Rosacea

Practice Essentials

Rosacea is a common condition characterized by symptoms of facial flushing and a spectrum of clinical signs, including erythema, telangiectasia, coarseness of skin, and an inflammatory papulopustular eruption resembling acne.^{[1, 2]} See the images below.

View Image

Mild papules and erythema. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/imagedetail/2367).

View Image

Moderate papules and early pustules. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/imagedetail/2369).

View Image

Severe erythema, papules, and pustules. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/imagedetail/2371).

Classification and diagnosis

Based on specific clinical signs and symptoms, an expert committee assembled by the National Rosacea Society explicitly defined and classified rosacea into the following subtypes:

• Erythematotelangiectatic type
• Papulopustular
• Phymatous
• Ocular

Although didactically successful, the subtype designations were widely used individually and construed as distinct disorders, ignoring the frequent simultaneous occurrence of more than one subtype and potential progression of one subtype to another.

In 2016, the global rosacea consensus panel recommended a new classification: at least one diagnostic or two major phenotypes are required for the diagnosis of rosacea.^[3]

Diagnostic phenotypes

A diagnosis of rosacea may be considered in the presence of one of the following diagnostic cutaneous signs:

• Fixed centrofacial erythema in a characteristic pattern that may periodically intensify
• Phymatous changes: Patulous follicles, skin thickening or fibrosis, glandular hyperplasia, and bulbous appearance of the nose (rhinophyma is the most common form)

Major phenotypes

Without a diagnostic phenotype, the presence of two or more of the following major features may be considered diagnostic:

• Papules and pustules
• Flushing: Frequent and typically prolonged
• Telangiectasia: Predominantly centrofacial in phenotypes I-IV, rarely seen in darker phenotypes
• Ocular manifestations

Secondary phenotypes

The following secondary signs and symptoms may appear with one or more diagnostic or major phenotypes:

• Burning and stinging
• Edema: Facial edema
• Dry appearance: Central facial skin may be rough and scaly

Ocular rosacea

Major features of ocular rosacea are as follows:

• Lid margin telangiectasia
• Interpalpebral conjunctival injection
• Spade-shaped infiltrates in the cornea
• Scleritis and sclerokeratitis

Secondary features of ocular rosacea are as follows:

• "Honey crust" and collarette accumulation at the base of the lashes
• Irregularity of the lid margin
• Evaporative tear dysfunction (rapid tear breakup time)

Although ocular manifestations may precede the cutaneous signs by years, in many cases they develop concurrently with dermatologic manifestations.

The diagnosis of rosacea is made clinically, based on the 2016 global rosacea consensus that one diagnostic or two major phenotypes are required for the diagnosis of rosacea. A skin biopsy is sometimes performed to exclude other cutaneous diseases, such as lupus or sarcoidosis.

See Clinical Presentation for more detail.

Histological findings

Histologic findings include the following:

• Nonpustular lesions show a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate, accompanied by occasional multinucleated cells, plasma cells, neutrophils, and eosinophils
• Papulopustular lesions demonstrate more pronounced granulomatous inflammation and sometimes perifollicular abscesses
• Demodex folliculorum may be abundant in nearby follicles

See Workup for more detail.

Management

Laser treatment

Vascular lasers, the mainstay of rosacea therapy, use wavelengths that allow selective absorption by oxyhemoglobin, leading to vessel reduction and causing minimal scarring or damage to surrounding tissue.

Surgery

Permanent telangiectasia may be treated by electrosurgery or the 585-nm pulsed dye laser. However, facial erythema is not improved, and new telangiectasias develop with the passage of time.

Cosmetic improvement of rhinophyma may be produced by mechanical dermabrasion, carbon dioxide laser peel, and surgical shave techniques.

Deterrence

Before the initiation of therapy, the triggering factors that exacerbate the patient's rosacea should be identified and avoided if possible. Common triggering factors include the following^{[4, 5]} :

• Hot or cold temperatures
• Wind
• Hot drinks
• Caffeine
• Exercise
• Spicy food
• Alcohol
• Emotions
• Topical products that irritate the skin and decrease the barrier
• Medications that cause flushing

In addition, the use of daily broad-spectrum sunscreen is recommended for all patients with rosacea.^[6]

See Treatment and Medication for more detail.

• References

Background

Rosacea is a common condition characterized by symptoms of facial flushing and a spectrum of clinical signs, including erythema, telangiectasia, coarseness of skin, and an inflammatory papulopustular eruption resembling acne.^{[1, 2]}

An expert committee assembled by the National Rosacea Society explicitly defined and classified rosacea into four different subtypes (erythematotelangiectatic type, papulopustular, phymatous, and ocular) based on specific clinical signs and symptoms. Although didactically successful, the subtype designations were widely used individually and construed as distinct disorders, ignoring the frequent simultaneous occurrence of more than one subtype and potential progression of one subtype to another. In 2016, the global rosacea consensus panel recommended a new classification: at least one diagnostic or two major phenotypes are required for the diagnosis of rosacea.^[3] Currently, the therapeutics of rosacea empirically target the signs and symptoms of the disease because investigators do not understand the details of its pathophysiology. The classification systems aide clinicians in treatment by highlighting the preponderance of one or more of the clustering signs of presentation and, thus, help to specify which therapeutic approach to initiate.

The diagnosis of rosacea is made clinically, based on the 2016 global rosacea consensus that one diagnostic or two major phenotypes are required for the diagnosis of rosacea. Skin biopsy may be necessary to exclude other disease states that mimic the clinical presentation of rosacea. For example, the clinician must exclude polycythemia vera, connective-tissue diseases (eg, lupus erythematous, dermatomyositis, mixed connective-tissue disease), photosensitivity, carcinoid syndrome, mastocytosis, long-term application of topical steroids, contact dermatitis, and photosensitivity before making the diagnosis of rosacea.

Rosacea is defined by persistent erythema of the central portion of the face lasting for at least 3 months. Supporting criteria include flushing, papules, pustules, and telangiectasias on the convex surfaces. Secondary characteristics are burning and stinging, edema, plaques, a dry appearance, ocular manifestations, and phymatous changes. The prevalence of these findings designates the subclassification of the presentation and, additionally, the therapeutic options.^{[7, 8, 9]}

Erythematotelangiectatic type

Central facial flushing, often accompanied by burning or stinging, is the predominant sign in erythematotelangiectatic rosacea (ETR). The redness usually spares the periocular skin. These patients typically have skin with a fine texture that lacks a sebaceous quality characteristic of other subtypes. The erythematous areas of the face at times appear rough with scale likely due to chronic, low-grade dermatitis. Frequent triggers to flushing include acutely felt emotional stress, hot drinks, alcohol, spicy foods, exercise, cold or hot weather, and hot baths and showers. These patients also report that the burning or stinging is exacerbated when topical agents are applied.

Papulopustular rosacea

Papulopustular rosacea (PPR) is the classic presentation of rosacea. Patients are typically women of middle age who predominately present with a red central portion of their face that contains small erythematous papules surmounted by pinpoint pustules. One may elicit a history of flushing. Telangiectasias are likely present but may be difficult to distinguish from the erythematous background in which they exist.

Phymatous rosacea

Phymatous rosacea is defined as marked skin thickenings and irregular surface nodularities of the nose, chin, forehead, one or both ears, and/or the eyelids. Four distinct histologic variants can occur with rhinophyma (associated changes of the nose) that include glandular, fibrous, fibroangiomatous, and actinic. The mainstays of treatment are isotretinoin topical application and surgical correction. This varies from other rosacea subtypes.

Ocular rosacea

Ocular manifestations may precede the cutaneous signs by years. Yet, frequently they develop concurrently with dermatologic manifestations. The ocular manifestations include blepharitis, conjunctivitis, inflammation of the lids and meibomian glands, interpalpebral conjunctival hyperemia, and conjunctival telangiectasias. Patients may describe eye stinging or burning, dryness, irritation with light, or foreign body sensation. Ocular rosacea, similar to phymatous rosacea, has a distinct therapeutic management. Therefore, dermatologists must ask their patients specifically about ocular symptoms and perform a thorough physical examination to rule out this type of rosacea.

• References

Pathophysiology

The etiology of rosacea is unknown. However, several factors, such as vasculature, climatic exposures, dermal matrix degeneration, chemicals and ingested agents, pilosebaceous unit abnormalities, microbial organisms, ferritin expression, reactive oxygen species (ROS), increased neoangiogenesis, and dysfunction of antimicrobial peptides (AMPs), likely play a role in its development.^[10] Furthermore, the distinct subtype of rosacea is likely determined by a patient's unique sensitivity to these triggers.

Vasculature

Increased blood flow to the blood vessels of the face and increased numbers of blood vessels that are closer to the surface of the face are thought to be responsible for the redness and flushing associated with rosacea. Furthermore, vasodilatation, the normal response to hyperthermia, is thought to be more pronounced or exaggerated in those individuals with rosacea.

Climatic exposures

Some evidence suggests that harsh climatic exposures damage cutaneous blood vessels and dermal connective tissue. This also includes exposure to solar irradiation, which may explain why rosacea predominately affects the facial convexities and has a tendency to flare in the spring. However, other studies suggest the contrary, in that most patients' symptoms do not worsen in the sunlight and do not flare with an acute exposure to ultraviolet (UV) light.

Dermal matrix degeneration

Rosacea involves associated damage to the endothelium and degeneration of the dermal matrix. However, it is not known whether the initial damage is in the dermal matrix and this leads to poor tissue support of cutaneous vessels, causing pooling of serum, inflammatory mediators, and metabolic waste, or whether the initial abnormality exists in the cutaneous vasculature and this leads to leaky vessels and delayed clearance of serum proteins, inflammatory mediators, and metabolic waste, thus resulting in matrix degeneration.

Chemicals and ingested agents

Spicy foods, alcohol, and hot beverages were traditionally thought to trigger flushing in patients with rosacea. However, most evidence does not support dietary factors playing a central role in the pathogenesis. Moreover, certain medications, such as amiodarone, topical steroids, nasal steroids, and high doses of vitamins B-6 and B-12, may cause flares for patients with rosacea.

Perivascular versus perifollicular inflammation

An inflammatory infiltrate may exist in a perivascular and/or a perifollicular location; however, evidence is conflicting regarding which location predominates. To answer this question, more studies need to be designed to categorize subtypes of rosacea because the answer varies depending on the subclassification.

Microbial organisms

Demodex species (mites that normally inhabit human hair follicles) may play a role in the pathogenesis of rosacea. Some studies suggest that Demodex prefers the skin regions that are affected in rosacea, such as the nose and cheeks.^[11] Research also supports that an immune response of helper-inducer T-cell infiltrates occurs, surrounding the Demodex antigens in patients with rosacea. Yet, conflicting evidence indicates that Demodex does not induce an inflammatory response in patients with rosacea. Moreover, Demodex is found in large numbers of healthy individuals without rosacea. More studies need to be performed to determine whether Demodex truly is pathogenic.

Additionally, inconclusive evidence suggests that Helicobacter pylori is associated with the etiology of rosacea. However, many of the studies have not controlled for confounding variables that influence H pylori prevalence, such as sex, age, socioeconomic status, and medications. Furthermore, these studies were not statistically powered to account for the ubiquitous nature of H pylori infection.

Ferritin expression

Iron catalyzes the conversion of hydrogen peroxide to free radicals, which leads to tissue injury by damaging cellular membranes, proteins, and DNA. At the cellular level, iron that is not metabolized is stored as ferritin. In a 2009 study, skin biopsy specimens from patients with rosacea were immunohistochemically analyzed, and the number of ferritin-positive cells was significantly higher in affected individuals compared with control subjects. Additionally, higher ferritin positivity correlated with more advanced subtypes of rosacea. Thus, increased release of free iron from proteolysis of ferritin can result in oxidative damage to the skin, which may contribute to the pathogenesis of rosacea.^[12]

Reactive oxygen species

Early in the inflammatory process, reactive oxygen species (ROS) are released by neutrophils, which are postulated to have a central role in the inflammation associated with rosacea. Free radicals, such as superoxide anions and hydroxyl radials, in addition to other reactive molecules, such as molecular oxygen, singlet oxygen, and hydrogen peroxide, comprise many of the ROS that lead to oxidative tissue damage. Several mechanisms explain how ROS result in skin inflammation, most notably the deactivation of natural defenses caused by excessive oxidant stress from ROS; chemical and oxidative modification of proteins and lipids by ROS; alteration of the lipid balance in rosacea patients, which, in normal proportions would suppress the creation of ROS; production of cytokines and other inflammatory mediators by keratinocytes, fibroblasts, and endothelial cells damaged by ROS; and the generation of ROS by cathelicidins, which are found in greater amounts in the facial skin of affected individuals.^[13]

Neoangiogenesis and vascular endothelial growth factor (VEGF) overexpression

Studies performed using video capillaroscopy on erythematotelangiectatic rosacea lesions showed increased neoangiogenesis and blood vessel enlargement. Multiple immunohistochemistry studies showed increased VEGF expression in vascular endothelium in lesional versus nonlesional skin of rosacea patients. Cuevas et al^[14] used topical dobesilate, an inhibitor of angiogenic growth factor, for the treatment of erythematotelagiectatic rosacea and reported an improvement in erythema and telangiectasia after 2 weeks.^[10]

Antimicrobial peptides

AMPs are small molecular weight proteins that are a part of the innate immune response and have demonstrated broad-spectrum antimicrobial activity against bacteria, viruses, and fungi. They are rapidly released upon injury and/or infection of the skin, and they have been implicated in the pathogenesis of many inflammatory skin diseases. Cathelicidins and β-defensins are 2 well-known types of AMPs, of which the former has been shown to be expressed in abnormally high levels in patients with rosacea.

Specifically, the LL-37 peptide form of cathelicidin, in addition to proteolytically processed forms of LL-37, have been found in significantly different amounts in rosacea patients compared with healthy individuals. LL-37 is expressed by polymorphonuclear leukocytes and lymphocytes. LL-37 interacts with endothelial cells and stimulates angiogenesis both in vitro and in vivo. It also modulates the expression of VEGF.^[10] Injection of LL-37 and these novel peptides derived from LL-37 into mice induced inflammation, erythema, and telangiectasia; therefore, researchers hypothesized that an excess of cathelicidins coupled with abnormal processing caused disease.^[15]

• References

Etiology

A rosacealike syndrome (including perioral dermatitis) can result from the indiscriminate use of potent corticosteroids on the face. A number of aggravating factors may be recognized. Excess wind and UV light (weathering) exposure may accelerate the disease process. See Pathophysiology for more information.

• References

Epidemiology

Accurate incidence data are not available; however, rosacea is a common skin condition that disproportionately affects persons of fair-skinned European and Celtic origin. A study in Sweden revealed an incidence of 1 in 10 middle-class workers. The caseating granulomatous variant (acne agminata) may more commonly occur in people of Asian or African origin.

• References

Prognosis

A spectrum of clinical features is seen, and progression may be step-wise. The condition ranges from minor cosmetic disability to severe disfiguring disease. In most patients who receive treatment, a stable state is reached with variable residual symptomatology. The disease takes a chronic relapsing or progressive course for some patients.

• References

Patient Education

Patients should be advised to avoid known exacerbating factors, such as hot or cold temperatures, wind, hot drinks, caffeine, exercise, spicy food, alcohol, strong emotions, topical products that irritate the skin and decrease the barrier, and medications that cause flushing. Patients should be encouraged to use a noncomedogenic, high-factor sunscreen when exposed to sunlight and wind.

For patient education resources, see the Skin Conditions and Beauty Center.

• References

History

Patients are likely to have a background of facial flushing, often dating to childhood or the early teens. In adult life, flushing may be increasingly precipitated by hot drinks, heat, emotion, and other causes of rapid body temperature changes. Some patients report flushing with alcohol, which is not specific.

The symptoms are usually intermittent but can progressively lead to permanently flushed skin. The latter may be described as high color and is associated with the development of permanent telangiectasia. Additionally, a few individuals report a gritty quality of the eyes and facial edema.

• References

Physical Examination

The disease consists of a spectrum of symptoms and signs, with most patients failing to develop every stage of disease. Variable erythema and telangiectasia are seen over the cheeks and the forehead. Inflammatory papules and pustules may be predominantly observed over the nose, the forehead, and the cheeks. Extrafacial involvement uncommonly occurs over the neck and the upper part of the chest. Prominence of sebaceous glands may be noted, with the development of thickened and disfigured noses (rhinophyma) in extreme cases. Unlike acne, patients generally do not report greasiness of the skin; instead, they may experience drying and peeling. The absence of comedones is another helpful distinguishing feature. Ocular lymphedema may be prominent but is uncommon. The condition generally does not produce scarring.

Rhinophyma may occur as an isolated entity, without other symptoms or signs of rosacea. Rhinophyma can be disfiguring and therefore distressing for patients. Some authorities consider rhinophyma to represent a different disease process, although phymatous rosacea is considered one of the four subtypes of rosacea.^[16]

Lymphedema may be marked periorbitally, and, on occasion, it is the presenting symptom.

Symptoms of ocular rosacea may be accompanied by conjunctival injection, and, rarely, chalazion and episcleritis may occur.

Rosacea fulminans (pyoderma faciale) is fortunately a rare complication and is characterized by the development of nodules and abscesses with sinus tract formation accompanied by systemic signs. Patients often have low-grade fever, elevated ESR, and possibly elevated white blood cell count.

Both seborrhea and seborrheic dermatitis/blepharitis are not uncommonly observed in patients with rosacea. The reasons for these associations are not well understood.

A rare granulomatous variant of rosacea (acne agminata/lupus miliaris disseminatus faciei) can manifest with inflammatory erythematous or flesh-colored papules distributed symmetrically across the upper part of the face, particularly around the eyes and the nose. The lesions tend to be discrete, and surrounding erythema is not a marked feature but may be present. These patients often do not have a history of flushing. This pattern of rosacea is sometimes associated with scarring and may be resistant to conventional treatment.

See Practice Essentials for details on the 2016 global rosacea consensus that one diagnostic or two major phenotypes are required for the diagnosis of rosacea.

• References

Complications

Rosacea keratitis and keratoconjunctivitis sicca are recognized complications. Rosacea fulminans is a rare complication. Scarring generally does not occur.

• References

Laboratory Studies

The diagnosis is made clinically.

• References

Procedures

A skin biopsy is sometimes performed to exclude other cutaneous diseases, such as lupus or sarcoidosis.

• References

Histologic Findings

The histologic features of rosacea depend on the stage of disease. Nonpustular lesions show a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate, accompanied by occasional multinucleated cells, plasma cells, neutrophils, and eosinophils. Papulopustular lesions demonstrate more pronounced granulomatous inflammation and sometimes perifollicular abscesses. Demodex folliculorum may be abundant in nearby follicles. See the image below.

View Image

Histopathology of rosacea. Perifollicular chronic inflammation and vascular ectasia. Courtesy of Dirk Elston, MD.

• References

Medical Care

Before the initiation of therapy, the triggering factors that exacerbate the patient's rosacea should be identified and avoided if possible. These factors may be unique to each individual patient. Common triggering factors include hot or cold temperatures, wind, hot drinks, caffeine, exercise, spicy food, alcohol, emotions, topical products that irritate the skin and decrease the barrier, or medications that cause flushing.^{[4, 5]} Some patients find that regular facial massage reduces lymphedema. Rosacea fulminans is treated with moderately high doses of prednisolone (30-60 mg/d) followed by oral isotretinoin.

For more information on agents used to treat rosacea, see Medication.

Sunscreen

The use of daily broad-spectrum sunscreen is recommended for all patients with rosacea.^[6] A sunscreen that protects against both UV-A and UV-B light should be selected. Physical blockers such as titanium dioxide and zinc oxide are well tolerated. Additionally, the sunscreen should contain protective silicones such as dimethicone or cyclomethicone. Green-tinted sunscreens can provide coverage of the erythema.

The patient is encouraged to avoid astringents, toners, menthols, camphor, waterproof cosmetics requiring solvents for removal, or products containing sodium lauryl sulfate.

Laser

Nonablative laser is effective against rosacea by remodeling of the dermal connective tissue and improving the epidermal barrier.^[17] The major disadvantage of this therapy is its cost because it is not covered by insurance. It requires 1-3 treatments 4-8 weeks apart to achieve the best results.

Vascular lasers are the mainstay of rosacea therapy. These include pulsed dye laser (585 or 595 nm), the potassium-titanyl-phosphate laser (532 nm), and the diode-pumped frequency-doubled laser (532 nm). These wavelengths allow selective absorption by oxyhemoglobin, leading to vessel reduction with minimal damage to surrounding tissue or scarring. To be effective against deeper facial vessels, longer wavelengths of lasers are required, including the diode laser (810 nm), the long-pulsed Alexandrite laser (755 nm), and the long-pulsed Nd:YAG laser (1064 nm).

Intense pulsed-light therapy is a multichromatic laser with different targets, including melanin and hemoglobin. Therefore, it is also useful for facial rejuvenation, affecting vascular lesions, pigmented lesions, and hair.

• References

Surgical Care

Permanent telangiectasia may be treated by electrosurgery or the 585-nm pulsed dye laser. However, facial erythema is not improved, and new telangiectasias develop with the passage of time. Cosmetic improvement of rhinophyma may be produced by mechanical dermabrasion, carbon dioxide laser peel, and surgical shave techniques.

• References

Diet

Dietary modulation should aim at avoidance of triggers.

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Topical metronidazole is commonly used as a first-line agent. Topical azelaic acid, sulfacetamide products, and topical acne medications are also commonly used. Topical and oral antibiotics are also very effective, and for oral rosacea, they are usually considered as a first-line therapy.  In many cases, oral and topical antibiotics are used in combination; the oral treatment may be eventually withdrawn and the topical treatment is used alone as maintenance therapy. However, in patients with ocular involvement, oral therapy needs to be maintained. In patients who require a systemic antibiotic, evidence suggests that the newer regimen of 20-50 mg q12h of doxycycline is as effective as the older regimen of 100 mg of doxycycline^[18] For many patients, this could represent a significant cost reduction.

Retinoids are advocated by some authorities.^{[19, 20, 21]}

A topical form of the alpha-2 agonist brimonidine was approved by the FDA in August 2013 for treatment of erythema associated with rosacea. Approval was based on data collected from more than 550 patients enrolled in two phase 3 clinical studies of one-month duration. The results from both studies showed that adults who used brimonidine topical gel demonstrated significantly greater improvement in the facial redness of rosacea than those who used vehicle gel alone.^[22] In addition, a long-term study in 276 subjects who used brimonidine topical gel for up to 12-months was also conducted.

Another topical alpha agonist, oxymetazoline, was approved in 2017 for persistent facial erythema associated with rosacea in adults. Approval was based on two randomized clinical trials (n=885) that compared the active drug with the cream vehicle. Once-daily topical application of oxymetazoline cream 1% was proven to reduce persistent facial erythema associated with rosacea through 12 hours. The primary efficacy endpoint was at day 29 and defined as the proportion of patients with at least a 2-grade reduction in erythema (improvement) from baseline on both the clinician erythema assessment (CEA) and subject self-assessment (SSA) (composite success).^[23]

Topical ivermectin (Soolantra) has been approved by the FDA for treatment of the inflammatory lesions of rosacea. Stein et al reported in 2014 that ivermectin 1% cream was safe and effective for the treatment of inflammatory lesions from papulopustular rosacea, based on 2 randomized, controlled, double-blind, identically designed studies of ivermectin 1% cream versus vehicle applied once daily for 12 weeks.^[24] Several case reports have described successful rosacea treatment with topical acaricidal agents,^{[25, 26, 27]} most recently in a 12-year-old girl with D folliculorum –associated rosacea who had complete resolution of her symptoms following a single dose of oral ivermectin.^[28] Phase 3 randomized clinical trials to study effects of topical ivermectin 1% cream on rosacea have been completed; these trials compared the safety and efficacy of 1% ivermectin with 0.75% metronidazole cream and 15% azelaic acid gel.^{[29, 30, 31]}

In addition to the agents listed below, anecdotal evidence indicates effective treatment of rosacea with medications that reduce flushing, including beta-blockers, clonidine, naloxone, ondansetron, and selective serotonin reuptake inhibitors.

Topical and opthalmic fusidic acid is available in Canada, but not in the U.S. It is used for the treatment of ocular rosacea. Fusidic acid is a topical antibacterial that inhibits bacterial protein synthesis, causing bacterial death. Rosacea may respond to topical fusidic acid for at least 3 months.

Oral contraceptive therapy has been helpful in patients who provide historical information of worsening rosacea with their hormonal cycle.

Dapsone has been used in severe, refractory rosacea, and dapsone has been particularly beneficial for patients who cannot take isotretinoin.^[32]

• References

Tacrolimus ointment (Protopic)

• Dosing, Interactions, etc.

Clinical Context:  Tacrolimus ointment reduces itching and inflammation by suppressing the release of cytokines from T cells. It also inhibits transcription of genes encoding IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in the early stages of T-cell activation. Additionally, it may inhibit the release of preformed mediators from skin mast cells and basophils, and may down-regulate the expression of FCeRI on Langerhans cells. Tacrolimus ointment can be used in patients as young as 2 years. Drugs of this class are more expensive than topical corticosteroids. It is available as ointment in concentrations of 0.03% and 0.1% and is indicated only after other treatment options have failed.

• References

Class Summary

These agents inhibit immune reactions resulting from diverse stimuli.

• References

Metronidazole gel 0.75% or 1% (MetroGel, Noritate, MetroLotion)

• Dosing, Interactions, etc.

Clinical Context:  Metronidazole is an imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa.

Oral metronidazole has been shown to be beneficial against papules and pustules of acne rosacea.

Topical applications are helpful for mild disease and as an adjuvant to systemic therapy.

• References

Erythromycin (E.E.S., Erythrocin, Ery-Tab) tab or 2% topical solution

• Dosing, Interactions, etc.

Clinical Context:  Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used for the treatment of staphylococcal and streptococcal infections.

In children, age, weight, and severity of infection determine the proper dosage. When twice-daily dosing is desired, half the total daily dose may be taken every 12 hours. For more severe infections, double the dose.

Erythromycin can be used when tetracyclines are not tolerated or are contraindicated.

It is used for the treatment of ocular rosacea.

• References

Clindamycin topical (Cleocin T, Clindagel, Evoclin)

• Dosing, Interactions, etc.

Clinical Context:  Clindamycin is a semisynthetic antibiotic produced by 7(S)-chloro substitution of 7(R)-hydroxyl group of its parent compound lincomycin. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin widely distributes in the body without penetration of the CNS. It is protein bound and excreted by the liver and kidneys.

Upon application to skin, drug is converted to active component, which inhibits the microorganism.

Available as topical solution, lotion, or gel for external use. Solution contains equivalent of 10 mg/mL clindamycin.

Effective against mild-to-moderate papulopustular rosacea.

• References

Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Tetracycline inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). It has anti-inflammatory activity. Improvement is evident within 2-4 months after commencement of therapy.

• References

Minocycline (Dynacin, Minocin, Solodyn)

• Dosing, Interactions, etc.

Clinical Context:  Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible P acnes. The extended-release tablet (Solodyn) has a variety of doses ranging from 45 mg up to 135 mg and can be administered once daily.

• References

Doxycycline (Oracea, Doryx, Periostat, Vibramycin)

• Dosing, Interactions, etc.

Clinical Context:  Doxycycline is a broad-spectrum, synthetically derived, bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations.

Doxycycline inhibits protein synthesis and, thus, bacterial growth, by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

• References

Clarithromycin (Biaxin, Biaxin XL)

• Dosing, Interactions, etc.

Clinical Context:  Clarithromycin is a semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl tRNA from ribosomes, causing bacterial growth inhibition.

• References

Class Summary

Since the 1950s, oral antibiotics have been prescribed off label for treatment because microorganisms were thought to be the underlying cause of disease. In current practice, experts do not believe bacterial infection plays a part in the pathogenesis of rosacea; however, the antibiotics, particularly the tetracyclines, continue to be used for their anti-inflammatory properties. Since 2006, nonantibiotic dosing of doxycycline has become first-line treatment for many clinicians. In many cases, oral and topical antibiotics are used in combination; the oral treatment may be eventually withdrawn and the topical treatment is used alone as maintenance therapy. However, in patients with ocular involvement, oral therapy needs to be maintained.

In patients who require a systemic antibiotic, evidence suggests that the newer regimen of 20-50 mg q12h of doxycycline is as effective as the older regimen of 100 mg of doxycycline. For many patients, this could represent a significant cost reduction.

• References

Tretinoin topical (Avita, Retin-A, Retin-A Micro)

• Dosing, Interactions, etc.

Clinical Context:  Tretinoin is structurally related to vitamin A. It may be helpful for recalcitrant disease, but recurrence is common. Long-term, low-dose therapy may be suitable for selected patients.

Tretinoin may cause skin irritation in some patients. It has been linked to the promotion of angiogenesis; however, it has not demonstrated increased telangiectasias.

Tretinoin inhibits microcomedo formation and eliminates lesions. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. It is available as 0.025%, 0.05%, and 0.1% creams. It is also available as 0.01% and 0.025% gels.

• References

Isotretinoin (Amnesteem, Claravis, Sotret)

• Dosing, Interactions, etc.

Clinical Context:  Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Isotretinoin may be helpful for recalcitrant disease, but recurrence is common. Long-term, low-dose therapy may be suitable for selected patients.

A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.

• References

Class Summary

These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They modulate keratinocyte differentiation, and they have been shown to reduce the risk of skin cancer formation in patients who have undergone renal transplantation.

• References

Prednisolone (Millipred, Orapred, Veripred, Flo-Pred)

• Dosing, Interactions, etc.

Clinical Context:  Moderately high doses may be helpful in rosacea fulminans. Prednisolone decreases inflammation by suppressing the migration of PMN leukocytes and reducing capillary permeability. Use it in combination with isotretinoin. Rosacea fulminans is treated with moderately high doses of prednisolone (30-60 mg/d) followed by oral isotretinoin.

• References

Class Summary

These agents are relatively contraindicated, except as a short course in rosacea fulminans.

• References

Spironolactone (Aldactone)

• Dosing, Interactions, etc.

Clinical Context:  Spironolactone competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. Aldosterone inhibitors help block the renin-angiotensin system and help prevent potassium loss in distal tubules. The body conserves potassium, and less oral potassium supplementation is needed.

• References

Amiloride

• Dosing, Interactions, etc.

Clinical Context:  Amiloride is an antikaliuretic drug with weak natriuretic, diuretic, and antihypertensive activity. It decreases the enhanced urinary excretion of magnesium that occurs when a thiazide or loop diuretic is used alone. It exerts a potassium-conserving effect in patients receiving kaliuretic diuretic agents.

• References

Triamterene (Dyrenium)

• Dosing, Interactions, etc.

Clinical Context:  Triamterene inhibits reabsorption of sodium ions in exchange for potassium and hydrogen ions at the segment of the distal tubule that is under the control of adrenal mineralocorticoids (especially aldosterone). This activity is not directly related to aldosterone secretion or antagonism, and it is a result of a direct effect on the renal tubule.

The fraction of filtered sodium reaching this distal tubular exchange site is relatively small, and the amount that is exchanged depends on the level of mineralocorticoid activity; thus, the degree of natriuresis and diuresis produced by inhibition of the exchange mechanism is necessarily limited.

Increasing the amount of available sodium and the level of mineralocorticoid activity by using more proximally acting diuretics increases the degree of diuresis and potassium conservation. Triamterene may occasionally cause increases in serum potassium, which can result in hyperkalemia. It does not produce alkalosis, because it does not cause excessive excretion of titratable acid and ammonium.

• References

Class Summary

Potassium-sparing diuretics can be used to reduce morbidity.

• References

Benzoyl peroxide (Benzig, PanOxyl, Zapzyt, Acne Clear Maximum Strength)

• Dosing, Interactions, etc.

Clinical Context:  Free-radical oxygen is released upon administration and oxidizes bacterial proteins in sebaceous follicles, decreasing the quantity of irritating free fatty acids and of anaerobic bacteria. It is converted on skin into benzoic acid, which has keratolytic and comedolytic effects. However, it can be quite irritating in patients with barrier dysfunction and can cause further erythema. Benzoyl peroxide is available over the counter and by prescription. It is available in 2.5%, 5%, and 10% gels, lotions, creams, or washes.

• References

Azelaic acid (Azelex, Finacea)

• Dosing, Interactions, etc.

Clinical Context:  Azelaic acid is available in 2 strengths, as a 15% gel or foam (Finacea), or azelaic acid 20% cream (Azelex). It is effective against mild-to-moderate papulopustular rosacea. Azelaic acid can be used twice daily as initial treatment. It may reduce the production of ROS by neutrophils. Some patients report transient burning or stinging.

• References

Sodium sulfacetamide and sulfur (Klaron, Ovace)

• Dosing, Interactions, etc.

Clinical Context:  Sodium sulfacetamide and sulfur contains 5% sulfur and 10% sodium sulfacetamide. It is used topically for acne rosacea. Sodium sulfacetamide has antibacterial properties, whereas sulfur is considered an antiseptic with keratolytic action.

• References

Ivermectin topical (Soolantra)

• Dosing, Interactions, etc.

Clinical Context:  The mechanism by which ivermectin topical treats rosacea lesions is unknown. It is indicated for inflammatory lesions caused by rosacea.

• References

Class Summary

Some products in this category can be effective in patients with papules, pustules, and the phymatous and glandular types of rosacea.

• References

Oxymetazoline topical (Rhofade)

• Dosing, Interactions, etc.

Clinical Context:  Oxymetazoline topical is an alpha1 agonist that elicits vasoconstriction of the cutaneous microvasculature. It is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.

• References

Brimonidine topical (Mirvaso)

• Dosing, Interactions, etc.

Clinical Context:  Brimonidine is an alpha-2 adrenergic agonist. It is indicated for persistent facial erythema of rosacea in adults.

• References

Class Summary

Topical alpha1 and alpha 2 agonists have been approved by the FDA to treat rosacea.

• References