Rosacea PDF

Rosacea Jason K. Rivers, MD, FRCPC, FAAD Date of Revision: July 17, 2024 Peer Review Date: June 30, 2023 Introduction Rosacea is a chronic, inflammatory, cutaneous vascular disorder commonly diagnosed by dermatologists. Global prevalence of rosacea is estimated to be 5%, predominantly affecting tho...

Rosacea Jason K. Rivers, MD, FRCPC, FAAD Date of Revision: July 17, 2024 Peer Review Date: June 30, 2023 Introduction Rosacea is a chronic, inflammatory, cutaneous vascular disorder commonly diagnosed by dermatologists. Global prevalence of rosacea is estimated to be 5%, predominantly affecting those 45–60 years of age, with no difference in prevalence among the sexes.​ Rosacea is often misdiagnosed as adult acne. It is usually initially characterized by recurrent transient erythema, flushing and telangiectasia of the central face, which is visible in lightly pigmented skin but may not be visible in darkly pigmented skin or instead appear dusky to dark brown, grey, or light to dark purple. Progression to a more inflammatory condition involving persistent erythema and the presence of papules and pustules is common but not inevitable. Irreversible phymatous changes develop in a small proportion of patients, more commonly in males. (Note: Studies presenting this finding classify patients as male or female; CPhA is aware these terms may not reflect the identity of the individual patient presenting and are not inclusive of all patients.)​ More than 50% of patients with rosacea have eye involvement characterized by irritation, dryness, blepharitis and conjunctivitis, which can be present before skin symptoms are apparent.​ See Table 1 for an approach to the diagnosis and classification of rosacea. See Table 2 for images of the various phenotypes on various skin colours. Table 1: Phenotype Approach to the Diagnosis and Classification of Rosacea​ Phenotype Description Diagnostic Features Persistent centrofacial erythema in a characteristic pattern (forehead, nose, cheeks, chin) that (presence of 1 or more is may periodically intensify due to triggers (see Table 3) diagnostic) Erythema presents as redness in lightly pigmented skin but may not be easily visualized in darkly pigmented skin or appear dusky to dark brown, grey, or light to dark purple Phymatous changes (including widening/spreading follicles, skin thickening or fibrosis, glandular hyperplasia, bulbous appearance of the nose) Major Features Flushing—may not be easy to visualize in darkly pigmented skin but the patient may note a (presence of 2 or more may be warm sensation considered diagnostic) Papules and pustules Telangiectasia (small, red, spidery clusters of dilated capillaries that may be hard to see in darkly pigmented skin) Ocular manifestations strongly suggestive of rosacea: lid margin telangiectasia, interpalpebral conjunctival injection, spade-shaped infiltrates in the cornea, scleritis and sclerokeratitis Secondary/Minor Features Burning sensation (these features may appear Stinging sensation along with 1 or more diagnostic Edema or major features) Dryness Ocular manifestations not specific to rosacea: “honey crust” and collarette of scale accumulation at the base of the lashes, irregularity of the lid margin, rapid tear breakup time Reprinted with permission from Elsevier. Gallo RL, Granstein RD, Kang S et al. Standard classification and pathophysiology of rosacea: the 2017 update by the National Rosacea Society Expert Committee J Am Acad Dermatol 2018;78(1):148-55. Table 2: Photos of Rosacea Phenotypes Photo 1: Papulopustular rosacea Photo 2: Papular rosacea DermNet NZ National Rosacea Society Photo 3: Papular rosacea Photo 4: Erythematotelangiectatic rosacea DermNet NZ DermNet NZ Photo 5: Erythematotelangiectatic rosacea Photo 6: Papulopustular and ocular rosacea  Courtesy of Dr. Jason Rivers DermNet NZ Photo 7: Papulopustular and ocular rosacea Photo 8: Rhinophyma DermNet NZ DermNet NZ The pathophysiology of rosacea has not been clearly elucidated. It is thought to involve genetics, environment, neurovascular dysregulation and increased activation of the immune system.​ The molecular mechanism by which triggers such as Demodex folliculorum infestation and UV exposure may activate some of these pathways is unclear. There is increasing evidence that the presence of rosacea may be a predisposing factor or a marker for systemic disease, as associations with conditions such as migraine, inflammatory bowel disease, depression and cardiovascular disease, among others, have been reported.​ ​ Table 3: Triggers That Can Worsen Rosacea​ ​  Sunlight Medications Heat vasodilators e.g., Wind calcium channel blockers Exercise niacin (nicotinic acid) Hot beverages nitrates Spicy foods, vinegar phosphodiesterase-5 inhibitors (e.g., Alcohol sildenafil) Use of astringents (alcohol- or acetone-based products) topical corticosteroids (unless low potency or for brief periods only) Emotional stress medications causing dry eyes (e.g., anticholinergics) could aggravate ocular rosacea Goals of Therapy Increase awareness of triggers for cutaneous rosacea outbreaks and how to avoid them Increase patient’s awareness of signs and symptoms of ocular rosacea and how to manage them Reduce erythema, flushing, telangiectasia and inflammatory lesions (papules and pustules) Improve appearance of the skin when it is affecting the patient’s quality of life Reduce the number and severity of recurrences of cutaneous and ocular rosacea Investigations Diagnosis: family history onset usually in late 20s to 40s, i.e., later than usual onset of acne vulgaris history of recurrent bouts of facial papules and pustules, prolonged flushing and/or persistent colour change (dusky to dark brown, grey, or light to dark purple in darkly pigmented skin or pink/red in lightly pigmented skin) history of eye irritation, grittiness, blepharitis, dry eyes or recurrent styes flare-up of rosacea following sun exposure Physical examination: presence of persistent erythema of the central face that appears as redness in lightly pigmented skin but may be challenging to detect in darkly pigmented skin or appear dusky to dark brown, grey, or light to dark purple presence of papules or pustules, absence of comedones presence of telangiectasia (see Table 1) evidence of conjunctivitis, blepharitis, stye formation or complaint of dry eyes phymatous changes (not common) (see Table 1) Differential diagnosis: acne vulgaris, perioral dermatitis, seborrheic dermatitis, photosensitivity reactions, discoid lupus erythematosus, “steroid rosacea” (caused by application of topical corticosteroids to the face) Therapeutic Choices Nonpharmacologic Choices Information about the nonpharmacologic management of the various phenotypes of rosacea can be found in Table 4 and Figure 1. Pharmacologic Choices Information about the pharmacologic management of the various phenotypes of rosacea can be found in Table 4 and Figure 1. Treatment for each phenotype/feature may overlap with others and often involves a combination of therapies. Table 4: Treatment of Rosacea by Phenotype Phenotype/Feature Treatment Options Comments All patients/all phenotypes Avoid triggers that can worsen See Table 3. rosacea Regular use of a broad-spectrum, See Sunburn. The sun and other climatic influences, such high SPF (≥30) sunscreen as intense cold or harsh winds, may cause an exacerbation. General skin care for sensitive skin Includes the use of surfactants, i.e., nonsoap cleansers and fragrance-free moisturizers, and the avoidance of astringents.​ Camouflage makeup Patients with darkly pigmented skin may require professional cosmetic support to find the correct tone of tinted foundation for their specific skin colour. Green-tinted or yellow-tinted foundation is effective for hiding the redness of rosacea in lightly pigmented skin.​ Flushing Possibly topical brimonidine There is a lack of quality evidence for treatment of flushing: topical brimonidine is a possible option based on case reports and consensus statements only​ (see Persistent erythema below). Persistent erythema (with Topical brimonidine Topical brimonidine gel appears to be safe and effective​ periodic intensification with for treatment of the general facial redness associated triggers) with rosacea, presumably acting by constricting dilated blood vessels (it has no effect on telangiectatic blood vessels). It can be considered in those for whom erythema is a cosmetic concern. Onset of effect occurs 30 min after application and can last up to 12 h. Rebound erythema is a significant concern for some patients. Vascular laser systems Although evidence is limited and of low quality,​ ​ ​ ​ Broadband light and intense pulsed these methods are commonly used in practice and can light devices significantly improve persistent erythema after 1–3 treatments. The energy from these devices is selectively targeted at the contents of the blood vessels that are causing the redness, while minimizing damage to adjacent tissues. Use caution in patients with darkly pigmented skin as hyper- or hypopigmentation may develop if these devices are used at high fluences. Inflammatory Topical metronidazole Considered first-line agent.​​​​​ Mechanism of papules/pustules action is thought to be by an anti-inflammatory effect achieved by reducing reactive oxygen species. In practice, treatment is often started with metronidazole, as it is generally well tolerated. Treatment duration will depend upon the severity of symptoms, but improvement can generally be expected in 4–8 wk. Counsel patients that topical treatment may need to be continued indefinitely; relapse is to be expected upon discontinuation. If response to metronidazole is inadequate, try an alternative topical therapy or combination with another topical therapy. Add oral antibiotics if the response to topical agents alone is inadequate.​ Topical azelaic acid Considered first-line agent.​ ​ ​ ​ ​ Mechanism of action is thought to be by an anti-inflammatory effect achieved by reducing reactive oxygen species. Using moisturizer before or after azelaic acid may lessen any associated irritation. Also see metronidazole. Topical ivermectin Considered first-line agent.​ ​ ​ ​ ​ Oral ivermectin is a known acaricide, and it is therefore postulated that topical ivermectin improves rosacea by decreasing the Phenotype/Feature Treatment Options Comments number of Demodex mites present. The exact mechanism of action in rosacea has not been elucidated but is thought to involve an immunomodulatory effect. Also see metronidazole. Oral doxycycline Oral antibiotics have been shown to be effective and may Oral tetracycline be added to topicals when the response is inadequate or the condition is moderate to severe.​ ​ ​ ​ ​ The rationale for the use of antibiotics resides with their anti- inflammatory benefits, rather than their antimicrobial properties. They are generally used for up to 3 months and then reassessed. Other oral antibiotics (including minocycline, trimethoprim, erythromycin and metronidazole) do not have high-quality evidence supporting their use in rosacea and should be considered only when doxycycline or tetracycline cannot be used. Minocycline has been associated with rare but serious side effects, resulting in many experts using doxycycline or tetracycline as first-line treatments and reserving minocycline for second-line use when needed.​ Low- dose (subantimicrobial) doxycycline is available and appears to have similar efficacy but less gastrointestinal effects;​ ​ it theoretically has less risk of antimicrobial resistance than standard-dose doxycycline.​ It may be an option for patients in whom gastrointestinal effects of standard-dose doxycycline are of concern. Low-dose isotretinoin An effective and useful option for the management of patients with treatment-resistant papules and pustules.​​ ​ ​ ​ Telangiectasia Vascular laser systems Although evidence is limited and of low quality,​​​ Broadband light and intense pulsed these methods are commonly used in practice and can light devices significantly improve telangiectasia after 1–3 treatments. The energy from these devices is selectively targeted at the contents of the blood vessels that are visible on the skin, while minimizing damage to adjacent tissues. Vascular lasers also target melanin to some degree and therefore caution must be exercised when using these devices in darkly pigmented skin. Phyma Oral doxycycline May be considered in the treatment of clinically inflamed Oral tetracycline phyma based on anecdotal evidence.​ ​ ​ ​ Topical retinoids Despite a lack of evidence, some experts support the use Oral low-dose isotretinoin of topical retinoids or oral low-dose isotretinoin to reduce the progression of mild to moderate phyma, as few noninvasive treatment options are available.​ ​ Laser resurfacing In clinically noninflamed phyma, treatment with physical Electrosurgery modalities is a worthwhile option to improve the appearance of phymatous features. Risks such as postprocedural swelling and redness, possibly persisting weeks or longer, are offset by the potential for excellent outcomes.​ ​ ​ ​ There is an increased risk of post- procedure dyschromia and scarring when these procedures are used in darkly pigmented skin. Ocular Eyelid hygiene Mild ocular involvement can be managed with good eyelid Artificial tears hygiene and use of artificial tears (see Figure 1). Eyelid hygiene generally includes gentle washing of the lid/lashes twice daily with warm water, baby shampoo​[a] or a commercial lid-care product. Diluted baby shampoo was found to decrease bacterial load on the eyelid skin by >96% in 1 study.​  Phenotype/Feature Treatment Options Comments A systematic review​ found there may be a role for long- chain omega-3 fatty acids supplementation in the management of dry eye disease (including ocular rosacea), although the evidence is inconsistent. Available evidence is limited and uncertain about the use of tea tree oil for Demodex blepharitis.​ Oral doxycycline There is little scientific evidence available to guide Oral tetracycline treatment of moderate to severe ocular rosacea. A systematic review was not able to make any recommendations about the use of oral antibiotics in the treatment of chronic blepharitis due to various etiologies including rosacea;​ however, some experts recommend the addition of oral antibiotics ​ ​ (see Table 6); they are reported to be effective anecdotally. When symptoms subside, discontinue oral antibiotics and maintain lid hygiene and use of artificial tears. Topical cyclosporine eye drops Patients with persistent or severe ocular involvement should be referred to an ophthalmologist. Topical cyclosporine eye drops can then be considered.​ ​ ​ [a] There is no consensus on how to cleanse the eyelashes/lid margins with baby shampoo. Some sources recommend creating a lather similar to what would be used to wash hands with liquid soap; others recommend use of undiluted baby shampoo. In both cases, it is recommended to apply the shampoo to a wet washcloth or cotton swab and gently scrub the lid margins/eyelashes and then rinse with warm water. Choices during Pregnancy and Breastfeeding Prepregnancy Considerations Oral isotretinoin must be stopped at least 1 month prior to becoming pregnant.​ Small amounts of isotretinoin are found in semen; however, safety reporting has not indicated any risk of harm to a fetus due to paternal exposure to isotretinoin, and special precautions are not required. Patients who are still concerned can use condoms or postpone conception until their treatment course is completed.​ Tetracyclines are cleared from the body within 1 week of discontinuation. Management of Rosacea during Pregnancy Topical therapy for rosacea is favoured. Topical azelaic acid is minimally absorbed​ and considered safe for use in pregnancy.​ ​ Metronidazole has demonstrated mutagenic and carcinogenic potential following systemic use in animal studies;​ however, studies in humans have not confirmed this risk.​ Minimal absorption occurs with topical metronidazole and it is considered safe for use in pregnancy.​ ​ There are no human data on the safety of topical brimonidine during pregnancy. One pharmacokinetic analysis indicated that systemic levels are lower with cutaneous use than with use of the ophthalmic product,​ for which there are a few case reports showing no harm to infants exposed during pregnancy.​ ​ Animal studies with oral brimonidine have not shown teratogenicity or developmental harm.​ Safety of topical ivermectin during pregnancy has not been established. Systemic absorption of topical ivermectin appears to be much lower than with oral ivermectin;​ however, safety of oral ivermectin in pregnancy has not been established.​ Tetracycline, doxycycline and minocycline are considered contraindicated as second- and third-trimester exposure can cause dental staining and enamel hypoplasia in the baby.​ ​ ​ Inadvertent exposure during the first few weeks of pregnancy is unlikely to cause harm.​ Tetracyclines can also temporarily inhibit fetal bone development, but the effect is rapidly reversible on discontinuation of the drug and no permanent effects have been observed.​ ​ Oral isotretinoin is teratogenic. Pregnancy must be avoided 1 month before, during and 1 month after therapy. Patients with child-bearing potential taking isotretinoin must adhere to the manufacturer’s pregnancy prevention program, and close supervision by the treating physician is necessary.​ Management of Rosacea during Breastfeeding Azelaic acid and metronidazole are both considered safe to use while breastfeeding due to limited systemic absorption and/or low transfer into breast milk.​ ​ ​ ​ Care should be taken to avoid direct contact of the infant’s skin with the treated areas. There are no human data on the safety of topical brimonidine during breastfeeding. One pharmacokinetic analysis indicated that systemic levels are lower with cutaneous use than with use of the ophthalmic product,​ for which there are a few case reports showing no harm to nursing infants during maternal use.​ ​ Safety of topical ivermectin during breastfeeding has not been studied. Limited data show low levels of ivermectin are transferred into breast milk after oral administration.​​ Topical use of ivermectin should theoretically result in even lower levels in breast milk due to reduced systemic absorption and would not be expected to cause any adverse effects in breastfed infants.​ Tetracycline, doxycycline and minocycline are transferred into breast milk in low concentrations. Tooth discoloration and impaired bone growth could theoretically occur in breastfed infants of patients being treated with these agents. Studies have shown this to be a remote risk, as serum levels in exposed infants were found to be undetectable, and short-term use of tetracycline, doxycycline or minocycline is considered compatible with breastfeeding.​ ​ However, as a theoretical precaution, prolonged or repeated courses (as may be the case in the treatment of rosacea) should be avoided while breastfeeding.​ The safety of oral isotretinoin during breastfeeding has not been documented and it is not recommended.​ A discussion of general principles on the use of medications in these special populations can be found in Drugs Use during Pregnancy and Drug Use during Breastfeeding. Other specialized reference sources are also provided in these appendices. Therapeutic Tips Rosacea may be underdiagnosed in patients with darkly pigmented skin due to challenges in discerning erythema and telangiectasia. This can lead to delayed treatment and increased likelihood of progressive disease.​ Sun protection is very important in the management of rosacea. Some medications may trigger or exacerbate rosacea (see Table 3). Green-tinted or yellow-tinted foundation is effective for hiding the redness of rosacea in lightly pigmented skin. Patients with darkly pigmented skin may require professional cosmetic support to find the correct tone of tinted foundation for their specific skin colour.​ Avoid topical corticosteroids; they can precipitate or worsen rosacea by adding to the dermal dystrophy that characterizes the disorder. When evaluating patients with cutaneous rosacea, inquire about ocular symptoms and examine the eyelids. Counsel patients that following treatment for erythema (particularly with brimonidine), telangiectases may appear to be more pronounced because the redness surrounding them has been reduced (posterythema-revealed telangiectasia). This prevents worries that the therapy “produced” or worsened the telangiectases. Treatment with vascular laser systems can be highly effective for telangiectasia. These procedures should be performed by skilled practitioners, particularly when treating patients with darkly pigmented skin due to the increased risk of dyschromia. Algorithms Figure 1: Treatment of Rosacea  [a] Based on case reports and consensus statements only.​ [b] There is no consensus on how to cleanse the eyelashes/lid margins with baby shampoo. Some sources recommend creating a lather similar to what would be used to wash hands with liquid soap; others recommend use of undiluted baby shampoo. In both cases, it is recommended to apply the shampoo to a wet washcloth or cotton swab and gently scrub the lid margins/eyelashes and then rinse with warm water. Abbreviations IPL = intense pulsed light Drug Tables Table 5: Topical Treatment of Rosacea Drug/​Cost[a] Dosage Adverse Effects Comments Drug Class: Acaricides ivermectin 1% cream applied once daily Dry skin, pruritus, skin-burning Beneficial effects may continue Rosiver sensation. after treatment cessation. $225 Drug Class: Alpha2-adrenergic Agonists brimonidine 0.33% gel applied once daily Erythema, flushing, skin-burning May start to reduce redness tartrate Apply small, pea-sized amount to sensation, contact dermatitis, within 30 min with peak effect at Onreltea each of the 5 areas of the face (i.e., headache. 3 h. forehead, chin, nose, each cheek) Cardiovascular effects may occur due Wash hands immediately after $140 applying. and avoid the eyes and eyelids, lips, to systemic absorption if applied to mouth, and inside of the nose damaged skin or accidentally Rebound redness/flushing can ingested orally. Keep out of reach of occur on withdrawal. children. Drug Class: Dicarboxylic Acids azelaic acid 15% gel applied BID Initial mild, transient burning, tingling Can be used for initial therapy or Finacea or stinging; pruritus; scaling; xerosis; for long-term maintenance. inflammation; contact dermatitis. If discontinued, relapse can occur. $45  Drug/​Cost[a] Dosage Adverse Effects Comments Drug Class: Nitroimidazoles metronidazole 0.75% gel or cream, or 1% cream or Local irritation. May need up to 12 wk of therapy 0.75%, 1% gel applied as thin film daily or BID to show pronounced MetroGel, × 9 wk, then as needed improvement. Can be used in Noritate combination with oral tetracyclines. $40 There does not appear to be any significant difference in efficacy among varying strengths and vehicles.​ If discontinued, relapse can occur. [a] Cost of smallest available pack size, unless otherwise specified; includes drug cost only. Table 6: Systemic Treatment of Rosacea Drug/​Cost[a] Dosage Adverse Effects Drug Interactions Comments Drug Class: Retinoids isotretinoin 0.2–0.3 mg/kg/day Teratogenicity (major No clinically significant For recalcitrant cases. Absorica LD, × 4–5 months concern). interaction reported with oral Provides worthwhile benefit, Accutane, Cheilitis, dry skin, contraceptives; however, but not consistently. Clarus, mucocutaneous effects, manufacturer states that Uncertain if permanent Epuris myalgia, possible microdosed progesterone remission can be induced. psychiatric effects. (minipill) is not suitable for Requires at least 2 types of $60–80​[b] patients taking isotretinoin. contraception when used in Tetracyclines: rare cases of patients with childbearing benign intracranial potential. hemorrhage (pseudotumor cerebri). Drug Class: Tetracyclines doxycycline 100 mg daily × 12 wk GI effects, yeast Serum concentrations of No food restriction required. generics overgrowth, doxycycline may be reduced Useful for improving ocular photosensitivity. Has by carbamazepine, chronic rosacea. Recurrences of