Significant Progress in Rosacea Research

09/17/2014

Though today it is well-established that rosacea is 1 of the most common dermatological disorders, 25 years ago it was considered a rare disease, and the FDA believed fewer than 200,000 people were affected. Since then, knowledge of rosacea has vastly increased. 

Based on prevalence rates in global epidemiological studies, it is now estimated that more than 16 million Americans experience rosacea. The National Rosacea Society (NRS) has played a leading role to help classify rosacea, disseminate knowledge and fund research. The Society has provided educational materials and other social network support to many people afflicted with this cosmetically disabling and often symptomatic disorder.

Despite its prevalence, the cause of rosacea and the links between it, its subsets and various precipitating environmental factors remain controversial and often unknown. To learn more, the NRS instituted a research grants program. So far, the program has awarded a total of $1.4 million to fund 58 studies. The money has often provided seed money to explore new avenues of research. The money has been well spent, in my opinion. Many exciting discoveries have been made.

 

New Insights

Flushing is common, and involves both the nervous system and inflammation. The nervous system may be very important not only for mediating flushing but also for mediating inflammation. For example, specific proteins are elicited in flushing reactions provoked by the rosacea trigger niacin, an essential vitamin contained in an extensive range of foods.1 In another study, researchers noted how emotional triggers such as stress can activate the sympathetic nervous system to release chemicals that both lead to the papules and pustules of inflammation as well as to dilation of blood vessels, resulting in flushing.2 Other investigators studied flushing accompanied by stinging, burning and itching sensations. These symptoms result at least in part from nerve activation and release of the neuropeptide called pituitary adenylate cyclase-activating polypeptide (PACAP).3 Researchers also found that the immune system of individuals with subtype 1 (erythematotelangiectatic) rosacea, characterized by flushing and redness, showed significantly increased reactivity of non-neuronal transient receptor potential ion channels that are activated by capsaicin, a substance present in spicy food.4 

In a key finding, a dysfunction of the innate immune system may elicit at least some of the inflammation associated with the development of papules and pustules and maybe also facial redness.5 Investigators discovered that when the innate immune system faces insults such as sun exposure, emotional stress and ingestion of hot or spicy foods — all triggers of rosacea flare-ups — receptors recognize these potential dangers and protect the body by prompting the production of protective molecules known as defensins. In rosacea patients, the defensin called cathelicidin and its derivative LL37 are increased in the epidermis, apparently due to an overabundance of the activating molecule kallikrein 5. Rosacea patients also have elevated levels of toll-like receptor 2 on cells. Binding of toll-like receptor to ligands like bacteria activate kallikrein 5 to increase amounts of cathelicidin and LL37.

Other research suggests that mast cells, located at the interface between the nervous and vascular systems, may be a “missing link” between certain rosacea triggers and inflammation. When exposed to the neuropeptide PACAP, mast cells produce enzymes that also trigger the production of cathelicidins.6 

A greater presence of Demodex mites on the facial skin of rosacea patients may be an additional pathogenic factor. The inflammation of rosacea may be in some way related to the mite itself or to bacteria residing on the mite. Investigators found that Bacillus oleronius, a bacteria carried by Demodex mites, can stimulate an immune response in individuals with rosacea. Treatment with various antibiotics may resolve Demodex-induced papules and pustules by destroying these bacteria carried inside the mite. 

Another researcher suggested both an indirect and a direct role for the mites themselves in the development of the disorder.7 Skin infections and disruption of the skin barrier stimulate toll-like receptors to induce cathelicidin production. The complaint of sensitive skin in rosacea patients often disappears when the number of mites is reduced to normal by treatment. 

Increased Awareness

In its 15th year of existence, the NRS research grants program has not only funded research, but also spurred interest in an area that had been largely dormant. In addition, the NRS convened a consensus committee and review panel of international experts to develop standard classification and grading systems, as well as the standard management options for rosacea. The results were published in scholarly journals and have been widely adopted. 

Adoption of the standard classification and grading systems has provided uniformity in study protocols to aid in performing research, analyzing results and comparing data from different sources. They have provided a common terminology and reference for the diagnosis, treatment and assessment of results in clinical practice.8 For example, providers and pharmaceutical studies now focus on specific subsets of rosacea patients for targeted therapies.

Along with this progress, an array of new products has arrived to treat rosacea’s various signs and symptoms. There are now novel topical therapies and anti-inflammatory oral medications for papules and pustules, and a topical formulation for facial erythema. Pharmaceutical and cosmetic companies continue to develop more new treatments. The NRS supports these efforts, although its research program does not fund product development studies, as they are considered more appropriately funded by commercial sources. However, researchers and clinicians have discovered new targets for treatments and care. Also, the NRS has developed a full range of patient education materials for health professionals to help teach their patients how to use these new treatments and aid effective management and support.

Grants Information

Researchers interested in applying for study grants may obtain forms and instructions through the research grants section of the NRS website (www.rosacea.org). They can also contact the Society by mail National Rosacea Society, 196 James Street, Barrington, IL 60010, by phone 888-662-5874 or by e-mail rosaceas@aol.com. 

Because the etiology of rosacea is unknown, high priority is given to research in such areas as the pathogenesis, progression, mechanism of action, cell biology and potential genetic factors of this conspicuous and often life-disruptive condition. Studies may also be funded in such areas as epidemiology, predisposition, quality of life and associations with environmental and lifestyle factors. 

The next deadline for submitting proposals to receive NRS research grants is May 8, 2015.

In summary, the NRS supports patients with rosacea as an advocate and as a provider of information. Donations are welcome. The NRS continues to support its research grants program to advance knowledge of rosacea in all its forms. 

 

Dr. Dahl is chairman of the National Rosacea Society Medical Advisory Board.

 

Disclosure: The author reports no relevant financial relationships.

 

 

References

1. New study identifies cause of flushing. Rosacea Review. Winter 2010.

2. Seiffert K, Ding W, Wagner JA, Granstein RD. ATPgammaS enhances the production of inflammatory mediators by a human dermal endothelial cell line via purinergic receptor signaling. J Invest Dermatol. 2006;126(5):1017-1027.

3. Seeliger S, Buddenkotte J, Schmidt-Choudhury, et al. Pituitary adenylate cyclase activating polypeptide: an important vascular regulator in human skin in vivo. Am J Pathol. 2010;177(5):2563-2575.

4. Sulk M, Seeliger S, Aubert J, et al. Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. 

J Invest Dermatol. 2012;132(4):1253-1262.

5. Yamasaki K, DiNardo A, Bardan A, et al. Increased serine protease activity and cathelicidins promotes skin inflammation in rosacea. Nat Med. 2007;13(8):975-980.

6. Muto Y, Wang Z, Vanderberghe M, Two A, Gallo RL, Di Nardo A. Mast cells are key mediators of cathelicidins-initiated skin inflammation in rosacea. J Invest Dermatol. Published online ahead of print. May 20, 2014.

7. Forton FM. Papulopustular rosacea, skin immunity and Demodex: pityriasis folliculorum as a missing link. J Eur Acad Dermatol Venereol. 2012;26(1):19-28.

8. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46(4):584-587.