Sjögren Syndrome

Diagnosis

Indications for Testing

  • Dry eyes and mouth

Criteria for Diagnosis

  • International consensus criteria
  • Criteria for Diagnosing Sjögren Syndrome

    American-European Consensus Criteria for Sjögren Syndrome

    1. Ocular symptoms (≥1 present)
      • Symptoms of dry eyes for ≥3 months
      • Foreign body sensation in the eyes
      • Use of artificial tears ≥3 per day
    1. Oral symptoms (≥1 present)
      • Symptoms of dry mouth for at least 3 months
      • Recurrent or persistently swollen salivary glands
      • Need for liquids to swallow dry foods
    1. Ocular signs (≥1 present)
      • Abnormal Schirmer test (without anesthesia; ≤5 mm/5 minutes)
      • Positive vital dye staining of the eye surface
    1. Histopathology
      • Lip biopsy showing focal lymphocytic sialoadenitis (focus score ≥1 per 4 mm2)
    1. Oral signs (at least one present)
      • Unstimulated whole salivary flow (≤1.5 ml/15 minutes)
      • Abnormal parotid sialography
      • Abnormal salivary scintigraphy
    1. Autoantibodies (at least one present)
      • Anti-SSA (Ro) or anti-SSB (La)

    Primary Sjögren syndrome diagnosis – (a) any 4 of the 6 criteria (must include either IV or VI); or (b) any 3 of the 4 objective criteria (III, IV, V, VI)

    Secondary Sjögren syndrome diagnosis in patients with another well-defined major connective tissue disease – the presence of one symptom (I or II) plus 2 of the 3 objective criteria (III, IV and V) is indicative of Sjögren

Laboratory Testing

  • Nonspecific tests – not specific for Sjögren syndrome; abnormal results may be seen in other connective tissue diseases
    • C-reactive protein (CRP)
    • Immunoglobulins – marked hypergammaglobulinemia (IgG>IgA>IgM)
    • Total protein – elevated
    • CBC – usually normal
    • IgM rheumatoid factor may be positive
  • Antibody testing
    • Initial testing – ANA followed by extractable nuclear antibody (ENA) if positive
    • SS antibodies – although not specific for Sjögren syndrome, antibodies are relatively sensitive; may be useful to order panel screening for connective tissue diseases if Sjögren is not high probability 
      • Strong association between SSA antibodies and vasculitis in Sjögren syndrome
      • Several studies identify SSB antibodies as serological marker for SS-sicca complex
        • SSB antibodies detected in approximately 60% of SS-sicca complex patients

Histology

  • Labial gland biopsy – predominate lymphocytic infiltration
    • Should contain >50 lymphocytes with normal appearing acini per 4 mm2 of glandular tissue
    • Sjögren syndrome focus score = number of lymphocyte aggregates x 4 ÷ area of salivary gland parenchyma
      • Focus score ≥1 considered diagnostic

Other Testing

  • Objective ocular involvement – Schirmer test or Rose bengal staining
  • Objective salivary gland involvement – sialography, scintigraphy or sialometry

Differential Diagnosis

Clinical Background

Sjögren syndrome is a slowly progressive autoimmune disease characterized by lymphocytic infiltration of exocrine glands resulting in dry eyes and dry mouth.

Epidemiology

  • Prevalence – 2-4/100,000 in U.S.
    • Second most common autoimmune disease
  • Age – peak is 40-60 years
  • Sex – M<F, 1:9   

Risk Factors

  • Genetic predisposition (multigenetic factors)
    • Family history of Sjögren syndrome

Pathophysiology

  • Mononuclear infiltrate with loss of ductal cells and relative preservation of acinar cells in secretory glands
  • Leads to loss of secretory capacity of the gland
  • Infiltration of cells may also be systemic, causing multi-organ disease

Clinical Presentation

  • Head, eyes, ears, nose and throat (HEENT)
    • Dry eye (xerophthalmia, keratoconjunctivitis sicca)
    • Dry mouth (xerostomia) – increased incidence of dental caries
    • Enlargement of salivary glands
  • Musculoskeletal – arthritis, arthralgias, myalgias
  • Dermatologic – palpable purpura, cryoglobulinemia, Raynaud phenomena, alopecia
  • Endocrine – autoimmune thyroiditis
  • Neurologic – peripheral neuropathy, cranial neuropathies
  • Pulmonary – interstitial pneumonitis, tracheobronchial sicca
  • Complications

Treatment

  • Xerophthalmia – artificial tears, topical cyclosporine
  • Xerostomia – pilocarpine or cevimeline derivatives

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA 0050080
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody

Aids in initial diagnosis of connective tissue disease

Reflex pattern – all ELISA results reported as detected are further tested by IFA using HEp-2 substrate with an IgG-specific conjugate

ANA ELISA screen is designed to detect antibodies against dsDNA, histone, SS-A (Ro), SS-B (La), Smith, snRNP/Sm, Scl-70, Jo-1, centromere, and an extract of lysed HEp-2 cells

Low titer ANA common with advancing age; certain drugs may also cause low titer ANA

ANA ELISA assays have been reported to have lower sensitivities for antibodies associated with nucleolar and specked ANA-IFA patterns

Recommend cutaneous direct immunofluorescence testing of active edge of new lesion (lesional biopsy) if dermatologic manifestations are present
Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflexes to ANA, IgG by IFA and to dsDNA, RNP, Smith, SSA 52, SSA 60, and SSB Antibodies, IgG 0050317
Method: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay

Aids in initial diagnosis of connective tissue disease

Reflex pattern – if ANA IgG is detected by ELISA, then ANA IgG by IFA (using HEp-2 substrate) will be added; if ANA, IgG by IFA is confirmed positive with a titer of 1:40 or greater, then a titer and pattern will be reported; in addition, samples positive for ANA, IgG by IFA will reflex to double-stranded DNA (dsDNA) antibody, IgG by ELISA, RNP (U1) (Ribonucleic Protein) (ENA) antibody, IgG, Smith (ENA) antibody, IgG, SSA 52 and 60 (Ro) (ENA) antibodies, IgG, and SSB (La) (ENA) antibody, IgG. If double-stranded DNA (dsDNA) antibody, IgG by ELISA is detected, then double-stranded DNA (dsDNA) antibody, IgG by IFA (using Crithidia luciliae) will be added

   
Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA 52, SSA 60, and SSB) 0050652
Method: Semi-Quantitative Multiplex Bead Assay

First-line test for connective tissue disease screening

   
C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Preferred test to detect inflammatory processes

   
Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Initial test in the workup of immunoglobulin disorders

In adults and older children with suspected hypogammaglobulinemia, order in conjunction with serum protein electrophoresis and immunofixation

   
Protein, Total, Serum or Plasma 0020029
Method: Quantitative Spectrophotometry

Nonspecific testing

Often elevated in Sjögren syndrome

   
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Nonspecific testing

Evaluate white blood cell count

   
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Sedimentation Rate, Westergren (ESR) 0040325
Method: Visual Identification

Nonspecific test used to detect inflammation associated with infections, cancers, and autoimmune diseases

Often elevated in Sjögren syndrome

Connective Tissue Diseases Profile 0051668
Method: Semi-Quantitative Multiplex Bead Assay

Confirmatory tests for specific connective tissue disease

Panel consists of Smith (ENA), RNP, SSA, SSB, Jo-1, RPP, centromere and Scl-70 antibodies

Systemic Sclerosis Panel 2012057
Method: Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multiplex Bead Assay/ Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Recommended panel for the diagnosis of systemic sclerosis

Components include anti-nuclear antibody (ANA); scleroderma (Scl-70); and RNA polymerase III

SSA 52 and 60 (Ro) (ENA) Antibodies, IgG 2012074
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test or if ANA IFA is negative and  Sjögren's syndrome, SLE, or myositis is strongly suspected

SSB (La) (ENA) Antibody, IgG 0050692
Method: Semi-Quantitative Multiplex Bead Assay

Order as secondary screen based on results of ANA test