Root cause–based dry eye classification and the shift toward precision medicine

Dry eye disease affects a significant portion of patients across ophthalmology practices, yet the field's understanding of the condition has shifted considerably in recent years. The recent TFOS DEWS III report moved away from the traditional aqueous-deficient vs evaporative dichotomy in favor of classifying dry eye by root cause, while new therapies, including anti-TNFα biologics, topical perfluorohexyloctane, and neurostimulation devices, are pushing the field toward mechanism-based, non-drop treatment approaches.

In this Q&A, Esen K. Akpek, MD, the Bendann Professor of Ophthalmology and Rheumatology at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, speaks with Ophthalmology Times in recognition of Dry Eye Awareness Month. Akpek explains how identifying a patient's underlying disease mechanism, rather than relying on a one-size-fits-all algorithm, changes the initial workup and treatment selection for general ophthalmologists, where newer biologic and device-based therapies fit alongside established treatments like topical cyclosporine and lifitegrast, and why many patients describe dry eye through indirect complaints such as fluctuating vision or digital eye fatigue rather than naming the condition outright. The exchange closes with her perspective on the field's greatest unmet need: reliable biomarkers and patient-centered outcome measures that can guide a true precision medicine approach to dry eye care.

This interview has been lightly edited for length and clarity.

Ophthalmology Times: TFOS DEWS III moved away from older labels like "aqueous-deficient vs evaporative" in favor of subtyping by root cause. For a general ophthalmologist who isn't a dry eye subspecialist, how does identifying a root cause for a patient's dry eye change your approach to their initial workup?

Esen K. Akpek, MD: The shift in TFOS DEWS III from the traditional dichotomy of "aqueous-deficient" vs "evaporative" dry eye to a root cause–based classification promotes the practice of identifying the underlying mechanisms driving the entire ocular surface dysfunction in each individual patient, rather than focusing solely on tear film abnormalities.

For the general ophthalmologist, this begins with a targeted history and a systematic lacrimal functional unit examination. The clinician should evaluate for common etiologies such as meibomian gland dysfunction (MGD), autoimmune diseases including Sjögren's disease, medication-induced tear dysfunction, contact lens wear, eyelid abnormalities, neurotrophic disease, ocular allergy, exposure-related conditions, and environmental or behavioral factors. Ancillary testing—including tear osmolarity, matrix metalloproteinase-9 (MMP-9), meibography, corneal sensitivity assessment and Schirmer tear production, which can be easily performed by an ophthalmic technician, may further help identify the predominant pathogenic mechanism when available. Ocular surface staining using vital dyes should always be performed by the clinician to detect the presence and degree of epithelial damage.

Establishing the root cause has important implications for both diagnostic evaluation and treatment selection. For example, a patient with MGD benefits from therapies directed at improving meibomian gland function, whereas a patient with suspected Sjögren's disease requires laboratory testing for systemic autoimmune disease and may benefit from systemic collaboration with rheumatology. Similarly, recognizing neurotrophic keratopathy, medication toxicity, or exposure keratopathy prompts interventions that differ substantially from conventional dry eye therapy that target tear fluid.

Equally important, identifying the underlying etiology allows clinicians to address modifiable risk factors rather than simply prescribing artificial tears. Treating the disease process—not just the symptoms—can improve long-term outcomes, reduce chronic inflammation, and prevent progressive ocular surface damage.

OT: With several new agents—including anti-TNFα biologics now in phase 3—entering an already crowded market, how should clinicians be deciding where a new option fits versus what's already in the toolkit?

Akpek: New agents, including anti-TNFα biologics and other targeted immunomodulators, will likely expand our options for patients with persistent inflammatory disease that has not responded adequately to existing therapies. However, they should complement—not replace—our current treatment paradigm. Established therapies, such as topical cyclosporin and lifitegrast, short courses of corticosteroids, tear conservation strategies, management of MGD, and environmental and behavioral modifications, remain highly effective for many patients and should continue to serve as the foundation of treatment.

The decision to incorporate a newer agent should be based on several factors: the underlying disease mechanism, severity of inflammation, symptom burden, objective clinical findings, prior treatment response, safety profile, tolerability, dosing convenience, and cost. Importantly, we need robust comparative effectiveness studies and biomarkers that help predict which patients are most likely to benefit from a particular therapy. Precision medicine remains the ultimate goal.

I also believe that future management of dry eye will become increasingly personalized. Rather than a stepwise "one-size-fits-all" algorithm, we are moving toward mechanism-based therapy, where treatments are matched to specific inflammatory pathways or disease endotypes. Ultimately, the success of any new therapy will depend not only on its efficacy in clinical trials but also on its ability to address an unmet clinical need, demonstrate meaningful benefits over existing treatments, and fit into an individualized, evidence-based approach to dry eye management.

OT: Topical perfluorohexyloctane and intranasal neurostimulation have both reached approval in recent years, representing two very different mechanisms—one lipid-based, one neural. Do you see momentum shifting toward non-drop, device- or mechanism-based approaches?

Akpek: I believe we are witnessing a fundamental shift away from viewing dry eye disease as simply a condition that requires another eye drop. The approval of topical perfluorohexyloctane and intranasal or topical neurostimulation reflects a broader movement toward mechanism-based therapies that target distinct aspects of dry eye pathophysiology rather than relying solely on tear supplementation.

Topical perfluorohexyloctane addresses excessive tear evaporation by stabilizing the lipid layer and reducing evaporative loss, whereas intranasal or topical neurostimulation helps physiologic tear production. Although these therapies employ very different mechanisms, they share a common philosophy: respair normal ocular surface function by targeting the underlying biological defect rather than simply replacing tears.

I expect this trend to continue. Future innovations are likely to include additional device-based therapies, neuromodulation technologies, targeted biologics, ocular surface regenerative approaches, and drug-delivery systems that provide sustained treatment with less dependence on frequent eye drop administration. This is particularly important because adherence to topical therapy remains a significant challenge. In addition, frequent instillation of water-based eyedrops may inadvertently wash away endogenous tear film components, including biologically active proteins, lipids, mucins, and growth factors that are essential for maintaining ocular surface homeostasis. Repeated dilution and removal of these native tear constituents may impede restoration of tear film stability and ocular surface equilibrium, potentially limiting long-term recovery of the ocular surface.

Ultimately, I envision dry eye management becoming increasingly personalized and multimodal. Instead of asking whether a therapy is a drop, a device, or a biologic, clinicians will ask which pathogenic pathway is driving an individual patient's disease and select therapies that specifically address that mechanism. That evolution toward precision medicine, rather than the delivery platform itself, is what I believe will define the next generation of dry eye treatment.

OT: Have you found that some patients describe dry eye through indirect complaints such as fluctuating vision, eye fatigue, or difficulty using digital devices? How do you uncover the underlying cause?

Akpek: One of the most important lessons in dry eye disease is that patients often do not present by saying, "My eyes are dry." Instead, they describe the functional consequences of ocular surface dysfunction. They may complain of fluctuating or blurry vision, eye fatigue, difficulty reading, reduced endurance during computer use, or discomfort that worsens with prolonged visual tasks that require gazing.

Our own research has highlighted the importance of evaluating functional vision. We have demonstrated that corneal fluorescein staining is not merely a marker of epithelial damage but has a measurable impact on reading performance. Even relatively modest punctate epithelial erosions can disrupt the smooth optical surface of the cornea, degrade tear film quality, increase higher-order aberrations, and ultimately reduce reading speed. Reading is one of the most visually demanding tasks patients perform every day, making it a meaningful and patient-centered functional outcome.

This helps explain why many patients complain of "eye fatigue" or "difficulty reading" even when conventional measures such as visual acuity remain normal. High-contrast visual acuity is measured under ideal conditions and often fails to capture the dynamic visual disturbances caused by tear film instability. Reading speed, on the other hand, reflects real-world visual function and may be a more sensitive indicator of the impact of ocular surface disease on patients' daily lives.

OT: What's the biggest unmet need in dry eye disease right now?

Akpek: I believe the greatest unmet need in dry eye disease is precision medicine. Dry eye is not a single disease but a heterogeneous group of disorders with diverse underlying mechanisms. Yet, in clinical practice, we still rely largely on a one-at-a-time, trial-and-error approach. This is largely because we lack reliable biomarkers that identify the dominant disease pathway in an individual patient.

Equally important is the need for better diagnostic tools. Many of our current tests have limited sensitivity, specificity, and reproducibility, and they often correlate poorly with patients' symptoms. In addition, measuring the signs at rest, in clinical setting, may not be representative of real-world severity. We need objective biomarkers that can identify disease earlier, classify biologically distinct subtypes, monitor treatment response, and guide therapeutic decisions. This is one of the motivations behind our own work investigating tear-based immune biomarkers using high-dimensional spectral flow cytometry and machine learning to better characterize ocular surface inflammation and move toward personalized treatment strategies.

Another major unmet need is the development of clinically meaningful outcome measures. Historically, dry eye clinical trials have focused on signs such as corneal staining or symptom questionnaires, but these measures do not always capture how the disease affects patients' daily lives. In our research, we have been studying reading speed as a functional outcome because reading is one of the most visually demanding tasks people perform. We have shown that corneal fluorescein staining can significantly impair reading performance, even when standard visual acuity remains normal. Incorporating objective measures of visual function into clinical trials and routine practice would provide a more patient-centered assessment of treatment benefit.

Finally, earlier recognition remains a critical challenge. Dry eye is often viewed as a nuisance condition, yet for many patients it is a chronic inflammatory disease that profoundly affects quality of life, work productivity, and visual function. Earlier diagnosis, identification of the underlying cause, and timely intervention could prevent progression and improve long-term outcomes.