Dry eye disease (DED) is everywhere in our practices. Industry survey data puts approximately 47% of American adults reporting frequent or occasional DED symptoms—roughly 150 million people.1 The 2025 international NESTS study found that 58% of the general population reports dry eye symptoms, yet only 1 in 5 has ever received a formal diagnosis.2
Peer-reviewed estimates put the formally diagnosed population at approximately 16 million Americans,3 though the true burden is far greater: while 38 million live with chronic DED, only 1.5 million are actively treated, and 40% of those who eventually seek care waited 6 months or more to do it.4
We are missing this disease, not because we lack the tools, but because the framework hasn’t matched the scale of the problem. The publication of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop III (DEWS III) report in 2025 provides a timely framework to address that gap.5
Developed by 80 experts from 18 countries, DEWS III establishes an updated global consensus on the subclassification, diagnostic methodology, and management of DED.5
Updated DED definition from TFOS DEWS III
DEWS III defines dry eye as a multifactorial, symptomatic disease characterized by loss of homeostasis of the tear film and/or the ocular surface, in which tear film instability, hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.5,6
Two changes from DEWS II are worth noting.7 First, “symptomatic” is now a qualifying term, patient-reported symptoms are a diagnostic prerequisite, not an afterthought. Second, homeostatic disruption now includes “and/or the ocular surface,” capturing a broader range of ocular surface pathology than was previously recognized in the DEWS II definition.
DEWS III also makes explicit what clinical language has long obscured: dry eye is a disease, not a syndrome.6 A syndrome is a cluster of symptoms without a unified or well-understood etiology, whereas a disease is defined by underlying pathophysiology, identifiable drivers, and a clear rationale for targeted therapy.
This distinction supports a more precise clinical framework built around identifiable drivers and intervention rather than descriptive symptom clustering.
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TFOS DEWS III: Diagnosis and Driver-Based Treatment
Use this cheat sheet to integrate clinical pearls from TFOS DEWS III into your practice to identify and manage patients with ocular surface disease.
Reframing the clinical approach to DED
The biggest shift in DEWS III is not definitional—it is operational. The DEWS II stepwise ladder, where therapy was escalated incrementally based on severity, is gone. In its place is an etiological driver-matched framework that calls for targeted, concurrent intervention from the point of diagnosis.5,6,8
Etiological drivers are now organized into three clinical domains:6
- Tear film deficiencies: Lipid deficiency, aqueous deficiency, and mucin/glycocalyx deficiency.
- Eyelid anomalies: Blink and lid closure abnormalities, and lid margin disease.
- Ocular surface abnormalities: Anatomical misalignment, neural dysfunction, ocular surface cellular damage, and primary inflammation/oxidative stress.
Figure 1: The transition from the severity-based treatment ladder of TFOS DEWS II to the driver-based, mechanism-targeted framework of TFOS DEWS III, emphasizing early combination therapy and interventional procedures directed at tear film deficiencies, eyelid anomalies, and ocular surface abnormalities.
Figure 1: Courtesy of Bradley A. Daniel, OD, FAAO, FAAOMS, Dipl. ABO.
We are no longer assigning a broad category and reaching for the same ladder. We are mapping the active drivers and selecting targeted therapies accordingly.8,9
Neural dysfunction and the lacrimal functional unit
This is the section of DEWS III that should fundamentally change how we approach our most confusing patients. Neurosensory abnormalities are now recognized as a primary etiological driver of dry eye disease, not a secondary consideration.5,10 The patient with debilitating pain and minimal clinical findings reflects a neuropathic phenotype, whereas the patient with significant staining and few symptoms reflects a neurotrophic phenotype.
Both respond poorly to conventional surface-directed therapy and require distinct management strategies.11 This shifts the focus away from surface-only treatment toward a broader evaluation of corneal sensitivity, neural signaling, and the lacrimal functional unit (LFU).
The LFU consists of the cornea, conjunctiva, lacrimal glands, meibomian glands, goblet cells, and the interconnecting sensory and autonomic neural pathways that regulate tear production and ocular surface homeostasis. Stimulating this unit generates endogenous tears with the full biological complement of mucins, growth factors, antimicrobial peptides, and lipids that no artificial tear can replicate.12
Figure 2: A mechanistic comparison of neuromodulatory therapies targeting the LFU: acoltremon (TRYPTYR) activates TRPM8 receptors on corneal nerve endings, while varenicline nasal spray (TYRVAYA) stimulates nicotinic acetylcholine receptors within the nasal mucosa. Both converge through the trigeminal pathway (CN V1) to the lacrimal glands, meibomian glands, and goblet cells resulting in increased basal tear production with a full complement of proteins, growth factors, immunoglobulins, mucins, and lipids.
Figure 2: Courtesy of Bradley A. Daniel, OD, FAAO, FAAOMS, Dipl. ABO.
Varenicline nasal spray (TYRVAYA, Viatris) was the first agent in this class, stimulating the LFU via the trigeminal parasympathetic reflex to increase basal tear production through nasolacrimal neuroactivation.8,13
Acoltremon ophthalmic solution 0.003% (TRYPTYR, Alcon) represents the latest neuromodulator in this space, acting as a first-in-class TRPM8 receptor agonist for the signs and symptoms of dry eye disease.14 It targets cold-sensing thermoreceptors on corneal and eyelid nerve fibers to rapidly increase basal tear production, representing a mechanistically distinct approach with a defined role in the DEWS III framework.8,14
Diagnostic algorithm and clinical evaluation of DED
Symptom-sign correlation in DED is notoriously poor, which is precisely why DEWS III moves away from severity grading toward a three-step diagnostic algorithm:6,15
- Symptom screening: Administer the validated six-item Ocular Surface Disease Index (OSDI-6). A score of four or higher is required to proceed. Symptoms are the gatekeeper.15
- Homeostasis markers: Confirm loss of homeostasis with at least one objective test:
- Non-invasive tear breakup time (NIBUT) less than 10 seconds
- Fluorescein tear breakup time (FTBUT) less than 5 seconds
- Tear osmolarity of 308 mOsm/L or higher in either eye; an inter-eye osmolarity difference of 8 mOsm/L or greater is also positive, as asymmetry can reflect early or laterally dominant disease even when absolute values appear normal6
- Ocular surface staining: An alternative confirmatory route when Step 2 markers are negative or unavailable. Positive criteria include:
- More than 5 corneal fluorescein punctate spots, and/or more than 9 conjunctival lissamine green punctate spots, and/or lid margin lissamine green staining of 2 mm or more in length and 25% or more in width.
- Meeting any one of these thresholds alongside a positive OSDI-6 confirms the diagnosis of DED.6
Once DED diagnosis is confirmed, post-diagnostic testing maps the specific etiological drivers present, and that map drives therapy selection.6
Short on time? Check out the cheat sheet TFOS DEWS III: Diagnosis and Driver-Based Treatment!
DED management: Driver-based combination therapy
DED is multifactorial. Isolating one pathway while deferring others allows progression and delays recovery.5,8 DEWS III is explicit: concurrent, driver-targeted combination therapy is the standard, not the escalation.
Consider the case: a patient with severe ocular rosacea and systemic lupus erythematosus, advanced evaporative DED, and significant meibomian gland atrophy in the presence of Demodex blepharitis. The etiological profile calls for layered intervention.
For example, cyclosporine 0.1% (VEVYE, Harrow) is selected not merely as an immunomodulator, but specifically because its semifluorinated alkane vehicle significantly enhances cyclosporine delivery to the ocular surface and its greater residence time may supplement the critically deficient lipid layer. Perfluorohexyloctane ophthalmic solution (MIEBO, Bausch + Lomb), another semifluorinated alkane, serves as a specialized anti-evaporative therapy for patients whose disease is predominantly evaporative.16
Concurrent treatment with lotilaner ophthalmic solution 0.25% (XDEMVY, Tarsus Pharmaceuticals) targets the underlying Demodex burden and associated lid margin inflammation contributing to MGD and tear film instability. A short course of topical corticosteroid is added for rapid inflammatory control during initiation of chronic therapy. Adjunctive oral doxycycline is initiated to reduce meibomian gland inflammation and improve meibum quality and stability.8
Before introducing any energy-based procedural treatment, such as intense pulsed light (IPL), radiofrequency (RF), low-level light therapy (LLLT), or thermal pulsation, mechanical clearance of fibrotic debris from obstructed gland orifices should come first via microblepharoexfoliation or intraductal meibomian gland probing to restore gland patency, establishing the proper environment for downstream intervention.17,18
Video 1: Intraductal meibomian gland probing (Maskin Probe, MGDinnovations) providing mechanical relief of gland obstruction and restoration of ductal patency in obstructive meibomian gland dysfunction.
Video 1: Courtesy of Bradley A. Daniel, OD, FAAO, FAAOMS, Dipl. ABO.
This is multi-driver-focused, concurrent combinatory therapy. Not a ladder. A map.
The interventional dry eye philosophy
The DEWS III framework provides robust evidence-based support for an interventional approach to dry eye care. Rather than a passive, observation-first model, DEWS III directs clinicians to identify and address etiological drivers at the point when homeostasis is first compromised, before overt ocular surface damage occurs.5,8
Examples of matching etiological drivers with appropriate treatment
Figure 3: Slit lamp photo demonstrating inferior tear film instability with reduced tear meniscus height and early tear breakup, consistent with advanced evaporative DED driven by obstructive meibomian gland dysfunction with fibrotic gland atrophy; mechanical obstruction required microblepharoexfoliation and intraductal probing to restore gland patency prior to thermal intervention.
Figure 3: Courtesy of Bradley A. Daniel, OD, FAAO, FAAOMS, Dipl. ABO.
Figure 4: Fluorescein staining under cobalt blue illumination using a Wratten #12 yellow filter demonstrating dense inferior punctate epithelial erosions with early coalescence, consistent with ocular surface disease driven by tear film instability, lipid deficiency, and secondary surface inflammation.
Figure 4: Courtesy of Bradley A. Daniel, OD, FAAO, FAAOMS, Dipl. ABO.
Figure 5: Slit lamp photos of the upper lid margin demonstrating prominent collarettes at the base of the eyelashes, consistent with Demodex blepharitis, with concurrent lid margin inflammation and obstructive meibomian gland dysfunction; a focal chalazion (left image) is also present, reflecting localized meibomian gland obstruction and chronic lipogranulomatous inflammation contributing to tear film instability.
Figure 5: Courtesy of Bradley A. Daniel, OD, FAAO, FAAOMS, Dipl. ABO.
This approach is philosophically analogous to the broader goal of glaucoma management: preventing structural damage and disease progression from the point of first diagnosis, rather than waiting for irreversible loss before escalating intervention.
Walkthrough of managing multifactorial DED
Consider a patient with rheumatoid arthritis and keratoconjunctivitis sicca, reporting stability on cyclosporine 0.05%, who presents with asymptomatic tear film instability on routine re-evaluation, evidenced by elevated osmolarity and reduced tear volume.
Critically, the right eye carries an additional history of a prior traumatic corneal abrasion and a retinal detachment repair performed within the previous year—iatrogenic and mechanical insults well recognized for their capacity to disrupt corneal innervation, alter neurotrophic signaling, and accelerate neurosensory deterioration.11,12
Diagnostics
Rather than observing the changes, corneal sensitivity testing is performed and reveals reduced sensitivity in the right eye greater than the left, consistent with the clinical history, confirming the emergence of a neurodysfunction driver. In this clinical context, there are two mechanistically complementary options to consider.
Treatment
Neuromodulatory therapy with acoltremon (TRYPTYR) can be added to increase endogenous basal tear production via the LFU, stimulating the trigeminal pathway to drive secretion from the lacrimal glands, meibomian glands, and goblet cells.9
Additionally, in cases where corneal nerve damage is the primary concern, cenegermin ophthalmic solution 0.002% (OXERVATE, Dompé) offers a neurotrophic approach, delivering recombinant human nerve growth factor directly to promote corneal nerve regeneration and restore neurotrophic signaling.8,11
These represent distinct but complementary strategies: one stimulates tear production through existing neural pathways, while the other targets the underlying nerve damage itself. The appropriate choice, or combination, depends on the severity and nature of the neurodysfunction identified. This is multi-driver, interventional dry eye care in practice: systematic diagnostic mapping, real-time driver identification, and deliberate modification of the treatment plan.
DEWS III supports a shift toward upstream, proactive management. Advanced procedures including IPL, RF, LLLT, thermal pulsation, microblepharoexfoliation, and intraductal meibomian gland probing are not reserve-line treatments to be deferred until disease is advanced. They are appropriate, evidence-supported interventions to be deployed when the etiological profile indicates their use.17,18
Key takeaways:
- The binary classification of aqueous-deficient versus evaporative DED is no longer sufficient. DEWS III organizes disease into three etiological domains (tear film deficiencies, eyelid anomalies, and ocular surface abnormalities) and expects us to map specific drivers, not assign broad categories.
- Neurosensory dysfunction is a primary driver, not a footnote. The symptom-sign disconnect is a clinical phenotype that calls for a targeted neuromodulatory response.
- Combination therapy is the standard. DEWS III supports concurrent, driver-matched intervention from the point of diagnosis—waiting for disease to worsen before adding therapies is inconsistent with the framework.
- Procedural care is frontline care. IPL, RF, LLLT, thermal pulsation, microblepharoexfoliation, and meibomian gland probing are evidence-supported interventions indicated when the etiological profile calls for them—not advanced or elective options.
- DEWS III is the evidence base for interventional optometry. Earlier intervention, driver-matched diagnostics, and multimodal therapy validate the proactive philosophy that defines modern interventional medicine.
Conclusion
DEWS III represents a meaningful evolution in the evidence-based management of dry eye disease and ocular surface disease more broadly. Its most significant contribution is not a redefinition of the disease, but a restructuring of how it is diagnosed and managed: from severity-based escalation to driver-based, simultaneous, targeted intervention.
The formal recognition of neurosensory abnormalities as a primary etiological driver, the expanded etiological classification system, and the streamlined diagnostic algorithm collectively provide the clinical infrastructure for more precise, individualized care across the full spectrum of ocular surface disease.5,6,8
