Sjogren Syndrome

Sjogren syndrome (SS) is an autoimmune disorder characterized by lymphocytic inflammation and destruction of lacrimal and salivary glands and other exocrine organs. The classic clinical triad consists of dry eyes, dry mouth and parotid gland enlargement but other features are common and can affect all organ systems. The condition is classified as primary when it exists in isolation, and secondary when associated with another disease, commonly rheumatoid arthritis or systemic lupus erythematosus. Primary SS affects females more frequently than males. Although in clinical practice the diagnosis may be made on less stringent grounds, the American College of  Rheumatology (ACR) criteria for diagnosis specify, in patients with a clinical picture suggestive of Sjogren Syndrome.

Symptoms of Sjogren Syndrome

The most common ocular symptoms of Sjogren Syndrome are feeling of dryness, grittiness and burning that characteristically worsen over the course of the day. Stringy discharge, transient blurring of vision, redness and crusting of the lids are also common. Lack of emotional or reflex tearing is unusual. The symptoms of KCS are frequently exacerbated on exposure to conditions associated with increased tear evaporation (e.g. air-conditioning, wind and central heating) or prolonged reading or video display unit use, when blink frequency is reduced.

Signs of Sjogren Syndrome

• Posterior (seborrhoeic) blepharitis with meibomian gland dysfunction is often present.

• Conjunctiva
  • Redness.
  • Staining with fluorescein and rose Bengal
  • Keratinization.
  • Conjunctivochalasis is a common response to, and exacerbating factor for, the chronic irritation of dry eye, such that a self-sustaining cycle is maintained. It also commonly occurs in other ocular surface disease.

• Tear film
  • In the normal eye, as the tear film breaks down the mucin layer becomes contaminated with lipid but is washed away.
  • In the dry eye, the lipid-contaminated mucin accumulates in the tear film as particles and debris that move with each blink.
  • The marginal tear meniscus (strip) is a crude measure of the volume of aqueous in the tear film. In the normal eye the meniscus is 0.2–0.4mm in height, but in dry eye becomes thin or absent.

• Cornea
  • Punctate epithelial erosions that stain well with fluorescein.
  • Filaments consist of strands of mucus and debris such as shed epithelial cells, and are typically attached at one end to the corneal surface; they stain well with rose Bengal but less so with fluorescein.
  • Mucous plaques with similar constituents may occur in severe dry eye. They consist of semi-transparent, white-to-grey, often slightly elevate lesions of varying size.

• Complications can be vision-threatening and include epithelial breakdown, melting, perforation and bacterial keratitis.

Investigation of Sjogren Syndrome

The aim of investigation is to confirm and quantify a clinical diagnosis of dry eye. Unfortunately, although the repeatability of symptoms is good, that of clinical tests is poor, as is the correlation between symptoms and tests. The reliability of tests improves as the severity of dry eye increases. The tests measure the following parameters:

• Stability of the tear film as related to its break-up time (BUT).
• Tear production (Schirmer, fluorescein clearance and tear osmolarity).
• Ocular surface disease (corneal stains and impression cytology).

There is no clinical test to confirm the diagnosis of evaporative dry eye. It is therefore a presumptive diagnosis based on the presence of associated clinical findings. It is suggested the tests are performed in the following order because the Schirmer strip paper can damage the ocular surface and cause staining.

Tear film break up time

The tear film BUT is abnormal in aqueous tear deficiency and meibomian gland disorders. It is measured as follows:

• Fluorescein 2% or an impregnated fluorescein strip moistened with non-preserved saline is instilled into the lower fornix.
• The patient is asked to blink several times.
• The tear film is examined at the slit lamp with a broad beam using the cobalt blue filter. After an interval, black spots or lines appear in the fluorescein-stained film indicating the formation of dry areas.
• The BUT is the interval between the last blink and the appearance of the first randomly distributed dry spot. A BUT of less than 10 seconds is suspicious.
• The development of dry spots always in the same location may indicate a local corneal surface abnormality (e.g. epithelial basement membrane disease) rather than an intrinsic instability of the tear film.

Schirmer test

The Schirmer test is a useful assessment of aqueous tear production. The test involves measuring the amount of wetting of a special (no. 41 Whatman) filter paper, 5 mm wide and 35 mm long. The test can be performed with or without topical anaesthesia. In theory, when performed with an anaesthetic (Schirmer 2) basic secretion is measured and without anaesthetic (Schirmer 1) it measures maximum basic plus reflex secretion. In practice, however, topical anaesthesia cannot abolish all sensory and psychological stimuli for reflex secretion. The test is performed as follows:

• Excess tears are delicately dried. If topical anaesthesia is applied the excess should be removed from the inferior fornix with filter paper.
• The filter paper is folded 5 mm from one end and inserted at the junction of the middle and outer third of the lower lid, taking care not to touch the cornea or lashes.
• The patient is asked to keep the eyes gently closed.
• After 5 minutes the filter paper is removed and the amount of wetting from the fold measured.
• Less than 10 mm of wetting after 5 minutes without anaesthesia or less than 6 mm with anaesthesia is considered abnormal.

Results can be variable and a single Schirmer test should not be used as the sole criterion for diagnosing dry eye, but repeatedly abnormal tests are highly supportive.

Ocular surface staining

• Fluorescein stains corneal and conjunctival epithelium where there is sufficient damage to allow the dye to enter the tissues.
• Rose Bengal is a dye that has an affinity for dead or devitalized epithelial cells that have a lost or altered mucous layer. Corneal filaments and plaques are also shown up more clearly by the dye and the use of a red-free filter may help visualization. A 1% solution of rose Bengal or a moistened impregnated strip can be used. The dye may cause intense stinging that can last for up to a day, particularly in patients with severe KCS; to minimize irritation a very small drop should be used, immediately preceded by a drop of topical anaesthetic, and the excess washed out with saline.
• Lissamine green stains in a similar fashion to rose Bengal but causes less irritation and may be preferred.
• The pattern of staining may aid diagnosis:
  • Interpalpebral staining of the cornea and conjunctiva is common in aqueous tear deficiency.
  • Superior conjunctival stain may indicate superior limbic keratoconjunctivitis.
  • Inferior corneal and conjunctival stain is often present in patients with blepharitis or exposure.

Rare test performed rarely in clinical practice.

• Fluorescein clearance test and the tear function index may be assessed by placing 5 µl of fluorescein on the ocular surface and measuring the residual dye in a Schirmer strip placed on the lower lateral lid margin at set intervals. Delayed clearance is observed in all dry eye states.
• Tear film osmolarity measurement techniques are available; this may be a particularly accurate means of diagnosis.
• Tear constituent measurement. Tear samples can be assayed for the presence of markers known to be elevated (e.g. matrix metalloproteinase-9) or decreased (e.g. lactoferrin) in dry eye.
• Phenol red thread test uses a thread impregnated with a pH-sensitive dye. The end of the thread is placed over the lower lid and the length wetted (the dye changes from yellow to red in tears) is measured after 15 seconds. A value of 6 mm is abnormal. It is comparable to the Schirmer test but takes less time to perform.
• Tear meniscometry is a technique to quantify the height and thus the volume of the lower lid meniscus.
• Impression cytology can determine goblet cell numbers.

Other investigation of Sjogren Syndrome

Treatment

The underlying causative processes of dry eye are generally not reversible and management is therefore structured around the control of symptoms and the prevention of surface damage.
DEWS have produced guidelines based on earlier International Taskforce Guidelines for Dry Eye, in which suggested treatment
options depend on the level of severity of disease graded from 1 to 4. The DEWS guidelines can also be applied in a graded approach, proceeding to the next level if the preceding measures are inadequate.

Level 1

• Education and environmental/dietary modifications
  • Establishment of realistic expectations and emphasis on the importance of compliance.
  • Lifestyle review including the importance of blinking whilst reading, watching television or using a computer screen (which should be orientated below eye level to minimize palpebral aperture size), and the management of contact lens wear.
  • Environmental review, e.g. increasing humidity may be possible for some environments.
  • Instillation aids for eye drops (manufacturer-supplied or makeshift, such as nut-crackers to hold plastic bottles) should be advocated for patients with reduced dexterity (e.g. rheumatoid arthritis).
  • Caution the patient that laser refractive surgery can exacerbate dry eye.

• Systemic medication review to exclude contributory effects and eliminate offending agents. Discontinuation of toxic/preserved topical medication if possible.
• Artificial tear substitutes including gels and ointments some authorities advocate that use of preserved drops should fall within level 1, and categorize non-preserved drops as a level 2 measure. Mucolytic agents may be specifically indicated for some patients.
• Eyelid therapy. Basic measures such as warm compresses and lid hygiene for blepharitis; reparative lid surgery (e.g. entropion, ectropion, excessive lid laxity or scleral show) may be considered as an early measure. Nocturnal lagophthalmos can be addressed by taping the lids closed at bedtime, wearing swimming goggles during sleep, or in extreme cases by lateral tarsorrhaphy.

Level 2

• Non-preserved tear substitutes are categorized as level 2 treatment by some authorities.
• Anti-inflammatory agents such as topical steroids, oral omega fatty acids and other agents such as topical ciclosporin.
• Tetracyclines (for meibomianitis, rosacea).
• Punctal plugs.
• Secretagogues, e.g. pilocarpine, cevilemine, rebamipide.
• Moisture chamber spectacles and spectacle side shields.

Level 3

• Serum eye drops. Autologous or umbilical cord serum.
• Contact lenses.
• Permanent punctal occlusion.

Level 4

• Systemic anti-inflammatory agents.
• Surgery
  • Eyelid surgery, such as tarsorrhaphy.
  • Salivary gland autotransplantation.
  • Mucous membrane or amniotic membrane transplantation for corneal complications.

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