428039
    title: "[Rhinophyma in a black African male patient]."
    findings: []