Dry Eye Disease

Complex MONDO:0006733 Pathograph 28 Show in embeddings browser Ocular surface disorder Lacrimal system disorder

Dry eye disease is a multifactorial, symptomatic ocular-surface disease in which homeostasis of the tear film and/or ocular surface is lost. Tear-film instability and hyperosmolarity, ocular-surface inflammation and damage, and neurosensory abnormalities can contribute in different combinations. Lipid, aqueous, and mucin/glycocalyx deficiencies; eyelid abnormalities; and primary ocular-surface or neural processes are overlapping etiologic drivers rather than mutually exclusive disease categories.

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12
Pathophys.
7
Phenotypes
1
Hypotheses
1
Gaps
28
Pathograph
4
Medical Actions
5
Subtypes
1
Differentials
1
Deep Research
◆

Subtypes

5
Aqueous tear-deficient dry eye disease
A clinical form in which insufficient aqueous tear production is a dominant driver. It includes Sjögren-associated and non-Sjögren forms and may overlap with evaporative disease.
  • Sjögren-Associated ADDE
  • Non-Sjögren ADDE
Show evidence (2 references)
PMID:35681232 SUPPORT Other
"Clinically, DED can be divided into two main types, aqueous tear-deficient dry eye and evaporative dry eye [2]."
This review explicitly identifies aqueous-deficient DED as a principal clinical form.
PMID:35681232 SUPPORT Other
"Aqueous tear-deficient dry eye can be subdivided into two categories, Sjögren’s dry eye type and non-Sjögren’s dry eye type."
This review explicitly identifies its Sjögren and non-Sjögren subdivisions.
Sjögren-associated aqueous tear-deficient DED
Aqueous tear-deficient DED occurring as an ocular manifestation of Sjögren syndrome. This form can be severe and may coexist with meibomian-gland or other evaporative contributors.
Show evidence (1 reference)
PMID:35681232 SUPPORT Other
"Aqueous tear-deficient dry eye can be subdivided into two categories, Sjögren’s dry eye type and non-Sjögren’s dry eye type."
The review recognizes Sjögren-associated dry eye as a subdivision of aqueous tear-deficient DED.
Non-Sjögren aqueous tear-deficient DED
Aqueous tear-deficient DED without Sjögren syndrome, including lacrimal functional impairment arising through other etiologies.
Show evidence (1 reference)
PMID:35681232 SUPPORT Other
"Aqueous tear-deficient dry eye can be subdivided into two categories, Sjögren’s dry eye type and non-Sjögren’s dry eye type."
The review recognizes non-Sjögren dry eye as the other subdivision of aqueous tear-deficient DED.
Evaporative dry eye disease
A clinical form dominated by excessive tear evaporation, commonly with meibomian gland dysfunction or other eyelid and ocular-surface contributors.
Show evidence (1 reference)
PMID:40472874 SUPPORT Other
"Pathophysiological distinctions between aqueous deficient and more evaporative forms of DED have been clarified, with the latter most commonly characterized by a muted inflammatory response at the ocular surface, meibomian gland dysfunction, and conceivably phenotypic changes in corneal epithelial cells."
The current consensus digest characterizes the evaporative form and its frequent meibomian-gland contribution.
Mixed aqueous-deficient and evaporative DED
A common overlapping form in which aqueous deficiency and excessive evaporation contribute together rather than defining mutually exclusive disease categories.
Show evidence (1 reference)
PMID:35681232 SUPPORT Other
"Studies have shown that many patients have both aqueous tear-deficient and evaporative dry eye, and both types share the common feature of inflammation [3]."
This supports an overlapping mixed form rather than a forced binary classification.
◈

Mechanistic Hypotheses

1
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
multidriver_tear_film_homeostasis_model CANONICAL
Evidence balance 2 support
DED is modeled as a heterogeneous loss-of-homeostasis state. Different combinations of tear-film deficiency, eyelid dysfunction, ocular-surface stress, inflammation, epithelial damage, and neurosensory dysfunction can converge on symptoms; no single downstream node is asserted to be present or dominant in every patient.
Pathograph links
Meibomian Gland Dysfunction -> Lipid Tear-Film Deficiency INDIRECT KNOWN INTERMEDIATES Meibomian-gland dysfunction reduces or alters the lipid supplied to the tear film, thereby establishing a lipid-deficient evaporative driver. Intermediates: impaired meibum delivery to the tear-film lipid layer
Lipid Tear-Film Deficiency -> Tear-Film Instability and Hyperosmolarity INDIRECT KNOWN INTERMEDIATES Loss of an effective lipid layer increases evaporation and destabilizes the tear film. Intermediates: increased tear evaporation
Aqueous Tear Deficiency -> Tear-Film Instability and Hyperosmolarity INDIRECT KNOWN INTERMEDIATES Reduced aqueous volume decreases tear-film reserve and increases concentration and instability at the ocular surface. Intermediates: reduced aqueous tear volume
Aqueous Tear Deficiency -> Decreased lacrimation DIRECT Reduced aqueous secretion is clinically expressed as decreased lacrimation.
Mucin and Glycocalyx Tear-Film Deficiency -> Tear-Film Instability and Hyperosmolarity INDIRECT KNOWN INTERMEDIATES Mucin or glycocalyx deficiency reduces tear-film wetting and retention, promoting breakup and osmotic stress. Intermediates: impaired tear spreading and ocular-surface retention
Blink and Lid-Closure Abnormality -> Tear-Film Instability and Hyperosmolarity INDIRECT KNOWN INTERMEDIATES Reduced or incomplete blinking permits greater evaporative loss and prevents uniform replenishment of the tear film. Intermediates: impaired tear and lipid redistribution with increased interblink evaporation
Lid-Margin Abnormality -> Tear-Film Instability and Hyperosmolarity INDIRECT KNOWN INTERMEDIATES Lid-margin disease can destabilize the tear film through altered spreading and lipid delivery. Intermediates: disrupted tear-film spreading and lipid delivery
Ocular-Surface Anatomical Misalignment -> Tear-Film Instability and Hyperosmolarity INDIRECT KNOWN INTERMEDIATES Anatomical misalignment can produce uneven tear coverage and local instability. Intermediates: uneven tear distribution and exposed ocular-surface regions
Tear-Film Instability and Hyperosmolarity -> Ocular-Surface Osmotic and Oxidative Stress INDIRECT KNOWN INTERMEDIATES Hyperosmolar exposure can increase oxidative stress in corneal epithelial cells, although oxidative stress can also arise through other DED drivers.
Tear-Film Instability and Hyperosmolarity -> Ocular-Surface Innate and Adaptive Inflammation INDIRECT KNOWN INTERMEDIATES Hyperosmolar stress can amplify cytokine and MAPK-mediated inflammation when this inflammatory arm is active.
Tear-Film Instability and Hyperosmolarity -> Blurred vision DIRECT Tear-film breakup produces a fluctuating optical surface and can therefore manifest as intermittent blurred or fluctuating vision.
Ocular-Surface Osmotic and Oxidative Stress -> Ocular-Surface Innate and Adaptive Inflammation INDIRECT KNOWN INTERMEDIATES Reactive oxygen species and inflammatory signaling can reinforce one another in experimental DED.
Ocular-Surface Osmotic and Oxidative Stress -> Corneal and Conjunctival Epithelial Damage INDIRECT KNOWN INTERMEDIATES Sustained oxidative stress can contribute to epithelial DNA damage and loss of ocular-surface integrity.
Ocular-Surface Innate and Adaptive Inflammation -> Corneal and Conjunctival Epithelial Damage INDIRECT KNOWN INTERMEDIATES Persistent effector-cell activity and cytokine signaling can damage corneal and conjunctival epithelial tissues and restart innate responses.
Ocular-Surface Innate and Adaptive Inflammation -> Conjunctival hyperemia INDIRECT KNOWN INTERMEDIATES Ocular-surface inflammation can produce conjunctival redness through local inflammatory vascular responses. Intermediates: inflammatory vasodilation of conjunctival vessels
Corneal and Conjunctival Epithelial Damage -> Neurosensory Dysfunction and Ocular Pain INDIRECT KNOWN INTERMEDIATES Ocular-surface injury can alter corneal-nerve structure or signaling and contribute to pain, while pain can also persist through peripheral or central neural mechanisms that are not proportional to surface damage.
Corneal and Conjunctival Epithelial Damage -> Keratoconjunctivitis sicca DIRECT Damage and dryness affecting both corneal and conjunctival epithelia are clinically expressed as keratoconjunctivitis sicca.
Neurosensory Dysfunction and Ocular Pain -> Ocular pain DIRECT Altered peripheral or central sensory processing can directly produce ocular pain.
Neurosensory Dysfunction and Ocular Pain -> Photophobia INDIRECT UNKNOWN INTERMEDIATES Altered ocular sensory processing can accompany the light sensitivity reported in DED, although the intervening circuitry is not asserted here.
Neurosensory Dysfunction and Ocular Pain -> Corneal foreign body sensation INDIRECT UNKNOWN INTERMEDIATES Abnormal ocular-surface sensory signaling can manifest as foreign-body sensation even when no foreign material is present.
Show evidence (2 references)
PMID:40451408 SUPPORT Other
"Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors."
The current TFOS DEWS III definition supports a multidriver model centered on loss of tear-film and/or ocular-surface homeostasis.
PMID:40472874 SUPPORT Other
"Pathophysiological distinctions between aqueous deficient and more evaporative forms of DED have been clarified, with the latter most commonly characterized by a muted inflammatory response at the ocular surface, meibomian gland dysfunction, and conceivably phenotypic changes in corneal epithelial cells."
This qualifies the model: inflammatory intensity and dominant drivers differ across DED forms, so the pathograph is not a mandatory linear sequence for every patient.
?

Discussions and Knowledge Gaps

1
Can controlled topical carbon-monoxide delivery reproduce the reported antioxidant, anti-inflammatory, and epithelial-reparative effects safely in human DED, and in which etiologic endotypes would its multi-target mechanism be appropriate?
HUMAN MODEL MISMATCH OPEN dry_eye_co_nanoplatform_human_translation
Attached to
treatments#Visible-Light-Activated Carbon-Monoxide Nanoplatform (Preclinical) pathophysiology#Ocular-Surface Osmotic and Oxidative Stress pathophysiology#Ocular-Surface Innate and Adaptive Inflammation
The cited efficacy and mechanism data come from a five-day murine DED study. DED is heterogeneous, evaporative forms can have muted inflammation, and CO exposure has a narrow safety context. Translation therefore requires endotype selection, ocular and systemic safety assessment, controlled dose and light-delivery studies, and randomized human efficacy data.
Show evidence (1 reference)
PMID:42439592 SUPPORT Model Organism
"In a murine DED model, topical administration of MCF for 5 days achieved 84% corneal epithelial recovery and alleviated corneal inflammation and tissue injury."
The evidence is explicitly limited to a short murine study, motivating the human-translation gap.
⚙

Pathophysiology

12
Meibomian Gland Dysfunction
Dysfunction of the tarsal (meibomian) glands is a major, but not universal, evaporative DED driver. Altered delivery or quality of meibum compromises the tear-film lipid layer and increases evaporative stress.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
meibomian gland UBERON:0001818 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in meibomian gland, annotated with tarsal gland (UBERON:0001818). UBERON:0001818 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Lipid Tear-Film Deficiency Meibomian-gland dysfunction reduces or alters the lipid supplied to the tear film, thereby establishing a lipid-deficient evaporative driver. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40467022 SUPPORT Other
"Meibomian gland dysfunction, a primary contributor to DED, is typically treated with warm compresses and a wide variety of in-office treatments, including device-driven technologies to warm the eyelids, intense pulsed light therapy, low-level light therapy, and other new and emerging technologies."
The current consensus identifies meibomian gland dysfunction as a primary DED contributor and anchors it to gland-directed therapy.
Lipid Tear-Film Deficiency
Insufficient or compositionally abnormal tear-film lipid permits excessive evaporation. It may arise from meibomian gland dysfunction or other lipid delivery abnormalities.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
tear film UBERON:0022287 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in tear film (UBERON:0022287). UBERON:0022287 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tear-Film Instability and Hyperosmolarity Loss of an effective lipid layer increases evaporation and destabilizes the tear film. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary..."
TFOS DEWS III lists lipid deficiency as a distinct tear-film driver.
Aqueous Tear Deficiency
Inadequate aqueous secretion from the lacrimal apparatus reduces tear volume and promotes hyperosmolar stress. Sjögren and non-Sjögren forms are modeled explicitly, and aqueous deficiency can coexist with evaporation.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
lacrimal gland UBERON:0001817 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lacrimal gland (UBERON:0001817). UBERON:0001817 is an anatomical location from the Uberon multi-species anatomy ontology. tear film UBERON:0022287 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in tear film (UBERON:0022287). UBERON:0022287 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tear-Film Instability and Hyperosmolarity Reduced aqueous volume decreases tear-film reserve and increases concentration and instability at the ocular surface. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Decreased lacrimation Reduced aqueous secretion is clinically expressed as decreased lacrimation. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary..."
TFOS DEWS III lists aqueous deficiency as its own tear-film driver.
Mucin and Glycocalyx Tear-Film Deficiency
Reduced secreted mucin or disruption of the epithelial glycocalyx impairs tear spreading, lubrication, and surface retention. This component can coexist with aqueous or lipid deficiency.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
conjunctival goblet cell CL:2000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves conjunctival goblet cell, annotated with conjunctiva goblet cell (CL:2000084). CL:2000084 is a cell type from the Cell Ontology.
conjunctiva UBERON:0001811 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in conjunctiva (UBERON:0001811). UBERON:0001811 is an anatomical location from the Uberon multi-species anatomy ontology. tear film UBERON:0022287 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in tear film (UBERON:0022287). UBERON:0022287 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tear-Film Instability and Hyperosmolarity Mucin or glycocalyx deficiency reduces tear-film wetting and retention, promoting breakup and osmotic stress. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary..."
TFOS DEWS III lists mucin/glycocalyx deficiency as a distinct tear-film driver.
Lid-Margin Abnormality
Structural or inflammatory abnormalities of the eyelid margin can interfere with tear-film lipid delivery and normal spreading independently of other tear-component deficiencies.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
margin of eyelid UBERON:0034772 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in margin of eyelid (UBERON:0034772). UBERON:0034772 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tear-Film Instability and Hyperosmolarity Lid-margin disease can destabilize the tear film through altered spreading and lipid delivery. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary..."
TFOS DEWS III names lid-margin anomaly separately from blink/lid-closure anomaly.
Ocular-Surface Anatomical Misalignment
Malalignment of the ocular surface or apposing lids can prevent uniform tear distribution and create locally exposed, unstable tear-film regions.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology. conjunctiva UBERON:0001811 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in conjunctiva (UBERON:0001811). UBERON:0001811 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Tear-Film Instability and Hyperosmolarity Anatomical misalignment can produce uneven tear coverage and local instability. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"Subclassification was separated into tear film deficiencies (lipid, aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid margin) and ocular surface abnormalities (anatomical misalignment, neural dysfunction, ocular surface cell damage/disruption and primary..."
TFOS DEWS III identifies anatomical misalignment as its own ocular-surface driver.
Tear-Film Instability and Hyperosmolarity
An unstable tear film exposes the corneal and conjunctival epithelia to fluctuating desiccating and hyperosmolar stress. The importance of this node varies among individuals and can be driven by aqueous deficiency, evaporation, or mixed mechanisms.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
response to hyperosmotic stress GO:0006972 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to hyperosmotic stress, annotated with hyperosmotic response (GO:0006972). GO:0006972 is a biological process from the Gene Ontology.
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology. conjunctiva UBERON:0001811 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in conjunctiva (UBERON:0001811). UBERON:0001811 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ocular-Surface Osmotic and Oxidative Stress Hyperosmolar exposure can increase oxidative stress in corneal epithelial cells, although oxidative stress can also arise through other DED drivers. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Ocular-Surface Innate and Adaptive Inflammation Hyperosmolar stress can amplify cytokine and MAPK-mediated inflammation when this inflammatory arm is active. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Blurred vision Tear-film breakup produces a fluctuating optical surface and can therefore manifest as intermittent blurred or fluctuating vision. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"Dry eye is a multifactorial, symptomatic disease characterized by a loss of homeostasis of the tear film and/or ocular surface, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities are etiological factors."
Tear-film instability and hyperosmolarity are named etiologic factors in the current consensus definition.
Ocular-Surface Osmotic and Oxidative Stress
Desiccating and hyperosmolar exposure can increase reactive oxygen species and oxidative injury in corneal epithelial cells. Oxidative stress is a contributor within a heterogeneous network, not a universal single cause of DED.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
corneal epithelial cell CL:0000575 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves corneal epithelial cell (CL:0000575). CL:0000575 is a cell type from the Cell Ontology.
response to oxidative stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves response to oxidative stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology.
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ocular-Surface Innate and Adaptive Inflammation Reactive oxygen species and inflammatory signaling can reinforce one another in experimental DED. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Corneal and Conjunctival Epithelial Damage Sustained oxidative stress can contribute to epithelial DNA damage and loss of ocular-surface integrity. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (2 references)
PMID:34575438 SUPPORT In Vitro
"Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles (PLGA NP) were cytoprotective against oxidative stress in vitro"
Cultured-cell results establish an experimentally tractable oxidative-stress component but do not establish its magnitude across human DED endotypes.
PMID:34575438 SUPPORT Model Organism
"significantly reduced ocular surface damage and oxidative stress-associated DNA damage in corneal epithelial cells in the mouse desiccating stress/scopolamine model for dry eye disease in vivo."
The mouse-model result supports oxidative injury in an experimental DED context while preserving its non-human evidence scope.
Ocular-Surface Innate and Adaptive Inflammation
In inflammatory DED contexts, epithelial and innate immune signaling recruit macrophages and antigen-presenting cells, while CD4-positive T-cell responses can sustain cytokine production and tissue injury. The intensity of this arm differs across etiologic forms.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology. CD4-positive, alpha-beta T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology.
inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Downstream
Corneal and Conjunctival Epithelial Damage Persistent effector-cell activity and cytokine signaling can damage corneal and conjunctival epithelial tissues and restart innate responses. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Conjunctival hyperemia Ocular-surface inflammation can produce conjunctival redness through local inflammatory vascular responses. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (2 references)
PMID:34421626 SUPPORT Other
"Immune response can be divided into innate immunity and adaptive immunity. The inherent response is the innate immunity of the human body, known as the first natural defense line, which mainly includes macrophages, monocytes, dendritic cells, neutrophils and natural killer cells, etc. Adaptive..."
This review supports involvement of both innate and adaptive immune arms and identifies macrophages among the innate participants.
PMID:34421626 SUPPORT Other
"The abundant presence of CD4+ T cells in the adaptive immune response and cyclosporine in the treatment of DED suggest that adaptive immunity also plays an important role in DED."
The review specifically supports a CD4-positive T-cell contribution to the adaptive inflammatory arm.
Corneal and Conjunctival Epithelial Damage
Stress and inflammation can disrupt corneal and conjunctival epithelial integrity. Damage can include punctate staining, epithelial-cell loss, and, in severe disease, more extensive surface lesions.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
corneal epithelial cell CL:0000575 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves corneal epithelial cell (CL:0000575). CL:0000575 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology. conjunctiva UBERON:0001811 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in conjunctiva (UBERON:0001811). UBERON:0001811 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neurosensory Dysfunction and Ocular Pain Ocular-surface injury can alter corneal-nerve structure or signaling and contribute to pain, while pain can also persist through peripheral or central neural mechanisms that are not proportional to surface damage. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Keratoconjunctivitis sicca Damage and dryness affecting both corneal and conjunctival epithelia are clinically expressed as keratoconjunctivitis sicca. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:34421626 SUPPORT Other
"In dry eyes, the apoptosis of lacrimal acinus, conjunctival epithelium, corneal epithelium, and corneal endothelial cells is abnormally increased, resulting in damage and destruction of eye tissues"
This review supports apoptosis and damage across the corneal, conjunctival, and lacrimal compartments.
Neurosensory Dysfunction and Ocular Pain
Altered corneal-nerve integrity and peripheral or central sensory processing can generate ocular discomfort or pain. Neural dysfunction can coexist with epithelial damage or become partly dissociated from measured surface signs.
Multidriver Tear-Film and Ocular-Surface Homeostasis Model
cornea UBERON:0000964 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cornea (UBERON:0000964). UBERON:0000964 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ocular pain Altered peripheral or central sensory processing can directly produce ocular pain. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Photophobia Altered ocular sensory processing can accompany the light sensitivity reported in DED, although the intervening circuitry is not asserted here. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Corneal foreign body sensation Abnormal ocular-surface sensory signaling can manifest as foreign-body sensation even when no foreign material is present. Multidriver Tear-Film and Ocular-Surface Homeostasis Model
Show evidence (1 reference)
PMID:40472874 SUPPORT Other
"Ocular pain perception is linked to structural integrity of corneal nerves, functional capacities of neurons, and activity of the central and peripheral nervous systems."
This directly supports a neurosensory contribution to ocular pain in DED.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dry Eye Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Cardiovascular 2
Keratoconjunctivitis sicca HP:0001097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Keratoconjunctivitis sicca (HP:0001097). HP:0001097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40146145 SUPPORT Human Clinical
"Dry eye disease (DED), alternatively termed keratoconjunctivitis sicca, stands as a prevalent ocular surface ailment impacting millions of individuals globally."
The human clinical-trial report identifies keratoconjunctivitis sicca as an alternative clinical term for DED.
Conjunctival hyperemia HP:0030953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conjunctival hyperemia (HP:0030953). HP:0030953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34421626 SUPPORT Other
"These include dryness, foreign body sensation, burning sensation, itching sensation, photophobia, red eyes, blurred vision, fluctuating vision, and visual fatigue."
The review explicitly includes red eyes in the DED symptom spectrum; conjunctival hyperemia provides the structured phenotype.
Eye 2
Photophobia HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34421626 SUPPORT Other
"These include dryness, foreign body sensation, burning sensation, itching sensation, photophobia, red eyes, blurred vision, fluctuating vision, and visual fatigue."
This review explicitly includes photophobia in the DED symptom spectrum.
Blurred vision HP:0000622 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Blurred vision (HP:0000622). HP:0000622 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34421626 SUPPORT Other
"These include dryness, foreign body sensation, burning sensation, itching sensation, photophobia, red eyes, blurred vision, fluctuating vision, and visual fatigue."
This review explicitly includes blurred and fluctuating vision in the DED symptom spectrum.
Constitutional 1
Ocular pain HP:0200026 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ocular pain (HP:0200026). HP:0200026 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40472874 SUPPORT Other
"Ocular pain perception is linked to structural integrity of corneal nerves, functional capacities of neurons, and activity of the central and peripheral nervous systems."
This supports ocular pain as a neurosensory manifestation of DED.
Other 2
Decreased lacrimation HP:0000633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased lacrimation (HP:0000633). HP:0000633 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35681232 SUPPORT Other
"Clinically, DED can be divided into two main types, aqueous tear-deficient dry eye and evaporative dry eye [2]."
The review recognizes reduced aqueous tear production as a defining DED form; HP:0000633 provides the corresponding clinical phenotype.
Corneal foreign body sensation HP:0034804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Corneal foreign body sensation (HP:0034804). HP:0034804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34421626 SUPPORT Other
"These include dryness, foreign body sensation, burning sensation, itching sensation, photophobia, red eyes, blurred vision, fluctuating vision, and visual fatigue."
The review explicitly lists foreign-body sensation among DED symptoms.
💊

Medical Actions

4
Tear-Film Replenishment and Conservation
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Ocular lubricants and other tear supplements are first-line measures used to replenish or conserve the tear film. Formulation and frequency should be matched to the individual's deficient tear component and symptom burden.
Mechanism Target:
RESTORES Tear-Film Instability and Hyperosmolarity — Tear supplements aim to restore a more stable and adequately hydrated ocular-surface environment.
Show evidence (1 reference)
PMID:40467022 SUPPORT Other
"First-line management focuses on methods to replenish, conserve, and stimulate the tear film, with an emphasis on ocular supplements, which remain the cornerstone of DED treatment."
The consensus directly supports tear-film replenishment and conservation as the mechanism targeted by first-line ocular supplements.
Show evidence (1 reference)
PMID:40467022 SUPPORT Other
"First-line management focuses on methods to replenish, conserve, and stimulate the tear film, with an emphasis on ocular supplements, which remain the cornerstone of DED treatment."
The current TFOS consensus places tear-film replenishment, conservation, and stimulation at the center of first-line management.
Meibomian-Gland-Directed Lid Warming and Hygiene
Category: Therapeutic Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Warm compresses, lid hygiene, and selected in-office eyelid-warming approaches address meibomian gland dysfunction when a lipid-deficient, evaporative driver is present; they are not universal therapy for every DED endotype.
Mechanism Target:
MODULATES Meibomian Gland Dysfunction — Lid warming and hygiene target meibomian-gland and lid-margin contributors to tear-film lipid deficiency and evaporation.
Show evidence (1 reference)
PMID:40467022 SUPPORT Other
"Meibomian gland dysfunction, a primary contributor to DED, is typically treated with warm compresses and a wide variety of in-office treatments, including device-driven technologies to warm the eyelids, intense pulsed light therapy, low-level light therapy, and other new and emerging technologies."
The consensus explicitly links lid warming to the meibomian-gland driver represented by this dedicated target.
Show evidence (1 reference)
PMID:40467022 SUPPORT Other
"Meibomian gland dysfunction, a primary contributor to DED, is typically treated with warm compresses and a wide variety of in-office treatments, including device-driven technologies to warm the eyelids, intense pulsed light therapy, low-level light therapy, and other new and emerging technologies."
This supports driver-directed warming approaches for DED with meibomian gland dysfunction.
Topical Cyclosporin A for Inflammatory DED
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cyclosporin A CHEBI:4031 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclosporin A (CHEBI:4031). CHEBI:4031 is a therapeutic agent from Chemical Entities of Biological Interest.
Topical 0.05% cyclosporin A is a T-cell-directed anti-inflammatory option for selected moderate-to-severe inflammatory DED. A 12-week randomized formulation-comparison trial found improvement from baseline with both aqueous solution and oil emulsion alongside lubricant drops; it did not compare cyclosporin with placebo or establish benefit for all DED forms.
Mechanism Target:
INHIBITS Ocular-Surface Innate and Adaptive Inflammation — Cyclosporin A suppresses the T-cell-associated inflammatory arm selected for treatment in inflammatory DED.
Show evidence (1 reference)
PMID:40467022 SUPPORT Other
"DED caused by certain etiological drivers can benefit from anti-inflammatory therapies, including topical and oral corticosteroids, T-cell immunomodulatory drugs, and a wide variety of pharmacological agents"
The consensus identifies T-cell immunomodulatory therapy as a driver-directed means of inhibiting the inflammatory arm.
Show evidence (2 references)
PMID:40467022 SUPPORT Other
"DED caused by certain etiological drivers can benefit from anti-inflammatory therapies, including topical and oral corticosteroids, T-cell immunomodulatory drugs, and a wide variety of pharmacological agents"
The consensus supports anti-inflammatory therapy for selected etiologic drivers rather than undifferentiated use in all DED.
PMID:40146145 SUPPORT Human Clinical
"Both the groups showed comparable values at baseline. After treatment, there was statistically significant improvement over baseline values in both groups at 4, 8, and 12 weeks."
The randomized human trial supports improvement with both topical 0.05% cyclosporine formulations, while its active-formulation comparison and short follow-up limit broader efficacy inference.
Visible-Light-Activated Carbon-Monoxide Nanoplatform (Preclinical)
Category: Therapeutic Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: carbon monoxide CHEBI:17245 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carbon monoxide (CHEBI:17245). CHEBI:17245 is a therapeutic agent from Chemical Entities of Biological Interest.
TiZr-MOF/CO@F127 is a visible-light-activated, F127-hydrogel nanoplatform designed for controlled corneal carbon-monoxide delivery. Five days of topical treatment reduced oxidative and inflammatory readouts and improved epithelial recovery in a murine DED model. This is preclinical evidence only: human ocular safety, dose control, light-delivery parameters, and clinical efficacy have not been established, so this is not a clinical recommendation.
Mechanism Target:
INHIBITS Ocular-Surface Osmotic and Oxidative Stress — The platform was reported to scavenge reactive oxygen species.
Show evidence (1 reference)
PMID:42439592 SUPPORT Model Organism
"Mechanistically, CO scavenged reactive oxygen species, suppressed MMP-9 expression, promoted macrophage polarization from M1 to M2 phenotype, reduced inflammatory cytokine production, and enhanced corneal epithelial proliferation."
The murine study directly reports reactive-oxygen-species scavenging by the carbon-monoxide intervention.
INHIBITS Ocular-Surface Innate and Adaptive Inflammation — The platform reduced inflammatory cytokines and MMP-9 and shifted macrophage polarization in the murine model.
Show evidence (1 reference)
PMID:42439592 SUPPORT Model Organism
"Mechanistically, CO scavenged reactive oxygen species, suppressed MMP-9 expression, promoted macrophage polarization from M1 to M2 phenotype, reduced inflammatory cytokine production, and enhanced corneal epithelial proliferation."
The murine study directly reports suppression of inflammatory mediators and a macrophage-polarization shift.
RESTORES Corneal and Conjunctival Epithelial Damage — The platform enhanced corneal epithelial proliferation and recovery in mice.
Show evidence (1 reference)
PMID:42439592 SUPPORT Model Organism
"In a murine DED model, topical administration of MCF for 5 days achieved 84% corneal epithelial recovery and alleviated corneal inflammation and tissue injury."
This directly supports epithelial recovery as a treatment target in the mouse model.
Show evidence (2 references)
PMID:42439592 SUPPORT Model Organism
"In a murine DED model, topical administration of MCF for 5 days achieved 84% corneal epithelial recovery and alleviated corneal inflammation and tissue injury."
This directly supports short-term efficacy in a murine model and does not establish human benefit.
PMID:42439592 SUPPORT Model Organism
"Mechanistically, CO scavenged reactive oxygen species, suppressed MMP-9 expression, promoted macrophage polarization from M1 to M2 phenotype, reduced inflammatory cytokine production, and enhanced corneal epithelial proliferation."
The murine study supports the three modeled treatment targets while remaining preclinical.
🌍

Environmental Factors

5
Prolonged Digital Screen Use
prolonged digital screen use Relation: this environmental factor is this exposure This environmental factor is prolonged digital screen use.
Longer use of computers, tablets, phones, and other digital displays is associated with DED symptoms and diagnosis. Reduced blink rate and less complete blinking are the principal proposed intermediates, so this factor is linked specifically to the blink/lid-closure driver rather than treated as a direct cause of every DED endotype.
Show evidence (1 reference)
PMID:34531649 SUPPORT Other
"Extensive cross-sectional studies have shown that digital screen use duration is associated with an increased risk of severe symptoms and clinical diagnosis of dry eye disease in adults."
The review reports a duration-associated human risk signal while the cross-sectional design prevents a stronger causal claim.
Mechanism Target:
PREDISPOSES Blink and Lid-Closure Abnormality — Digital screen tasks can reduce blink rate and completeness, increasing the time during which tears evaporate between blinks.
Show evidence (1 reference)
PMID:34531649 SUPPORT Other
"The most prevalent hypothesis to explain the link between digital screen use and dry eye is digital screen use influences blinking dynamics by reducing both blink rate and blink completeness, leading to increased ocular surface dryness."
The review identifies altered blink rate and completeness as the proximal mechanism connecting screen use with ocular dryness.
Low Ambient Humidity or Airflow
exposure to low ambient humidity or airflow across the eye Relation: this environmental factor is this exposure This environmental factor is exposure to low ambient humidity or airflow across the eye.
Dry ambient air and direct airflow increase evaporative demand at the ocular surface. Human observational evidence supports lower humidity as a risk condition, while controlled low-humidity mouse models directly demonstrate excessive tear-film evaporation.
Show evidence (1 reference)
PMID:34206755 SUPPORT Human Clinical
"conversely, each SD increment of relative humidity (RH) had a protective effect against the risk of DES."
In this female Taiwanese cohort, higher humidity was inversely associated with DES; the population and observational design are retained as limits.
Mechanism Target:
EXACERBATES Tear-Film Instability and Hyperosmolarity — Low humidity increases tear evaporation, reducing tear-film stability and increasing desiccating stress.
Show evidence (1 reference)
PMID:35681232 SUPPORT Model Organism
"Administration of scopolamine reduces aqueous tear production and the low humidity environment causes excessive evaporation of the tear film."
The controlled-environment mouse model demonstrates excessive tear-film evaporation as the intermediate produced by low humidity.
Ambient Air Pollution
ambient air pollution exposure ECTO:8000036 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is ambient air pollution exposure, annotated with exposure to air pollution (ECTO:8000036). ECTO:8000036 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Long-term ambient pollutant exposure has been associated with increased dry eye prevalence. The available study was observational and limited to women, so the factor is modeled as a predisposition with unasserted intermediates.
Show evidence (1 reference)
PMID:34206755 SUPPORT Human Clinical
"significant associations of ambient NO2 concentration, RH and temperature with DES indicated the importance of increased environmental protection in the female population."
This summarizes the study's environmental associations while preserving its female-population scope.
Mechanism Target:
PREDISPOSES Tear-Film Instability and Hyperosmolarity — Air-pollution exposure is placed upstream of the canonical tear-film homeostasis node, without asserting a specific molecular intermediate from this association study.
Show evidence (1 reference)
PMID:34206755 SUPPORT Human Clinical
"After considering hormone supplementation, arthritis, and allergy, the SD increment of NO2 and temperature were associated with the PRs of DES."
The adjusted female-cohort association supports predisposition but not a direct mechanistic edge, hence unknown intermediates.
Contact Lens Wear
contact lens wear Relation: this environmental factor is this exposure This environmental factor is contact lens wear.
Contact lens wear is a recognized extrinsic and iatrogenic contributor to DED. Because the cited consensus does not resolve one universal route, the link to tear-film instability retains unknown intermediates.
Show evidence (1 reference)
PMID:34531649 SUPPORT Other
"Extrinsic risk factors for DED may include contact lens wear, environmental conditions (eg, low humidity or airflow on the eye), topical or systemic medications, lack of hygienic practices for eyelids and eyelashes, eye beauty trends, and eye cosmetic product ingredients and applications."
The review explicitly lists contact lens wear among extrinsic DED risk factors.
Mechanism Target:
PREDISPOSES Tear-Film Instability and Hyperosmolarity — Contact lens wear can disrupt ocular-surface homeostasis through routes that vary by lens, wearer, and exposure context.
Show evidence (1 reference)
PMID:40472874 SUPPORT Other
"Iatrogenic DED can result from medications, contact lenses, and surgical procedures."
The current consensus supports contact lenses as an iatrogenic DED contributor but does not specify one obligatory intermediate.
Topical or Systemic Medication Exposure
topical or systemic medication exposure ECTO:0000509 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is topical or systemic medication exposure, annotated with exposure to drug (ECTO:0000509). ECTO:0000509 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Some topical and systemic medications can cause or predispose to iatrogenic DED. This entry remains drug-class agnostic because the cited consensus supports the category without assigning every medication the same route.
Show evidence (1 reference)
PMID:34531649 SUPPORT Other
"Extrinsic risk factors for DED may include contact lens wear, environmental conditions (eg, low humidity or airflow on the eye), topical or systemic medications, lack of hygienic practices for eyelids and eyelashes, eye beauty trends, and eye cosmetic product ingredients and applications."
The review explicitly lists topical and systemic medications among extrinsic risk factors.
Mechanism Target:
PREDISPOSES Tear-Film Instability and Hyperosmolarity — Medication exposure can disturb tear-film or ocular-surface homeostasis, with the operative route depending on the agent.
Show evidence (1 reference)
PMID:40472874 SUPPORT Other
"Iatrogenic DED can result from medications, contact lenses, and surgical procedures."
The consensus supports medications as an iatrogenic DED contributor; the edge conservatively leaves agent-specific intermediates unresolved.
🔬

Diagnosis

1
Symptom Screening Plus Objective Tear-Film or Ocular-Surface Abnormality
The TFOS DEWS III diagnostic pathway begins with an OSDI-6 symptom score of at least 4 and requires at least one objective abnormality: non-invasive tear break-up time under 10 seconds, qualifying tear hyperosmolarity, or specified corneal, conjunctival, or lid-margin staining.
clinical evaluation NCIT:C124351 NCI Thesaurus (NCIT)
Results: OSDI-6 score >=4 plus non-invasive break-up time <10 seconds, tear osmolarity >=308 mOsm/L in either eye or interocular difference >8 mOsm/L, or staining above the TFOS DEWS III thresholds supports diagnosis after differential diagnosis and ocular examination.
Show evidence (1 reference)
PMID:40451408 SUPPORT Other
"The recommended screening questionnaire is the OSDI-6 with a cut-off score ≥4. A positive result together with a non-invasive breakup time <10s or alternatively tear film hyperosmolarity (≥308mOsm/L in either eye or an interocular difference >8mOsm/L) or alternatively >5 corneal fluorescein..."
This is the current consensus symptom-plus-sign diagnostic algorithm and preserves the published cutoffs.
📊

Prevalence

1
Adults worldwide
Point Prevalence 27500.0 per 100,000 (5000.0–50000.0) >1 in 1,000
Reported adult worldwide prevalence range is 5% to 50%. The normalized midpoint is 27,500 per 100,000, with the reported bounds retained as 5,000-50,000 per 100,000; variation reflects heterogeneous definitions and populations.
Show evidence (1 reference)
PMID:40146145 SUPPORT Human Clinical
"The prevalence of DED among adults worldwide ranges from 5% to 50%."
The clinical paper reports the worldwide adult prevalence range used for the structured bounds; the midpoint is explicitly derived rather than presented as a separate source estimate.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Dry Eye Disease:

Sjögren syndrome MONDO:0010030
Overlapping Features Sjögren syndrome is an important systemic cause to evaluate when aqueous tear deficiency or keratoconjunctivitis sicca is prominent. In this entry, Sjögren-associated ADDE is an etiologic DED form, while the systemic autoimmune disorder remains a separate DisMech disease entry.
Distinguishing Features
  • Exocrine-gland dysfunction with xerostomia supports systemic Sjögren syndrome rather than isolated non-Sjögren DED.
  • Extraglandular autoimmune manifestations can further distinguish Sjögren syndrome from entry-local ocular-surface disease.
Show evidence (1 reference)
ORPHA:289390 SUPPORT Other
"A rare systemic autoimmune disease characterized by exocrine gland dysfunction, resulting predominately in keratoconjunctivitis sicca and xerostomia"
Orphanet identifies the systemic autoimmune and exocrine-gland context that distinguishes Sjögren-associated DED from isolated ocular disease.
{ }

Source YAML

click to show 
name: Dry Eye Disease
creation_date: "2026-08-08T19:58:02Z"
category: Complex
synonyms:
- Dry eye syndrome
- Keratoconjunctivitis sicca
description: >-
  Dry eye disease is a multifactorial, symptomatic ocular-surface disease in
  which homeostasis of the tear film and/or ocular surface is lost. Tear-film
  instability and hyperosmolarity, ocular-surface inflammation and damage, and
  neurosensory abnormalities can contribute in different combinations. Lipid,
  aqueous, and mucin/glycocalyx deficiencies; eyelid abnormalities; and primary
  ocular-surface or neural processes are overlapping etiologic drivers rather
  than mutually exclusive disease categories.
parents:
- Ocular surface disorder
- Lacrimal system disorder
disease_term:
  preferred_term: Dry eye disease
  term:
    id: MONDO:0006733
    label: dry eye syndrome
has_subtypes:
- name: Aqueous-Deficient DED
  display_name: Aqueous tear-deficient dry eye disease
  classification: clinical_etiologic_form
  children:
  - Sjögren-Associated ADDE
  - Non-Sjögren ADDE
  description: >-
    A clinical form in which insufficient aqueous tear production is a dominant
    driver. It includes Sjögren-associated and non-Sjögren forms and may overlap
    with evaporative disease.
  evidence:
  - reference: PMID:35681232
    reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, DED can be divided into two main types, aqueous tear-deficient
      dry eye and evaporative dry eye [2].
    explanation: >-
      This review explicitly identifies aqueous-deficient DED as a principal
      clinical form.
  - reference: PMID:35681232
    reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aqueous tear-deficient dry eye can be subdivided into two categories,
      Sjögren’s dry eye type and non-Sjögren’s dry eye type.
    explanation: >-
      This review explicitly identifies its Sjögren and non-Sjögren
      subdivisions.
- name: Sjögren-Associated ADDE
  display_name: Sjögren-associated aqueous tear-deficient DED
  classification: clinical_etiologic_form
  description: >-
    Aqueous tear-deficient DED occurring as an ocular manifestation of Sjögren
    syndrome. This form can be severe and may coexist with meibomian-gland or
    other evaporative contributors.
  evidence:
  - reference: PMID:35681232
    reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aqueous tear-deficient dry eye can be subdivided into two categories,
      Sjögren’s dry eye type and non-Sjögren’s dry eye type.
    explanation: >-
      The review recognizes Sjögren-associated dry eye as a subdivision of
      aqueous tear-deficient DED.
- name: Non-Sjögren ADDE
  display_name: Non-Sjögren aqueous tear-deficient DED
  classification: clinical_etiologic_form
  description: >-
    Aqueous tear-deficient DED without Sjögren syndrome, including lacrimal
    functional impairment arising through other etiologies.
  evidence:
  - reference: PMID:35681232
    reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aqueous tear-deficient dry eye can be subdivided into two categories,
      Sjögren’s dry eye type and non-Sjögren’s dry eye type.
    explanation: >-
      The review recognizes non-Sjögren dry eye as the other subdivision of
      aqueous tear-deficient DED.
- name: Evaporative DED
  display_name: Evaporative dry eye disease
  classification: clinical_etiologic_form
  description: >-
    A clinical form dominated by excessive tear evaporation, commonly with
    meibomian gland dysfunction or other eyelid and ocular-surface contributors.
  evidence:
  - reference: PMID:40472874
    reference_title: "TFOS DEWS III: Digest."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathophysiological distinctions between aqueous deficient and more
      evaporative forms of DED have been clarified, with the latter most
      commonly characterized by a muted inflammatory response at the ocular
      surface, meibomian gland dysfunction, and conceivably phenotypic changes
      in corneal epithelial cells.
    explanation: >-
      The current consensus digest characterizes the evaporative form and its
      frequent meibomian-gland contribution.
- name: Mixed DED
  display_name: Mixed aqueous-deficient and evaporative DED
  classification: clinical_etiologic_form
  description: >-
    A common overlapping form in which aqueous deficiency and excessive
    evaporation contribute together rather than defining mutually exclusive
    disease categories.
  evidence:
  - reference: PMID:35681232
    reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Studies have shown that many patients have both aqueous tear-deficient and
      evaporative dry eye, and both types share the common feature of
      inflammation [3].
    explanation: >-
      This supports an overlapping mixed form rather than a forced binary
      classification.
prevalence:
- population: Adults worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 27500.0
  rate_low: 5000.0
  rate_high: 50000.0
  notes: >-
    Reported adult worldwide prevalence range is 5% to 50%. The normalized
    midpoint is 27,500 per 100,000, with the reported bounds retained as
    5,000-50,000 per 100,000; variation reflects heterogeneous definitions and
    populations.
  evidence:
  - reference: PMID:40146145
    reference_title: "Comparative evaluation of aqueous solution and oil emulsion formulations of 0.05% cyclosporine eye drops in dry eye disease - A randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of DED among adults worldwide ranges from 5% to 50%.
    explanation: >-
      The clinical paper reports the worldwide adult prevalence range used for
      the structured bounds; the midpoint is explicitly derived rather than
      presented as a separate source estimate.
differential_diagnoses:
- name: Sjögren syndrome
  disease_term:
    preferred_term: Sjogren syndrome
    term:
      id: MONDO:0010030
      label: Sjogren syndrome
  description: >-
    Sjögren syndrome is an important systemic cause to evaluate when aqueous
    tear deficiency or keratoconjunctivitis sicca is prominent. In this entry,
    Sjögren-associated ADDE is an etiologic DED form, while the systemic
    autoimmune disorder remains a separate DisMech disease entry.
  distinguishing_features:
  - Exocrine-gland dysfunction with xerostomia supports systemic Sjögren syndrome rather than isolated non-Sjögren DED.
  - Extraglandular autoimmune manifestations can further distinguish Sjögren syndrome from entry-local ocular-surface disease.
  evidence:
  - reference: ORPHA:289390
    reference_title: "Primary Sjögren disease"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rare systemic autoimmune disease characterized by exocrine gland
      dysfunction, resulting predominately in keratoconjunctivitis sicca and
      xerostomia
    explanation: >-
      Orphanet identifies the systemic autoimmune and exocrine-gland context
      that distinguishes Sjögren-associated DED from isolated ocular disease.
mechanistic_hypotheses:
- hypothesis_group_id: multidriver_tear_film_homeostasis_model
  hypothesis_label: Multidriver Tear-Film and Ocular-Surface Homeostasis Model
  status: CANONICAL
  description: >-
    DED is modeled as a heterogeneous loss-of-homeostasis state. Different
    combinations of tear-film deficiency, eyelid dysfunction, ocular-surface
    stress, inflammation, epithelial damage, and neurosensory dysfunction can
    converge on symptoms; no single downstream node is asserted to be present
    or dominant in every patient.
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dry eye is a multifactorial, symptomatic disease characterized by a loss
      of homeostasis of the tear film and/or ocular surface, in which tear film
      instability and hyperosmolarity, ocular surface inflammation and damage,
      and neurosensory abnormalities are etiological factors.
    explanation: >-
      The current TFOS DEWS III definition supports a multidriver model centered
      on loss of tear-film and/or ocular-surface homeostasis.
  - reference: PMID:40472874
    reference_title: "TFOS DEWS III: Digest."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathophysiological distinctions between aqueous deficient and more
      evaporative forms of DED have been clarified, with the latter most
      commonly characterized by a muted inflammatory response at the ocular
      surface, meibomian gland dysfunction, and conceivably phenotypic changes
      in corneal epithelial cells.
    explanation: >-
      This qualifies the model: inflammatory intensity and dominant drivers
      differ across DED forms, so the pathograph is not a mandatory linear
      sequence for every patient.
pathophysiology:
- name: Meibomian Gland Dysfunction
  description: >-
    Dysfunction of the tarsal (meibomian) glands is a major, but not universal,
    evaporative DED driver. Altered delivery or quality of meibum compromises
    the tear-film lipid layer and increases evaporative stress.
  biological_scale: TISSUE
  role: trigger
  subtypes:
  - Evaporative DED
  - Mixed DED
  locations:
  - preferred_term: meibomian gland
    term:
      id: UBERON:0001818
      label: tarsal gland
  evidence:
  - reference: PMID:40467022
    reference_title: "TFOS DEWS III: Management and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Meibomian gland dysfunction, a primary contributor to DED, is typically
      treated with warm compresses and a wide variety of in-office treatments,
      including device-driven technologies to warm the eyelids, intense pulsed
      light therapy, low-level light therapy, and other new and emerging
      technologies.
    explanation: >-
      The current consensus identifies meibomian gland dysfunction as a primary
      DED contributor and anchors it to gland-directed therapy.
  downstream:
  - target: Lipid Tear-Film Deficiency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired meibum delivery to the tear-film lipid layer
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Meibomian-gland dysfunction reduces or alters the lipid supplied to the
      tear film, thereby establishing a lipid-deficient evaporative driver.
    evidence:
    - reference: PMID:35681232
      reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The tear film is mainly composed of three protein components, including
        the mucin layer (secreted by goblet cells on the conjunctiva), the
        aqueous layer (secreted by the lacrimal gland), and the lipid layer
        (secreted by the meibomian gland).
      explanation: >-
        The review identifies the meibomian gland as the source of the tear-film
        lipid layer, supporting this known intermediate.
- name: Lipid Tear-Film Deficiency
  description: >-
    Insufficient or compositionally abnormal tear-film lipid permits excessive
    evaporation. It may arise from meibomian gland dysfunction or other lipid
    delivery abnormalities.
  biological_scale: TISSUE
  role: trigger
  subtypes:
  - Evaporative DED
  - Mixed DED
  locations:
  - preferred_term: tear film
    term:
      id: UBERON:0022287
      label: tear film
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subclassification was separated into tear film deficiencies (lipid,
      aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
      margin) and ocular surface abnormalities (anatomical misalignment, neural
      dysfunction, ocular surface cell damage/disruption and primary
      inflammation/oxidative stress) components
    explanation: >-
      TFOS DEWS III lists lipid deficiency as a distinct tear-film driver.
  downstream:
  - target: Tear-Film Instability and Hyperosmolarity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased tear evaporation
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Loss of an effective lipid layer increases evaporation and destabilizes
      the tear film.
    evidence:
    - reference: PMID:40451408
      reference_title: "TFOS DEWS III: Diagnostic Methodology."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Subclassification was separated into tear film deficiencies (lipid,
        aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
        margin) and ocular surface abnormalities (anatomical misalignment, neural
        dysfunction, ocular surface cell damage/disruption and primary
        inflammation/oxidative stress) components
      explanation: >-
        The consensus classifies lipid deficiency as an etiologic component of
        the loss-of-homeostasis state that includes tear-film instability.
- name: Aqueous Tear Deficiency
  description: >-
    Inadequate aqueous secretion from the lacrimal apparatus reduces tear volume
    and promotes hyperosmolar stress. Sjögren and non-Sjögren forms are modeled
    explicitly, and aqueous deficiency can coexist with evaporation.
  biological_scale: TISSUE
  role: trigger
  subtypes:
  - Sjögren-Associated ADDE
  - Non-Sjögren ADDE
  - Mixed DED
  locations:
  - preferred_term: lacrimal gland
    term:
      id: UBERON:0001817
      label: lacrimal gland
  - preferred_term: tear film
    term:
      id: UBERON:0022287
      label: tear film
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subclassification was separated into tear film deficiencies (lipid,
      aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
      margin) and ocular surface abnormalities (anatomical misalignment, neural
      dysfunction, ocular surface cell damage/disruption and primary
      inflammation/oxidative stress) components
    explanation: >-
      TFOS DEWS III lists aqueous deficiency as its own tear-film driver.
  downstream:
  - target: Tear-Film Instability and Hyperosmolarity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced aqueous tear volume
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Reduced aqueous volume decreases tear-film reserve and increases
      concentration and instability at the ocular surface.
    evidence:
    - reference: PMID:35681232
      reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        If any layer displays insufficient secretion or excessive
        evapotranspiration, corneal epithelial cells become damaged under
        hyperosmotic conditions.
      explanation: >-
        The review connects insufficient tear-layer secretion with
        hyperosmotic ocular-surface stress.
  - target: Decreased lacrimation
    causal_link_type: DIRECT
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: Reduced aqueous secretion is clinically expressed as decreased lacrimation.
    evidence:
    - reference: PMID:35681232
      reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Clinically, DED can be divided into two main types, aqueous tear-deficient
        dry eye and evaporative dry eye [2].
      explanation: >-
        The review recognizes aqueous tear deficiency as a clinical DED form.
- name: Mucin and Glycocalyx Tear-Film Deficiency
  description: >-
    Reduced secreted mucin or disruption of the epithelial glycocalyx impairs
    tear spreading, lubrication, and surface retention. This component can
    coexist with aqueous or lipid deficiency.
  biological_scale: TISSUE
  role: trigger
  locations:
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  - preferred_term: tear film
    term:
      id: UBERON:0022287
      label: tear film
  cell_types:
  - preferred_term: conjunctival goblet cell
    term:
      id: CL:2000084
      label: conjunctiva goblet cell
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subclassification was separated into tear film deficiencies (lipid,
      aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
      margin) and ocular surface abnormalities (anatomical misalignment, neural
      dysfunction, ocular surface cell damage/disruption and primary
      inflammation/oxidative stress) components
    explanation: >-
      TFOS DEWS III lists mucin/glycocalyx deficiency as a distinct tear-film
      driver.
  downstream:
  - target: Tear-Film Instability and Hyperosmolarity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired tear spreading and ocular-surface retention
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Mucin or glycocalyx deficiency reduces tear-film wetting and retention,
      promoting breakup and osmotic stress.
    evidence:
    - reference: PMID:35681232
      reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The tear film is mainly composed of three protein components, including
        the mucin layer (secreted by goblet cells on the conjunctiva), the
        aqueous layer (secreted by the lacrimal gland), and the lipid layer
        (secreted by the meibomian gland).
      explanation: >-
        The review identifies conjunctival goblet cells as the source of the
        mucin component of the tear film.
- name: Blink and Lid-Closure Abnormality
  description: >-
    Reduced or incomplete blinking and impaired lid closure limit redistribution
    of aqueous tears and meibomian lipids and prolong ocular-surface exposure
    between blinks.
  biological_scale: TISSUE
  role: trigger
  locations:
  - preferred_term: eyelid
    term:
      id: UBERON:0001711
      label: eyelid
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subclassification was separated into tear film deficiencies (lipid,
      aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
      margin) and ocular surface abnormalities (anatomical misalignment, neural
      dysfunction, ocular surface cell damage/disruption and primary
      inflammation/oxidative stress) components
    explanation: >-
      TFOS DEWS III separates blink and lid-closure anomalies as an eyelid driver.
  downstream:
  - target: Tear-Film Instability and Hyperosmolarity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - impaired tear and lipid redistribution with increased interblink evaporation
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Reduced or incomplete blinking permits greater evaporative loss and
      prevents uniform replenishment of the tear film.
    evidence:
    - reference: PMID:34531649
      reference_title: The Relationship Between Dry Eye Disease and Digital Screen Use.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A commonly accepted hypothesis for the relationship between digital
        screen use and dry eye disease is that digital screen use changes
        blinking dynamics, leading to ocular dryness.
      explanation: >-
        The review supports altered blinking as the known intermediate from
        screen exposure to ocular dryness.
- name: Lid-Margin Abnormality
  description: >-
    Structural or inflammatory abnormalities of the eyelid margin can interfere
    with tear-film lipid delivery and normal spreading independently of other
    tear-component deficiencies.
  biological_scale: TISSUE
  role: trigger
  locations:
  - preferred_term: margin of eyelid
    term:
      id: UBERON:0034772
      label: margin of eyelid
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subclassification was separated into tear film deficiencies (lipid,
      aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
      margin) and ocular surface abnormalities (anatomical misalignment, neural
      dysfunction, ocular surface cell damage/disruption and primary
      inflammation/oxidative stress) components
    explanation: >-
      TFOS DEWS III names lid-margin anomaly separately from blink/lid-closure
      anomaly.
  downstream:
  - target: Tear-Film Instability and Hyperosmolarity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disrupted tear-film spreading and lipid delivery
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: Lid-margin disease can destabilize the tear film through altered spreading and lipid delivery.
    evidence:
    - reference: PMID:40451408
      reference_title: "TFOS DEWS III: Diagnostic Methodology."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Subclassification was separated into tear film deficiencies (lipid,
        aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
        margin) and ocular surface abnormalities (anatomical misalignment, neural
        dysfunction, ocular surface cell damage/disruption and primary
        inflammation/oxidative stress) components
      explanation: >-
        The diagnostic consensus includes lid-margin abnormality among etiologic
        components that inform DED management.
- name: Ocular-Surface Anatomical Misalignment
  description: >-
    Malalignment of the ocular surface or apposing lids can prevent uniform tear
    distribution and create locally exposed, unstable tear-film regions.
  biological_scale: TISSUE
  role: trigger
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Subclassification was separated into tear film deficiencies (lipid,
      aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
      margin) and ocular surface abnormalities (anatomical misalignment, neural
      dysfunction, ocular surface cell damage/disruption and primary
      inflammation/oxidative stress) components
    explanation: >-
      TFOS DEWS III identifies anatomical misalignment as its own ocular-surface
      driver.
  downstream:
  - target: Tear-Film Instability and Hyperosmolarity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - uneven tear distribution and exposed ocular-surface regions
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: Anatomical misalignment can produce uneven tear coverage and local instability.
    evidence:
    - reference: PMID:40451408
      reference_title: "TFOS DEWS III: Diagnostic Methodology."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Subclassification was separated into tear film deficiencies (lipid,
        aqueous and mucin/glycocalyx), eyelid anomalies (blink/lid closure and lid
        margin) and ocular surface abnormalities (anatomical misalignment, neural
        dysfunction, ocular surface cell damage/disruption and primary
        inflammation/oxidative stress) components
      explanation: >-
        The consensus places anatomical misalignment among DED etiologic
        components, supporting this driver-to-homeostasis edge.
- name: Tear-Film Instability and Hyperosmolarity
  description: >-
    An unstable tear film exposes the corneal and conjunctival epithelia to
    fluctuating desiccating and hyperosmolar stress. The importance of this node
    varies among individuals and can be driven by aqueous deficiency,
    evaporation, or mixed mechanisms.
  role: mediator
  biological_scale: TISSUE
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  biological_processes:
  - preferred_term: response to hyperosmotic stress
    term:
      id: GO:0006972
      label: hyperosmotic response
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dry eye is a multifactorial, symptomatic disease characterized by a loss
      of homeostasis of the tear film and/or ocular surface, in which tear film
      instability and hyperosmolarity, ocular surface inflammation and damage,
      and neurosensory abnormalities are etiological factors.
    explanation: >-
      Tear-film instability and hyperosmolarity are named etiologic factors in
      the current consensus definition.
  downstream:
  - target: Ocular-Surface Osmotic and Oxidative Stress
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Hyperosmolar exposure can increase oxidative stress in corneal epithelial
      cells, although oxidative stress can also arise through other DED drivers.
    evidence:
    - reference: PMID:34575438
      reference_title: "Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        hyperosmolar conditions cause oxidative stress in cultured corneal
        epithelial cells
      explanation: >-
        The experimental paper's background synthesis supports a
        hyperosmolarity-to-oxidative-stress link while distinguishing human
        observations from cultured-cell evidence.
  - target: Ocular-Surface Innate and Adaptive Inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Hyperosmolar stress can amplify cytokine and MAPK-mediated inflammation
      when this inflammatory arm is active.
    evidence:
    - reference: PMID:34421626
      reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        After the occurrence of dry eye, the high osmotic state of patients can
        prevent the defense system from taking effect, and further aggravate the
        immune inflammatory response by directly activating the MAPK pathway to
        activate interleukin and tumor necrosis factor
      explanation: >-
        This review supports hyperosmotic amplification of inflammatory
        signaling while not implying that inflammation is equally prominent in
        every DED form.
  - target: Blurred vision
    causal_link_type: DIRECT
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Tear-film breakup produces a fluctuating optical surface and can therefore
      manifest as intermittent blurred or fluctuating vision.
    evidence:
    - reference: PMID:34421626
      reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These include dryness, foreign body sensation, burning sensation,
        itching sensation, photophobia, red eyes, blurred vision, fluctuating
        vision, and visual fatigue.
      explanation: >-
        The review explicitly places blurred and fluctuating vision within the
        DED symptom spectrum; the edge assigns this optical phenotype to the
        tear-film-instability arm.
- name: Ocular-Surface Osmotic and Oxidative Stress
  description: >-
    Desiccating and hyperosmolar exposure can increase reactive oxygen species
    and oxidative injury in corneal epithelial cells. Oxidative stress is a
    contributor within a heterogeneous network, not a universal single cause of
    DED.
  role: mediator
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: corneal epithelial cell
    term:
      id: CL:0000575
      label: corneal epithelial cell
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  evidence:
  - reference: PMID:34575438
    reference_title: "Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles
      (PLGA NP) were cytoprotective against oxidative stress in vitro
    explanation: >-
      Cultured-cell results establish an experimentally tractable
      oxidative-stress component but do not establish its magnitude across
      human DED endotypes.
  - reference: PMID:34575438
    reference_title: "Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      significantly reduced ocular surface damage and oxidative
      stress-associated DNA damage in corneal epithelial cells in the mouse
      desiccating stress/scopolamine model for dry eye disease in vivo.
    explanation: >-
      The mouse-model result supports oxidative injury in an experimental DED
      context while preserving its non-human evidence scope.
  downstream:
  - target: Ocular-Surface Innate and Adaptive Inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Reactive oxygen species and inflammatory signaling can reinforce one
      another in experimental DED.
    evidence:
    - reference: PMID:42439592
      reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Dry eye disease (DED) is a multifactorial ocular disorder driven by a
        reinforcing cycle of oxidative stress, inflammation, and epithelial
        damage, rendering single-target therapies ineffective.
      explanation: >-
        The murine therapeutic study frames oxidative stress, inflammation, and
        epithelial damage as a reinforcing experimental disease circuit.
  - target: Corneal and Conjunctival Epithelial Damage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Sustained oxidative stress can contribute to epithelial DNA damage and
      loss of ocular-surface integrity.
    evidence:
    - reference: PMID:34575438
      reference_title: "Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        significantly reduced ocular surface damage and oxidative
        stress-associated DNA damage in corneal epithelial cells in the mouse
        desiccating stress/scopolamine model for dry eye disease in vivo.
      explanation: >-
        Reduction of both oxidative DNA damage and ocular-surface damage by an
        antioxidant intervention supports this edge in a mouse model.
- name: Ocular-Surface Innate and Adaptive Inflammation
  description: >-
    In inflammatory DED contexts, epithelial and innate immune signaling recruit
    macrophages and antigen-presenting cells, while CD4-positive T-cell responses
    can sustain cytokine production and tissue injury. The intensity of this arm
    differs across etiologic forms.
  role: mediator
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: CD4-positive, alpha-beta T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Immune response can be divided into innate immunity and adaptive immunity.
      The inherent response is the innate immunity of the human body, known as
      the first natural defense line, which mainly includes macrophages,
      monocytes, dendritic cells, neutrophils and natural killer cells, etc.
      Adaptive immunity is acquired immunity, which generally forms a highly
      targeted immune process after the invasion of certain pathogenic
      microorganisms. The two immune modes are jointly involved in the immune
      regulation of dry eye disease
    explanation: >-
      This review supports involvement of both innate and adaptive immune arms
      and identifies macrophages among the innate participants.
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The abundant presence of CD4+ T cells in the adaptive immune response and
      cyclosporine in the treatment of DED suggest that adaptive immunity also
      plays an important role in DED.
    explanation: >-
      The review specifically supports a CD4-positive T-cell contribution to
      the adaptive inflammatory arm.
  downstream:
  - target: Corneal and Conjunctival Epithelial Damage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Persistent effector-cell activity and cytokine signaling can damage
      corneal and conjunctival epithelial tissues and restart innate responses.
    evidence:
    - reference: PMID:34421626
      reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In this stage, the proliferation and amplification of T cells in the
        ocular surface cause injury, restart the acute proinflammatory innate
        response, and with the loss of immune regulation, trigger a vicious
        cycle of pathological immune response
      explanation: >-
        The review describes how ocular-surface T-cell activity contributes to
        injury and inflammatory reinforcement.
  - target: Conjunctival hyperemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - inflammatory vasodilation of conjunctival vessels
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Ocular-surface inflammation can produce conjunctival redness through
      local inflammatory vascular responses.
    evidence:
    - reference: PMID:34421626
      reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These include dryness, foreign body sensation, burning sensation,
        itching sensation, photophobia, red eyes, blurred vision, fluctuating
        vision, and visual fatigue.
      explanation: >-
        The review lists red eyes among DED symptoms; the edge makes the
        inflammation-to-conjunctival-hyperemia interpretation explicit.
- name: Corneal and Conjunctival Epithelial Damage
  description: >-
    Stress and inflammation can disrupt corneal and conjunctival epithelial
    integrity. Damage can include punctate staining, epithelial-cell loss, and,
    in severe disease, more extensive surface lesions.
  role: outcome
  biological_scale: TISSUE
  cell_types:
  - preferred_term: corneal epithelial cell
    term:
      id: CL:0000575
      label: corneal epithelial cell
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  - preferred_term: conjunctiva
    term:
      id: UBERON:0001811
      label: conjunctiva
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In dry eyes, the apoptosis of lacrimal acinus, conjunctival epithelium,
      corneal epithelium, and corneal endothelial cells is abnormally increased,
      resulting in damage and destruction of eye tissues
    explanation: >-
      This review supports apoptosis and damage across the corneal,
      conjunctival, and lacrimal compartments.
  downstream:
  - target: Neurosensory Dysfunction and Ocular Pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Ocular-surface injury can alter corneal-nerve structure or signaling and
      contribute to pain, while pain can also persist through peripheral or
      central neural mechanisms that are not proportional to surface damage.
    evidence:
    - reference: PMID:40472874
      reference_title: "TFOS DEWS III: Digest."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Ocular pain perception is linked to structural integrity of corneal
        nerves, functional capacities of neurons, and activity of the central
        and peripheral nervous systems.
      explanation: >-
        The current consensus digest supports both corneal-nerve and broader
        peripheral/central contributions, qualifying a simple damage-to-pain
        relationship.
  - target: Keratoconjunctivitis sicca
    causal_link_type: DIRECT
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Damage and dryness affecting both corneal and conjunctival epithelia are
      clinically expressed as keratoconjunctivitis sicca.
    evidence:
    - reference: PMID:40146145
      reference_title: "Comparative evaluation of aqueous solution and oil emulsion formulations of 0.05% cyclosporine eye drops in dry eye disease - A randomized clinical trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dry eye disease (DED), alternatively termed keratoconjunctivitis sicca,
        stands as a prevalent ocular surface ailment impacting millions of
        individuals globally.
      explanation: >-
        The clinical report identifies keratoconjunctivitis sicca as the
        ocular-surface manifestation represented by this damage node.
- name: Neurosensory Dysfunction and Ocular Pain
  description: >-
    Altered corneal-nerve integrity and peripheral or central sensory processing
    can generate ocular discomfort or pain. Neural dysfunction can coexist with
    epithelial damage or become partly dissociated from measured surface signs.
  role: outcome
  locations:
  - preferred_term: cornea
    term:
      id: UBERON:0000964
      label: cornea
  evidence:
  - reference: PMID:40472874
    reference_title: "TFOS DEWS III: Digest."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ocular pain perception is linked to structural integrity of corneal
      nerves, functional capacities of neurons, and activity of the central and
      peripheral nervous systems.
    explanation: >-
      This directly supports a neurosensory contribution to ocular pain in DED.
  downstream:
  - target: Ocular pain
    causal_link_type: DIRECT
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: Altered peripheral or central sensory processing can directly produce ocular pain.
    evidence:
    - reference: PMID:40472874
      reference_title: "TFOS DEWS III: Digest."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Ocular pain perception is linked to structural integrity of corneal
        nerves, functional capacities of neurons, and activity of the central
        and peripheral nervous systems.
      explanation: >-
        The consensus directly connects neural integrity and function with
        ocular pain perception.
  - target: Photophobia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Altered ocular sensory processing can accompany the light sensitivity
      reported in DED, although the intervening circuitry is not asserted here.
    evidence:
    - reference: PMID:34421626
      reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These include dryness, foreign body sensation, burning sensation,
        itching sensation, photophobia, red eyes, blurred vision, fluctuating
        vision, and visual fatigue.
      explanation: >-
        The review explicitly includes photophobia in the DED symptom spectrum;
        the causal route is conservatively left with unknown intermediates.
  - target: Corneal foreign body sensation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - multidriver_tear_film_homeostasis_model
    description: >-
      Abnormal ocular-surface sensory signaling can manifest as foreign-body
      sensation even when no foreign material is present.
    evidence:
    - reference: PMID:34421626
      reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These include dryness, foreign body sensation, burning sensation,
        itching sensation, photophobia, red eyes, blurred vision, fluctuating
        vision, and visual fatigue.
      explanation: >-
        The review explicitly includes foreign-body sensation among DED
        symptoms; omitted neural intermediates are not over-specified.
phenotypes:
- category: Ophthalmologic
  name: Keratoconjunctivitis sicca
  diagnostic: true
  description: >-
    Dryness and irritation of the cornea and conjunctiva are the defining
    ocular-surface manifestation; keratoconjunctivitis sicca is also a commonly
    used clinical name for DED.
  phenotype_term:
    preferred_term: Keratoconjunctivitis sicca
    term:
      id: HP:0001097
      label: Keratoconjunctivitis sicca
  evidence:
  - reference: PMID:40146145
    reference_title: "Comparative evaluation of aqueous solution and oil emulsion formulations of 0.05% cyclosporine eye drops in dry eye disease - A randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dry eye disease (DED), alternatively termed keratoconjunctivitis sicca,
      stands as a prevalent ocular surface ailment impacting millions of
      individuals globally.
    explanation: >-
      The human clinical-trial report identifies keratoconjunctivitis sicca as
      an alternative clinical term for DED.
- category: Ophthalmologic
  name: Ocular pain
  description: >-
    Ocular pain or discomfort can reflect corneal-nerve injury, altered neuronal
    function, or peripheral and central sensory processing.
  phenotype_term:
    preferred_term: Ocular pain
    term:
      id: HP:0200026
      label: Ocular pain
  evidence:
  - reference: PMID:40472874
    reference_title: "TFOS DEWS III: Digest."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ocular pain perception is linked to structural integrity of corneal
      nerves, functional capacities of neurons, and activity of the central and
      peripheral nervous systems.
    explanation: >-
      This supports ocular pain as a neurosensory manifestation of DED.
- category: Ophthalmologic
  name: Photophobia
  description: Light sensitivity can occur among the heterogeneous ocular symptoms of DED.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These include dryness, foreign body sensation, burning sensation, itching
      sensation, photophobia, red eyes, blurred vision, fluctuating vision, and
      visual fatigue.
    explanation: >-
      This review explicitly includes photophobia in the DED symptom spectrum.
- category: Ophthalmologic
  name: Blurred vision
  description: Tear-film instability can produce intermittent or fluctuating blurred vision.
  phenotype_term:
    preferred_term: Blurred vision
    term:
      id: HP:0000622
      label: Blurred vision
  evidence:
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These include dryness, foreign body sensation, burning sensation, itching
      sensation, photophobia, red eyes, blurred vision, fluctuating vision, and
      visual fatigue.
    explanation: >-
      This review explicitly includes blurred and fluctuating vision in the DED
      symptom spectrum.
- category: Ophthalmologic
  name: Decreased lacrimation
  description: >-
    Reduced aqueous tear production is the defining secretory manifestation of
    aqueous tear-deficient DED, including Sjögren and non-Sjögren forms.
  phenotype_term:
    preferred_term: Decreased lacrimation
    term:
      id: HP:0000633
      label: Decreased lacrimation
  evidence:
  - reference: PMID:35681232
    reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, DED can be divided into two main types, aqueous tear-deficient
      dry eye and evaporative dry eye [2].
    explanation: >-
      The review recognizes reduced aqueous tear production as a defining DED
      form; HP:0000633 provides the corresponding clinical phenotype.
- category: Ophthalmologic
  name: Corneal foreign body sensation
  description: >-
    A gritty or foreign-body sensation can occur from ocular-surface irritation
    and abnormal sensory signaling despite the absence of retained material.
  phenotype_term:
    preferred_term: Corneal foreign body sensation
    term:
      id: HP:0034804
      label: Corneal foreign body sensation
  evidence:
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These include dryness, foreign body sensation, burning sensation, itching
      sensation, photophobia, red eyes, blurred vision, fluctuating vision, and
      visual fatigue.
    explanation: >-
      The review explicitly lists foreign-body sensation among DED symptoms.
- category: Ophthalmologic
  name: Conjunctival hyperemia
  description: >-
    Conjunctival redness can accompany the inflammatory and epithelial-injury
    arms of DED.
  phenotype_term:
    preferred_term: Conjunctival hyperemia
    term:
      id: HP:0030953
      label: Conjunctival hyperemia
  evidence:
  - reference: PMID:34421626
    reference_title: "Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These include dryness, foreign body sensation, burning sensation, itching
      sensation, photophobia, red eyes, blurred vision, fluctuating vision, and
      visual fatigue.
    explanation: >-
      The review explicitly includes red eyes in the DED symptom spectrum;
      conjunctival hyperemia provides the structured phenotype.
diagnosis:
- name: Symptom Screening Plus Objective Tear-Film or Ocular-Surface Abnormality
  description: >-
    The TFOS DEWS III diagnostic pathway begins with an OSDI-6 symptom score of
    at least 4 and requires at least one objective abnormality: non-invasive
    tear break-up time under 10 seconds, qualifying tear hyperosmolarity, or
    specified corneal, conjunctival, or lid-margin staining.
  diagnosis_term:
    preferred_term: clinical evaluation
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  results: >-
    OSDI-6 score >=4 plus non-invasive break-up time <10 seconds, tear osmolarity
    >=308 mOsm/L in either eye or interocular difference >8 mOsm/L, or staining
    above the TFOS DEWS III thresholds supports diagnosis after differential
    diagnosis and ocular examination.
  evidence:
  - reference: PMID:40451408
    reference_title: "TFOS DEWS III: Diagnostic Methodology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommended screening questionnaire is the OSDI-6 with a cut-off score
      ≥4. A positive result together with a non-invasive breakup time <10s or
      alternatively tear film hyperosmolarity (≥308mOsm/L in either eye or an
      interocular difference >8mOsm/L) or alternatively >5 corneal fluorescein
      and/or >9 conjunctival lissamine green punctate spots and/or lid margin
      lissamine green staining of ≥2mm length & ≥25 % width, gives a diagnosis of
      dry eye.
    explanation: >-
      This is the current consensus symptom-plus-sign diagnostic algorithm and
      preserves the published cutoffs.
environmental:
- name: Prolonged Digital Screen Use
  presence: Risk factor
  exposure_term:
    preferred_term: prolonged digital screen use
  description: >-
    Longer use of computers, tablets, phones, and other digital displays is
    associated with DED symptoms and diagnosis. Reduced blink rate and less
    complete blinking are the principal proposed intermediates, so this factor
    is linked specifically to the blink/lid-closure driver rather than treated
    as a direct cause of every DED endotype.
  effect: Predisposes to ocular-surface dryness by altering blink dynamics.
  influences_mechanisms:
  - target: Blink and Lid-Closure Abnormality
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Digital screen tasks can reduce blink rate and completeness, increasing
      the time during which tears evaporate between blinks.
    evidence:
    - reference: PMID:34531649
      reference_title: The Relationship Between Dry Eye Disease and Digital Screen Use.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The most prevalent hypothesis to explain the link between digital screen
        use and dry eye is digital screen use influences blinking dynamics by
        reducing both blink rate and blink completeness, leading to increased
        ocular surface dryness.
      explanation: >-
        The review identifies altered blink rate and completeness as the
        proximal mechanism connecting screen use with ocular dryness.
  evidence:
  - reference: PMID:34531649
    reference_title: The Relationship Between Dry Eye Disease and Digital Screen Use.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Extensive cross-sectional studies have shown that digital screen use
      duration is associated with an increased risk of severe symptoms and
      clinical diagnosis of dry eye disease in adults.
    explanation: >-
      The review reports a duration-associated human risk signal while the
      cross-sectional design prevents a stronger causal claim.
- name: Low Ambient Humidity or Airflow
  presence: Risk factor and exacerbating condition
  exposure_term:
    preferred_term: exposure to low ambient humidity or airflow across the eye
  description: >-
    Dry ambient air and direct airflow increase evaporative demand at the ocular
    surface. Human observational evidence supports lower humidity as a risk
    condition, while controlled low-humidity mouse models directly demonstrate
    excessive tear-film evaporation.
  effect: Predisposes to and can exacerbate evaporative tear-film instability.
  influences_mechanisms:
  - target: Tear-Film Instability and Hyperosmolarity
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Low humidity increases tear evaporation, reducing tear-film stability and
      increasing desiccating stress.
    evidence:
    - reference: PMID:35681232
      reference_title: Interleukin-20 is involved in dry eye disease and is a potential therapeutic target.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Administration of scopolamine reduces aqueous tear production and the
        low humidity environment causes excessive evaporation of the tear film.
      explanation: >-
        The controlled-environment mouse model demonstrates excessive tear-film
        evaporation as the intermediate produced by low humidity.
  evidence:
  - reference: PMID:34206755
    reference_title: "Exposure to Ambient NO(2) Increases the Risk of Dry Eye Syndrome in Females: An 11-Year Population-Based Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      conversely, each SD increment of relative humidity (RH) had a protective
      effect against the risk of DES.
    explanation: >-
      In this female Taiwanese cohort, higher humidity was inversely associated
      with DES; the population and observational design are retained as limits.
- name: Ambient Air Pollution
  presence: Risk factor
  exposure_term:
    preferred_term: ambient air pollution exposure
    term:
      id: ECTO:8000036
      label: exposure to air pollution
  description: >-
    Long-term ambient pollutant exposure has been associated with increased dry
    eye prevalence. The available study was observational and limited to women,
    so the factor is modeled as a predisposition with unasserted intermediates.
  effect: Associated with increased susceptibility to dry eye syndrome.
  influences_mechanisms:
  - target: Tear-Film Instability and Hyperosmolarity
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Air-pollution exposure is placed upstream of the canonical tear-film
      homeostasis node, without asserting a specific molecular intermediate from
      this association study.
    evidence:
    - reference: PMID:34206755
      reference_title: "Exposure to Ambient NO(2) Increases the Risk of Dry Eye Syndrome in Females: An 11-Year Population-Based Study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        After considering hormone supplementation, arthritis, and allergy, the
        SD increment of NO2 and temperature were associated with the PRs of DES.
      explanation: >-
        The adjusted female-cohort association supports predisposition but not a
        direct mechanistic edge, hence unknown intermediates.
  evidence:
  - reference: PMID:34206755
    reference_title: "Exposure to Ambient NO(2) Increases the Risk of Dry Eye Syndrome in Females: An 11-Year Population-Based Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      significant associations of ambient NO2 concentration, RH and temperature
      with DES indicated the importance of increased environmental protection
      in the female population.
    explanation: >-
      This summarizes the study's environmental associations while preserving
      its female-population scope.
- name: Contact Lens Wear
  presence: Risk factor
  exposure_term:
    preferred_term: contact lens wear
  description: >-
    Contact lens wear is a recognized extrinsic and iatrogenic contributor to
    DED. Because the cited consensus does not resolve one universal route, the
    link to tear-film instability retains unknown intermediates.
  effect: Can trigger or predispose to iatrogenic dry eye disease.
  influences_mechanisms:
  - target: Tear-Film Instability and Hyperosmolarity
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Contact lens wear can disrupt ocular-surface homeostasis through routes
      that vary by lens, wearer, and exposure context.
    evidence:
    - reference: PMID:40472874
      reference_title: "TFOS DEWS III: Digest."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Iatrogenic DED can result from medications, contact lenses, and surgical
        procedures.
      explanation: >-
        The current consensus supports contact lenses as an iatrogenic DED
        contributor but does not specify one obligatory intermediate.
  evidence:
  - reference: PMID:34531649
    reference_title: The Relationship Between Dry Eye Disease and Digital Screen Use.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Extrinsic risk factors for DED may include contact lens wear,
      environmental conditions (eg, low humidity or airflow on the eye), topical
      or systemic medications, lack of hygienic practices for eyelids and
      eyelashes, eye beauty trends, and eye cosmetic product ingredients and
      applications.
    explanation: >-
      The review explicitly lists contact lens wear among extrinsic DED risk
      factors.
- name: Topical or Systemic Medication Exposure
  presence: Risk factor
  exposure_term:
    preferred_term: topical or systemic medication exposure
    term:
      id: ECTO:0000509
      label: exposure to drug
  description: >-
    Some topical and systemic medications can cause or predispose to iatrogenic
    DED. This entry remains drug-class agnostic because the cited consensus
    supports the category without assigning every medication the same route.
  effect: Can trigger or predispose to iatrogenic dry eye disease.
  influences_mechanisms:
  - target: Tear-Film Instability and Hyperosmolarity
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Medication exposure can disturb tear-film or ocular-surface homeostasis,
      with the operative route depending on the agent.
    evidence:
    - reference: PMID:40472874
      reference_title: "TFOS DEWS III: Digest."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Iatrogenic DED can result from medications, contact lenses, and surgical
        procedures.
      explanation: >-
        The consensus supports medications as an iatrogenic DED contributor;
        the edge conservatively leaves agent-specific intermediates unresolved.
  evidence:
  - reference: PMID:34531649
    reference_title: The Relationship Between Dry Eye Disease and Digital Screen Use.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Extrinsic risk factors for DED may include contact lens wear,
      environmental conditions (eg, low humidity or airflow on the eye), topical
      or systemic medications, lack of hygienic practices for eyelids and
      eyelashes, eye beauty trends, and eye cosmetic product ingredients and
      applications.
    explanation: >-
      The review explicitly lists topical and systemic medications among
      extrinsic risk factors.
treatments:
- name: Tear-Film Replenishment and Conservation
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Ocular lubricants and other tear supplements are first-line measures used to
    replenish or conserve the tear film. Formulation and frequency should be
    matched to the individual's deficient tear component and symptom burden.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Tear-Film Instability and Hyperosmolarity
    treatment_effect: RESTORES
    description: >-
      Tear supplements aim to restore a more stable and adequately hydrated
      ocular-surface environment.
    evidence:
    - reference: PMID:40467022
      reference_title: "TFOS DEWS III: Management and Therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        First-line management focuses on methods to replenish, conserve, and
        stimulate the tear film, with an emphasis on ocular supplements, which
        remain the cornerstone of DED treatment.
      explanation: >-
        The consensus directly supports tear-film replenishment and conservation
        as the mechanism targeted by first-line ocular supplements.
  evidence:
  - reference: PMID:40467022
    reference_title: "TFOS DEWS III: Management and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      First-line management focuses on methods to replenish, conserve, and
      stimulate the tear film, with an emphasis on ocular supplements, which
      remain the cornerstone of DED treatment.
    explanation: >-
      The current TFOS consensus places tear-film replenishment, conservation,
      and stimulation at the center of first-line management.
- name: Meibomian-Gland-Directed Lid Warming and Hygiene
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Warm compresses, lid hygiene, and selected in-office eyelid-warming
    approaches address meibomian gland dysfunction when a lipid-deficient,
    evaporative driver is present; they are not universal therapy for every DED
    endotype.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Meibomian Gland Dysfunction
    treatment_effect: MODULATES
    description: >-
      Lid warming and hygiene target meibomian-gland and lid-margin contributors
      to tear-film lipid deficiency and evaporation.
    evidence:
    - reference: PMID:40467022
      reference_title: "TFOS DEWS III: Management and Therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Meibomian gland dysfunction, a primary contributor to DED, is typically
        treated with warm compresses and a wide variety of in-office treatments,
        including device-driven technologies to warm the eyelids, intense pulsed
        light therapy, low-level light therapy, and other new and emerging
        technologies.
      explanation: >-
        The consensus explicitly links lid warming to the meibomian-gland driver
        represented by this dedicated target.
  evidence:
  - reference: PMID:40467022
    reference_title: "TFOS DEWS III: Management and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Meibomian gland dysfunction, a primary contributor to DED, is typically
      treated with warm compresses and a wide variety of in-office treatments,
      including device-driven technologies to warm the eyelids, intense pulsed
      light therapy, low-level light therapy, and other new and emerging
      technologies.
    explanation: >-
      This supports driver-directed warming approaches for DED with meibomian
      gland dysfunction.
- name: Topical Cyclosporin A for Inflammatory DED
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Topical 0.05% cyclosporin A is a T-cell-directed anti-inflammatory option for
    selected moderate-to-severe inflammatory DED. A 12-week randomized
    formulation-comparison trial found improvement from baseline with both
    aqueous solution and oil emulsion alongside lubricant drops; it did not
    compare cyclosporin with placebo or establish benefit for all DED forms.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclosporin A
      term:
        id: CHEBI:4031
        label: cyclosporin A
  target_mechanisms:
  - target: Ocular-Surface Innate and Adaptive Inflammation
    treatment_effect: INHIBITS
    description: >-
      Cyclosporin A suppresses the T-cell-associated inflammatory arm selected
      for treatment in inflammatory DED.
    evidence:
    - reference: PMID:40467022
      reference_title: "TFOS DEWS III: Management and Therapy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        DED caused by certain etiological drivers can benefit from
        anti-inflammatory therapies, including topical and oral corticosteroids,
        T-cell immunomodulatory drugs, and a wide variety of pharmacological agents
      explanation: >-
        The consensus identifies T-cell immunomodulatory therapy as a
        driver-directed means of inhibiting the inflammatory arm.
  evidence:
  - reference: PMID:40467022
    reference_title: "TFOS DEWS III: Management and Therapy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DED caused by certain etiological drivers can benefit from
      anti-inflammatory therapies, including topical and oral corticosteroids,
      T-cell immunomodulatory drugs, and a wide variety of pharmacological agents
    explanation: >-
      The consensus supports anti-inflammatory therapy for selected etiologic
      drivers rather than undifferentiated use in all DED.
  - reference: PMID:40146145
    reference_title: "Comparative evaluation of aqueous solution and oil emulsion formulations of 0.05% cyclosporine eye drops in dry eye disease - A randomized clinical trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both the groups showed comparable values at baseline. After treatment,
      there was statistically significant improvement over baseline values in
      both groups at 4, 8, and 12 weeks.
    explanation: >-
      The randomized human trial supports improvement with both topical 0.05%
      cyclosporine formulations, while its active-formulation comparison and
      short follow-up limit broader efficacy inference.
- name: Visible-Light-Activated Carbon-Monoxide Nanoplatform (Preclinical)
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    TiZr-MOF/CO@F127 is a visible-light-activated, F127-hydrogel nanoplatform
    designed for controlled corneal carbon-monoxide delivery. Five days of
    topical treatment reduced oxidative and inflammatory readouts and improved
    epithelial recovery in a murine DED model. This is preclinical evidence only:
    human ocular safety, dose control, light-delivery parameters, and clinical
    efficacy have not been established, so this is not a clinical recommendation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carbon monoxide
      term:
        id: CHEBI:17245
        label: carbon monoxide
  target_mechanisms:
  - target: Ocular-Surface Osmotic and Oxidative Stress
    treatment_effect: INHIBITS
    description: The platform was reported to scavenge reactive oxygen species.
    evidence:
    - reference: PMID:42439592
      reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mechanistically, CO scavenged reactive oxygen species, suppressed MMP-9
        expression, promoted macrophage polarization from M1 to M2 phenotype,
        reduced inflammatory cytokine production, and enhanced corneal epithelial
        proliferation.
      explanation: >-
        The murine study directly reports reactive-oxygen-species scavenging by
        the carbon-monoxide intervention.
  - target: Ocular-Surface Innate and Adaptive Inflammation
    treatment_effect: INHIBITS
    description: >-
      The platform reduced inflammatory cytokines and MMP-9 and shifted
      macrophage polarization in the murine model.
    evidence:
    - reference: PMID:42439592
      reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mechanistically, CO scavenged reactive oxygen species, suppressed MMP-9
        expression, promoted macrophage polarization from M1 to M2 phenotype,
        reduced inflammatory cytokine production, and enhanced corneal epithelial
        proliferation.
      explanation: >-
        The murine study directly reports suppression of inflammatory mediators
        and a macrophage-polarization shift.
  - target: Corneal and Conjunctival Epithelial Damage
    treatment_effect: RESTORES
    description: The platform enhanced corneal epithelial proliferation and recovery in mice.
    evidence:
    - reference: PMID:42439592
      reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In a murine DED model, topical administration of MCF for 5 days achieved
        84% corneal epithelial recovery and alleviated corneal inflammation and
        tissue injury.
      explanation: >-
        This directly supports epithelial recovery as a treatment target in the
        mouse model.
  evidence:
  - reference: PMID:42439592
    reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In a murine DED model, topical administration of MCF for 5 days achieved
      84% corneal epithelial recovery and alleviated corneal inflammation and
      tissue injury.
    explanation: >-
      This directly supports short-term efficacy in a murine model and does not
      establish human benefit.
  - reference: PMID:42439592
    reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mechanistically, CO scavenged reactive oxygen species, suppressed MMP-9
      expression, promoted macrophage polarization from M1 to M2 phenotype,
      reduced inflammatory cytokine production, and enhanced corneal epithelial
      proliferation.
    explanation: >-
      The murine study supports the three modeled treatment targets while
      remaining preclinical.
discussions:
- discussion_id: dry_eye_co_nanoplatform_human_translation
  prompt: >-
    Can controlled topical carbon-monoxide delivery reproduce the reported
    antioxidant, anti-inflammatory, and epithelial-reparative effects safely in
    human DED, and in which etiologic endotypes would its multi-target mechanism
    be appropriate?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - treatments#Visible-Light-Activated Carbon-Monoxide Nanoplatform (Preclinical)
  - pathophysiology#Ocular-Surface Osmotic and Oxidative Stress
  - pathophysiology#Ocular-Surface Innate and Adaptive Inflammation
  rationale: >-
    The cited efficacy and mechanism data come from a five-day murine DED study.
    DED is heterogeneous, evaporative forms can have muted inflammation, and CO
    exposure has a narrow safety context. Translation therefore requires
    endotype selection, ocular and systemic safety assessment, controlled dose
    and light-delivery studies, and randomized human efficacy data.
  evidence:
  - reference: PMID:42439592
    reference_title: "Visible-Light-Induced Release of Carbon Monoxide: Multifunctionally Treatment for Dry Eye Disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In a murine DED model, topical administration of MCF for 5 days achieved
      84% corneal epithelial recovery and alleviated corneal inflammation and
      tissue injury.
    explanation: >-
      The evidence is explicitly limited to a short murine study, motivating the
      human-translation gap.
datasets: []
📚

References & Deep Research

Deep Research

1
Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Dry Eye Disease. Core disease mechanisms, molecular and cellular pathways,...
Asta Scientific Corpus Retrieval 19 citations 2026-08-08T12:59:52.495221

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Dry Eye Disease. Core disease mechanisms, molecular and cellular pathways,...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 19
  • Snippets retrieved: 20

Relevant Papers

[1] Interleukin-20 is involved in dry eye disease and is a potential therapeutic target

  • Authors: Hsiao-Hsuan Wang, Wei‐Yu Chen, Yi-Hsun Huang, S. Hsu, Y. Tsao et al.
  • Year: 2022
  • Venue: Journal of Biomedical Science
  • URL: https://www.semanticscholar.org/paper/975c97a82ceb1de42cb3a06c69f9310d97e6950e
  • DOI: 10.1186/s12929-022-00821-2
  • PMID: 35681232
  • PMCID: 9178884
  • Citations: 58
  • Summary: The functions of IL-20 were demonstrated in DED and presented a potential therapeutic option for this condition and the anti-IL-20 antibody 7E was established to neutralize IL- 20 activity.
  • Evidence snippets:
  • Snippet 1 (score: 0.552) > Dry eye disease (DED) is the most common disease in ophthalmology, affecting millions of people worldwide. Currently, the world's population is becoming an aging society, and DED may become a serious problem [1]. DED is characterized by a prolonged dry state of the cornea and conjunctiva of the outer layer of the eye, causing the eyes of patients to feel dry, red, itchy, and sensitive to external stimuli. The etiology and pathogenesis of DED are complex and multifactorial and may involve autoimmune diseases, contact lens use, hormonal changes, chronic inflammation, environmental factors, and infection. Patients with severe DED may even present with excessive eye watering, burning sensation, thick secretions, and blurred vision. Clinically, DED can be divided into two main types, aqueous tear-deficient dry eye and evaporative dry eye [2]. Aqueous tear-deficient dry eye can be subdivided into two categories, Sjögren's dry eye type and non-Sjögren's dry eye type. Evaporative dry eye has been subdivided to distinguish between those eyelid and ocular surface conditions that depend on intrinsic causes and those that arise from extrinsic influences. Studies have shown that many patients have both aqueous tear-deficient and evaporative dry eye, and both types share the common feature of inflammation [3]. It is essential to understand the pathogenesis and molecular mechanism of DED to facilitate drug development. Currently, no available drugs can effectively cure DED, and many cause negative side effects. Therefore, there is an urgent need to understand the pathogenesis of DED and to develop novel therapeutic strategies for DED treatment. > The cornea functions to protect the eyes from dust and bacteria and to focus vision. Normally, eyes are protected by the tear film outside the cornea. The tear film is mainly composed of three protein components, including the mucin layer (secreted by goblet cells on the conjunctiva), the aqueous layer (secreted by the lacrimal gland), and the lipid layer (secreted by the meibomian gland).

[2] Recent Developments About the Pathogenesis of Dry Eye Disease: Based on Immune Inflammatory Mechanisms

  • Authors: Lifei Yu, Chunjing Yu, He Dong, Yan-dong Mu, Rui Zhang et al.
  • Year: 2021
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/c11a61f7972873d2371f827b9ec72169fb6ef5b5
  • DOI: 10.3389/fphar.2021.732887
  • PMID: 34421626
  • PMCID: 8375318
  • Citations: 67
  • Influential citations: 6
  • Summary: This review will systematically review the previous research on the treatment of DED in immune inflammation, analyze the latest views and research hotspots, and provide reference for the prevention and treatment ofDED.
  • Evidence snippets:
  • Snippet 1 (score: 0.545) > Dry eye disease (DED) is newly defined as eye surface disease caused by a variety of factors, tear film instability, increased osmotic pressure, ocular surface inflammation and damage, and neurosensory abnormalities play a pathogenic role, characterized by the loss of tear film balance accompanied by eye symptoms. These include dryness, foreign body sensation, burning sensation, itching sensation, photophobia, red eyes, blurred vision, fluctuating vision, and visual fatigue. In severe cases, corneal epithelial exfoliation, filamentous adhesion, and conjunctival lesions may occur (Stapleton et al., 2017). The global prevalence of dry eye disease is 5-50%, while the incidence in China is 45%, which is a high incidence area (Guo et al., 2010;Farrand et al., 2017;Stapleton et al., 2017). With the popularity of electronic products, makeup, contact lenses, environmental pollution and other influences, the number of patients with dry eye disease will continue to rise at a rate of more than 10% per year, and tend to be younger. The pathogenesis of dry eye has not yet been fully elucidated, but the eye surface immune inflammatory response as the focus of the mechanism has been increasingly concerned. In the classification of etiology, Dry Eye Workshop II regards the imbalance of tear film homeostasis as the main feature of dry eye and the core of pathophysiology, whether it is water-based tear deficiency type or over-evaporation type (Nelson et al., 2017). This process is caused by the increase of Th17 and chemokines in the ocular surface of DED patients, which breaks the normal ocular surface immune balance and leads to the immune homeostasis in the tear membrane (Kodati et al., 2014). In the clinical treatment of DED, anti-inflammatory drugs represented by cyclosporine A and immunomodulatory drugs represented by lifitegrast can play a good ameliorative effect (Wan et al., 2015;Perez et al., 2016). Therefore, it is of strategic significance to further study the immune inflammatory mechanism of DED.

[3] Oxidative Stress in Dry Eye Disease: A Bibliometric Analysis

  • Authors: Yifan Lei, Xinyun Huang, Haodong Guo, Rongqing Huang, Yajun Shi et al.
  • Year: 2025
  • Venue: Clinical Ophthalmology (Auckland, N.Z.)
  • URL: https://www.semanticscholar.org/paper/2e69ebb670f20e4886d4a07c814449a2c2818aea
  • DOI: 10.2147/OPTH.S532001
  • PMID: 40689240
  • PMCID: 12276749
  • Citations: 2
  • Summary: This study provides the first bibliometric approach to hot topics and emerging trends in the field of oxidative stress in DED and explores prospective anti-oxidative stress strategies for future clinical interventions.
  • Evidence snippets:
  • Snippet 1 (score: 0.506) > Dry eye disease (DED) is a multifactorial ocular surface disease characterized by an imbalance in tear film homeostasis, leading to symptoms such as ocular discomfort and visual impairment. 1 The disease affects millions of people worldwide, particularly in the aged population, and the prevalence continues to rise due to population aging and increased exposure to screens. 2 While multiple factors contribute to the pathophysiology of DED, oxidative stress has emerged as one of the key drivers and one link to the central mechanisms of the disease. 3,4 Basically, it occurs due to the disrupted balance between the antioxidant and pro-oxidative systems. 3 5][6] At the same time, inflammatory pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) are activated, forming a vicious cycle of oxidation-inflammation, leading to reduced tear secretion, abnormal lipid composition, and decreased mucin expression, which ultimately exacerbate tear film instability and tear hyperosmolarity 7,8 Prolonged exposure of the ocular surface to environmental stresses such as ultraviolet radiation, air pollution, and dryness predisposes to oxidative damage. 9 Systemic factors such as diabetes mellitus, 10 autoimmune diseases, and aging can further exacerbate oxidative stress, leading to pathological changes such as decreased tear film stability and lipid layer abnormalities in patients with DED. 3 In recent years, there has been an explosion of research into the role of oxidative stress in the pathogenesis of DED, the identification of relevant biomarkers, and targeted therapeutic strategies. These studies span the interdisciplinary fields of molecular biology, epigenetics, clinical ophthalmology, and biomaterials. Despite the proliferation of papers, researchers still face significant challenges in integrating existing evidence and identifying future directions due to the heterogeneity of research models and difficulties in the clinical translation of oxidative damage markers. > Bibliometric methods allow researchers to systematically identify high-impact studies, core authors/institutions, and emerging topics in their field. Such analyses not only reveal the evolutionary pulse of the discipline but also provide a basis for prioritizing the allocation of resources.

[4] Recent developments on dry eye disease treatment compounds

  • Authors: B. Colligris, H. Alkozi, J. Pintor
  • Year: 2013
  • Venue: Saudi Journal of Ophthalmology
  • URL: https://www.semanticscholar.org/paper/e7bc127d66090092496177d6b498d9fdebff9677
  • DOI: 10.1016/j.sjopt.2013.12.003
  • PMID: 24526854
  • PMCID: 3923205
  • Citations: 54
  • Influential citations: 2
  • Summary: The corresponding literature and patents are revised assembling the new treatment approaches of novel and future pharmaceutical compounds destined for the dry eye disease treatment, with the most frequent categories of compounds presented are secretagogues and anti-inflammatory drugs.
  • Evidence snippets:
  • Snippet 1 (score: 0.463) > Current topical treatments for dry eye patients include the use of lubricants and anti-inflammatory drugs. However, lubricants only suppress negative symptoms temporarily, and chronic use of topical steroids is related to severe ocular side effects such as cataract and glaucoma. Further research is necessary toward the action mechanisms of new mucin and tear secretagogues compounds possibly possessing antiinflammatory properties. Additionally further research is needed on understanding the immunomodulatory and inflammatory mechanisms of the conjunctiva. > The deeper understanding of the cellular mechanisms implicated in dry eye is necessary not only to improve symptoms but also to restore the homeostasis of the ocular surface. The pursuit of effective dry eye treatment strategies is delayed by the absence of an accepted set of definitive criteria for evaluating disease severity. There is a lack of an objective test for the diagnosis of the severity of the disease, because symptoms' evaluation is insufficient as a measurement factor. There are several proposals for a novel objective testing such as molecular markers 86,87 or evaluation of the tear film osmolarity 88,89 but for the moment none of them advanced after the pre-clinical test.

[5] Animal models of dry eye: a critical assessment of opportunities and limitations.

  • Authors: S. Barabino, S. Barabino, Reza Dana
  • Year: 2004
  • Venue: Investigative ophthalmology & visual science
  • URL: https://www.semanticscholar.org/paper/33dec41e83bab9ab4778a591a43dcffcf07c1f4f
  • DOI: 10.1167/IOVS.03-1055
  • PMID: 15161821
  • Citations: 163
  • Influential citations: 9
  • Summary: It is shown that interruption of neuronal stimulation for tear secretion, defects in transmembrane and secretory mucin expression, and Meibomian gland dysfunction can all lead to various forms of KCS, and the pathogenic mechanisms in dry eye are not limited to those involved in lacrimal inflammation.
  • Evidence snippets:
  • Snippet 1 (score: 0.463) > Dry eye syndrome, or keratoconjunctivitis sicca (KCS), affects tens of millions of people worldwide, representing one of the most common ocular diseases. The National Eye Institute Industry Workshop on Clinical Trials in Dry Eyes produced a classification that essentially separates dry eye syndrome into two major types: tear-deficient forms (including Sjögren’s syndrome and non-Sjögren’s tear-deficient) and evaporative forms. Recently, it has become clear that the immunopathogenesis of dry eye is complex and multifactorial. Sjögren’s syndrome, which is the classic form of exocrine deficiency associated with KCS, is characterized by a chronic inflammatory infiltration of the lacrimal and salivary glands. The predominant cell type is CD4 T cells that appear to have a defect in Fas-mediated apoptosis, thereby rendering their infiltration into exocrine tissue damaging. However, exactly what factors incite the infiltration of glands by T cells remains unknown. Recently, the observation that lacrimal gland acinar cells may express class II major histocompatibility complex (MHC) molecules, cathepsins B and D, and ribonucleoprotein particle La/SSB proteins has provided some support (but no definitive proof) for the thesis that these cells may be involved in aberrant presentation of autoantigens, thereby potentially capable of priming autoreactive T cells. But the pathogenic mechanisms in dry eye are not limited to those involved in lacrimal inflammation. Indeed, interruption of neuronal stimulation for tear secretion, defects in transmembrane and secretory mucin expression, and Meibomian gland dysfunction can all lead to various forms of KCS. Numerous animal models have been developed to reflect the multiplicity of pathophysiologic mechanisms involved in KCS. Understanding the unique characteristics of these different models of dry eye, and their limitations, will provide a better insight into their use in mechanistic and therapeutic study design.

[6] Changes in human tear metabolome following topical 0.05% cyclosporine A on primary Sjögren’s syndrome

  • Authors: Yingsi Li, Meiting Huang, Luoying Xie, Xiaoming Yan, Wenjing Song
  • Year: 2025
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/36fbac55268fea8848cf5c22ce135cab4dc5fb15
  • DOI: 10.3389/fmed.2025.1653585
  • PMID: 41210869
  • PMCID: 12592072
  • Summary: Analysis of tear metabolome and the therapeutic impact of 0.05% cyclosporine A eye drops in patients with dry eye disease linked to primary Sjögren’s syndrome underscores significant alterations in tear metabolites at the ocular surface in pSS patients receiving 0.05% CsA.
  • Evidence snippets:
  • Snippet 1 (score: 0.459) > Dry eye disease (DED) is a chronic condition with multifactorial etiologies that affects millions globally (1,2). Sjögren's syndrome (SS) is an autoimmune disease that affects the lacrimal and salivary glands, significantly contributing to aqueous-deficient dry eye and resulting in severe ocular surface damage and visual impairment (3). Whether primary or secondary, the majority of SS cases exhibit meibomian gland dysfunction (MGD), characterized by palpebral margin epithelial metaplasia, obstruction of meibomian gland (MG) orifices, and deficiencies in meibum secretion (4). Inflammation plays a pivotal etiological role in the pathophysiology of DED (2). Chronic ocular surface inflammation increases pro-inflammatory cytokine release, leading to corneal and conjunctival tissue damage (5). Consequently, anti-inflammatory strategies are essential for the treatment of Cyclosporine A (CsA), a common immunomodulator, effectively treats DED and other ocular surface diseases by preventing T-cell infiltration, activation, and proliferation and by inhibiting the transcription of inflammatory cytokine genes such as interleukin-2 and interleukin-4 (6)(7)(8). Its mechanism involves forming a complex with cyclophilin to inhibit calcineurin activity, thereby preventing the nuclear translocation and activation of transcription factors in activated T cells (6,7). The application of topical CsA enhances tear production, preserves ocular surface integrity through its antiapoptotic and immunomodulatory properties, and mitigates ocular discomfort associated with DED (9)(10)(11). Tears, complex fluids containing proteins, lipids, electrolytes, and metabolites, are crucial for identifying biomarkers of ocular surface disorders. Metabolomics, an emerging analytical approach, offers the potential to identify biomarkers and elucidate disease pathways that are more closely aligned with biological phenotypes compared to proteomics.

[7] Differentially Expressed Tear Proteins in Sjögren's Syndrome Keratoconjunctivitis Sicca

  • Authors: Stephen P. Yoon, Zhiyuan Yu, S. Pflugfelder, C. D. de Paiva
  • Year: 2023
  • Venue: Translational Vision Science & Technology
  • URL: https://www.semanticscholar.org/paper/754616bb5eef76c12f8f5fe5b7cdb2b575c09740
  • DOI: 10.1167/tvst.12.6.8
  • PMID: 37310735
  • PMCID: 10275389
  • Citations: 13
  • Influential citations: 1
  • Summary: The results suggest tear protein concentrations are altered in patients with SS KCS compared to controls, and indicate that hundreds of factors can be assayed in tear proteins collected from a Schirmer strip.
  • Evidence snippets:
  • Snippet 1 (score: 0.454) > Sjögren's syndrome (SS) is an autoimmune disease affecting the exocrine lacrimal and salivary glands, which can lead to keratoconjunctivitis sicca (KCS) and xerostomia. Changes in tear composition combined with systemic factors contribute to an inflammatory cycle and ocular surface disease. 1 The activation of stress signaling pathways from desiccation triggers the production of inflammatory mediators, inflammatory cell recruitment, dendritic cell (DC) maturation, and the activation of an adaptive T-cell mediated response. 2 urrent methods of diagnosis for KCS focus on measures of eye irritation using symptom questionnaires and ocular surface dye staining. Patients with aqueous deficient dry eye typically have increased scores on symptom questionnaires (such as the Symptom Assessment Questionnaire in Dry Eye [SANDE]), corneal fluorescein (CF) staining, and conjunctival (CJ) lissamine green staining, and decreased tear break-up times (TBUT). 3 Identifying disease-relevant biomarkers in SS KCS could improve diagnostic sensitivity, specificity, and classification, and identify disease relevant therapeutic targets. > The mechanism(s) driving the pathophysiology of SS KCS are not completely understood. Genetic and proteomic analysis in SS may help identify key immune mediators involved in the pathogenesis of KCS and therapeutic targets. Our group has previously identified differentially expressed gene (DEG) pathways as possible biomarkers in SS KCS in cells obtained via conjunctival impression cytology. 4 These DEG biomarkers correlated with clinical markers for dry eye. In addition to changes in the conjunctiva, tear proteomic analysis in SS has shown dysregulated expression of proteins involved in inflammation, immunity, and oxidative stress. 5 Schirmer strips are widely available in clinical settings and provide an accessible method to sample tear fluid in patients with SS KCS for proteomics analysis. The purpose of this study was to compare levels of immune-related tear proteins of healthy subjects and patients with SS KCS collected by Schirmer strips using the RayBiotech L507 proteomic array.

[8] Metabolomic Alterations in the Tear Fluids of Patients With Superior Limbic Keratoconjunctivitis

  • Authors: Y. Zong, Chaofan Cheng, Kunke Li, R. Xue, Ziyan Chen et al.
  • Year: 2022
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/48dc312841e912115e635b294a226815110dcb6c
  • DOI: 10.3389/fmed.2021.797630
  • PMID: 35118093
  • PMCID: 8804220
  • Citations: 9
  • Summary: SLK has a specific metabolomic profile, of which some key elements can serve as potential biomarkers of SLK for diagnostic and prognostic purposes, and this study reveals that linoleic acid metabolism was the most significantly changed pathway.
  • Evidence snippets:
  • Snippet 1 (score: 0.450) > Metabolomics is focused on a comprehensive analysis of metabolites in a biological system and metabolic changes in response to pathophysiological stimuli, genetic modifications and/or environmental perturbations (12). The main analytical techniques adopted are nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-tandem mass spectrometry (GC-MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Metabolomics has been widely used to assess biological systems, providing molecular information related to phenotypes since metabolites are the ultimate product of gene, mRNA and protein activity (17). Moreover, in terms of the high-throughput profiling of the whole metabolome in a disease condition, identifying biomarkers becoming possible (18,19). With advances in technology, untargeted LC-MS metabolomic analysis of tear fluid has been applied in clinical and animal studies of several eye diseases, such as keratoconus (12,15,20), dry eye (13,21), and multiple sclerosis (16). Studies of metabolomics used in eye diseases have been summarized in a recent review article (12). As the reviewers suggested, to date, possible biomarker candidates for dry eye disease are lipid metabolites and androgens, and those for keratoconus are cytokeratins, urea, citrate cycle, and oxidative stress metabolites. In addition, palmitoylcarnitine, sphingolipids, vitamin-D-related metabolites, and steroid precursors may be related to glaucoma, and the dysregulation of amino acid and carnitine metabolism is critical in the development and progression of diabetic retinopathy (12). > In the present study, we analyzed tear samples obtained from a clinical cohort of 42 subjects and investigated the tear metabolomic differences between SLK patients and healthy controls. We aimed to identify the metabolites in tears that are pathologically relevant to SLK. In addition, we constructed a potential metabolite biomarker model to assist us in distinguishing SLK from a healthy status.

[9] Current Advances in Regenerative Strategies for Dry Eye Diseases: A Comprehensive Review

  • Authors: Basanta Bhujel, Seheon Oh, Chang-Min Kim, Ye-Ji Yoon, H. Chung et al.
  • Year: 2023
  • Venue: Bioengineering
  • URL: https://www.semanticscholar.org/paper/258d79070e0785ee699b011a1afb3234f345e10f
  • DOI: 10.3390/bioengineering11010039
  • PMID: 38247916
  • PMCID: 10813666
  • Citations: 16
  • Summary: This article specifically explores the different strategies reported so far for treating dry eye disease and discusses their potential as long-term cures while also considering the factors that limit their feasibility and effectiveness.
  • Evidence snippets:
  • Snippet 1 (score: 0.448) > The pathogenesis of dry eye is complex and not fully understood. Current research on the dry eye mechanism predominantly concentrates on the following areas:
  • Snippet 2 (score: 0.448) > The pathogenesis of dry eye is complex and not fully understood. Current research on the dry eye mechanism predominantly concentrates on the following areas:

[10] Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress

  • Authors: A. Ghosh, Rubina Thapa, H. N. Hariani, Michael Volyanyuk, S. D. Ogle et al.
  • Year: 2021
  • Venue: Pharmaceutics
  • URL: https://www.semanticscholar.org/paper/952fbcf295b69ca3e897e9019543ea851088c7d8
  • DOI: 10.3390/pharmaceutics13091362
  • PMID: 34575438
  • PMCID: 8471707
  • Citations: 24
  • Summary: Xanthohumol-encapsulating poly(lactic-co-glycolic acid) nanoparticles (PLGA NP) were cytoprotective against oxidative stress in vitro, and significantly reduced ocular surface damage and oxidative stress-associated DNA damage in corneal epithelial cells in the mouse desiccating stress/scopolamine model for dry eye disease in vivo.
  • Evidence snippets:
  • Snippet 1 (score: 0.447) > Dry eye disease is an umbrella term describing various subtypes of the disease. Dry eye disease poses a substantial burden on the affected individual and society as a whole. Existing pharmacologic management for dry eye disease targets T cell-mediated inflammatory pathways and in the United States consists of ophthalmic formulations of cyclosporine (Restasis ® or Cequa™) or the lymphocyte function-associated antigen 1 inhibitor, lifitegrast (Xiidra ® ). Both agents are associated with limited efficacy and adverse effects in up to 25% of patients [1][2][3], highlighting an urgent unmet clinical need for novel efficacious and well-tolerated therapeutics. > Previous studies have implicated the generation of reactive oxygen species (ROS) and the ensuing elevated levels of cellular oxidative stress as a key contributor to the pathophysiology of dry eye disease (reviewed in [4]). Specifically, elevated levels of oxidative stress have been identified in patients with dry eye disease [5,6], while hyperosmolar conditions cause oxidative stress in cultured corneal epithelial cells [7]. We have recently shown significant oxidative DNA damage in the corneal epithelium of mice exposed to dry eye-inducing conditions of desiccating environment with scopolamine [8]. Similarly, lacrimal gland dysfunction as a result of mitochondrial oxidative stress produces an ocular phenotype reminiscent of dry eye disease in mice [9,10]. > Notably, a mitochondrially-targeted antioxidant, SkQ1 (Visomitin), exerts anti-inflammatory effects in human conjunctival epithelial cells in vitro [11], and has shown therapeutic benefit in US Phase 2 clinical trials following approval in Russia in 2011 [12], providing proof-of-concept evidence supporting the development of therapeutic approaches using antioxidants to treat dry eye disease. > Major challenges associated with dry eye disease management are low patient satisfaction and poor compliance with dosing regimens [13]. Therefore, one important drug development consideration for topical ophthalmic formulations is to enhance ocular surface retention times that minimize the number of instillations.

[11] Diquafosol Improves Corneal Wound Healing by Inducing NGF Expression in an Experimental Dry Eye Model

  • Authors: Chieun Song, Hyemin Seong, Woong-Sun Yoo, Mee-Young Choi, Réka Dorottya Varga et al.
  • Year: 2024
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/80aee03e77c076a735fc9e12ee5fa3893ccda857
  • DOI: 10.3390/cells13151251
  • PMID: 39120282
  • PMCID: 11311477
  • Citations: 7
  • Influential citations: 1
  • Summary: Treatment with cyclosporine or diquafosol restored cell viability and wound healing and reduced corneal damage by hyperosmolarity, and treatment with cyclosporine or diquafosol resulted in decreased apoptosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Dry eye disease (DED) is a complex, multifactorial condition characterized by a loss of tear film homeostasis, ocular surface inflammation, and damage [2]. The condition can be classified into two primary types: aqueous tear-deficient dry eye, resulting from decreased tear production, and evaporative dry eye, caused by excessive tear evaporation. Both types lead to increased tear osmolarity, triggering inflammation and subsequent damage to the ocular surface [2,3]. Given the heterogeneous nature of DED, it is crucial to tailor treatments based on the specific clinical phenotypes of the disease [5]. Our study explored the therapeutic mechanisms of CsA and DQS in an experimental dry eye model induced by hyperosmolarity. Hyperosmolar stress is a key driver in DED pathogenesis, leading to an inflammatory cascade and corneal surface damage [5]. CsA is a potent immunomodulator that inhibits T-cell activation and downregulates several inflammatory cytokines, thereby reducing ocular surface inflammation. Its efficacy in treating inflammatory ocular surface diseases was first reported by Laibovitz et al. [7]. Topical CsA has been shown to reduce cell-mediated inflammatory responses, improving tear film stability and reducing ocular surface inflammation [8,9]. DQS, on the other hand, is a dinucleotide derivative that functions as an agonist of the purinergic P2Y2 receptor [11], stimulating mucin and water secretion from conjunctival epithelial cells and accessory lacrimal glands. This action helps to stabilize the tear film and protect the ocular surface from desiccation [12,13]. Our findings highlight that CsA and DQS exhibit distinct effects on DED, suggesting that their clinical applications should be differentiated based on the underlying pathophysiology and phenotype of the disease. > Our findings demonstrate that both CsA and DQS mitigate hyperosmolarity-induced cellular damage by modulating inflammatory responses and promoting corneal epithelial cell survival. As previously published papers have stated, both CsA and DQS decrease the cell viability of HCECs at higher concentrations [18,19].

[12] Recent advances and prospects of nanoparticle-based drug delivery for diabetic ocular complications

  • Authors: Siqi Wang, Hongyu Yang, Jiaying Zheng, Aiyang Tong, Sen Mu et al.
  • Year: 2025
  • Venue: Theranostics
  • URL: https://www.semanticscholar.org/paper/163a5e270633cb64dc21b5f88a0122037d30841a
  • DOI: 10.7150/thno.108691
  • PMID: 40093887
  • PMCID: 11905120
  • Citations: 16
  • Influential citations: 1
  • Summary: This review highlights several common ocular complications associated with DM, focusing on their pathogenesis and treatment strategies, and emphasis is placed on the innovative applications and potential of nanotechnology in treating diabetic ocular complications.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > The eye is a vital organ in the human body. Diabetic eye complications primarily result from chronic hyperglycemia, which affects multiple ocular structures and contributes significantly to various eye diseases [1]. The increasing prevalence of diabetes mellitus (DM) has led to a rise in the incidence of ocular complications. Prominent among these complications are diabetic keratopathy, diabetic retinopathy (DR), cataracts, and glaucoma. These ocular manifestations cause considerable physical discomfort for affected individuals and impose a substantial economic burden on patients and healthcare systems (Figure 1). > Following extensive research over the years, significant progress has been made in understanding the pathogenesis of diabetic ocular diseases; however, the mechanisms underlying diabetic dry eye and other ocular lesions remain incompletely understood, which hampers the development of effective clinical treatment strategies. Several common pathogenic mechanisms of hyperglycemia have been proposed, such as increased polyol pathway flux, overactivation of the hexosamine pathway, accumulation of intracellular advanced glycation end products (AGEs), activation of the protein kinase C (PKC) pathway, inflammatory responses, and oxidative stress [2,3]. These mechanisms are summarized below. Since the proposal of a unified mechanism for diabetic complications, growing evidence indicates that reactive oxygen species (ROS) activate multiple signaling pathways, with oxidative stress induced by ROS being a key pathogenic factor in DM and its complications [4] (Figure 2). > The most commonly employed treatment approaches can be categorized into three types [5,6]: > (1) Topical administration, primarily for anterior segment diseases; (2) Intraocular administration, which provides superior efficacy compared to topical Ivyspring International Publisher treatments; and (3) Oral administration, notable for its high patient compliance. These traditional drug delivery systems are cost-effective, convenient, and generally safe. However, the eye's complex physiological barriers and anatomical structures hinder the entry and penetration of drugs into intraocular tissues, often resulting in suboptimal therapeutic outcomes for ocular drug delivery. Tear turnover, blinking, and nasolacrimal drainage rapidly eliminate many topical eye drops [7].

[13] Ion Channels as Potential Drug Targets in Dry Eye Disease and Their Clinical Relevance: A Review

  • Authors: C. Harrell, V. Volarevic
  • Year: 2024
  • Venue: Cells
  • URL: https://www.semanticscholar.org/paper/94b706c0219cff096c0eda7f5707798410b5ff12
  • DOI: 10.3390/cells13232017
  • PMID: 39682765
  • PMCID: 11639998
  • Citations: 9
  • Influential citations: 1
  • Summary: Current knowledge about the molecular mechanisms responsible for the inflammation-induced modification of ion channels leading to tear hyperosmolarity and immune cell dysfunction in DED patients are summarized and d-MAPPS™ Hypo-Osmotic Ophthalmic Solution is emphasized, an important novel approach for DED treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.437) > Dry eye disease (DED) is a common eye condition affecting over half the world's population [1]. This multifactorial disorder, affecting both the lacrimal system and the ocular surface, is characterized by a deficiency in the quality and/or quantity of tear fluid [1]. DED has two primary subtypes: evaporative dry eye (EDE), caused by excessive evaporation of tear fluid, and aqueous tear-deficient dry eye (ADDE), characterized by the lacrimal glands' inefficiency or failure to produce tears [2,3]. In clinical settings, DED is often seen as a "combination" or "hybrid" form of these two types, where each type gains certain clinical characteristics from the other, initiating and worsening its pathology [2,3]. > Many factors, including aging, eye injury, surgical interventions, poor nutrition, environmental allergens, and chemical hazards, can cause dysfunction of ion channel proteins and generate a detrimental immune response, leading to the development and progression of DED [4,5]. Tear hyperosmolarity (caused by alterations in ion channels) and ocular inflammation (caused by enhanced activation of immune cells and massive production of inflammatory cytokines) create a vicious cycle, aggravating all main DED-related signs and symptoms (ocular discomfort, pain, and vision problems) [1,5,6]. > Accordingly, many experimental and clinical studies have focused on examining the ion channel-dependent effects on the development of DED-associated pathology [1,[3][4][5][6]. The delineation of signaling pathways which were elicited in eye-infiltrated immune cells during DED progression has paved the way for designing new immunoregulatory therapeutic agents capable of suppressing detrimental immunity, attenuating DED-related signs and symptoms [1]. > This manuscript summarizes current knowledge about the molecular mechanisms responsible for inflammation-induced modification of ion channels leading to tear hyperosmolarity and immune cell dysfunction in DED patients.

[14] Managing dry eye disease – a review of selected traditional Chinese medicine and some of their metabolites focusing on molecular mechanisms and signaling pathways

  • Authors: Yixuan Lu, Yuhang Li, Zhen-yu Zhao, Yue Liu, Jiadi Wang et al.
  • Year: 2026
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/4c4d84d535379ceba314cf562668325271bd63fd
  • DOI: 10.3389/fphar.2026.1693198
  • PMID: 41988530
  • PMCID: 13076346
  • Summary: The mechanisms by which TCM-derived metabolites, botanical drug extracts, and TCM formulas are reported to modulate interconnected pathological processes underlying DED are described to establish a theoretical framework for intervention optimization and offer a robust foundation for future clinical translation.
  • Evidence snippets:
  • Snippet 1 (score: 0.436) > Dry eye disease (DED) is a prevalent global health issue that negatively impacts quality of life. It is also associated with the risk of corneal ulceration, scarring, and even blindness in severe cases. The complex, multifactorial pathology of DED, often conceptualized as a vicious cycle involving tear film instability, hyperosmolarity, inflammation, and apoptosis, complicates treatment. Traditional Chinese Medicine (TCM) offers a potential therapeutic approach by targeting multiple components and pathways. This review systematically describes the mechanisms by which TCM-derived metabolites, botanical drug extracts, and TCM formulas are reported to modulate interconnected pathological processes underlying DED to establish a theoretical framework for intervention optimization. A systematic literature search was conducted on 23 April 2025, across seven electronic databases (PubMed, Web of Science, Embase, SinoMed, CNKI, Wanfang, and VIP) using a comprehensive strategy combining MeSH terms and keywords related to DED, TCM, and signaling pathways. DED involves alterations in several important signaling pathways associated with inflammation, oxidative stress, and apoptosis. These include PI3K/AKT, MAPK, NF-κB, NLRP3, Nrf2, SIRT, AMPK, and VEGF. TCM formulas represent a multi-target approach with an ability to simultaneously target single or multiple signaling pathways involved in DED pathology. This is proposed to counteract key interlinked processes of inflammation, apoptosis, and oxidative stress, and promotes tear film stability in cellular and animal models, thereby highlighting its pharmacological potential. The multi-component, multi-target, and multi-pathway approach of TCM may offer a strategic advantage for managing the multifactorial pathology of DED through the potential to simultaneously regulate multiple interactive signaling networks. This review describes the molecular mechanisms underlying these traditional treatment practices and offers a robust foundation for future clinical translation.

[15] A Practical Approach to Severity Classification and Treatment of Dry Eye Disease: A Proposal from the Mexican Dry Eye Disease Expert Panel

  • Authors: A. Rodríguez-Garcia, Alejandro Babayan-Sosa, A. Ramirez-Miranda, Concepcion Santa Cruz-Valdes, E. Hernández-Quintela et al.
  • Year: 2022
  • Venue: Clinical Ophthalmology (Auckland, N.Z.)
  • URL: https://www.semanticscholar.org/paper/f78081e5df4fdc77e341aee0a5047e40e2492984
  • DOI: 10.2147/OPTH.S351898
  • PMID: 35520107
  • PMCID: 9061212
  • Citations: 16
  • Summary: A practical DED classification system based on disease severity to help clinicians discriminate cases needing referral to subspecialty clinics from those they could attend and a systematic management approach and general management considerations to improve patients’ therapeutic outcomes according to disease severity are proposed.
  • Evidence snippets:
  • Snippet 1 (score: 0.427) > The Industry Workshop on Clinical Trials in DED, held in 1995 under the auspices of the National Eye Institute (NEI), shaped the first formal definition of DED. 16 Three major concepts are inherent to this definition, (1) the recognition that an abnormal tear film is the primary pathophysiological mechanism of DED; (2) the pathology arises from either an aqueous deficiency or excessive tear film evaporation; and (3) DED causes discomfort symptoms". 1,16 This report established a solid foundation that launched translational, clinical, and basic scientific research to improve the diagnosis and treatment. 1 However, the NEI workshop DED definition was incomplete, lacking critical aspects of the pathogenesis and symptomatology of the disease. > Due to the growing evidence concerning diagnosis and therapeutics of dry eye, the first Tear Film & Ocular Surface Dry Eye Workshop (TFOS DEWS) held in 2007 proposed a definition including its multifactorial origin, the increase in tear osmolarity, and inflammation of the ocular surface as crucial pathogenic findings, 17,18 and the presence of visual disturbances among relevant symptoms. 19 This definition recognized dry eye as a disease, resulting from a complex abnormal interaction between the tear film and the ocular surface, suggesting that DED results from an alteration in ≥1 portions of the intertwined "functional unit" comprised by the conjunctiva, cornea, accessory lacrimal and Meibomian glands, the main lacrimal gland, eyelids, and motor and sensory nerves. 20,21 he TFOS DEWS II (2017) produced an evidence-based definition, recognizing the loss of tear film homeostasis as the conveying element in DED, reasserting ocular symptoms as the central feature of DED, and expanding the pathophysiological understanding of the disease by adding the neurosensory abnormalities. 1,22 However, this definition does not account for differences in symptom duration. 20 For example, although patients with DED associated with Sjögren syndrome and those with recent refractive surgery may present similar dry eye symptoms, the former is unlikely to improve over time, while the latter is expected to exhibit significant improvement. 20

[16] Oxidative Stress in the Anterior Ocular Diseases: Diagnostic and Treatment

  • Authors: A. Dammak, Cristina Pastrana, Alba Martín-Gil, Carlos Carpena-Torres, Assumpta Peral Cerda et al.
  • Year: 2023
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/610ba39ffe207a56271f5612d5241950983950e3
  • DOI: 10.3390/biomedicines11020292
  • PMID: 36830827
  • PMCID: 9952931
  • Citations: 95
  • Influential citations: 2
  • Summary: The oxidative stress and inflammatory processes in the front of the eye is analysed to provide a better understanding of the pathomechanism, the importance of biomarkers for the diagnosis of eye diseases, and the recent treatment of anterior ocular diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > The eye is a metabolically active structure, constantly exposed to solar radiations making its structure vulnerable to the high burden of reactive oxygen species (ROS), presenting many molecular interactions. The biomolecular cascade modification is caused especially in diseases of the ocular surface, cornea, conjunctiva, uvea, and lens. In fact, the injury in the anterior segment of the eye takes its origin from the perturbation of the pro-oxidant/antioxidant balance and leads to increased oxidative damage, especially when the first line of antioxidant defence weakens with age. Furthermore, oxidative stress is related to mitochondrial dysfunction, DNA damage, lipid peroxidation, protein modification, apoptosis, and inflammation, which are involved in anterior ocular disease progression such as dry eye, keratoconus, uveitis, and cataract. The different pathologies are interconnected through various mechanisms such as inflammation, oxidative stress making the diagnostics more relevant in early stages. The end point of the molecular pathway is the release of different antioxidant biomarkers offering the potential of predictive diagnostics of the pathology. In this review, we have analysed the oxidative stress and inflammatory processes in the front of the eye to provide a better understanding of the pathomechanism, the importance of biomarkers for the diagnosis of eye diseases, and the recent treatment of anterior ocular diseases.

[17] Síndrome de ojo seco asociado a fármacos sistémicos

  • Authors: E. O. G. Hernández, Jesús Guerrero Becerril
  • Year: 2020
  • Venue: Anales Médicos de la Asociación Médica del Centro Médico ABC
  • URL: https://www.semanticscholar.org/paper/85e3494d9ddcd1d5e3ff788e3bb9133fcd19ee36
  • DOI: 10.35366/97465
  • Summary: The purpose of this review is to briefly summarize the most common systemic medications and the possible mechanism related to dry eye disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > Dry eye syndrome is a very common cause of ophthalmological consultation, it is a condition characterized by high tear osmolarity, tear film instability and ocular surface inflammation. The main etiologies are age, feminine gender, meibomian gland dysfunction, contact lens use, environmental factors and systemic drugs. The main mechanisms that cause dry eye are reduction in tear production, alteration of the corneal nerves or a direct toxicity to the lacrimal gland. Many drugs are related to dry eye syndrome, this are important in daily medical practice due to the frequent use. Some of the group of drugs that have been related to dry eye syndrome are: NSAIDs (nonsteroidal anti-inflammatory drugs), gastric protector drugs, antihypertensive agents, anxiolytics, oral contraceptives, antidepressants, antipsychotics, antihistamines and drugs for treating Parkinson’s disease, among others. The purpose of this review is to briefly summarize the most common systemic medications and the possible mechanism related to dry eye disease.

[18] Classifying Dry Eye Disease Patients from Healthy Controls Using Machine Learning and Metabolomics Data

  • Authors: Sajad Amouei Sheshkal, Morten Gundersen, M. Riegler, Ø. Utheim, K. Gundersen et al.
  • Year: 2024
  • Venue: Diagnostics
  • URL: https://www.semanticscholar.org/paper/a813a14498d134a77d46cad08f48339a12ed6fbc
  • DOI: 10.3390/diagnostics14232696
  • PMID: 39682603
  • PMCID: 11640104
  • Citations: 10
  • Influential citations: 1
  • Summary: The results show that the logistic regression model with L2 regularization can outperform more complex models on an imbalanced data set with a small sample size and a high number of features, while also avoiding overfitting and delivering consistent performance across cross-validation folds.
  • Evidence snippets:
  • Snippet 1 (score: 0.420) > Dry Eye Disease (DED) is a multifaceted disorder characterised by a disruption in the composition, integrity, and stability of the tear film due to various internal and external factors. It is one of the most common reasons people seek eye care, with a severity spectrum ranging from minor, fleeting discomfort to severe, persistent pain and visual function impairment. This progression not only presents a substantial economic and healthcare challenge but also significantly impacts the quality of life of sufferers and the broader community. The incidence of DED notably increases following cataract surgery, highlighting the critical need for ophthalmologists to thoroughly evaluate for existing DED and to implement proactive treatment approaches. The presence of DED before surgery, can also complicate the precision of pre-surgical measurements, necessitate the reduction of intra-operative factors that could harm the ocular surface, and require the adoption of post-surgical care protocols to prevent the worsening of DED symptoms [1]- [6]. Clinical signs and symptoms are currently used to diagnose dry eye disease; however, the correlation between signs and symptoms is weak, leading to challenges in diagnosing and monitoring DED [7]. > Advancements in omics technologies allow researchers to explore the genome, transcriptome, proteome, and more, providing in-depth insights into the molecular mechanisms underlying diseases. Despite their utility, single omics approaches are insufficient for comprehensively understanding the intricate interactions between genes, RNA, proteins, and environmental factors. Metabolomics distinguishes itself by revealing how metabolites, the dynamic output of gene, mRNA, and protein function, respond to various internal and external stimuli. This makes metabolomics a crucial instrument for unraveling complex biological processes and deepening our understanding of the origins, progression, and treatment outcomes of diseases [1]. > In the context of DED, metabolomics holds the promise of identifying disease-specific metabolite profiles. These profiles can play an important role in enhancing the early diagnosis of DED, and in elucidating its etiology and pathology [1]. By identifying specific metabolic pathways and therapeutic targets, metabolomics can guide the choice of personalized treatment plans and improve the prediction of patient outcomes [1].

[19] Comparative evaluation of aqueous solution and oil emulsion formulations of 0.05% cyclosporine eye drops in dry eye disease – A randomized clinical trial

  • Authors: Ayesha A Salam, Seema Sen, N. Lomi, Noopur Gupta, M. Vanathi et al.
  • Year: 2025
  • Venue: Indian Journal of Ophthalmology
  • URL: https://www.semanticscholar.org/paper/654d0b1a651be983ac8cf834e80947c784d8222f
  • DOI: 10.4103/IJO.IJO_1850_24
  • PMID: 40146145
  • PMCID: 12097410
  • Citations: 1
  • Summary: Both aqueous solution and oil emulsion 0.05% cyclosporine formulations appear to be equally effective in the management of dry eye disease with a comparatively better response with oil emulsion formulations.
  • Evidence snippets:
  • Snippet 1 (score: 0.418) > Dry eye disease (DED), alternatively termed keratoconjunctivitis sicca, stands as a prevalent ocular surface ailment impacting millions of individuals globally. The prevalence of DED among adults worldwide ranges from 5% to 50%. [1] cording to the DEWS 2 (Dry Eye Workshop 2) report of 2017 -"Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles." [2] e main management modality for DED is the use of ocular lubricants. From numerous studies, we already know that tear hyperosmolarity plays a central mechanism in the pathophysiology of DED. [3] This in turn is said to damage the ocular surface by initiating inflammation (directly as well as indirectly). Thus, the primary focus for the management of DED lies in addressing the relentless inflammatory cycle. However, the use of topical steroids for a long period can be harmful because of the large number of adverse effects associated with it. Hence, the treatment of DED also entails the utilization of topical non-glucocorticoid immunomodulatory drugs like cyclosporine eyedrops which target the T cells and produce anti-inflammatory action by inhibiting the nuclear factor κB (NFκB) activation and also by inhibiting calcineurin thereby blocking the release of interleukin 2. > Different concentrations of topical cyclosporine are available in the market. For this study, we specifically selected a concentration of 0.05% of cyclosporine eye drops. This choice Cite this article as: Salam AA, Sen S, Lomi N, Gupta N, Vanathi M, Tandon R. Comparative evaluation of aqueous solution and oil emulsion formulations of 0.05% cyclosporine eye drops in dry eye disease -A randomized clinical trial. Indian J Ophthalmol 2025;73:577-81.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.