AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sjögren syndrome (SS) is an autoimmune disorder characterized by salivary and lacrimal gland dysfunction, resulting in keratoconjunctivitis sicca (KCS) and xerostomia (ie, dry mouth) as a result of immune lymphocytes that infiltrate these secretory glands. Nasal and vaginal mucous membranes are also commonly affected. Other systemic manifestations, most commonly rheumatoid arthritis and systemic lupus erythematosus, can be associated. Although several reports of this condition were documented in the late 1800s, Henrik Sjögren, a Swedish ophthalmologist, described the clinical and pathological findings of this syndrome affecting menopausal women in a classic monograph in 1933.

Sjögren syndrome may occur alone (primary) or in conjunction with other autoimmune diseases (secondary). Primary Sjögren syndrome has 2 subsets: patients with systemic immune dysfunction but no defined connective tissue dysfunction, and patients who lack evidence of systemic immune dysfunction or defined connective tissue disease. Secondary Sjögren syndrome occurs in patients who have defined connective tissue disease. The most commonly associated connective tissue diseases are rheumatoid arthritis and systemic lupus erythematosus, but Sjögren syndrome has also been reported in conjunction with progressive systemic sclerosis, Hashimoto thyroiditis, polymyositis, polyarteritis nodosa, and Waldenström macroglobulinemia.

Pathophysiology

The pathogenesis of Sjögren syndrome has not been fully elucidated, but the central role of glandular epithelial cells has been identified as key to understanding the disease. An environmental stimulus (eg, viral infection) is believed to trigger inappropriate apoptosis of glandular epithelial cells, producing autoantigens that trigger lymphocytic infiltration of the secretory glands with subsequent production of autoantibodies and cytokines. Dysfunction of residual glandular epithelial cells may also contribute to deficient tear production. Additionally, it has been demonstrated that there is a reduced rate of apoptosis among immune-stimulated lymphocytes, thus exacerbating the loss of glandular secretory function.

Studies have shown that CD4+ T lymphocytes play a key role in the pathogenesis of Sjögren syndrome. T cells have been demonstrated to induce apoptosis of epithelial cells by 3 mechanisms: Fas-FasL interaction, protease release, and cytokine production. FasL is expressed on activated T lymphocytes. Binding of activated T lymphocytes with ubiquitously expressed Fas antigen leads to apoptosis of susceptible epithelial cells.

Patients with Sjögren syndrome demonstrate an imbalance in cytokine production. In addition, in primary Sjögren syndrome, there is increased expression of IFN in the minor salivary glands. Studies have confirmed that primary Sjögren syndrome has a systemic expression, including extraglandular manifestations in the lungs (interstitial pneumonitis) and the kidneys (interstitial nephritis).

Sjögren syndrome is also characterized by increased B cell activity. An antigen-driven B cell response has been proposed to occur in the salivary glands of patients with Sjögren syndrome. Patients with Sjögren syndrome are at an increased risk of developing B cell non-Hodgkin lymphoma and other lymphoproliferative disorders. In fact, 5% of patients with primary Sjögren syndrome develop B cell non-Hodgkin lymphoma. This increased risk has been attributed to B cell hyperactivity and reduced natural killer cell activity.

Frequency

United States

The incidence has been estimated by the San Diego criteria as 0.5%.

International

The European study group estimates an incidence of 3-5%.

Mortality/Morbidity

Severe dry eyes can cause corneal scarring, ulceration, infection, and even perforation.

Sex

The female-to-male ratio is 9:1.

Age

Although primarily a disease of postmenopausal women, age can range from 22-70 years, with the average age being 43 years. There is often a delay of 5-10 years between disease onset and diagnosis.

Sjögren syndrome has also been reported in children who developed recurrent parotid gland enlargement.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

Physical

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 consists of 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, all criteria below should be met; however, 3 of the 4 criteria are sufficient for a presumptive diagnosis. The most comprehensive diagnostic criteria include the following:  
• • An abnormally low Schirmer test with clinical evidence of 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])
• Three objective findings are useful in determining the ocular component of Sjögren syndrome, as follows:
• •  Absence of nasal-lacrimal reflex tearing
  • Degree of ocular surface alteration by rose bengal or fluorescein staining
  • Presence of autoantibodies in serum
• Accelerated tear break-up time may be noted.
• Nasal stimulation may dramatically increase tearing in patients who do not have Sjögren syndrome.

Causes

• The etiology of Sjögren syndrome is likely multifactorial. A combination of viral, genetic, neural, and environmental factors is thought to be involved. Viruses, such as Epstein-Barr virus (EBV), hepatitis C virus, enteroviruses, and human T-lymphotropic virus (HTLV), have been implicated as triggers in the development of 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. 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.
• The exact etiology for the pathologic changes that occur in Sjögren syndrome has not been determined. EBV may play a role. One study found that parotid saliva samples and salivary gland biopsy specimens from 8 of 20 patients with Sjögren syndrome contained EBV DNA by slot blot hybridization. Another study using polymerase chain reaction (PCR) reported detection of 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. 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.
• Tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine, has been found to be increased in the glands of patients with Sjögren syndrome. Local inhibition of TNF-alpha has been studied in animal models with promising therapeutic results.
• Patients with dry eye associated with Sjögren syndrome have been found to have elevated levels of interleukin 6 (IL-6) and 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) in a study by Yoon et al.¹
• Two types of pathologic changes have been observed in the salivary glands: the benign epithelial lesion occurring primarily in the parotid glands and the focal lymphocytic sialadenitis occurring in other major and minor salivary glands. These benign lymphoepithelial lesions may be associated with or transform into lymphomas.
• Immunogenetics  
• • In 1977, HLA-DR3 and HLA-Dw3 were reported to be associated with Sjögren syndrome. Another study found that primary Sjögren syndrome had a significantly increased frequency of HLA-B8 and HLA-DR3, whereas patients with secondary Sjögren syndrome had an increased frequency of HLA-DR4.
  • HLA-type is correlated strongly with the production of SS-A (Ro) and SS-B (La) autoantibodies. Both Ro and La positivity is seen most commonly with primary Sjögren syndrome, and these patients usually have HLA-B8 haplotype.
• 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 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Superficial punctate keratopathy
Filamentary keratopathy
Neurotrophic keratopathy
Exposure keratopathy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory tests
• • Tear osmolarity
  • Fluorescein clearance test
  • Tear function index
• All of these tests have variable specificity and sensitivity. Controversy surrounds the validity of many of these objective tests.

Imaging Studies

• Parotid flow rate can determine xerostomia. Radionuclide scan and sialography of the parotid glands are other methods to assess salivary gland function.

Other Tests

• 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. Controversy surrounds the validity of many of these objective tests.

Procedures

• Biopsy of accessory salivary glands is preferred over biopsy of lacrimal glands because of 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.

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. 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.

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.³ 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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• After diagnosing Sjögren syndrome, treatment is aimed at providing symptomatic relief by lubricating the ocular surface. Artificial tears and lubricating ointments form the mainstay of treatment. A large variety of preparations is available, but none is as efficacious as the patient's own tears. Topical autologous serum eye drops have demonstrated therapeutic benefit, but preparation is labor-intensive and expensive. Lubricating preparations provide only temporary symptomatic relief.
• To avoid toxicity from preservatives (eg, benzalkonium chloride), preservative-free, small-dose units are recommended. 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. Sustained release lubricant preparations (eg, Lacrisert) were designed to dissolve slowly over a 12-hour period; however, problems of blurry vision and displacement occurred.
• Existing tears of the patient can be conserved by using 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 also significantly improves patient comfort. Humidification 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, prophylactic antibiotic drops must be used concurrently. In some cases, short-term results have been achieved with amniotic membranes, particularly in the presence of active corneal ulceration.
• Agents to increase tear secretion, such as bromhexine and 3-isobutyl 1-methylxanthine (IBMX), have been tried outside of the United States. No decrease in rose bengal staining or subjective improvement in ocular irritation was noted with the use of bromhexine. Agents to stimulate muscarinic receptors (pilocarpine and cevimeline) have been approved by the US Food and Drug Administration (FDA) for oral use.
• Cyclosporin A, a powerful suppressor of T-cell function, has been evaluated for treatment of Sjögren syndrome. In one study, oral cyclosporin A (5 mg/kg/d) versus placebo was used in a double-masked trial for treatment of primary Sjögren syndrome. A subjective improvement of dry mouth symptoms occurred in most patients; however, 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.
• The importance of T cell activation in the development of Sjögren syndrome has enabled use of successful therapeutic modalities based on inhibition of T cell activation. A pilot trial of 1% cyclosporin A ophthalmic ointment showed marked subjective improvement of symptoms when compared to 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 FDA-approved as a treatment of dry eye.
• It was 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 histological parameters in primary Sjögren syndrome. It was therefore concluded that the risks of long-term corticosteroid use outweigh the possible benefits.
• In 1985, Tseng et al reported the use of tretinoin (all trans-retinoic acid) ointment for treating various dry eye conditions, including keratitis sicca associated with Sjögren syndrome. The trial was not randomized. All research subjects reported symptomatic improvement and demonstrated decreased rose bengal staining and reduced squamous metaplasia. These findings, however, were not duplicated in a multicenter, placebo-controlled, double-masked trial. In fact, the double-masked trial failed to find a beneficial effect of tretinoin.
• 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 a novel device designed to promote meibomian sebum release into the tear film in response to thermal energy.⁴
• 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 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.  Systemic immunosuppressive agents may be necessary to improve tear production and to resolve severe keratoconjunctivitis in recalcitrant primary or secondary Sjögren syndrome. 
• 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. Future therapeutic modalities may include local delivery of an antiapoptotic or immunomodulatory transgene to reduce lacrimal gland inflammation.

Consultations

• A consultation with an internist or a rheumatologist may be warranted if a systemic autoimmune process is suspected.
• Patients with Sjögren syndrome have a higher incidence of dental and gynecological problems and should be seen for routine dental and gynecological care.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Artificial tears and lubricating ointments are widely available as nonprescription items. Individual formulations have proprietary pH, retention time, osmolarity, and viscosity characteristics. In general, these therapies are available compounded with preservatives or in a nonpreserved sterile state. For individuals who are sensitive, nonpreserved preparations are frequently selected. 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.

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.
 
Tretinoin was found to be effective in increasing comfort and reducing rose bengal staining in squamous metaplasia in one study. Numerous subsequent studies have failed to confirm any positive benefit of this medication when used independently or in conjunction with surface lubricants.

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 form of therapy is infrequently used because of problems associated with insertion, comfort, blurred vision, and the tendency for displacement.
 
Bromhexine and IBMX are used outside of the United States. Although they are available in Europe, no documentation exists that their use is associated with subjective or objective improvement. The mode of action is to increase lacrimal gland secretion directly. 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. Oral pilocarpine has been approved by the FDA for use in the treatment of Sjögren syndrome.

Topical 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.

Drug Category: Immunosuppressants

Cyclosporin A 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.

Drug Category: Corticosteroids

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients should receive follow-up care as needed.

Deterrence/Prevention

• Wearing spectacles or goggles is beneficial in preventing ocular surface drying secondary to exposure.
• The placement of air conditioning or heating ducts at home and at the workplace should be considered.
• Avoidance of desiccating environments, such as proximity of open fireplaces or smoke-filled rooms, should be considered.
• Systemic medications also can adversely affect the ocular surface. Reduction or elimination of such medications could decrease the drying of the ocular surface.

Complications

• Severe dry eyes can cause corneal scarring, ulceration, infection, and even perforation.

Prognosis

• While the prognosis is good for most patients, eyes with corneal infection, ulceration, or perforation have a much more guarded prognosis.

Patient Education

• Patients should know to seek ophthalmic care if their eyes become red or painful, or if they develop a mucopurulent discharge.
• For excellent patient education resources, visit eMedicine's Arthritis Center. Also, see eMedicine's patient education article Sjögren Syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• In any of these individuals 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.
• 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. The use of a prophylactic antibiotic is the standard of care.
• In the presence of a significantly compromised ocular surface, there is some reluctance to use topical anesthetic and applanation tonometry. While 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.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Feb 19, 2008