Pathophysiology: The characteristic abnormality found on the lacrimal or salivary gland biopsy is the lymphocytic infiltration in the glandular lobules. The predominant cells are memory CD4⁺ T cells, suggesting a central role in the pathogenesis of this disorder. Activated B cells also are found in the lesions, which may be responsible for the production of the autoantibodies to autoantigens Ro (SS-A) and LA (SS-B). Anti-Ro (SS-A) is found in 40-45% and anti-LA (SS-B) in 50% of patients with Sjögren syndrome. Because these autoantibodies also are observed in other autoimmune disorders, including SLE, further diagnostic tools must be used for the correct diagnosis.

A higher incidence of Sjögren syndrome exists in family members of these patients. The association of Sjögren syndrome with human leukocyte antigen (HLA)-B8, HLA-Dw3, HLA-DR3, and with the DQA1*0501 allele supports the notion of genetic susceptibility.

Frequency:

• In the US: Although Sjögren syndrome has been recognized in patients of all ages, it primarily affects women in the fourth and fifth decades of life. It is rare in childhood, with a 3-year-old girl being the youngest reported patient. Overall, Sjögren syndrome is the second most common autoimmune disorder, after rheumatoid arthritis. Between half a million and 2 million individuals suffer from this disease in the United States.

• Internationally: Epidemiological studies from different ethnic groups show prevalence rates similar to those in the United States.

Mortality/Morbidity:

• Although most patients have a mild and benign course, they often suffer from painful eye irritation, severe dental caries, and dyspareunia. Because of the insidious nature of these symptoms, the patients often do not seek medical attention until more severe symptoms appear years later.

• Lymphoproliferative disorders increase 40-fold in Sjögren syndrome. Although significant lymphoproliferation usually remains confined to the salivary and lacrimal glands, extraglandular lymphoproliferation (eg, lymphadenopathy, hepatosplenomegaly) sometimes resembles lymphoma (eg, pseudolymphoma) but may herald frank malignancies, including non-Hodgkin lymphoma, Waldenström macroglobulinemia, and B-cell lymphoma.

Sex: The female-to-male ratio is approximately 9:1.

Age:

• Sjögren syndrome is relatively rare in childhood; the peak incidence is around fourth and fifth decades of life.

History:

• Sicca syndrome

• Keratoconjunctivitis - Dry eyes with reduced tear production with gritty or sandy sensation under the lids; red eyes; photosensitivity

• Xerostomia - Decreased saliva production leading to difficulties with chewing, swallowing, and even speech; abnormality in taste and smell; dental caries; mucosal burning sensation; sensitivity to spicy and acidic foods and beverages; increased risk for oral candidiasis; hoarseness of voice

• Musculoskeletal

• Arthralgia, morning stiffness, nonerosive arthritis

• Myalgia, muscle weakness

• Cutaneous

• Raynaud phenomenon

• Nonthrombocytopenic purpura, especially of lower extremities

• Nasal, vaginal, and cutaneous dryness

• Gastrointestinal

• Dysphagia, nausea, epigastric pain

• Achalasia (in children)

• Achlorhydria, chronic atrophic gastritis

• Primary biliary cirrhosis

• Pulmonary

• Dyspnea due to mild interstitial disease

• Dry cough

• Renal - Interstitial nephritis

• Other - Fatigue, depression

Physical:

• Parotid gland enlargement

• Corneal ulceration, vascularization

• Vasculitic lesions - Purpura

• Lymphadenopathy

• Autoimmune thyroiditis

• Neuromuscular

• Peripheral sensorimotor neuropathy

• CNS disorders, such as movement disorder, transverse myelopathy, encephalopathy, aseptic meningitis, and dementia, have been described in some studies.

• Arthritis

• Intermittent synovitis

• Chronic nonerosive polyarthritis - Jaccoud arthropathy seen in adults

• Oral cavity

• Mild erythema and thinning of the mucosa

• Erythema, fissuring, coating and depapillation of the dorsal tongue

• Traumatic erosions and ulcers, angular cheilitis, and chapped lips

• Frothy, ropey, and thickened saliva

Causes: Multiple etiological factors likely are involved in the pathogenesis of Sjögren syndrome.

• Sex hormone: As with other autoimmune disorders, a female preponderance exists in Sjögren syndrome. This suggests that sex hormones may play a role in shaping the autoimmune response.

• Genetics: The association of certain HLAs suggests that genetic factors likely play a role in the pathogenesis of Sjögren syndrome. Patients with HLA-B8, HLA-Dw3, and HLA-DR3 have a high incidence of autoantibody production and extraglandular manifestations. The majority of patients also have the DQA1*0501 allele, which may have a role in the pathogenesis of this disease.

• Environmental factors: Epstein-Barr virus (EBV) replicates in the salivary glands during primary infection and remains latent in these organs. EBV-DNA is recovered from salivary glands and saliva of these patients. Its etiopathological role cannot be proven. HIV, human T-cell leukemia-lymphoma virus type 1 (HTLV-1), and cytomegalovirus (CMV) also are under scrutiny as possible inciting agents that lead to lymphoproliferation observed in the end organs.

• Autoantibodies: Presence of anti-Ro (SS-A) and anti-La (SS-B) is associated with earlier onset, longer duration, and more extraglandular manifestations of primary Sjögren syndrome.

• Inflammatory reactivity: In situ evidence suggests that proinflammatory cytokines, interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor (TNF) are produced in the salivary glands. These are found in the infiltrating lymphocytes as well as the epithelial cells. This suggests that the infiltrating lymphocytes (ie, predominantly CD4 T cells) play a role in the perpetuation of the disease process.

Lab Studies:

• CBC, differential: Mild anemia, leukopenia

• Erythrocyte sedimentation rate (ESR): Elevated ESR is observed in 80-90% of patients; however, C-reactive protein (CRP) usually is normal.

• Immunoglobulin levels: Hypergammaglobulinemia, up to several grams of IgG, is observed in 80% of patients.

• Autoantibodies

• Antinuclear antibody (ANA) and rheumatoid factor (RF) - Usually elevated.

• Anti-Ro (SS-A), Anti-La (SS-B)

• Other autoantibodies to thyroglobulin, thyroid microsomal, mitochondrial, smooth muscle, and salivary duct

• 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 5 mm of wetting suggests decreased tear production.

• Rose Bengal staining: The dye stains the damaged corneal epithelium and indicates keratoconjunctivitis.

Imaging Studies:
 

• Sialography - A sensitive and specific radiographic technique to find evidence of sialectasis

• Technetium-99 pertechnetate scintigraphy - Delayed uptake in Sjögren syndrome and correlated with pathological changes

• Magnetic resonance imaging (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:

• Questionnaire for salivary hypofunction:
  • 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?

  Positive responses to all 4 questions indicate major salivary gland hypofunction (adapted from Fox and others, 1998).

• Sialometry - Quantification of whole saliva or individual gland secretions at unstimulated (resting) or stimulated flow rates. For salivary hypofunction, the flow rate for unstimulated whole saliva is less than 0.1 mL/min, while 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 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.

• 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 immunoglobulin A, lactoferrin, total protein, and sodium and chloride ions. In addition, decreases in lysozyme and potassium and phosphate ions are found. Although still considered experimental, these changes in salivary constituents may help to predict disease progression and prognosis.

Procedures:

• Salivary gland biopsy

• The pathological findings are very useful in diagnosis.

• Because relative ease and lack of complications, labial minor salivary gland biopsy is preferred over parotid gland biopsy, which can result in facial nerve damage.

• In order to ensure that a representative sample has been obtained for histopathologic examination, it is important to harvest between 5 and 10 lobules of minor salivary glands.

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 CD4⁺ memory T lymphocytes. Initially, a focal periductal pattern is observed with eventual confluence of the inflammatory infiltrate that replaces the acini. Periductal and perivascular hyaline deposits may be observed. Unlike the parotid gland lesions, rarely, epimyoepithelial islands are seen 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 is the disease correlation.

When there is enlargement of the major glands, 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. There is hyperplasia of the ductal epithelium and myoepithelial cells that form epimyoepithelial islands within the lymphoid tissues. Formation of germinal centers may be seen. 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.

Medical Care:

• Xerostomia - Stimulation of salivary flow with sialagogues, such as pilocarpine or cevimeline; mechanical stimulation through the use of sugarless chewing gum or lozenges; topical tissue hydration or lubrication from drinking water or the use of artificial saliva

• Oral hygiene

• Caries control - Good oral hygiene; diet control with attention to decreasing refined sugars, simple carbohydrates, and high acidity foods and beverages; topical fluorides and remineralizing toothpastes and solutions to enhance remineralization of the teeth

• Oropharyngeal candidiasis - Topical and systemic antifungal agents; daily cleaning of removable oral prostheses or appliances

• Gingivitis/periodontitis - Good plaque control; antimicrobial agents such as chlorhexidine gluconate 0.12% oral rinse

• Keratoconjunctivitis - Artificial tears

Surgical Care:

• Parotid enlargement - Fine needle aspiration (FNA) or open biopsy may be required to exclude cystic or neoplastic disease.

Consultations:

• Ophthalmology - To obtain evidence of keratitis by slit lamp examination

• Dentistry - Dental care

• Surgery - For salivary gland biopsy

• Rheumatology - For diagnosis and long-term care

• Drink plenty of fluids with the meals to aid in the chewing, tasting, and swallowing of foods. If tolerated, encourage the intake of dairy products, especially low-fat milk, yogurt, and cheese. Milk provides increased oral lubrication, while cheese has a beneficial anticaries effect.

• Avoid dry crunchy foods because they are too difficult to swallow and may irritate the mucosa.

• Avoid spicy or acidic foods and beverages.

• Avoid simple carbohydrates, such as sucrose and highly processed refined foods, such as pastries and cookies, in order to decrease risk for dental caries. If sweetener substitutes are used, monitor the intake because some products may cause abdominal distress.

• Eat foods at moderate temperatures. Liquefy or puree foods if swallowing is a problem. If increase in calories is needed due to an eating disorder, consider liquid nutritional supplements.

• Alcoholic beverages and caffeinated drinks, such as coffee, tea, or cola, increase oral dryness. Avoid mouth rinses that contain alcohol because they cause desiccation of the mucosa.

Activity:

• Discourage smoking.

• Instruct patient to avoid windy and low-humidity environments.

• The family dwelling should be well humidified.

Primary Sjögren syndrome usually follows a benign course, and conservative management is indicated. Therapeutic approaches may include increasing lubrication with artifical tears, stimulation of salivary flow with sugar-free gum or lozenges, and vaginal lubricants. Saliva substitutes (eg, carboxymethylcellulose) usually are not effective. Cholinergic agonists have been shown to help increase salivary secretion and are approved by the FDA for this use. Treatment of the associated autoimmune disorders in secondary Sjögren syndrome is not affected by the presence of primary Sjögren syndrome.
 

Drug Category: Cholinergic agonists -- Stimulate salivary secretion.

Drug Category: Immunosuppressive agents -- Used to treat extraglandular disease (ie, interstitial pneumonitis, glomerulonephritis, vasculitis, pseudolymphoma, malignancy).

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) -- Use of NSAIDs similar to those used for juvenile arthritis may be used to treat polyarthritis associated with Sjögren syndrome.

Drug Category: Disease-modifying antirheumatic drugs (DMARDs) -- Used for polyarthritis not controlled with NSAIDs. Methotrexate (MTX) has been shown to be effective in managing polyarthritis. Other DMARDs (eg, hydroxychloroquine, sulfasalazine, D-penicillamine) may be synergistic when coadministered with methotrexate.

Further Outpatient Care:

• Routine follow-up care by a rheumatologist, ophthalmologist, and dentist

Deterrence/Prevention:

• Caries prevention

• Personal dental plaque measures include twice daily cleaning of the teeth with a toothbrush, using a fluoride-containing dentifrice, and daily use of dental floss; increase the number of professional cleanings to 3 to 4 times a year if carious lesions develop

• Daily home use of topical fluorides, especially gels or toothpastes that contain 1.1% sodium fluoride or remineralizing gels with 0.05% sodium fluoride, sodium phosphate, and calcium carbonate

• If the patient has severe xerostomia, use custom fluoride trays or carriers to apply the topical fluorides.

• Concurrent use of chlorhexidine gluconate oral rinse for 2-week periods when high numbers of Streptococcus mutans are found in saliva (>1X10⁶ counts/mL saliva)

• Limit the intake of sugary food and beverages between meals. Use sweetener alternatives, if tolerated, such as aspartame, saccharin, sorbitol, and xylitol.

• Prevention of oral mucosal lesions

• Chapped lips - Repeated use of water- or lanolin-based lip moisturizers (Avoid lip products that are medicated with menthol or phenol because they cause further drying.)