Dry eye disease (DED) is a chronic immune-mediated disorder that reflects systemic dysregulation.1 Although it may be ubiquitous in ophthalmology, our familiarity with DED should not lull us into forgetting how complicated its diagnosis, management, and longitudinal care is for patients with autoimmune disorders.
For symptomatic patients, DED and reduced quality of life may lead to significant emotional and psychological effects including anxiety, depression, and social withdrawal.
Addressing a challenging pathophysiology
In common autoimmune conditions like Sjögren's syndrome, rheumatoid arthritis, and systemic lupus, the whole body becomes an unwitting casualty of systemic inflammation.2
Specifically for the ocular surface, immune-mediated damage to the lacrimal glands and ocular tissue triggers chronic inflammation, T-cell infiltration, and cytokine release. The result is reduced tear production, tear film instability, epithelial compromise such as punctate keratopathy,3 and symptomatic DED that significantly impairs quality of life.
DED symptoms vary widely, ranging from no symptoms to burning, foreign-body sensation and grittiness as well as fluctuating vision and visual fatigue during tasks like reading or computer work. Paradoxically, some patients with an advanced autoimmune disease report fewer DED symptoms due to reduced corneal sensitivity from chronic inflammation.4,5
A subset of these patients may develop neurotrophic keratitis (NK).6 The disconnect between clinical signs and subjective symptoms complicates recognition and emphasizes the need for vigilant assessment.
Red flags identified during an ocular assessment
During an ocular evaluation, I carefully assess for both signs and symptoms of DED. Symptoms can be quantified using a validated dry eye questionnaire such as SPEED or OSDI.
Evaluation of clinical signs requires a comprehensive ocular evaluation, including assessment of the cornea, limbus, conjunctiva, eyelids, meibomian glands, tear film, and lacrimal glands along with objective testing to support a diagnosis of autoimmune-related DED.
In addition to traditional diagnostic tools such as fluorescein and lissamine green staining, tear breakup time, and Schirmer testing, evaluation can include advanced biomarker analysis and tear film metrics including tear osmolarity and matrix metalloproteinase-9 (MMP-9) inflammatory markers.
Additional objective imaging and functional tools such as iTrace (Tracey Technologies) for optical quality, anterior segment OCT for corneal and tear meniscus assessment, meibography, corneal topography, and tomography, can provide valuable insight into structural and refractive changes associated with DED. The presence of corneal staining in the absence of symptoms should prompt heightened suspicion for neurotrophic keratitis and careful assessment of corneal sensitivity.
Red flags
Ocular red flags that should prompt consideration of an autoimmune workup include severe aqueous deficiency in a younger patient,7 a reduced tear meniscus, and low Schirmer scores suggestive of Sjögren’s syndrome.
Staining out of proportion to patient symptoms should also raise concern of neurotrophic keratitis.8 Additional warning signs include corneal thinning or melting, which may indicate uncontrolled systemic inflammatory disease, such as rheumatoid arthritis. A targeted review of systems is essential, including questions about parotitis, xerostomia, and arthritis.9,10
Taking a broader clinical view
Ophthalmologists should interpret DED findings within the context of systemic autoimmune disease rather than as an isolated ocular condition. Beyond the ocular surface, systemic inflammation can adversely affect the central nervous system.11,12
Cytokines released during autoimmune flares may disrupt neurotransmitter regulation and contribute to physical, cognitive, and ocular fatigue that often overlaps with mood disturbances.13 This constellation of symptoms is common; for instance, up to 70% of patients with Sjögren’s disease report fatigue related to their condition.14
In patients with clinical features suggestive of Sjögren’s syndrome, early antibodies can be assessed using a specialized Sjögren’s panel. This includes the traditional SS-A and SS-B antibodies as well as early markers such as salivary gland protein-1, parotid secretory protein, and carbonic anhydrase-6, which may reveal disease in patients who test negative for traditional markers.15
Using this approach not only improves diagnostic sensitivity and guides systemic evaluation in collaboration with rheumatology, but it can also reduce the need for more invasive procedures, such as a lip biopsy.
Initial and ongoing management strategies
Managing autoimmune-related DED is inherently multidisciplinary and should be tailored to disease severity, underlying mechanisms (e.g., aqueous deficient vs. evaporative DED), and individual tolerability. Clinical decision-making is guided by The Tear Film & Ocular Surface Society Dry Eye Workshop (TFOS DEWS) II, which describes DED as a progressive disorder driven by loss of homeostasis and immune activation.16,17
Equally important is controlling the underlying systemic autoimmune condition, as effective systemic management can reduce ocular inflammation, improve treatment response, and help prevent disease progression.
Latest information from TFOS DEWS III
The TFOS DEWS II report outlined a stepwise approach to DED management, starting with patient education, environmental modification, omega-3 supplementation, and lid hygiene for baseline support along with preservative-free lubrication.
Therapy progresses to topical anti-inflammatory agents/short-term topical corticosteroids to control flare-ups, topical immunomodulators, and procedural intervention as dictated by objective signs findings.16
DEWS III further emphasized the role of biomarkers, neurosensory abnormalities, and early recognition of systemic contributors such as Sjögren’s syndrome, noting that patients with autoimmune disease often present with advanced DED despite relatively modest symptom scores.17
The inclusion of advanced diagnostics allows for objective monitoring of disease progression and response to therapy. This framework supports a proactive clinical approach: Initiate treatment of ocular inflammation early, address meibomian obstruction concurrently, and monitor response to treatment to prevent progressive complications, including NK and vision loss.
The evolving treatment landscape
Cyclosporine and lymphocyte-function inhibitors such as lifitegrast remain cornerstone therapies for moderate-to-severe DED. For many years, treatment options were limited to cyclosporine ophthalmic emulsion 0.05% (RESTASIS, AbbVie), later joined by lifitegrast ophthalmic solution 5% (XIIDRA, Bausch + Lomb), and cyclosporine ophthalmic solution 0.09% (CEQUA, Sun Ophthalmics).
Today, newer formulations and additional therapies allow more targeted management of ocular surface disease and offer improved drug delivery. These include cyclosporine ophthalmic solution 0.1% in perfluorobutylpentane (VEVYE, Harrow) and agents targeting evaporative DED such as perfluorohexyloctane (MIEBO, Bausch + Lomb)
Neurostimulation
The treatment landscape has further expanded to include neurostimulation, beginning with varenicline nasal solution 0.03% (TYRVAYA, Viatris) and more recently acoltremon (TRYPTYR, Alcon), the first FDA-approved topical ophthalmic neurostimulator.
Concurrently, recognition of lid-driven inflammation has grown, with lotilaner ophthalmic solution 0.25% (XDEMVY, Tarsus Pharmaceuticals) now available for Demodex blepharitis, a condition that frequently coexists with and exacerbates DED.
Cyclosporine ophthalmic solution 0.1%
In my clinical experience, patients have shown good adherence to cyclosporine ophthalmic solution 0.1% (VEVYE). I have observed improvement in both subjective symptoms and corneal staining in patients treatment with this formulation, and patients frequently report that the drops are comfortable upon instillation.
These observations are consistent with pooled data from the pivotal ESSENCE-1 and ESSENCE-2 trials, which demonstrated clinically meaningful improvements in corneal staining by Days 15 and 29, along with significant symptom relief and good tolerability.18
Long-term extension data from the ESSENCE-2 open-label extension study confirm the safety and tolerability of water-free cyclosporine 0.1% ophthalmic solution over 52 weeks.19 Corneal staining improvements occurred early and stabilized over time, while tear production and symptoms improved continuously throughout the treatment period. Mild instillation site pain was the most common adverse event reported by 6.5% of patients. All cases were mild.
Targeting therapy is key
Beyond topical immunomodulatory therapy, management should be individualized according to the type and severity of the patient’s DED.
The following interventions may be considered to target specific pathophysiologic mechanisms and to complement ongoing topical therapy:
- Neurostimulation via nasal or topical modalities may augment basal tear production.
- Device-based therapies address meibomian gland obstruction through approaches such as:
- Thermal pulsation
- Meibomian duct probing
- Intense pulsed light
- Punctal occlusion can be beneficial in patients with significant aqueous tear deficiency. Adjunctive autologous or serum tears may be considered to support epithelial healing, typically in the setting of moderate to advanced disease.
In autoimmune patients with ocular inflammation, early initiation of immunomodulatory therapy is often warranted, particularly when systemic involvement is present. A stepwise treatment approach typically begins with corticosteroids for acute control, followed by conventional immunosuppressants/immunomodulator and sometimes biologics.
Multidisciplinary management involving ophthalmology and rheumatology is essential for optimizing both ocular and systemic disease control. Close ophthalmologic monitoring is crucial, including regular assessment of corneal sensation and epithelial integrity to detect neurotrophic keratitis and other vision-threatening complications early.
Patients on aggressive immunosuppression warrant heightened surveillance for infectious keratitis and treatment-related toxicities.
Patient counseling
An essential, though sometimes underemphasized, aspect of care is effective patient communication. Many patients with autoimmune-related DED have undergone numerous therapies with limited relief. Taking the time to counsel these patients is critical, ensuring they understand why their disease course may differ and how targeted therapies are intended to address the underlying disease mechanisms.
Visual tools such as slit-lamp photography documenting staining patterns, sequential tear osmolarity measurements, and advanced imaging, such as iTrace, anterior segment OCT, corneal topography, and tomography, allow patients (and clinicians) to visualize structural and functional changes over time.
These comparisons not only reinforce the value of therapy but also promote engagement and adherence to what are often long-term treatment plans. Partnering with patients in this manner fosters trust, supports shared decision-making, and ultimately contributes to more sustained clinical outcomes.
Conclusion
Autoimmune disease and other systemic inflammatory conditions often involve significant ocular manifestations, compelling us to look beyond the tear film. This emphasizes the importance of a comprehensive evaluation using modern diagnostic tools and thoughtful, evidence-based management. While advances in immunomodulatory therapies have expanded our ability to provide more targeted and effective care, multidisciplinary collaboration remains essential.
As our understanding of immune-mediated ocular surface disease continues to advance, our diagnostic precision and therapeutic strategies must evolve in parallel. With an expanding array of diagnostic tools and treatment options, eyecare proefssionals are now better equipped than ever to improve not only the clinical signs and symptoms but also the quality of life in patients affected by autoimmune-related dry eye disease.
