Sjögren Syndrome

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

Ocular symptoms (≥1present)
- Symptoms of dry eyes for ≥3 months
- Foreign body sensation in the eyes
- Use of artificial tears ≥3 per day

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

Ocular signs (≥1 present)
- Abnormal Schirmer test (without anesthesia; ≤5 mm/5 minutes)
- Positive vital dye staining of the eye surface

Histopathology
- Lip biopsy showing focal lymphocytic sialoadenitis (focus score ≥1 per 4 mm²)

Oral signs (at least one present)
- Unstimulated whole salivary flow (≤1.5 ml/15 minutes)
- Abnormal parotid sialography
- Abnormal salivary scintigraphy

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; results may be seen in other connective tissue diseases
- ESR/CRP – frequently elevated
- 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

Multisystemic symptoms
- Other connective tissue disease with overlap features
  - Mixed connective tissue disease (MCTD)
  - Scleroderma – systemic sclerosis
  - Rheumatoid arthritis
- Lymphoma (B or T-cell)
- Vasculitis
- Chronic infection
  - Endocarditis
  - HIV
Xerostomia
- Drug-induced
- Sarcoidosis
- Hepatitis C (HCV)
- HIV
- Amyloidosis
- Diabetes mellitus
- Head and neck radiation
- Depression
Xerophthalmia
- Allergic conjunctivitis
- Sarcoidosis
- Rosacea
- Blepharitis
Dysphagia
- Gastroesophageal reflux disease (GERD)
- Gastritis
- Gastroesophageal cancer
- Achalasia
Neurologic symptoms
- Multiple sclerosis
- Diabetes mellitus
- Vasculitis
- Sarcoidosis
Musculoskeletal symptoms
- Rheumatoid arthritis
- Fibromyalgia
- Polymyositis
- Other connective tissue diseases
- Osteoarthritis

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

Epidemiology

Prevalence – 2-4,000,000 persons 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
- 20- to 40-fold increased risk of lymphoma, mostly mucosally associated lymphoid tumors (MALT)
- Often associated with other connective tissue diseases (termed secondary Sjögren syndrome) – usually develops ~10 years after initial onset of primary connective tissue disease)
- Rheumatoid arthritis (RA)
- Systemic lupus erythematous (SLE)
- Primary biliary cirrhosis (PBC)
- Autoimmune thyroid disease (thyroiditis)

Treatment

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

Tests generally appear in the order most useful for common clinical situations

Test name: Anti-Nuclear Antibodies (ANA), IgG by ELISA with Reflex to ANA, IgG by IFA

ARUP #: 0050080

Methodology: Qualitative Enzyme-Linked Immunosorbent Assay (ELISA)/Semi-Quantitative Indirect Fluorescent Antibody (IFA)

Use:

First-line test for connective tissue disease screening

All ELISA results reported as Detected are further tested by IFA

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

Limitations:

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

Follow-up: Recommend cutaneous direct immunofluorescence testing of active edge of new lesion (lesional biopsy) if dermatologic manifestations are present

Test name: Anti-Nuclear Antibody (ANA), IgG by ELISA with Reflexes to ANA by IFA and to dsDNA, RNP, Smith, SSA, and SSB Antibodies

ARUP #: 0050317

Methodology: Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody/Semi-Quantitative Multi-Analyte Fluorescent Detection

Use:

First-line test for connective tissue disease screening

If ELISA screen is positive, then IFA using HEp-2 substrate will be added; if confirmed by IFA, titer and pattern will be reported and testing for dsDNA antibody and ENA antibodies will be added

Test name: Extractable Nuclear Antigen Antibodies (RNP, Smith, SSA, & SSB)

ARUP #: 0050652

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Use:

First-line test for connective tissue disease screening

Test name: Sedimentation Rate, Westergren (ESR)

ARUP #: 0040325

Methodology: Westergren

Use:

Non-specific testing

Often elevated in Sjögren syndrome

Test name: C-Reactive Protein

ARUP #: 0050180

Methodology: Quantitative Immunoturbidimetric

Use:

Non-specific testing

Often elevated in Sjögren syndrome

Test name: Immunoglobulins (IgA, IgG, IgM), Quantitative

ARUP #: 0050630

Methodology: Quantitative Nephelometry

Use:

Non-specific testing

Includes IgA, IgG, IgM

Test name: Protein, Total, Plasma or Serum

ARUP #: 0020029

Methodology: Quantitative Spectrophotometry

Use:

Non-specific testing

Often elevated in Sjögren syndrome

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Non-specific testing

Evaluate white blood cell count

Additional Tests Available

Test name: Connective Tissue Diseases Profile

ARUP #: 0051668

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Aid in identifying specific connective tissue disease

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

Test name: Extractable Nuclear Antigen Antibodies (RNP, Smith, Scleroderma, SSA, & SSB)

ARUP #: 0050653

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Clarify pattern result from ANA

Assay may help differentiate among mixed connective tissue disease, rheumatoid arthritis, scleroderma, Sjögren syndrome and systemic lupus erythematosus

Test name: SSA (Ro) (ENA) Antibody, IgG

ARUP #: 0050691

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Order as secondary screen based on results of ANA test

Test name: SSB (La) (ENA) Antibody, IgG

ARUP #: 0050692

Methodology: Semi-Quantitative Multi-Analyte Fluorescent Detection

Comments:

Order as secondary screen based on results of ANA test