Dry Eye in Sjogren's Syndrome
The purpose of this article is to describe the ophthalmologic features of Sjögren syndrome. If you wish to learn more about the disease itself, please refer to another expert's consult website.
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. Sjögren syndrome may occur alone (primary) or in association with another autoimmune disease (secondary).
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, nose, throat, trachea, or vagina. Systemic complications may develop, resulting in disease or dysfunction of the heart, lungs, liver, renal system, nervous system, muscles, joints, skin, vasculature, 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). Severe dry eyes can cause corneal scarring, ulceration, infection, and even perforation; thus, although the prognosis is good for most patients with Sjögren syndrome and ophthalmologic features, individuals with complications have a much guarded prognosis.The differential diagnosis includes conditions such as adult blepharitis, dry eye syndrome, and juvenile idiopathic arthritis uveitis, as well keratopathies (superficial punctate, filamentary, neurotrophic, exposure).
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. 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. 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 plays a role in the lacrimal gland pathology of Sjögren syndrome. Human T-cell lymphotrophic virus type-1 (HTLV-1) has also been implicated.
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. 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). 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. 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 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. 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. The SS ATD group also demonstrated decreased meibomian gland expressibility with a deficient lipid layer. Whether due to an altered ocular environment, chronic topical medication use, or both, patients with Sjögren syndrome also demonstrate a disruption of the natural flora with a marked increase in antibiotic-resistant organisms in comparison to controls.
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
- 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 síndrome. 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 does not rule out Sjögren syndrome and should be followed by biopsy when clinical suspicion is high.
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 or 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 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 mm 2 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.
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. 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.
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. Fluid-ventilated, gas permeable scleral lenses have been successful in treating severe ocular surface diseases including Sjögren syndrome. 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 5, 10, or 15 mL dispensers or in 1/8 ounce ointment form.
Tear secretion preservation Preservation of existing tear film can be achieved through punctal occlusion to decrease tear drainage. Additionally, a small lateral tarsorrhaphy can decrease the ocular surface area 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 results in the treatment of dry eye have been achieved with amniotic membranes, particularly in the presence of active corneal ulceration.
Tear Production/Secretion Augmentation 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. This may account for subjective reports of reduced ocular discomfort in Sjögren syndrome after 1-2 months of oral pilocarpine treatment.
Immunomodulators Systemic immunosuppressive agents may be necessary to improve tear production and to resolve severe keratoconjunctivitis in recalcitrant primary or secondary Sjögren syndrome. 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. Further studies of TNF-alpha antibodies are therefore needed to determine therapeutic effect.
Cyclosporin A Cyclosporin A, a powerful suppressor of T-cell function, has been evaluated for treatment of Sjögren syndrome. Although this agent has been used orally to suppress T-cell function in patients who have had organ transplants, in Sjögren syndrome, its use is experimental and reports have not been encouraging. Cyclosporin A 1% or 2% in liquid or ointment form has been used topically following the initial report that its use increased lacrimal gland function in dogs. 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. 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.
Tear Replacement 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. Topical autologous serum eye drops have demonstrated therapeutic benefit, but preparation is labor-intensive and expensive. Lubricating preparations provide only temporary symptomatic relief. 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. Most practitioners believe that the use of liquid tear substitutes with preservatives 4-6 times a day is reasonable, but, at higher usage levels, nonpreservative forms may 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 rods can be placed in the inferior fornix and are expected to 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.
Autologous Serum Eyedrops Takashi et al found that autologous serum eyedrops were effective in the treatment of severe dry eye disease, as evidenced by improvement of tear stability and ocular surface vital staining scores. Mean BUT and fluorescein and rose bengal staining scores, as well as subjective symptom scores, showed significant improvement in the patients assigned to autologous serum eyedrops compared with subjects assigned to preservative-free artificial tears after 2 weeks of treatment. Thirty-seven eyes of twenty severe dry eye patients without punctal occlusion were enrolled in this study. After 2 weeks of washout, they were randomly assigned to two groups. Group A patients used only preservative-free artificial tears, and group S patients used only autologous serum eyedrops. They evaluated the results of Schirmer test, fluorescein and rose bengal staining scores, tear film breakup time (BUT), and subjective symptom scores before and 2 weeks after treatment.
Filament mechanical removal Filamentary keratitis is a condition in which strands (“filaments”) composed of degenerated epithelial cells and mucus develop on and adhere to the corneal surface causing pain and foreign body sensation. Since filamentary keratopathy is very symptomatic (mild to severe foreign body sensation that is exacerbated by blinking and is associated with photophobia, blepharospasm, and epiphora, red eye), it is worthwhile to describe the management of both filaments and adherent mucus to the cornea. First line treatment includes topical therapy with lubricant drops and ointment. Low water-content bandage contact lenses may be helpful temporarily in cases that do not respond to lubrication alone. The bandage contact lens should be used in combination with artificial tears and prophylactic topical antibiotic. Single filaments can be removed by use of fine forceps after topical anesthesia of the eye. Care should be taken to avoid disrupting the epithelium at the base of the filament if possible. Manual removal of the filaments may help in alleviating symptoms temporarily but is only a temporizing measure and is not successful without concurrent medical treatment. If numerous filaments are present or there is extensive mucus adherent to the cornea, a more reasonable approach is the use of topical mucolytic drugs. Acetylcysteine 10% instilled 3 times per day for 2 or 3 weeks usually removes both filaments and mucus.
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 air conditioning or heating ducts at home and at the workplace should also be considered. Systemic medications 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.
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