Gaps remain in scientific knowledge underlying the pathophysiology of rosacea.[20]Elewski BE, Draelos Z, Dréno B, et al. Rosacea - global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group. J Eur Acad Dermatol Venereol. 2011 Feb;25(2):188-200.
http://www.ncbi.nlm.nih.gov/pubmed/20586834?tool=bestpractice.com
Pathways that lead to the development of rosacea are not well understood.
Abnormalities in immune response
Symptoms may be caused or exacerbated by dysregulation of innate immune responses.[10]Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009 Aug;55(2):77-81.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745268
http://www.ncbi.nlm.nih.gov/pubmed/19481425?tool=bestpractice.com
[21]Yamasaki K, Di Nardo A, Bardan A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med. 2007 Aug;13(8):975-80.
http://www.ncbi.nlm.nih.gov/pubmed/17676051?tool=bestpractice.com
Cathelicidin LL-37 has been reported to induce skin inflammation through activation of the NLRP3 inflammasome in vitro and in mice.[22]Yoon SH, Hwang I, Lee E, et al. Antimicrobial peptide LL-37 drives rosacea-like skin inflammation in an NLRP3-dependent manner. J Invest Dermatol. 2021 Dec;141(12):2885-94.e5.
http://www.ncbi.nlm.nih.gov/pubmed/33745908?tool=bestpractice.com
[23]Zhang J, Jiang P, Sheng L, et al. A novel mechanism of carvedilol efficacy for rosacea treatment: Toll-like receptor 2 Inhibition in macrophages. Front Immunol. 2021 Jul 12;12:609615.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.609615/full
http://www.ncbi.nlm.nih.gov/pubmed/34322115?tool=bestpractice.com
Mast cell numbers are increased in the dermis of patients with rosacea, and have been shown in a mouse model to be key mediators of cathelicidin-initiated skin inflammation.[24]Muto Y, Wang Z, Vanderberghe M, et al. Mast cells are key mediators of cathelicidin-initiated skin inflammation in rosacea. J Invest Dermatol. 2014 Nov;134(11):2728-36.
https://www.jidonline.org/article/S0022-202X(15)36555-6/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/24844861?tool=bestpractice.com
Increased expression of Toll-like receptor 2 (TLR2) has been observed in the epidermis of patients with rosacea, but not in other inflammatory skin disorders such as atopic dermatitis or psoriasis.[23]Zhang J, Jiang P, Sheng L, et al. A novel mechanism of carvedilol efficacy for rosacea treatment: Toll-like receptor 2 Inhibition in macrophages. Front Immunol. 2021 Jul 12;12:609615.
https://www.frontiersin.org/articles/10.3389/fimmu.2021.609615/full
http://www.ncbi.nlm.nih.gov/pubmed/34322115?tool=bestpractice.com
[25]Yamasaki K, Kanada K, Macleod DT, et al. TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J Invest Dermatol. 2011 Mar;131(3):688-97.
https://www.jidonline.org/article/S0022-202X(15)35179-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/21107351?tool=bestpractice.com
The adaptive immune system may also play a role in rosacea.[26]Steinhoff M, Schauber J, Leyden JJ. New insights into rosacea pathophysiology: a review of recent findings. J Am Acad Dermatol. 2013 Dec;69(6 suppl 1):S15-26.
http://www.ncbi.nlm.nih.gov/pubmed/24229632?tool=bestpractice.com
One study showed activation of the T-helper (Th) 1/Th17 pathway in patients with rosacea.[27]Buhl T, Sulk M, Nowak P, et al. Molecular and morphological characterization of inflammatory infiltrate in rosacea reveals activation of Th1/Th17 pathways. J Invest Dermatol. 2015 Sep;135(9):2198-208.
https://www.jidonline.org/article/S0022-202X(15)38995-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/25848978?tool=bestpractice.com
Inflammatory reactions to micro-organisms
Micro-organisms associated with the development of rosacea include Helicobacter pylori, Demodex folliculorum, Staphylococcus epidermidis, and Chlamydia pneumoniae; however, studies have been inconclusive.[19]Holmes AD. Potential role of microorganisms in the pathogenesis of rosacea. J Am Acad Dermatol. 2013 Dec;69(6):1025-32.
http://www.ncbi.nlm.nih.gov/pubmed/24011460?tool=bestpractice.com
[28]Abokwidir M, Fleischer AB Jr. Additional evidence that rosacea pathogenesis may involve demodex: new information from the topical efficacy of ivermectin and praziquantel. Dermatol Online J. 2015 Sep 17;21(9):13030/qt13v249f5.
http://www.ncbi.nlm.nih.gov/pubmed/26437294?tool=bestpractice.com
[29]Parodi A, Paolino S, Greco A, et al. Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication. Clin Gastroenterol Hepatol. 2008 Jul;6(7):759-64.
http://www.ncbi.nlm.nih.gov/pubmed/18456568?tool=bestpractice.com
[30]Jørgensen AR, Egeberg A, Gideonsson R, et al. Rosacea is associated with Helicobacter pylori: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2017 Dec;31(12):2010-5.
http://www.ncbi.nlm.nih.gov/pubmed/28543746?tool=bestpractice.com
Vascular dysfunction
Flushing episodes are very common in people with rosacea, suggesting that vascular hyper-reactivity and increased blood flow may contribute to the pathogenesis.[10]Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci. 2009 Aug;55(2):77-81.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745268
http://www.ncbi.nlm.nih.gov/pubmed/19481425?tool=bestpractice.com
Studies have demonstrated a measurable increase in blood flow in skin lesions.[31]Sibenge S, Gawkrodger DJ. Rosacea: a study of clinical patterns, blood flow, and the role of Demodex folliculorum. J Am Acad Dermatol. 1992 Apr;26(4):590-3.
http://www.ncbi.nlm.nih.gov/pubmed/1534568?tool=bestpractice.com
[32]Guzman-Sanchez DA, Ishiuji Y, Patel T, et al. Enhanced skin blood flow and sensitivity to noxious heat stimuli in papulopustular rosacea. J Am Acad Dermatol. 2007 Nov;57(5):800-5.
http://www.ncbi.nlm.nih.gov/pubmed/17658664?tool=bestpractice.com
Ultraviolet exposure
Exposure to ultraviolet (UV) light can lead to inflammation, neoangiogenesis, telangiectasia, and fibrosis.[11]Morgado-Carrasco D, Granger C, Trullas C, et al. Impact of ultraviolet radiation and exposome on rosacea: key role of photoprotection in optimizing treatment. J Cosmet Dermatol. 2021 Nov;20(11):3415-21.
https://onlinelibrary.wiley.com/doi/10.1111/jocd.14020
http://www.ncbi.nlm.nih.gov/pubmed/33626227?tool=bestpractice.com
UV radiation may be the cause of abnormalities in immune response via multiple mechanisms (e.g., activation of Toll-like receptor 2 [TLR-2]; production of reactive oxygen species; and the release of cathelicidin LL-37 due to keratinocyte damage).[33]Woo YR, Lim JH, Cho DH, et al. Rosacea: molecular mechanisms and management of a chronic cutaneous inflammatory condition. Int J Mol Sci. 2016 Sep 15;17(9):1562.
https://www.mdpi.com/1422-0067/17/9/1562/htm
http://www.ncbi.nlm.nih.gov/pubmed/27649161?tool=bestpractice.com
[34]Kulkarni NN, Takahashi T, Sanford JA, et al. Innate immune dysfunction in rosacea promotes photosensitivity and vascular adhesion molecule expression. J Invest Dermatol. 2020 Mar;140(3):645-55.e6.
https://www.jidonline.org/article/S0022-202X(19)33154-9/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/31472105?tool=bestpractice.com
Genetics
A cohort study of fraternal twins concluded that the genetic contribution to rosacea was 46%.[13]Aldrich N, Gerstenblith M, Fu P, et al. Genetic vs environmental factors that correlate with rosacea: a cohort-based survey of twins. JAMA Dermatol. 2015 Nov;151(11):1213-9.
https://jamanetwork.com/journals/jamadermatology/fullarticle/2429555
http://www.ncbi.nlm.nih.gov/pubmed/26307938?tool=bestpractice.com
A genome-wide association study identified two significant single nucleotide polymorphisms (rs763035 and rs111314066) and three human leukocyte antigen (HLA) alleles (HLA-DRB1*, HLA-DQB1*, and HLA-DQA1*), consistent with the importance of the inflammatory response in the pathogenesis of rosacea.[35]Chang ALS, Raber I, Xu J, et al. Assessment of the genetic basis of rosacea by genome-wide association study. J Invest Dermatol. 2015 Jun;135(6):1548-55.
https://www.jidonline.org/article/S0022-202X(15)37273-0/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/25695682?tool=bestpractice.com
One case-control study found that the +405C/G polymorphism of the vascular endothelial growth factor (VEGF) gene increased the risk of rosacea.[36]Hayran Y, Lay I, Mocan MC, et al. Vascular endothelial growth factor gene polymorphisms in patients with rosacea: A case-control study. J Am Acad Dermatol. 2019 Aug;81(2):348-54.
http://www.ncbi.nlm.nih.gov/pubmed/31182382?tool=bestpractice.com