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Corresponding author: Victor Perez, MDProfessor of Ophthalmology2351 Erwin Rd.Duke Eye Center, DUMC 3802Durham, NC 27710Phone: (919) 684-5769Email: victor.perez.quinones@duke.edu

Noninfectious Keratitis: An Expert Panel Recommendation

This work was supported by an unrestricted medical writing grant from Mallinckrodt Pharmaceuticals, and is based on a virtual roundtable discussion hosted by Evolve Medical Education LLC. This paper is being distributed with the Journal of Cataract & Refractive Surgery (JCRS). It has not been peer reviewed by JCRS.

Victor L. Perez, MD1

Brandon Ayres, MD2

Melissa Toyos, MD3 Rolando Toyos, MD3

1 Duke Eye Center, Durham, North Carolina2 Wills Eye Hospital, Philadelphia, Pennsylvania3 Toyos Clinic, Nashville, Tennessee

ABSTRACTAn expert panel of US physicians met via a 2-hour

webinar to discuss treatment of specific noninfectious keratitis disorders and to evaluate newer therapies as part of a step-wise treatment regimen. The panel eval-uated treatments for ocular surface disease (including dry eye), for ocular manifestations of autoimmune disorders, for peripheral ulcerative keratitis, and for neurotrophic keratitis. Steroid treatment remains first-line therapy, but the commercial introduction of other classes of medicines to treat ocular inflamma-tion has broadened the field.

INTRODUCTIONKeratitis—inflammation of the cornea—can be

caused by any number of infectious or noninfectious stimuli,1 and treatment of infectious keratitis will depend upon the underlying etiology. Noninfectious keratitis, however, can result from contact lens wear, dry eye, allergies, foreign body, corneal injury (trauma, chemical exposure), or ultraviolet exposure,2 or as the manifestation of an autoimmune systemic dis-order. Treatment for noninfectious keratitis is not as

clear-cut because of its highly variable nature.Noninfectious keratitis does not seem to be limited

to a particular age. A Chinese study found noninfec-tious corneal diseases occur mainly in people aged 10 to 19 years, but in patients 80 years or older, the most common cause was Terrien-marginal degeneration and Mooren ulcer.3

Some autoimmune disorders may lead to non-infectious keratitis,4-6 and the most severe ocular manifestation of autoimmune disorders is peripheral ulcerative keratitis (PUK).6 PUK is rare, and Mooren’s ulcer, senile marginal degeneration, sclerokeratitis and peripheral corneal melt of rheumatoid origin are some other potential causes (Figure 1).7 There is emerging anecdotal evidence that treatment of the ocular symp-toms may affect or improve the systemic disease.

Other common causes of noninfectious keratitis (after PUK) include vernal ulcers, staphylococcal mar-ginal keratitis, contact-lens related sterile infiltrates, and phlyctenular keratitis.7,8 Some disorders have been associated with several subsets of keratitis; for example, Salzmann nodular corneal dystrophy has been associated with phlyctenular keratitis, interstitial

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keratitis, vernal keratitis, and Thygeson superficial punctate keratitis.9 Neurotrophic keratitis may lead to decreased ocular surface sensation and dry eye.10

Infectious and noninfectious keratitis may overlap each other (as in the case of contact lens wear as a causal factor). Noninfectious keratitis may become infectious by pathogenic or nonpathogenic microbes, which can lead to sight-threatening complications.7 While infectious keratitis often has a finite duration and set treatment regimens, the inflammatory com-ponents of noninfectious keratitis can be chronic and persistent, often requiring a step-wise approach to disease management. Managing and resolving the inflammatory component remains part of a carefully managed active process.11

For refractory disease, patients may be managed surgically. Intense pulsed light (IPL) and conjunctival resection may also be considered (the latter for cases of PUK).

The recent increase in commercially available treat-ments for ocular inflammation, dry eye, and neu-rotrophic keratitis means clinicians have numerous treatment options in their armamentarium, which

then must be assessed for efficacy in comparison to older treatments and in developing a treatment regimen to include these newer agents. Treating the ocular disorder must be accomplished in the setting of the patient’s overall health, and in the case of auto-immune disorders, often in a comanaged situation. The panel developed this paper, therefore, intended to serve as a potential guideline for the treatment and management of noninfectious keratitis.

PATIENT EVALUATIONSKeratitis is typically classified by location, severity,

and cause.12 Superficial keratitis affects only the sur-face layer of the cornea, whereas stromal keratitis or interstitial keratitis affect deeper layers of the cornea. Keratitis can be acute or chronic, may be unilateral or bilateral. Allergies to airborne pollens and autoim-mune disorders can lead to noninfectious keratitis. Corneal ulcers and stem cell deficiency can be signs of vernal keratoconjunctivitis (typically considered the most severe form of ocular allergy).13 Noninfectious keratitis has also been associated with systemic dis-orders. In some cases of rheumatoid arthritis (RA), patients may develop marginal corneal ulceration with thinning of the cornea.12

Ulcerative inflammation of the cornea is associated with autoimmune diseases, and RA is the most fre-quent underlying cause.14 Development of PUK asso-ciated with systemic autoimmune disease may repre-sent the progression of a potentially life-threatening disease,14 as the mortality after a diagnosis of PUK can be higher than 50% (although the percentage drops significantly for those on immunosuppressive thera-pies).15 Ocular manifestations are a significant comor-bidity of autoimmune disorders, including RA, but evidence is emerging that suggests PUK may not be as prevalent as once thought.16 For instance, Vignesh and Srinivasan found only 1% of patients with RA pre-sented with PUK and sclerosing keratitis.16 The same group found multiple ocular manifestations of RA, including filamentary keratitis, episcleritis, sclerosing keratitis, and scleritis in addition to PUK.16 The pro-gression of PUK can be compounded by the presence of dry eye.

Figure 1. PUK (white lesion) can be readily seen upon exam.

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Patients with keratitis may be comanaged by rheumatologists, dermatologists, or a primary care physician when the initial presentation is outside the ocular system. For example, systemic diseases such as rosacea are also associated with ocular inflamma-tion (via abnormal blood vessels in the lid margins), although the large majority of patients noting ocu-lar complaints are overlooked.17-19 At present, there is no “gold standard” treatment for ocular rosacea, with topical treatment often insufficient and oral treatment providing only moderate benefits.19 For these patients, IPL can be effective; its use in treating skin rosacea has been well accepted for more than a decade.20-22 Numerous review publications support this technology’s use in treating dry eye as well.23,24

Nearly half the patients with RA will have clinical features of dry eye and more than one-third are symp-tomatic.15 Patients with RA will not show symptoms or signs of ocular involvement until later in their disease progression.16 Further, these patients present with both aqueous-deficient and evaporative dry eye.

Vascularization of the peripheral cornea (with or without epithelial defect), stem cell deficiency (with either limbal or corneal changes), and corneal thin-ning also indicate keratitis. If the stromal presentation of blood cells is superficial, stem cell deficiency should be considered whereas if the presentation is deep, allergies may be a more appropriate diagnosis.

TARGETING TREATMENTThe members of this panel believe steroids should

remain the first-line treatment for most incidents of keratitis, but that in today’s clinical environment physicians should have a low threshold to consider additional or alternative therapies that provide better safety profiles; we further advocate comanagement with other specialties when autoimmune disorders are present. The Table provides a brief overview of our recommendations.

In general, we advocate a 4- to 6-week cycle of ste-roids at the maximum, with an aggressive schedule for titration and a switch to a steroid-sparing or ste-roid-eliminating treatment. Pseudophakic patients can titrate at a slower rate because the threat of

cataract formation is nonexistent. Anecdotally, two panelists (MT and RT) have patients who, upon pre-sentation to an ophthalmologist, had an history of oral steroid use lasting 10 to 15 years.

Ocular Surface DiseaseIn 2017, the TFOS DEWS II report noted “many of

the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation” for a variety of rea-sons.25 TFOS DEWS II recommended tear replacement approaches, tear conservation approaches, tear stim-ulation approaches, and antiinflammatory therapy as overarching categories of therapy.

Topical corticosteroids had been the mainstay in targeting the inflammatory components25; in dry eye topical cyclosporine and lifitegrast (Xiidra, Shire)26-28 have become most clinicians’ preferred pharmaceu-tical therapy if topical lubricants are deemed ineffec-tive. Topical nonsteroidal antiinflammatory drugs, however, have not been shown to have a consistent safety profile for patients with dry eye.25 Biologics have shown promise, specifically recombinant human nerve growth factor (rhNGF), tumor necrosis factor inhibitors, and antiinterleukin-17 (IL-17) therapy.25 Of interest, neuropeptides have been studied in moder-ate and severe neurotrophic keratitis in patients with concomitant dry eye.25 For patients with refractory or more severe ocular surface disease, surgical approach-es may be warranted.

Inflammatory cells (including lymphocytes, mono-cytes/macrophages, and neutrophils) express mela-nocortin receptors.29 The literature finds adrenocorti-cotropic hormone (ACTH) to be more effective than corticosteroids, and steroid-sparing.30-32 Although the mechanism of action is not fully understood, anecdot-al evidence suggests ACTH is not only beneficial in treat-ing ocular inflammation, but also in alleviating symp-toms when there is an associated systemic disorder.

This panel also recommends topical treatments, including T-cell modifiers. These treatments include cyclosporine, lifitegrast, and tacrolimus. Both tacro-limus and cyclosporine block T-lymphocyte activi-ty.25 The exact mechanism of action of lifitegrast is

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TABLE. NONINFECTIOUS KERATITIS MANAGEMENT RECOMMENDATIONSLevel 1: Mild Ocular Disease Level 2: Moderate Ocular Disease Level 3/4: Severe Ocular Disease

Ocular Sur face DiseaseClinical Features/Presentation

Blurred vision, episodic foreign body sensation, Low tear film, conjunctival staining, +MMP-9, elevated tear film osmolarity

Blurred vision with FBS daily. Signs of ocular inflammation, and staining on peripheral cornea

Severe symptoms, diffuse staining on cornea, fila-ments, ulceration of cornea, stem cell changes

Treatment Ar tificial tears, nutritional supplements PFATs, prescription anti-inflammatory, plugs PFATs, topical steroid, prescription anti-inflammato-ry, systemic immunosuppression

Management OTC medications and disease state education

Star t with prescription topical antiinflam-matory, PFAT, consider plugs if minimal signs of inflammation on tear film testing.

Use of topical steroid and work up for inflammatory disease. Consider use of oral immunomodulator aggressive topical treatment . Consider placement of self-retaining AMT

Autoimmune DisordersClinical Features/Presentation

Mild ocular injection, ocular ache, mild anterior chamber reaction

Moderate symptoms, significant corneal staining, signs of inflammation in tear film (MMP-9, tear film osmolarity)

Severe staining, diffuse corneal staining, signs of ocular inflammation, corneal erosions, filaments

Treatment Prescription topical antiinflammatory agents

Topical anti-inflammatory agentsTopical steroid, NPAT, punctal plugs

PFATs, topical steroid, prescription antiinflammatory, systemic immunosuppression

Management PFAT, nutritional therapy, and topical pre-scription cyclosporine or lifitegrast

Consider topical steroid and NSAID. Must control inflammatory disease with systemic immunomodulator

Institute systemic immunomodulator. Aggressive topical treatment with steroid and NSAID. Consider placement of self-retaining AMT or another ocular sur face surgery if warranted.

Proliferative Ulcerative KeratitisClinical Features/Presentation

Ocular pain and photophobia, foreign body sensation, ocular injection, inflam-matory infiltrate at limbus

Moderate to severe pain, limbal injection, and crescent shaped epithelial defect with thinning

Severe pain and injection. Peripheral epithelial defect with thinning/per foration

Treatment Topical prescription antiinflammatory, oral NSAID, topical lubrication

Consider steroid sparing agents, topical steroid drops (difluprednate) MMP-9 inhibitor

Oral steroidSystemic immunosuppressionMMP-9 inhibitorLubricationSelf-retaining amniotic membrane

Management Work up for inflammatory disease, initiate treatment with topical anti-inflammatory

Aggressive topical lubrication and consider comanagement with rheumatology. Treat with full strength topical steroid and begin systemic steroid sparing agents.

Immediate induction of topical steroid with a steroid sparing agent . Use of MMP-9 inhibitor (doxycycline, vitamin C, etc .). May need to use self-retaining AMT. Consider surgical intervention if no improvement , per foration, or impending per foration with multilay-er AMT, or patch graft .

Neurotrophic KeratitisClinical Features/Presentation

No pain, elevated epithelial ridge with sur face staining

Small epithelial defect with rolled edges, diffuse corneal staining

Large epithelial defect with rolled edges and corne-al haze, diffuse corneal stain, stem cell changes

Treatment Punctal plugs, NPAT, ointments and gels Plugs, PF ar tificial tears, BCL , self-retaining AMT

Plug, PFAT, AMT, tarsorrhaphy

Management Aggressive lubrication and placement of punctal plugs

Place plugs and encourage topical drops, consider BCL if epithelium does not close, consider recombinant nerve growth factor (ie, Oxervate)

Plug punctum and use PFATs and ointment . Place self-retaining AMT and consider tarsorrhaphy. Also consider use of recombinant nerve growth factor

MMP-9=matrix metallopeptidase; FBS=foreign body sensation; PFAT=preservative-free ar tificial tears; OTC=over the counter; AMT=amniotic membrane transplanta-tion; NPAT=nonpreserved ar tificial tear; NSAID=nonsteroidal anti-inflammatory drug; BCL=bandage contact lens

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unknown, but is theorized to involve blocking the interaction between lymphocyte function-associated antigen-1 (LFA-1) and its ligand intracellular adhesion molecule (ICAM-1).33

Blood-derived eye drops can supply a mixture of growth factors and cytokines and can promote the healing of natural tears,34 but more research and ran-domized clinical trials are necessary before this panel can comment.

Autoimmune DisordersThe underlying autoimmune disorder should dictate

treatment. Comanagement with a rheumatologist is recommended when treatment involves biologics.

Ocular rosacea typically is treated with a step-wise approach; the disorder can lead to severe and recal-citrant blepharitis. Treatment progresses from lid hygiene and artificial tears to topical and oral antiin-flammatory medications. One review suggested oral tetracycline (titrated to clinical response), oral doxy-cycline, or a combination of the two.18 However, the specific mechanisms of action in how these medica-tions address ocular rosacea remain unknown.35 Oral doxycycline, minocycline, and azithromycin have been studied extensively,35 but results have been varied and side effects remain a common complication. In its review, the American Academy of Ophthalmology noted only a modest level of evidence exists to sup-port using these treatments.36 The American Acne and Rosacea Society recommends IPL to address spe-cific clinical manifestations that exhibit limited or no response to available medical therapies, and this panel concurs.37 Topical cyclosporine is also an effective treatment for rosacea-associated ocular complica-tions.19 Periocular steroids may be considered if the patient is on the verge of a keratitis flare; this panel recommends difluprednate in those instances. IPL is also effective in rosacea-associated meibomian gland dysfunction.38 Because it is more targeted than oral or topical products, this panel recommends use of IPL for the treatment of ocular rosacea. This panel recom-mends only short-term use of corticosteroids.

Rituximab (Rituxan, Genentech) has also been used successfully for treating severe scleritis and PUK

associated with not only RA, but Sjogren syndrome and in cases resistant to Wegener granulomatosis treated with antitumor necrosis factor.39

Repository corticotropin injection (RCI; H.P. Acthar Gel, Mallinckrodt) is biologically derived and includes a 1-39 peptide chain. Among its 19 approved indi-cations is the treatment of severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa (including keratitis). Of note, H.P. Acthar Gel is also approved as an adjunct therapy for short-term administration in select cases of RA.

When choosing a systemic steroid treatment, this panel advocates a maximum prednisone dosage of 1 mg/kg/day, and to consider the side effect profile of endogenous versus synthetic steroids. Systemic ste-roids should be used as induction agents only. RCI has a preferable side effect profile, but optimal dosing and treatment duration have yet to be established.

Immunosuppressive agents and/or TNF-blockers are often used to treat autoimmune disorders; these may include adalimumab (Humira, AbbVie), etaner-cept (Enbrel, Amgen), hydroxychloroquine (Plaquenil, Sanofi-Aventis), or infliximab (Remicade, Janssen Immunology). Antimetabolite therapy may include agents such as methotrexate, mycophenolate, or aza-thioprine. It is common for these agents to be admin-istered by nonophthalmic health care providers.

Because of its safety profile, this panel recommends the use of RCI in lieu of methotrexate.

PUKIf there is an infective cause or secondary infection,

treating the infection must take precedence over addressing the noninfectious components.15

First-line treatment of PUK during acute phases is pri-marily systemic corticosteroids, but immunosuppres-sive and cytotoxic agents are required for treatment of PUK associated with multisystem disorders.14,40 PUK is often contiguous with adjacent conjunctival, episcleral, and scleral inflammation, but this adjacent tissue can sometimes aggravate the course of PUK and cause serious corneal complications.14 Necrotizing scleritis is often present in the region adjacent to PUK when autoimmune disorders are present.14

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Aggressive systemic treatment is often warranted in cases of collagen vascular disease-related PUK to delay the progression of corneal destruction.4,41 In cases where disease-modifying antirheumatic drugs, biologic therapy, or high-dose systemic corticosteroids are unsuccessful, rituximab has been used with some success.42

A recent study in the United Kingdom evaluated PUK and corneal melt over a 10-year single center review and found all patients had initially been pre-scribed systemic corticosteroids, and all but two of the 70 were treated with steroid-sparing immuno-suppressive agents as well. Among the medications prescribed were prednisolone, methotrexate, myco-phenolate, tacrolimus, and azathioprine.43 Necrotizing PUK may occur in the absence of raised inflammatory markers of RA.15

Rescue therapy and pulsed intravenous glucocorti-coid therapy, followed by high-dose oral glucocorti-coids in conjunction with steroid-sparing antiprolifer-ative agents (eg, mycophenolate mofetil, methotrex-ate, and azathioprine) or T-cell inhibitors (eg, cyclo-sporine, tacrolimus), if the patient is not already on disease-modifying antirheumatic drugs (DMARDs) are necessary to rapidly control inflammation.44 Severely active necrotizing disease associated with scleritis warrants the use of pulsed oral or pulsed intravenous cyclophosphamide therapy.44

The literature also notes treatment with alkylating agents such as chlorambucil and cyclophosphamide may be effective, with cyclophosphamide more com-monly used in the treatment of PUK, when PUK is associated with a connective tissue disorder.14

Filamentary KeratitisPatient presentation often includes complaints

of foreign body sensation or photophobia, but may also have redness, epiphora, or blepharospasm. Filamentary keratitis is associated with dry eyes, superficial punctate keratopathy, ptosis, and tear film stasis.45 Pronkin et al found nearly 90% of patients with filamentary keratitis had endocrine pathology, rheumatoid disease, or a combination of both, leading them to suggest this disorder is not a form of severe dry eye but a separate dystrophic corneal disorder

with dry eye as its symptom.46 Indeed, several condi-tions are associated with filamentary keratitis, includ-ing aqueous tear deficiency and exposure syndromes, occlusion syndromes, postsurgical syndromes, mani-festations of systemic and autoimmune disorder; cer-tain medications have been associated with this type of keratitis as well.45

Acute presentations can resolve spontaneously, but often the disease is chronic, and initial treatment will depend on the underlying etiology.45 Initial treatment is topical tear film substitutes, but other medical treatments include topical cyclosporine, oral tetracy-cline derivatives, omega-3 fatty acid supplementation, topical azithromycin, and lid hygiene.45 Other poten-tial treatments include N-acetylcysteine and bandage contact lenses (BCL). N-acetylcysteine, however, is not available commercially and without a preserva-tive-free formulation, may only be minimally useful.45 BCLs have shown success when other ocular lubrica-tion treatments have failed.45 Targeting the inflamma-tion with short bursts of topical methylprednisolone has been successful, as has treatment with topical nonsteroidal antiinflammatory drugs but the latter can be toxic to damaged epithelium.45

Neurotrophic KeratitisTrigeminal nerve damage may cause neurotrophic

keratitis (also referred to as neurotrophic keratop-athy), and can results from a variety of entities that impair corneal innervation, with treatment based on disease severity.47,48 All stages of the disease cause some vision loss and profound vision loss can occur if left untreated (Figure 2).48

In Europe, extracellular matrix regenerators (RGTA; Cacicol, Thea) are becoming an efficient and accessi-ble therapy for neurotrophic keratitis.49 These heparin sulfate analogs have been to protect and stabilize the action of growth factors and case studies in patients with neurotrophic keratitis resistant to conventional therapies reported positive results after treatment with the matrix therapy.

Nexagon, a 30-base antisense oligomer (Eyevance Pharmaceuticals), may have potential in the treatment of persistent corneal epithelial defects, but

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more data is needed before this panel can endorse the treatment. Nexagon is a first-in-class unmodified antisense oligodeoxynucleotide that inhibits a cell membrane hemichannel forming protein, connexin43 (Cx43). Nexagon inhibits Cx42 overexpression and the inflammatory cascade to reestablish limbal micro-vasculature and promote regeneration of the corneal epithelium.50

More recently, recombinant human nerve growth factor (cenegermin, Dompe) was recently approved in Europe after several studies found it improved corneal sensitivity and promoted corneal epithelial healing in moderate and severe neurotrophic keratitis.48,51,52 The US Food and Drug Administration approved the drug in August 2018, making it the first commercially avail-able drug with this indication in the United States.53

There is some suggestion in the literature that platelet-rich plasma (PRP) may be beneficial in neurotrophic keratitis.54-57 Alio et al enrolled 44 eyes (28 patients) with dormant corneal ulcers secondary

to corneal surgery and treated them with autologous PRP during the course of 6 weeks. Of the eyes, 28 (65.1%) improved VA by at least 1 Snellen line, while just below 60% had a decrease in ulcer size or even a total closure.55 Sanchez-Avila et al also found plasma rich in growth factors (PRGF) to be a potentially safe and effective treatment option for patients with stages 2 to 3 of neurotrophic keratitis. Guadilla et al published earlier that PRGF may be more effective than 20% autologous serum in patients with lower grade neurotrophic keratitis, and suggested PRGF may have a greater effect on cell proliferation.57

In this panel, experience with using PRGF is limited, but encouraging responses have been seen with PRP for the treatment of neurotrophic keratitis.

Autologous serum for the treatment of persistent epithelial defects has shown promise as well, with a cure rate of 43.8% within 2 weeks and 62.5% within 1 month.58 A more recent review showed amniotic membrane to be a superior treatment than autol-ogous serum or artificial tears in corneal epithelial wound healing.59

CONCLUSIONThe treatment of noninfectious keratitis is as varied

as its causes. In general, artificial tears and antiinflam-matory agents may be sufficient for mild cases. For moderate to severe cases, however, topical steroids, steroid-sparing agents, immunosuppressive agents, and/or amniotic membrane transplantation may be warranted. In cases of autoimmune disorders, coman-agement with a rheumatologist is recommended, as treatment may include the use of biologics.

ACKNOWLEDGEMENTSThe authors report the following financial disclosures: Dr. Ayres is a consultant for Alcon, Allergan, Avedro,

Biotissue, Omeros, Shire, and Sight Sciences.Dr. Perez is a consultant for Alcon, Cambium,

Dompe, Mallinckrodt, and Shire; he has an ownership equity in OB Tears.

Dr. (M.) Toyos is a consultant for Bausch + Lomb, Carl Zeiss Meditec, Eyevance, Iridex, Mallinckrodt Pharmaceuticals, Shire, and Sun Pharmaceuticals.

Figure 2. Sodium fluorescein (NaFL) staining allows for better visualization of a neurotrophic keratitis lesion.

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She is a researcher or on the speakers’ bureau for Bausch + Lomb, Carl Zeiss Meditec, DigiSight, Gilead Sciences, Iridex, Lumenis, Kala, Magellan, Mallinckrodt Pharmaceuticals, MIXTO Lasering, Ocular Technologies, Oculos Clinical Research, Opternative, ReVitaLid, Shire, and Sun Pharmaceuticals.

Dr. (R.) Toyos is a consultant for Bausch + Lomb, Carl Zeiss Meditec, Eyevance, Iridex, Mallinckrodt Pharmaceuticals, Shire, and Sun Pharmaceuticals. He is a researcher or on the speakers’ bureau for Bausch + Lomb, Carl Zeiss Meditec, DigiSight, Gilead Sciences, Iridex, Lumenis, Kala, Magellan, Mallinckrodt Pharmaceuticals, MIXTO Lasering, Ocular Technologies, Oculos Clinical Research, Opternative, ReVitaLid, Shire, and Sun Pharmaceuticals.

Michelle Dalton, ELS, provided independent medial writing and editorial support; this support was funded by Evolve Medical Education LLC.

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