• Ferritin positive cells are much more prevalent in rosacea sufferers
• Severe rosacea sufferers have significantly more ferritin positive cells
• Blood peroxide levels are higher in rosacea sufferers
• Total anti-oxidative levels are significantly lower in rosacea patients

The conclusion of the paper is that exposure to UV light results in ferritin positive cells that are fundamental to the resulting oxidative stress.

What is Oxidative Stress?

Oxidative stress has to do with the amount of reactive oxygen species present in our bodies. When there are too many, damage to cell components result.

In broad terms, antioxidants are helpful when the balance is wrong and too many ROS are present.

It is a complicated science; oxidative stress has been linked to many diseases and needs to carefully dissected to understand any real implications for a particular disease.

We do know that rosacea is the end result of an inflammatory pathway. We need to describe the entire system before we can say that we have rosacea licked.

The role of oxidative stress and iron in pathophysiology of rosacea

Lijec Vjesn. 2011 Jul-Aug;133(7-8):288-91.

[Article in Croatian], Tisma VS, Poljak-Blazi M., Poliklinicki odjel za kozne i spolne bolesti, KB Dubrava, Zagreb.

Rosacea is a common skin disease of unknown etiology.

The aim of the present paper is to explain the role of oxidative stress triggered by UV light and iron metabolism in the pathophysiology of rosacea.

It was recently described that the number of ferritin positive cells was significantly higher in skin samples of rosacea patients compared to controls of healthy skin samples.

The presence of ferritin was significantly higher in patients with the severe stage of disease. In addition, serum peroxide levels were significantly higher and serum total antioxidative potential levels were significantly lower in rosacea patients than in healthy controls.

These results support the role of oxidative stress and affected metabolism of iron in etiology of rosacea.

The higher presence of ferritin in skin cells of rosacea patients explains the exacerbation of symptoms by exposure to UV light, that releases ferritin free iron, which is fundamental in the generation of oxidative stress.

This paper appears to be a followup to a 2009 paper , Oxidative stress and ferritin expression in the skin of patients with rosacea, J Am Acad Dermatol. 2009 Feb;60(2):270-6.

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In 2008 Rosacea News highlighted a paper that suggested that treating patients with rosacea and SIBO with Rifaximin would improve both their SIBO and rosacea symptoms. That posting has attracted a lot of interest, heading towards 100 comments. Two threads in the online support forums are also growing.

In 2010 an article in the St. Louis-Dispatch also highlighted the work or Dr. Weinstock, a Gastroenterologist, in explaining the success in treating some rosacea patients with Xifaxan (brand name for rifaximin 200mg).

Large Clinical Trial

The recent article, extracted below, mentions that a further large randomized clinical trial is underway. That trial (which looks to be NCT01359228) will study 100 patients in two groups – the active group to receive a dosage of Xifaxan 550mg, 3 times a day for 14 days – and the inactive arm to receive placebo (and then cross over).

This is great news! Rifaximin will get a thorough testing as a general treatment for rosacea symptoms.

Latest Publicity

Treating Intestinal Bacteria May Improve Rosacea

11/28/11

By: HEIDI SPLETE, Internal Medicine News Digital Network

FROM THE ANNUAL MEETING OF THE AMERICAN COLLEGE OF GASTROENTEROLOGY

NATIONAL HARBOR, MD. – Treating patients with both rosacea and small intestinal bacterial overgrowth with the drug rifaximin was associated with improved rosacea symptoms in some patients, in a small, preliminary study. The findings were presented at the annual meeting of the American College of Gastroenterology.

..

A total of 32 rosacea patients were positive for SIBO, and 28 of these (including all ocular rosacea patients) received 1200 mg/day of rifaximin (two 200-mg tablets 3 times daily) for 10 days. Of the treated patients, 46% showed clearance of, or marked improvement in, rosacea symptoms, while another 25% showed moderate improvement.

"All four patients with ocular rosacea and SIBO reported marked improvement in conjunctivitis, sclera erythema, and dry eyes following treatment with rifaximin," Dr. Weinstock noted.

VITALS

Major Finding: Of 28 adults with both rosacea and small intestinal bacterial overgrowth (SIBO), 46% of those treated with rifaximin for 10 days showed improvement in rosacea symptoms.

Data Source: A prospective study of 32 adults with rosacea and SIBO.

Disclosures: The study was supported by a grant from Salix Pharmaceuticals, maker of rifaximin.

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Firmly in the pure speculation category is a recent paper that proposes that pityriasis folliculorum (or demodex mite infestation) is the missing link in our understanding of rosacea.

Plainly put, Dr. Forton, a dermatologist from Belgium, suggests that rosacea is a two stage disease where 1) demodex mites are allowed to proliferate unchecked and then 2) some mites migrate to the dermis where an immune response leads to the inflammation of rosacea.

The first stage is important because in this theory, the absence of an immune response is able to keep the demodex mites from becoming an infestation.

The author suggests that further research into why there is no immune response during this first stage may lead to further understanding about rosacea.

What We Do Know

1. We know that a certain bacteria from demodex Bacillus oleronius – can induce an increased immune response in rosacea suffers.
2. We know that demodex mites are found in normal healthy skin.
3. Studies have found that in some rosacea sufferers demodex mites are more common.
4. Arguments still focus on whether demodex mites just enjoy the environment of rosacea skin, or are there making it worse.

My Thoughts

This theory is pretty far fetched I would have thought. We still can’t say what it is about the mites that find them prevalent in some rosacea sufferers, or for sure what link there is between demodex bacteria and an inflammatory response.

Some people do report a decrease in symptoms when they eradicate the mites, but showing that this applies more widely or proving demodex were the actual cause is elusive.

Demodex mites have always been an easy target for those looking for the cause of rosacea. Easy because the mites are easy to find – what has proved harder though is nailing a provable link.

We do need more research. Demodex have been the subject of an enormous amount of rosacea research, so it pains me to say this !

New Abstract

Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link.

J Eur Acad Dermatol Venereol. 2011 Oct 24., Forton FM, Dermatologist, Private practice, rue Franz Binjé, Brussels, 8-1030 Belgium.

Papulopustular rosacea (PPR) is a common facial skin disease, characterized by erythema, telangiectasia, papules and pustules.

Its physiopathology is still being discussed, but recently several molecular features of its inflammatory process have been identified: an overproduction of Toll-Like receptors 2, of a serine protease, and of abnormal forms of cathelicidin.

The two factors which stimulate the Toll-like receptors to induce cathelicidin expression are skin infection and cutaneous barrier disruption: these two conditions are, at least theoretically, fulfilled by Demodex, which is present in high density in PPR and creates epithelial breaches by eating cells.

So, the major pathogenic mechanisms of Demodex and its role in PPR are reviewed here in the context of these recent discoveries. In this review, the inflammatory process of PPR appears to be a consequence of the proliferation of Demodex, and strongly supports the hypothesis that:

(1) in the first stage a specific (innate or acquired) immune defect against Demodex allows the proliferation of the mite;

(2) in the second stage, probably when some mites penetrate into the dermis, the immune system is suddenly stimulated and gives rise to an exaggerated immune response against the Demodex, resulting in the papules and the pustules of the rosacea.

In this context, it would be very interesting to study the immune molecular features of this first stage, named "pityriasis folliculorum", where the Demodex proliferate profusely with no, or a low immune reaction from the host: this entity appears to be a missing link in the understanding of rosacea.

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My skin was great. I have had beautiful skin all my life, but now wham! rosacea has reared its ugly head.

Well the NRS Blog has an answer to this plea. It is all about your risk profile. If you are over 30 with fair skin, have a relative with rosacea and are of Northern European Ancestry then the statistics suggest that you are at risk for having rosacea.

Sorry, but sometimes it is just down to sheer probability.

Risks Answer ‘Why Me?’

Tuesday, April 19, 2011

“Why me?” is a question many ask when they find themselves with the embarrassing effects of rosacea – which may include facial redness, visible blood vessels, bumps, pimples, eye irritation and other symptoms if left untreated. While rosacea can strike all segments of the population, surveys by the National Rosacea Society have revealed a profile of those most at risk for this conspicuous and chronic condition:

Other Reasons

Of course if you are outside the common risk profile, you could still have rosacea. Other common reasons include over use of steroids, exposure to the sun and elements, stress, tendency to flush and more.

There is Hope!

It might feel unfair, but now that you have a diagnosis of rosacea, you are already on the way to relief. Here are some articles that will get you started.

• Tips for Getting Started
• Frequently Asked Questions
• Just Diagnosed with Rosacea
• The one thing I wish I was told about Treating Rosacea
• Top 5 cheapest rosacea treatments
• Official Rosacea Treatments
• Rosacea Treatments for each symptom

[update:] There is also a thread at the Rosacea Community Forum that you might find helpful: Why did I get rosacea NOW in my 40′s?

Gallo’s interest is piqued by the possibility of a coordinated defense effort from the permeability and antimicrobial barriers of the skin.

Ahrens was able to show that certain Antimicrobial peptides (AMPs), called beta-defensins were upregulated (i.e. they became more prevalent and sensitive) in response to an insult to the skin for eg. a tape strip being removed.

This looks to be another small step in understanding the immune system and thus potentially help in skin disorders. Dr. Gallo has been active in researching related AMPs, namely Cathelicidin.

The coordinated response of the physical and antimicrobial peptide barriers of the skin, Borkowski AW, Gallo RL., J Invest Dermatol. 2011 Feb;131(2):285-7.

Division of Dermatology, Department of Medicine, University of California at San Diego and VA San Diego Health Care System, San Diego, California, USA.

Antimicrobial peptides (AMPs) are an essential and multifunctional element for immune defense of the skin during infection and injury. In this issue, Ahrens et al. characterize the response of β-defensins, a class of AMPs, following acute and chronic challenges to the permeability barrier of the skin. Their findings suggest that the antimicrobial and permeability barriers of the skin are closely linked.

Comment on:

Mechanical and metabolic injury to the skin barrier leads to increased expression of murine β-defensin-1, -3, and -14 (J  Invest Dermatol. 2011 Feb;131(2):443-52.)

Ahrens K, Schunck M, Podda GF, Meingassner J, Stuetz A, Schröder JM, Harder J, Proksch E., Department of Dermatology, University of Kiel, Kiel, Germany.

Protection of the skin against microbiological infection is provided by the permeability barrier and by antimicrobial proteins. We asked whether the expression of murine β-defensins (mBDs)-1, -3, and -14-orthologs of human β-defensins hBD-1, -2, and -3, respectively–is stimulated by mechanically/physicochemically (tape stripping or acetone treatment) or metabolically (essential fatty acid-deficient (EFAD) diet) induced skin barrier dysfunction.

Both methods led to a moderate induction of mBD-1 and mBD-14 and a pronounced induction of mBD-3 mRNA. Protein expression of the mBDs was increased as shown by immunohistology and by western blotting. Artificial barrier repair by occlusion significantly reduced the increased expression of mBD-14 after mechanical injury and of all three mBDs in EFAD mice, supporting an interrelationship between permeability and the antimicrobial barrier. mBD-3 expression was stimulated in vitro by tumor necrosis factor-α (TNF-α), and a neutralizing anti-TNF-α antibody significantly reduced increased mBD-3 expression after barrier injury in mouse skin, indicating that induction of mBD-3 expression is mediated by cytokines. The expression of mBD-14 was stimulated by transforming growth factor-α and not by TNF-α.

In summary, we demonstrated upregulation of mBD1, -3, and -14 after mechanically and metabolically induced skin barrier disruption, which may be an attempt to increase defense in the case of permeability barrier dysfunction.

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Whilst the trial only directly mentions LL-37 and MMP I would expect other well known markers to be measured as well.

If the researchers include markers that can be proven to be indicative of rosacea disease, and these markers show a statistical difference compared to placebo participants, then this study could then lead to something important regarding the progression of rosacea.

Evaluation of Rosacea-related Inflammatory Biochemical Markers in Adult Skin When Treated With Oracea  vs Placebo

The objective of this study is to determine the clinical effects of doxycycline 40 mg (30 mg immediate release and 10 mg delayed release beads) capsules (Oracea) as compared to placebo in the skin of adults with papulopustular rosacea and to identify a correlation, if any, with rosacea-related inflammatory markers.

Mean change from baseline to week 12 in biochemical markers of rosacea and expression in skin samples. A biological marker is a substance used as an indicator of a biological state such as rosacea. Biochemical markers are serine protease activity and expression, metalloprotease activity and expression, and production of leucine leucine-37 [LL-37] peptide.

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Standard forms of rosacea

In 2002 the National Rosacea Society sponsored Rosacea Expert  Committee proposed the existence of 4 main rosacea subtypes. Rosacea sufferers are familiar with the designations of Erythematotelangiectatic, Papulopustular, Phymatous and Ocular Rosacea. The subtypes were based on the most common patterns or groupings of symptoms.

The so-called Standard Classification of Rosacea was written as a starting point to facilitate the development of ways to diagnose and treat rosacea. The committee has always been open to updating the classification system.

Standard classification of rosacea:

FUTURE

As a provisional standard classification system, it is likely to require modification in the future as the pathogenesis and subtypes of rosacea become clearer, and as its relevance and applicability are tested by investigators and clinicians. The committee welcomes reports on the usefulness and limitations of these criteria.

The expert committee noted that the subtype definitions were independent of understanding what causes rosacea to develop, as this is still an active area of research.

Time for a New Subtype

Now a group of 6 doctors and researchers is proposing a new subtype. This paper describes their conclusions after describing “14 patients with rosacea and prominent neurologic symptoms that represent another distinct subset of rosacea meriting a unique approach to management”.

The researchers are proposing a new group of rosacea symptoms that might at first glance seem quite similar to subtype 1, erythematotelangiectatic rosacea.

Subtype 1 is described as “mainly characterized by flushing and persistent central facial erythema. The appearance of telangiectases is common but not essential for a diagnosis of this subtype. Central facial edema, stinging and burning sensations, and roughness or scaling may also be reported. A history of flushing alone is common among patients presenting with erythematotelangiectatic rosacea”.

This proposed subtype is based upon strikingly prominent neurologic symptoms.

One of the authors, Kevin C. Wang MD PhD, kindly provided a copy of this article in order to write this and further reviews.

Neurogenic Rosacea: A Distinct Clinical Subtype Requiring a Modified Approach to Treatment

Tiffany C. Scharschmidt, MD; John M. Yost, MD, MPH; Sam V. Truong, MD; Martin Steinhoff, MD, PhD; Kevin C. Wang, MD, PhD;Timothy G. Berger, MD

Arch Dermatol. 2011;147(1):123-126.

Rosacea is generally categorized into 4 distinct clinical subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular. Granulomatous rosacea, rosacea fulminans, and perioral dermatitis have been described as additional variants.  Herein we describe 14 patients with rosacea and prominent neurologic symptoms, who represent another distinct subset of rosacea meriting a unique approach to management.

Methods
Patients with prominent neurologic symptoms in addition to classic features of rosacea were identified during routine appointments at a major teaching hospital. Details regarding medical history, disease symptoms and triggers, and response to treatments were obtained via clinic visits and telephone interviews. The study was approved by the institutional review board of the University of California, San Francisco.

Comment

We propose that this group of patients with strikingly prominent neurologic symptoms represents an under recognized subgroup of rosacea that we term neurogenic rosacea. By highlighting and formally naming this subgroup, we hope to increase awareness and recognition of these patients and aid the practicing dermatologist in their therapeutic management

Financial Disclosure

Dr Steinhoff serves as a consultant for and holds a research grant and patent with Galderma.

Dr Berger is a consultant for Prescription Solutions and serves as a nonsalaried principal investigator in other research studies involving GlaxoSmithKline, Clinsys Clinical Research Inc, Merz Pharmaceuticals, and Pharmanet.

A Good Idea?

What do you think? Is rosacea already complicated enough that another subtype is only going to make diagnosis and care trickier? Alternatively are you pleased to see these neurological symptoms get their own label?

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This abstract promises to tell us everything we need to know about the possible role of micro-organisms in the way that the disease Rosacea starts and develops.

Even though the role of published research is not to provide reading material for the general public, I still look to journal articles to move the science forward.

This paper promises to review the currently available literature relating to how some micro-organisms might play a role in the way that disease rosacea progresses.

I don’t have access to the full text, but following  is some background information that will hopefully prove helpful.

Although not mentioned in the abstract, I would hope that the paper would also discuss the role of Small Intestinal Bacterial Overgrowth in rosacea.

Helicobacter Pylori

Long part of the rosacea folklore, Helicobacter Pylori is a bacteria that lives in the cell lining of the stomach. The link between HP and rosacea is muddied by the fact that the common treatment for h. pylori is also a possible treatment for rosacea in it’s own right. Here is a quote from the NRS:

H. pylori May Not Be a Rosacea Factor

A recent study suggested that treatment of Helicobacter pylori, a bacterium associated with peptic ulcers and other gastric disorders, may benefit the often small portion of rosacea patients who harbor this infection. However, another study has found that H. pylori itself does not appear to be a major factor.

…

"It should not be surprising that rosacea symptoms may improve during treatment for H. pylori, since antibiotics have long been successfully used to treat rosacea in all patients," said Dr. Larry Millikan, chairman of dermatology, Tulane University. "Smaller dosages of oral antibiotics are routinely prescribed to bring rosacea under immediate control, along with long-term use of topical antibiotics to maintain remission."

In a more recent controlled clinical study of 44 rosacea patients with H. pylori infection in the United States, half of the patients were treated for H. pylori and half were not. When examined two months after treatment, there was no statistical difference in rosacea symptoms between the treated and untreated groups.

Demodex Folliculorum

Also a long standing member of the rosacea folklore is the issue of demodex mites.

Always held back as a theory by the fact the demodex is found in both rosacea and non-rosacea skin, and researchers being unable to show whether the mites cause, or just like living in rosacea skin, demodex folliculorum has recently become interesting again.

This new interest has been sparked by a study that showed that a particular type of demodex bacteria was responsible for a greater immune response in rosacea sufferers.

Like all good theories, demodex mites needs more research to prove how strong the link is between their presence and rosacea symptoms.

staphylococcus epidermis

This is one of the organisms that is a normal part of human skin flora, i.e. it is normal to find it living in our skin. Typically it only causes problems for people who are immune compromised.

A 2010 study summarised here: Skin Bacteria Thrives in Rosacea Patients shows that researchers were able to prove that this bacteria was more prevalent in the pustules of rosacea and in the eyelids of people who suffer from facial rosacea lesions.

Would I sound too much like a broken record if I were to say that more research is needed here to prove or disprove this link?

clamydia pnuemonia

According to wikipedia, Chlamydophila pneumoniae is a small bacterium that infects humans and is a major cause of pneumonia.

At least one study has been able to show some link; concluding “preliminary data imply a possible link between C. pneumoniae and acne rosacea as well as suggest a need for further investigation with clinical trials.” Interesting the treatment used in that study, Azithromycin is also effective against H. Pylori.

One place to read more about CpN is RSRP: Chlamydia pneumoniae.

The potential role of microorganisms in the development of rosacea, J Dtsch Dermatol Ges. 2010 Nov 8.

Lazaridou E, Giannopoulou C, Fotiadou C, Vakirlis E, Trigoni A, Ioannides D., First Department of Dermatology-Venereology, Aristotle University Medical School, Thessaloniki, Greece.

Rosacea is a chronic cutaneous disorder characterized by centrofacial persisting erythema, telangiectases, papules, pustules, edema, phymas and ocular involvement. Despite being one of the most common skin disorders, its pathogenesis remains unclear and controversial. Although the disease triggering factors are well recognized, the underlying causes of rosacea have not yet been identified.

Several different postulates about its pathogenesis can be found in the medical literature. Abnormalities of the pilosebaceous unit, as well as genetic, vascular, inflammatory, environmental and microbial factors have been described.

The microorganisms that have been associated include Helicobacter pylori, Demodex folliculorum, Staphylococcus epidermidis, and Chlamydia pneumonia; all the studies have been inconclusive. We review currently available scientific data on the potential pathogenetic role of microorganisms in the development of rosacea.

How neat would it be to say that you belong to the Aristotle University Medical School – sounds impressive hey.

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The notes are titled Acne and Rosacea: Inflammatory mechanisms and their impact on therapy and were part of Symposium S012. The Symposium was titled What’s Breaking Out: Acne and Rosacea. Dr. Bhatia was the first speaker, and was down to cover this material in 30 minutes.

The handouts are snapshots of the 41 slides in the presentation slides and naturally a lot more information would have been available at the presentation itself.

Following are some slide titles and extracts to whet your appetite. For the full handouts see the PDF link above. This stuff is pretty technical, so don’t feel too bad if there is unfamiliar terminology being used.

Acne and Rosacea:
Inflammatory mechanisms
and their impact on therapy
Neal Bhatia, M.D.
Assistant Clinical Professor
University of Wisconsin Medical School
2010 Summer AAD Symposium 012

Neal Bhatia, M.D., Assistant Clinical Professor
University of Wisconsin Medical School.

So what makes a papule ?

So what makes a pustule ?

Increased potential for scarring, necrosis, and nodules due to brisk inflammation.

Flushing vs. Blushing

Vascular elements of Rosacea.

What to remember about Demodex:

It is the density of mites or their extrafolicular location that induces hypersensitivity.

Impact of Photodamage

How does vasculopathy affect inflammation?

Anti-inflammatory activity of tetracyclines

Cathelicidins 101

Stratum Corneum Tryptic Enzyme trigger inflammation

Kallikrein 5 and Rosacea

Azelaic Acid suppresses KLK5 in keratinocytes in rosacea.

Retinoids and Inflammation

Doxycycline Mechanisms of Action

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Following on from a study that was able to show the reason that Finacea was able to adjust the inflammatory response in the skin, is this JAAD Poster session abstract.  This paper is looking at how the active ingredient in Finacea, azelaic acid can decrease the expression of 2 substances thought to be important in rosacea – kallikrein 5 (KLK5) and cathelicidin.

The lead author Richard Gallo is known for his research on cathelicidin. It is encouraging to see further research on how treatments might be proven and even developed based on the body of cathelicidin research.

Finacea seems to very much be the younger, less known brother to the market leader Metrogel, but the body of research linking Finacea to the ability to reduce processes active in rosacea might see Finacea gain a much bigger profile.

Azelaic acid gel alters kallikrein 5 and cathelicidin expression in epidermal keratinocytes, critical elements in the pathogenesis of rosacea

J Am Acad Dermatol 2010;60:AB1. Abstract P103, American Academy of Dermatology, 68th Annual Meeting, March 5–9, 2010, Miami, Florida (JAAD Poster Abstracts, March 2010 / Volume 62 / Number 3)

Richard Gallo, MD, PhD, VA San Diego Medical Center, San Diego, CA, United States; Kenshi Yamasaki, MD, PhD, Division of Dermatology, La Jolla, CA, United States

Recent observations have shown that facial skin from patients with rosacea produces excess amounts of the serine protease kallikrein 5 (KLK5), and abnormal forms of the antimicrobial peptide cathelicidin (CAMP).

In mice, abnormal CAMP and KLK5 expression influences inflammation, and administration of the forms of human CAMP found in rosacea results in inflammation, angiogenesis, and vascular telangiectasia.

In this study, we sought to further confirm the critical role of KLK5 and CAMP in rosacea by examining if the effects of a current human beneficial therapy correlated with changes in the expression of these genes.

We measured KLK5 in cultured normal human epidermal keratinocytes (NHEKs) and found that differentiated keratinocytes in high calcium media (1.6mM) greatly increased both KLK5 mRNA and protein compared to undifferentiated cells.

The addition of azelaic acid (AzA; 10-8 to 10-9M) to differentiated NHEKs significantly decreased KLK5 in media (vehicle; 91.26 6 22.58 ng/mL, 10-8M AzA; 41.69 6 15.08 ng/mL).

Total protease activity was also significantly less in media recovered from keratinocytes treated with 10-8M AzA.

Furthermore, mice treated once a day for 9 days with topical application of AzA gel 15% (Intendis; Berlin, Germany) showed significantly less KLK5 and CAMP mRNA compared with mouse skin treated with the vehicle alone (relative expression of KLK5 and CAMP was 55% and 32% of control, respectively).

In conclusion, because an excess of KLK5 and cathelicidin has been hypothesized to contribute to the development of rosacea, finding that an effective treatment for rosacea can decrease expression of these molecules further supports the involvement of KLK5 and cathelicidin in the pathogenesis of this disease.

REFERENCE
1. Yamasaki K, Di Nardo A, Bardan A,MurakamiM, Ohtake T, Coda A, et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 2007;13:975-80.

Commercial support: This study was funded by Intendis. Note: Intendis are the makers of Finacea.

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