Rosacea is a common inflammatory dermatologic condition that affects the midface and eyes.[1, 2, 3, 4] Although the etiology of rosacea is not fully understood, an augmented response of the innate immune system and neurovascular pathways to certain triggers are considered to be major factors in the chronic inflammatory process associated with this condition.[5] The nose, cheeks, forehead, chin, and glabella are the most commonly affected areas. Clinical features include flushing, telangiectasias, erythema, papules and pustules, and rhinophyma. More than 50% of patients with rosacea have ocular manifestations, and ocular findings may be the first manifestation of rosacea in some patients.
See the image below.
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Typical dermatologic findings of rosacea, including midfacial papules, pustules, and rhinophyma.
Manifestations of ocular rosacea range from minor irritation, foreign body sensation, dryness, and blurry vision to severe ocular surface disruption and inflammatory keratitis. Patients frequently describe a gritty feeling, and they commonly experience Blepharitis and conjunctivitis. Other ocular findings include lid margin and conjunctival telangiectasias, eyelid thickening, eyelid crusts and scales, chalazia and hordeolum, punctate epithelial erosions, corneal infiltrates, corneal ulcers, corneal scars, and vascularization. Sight-threatening disease is rare with rosacea; however, keratitis can result in sterile corneal ulceration and eventual perforation if not treated aggressively.[6, 7]
Ocular rosacea is most frequently diagnosed when patients also suffer from cutaneous disease. However, ocular signs and symptoms may occur prior to cutaneous manifestations in 20% of patients with rosacea. No correlation exists between the severity of ocular disease and the severity of facial rosacea.
The symptoms of rosacea can be treated effectively; however, rosacea is a chronic condition with exacerbations and remissions, which requires long-term therapy to maintain symptomatic control.
The precise pathophysiology of rosacea remains unclear[8, 9] but is comprised of both vascular dysregulation and altered immune system responses and inflammatory changes.[10] Recent research has shown an upregulation of proinflammatory and vasoregulatory genes in rosacea patients. Alterations in the innate immune system responses include an overabundance of cathelicidin (an antimicrobial peptide), along with kallikrein-5, an enzyme involved in processing cathelicidin. Moreover, toll-like receptor 2 activity in the innate immune system is increased in patients with rosacea.[5]
A variety of rosacea triggers have been described including skin colonization with Demodex mites (along with bacteria in their gut)[11] and Staphylococcus epidermidis.[12] Eradication of Helicobacter pylori has been shown to improve rosacea in some patients, and the organism may play a role in the pathogenesis of inflammation of inflammation in rosacea.
Four distinct rosacea subtypes have been described: erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea, and ocular rosacea.
More than 10% of the general population exhibits dermatologic characteristics of rosacea; of these, up to 60% experience ocular complications.
International
An epidemiological study in Sweden showed a 10% prevalence of rosacea.[13] A study in Estonia showed a 22% prevalence rate of rosacea, as determined by the American National Rosacea Society Expert Committee (NRSEC) classification.[14]
Mortality/Morbidity
While rosacea is not a life-threatening disease, it is a source of much morbidity because of pruritus, burning, and psychosocial impairments. Approximately 5% of patients with rosacea manifest corneal disease, which can rarely be severe and lead to blindness via corneal ulceration, perforation, secondary infections, or corneal opacification from complete vascularization.
Race
Rosacea is recognized much more commonly in fair-skinned, white patients than in dark-skinned patients. However, because dark skin tones may mask erythema of rosacea, its incidence in this population is likely underreported.
Sex
Women are affected with the papulopustular and erythematotelangiectatic rosacea subtypes twice as often as men; however, the phymatous rosacea subtype develops much more frequently in men. Ocular rosacea affects both sexes equally.
Age
All ages can be affected, including pediatric patients.[15] Peak incidence occurs in the fourth to seventh decades of life.
Young children with chalazion may have ocular rosacea but may be uncooperative for slit-lamp examination.
Informing patients of the chronic, relapsing nature of rosacea is important so that patient expectation matches available therapy and patient follow-up care is maximized.
Ophthalmologists may underdiagnose rosacea because of a lack of familiarity with the dermatologic manifestations of the disease.
Flushing triggers: These include alcohol, hot beverages, tobacco, spicy foods, vasodilating medications, and emotional stress.
UV light: This is postulated to decrease the competence of already dilated cutaneous vasculature, increasing persistent erythema and telangiectasias.
Demodex: This mite, which is part of the skin's normal flora, leads to stimulation of the innate immune system. Bacteria in the gut of Demodex may be the inciting factor rather than the Demodex itself.[11]
S epidermidis: Hyper-reactivity of the innate immune system in rosacea patients makes them sensitive to this normal skin flora.[12]
H pylori: This is postulated to be strongly correlated with rosacea. This is possibly due to a flush-inducing toxin present in H pylori.
Positive family history: Some studies have shown a higher rate of positive family history of rosacea in patients with this dermatologic disorder than in skin-healthy controls.[18]
Smoking: Some studies have shown an increased history of smoking in patients with rosacea as compared with skin-healthy controls.[18, 19]
The diagnosis of ocular rosacea is established clinically and is often aided by dermatologic findings. Laboratory studies are not indicated. In cases of neovascularization and atypical presentation, ocular surface squamous neoplasia (OSSN) should be excluded.
The conjunctiva in ocular rosacea is infiltrated by inflammatory cells, T-helper/T-suppressor (CD4) cells, phagocytic cells, and antigen-presenting cells. In addition, increased vascular dilation and occasionally granulomatous changes are present. None of these changes are specific for rosacea.
Patients with rosacea typically have a mean increase of nearly all cell types, but especially T-helper cells.
Hoang-Xuan et al demonstrated a 3.5-fold increase in the ratio of CD4 cells to CD8 cells in the conjunctiva of patients with rosacea, most resembling a type IV hypersensitivity reaction.[20]
Rosacea is caused by inherent defects in the body's immune system and vasoregulatory processes. Treatment is directed toward symptomatic control and disease prevention rather than cure.
When treating ocular rosacea, a stepwise approach can be undertaken, using first lid hygiene and artificial tears, followed by topical and oral anti-inflammatory medications, with late surgical intervention as required. Contact lenses should be avoided until the ocular rosacea is controlled.
Lid hygiene
Hot compresses applied to the eyelid margins can help to liquefy the thick meibomian gland secretions and, thus, facilitate their expression. Mild, nonirritating cleaning solutions, such as dilute baby shampoo or commercially prepared eyelid scrubs, can also be applied to the eyelids to remove clogging debris. Additionally, light pressure applied to the eyelids can aid in gland expression. Thermal pulsation to the eyelid (Lipiflow, Intense Pulse Light) is a technique used in the treatment of blepharitis. BlephEx is another emerging technique for the treatment of blepharitis. Some studies have shown improvements in Demodex colony counts and inflammation with the use of 50% tea tree oil scrubs.[21]
Artificial tears
Because of the frequency of application, nonpreserved artificial tears are recommended for use. Tears should be applied liberally throughout the day, and, if necessary, a lubricating ointment may be used at night. This ointment may contain an antibiotic preparation.
Immunosuppressive agents
Cyclosporine inhibits various T-cell activities, and topical formulations of cyclosporine have been successfully used for ophthalmic inflammatory conditions. Twice-daily instillations of topical cyclosporine have proven more efficacious than artificial tears in the management of the ocular surface changes and subjective symptoms of ocular rosacea.[22]
Antibiotics
Patients with ocular rosacea who are asymptomatic and without worsening eye disease should not be placed on oral antibiotics.
Tetracyclines represent the most common and most effective treatment regimen for rosacea. These drugs are believed to be effective not primarily as antibiotics but rather through a secondary effect that they exert on the meibomian glands. Tetracyclines decrease bacterial lipase, thereby altering the fatty acid composition of the meibomian gland secretions and improving their solubility. These medications also inhibit collagenase; therefore, they are effective in protecting the cornea from impending perforation secondary to inflammatory responses.
Adverse effects are predominantly GI, including diarrhea and, rarely, pancreatitis and pseudomembranous colitis. In these patients, enteric-coated tetracyclines such as Doryx (a form of enteric-coated doxycycline) are a promising option. The special coating prevents the medication from dissolving in the stomach where it may induce GI upset. Instead, the medication is broken down in the small intestine from where it readily enters the blood stream. More severe but much less common adverse effects include benign intracranial hypertension and renal tubular damage (Fanconi syndrome) from outdated medications. Additionally, tetracyclines cross the placenta and can cause permanent discoloration of teeth as well as fetal bone growth retardation.
Tetracyclines generally are effective for rosacea in doses much lower than those given for antibiotic effect, and, once the disease has come under control, the dose may be tapered to a lower, suppressive dose and maintained indefinitely. Because of the chronic, relapsing nature of rosacea, the medication may be used chronically at suppressive doses or discontinued and restarted if and when symptoms recur.
Among this class of medications, tetracycline and doxycycline are most commonly used. These two medications are quite similar in their mechanism of action, adverse effect profile, and efficacy, but slight differences do exist. Tetracycline has a shorter half-life and, thus, is dosed 4 times per day, as opposed to doxycycline, which is given twice per day or once per day. Frucht-Pery et al reported a more rapid therapeutic response to tetracycline; however, no difference was found at 6 months.[15]
In 2006, the first FDA-approved oral treatment for rosacea became available: a controlled-release form of doxycycline called Oracea (Galderma Laboratories L.P). The 40-mg tablet is a combination of 30 mg of immediate-release and 10 mg of delayed-release doxycycline. The low dose enables the medication to have anti-inflammatory properties without exerting significant antibacterial properties, allowing for a more improved side effect profile and decrease rates of bacterial resistance.
Topical azithromycin eye drops have also gained popularity in the treatment of ocular rosacea. Ocular rosacea often results in severe and recalcitrant blepharitis. Azasite (azithromycin 1%, Inspire Pharmaceuticals) currently FDA approved only to treat bacterial conjunctivitis has found an off label use in the treatment of meibomian gland dysfunction.
Erythromycin can be taken orally for patients intolerant to, or too young for, tetracyclines. Erythromycin ointment applied to the lid margins once or twice daily can provide lubrication for the eye and reduce the bacterial overgrowth contributing to lid margin disease.
Clarithromycin has shown efficacy in treating rosacea. This compound exhibits anti-inflammatory effects as well as activity against H pylori. Torresani compared clarithromycin and doxycycline and found equivalent therapeutic responses and a milder adverse effect profile for clarithromycin.[25]
Metronidazole
Metronidazole exhibits antimicrobial (antibacterial and antiparasitic), anti-inflammatory, and immunosuppressive properties and has been found to be effective against rosacea. In fact, oral metronidazole has been advocated as first-line therapy. Adverse effects include gastrointestinal irritation and a disulfiramlike action; thus, abstinence from alcohol is required.
Topical metronidazole is quite effective in treating skin lesions in rosacea. While not approved for ophthalmic use, in a pilot study, Barnhorst et al found the topical compound to be safe and effective in treating eyelid involvement in ocular rosacea.[26]
Topical steroids
Topical steroids can prove useful for short-term exacerbations of lid disease and management of inflammatory keratitis. However, steroids should be used cautiously and discontinued as soon as possible to prevent corneal melting. Topical steroids may lead to rosacea exacerbations and should be avoided if possible.
Retinoids
Vitamin A derivatives, such as oral isotretinoin and topical tretinoin, have been found effective in reducing the inflammatory lesions in rosacea. This appears to be accomplished via the suppression of sebum production and a subsequent reduction in sebaceous follicle size. Additionally, tretinoin may help restore sun-damaged skin through the increased production of type 1 collagen in damaged regions. Both compounds can actually cause severe erythema and blepharoconjunctivitis, worsen telangiectasias, and lead to severe keratitis. Additionally, retinoids are extremely teratogenic and, thus, must never be used during pregnancy. Therefore, the use of retinoids is commonly reserved for cases in which multiple agents have failed.
Antiulcer therapy
H pylori plays an as yet undetermined role in rosacea, and some have advocated H pylori eradication in the treatment of rosacea. Thus, in some cases of rosacea, antiulcer combination regimens, such as amoxicillin or clarithromycin, metronidazole, bismuth, and an H2 antagonist, have been used with varying efficacy.
Other treatments
Other treatments in the treatment of rosacea include intense pulsed light therapy, ablative lasers, and electrosurgical loop.[27]
Treatment of dry eye - Punctal occlusion can be accomplished via permanent silicone plugs or punctal cauterization.
Amniotic membrane - Amniotic membrane has anti-inflammatory properties and promotes reepithelization of the cornea. It can be used to reconstruct the corneal surface in severe cases of rosacea when a nonhealing epithelial defect, corneal ulceration, or limbal stem cell deficiency are present.
Treatment of corneal perforations
Cyanoacrylate tissue adhesive
Lamellar keratoplasty
Penetrating keratoplasty
Restoration of vision from corneal disease
Penetrating keratoplasty
The success rate for graft survival is generally much lower than for noninflammatory conditions because of the increased vascularization of the host cornea.
Eyes undergoing penetrating keratoplasty are more likely to experience graft rejection than eyes without rosacea because of the increased inflammatory response and the relatively increased corneal vasculature.
Rosacea is a chronic condition, and long-term management is necessary to control this disease.
Dermatology and ophthalmology visits may be necessary, and they could initially be frequent to gain control over the symptoms or to protect an endangered cornea.
Clinical Context:
Inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). Has anti-inflammatory activity. Also a potent collagenase inhibitor.
Clinical Context:
DOC; inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). Has anti-inflammatory activity. Also a potent collagenase inhibitor.
Clinical Context:
Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes causing RNA-dependent protein synthesis to arrest. Effective through secondary, anti-inflammatory action.
Clinical Context:
This ophthalmic macrolide antibiotic is indicated for bacterial conjunctivitis may be used off label in the treatment of meibomian gland dysfunction.
Clinical Context:
Structurally related to vitamin A. Reduces sebum production and sebaceous follicle size. Makes keratinocytes in sebaceous follicles less adherent and easier to remove. May help restore sun-damaged skin. Long-term, low-dose therapy may be suitable for selected patients.
Inhibits microcomedo formation and eliminates lesions present. Available as 0.025%, 0.05%, and 0.1% creams. Available also as 0.01% and 0.025% gels.
Clinical Context:
Used to relieve dry eyes caused by suppressed tear production secondary to ocular inflammation. Thought to act as partial immunomodulator. Exact mechanism of action is not known.
Clinical Context:
Artificial tears are used to increase lubrication of the eye. Nonpreserved artificial tears are recommended for use. Tears should be applied liberally throughout the day, and, if necessary, a lubricating ointment may be used at night. This ointment may contain an antibiotic preparation.
Lubricants act as humectants in the eye. The ideal artificial lubricant should be preservative-free; contain potassium, bicarbonate, and other electrolytes; and have a polymeric system to increase its retention time. Lubricating drops are used to reduce morbidity and to prevent complications. Lubricating ointments prevent complications from dry eyes. Ocular inserts reduce symptoms resulting from moderate to severe dry eye syndromes.
What is ocular rosacea?What is the pathophysiology of ocular rosacea?What is the prevalence of ocular rosacea in the US?What is the global prevalence of ocular rosacea?What is the mortality and morbidity associated with ocular rosacea?What are the racial predilections of ocular rosacea?What are the sexual predilections of ocular rosacea?Which age groups have the highest prevalence of ocular rosacea?What are the facial signs and symptoms of ocular rosacea?What are the ocular signs and symptoms of rosacea?Which facial findings are characteristic of ocular rosacea?Which ocular findings are characteristic of rosacea?What causes ocular rosacea?What are the differential diagnoses for Ocular Rosacea?What is the role of lab tests in the workup of ocular rosacea?What is the role of imaging studies in the workup of ocular rosacea?Which histologic findings are characteristic of ocular rosacea?What is the role of metronidazole in ocular rosacea treatment?What is the role of antiulcer therapy in ocular rosacea treatment?Which nonpharmacologic therapies have been used in the treatment of ocular rosacea?How is ocular rosacea treated?What is the role of lid hygiene in ocular rosacea treatment?What is the role of artificial tears in ocular rosacea treatment?When are antibiotics indicated in ocular rosacea treatment?What is the role of tetracyclines in ocular rosacea treatment?What is the role of topical steroids in ocular rosacea treatment?What is the role of retinoids in ocular rosacea treatment?What is the role of surgery in the treatment of ocular rosacea?Which specialist consultations are beneficial to patients with ocular rosacea?Which dietary modifications are used in the treatment of ocular rosacea?Which activity modifications are used in the treatment of ocular rosacea?What is the goal of drug treatment for ocular rosacea?Which medications in the drug class Ophthalmic Lubricants are used in the treatment of Ocular Rosacea?Which medications in the drug class Immunosuppressants are used in the treatment of Ocular Rosacea?Which medications in the drug class Corticosteroids are used in the treatment of Ocular Rosacea?Which medications in the drug class Retinoid-like Agents are used in the treatment of Ocular Rosacea?Which medications in the drug class Antibiotics are used in the treatment of Ocular Rosacea?
Jitander Dudee, MD, MA(Cantab), FACS, FRCOphth, Ophthalmologist, Medical Vision Institute, PSC
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Christopher J Rapuano, MD, Professor, Department of Ophthalmology, Sidney Kimmel Medical College of Thomas Jefferson University; Director of the Cornea Service, Co-Director of Refractive Surgery Department, Wills Eye Hospital
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cornea Society, AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab<br/>Serve(d) as a speaker or a member of a speakers bureau for: Avedro; Bio-Tissue; Shire<br/>Received income in an amount equal to or greater than $250 from: AAO, OMIC, Avedro; Bio-Tissue; GSK, Kala, Novartis; Shire; Sun Ophthalmics; TearLab.
Chief Editor
Edsel Ing, MD, MPH, FRCSC, Associate Professor, Department of Ophthalmology and Vision Sciences, University of Toronto Faculty of Medicine; Active Staff, Michael Garron Hospital (Toronto East Health Network); Consulting Staff, Hospital for Sick Children and Sunnybrook Hospital, Canada
Disclosure: Nothing to disclose.
Additional Contributors
Bhairavi Kharod-Dholakia, MD, North Georgia Eye Clinic
Disclosure: Nothing to disclose.
C Diane Song, MD, Chief of Ophthalmology, Asheville Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Evan S Loft, MD, Clinical Assistant Professor, Department of Ophthalmology, Emory University
Disclosure: Nothing to disclose.
J Bradley Randleman, MD, Associate Professor, Department of Ophthalmology, Section of Cornea, External Disease and Refractive Surgery, Emory University School of Medicine; Director of Cornea, External Disease and Refractive Surgery Fellowship, Emory University; Physician Member, Section of Ophthalmology, The Emory Clinic
Disclosure: Nothing to disclose.
Joshua A Zeichner, MD, Assistant Professor, Director of Cosmetic and Clinical Research, Mount Sinai School of Medicine; Chief of Dermatology, Institute for Family Health at North General
Disclosure: Received consulting fee from Valeant for consulting; Received grant/research funds from Medicis for other; Received consulting fee from Galderma for consulting; Received consulting fee from Promius for consulting; Received consulting fee from Pharmaderm for consulting; Received consulting fee from Onset for consulting.
Sheetal M Shah, MD, Assistant Professor of Ophthalmology in Cornea and External Diseases, Department of Ophthalmology, Emory Eye Center and Emory Vision, Emory University School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the assistance of Ryan I Huffman, MD, with the literature review and referencing for this article.
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