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Surface Matters | Nov/Dec '20

Ocular Rosacea: Essentials for Providers

An overview of diagnostic and treatment considerations.

Rosacea is a common skin condition that affects more than 16 million Americans.1 Under the umbrella of rosacea, ocular rosacea is a subtype that is present in up to 58% to 72% of people with rosacea-like features.2-4 Although dermatologic rosacea generally affects more women than men, ocular rosacea affects both sexes equally.3 The age distribution of people with ocular rosacea is similar to rosacea in that the condition affects mostly middle-aged adults.3

Patients with ocular rosacea may experience ocular and periorbital redness; eye discomfort such as foreign body sensation, burning, dryness, or itching; light sensitivity; and blurry vision. Signs include conjunctival and marginal telangiectasias, periocular erythema, blepharitis, meibomian gland dysfunction (MGD), recurrent hordeola or chalazia, and corneal involvement such as corneal infiltrates, ulcers, and keratitis.5 Sight-threatening consequences, although rare, can occur due to corneal involvement, which is present in one-third of patients with ocular rosacea.2,6

As many as 20% of patients with ocular rosacea have ocular findings before dermatologic findings, and 90% of patients with ocular rosacea have only subtle skin changes.4,7 Ocular rosacea’s association with MGD and blepharitis make the condition an important contributor to dry eye disease (DED), and, given the discordance between ocular and dermatologic findings, it is likely that ocular rosacea is underdiagnosed.

OPHTHALMIC CONSIDERATIONS

The most common manifestations of ocular rosacea are MGD, blepharitis, and eyelid conditions such as lid margin telangiectasia and lid margin notching. Inflammatory papules or pustules along the lid or lash line may also be noted. As such, ocular rosacea should be included in the differential diagnosis when evaluating patients who present with blepharitis or MGD. An example of the characteristic MGD with clogged meibomian glands is shown in the Video. Of note, the MGD, blepharitis, and lid manifestations can bring numerous inflammatory mediators such as interleukin (IL)-1α (IL-1α), IL-1ß, and matrix metalloproteinase-9 (MMP-9) to the eyelids and ocular surface; this, in combination with decreased meibomian gland secretions, can result in DED.8-10

Variations in local and systemic microbiomes may play a role in the pathogenesis, severity, and different phenotypes of rosacea. There is a significant association between facial and ocular rosacea and Demodex mites on the eyelashes, which may be related to the inflammatory presence of the mites, bacteria harbored inside the mites, or physical blockage of the meibomian gland causing eyelid margin inflammation. However, the exact role of Demodex in the pathophysiology of ocular rosacea is not entirely clear, as the amount of ocular irritation and symptomatology can vary widely among individuals who harbor Demodex. Despite the incomplete knowledge of the exact mechanism, there is a known association between Demodex and rosacea; therefore, microscopic evaluation for Demodex can be helpful in determining management plans.

Additionally, a patient may present with visual impairment resulting from ocular surface disease, corneal involvement, or periorbital edema causing eyelid edema. In particular, the corneal manifestations, seen in one-third of patients with dermatologic rosacea, progress from superficial punctate keratitis in the inferior third to peripheral neovascularization. Stromal ulceration, or rarely corneal perforation, can occur. Tear film abnormalities including tear film insufficiency, debris in the film, a foamy-appearing inferior tear meniscus, or diminished tear break-up time may be evident.3 The most common conjunctival manifestations are hyperemia (as seen in rosacea conjunctivitis) and papillary reaction. Cicatrizing conjunctivitis has been reported rarely, with one reported case mimicking trachoma by affecting the upper lids.11

MANAGEMENT

The treatment of ocular rosacea is based on both signs and symptoms of the disease. Given that many of the condition’s eyelid manifestations lead to MGD and DED, a majority of the treatments for ocular rosacea mimic those used for MGD and DED. Mild ocular rosacea can be managed with conservative measures such as warm compresses, artificial tears, and lid hygiene products (eg, baby shampoo scrubs and medicated formulations).

Warm compresses can help with MGD; however, some patients with ocular rosacea may find heat to be irritating to the inflamed eyelid skin. In-office procedures such as thermal pulsation or manual expression of the meibomian glands may be a better option in patients who are unable to tolerate warm compresses.

Lipid-based artificial tears are useful for supplementing the lipid portion of the tear film.13 In addition to decreasing overly rapid tear evaporation and improving tear spreading, lipid-based artificial tears have been shown to reduce corneal surface irregularities and decrease the levels of proinflammatory cytokines (IL-1β, IL-17, IP-10) in the conjunctiva.13 In a recent randomized controlled trial, a lipid-based artificial tear containing flaxseed oil and trehalose yielded significant improvement in dry eye signs compared to a nonlipid-based artificial tear.13 It is thought that these fatty acids can be converted into antiinflammatory molecules, including prostaglandins (which inhibit lymphocyte and neutrophil function) and lipoxin A4 (which can enhance ocular wound healing by modulating T-cell responses).13

Eyelid and lash cleansing are also important components of care, especially given the link between ocular rosacea, microbiome alterations, and Demodex infestation. Medicated lid hygiene products with hypochlorous acid can be beneficial. Hypochlorous acid, a naturally occurring substance produced by leukocytes, acts as an antibacterial agent and neutralizes the toxins produced by bacteria known to cause ocular irritation.14 It also reduces the bacterial load on the eyelids and has shown broad spectrum antimicrobial activity in vitro. Tea tree oil–based solutions such as Cliradex (4% terpinen-4-ol, Bio-Tissue) can have an antiinflammatory effect on the eyelid skin, likely largely due to the antimicrobial effect of tea tree oil against Demodex. However, tea tree oil may also directly mediate the oxidative response of leukocytes.15 In-office solutions for microblepharoexfoliation such as BlephEx (BlephEx) can be useful for removing biofilms from the eyelid margins as an adjunct or alternative to lid scrubs. BlephEx lid exfoliation has been shown to reduce MMP-9 on the ocular surface, possibly through reduction of bacterial load and elimination of inflammatory factors such as Demodex from the lids.16

For patients with ocular surface inflammation, topical prescription drops are of benefit. Examples include topical cyclosporine 0.05% (Restasis, Allergan) or 0.09% (Cequa, Sun Pharmaceuticals) and topical lifitegrast 5% (Xiidra, Novartis), which all act to increase aqueous tear production and decrease ocular surface inflammation.17 Patients can also be advised to consume omega-3 fatty acid supplementation, which may have beneficial effects on meibomian gland secretion and inflammation; evidence for their use, however, is mixed, as a recent large, multicenter randomized controlled trial found no difference between omega-3 supplementation and placebo on signs and symptoms of DED.18,19 In addition, the periocular skin manifestations of rosacea can be treated topically, with agents such as topical metronidazole in 0.75% or 1% formulations (Rosadan, G&W Laboratories) or azelaic acid in 15% gel or 20% cream (Azelex, Allergan). Other topical skin treatments include clindamycin, erythromycin, pimecrolimus, tacrolimus, and tretinoin, although tretinoin is not recommended for use around the eyes due to risk of meibomian gland destruction.20

Although steroids may exacerbate symptoms of ocular rosacea, their antiinflammatory effects may provide relief if used short-term and at a low dose. Topical steroids have traditionally been used along with the conservative measures mentioned previously as part of treatment for ocular rosacea. An example of a topical corticosteroid regimen is loteprednol etabonate 0.5% (Lotemax, Bausch + Lomb) four times daily and tapered by one dose per week over 4 weeks. Topical steroids can be especially useful for sterile corneal infiltrates and lid inflammation, although they should be tapered as early as possible to prevent unwanted adverse effects.21

Intense pulsed light (IPL) therapy is a noninvasive treatment in which high-intensity polychromatic light of 515 to 1,200 nm is applied to the periocular, preauricular, and eyelid skin. IPL is thought to improve DED and MGD by decreasing inflammation,22,23 and treatments are usually performed one to four times, 4 to 6 weeks apart. It is possible that IPL may cause coagulation and thrombosis of abnormal surface vessels and address the abnormal vasodilation seen in rosacea.22,23 Given the likely vascular mechanism of IPL’s action, it has been suggested that patients with ocular rosacea who also have associated lid margin telangiectasias and inflammation are the best candidates for IPL.15

Systemic therapies are extremely beneficial when topical treatments fail to fully control the signs and symptoms of rosacea. Doxycycline 40 mg (Oracea, Galderma) administered daily is considered a first-line oral medication option. Doxycycline has antiinflammatory and possibly antiangiogenic effects and specifically inhibits matrix metalloproteinases (MMPs) at lower doses than needed for antimicrobial activity. MMP-1 and MMP-9 in particular are known to induce angiogenesis and are decreased by doxycycline.24 Doxycycline has also been shown to decrease levels of inflammatory cytokines such as IL-1α, IL-1β, and TNF-α.25 Other oral medications that can be used for ocular rosacea include tetracyclines (500 mg twice daily), which also decrease MMPs and various cytokines, and azithromycin (500 mg daily), which may downregulate cytokines such as IL-6, IL-8, and TNF-α.26

For severe ocular rosacea, further intervention may be necessary. Punctal occlusion for dry eye may be considered; however, if a patient has symptoms or signs of DED, then reversal of the ocular surface inflammation should be completed before punctal plug placement. Recurrent or persistent styes or chalazia should be excised and sent for pathologic examination to rule out alternate causes such as sebaceous cell carcinoma. Corneal thinning or perforation, although rare, may require surgical intervention such as tissue adhesive, amniotic membrane transplantation, patch grafts, or even corneal transplantation.

CONCLUSION

Ocular rosacea is a common contributor to MGD and DED. Because it can lead to significant discomfort and morbidity, ophthalmologists and dermatologists alike should consider ocular rosacea in their differential diagnosis. The most common manifestations are MGD, blepharitis, and DED, with inflammation playing an integral role in the pathophysiology and sequelae of this disease. Improving our mechanistic understanding of its pathophysiology may shed light on how best to manage this condition. For example, understanding whether the ocular surface microbiome alterations seen in rosacea are cause or effect will allow for more targeted management. Additional randomized controlled trials are also needed to evaluate newer treatments and combinations of therapies in patients with ocular rosacea in order to determine the most optimal management strategies.

1. National Rosacea Society. Accessed August 4, 2020. www.rosacea.org

2. Ghanem VC, Mehra N, Wong S, Mannis MJ. The prevalence of ocular signs in acne rosacea: comparing patients from ophthalmology and dermatology clinics. Cornea. 2003;22(3):230-233.

3. Vieira AC, Mannis MJ. Ocular rosacea: common and commonly missed. J Am Acad Dermatol. 2013;69(6 Suppl 1):S36-S41.

4. Redd TK, Seitzman GD. Ocular rosacea. Curr Opin Ophthalmol. 2020;31(6):503-507.

5. Tan J, Berg M. Rosacea: current state of epidemiology. J Am Acad Dermatol. 2013;69(6 Suppl 1):S27-S35.

6. Karamursel Akpek E, Merchant A, Pinar V, Foster CS. Ocular rosacea: patient characteristics and follow-up. Ophthalmology. 1997;104(11):1863-1867.

7. Jabbehdari S, Memar OM, Caughlin B, Djalilian AR. Update on the pathogenesis and management of ocular rosacea: an interdisciplinary review [published online June 25, 2020]. Eur J Ophthalmol. doi:10.1177/1120672120937252

8. Barton K, Monroy DC, Nava A, Pflugfelder SC. Inflammatory cytokines in the tears of patients with ocular rosacea. Ophthalmology. 1997;104(11):1868-1874.

9. Lam-Franco L, Perfecto-Avalos Y, Patiño-Ramírez BE, Rodríguez García A. IL-1α and MMP-9 tear levels of patients with active ocular rosacea before and after treatment with systemic azithromycin or doxycycline. Ophthalmic Res. 2018;60(2):109-114.

10. Palamar M, Degirmenci C, Ertam I, Yagci A. Evaluation of dry eye and meibomian gland dysfunction with meibography in patients with rosacea. Cornea. 2015;34(5):497-499.

11. Ravage ZB, Beck AP, Macsai MS, Ching SST. Ocular rosacea can mimic trachoma: a case of cicatrizing conjunctivitis. Cornea. 2004;23(6):630-631.

12. Asoklis R, Malysko K. Ocular rosacea. N Engl J Med. 2016;374(8):771-771.

13. Lim A, Wenk MR, Tong L. Lipid-based therapy for ocular surface inflammation and disease. Trends Mol Med. 2015;21(12):736-748.

14. Epitropoulos AT. Lid hygiene product helps reduce blepharitis, MGD symptoms. Ophthalmology Times. November 15, 2015. Accessed September 19, 2020.

15. Caldefie-Chézet F, Guerry M, Chalchat JC, et al. Anti-inflammatory effects of Melaleuca alternifolia essential oil on human polymorphonuclear neutrophils and monocytes. Free Radic Res. 2004;38(8):805-811.

16. Connor CG, Narayanan S, Miller W. Reduction in inflammatory marker matrix metalloproteinase-9 following lid debridement with BlephEx. Invest Ophthalmol Vis Sci. 2017;58(8):498-498.

17. Schechter BA, Katz RS, Friedman LS. Efficacy of topical cyclosporine for the treatment of ocular rosacea. Adv Ther. 2009;26(6):651-659.

18. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-356.

19. Hussain M, Shtein RM, Pistilli M, et al. The Dry Eye Assessment and Management (DREAM) extension study: a randomized clinical trial of withdrawal of supplementation with omega-3 fatty acid in patients with dry eye disease. Ocul Surf. 2020;18(1):47-55.

20. Safran AB, Halioua B, Roth A, Saurat J-H. Ocular side effects of oral treatment with retinoids. Retinoids: 10 Years On. 1991;315-326.

21. Kilic Muftuoglu I, Aydin Akova Y. Clinical findings, follow-up and treatment results in patients with ocular rosacea. Turk J Ophthalmol. 2016;46(1):1-6.

22. Seo KY, Kang SM, Ha DY, Chin HS, Jung JW. Long-term effects of intense pulsed light treatment on the ocular surface in patients with rosacea-associated meibomian gland dysfunction. Cont Lens Anterior Eye. 2018;41(5):430-435.

23. Vegunta S, Patel D, Shen JF. Combination therapy of intense pulsed light therapy and meibomian gland expression (IPL/MGX) can improve dry eye symptoms and meibomian gland function in patients with refractory dry eye: a retrospective analysis. Cornea. 2016;35(3):318-322.

24. Quarterman MJ, Johnson DW, Abele DC, et al. Ocular rosacea: signs, symptoms, and tear studies before and after treatment with doxycycline. Arch Dermatol. 1997;133(1):49-54.

25. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithelium in experimental dry eye. Exp Eye Res. 2006;83(3):526-535.

26. Voils SA, Evans ME, Lane MT, Schosser RH, Rapp RP. Use of macrolides and tetracyclines for chronic inflammatory diseases. Ann Pharmacother. 2005;39(1):86-94.

author
Melissa Yuan, BA
author
Anna Marmalidou, MD
  • Postdoctoral research fellow, Massachusetts Eye and Ear Infirmary, Boston
  • annamarm@gmail.com
  • Financial disclosure: None
author
Ashley Brissette, MD, MSc, FRCSC
  • Assistant Professor of Ophthalmology, Weill Cornell Medicine, New York
  • asb9040@med.cornell.edu; Twitter @abrissettemd; Instagram @abrissettemd
  • Financial disclosure: Alcon, Allergan, Bruder, Carl Zeiss Meditec, Eyevance, Kala, Sun Pharmaceuticals
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Nov/Dec '20