Pediatric Sjogren Syndrome Workup

Diagnosis of primary Sjögren syndrome is made in adults if the serology or histopathology is positive and if 4 of the American-European Consensus Group (AECG) criteria for adult patients are met ^[25] :

Mandatory criteria are as follows:

• Characteristic histopathologic features on minor salivary gland biopsy findings: In minor salivary glands (obtained through normal-appearing mucosa) focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score of greater than 1, defined as a number of lymphocytic foci (that are adjacent to normal-appearing mucous acini and contain >50 lymphocytes) per 4 mm² of glandular tissue OR

• Serology: Anti-Ro (SS-A) or anti-La (SS-B)

AECG adult criteria are as follows (4 adult criteria needed):

• At least 1 positive response to the ocular symptom questions (see Screening Questions, below)

• At least 1 positive response to the oral symptom questions (see Screening Questions, below)

• Ocular signs - Positive Schirmer tear test or Rose-Bengal stain findings

• Salivary gland involvement revealed by at least 1 testing modality (salivary scintigraphy, parotid sialography, unstimulated salivary flow)

• Exclusion criteria - Preexisting lymphoma, human immunodeficiency virus (HIV), hepatitis C, sarcoidosis, graft versus host disease (GVHD)

Criteria for pediatric patients have been proposed but not prospectively validated. ^[26] Only 76% sensitivity has been noted in studies of retrospective patients. ^[22] 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 primary pediatric Sjögren syndrome. Diagnosis is based on the presence of 4 or more of the following proposed pediatric diagnostic criteria:

• Exclusion of all other autoimmune diseases

• Oral symptoms - Dry mouth, parotitis, and parotid gland enlargement

• Ocular symptoms - Recurrent conjunctivitis and keratoconjunctivitis sicca

• Other mucosal symptoms - Recurrent vaginitis or vulvovaginitis

• Systemic symptoms - Fever of unknown origin, noninflammatory arthralgias, and hypokalemic paralysis

• Presence of anti-Ro (SS-A), anti-La (SS-B), high titer ANA, or RF

• Elevated serum amylase levels

• Leukopenia and high erythrocyte sedimentation rate (ESR)

• Polyclonal hyperimmunoglobulinemia

• Renal tubular acidosis ^[23]

• Histologic proof of lymphocytic infiltration of salivary gland or other organs

• Objective documentation of ocular dryness - Schirmer tear test or Rose Bengal stain findings

• Objective documentation of parotid gland enlargement - Sialography findings

On a complete blood count (CBC) with differential, mild anemia and leukopenia are often present in patients with Sjögren syndrome. Elevated erythrocyte sedimentation rate (ESR) is observed in 80-90% of patients, which may be related to hypergammaglobulinemia; however, C-reactive protein (CRP) levels are usually within the reference range. Hypergammaglobulinemia, up to several grams of immunoglobulin G (IgG), is observed in 70-80% of pediatric and adult patients.

ANA and rheumatoid factor RF levels are usually elevated in children. Anti-Ro (SS-A) and anti-La (SS-B) are also 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) autoantibodies. Cryoglobulins and, occasionally, antiphospholipid antibodies are noted. ^[27]

In Rose Bengal staining, the dye stains damaged corneal epithelium and indicates keratoconjunctivitis. This is not often performed in children.

Schirmer tear 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.

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. ^[28] Although still considered experimental, these changes in salivary constituents are of unknown predictive value.

Sialography is a sensitive and specific radiographic technique for detecting sialectasis. However, 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. ^{[10, 29]}

Technetium-99m (^99m Tc) pertechnetate scintigraphy shows delayed uptake in Sjögren syndrome; often in correlation with pathologic changes.

Magnetic resonance imaging (MRI) visualizes the glandular parenchyma and aids in the evaluation of cystic or solid masses. In addition, the volumetric estimate of the gland size can be determined.

The pathologic findings from biopsy are very useful in diagnosis and are often obtained in juvenile primary Sjögren syndrome workup. Because of its 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. (See the image below.)

Biopsy of the minor salivary glands of the lower lip may be useful in the diagnosis of Sjögren syndrome. A 1.5- to 2-cm incision of normal-appearing mucosa allows for the harvesting of 5 or more salivary gland lobules.

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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. (See the images below.) ^[7]

Low-power photomicrograph of a minor salivary gland lobule showing multiple lymphocytic foci that are replacing the acinar structures (hematoxylin-eosin, 40 X).

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Intermediate-power photomicrograph demonstrating a chronic inflammatory aggregate of more than 50 lymphocytes and plasma cells with a periductal pattern. The inflammatory focus is adjacent to normal appearing acini (hematoxylin-eosin, 200 X).

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High-power photomicrograph of the chronic inflammatory aggregate consists of lymphocytes and plasma cells around a ductal structure (hematoxylin-eosin, 400 X).

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Unlike the parotid gland lesions, epimyoepithelial islands are rarely observed in the lymphocytic background. The finding of more than 1 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 correlation with a disease diagnosis. However, a negative biopsy finding cannot completely exclude a diagnosis of Sjögren syndrome. Biopsy findings may also be used to rule out granulomatous (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. In adult patients, a 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 the questionnaire of adult salivary hypofunction, positive responses to all 4 of the following questions indicate major salivary gland hypofunction ^[30] : (1) Do you sip liquids to aid in swallowing dry foods? (2) Does your mouth feel dry when eating a meal? (3) Do you have difficulties swallowing any foods? (4) Does the amount of saliva in your mouth seem to be too little?

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: (1) Have you had persistent dry eyes daily for more than 3 months? (2) Do you have recurrent sensation of sand or gravel in your eyes? (3) Do you use tear substitutes more than 3 times daily?

A study by Cornec et al reported that the diagnostic performance of the American College of Rheumatology classification criteria for Sjögren's syndrome is notably improved by adding the salivary gland ultrasonography score. The study concluded that salivary gland ultrasonography should be included in future classification criteria for Sjögren's syndrome. ^{[31, 32]}