Pathogenesis of rosacea: Breakthroughs hold promise for therapeutic developments

Pathogenesis of rosacea: Breakthroughs hold promise for therapeutic developments
By Cheryl Guttman

San Diego — Understanding the pathogenesis of rosacea has been advanced by recent research and is expected to provide an important foundation for developing novel, rational approaches to therapy in the future, says Richard L. Gallo, M.D., Ph.D., professor and chief, division of dermatology, University of California, San Diego.

Dr. Gallo discusses findings from a series of research studies that show there is a dysfunction in antimicrobial peptide production and processing in rosacea and that it can arise via multiple pathways.

"This information indicates no one gene or stimulus can explain rosacea in all patients, and therefore, it is consistent with our longstanding frustration in trying to identify a solitary etiologic trigger,

" Dr. Gallo says.

Skin’s immune system

"Now, understanding of these antimicrobial peptides as a critical element of rosacea should offer us new targets of therapy," Dr. Gallo tells Dermatology Times.

Dr. Gallo and colleagues approached their investigations of rosacea pathogenesis from a biochemical and genetic standpoint, considering the key elements of the biology of the disease and their understanding of the functioning of the innate immune system of the skin.

Based on this knowledge, they hypothesized that rosacea reflects an abnormality in the reaction of the early response system to the variety of elements that have been identified as rosacea triggers.

More specifically, they hypothesized that elements of the antimicrobial peptide system and enzymes controlling that system may represent a "choke point" in the communication between the multiple different disease stimuli and the various clinical subtypes of rosacea.

Immunohistochemistry

A series of studies were designed to construct proof for this hypothesis. The first investigated levels of cathelicidin antimicrobial peptides in facial skin and showed significantly higher expression in patients with rosacea compared with unaffected controls as measured by immunohistochemistry, Enzyme-Linked ImmunoSorbent Assay (ELISA) and gene expression. Evaluation with mass spectroscopy showed the size of the cathelicidin peptides was also abnormal in the skin of all rosacea patients compared with controls, indicating a difference in proteolytic processing.

"The differences between rosacea patients and our control samples — uninvolved edges of basal cell carcinoma excisions — were dramatic, and the findings were somewhat surprising to us.

"However, it was the difference in peptide size that really led us to believe we had come upon something important," Dr. Gallo says.

Consistent with that belief, the researchers also found that all rosacea patients had abnormally increased activity of the serine protease enzymes responsible for cathelicidin peptide processing.

In previous research, Dr. Gallo and colleagues had already identified the genes for individual cathelicidin-processing enzymes. Based on that information, they evaluated the expression of the gene for stratum corneum tryptic enzyme (SCTE, kallikrein 5) in facial skin of rosacea patients and found it was also elevated and specifically in areas where the processed cathelicidin peptides were found.

Further experiments aimed to establish significance for the laboratory findings by demonstrating a cause and effect relationship. Applying Koch’s postulates, these experiments investigated the hypothesis that if the unique peptides found only in rosacea skin were important in disease pathogenesis, they could induce findings consistent with the clinical presentation of rosacea.

Cathelicidin peptides

A first in vitro experiment showed that production of pro-inflammatory cytokines by cultured keratinocytes was significantly greater when the skin cells were co-incubated with processed cathelicidin peptides found in rosacea skin compared with peptides from normal skin.

"Although supportive, this finding was not overly convincing. The results of a second experiment blew us away," Dr. Gallo says.

The latter research involved a murine model and evaluated the responses to dorsal skin injections of physiologically relevant concentrations of peptides from normal and rosacea skin.

After just two days of twice daily treatment, the animals injected with the rosacea-related peptides developed a phenotype that reproduced rosacea with the presence of inflammation, a vascular response, and ectasia.Adding strength to the cause and effect relationship was the observation of a dose-related response.

The research has now entered a new phase where studies are evaluating potential correlations between the proposed pathogenic pathway and both gene abnormalities and effective treatments.

These are our last questions, but really represent the beginning of our research project, not the end," Dr. Gallo says.

Available evidence is still limited, but so far, it is entirely consistent with the existing hypothesis. One line of support is derived from an "experiment of nature," which is the finding that a polymorphism of the vitamin D receptor gene leading to excessive production of processed cathelicidin peptides is associated with rosacea fulminans.

Isotretinoin

In addition, it is also known that isotretinoin, which has been found to have beneficial effects in rosacea, influences genes involved in the cathelicidin and SCTE expression system.

Findings from a study examining serine protease levels in facial skin of rosacea patients after they start, stop, and restart minocycline therapy are preliminary but so far are providing a dramatic demonstration of how tetracyclines can affect this innate immune response pathway.

Dr. Gallo says that marked decreases in SCTE levels have been observed after the initiation of minocycline therapy and occur in parallel with improvement in clinical disease activity.

Subsequent minocycline withdrawal and re-initiation corresponded to increases and decreases, respectively, in enzyme activity.

"The effects of minocycline withdrawal and rechallenge on SCTE show the initially observed change with minocycline initiation was not a coincidence and suggest that indeed, tetracycline affects the enzymes that we hypothesize are involved in the pathogenesis of rosacea," Dr. Gallo says. DT

Disclosure: The research has been supported in part by a seed grant from the National Rosacea Society.

Acne rosacea causes

Acne rosacea is a chronic disorder of unknown cause that affects the central face. At least 13 million people are affected by this noncurable disorder. It is characterized by two clinical components: a vascular change consisting of intermittent or persistent erythema and flushing and an acneiform eruption with papules, pustules, cysts, and sebaceous hyperplasia. There is no correlation between the sebum excretion rate and the severity of Acne rosacea. Lesional blood flow as measured by laser Doppler is three to four times that of controls. Onset is most often between the ages of 30 and 50; pediatric cases have also been reported. Although women are affected three times as frequently as men, the disease may become more severe in men. Acne rosacea is much more common in light-skinned, fair-complexioned individuals but may also occur in darker skin types. It is estimated that 10% of individuals in Sweden have Acne rosacea.
There is speculation that a defect in the trigeminal afferent nerve pathway contributes to a predisposition to facial flushing. Over time, after repeated bouts of flushing, the vessels become ectatic and there is permanent vasodilatation. Hot liquids are thought to promote erythema and flushing when they heat up the tissues of the oral mucosa, leading to a countercurrent heat exchange with the carotid artery. A further signal from the carotid body is then relayed to the hypothalamus (the body's thermostat), which signals the body to dissipate heat through flushing and vasodilatation because of the perceived increase in core body temperature.
Helicobacter pylori, a microaerophilic gram-negative bacteria implicated in gastric ulcer disease, has been theorized to be the inciting organism in Acne rosacea on the basis of an increased incidence of dyspepsia in this population and the responsiveness of Acne rosacea to metronidazole. Fifty percent of the world's population and 25% of the US population may have antibodies to this organism. Colonization is associated with increased levels of serum gastrin, which can cause flushing. Also, H. pylori infection can increase levels of histamine, prostaglandins, leukotrienes, and various other cytokines. Therapy to eradicate this organism usually consists of a combination of oral metronidazole, amoxicillin, and omeprazole. Conflicting studies regarding this association with Acne rosacea have recently been in the literature. In general, it is felt that strong support for a link between H. pylori infection and Acne rosacea is lacking. Large case control studies would be needed to prove this association because of the high baseline incidence of this exposure.
Infection with Demodex mites is common, with infection approaching 100% in sensitive tests of healthy adults. Some have hypothesized that infection with Demodex is a cause of Acne rosacea. There is controversy within the literature whether this is the case. In one study, there was a link between higher mite counts and papulopustular but not erythematotelangiectatic Acne rosacea. It is unclear whether Demodex is pathologic or just normal skin flora.

Rosacea causes (2)

Acne Rosacea is usually preceded by degenerative changes of the perivascular, and possibly vascular, collagen and elastic tissues in inherently susceptible individuals exposed to climatic factors. These dermal changes are believed to lead to small vessel dilatation resulting in flushing, apparent vessels under the skin surface, and redness. Eventually, the dilated vessels become incompetent with perivascular leakage of potentially inflammatory substances.
Different mediators, including the neurotransmitter peptide substance P, histamine, serotonin, and prostaglandins, have been proposed to be involved in the erythematous response. It is also possible that none of these is responsible but that the reaction is triggered by another, still unknown mechanism.
The presence of microorganisms has also been examined as a potential contributing factor to Acne Rosacea, but results have been inconclusive. Demodex folliculorum mites are merely commensals and do not, in contrast to former belief, play a significant part in the development of Acne Rosacea, although an inflammatory reaction to the mites may be important in this condition. This is different from Demodex folliculorum folliculitis (demodicosis, demodicidosis). Some reports suggest that patients with Acne Rosacea have an increased prevalence of Helicobacter pylori infection, although other reports fail to confirm this association. Eradication of H. pylori has been occasionally associated with an improvement of Acne Rosacea symptoms. Study results are inconsistent, but it has been suggested that H. pylori synthesizes gastrin, which may stimulate flushing.
Acne Rosacea is considered by some authors as a seborrheic disease. Many patients with Acne Rosacea, however, do not show signs of excessive sebaceous activity although others do. One report says that there is no significant association between Acne Rosacea and seborrhea. It is not a primary disease of sebaceous follicles in contrast to acne vulgaris. Comedones are absent and the initial findings are not related to follicles, though papulopustules are follicular bound.
No acceptable evidence of genetic predisposition has been reported so far, although more than one case in a family is often encountered.

Rosacea causes

Acne Rosacea is a relatively common disease, especially in fair-skinned people of Celtic or northern European heritage, hence the term curse of the Celts. It is rarer in dark-skinned people, particularly so with American and African blacks. The disease is estimated to affect at least 5 percent of Americans, or some 13 million people. Although it is said that women are more often affected than men in earlier stages (3:1 ratio), men develop the tissue and sebaceous gland hyperplasia leading to rhinophyma much more frequently. Although Acne Rosacea tends to be milder in women, it can lead to severe emotional distress owing to its chronic course.
The importance of sun-damaged skin in Acne Rosacea cannot be stressed enough. Acne Rosacea is always associated with solar elastosis and often with heliodermatosis. This is a consistent background on which Acne Rosacea is superimposed. However, an increase in ultraviolet sensitivity has not been demonstrated in Acne Rosacea sufferers, nor is the disease more common in outdoor workers.
There is also a wide spectrum of Acne Rosacea manifestations. Especially in young sufferers there may be a history of acne giving rise to variants of two independent facial diseases that are difficult to recognize and treat. It is important to realize that Acne Rosacea and acne can coexist, though normally Acne Rosacea begins and reaches its peak incidence decades after acne declines.
Although the precise cause of Acne Rosacea remains a mystery, various factors have been suspected to contribute to this condition. None of them, however, has been definitely confirmed. Acne Rosacea sufferers are constitutionally predisposed to flushing and blushing. Migraine headaches have been shown to be two or three times more common in Acne Rosacea sufferers than among age- and gender-matched control subjects, suggesting the possibility of a more generalized vascular pathogenesis. The fact that vasomotor lability is especially pronounced during menopause and that a significant number of Acne Rosacea sufferers are perimenopausal women supports this hypothesis. Experimental studies show that the involved skin responds normally to various vasoactive chemicals, with facial blood vessels maintaining their capacity for dilatation and constriction. The basic abnormality seems to be a microcirculatory disturbance of the function of the facial angular veins directly involved in the brain-cooling vascular mechanism.