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Expert shares new insights on the pathophysiology of rosacea.

NEWPORT BEACH, CALIF. -- In the clinical opinion of Richard L. Gallo, MD, PhD, current nomenclature for the diagnosis of rosacea could use a makeover.

"Currently, we're still operating with an almost 20-year-old set of diagnostic subtypes of rosacea," Dr. Gallo said at the annual meeting of the Pacific Dermatologie Association. He plans to participate in consensus meeting of experts who will convene this fall in an effort to update and modify these diagnostic criteria.

According to current nomenclature, subtype 1 is erythematotelangiectatic rosacea characterized by facial redness; subtype 2 is papulopustular (PPR), marked by bumps and pimples; subtype 3 is phymatous, characterized by enlargement of the nose; and subtype 4 is ocular, marked by eye irritation. Dr. Gallo pointed out that it's rare to see just one of these subtypes in rosacea patients, with the exception of the erythematotelangiectatic rosacea (ETR). "There is a large population with ETR alone," he said." Most patients with the papulopustular subtype have aspects of ETR. There is a mix of subtypes of rosacea, and we clearly need to modify our diagnostic criteria."

Secondary rosacea features may include burning or stinging, plaque, dry appearance and scale, edema, ocular manifestations, peripheral location, and phymatous changes. Work by several researchers in recent years has shed light on the pathophysiology of rosacea. "We're learning that there are many aspects to this disease that both trigger it and result in progression of the disease," said Dr. Gallo, professor and chair of the department of dermatology at the University of California, San Diego. "It seems to have biological triggers that exist both in the environment and initiate from internal sources. We're understanding more about the nature of those, at least specific molecules externally from microbes and so forth. Internally we understand more about the unique inflammatory signals."

For example, he and other researchers began to look at the innate immune system patients with rosacea and identified LL37, a multifunction peptide that plays a role in a number of skin diseases, as something that can promote inflammation (Nat Med. 2007;13[8]:975-80). "It also promotes the vascular changes [that occur with the disease]," Dr. Gallo said. "We're now learning how a dysregulation of enzymes in the skin contributes to making too much of these types of peptides. Therefore, treatment approaches that might modify enzymatic activity become useful." Researchers have also discovered that some of the innate recognition molecules like toll-like receptor 2 (TLR2) are overexpressed in rosacea patients. "Similarly, in terms of the vascular signals, a number of labs are identifying some of the newer vascular transmitters that seem to be uniquely elevated in rosacea, so there's great reason to be optimistic that given the increased specificity and understanding of what uniquely makes this disease happen, we'll be able to target it in a safe way."

A number of published studies have supported these notions, including an analysis of 275 twin pairs (JAMA Dermatol. 2015; 151[11]: 1213-9). The researchers found that, compared with fraternal twins, identical twins had a higher association of National Rosacea Society scores (P = .04), "supporting the concept that there are fundamental genetic factors that are influencing disease," Dr. Gallo said. Environmental factors found to be associated with rosacea include lifetime UV exposure, smoking, obesity, and alcohol use.





In an assessment of the genetic basis of rosacea by genome-wide association study, researchers identified one confirmed single-nucleotide polymorphism that could be associated with rosacea (J Invest Dermatol. 2015;135[6]:154855). It was located in an intergenic region between HLA-DRA and BTNL2, "which is consistent with the overall concept that there is perhaps a genetic abnormality that is leading to increased amino modulation of difficulties," Dr. Gallo said. For another recent study, researchers analyzed 14 randomized or case control trials involving rosacea patients (Int J Med Sci. 2015;12[5]:38796). They concluded that vasculature, chronic inflammatory responses, environmental triggers, food and chemicals ingested, and microorganisms either alone or in combination are responsible for rosacea.

Dr. Gallo went on to highlight findings from several studies that link rosacea to an increased risk for certain comorbidities. One, a nationwide case-control study from Taiwan that comprised 35,553 rosacea patients, found that the disease was significantly associated with a risk of certain cardiovascular comorbidities (J Acad Dermatol. 2015;73:249-54). These included dyslipidemia (odds ratio, 1.41), coronary artery disease (OR, 1.35), and hypertension (OR, 1.17). A separate analysis, based in 93,314 participants in the Nurse's Health Study, found that rosacea was significantly associated with a risk of coronary artery disease (OR, 2.2). The researchers also observed that comorbidities seemed to increase with duration of the disease (Clin Gastroenterol Hepatol. 2016;14[2]:220-5). Another smaller case-control study of 65 patients and 65 controls found an increased risk with rosacea for coronary artery disease, hyperlipidemia, hypertension, and gastroesophageal reflux disease (J Am Acad Dermatol. 2015;73[4]:604-8).

A recent analysis of 75,088 participants in the Nurses' Health Study found that women with rosacea faced an increased risk of thyroid cancer (HR, 1.59) and basal cell carcinoma (HR, 1.50; Br J Cancer 2015;113[3]:5203). Rosacea may also impact one's risk for developing certain neurological conditions. One study found an increased risk for dementia (HR, 1.42) and Alzheimer's disease (HR, 1.92; Ann Neurol. 2016;79:921-8), while another found an increased risk for Parkinson's disease (an adjusted incident ratio of 1.71 in patients with rosacea, compared with the referent population; JAMA Neurol. 2016;73[5]:529-34).

As for therapy, a recent Cochrane systematic review found strong evidence supporting benefits of several therapies over placebo, including metronidazole, azelaic acid, brimonidine, tetracycline, doxycycline 40 mg, ivermectin, and isotretinoin (Br J Dermatol. 2015;173[3]:651-2). A separate, 7-year retrospective study of 275 adults with rosacea published online in the Journal of Dermatology on Oct. 28, 2015, found that patients with the PPR subtype had a better overall prognosis, compared with their counterparts with the other subtypes. Overall, the median time to complete remission was 56 months. Complete remission was achieved in 46% of those with PPR subtype, compared with 19% of those with mixed subtype and 11% of those with ETR subtype.

Dr. Gallo disclosed that he has received research grants from the National Institutes of Health, Allergan, L'Oreal, Colgate-Palmolive, Regeneran, GSK, Galderma, and Bayer. He is a consultant for Allergan, Colgate-Palmolive, Sente, Matrisys, Dermata, Alnylam, Abbvie, Roche, and Promius.


Expect to see a shift in how we categorize our rosacea patients. There is a movement afoot to replace the current subtype classification with a more broad and inclusive description of rosacea diagnostic features. This is based on the idea that a rosacea patient seldom fits easily into just one subtype; usually, they have features of more than one subtype. We must also treat multiple features of rosacea and not just treat a subtype of lesions. For example, a patient with papulopustular rosacea may also have considerable background erythema. Of course, we need to target both of these manifestations.

We also need to target rosacea at its root. Fortunately, we are learning a lot about the pathogenesis of the disease. Dr. Gallo has performed much of the research that has investigated the role of innate immunity in the pathogenesis of rosacea. He and others have found upregulation of the cathelicidin LL-37 and the pattern recognition receptor TLR-2. Certainly, the more we understand about what causes rosacea the better equipped we will be to try to alter it.

Over the last few years, there have been numerous publications that show an association between rosacea and other disease states. These include cardiovascular disease, Parkinson's disease, and gliomas, just to name a few. We must remember that these studies only show an association; they do not suggest any type of cause and effect. It may be that these conditions share common inflammatory pathways that result in common risks. It may be that there are other confounding environmental factors that put patients at risk for many overlapping diagnoses. For now, continue to recommend that your rosacea patients have routine, age-appropriate health care. I do not think that it is appropriate to recommend any additional screening based on these findings.



Caption: Subtype 1: Erythematotelangiectatic rosacea

Caption: Subtype 2: Papulopustular rosacea

Caption: Subtype 3: Phymatous rosacea

Caption: Subtype 4: Ocular rosacea
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Author:Brunk, Doug
Publication:Dermatology News
Article Type:Report
Date:Jul 1, 2017
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