Sjögren Syndrome

Sjögren syndrome is a slowly progressive autoimmune disease characterized by lymphocytic infiltration of exocrine glands resulting in dry eyes and dry mouth. Common laboratory testing includes antinuclear antibody (ANA), anti-SSA (Ro), anti-SSB (La), and rheumatoid factor (RF) tests; however, these tests are not specific to Sjögren syndrome.

Tabs Content

Clinical Overview

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

I. Ocular symptoms (≥1 present)

Symptoms of dry eyes for ≥3 months
Foreign body sensation in the eyes
Use of artificial tears ≥3 per day

II. 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

III. Ocular signs (≥1 present)

Abnormal Schirmer test (without anesthesia; ≤5 mm/5 minutes)
Positive vital dye staining of the eye surface

IV. Histopathology

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

V. Oral signs (at least one present)

Unstimulated whole salivary flow (≤1.5 ml/15 minutes)
Abnormal parotid sialography
Abnormal salivary scintigraphy

Vi. 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)
  - Preferred test to detect inflammatory processes (Choosing Wisely: 20 Things Physicians and Patients Should Question, 2017; American Society for Clinical Pathology)
  - Frequently elevated
  - If CRP not available, order erythrocyte sedimentation rate (ESR)
- 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
- IgG4-related disease
Xerophthalmia
- Allergic conjunctivitis
- Sarcoidosis
- Rosacea
- Blepharitis
- Age related sicca
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

Background

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
- 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

ARUP Lab Tests

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.

Nuclear Antibody (ANA) by IFA, IgG (INACTIVE as of 11/12/18: Refer to 3000082 in the November Hotline) 0050639
Method: Semi-Quantitative Indirect Fluorescent Antibody

Recommended Use

Preferred ANA screening test for connective tissue diseases

If positive, patterns reported include homogeneous, speckled, centromere, nucleolar, nuclear dots, or cytoplasmic; all positive results are reported with endpoint titers

Limitations

A negative ANA by IFA test does not rule out the presence of connective tissue disease

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

Recommended Use

Aid 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

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 than ANA IFA for systemic autoimmune rheumatic diseases

Follow-up

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

Recommended Use

Aid 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

Recommended Use

Recommended for the differential diagnosis of SLE and Sjögren syndrome

C-Reactive Protein 0050180
Method: Quantitative Immunoturbidimetry

Recommended Use

Preferred test to detect acute phase inflammation (eg, autoimmune diseases, connective tissue disease, rheumatoid arthritis, infection, or sepsis)

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

Recommended Use

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

Recommended Use

Nonspecific testing

Often elevated in Sjögren syndrome

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

Recommended Use

Nonspecific testing

Evaluate white blood cell count

Medical Reviewers

Tebo, Anne E., PhD, D(ABMLI), Medical Director, Immunology at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

Guidelines

Choosing Wisely. An initiative of the ABIM Foundation. [Accessed: Jun 2018]
Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, Gottenberg J, Bootsma H, Mariette X, Vitali C, EULAR Sjögren's Task Force. EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome. Ann Rheum Dis. 2010; 69(6): 1103-9. PubMed

General References

Amarasena R, Bowman S. Sjögren's syndrome. Clin Med (Lond). 2007; 7(1): 53-6. PubMed

Fox PC. Autoimmune diseases and Sjogren's syndrome: an autoimmune exocrinopathy. Ann N Y Acad Sci. 2007; 1098: 15-21. PubMed

Kruszka P, O'Brian RJ. Diagnosis and management of Sjögren syndrome. Am Fam Physician. 2009; 79(6): 465-70. PubMed

Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X. Primary Sjogren syndrome. BMJ. 2012; 344: e3821. PubMed

Stinton LM, Fritzler MJ. A clinical approach to autoantibody testing in systemic autoimmune rheumatic disorders. Autoimmun Rev. 2007; 7(1): 77-84. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology^®

Copple SS, Giles R, Jaskowski TD, Gardiner AE, Wilson AM, Hill HR. Screening for IgG antinuclear autoantibodies by HEp-2 indirect fluorescent antibody assays and the need for standardization. Am J Clin Pathol. 2012; 137(5): 825-30. PubMed

Patil DT, Bennett AE, Mahajan D, Bronner MP. Distinguishing Barrett gastric foveolar dysplasia from reactive cardiac mucosa in gastroesophageal reflux disease. Hum Pathol. 2013; 44(6): 1146-53. PubMed

Tebo AE. Recent approaches to optimize laboratory assessment of antinuclear antibodies. Clin Vaccine Immunol. 2017; 24(12): PubMed

Testing Algorithms

Antinuclear Antibody Testing Algorithm

Read more about Antinuclear Antibody Testing Algorithm

Last Update: July 2018


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	Sjögren Syndrome. ARUP Consult^©. Retrieved October 15, 2018, from: https://arupconsult.com/content/sjogren-syndrome

Sjögren Syndrome

Diagnosis

Indications for Testing

Criteria for Diagnosis

Laboratory Testing

Histology

Other Testing

Differential Diagnosis

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

Treatment

ARUP Lab Tests

Medical Reviewers

References

Guidelines

General References

References from the ARUP Institute for Clinical and Experimental Pathology®

Antinuclear Antibody Testing Algorithm

References from the ARUP Institute for Clinical and Experimental Pathology^®