Refractory dry eye in patients with systemic comorbidities can be challenging to manage because the underlying condition or its treatments may contribute to ocular surface disease. In this Q&A conversation with the Eye Care Network, Sezen Karakus, MD, discusses the importance of assessing systemic disease activity, reviewing medications, and coordinating with other specialists. Management often requires a combination of topical, regenerative, and neurotrophic therapies tailored to the individual patient’s clinical and systemic context.

Note: Transcript edited lightly for clarity and length.

How do you approach refractory dry eye in patients with systemic comorbidities?

Sezen Karakus, MD: My approach depends heavily on the specific systemic condition involved. When I suspect that the systemic disease is contributing to refractory dry eye, I coordinate closely with the patient’s other specialists to determine whether their underlying condition is adequately controlled and whether medication adjustments could support ocular improvement.

For autoimmune diseases such as Sjögren disease or rheumatoid arthritis, it is important to assess whether there is active systemic inflammation. Not all patients with these diagnoses require systemic therapy, but uncontrolled disease can make the ocular surface much harder to manage. In those cases, I work closely with the rheumatologist. For inflammatory skin diseases, especially atopic dermatitis, involving dermatology to consider systemic treatment can be very helpful even when the eyes are the only area that appears severely affected. And in many patients, it is not the systemic disease itself but medications used for allergies, depression, or anxiety that drive dryness.

Metabolic disorders like diabetes are another major contributor. Poor glycemic control can present with a “dry-eye–like” picture that is actually early neurotrophic keratitis, with significant surface staining, minimal symptoms aside from blurry vision, and poor response to topical therapy. Neurologic conditions such as Parkinson’s disease, multiple sclerosis, and Sjögren-related small fiber neuropathy can similarly reduce corneal sensation and present as refractory “dry eye” that is more neurotrophic in nature.

On the other end of the spectrum, pain syndromes, fibromyalgia, and small fiber neuropathies may cause severe dry eye like symptoms without corresponding surface staining, pointing toward a neuropathic pain component.

When inflammation is severe and not responsive to commercially available immunomodulators, I frequently use compounded cyclosporine 1% as a stronger immunomodulatory treatment, sometimes with a temporary course of topical steroids. I also frequently use autologous serum eye drops for their dual anti-inflammatory and regenerative effects. These are particularly valuable when neurotrophic keratitis or neuropathy is part of the picture. Recombinant human nerve growth factor (cenegermin) (Oxervate; Dompé US Inc) is another important option when neurotrophic disease is masquerading as refractory dry eye.

Which biologics or new topical therapies show the most promise?

Karakus: Autologous serum eye drops have long been a workhorse for difficult cases, and they remain one of the most effective regenerative treatments we have. More recently, platelet-rich plasma or platelet-rich growth factor drops have emerged as alternatives with supportive evidence, though access can be limited in many regions. We also now have cenegermin, recombinant human nerve growth factor, as a topical treatment option for cases with neurotrophic features.

Beyond these regenerative therapies, it has been exciting to see the landscape expand beyond T-cell–directed anti-inflammatory agents. Neurostimulation has become an important new category with intranasal varenicline spray (Tyrvaya; Viatris) and the newly approved topical acoltremon (Tryptyr; Alcon), both aimed at increasing tear production with possible additional off-target benefits. The latter, a TRPM8 receptor agonist, is an especially promising addition expected to provide broader benefits to the treatment landscape. These options have been very meaningful, particularly when combined with anti-inflammatory therapy.

A third category targets the lipid layer, with perfluorohexyloctane (Miebo; Bausch + Lomb) offering a novel way to reduce evaporation and stabilize the tear film. Because dry eye is fundamentally a multifactorial disease with overlapping mechanisms, having these different therapeutic classes allows for much more personalized and mechanism-specific care. It is encouraging to see even more innovations in the pipeline.

How has diagnostic technology improved your treatment personalization?

Karakus: My most powerful diagnostic tools remain a detailed symptom history, fluorescein and lissamine green staining, a thorough slit-lamp examination, and even the basic Schirmer test. These fundamentals still guide most of my treatment decisions.

To assess a potential neuropathic component, I use a proparacaine challenge, which is simple but extremely informative. When available, I also use point-of-care MMP-9 testing, which can help confirm an inflammatory phenotype. And because I view corneal nerves and neuroimmune signaling as central to ocular surface disease, I value having access to in vivo confocal microscopy to assess the subbasal nerve plexus and visualize immune cell activity within these layers. These tools allow me to match treatment more precisely to each patient’s underlying biology.

Are there innovations in tear film monitoring or ocular surface imaging on the horizon?

Karakus: There are several technological advances that allow us to measure tear break-up time more precisely and analyze the tear film for additional biomarkers that may help differentiate disease subtypes and personalize treatment. These developments are very exciting, but we still need to understand how they will practically guide us in choosing among the many treatments now available. Tear biomarker research, and similar biomarker work, is important, not only about improving diagnostics but may also help identify potential therapeutic targets.

However, it is important to remember that “dry eye” is a broad umbrella term with many overlapping mechanisms, countless possible combinations, and each mechanism involved may be at a different stage. This is why every case is different and personalized treatment is essential. Further dissecting these mechanisms and separating one driver from another is crucial, even if achieving complete separation may not be realistic. Both current and emerging technologies are especially valuable in the research space for moving us toward that goal.

They will only become truly important in routine clinical care if they can meaningfully inform treatment decisions, something that becomes increasingly critical as more drug classes emerge and the treatment landscape grows both more exciting and more overwhelming for clinicians.

Sezen Karakus, MD
E: [email protected]
Karakus is assistant professor of ophthalmology, Wilmer Eye Institute, and associate director, The Jerome L. Greene Sjögren’s Disease Center at Johns Hopkins University in Baltimore, Maryland.
Financial disclosure: Grant recipient and consultant for Dompé US. Inc.