Sjogren’s Syndrome

Background

• One of the three most common systemic autoimmune diseases; characterised by dry mucous membranes (dry eyes/mouth)
• Classified as either primary or secondary
  • Primary Sjogren’s is a solitary disease
  • Secondary Sjogren’s is associated with another autoimmune condition
    • Commonly rheumatoid arthritis.
    • Connective tissue diseases e.g. SLE, scleroderma are also common
• Prevalence between 0.4% and 0.8%.  Prevalence rises with age (average age of onset 30-50.  Much more common in females (9:1)
• Can be difficult to diagnose- several classification criteria have been published to aid diagnosis (see below)

Pathophysiology

• The exact cause and pathogenesis of SS is poorly understood, though it is likely to be multifactorial
• It has been proposed that an initial insult triggers a number of immune reactions eventually leading to the symptoms of SS

1. The initial insult
   1. Environmental factors
      1. Viral infection has been proposed but no single virus implicated (EBV, HCV, CMV, HIV, HTLV-1)
      2. The cell damage/death caused by viral infection (or other cause) can cause ER remodelling and interaction with Ro (SS-A) proteins to increase their antigenicity and expression on glandular surfaces/
         1. La (SS-B) can also interact with viruses to increase antigenicity
            1. see http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2362.2010.02342.x/full
2. Innate immune response
   1. Production of cytokines by the injured gland that upregulate chemokines and cell adhesive molecules into the vasculature (endothelial venules) to promote lymphocyte/dendrocyte migration to the gland
3. Humoral immune response
   1. production of antibodies to SS-A antigen by HLA-DR-positive antigen-presenting cells by B lymphocytes under the influence of T-helper lymphocytes
      1. formation of immune complexes containing anti-SS-A that bind to the dendritic cells in the gland by their Toll receptor and Fc-gamma
         1. production of interferons, which further activates the innate immune response, activates metalloproteinases and apoptosis

• This is thought to occur in genetically predisposed individuals e.g. HLA-DR3
• Results in lymphocytic infiltration of exocrine glands

Presentation

• The predominant symptoms of SS are dry eyes (xerophthalmia) and dry mouth (xerostomia) that usually presents in women aged 40-60
  • may present as
    • difficulty eating/swallowing (particularly dry foods), tongue sticking to the roof of mouth
    • difficulty talking
    • dental/periodontal disease
    • altered taste
    • oral candidiasis
    • painful/red eye (gritty)
  • However these are relatively non-specific for SS
    • Age-related change
    • Drugs (antihistamines, anticholinergics, antidepressants (TCAs and SSRIs), diuretics, beta blockers etc)
    • Dehydration
    • Vitamin A deficiency
    • Radiotherapy
    • Rosacea
    • Amyloidosis, Sarcoidosis, Lymphoma
  • This may be hard to diagnose and overlooked in many patients
• Other features of dysfunctional exocrine glands
  • dry cough (trachea/bronchi)
  • vaginal dryness and dyspareunia
  • nasal dryness and nosebleeds
  • dry skin (xerosis)
  • signs of malabsorption (pancreas- can even result in pancreatitis (acute or chronic)
    • NB raised serum amylase in patients with SS is more likely to be caused by parotitis
• Bilateral parotitis (or inflammation of other salivary glands e.g. submandibular)
  • Often recurrent/chronic swollen glands (often described as having no apparent cause)
  • Discomfort is usually mild-moderate (rarely severe)
• Arthralgia/arthritis can be a feature of primary SS
  • Usually asymmetrical and can affect both large and small joints
  • Pain/stiffness is usually milder than Rheumatoid disease
• Fatigue is common
• Extraglandular features
  • Periepithelial infiltration (relatively common)
    • Interstitial nephritis
      • renal stones
      • tubular acidosis
      • osteomalacia
      • nephrogenic diabetes insipidus
      • hypokalaemia
    • bronchiolitis
  • Extraepithelial extraglandular (related to B-cell hyperactivity, hypergammaglobulinaemia and immune complex formation) – all relatively uncommon
    • Purpuric rash
    • Glomerulonephritis
    • Peripheral neuropathy
    • Reynaud’s phenomenon
    • • Polyneuropathy is a rare feature

On examination

• Eyes
  • May be dilatation of conjunctival vessels
  • Look for corneal lesions
  • May be blepharitis
  • Look at tear film (may be reduced/absent)
• Dry mouth
• Enlarged salivary glands
• May be features of other inflammatory diseases

Investigations

• Blood tests
  • FBC is usually normal
    • possible anaemia of chronic disease
    • Abnormal WCC may suggest lymphoma, coexistant SLE or may in fact be a feature of SS
    • ESR/PV may be elevated or normal
  • Rheumatoid factor
    • Often high (higher than patients with RA)
  • Anti-Ro/Anti-La
    • Present in 60-70% of patient with primary SS (not secondary)
    • Usually associated with worse disease pathology/symptoms
    • Rarely ever present in non-SS sicca syndrome
  • Other antibodies e.g. Anti-CCP, ANA, antiphospholipid antibodies etc may also be positive (particularly in secondary disease- but even without other disease)
  • U&Es and LFTs may indicate some extraglandular involvement e.g. raised creatinine (can occur in up to 50%)
• Imaging (not particular diagnostic but may gauge severity of disease- not usually routine)
  • Parotid ultrasound
  • Sialography and Salivary Scintigraphy may show gland dysfunction but is not specific for SS
  • MRI may identify features of chronic salivary gland inflammation
  • CT may identify associated lymphoma (rare)
• Rarely is a biopsy performed, although biopsy/histology are the most definitive test

Diagnostic criteria 

Set up to try and aid diagnosing SS:

• Ocular symptoms (at least one of):
  • Dry eyes >3 months
  • Foreign body sensation in the eyes
  • Use of artificial tears >3x per day
• Oral symptoms (at least one of)
  • Dry mouth >3 months
  • Recurrent or persistently swollen salivary glands
  • Need liquids to swallow dry foods
• Ocular signs (at least one of)
  • Schirmer’s test =<5mm/5 mins (without analgesia)
    • Blotting paper in the lower eyelid
  • Positive vital dye staining (van Bijsterveld >=4)
    • Involves putting a dye onto the eye and examining for surface damage (score severity 0-3; in conjunctiva left, right and over the cornea (max 9))
• Histopathology
  • Lip biopsy showing focal lymphocytic sialoadenitis (focus score >=1 per 4 square mm)
• Oral signs (at least one of)
  • Unstimulated whole salivary flow (=<1.5ml in 15mins)
  • Abnormal parotid sialography
  • Abnormal salivary scintigraphy
• Autoantibodies
  • Either Anti-SSA (Ro) or Anti-SSB (La)

For Primary Sjogren’s- EITHER Any 4 of 6 criteria, one of which must be histopathology or autoantibodies OR Any 3 of the 4 objective criteria (last 4- signs and investigations)

For secondary Sjogren’s- In patients with another well-defined major connective tissue disease, the presence of one symptom plus 2/3 objective criteria is indicative of secondary SS

Management

Management is essentially symptom control

• Eyes
  • Artificial tears
  • If more severe, blockage of the puncta by electrocautery can be used
    • Prior to surgery, puncta blockers may be trialed to check efficacy
  • Pilocarpine may also be used
  • Hydration glasses
• Oral
  • Artificial saliva
  • Pilocarpine
  • Dental hygiene
• Joint pain and myalgia is best managed with hydrochloroquine

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