Guide

NOTE:

Diet Triggers seem to be the more popular rosacea trigger to discuss. However, one must understand rosacea triggers in general before considering the list below. One must always remember that these proposed diet triggers are based upon purely anecdotal reports. You may  be interested in what the role diet plays in rosacea?

Rosacea Diet Trigger List

Alcohol * [7]

Animal Diet

Avocados *

Bananas *

Broad-leaf beans and pods *

Capsaicin +

Carbohydrate [5]

Cheese *

Chili +

Chocolate *

Citrus fruits *

Coconut Oil [3]

Coffee +

Curry +

Eggplant *

Figs *

Foods high in histamine *

Gluten [6]

High Carbohydrate Diet **

Hot drinks *

Lima beans *

Liver *

Marinated meats *

Navy beans *

Pea *

Peppers +

Raisins

Red plums *

Salicylates [4]

Sour cream *

Soy +

Sour Cream

Soy sauce *

Spicy food *

Spinach *

Sugar **

Thermally hot foods *

Tomatoes *

Vanilla *

Vinegar

Vitamin B Complex Supplement [1]

Vitamin E [2]

Yogurt

Sources:

* National Rosacea Society Trigger List

** Rosacea 101—Rosacea Diet

# Flushing Syndromes

## Dermis

^ Rosacea Support Group

+ Ken Landow, MD

The source of the above list was complied based upon Rosacea 101: Includes the Rosacea Diet, iUniverse, 2007, by Brady Barrows with the author's permission. I have continued to add more diet triggers upon any anecdotal evidence discovered since the publication of my book.

Chemical Triggers

More info on Triggers

End Notes

[1] Actas Dermosifiliogr. 2011 Feb 4.
Rosacea Triggered by a Vitamin B Complex Supplement.
Martín JM, Pellicer Z, Bella R, Jordá E.

Actas Dermosifiliogr. 2011 Feb 4.

[2] There is one anecdotal report that Vitamin E is a rosacea trigger in at least one rosacea sufferer. This has not been substantiated by any other reports. For more info read cherylarose's post.

[3] One anecdotal report by Mister88

[4] christine123 posted on September 4, 2012 #17

[5] Rosacea 101: Includes the Rosacea Diet

[6] Julie Rangel Oliver and Stephanie Amarante in Rosacea (English), Facebook 

Jacqui C., It Works for Me, Category, Food & Beverages, NRS

[7] What About Alcohol and Rosacea?

Here is a possible trigger list for topical irritants for rosacea:

Acne Products **

Acetone *

Alcohol *

Alpha hydroxy acids ^

Anti-Aging **

Astringents ^

Azelaic acid ^

Benzoyl Peroxide ^

Beta-Hydroxy Acids **

Exfoliants ^

Fragrance +

Hair Sprays *

Hydro-alcoholic *

Perfume +

Retinoids ^

Skin Peels ^

Salicylic Acid **

Soap +

Steroids *

Sunscreen +

Toners ^

Triclosan ^

Witch Hazel *

Some environmental triggers:

Hot baths *

HIV +

Humidity *

Saunas *

Simple overheating *

Sun *

Strong winds *

Ultraviolet radiation ##

Washcloths *+

Physiological Triggers

Anger #

Anxiety *

Caffeine withdrawal *

Chronic cough *

Embarrassment #

Exercise *

Frequent flushing *

Hot Flashes #

“Lift and load” jobs *

Menopause *

Straining #

Stress *

Valsalva maneuver #

Oral Drugs that may trigger rosacea:

Amyl nitrite #

Butyl nitrite #

Bromocriptine #

Calcium channel blockers #

Chlorpropamide (Diabinese)

with alcohol +

Cholinergic drugs #

Cyclosporine #

Cyproterone acetate #

Disulfiram (Antabuse) +

Doxorubicin +

Interferon +

Nicotinic acid #

Niacin +

Nifedipine +

Nitroglycerin +

Morphine #

Opiates #

Oral triamcinolone #

Prostaglandin E +

Rifampin (Rifadin) # +

Sildenafil citrate #

Tamoxifen #

Thyrotropin Releasing

Hormone (TRH) #

Topical steroids *257

Vasodilators *

Vancomycin +

* National Rosacea Society Trigger List

** Rosacea 101—Rosacea Diet

# Flushing Syndromes

## Dermis

^ Rosacea Support Group

+ Ken Landow, MD

Source for the above triggers:

Rosacea 101 by Brady Barrows page 46

Diet Triggers

More info on Triggers

Heat or cold exposure is just about on every rosacea trigger list. Even in the general population heat or cold usually produces a red face. For a rosacean this is not a good idea since it irritates rosacea further.

"Ozkol et al. reported that frequently exposed to heat from using a tandoor oven exhibited a significantly higher incidence of rosacea than control subjects." [1]

For a list of environmental exposure triggers click here.

End Notes

[1] 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

According to the JAAD, May 2010, "UV radiation exposure does not appear to affect the prevalence of PPR." This is one of the few studies ever done on this theory about rosacea. Hopefully more studies will be done in the future. [1] Another report in 2013 says UV exposure may be the cause of "telangiectasias with actinic elastosis." [7] So the evidence isn't nailed down that this theory is the correct one. For years we have reports like the ones below that focus on sun or light damage being a culprit in the cause of rosacea. However, it is important to note that recently more reports on UV radiation exposure may have some link to rosacea.

"A very important background feature is sun damage. Rosacea is always associated with solar elastosis and often with heliodermatosis. Fair-skinned patients with rosacea type I will often give a history of sun sensitivity." [2]

"The general consensus among clinicians is that rosacea is a photoaggravated disorder." [3]

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. The nervous system may be involved, because exertion, emotions, and weather trigger the disease, in addition to other triggers such as heat, certain types of food, alcoholic beverages, various topical balms and cosmetics, and various drugs. We're clear that blood vessels are dilated but don't know if that comes first or later. A new area of research suggests that lymphatic vessels are involved." [4]

One study suggests "that sun exposure has a different influence on each subtype of rosacea." [5]

"The degree of sun exposure had significant correlation with the development and severity of the erythematotelangiectatic subtype (p<0.05), while it had no correlation with the papulopustular, ocular and phymatous subtypes." [5]

One anecdotal report says rosacea was caused by being exposed to sunlight in an office with windows and concluded, "I am happy to say that its been about 3 months that I have been back to my original office without the windows....and the redness on my face is completely gone." [6]

Another reports concluded, "The association of large telangiectasias with actinic elastosis may indicate a causative role of exposure to UV radiation." [7]

Still another report says, "UV-B irradiation and microbial components increase vitamin D3 and TLR2 expression in keratinocytes leading to an increase of cathelicidin production." [8]

However, on the flip side, one report says, "The majority of subjects with atopic eczema, acne vulgaris or seborrheic dermatitis experienced improvement after exposure to sunlight. Individuals with rosacea also experienced improvement more often than impairment from exposure to sunlight." [9]

"Many chronic inflammatory cutaneous diseases, such as rosacea and psoriasis, are known to be associated with dermal remodeling after UV irradiation....the production of ROS and ER stressors after UV radiation provide a logical framework explaining UV radiation as a triggering factor for rosacea." [10]

Actinic Folliculitis (AF) should be ruled out in a differential diagnosis. 
Ruling out Photosensitivity diseases from Rosacea
EM Radiation a Rosacea Trigger?
Florescent Lights and Rosacea

End Notes

[1] Papulopustular rosacea: prevalence and relationship to photodamage.
McAleer MA, Fitzpatrick P, Powell FC.
J Am Acad Dermatol. 2010 Jul;63(1):33-9. Epub 2010 May 11.

[2] Rosacea: classification and treatment.
T Jansen and G Plewig
J R Soc Med. 1997 March; 90(3): 144–150.

[3] Ultraviolet light and rosacea.
Murphy G.
Cutis. 2004 Sep;74(3 Suppl):13-6, 32-4.

[4] Rosacea: turning all stones for source of pathology
June 1, 2004, By: Rebecca Bryant
Dermatology Times, Modern Medicine

[5] Ann Dermatol. 2009 Aug;21(3):243-9. doi: 10.5021/ad.2009.21.3.243. Epub 2009 Aug 31.
Clinical evaluation of 168 korean patients with rosacea: the sun exposure correlates with the erythematotelangiectatic subtype.
Bae YI, Yun SJ, Lee JB, Kim SJ, Won YH, Lee SC.
Ann Dermatol. 2009 Aug;21(3):243-9. Epub 2009 Aug 31.

[6] Sara45, The Rosacea Forum, Sept. 17, 2012

[7] Ann Dermatol Venereol. 2013 Jan;140(1):21-9. doi: 10.1016/j.annder.2012.10.592. Epub 2012 Dec 21.
A histological and immunohistological study of vascular and inflammatory changes in rosacea.
Perrigouard C, Peltre B, Cribier B.

Micrograph of Chlamydia pneumoniae in an epithelial cell image courtesy of Wikimedia Commons

Chlamydophila pneumoniae has been implicated with a possible role in the etiology of rosacea and remains another theory to add to the long list.

At least one report suggests Chlamydophila pneumoniaeas a cause of rosacea and states, “These preliminary data suggest the need for further investigation with clinical trials to study long-term tolerability and efficacy and also strongly implicate C pneumoniae in the pathogenesis of acne rosacea.” [1]

There is some discussion on this at RF [2] and at the RRF Wiki. [3]

You might want to know more about this subject by clicking here.

End Notes

[1] The role of Chlamydia pneumoniae in the etiology of acne rosacea: response to the use of oral azithromycin.

Fernandez-Obregon A, Patton DL; Cutis. 2007 Feb;79(2):163-7

[2] The Rosacea Forum thread on CPn

See also:

Testing for Chlamydia Pneumoniae (Cpn) infection - Rosacea Forum's Unofficial Study

[3] RRF Wiki

Another theory on the cause of rosacea is that irritable bowel syndrome is related to rosacea. "Rosacea may be a symptom of an unhealthy gastrointestinal system and healing the entire gastrointestinal system may be the basis for eliminating rosacea. Many people with rosacea also have been diagnosed with Irritable Bowel Syndrome (IBS), Crohn's Disease or some form of Colitis." [1]

"Our meta-analysis confirmed a significant bi-directional association in occurrence of IBD and rosacea." [2]

We need more citations on this theory but a possible clue could be found in a related subject, my SIBO and Rosacea post which has more citations and papers than IBS.

However, in Googling this subject I ran across this interesting article written in 1896 by Dr. Leviseur:

"There are a number of skin diseases which occur in connection with disturbance of the stomach and intestine. This fact is well supported by clinical evidence, but, viewed from the more elevated standpoint of theoretical science, it must be admitted that the true nature of this connection is far from being clearly understood….All writers agree that a large percentage of cases of acne rosacea is caused by indigestion…..These patients have factor ex ore, especially in the morning, sour eructations, constipation, and perhaps a distressing feeling of fulness after meals; in short, all the symptoms of a mild fermentative gastritis…..In severe cases lavage is indicated and has sometimes a surprisingly good effect on the skin eruption. It must not, however, be expected that the mechanical removal of the fermenting masses stops the fermentation; the latter will promptly start again with the very next food supply. Careful dieting is almost always necessary; the amount of carbohydrates should be limited; alcohol, tea pastry, the coarser vegetables and milk should be forbidden. Bismuth, carbonate of sodium, creosote, carbolic acid, thymol, and ichthyic may be employed. I have had good results from the use of fluid extract of ergot…..It would carry me too far if I were to consider the various drug eruptions which appear in connection with gastrointestinal disturbances, as for instance erythema after the use of quinine, antipyrin, turpentine, balsam of copaiba, sandalwood oil, arsenic, etc….." [3]

Is inflammatory bowel disease (IBD) the same thing as Irritable Bowel Syndrome (IBS)? Answer

Skin manifestations associated with irritable bowel syndrome

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End Notes

[1] Dr. David Dahlman, a Chiropractic Physician with a degree in Nutrition

[2] Clin Res Hepatol Gastroenterol. 2018 Oct 30;
The relationship between inflammatory bowel disease and rosacea over the lifespan: A meta-analysis.
Han J, Liu T, Zhang M, Wang A

[3] Remarks of Some Skin Diseases Occurring in Connection with Gastro-Intestinal Disturbances
by Fred. J. Leviseur, M.D.
Medical record, A Weekly Journal of Medicine and Surgery
Volume 50, No. 3, Whole No. 1341, New York, July 18, 1896, p 84, 85
edited by George Frederick Shrady, Thomas Lathrop Stedman

Image courtesy of Wikimedia Commons

This post has been promoted to an article

SIBO refers to "Small bowel bacterial overgrowth syndrome (SBBOS), or small intestinal bacterial overgrowth (SIBO), also termed bacterial overgrowth; is a disorder of excessive bacterial growth in the small intestine." [1]

It has also been called Dysbiosis (sometimes called dysbacteriosis).

The presence of small intestinal bacterial overgrowth (SIBO) in patients with rosacea has been investigated and the results of this study says, "We found an increased prevalence of SIBO in patients with rosacea compared to controls (40/60 vs 3/60, respectively, p<0.001). Oro-cecal transit time resulted significantly delayed in patients with SIBO than in controls (p<0.01). After SIBO eradication we obtained a complete recovery of cutaneous lesions in 17/20 (85%) and a relevant improvement in 2/20 (10%) patients, while those treated with placebo remained unchanged (14/16) or even worsened (2/16), (p<0,001). These latter patients were subsequently switched to rifaximin therapy with complete resolution of rosacea in 14/16 and significant improvement in the remaining 2 cases.

CONCLUSION: Our study shows the high prevalence of SIBO in patients with rosacea and emphasizes the clinical effectiveness of its eradication in inducing almost complete remission of cutaneous lesions." [2]

Another report shows similar results. [3]

You might notice that the article [Clin Gastroenterol Hepatol] says that "Patients positive for SIBO were randomized to receive rifaximin 1200 mg/day for 10 days or placebo...These latter patients were subsequently switched to rifaximin therapy with complete resolution of rosacea in 14/16 and significant improvement in the remaining 2 cases."[2]

Wikipedia says that Rifaximin is "a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that the drug will not pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics....It is currently sold in the U.S. under the brand name Xifaxan by Salix Pharmaceuticals. It's also sold in Europe under the name Spiraxin and Zaxine.."

Another source says "Rifaximin is effective in treatment of SIBO in IBS and controlled trials are warranted."

There is also evidence that SIBO occurs "in patients suffering from scleroderma" as well. [4]

An EIR Report on SIBO says that according "to Dr. Leo Galland, a specialist in dysbiosis related illness, the best diet to aid in the treatment of SIBO is very similar to that used to treat yeast overgrowth. This being a diet free of simple sugars and grains/cereals and low in fruit and starchy vegetables depending on individual tolerance. This diet restricts the nutrition available for bacteria in the upper GI tract to proliferate and reduces the excess alcohols and organic acids that are produced as a result of bacterial fermentation." [5] This is similar to the Rosacea Diet, reducing sugar/carbohydrate. 

A report in 2013 concluded: "This study demonstrated that rosacea patients have a significantly higher SIBO prevalence than controls. Moreover, eradication of SIBO induced an almost complete regression of their cutaneous lesions and maintained this excellent result for at least 9 months. [6]

"For example, rosacea has an association with SIBO (small intestine bacteria overgrowth). In one study, there was a higher number of patients with rosacea who tested positive for SIBO than the group without the skin disease. The researchers randomly assigned the patients with a positive SIBO breath test to either take a placebo or rifaximin (an antibiotic) therapy at 1200 mg/day for 10 days to clear the SIBO. Some patients also underwent the therapy despite having a negative breath test. Upon treating the SIBO, 20 of 28 patients had a clearance of cutaneous lesions, while there was either no change or worsening of the lesions in those who were on the placebo. The researchers then switched the patients taking the placebo to the antibiotic treatment, resulting in 17 of the 20 experiencing an eradication of SIBO. Out of that group, 15 also saw a complete resolution of their rosacea. The improvement of rosacea lasted for at least 9 months. There was no change in rosacea in 13 of the 16 patients who tested negative for SIBO. This study demonstrates that not only is there a strong association between SIBO and rosacea, but that treating the SIBO improved rosacea." [7]

Certain foods common in diets of US adults with inflammatory bowel disease

You may want to consider the Rosacea Diet.

Anecdotal Rifaximin Treatment Reports

philfaebuckie

Etcetera 

IBS and Rosacea

IBD and Rosacea

HLA-DRA Locus and Rosacea

Gastrointestinal Rosacea [GR], aka, Gut Rosacea

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End Notes

[1] Image courtesy of Wikimedia Commons, 

http://en.wikipedia....growth_syndrome

[2] SMALL INTESTINAL BACTERIAL OVERGROWTH IN ROSACEA: CLINICAL EFFECTIVENESS OF ITS ERADICATION.
United European Gastroenterology Week
Clin Gastroenterol Hepatol. 2008 Jul;6(7):759-64. Epub 2008 May 5
Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, Parodi AU, Savarino V

[3] Journal of the American Academy of Dermatology
Volume 68, Issue 5, Pages 875–876, May 2013
Rosacea and small intestinal bacterial overgrowth: Prevalence and response to rifaximin
Leonard B. Weinstock, MD, Martin Steinhoff, MD, PhD

[4] Small intestinal bacterial overgrowth in patients suffering from scleroderma: clinical effectiveness of its eradication.
Parodi A, Sessarego M, Greco A, Bazzica M, Filaci G, Setti M, Savarino E, Indiveri F, Savarino V, Ghio M.
Am J Gastroenterol. 2008 May;103(5):1257-62. Epub 2008 Apr 16.

[5] Antibacterial Treatment, For The Treatment Of Bacterial Dysbiosis, Small Intestinal Bacterial Overgrowth (SIBO), Bacterial Overgrowth, Environmental Illness Report

[6] Clin Gastroenterol Hepatol.
Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication
By A. Parodi A et al. • ProHealth.com • April 12, 2013

[7] The Gut-Skin Axis: The Importance of Gut Health for Radiant Skin, Deanna Minich, Ph.D., Contributor, Huff Post

Image courtesy of Wikimedia Commons

If you were around in August 2007, there were headlines such as, Scientists unmask the cause of rosacea, [1] and UCSD Researchers Discover Cause of Rosacea [2] not to mention all the other headlines which created quite a stir in all the online rosacea groups and brought a lot of hope for rosacea sufferers. These articles seemed to conclude that rosacea’s mystery is resolved and within time a treatment would be found to eradicate rosacea. These startling headlines were the result of a paper published by researchers at UCSD associated with Richard L Gallo, et.al, in a study published by Nature Medicine [3]. This paper concluded:

“These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease.” 

If you will notice in the above statement that the findings suggest an explanation for the pathogenesis of rosacea. Gallo, et.al, never said they found the cause of rosacea. The newspapers came to the conclusion that now all the mystery of rosacea is over and we now have the cause nailed down. All we have to do is wait for the treatment. This is not exactly the truth. While the research of Gallo, et.al, at UCSD is remarkable and insightful, the jury is still out on what causes rosacea. And while the jury is still out, there is more news worth mentioning that may be related to cathelicidin, peptides or antigenic proteins.

You might want to read this thread on Gallo's research.

You may also view a Medscape video lecture by Dr. Gallo, New Insights Into the Science of Treating Rosacea, where he discusses the innate immunity and cathelicindin.

An interesting read if you understand this subject well is an article published in Antimicrobial Agents and Chemotherapy, entitled, Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus-Derived Proteinases. [4]

What Does Cathelicidin Have To Do With Rosacea?

Wikipedia in its article on Cathelcidin says, "Cathelicidin-related antimicrobial peptides are a family of polypeptides found in lysosomes of macrophages and polymorphonuclear leukocytes (PMNs), and keratinocytes."

After reading the above, this is where we meager uneducated rosacea sufferers start to yawn, get lost, or say 'who cares?' So get on your thinking caps and follow with me.

Cathelicidin is a peptide.  Antimicrobial Peptides (AMPs), "also called host defense peptides (HDPs) are part of the innate immune response found among all classes of life." Wikipedia

"Peptides (from Gr.: πεπτός, peptós "digested"; derived from πέσσειν, péssein "to digest") are biologically occurring short chains of amino acid monomers linked by peptide (amide) bonds." Wikipedia If you forgot what amino acid monomers are, amino acids are the building blocks of protein and make up the 'the second-largest component (water is the largest) of human muscles, cells and other tissues." Wikipedia "A monomer (/ˈmɒnəmər/ mon-ə-mər[1]) (mono-, "one" + -mer, "part") is a molecule that may bind chemically or supramolecularly to other molecules." Wikipedia

So breaking this down, Cathelicidin is related to a family of anti-microbial (an antimicrobial is an agent that kills microorganisms or inhibits their growth) peptides (short chains of amino acids) found in lysomes (a membrane-bounded organelle [a specialized subunit within a cell that has a specific function] found in most animal cells) of macrophages (a type of white blood cell) and polymorphonuclear leukocytes (a category of white blood cells) and and keratinocytes (predominant cell type in the outermost layer of the skin).

The nutshell version is that Cathelicidin is a killer of microscopic organisms that is at the cellular level found in white blood cells and also found in cells on the skin. 

In the article in Nature magazine [3] the paper mentions that in rosacea patients the cathelicidin levels were abnormally high suggesting that the redness is caused by an abnormal immune system response. The conclusion of the article says, "These findings confirm the role of cathelicidin in skin inflammatory responses and suggest an explanation for the pathogenesis of rosacea by demonstrating that an exacerbated innate immune response can reproduce elements of this disease." [3] (Italics added)

"However, following injury or inflammatory skin diseases such as psoriasis and rosacea, expression of the cathelicidin antimicrobial peptide LL37 breaks tolerance to self-nucleic acids and triggers inflammation." [7]

"Dysregulation of the innate immune response increases the secretion of antimicrobial peptides (AMP) and cytokines, via activation of toll-like receptor 2 (TLR-2). The main AMP is cathelicidin, which is cleaved by kallikrein 5 (KLK-5) into the active peptide LL-37. This is the fundamental mediator for activating and controlling numerous processes: release of cytokines and metalloproteinases (MMP) by leukocytes, mast cells, and keratinocytes, regulation of the expression of extracellular matrix components, and increased proliferation of endothelial cells, causing angiogenesis. MMP-2 and MMP-9 are elevated on the skin of patients, exerting inflammatory, angiogenic, and dermal framework disruption functions in addition to helping in the activation of KLK-5, retrofeeding the system. MMP-9 is directly stimulated by the mite Demodex folliculorum (Df)." [8]

AMPs in Clinical Development

There is much excitement with using AMPs and ACPs in treating cancer. 

"As shown here, different microbial infections and/or cancer-targeting peptides are in clinical trials, with approval for clinical application expected for the next few years (at least 10 in the next 5 years). Moreover, that number should tend to increase due to advances in the rational design of peptides, minimizing or eliminating cytotoxic effects. In addition, advances in the large-scale synthesis of peptides has made this process cheaper, thus making peptide-based therapies likely to become more accessible to patients." [5]

Associated Diseases
"In addition, the association between cardiovascular diseases and rosacea might also be explained by enhanced expression of the cathelicidin, which has been observed both in the course of atherosclerosis and rosacea." [6]

Independent Rosacea Research
Could a group of rosacea sufferers in a non profit organization like the RRDi collectively get together and sponsor their own research on rosacea? For example, if 10K members each donated a dollar, could it be possible that this money could be used to sponsor their own independent rosacea research on a cathlecidin?  What do you think? If you want to do something about this read this post. 

Conclusion

All this started due to Gallo, et al, in 2007 and we continue to watch for more developments. 

Etcetera

Rosacea Theories Revisited.

Other Cytokines to Consider

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End Notes

[1] Scientists unmask the cause of rosacea
August 06, 2007 | Alison Williams, Los Angeles Times Staff Writer

[2] UCSD Researchers Discover Cause of Rosacea
UCSD News Center

[3] Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea
Kenshi Yamasaki, Anna Di Nardo, Antonella Bardan, Masamoto Murakami, Takaaki Ohtake, Alvin Coda, Robert A Dorschner, Chrystelle Bonnart, Pascal Descargues, Alain Hovnanian, Vera B Morhenn & Richard L Gallo
Nature Medicine 13, 975 – 980 (2007)
Published online: 5 August 2007 | doi:10.1038/nm1616

[4] Antimicrob Agents Chemother. 2004 December; 48(12): 4673–4679.
doi: 10.1128/AAC.48.12.4673-4679.2004
PMCID: PMC529204
Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus-Derived Proteinases
Magdalena Sieprawska-Lupa, Piotr Mydel, Katarzyna Krawczyk, Kinga Wójcik, Magdalena Puklo, Boguslaw Lupa, Piotr Suder, Jerzy Silberring, Matthew Reed, Jan Pohl, William Shafer, Fionnuala McAleese, Timothy Foster, Jim Travis, and Jan Potempa

[5] Front Chem. 2017; 5: 5.
Published online 2017 Feb 21. doi:  10.3389/fchem.2017.00005
PMCID: PMC5318463
Peptides with Dual Antimicrobial and Anticancer Activities
Mário R. Felício, Osmar N. Silva, Sônia Gonçalves, Nuno C. Santos, and Octávio L. Franco

[6] 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

[7] Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors.
Sci Rep. 2018 Mar 05;8(1):4032
Takahashi T, Kulkarni NN, Lee EY, Zhang LJ, Wong GCL, Gallo RL

[8] An Bras Dermatol. 2020 Nov-Dec; 95(Suppl 1): 53–69.
Consensus on the therapeutic management of rosacea – Brazilian Society of Dermatology
Clivia Maria Moraes de Oliveira, Luiz Mauricio Costa Almeida, Renan Rangel Bonamigo, Carla Wanderley Gayoso de Lima, Ediléia Bagatinf

"The nervous system may be involved, because exertion, emotions, and weather trigger the disease, in addition to other triggers such as heat, certain types of food, alcoholic beverages, various topical balms and cosmetics, and various drugs. We're clear that blood vessels are dilated but don't know if that comes first or later." [1]

"Patients with rosacea have a significantly increased risk of neurologic disorders such as migraine, depression, complex regional pain syndrome, and glioma. Enhanced expression of matrix metalloproteinase (MMP) is observed in these neurologic disorders as well as in rosacea, which might explain the possible shared pathogenic mechanisms between these conditions." [2]

"Recently, an increased interest has been shown in the potential associations between neurodegenerative diseases and rosacea. For example, a nationwide cohort study from Denmark explored the relationship between rosacea and neurodegenerative diseases such as Parkinson’s disease. MMPs are believed to be associated with the neurodegenerative diseases and an increased expression of MMP-1 and MMP-9 has also been observed in rosacea. In addition, another Danish study found that rosacea was significantly associated with dementia, especially Alzheimer disease. AMPs, MMP, and inflammatory cascades, which have a shared impact on both rosacea and Alzheimer disease, are considered to be involved in the underlying mechanism. Together, these findings suggest that a pathogenic link might therefore exist between rosacea and neurodegenerative diseases." [2]

"We found a significantly higher prevalence and risk of incident migraine especially in female patients with rosacea. These data add to the accumulating evidence for a link between rosacea and the central nervous system." [3]

"Currently, it is clear that the innate immune and the sensory and autonomic nervous systems are overstimulated with dysregulated interactions, leading to a chronic pathological inflammatory state." [4]

"Thus, an activated nervous system in the skin correlates well with the early phase of rosacea, although it is still unclear whether neuronal activation precedes or follows the inflammatory infiltrate. The extent to which the autonomic and/or sensory nervous system is involved in the neuronal dysregulation during rosacea has received considerable attention, as modulation of α-adrenergic receptors or β-adrenergic blockers is helpful in some patients (Craige and Cohen, 2005; Shanler and Ondo, 2007; Gallo et al., 2010)." [5]

"Both augmented innate immune response and neurovascular/neuroimmune dysregulation appear to work in concert in signaling into motion the underlying vasodilation and cascades of inflammation, which produce intermittent flares of diffuse facial erythema." [6]

"According to Morrison (2012) in the study of the autonomic nervous system (using the vegetative index of Kerdo) the prevalence of parasympathetic tone of the autonomic nervous system has been found in Rosacea patients." [7]

"NRS-funded researcher Dr. Martin Steinhoff, director of the Charles Institute of Dermatology at the University College Dublin School of Medicine, and colleagues at the University of California-San Francisco have documented that the nervous system is intimately linked with the vascular system in producing the typical signs and symptoms of rosacea, which suggests that both the flushing and inflammation of rosacea may be part of the same continuum." [8]

Also see this post about Psychology and Rosacea.

End Notes

[1] Rosacea: turning all stones for source of pathology
Publish date: Jun 1, 2004
By: Rebecca Bryant, Dermatology Times, Modern Medicine

[2] 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,

[3] Prevalence and risk of migraine in patients with rosacea: A population-based cohort study.
J Am Acad Dermatol. 2016 Nov 3;
Egeberg A, Ashina M, Gaist D, Gislason GH, Thyssen JP

[4] Clin Cosmet Investig Dermatol. 2015; 8: 159–177.
Published online 2015 Apr 7. doi:  10.2147/CCID.S58940
PMCID: PMC4396587
Update on the management of rosacea
Allison P Weinkle, Vladyslava Doktor, and Jason Emer

[5] J Investig Dermatol Symp Proc. Author manuscript; available in PMC 2013 Jul 8.
Published in final edited form as:
J Investig Dermatol Symp Proc. 2011 Dec; 15(1): 2–11.
doi:  10.1038/jidsymp.2011.7
PMCID: PMC3704130
NIHMSID: NIHMS479650
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

[6] J Clin Aesthet Dermatol. 2012 Mar; 5(3): 26–36.
PMCID: PMC3315876
Advances in Understanding and Managing Rosacea: Part 2
The Central Role, Evaluation, and Medical Management of Diffuse and Persistent Facial Erythema of Rosacea
James Q. Del Rosso, DO, FAOCD

[7] Georgian Med News. 2013 Jan;(214):23-8.
[New possibilities in the treatment of early stages of rosacea].
Tsiskarishvili NV1, Katsitadze A, Tsiskarishvili Ts.

[8] Causes of Rosacea: Neurovascular System, NRS

H. pylori reaches the epithelium of the stomach image courtesy of Wikimedia Commons

H Pylori (Helicobacter Pylori) has been a controversy with rosacea for some time now. Some experts dismiss H Pylori’s role in rosacea and yet it remains a controversy since other rosacea experts continue to discuss H Pylori as a possible factor in rosacea. The reason why this is such a controversy is that treatment for H Pyori eradication improves rosacea is so many cases. For example, "This study was designed to examine the prevalence of gastric Helicobacter pylori (Hp) infection verified by 13C-UTB-test, CLO, Hp culture and serology (IgG) in patients with rosacea....The eradication of Hp leads to a dramatic improvement of symptoms of rosacea and reduction in related gastrointestinal symptoms, gastritis, hypergastrinemia and gastric acid secretion; and 3) Rosacea could be considered as one of the major extragastric symptoms of Hp infection probably mediated by Hp-related cytotoxins and cytokines." [20]

Gastrointestinal Rosacea
When treatment for rosacea improves by treating for gastrointestinal issues, i.e., eradicating H Pylori, it is called Gastrointestinal Rosacea [GR].

H Pylori
A report published by Dovepress in May 2017 says about H Pylori, "There is not sufficient evidence regarding how determinant the role of H. pylori is." [16] Another report on this subject published in the J Eur Acad Dermatol Venereol also in May 2017 "found weak associations between rosacea and Helicobacter pylori infection as well as an effect of Helicobacter pylori therapy on rosacea symptoms." [15]

A report in 2013 states, "There still proves to find a correlation of Hp infection with patients with rosacea but it can still be hypothesised as a cutaneous manifestation of an internal peptic ulcer disease." [11]

A report in January 2010 states that “Helicobacter pylori infection is implicated in the pathogenesis of extradigestive diseases such as acne rosacea…” A report by Mc Leer, Lacey and Powell in 2009 listed H Pylori as a possible factor in the pathophysiology in rosacea.

Another report in 2012 concluded:
"We concluded that H. pylori has a significant role in rosacea patients who had dyspeptic symptoms. The PPR type is more influenced by H. pylori and this is regarded as being because of certain virulent strains that increase the inflammatory response in gastric mucosa and also in cutaneous lesions." [9]

One report in 2003 suggests “some form of relationship between rosacea and H. pylori infection.” Two reports in 1996 suggested H Pylori’s role in rosacea with titles such as “Eradication of Helicobacter pylori as the only successful treatment in rosacea” and “Acne rosacea and Helicobacter pylori betrothed.” Rebora suggested in 1995 that the “role of H. pylori is more probable in erythrotic rosacea than in its papulopustular and granulomatous stages.” [1] These are just a few reports suggesting H Pylori as a factor in rosacea.

When you consider the fact that H Pylori was ‘officially’ discovered in 1986 by Drs Marshall and Warren in Australia who both won the Nobel Prize in 2005 for this discovery and changed the textbooks about how bacteria can survive in the human stomach and its relation to ulcers and other gastric problems and the fact that this gram negative bacteria is considered an infection that half the world’s population is carrying with most being totally asymptomatic it is a wonder that anyone can even connect H Pylori with rosacea at all. Yet the reports on H Pylori and rosacea keep coming out despite the fact that many reports negate H Pylori’s role in rosacea.

While there are many older reports suggesting H Pylori having some role in rosacea, newer reports dismiss this role. For instance, the late Dr. Kligman noted H Pylori’s controversial role in rosacea in his 2003 report. [2]

A report released in 2002 mentions ‘promising recent reports of beneficial H. pylori eradication’ in many cutaneous skin diseases except rosacea. [3]

A study published in May 2010 concluded, “There is no association between Helicobacter pylori infection and rosacea in current study.” [4]

Nevertheless, there are reports of H Pylori associated with rosacea indicating that eradicating H Pylori clears rosacea and discuss the possible cutaneous pathology of H Pylori to an autoimmune mechanism. A report in 2009 says, a “few case reports have documented associations between Helicobacter pylori infection and rosacea.” [5]

What is H Pylori and how does it relate to rosacea?
H Pylori is a gram negative bacteria that is considered an infection and harmful to humans.

According to one report, “more than 50% of the human population have long-term Helicobacter pylori infection.” [3] Wikipedia says that the diagnosis of H Pylori is done with different tests that are not failsafe and sometimes results in false positives. How anyone can know for sure that 50% of the human population is infected with H Pylori is quite suspect. The percentage of ‘infection’ of H Pylori, if indeed it is an infection, may be more or less than 50% .

According to Wikipedia, “Helicobacter pylori is a Gram-negative, microaerophilic bacterium that can inhabit various areas of the stomach, particularly the antrum. It causes a chronic low-level inflammation of the stomach lining and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer. Over 80% of individuals infected with the bacterium are asymptomatic.”

So, if 80% of individuals are asymptomatic and they only discovered H Pylori in 1986 how do they know that H Pylori is a human pathogen? There is an amusing article, “So, What’s Your Problem with Gram-Negative Bacteria??,” that gets you thinking. Do you really think that medical science knows everything about H Pylori in a little over twenty years? Obviously sometimes H Pylori is a human pathogen and runs amuck causing us problems. But in 80% of individuals H Pylori is asymptomatic and obviously is in the stomach for some reason, possibly for some nefarious purpose such as an ulcer, but it is quite possible for some beneficial purpose as well. Could it be possible that a gram negative bacteria serves some useful purpose that as yet hasn’t been discovered? For instance, E. coli can help people and animals to digest food and help in providing vitamins but sometimes runs amuck causing some serious food poisoning. Could H Pylori have some beneficial yet undiscovered function for humans yet sometimes cause issues like E. coli does?

Could H Pylori be asymptomatic because it is helping us for some reason yet undiscovered, and sometimes for some yet undiscovered reason turns into a monster that causes problems like ulcers and rosacea?

SIBO has been associated with rosacea with gram negative bacteria associated with it such as H Pylori. One report says, “Gastric acid suppresses the growth of ingested bacteria, thereby limiting bacterial counts in the upper small intestine. Diminished acid production (hypochlorhydria) is a risk factor for SIBO, and can develop after colonization with Helicobacter pylori or as a consequence of aging. [6]

Gram Negative Folliculitis, a rosacea mimic, is an acne condition caused by Gram-negative organisms which usually develops in patients who have received systemic antibiotics for prolonged periods. This is quite odd when you consider that eradicating H Pylori, a gram negative bacterium, clears rosacea in some cases. This certainly raises some questions about using long term antibiotic treatment for rosacea, doesn’t it? More info on the long term antibiotic risks you should consider.

Since eradicating H Pylori involves the use of antibiotics it would be difficult to really know if the H Pylori is truly a factor in rosacea since antibiotics have been used for many years to successfully treat rosacea. If it were possible to eradicate H Pylori without using antibiotics and rosacea clears up, then, there would be some substantial evidence of H Pylori being a factor in rosacea

According to Wikipedia, “The standard first-line therapy is a one week “triple therapy” consisting of a proton pump inhibitors such as omeprazole, Lansoprazole and the antibiotics clarithromycin and amoxicillin. Variations of the triple therapy have been developed over the years…”  Proton pump inhibitors have been also listed as a systemic comorbidity in rosacea!

Since antibiotics are usually used in the eradication of H Pylori you can see why it would be difficult to know whether the clearing of rosacea is due to the eradication of the H Pylori or simply because antibiotics have been used successfully to treat rosacea for over fifty years.

Nevertheless, there are anecdotal reports that treatment for gastric problems has cleared rosacea.

For instance, one anecdotal report suggests that after treating a patient with gastritis and evidence of GERD that the rosacea cleared. [7] According to Wikipedia, “In 1999, a review of existing studies found that, on average, 40% of GERD patients also had H Pylori infection. The eradication of H. pylori can lead to an increase in acid secretion, leading to the question of whether H. pylori-infected GERD patients are any different than non-infected GERD patients. A double-blind study, reported in 2004, found no clinically significant difference between these two types of patients with regard to the subjective or objective measures of disease severity.“

A few other anecdotal reports have suggested digestive issues related to their rosacea. [8] There may be other anecdotal reports suggesting H Pylori eradication clears rosacea which I plan on adding to this page. If you have thoughts on this subject I suggest you post them here. 

Bonnie [10] reports that in Dr. Jonathan V. Wright's NUTRITION & HEALING Newsletter, February 2010, Getting to the root of Rosacea - in your stomach, Dr. Wright is reported to have said:

"It's sad that information about the very common connection between acne rosacea and low stomach acid has been lost. In 1948, an article about Rosacea in a major medical journal stated that "every Dermatologist knows" about this connection. In 2009, hardly any dermatolgists know about it. It's also important to note that 2/3 of individuals with Rosacea are actually infected with Helicobacter Pylori bacteria, a common cause of low stomach acid." This report cites no clinical papers on this subject. 

A report in 2006 concluded, "based upon these results, the relation between Helicobacter pylori and rosacea is supported, and infection should be investigated in these patients because an appreciable percentage of patients diagnosed with rosacea and Helicobacter pylori infection can benefit from eradication therapy, mainly in the papulopustular subtype." [12]

"H. pylori appears contribute to several inflammatory skin diseases. Rosacea is the most common skin disease potentially associated with H. pylori. In one study, H. pylori was present in 81% of rosacea patients who also had gastric complaints, and almost all of those patients harbored cagA+ strains. A similar Egyptian study found that both cagA and the s1m1 allele of vacA were more prevalent in papular rosacea patients. The papular rosacea patients responded better to eradication therapy than the erythematous rosacea patients. A limited study of ocular rosacea patients reports that the seven ocular rosacea patients responded better to H. pylori eradication therapy than did rosacea patients without ocular symptoms." [13]

"H. pylori has proven to be a more complex pathogen than early research indicated. Multiple surface carbohydrate structures, outer membrane proteins, and toxins interact to modify host cell signaling and the immune response.....Thirty years after its discovery, H. pylori remains an enigmatic pathogen with many secrets yet to be revealed." [13]

"The prevalence of Helicobacter pylori infection was also found to be higher in patients with rosacea than in controls [70]. However, other studies have failed to demonstrate a relationship between H. pylori and rosacea [14]. 

"This meta-analysis found weak associations between rosacea and Helicobacter pylori infection as well as an effect of Helicobacter pylori therapy on rosacea symptoms, albeit that these did not reach statistical significance. Whether a pathogenic link between the two conditions exists, or whether Helicobacter pylori infection represents a proxy for other factors remains unknown." [15]

"Although a possible pathogenetic link between H. pylori and rosacea is advocated by many authors, evidence is still interpreted differently by others." [17]

"Of 167 patients, 150 received H. pylori eradication therapy, demonstrating a 92% (138/150) cure rate.....The present study concluded that H. pylori eradication leads to improvement of rosacea." [18]

"Prevalence of H. pylori infection was significantly higher in patients with rosacea than control group, whereas SIBO prevalence was comparable between the two groups. Eradication of H. pylori infection led to a significant improvement of skin symptoms in rosacea patients." [29]

"Some studies consider it as one of the recently identified human bacterial pathogens, and special attention is paid to the evidence suggesting that it is probably part of the composition of the human microbiome as a commensal (commensal from French to English is a table companion) or even a symbiont. The presented data discussing the presence or absence of the effect of H. pylori on human health suggest that there is an apparent ambiguity of the problem....On the other hand, the high prevalence of H. pylori in the population and its asymptomatic coexistence with humans in most of the world’s population indicates its persistence in the body as a representative of the microbiome and as a nonpathogenic microorganism." [22]

H Pylori Causes Low Gastric Acid 

It is has been known for some time that H Pylori reduces gastric acid. You should read this post about Low Gastric Acid and Rosacea. 

Reply to this Topic

There is a reply to this topic button somewhere on the device you are reading this post. If you never heard about this topic and you learned about it here first, wouldn't it be a gracious act on your part to show your appreciation for this topic by registering with just your email address and show your appreciation with a post?  And if registering is too much to ask, could you post your appreciation for this topic by finding the START NEW TOPIC button in our guest forum where you don't have to register?  We know how many have viewed this topic because our forum software shows the number of views. However, most rosaceans don't engage or show their appreciation for our website and the RRDi would simply ask that you show your appreciation, please, simply by a post.  

End Notes

[1] Helicobacter pylori infection and autoimmune disease such as immune thrombocytopenic purpura
Ohta M.
Kansenshogaku Zasshi. 2010 Jan;84(1):1-8

The pathophysiology of rosacea.
Mc Aleer MA, Lacey N, Powell FC
G Ital Dermatol Venereol. 2009 Dec;144(6):663-71.

Helicobacter pylori and rosacea.
Zandi S, Shamsadini S, Zahedi MJ, Hyatbaksh M
East Mediterr Health J. 2003 Jan-Mar;9(1-2):167-71.

Eradication of Helicobacter pylori as the only successful treatment in rosacea
Kolibásová K, Tóthová I, Baumgartner J, Filo V.
Arch Dermatol. 1996 Nov;132(11):1393.

Acne rosacea and Helicobacter pylori betrothed
Wolf R.
Int J Dermatol. 1996 Apr;35(4):302-3

May Helicobacter pylori be important for dermatologists?
Rebora A, Drago F, Parodi A.
Dermatology. 1995;191(1):6-8

[2] A Personal Critique on the State of Knowledge of Rosacea
Albert M. Kligman, M.D., Ph.D.

[3] Helicobacter pylori infection in skin diseases: a critical appraisal.
Wedi B, Kapp A.
Am J Clin Dermatol. 2002;3(4):273-82.

[4] Risk factors associated with rosacea.
Abram K, Silm H, Maaroos HI, Oona M.
J Eur Acad Dermatol Venereol. 2010 May;24(5):565-71. Epub 2009 Oct 23.

[5] Helicobacter pylori infection and dermatologic diseases.
HERNANDO-HARDER AC, BOOKEN N, GOERDT S, SINGER MV, HARDER H.
Eur J Dermatol. 2009 Sep-Oct;19(5):431-44. Epub 2009 Jun 15.

[6] Small Intestinal Bacterial Overgrowth: A Comprehensive Review
Andrew C. Dukowicz, MD, Brian E. Lacy, PhD, MD, and Gary M. Levine, MD
Gastroenterology & Hepatology Volume 3, Issue 2 February 2007

[7]ice2meetyu’s report July 4, 2010

[8] Rosacea and digestive problems

[9] Role of Helicobacter pylori in common rosacea subtypes: A genotypic comparative study of Egyptian patients.
El-Khalawany M, Mahmoud A, Mosbeh AS, Abd Alsalam F, Ghonaim N, Abou-Bakr A.
J Dermatol. 2012 Oct 5. doi: 10.1111/j.1346-8138.2012.01675.x

[10] Bonnie's report at RSG

[11] Kathmandu Univ Med J (KUMJ). 2012 Oct-Dec;10(40):49-52.
The study of prevalence of helicobacter pylori in patients with acne rosacea.
Bhattarai S, Agrawal A, Rijal A, Majhi S, Pradhan B, Dhakal SS.
Department of Dermatology and Venereology, B.P.Koirala Institute of Health Sciences, Dharan, Nepal.

"Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over this, vasculogenesis is the term used for spontaneous bloodvessel formation, and intussusception is the term for new blood vessel formation by splitting off existing ones. Angiogenesis is a normal process in growth and development, as well as in wound healing. However, this is also a fundamental step in the transition of tumors from a dormant state to a malignant state. VEGF (Vascular Endothelial Growth Factor) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network." [1]

"Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis." Wikipedia

"Vascular endothelial growth factor (VEGF ) is an important signaling protein involved in both vasculogenesis (the de novo formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). As its name implies, VEGF activity has been mostly studied on cells of the vascular endothelium, although it does have effects on a number of other cell types (e.g. stimulation monocyte/macrophage migration, neurons, cancer cells, kidney epithelial cells). In vitro, VEGF has been shown to stimulate endothelial cell mitogenesis and cell migration. VEGF is also a vasodilator and increases microvascular permeability and was originally referred to as vascular permeability factor." [2]

"Dr. Sandra Cremers, assistant professor of ophthalmology at Harvard Medical School, was awarded $25,000 for a study evaluating the role of angiogenesis (new blood vessel formation) in ocular rosacea. Dr. Cremers will investigate the levels of angiogenesis markers, such as vascular endothelial growth factor (VEGF ), in the conjunctiva and eyelids of patients with severe ocular rosacea, compared with normal subjects. She postulates that defining the role of angiogenesis in the development of ocular rosacea may bring focus to future research on this common rosacea subtype, and eventually lead to the development of an effective treatment." [3]

Dr. Cremers is a volunteer RRDi MAC member.

"Recently an increased of VEGF in Rosacea, a major mitogen for dermal microvascular endothelial cells is also reported." [4]

"VEGF, IL-2, IL-8 may be directly related to the mechanism of the development of cardiovascular disease in rosacea patients" [5]

"The principal subtype of rosacea includes erythematotelangiestatic rosacea, which is characterized by uncontrolled angiogenesis. Angiogenic growth factors such as fibroblast growth factors (FGF) and vascular endothelial growth factor (VEGF) are currently targets of intense effort to inhibit deregulated blood vessel formation in diseases such as cancer. Here we report a 33-years-old woman with erythematotelangestatic rosacea who responds to a daily treatment of topically applied dobesilate, an inhibitor of FGF, with an improvement in erythema and telangectasia after two weeks. Thus, dobesilate might be useful in the treatment of rosacea and other diseases that depend on pathologic angiogenesis." [6]

"It should be also taken into account that, being FGF a necessary mediator of VEGF activity, dobesilate also inhibits this last signalling system, as it has been also recently described. The case report presented here is a representative example of five enrolled rosacea patients from a study directed to assess the long-term clinical benefit of dobesilate in rosacea. Taken together these data support a new therapeutic modality for a safe and efficient topical treatment of rosacea." [7]

"The present findings indicate that +405C/G polymorphism of the VEGF gene increases the risk of rosacea." [8]

"The Hippo signaling pathway plays a key role in regulating organ size and tissue homeostasis. Hippo and two of its main effectors, yes-associated protein (YAP) and WWTR1 (WW domain-containing transcription regulator 1, commonly listed as TAZ), play critical roles in angiogenesis.... Our findings suggest that YAP/TAZ inhibitors can attenuate angiogenesis associated with the pathogenesis of rosacea and that both YAP and TAZ are potential therapeutic targets for patients with rosacea." [10]

Treatment

"ART ameliorated rosacea-like dermatitis by regulating immune response and angiogenesis, indicating that it could represent an effective therapeutic option for patients with rosacea." [9]

"Our results indicate that the blockade of YAP/TAZ contributes to anti-angiogenic responses in rosacea and VEGF-related angiogenesis. We suggest that YAP/TAZ can serve as a therapeutic target for rosacea and other inflammatory skin diseases associated with angiogenesis." [10]

"Besides, aspirin administration decreased the microvessels density and the VEGF expression in rosacea-like skin. We further demonstrated that aspirin inhibited the activation of NF-κB signaling and the release of its downstream pro-inflammatory cytokines." [11]

End Notes

[1] http://en.wikipedia....ki/Angiogenesis

[2] http://en.wikipedia.org/wiki/VEGF

[3] http://www.rosacea.o...arded/index.php

[4] New aspects of the pathogenesis of rosacea
Sabine Fimmel, Mohamed Badawy Abdel-Naser, Heinz Kutzner, Albert M. Kligman, Christos C. Zouboulis
Arch Dermatol Res, DOI 10.1007/s00403-007-0816-z, 5 June 2007, Revised 28 September 2007 / Accepted 19 November 2007, Springer - Verlag 2007 Full Text

[5] RISK-FACTORS OF CARDIOVASCULAR DISEASE IN PATIENTS WITH ROSACEA

[6] Eur J Med Res. 2005 Oct 18;10(10):454-6.
Therapeutic response of rosacea to dobesilate.
Cuevas P, Arrazola JM.

[7] BMJ Case Rep. 2011; 2011: bcr0820114579.
Published online 2011 Oct 19. doi:  10.1136/bcr.08.2011.4579
PMCID: PMC3207764
Long-term effectiveness of dobesilate in the treatment of papulopustular rosacea
Pedro Cuevas, Javier Angulo, and Guillermo Giménez-Gallego

[8] J Am Acad Dermatol. 2019 Jun 07;:
Vascular endothelial growth factor gene polymorphisms in patients with rosacea: A case-control study.
Hayran Y, Lay I, Mocan MC, Bozduman T, Ersoy-Evans S

[9] Biomedicine & Pharmacotherapy, Volume 117, September 2019, 109181
Artemisinin, a potential option to inhibit inflammation and angiogenesis in rosacea
XinYuana, Ji Li, Yangfan Li. Zhili Deng, Lei Zhou, Juan Long, Yan Tang. Zhihong Zuo, Yiya Zhang. Hongfu Xie

[10] Int J Mol Sci. 2021 Jan; 22(2): 931.
Inhibition of Hippo Signaling Improves Skin Lesions in a Rosacea-Like Mouse Model
Jihyun Lee, Yujin Jung, Seo won Jeong, Ga Hee Jeong, Gue Tae Moon, and Miri Kim

[11] Aspirin alleviates skin inflammation and angiogenesis in rosacea

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

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: 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,

[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 Dermatology
Clivia 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: 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

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.