I. Subjective dry eyeb
II. Objective dry eye (Schirmer’s without anesthesia ≤5 mm at 5 min or vital dye staining of ocular surface ≥4 according to van Bijsterveld’s scoring)
III. Subjective dry mouthc
IV. Objective dry mouth (unstimulated whole salivary flow ≤1.5 ml in 15 min or parotid sialography showing diffuse sialectasias without obstruction of major ducts; salivary scintigraphy showing delayed uptake, reduced concentration and/or delayed excretion of tracer)
V. Positive SSA and/or SSB
VI. Minor labial salivary gland biopsy
While many ophthalmologists commonly use fluorescein staining of the cornea in their ocular surface evaluation, few routinely assess staining of the conjunctiva, with only 5–10% of eye care professionals routinely performing this procedure [9, 10]. It is crucial to include conjunctival staining with lissamine green in the ocular surface evaluation, as this is needed to assess the ocular criteria for SS and can also reveal ocular surface changes that will not be detected through the use of fluorescein staining alone. The current underutilization of conjunctival staining may contribute to the under-referral of dry eye patients for SS workups and delays in diagnosis.
On exam, she has evidence of 2+ meibomian gland dysfunction (MGD) (scale 0–3) with a tear break-up time (TBUT) of 4 s (normal >10 s) in both eyes. Her right eye has 1+ scattered punctate staining (scale 0–3) of her cornea with fluorescein, but no central staining, confluence, or corneal filaments. Her left cornea does not stain with fluorescein. After lissamine green administration, she has 1+ nasal conjunctival staining in her right eye (scale 0–3) and 3+ staining nasally in her left eye ( Fig. 5.1 ). Unanesthetized Schirmer testing measured her tear production to be 5 mm/5 min in the right eye and 6 mm/5 min in the left eye (normal > 10 mm/5 min).
(Case 1) External photograph showing 3+ lissamine green staining of nasal conjunctiva of left eye
What Is Your Assessment? What Is the Ocular Staining Score (OSS) and How Is It Interpreted?
This patient has evidence of evaporative dry eye in addition to some signs of aqueous deficiency. This patient has an ocular staining score (OSS) of 2 in her right eye and 3 in her left eye. The OSS is a scoring system used as part of the American College of Rheumatology (ACR) –Sjögren’s International Clinical Collaborative Alliance (SICCA) criteria for SS. Whitcher and colleagues described the OSS scoring system in detail and proposed a cutoff for abnormal OSS of 3 or more . Briefly, the OSS score is a sum of corneal staining with fluorescein (score of 0–3) and conjunctival staining with lissamine green (score of 0–3 for each area—nasal and temporal). An additional point is given for corneal staining for any of the following: (1) patches of confluent staining, (2) staining in the central cornea or pupillary area, and (3) the presence of one or more filaments. It is important to use the OSS (score 0–12) when evaluating a dry eye patient for possible SS.
In addition, the patient has evidence of aqueous tear deficiency with a low Schirmer score in the right eye and a borderline score in the left eye. Although this patient did not demonstrate any filaments, the presence of filaments should always raise the suspicion for SS.
How Would You Manage the Patient at This Point?
We would recommend immediately stopping all bottled tears and switching to frequent preservative-free artificial tears. It is important to treat both the aqueous deficient and evaporative components of her ocular surface disease. Patients with low or borderline low Schirmer scores (i.e., Schirmer ≤5 mm/5 min) typically will not have any excess tearing after punctal occlusion, and we have a low threshold for punctal occlusion in these patients (typically after controlling ocular surface inflammation). To address her MGD, we would also recommend starting warm compresses twice daily, lid hygiene, oral omega-3 fatty acid supplements, and/or oral doxycycline or azithromycin.
The patient returns for a follow-up visit 4 months later and feels that her symptoms are about the same. Her ocular exam remains unchanged except that her TBUT has increased slightly to 6 s in each eye. However, she is now experiencing dry mouth symptoms and some fatigue.
What Is Your Assessment and What Are Your Next Steps?
At this point, we would refer the patient to a rheumatologist for a workup. She has evidence of both aqueous tear deficiency and evaporative dry eye. In addition, she has extraocular symptoms that are suspicious for possible SS, and she has not had any significant improvement after 4 months of treatment. In general, a referral to a rheumatologist should be considered when a patient has any of the following: (1) signs of severe ocular surface disease, (2) positive OSS (OSS > 3 in either eye) or unanesthetized Schirmer ≤5 mm/5 min in either eye and positive ROS, or (3) positive OSS or unanesthetized Schirmer ≤5 mm/5 min in either eye and is refractory to treatment. The length of time when a patient is considered refractory to treatment varies by each individual, but in general, we would consider someone refractory after 4–6 months of appropriate therapy.
What Are Your Next Management Steps?
We would start topical cyclosporine or lifitegrast twice daily. To treat her MGD, we would consider oral doxycycline or azithromycin (if not started previously) and/or topical erythromycin ointment at bedtime. At this point, one could also consider a short course of topical steroids such as loteprednol drops or tobramycin/dexamethasone ointment with careful monitoring for side effects such as increased intraocular pressure. The patient should then return in about 3–4 months to assess for any improvement (sooner if topical steroids are started).
The patient was evaluated by her rheumatologist and has negative bloodwork for SSA, SSB, rheumatoid factor (RF), and antinuclear antibody (ANA). She then undergoes a labial salivary gland biopsy that comes back positive. The biopsy showed focal lymphocytic sialadenitis with a focus score of 1.7/4 mm 2 , which was above the required diagnostic threshold of ≥1/4 mm 2 .
Can You Have SS with Negative Bloodwork?
Negative bloodwork for the traditional SS antibodies (SSA, SSB, RF, and ANA) does not rule out this diagnosis since about 40% of patients with SS lack immunologic markers in the serum. This “seronegative” subset of SS patients may have a lower rate of extraglandular manifestations .
The Sjo kit (Bausch & Lomb) allows for in-office testing of an expanded set of blood tests, which includes three novel antibodies that were described in a mouse model for SS . In that study, the authors found that these novel antibodies appeared earlier than traditional SS antibodies in their mouse model. However, understanding the significance of these antibodies in humans requires further clinical study.
In a seronegative patient whose signs and symptoms are suggestive of SS, a minor salivary gland biopsy is a reasonable next step in the workup. Other conditions which can lead to both dry eye and dry mouth should also be entertained. These include chronic sialadenitis, sialadenosis, complications of radiation therapy, sarcoidosis, HIV, IgG4-related disease, chronic hepatitis C, and medication side effects.
What Are the Current Classification Criteria for SS?
It is important to work with the patient’s rheumatologist to apply published classification criteria that meet the case definition for SS. In the past decade, two sets of classification criteria have been most commonly used (Tables 5.1 and 5.2): (1) the American European Consensus Group (AECG) criteria  and (2) the American College of Rheumatology (ACR)/Sjögren’s International Clinical Collaborative Alliance (SICCA) criteria . Both criteria sets have strengths and weaknesses but greater than 90% sensitivity and specificity for classification of a patient as having SS [14, 15]. More recently, a new set of classification criteria (ACR/European League Against Rheumatism (EULAR)) has been developed in an attempt to reconcile differences between the AECG and ACR/SICCA criteria . The 2016 ACR-EULAR criteria (Table 5.3) have now been endorsed by both the American College of Rheumatology and the European League Against Rheumatism and will likely be more widely utilized in the future than older criteria sets.
American College of Rheumatology (ACR)/SICCA Sjögren’s syndrome classification criteria : Classification of SS applies to individualsa with signs or symptoms suggestive of SS requires two out of the three objective criteria
Keratoconjunctivitis sicca with ocular staining score (OSS) ≥3b
Positive serum anti-SSA/Ro and/or anti-SSB/La or (positive rheumatoid factor and ANA titer ≥1:320)
Labial salivary gland biopsy exhibiting focal lymphocytic sialadenitis with a focus score of ≥1 focus/4 mm2
American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren’s syndrome 
The classification of primary Sjögren’s syndrome (SS) applies to any individual who meets the inclusion criteriaa, does not have any of the conditions listed as exclusion criteriab, and has a score of ≥4 when the weights from the five criteria items below are summed
Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm2
Ocular staining score ≥5 (or van Bijsterveld’s score ≥4 in at least one eye)
Schirmer test ≤5 mm/5 min without anesthesia in at least one eyec
Unstimulated whole saliva flow rate ≤0.1 mL/min
While all of the above classification criteria were originally developed to define homogeneous populations of patients for research studies including clinical trials, these criteria also provide a framework for diagnostic testing as well. Therefore, in clinical practice, any patient who fulfills any of the three aforementioned criteria sets can be considered to have SS.
What Is the Role of Punctal Occlusion in SS?
Because patients with SS often have low aqueous tear production, punctal occlusion plays an important role in the management of ocular surface disease in these patients. The decision of whether to perform total punctal occlusion (i.e., both the lower puncta and upper puncta) or to initially only occlude the lower puncta should be based on the severity of the aqueous tear deficiency at the time of evaluation. For SS patients with mild or moderate aqueous tear deficiency, punctal occlusion can be performed in a staged fashion with initial occlusion of the lower puncta followed at a later date by occlusion of the upper puncta if needed. In patients with severely diminished aqueous tear production, immediate total punctal occlusion is indicated as occlusion of the lower puncta alone is unlikely to have any meaningful effect on the patient’s signs and symptoms. In these cases, the small amount of aqueous tears being produced is mostly lost to evaporation. If one is considering total punctal occlusion, it is best to first perform a trial with plugs (dissolvable or non-dissolvable) followed by punctal cauterization if there is a positive clinical response and no epiphora. In addition, the degree of aqueous tear deficiency should be reassessed after the initiation of any oral secretagogues for the treatment of dry mouth in order to avoid possible epiphora. Topical steroids are initiated prior to the insertion of punctal plugs in order to decrease the buildup of inflammatory factors that may be present in the tear film.
What Are Other Treatment Options for This Patient?
Other treatment options that could be considered in the future for this patient include:
Autologous serum drops: We typically start with a 20% compounded preparation every 2 h. While we previously had concerns about the serum having an inflammatory effect on the ocular surface, this has not been the case as nearly all patients have a positive response to this treatment.
Oral secretagogues (cevimeline 30 mg PO t.i.d. or pilocarpine 5 mg PO t.i.d. and qhs) are also effective in select SS patients.
Scleral lenses including PROSE (prosthetic replacement of the ocular surface ecosystem) lens are highly effective for SS patients. The patient must be able to learn how to handle the lenses (not a very good choice for elderly patients). Fitting these lenses requires special expertise.
Intense pulsed light (IPL) and Lipiflow® Thermal Pulsation System may be considered, but the effects are generally temporary, and, since MGD is not a primary problem in these patients, we don’t recommend it very often.
We would also work closely with her rheumatologist who might choose to start systemic immunosuppressive therapy. In a patient who is very symptomatic with significant signs of inflammation (injection), a course of oral prednisone (alongside their topical therapy) can help suppress the inflammation more rapidly and give the patient more immediate relief.
A 66-year-old Caucasian woman with a history of SS presents with decreased vision and glare in her right eye greater than her left eye, which has gradually worsened over the past year. She has a moderate cataract in the right eye with 2+ nuclear and 1+ cortical lens changes. She elects to have cataract surgery in the right eye to improve visual acuity and symptoms of glare.
What Are Important Preoperative Considerations When Planning Cataract Surgery for Patients with Sjögren’s Syndrome?
It is important to evaluate a patient’s preoperative dry eye regimen and to assess how well it is working. As with all SS patients, we recommend performing a full ocular surface exam as outlined above. Surgery should be delayed until the ocular surface is optimized as much as possible. Ideally, there should be no or minimal corneal/conjunctival staining, the lid margin and lashes should be clean, and topography and keratometry measurements should remain stable over two visits. Keratometry and A scan measurements should be performed prior to the instillation of any eye drops, particularly topical anesthetic agents.
Visual quality has been shown to be worse in dry eye disease, and outcomes after cataract surgery in patients with SS have been shown to be less favorable as compared to patients with dry eye who do not have connective tissue disease . Thus, the threshold to proceed with surgery in patients with SS should be higher, and the patient should be well informed about possible complications and a potentially difficult postoperative period.
What Role Do In-office Tests Such as MMP-9 Testing and Tear Osmolarity Play in Preoperative Surgical Planning for SS Patients?
Matrix metalloproteinase-9 (MMP-9) is an inflammatory marker that has been found to be elevated in the tears of patients with dry eye. Rapid in-office testing is both sensitive and specific for identifying inflammatory dry eye and ocular surface disease . This has been postulated to help with earlier diagnosis of dry eye and may allow for more targeted perioperative therapeutic management, which is expected to reduce complications from surgery [19, 20]. However, further studies are needed to clarify the role of MMP-9 testing in patients with ocular surface disease.