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THE SJOGREN'S PARADOX

Practitioners should not forget about this often-overlooked condition when evaluating their dry eye patients.

By: Roxanna Potter, OD
Contact Lens Spectrum July 1, 2021 Vol 36, Issue July 2021 Page(s): 30-32, 34-36

Paradox: a seemingly absurd or self-contradictory statement or proposition that when investigated or explained may prove to be well founded or true. And now, you are probably asking yourself why this is the start of a Sjögren’s article. Well, with respect to patients who have Sjögren’s, those who have severe signs can have few or no symptoms, and those who have severe symptoms can have little or no signs. That is a slit lamp paradox but an important tidbit to consider when seeing dry eye patients.

BACKGROUND, INCIDENCE, AND PATHOLOGY

Sjögren’s was first described in 1933 by Dr. Henrik Sjögren, an ophthalmologist in Sweden.1 He reported on 19 women who had both dry eye and dry mouth and determined that they also had lymphocytic infiltration of the lacrimal and salivary glands. These women also had associated systemic manifestations.

It is estimated that dry eye affects approximately 8% of the 108 million Americans who are older than 50 years. Furthermore, one in 10 of these patients has underlying Sjögren’s.2 However, it is interesting to note that nearly two-thirds of patients remain undiagnosed with Sjögren’s.3

Sjögren’s is the second most common autoimmune rheumatological disease, with rheumatoid arthritis being the first.4 It can occur at all ages, with peak incidence in the fourth and fifth decades, and it has a strong predilection for females, who represent 95% of patients.4 Sjögren’s is classified as a chronic inflammatory autoimmune disease that can be histopathologically characterized by lymphocytic infiltration into the exocrine glands—specifically, the lacrimal and salivatory glands, leading to dry eye (keratoconjunctivitis sicca) and dry mouth (xerostomia)—as well as other organs that are attacked by the autoimmune process.5,6 The infiltration of lymphocytes into the salivary and lacrimal glands leads to the destruction of these glands and to a subsequent impact on function and secretion.4,7

Sjögren’s can be divided into two categories. Primary Sjögren’s refers to cases in which there is no other associated systemic connective tissue disease. Secondary Sjögren’s consists of features of primary Sjögren’s together with clinical features of autoimmune connective tissue diseases. These connective tissue diseases most commonly include rheumatoid arthritis, systemic lupus erythematosus, polyarteritis nodosa, Wegener’s granulomatosis, systemic sclerosis, primary biliary sclerosis, or mixed connective tissue disease.4 The exact triggers leading to the autoimmune process are not fully known. Risk factors include a genetic profile, non-major histocompatibility complex (MHC) androgen status, and exposure to environmental agents such as a virus or pollution.4

The pathogenesis of Sjögren’s is multifactorial. It is postulated that environmental factors trigger the inflammation cascade in individuals who have a genetic predisposition to the disorder. Infiltrating cells (B- and T-cells, dendritic cells) interfere with gland function at several points. The destruction of gland function by cell-mediated mechanisms, the secretion of cytokines that activate interferons, the production of autoantibodies that interfere with muscarinic receptors that damage function, and, finally, the infiltrating cells disrupt the secretion of metalloproteinases (MMPs) that interfere with interaction with the extracellular matrix and disrupt gland function. This disruption leads to a cycle that ignites the inflammation storm and ultimately leads to systemic production of autoantibodies to the ribonucleoprotein particles SS-A/Ro and SS-B/La, which are MMPs.8 These two autoantibodies (SS-A/Ro and SS-B/La) are considered immunological hallmarks of the disease; they are found in 50% to 70% of patients and are associated with more severe disease.6,9 Through a blood serum test, these immunological hallmarks are used in detection of the disease.6

Eyecare providers are no strangers to the symptoms of dry eye and are certainly familiar with the definition of dry eye. When directing our attention to dry eye due to Sjögren’s, symptoms of dryness, irritation, and pain are often the first to appear.6 Symptoms of dry eye are persistent or more severe, and Sjögren’s patients compared to non-Sjögren’s patients have chronic pain.7 Conversely, patients who have Sjögren’s-related dry eye and who have higher ocular surface staining scores have less severe symptoms of ocular discomfort compared to patients who have non-Sjögren’s-related dry eye.2 In one 2020 study, photosensitivity was found to be prevalent, particularly in women, and results show that almost 50% of patients experience significant photosensitivity and that 25% of patients experience severe photosensitivity.10 Patients who have Sjögren’s experience significant fluctuations in vision with blinking, blurred vision, eye fatigue, and difficulty with reading despite visual acuity results of potentially 20/20.2

THE IMPORTANCE OF THE LACRIMAL UNIT

The lacrimal functional unit (LFU) is defined as an integrated system comprising the lacrimal glands, ocular surface (cornea, conjunctiva, and meibomian glands), and lids as well as the sensory and motor nerves that connect them.11 The lacrimal gland and its efferent and afferent nerves in the conjunctiva and cornea are responsible for the aqueous production of the tear film. The tear reflex is dependent on intact nerve terminals in the cornea. In patients who have Sjögren’s (particularly primary Sjögren’s), both the density of the sensory nerve fibers and their function are reduced compared to in healthy subjects.6 The impairment of the corneal nerves can lead to a reduction of dry eye symptoms but also simultaneously exterminates the tear reflex, thus depleting tear production even further.12 Inflammation and destruction of the cells and ducts of the lacrimal unit combined with the decrease in proper feedback of the sensory nerves leads to decreased tear flow, resulting in keratoconjunctivitis sicca. If the inflammation and decreased tear production are severe enough, keratinization of the conjunctiva and corneal epithelia occurs.6,13 The reduction of the neural feedback loop over time may be the reason behind a notable increase in ocular surface staining in patients who have less severe symptoms of ocular discomfort.3 Thus, the paradox that is Sjögren’s continues.

The meibomian gland is significantly more damaged in Sjögren’s patients (57.9%) than in non-Sjögren’s patients.7,14 This can further complicate diagnosis, as dry eye related to Sjögren’s is commonly lumped into the category of aqueous deficient dry eye; however, damage to the meibomian gland as a result of chronic inflammation and androgen deficiency leads to meibomian gland disease and evaporative dry eye, furthering the paradox.7,14

TESTING AND DIAGNOSIS

Often, case histories will unveil typical symptoms related to dry eye. It is feasible, however, that many of us do not move forward with the exact battery of tests that are required to specifically lead to the diagnosis of Sjögren’s. Additionally, patients who have primary Sjögren’s may go undetected for 10 years; research shows that one-third of patients who have confirmed dry eye do not get diagnosed with actual Sjögren’s for a decade.15,16 This is particularly problematic for primary Sjögren’s patients, as those who have secondary Sjögren’s may be easier to diagnose due to their underlying connective tissue disease that may have been diagnosed by another specialty. It is that underlying connective tissue disease accompanied with dry eye symptoms that will lead to a link with secondary Sjögren’s.

At least four of six signs and symptoms must be present to confirm diagnosis. These include dry eye symptoms with and without artificial tear use, dry mouth symptoms, Schirmer’s I test, positive minor salivary gland biopsy, non-stimulating total sialometry (saliva flow measurement), and salivary gammagraphy or sialography (imaging).17 Symptoms must be present without a history of cervical radiography, hepatitis C virus infection, acquired immunodeficiency disease (AIDS), pre-existing lymphoma, sarcoid, graft-versus-host disease, and anticholinergic use (see sidebars on pages 34 and 35).17

Corneal vital staining is perceived to be a requisite for a dry eye diagnosis and long-term monitoring. Lissamine green is considered the gold standard for evaluation and grading of the conjunctiva, while fluorescein remains the gold standard for corneal staining grading as well as assessing tear breakup time (TBUT).7,18 To assess aqueous secretion, Schirmer’s I (without anesthesia) is commonly utilized for diagnosis; a result of more than 10mm of moisture after five minutes is considered normal. Some studies on dry eye related to Sjögren’s suggest that Schirmer’s III (nasal stimulation) can be used for severe cases, although it is not particularly needed for confirmation.7 Meibography, which uses infrared light to observe meibomian gland morphology, can be useful in assessing meibomian gland dysfunction in patients who have Sjögren’s.19 As mentioned, some eyecare providers can use confocal microscopy to track dry eye in Sjögren’s patients.6

Dry eye disease questionnaires are vital for the diagnosis of dry eye in the Sjögren’s population. The Ocular Surface Disease Index (OSDI) is commonly utilized by many practitioners. It contains 12 questions related to dry eye symptoms that survey the patients’ symptoms over the past two weeks. The Dry Eye Questionnaire (DEQ) is used by some for measuring intensity of symptoms throughout the day. The Symptom Assessment Questionnaire in Dry Eye (SANDE) uses visual analog scales for assessing the frequency and severity of symptoms. Additionally, the Dry Eye Related Quality of Life Score (DEQS) has been reported in the literature as a useful metric for tracking and assessing patients’ symptoms.6,7

The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed an international consensus disease activity index, the EULAR Sjögren’s Syndrome Reported Index (ESSPRI) and EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI). These questionnaires are commonly used in other specialties such as rheumatology to monitor Sjögren’s disease activity. However, they have limited use in the scope of eye care, as both include limited assessments related to ocular status.15,20,21

TREATMENT

As with any dry eye patient, many eyecare practitioners will initiate artificial tears and/or lubrication with ointment at the onset of symptoms as a form of palliative treatment. Preservative-free artificial tears are recommended for patients who use tear supplements more than six times per day to avoid ocular surface toxicity.6 Ophthalmic inserts containing hydroxypropyl cellulose can be an alternative for artificial tears or can be used in conjunction with them; however, I have not found them to be readily available, and patients tend to have poor tolerance of them due to foreign body sensation.

Topical immunosuppressants such as cyclosporine are recommended if a trial of artificial tear supplementation does not adequately control symptoms. This line of therapy can be particularly useful for Sjögren’s patients, as these agents inhibit calcium-dependent events in T-cells, thus inhibiting migration of immune cells and subsequent activation of T-cells. This action delays the release of proinflammatory cytokines that increase the inflammation cycle.22 Topical tacrolimus has been reported in the literature as a treatment option for Sjögren’s patients. This medication is an immunosuppressant that is 10 times more potent compared to cyclosporine.7 However, cyclosporine has been found to be a superior agent for inflammation and corneal staining reduction after six months when used for dry eye;23 it is worth noting that there are limited studies on the comparison of the two, so watch for future studies. Lifitegrast is a more recently introduced treatment for dry eye. This topical medication acts as an integrin inhibitor known to antagonize lymphocytic function of associated antigen-1 (LFA-1).24

CLASSIFICATION CRITERIA

As patients may exhibit some or all of the signs and symptoms of Sjögren’s, it is imperative that eyecare practitioners consider the following criteria areas: 1) ocular symptoms, 2) oral symptoms, 3) ocular signs, 4) histopathology, 5) salivary gland involvement, and 6) autoantibodies.

According to the American-European Consensus Group classifications,17 ocular symptoms are present if patients answer affirmatively to at least one of these questions: Have you had dry eye for more than three months?; Do you often have a sensation of sand or gravel in your eyes?; and Is it necessary for you to utilize tear substitutes more than three times daily? In addition, the Sjögren’s Foundation recommends asking: When you have eye dryness, discomfort, or irritation, does this impact your activities (e.g., do you stop or reduce your time doing them)?; and Do you think you have dry eye?30

To identify ocular signs (i.e., objective evidence), practitioners should look for positive results with either a Schirmer’s I test performed without anaesthesia (≤ 5mm in five minutes) or with a rose bengal or other ocular dye score (≥ 4 according to van Bijsterveld’s scoring system).

There are also oral, histopathology, salivary gland, and autoantibody evaluations and scores that should be considered.17

Autologous serum tears have been found to be an effective treatment as well. The mechanism of action that has been proven helpful for dry eye patients lies in their ability to inhibit the release of proinflammatory cytokines and to increase the number of goblet cells and mucin in the conjunctiva.25 Autologous serums inhibit inflammation due to the presence of nutrients such as vitamins, growth factors, and fibronectin that are present in human blood serum.25

In our institution, we utilize compounded autologous serum tears derived from a patient’s own blood serum because we have many pharmacies available to perform this service. For those who have limited access to compounding pharmacies, there are standard kits approved by the U.S. Food and Drug Administration to prepare plasma-related eye drops.6

Systemic treatment of patients who have Sjögren’s focuses on immunomodulating drugs, but research demonstrates that these agents come up short for treatment of ocular manifestations of Sjögren’s.26 Pilocarpine and cevimeline are prescribed for systemic treatment but offer little relief for ocular symptoms.6

Minor surgical treatments that are beneficial to this patient population and that are relatively common dry eye treatments include punctal plugs, punctal cauterization, and, in some cases, a small lateral tarsorrhaphy for more severe disease.6

CONTACT LENS OPTIONS

Prior to the surge of scleral lens popularity and availability, therapeutic soft contact lenses could be utilized in cases of ocular surface disease and dry eye.27 In my experience, patients who have existing Sjögren’s and who have exhausted all other treatment options will find relief from therapeutic soft lenses; these lenses will act as a “bandage” contact lens and will protect the eye from external factors such as wind and blowing air. While many reading this may argue that severe dry eye patients are not good candidates for soft lenses, I am sure that some of you who are reading this article agree with me.

Naturally, scleral lenses offer relief for dry eye patients, as these lenses rest on the less sensitive conjunctival tissue and bathe the cornea with fluid (Figure 1). Fadel et al published a paper on the therapeutic impact of scleral lenses on patients who have Sjögren’s.28 For me, patient selection is critical, and it is imperative to offer a diagnostic fitting with several types and diameters of lenses, as the patients’ level of ocular pain can sometimes prove to be counterproductive in the fitting process.

Figure 1. (A) Cornea of a Sjögren’s patient before scleral lens wear; (B) the same cornea after scleral lens wear; and (C) the scleral lens on the same eye. Photos courtesy of Karen Lee, OD
Figure 1. (A) Cornea of a Sjögren’s patient before scleral lens wear; (B) the same cornea after scleral lens wear; and (C) the scleral lens on the same eye. Photos courtesy of Karen Lee, OD

THE IMPACT OF SJÖGREN’S

Sjögren’s is more than the symptoms that it produces with respect to dry eye and systemic symptoms. It has a dramatic negative impact on patients’ quality of life. As previously mentioned, it can take up to a decade before a confirmed Sjögren’s diagnosis for dry eye symptoms is made. Moreover, eyecare providers often underestimate the importance of Sjögren’s; this can affect patients’ quality of life, as they are not typically sent for systemic workups.15

Sjögren’s has a significant impact on the visual system that affects patients’ ability to work and results in lower productivity. It can be particularly burdensome to those who have desk jobs that necessitate computer use. Research has reported that Sjögren’s-related dry eye is more burdensome compared to the systemic manifestations of this disease.15 In addition, dry eye Sjögren’s patients are particularly vulnerable to a decline in physical and emotional wellbeing and are prone to depression.

Finally, Sjögren’s-related dry eye is more than just symptoms and dryness. This disease can lead to episodes of uveitis, episcleritis/scleritis, optic neuropathy, retinal vasculitis, cicatrizing conjunctivitis, corneal ulcers (Figure 2), or—worse—corneal melts or perforation. These conditions are reported more commonly in primary Sjögren’s.6

Figure 2. A patient who has an active corneal ulcer/defect with inflammation due to severe Sjögren’s and underlying rheumatoid arthritis. Photo courtesy of Christopher Hood, MD, Kellogg Eye Center
Figure 2. A patient who has an active corneal ulcer/defect with inflammation due to severe Sjögren’s and underlying rheumatoid arthritis. Photo courtesy of Christopher Hood, MD, Kellogg Eye Center

Sjögren’s can also have systemic consequences such as peripheral neuropathies, myelitis, meningitis, and visceral organ involvement. Malignancies are also to be expected in patients who have this disease, and they have an increased risk of cancer including non-Hodgkin’s lymphoma and thyroid cancer compared to the general population.29

PRIMARY SJÖGREN’S

In patients who do not have any potentially associated disease, primary Sjögren’s may be identified by the presence of any four of the six criteria categories (ocular symptoms, oral symptoms, ocular signs, histopathology, salivary gland involvement, and serology); this is true as long as histopathology or serology is positive. Alternatively, primary Sjögren’s exists if any three of the first four criteria are present. Finally, there is a classification tree procedure that represents a valid alternative method for classification, although it should be more properly used in clinical-epidemiological survey.

SECONDARY SJÖGREN’S

In patients who have a potentially associated disease (for instance, another well-defined connective tissue disease), the presence of ocular or oral symptoms plus any two from among ocular signs, histopathology, or salivary gland involvement may indicate secondary Sjögren’s.

Exclusion criteria include past head and neck radiation treatment, hepatitis C infection, acquired immunodeficiency disease (AIDS), pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and the use of anticholinergic drugs.

SUMMARY

In conclusion, while we often encounter dry eye patients, we must not forget to have Sjögren’s (particularly primary Sjögren’s) on the forefront of our diagnosis differential. With the knowledge that many of these patients are under-referred for testing and that there is a lag time in diagnosis, it is critical that eyecare providers continue to advocate for their patients. This patient population also serves as an opportunity for us to play a vital role in co-management in the healthcare community. CLS

REFERENCES

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  30. Sjögren’s Foundation. Ocular Management in Sjögren’s Patients. Available at https://www.sjogrens.org/sites/default/files/inline-files/SF_PCG-Ocular.pdf . Accessed June 11, 2021.

Dr. DeLoss is currently serving as an assistant professor at the University of Michigan, Kellogg Eye Center Department of Ophthalmology & Visual Science. The author reports no conflicts of interest.

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