Blood-based inflammatory biomarkers: An overlooked tool for personalizing dry eye therapy - and the potential systemic effects of eye drop inactive ingredients

doi:10.15406/aovs.2025.15.00489

Advances in

eISSN: 2377-4290

Ophthalmology & Visual System

Mini Review Volume 15 Issue 2

Blood-based inflammatory biomarkers: An overlooked tool for personalizing dry eye therapy - and the potential systemic effects of eye drop inactive ingredients

Daniel Friederich

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Clinical Optometrist and Dry Eye Specialist, Vision Care Consultants, USA

Correspondence: Daniel Friederich, Clinical Optometrist and Dry Eye Specialist, Vision Care Consultants, 12121 Tesson Ferry Professional Center, St. Louis, MO 63128, USA, Tel 314.843.5700, Fax 314.843.1353

Received: July 12, 2025 | Published: August 21, 2025

Citation: Friederich D. Blood-based inflammatory biomarkers: An overlooked tool for personalizing dry eye therapy - and the potential systemic effects of eye drop inactive ingredients. Adv Ophthalmol Vis Syst. 2025;15(2):70-71. DOI: 10.15406/aovs.2025.15.00489

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Abstract

Dry eye disease (DED) is traditionally diagnosed and managed using symptom scores and ocular surface tests. However, mounting evidence links serum inflammatory markers, including CXCL9/10, CCL19/20, and TNF-α, to disease severity, suggesting that a simple blood draw could soon complement conventional chairside evaluations. Meanwhile, many commonly used artificial tears still contain benzalkonium chloride and other “inactive” excipients that can enter the systemic circulation and exacerbate inflammation. This review synthesizes current evidence on blood-based DED biomarkers, highlights data regarding the systemic absorption and toxicity of ophthalmic inactive ingredients, and presents a clinical vignette in which a patient with polypharmacy intolerance experienced rapid symptom relief after switching to a preservative-free, organic eye drop. These findings support a paradigm shift toward integrating blood-based testing and excipient minimization for more personalized and biocompatible care.

Keywords: benzalkonium chloride, CXCL10, dry eye disease, excipient toxicity, inflammatory biomarkers, personalized therapy, systemic absorption, TNF-α

Abbrevation

DED, dry eye disease; TBUT, tear film break-up time; BAK, benzalkonium chloride; CMC, Carboxymethylcellulose

Introduction

Why look beyond the surface?

Dry eye disease (DED) affects an estimated 16 million Americans, yet standard diagnostics—such as tear film break-up time (TBUT), Schirmer’s test, and symptom questionnaires—often poorly correlate with underlying pathophysiology. A recent large-scale, hypothesis-free proteomics study found that highly symptomatic DED is associated with elevated serum levels of CXCL9, CXCL10, CCL19, CCL20, and TNF-α.^1,2 A 2024 clinical trial further demonstrated that cyclosporine treatment improved both ocular symptoms and systemic IL-6 and TNF-α levels, reinforcing the connection between ocular and systemic inflammation.³ These findings suggest that routine laboratory panels could help subtype patients, monitor treatment response, and detect systemic comorbidities contributing to ocular surface inflammation.

The elephant in the room: “Inactive” excipients

Many artificial tears continue to contain benzalkonium chloride (BAK) or similar preservatives at concentrations of 0.004%–0.02%. BAK is known to cause epithelial toxicity, mitochondrial dysfunction, and trabecular meshwork damage. Even preservative-free formulations often contain excipients that may be systemically absorbed and potentially harmful, especially in individuals with autoimmune or inflammatory conditions.^4–10

Three excipients warrant special consideration:

Boric Acid: Used as a pH adjuster and antimicrobial, boric acid is considered safe in trace amounts but is a known reproductive toxin at higher exposures and can be absorbed via mucosal surfaces, including the nasolacrimal pathway.
Propylene Glycol: A solvent and humectant classified as “generally recognized as safe” for ingestion but linked to allergic reactions, skin irritation, and, at elevated systemic levels, renal or central nervous system effects—particularly in children and sensitive individuals.
Carboxymethylcellulose (CMC): A viscosity-enhancing agent valued for prolonging ocular surface contact. While not overtly toxic, CMC is a synthetic polymer that may disrupt mucin layer function, posing potential issues for chemically sensitive patients.

Topical eye drops are not confined to the ocular surface: up to 80% of the instilled volume drains through the nasolacrimal duct, allowing absorption through the richly vascularized nasal mucosa. This pathway bypasses hepatic first-pass metabolism and may result in chronic, low-level systemic exposure to these ingredients. A 2025 review published in MDPI discussed the potential cardiovascular, neurologic, and immunologic consequences of such absorption.¹¹

Collectively, these so-called inactive ingredients may exert significant biological activity, particularly in predisposed individuals.

Why serum markers, not just tears?

Tear-film cytokines and chemokines provide valuable, ocular-surface-proximal signals; however, several practical and biological factors limit their use as a sole index of disease activity. First, sampling variability is high: low-volume collections are susceptible to reflex tearing, dilution by instilled anesthetic, and diurnal fluctuation. Second, tear assays are not yet widely standardized across platforms, producing inter-lab variability. Third, tear measurements primarily reflect local ocular-surface inflammation and may miss systemic inflammatory drivers that perpetuate disease. Serum markers, in contrast, benefit from standardized phlebotomy and CLIA-certified laboratory platforms; they are amenable to longitudinal, reproducible quantification; and they capture the patient’s systemic inflammatory milieu - including comorbid autoimmune disease and low-grade inflammation possibly aggravated by chronically absorbed ophthalmic excipients. In clinical decision-making, serum markers are therefore not a replacement for tear analytics but a complementary, scalable tool that anchors ocular findings within whole-patient biology.

Pragmatically, serum testing is already embedded in primary care and rheumatology workflows. Incorporating a limited dry-eye–relevant panel (e.g., CRP, TNF-α, CXCL9/10) allows optometrists and ophthalmologists to (1) subtype patients with disproportionate symptom burden, (2) screen for systemic inflammation that may merit co-management, and (3) track treatment response when excipient minimization or anti-inflammatory therapy is initiated. This systems-level perspective is difficult to obtain from tear metrics alone and may explain part of the symptom–sign discordance frequently observed in DED.

Multiple observational studies report higher circulating levels of chemokines such as CXCL9/CXCL10 and cytokines including TNF‑α and IL‑6 in patients with symptomatic dry eye compared with controls, with severity gradients paralleling serum signal strength.^12–14 Interventional data - though still limited - suggest that therapies reducing ocular surface inflammation are associated with concordant decreases in systemic inflammatory markers over follow‑up.¹⁵ Collectively, these findings support the biological plausibility that dry eye in a subset of patients reflects, or contributes to, a broader inflammatory state detectable in blood.

At the same time, tear analytics remain valuable for proximal pathophysiology (e.g., MMP‑9 positivity, osmolarity elevation). A practical framework is to pair a focused serum panel at baseline and 8–12 weeks with standard ocular metrics (TBUT, corneal/conjunctival staining, OSDI), using discordance to trigger evaluation for systemic contributors and concordance to document global improvement. Future prospective studies should predefine dual primary outcomes - ocular and serum - to clarify causal pathways and optimize cut‑points for clinical use (Table 1).

Step	Action	Rationale
1	Baseline serum panel (e.g., CRP, TNF-α, and CXCL10)	Objectively assesses the systemic inflammatory burden and provides a reference for therapy.
2	Excipient audit of current eye drops	Identifies BAK and other excipients with known potential for systemic absorption.
3	Transition to preservative-free/organic formulation	Reduces ocular and systemic toxic load; real-world evidence supports better tolerance and improved IOP control.
4	Reassess serum markers at 8–12 weeks	Evaluates systemic impact; aligns with standard DED follow-up intervals.
5	Adjust therapy based on systemic and ocular outcomes	Advances the paradigm toward precision medicine in ocular surface disease.

Table 1 Bridging the two worlds - a practical roadmap.

Conclusion

Blood-based inflammatory markers provide a rapid and objective means of assessing dry eye severity and may prove useful for monitoring treatment response. However, at present their role remains investigational, and the clinical utility of routine biomarker monitoring should only be recommended once further prospective studies have validated their predictive and longitudinal value. In the meantime, minimizing systemic exposure to inactive excipients and prioritizing preservative-free, organic, biocompatible formulations remain pragmatic steps toward whole-body-conscious management of DED.