Rosacea - Background

• Rosacea:
  Rosacea is typicaly construed as a chronic (acneiform) dermatosis, presenting with an inflammatory vascular response of the facial pilosebaceous glands, and characterized by episodic flushing / erythema as a response to variable stimuli, with possible accompanying papules, pustules or nodules, as well as potential telangiectasia (small, visible dilated cutaneous blood vessels), manifesting in an irregular pattern of alternating excerbation and remission. Rosacea commonly appears after the third, and peaks in the fourth and fifth decades, affecting more fair-skinned individuals, with a threefold likelihood of occurrence in women over men.
  
  

• Etiology and Pathogenesis:
  Rosacea's precise etiology is largely undetermined, although it is known that both genetic and triggering environmental factors are contributory. Environmental triggers include (1) climatic factors: solar photo-exposure, extreme temperatures, harsh wind, (2) dietary: spicy food, caffeine, alcohol (via peripheral vasodilation), (3) psychological: emotional stress, (4) dermal-irritant: irritating or caustic skin agents.
  
  Under various assaultive triggers, neutrophils and other immune cells release a spectrum of proinflammatory by-products, with vasodilation triggered via oxidants and cytokines, in turn weakening vessel structure to cause inflammatory papules and pustules; concurrently the release of MMPs (matrix metalloproteinases), critical to conective tissue degradtion, is stimulated. It is thought that various MMPs (elastase, collagenase, and gelatinase) induce degradation of elastin and collagen in the capillary extracellular matrix and yield vasculature structural instability. The release of cytokines, especially interleukin (IL)-1 and tumor necrosis factor (TNF) then play a causative role in the inflammatory vascular response via the stimulation of collagenase production and histamine release, triggering vasodilation along withvascular permeability. This is the basis of rosacea treatments that target the neutrophil function modulation and other core components of the inflammatory vascular response.
  
  

• Microbial Influence:
  
  (1) Demodex folliculorium mites may be a causative agent, possibly by inducing a hypersensitivity reaction, and although the evidence of direct pathogenetic role is not to date has not been wholly compelling (see Del Rosso in Expert Opin Pharmacother: Medical Treatment of Rosacea with Emphasis on Topical Therapies), the recent findings (as yet unpublished) of Kavanagh et al. for the National Rosacea Society: Characterisation of Role of Bacterial Antigens in the Induction and Persistence of Rosacea, suggest that the bacterium Bacillus oleronius associated with the microscopic Demodex mite can stimulate an antigen immune system response with high levels of T-cell proliferation evidencing as papules and pustules, in a large percentage of subtype 2 (papulopustular) rosacea patients. It is certainly true, and highly suggestive, as Dr. Kavanagh has reasoned, that the oral antibiotics typically used in rosacea therapy destroy B. oleronius, while the antibiotics typically not active against these bacteria generally have not proven effective rosacea management. The researchers are currently developing antibodies against B. oleronius produced antigen. Evidencewatch will report further on this develop as the research appears.
  
  (2)There may be an association between rosacea and concurrent gastrointestinal infection with gram-negative bacterium Helicobacter pylori, although Herr and You in J Korean Med Sci: Relationship Between Helicobacter pylori and Rosacea: It May Be a Myth found no significant resolution of rosacea lesions and symptoms with treatment of the H. pylori infection, casting serious doubt on that bacteium's role in the pathogenesis of rosacea.
  
  (3) Gastric hyochlorhydria, and
  (4) Ulcerative colitis may be implicated
  although again the evidence base is insufficient to support these claims persuasively to date.

• Management:
  Rosacea management is targeted to (1) controll the acneiform lesions,(2) attenuate flushing and reduce its episodic recurrence, (3) retard the formation of telangiectases, and (4) prevent rhinophyma (swelling and growth of the nose and central facial areas). Reduced consumption of products that may trigger flushing may help limit the development of telangiectases, although complete elimination of all triggers is unrealistic. Some of these triggering products may be caffeine, alcohol, and spicy food, use of fluorinated corticosteroids, ACE inhibitors, vasodilators (including niacin and niacinamide formulations), sildenafil, and the statin simvastatin, all of which may increase rosacea flushing. Use of an effective sunscreen daily, with SPF of at least 15, to protect the skin from UV A and B exposure, although here too rosacea sufferers may find some of the topical agents and compounding components themselves irritating to the skin, so that discovering an acceptable preparation may require considerable expenditue of effort by the patient. Most patients will require topical and/or oral agents, rarely surgical interventions.
  
  

• Evidence-based Efficacy of Standard Treatment:
  In terms of topical therapies, both topical metronidazole and azelaic cream are efficacious in the treatment of rosacea. As to oral agents, oral tetracycline shows the greatest support in methodologically high-quality studies, while some lesser support exists for oral metronidazole (on the basis of one small study). See Cochrane Review: Interventions for Rosacea.
  
  

• Methodological Problems:
  The Cochrane reviewers concluded in general that: "the quality of studies evaluating rosacea treatments was generally poor" and that with respect to other therapies and agents, "good RCTs are urgently needed". Comparably, Gupta and Chaudhry (Dermatology: Evaluating the Quality of Rosacea Studies: Implications for the Patient and Physician) surveyed 42 studies (from 1996 - 2002) to determine quality of the clinical trials involved, finding only 13 that could be rated as high-quality studies, with no association between the quality of the study and how often it was cited.
  
  In another study (Int J Dermatol: Critical Review of the Manner in which the Efficacy of Therapies for Rosacea are Evaluated), the same authors foundreasonable consistency of criteria for judging treatment efficacy on the basis of effect of the intervention on papules and pustules (often with manual lesional counts of papules and pustules), erythema, and telangiectasia. However, they found substantial variation in ethodology chosen for the comparison of erythema and telangiectasias, so that although there are commonly used parameters for measuring the efficacy of rosacea treatments, there were substantially different approaches (color scales, color grading, etc.) by which these parameters were measured in the various trials. They concluded that such dissimilarities render problematic comparisons between clinical trials. They consequently call for "a greater degree of uniformity in the manner in which the various parameters are evaluated" to "enable a more objective comparison between the studies".
  
  

• Topical Therapies:
  
  Metronidazole:
  Metronidazole is first-line topical therapy for rosacea; metronidazole is an imidazole ring-based antiprotozoal and antibacterial agent, withsome degree of anti-inflammatory an antioxidant properties, although it is now thought that metronidazole's efficacy in improving rosacea symptoms is not primarily via antibiotic action but rather by its activity of neutrophil-generated oxidant reduction; this oxidant reduction serves to inhibit oxidative tissue injury and interrupt the inflammatory cascade inducing and sustaining rosacea symptomology. Originally prescribed as a twice daily regimen of metronidazole .75%, cream or gel, once daily is comparably efficacious (see Lowe in Adv Ther: Use of Topical Metronidazole in Moderate to Severe Rosacea) and is generally well-tolerated. Metronidazole appears to be especially effective on acneiform lesions, with some reduction of erythema but no clinically appreciable effect on telangiectases, and with effectiveness evidencing plateau after eight weeks (see the study of Boni et al., Arch Dermatol: A Comparison of 15% Azelaic Acid Gel and 0.75% Metronidazole Gel in the Topical Treatment of Papulopustular Rosacea)
  
  Azelaic acid:
  Azelaic acid, a naturally occurring dicarboxylic acid used for the treatment of acne, has also been employed as an anti-inflammatory agent for treating rosacea, as 15% azelaic acid gel twice daily, reducing the inflammation of papules and pustules associated with moderate rosacea. Like metronidazole, azelaic acid had no clinically appreciable effect on telangiectases, but in contrast to metronidazole, azelaic acid retains efficacy without plateau out to 15 weeks (study's terminus). Although neither agent demonstrated any serious or systemic treatment-related adverse events, global and overall assessment of improvement showed significant therapeutic advantage for azelaic acid over metronidazole. Azelaic acid, like metronidazole, is thought to inhibit immune-derived reactive oxygen species (ROS).
  
  Isotretinoin may be warranted in phymatous rosacea. Because it can exacerbate keratitis and blepharitis, this agent is not recommended for ophthalmic rosacea. Duration of therapy is usually five to six months. Adverse effects of isotretinoin use include dry eyes, nose, and lips; skin fragility; photosensitivity; joint pain; headaches; vision changes; thinning hair; mood swings; and epistaxis. Because of reported cases of neutropenia associated with use of isotretinoin, a complete blood cell count is warranted at baseline and at the end of the first month of therapy. The following laboratory studies should be obtained monthly: a hepatic function panel to monitor transaminases, a lipid panel to monitor for triglyceride elevations, and -- in wom en of childbearing age -- a serum pregnancy test. Because isotretinoin is teratogenic, women of childbearing age should use two forms of birth control during therapy. Although oral metronidazole has been suggested in the treatment of rosacea, it is not approved by the FDA for this use. Furthermore, it may not be appropriate for long-term therapy because of a risk of developing neuropathy.
  
  Other Topical Antimicrobials:
  Clindamycin 1% (available in cream, lotion, or gel) and erythromycin 2% are also recommended for rosacea treatment. These can improve the acneiform lesions but have little or no effect on erythema, flushing, or telangiectasia formation. Erythromycin can cause nausea and vomiting.
  Another oral antibiotics with possible benefitsis trimethoprim- sulfamethoxazole. Adverse effects of trimethoprim-sulfamethoxazole include a decreased white blood cell count and skin eruptions. Because of the risk of life-threatening adverse reactions (eg, toxic epidermal necrolysis), trimethoprim-sulfamethoxazole should be used only as a last resort.
  Sodium sulfacetamide 10% lotion, alone or in combination with sulfur 5%, is also reported as beneficial for both rosacea and seborrheic dermatitis. The combination product is available as a facial cleanser. Sodium sulfacetamide has antibacterial properties, and sulfur is an antiseptic with keratolytic properties. They have been shown to have an anti-inflammatory benefit, but their exact mechanism of action in treating rosacea is unknown.
  Topical imidazoles (eg, ketoconazole cream) have also been suggested. These antifungal agents decrease acneiform lesions caused by gram-positive bacteria; they also have some anti-inflammatory effect. Topical retinoids can decrease acneiform lesions and reduce erythema. They can be irritating, however, and may not be tolerable.
  Some researchers have suggsted use of antiparasitic medications (eg, lindane, permeth rin) to eliminate Demodex mites. The treatment regimen is generally once daily for two to five days, and sodium sulfacetamide/sulfur may be added as an adjunctive therapy. However, rigorous data on the use of topical benzoyl peroxide, tretinoin, and clindamycin in rosacea treatment is limited.
  
  

• Tetracyclines:
  Patients with moderate to severe symptoms are traditionally treated with a course of oral antibiotics concurrent with topical therapy. Once symptoms are under control, topical therapy is continued indefinitely to maintain remission. Members of the tetracycline family of antibiotics (eg, tetracycline, doxycycline, minocycline) have historically been administered as the standard oral therapy for rosacea. Traditionally, these medications were administered at high doses to gain initial control of symptoms, and then at lower doses indefinitely for maintenance of remission. Clinicians noted that the lower doses were efficacious at maintaining control of symptoms, an effect believed to be due to the anti-inflammatory, rather than the antimicrobial, properties of the drugs. Tetracyclins decrease the number of acneiform lesions and reduces erythema and flushing. Tetracyclines also appear to prevent connective tissue damage, both directly and indirectly. They are potent inhibitors of the major MMPs that degrade connective tissue and modulate inflammation during an inflammatory response. In addition, they are able to regulate the expression of proinflammatory mediators, including cytokines such as IL-1 and TNF, thereby inhibiting breakdown of the extracellular matrix and further potentiation of the immune response. Tetracycline's adverse effects include gastrointestinal upset, photosensitivity, and interference with the efficacy of oral contraceptives. A small percentage of patients experience vertigo with the initial doses of the newer tetracyclines. Patients should therefore be counseled to take this medication at night until such symptoms, if they occur, subside.
  
  Long-term use of minocycline, another oral treatment option, has been reported to cause a slate-gray skin discoloration, predominantly of the lower extremities. Patients using minocycline should be seen at least two to three times per year and counseled to check their skin and gums every month for possible discoloration. If present, the discoloration will fade when the medication is withdrawn but can take months or years to resolve completely.
  
  While tetracyclines are the mainstay of oral therapies for rosacea, oral metronidazole and isotretinoin are sometimes used, although the evidence for their efficacy is limited. (As noted above, isotretinoin in particular can cause severe side effects).
  
  

• Subantimicrobial-dose (SD) Tetracyclines:
  Subantimicrobial-dose tetracyclines retain anti-inflammatory properties. While the use of oral antibiotics in the treatment of rosacea has proven effective, there is considerable concern over their long-term use, as the development of bacterial resistance has become a justifiable fear. The concurrent use of systemic and
  topical therapies with complementary mechanisms of action is one treatment strategy developed to potentially minimize the risk of creating resistant microorganisms.
  
  A more effective strategy may be the use of subantimicrobial-dose (SD) antibiotics. The anti-inflammatory properties of the tetracyclines are completely independent of their antimicrobial activity, and are maintained at subantimicrobial doses. Of the commercially available tetracyclines, doxycycline is the strongest inhibitor of collagenase activity. It is also the best tolerated in terms of long-term use, and is relatively inexpensive. SD doxycycline has been approved for use for up to 12 months in the treatment of chronic adult periodontitis, a disease resulting from the spread of the inflammatory response to gingivitis from the gums to the surrounding tissues. SD doxycycline 20 mg administered twice daily for up to 18 months does not alter or contribute to antibiotic susceptibility patterns of normal flora, and does not create cross-sectional or longitudinal differences in doxycycline-resistant bacteria. In addition, this dosing regimen achieves maximal plasma concentration levels significantly lower than the minimum inhibitory concentration (MIC) required to produce an antimicrobial effect at all timepoints. SD doxycycline 50 mg administered once daily produces plasma concentrations that exceed the MIC for approximately 2 to 3 hours. See Bikowski in Skinmed: Subantimicrobial Dose Doxycycline for Acne and Rosacea.
  
  A multicenter, double-blind, randomized, placebo-controlled study examined the use of SD doxycycline in the treatment of acne (Biwoski in Arch Dermatol: Effects of Subantimicrobial-Dose Doxycycline in the Treatment of Moderate Acne). Forty adults with moderate facial acne completed the 6-month study. The treatment group (n=21) received doxycycline hyclate 20 mg twice daily, a dose that was shown to be effective at treating periodontitis without affecting the host microflora or creating antibiotic-resistant organisms. The placebo group (n=19) was given a matching placebo pill twice daily.The primary efficacy parameters were the change from baseline in the numbers of inflammatory lesions (papules, pustules, nodules), noninflammatory lesions (open and closed comedones) and total lesions (inflammatory plus noninflammatory). The treatment group experienced a significant reduction in the number of comedones (P <.01), the number of inflammatory lesions (P =.04), and the number of total lesions (P <.01). In addition, no change in the composition of the normal skin flora was noted in either the treatment group or placebo group, and the treatment did not result in the emergence of organisms resistant to doxycycline, minocycline, tetracycline, erythromycin, clindamycin, or vancomycin. SD doxycycline was well-tolerated by patients.
  
  Recently, Phase III trials were conducted examining the use of SD doxycycline for the treatment of rosacea (see Collagenex Press Release: CollaGenex Pharmaceuticals Reports Positive Outcome of Phase 3 Clinical Study Evaluating Periostat as a Treatment for Rosacea). The 16-week, multicenter, randomized, double-blind, placebo-controlled study was completed by 108 adults with rosacea. In order to enroll in the study, patients were to have between 10 and 30 pustules or papules, and fewer than 2 nodules. Patients received either 20 mg SD doxycyline twice daily or placebo. The primary efficacy parameters were the change in total lesion count from baseline, the change in erythema score from baseline, the change in global severity score from baseline, and the percentage of patients whose global severity score reached zero. The group receiving SD doxycycline saw a significant change in lesion count from baseline, a change that was significantly better than that seen in the placebo group. Global severity scores in patients treated with SD doxycycline also revealed a significant improvement, and a large proportion of patients in the treatment group had global severity scores of 0 (clear) or 1 (mild) at the end of the study. SD doxycycline was well-tolerated, with patients in both the treatment and placebo groups experiencing similar rates of adverse events. Already proven effective for the treatment treatment of periodontitis and with encouraging results in acne, SD doxycycline may yet emerge as a safe, targeted therapy for rosacea, although more high-quality controlled studies are needed before determining the exact placement of SD doxycycline in the rosacea treatment spectrum of agents.
  
  

• Non-Approved Therapies:
  Tacrolimus, an immunomodulator which, as a topical agent, is approved for the treatment of atopic eczema, has been shown to be effective in patients with steroid-induced rosacea. Tacrolimus ointment has been applied in a concentration of 0,075% and 0,1% for rosacea. Ascomycin, another immunomodulator, has been reported to be effective in rosacea in a concentration of 1%.
  
  Infestation with demodex folliculorum mites has been discussed as an etiologic factor in some cases of rosacea or rosacea-like skin lesions. Thus, antiinfectives such as permethrin 5% cream, lindane and benzoyl benzoat have been recommended for stage II-rosacea.
  
  Dapsone, an antibiotic and antiparasitic agent, has been reported effective in a systemic dosage of 100 mg daily in rosacea fulminans.
  
  Clonidine, a centrally active antihypertensive agent, has been shown to reduce facial flushing. However small doses, which do not cause a decrease in blood pressure, are said to have little or no effect.
  
  Propranolol, a non-cardioselective beta-blocker has also been reported to be helpful in reducing flushing. A dosage of 40 mg twice daily has been recommended for this indication.
  
  See DermIS: Rosacea Treatment - Non-approved Therapies.
  
  

• Surgical:
  Rhinophyma is best treated with various surgical and dermatologic modalities, including laser ablation, dermabrasion, planing with a scalpel or razor, electrocautery, and tissue ablation with a CO2 laser. Telangiectasias can be successfully removed by vascular laser or electrocautery.
  
  

• Summary:
  Rosacea is a common, chronic condition affecting the centrofacial skin. Its prominent facial symptoms can have a significant social and psychological impact on patients. While the exact cause of rosacea is yet unknown, treatment modalities that have an anti-inflammatory mechanism of action have proven efficacious. Tetracycline antibiotics, commonly prescribed for this condition, have anti-inflammatory, as well as antimicrobial, properties. Their anti-inflammatory properties are maintained at subantimicrobial doses, allowing their long-term use without fear of creating antibiotic-resistant organisms. SD doxycycline has been used to successfully
  treat periodontitis and moderate acne, and may be of significant use in the treatment of rosacea.