The Ocular Manifestations of Atopic Dermatitis and Rosacea Andrew S. Eiseman, MD Corresponding author Andrew S. Eiseman, MD Eye Clinic, Walter Reed Army Medical Center, Washington, DC 20307, USA. E-mail: Andrew.Eiseman@na.amedd.army.mil are discussed, and the importance of including an ocular assessment in their evaluation, even if the dermatologic abnormality appears to be well-controlled, is illustrated. Current Allergy and Asthma Reports 2006, 6:292 –298 Current Science Inc. ISSN 1529-7322 Copyright © 2006 by Current Science Inc. Atopic Dermatitis and Keratoconjunctivitis Atopic dermatitis and rosacea are chronic diseases that have both dermatologic and ocular manifestations. The occurence of ocular disease is often proportionately higher than that of dermatologic disease. Even if the skin abnormalities appear well controlled, these patients require ophthalmic evaluation as well. Optimal management usually requires a team approach that includes internists, dermatologists, and ophthalmologists. Both disorders are characterized by acute exacerbations and require maintenance therapy for control. Exacerbations need aggressive treatment to limit ocular signs and symptoms and to reduce ocular inﬂammation that can lead to permanent visual loss. Topical corticosteroid use, although at times needed, should be minimized for both disorders. Future research will continue to emphasize the use of steroid-sparing and immune-modulating agents that have the potential to provide long-lasting anti-inﬂammatory control with a more favorable side-effect proﬁle. Introduction Many eyelid abnormalities associated with dermatologic diseases are easy to identify because they are quite similar to the skin changes found on other parts of the body. However, several dermatologic diseases not only have eyelid abnormalities but ocular abnormalities as well. These ocular manifestations can be signiﬁcant, and they may be out of proportion to the skin changes observed. If not identiﬁed early and managed appropriately, they can lead to severe signs and symptoms and even loss of vision that can be permanent. Two of the most common dermatologic diseases that have the potential for signiﬁcant ocular ﬁndings that are often out of proportion to the skin changes are atopic dermatitis and rosacea. In this article, the ocular manifestations of these disorders Eczematous dermatitis, hay fever, allergic asthma, and perennial allergic rhinitis make up the “major” atopies. Atopy is quite common, affecting up to 20% of the population . Approximately 2% of the population is affected by atopic dermatitis, with most initial manifestations beginning in childhood . Atopic dermatitis affecting the eyelids is one of the most common causes of chronic eyelid dermatitis. Svensson and Moller  found that 39% of their population affected with eyelid dermatitis had atopic disease. Nethercott et al.  found that of the 79 patients in their study who were affected with eyelid dermatitis, 23% had atopic dermatitis. Although the eyelid manifestations of those affected with atopic disease are common, they are not particularly distinguishing. Care must be taken when evaluating these patients to ensure that the correct diagnosis is determined. Differential diagnosis Pruritic and inﬂamed eyelids with edema, erythema, and scaling are common presenting signs and symptoms and must be differentiated from the more common conditions of contact and irritant dermatitis. Patients with contact and irritant dermatitis can also present with the ocular symptoms of itching and burning. However, the intense signs of ocular inﬂammation and scarring are usually absent. A careful history, including a family history, and patch testing can be very helpful in separating those patients with allergic contact dermatitis from those with atopic disease. A familial predisposition to atopic disease is found in more than 50% of these patients . It may be difﬁcult to ﬁnd the underlying causative agent in allergic contact disease. Therefore, it is also important to carefully evaluate the patient for other signs of atopic disease. Patients with atopic dermatitis have a second atopic disease 75% to 80% of the time . Some patients present with more ocular signs and symptoms than skin ﬁndings. Ocular swelling, itch, and irritation can be due to atopic keratoconjunctivitis, The Ocular Manifestations of Atopic Dermatitis and Rosacea Eiseman 293 Figure 1. Patient with atopic dermatitis affecting the eyelids shows thickened skin with mild scaling. The eyelid margins are erythematous, and multiple eyelashes are missing (madarosis). The conjunctival vessels show mild engorgement as well. Table 1. Ocular manifestations of atopic dermatitis Eyelid ﬁndings Swelling, erythema, scaling, and ﬁssures Licheniﬁcation and thickening Ectropion Blepharitis Madarosis (lash loss), trichiasis (lash misdirection) Bacterial colonization and viral infections Ocular ﬁndings Eyelid and periocular ﬁndings Conjunctival erythema and swelling Atopic dermatitis that affects the eyelids can present with a host of symptoms, usually including bilateral itching, burning, tearing, photophobia, and thick, stringy, ropy discharge. The signs of the disease include eyelid swelling with erythema and a scaly, thickened, and wrinkled appearance of the skin (Table 1). With chronicity, licheniﬁcation can occur, which is thickening and accentuation of the normal skin lines [2,6]. The lids may become indurated, and eyelid malpositions, such as ectropion, can occur. A chronic cycle of rubbing and scratching can also lead to changes such as ﬁssures, especially near the lateral canthus . Several periorbital markers of atopy have also been described. The Dennie-Morgan fold is a crease from the inner canthus extending laterally to the midpupillary line of the lower eyelid [2,6]. Periorbital darkening, known as the “allergic shiner,” is also commonly encountered . Hertoghe’s sign is seen in severe forms of atopic lid disease and is identiﬁed by the absence of lateral eyebrows . Eyelid margin inﬂammation, known as blepharitis, is also commonly seen. It presents with morning crusting, eyelid hyperemia, and eyelash abnormalities . Madarosis is loss of eyelashes and trichiasis is misdirection of eyelashes (Fig. 1). Trichiasis can be very annoying to the patient, especially when the lashes are in contact with the surface of the eye (Fig. 1). Chronic colonization with bacteria is another problem commonly associated with the skin abnormalities of atopic disease. Staphylococcus aureus is found on the skin of only 5% to 10% of healthy persons and is usually conﬁned to the vestibulum nasi, axilla, perineum, and the interdigital spaces of the feet [7,8•]. In patients with atopic dermatitis, S. aureus colonizes 40% to 90% of the patients, and it is found on even normal-appearing skin [7,8•]. It is postulated that the organism comes from the ﬁngernails and is spread by frequent rubbing and itching. More than 90% of the S. aureus phagotypes derived from the skin match those from the ﬁngernails [7,8•]. Such bacterial colonization must be taken into account when ocular surgeries are planned. Thorough preoperative disinfection with a povidone iodine preparation is mandatory. Some even suggest that bacterial isolation should be performed preoperatively so that antibiotic sensitivities can be determined for use during the perioperative period [7,8•]. Symblepharon Limbal papillae Corneal erosions, ulcers, neovascularization, and scarring Keratoconus Anterior and posterior subcapsular cataracts but they can also be due to seasonal or perennial allergic conjunctivitis, giant papillary conjunctivitis, and vernal keratoconjunctivitis. Allergic conjunctivitis is a commonly encountered entity that occurs seasonally in response to a wide variety of airborne allergens. It is characterized by itching, burning, redness, tearing, chemosis (conjunctival swelling), and lid edema, and is often found with concomitant allergic rhinitis and/or sinusitis . Perennial allergic conjunctivitis presents in a similar fashion but is less common and occurs without seasonal dependence. Perennial allergens, such as house dust mites, animal danders, and mold, may be the underlying provoking agents . Giant papillary conjunctivitis is an inﬂammatory reaction of the upper tarsal conjunctiva usually thought to be due to a reaction to a foreign body on the external ocular surface . The most common offending agents are contact lenses and products associated with their use. Although the symptoms may be severe and troublesome to the patient, these disorders are not usually accompanied by the sight-threatening, severe ocular inﬂammation that is the hallmark of atopic disease. The other disorder that can mimic atopic disease and potentially has sight-threatening ﬁndings is vernal keratoconjunctivitis. It is sometimes difﬁcult to distinguish between the two, but vernal keratoconjunctivitis is more likely to have seasonal variation, is more likely to resolve spontaneously, and is more likely to present at an earlier age, typically in the second decade of life [5,6]. Atopic keratoconjunctivitis can begin in the teenage years, but occurs more often in the third or fourth decades of life [5,6]. Finally, vernal disease more commonly affects the superior conjunctiva with papillae as compared to the more common inferior eyelid disease of atopic keratoconjunctivitis . 294 Ocular Allergy Atopic dermatitis patients are also prone to severe herpes simplex infections that can include eczema herpeticum or Kaposi’s varicelliform eruption. This disorder is a generalized vesicular eruption that can be seen in the dermatitic skin of the atopic individual and can be lifethreatening. In the periorbital area, it can present with umbilicated vesicles, reddened conjunctiva, and keratitis (corneal infection) [2,8•]. Atopic individuals seem to be particularly prone to herpes simplex keratitis, and it is commonly bilateral with frequent recurrences and slow healing, even with appropriate antiviral therapy [2,6,8•]. The slow healing also makes these patients prone to secondary bacterial infections because of the previously mentioned bacterial colonization. Atopic dermatitis patients are also prone to infections with viral warts and molluscum contagiosum [2,8•]. Ocular manifestations The ocular ﬁndings of atopic keratoconjunctivitis can be signiﬁcant and can lead to visual loss if not managed appropriately (Table 1). Severe ocular surface inﬂammation is the rule, and this can lead to erythematous and chemotic conjunctiva. Tarsal conjunctival papillary hypertrophy is common as are limbal papillae that give the appearance of gelatinous nodules adjacent to the cornea [2,6]. Chronic disease can lead to conjunctival scarring with shortening of the inferior fornix and symblepharon formation [2,6]. Corneal ﬁndings mostly affect the inferior third of the cornea, with punctuate erosions and neovascularization [2,6]. However, visual acuity can be reduced by corneal haze, microcysts, thinning, and extension of the new blood vessels into the central cornea. Corneal ulceration can also occur, and these ulcers can be infectious or noninfectious [2,6]. The noninfectious ulcers present as persistent epithelial defects with corneal thinning and can occur in up to 37.8% of the patients . Corneal ectasias such as keratoconus have also been shown to occur frequently in patients with atopic disease. A study by Foster and Calonge  found a 6.7% rate of keratoconus in 45 patients. Tuft et al.  found that six of their 37 patients had keratoconus, for a rate of 18%. Harrison et al.  also found an increased rate of kerataconus among atopic patients. They also found that patients with atopy and keratoconus did not differ in regard to sex, age of onset, or rate of keratoplasty. However, patients with very high levels of systemic IgE did appear to be more prone to corneal transplant rejections . It is unclear why atopic individuals have a greater rate of keratoconus but it may be due to excessive eye rubbing or a genetic predisposition. Lenticular abnormalities are also commonly identiﬁed in atopic individuals. Whether cataracts are truly a manifestation of atopy or a complication of corticosteroid treatment is still under debate. Some believe that atopic individuals are predisposed to cataract formation, whereas others believe that cataract progression is has- tened by the concomitant use of steroids. Cataracts in atopic individuals tend to be subcapsular with posterior subcapsular cataracts being more common than anterior subcapsular cataracts [2,6]. The appearance of cataracts from atopy is indistinguishable from those induced by steroids, making the cause and effect relationship even harder to prove. When a patient presents with signiﬁcant eyelid or ocular disease, it is important to remember that atopic dermatitis is a systemic disorder. The skin disease usually presents before the ocular disease. The infantile stage begins between 6 months and 2 years of age and usually affects the extensor surfaces, such as the tops of the feet, the backs of the hands, the knees, and the face. When the patients are older, usually the ﬂexural sites are affected—for example, the antecubital fossae and behind the knees [2,6]. Cutaneous infections can complicate the skin disease, and the constant scratching and rubbing can lead to permanent scarring. Many of these patients also suffer from psychoneurotic behavior, such as poor compliance and medication abuse. Foster and Cologne  found psychoneurotic problems in 33% of their study population. Pathogenesis The exact underlying pathogenesis of atopic dermatitis and atopic keratoconjunctivitis is unknown. However, both type I and type IV hypersensitivity reactions appear to be involved [1,6]. Elevated serum and tear levels of IgE are characteristic of exacerbations of atopic keratoconjunctivitis, and during remissions, these levels decline . Cell-mediated immunity defects have been found in the skin, but there is still no clear evidence of a systemic defect in cell-mediated immunity . Recent research efforts have concentrated on the basis for the increased IgE synthesis and how it is related to defects in T-cell regulation. Interleukin (IL)-4 from T cells acts as a switch factor to commit B cells to the IgE pathway . In contrast, interferon (IFN)-γ inhibits IgE synthesis and IL-4–induced IgE synthesis . Thus, the ﬁnding that atopic dermatitis patients have decreased levels of IFN-γ from a post-transcriptional defect and that they have increased levels of IL-4 is important in planning future immune-modulating therapies [10,11]. It also gives a rationale for the use of IFNγ as a therapeutic agent. A recent study showed that the administration of IFN-γ not only decreased the production of IgE but it also improved the skin disease in patients with atopic dermatitis . Treatment The treatment of eyelid atopic dermatitis and atopic keratoconjunctivitis can be very challenging and requires a compliant patient and a dedicated physician. The underlying goal is the preservation of vision and the reduction of symptoms while carefully managing the side-effect proﬁle of the therapeutic agents used. Usually, a chronic regimen of agents that can be used on The Ocular Manifestations of Atopic Dermatitis and Rosacea a long-term basis is used, and then exacerbations are treated aggressively to prevent damage. The mainstay of treatment is designed to break the “itch-scratch” cycle that can cause mechanical degranulation of mast cells, further traumatize the inﬂamed skin, and increase the risk for secondary infection [2,6]. It is also important to remember that atopic dermatitis is a systemic disease and that it may be helpful to manage the patient with a team that includes dermatologists, ophthalmologists, and allergists. Patients should be instructed to avoid known inciting allergens and to use cool compresses and bland emollients to help with itching of the eyelid skin. Bland emollients include ointment-based agents without preservatives or fragrances, such as white petrolatum and Aquaphor (Beiersdorf, Norwalk, CT) . These agents also help restore the epidermal barrier function of the skin by decreasing xerosis . Antihistamines can also be prescribed to diminish skin itch. The nonsedating agents can be used during the day, and the more sedating ones can be used before bed. Periodic exacerbations of skin disease can be treated with short courses of low-dose topical corticosteroid. Fluorometholone 0.1% ophthalmic ointment can be used two to three times a day on the eyelid skin and then tapered over a week or two. Because it is an ophthalmic ointment, it is much less irritating (if some gets in the eye) than skin preparations used on the eyelid skin. When using steroids, the philosophy of using the lowest dose possible for the shortest time possible is important to prevent the complications of long-term steroid use around the eye, such as glaucoma, cataract, skin atrophy, telangiectasia, and infection. If frequent topical steroid application is necessary, one should consider starting the immune-modulating agent tacrolimus. Tacrolimus 0.1% ointment twice a day has been shown in several studies to be a safe and effective treatment option for patients with moderate-to-severe eyelid dermatitis [12•,13]. Tacrolimus works by blocking Tlymphocyte activation and by inhibiting the production of proinﬂammatory cytokines. Side effects appear to be minimal and include itching and burning at the site of application with a decrease in these symptoms as skin inﬂammation improves [12•]. Systemic absorption of the topical agent has been shown to be minimal without associated adverse sequelae [12•]. The treatment philosophy for atopic keratoconjunctivitis is similar to the treatment of the eyelid dermatitis. A regimen of agents that are safe for long-term use should be instituted to include a preservative-free artiﬁcial tear preparation and a mast-cell stabilizer antihistamine combination. There are several of these combination eye drops available, including olopatadine 0.1% and ketotifen 0.025%, and they can be used two to three times a day. Topical vasoconstrictors should be avoided because they can cause rebound hyperemia with long-term use. Eiseman 295 Topical nonsteroidal agents may also have a role in treating both ocular inﬂammation and pruritis. Ketorolac tromethamine 0.5% can be used up to four times a day and works by inhibiting prostaglandin synthetase . Topical nonsteroidal agents may sting upon instillation, and there has been some evidence to suggest that they can cause corneal abnormalities, including corneal melting, that can result in ocular perforation. Although the evidence for corneal melts is anecdotal, it may be best to only prescribe these agents when the patient is being carefully followed by an ophthalmologist. Severe exacerbations can be treated with topical corticosteroids. They block the formation of arachidonic acid metabolites by inhibiting phospholipase A 2, which in turn prevents leukocyte immigration . As with the treatment of the skin disease, the lowest dose of topical steroid should be used for the shortest amount of time. This will reduce the ocular inﬂammation while minimizing the complications of steroid use that include infections, glaucoma, cataracts, and the possibility of corneal melts. Topical corticosteroids should only be administered by ophthalmologists. New agents are currently under investigation that can reduce the ocular inﬂammation while minimizing the risks of steroid administration. One such item is topical cyclosporine 0.05%. Cyclosporine acts speciﬁcally and reversibly on T lymphocytes and inhibits the release of lymphokines by activated T cells. A recent study showed that topical cyclosporine appears safe and has some effect in alleviating the signs and symptoms of severe atopic keratoconjunctivitis that is refractory to topical steroid treatment [14•]. Additional research using immune-modulating agents may give hope to patients with severe resistant disease or to those who are suffering from the side effects of topical steroids. Rosacea Rosacea is a chronic disorder affecting the sebaceous glands of the face. It is characterized by inﬂammatory papules and pustules, facial ﬂushing, erythema and telangiectasia, ocular lesions, and occasionally by connective tissue hypertrophy resulting in rhinophyma [2,15]. Rosacea may be found in up to 10% of the general population and mostly affects adult white women at a rate two to three times greater than that for men . Disease severity may be worse in men, and ocular complications may be worse in men as well. Rosacea typically affects patients who are between the ages of 40 and 50, whereas ocular rosacea appears more common between the ages of 50 and 60 [2,15,16]. Ocular rosacea occurs in patients with rosacea from 3% to 58% of the time, depending on the series studied [2,15,16]. Ocular disease is independent of the severity of the skin disease and seems to occur with equal frequency in men and women [2,15,16]. 296 Ocular Allergy Table 2. Ocular manifestations of rosacea Periorbital lymphedema Eyelid margin erythema and telangiectasia Blepharitis, and inspissated meibomian gland oriﬁces Hordeola (styes) and chalazia Bacterial colonization Dry eye Corneal erosions, vascularization, and thinning Episcleritis, scleritis, iritis, and vitritis Dermatologic ﬁndings Rosacea is a clinical diagnosis, and in patients with skin and ocular disease, 53% develop their skin lesions ﬁrst, 20% develop their ocular disease ﬁrst, and 27% develop them simultaneously . There are four stages of rosacea. The ﬁrst is characterized by recurrent ﬂushing of the face, which may extend to the neck, presternal area, and shoulders. Flushing is often triggered by hot beverages, tobacco, alcohol, spicy foods, and emotional stress . The second stage is vascular. After recurrent episodes of ﬂushing, the forehead, cheeks, nose, and neck show persistent erythema from an increased number of erythrocytes in a mildly inﬂamed superﬁcial vasculature . The third stage is inﬂammatory. It is characterized by papules and pustules. Rosacea can be distinguished from acne vulgaris by the absence of comedones and by conﬁnement of the lesions to the ﬂush areas . The last stage, rhinophyma, is the least common. It is seen almost exclusively in men after decades of chronic disease . Ocular manifestations Ocular rosacea can be severe even if the dermatologic involvement is minor (Table 2). Symptoms can be out of proportion to the ﬁndings and include burning, redness, itching, foreign-body sensation, tearing, dryness, photophobia, and lid fullness and swelling [2,15]. The primary defect in ocular rosacea is related to meibomian gland dysfunction and includes inﬂammation of the glands with dilation and plugging of the gland oriﬁces . Pressure on the eyelids below the gland openings will often produce a thick toothpaste-like secretion. Chronic inﬂammation can result in complete loss of secretion and gland drop-out with hyperkeratinization of the ductal epithelium [2,15]. These gland abnormalities lead to eyelid disease that includes blepharitis, hordeola, chalazia, and telangiectasias . The eyelids often become thickened with prominent vascularization, keratinization, and inspissated meibomian gland oriﬁces that may be reduced in number . Signs of blepharitis include collarettes around lashes, loss of lashes, whitening of lashes, misdirected lashes, and erythema of the lid margin (Fig. 2). Telangiectatic vessels can be seen crossing the eyelid margin . Internal hordeola often develop and represent individual inﬂamed meibomian glands. Chalazia, or sterile lipogranulomas, also occur due Figure 2. Patient with rosacea shows signiﬁcant eyelid inﬂammation with débris in lashes (blepharitis), conjunctival injection, and medial corneal inﬁltration (keratitis). Note the nasal changes as well (rhinophyma). to extravasation of the meibomian gland secretions into the lid . Recurrent chalazia are twice as common in patients with rosacea, and 57% of the patients presenting with chalazia have signs of rosacea [2,17]. Staphylococcal colonization is also quite common and can contribute to ocular complications as well [15,16]. Conjunctival hyperemia is one of the more common ﬁndings in ocular rosacea, and it is usually found widely dispersed in the interpalpebral zone, although it can also be found more focally with conjunctival induration (Fig. 2). These conjunctival signs can be worsened by decreased tear production that is found in more than one third of the patients with ocular rosacea [2,15]. However, tear abnormalities are not only due to decreases in the aqueous component of the tear ﬁlm. Qualitative abnormalities also occur and are due to the abnormal lipid secretions from the meibomian glands. The lipid layer of the tear ﬁlm usually stabilizes the tear ﬁlm and prevents rapid evaporation. Abnormalities of this function can be seen by abnormally fast tear break-up times. A dry spot occurring in the tear ﬁlm in less than 10 seconds after a blink to redistribute ﬂuorescein dye is considered abnormal . Corneal ﬁndings in ocular rosacea are also common and include inferior punctuate keratopathy and superﬁcial vascularization of the peripheral cornea with a wedge-shaped subepithelial inﬁltrate [2,15,16]. Vascularization can encroach on the visual axis and lead to decreased vision, as can inﬂammatory episodes that can lead to deeper corneal scarring, ulceration, thinning, and, rarely, perforations [2,15,16]. Secondary bacterial infections can also be seen, especially with the incidence of bacterial colonization previously discussed. Other ocular manifestations of rosacea have been reported, but The Ocular Manifestations of Atopic Dermatitis and Rosacea with much lower frequency. These include chronic periorbital lymphedema, also known as blepharophyma, and episcleritis, scleritis, iritis, and vitritis [2,15,16,18,19]. Pathogenesis The cause of rosacea is unknown, but there are many hypotheses, and several associations exist. Some believe it is primarily a vascular disease, as facial blood ﬂow in affected patients is three to ﬁve times that of normal controls . Sunlight-induced damage also seems to play a role, as increased levels of solar elastosis are evident in histopathologic specimens of skin involved with rosacea. Further evidence for this comes from the occurrence of rosacea in sun-exposed skin, its prevalence in older, fair-skinned individuals, and its increase in frequency during the springtime months [15,16]. A cell-mediated immune hypersensitivity may play a role because histopathologic specimens show inﬂammatory cell inﬁltration with granuloma formation, and rosacea patients have a higher incidence of autoimmune disease . Associations also exist between rosacea and gastrointestinal disorders, especially gastric disease. Studies have identiﬁed achlorhydria in some and increases in Helicobacter pylori in others [15,16]. Whether H. pylori colonization is truly a cause or just an associated ﬁnding is still unclear. Demodex mites have also been proposed as a possible inﬂammatory agent because increased numbers of mites have been found on rosacea-affected skin when compared to controls . Antibodies to Demodex have also been found in affected skin and in conjunctival epithelium of inﬂamed eyes [15,16]. The role of these antibodies is not known, but they may play a proinﬂammatory role or be a causative agent in a subset of patients [15,16]. The sebaceous and meibomian glands of rosacea patients exhibit abnormalities to include keratinization of epithelial cells that leads to thickened secretions and plugging of the oriﬁces with subsequent trapping of secretions as well . The meibomian glands also produce an increased amount of free fatty acids that may cause tearﬁlm instability and irritation to the ocular tissues [15,16]. Whether this increase in free fatty acids is due to a primary biochemical abnormality or due to bacterial lypolytic exoenzymes that split neutral lipids into free fatty acids or a combination of both is not known [15,16,20]. Bacterial colonization, especially with Propionibacterium acnes and S. aureus, is quite common in rosacea patients, and these bacteria are known to contain the lipases discussed earlier [15,16,20]. No one theory adequately explains the development of all of the signs and symptoms of rosacea. Rosacea is probably a combination of several factors that act together to produce the clinical entity observed. Treatment Rosacea is a chronic disease with intermittent exacerbations that cannot be cured. However, the disease can be controlled with maintenance therapy and more aggres- Eiseman 297 sive treatment to control exacerbations. The ﬂushing and erythema stage is difﬁcult to treat, and there is currently no satisfactory treatment . Patients should be advised to avoid exposure factors, such as sunlight, heat, hot drinks, spicy food, and other known triggers, to minimize ﬂushing. Broad-brim hats and sunscreen can also be helpful. The mainstay of treatment is oral antibiotic therapy, and tetracycline and its derivatives, such as doxycycline, are most effective. These drugs are incorporated into the sebum and alter the interaction of sebum and bacteria by decreasing the concentration of free fatty acids [15,16]. They also decrease the production of microbial inﬂammatory mediators and can produce signiﬁcant positive effects on ocular disease even without decreasing the number of bacteria on the lids [15,16]. Side effects include gastrointestinal upset, vaginal yeast infections, photosensitivity, and decreased effectiveness of oral contraceptives [2,15]. Tetracycline 250 mg four times a day for 6 to 8 weeks followed by 250 mg a day for a total of 3 months has shown to be effective in all ocular lesions [2,16]. An alternative that minimizes the gastrointestinal upset and increases compliance is doxycycline 100 mg twice a day for 6 to 8 weeks followed by 100 mg a day for a total of 3 months. Moderate-to-severe skin involvement can be treated with metronidazole gel 0.75% twice a day. It has been shown to decrease papules and pustules and can help somewhat with erythema as well . It is well-tolerated but may increase the number of visible telangiectasias . An ocular preparation is not available, and, therefore, eyelid application should be done with care. Other topical agents that have shown effectiveness for the treatment of papules and pustules include topical 0.1% tretinoin cream twice a day [2,15]. These agents can cause skin irritation and erythema and should be used with care on the eyelids. The treatment of eyelid disease revolves around treating the blepharitis. Warm compresses are effective at melting and unplugging the meibomian glands, and this may speed the resolution of hordeola and chalazia as well. Gentle massage of the tarsal plate can help express secretions from the glands . Eyelid-margin scrubs with a dilute solution of baby shampoo can remove oil and débris, and the application of an ophthalmic antibiotic such as erythromycin or bacitracin once or twice a day can decrease bacterial lipases that can produce free fatty acids [2,15]. Dry eye should be aggressively treated with preservative-free artiﬁcial tears at least four times a day. If this is not effective enough, temporary or permanent punctal occlusion can be used. Steroids should only be used for more severe inﬂammation that is refractory to other treatments or if iritis is encountered. The lowest dose for the shortest time should be used under the direct supervision of an ophthalmologist to reduce the complications of cataract, glaucoma, and infection. 298 Ocular Allergy Conclusions Atopic dermatitis and rosacea are two chronic diseases that have both dermatologic and ocular manifestations. The ocular disease can be proportionately higher than the dermatologic disease, and, even if the skin abnormalities appear well-controlled, these patients require ophthalmic evaluation as well. Optimal management usually requires a team approach that includes internists, dermatologists, and ophthalmologists. Both disorders require maintenance therapy for control, but even with adequate maintenance therapy, acute exacerbations are common. Exacerbations need aggressive treatment to limit ocular signs and symptoms and to reduce ocular inﬂammation that can lead to permanent visual loss. Topical corticosteroid use should be minimized for both disorders. If they are required, the lowest dose should be used for the shortest time to reduce ocular inﬂammation and complications. Future research will probably continue to emphasize the use of steroidsparing and immune-modulating agents that have the potential to provide long-lasting anti-inﬂammatory treatment with a better side-effect proﬁle. Acknowledgments The views expressed in this manuscript are those of the author and do not reﬂect the ofﬁcial policy of the Department of the Army, the Department of Defense, or the United States Government. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1. 2. 3. 4. Foster CS, Calonge M: Atopic keratoconjunctivitis. 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