Page 1 of 21
`
`Mark B. Abelson, MD, CM, FRCSC, FARVO,
`and Lisa Smith, Andover, Mass.
`PUBLISHED 5 MAY 2015
`A Stepwise Approach To
`Acute Dry Eye
`How to approach the occasional situation in
`which this chronic condition suddenly
`becomes acute.
`
`Dry-eye disease is well-recognized as a complex, chronic
`disease that needs chronic therapy. Superimposed on the
`intricate landscape of oxidative processes, immunological
`priming, autoimmunity and inflammatory responses are
`bouts of acute distress brought on by a constellation of
`extrinsic and intrinsic factors. Dry-eye-associated
`discomfort typically waxes and wanes, based on behavior
`and environment, as well as diurnal and seasonal
`biorhythms. Dry-eye subjects also use behavioral
`modification to optimize comfort and visual function.
`
`https://www.reviewofophthalmology.com/article/a-stepwise-approach-to-acute-dry-eye
`
`MYLAN - EXHIBIT 1074
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
`
`
`Mark B. Abelson, MD, CM, FRCSC, FARVO,
`and Lisa Smith, Andover, Mass.
`PUBLISHED 5 MAY 2015
`A Stepwise Approach To
`Acute Dry Eye
`How to approach the occasional situation in
`which this chronic condition suddenly
`becomes acute.
`
`Dry-eye disease is well-recognized as a complex, chronic
`disease that needs chronic therapy. Superimposed on the
`intricate landscape of oxidative processes, immunological
`priming, autoimmunity and inflammatory responses are
`bouts of acute distress brought on by a constellation of
`extrinsic and intrinsic factors. Dry-eye-associated
`discomfort typically waxes and wanes, based on behavior
`and environment, as well as diurnal and seasonal
`biorhythms. Dry-eye subjects also use behavioral
`modification to optimize comfort and visual function.
`
`https://www.reviewofophthalmology.com/article/a-stepwise-approach-to-acute-dry-eye
`
`MYLAN - EXHIBIT 1074
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
`
`
`Page 2 of 21
`
`Nevertheless, a few times a year, dry-eye subjects can fall
`off the wagon: an extended stay in the sauna; cleaning the
`attic; painting the house; an airplane trip; or hiking, skating
`or mountain biking on a dry, windy day. This is reckless
`behavior for a dry-eye subject who, like a Flying Wallenda,
`has to climb gingerly back up on the high wire after falling
`off.
`
`Non-environmental factors can also bring about an acute
`attack of dry eye. We need to ask questions: Did the
`patient have a recent bout of the flu, a gastrointestinal
`virus, a fever or episodes of vomiting that may have led to
`dehydration? Alternatively, is the patient experiencing the
`onset of menopause, which may have exacerbated a
`previously milder type disease? The introduction of new
`medications, such as an antihistamine, or a new
`antidepressant or antihypertensive therapy may also be
`responsible for acute worsening of dry eye.
`
`These acute episodes require not only stepping up the
`maintenance therapy, but also additional pulses of more
`robust therapeutic options to bring the patient back from
`the precipice. This month we’ll speak to the acute versus
`chronic presentations of dry eye and discuss how to
`recognize and treat them, as well as how to educate the
`
`https://www.reviewofophthalmology.com/article/a-stepwise-approach-to-acute-dry-eye
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`Page 3 of 21
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`patient in recognizing and pre-empting the downward cycle
`of ocular surface discomfort and damage.
`
`Clinical Presentation
`
`When a dry-eye patient presents with an abrupt worsening
`of her disease, what she’s feeling is acute, severe
`discomfort.
`
`When patients begin to suffer
`from acute dry eye,
`environmental factors often play
`a role. An airplane trip alone can
`be enough to bring on an acute
`episode of the disease.
`Innate protective blink mechanisms are overwhelmed by
`these acute challenges, and normal blink patterns are
`therefore altered, resulting in compromised visual function
`that is perceptible to the patient. To the clinician, the eyes
`1
`are very red, with prominent horizontal vessels in the
`interpalpebral fissure as well as under the lid. These are
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`Page 4 of 21
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`signs that the discomfort is not only environmental, but also
`endogenous in origin. There is occasionally scleritis, and
`there is profuse rose bengal and fluorescein staining.
`
`What has occurred is acute damage juxtaposed on the
`baseline chronic inflammatory state of dry eye. The body
`responds to this damage with a wound-healing process
`that is remarkably the same in all tissues: mounting of an
`inflammatory response; clearing away of the dead cells
`and tissues; and gradual mitotic renewal of the epithelial
`surface. This reparative process is impaired in the dry-eye
`patient due to a dysfunctional tear film in which the balance
`of tear constituents such as mucins and lipids is disrupted,
`2
`a situation that can prolong the reparative process and
`delay the biological cleanup to the point that it lasts weeks
`in the dry-eye patient instead of hours or days as in a
`normal subject.
`
`Most research in the past decade on dry-eye disease
`points to inflammatory processes at its origin. Even if we
`limit our discussion to non-systemic, non-Sjögren’s
`activation of dry eye, local inflammation plays a significant
`role. As with all inflammation, there are chronic and acute
`pathways that converge and diverge with different signals,
`but all must begin with an initiating, immunologically
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`priming event. The most challenging aspect of dry-eye
`research has been to pull apart these threads and try to
`identify which cell or pathway may be the initial instigating
`player. By the time the patient is bothered enough to go to
`the doctor, his or her clinical dry-eye disease is usually in
`its chronic stages and the continuous cycles of tear film
`instability are causing mounting inflammation. However, in
`the case of a dry-eye attack or exacerbation, the clinician
`has a chance to observe the disease in its acute, early
`stage. Understanding what happens at the inception of dry
`eye can give us greater insight on how best to manage
`acute exacerbations of the disease.
`
`Initial Steps in Acute Cases
`
`One of the earliest players in dry-eye disease is interleukin
`17 (IL-17), found in a subset of T cells called CD4+ T cells
`because they express the CD4 glycoprotein on their
`surface. CD4+ T cells mature along four distinct paths
`3-6
`determined by the pattern of signals they receive during
`antigen presentation; these are defined as Th1, Th2, Th17
`and regulatory T or T
`cells. This nomenclature is based
`regs
`on the primary cytokine secreted by each cell population:
`Th1 cells secrete interferon-gamma (IFN-γ); Th2 cells
`secrete interleukin-4, IL-5 and IL-13; and Th17 cells
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`secrete IL-17. CD4+ T cells are responsible for
`4
`surveillance of the ocular surface for infectious or noxious
`stimuli and, in systemic disease, are most notorious for
`their role in the pathophysiology of HIV infection, many
`neoplasms and autoimmune diseases such as diabetes.
`IL-13 and T
`are the good guys of this family because of
`regs
`their anti-inflammatory activity and the latter cells’ essential
`role in immune tolerance, both of which are dysfunctional
`in dry-eye disease.
`
`Several mouse models of CD4+ T cell biology have been
`key to understanding the role of these cells in the induction
`of dry eye.
`In one of these, mice were kept in an adverse
`3-6
`desiccating environment for 14 hours, and then watched
`for the next four months under normal environmental
`conditions. Their dry-eye disease peaked at 14 days, and
`3
`then slowly improved. However, even after 126 days, the
`corneal staining never returned to normal, demonstrating
`that chronic inflammation continued even months after the
`initial 14-day exposure trigger. In this study the acute
`phase of dry-eye disease was characterized by
`predominance of interferon-gamma (IFN-γ) and IL-17. After
`the adverse exposure had ceased, only IL-17 remained
`elevated. This IL-17 response was associated with
`lymphangiogenesis, or the growth of lymph vessels in and
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`around the cornea, a key event to priming the region for
`more antigen presenting cells and a richer immune
`response. Even more suggestive, when naïve mice receive
`Th17 cells, isolated from chronic dry-eye animals they
`developed disease much more quickly, peaking at day six
`versus day 14; their symptoms were also more severe than
`normal mice. If instead, T cells from mice in the acute
`phase were transferred, only slightly more severe disease
`was seen compared to normals. In both cornea and
`conjunctiva, chronic dry-eye mice were found to have the
`highest quantity of effector memory T cells, which contain
`twice the amount of IL-17 as in other T cells. What these
`fascinating experiments tell us is that the acute phase of
`dry eye is a function of both IL-17 and IFN-γ-containing
`Th1 cells and Th17 cells but that, in the chronic phase,
`Th17 cells predominate, propagating and priming the
`reaction by revving up lymphangiogenesis. These effector
`3
`memory T cells are called this exactly because they are the
`immune system’s permanent memory of a particular
`disease response, the key distinguishing element between
`chronic and self-limiting immune responses.
`7
`
`From this look at what might occur at the very onset of dry
`eye, you then have to imagine a domino effect, not just
`going forward, but also going backward and branching out
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`in many directions. These dominoes can be chemokines,
`such as CXCL9, -10, -11 and CXCR3, which recruit cells to
`the cornea and conjunctiva, amplifying the original signal
`sent out by cytokines. Soluble and cellular inflammatory
`6
`mediators such as HLA-DR and ICAM-1 on the
`conjunctival epithelium are universal features of dry eye.
`7
`Metalloproteinases such as MMP-9 are enzymes that lyse
`substrates in the corneal epithelial basement membrane
`and tight junctions, such as ZO-1 and occludin, both of
`which maintain epithelial integrity. These also are found
`increased in tear fluid of dry-eye patients and might be
`directly related to keratitis and staining.
`IL-13, which is a
`10
`“white hat” of the cytokine family, promotes goblet cell
`proliferation, dampens the inflammatory effects of IFN-γ,
`and is also decreased in dry eye. Oxidative stress as a
`11
`result of chronic inflammation then does damage to cells
`and tissues, leading to more antigenic presentation of self-
`material and further promotion of local inflammatory
`responses.
`12
`
`Clinical Ramifications
`The profound implications of inflammatory and oxidative
`processes are well-recognized in all branches of medicine.
`In dry eye, these processes lead to a dysfunctional lacrimal
`functional unit, which is how all of the components that
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`ultimately participate in forming and preserving an optimal
`tear film are denoted. These include lacrimal and
`meibomian glands, goblet cells, the cornea and conjunctiva
`the lids, and the sensory and motor nerves that
`communicate among all of these elements. A breakdown in
`any of these will lead to altered rheological properties and
`hyperosmolarity of tears, decreased corneal sensitivity and
`alterations in blink, and imperfectly anchored or dissolved
`mucins, all of which culminate in either aqueous-deficient
`or evaporative dry-eye disease.
`13
`
`Second Step: How to Treat
`First, it’s possible that an evaporative dry-eye patient who
`changes his medication regime can present with aqueous-
`deficient dry eye. Conversely, a classic case of aqueous
`deficiency may be complicated by the onset of meibomian
`gland dysfunction. If the patient is only on tear
`supplementation, stepping up tear production with
`continuous Restasis therapy (cyclosporine emulsion
`0.05%) is certainly advisable, coupled with adding an
`ointment at night such as Systane Ultra Nighttime Ointment
`(Alcon), and perhaps changing the tear substitute to a
`more viscous, retentive gel such as GenTeal Gel, Systane
`Ultra (Alcon) or Refresh Celluvisc (Allergan). However,
`addition of a single pulse of steroid therapy for squelching
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`these acute inflammatory episodes of dry eye might be the
`single best indication for steroid therapy for this disease.
`The discrete nature of these episodes, brought on by an
`identified intrinsic or extrinsic source, allows for an
`appropriate use of a drug that we all know to not use
`indiscriminately.
`
`Hypersecretion from the
`meibomian glands is one sign
`that meibomian gland
`dysfunction may play a role in
`the patient’s dry-eye complaints.
`Of course, if the exacerbated dry eye is due to a
`medication change, alternatives should be discussed with
`the patient and decided upon in collaboration with the
`patient and his primary-care physician.
`
`Corticosteroids and Dry Eye
`Corticosteroids mediate their anti-inflammatory effects
`primarily through modulation of the cytosolic glucocorticoid
`receptor at the genomic level.
`In the eye, we have
`14
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`fluorometholone, prednisolone acetate and
`dexamethasone to choose from, as well as the newer
`additions such as loteprednol etabonate. Different from
`conventional synthetic corticosteroids, loteprednol
`etabonate 0.5% suspension is designed as a site-active
`corticosteroid that undergoes relatively rapid metabolism to
`inactive metabolite, thus improving its safety profile relative
`to traditional steroids.
`15
`
`Studies have investigated various topical steroids in dry
`eye.
`Loteprednol was first investigated versus placebo
`16-19
`in 64 patients with four weeks of treatment. While primary
`endpoints were not met, in the subset of patients with at
`least moderate clinical inflammation there was significant
`improvement with loteprednol.
`14
`
`A more recent trial evaluated the effect of the addition of
`loteprednol two weeks prior to initiation of cyclosporine
`treatment. In 118 patients, loteprednol was found to
`provide a more rapid relief of dry-eye signs and symptoms,
`with greater efficacy than cyclosporine or artificial tears
`alone.
`In a Korean study, 32 patients with moderate to
`17
`severe dry eye were treated for eight weeks with 1%
`methylprednisolone q.i.d. in addition to artificial tears.
`Corneal and conjunctival staining and tear-film breakup
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`time were significantly improved from baseline, tear
`osmolarity decreased, and IL-1, IL-8 and monocyte chemo-
`attractant protein-1 were all significantly decreased at eight
`weeks compared to baseline. Thus, short-term steroid
`treatment was shown to improve all signs of dry eye in
`tandem with a lowering of tear cytokine levels.
`18
`
`In another study of 100 patients, the difference between
`preserved and non-preserved therapies was assessed
`using active therapies and tear supplementation. Half of
`the patients were treated with preservative-free sodium
`hyaluronate and 0.1% fluorometholone eye drops in the
`first month, continuing with the tears and Restasis for the
`second and third months. The other 50 patients were
`treated with identical preserved therapies. Researchers
`found that non-preserved therapies were more effective
`than their preserved counterparts in improving the
`following: symptoms; TFBUT; Schirmer’s I scores;
`impression cytology; IL-1β; IL-6; IL-12; and TNF-α. Non-
`preserved therapies also increased tears’ antioxidant
`contents. The authors speculate that benzalkonium
`chloride from the active and tear therapies causes
`significant oxidative/inflammatory damage that exacerbates
`dry-eye disease. While this study did not have a no-steroid
`arm, it was clear that all signs, symptoms and markers
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`improved with treatment compared to baseline.
`
`19
`
`In mouse models, various non-steroidal, anti-inflammatory
`drugs, corticosteroids and doxycycline were evaluated in a
`botulinum toxin B-induced mouse model of dry eye. While
`tear substitutes did not improve any sign of dry eye,
`fluorometholone, nepafenac and doxycycline all
`significantly improved corneal staining within two weeks.
`Topical ketorolac, diclofenac and bromfenac were less
`effective and slower to show any effect. Aqueous tear
`production started to return to baseline within two weeks,
`although not significantly; however, all other groups still
`had reduced tear production even as far out as four
`weeks.20 In a similar animal model, only topical
`fluorometholone was shown to improve tear production and
`signs, and NSAIDs were ineffective.
`21
`
`Dexamethasone was investigated preclinically in a rabbit
`model of dry eye involving lacrimal gland inflammation
`initiated by injection of the T cell mitogen, concanavalin A
`(ConA) followed by exposure to an adverse-environment
`chamber. This mitogen induces lymphocytic infiltration,
`necrosis and fibroplasia of lacrimal glands. Clinical
`manifestations of reduced TFBUT, tear clearance and
`corneal staining were all inhibited by topical pre-treatment
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`with dexamethasone 0.1% q.i.d. Post-exposure therapeutic
`efficacy was also shown when dexamethasone was
`administered two days following injection of ConA.
`22
`
`The anti-inflammatory properties of dexamethasone and
`other synthetic glucocorticoids are not the only properties
`that can profoundly affect the status of dry-eye disease.
`Dexamethasone in particular is known to modify a wide
`variety of immune functions by promoting a tolerogenic
`immune response.
`It has been shown to alter the
`23
`phenotype and function of dendritic cells, attenuating their
`priming responses. In a groundbreaking study,
`dexamethasone was used as an adjuvant to peptide
`antigens to induce expansion of antigen specific CD4+
`Fox3+ T , the “good-guy” regulatory T cells that dampen
`regs
`immune responses through heightened tolerogenesis.
`24
`Myeloid-derived suppressor cells also suppress T cell
`proliferation and function while promoting the good T .
`regs
`All of these immune-modifying properties of
`dexamethasone can benefit the dry-eye patient, not only by
`inhibiting the inflammation that has already occurred as a
`result of the initiated immunological priming, but also by
`preventing those initiating immune responses from
`recurring by rendering actively primed cells antigen-
`tolerant.
`
`23
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`Exploring different formulations of corticosteroids, or
`different platforms for their delivery, might be the ideal
`choice for treating acute episodes of dry-eye disease
`without worrying about steroid abuse or toxic effects with
`chronic use. One exciting new prospect in ophthalmic
`steroid development is the resorbable polyethylene glycol-
`based hydrogel punctal plug depot delivery system (Ocular
`Therapeutix). Inserted non-invasively through the inferior
`punctum, the plug resides within the canaliculus, delivering
`a four-week release of the corticosteroid to the ocular
`surface. The hydrogel is conjugated with fluorescein to
`provide confirmation of the product’s presence. This
`delivery system for dexamethasone contains approximately
`0.4 mg active drug and is designed to provide a sustained
`and tapered release of therapeutic levels for up to 30 days.
`Over time, and through hydrolysis, the depot-drug softens,
`liquefies and is cleared through the nasolacrimal duct. A
`product such as this could be inserted at the time of the
`visit, providing the dry-eye patient with one month of
`complete coverage, allowing for ideal treatment
`compliance in a discrete period, while eliminating potential
`washout of the supplemental tear substitute and/or other
`active therapy such as Restasis. This drug-eluting plug is
`already entering Phase III clinical trials for postoperative
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`inflammation, and has shown significant clinical efficacy
`compared with placebo, with 100-percent retention through
`day 14, and 97 percent through day 30. In this study, no
`long-term spikes in IOP were encountered, and the
`placebo subjects were prescribed significantly more rescue
`medication (ocutx.com/pipeline/dexamethasone-punctum-
`plug). This concept might be ideal for a dry-eye drug
`treating a spike of acute inflammation for several reasons:
`A constant, slow release of the active drug ensures
`effective concentrations; the choice of a local steroid allows
`for anti-inflammatory and anti-immune effects, altering the
`course of future localized autoimmune responses to
`noxious stimuli; and the unique pharmacokinetics improve
`the safety profile of the corticosteroid.
`
`To conclude, IL-17-rich CD4+ T cells appear to be at the
`origin of the immune response brought on by an acute
`environmental challenge; however, IL-17 T cells then
`sustain the memory of the disease long after the acute
`environmental onslaught has finished. Choosing a steroid
`like dexamethasone during these acute overlays of dry eye
`might benefit the patient not only in the short term by
`quenching the inflammatory reaction, but also might
`dampen responses to future environmental exposures,
`promoting a non-pathological response to adverse stimuli.
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`We look forward to more studies into this fascinating area
`of dry-eye research and hope to be able to use key pieces
`of this new information to better the treatment and lives of
`our patients. REVIEW
`
`Dr. Abelson is a clinical professor of ophthalmology at
`Harvard Medical School. Ms. Smith is a medical writer at
`Ora Inc.
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`Copyright © 2017 Jobson Medical Information LLC unless otherwise noted.
`All rights reserved. Reproduction in whole or in part without permission is prohibited.
`
`https://www.reviewofophthalmology.com/article/a-stepwise-approach-to-acute-dry-eye
`
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