Focus on Dry Eye

How systemic disease influences dry eye

Recognizing the signs and symptoms early is key to effective management.

By Samantha Herretes, MD; Carolina Betancurt, OD; Juan C. Murillo, MD; Kendall E. Donaldson, MD, MS; Victor L. Perez, MD

Dry eye syndrome affects 5% to 30% of the population age 50 or older.¹ Symptoms range from mild to severe, often affecting patient quality of life. Several diagnostic tests are available, although the current lack of a “gold standard” may make the diagnosis challenging at times. What’s more, a variety of systemic immunological conditions may affect the ocular surface and influence this multifactorial disease, among them Sjögren’s syndrome, lupus, thyroid disease, rheumatoid arthritis, graft-versus-host disease and ocular cicatricial pemphigoid.

Figure 1: Filamentary keratitis is a common finding in patients with Sjögrens syndrome.

Patients with dry eye need to undergo a detailed examination that includes a symptom questionnaire and careful medical history, as the signs can represent the earliest manifestations of a systemic immunologic disorder. Adding to the complexity of a case is the potential that a patient with a certain immunologic condition may be predisposed to suffer from additional immunologic disorders as well.

All patients should undergo a complete dry-eye work-up (box, “The comprehensive dry eye evaluation”) that includes best-corrected visual acuity, measurement of IOP, and surface evaluation that involves the quality-of-life questionnaire, tear break-up time, vital dyes with fluorescein and lissamine green, and Schirmer test. We recommend physicians develop a customized, standardized work-up they can reliably reproduce in the clinic. This article reviews how common systemic diseases influence dry eye and management strategies.

THE COMMON DRY EYE CULPRITS

Sjögren’s syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disorder of the exocrine glands that produces dry eye and dry mouth due to involvement of the salivary and lacrimal glands. It may also present with systemic signs and symptoms such as arthralgia, myalgia and Raynaud’s syndrome. Primary SS is a systemic disorder more common in women, with a prevalence of 0.5% in the general population.² SS may also develop secondary to other connective tissue diseases.

Ocular signs and symptoms. The most frequent ocular manifestation is keratoconjunctivitis sicca, which may be progressive and more severe than other cases of non-SS dry eye.³ Patients often present with epithelial damage and filamentary keratitis (Figure 1).

Evaluation and testing. Besides the complete dry eye evaluation, the physician should order certain laboratory tests, such as a complete metabolic panel, CBC, as well as testing for antinuclear antibodies (ANA), antibodies to SS-A (Ro) and SS-B (La) and rheumatoid factor.

Management. Referral to an immunologist is often necessary. Secretagogues and systemic immunomodulation as well as biopsy of salivary glands are required, because antibody titers may frequently be negative. Patients with severe disease may need to be referred to an ocular surface specialist for aggressive management of their ocular surface disease.

Systemic lupus erythematosus (SLE)

Associated symptoms in patients with SLE may include skin and joint manifestations as well as oral ulcers.⁴

Ocular signs and symptoms. Ocular surface findings are commonly related to keratoconjunctivitis sicca, meibomian gland dysfunction, plaque-like lesions of the lower lid, forniceal shortening and symblepharon. Secondary SS is frequently present in these patients, manifesting as severe dry eye in some cases.⁵

Evaluation and testing. Laboratory tests such as ANA, SS-A, SS-B, anti double-stranded DNA (ds-DNA) are important for the diagnosis.

Management. An immunologist or rheumatologist must evaluate patients with SLE if they require systemic immunosuppressive therapy.

Rheumatoid arthritis (RA)

RA is a chronic inflammatory disease of unknown etiology that involves multiple joints.

Ocular signs and symptoms. Keratoconjunctivitis sicca is the most frequent ocular complication of RA.⁶ Many patients may have associated SS, manifesting with progressive dry eye and severe ocular surface involvement. Interestingly, patients with SS and RA have increased risk of developing non-Hodgkin’s lymphoma.⁷

Management. Patients with RA must be managed jointly with an immunologist because they often require systemic immunomodulation with drugs such as methotrexate (Rheumatrex, DAVA Pharmacueticals, Fort Lee, N.J.; Trexall, Duramed Pharmaceuticals, Somerset, N.J. ) and tumor necrosis factor inhibitors.

Thyroid disease

Graves disease is a systemic autoimmune process that affects the thyroid gland as well as many other tissues.

Ocular signs and symptoms. Ophthalmopathy may present in 40-50% of patients with Graves disease due to inflammation of the orbital connective tissue and soft-tissue enlargement in the orbit.⁸ Manifestations are usually bilateral and may include proptosis, eyelid retraction, lagophthalmos, entropion, cicatricial myopathy and diplopia.⁹

The ocular surface is usually affected due to inflammation and exposure, with signs of dry eye as well as the presence of chemosis, conjunctival injection, superficial punctate keratopathy and elevated tear film osmolarity. This may damage the tear film and cornea, leading to ocular discomfort, pain, and decreased visual acuity.^8,9 Graves disease may also frequently be associated with superior limbic keratopathy.

Evaluation and testing. When evaluating a patient with exposure keratopathy and suspected thyroid disease, a full dry eye work-up is indicated, as well as exophthalmometry and assessment of lid retraction, lagophthalmos and presence or absence of Bell’s reflex.

Patients should undergo a complete thyroid workup, including serum levels of T3, free T4 and TSH for screening of thyroid status, as well as investigating for the presence of thyroid-specific antibodies (anti-thyroglobulin, anti-thyroid peroxidase and anti-TSH receptor). Imaging such as orbital ultrasound or CT scan can also be helpful.

Management. If the work-up reveals any abnormalities, refer the patient to an internist or endocrinologist. Initial treatments for the dry eye may include topical lubricants and anti-inflammatory medications. When lid retraction is severe (that is, more than 4 mm of scleral show), or the dry eye is refractory to treatment, refer the patient to an ocular surface or oculoplastics specialist, who can provide treatment to avoid complications such as corneal ulceration, melting and perforation.

Graft-vs.-host disease

Allogeneic bone marrow transplantation is currently the treatment of choice for various hematologic malignancies. Its use has increased and the survival rate is higher than it was several years ago. Graft-vs.-host disease (GVHD) is a frequent complication in which the donor cells produce an immunologic attack on recipient organs or tissues.

Ocular signs and symptoms. Ocular involvement may occur in 60% to 90% of transplanted patients, affecting the lacrimal gland and ocular surface, producing inflammation and cicatricial scarring.¹⁰ Acute GVHD presents mostly with conjunctival hyperemia, chemosis and pseudo-membrane formation, whereas dry eye, chronic blepharitis and meibomian gland dysfunction are the most common ocular manifestations of chronic GVHD.¹¹ This may lead to corneal punctate keratopathy, formation of filaments, epithelial erosions, sterile corneal stromal necrosis and perforations in severe cases.¹¹

Management. Patients with ocular GVHD must be evaluated together with the oncology department to manage and control systemic immunosuppression that is usually necessary. Topical anti-inflammatory treatment is beneficial in these patients, as well as autologous serum eyedrops.

Figure 2: Note the lid thickening, forniceal shortening and trichiasis that are characteristic of ocular cicatricial pemphigoid.

Ocular cicatricial pemphigoid (OCP)

This autoimmune blistering disorder mainly affects the conjunctiva, but as a systemic disorder it frequently affects other areas of the body as well.¹² It occurs most commonly in elderly patients, and often has a very poor prognosis.

Ocular signs and symptoms. OCP is a bilateral, but often asymmetric, disease, with varying degrees of corneal epithelial damage, tear abnormalities, meibomian gland dysfunction, dry eye, chronic conjunctivitis with subepithelial fibrosis, foreshortening of the fornices, trichiasis and symblepharon formation (Figure 2).¹²

Evaluation and testing. A high level of clinical suspicion is needed for the diagnosis of OCP. If it is suspected, a conjunctival biopsy using immunofluorescence is in order.¹² A negative biopsy does not exclude the diagnosis, and a repeat biopsy may be indicated in cases with high clinical suspicion. Furthermore, a thorough medical evaluation is indicated.

Management. Specialists in ocular surface, oculoplastics and immunology must work cooperatively for optimal patient care.

TREATMENTS

Initial treatment

Initial treatment for all of these conditions is similar (Table), with topical lubricant drops or ointments. Preservative-free formulations are recommended if dosing is more than four times a day.¹¹ Continuous or pulsed therapy with topical anti-inflammatory agents such as corticosteroids alleviate local inflammation.

Cyclosporin A (CsA) is another anti-inflammatory medication that can be used as a commercially available (0.05%, Restasis, Allergan, Irvine, Calif.) or as a compounded (0.5% – 2%) formulation.¹¹ Topical CsA inhibits calcineurin and T-cell activation and proliferation, and decreases inflammation in the conjunctiva and lacrimal glands. Furthermore, it increases goblet cell density and decreases epithelial cell death.^11,13

Punctal plugs and other treatments

Punctal plugs may be an option in some patients to decrease tear drainage. However, the initial treatment must always address ocular surface inflammation before punctal occlusion.

In patients with dry eye refractory to initial treatment, autologous serum tears may be beneficial.^14,15 In severe cases, the use of therapeutic bandage contact lenses may be helpful to protect the cornea from exposure and mechanical friction of the eyelids.⁹ Specific centers may offer scleral devices such as the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE),¹⁶ which is a custom-made lens-like device with a vaulted area that can be filled with fluid, providing constant lubrication of the ocular surface, while maintaining adequate oxygen supply to the cornea and correcting refractive errors (Figure 3, page 51).

Figure 3: Two views of the PROSE device in a patient with severe keratoconjunctivitis sicca.

All cases of dry eye in association with systemic immunologic conditions should be managed very carefully and seen in conjunction with other necessary specialists (immunology, ocular surface, oculoplastics) in order to provide the best topical, systemic and surgical treatment options for each case in particular. OM

REFERENCES

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14. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum preparation in Sjögren’s syndrome. Br J Ophthalmo.l 1999;83:390-395.

15. Ogawa Y, Okamoto S, Mori T, et al. Autologous serum eyedrops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2003;31:579-583.

16. Dimit R, Gire A, Pflugfelder SC, Bergmanson JP. Patient ocular conditions and clinical outcomes using a PROSE scleral device. Cont Lens Anterior Eye. 2013;36:159-163.

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