eMedicine Specialties > Pediatrics: General Medicine > Rheumatology

Sjogren Syndrome: Differential Diagnoses & Workup

Author: Eyal Muscal, MD, Assistant Professor, Section of Pediatric Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital
Coauthor(s): Marietta Morales de Guzman, MD, Assistant Professor, Department of Pediatrics, Baylor College of Medicine; Consulting Staff, Section of Pediatric Rheumatology, Department of Pediatrics, Texas Children's Hospital, Ben Taub General Hospital; Lawrence K Jung, MD, Chief, Division of Pediatric Rheumatology, Children's National Medical Center; Catherine M Flaitz, DDS, MS, Professor of Oral and Maxillofacial Pathology and Pediatric Dentistry, Department of Diagnostic Sciences, University of Texas Health Sciences Center at Houston, Dental Branch
Contributor Information and Disclosures

Updated: Sep 18, 2009

Differential Diagnoses

Eating Disorder: Anorexia
Mononucleosis and Epstein-Barr Virus Infection
Eating Disorder: Bulimia
Mumps
Graft Versus Host Disease
Sarcoidosis
Hepatitis C
Systemic Lupus Erythematosus
Herpes Simplex Virus Infection
Systemic Sclerosis
Human Immunodeficiency Virus Infection
Vasculitis and Thrombophlebitis
Infections in the Immunocompromised Host
Lymphoproliferative Disorders
Mixed Connective Tissue Disease

Other Problems to Be Considered

Medications that cause sicca symptoms (anticholinergic)
Recurrent juvenile parotitis
Oropharyngeal candidiasis
Gingivitis/periodontitis
Retrograde bacterial sialadenitis
Halitosis
Superficial mucoceles
Compromised nutrition
Dryness of the nasal and vaginal mucosa and skin
Pregnancy complications due to autoantibodies

Workup

Laboratory Studies

The following studies are indicated in Sjögren syndrome:

  • CBC count with differential: Mild anemia and leukopenia are often present.
  • Erythrocyte sedimentation rate (ESR): Elevated ESR is observed in 80-90% of patients, often related to hypergammaglobulinemia; however, C-reactive protein (CRP) levels are usually within the reference range.
  • Immunoglobulin levels: Hypergammaglobulinemia, up to several grams of immunoglobulin G (IgG), is observed in 70-80% of both pediatric and adult patients.
  • Autoantibodies
    • Antinuclear antibody (ANA) and rheumatoid factor (RF) levels are usually elevated in children.
    • Anti-Ro (SS-A) and anti-La (SS-B) are usually present in children.
    • Various autoantibodies may be found in patients with Sjögren syndrome; however, the clinical or diagnostic implication is often unclear. Autoantibodies include thyroglobulin, thyroid microsomal, mitochondrial, smooth muscle, parietal, peroxisomal, muscarinic receptors, and salivary duct (often present in adults with Sjögren syndrome).
    • Cryoglobulins and, occasionally, antiphospholipid antibodies are noted.
  • Rose Bengal staining: The dye stains damaged corneal epithelium and indicates keratoconjunctivitis. This is not often performed in children.
  • Schirmer tear test: This test is used to evaluate tear production by lacrimal glands. A strip of filter paper is placed beneath the lower lid, and wetting of the paper is measured at 5 minutes. Less than 10 mm of film is abnormal, and less than 5 mm of wetting suggests decreased tear production and sicca syndrome. This test is performed more often in pediatric patients.

Imaging Studies

  • Sialography - A sensitive and specific radiographic technique to find evidence of sialectasis (Sialography sensitivity has not been reported in the pediatric literature. These techniques are not commonly used at most pediatric centers; however, their use has been described by multiple investigators.8,17 )
  • Technetium Tc 99 pertechnetate scintigraphy - Delayed uptake in Sjögren syndrome; often correlates with pathological changes
  • MRI - Visualization of the glandular parenchyma, in particular for the evaluation of cystic or solid masses (In addition, the volumetric estimate of the gland size can be determined.)

Other Tests

  • In the questionnaire of adult salivary hypofunction, positive responses to all 4 of the following questions indicate major salivary gland hypofunction.18
    • Do you sip liquids to aid in swallowing dry foods?
    • Does your mouth feel dry when eating a meal?
    • Do you have difficulties swallowing any foods?
    • Does the amount of saliva in your mouth seem to be too little?
  • Sialometry is the quantification of whole saliva or individual gland secretions at unstimulated (resting) or stimulated flow rates. These procedures are not commonly used in pediatric patients.
  • For salivary hypofunction, the flow rate for unstimulated whole saliva is less than 0.1 mL/min, whereas the rate for stimulated whole saliva is less than 0.5 mL/min. The collection period is a minimum of 5 minutes and often up to 15 minutes. When secretions from the parotid gland are evaluated, the modified Carlson-Crittenden collector is placed over the Stensen duct. Isolation of the salivary gland orifices in the floor of the mouth and gentle suction are used to collect submandibular and sublingual secretions together. Besides demonstrating salivary hypofunction, these methods can be used to evaluate the effectiveness of secretogogue therapy.
  • On sialochemistry, collected secretions can be chilled, frozen, and evaluated for electrolytes, immunoglobulins, and protein constituents. Although not diagnostic for Sjögren syndrome, a profile has been observed, including an increase in secretory levels of immunoglobulin A, lactoferrin, total protein, and sodium and chloride ions. In addition, decreased levels of lysozyme and potassium and phosphate ions are found. A change in the proteomic signature of a salivary peptide complex was noted in a boy who had clinical improvement of his Sjögren syndrome.19 Although still considered experimental, these changes in salivary constituents are of unknown predictive value.
  • Less than 50% of pediatric patients report ocular symptoms, whereas older patients with Sjögren syndrome more frequently report them. Ocular screening questions include the following:
    • Have you had persistent dry eyes daily for more than 3 months?
    • Do you have recurrent sensation of sand or gravel in your eyes?
    • Do you use tear substitutes more than 3 times daily?

Procedures

  • Salivary gland biopsy
    • The pathological findings are very useful in diagnosis and are often obtained while diagnosing juvenile primary Sjögren syndrome.
    • Because of the relative ease and lack of complications, labial minor salivary gland biopsy is preferred over parotid gland biopsy, which can result in facial nerve damage. However, minor salivary gland biopsy requires sufficient expertise to ensure adequacy of tissue collection.
    • In order to ensure that a representative sample has been obtained for histopathologic examination, harvesting 5-10 lobules of minor salivary glands is crucial.

Histologic Findings

  • The characteristic histopathologic findings of the minor salivary glands include an inflammatory infiltrate adjacent to normal-appearing acinar structures. The inflammatory infiltrate consists of primarily lymphocytes and fewer plasma cells. Most of the infiltrating lymphocytes are activated CD4+ memory T lymphocytes. A focal periductal pattern is initially observed, with eventual confluence of the inflammatory infiltrate that replaces the acini. Periductal and perivascular hyaline deposits may be observed.4
  • Unlike the parotid gland lesions, epimyoepithelial islands are rarely observed in the lymphocytic background. The finding of more than one focus of 50 or more inflammatory cells within a 4-mm2 area of glandular tissue supports the diagnosis of Sjögren syndrome. The greater the number of foci, the greater the disease correlation. A negative biopsy finding cannot completely exclude a diagnosis of Sjögren syndrome. Biopsies may also be used to rule out sarcoid or amyloid lesions.
  • When the major glands are enlarged, a benign lymphoepithelial lesion (BLEL) may develop. The characteristic features include a dense lymphocytic infiltrate that is associated with the destruction of salivary gland acini, while the ductal epithelium persists. Hyperplasia of the ductal epithelium and myoepithelial cells forms epimyoepithelial islands within the lymphoid tissues. Formation of germinal centers may be observed. Determination of monoclonality of the lymphocytic infiltrate by immunohistochemical or gene rearrangement studies may be necessary in order to exclude a low-grade B-cell lymphoma in adult patients.

Staging

  • Diagnostic and classification schema: Diagnosis is made if the serology or histopathology is positive and if 4 of the following American-European Consensus Group (AECG) criteria for adult patients are met:
    • At least one positive response to the ocular symptoms questions (see Other Tests)
    • At least one positive response to the oral symptoms questions (see Other Tests)
    • Ocular signs (positive Schirmer tear test or Rose-Bengal stain findings)
    • Histopathological features on minor salivary gland biopsy findings
    • Salivary gland involvement revealed by at least one testing modality (salivary scintigraphy, parotid sialography, unstimulated salivary flow)
    • Anti-Ro (SS-A) or anti-La (SS-B)
    • Exclusion criteria - Preexisting lymphoma, HIV, hepatitis C, sarcoidosis, graft versus host disease (GVHD)
  • Proposed criteria for pediatric patients have been proposed but not prospectively validated.20 Only 76% sensitivity has been noted in compilation of retrospective patients.14 The clinical judgment of a pediatric rheumatologist is the criterion standard. However, the proposed pediatric criteria appear more sensitive than adult AECG criteria in classifying pediatric Sjögren syndrome. Diagnosis is based on the presence of 4 or more of the following proposed pediatric diagnostic criteria:
    • Clinical symptoms
      • Oral symptoms (dry mouth, parotitis, parotid gland enlargement)
      • Ocular symptoms (recurrent conjunctivitis, keratoconjunctivitis sicca)
      • Other mucosal symptoms (recurrent vaginitis, vulvovaginitis)
      • Systemic symptoms (fever of unknown origin, noninflammatory arthralgias, hypokalemic paralysis)
    • Immunologic abnormalities - Presence of anti-Ro (SS-A), anti-La (SS-B), high titer ANA, or RF
    • Other laboratory finding abnormalities or additional investigations
      • Elevated serum amylase levels
      • Leukopenia, high ESR
      • Polyclonal hyperimmunoglobulinemia
      • Renal tubular acidosis
      • Histological proof of lymphocytic infiltration of salivary gland or other organs
      • Objective documentation of ocular dryness (Rose Bengal stain findings, Schirmer tear test findings)
      • Objective documentation of parotid gland enlargement (sialography findings)
    • Exclusion of all other autoimmune disease

More on Sjogren Syndrome

Overview: Sjogren Syndrome
Differential Diagnoses & Workup: Sjogren Syndrome
Treatment & Medication: Sjogren Syndrome
Follow-up: Sjogren Syndrome
Multimedia: Sjogren Syndrome
References
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Further Reading

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Keywords

Sjogren syndrome, Sjögren's syndrome, Sjögren syndrome, Sicca syndrome, keratoconjunctivitis, xerostomia, polyarthritis, parotitis, salivary gland enlargement, recurrent parotitis, autoimmune exocrinopathy, systemic lupus erythematosus, SLE, rheumatoid arthritis, scleroderma, biliary cirrhosis, lymphoproliferative disease, non-Hodgkin lymphoma, Waldenström macroglobulinemia, B-cell lymphoma, keratoconjunctivitis, Raynaud phenomenon, Epstein-Barr virus, EBV, HIV, cytomegalovirus, treatment, diagnosis

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Contributor Information and Disclosures

Author

Eyal Muscal, MD, Assistant Professor, Section of Pediatric Rheumatology, Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital
Eyal Muscal, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Rheumatology, and Clinical Immunology Society
Disclosure: Nothing to disclose.

Coauthor(s)

Marietta Morales de Guzman, MD, Assistant Professor, Department of Pediatrics, Baylor College of Medicine; Consulting Staff, Section of Pediatric Rheumatology, Department of Pediatrics, Texas Children's Hospital, Ben Taub General Hospital
Marietta Morales de Guzman, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Rheumatology, and Texas Pediatric Society
Disclosure: Nothing to disclose.

Lawrence K Jung, MD, Chief, Division of Pediatric Rheumatology, Children's National Medical Center
Lawrence K Jung, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Rheumatology, Clinical Immunology Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Catherine M Flaitz, DDS, MS, Professor of Oral and Maxillofacial Pathology and Pediatric Dentistry, Department of Diagnostic Sciences, University of Texas Health Sciences Center at Houston, Dental Branch
Catherine M Flaitz, DDS, MS is a member of the following medical societies: American Academy of Oral and Maxillofacial Pathology, American Academy of Oral Medicine, American Academy of Pediatric Dentistry, American Dental Association, International Association for Dental Research, and International Association of Oral Pathologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

David D Sherry, MD, Director, Clinical Rheumatology, Attending Physician, Pain Management, The Children's Hospital of Philadelphia; Professor of Pediatrics, University of Pennsylvania
David D Sherry, MD is a member of the following medical societies: American College of Rheumatology and American Pain Society
Disclosure: Nothing to disclose.

CME Editor

Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine
Daniel Rauch, MD, FAAP is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, and Society of Hospital Medicine
Disclosure: Baxter Honoraria Consulting

 
 
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