Guide

Michael Detmar, M.D., says about rosacea, "A new area of research suggests that lymphatic vessels are involved." Rosacea: turning all stones for source of pathology, Rebecca Bryant, Dermatology Times, Modern Medicine "The process of diffusion and extension of the chin can be attributed to lymphedema, which is a chronic inflammation, due to mechanical failure of the lymphatic system, caused by persistent inflammation of rosacea." [1] "Lymphatic failure results in a sustained inflammatory response -- the persistent redness that typically appears as rosacea progresses." The Anatomy of a Rosacea Flare-up, Lynn Drake, MD, Editor, Rosacea Review, Summer 2000, National Rosacea Society "The group observed that the lymphatic vessels also may be involved in the initial process of rosacea, which can result in swelling, and noted that neuropeptides affect the function of lymph vessels as well." Causes of Rosacea: Neurovascular System, National Rosacea Society "It is believed that facial swelling in rosacea may be due to increased blood flow during flushing. If dilated vessels become "leaky," extra fluid may accumulate in the tissues faster than the lymphatic system, which transports fluids throughout the body, can remove it." Facial Swelling May Be More Common with Rosacea, Rosacea Review, Lynn Drake, MD, Editor, Fall 2000, National Rosacea Society "Lymphatic vessels are responsible for the active removal of all of these inflammatory components and are key to rosacea clearance. However, most clinical studies on rosacea lymphatic vessels shows that they are physically damaged, functionally inactive, broken, or too inflamed to help clear facial inflammation — resulting in long-term inflammatory side effects and rosacea progression." [2] "Skin conditions such as acne or rosacea, among others, benefit from this same cleansing effect. Manual lymph drainage is most commonly used as a component of complex decongestive therapy to treat lymphedema. However, it is a powerful and profound stand-alone massage technique." [3] "Our results suggest that lymphatic vessels are already involved in the initiation process of rosacea but not in later subtypes, although clinically visible signs of edema are described at later stages (Crawford et al., 2004). Although the early involvement of lymphatic tissue was suggested before, augmentation of lymphatic tissue was previously attributed mainly to lymphangiogenesis (Gomaa et al., 2007). Our morphometric results show no enhancement in vessel number when compared with HS. Furthermore, our RT-PCR results showed that most of the genes involved in growth and elongation of lymphatic capillaries were only slightly or not at all upregulated. LYVE1, a gene having a key role in metabolism, binding, and transport of hyaluronic acid from tissues to lymphatic vessels and in transplacement of leukocytes in lymphatic vessels and lymph nodes (Jackson, 2009), was even downregulated (Figure 6b)." [4] "Dr Bill Henry of Pro Bono Bio explains: “Redness associated with rosacea is due [largely] to accumulation of chemicals within the affected tissue [because of] malfunctioning of lymphatic drainage. Rossoseq exploits Sequessome technology, which is based on tiny spheres of hydrophilic phospholipid that have been engineered to penetrate the skin and improve the functioning of the water-based lymphatic system.” " [5] "In a study of skin samples with and without rosacea, Dr. Amal Gomaa and colleagues at Boston University found evidence of angiogenesis in both the blood and lymphatic circulatory systems in skin with rosacea lesions." [6] "Manual Lymphatic Drainage is a specialized, advanced massage technique, especially suited to sensitive and Rosacea skins." [7] Lymphedema People has a page dedicated to rosacea lymphedema. [8] "Lymphedema, also known as lymphoedema and lymphatic edema, is a condition of localized fluid retention and tissue swelling caused by a compromised lymphatic system, which normally returns interstitial fluid to the bloodstream." Wikipedia. cf123 at RF "decided to start experimenting with the idea by giving my face a massage (firm but gentle, minimal friction) to facilitate lymphatic flow, i.e. to mix the fluid around and let it homogenize, and hopefully drain away or detoxify through my lymphatic and immune systems" which is similar to Manual Lymphatic Drainage (MLD). Les Nouvelles Esthétiques & Spa claims, "Fortunately the lymphatic flow can be stimulated through movement, and skin care professionals use this technique in the treatment room to benefit clients who suffer with rosacea, acne, puffiness and overall sluggish skin, as well as post surgery inflammation and bruising." [9] "The reality is that you have twice as much lymph fluid in your body as blood. The lymph continuously bathes each cell and drains away the waste in a circulatory system powered only by your breathing and movements. If the movement of the lymph stopped entirely you would die in a matter of hours." [10] End Notes [1] An Bras Dermatol. 2012 Nov-Dec; 87(6): 903–905. Gnatophyma - A rare form of rosacea Ana Carolina Lisboa de Macedo, Fernanda Dias Pacheco Sakai, Rossana Cantanhede Farias de Vasconcelos, and Artur Antonio Duarte [2] Treat Facial Inflammation, Flushing and Swelling by Repairing Lymphatic Vessels [Pt.1], Rosalyn [3] Manual Lymph Drainage – MLD, John Mulligan, RMT/CLT-LANA Lymphedema Therapy, Education & Consulting [4] JID, December 2011Volume 15, Issue 1, Pages 53–62 Neurovascular and Neuroimmune Aspects in the Pathophysiology of Rosacea Verena D. Schwab, Mathias Sulk, Stephan Seeliger, Pawel Nowak, Jerome Aubert, Christian Mess, Michel Rivier, Isabelle Carlavan, Patricia Rossio, Dieter Metze, Jörg Buddenkotte, Ferda Cevikbas, Johannes J. Voegel, Martin Steinhoff [5] Red alert: New hope for rosacea skin condition, Irish Examiner, Sunday, August 31, 2014 [6] Update on Angiogenesis Posted: 03/19/2008, National Rosacea Society [7] Shed the Red: Managing Rosacea Booklet, The International Dermal Institute [8] Lymphedema People Rosacea [9] Hands-On Detox How to Stimulate Lymph Flow for Healthy Skin, Rhonda Allison, Les Nouvelles Esthétiques & Spa [10] Why the Lymphatic System Matters, Acu-Na Wellness Center

“Therefore, it is important to pay attention to the psychological status of rosacea patients. Psychological counseling and intervention are necessary to better prevent and treat rosacea.” [1] This post has been promoted to an article end notes [1] PubMed RSS Feed - -Quality of life, sleep and anxiety status among patients with rosacea in the Yunnan plateau region: A 2-year retrospective study

This post has been promoted to an article

Conidiophores of Aspergillus, image courtesy of Wikimedia Commons Bacteria has been implicated in rosacea with a huge amount of clinical papers on this subject. Demodex is now without a doubt linked to a significant number of rosacea cases. We have papers indicating treatment for one particular protozoa improves rosacea, however virus has not been ruled out in rosacea, nor archea has been ruled out in rosacea. The human microbiome includes the skin which contains a number of different microbes. "The prevalence of fungal infections has been steadily increasing which is in part highly attributable to a growing immunocompromised population as well as an increase in worldwide travel." [8] Fungus and Rosacea Fungus has not been ruled completely out in its connection with rosacea and has been one theory on what causes rosacea at least in some cases, and should be ruled out. For example, the Cleveland Clinic reports, "Other theories suggest that the condition is caused by microscopic skin mites, fungus, psychological factors, or a malfunction of the connective tissue under the skin." [bold added] Seborrheic Dermatitis, a co-existing condition with rosacea at times, has been associated with fungus, particularly Malassezia yeast, and is some cases responds well to antifungal treatments. [7] Candida albicans (a fungus or yeast) and rosacea have been linked in a few research papers. One report said that a “patient was treated with intermittent pulses of itraconazole for the candidasis and doxycycline initially before being substituted with isotretinoin 6 months later for the rosacea.” and the outcome was that “the patient’s candidiasis responded well and has been in remission for 3 months while his rosacea continues to improve.”[1] Antibiotic resistance and bacterial overgrowth are other complications of long term antibiotic treatment for rosacea. Walter Last dubs this 'antibiotic syndrome.' [2] "The use of invasive devices and broad spectrum antibiotics has increased the rate of candidal superinfections." [3] One report said, "These findings suggest that S. salivarius K12 may inhibit the invasion process of C. albicans into the mucous surfaces or its adhesion to denture acrylic resins by mechanisms not associated with the antimicrobial bacteriocin activity. S. salivarius K12 may be useful as a probiotic as a protective tool for oral care especially with regards to candidiasis." [4] Candida Albicans And Rosacea Chronic Mucocutaneous Candidiasis (CMC) in Demodectic Rosacea "CMC was diagnosed in our patient despite poor clinical features. Sequencing of the genome revealed STAT1GOF mutation. This mutation affects production of IL-17, an important cytokine in mucocutaneous defense against Candida. The association with mycobacterial adenitis is rare and continues to be poorly understood. The presence of atypical rosacea in this setting is suggestive of this entity. Antifungal therapy and prevention of complications are necessary to reduce the morbidity and mortality associated with this condition." [5] [bold added] "Researchers found that the risk for rosacea, as well as the skin disorders atopic eczema and onychomycosis (toenail fungus), increased with the presence of systemic low-grade inflammation – a chronic condition that may not cause visible symptoms yet contributes to the pathogenesis of many noncommunicable diseases, including atherosclerosis, type 2 diabetes, metabolic syndrome and others." [bold added] [6] Fungal Infection Activates Inflammasomes "As part of the innate immune system, inflammasomes play an important role in the induction of inflammatory cascades and coordination of host defenses, both via the activation and secretion of pro-inflammatory cytokines and the induction of a specialized form of immune-stimulatory programmed cell death termed pyroptosis. Traditionally, inflammasomes have mainly been studied in professional innate immune cells such as macrophages. More recently, however, several studies described various epithelial inflammasomes and highlighted their crucial role as a first line of defense. Since epithelial cells line important barrier tissues such as the intestines, their inflammasomes are optimally positioned to recognize invading microbes at the first point of interaction." [9] "Inflammasomes are important sentinels of an organism's innate immune defense system," said corresponding author and founding member of the inflammasome field Thirumala-Devi Kanneganti, Ph.D., of the St. Jude Immunology department. "Our prior work showed that fungal pathogens activate the inflammasome, but the exact mechanism of action for inflammasome engagement was unknown." [10] Fungus and Demodex Mites Fungus has been associated with demodex mites. [11] Anti-Fungal Treatments (antimycotic medication) Allylamines: terbinafine [7] Amphotericin B Benzylamines: butenafine [7] Clotrimazole [7] Fosfluconazole Hydroxypyrones: Ciclopirox [7] Imidazoles: bifonazole, climbazole, cotrimoxazole, ketoconazole (topical 2%), miconazole [7] Isavuconazonium Posaconazole Solanum chrysotrichum [7] Steroids [7] Triazoles: fluconazole [7] Voriconazole lithium [7] zinc pyrithione [7] Et Cetera More info on bacterial overgrowth and antibiotic resistance. End Notes [1] Autosomal Dominant Familial Chronic Mucocutaneous Candidiasis Associated with Acne Rosacea HL Ee, HH Tan, SK Ng; Ann Acad Med Singapore 2005; 34:571-4 • Full Article [2] CANDIDA and the ANTIBIOTIC SYNDROME By Walter Last [3] Candida sepsis following transcervical chorionic villi sampling. A Paz, R Gonen, and I Potasman Infectious Diseases, Bnai Zion Medical Center, Rappaport Faculty of Medicine, Technion, Hafa, Israel [4] Effect of Streptococcus salivarius K12 on the in vitro growth of Candida albicans and its protective effect on oral candidiasis model. Ishijima SA, Hayama K, Burton JP, Reid G, Okada M, Matsushita Y, Abe S. Appl Environ Microbiol. 2012 Jan 20. [5] Ann Dermatol Venereol. 2019 Oct 30;: Chronic mucocutaneous candidiasis with STAT1 gain-of-function mutation associated with herpes virus and mycobacterial infections. Baghad B, Benhsaien I, El Fatoiki FZ, Migaud M, Puel A, Chiheb S, Bousfiha AA, Ailal F [6] New Study Shows Rosacea Associated With Low-Grade Inflammation, NRS, 12/04/2017 [7] Cochrane Database Syst Rev. 2015 May; 2015(5): CD008138. Topical antifungals for seborrhoeic dermatitis Monitoring Editor: Enembe O Okokon,corresponding author Jos H Verbeek, Jani H Ruotsalainen, Olumuyiwa A Ojo, Victor Nyange Bakhoya, and Cochrane Skin Group [8] Curr Dermatol Rep. 2020; 9(2): 152–165. Published online 2020 Mar 5. doi: 10.1007/s13671-020-00295-1 PMCID: PMC7224073 New Developments in Bacterial, Viral, and Fungal Cutaneous Infections Samuel Yeroushalmi, Joshua Yoseph Shirazi, Adam Friedman [9] Inflammasome, Wikipedia [10] Research reveals how a fungal infection activates inflammation, December 2, 2020, St. Jude Children's Research Hospital, Science Daily [11] Fungus and Demodex Mites

An article in the June 1, 2004 Dermatolgy Times by Rebecca Bryant quotes Michael Detmar, M.D., as saying, "Bacteria are likely involved because what works to some extent as a treatment are antibiotics. Also there appears to be a relationship to photo damage." Rosacea: turning all stones for source of pathology, Jun 1, 2004, Rebecca Bryant, Modern Medicine "A bacterial cause for the disease has been hypothesized, but no consistent findings of one bacteria have been demonstrated." Acne Rosacea, Marian S. Macsai, Mark J. Mannis, and Arthur C. Huntley, Chapter 41, DISEASE ENTITY, 1996 by Lippincott-Raven Publishers At least five different types of bacteria have been implicated, suggested or investigated with rosacea: Helicobacter Pylori Chlamydophila pneumoniae Propionibacterium Bacillus oleronius [1] Staphylococcus epidermidis [2] Staphylococcus aureus [3] Also see Microorganisms End Notes [1] Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Lacey N, Delaney S, Kavanagh K, Powell FC. Br J Dermatol. 2007 Sep;157(3):474-81. Epub 2007 Jun 26 Positive correlation between serum immuno-reactivity to Demodex-associated Bacillus proteins and Erythematotelangiectic Rosacea. O'Reilly N, Menezes N, Kavanagh K. Br J Dermatol. 2012 Jun 18. doi: 10.1111/j.1365-2133.2012.11114.x. Demodex-associated Bacillus proteins induce an aberrant wound healing response in a corneal epithelial cell line (hTCEpi). O'Reilly N, Gallagher C, Katikireddy K, Clynes M, O'Sullivan F, Kavanagh K. Invest Ophthalmol Vis Sci. 2012 Apr 24. The potential role of Demodex folliculorum mites and bacteria in the induction of rosacea. Stanislaw Jarmuda, Niamh O'Reilly, Ryszard Zaba, Oliwia Jakubowicz, Andrzej Szkaradkiewicz and Kevin Kavanagh. Journal of Medical Microbiology, 2012 DOI: 10.1099/jmm.0.048090-0 Article at PubMed Media reports have highlighted demodectic rosacea. More info [2] Staphylococcus epidermidis: A possible role in the pustules of rosacea. J Am Acad Dermatol. 2010 Oct 11; Authors: Whitfeld M, Gunasingam N, Leow LJ, Shirato K, Preda V J Am Acad Dermatol. 2010 Oct 11. [3] "No study in rosacea met our inclusion criteria....No studies could be included that assessed S. aureus colonization in patients with rosacea. Also in current review literature S. aureus is not implicated in the pathophysiology of rosacea ...As S. aureus is common at all depths of the skin...For patients with acne a relation between colonization and the disease was less evident and for rosacea no information about colonization could be obtained from the literature." A systematic review and meta-analysis on Staphylococcus aureus carriage in psoriasis, acne and rosacea J. E. E. Totté,corresponding author W. T. van der Feltz, L. G. M. Bode, A. van Belkum, E. J. van Zuuren, and S. G. M. A. Pasmans Eur J Clin Microbiol Infect Dis. 2016; 35: 1069–1077. Published online 2016 May 5. doi: 10.1007/s10096-016-2647-3

The current, as of this date, most popular theory on rosacea was postulated by Dr. Richard Gallo at UCSD, who began postulating the 'innate immune system dysfunction' theory which is a complicated theory. It has become one of the most discussed and hopefully closer to the truth about what is at the heart of rosacea's cause, first postulated in an article in the June 1, 2004 Dermatolgy Times by Michelle Stephenson, who quotes Richard L. Gallo, M.D., Ph.D., saying rosacea may be an 'abnormality in the innate immune system...caused by too much cathelicidin." Dr Gallo says, "if we believe that the disease is caused by too much cathelicidin, we could develop a strategy to block the effects of the cathelicidins by making molecules that mimic that protein but don't have the same effects." Source. This may eventually happen; see Anti-Sting Therapy for Rosacea? "Antimicrobial peptides are central effector molecules in skin immunology. The functions of antimicrobial peptides in skin diseases include the ability to act as cytokines or growth factors, driving disorders such as psoriasis and rosacea, as well as their action as natural antibiotics to control bacteria that influence diseases such as atopic dermatitis and acne." Dermatol Clin. 2017 Jan;35(1):39-50 The Critical and Multifunctional Roles of Antimicrobial Peptides in Dermatology. Takahashi T, Gallo RL "Abnormalities of innate immunity can increase the skin’s susceptibility to the external environment, which might represent an influential factor in initiating or aggravating rosacea. Additionally, studies have also recently been conducted to identify possible abnormalities in adaptive immunity in rosacea, which might contribute to further inflammatory responses in rosacea." Int J Mol Sci. 2016 Sep; 17(9): 1562. Published online 2016 Sep 15. doi: 10.3390/ijms17091562, PMCID: PMC5037831 Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory Condition Yu Ri Woo, Ji Hong Lim, Dae Ho Cho, and Hyun Jeong Park, "Recent molecular studies suggest that an altered innate immune response is involved in the pathogenesis of the vascular and inflammatory disease seen in patients with rosacea." Postgraduate Medicine, DOI: 10.3810/pgm.2009.09.2066 Updates on the Pathophysiology and Management of Acne Rosacea, Mohamed L. Elsaie, MD, MBA and Sonal Choudhary, MD, "Rosacea is increasingly being viewed as an immune-based disorder." Cutis. 2004 Jan;73(1 Suppl):5-8 Rosacea as an inflammatory disorder: a unifying theory?, Millikan LE "It is suggested that altered immune function plays a significant role in the pathogenesis of the disease." Involvement of immune mechanisms in the pathogenesis of rosacea. Br J Dermatol. 1982 Aug;107(2):203-8. Manna V, Marks R, Holt P. "Besides confirming the data in the literature on the positivity of the basal zone, anticollagen antibodies were found, and eluted antinuclear antibodies were detected against nuclei of cells in the epidermis and dermis, namely, scattered dermal, endothelial and eccrine duct cells." Br J Dermatol. 1980 Nov;103(5):543-51. Immunopathological studies on rosacea. Nunzi E, Rebora A, Hamerlinck F, Cormane RH. "Elevated ANA titers are commonly found in rosacea patients..." Postep Derm Alergol 2013; XXX, 1: 1-5 Antinuclear antibodies in rosacea patients Anna Woźniacka, Małgorzata Salamon, Daniel McCauliffe, Anna Sysa-Jędrzejowska "Expression of TLR2, TLR4 and iNOS was higher in rosacea samples than in normal skin controls. This research demonstrates early and late stage components of innate immunity in specimens of rosacea ratifying the existence of an altered innate immunity in its pathogenesis." Inate immunity in rosacea. Langerhans cells, plasmacytoid dentritic cells, Toll-like receptors and inducible oxide nitric synthase (iNOS) expression in skin specimens: case-control study. Arch Dermatol Res. 2018 Jan 12;: Moura AKA, Guedes F, Rivitti-Machado MC, Sotto MN "TLR3-stimulated epidermal keratinocytes and rosacea epidermis enhance the expression of glucocorticoid-synthetic enzymes, which would promote cortisol activation in the epidermis. The innate immunity modulates glucocorticoid-synthetic enzymes expression via the TLR3 pathway in epidermal keratinocytes." J Dermatol Sci. 2020 Aug 29;: TLR3 augments glucocorticoid-synthetic enzymes expression in epidermal keratinocytes; Implications of glucocorticoid metabolism in rosacea epidermis. Shimada-Omori R, Yamasaki K, Koike S, Yamauchi T, Aiba S "Individuals in our Down syndrome cohort had higher odds of a diagnosis with inflammatory and autoimmune presentations such as Alopecia areata (OR 6.06, p = 0.01), Other sepsis (OR 4.79, p < 0.001, Purpura and Other hemorrhagic conditions (OR 2.31, p < 0.001), and Rosacea (OR 3.11, p < 0.001)." Dysregulation of the Immune System in a Natural History Study of 1299 Individuals with Down Syndrome More info on Cathlecidin An interesting thread on this subject for your information. Theories Revisited

image courtesy of Wikimedia Commons "The pathophysiology of rosacea appears to be inflammatory, and most of the interventions modulate the inflammatory process in some way." The pharmacologic therapy of rosacea: a paradigm shift in progress., Bikowski JB., Cutis. 2005 Mar;75(3 Suppl):27-32; discussion 33-6. "Although the fundamental pathogenesis of rosacea remains unknown, inflammation is a central process in this disorder." Reactive oxygen species and rosacea., Jones D., Cutis. 2004 Sep;74(3 Suppl):17-20, 32-4. "...Many pharmacologic agents that effectively treat the symptoms of rosacea show anti-inflammatory and/or immunomodulating effects, providing further evidence that rosacea is an inflammatory disorder..." Rosacea as an inflammatory disorder: a unifying theory?, Millikan LE., Cutis. 2004 Jan;73(1 Suppl):5-8. "The stigmata of rosacea may be manifestations of an inflammatory process: neutrophilic dermatosis." The Proposed Inflammatory Pathophysiology of Rosacea: Rosacea as an Inflammatory Disorder, Larry Millikan, MD, Medscape "Based on the theory that rosacea shares the same inflammatory features of acne a recent study showed that, ..." P. Acnes Possible Factor in Rosacea, BenzaClin a significant Tx in lesion reduction, Beth Kapes, Dermatology Times Oracea, a popular prescription for rosacea, is used not for its antibiotic effect but instead for its an anti-inflammatory effect. One study in Finland looked at levels of C-reactive protein (CRP), commonly used in clinical studies as a strong marker for inflammation. The researchers found that individuals with slightly elevated blood levels of CRP were 1.7 times more likely to have rosacea than normal individuals. The study concluded, "low grade inflammation is present in several skin diseases," including rosacea. Acta Derm Venereol. 2017 Sep 13. doi: 10.2340/00015555-2795. The Association Between Low Grade Systemic Inflammation and Skin Diseases: A Cross-sectional Survey in the Northern Finland Birth Cohort 1966.Sinikumpu SP, Huilaja L, Auvinen J, Jokelainen J, Puukka K, Ruokonen A, Timonen M, Tasanen K. "Researchers from the University of Illinois at Chicago have identified a protein that is crucial for activating inflammation....Researchers led by Asrar Malik, Schweppe Family Distinguished Professor and head of pharmacology in the UIC College of Medicine, have now identified the channel, called TWIK2, and have studied its function in macrophages, a type of immune cell involved in fending off infections as well as clearing debris during inflammation. "Now that we have identified this crucial channel, it opens up the possibility of developing targeted new anti-inflammatory drugs to modify its function and help and reduce inflammation," said Malik. While some drugs currently exist that target potassium channels, drugs specific to the TWIK2 channel still need to be developed." [1] What is inflammation? Answer. Reply to this Topic There is a reply to this topic button somewhere on the device you are reading this post. End Notes [1] Key protein involved in triggering inflammation, University of Illinois at Chicago, Science Daily

http://rakabe.files.wordpress.com/2010/04/genetics.gif?w=300&h=204 One of the more popular theories on the cause of rosacea is the genetic theory. "A primary genetic cause for rosacea is suggested as single genes often control such mediators: enzymes, neuroendocrine transmitters, and cytokines are found in pathways to rosacea signs and symptoms. Currently, neither a specific cause nor a laboratory indicator of rosacea has been suggested." [1] The number one reason why the genetic theory persists is that rosacea does indeed tend to run in families. As Dr. Bernstein says about the cause, "it's probably some kind of combination of genetic and environmental factors" and "No specific rosacea-causing genes have been identified, but the condition tends to run in families — and almost always among those with fair skin." The genetic theory usually comes up when discussing the cause in just about every discussion. However, recent thought on this subject is that while rosacea may be genetic the evidence seems to point to the environmental factors. For instance, notice what this article concluded regarding this subject: "The epidemiological data have always indicated that Western diseases are determined overwhelmingly by diet and other non-genetic factors. Similarly, clinical data have frequently shown that many diseases can be reversed or accelerated by diet and other lifestyle choices. The crucial importance of the new genomic findings is therefore to show that genetic research does not after all contradict these environmental explanations of disease. Rather, it now very strongly supports them." [2] "Data regarding the inheritance of rosacea are scarce. Patients with rosacea have a markedly increased tendency to exhibit a positive family history than do control groups. Furthermore, owing to its higher prevalence among Northern Europeans, a genetic predisposition toward developing rosacea has been hypothesized; however, the specific genes related to this association have not yet been identified." [3] "This cohort study also indicated that approximately half of the factors affecting the pathophysiology of rosacea were genetic, whereas the remainders were environmental, such as smoking, alcohol consumption, skin cancer history, and age." [3[ "Collectively, the gene variants identified in this study support the concept of a genetic component for rosacea, and provide candidate targets for future studies to better understand and treat rosacea." [4] "Nevertheless, the potential genetic basis of this common, disfiguring yet incurable condition is not known. Evidence for a genetic component to rosacea has been hypothesized, with a retrospective study showing that rosacea patients have a greater than fourfold increased odds of having a family member with rosacea (Abram et al., 2010; Steinhoff et al., 2013), but the genes leading to this association are not known. This current study explores genes that associate with rosacea in a large population of individuals of European descent by genome-wide association study." [4] An interesting Medscape video lecture by Dr. Gallo, New Insights Into the Science of Treating Rosacea, which relates to this theory since the innate immune system and cathelicidin (LL-37) is discussed. "Data regarding the inheritance of rosacea are scarce. Patients with rosacea have a markedly increased tendency to exhibit a positive family history than do control groups. Furthermore, owing to its higher prevalence among Northern Europeans, a genetic predisposition toward developing rosacea has been hypothesized; however, the specific genes related to this association have not yet been identified." [5] "Our current hypothesis is that a genetic predisposition, together with trigger factors, leads to the clinical occurrence of transient flushing, which may be because of overstimulation of the sensory and/or autonomic nervous system in the skin and induction of innate immune responses. The concrete relationship between the skin nervous system and the innate immune system is still unclear." [6] "The genetic predisposition to carry the polymorphic variant rs3733631 in the TACR3 tachykinin receptor gene, and polymorphism in the glutathione S-transferase (GST) enzyme are related to the disease.13, 14, 15 Chang et al. identified that genes associated with rs763035 are expressed in rosacea skin samples and identified that three class II alleles of the major histocompatibility complex (MHC), including HLA-DRB1, HLA-DQB1, and HLA-DQA1, are involved." [7] "The results suggest that both innate and adaptive immune responses were involved in the etiology of rosacea. Five DEGs in the TLR signaling pathway may serve as potential therapeutic target genes." [8] While the genetic theory makes us feel like we can't do anything about it the environmental evidence suggests we can do something about it. This theory will no doubt continue to be studied and researched. End Notes [1] Rosacea: current thoughts on origin., Bamford JT., Semin Cutan Med Surg. 2001 Sep;20(3):199-206. [2] The Causes Of Common Diseases Are Not Genetic Concludes A New Analysis, Medical News Today, 07 Dec 2010 [3] Int J Mol Sci. 2016 Sep; 17(9): 1562.Published online 2016 Sep 15. doi: 10.3390/ijms17091562, PMCID: PMC5037831Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory ConditionYu Ri Woo, Ji Hong Lim, Dae Ho Cho, and Hyun Jeong Park, [4] J Invest Dermatol. 2015 Jun; 135(6): 1548–1555. Published online 2015 Mar 12. Prepublished online 2015 Feb 19. doi: 10.1038/jid.2015.53, PMCID: PMC4434179 Assessment of the Genetic Basis of Rosacea by Genome-Wide Association Study Anne Lynn S Chang, Inbar Raber, Jin Xu, Rui Li, Robert Spitale, Julia Chen, Amy K Kiefer, Chao Tian, Nicholas K Eriksson, David A Hinds, and Joyce Y Tung [5] Int J Mol Sci. 2016 Sep; 17(9): 1562. Published online 2016 Sep 15. doi: 10.3390/ijms17091562, PMCID: PMC5037831 Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory Condition Yu Ri Woo, Ji Hong Lim, Dae Ho Cho, and Hyun Jeong Park, Chris Jackson, Academic Editor [6] J Investig Dermatol Symp Proc. Author manuscript; available in PMC 2013 Jul 8. Clinical, Cellular, and Molecular Aspects in the Pathophysiology of Rosacea Martin Steinhoff, Jörg Buddenkotte, Jerome Aubert, Mathias Sulk, Pawel Novak, Verena D. Schwab, Christian Mess, Ferda Cevikbas, Michel Rivier, Isabelle Carlavan, Sophie Déret, Carine Rosignoli, Dieter Metze, Thomas A. Luger, and Johannes J. Voegel [7] An Bras Dermatol. 2020 Nov-Dec; 95(Suppl 1): 53–69.Consensus on the therapeutic management of rosacea – Brazilian Society of DermatologyClivia Maria Moraes de Oliveira, Luiz Mauricio Costa Almeida, Renan Rangel Bonamigo, Carla Wanderley Gayoso de Lima, Ediléia Bagatinf [8] Cytokine. 2021 Jan 30;141:155444 Identification of novel candidate genes in rosacea by bioinformatic methods. Sun Y, Chen LH, Lu YS, Chu HT, Wu Y, Gao XH, Chen HD

Around the year 2000, the most popular theory on the cause of rosacea was the vascular theory. Since then, other theories seem to have taken over this one. J Bradley Randleman, MD, and C Diane Song, MD in an article, Ocular Rosacea, stated that "...rosacea may be thought of as a disease spectrum with 2 primary etiologic components, vascular and inflammatory. The earliest manifestations of the disease are cutaneous vascular dilatory changes with subsequent increased blood flow in the form of telangiectasias and erythema...." Probably one of the reasons that the vascular theory was so popular back then was when Geoffrey Nase, Ph.D., popularized the theory in his book Beating Rosacea, and stated in his book, "rosacea is primarily a facial vascular disorder in which the affected blood vessels are functionally and structurally abnormal." In 2004, a leading rosacea expert, Dr. Frank Powell, stated in an article in Cutis, "A leading theory suggests a vascular basis...". According to the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, "Some researchers believe that rosacea is a disorder where blood vessels dilate too easily, resulting in flushing and redness." In Postgraduate Medicine, February, 1999, Dr. Millikan wrote, "The cause of rosacea is unknown, but it is commonly thought to be of vascular origin because of a clinical association with flushing, development of telangiectasia and tissue swelling, and ultimately, tissue proliferation and rhinophyma (enlargement of the nose)." "Flushing and burning sensations in the skin are considered to represent a main clinical feature in rosacea and are regarded as being primarily caused by neurovascular dysregulation. In patients with rosacea, dilatations of the precapillary arterioles lead to flushing and erythema and dilatations of the postcapillary venules result in edema caused by protein leakage and the recruitment of leukocytes." [1] This source refers to this as "Neurovascular Dysregulation." Now other theories are more popular such as the genetic, inflammatory, immune system dysfunction and others. For a complete list click here. End Notes [1] Int J Mol Sci. 2016 Sep; 17(9): 1562.Published online 2016 Sep 15. doi: 10.3390/ijms17091562, PMCID: PMC5037831Rosacea: Molecular Mechanisms and Management of a Chronic Cutaneous Inflammatory ConditionYu Ri Woo, Ji Hong Lim, Dae Ho Cho, and Hyun Jeong Park, Chris Jackson, Academic Editor

Matthew, Oliver Lawer has posted a question about what you posted above here. If you could reply to this post that would be a kindness.

Due to responsibilities Cathy Rupert, Treasurer for the RRDi and board member for over the past six years has resigned. We will miss her generous giving and volunteer spirit she has manifested over the past years. Cathy was instrumental in getting about a hundred copies of the journal into the hands of the MAC members and important individuals. Thanks Cathy for all your work.

The RRDi is now on Twitter and Facebook. This forum is the state of the art. We have over 600 members now in the RRDi. However, due to the expense of publishing the Journal of the RRDi our funds are now depleted. We could use some volunteers to recruit more members, get more donations and write articles for the next edition of the journal. If you want to do something, make a suggestion or give us an idea of how we can get rosaceans to come together in our community, please post.

This is to announce that volunteer members can receive a free G Suite account which includes a Gmail account associated with the RRDi domain. For more info click here.

Email from: From: Robert Brodell, MD Subject: Re: Please take five minutes to comment Date: July 21, 2010 10:52:08 AM HST To: Barrows Brady The best way to categorize acne rosacea would be into subgroups that are treated in the same manner......I like erythrotelangiectatic rosacea as a subset where infection is not a key issue and antibiotics might be less important than evolving vasoconstricting drugs, laser therapy and coverups. Papulopusular acne and many of the variants mentioned in the previous comment are related to demodex, bacterial infection, and pityrosporon yeast.....to the extent that most respond to antibiotics, I have always favored bacteria as a key part of the pathogenesis in most patients, though the antiinflammatory effects of antibiotics may explain their benefits as well. The subset that is associated with seborrheic dermatitis is best treated like rosacea, plus ketoconazole cream bid to cover the pityrosporon that induces seb derm. There will always be some controversy here, but this is the approach I would take if I were a thought leader! Robert Brodell, MD

From: Latkany, MD Robert Subject: RE: RRDi MAC Members Please Comment on Topic Date: July 6, 2010 10:33:48 AM HST To: Brady Barrows In general I would agree. However, if dividing the type of rosacea into subtypes helps explain different etiologies then it is necessary and will be helpful to guide physicians into different treatment directions. But until we better understand why people get rosacea this is all insignificant. Robert Latkany, MD __________________________________________________________________________________

This post has been promoted to an article The RRDi has now endorsed the new phenotype classification of rosacea.

We have received only one review of the Journal of the RRDi so far which has been a rather negative one from David Pascoe. We could use some positive ones but if you feel David is warranted in his criticism of our new journal please post your thoughts here as well. I have written my thoughts on David's review on my personal web site and also thought it would be fair to post it here as well. But please give us your reviews of our new journal in this thread. My thoughts on David's negative review can be read at this article: Is Rosacea a ‘Complicated Diagnosis Path’ and Mysterious Disorder? I would hope that members of the RRDi would read the Journal of the RRDi for themselves and decide what they think of the journal and then post a review here in this thread. Thanks

Jeffry B. Stock, Ph.D., has volunteered to serve on the RRDI MAC. Dr. Stock is on some cutting edge research for a treatment for rosacea at Signum Bioscience.

Lance Christiansen is no longer serving on the RRDi Board of Directors. We appreciate Lance's volunteering to serve the RRDi.

Welcome Nick to the RRDi. I googled it and haven't heard of using "0.375% lidocaine applied to specific sites modifies the state of the nervous system in the place where you applied and thus acts on the entire body." I had to have google translate the page. Have you actually tried this?

This is to announce that Begül Ya&#287;c&#305;-Küpeli, M.D. has volunteered to serve on the RRDi MAC. Dr. Begül Ya&#287;c&#305;-Küpeli, M.D. suffers from rosacea and is a Pediatric Oncologist. The RRDi is grateful for her volunteering.

I am pleased to announce the inaugural edition of the Journal of the Rosacea Research & Development Institute is now available from iUniverse. The proceeds of the sale of this journal will be used to further the journal's publication and lead to some novel rosacea research. This journal took over two years to develop and the RRDi had many volunteers to publish this. Joanne Whitehead, Ph.D., is the editor in chief of the Journal of the RRDi and she worked countless hours making this a reality. Thanks for your support by purchasing a copy.

Some of the MAC Members reply to questions by email to me and I then publish the answers for them. Here is a reply from Kosta Y. Mumcuoglu, PhD regarding this topic question: BEGIN REPLY: It is known that patients with papulopustular rosacea have a higher density of Demodex folliculorum mites on their faces than normal subjects but their role in initiating inflammation is disputed. It was reported that when the number of Demodex mites increases, there is a higher chance to develop a bacterial infection and inflammation, which could be considered as a result of the mite activity and damage caused. Selective antibiotics are effective in reducing the inflammatory changes of papulopustular rosacea, but their mode of action is unknown. Lately, a bacterium (Bacillus oleronius) was isolated from a D. folliculorum mite extracted from the face of a patient with papulopustular rosacea. To investigate whether this mite-related bacterium was capable of expressing antigens that could stimulate an inflammatory immune response in patients with rosacea, Lacey et al. (2007) investigated patients with rosacea and control subjects and found that in the presence of bacterial antigens, the proliferation of peripheral blood mononuclear cells was significantly higher in patients with rosacea than in control subject. Accordingly, it is thought that mite-related bacteria have the potential to stimulate an inflammatory response in patients with papulopustular rosacea. Li et al. (2010) investigated the correlation between ocular Demodex mite infestation and sero-positivity of the patients to B. oleronius in 49 patients with facial rosacea. Facial rosacea, lid margin, and ocular surface inflammation were documented by photography. There was a significant correlation between serum immunoreactivity (presence of the bacterium) and facial rosacea, lid margin inflammation, and ocular Demodex infestation. The Demodex count was significantly higher in patients with positive facial rosacea. The strong correlation provides a better understanding of co-morbidity between Demodex mites and their symbiotic B. oleronius in facial rosacea and blepharitis. Treatments directed to both warrant future investigation. References: Li J, O'Reilly N, Sheha H, Katz R, Raju VK, Kavanagh K, Tseng SC. Correlation between Ocular Demodex Infestation and Serum Immunoreactivity to Bacillus Proteins in Patients with Facial Rosacea. Ophthalmology. 2010 Jan 14. [Epub ahead of print] Lacey N, Delaney S, Kavanagh K, Powell FC. Mite-related bacterial antigens stimulate inflammatory cells in rosacea. Br J Dermatol. 2007 Sep;157(3):474-81. Kosta Y. Mumcuoglu, PhD END REPLY

This is to announce that two new MAC members have volunteered to serve on the RRDi MAC: Craig A. Elmets, M.D., Chairman, Department of Dermatology University of Alabama School of Medicine and Alan B. Fleischer Jr, M.D., Professor and Chair of the Department of Dermatology at Wake Forest University The RRDi appreciates these two physicians volunteering to help us.

Here are replies by email: From: Robert Brodell, MD Subject: Re: Questions for the RRDi MAC Members Date: February 12, 2010 2:49:14 AM HST To: Barrows Brady Misdiagnosed Rosacea Why do you think there are reports of misdiagnosed rosacea? The diagnosis is rosacea is easy of a patient has acne papules and pustules in association with a red face. However, some patients have a form of rosacea with mostly redness and telangiectasias. Without the acne component visible, the differential diagnosis includes chronic sun-damaged skin, flushing and blushing, acute lupus, drug induced erythema, and other conditions. In some cases, patients have a combination of several causes for their facial redness. While in most patients the diagnosis of acne rosacea is easy, some patients with facial redness due to other causes may be called rosacea, and some patients with rosacea may be missed even when physicians are smart and mean well. Robert Brodell, MD _____________________________________________________________ Reply from Brady Barrows to Dr. Brodell: Here is the evidence for misdiagnosed rosacea: Click Here _____________________________________________________________