Ophthalmologic Manifestations of Sjogren Syndrome

Sjögren syndrome is a chronic inflammatory disorder characterized by exocrine gland dysfunction and a variable systemic course. Lymphocytic infiltration of the lacrimal and salivary glands results in the classic sicca complex characterized by dry eyes (keratitis sicca or keratoconjunctivitis sicca [KCS]) and dry mouth (xerostomia).

Exocrine dysfunction at other sites may result in dryness symptoms involving the skin or the mucus membranes of the nose, throat, trachea, or vagina. Systemic complications may develop, resulting in disease or dysfunction of the heart, ^[1] lungs, ^[2] liver, renal system, ^[3] nervous system, ^[4] muscles, joints, skin, vasculature, ^[5] and blood. An increased incidence of lymphoma is well documented, and a subset of patients with certain clinical variables demonstrates increased mortality (purpura, mixed monoclonal cryoglobulinemia, and low C4 levels).

This article will focus on the ophthalmologic manifestations of Sjögren syndrome. Severe dry eyes can cause corneal ulceration, scarring, infection, and even perforation. Although the prognosis is good in most patients with Sjögren syndrome and ophthalmologic features, individuals with corneal complications have a more guarded prognosis.

The differential diagnosis includes conditions such as adult blepharitis, dry eye syndrome (KCS), and juvenile idiopathic arthritis/uveitis, as well other keratopathies (eg, superficial punctate, filamentary, Thygeson, neurotrophic, exposure).

Historical information

The first clinical description of Sjögren syndrome was by Mikulicz, who described a 42-year-old with bilateral parotid and lacrimal gland enlargement in 1892. In 1933, the Danish ophthalmologist Sjögren compiled a clinical and histopathologic description of a series of patients with the "sicca complex" of dry eyes and mouth. ^[6] Sjögren syndrome may occur alone (primary) or in association with another autoimmune disease (secondary).

For patient education information, see Sjögren's Syndrome and Corneal Ulcer.

See also Sjögren Syndrome and Pediatric Sjögren Syndrome.

Developments in the fields of immunology and molecular biology have contributed significantly to the understanding of the pathogenesis of Sjögren syndrome. One report in 1985 showed human leukocyte antigen DR (HLA-DR) expression in epithelial cells of salivary gland biopsy specimens taken from patients with Sjögren syndrome. ^[7] The predominant lymphocytic infiltrate consisted of helper T cells. Other studies found that lymphoproliferation in the lacrimal glands consisted predominantly of B and CD4 lymphocytes along with a small percentage of CD8 lymphocytes. Studies using polymerase chain reaction (PCR) reported detection of Epstein Barr virus (EBV) genomic sequences in peripheral blood mononuclear cells, lacrimal glands, and tears of patients with primary Sjögren syndrome. ^{[8, 9]}

EBV genomes can be detected in 35% of normal lacrimal glands. EBV genotype analysis by PCR revealed that only type I EBV genomes could be detected in 35% of normal lacrimal glands. EBV genotype analysis by PCR revealed that only type II EBV nuclear antigens (EBNA-2-deleted) gene sequences were amplified from normal lacrimal glands. In contrast, type I EBV genomes (but not EBNA-2-deleted EBV sequences) were amplified from lacrimal gland biopsy specimens obtained from patients with Sjögren syndrome. All of this information suggests that persistent EBV infection may play a role in the lacrimal gland pathology of Sjögren syndrome. Human T-cell lymphotrophic virus type-1 (HTLV-1) has also been implicated. ^[10] The genomic search for critical genes is difficult as a result of the multigenic pattern of inheritance and the strong role of undefined environmental factors.

Patients with dry eye associated with Sjögren syndrome have been found to have elevated levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF)–alpha in their tears. ^[11] The IL-6 level is associated with disease severity and was found to correlate with tear film and ocular surface parameters (eg, tear film break-up time, Schirmer test, tear clearance, goblet cell density, keratoepithelioplasty score). ^[11] Recently, Zhu et al found that co-stimulatory molecules Ox40 and Ox40L on peripheral blood mononuclear cells is higher in Sjögren patients than in normal controls. The levels correlated with clinical outcomes and therapeutic responses. ^[12]

Even in patients with Sjögren syndrome with marked sicca, biopsy specimens have revealed that 50% of glandular cells are still present. These results emphasize the importance of immune factors, such as cytokines, matrix metalloproteases, and autoantibodies, in decreasing neurosecretory circuits and inducing glandular dysfunction. An antibody against muscarinic M3 receptor has been implicated leading to the development of therapeutic orally administered agonists of the M3 receptor.

The keratoconjunctivitis in Sjögren syndrome is classically described as an aqueous tear deficiency. However, this assumption has been challenged in more recent years; some studies suggest that pathologic changes induce global tear dysfunction, including alterations in meibomian gland function. ^[13] An analysis of patients with Sjögren syndrome with aqueous tear deficiency (SS ATD) compared with non–SS ATD patients demonstrated increased evaporation in the SS ATD group relative to the non–SS ATD group. ^[13] The SS ATD group also demonstrated decreased meibomian gland expressibility with a deficient lipid layer. ^[13]

Whether due to an altered ocular environment, chronic topical medication use, or both, patients with Sjögren syndrome also demonstrate a disruption of the natural tear flora with a marked increase in antibiotic-resistant organisms in comparison to controls. ^[14]

Ocular signs and symptoms of Sjögren syndrome are similar to those seen in dry eye states. Subjective complaints of ocular irritation may vary and include the following:

• Burning

• Stinging

• Itching

• Foreign body sensation

• Lid irritation and swelling

• Photophobia

• Ocular fatigue

• Mucoid discharge

Dry eyes with or without Sjögren syndrome

Two important clues that the patient may have dry eyes include diurnal fluctuation and exacerbation of symptoms during specific activities or environmental conditions. It is common for symptoms to become worse at night or upon awakening, because tear production decreases during sleep. Air conditioning, smoky or windy conditions, and airplane travel may worsen the symptoms by creating excessive drying of the deficient tear film. Activities, such as reading, working at the computer, or watching television, may make the patient more symptomatic, as the blink rate decreases with prolonged visual effort.

Sjögren syndrome triad

Sjögren syndrome typically presents with a triad of dry eyes, dry mouth, and an autoimmune disease. At least 2 of the 3 clinical components need to be present to qualify for diagnosis. For a definitive diagnosis of Sjögren syndrome, there must be clinical evidence of KCS, objective evidence of decreased salivary gland flow, biopsy-proven lymphocytic infiltration of the labial salivary glands, and the presence of a systemic autoimmune process as manifested by the presence of serum autoantibodies. These criteria are further described in the Biopsy and Histologic Features section.Three objective findings are useful in determining the ocular component of Sjögren syndrome, as follows:

• Absence of nasal-lacrimal reflex tearing
• Ocular surface alteration by rose bengal or fluorescein staining
• Presence of autoantibodies in serum

Accelerated tear break-up time may be noted. Note that nasal stimulation may dramatically increase tearing in patients who do not have Sjögren syndrome.

In the presence of a significantly compromised ocular surface, there is some reluctance to use topical anesthetic and applanation tonometry. Although the intraocular pressure recording may not be necessary at each particular visit, it should clearly be performed and its results indicated on the chart at periodic intervals. Additionally with the anterior segment ocular surface disorder, routine follow-up care of the posterior segment also may be compromised. Care should be taken to perform either dilated fundus examinations or, at the very least, fundus examinations without dilatation at intervals that are appropriate for the patient's age and general status.

Laboratory tests to evaluate ophthalmologic manifestations of Sjögren syndrome include tear osmolarity, fluorescein clearance test, and tear function index. The following clinical tests may be useful to establish an aqueous tear deficiency:

• Reduced tear break-up time

• Schirmer test

• Rose bengal staining

• Lissamine green B staining

• Phenol red thread test

All of these tests have variable specificity and sensitivity; however, controversy surrounds the validity of many of these objective tests. One evaluation of the Schirmer test demonstrated a sensitivity of only 42% and a sensitivity of 76% for Sjögren syndrome. ^[15]

Serologic examination can include antinuclear antibody (ANA), rheumatoid factor (RF), or Sjögren syndrome specific antibodies (ie, anti-Ro [SS-A], anti-La [SS-B]). However, a significant number of patients with Sjögren syndrome will have typical sicca symptoms and pathologic findings but normal serology. Negative serology results do not rule out Sjögren syndrome and should be followed by biopsy when clinical suspicion is high. ^[16]

Other specific systemic markers are often ordered by the rheumatologist during evaluation.

A significant proportion of patients with sicca symptoms due to Sjögren syndrome will have negative serology; therefore, biopsy should be considered in seronegative patients when clinical suspicion is high. ^[16]

For a definitive diagnosis of Sjögren syndrome, all the following criteria should be met; however, 3 of the 4 criteria are sufficient for a presumptive diagnosis:

• An abnormally low Schirmer test result, together with clinical evidence of keratitis sicca (keratoconjunctivitis sicca [KCS]) defined by the presence of rose bengal or fluorescein staining

• Objective evidence of decreased salivary gland flow

• Evidence of lymphocytic infiltration of the labial salivary glands, proven by a biopsy specimen containing at least 4 glandular lobules with an average of at least 2 foci of 50 or more lymphocytes/4 mm² of tissue

• Evidence of a systemic autoimmune process as manifested by the presence of serum autoantibodies, including antinuclear antibody (ANA), rheumatoid factor (RF), or Sjögren syndrome specific antibodies (ie, anti-Ro [SS-A], anti-La [SS-B])

Biopsy of accessory salivary glands is preferred over biopsy of lacrimal glands because of their easy accessibility and less potential for complications. Under local infiltration with 2% lidocaine with epinephrine, 5 or 6 lobules of accessory salivary glands are removed and fixed in formalin. Impression cytology can also be used for diagnosis.

The Sjögren's International Collaborative Clinical Alliance assembled a large cohort of patients to aid in the establishment of standardized classification and diagnostic criteria for Sjögren syndrome. In an early report, a subgroup of patients with rapidly clinical progression was identified based on detectable changes in serial labial salivary gland biopsies. ^[17]

Histologic findings

Impression cytology of buccal mucosa may be helpful in establishing a diagnosis. In one study, this technique showed a 97% agreement with labial salivary gland biopsy. ^[18] Conjunctival impression cytology in early onset of Sjögren syndrome may show an increased number of goblet cells. In severe and long-standing cases, the conjunctiva shows loss of goblet cells and squamous metaplasia. Lymphocytic infiltration of the accessory lacrimal glands may also be identified on biopsy. In addition, histopathology of conjunctival specimens may show evidence of squamous metaplasia and keratinization of the conjunctival epithelium.

Normal conjunctival epithelial cells contribute to tear film stability through secretion of tear mucins, promotion of tear adherence to the glycocalyx, and provision of increased surface area for tear adherence via the microvilli. A transmission electron microscopy study by Koufakis et al evaluating conjunctival surface changes in patients with Sjögren syndrome demonstrated significant alterations of the apical conjunctival epithelium. ^[19] The study found a decreased number of microvilli per epithelial length, decreased microvillus height and height-width ratio, and a decreased number of secretory vesicles per epithelial cell in patients with Sjögren syndrome as compared with controls. ^[19] Furthermore, the ocular surface glycocalyx (OSG) in patients with Sjögren syndrome was either not detectable (in most cases) or severely altered in configuration compared with the OSG of healthy controls.

An in vivo confocal study by Villani et al demonstrated morphologic alterations in corneal thickness, cells, and nerves in patients with dry eye associated with Sjögren syndrome. ^[20] A decrease in the central corneal thickness was observed and was hypothesized to be due to inflammatory processes. In addition, a reduced number of subbasal plexus fibers was noted and may explain the phenomenon of decreased corneal sensitivity observed in patients with Sjögren syndrome. ^[20]

After diagnosing Sjögren syndrome, treatment is aimed at maintaining the integrity of the tear film through preservation, augmentation, and/or replacement of the deficient tear secretion.

Oral omega-6 essential fatty acids have been demonstrated to improve signs of ocular surface dryness and associated symptoms of ocular discomfort in Sjögren syndrome. ^[21]

Fluid-ventilated, gas permeable scleral lenses have been successful in treating severe ocular surface diseases including Sjögren syndrome. ^[22] BostonSight's PROSE (prosthetic replacement of the ocular surface ecosystem) are custom-made devices to support the ocular surface.

For many years, systemic corticosteroids have been used in a variety of inflammatory conditions. Due to limited efficacy and high incidence of complications, they are not widely used in Sjögren syndrome. Topical corticosteroids are widely available in a variety of dosages, often combined with antibiotics and preservatives, and may be useful for short-term treatment of ocular surface inflammatory conditions. They are usually available in 2.5-, 5-, 10-, or 15-mL dispensers or in 0.125-ounce ointment form.

Precautions

Note that patients with Sjögren syndrome who have well-controlled keratoconjunctivitis can develop exacerbations refractory to treatment following laser-assisted in situ keratomileusis (LASIK) surgery. ^[23] In addition, topical nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution in patients with Sjögren syndrome due to demonstrated reduction of corneal sensitivity in normal and dry eye patients and risk of corneal melting. ^[8]

In any individuals with Sjögren syndrome and ophthalmologic manifestations who are treated with immunosuppression, it is extremely important that the ophthalmologist be aware of the patient's status regarding follow-up laboratory studies. It is also important for these patients to have contact with their internist and/or immunologist. This should be noted clearly on the medical record at each patient visit.

Other considerations

One study found that significant subjective improvement occurred with anti-inflammatory treatment. However, this occurred despite no evidence for increased tear secretion, suggesting their effects may be independent of improved tear film dynamics. ^[24]

It was previously hypothesized that systemic use of corticosteroids or androgen hormones may suppress the immune-mediated component of lacrimal gland dysfunction present in Sjögren syndrome and improve lacrimal gland secretory function. However, a 6-month trial with oral prednisone, in which patients received 30 mg on alternate days, demonstrated no improvement in functional or histologic parameters in primary Sjögren syndrome. It was therefore concluded that the risks of long-term corticosteroid use outweigh the possible benefits.

The Wilmer Eye Institute at the Johns Hopkins University School of Medicine looked at interventional studies of treatments for Sjögren syndrome–associated dry eye from English-language articles published from 1975-2010. Their findings showed a lack of rigorous clinical trials to support therapy recommendations, with the efficacy of oral secretagogues greater in the treatment of oral dryness than ocular dryness. Although commonly prescribed to patients with Sjögren syndrome to lessen fatigue and arthralgias, oral hydroxychloroquine lacks strong evidence in its effectiveness for dry eye. ^[25]

Tretinoin (all trans -retinoic acid) was found to be effective in increasing comfort and reducing rose bengal staining in squamous metaplasia in one study. ^[26] In that nonrandomized trial, tretinoin ointment was used for treating various dry eye conditions, including keratitis sicca associated with Sjögren syndrome. Numerous subsequent studies have failed to confirm any positive benefit of this medication when used independently or in conjunction with surface lubricants.

Although many animal models have been studied, no clinical gene transfer studies have been performed on patients with Sjögren syndrome. Recombinant serotype 2 adeno-associated virus (rAAV2) vectors have shown promise as vectors for gene therapy in mouse models of Sjögren syndrome. ^[27] Future therapeutic modalities may include local delivery of an antiapoptotic or immunomodulatory transgene to reduce lacrimal gland inflammation.

Preservation of existing tear film can be achieved through punctal occlusion to decrease the rate of tear drainage. Additionally, a small lateral tarsorrhaphy can decrease the ocular surface area exposed to the environment and provide significant relief. Humidification of the environment decreases evaporative loss and can be achieved by wearing swimmer's goggles or taping a plastic shield or wrap over the eyelids.

Hydrophilic bandage lenses have been used for decades in the treatment of dry eye and still have a role; however, if nonpreserved medications and/or hydrophilic bandage lenses are used, one must always be aware of the significant potential for secondary infection. These risks should be explained to the patient prior to initiating these forms of therapy. Prophylactic antibiotic drops must be used concurrently (standard of care).

In some cases, short-term improved results in the treatment of dry eye have been achieved with amniotic membranes, particularly in the presence of active corneal ulceration.

Augmentation of tear production/secretion has been attempted with medications such as bromhexine and 3-isobutyl 1-methylxanthine (IBMX). These have been tried outside of the United States, although neither rose bengal staining nor ocular discomfort improved with the use of bromhexine. The mode of action is to increase lacrimal gland secretion directly.

Agents to stimulate muscarinic receptors (pilocarpine and cevimeline) have been approved by the US Food and Drug Administration (FDA) for oral use. Oral pilocarpine has been demonstrated to increase the number of goblet cells and to improve the overall health of the conjunctival epithelium in Sjögren syndrome as evidenced by impression cytology. ^[28] This may account for subjective reports of reduced ocular discomfort in Sjögren syndrome after 1-2 months of oral pilocarpine treatment.

Immunomodulators

It is theorized that systemic immunosuppressive agents may be necessary to improve tear production and to resolve severe keratoconjunctivitis in recalcitrant primary or secondary Sjögren syndrome. ^[29]

For the systemic component as well as for the treatment of local immune effects, modification of the immune response with methotrexate, antimalarials, cyclophosphamide, leflunomide, or tumor necrosis factor (TNF) antibody has been advocated. A pilot study and 1-year follow-up open trial with infliximab, a monoclonal antibody to TNF-alpha, demonstrated improvement in all tested objective and subjective measures of Sjögren syndrome disease activity. However, a follow-up randomized, double-blind, placebo-controlled trial with infliximab and etanercept, a human TNF-alpha-p75 receptor, demonstrated no benefit. More successful results have been obtained with B-cell–targeted therapies, which demonstrated efficacy in controlling glandular and systemic symptoms of Sjögren syndrome. Other therapies targeting T cells, various cytokines and chemokines, and Toll-like receptors (TLRs) are still in various stages of investigation. ^[30]

Cyclosporin A

Cyclosporin has been shown to block T-cell proliferation, an inflammatory response contributing to dry eye disease.. Although this agent has been used orally to suppress T-cell function in patients who have had organ transplants, its systemic use in Sjögren syndrome has not been encouraging. In one study, although oral cyclosporin A (5 mg/kg/d) led to subjective improvement of dry mouth symptoms compared with placebo in most patients with primary Sjögren syndrome, only 20% of patients noted improvement in ocular irritation. No difference in aqueous tear production evaluated by Schirmer testing was reported between the 2 groups.

Topical cyclosporin A 1% or 2% solution or ointment was initially reported to increase lacrimal gland function in dogs. Topical 0.05% cyclosporine (Restasis) was approved by the US Food and Drug Administration (FDA) for the treatment of keratoconjunctivitis sicca in 2003. It is widely and successfully used to promote tear production in patients with KCS with or without Sjögren syndrome. ^{[31, 32]}

Numerous topical preparations of cyclosporin or its analogs are now available.

More recently, an integrin lymphocyte function–associated antigen-1 (LFA-1) antagonist, 5% lifitegrast ophthalmic solution (Xiidra) was approved by the FDA for the treatment of dry eye. ^[33]

A large number of other topical prescription medications are currently in clinical trials. Another approach currently in trials utilizes a nasal spray to deliver selective nicotinic acetylcholine receptor (nAChR) agonists that harness the trigeminal parasympathetic pathway to improve tear film production.

A pilot trial of 1% cyclosporin A ophthalmic ointment showed marked subjective improvement of symptoms when compared with placebo. Patients treated with topical cyclosporin A had less ocular surface rose bengal staining than control subjects; however, there was no difference in Schirmer test values or tear break-up times between the 2 groups.

Topical 2% cyclosporin A solution has been reported to successfully treat paracentral corneal ulcers in patients with rheumatoid arthritis and secondary Sjögren syndrome. Cyclosporin A functions as a secretagogue for the lacrimal gland and also inhibits T-cell activation, thereby limiting lymphocyte-induced apoptosis of acinar cells. Apoptosis-related markers were found to decrease in conjunctival epithelium after 6 months of treatment with topical cyclosporin A. Topical cyclosporin A is approved by the US Food and Drug Administration (FDA) as a treatment of dry eye.

Meibomian therapy with Lipiflow

Lipiflow, a novel device approved by the FDA in 2011, targets the treatment of dry eyes caused by meibomian gland dysfunction. It acts by applying a combination of heat and pressure to the inner side of the eyelid to remove gland obstructions and stagnant gland secretions. Although the meibomian gland dysfunction is not the etiology of Sjögren syndrome, a publication by Spiteri et al demonstrated significant improvement in ocular comfort in patients with dry eye symptoms with and without Sjögren syndrome after using this device. ^[34]

Symptomatic relief through lubrication of the ocular surface can be achieved through artificial tears and lubricating ointments. A large variety of preparations is available as nonprescription items, but none is as efficacious as the patient's own tears. Individual formulations have proprietary pH, retention time, osmolarity, and viscosity characteristics. Lubricating preparations provide only temporary symptomatic relief.

Topical autologous serum eye drops have demonstrated therapeutic benefit, but preparation is labor-intensive and expensive.

In general, these therapies are available compounded with preservatives or in a nonpreserved sterile state. To avoid toxicity from preservatives (eg, benzalkonium chloride) or for individuals who are sensitive, preservative-free, small-dose units are recommended. Nonpreserved lubricating solutions provide less ocular surface toxicity over the long term.

In addition, lubricating ointments play an important role in moistening the ocular surface during sleep when tear production is decreased. Using lubricating ointment during the day can significantly blur vision.

Lacriserts in the form of small soluble cellulose rods can be placed in the inferior fornix and dissolve and biodegrade over a 12-hour period. This sustained-release lubricant preparation is infrequently used as therapy because of problems associated with insertion, comfort, blurred vision, and the tendency for displacement.

Recently, local radiotherapy to the lacrimal gland has been attempted with success, with full restoration of vision and regression of infiltration. ^[35]

Wearing spectacles or goggles is beneficial in preventing ocular surface drying secondary to exposure. In addition, avoidance of desiccating environments, such as proximity of open fireplaces or smoke-filled rooms, should be considered. The placement of humidification systems, either standalone or integrated within existing heating or cooling systems at home and at the workplace, should also be considered.

Systemic medications, most commonly antihistamines, antihypertensives, and antidepressants, can adversely affect the ocular surface. Reduction or elimination of such medications could decrease the drying of the ocular surface.

Patients should know to seek ophthalmic care if their eyes become red or painful, or if they develop a mucopurulent discharge.