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

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  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

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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