Rosacea



Rosacea


Eric F. Bernstein

Ryan B. Thorpe

Kevin Schomacker

Jason D. Bloom

Emil A. Tanghetti

Jayant D. Bhawalkar



BACKGROUND

Rosacea is a chronic inflammatory condition comprising facial flushing, telangiectasias, and inflammatory papules and pustules1 estimated to affect 16 million Americans.2 Rosacea is generally distributed on the convexities of the central face and is classified into 4 main subtypes: erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea.3 Although the exact pathomechanisms of rosacea are unknown, substantial recent advances in research support a multifactorial disease process, including roles for a dysregulated immune system, microbial overgrowth, aberrant neurovascular signaling, ultraviolet (UV) radiation exposure, reactive oxygen species, and genetic susceptibility.1,4

The prevalence of rosacea ranges from 1% to 22%,5 likely because of the methods utilized to gather epidemiologic data. For example, using a photograph database of 2,933 women volunteers from 4 international cities (Los Angeles, Akita, Rome, and London), researchers reported prevalence rates of rosacea in 9.6% of all races and 16% in white women,2 whereas retrospective database studies in the United States have reported far lower prevalence rates of 1.34%6 to 2.1%.7 In a recent community-based study aimed to support the notion that the true community prevalence of rosacea is underestimated by database, clinic-based studies, or survey studies, 11% of community members showed signs of rosacea when under direct observation.8 Furthermore,
when specifically using the classification system of the American National Rosacea Society Expert Committee, researchers in Estonia reported a prevalence rate of 22%, again suggesting that rosacea is more common than previously thought.9

Rosacea is more common in females, except for phymatous rosacea, which is more common in men.10 Communications on the prevalence of ocular rosacea ranges widely from 6% to 58% owing to the potential for high false-positive reports and the need to update the diagnostic criteria for ocular rosacea.5 Since the 1960s, however, ocular involvement has been reported to be in 50% of patients with rosacea.11 The most prevalent form of rosacea is the erythematotelangiectatic subtype. For example, of 168 Korean patients with rosacea, 96.4% were diagnosed with the erythematotelangiectatic subtype, 50.6% had the papulopustular subtype, 14.3% had ocular rosacea, and only 4.8% demonstrated phymatous changes. The mean age at diagnosis in this group of patients was 47.8 years12 Similarly, in a group of patients from Sweden, 81% had erythematotelangiectatic rosacea and 19% had papulopustular rosacea.13 Rosacea is more common in lighter skinned individuals and has not been found in all communities. For example, in a study comparing dermatologic diseases in the United Kingdom with a clinic in Kumasi, Ghana, no cases of rosacea were found in Ghana.14

Several environmental factors are associated with worse disease, including age, lifetime UV radiation exposure, body mass index, smoking, alcohol, cardiovascular comorbidity, and skin cancer comorbidity.15


PRESENTATION

Patients present with a complaint of redness, broken capillaries, poor complexion, or acneiform breakouts. The exacerbations of redness or papules typically occur following sun exposure or wine consumption, but these may occur following any of a number of triggers. In many cases, the patient is unaware of the underlying triggers.




PATHOGENESIS

Although the pathogenesis remains to be fully elucidated, leading proposed mechanisms include dysregulation of the innate immune system, vascular changes, reactive oxygen species, UV radiation, and microbial overgrowth.4 It is the interplay between these factors that likely underpins the clinical manifestations of rosacea.


Immune System Dysregulation

Several elements of the innate immune system are abnormally regulated in rosacea. Yamasaki et al. discovered that cathelicidin (LL-37), an antimicrobial peptide of the innate immune system,21,22 is both abnormally increased and in an abnormal form in rosacea skin. Also increased is kallikrein 5, the primary serine protease responsible for processing cathelicidin into active form. Investigators have shown that increased cathelicidin and serine protease activity result in increased skin inflammation in mice.4 Cathelicidin is also associated with other characteristic features of rosacea such as vasodilation and vascular proliferation.23 Cathelicidin is
induced by vitamin D, which is known to be activated by UV light, an established agitator of the disease.1 Toll-like receptor 2 (TLR2), a microbial pattern recognition receptor is also induced by vitamin D; blocking the TLR2 receptor inhibits cathelicidin production.24 Mast cells, immune cells of granulocytic heritage, are also found in increased numbers in the dermis of rosacea and happen to be one of the primary sources of cathelicidin. In one study, mice depleted of their mast cell stores did not develop rosacea-like features when injected with cathelicidin, whereas wild-type mice preloaded with mast cell stabilizers displayed increased levels of rosacea-like features as well as high amounts of chymase, tryptase, and matrix metalloproteinase-9 when injected with cathelicidin.22 Scientific explorations regarding the dysregulated immune system demonstrated in rosacea are ongoing.


Vascular Changes

Increased vascularity has historically been thought to play a role not only in developing rosacea but also in many of the symptoms of rosacea. Supporting this supposition is the successful treatment of rosacea with the topical selective alpha-1 adrenergic receptor agonist, oxymetazoline.25 Moreover, lesional skin is marked by increased VEGF, CD31, and D2-40 compared with non-lesional skin, further advancing increased vascularity as a contributing factor to rosacea.26 In addition, increased skin blood flow has been demonstrated in papulopustular rosacea skin but not in erythematotelangiectatic rosacea.27 Undoubtedly, laser therapy is uniquely positioned to target vascular contributions to the pathogenesis of rosacea.


Ultraviolet Radiation and Reactive Oxygen Species

UV exposure contributes to rosacea in a variety of mechanisms. Specifically, UV radiation increases reactive oxygen species in the skin,1 and UVB radiation and hydrogen peroxide are potent inducers of vascular endothelial growth factor28 and are known to amplify the kallikrein 5/cathelicidin cascade through TLR2 signaling.1 With regard to rosacea, reactive oxygen species are reported to alter matrix metalloproteinases, enhance inflammatory reactions, and degenerate cutaneous collagens. In fact, many treatments of rosacea may work by decreasing reactive oxygen species.21


Genetic Contributions

Although no specific gene or set of genes has been identified as causing rosacea, the suspected genetic component was supported by a 2015 study of 275 twin pairs. Employing the National Rosacea Society grading system17 and the well-accepted ACE statistical model, the genetic contribution to rosacea pathogenesis was calculated to be 46%.15 With time, genetic susceptibility genes will only become more defined and may relate to the immune system.


Microbial Overgrowth

Although this theory is not universally accepted, overgrowth of various microbes accused in the pathogenesis of rosacea may work in combination with the factors described above to result in rosacea. Supporting this theory, investigators have shown that the density of Demodex mites in the skin of patients with rosacea is higher than in normal controls (10.8 mites/cm2 vs 0.7 mites/cm2, respectively).29 It is important to note, however, that Demodex mites are normal colonizers of human skin, as the main food sources for these mites in all phases of development are epidermal cells and sebum components. This explains why the mites are found on areas of skin particularly rich in sebaceous glands, such as the nose, cheeks, forehead, and chin.30 Reports of normal rates of colonization of Demodex folliculorum and Demodex brevis, the 2 main species of mites on human skin, range from 20% to 80% in people unaffected by rosacea, with increased colonization rates as people age.

Facial itching in the absence of erythema is correlated with mite density, and antigens from bacteria found within Demodex can stimulate lymphocyte proliferation.31 Accordingly, some suggest that the pathogenesis of rosacea is due more to the bacteria living within the mite than the mite itself. For example, Bacillus oleronius, a bacteria found in Demodex in a symbiotic relationship, produces proteins more capable of stimulating blood mononuclear cell proliferation in patients with rosacea (16 of 22) than in control patients (5 of 17).32 Other investigators suggest that the mites may play a more active role by mechanically blocking hair follicles, secreting digestive enzymes, and/or triggering reactions of the immune system.30 Antibiotics used to treat rosacea may in part be effective because of activity against the bacteria. This is suggested by data showing that antibiotics useful in some patients, such as tetracyclines, do not have any activity against Demodex but are lethal to
the B oleronius. Chitin from Demodex, however, has been postulated to increase TLR2 expression. In fact, chitin-induced effects were largely not seen in one study in which TLR2 receptors were blocked.33

Demodex mites and B oleronius are not the only microbes implicated in rosacea. Staphylococcus epidermidis has also garnered some attention ever since researchers reported that pustules in papulopustular rosacea grew pure S epidermidis, whereas control cultures from unaffected areas on the same faces did not.34 Others have shown that the S epidermidis isolated from patients with rosacea exhibited different protein excretions at different amounts at different temperatures compared with controls. In addition, S. epidermidis from patients with rosacea is consistently beta-hemolytic compared with the nonhemolytic strains found on control subjects.35 Similar to the suggested mechanisms of the other microbes discussed earlier, S epidermidis also secretes molecules that increase defensins through TLR2 signaling.36

As can be derived from the earlier discussion, the pathogenesis of rosacea is complex and unsolved, but most agree that recent research indicates that the innate immune system, UV radiation, vascular changes, genetics, and microbial overgrowth may all play a role in the pathogenesis of rosacea and that it is the collaboration among these systems that results in the signs and symptoms of rosacea.

Jun 29, 2020 | Posted by in Dermatology | Comments Off on Rosacea
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