WHEN Dry Eye Isn’t Just DRY EYE
Underlying autoimmune disease may be more prevalent in patients with dry eye disease than previously thought.
By Virginia Pickles, Contributing Editor
Given the prevalence of dry eye in the United States — almost 5 million people in the 50+ age group have a physician-diagnosed dry eye, and an estimated 25 million have symptoms of it1,2 — ophthalmologists are challenged daily to efficiently diagnose the disease and devise an effective long-term treatment strategy. Most patients who seek treatment get relief, but some who present with moderate to severe signs and symptoms or who don’t respond well to standard therapies may have an underlying systemic autoimmune process at work. This article focuses primarily on Sjögren’s syndrome, the autoimmune disease most often associated with dry eye, and new research that suggests it may be more prevalent in patients with dry eyes than previously thought.
Overview
“Of all of the systemic autoimmune diseases that ophthalmologists are likely to diagnose as a result of a workup for dry eye, Sjögren’s syndrome is the most common and the most significant,” says Esen K. Akpek, MD, director of the Ocular Surface Disease and Dry Eye Clinic at the Wilmer Eye Institute at Johns Hopkins in Baltimore. “Early detection is critical because, unlike some other autoimmune diseases with ocular manifestations, Sjögren syndrome can lead to life-threatening complications, such as lymphoma, interstitial nephritis, autoimmune hepatitis and interstitial lung disease.”
Sjögren’s syndrome, which is more common in women than in men, is a chronic inflammatory autoimmune disease characterized by dry eyes and dry mouth, resulting from lymphocytic infiltration of lacrimal and salivary glands.3 Primary Sjögren’s syndrome occurs in otherwise healthy patients, whereas secondary Sjögren’s syndrome occurs when another rheumatologic disorder, such as rheumatoid arthritis or systemic lupus erythematosus, is present. Symptoms of Sjögren’s syndrome may overlap with or mimic symptoms of these other diseases.
According to some estimates, 1.3 million adults in the United States have primary Sjögren’s syndrome, although the range is broad, from 0.4 to 3.1 million people.4 Approximately 10% to 15% of patients with rheumatoid arthritis develop secondary Sjögren’s syndrome5; however, the prevalence of overlapping syndromes, especially mixed connective tissue disease, is unknown.6 According to the Sjögren’s Syndrome Foundation, it takes an average of 4.7 years for people with the disease to receive an accurate diagnosis.7
Evidence Building for Underdiagnosis
As the associate director of the Johns Hopkins Jerome L. Greene Sjögren’s Syndrome Center, Dr. Akpek has seen the long-term, severe, often irreversible, consequences of undiagnosed Sjögren’s syndrome. “Often, a patient has had periodic bouts of dry eye for years and has been using over-the-counter drops for relief but has never been worked up by an eye doctor,” she says. “Sometimes, severe findings of inflammatory disease, such as corneal melting with perforation, uveitis, scleritis or optic neuritis, are the first signs of Sjögren’s syndrome.”
Dr. Akpek has been involved in several studies to better understand the association of dry eye disease and Sjögren’s syndrome.
New Test May Facilitate Sjögren Diagnosis in Ophthalmology Practices
Detecting the underlying cause of a patient’s dry eye is important for several reasons, says Jodi Luchs, MD, director of cornea/external disease at South Shore Eye Care in Wantagh, N.Y. “Once I know a patient’s dry eye is associated with an autoimmune disease, I may treat it more aggressively, even if it doesn’t appear severe, and monitor the patient carefully to reduce the risk of long-term complications,” he says. “With this knowledge, I can also prognosticate about disease progression, which may be different from that of classic dry eye, and advise the patient, with the help of a rheumatologist, to be on the lookout for other systemic manifestations of that disease, whether it be on the skin, in the joints or elsewhere.”
Reaching a definitive diagnosis of Sjögren’s syndrome can be challenging, particularly in an ophthalmology practice, because multiple tests are required, and the gold standard is a salivary gland biopsy.1 What’s more, recent research suggests the traditional biomarkers for Sjögren syndrome (SS-A, SS-B, and antinuclear antibody) may not be sufficient to detect the disease at an early stage.2
A new test, Sjö (Nicox), is an advanced diagnostic panel for the early detection of Sjögren’s syndrome in patients with dry eye. It includes the traditional biomarkers as well as 3 novel proprietary biomarkers with high specificity and sensitivity for Sjögren syndrome.2
“Sjö is a blood test that can be performed in the office very quickly with a simple finger-stick,” Dr. Luchs says. “Integrating it into my practice has been seamless. The test can be performed by an ophthalmic technician. Everything we need is in the package, including alcohol, a lancet, filter paper, a bandage, even a prepaid mailer, ready to be sent to the lab.
“Results are usually available within 1 week,” Dr. Luchs says. “I particularly appreciate that I receive not only the test results for each of the individual markers but also an interpretation of those results. The concept is similar to receiving a radiologist’s report for an MRI. My patients appreciate that they can have the test done right there on the spot in a few minutes, rather than traveling to a lab somewhere and waiting to have it done.”
Dr. Luchs notes the test is not reimbursable to physicians performing the test, but in his experience, most insurance companies will cover the laboratory fee patients would incur for the test. He says the manufacturer offers assistance if a patient does not have coverage.
“With better tools to help us make the distinction between nonautoimmune dry eye and autoimmune-related dry eye, I believe we may learn that more of our patients with dry eye have an autoimmune disease lurking beneath the surface than we thought,” Dr. Luchs says.
References
1. Vitali C, Bombardieri S, Jonsson R, et al; European Study Group on Classification Criteria for Sjögren’s Syndrome. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002 Jun;61:554-558.
2. Shen L, Suresh L, Lindermann M, Xuan J, Kowal P, Malyavantham K, Ambrus JL Jr. Novel autoantibodies in Sjögren’s syndrome. Clin Immunol. 2012;145:251-255.
In a retrospective review of medical records of 220 patients with a primary diagnosis of dry eye disease, Dr. Akpek and colleagues found that 57 (25.9%) had an underlying rheumatic condition: 25 patients (11.4%) had rheumatoid arthritis (96% with rheumatoid arthritis had that diagnosis at presentation), and 24 (10.9%) had primary Sjögren’s syndrome.8 Only 8 patients (33.3%) with primary Sjögren’s syndrome carried the diagnosis at the time of presentation. “That percentage was a surprise to me,” Dr. Akpek says. “It was much higher than I had expected, even higher than the prevalence of uveitis in autoimmune disease.” In a subsequent study, Liew and colleagues set out to prospectively determine the prevalence and predictors of Sjögren’s syndrome in patients with clinically significant aqueous-deficient dry eye.9 They performed standard diagnostic tests, obtained medical histories, review of systems questionnaires and dry eye questionnaires. They also performed laboratory tests for Sjögren-specific antibodies A and B, rheumatoid factor and antinuclear antibody, but no lip biopsy was performed in this study.
Of 327 patients, 38 (11.6%) had Sjögren’s syndrome; 9 cases were newly diagnosed. Patients with Sjögren’s syndrome had significantly worse conjunctival and corneal staining, Schirmer test scores and symptoms, compared with patients without Sjögren’s syndrome. Patients with positive antinuclear antibody and rheumatoid factor were significantly more likely to have primary Sjögren’s syndrome.
Recently, Henrich and colleagues reported data from a retrospective review of patients with a primary diagnosis of dry eye. Their goal was to determine the frequency and types of inflammatory systemic disease in patients with dry eye and to identify clinical features suggesting their presence.10 Of 228 patients, 108 (47.4%) had a known diagnosis of inflammatory disease. Based on a review of systems and ocular examination, 81 of the patients underwent a further workup that revealed 25 additional diagnoses that were not known on presentation, including: occult thyroid eye disease (20), primary Sjögren’s syndrome (4) and Sjögren’s syndrome suspect (1). The researchers noted female sex, family history of autoimmune disease, self-reported joint pain or dry mouth, external signs of orbital inflammation and conjunctival chemosis were more common in patients with inflammatory systemic disease than in patients with no identifiable condition.
Take-home Message
Dr. Akpek urges all ophthalmologists to have a high index of suspicion for underlying inflammatory systemic disease and a low threshold for laboratory workups and appropriate referral when caring for patients with clinically significant dry eye. “I’m not suggesting that all dry eye patients should be worked up, but all dry eye patients should be examined very carefully, and their findings should be graded,” she says. “In anyone with clinically significant dry eye — staining, a low Schirmer score, high osmolarity, for example — we should always look for an underlying disease, especially if the patient has dental problems, dry mouth, fatigue, joint pain and swelling, gastrointestinal issues, family history of autoimmune diseases, thyroid disease and the like. A through review of systems check is very important.
“I have seen patients who have steroid-induced cataracts because they have “idiopathic” pulmonary fibrosis and are waiting for a lung transplant, and then I see that they have severe dry eye,” she says. “I work them up and learn that they have Sjögren’s syndrome. They have had Sjögren’s syndrome all along, and that’s the cause of their lung failure. Nobody noticed. Nobody listened when they said they had dry eye and dry mouth. This is a serious issue. Dry eye should not be trivialized.” ■
References
1. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136:318-326.
2. Schaumberg DA, Dana R, Burlin JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 2009;127:763-768.
3. Nguyen CQ, Peck AB. Unraveling the pathophysiology of Sjögren syndrome-associated dry eye disease. Ocul Surf. 2009;7:11-27.
4. Vitali C, Bombardieri S, Jonsson R, et al; European Study Group on Classification Criteria for Sjögren’s Syndrome. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002 Jun;61:554-558.
5. Ruffing V, Bingham CO. Rheumatoid arthritis signs and symptoms. Johns Hopkins Arthritis Center. http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms. Accessed August 10, 2014.
6. Gaubitz M. Epidemiology of connective tissue disorders. Rheumatology (Oxford). 2006;45 Suppl 3:iii3-iii4.
7. Sjögren’s Syndrome Foundation. https://www.sjogrens.org/home/about-the-foundation/breakthrough-goal-/2yearupdate. Accessed August 10, 2014.
8. Akpek EK, Klimava A, Thorne JE, MartinD, Lekhanont K, Ostrovsky A. Evaluation of patients with dry eye for presence of underlying Sjögren syndrome. Cornea. 2009;28:493-497.
9. Liew MS, Zhang M, Kim E, Akpek EK. Prevalence and predictors of Sjögren’s syndrome in a prospective cohort of patients with aqueous-deficient dry eye. Br J Ophthalmol. 2012;96:1498-1503.
10. Henrich CF, Ramulu PY, Akpek EK. Association of dry eye and inflammatory systemic diseases in a tertiary care-based sample. Cornea. 2014;33:819-825.
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