Rosacea » rosacea cause

we’ve all been exposed to demodex bacteria proteins ?

David Pascoe — Wed, 15 Jul 2009 13:43:19 +0000

An article published today in the Irish Times takes one more step in the direction of showing an association between demodex mites and rosacea. Readers of Rosacea News will know that a lot of research has tried to find a causative link between the presence of demodex mites and rosacea symptoms.

Some progress towards a link between the two was realised when a particular type of bacteria present in demodex, called Bacillus oleronius was isolated. This bacteria was then analysed and 2 resulting proteins were found to be quite interesting. These proteins were shown to induce an increased inflammatory response specifically in rosacea sufferers.

The Irish Times newspaper article quotes Dr. Kevin Kavanagh from NIU Waynooth (who has received NRS funding for demodex research), who says that a survey of 30 patients found 80% had been exposed to large amounts of 2 demodex bacteria proteins. This appears to me to be a new discovery. Immune tests were performed on the patients to show that the patients had been exposed to Bacillus bacterium inside Demodex mites.

We know from previous studies that “two antigenic proteins of size 62 and 83 kDa” isolated in Bacillus oleronius have the potential to stimulate an inflammatory response in patients with papulopustular rosacea. This is the first time I’ve see mention of a high proportion of rosacea sufferers been shown to been exposed to these 2 proteins.

This short article suggests that an immune response to these 2 proteins is a very common occurrence in rosacea sufferers. So common in fact that it warrants further investigation to see what this really means for rosacea diagnosis and treatment. At the least, a blood test to confirm rosacea seems like a real possibility.

Suggesting that eradicating Bacillus oleronius via antibiotics is the reason for their success in treating rosacea does seem a bit of a stretch. Perhaps interrupting how these proteins induce an inflammatory response is another way of understanding how this all fits together.

As this is just a discussion article in a newspaper, it will be useful to see the full article when it is published later this year. My feeling is that we are still only making baby steps along this path of logic. They are steps that seem to be in the right direction, but it sure takes a long time to get there.

From Study finds cause of rosacea, Tuesday, July 14, 2009, CLAIRE O’CONNELL.

BACTERIA ARE to blame for the inflammatory skin condition rosacea, according to a study involving Irish scientists.

…

Working with the Mater hospital, the researchers previously identified a Bacillus bacterium inside Demodex mites. The bacteria release two proteins that trigger an inflammation in patients with facial rosacea.

…

Immune tests on 30 patients found that 80 per cent had been exposed to large amounts of the two bacterial proteins, said Dr Kavanagh of the study, which is to be published in Ophthalmology later this year.

“Now that we know it’s primarily probably a bacterial disease, we know the proper way to treat it is with antibiotics at a low level over a long period of time,” Dr Kavanagh said, noting that washing the skin with dilute tea tree oil also killed the bacteria.

“The other implication is that we could do a simple blood test to say whether a patient has rosacea or not. That’s something we will investigate in the future.”

The article also mentions a link between demodex bacteria and ocular rosacea.

Glyco Mira developing anti-cathelicidin treatment ?

David Pascoe — Fri, 01 May 2009 06:31:45 +0000

A brief paragraph in a recent article in The Salt Lake Tribune looks quite interesting. A company called Glyco Mira (seemingly a company without a web site) is developing a drug that “may be able to cure the underlying problem that causes rosacea”. A pretty tall prediction for sure. So what are they talking about ? Glyco Mira have licensed and anti-inflammatory drug from the University of Utah.

A clue is found near the end of the article where the basic cause of rosacea is revealed to be “an inflammatory peptide”. So from this we can deduce that Glyco Mira are developing something that reduces the level of cathelicidin, the well publicised peptide linked to rosacea symptoms.

Utah’s innovative spirit on display in Salt Lake City

Business » Nine companies earn awards for new products., By Paul Beebe, The Salt Lake Tribune

Updated: 04/30/2009 09:12:44 PM MDT

Glyco Mira, a Salt Lake City-based drug development company, is working on an anti-inflammatory drug based on a technology it licensed from the University of Utah last year.

The company’s goal is to develop the drug to a point where it can be sold to another company, which would bring it to market. Profits would be used to fund research on other drugs, Chief Financial Officer Thomas Heath said.

The drug under development may be able to cure the underlying problem that causes rosacea, a skin disease showing increased redness or acne-like eruptions that affects mostly women.

“We chose rosacea because it’s a common ailment that’s poorly treated with antibiotics and steroid creams,” Heath said. “This product has the potential to treat the basic cause — an inflammatory peptide.”

Peptides consist of at least two amino acids. In normal quantities, the peptide in question helps prevent skin infections. Too much of it causes rosacea, Heath said.

We know that Vitamin D3 (cholecalciferol), the active form of Vitamin D is a regulator of cathelicidin. A previous Rosacea News article suggested that “another recent abstract is also promoting the synergy of Vitamin D3 and cathelicidins in opening doors for future research and discovery ;Vitamin D regulation of cathelicidin in the skin: toward a renaissance of vitamin D in dermatology?” and further “Recent work identified Vitamin D3 as a major factor involved in the regulation of cathelicidin. Therapies targeting control of cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.”

For more information on Vitamin D3, see the excellent supplement resources page: Vitamin D3.

Update: I have been contacted by someone from Glyco Mira who said that they are indeed “developing a line of modified polysaccharides (SAGEs) and are presently testing in rosacea models that will be 1st in class logic based therapy for rosacea.” They also indicated that they are targetting mid 2010 for an Investigational New Drug filing and human trials.

If anyone knows anything more about either Glyco Mira or the drug being licensed please post in the comments below.

SIBO eradication clears rosacea: are you serious ?

David Pascoe — Wed, 07 May 2008 03:28:49 +0000

This sort of abstract just make me shake my head. If you read quickly you will think that this abstract suggests that Small Intestinal Bacterial Overgrowth (SIBO) causes rosacea. What this abstract is saying that is that rosacea sufferers seem to have a higher incidence of SIBO than non rosacea sufferers. The secondary result is that eliminating SIBO clears rosacea. Well that is no surprise ! Antibiotics interrupt the inflammatory pathway that causes the papules and pustules of rosacea. We all know that. This just published abstract doesn’t tell us anything new, although at first glance it might look like it.

What would be interesting to explore further would be what causes the SIBO. Could that cause point back to something triggering papules and pustules ?

If you view the AbstractPlus you will see that SIBO has been linked by the same team to Scleroderma, abnormalities in acromegaly, and IBS.

Small Intestinal Bacterial Overgrowth in Rosacea: Clinical Effectiveness of Its Eradication ,Clin Gastroenterol Hepatol. 2008 May 2, Parodi A, Paolino S, Greco A, Drago F, Mansi C, Rebora A, Parodi AU, Savarino V.

Department of Internal Medicine, Gastroenterology Unit, University of Genoa, Genoa, Italy.

….

CONCLUSIONS: 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.

Update: there is a thread over a the forum SIBO diet/treatment, where Artist mentions that Rifaximin doesn’t leave the gut so doesn’t directly have any effect on the skin. This leads to the question of what inflammation has it blocked and what can we prove that this means ?

On a related note Seth Kendall speculates in his paper Remission of rosacea induced by reduction of gut transit time, that

“It is possible that intestinal bacteria are capable of plasma kallikrein–kinin activation and that flushing symptoms and the development of other characteristic features of rosacea result from frequent episodes of neurogenic inflammation caused by bradykinin-induced hypersensitization of facial afferent neurones.”

RGS5 gene can reverse angiogenesis

David Pascoe — Wed, 16 Apr 2008 23:59:03 +0000

From: Aussies stop cancer tumour frenzy

Researchers based at the Western Australian Institute for Medical Research have discovered a gene that can reverse angiogenesis – the growth of blood vessels inside a tumour.

Their work, led by associate Professor Ruth Ganss, is a world first and has been recognised by internationally-renowned scientific journal Nature in its weekly edition, published online today.
Professor Ganss described the gene, named RGS5, as a “master gene” which, when removed, can trigger a process capable of destroying cancerous tumours.

Also from New technique reverses growth of cancer blood vessels

Reversing abnormal vessel growth represents a fresh approach to tackling angiogenesis, with most current research focusing on how to block or kill tumour-feeding blood vessels.
She adds: “By understanding what is actually going on in the tumour itself, the ultimate hope is that we’ll be able to work on making current therapeutic approaches even more successful and reducing side effects of them.”

Even though this research relates to blood vessel growth in cancerous tumours, it could also be interesting for rosacea researchers looking for how angiogenesis is involved with development of rosacea.

angiogenesis: lymphatic and mast cell involvement

David Pascoe — Sun, 23 Mar 2008 04:23:28 +0000

The pathogenesis (how a disease progresses from mild to severe forms) of rosacea is a complicated and poorly understood process. Likewise the growth of new blood vessels, thought to be important in the development of rosacea, is also a complicated and mysterious process. The NRS has updated their blog with an Update on Angiogenesis.

This update refers to 2 recent studies, one linking the lymphatic system with angiogenesis and the second linking the increased presence of mast cells with the later stages of rosacea. Rosacea is certainly a complex disease involving many processes in the inflammatory pathway. It is only through baby steps that we begin to understand more of how this pathway operates.

From: Update on Angiogenesis

Results of two recent studies provide new understanding of how and when angiogenesis — the formation of new blood vessels — may contribute both to the initial development of rosacea and its persistent presence.
While the development of visible blood vessels, called telangiectasia, has long been recognized in rosacea, evidence of lymphatic vessel growth has not been previously reported, the researchers said. They also noted that study results suggested lymphatic involvement occurs at the beginning of the disease rather than later in its progress. The lymphatic circulatory system consists of vessels that carry a clear liquid that bathes the tissues of the body and may fight infection.
…
In another study of affected and unaffected skin, Dr. Kyriaki Aroni and colleagues of the University of Athens studied the potential role of angiogenesis and mast cells in rosacea. [2]
“It seems increasingly possible that rosacea pathology is a multifactorial process, which opens up areas of research with regard to potential links between different contributing factors,” the researchers said. Mast cells, connective tissue cells that release chemical substances in response to injury or allergic reaction, are known to augment inflammatory processes and occur in increased numbers in conditions associated with angiogenesis.

moderate exercise may help your rosacea

David Pascoe — Thu, 06 Mar 2008 02:33:33 +0000

Some rosacea sufferers report good results if they exercise moderately but regularly. It is well known that regular exercise is good for stress relief and of course your general well being. But what about improving your skin ? Is that possible ? This paper is suggesting that exercise can reduce the amount of cytokines generated as part of the inflammatory response that is believed to cause rosacea. Thus exercise could then lead to a better rate of healing for a skin insult or injury.

From: Exercise May Play Role In Reducing Inflammation In Damaged Skin Tissue

ScienceDaily (Dec. 4, 2007) — In recent years, researchers at the University of Illinois have uncovered a host of reasons for people to remain physically active as they age, ranging from better brain function to improved immune responses.

Now a new U. of I. study points to yet another benefit: a link between moderate exercise and decreased inflammation of damaged skin tissue

“One of the proposed mechanisms whereby aging adds to delayed healing is that the aged have hyper-inflammatory response to wounding,” Woods said. “The thought is that the exaggerated inflammatory response slows the healing process. So, in essence, what happened here is that the exercise reduced the exaggerated inflammatory response.”
Keylock explained that exercise may be contributing to that reduction in any number of ways.
“Increasing blood flow during the time of exercise is one (possibility),” he said. “We’ve shown in the past that has an effect on how certain immune cells – such as macrophages, function. “And if exercise can help decrease the amount of inflammatory cytokines put out by macrophages, maybe that would help decrease the inflammation, and therefore, speed healing.”
Cytokines are molecules that signal and direct immune cells, such as macrophages, to the site of an infection, Woods said. Macrophages play two critical roles in the wound-healing process, according to Keylock.
…

“This is going a bit beyond our results, but there are certain characteristics … a set of events that are followed when any tissue is damaged – not just skin, like in this study, but arterial walls or other internal organs,” he said. “First, there’s hemostasis, which is limiting blood leakage. Then there’s an inflammatory process, then a regenerative process. So, using this model, we may be able to get at whether exercise could have farther-reaching implications for tissue damage in general.
“There are probably some things unique to the skin, as opposed to these other tissues, so we can’t make leaps of faith,” he cautioned. “But if we study the inflammatory process, the regenerative process in one tissue might have implications for other tissues.”
Meanwhile, the benefits of regular, moderate exercise – essentially a brisk walk most days of the week – for older adults, are many.

collagenex: rosacea is a chronic inflammatory disease

how metrogel works II – free oxygen radicals

David Pascoe — Tue, 04 Sep 2007 01:48:14 +0000

Another recently published paper that seeks to understand the role of Reactive Oxygen Species in the development of rosacea. The inflammatory pathway that leads to rosacea symptoms is slowly gaining more and more attention.

All rosacea sufferers should do themselves a favor and do some reading on the role of inflammation in rosacea. This is the most exciting direction for rosacea research, in my opinion. Though it can feel like you are reading a foreign language, I’d encourage everyone to stick at it.

More links at the bottom, but 2 places to start: Examining Inflammation as a Common Factor in Theories of Rosacea Pathophysiology (via Collagenex’s RosaceaToday info site) and Role of Inflammation (put together by Dan in the RSRP).

Even though there is a bit of a love hate relationship with the metronidazole based rosacea treatments, examining how it works is leading to some new and useful research.

Properties of metronidazole on free oxygen radicals in a skin lipid model system.

J Pharm Pharmacol. 2007 Aug; 59(8):1125-30, Authors: Narayanan S, Hunerbein A, Getie M, Jackel A, Neubert RH

Reactive oxygen species (ROS) play a vital role in the pathophysiology of the skin disease rosacea, a chronic, genetically-determined and UV-triggered disease, leading to facial redness and blemishes and exhibiting a deep impact on a patient’s self-esteem and quality of life. ROS can cause oxidative damage to nucleic acids, sugars, proteins and lipids, thereby contributing to adverse effects on the skin.

Metronidazole has been the first-line topical agent therapy for many years; nevertheless the mechanism of action is still not well understood. The therapeutic efficacy of metronidazole has been attributed to its antioxidant effects, which can involve two pathways: decreased generation of ROS within tissues or scavenging and inactivation of existing ROS. Previous investigations have shown that metronidazole reduces ROS by decreasing ROS production in cellular in-vitro systems. The aim of the following study was to demonstrate that metronidazole additionally exhibits antioxidative properties in a cell-free system, by acting as an antioxidant scavenger.

A simple skin lipid model (oxidative) system and a complex skin adapted lipid system in conjunction with thiobarbituric acid (TBA) test, a quantitative assay for the detection of malondialdehyde (MDA) and therefore lipid peroxidation, were used to determine the antioxidative properties of metronidazole after UV irradiation. Results clearly show that metronidazole has antioxidative properties in a cell-free environment, acting as a free radical scavenger. Simple skin lipid model: in the presence of 10, 100 and 500 mug mL(-1)metronidazole the MDA concentration was reduced by 25, 36 and 49%, respectively. Complex skin lipid system: in the presence of 100 and 500 mug mL(-1)metronidazole the MDA concentration was reduced by 19 and 34%, respectively.

The results obtained in this study and from previous publications strongly suggest that metronidazole exhibits antioxidative effects via two mechanisms: decrease in ROS production through modulation of neutrophil activity and decrease in ROS concentration by exhibiting ROS scavenging properties. The remarkable clinical efficacy of metronidazole in the treatment of rosacea is probably due to its ability to decrease ROS via different mechanisms, thereby protecting skin components from induced damage.

Related Articles:

Cathelicidins make the news

David Pascoe — Thu, 09 Aug 2007 09:14:04 +0000

Lots of buzz at the moment about the publicity raised by a nature.com article about Cathelicidins.

Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea

Acne rosacea is an inflammatory skin disease that affects 3% of the US population over 30 years of age and is characterized by erythema, papulopustules and telangiectasia. The etiology of this disorder is unknown, although symptoms are exacerbated by factors that trigger innate immune responses, such as the release of cathelicidin antimicrobial peptides. Here we show that individuals with rosacea express abnormally high levels of cathelicidin in their facial skin and that the proteolytically processed forms of cathelicidin peptides found in rosacea are different from those present in normal individuals. These cathelicidin peptides are a result of a post-translational processing abnormality associated with an increase in stratum corneum tryptic enzyme (SCTE) in the epidermis.

In mice, injection of the cathelicidin peptides found in rosacea, addition of SCTE, and increasing protease activity by targeted deletion of the serine protease inhibitor gene Spink5 each increases inflammation in mouse skin. The role of cathelicidin in enabling SCTE-mediated inflammation is verified in mice with a targeted deletion of Camp, the gene encoding cathelicidin. 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.

This article is a result of a few years of research by Dr. Gallo. We’ve been reading about this research, some of it sponsored by the NRS, since at least the Fall of 2002.

The upside of this is that rosacea is getting publicity that it sorely needs. Nature is a very prestigious journal, so this publicity is excellent and will encourage Dr. Gallo and his colleagues to keep going.

The downside is that some of the follow up articles in the newspapers are overstated and give a false impression of the immediate implication of the research. There isn’t any new treatments just around the corner as a result of this research, and the cause/cure didn’t suddenly get hugely closer.

What is has shown, though, is that the inflammatory pathway that causes most rosacea symptoms is key to making good progress. While cathlecidins may be a key product of inflammation I’d be much more excited about seeing research that found the starting point of the inflammatory pathway. Blocking the inflammation at the source will always be more effective than trying to treat the downstream toxins.

Related Articles:

so just how does metrogel work ?

David Pascoe — Tue, 20 Mar 2007 07:58:00 +0000

I have mentioned a few times in the past that the way that metrogel helps rosacea is unknown. This statement deserves some clarification. Actually the way that metronidazole works is well known. How the effect of metrogel leads to a benefit in rosacea, well, that is something worth exploring some more later on.

You may wonder why there is so much emphasis on the metronidazole based products ? As much as metrogel and its friends metrocream, metrolotion, rozex, noritate (and indeed generic metrogel, also from fougera) are not a panacea for rosacea, they do represent the single most proven treatment specifically for rosacea. Thus newly diagnosed rosacea sufferers are quite likely to leave their doctor’s surgery with a script for metro-something. All the studies show that in many cases metrogel does indeed work. Further, other studies clearly show that combining metrogel with antibiotics results in better clearance.

So back to `how does it work ?’ Well my one sentence summary is “metronidazole breaks down into a substance that kills the DNA of the cells of some particular bacteria and protozoa”.

Thanks to Dan for sending me the following links ;

From DrugBank: Metronidazole

Pharmacology: Metronidazole, a synthetic antibacterial and antiprotozoal agent of the nitroimidazole class, is used against protozoa such as Trichomonas vaginalis, amebiasis, and giardiasis. Metronidazole is extremely effective against anaerobic bacterial infections and is also used to treat Crohn’s disease, antibiotic-associated diarrhea, and rosacea.

Mechanism of Action: Unionized metronidazole is selective for anaerobic bacteria due to their ability to intracellularly reduce metronidazole to its active form. This reduced metronidazole then disrupts DNA’s helical structure, inhibiting bacterial nucleic acid synthesis and resulting in bacterial cell death.

From Antibiotics that Inhibit Nucleic Acid Synthesis

Figure 11-8. Structure of metronidazole and its mechanism of action. Metronidazole enters an aerobic bacterium where, via the electron transport protein ferrodoxin, it is reduced. The drug then binds to DNA, and DNA breakage occurs.

(An anaerobic organism is any organism that does not require oxygen for growth. Protozoa are a particular type of single cell organisms.)

This naturally leads to the followup question – if eliminating the substances that metronidazole (and for the purposes of this argument, lets include systemic antibiotics as well) is active against leads to relief from some rosacea symptoms, what does that say about the possible cause of rosacea ? Now, that is a question that there isn’t much agreement about and something worth talking about some more, later.

Further Reading ;

pathogen infection (Chlamydia pneumoniae) cause theory

David Pascoe — Mon, 19 Mar 2007 03:41:00 +0000

A really interesting thread is going on in the rosacea-support group. Dan is airing some of his thoughts on how a pathogen might lead to the chronic inflammation we see in rosacea. Even though Dan clearly states he has no medical background (and indeed it is worth remembering this point) it is clear that he has done a lot of reading on this topic.

Message 93555: Rosacea and pathogen link? (be sure to read the followup posts at the bottom of the thread too).

Some more thoughts on a possible link: Chlamydia pneumoniae and Rosacea: A potential link?

Chlamydia pneumoniae may be something new to many (it was to me), so also see the wikipedia page: Chlamydophila pneumoniae and also the RSRP: Chlamydia pneumoniae