Acknowledgment
We wish to acknowledge Chuan Yu Wu for his asssistance in creating Fig. 6.1 .
Introduction
The term keratoconjunctivitis sicca , introduced by the Swedish ophthalmologist Henrik Sjögren, refers to aqueous insufficient dry eye disease (DED). , Sjögren’s syndrome is known for causing sicca, or dryness, of the eyes and mouth. However, Sjögren’s syndrome is a complex autoimmune disease with effects on the entire body including dermatitis, pneumonitis, vasculitis, and an increased risk of developing lymphoproliferative disorders.
Pathophysiology of Sjögren’s Syndrome
Sjögren’s syndrome is a systemic autoimmune/autoinflammatory disorder and there is likely an immunogenetic predisposition that Sjögren’s syndrome patients may share. Indeed, there are shared alleles in some major histocompatibility region of the human leukocyte antigens that have been identified in some Sjögren’s syndrome patient cohorts. Indeed, in the Sjögren’s International Collaborative Clinical Alliance (SICCA) cohort, there were notable differences in genome wide association study analysis particularly between cohort participants with Asian and European ancestry. There is also activation of interferon-based canonical pathways, which can affect innate immune factors in Sjögren’s syndrome patients. There also may be differentially expressed genes in the transcriptome profile of salivary glands, peripheral blood mononuclear cells, and serum in patients with primary Sjögren’s syndrome compared to Sjögren’s syndrome occurring in association with other autoimmune disease. While B-cells have been recognized to have a central role in the pathophysiology of Sjögren’s syndrome, T-cells, particularly follicular helper T-cells, may also play an important role, which seems intuitive considering that salivary and lacrimal glands have germinal center functions. ,
An Underdiagnosed Population in the Eye Clinic
DED is one of the most common diagnoses made in the eye clinic. Because DED is so common, general ophthalmologists are at the front line for treating DED patients. While most ophthalmologists who have been previously surveyed note that DED is not difficult to diagnose, a higher proportion of cornea specialists compared to comprehensive, or general, ophthalmologists agree that there is a need for additional treatment options for moderate to severe DED. , While there is a perception that DED is not difficult to diagnose and despite the prevalence of DED and patient-reported symptoms of dry eye, Sjögren’s syndrome is frequently underdiagnosed, which may start with an underreferral to appropriate specialists. ,
Suspecting, let alone making a diagnosis of, Sjögren’s syndrome may seem daunting to an ophthalmologist considering that the disease may present with protean manifestations and there have been numerous prior diagnostic classifications in use. None of the classification criteria prior to 2016 were accepted by both the American College of Rheumatology and European League Against Rheumatism until the ACR/EULAR diagnostic criteria were developed and validated. The ocular tests used as part of the diagnostic classification criteria for Sjögren’s syndrome can be easily performed by ophthalmologists. Additionally, ophthalmologists can further identify patients with a higher probability of being classified as Sjögren’s syndrome by asking some simple yet pointed questions.
Diagnostic Criteria for Sjögren’s Syndrome
Prior to 2012, there were 11 classification/diagnostic criteria sets for Sjögren’s syndrome, but none had ever been endorsed by the ACR or EULAR. In 2012, new classification criteria developed using the National Institutes of Health–funded SICCA registry were provisionally approved by the ACR and subsequently published. The provisional ACR criteria were based solely on objective tests (symptoms were considered as inclusion criteria for the target population to whom the criteria applied). Ultimately, an international set of classification criteria for Sjögren’s syndrome was developed from a subset of participants from the SICCA registry data and from two other large cohorts (Oklahoma Medical Research Foundation and Paris-Sud Kremlin Bicêtre) and validated using approaches approved by both ACR and EULAR committees ( Table 6.1 ).
| Test/Sign/Item | Score/Weight |
|---|---|
| Labial salivary gland biopsy demonstrating focal lymphocytic sialadenitis with focus score ≥1 foci/4 mm 2 | 3 |
| Anti-SSA/Ro antibody positive | 3 |
| Unstimulated whole salivary flow rate ≤0.1 mL/min | 1 |
| Ocular staining score (OSS) ≥5 in at least one eye | 1 |
| Schirmer I ≤ 5 mm at 5 min in at least one eye | 1 |
Symptoms and Signs of DED in Sjögren’s Syndrome
Symptoms
Patient’s with Sjögren’s syndrome may complain of dry eye, but this is a relatively common complaint in the eye clinic in general and isn’t specific for Sjögren’s syndrome itself. Asking more specific questions, including “Is your mouth dry when eating a meal?” and “Can you eat a cracker without drinking a fluid or liquid?” are most helpful in distinguishing between those who may be classified as Sjögren’s syndrome and those less likely to have Sjögren’s syndrome at that time. Symptoms of dry eye and how they affect functional activities can be assessed by a variety of questionnaires, including the ocular surface disease index and dry eye questionnaire (such as DEQ-5, a five-item questionnaire). , Perceptions of pain can be further evaluated using the ocular pain assessment survey and neuropathic pain symptom inventory questionnaires calibrated for ocular pain. Using questionnaires can be particularly helpful to quantify improvements in comfort and patient-reported activities in response to therapy.
Clinical Signs
Identifying patients with complaints of dry eye should proceed with testing to determine whether the patient has aqueous sufficient DED, aqueous deficient DED, a combination of aqueous sufficient and deficient DED, or neuropathic ocular pain. , Schirmer I (without anesthesia) should be performed first before procedures requiring staining of the cornea and conjunctiva are performed. A Schirmer I of ≤5 mm at 5 min is compatible with an abnormal Schirmer I test according to ACR/EULAR criteria. However, there is significant variability in the Schirmer I test, even in controls. , Nevertheless, given that Schirmer I is highly specific for identifying those with keratoconjunctivitis sicca compared to those without, this test can be complimentary to another test to identify keratoconjunctivitis sicca, the ocular staining score (OSS).
Staining of the cornea with fluorescein and staining of the nasal and temporal bulbar conjunctiva with lissamine green are components of the OSS ( Fig. 6.1 ). The OSS exhibits both a high specificity and sensitivity in identifying those with keratoconjunctivitis sicca compared to those without. Little is known about the progression of keratoconjunctivitis sicca in Sjögren’s syndrome.
SICCA 2-year follow-up showed modest progression of DED. We explored the phenotypic changes in features of Sjögren’s syndrome and in Sjögren’s syndrome status after 2 years. There were 771 participants who returned for 2-year follow-up and had the same examinations that were originally performed at baseline. Eighty-nine percent of follow-up participants still met Sjögren’s syndrome criteria. Additionally, 8% of those who did not meet Sjögren’s syndrome classification at baseline had converted to Sjögren’s syndrome at 2-year follow-up. An important parameter of DED, the OSS, progressed in at least 11% of those returning for follow-up, though this progression was not statistically associated with progression to Sjögren’s syndrome ( Table 6.1 ). However, 2 years is a relatively short follow-up. Nevertheless, those with corneal staining have a higher odds of having a labial salivary gland biopsy with a focus score of ≥1.
Determining if the DED in Sjögren’s syndrome progresses is important because if the disease is stable over time, we can be confident that therapy instituted when DED is detected may be sufficient in a patient’s long-term care. Alternatively, if DED progresses, then monitoring Schirmer I and OSS at each visit may be advisable as well and advancing therapies may be indicated.
Tear osmolarity has been suggested as biomarker to identify and categorize severity of DED. However, tear osmolarity also exhibits significant variability in Sjögren’s syndrome patients. , Additionally, in the SICCA registry cohort, tear osmolarity did not exhibit specificity or sensitivity in distinguishing between those with keratoconjunctivitis sicca and without.
Ancillary Imaging in Sjögren’s Syndrome Keratoconjunctivitis Sicca
Up to 30% of patients with Sjögren’s syndrome have a short fiber neuropathy as evidenced on biopsy of epidermal tissues. Short fiber neuropathy may also be seen elsewhere in the body, including the cornea, and offers the possibility of serving as additional biomarker in Sjögren’s syndrome. Those with DED have quantifiable abnormalities in the structure and density of the corneal subbasal nerve plexus. Longitudinal studies of patients with and without Sjögren’s and how abnormalities in the subbasal nerve plexus are associated with Sjögren’s syndrome are needed.
Ultrasonography of salivary glands can be helpful in identifying inflammation that correlates with histopathological features distinguishing Sjögren’s syndrome from undifferentiated connective tissue diseases. , Sonography has been used to identify the presence or lack of obviously detectable lacrimal glands in Sjögren’s syndrome. Indeed, the lack or “invisibility” of the lacrimal glands on ultrasonography has been suggested to serve as a marker of futility in using immunosuppressive medications seeking to rehabilitate their function.
Treatment of Sjögren’s Syndrome Dry Eye
Topical Therapy
Common and readily available options for managing DED include over-the-counter artificial tears. Their diverse formulations, relative cost-effectiveness, and lack of side effects make them the de facto first-line therapies. Artificial tears aim to supplement and replace one’s own tear production. However, artificial tears are entirely palliative as they fail to address the underlying pathophysiology that drives most types of DED. A systematic review that included 43 randomized controlled trials involving the treatment of DED with artificial tears identified that the quality of evidence was low for the various formulations of artificial tears that were compared to placebo (saline or mannitol vehicle) revealing that additional research is needed to form more robust conclusions about the effectiveness of artificial tears. Very few studies have compared the efficacy of different artificial tears to each other. A wide variety exists with differing levels of osmolarity, viscosity, pH, viscosity enhancing agents, and lipid supplementation. Additionally, preservative-free formulations are recommended when patients require frequent application of artificial tears. All of these factors play a role in patient preference.
Autologous serum tears are frequently used for patients with aqueous deficient DED (such as graft-versus-host disease and Sjögren’s syndrome). However, while there have been some randomized controlled trials evaluating the use of serum tears, the lack of consistency in reporting participant-reported symptoms and objective clinical measures make declaring serum tears as a therapy that is superior to over-the-counter artificial tears challenging. There is a need for “well-planned, large, high-quality RCTs … to examine participants with dry eye of different severities by using standardized questionnaires to measure participant-reported outcomes, as well as objective clinical tests and objective biomarkers to assess the benefit of AS therapy for dry eye.” Nevertheless, some have shown that serum tears have been associated with improvements in morphology in the corneal subbasal nerve plexus, which may be associated with symptomatic improvement in those with corneal neuropathic pain.
Topical antiinflammatory therapy can be an effective strategy in mitigating the inflammation that characterizes DED. Topical corticosteroids can abrogate the inflammatory processes that lead to ocular surface damage. Dexamethasone, prednisolone acetate, prednisolone sodium phosphate, methylprednisolone, fluorometholone, and others are common examples of the wide variety of corticosteroids that can be used. Multiple reviews have shown improvements in the ocular signs of DED (including corneal fluorescein staining, tear breakup time, and Schirmer score) with the use of topical corticosteroids. However, the goal with using topical corticosteroids is to use the lowest dose and lowest frequency needed to manage the signs and symptoms of DED. The side effects of topical corticosteroid use, including elevated intraocular pressure with progression to glaucoma, development of cataract, and increased risk of infectious keratitis require routine monitoring. However, when used judiciously, topical corticosteroids can be an effective therapy in the management of Sjögren’s syndrome DED.
Topical cyclosporine for ocular use was developed as it offers the possibility of immunomodulation as in corticosteroids, but without their significant side effects. Topical cyclosporine is now offered in a variety of concentrations, including 0.05% (Restasis, Allergan. Irvine, CA, USA), 0.09% (Cequa, Sun Pharmaceuticals Industries, Inc. Cranbury, NJ, USA), and 0.1% (Ikervis, Santen Pharmaceuticals Co. Ltd, Osaka, Japan). As a calcineurin-inhibitor, cyclosporine inhibits calcium-dependent interleukin (IL)-2 activation of lymphocytes thereby inhibiting inflammatory responses. On the ocular surface, topical cyclosporine may offer additional properties that make it more advantageous than steroids. Cyclosporine increases the number of mucus-producing conjunctival goblet cells (which can be associated with increased lubrication) through antiapoptotic effects. However, its efficacy (particularly with lower concentrations) is widely debated and multiple clinical trials have resulted in modest overall improvements in dry eye signs and symptoms compared to placebo. , Side effects of topical cyclosporine include discomfort when instilled into the eye and requirement for long-term (up to 6 months) therapy before effects may be appreciated. Tacrolimus is similar drug that blocks lymphocyte activity; however, it has a higher immunosuppressive potential. One randomized controlled trial saw improvements in ocular parameters after 7 days of treatment with topical 0.03% tacrolimus and even more improvement after 90 days.
Lifitegrast is an integrin antagonist that competitively binds to lymphocyte function–associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) thereby inhibiting T-cell migration into tissue, reducing cytokine release, and diminishing further T-cell recruitment into sites of inflammation. A recent review found that lifitegrast had statistically significant improvements in inferior corneal staining fluorescein scores and eye dryness scores. Lifitegrast seemed to exhibit a more expeditious onset of action compared to cyclosporine with symptoms improving in 14 days. Side effects of lifitegrast include eye irritation, dysgeusia, and reduced visual acuity though a clinical trial comparing five RCTs determined that lifitegrast is generally safe to use and well tolerated. There is currently no research that has been done directly comparing lifitegrast to cyclosporine.
Systemic Therapy
Systemic therapy for the treatment of DED in Sjögren’s syndrome is not typically employed. Systemic therapy for Sjögren’s syndrome is most frequently reserved when there is systemic extraglandular involvement. However, there is certainly precedent in managing other ocular inflammatory disorders with systemic immunomodulatory therapy.
Given that autoantibodies, hypergammaglobulinemia, a lymphoproliferative disorders can characterize Sjögren’s syndrome, B-cell targeted therapy is a logical choice. To date, there have been two larger randomized controlled trials using rituximab in Sjögren’s syndrome, but both failed to meet their endpoints. In one trial there was essentially no improvement in tear production. In the other there was a nonsignificant trend toward improving tear production although the clinical significance of the improvement is debatable. Finally, a metaanalysis concluded that rituximab had no clinical benefit in treating primary Sjögren’s syndrome. Despite these findings, other B-cell–directed therapies will likely be explored for Sjögren’s syndrome.
Hydroxychloroquine has been used in the treatment of Sjögren’s DED. Two randomized controlled trials found no difference between hydroxychloroquine and placebo when looking at signs of dry eye, pain, and systemic inflammation. ,
Muscarinic agonists are commonly used as well. Their use focuses on symptomatic treatment with efforts to increase tear production rather than target the autoimmune nature of the illness. One trial compared the use of pilocarpine oral drops with artificial saliva drops, and found pilocarpine to be more effective at enhancing salivary and lacrimal secretion.
Despite the systemic treatments discussed, a major drawback to any systemic therapy is the increased risk of side effects. Rituximab use has been associated with rash development, infusion reactions, and respiratory disorders. Hydroxychloroquine has been known to cause unintentional gastrointestinal symptoms. Muscarinic overstimulation can lead to gastrointestinal disorders, blurry vision, sweating, and bradycardia. Combine the unintentional effects of these therapies with the lack of evidence for clinical benefit and these therapies become less than desired choices for treatment.
Gut Microbiome
The gut microbiome displays a remarkable ability to affect host health. Perhaps modulating the gut microbiome can be used as a possible therapy in Sjögren’s syndrome? Murine models of gut dysbiosis have demonstrated altered immune responses. Pertaining to ocular health and disease, parenteral administration of antibiotics did not affect a murine model of autoimmune uveitis, but oral administration (with subsequent modulation of the gut microbiome) decreased intraocular inflammation. In another similar model, modulation of the gut microbiome seemed to exert its effects by modulating retina-specific T-cells. On the ocular surface, gut dysbiosis exerts profound influences on the conjunctiva’s ability to protect itself from pathogenic microbes. For example, in dysbiotic individuals, mucosal surfaces may be affected with a relative IgA deficiency. In a study of participants with Sjögren’s syndrome DED as well as those DED, but not meeting full criteria for Sjögren’s syndrome, their stool was compared to healthy controls (without DED) using 16S rRNA sequencing, there was clustering of several different bacterial classes that distinguished the DED participants from those without DED. Animal models suggest that fecal transplant may decrease ocular surface inflammation in DED. Modulation of the gut microbiome and its effects in murine models of DED offers exciting opportunities in treating DED in humans. Indeed, such therapy has been described in a variety of gut inflammatory conditions including in ulcerative colitis, checkpoint-inhibitor-induced colitis, and Clostridium difficile . Interest in the potential for modulating systemic disease such as Sjögren’s syndrome has given rise to a currently active clinical trial, the Fecal Microbial Transplant for Sjögren’s Syndrome study ( clinicaltrials.gov accessed February 22, 2021).
Future Considerations in Sjögren’s Syndrome Dry Eye Treatment
If a systemic process is responsible for driving lymphocytic infiltration of lacrimal glands leading to fibrosis and destruction, consideration may be made for systemic immunosuppression. There is an unmet need to prevent exocrine gland destruction perhaps even if there is no significant burden of disease elsewhere in the body. Systemic immunomodulatory therapy is used, for example, in other ocular inflammatory conditions where there is no systemic rheumatologic involvement. However, there is presently an ill-define way assessing lacrimal gland inflammation and fibrosis in a noninvasive way outside of magnetic resonance imaging (MRI), which is not routinely done. MRI of the salivary glands has been performed in Sjögren’s syndrome, but is not a routine procedure at most centers. Ultrasonography of the lacrimal glands could be applied in a similar manner as is done for salivary glands to see how much fibrosis is in the glands themselves and how much can be “saved” In sarcoidosis, lacrimal gland ultrasonography has the ability to detect lacrimal gland inflammation that is not identified on clinical exam alone. Currently, surrogate markers of tear production (Schirmer I and the OSS) are used to implicate lacrimal gland function, but these tests do not demonstrate the proportion of possibly functional gland that is preserved. Knowing this could stratify such patients into a category where systemic immunosuppression may have a greater impact than those with entirely fibrotic glands.
References
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