Published in Ocular Surface

Co-Morbid Systemic Disease That Complicates OSD

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12 min read

In this session from Eyes On Dry Eye, Preeya K. Gupta, MD, and Jacob Lang, OD, FAAO, discuss co-morbid systemic diseases and managing ocular surface disease.

Co-Morbid Systemic Disease That Complicates OSD
As eyecare providers, it is important to treat the eyes specifically but see the patient holistically. Systemic disease plays a large role in ocular surface disease (OSD), so it is important to maintain an awareness of the conditions that can not only cause dry eye disease (DED) but also masquerade as dry eye disease.

Learn more about managing OSD in patients with co-morbid systemic diseases.

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Treating dry eye patients with co-morbidities

You might be the first medical professional to identify and diagnose a systemic disease for the patient, enlightening them about the necessity of seeking additional care. Many diseases, left untreated, can progress to debilitating and even life-threatening stages.
When evaluating a dry eye patient, who has seen several other doctors with unsatisfactory results, it becomes a two-part challenge. First, to discover why the patient is still symptomatic. Secondly, to pinpoint any co-morbid diseases that could be complicating ocular surface disease.

Patient assessment…and reassessment

The first step is always a thorough patient assessment. Begin with defining and detailing the primary complaint. Ask the patient to narrow down what is causing them the most discomfort or annoyance: Is it burning? Watering? Blurred vision? Have them be as specific as possible so you can target treatment. Detail this in your notes to refer to on follow-up.
Surveys and questionnaires—SPEED, OSDI, DEQ-5, OPAS—are the most efficient way to track symptomatology. But, often with dry eye disease, there can be a disconnect between the symptoms and the clinical signs, so establishing objective parameters is equally important.
These are four of the most effective means of testing:
  1. Tear breakup time: Can easily be measured with a fluorescein strip.
  2. Corneal staining: When checking for corneal and conjunctival staining, you can also look at the pattern of the stain and how it moves.
  3. Tetracaine: Provides a straightforward means to test the nerve function and determine if the pain/discomfort might have a neuropathic root.
  4. Hyperosmolarity solutions: For example, Muro 128 (Sodium chloride hypertonic (Ophthalmic), Bausch + Lomb).

Patient education on dry eye disease

Once an anatomical baseline has been established, formulate a goal with the patient. Explain that, due to the complexities of dry eye disease, all symptoms are unlikely to be resolved on the first try, and medications/protocols will most likely need to be adjusted throughout the treatment process. Then, have the patient verify the aspect of their disease they are most eager to "fix." Work toward alleviating this symptom first.
Naturally, if there is any chronic condition that is causing ongoing damage to the ocular surface, this will take first priority. At the first follow-up, reassess the patient using both symptoms and clinical findings while referring back to their chief complaint and original test results as a reference point. Establish to what degree their primary symptom has been remedied.
Determine what aspect of the disease is currently causing the most disruption and adopt a new strategy if necessary. There will be instances in which their anatomy has improved beyond their symptoms, which can be frustrating to the patient and may require more aggressive treatment.

Pearl: Never underestimate meibomian glands. Meibomian glands are often undertreated and can be an important part of reaching patient satisfaction.

OSD that can masquerade as DED

There are many ocular, as well as underlying systemic diseases, that may present as ocular surface disease during the initial visit.

Stage 1 neurotrophic keratitis

This earliest stage of neurotrophic keratitis impersonates severe dry eye disease. However, since the problem lies in the impaired trigeminal innervation of the corneal and ocular tissues, even the most stringent dry eye regimen will not address the core issue.
However, patients can receive symptom relief from traditional dry eye treatments. First-line testing involves evaluating corneal sensitivity. Treatment entails nerve response modulators (i.e., low-dose Naltrexone, OXERVATE) and, in some cases, scleral lenses.  It is prudent to co-manage this disease with a neuro-ophthalmologist and/or neurologist.

Superior limbic keratoconjunctivitis (SLK)

With SLK, the constant movement of the superior redundant conjunctiva creates inflammation and symptoms of burning, pain, photophobia, and foreign body sensation. Along with a comprehensive slit lamp exam, corneal staining is extremely useful in diagnosis.

Filamentary keratitis

Among other risk factors, moderate to severe autoimmune diseases put patients at a higher incidence of developing filamentary keratitis. Hallmarks are inflammation, foreign body sensation, epiphora, and redness.
Debridement is the initial in-office treatment for filamentary keratitis. Using jeweler’s forceps, pinch the base of the filament and gently remove as many as possible. Prescribe an immunomodulator (i.e., cyclosporine or lifitegrast) as well as a topical steroid to acutely combat inflammation.
N-acetylcysteine has proved especially potent as an adjunctive therapy to manage filamentary keratitis but must be compounded, as it is not currently available as an ophthalmic solution. Also, consider a bandage contact lens if epithelial defects demand.

Floppy eyelid syndrome

Floppy eyelid syndrome is a structural condition often linked to obesity wherein the eyelid is not properly protecting the cornea or allowing for proper lubrication. It can result in ulceration, breakdown of the lid margin, and severe DED.
To check for this syndrome, have the patient look down and lift the lid. If you see deep into the superior fornix and, with minimal manipulation, can avert the lid, they likely have floppy eyelids. If medical treatment, such as an eye shield, proves ineffective, refer the patient to an oculoplastic surgeon for lid-tightening procedures.


Patients whose main complaint is watery and painful eyes may be suffering from a chronic blockage in the drainage system, such as canaliculitis or dacryocystitis. Referring to past history may reveal the prior use of punctal plugs.

Systemic diseases to keep in mind during exams

Often the eyes are a harbinger of larger inflammation, infection, or genetic predisposition to systemic diseases. To ensure the patient receives the proper evaluation and treatment from a primary care physician or specialist, it is crucial we recognize common systemic conditions and make the appropriate referrals as well as treat the ocular aspect.

Sjögren’s syndrome

One of the most relevant systemic diseases is Sjögren's syndrome (SS), an autoimmune disease linked to heart, kidney, and liver disease, as well as Raynaud’s, neurocognitive decline, and lymphoma.
Up to 85% of people with Sjögren’s syndrome report dry eye. Due to its prevalence and the possibility of dire-related illness, it is important to be cognizant of the signs and refer accordingly. If Sjögren’s is strongly suspected, refer the patient to their primary care physician or a rheumatologist for bloodwork and further testing.
Table 1 highlights the system for scoring Sjögren’s syndrome. A total score of ≥4 meets the official criteria for SS.
Anti-SSA(Ro) antibody positivity3
Biopsy (focal lymphocytic sialadenitis) with a focus score of 21 foci/square millimeter3
Abnormal ocular staining score of 25 in at least one eye1
Schirmer’s <5 at 5 minutes in at least one eye1
Unstimulated salivary flow rate ≤0.1mL/minute 1
Table 1: Courtesy of Shiboski et al.

Pearl: A diagnostic clue with Sjögren’s syndrome is diminished saliva. One question to determine whether Sjögren’s is the likely culprit is to ask the patient, “Can you eat a salty cracker?” When Sjögren’s is unlikely, the answer would be “Yes.”

Fabry’s disease

The presence of verticillata may indicate Fabry’s disease, an inherited lysosomal storage disease in which the enzyme sphingolipids build up on the walls of the blood vessels and other organs.
In the eye, it presents as neuropathic pain, telangiectasia, and angiokeratomas. Fabry’s disease can lead to renal failure, stroke, and deafness, and has an early mortality of 40 to 60 years.


Rosacea is an inflammatory condition that can appear either first on the skin or in the eye and then migrate to the other area. It is often mistaken for allergic conjunctivitis and presents as burning, itching, and redness. Recent research makes a connection between rosacea and gut microbiome, which is widely accepted to play an active role in inflammation.

Thyroid disease

Thyroid dysfunction is another cause of autoimmune ocular inflammation.
Thyroid eye disease symptoms include:
  • Orbital congestion.
  • Allergic conjunctivitis (minus pupillary reaction) that does not improve with allergy drops.
  • Unexplained changes in vision linked to low-grade chronic compressive optic neuropathy, which should be further investigated with optic nerve imaging with optical coherence tomography (OCT) and visual field testing.
Thyroid eye disease has also been associated with meibomian gland dysfunction, which contributes to tear film instability and evaporative dry eye. If you suspect that ocular surface symptoms are the result of thyroid eye disease, have the patient close their eyes. If this cannot be done with minimal force, it could be an early sign of thyroid eye disease, which is characterized by lid lag.
It is imperative for these patients to get their thyroid dysfunction under control as well as address the thyroid eye disease with new treatments like Teprotumumab (TEPEZZA). To eliminate the exposure issues that lead to OSD and corneal breakdown, an oculoplastic surgeon can also perform an eyelid graft, enabling the lid to completely cover the eye, which can make a profound difference.


As it is one of the leading causes of blindness, it would be remiss not to mention the ocular effects of diabetes. Diabetes is related to a range of ocular surface complications, including superficial punctate keratopathy, neurotrophic ulceration, and persistent and recurrent epithelial erosions. A comparative study found the prevalence of dry eye in diabetic patients to be over 50%.

Other diseases that present with dry eye components include:

  1. Vitamin A deficiency: One telltale sign of this vitamin deficiency is the keratinized epithelial cells, often triangular in shape, referred to as the Bitot’s spot.
  2. Sickle cell anemia: It is worth noting that hyphemas are often seen in patients with sickle cell.
  3. Sleep apnea: Often a result of obesity, sleep apnea is frequently accompanied by the exposure variety of DED.
  4. COVID-19: Any virus that affects the immune system can create ocular manifestations; several eye conditions have been connected to COVID, including an increased propensity for dry eye disease. Immune stimulation associated with the coronavirus vaccines may also play a part.

Pearl: Be cognizant of commensurate flares. Oftentimes, as part of their systemic condition, patients will experience remissions and relapses; it is simply the nature of many diseases. Dry eye flares run parallel and may require temporary adjuvant treatments, such as topical steroids.

Final thoughts

Though our focus is on the eye, it is undeniable that ophthalmologists and optometrists must also take into account the rest of the body. Understanding even the most subtle ocular manifestations of systemic disease makes us better diagnosticians.
In addition, to best serve our patients, we must know when and to whom to refer systemic suspects, as we may very well be the first—or only—healthcare provider the individual has visited regarding their symptoms.
Preeya K. Gupta, MD
About Preeya K. Gupta, MD

Dr. Gupta earned her medical degree at Northwestern University’s Feinberg School of Medicine in Chicago, and graduated with Alpha Omega Alpha honors. She fulfilled her residency in ophthalmology at Duke University Eye Center in Durham, North Carolina, where she earned the K. Alexander Dastgheib Surgical Excellence Award, and then completed a fellowship in Cornea and Refractive Surgery at Minnesota Eye Consultants in Minneapolis. She served on the faculty at Duke University Eye Center in Durham, North Carolina as a Tenured Associate Professor of Ophthalmology from 2011-2021.

Dr. Gupta has authored many articles in the peer-reviewed literature and serves as an invited reviewer to journals such as Ophthalmology, American Journal of Ophthalmology, and Journal of Refractive Surgery. She has also written several book chapters about corneal disease and ophthalmic surgery, as well as served as an editor of the well-known series, Curbside Consultation in Cataract Surgery. She also holds several editorial board positions.

Dr. Gupta serves as an elected member of the American Society of Cataract and Refractive Surgery (ASCRS) Refractive Surgery clinical committee, and is also is the Past-President of the Vanguard Ophthalmology Society. She gives presentations both nationally and internationally, and has been awarded the National Millennial Eye Outstanding Female in Ophthalmology Award, American Academy of Ophthalmology (AAO) Achievement Award, and selected to the Ophthalmologist Power List.

Preeya K. Gupta, MD
Jacob Lang, OD, FAAO
About Jacob Lang, OD, FAAO

Dr. Lang received his Doctor of Optometry degree from The New England College of Optometry in Boston, MA. Dr. Lang then completed a cornea and specialty contact lens residency in Boston, MA. He writes articles for several publications and is actively involved in lecturing to colleagues at various meetings locally and nationally. He is a Diplomat of the American Board of Optometry, a fellow of the American Academy of Optometry and an Adjunct Clinical Faculty for the Illinois College of Optometry and Salus University. He is also the residency coordinator for Associated Eye Care’s optometric residency program, is actively involved in lecturing on eye care innovations, and participates in ongoing clinical research.

Jacob Lang, OD, FAAO
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