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Sjogeren Syndrome


Pathogenesis: Harrisons'
Sjögren’s syndrome is characterized by both lymphocytic infiltration of the exocrine glands and B lymphocyte hyperreactivity. An oligomonoclonal B cell process, which is characterized by cryoprecipitable monoclonal immunoglobulins (IgMκ or IgAκ) with rheumatoid factor activity, is evident in up to 10% of patients.

Ro/SS-A autoantigen consists of two polypeptides (52 and 60 kDa, respectively) in conjunction with cytoplasmic RNAs, whereas the 48-kDa La/SS-B protein is bound to RNA III polymerase transcripts. 

The major infiltrating cells in the affected exocrine glands are activated T lymphocytes in mild lesions, whereas B cells prevail in severe lesions. Macrophages and dendritic cells are also found. 
The number of macrophages positive for interleukin (IL) 18 has been shown to be associated with parotid gland enlargement and low serum levels of the C4 component of complement, both of which are adverse predictors for lymphoma development.

Ductal and acinar epithelial cells appear to play a significant role in the initiation and perpetuation of autoimmune injury. These cells (1) express costimulatory molecules, and inappropriately the intracellular autoantigens Ro/SS-A and La/SS-B on their membranes, acquiring the capacity to provide signals essential for lymphocytic activation; (2) produce proinflammatory cytokines and lymphocyte attracting chemokines necessary for sustaining the autoimmune lesion and allowing the formation of ectopic germinal centers, a finding predicting lymphoma development; and (3) express functional receptors of innate immunity, particularly Toll-like receptors (TLRs) 3, 7, and 9, molecules which may account for the initiation of the autoimmune reactivity.

Clinical Features: 
  • Glandular Features : Xersotomia, Kerotaconjunctivitis sicca, Parotid gland involvement
  • Extraglandular features -- seen in 1/3rd patients but rare in patients with associated RA : 5 features 
    • Arthritis 
    • Raynaud's
    • Renal Tubular Acidosis 
    • Vasculitis 
    • Lymphoma

Clinical ManifestationPercentRemarks
Arthralgias/Arthritis60Usually non-erosive, leading to Jaccoud’s arthropathy
Raynaud’s phenomenon37In one-third of patients, precedes sicca manifestations
Lung involvement14Small airway disease/lymphocyte interstitial pneumonitis
Kidney involvement9Interstitial kidney disease is usually asymptomatic
Liver involvement6Primary biliary cirrhosis stage I
Immune-Complex mediated
Small vessel vasculitis Purpura, urticarial lesions
Peripheral neuropathy2Polyneuropathy, either sensory or sensorimotor
Glomerulonephritis Membranoproliferative
Lymphoma6Glandular MALTa lymphoma is most common

Diagnosis : Harrisons'

TABLE 354-5Revised International Classification Criteria for Sjögren’s Syndromea,b,c
  1. Ocular symptoms: a positive response to at least one of three validated questions.

    1. Have you had daily, persistent, troublesome dry eyes for >3 months?

    2. Do you have a recurrent sensation of sand or gravel in the eyes?

    3. Do you use tear substitutes more than three times a day?

  2. Oral symptoms: a positive response to at least one of three validated questions.

    1. Have you had a daily feeling of dry mouth for >3 months?

    2. Have you had recurrent or persistently swollen salivary glands as an adult?

    3. Do you frequently drink liquids to aid in swallowing dry foods?

  3. Ocular signs: objective evidence of ocular involvement defined as a positive result to at least one of the following two tests:

    1. Shirmer’s I test, performed without anesthesia (≤5 mm in 5 min)

    2. Rose Bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system)

  4. Histopathology: In minor salivary glands focal lymphocytic sialoadenitis, with a focus score ≥1.

  5. Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result to at least one of the following diagnostic tests:

    1. Unstimulated whole salivary flow (≤1.5 mL in 15 min)

    2. Parotid sialography

    3. Salivary scintigraphy

  6. Antibodies in the serum to Ro/SS-A or La/SS-B antigens, or both.

aExclusion criteria: past head and neck radiation treatment, hepatitis C infection, AIDS, preexisting lymphoma, sarcoidosis, graft-versus-host disease, use of anticholinergic drugs. bPrimary Sjögren’s syndrome: any four of the six items, as long as item IV (histopathology) or VI (serology) is positive; or any three of the four objective-criteria items (III, IV, V, VI). cIn patients with a potentially associated disease (e.g., another well-defined connective tissue disease), the presence of item I or item II plus any two from among items III, IV, and V may be considered indicative of secondary Sjögren’s syndrome.

EULAR SS DAI: is used to assess symptoms
  • First used in Bliss Study

  • Bliss Study (small study): Belimumab
    • 2 Lymphoma
    • 1 Pneumococcal Meningitis 
    • Even though a small study, first study with positive data 
  • HCQ in SS study previously was negative. 
  • Sjögren's syndrome Lancet 2005