bubble_chart Overview

Sjogren's syndrome is a chronic inflammatory autoimmune disease that affects the exocrine glands throughout the body, also known as autoimmune exocrine gland epithelial cell inflammation or autoimmune exocrine disease. It primarily targets the lacrimal and salivary glands, manifesting as dryness of the eyes and mouth; however, systemic involvement beyond the glands, such as the respiratory tract, digestive tract, urinary tract, nerves, muscles, and joints, can also be affected. Hadden (1888) first reported this condition, and Henrik Sjogren (1933) provided detailed documentation of 19 cases, after which it was named Sjogren's syndrome.

Sjogren's syndrome is further divided into primary and secondary types. The former refers to cases with keratoconjunctivitis sicca and oral dryness without accompanying connective tissue diseases (CTD, such as systemic lupus erythematosus or rheumatoid arthritis), while the latter refers to cases associated with other connective tissue diseases.

bubble_chart Epidemiology

This disease has a high incidence rate, and its prevalence in the general population is unclear. Reports indicate a population prevalence of 0.4–0.7%, which can rise to 3–4% in elderly individuals. The incidence is second only to rheumatoid arthritis. It can occur at any age but is more common in middle-aged women.

bubble_chart Pathogenesis

It remains unclear, but some believe this disease is an autoimmune disorder. Primary xerostomia and xerophthalmia are associated with the HLA-B₈-DRW₃ genetic phenotype, while patients with concomitant rheumatoid arthritis are linked to HLA-DRW₄. There have been reports of familial cases in the literature. Patients' sera show elevated IgM-type antibody titers against cytomegalovirus, and some evidence supports the role of Epstein-Barr virus in the pathogenesis of SS combined with RA.

NZB/NZW mice of a certain age exhibit extensive lymphocyte infiltration in their salivary gland ducts and display a series of autoimmune phenomena. It is believed that these mice have a primary β-cell hyperreactivity of polyclonal nature, directly targeting multiple self and non-self antigenic determinants. This leads to the production of various autoantibodies and immune complexes, including antibodies against suppressor T cells, resulting in their functional impairment and perpetuating β-cell hyperreactivity, thereby contributing to disease onset.

Human SS may share a similar disease mechanism. It has been demonstrated that small lymphocyte foci in the minor salivary glands of SS patients primarily consist of β-cells and plasma cells, while larger lesions are mainly composed of T-cell infiltrates at the center, surrounded by β-cells and plasma cells in the peripheral zone. Among T cells, the T_H subset predominates. In the early stages of the disease, tissue injury is caused by antigen recognition and/or β-cells and plasma cells migrating to the affected area. The mechanism may involve antibody-dependent cell-mediated lymphocytotoxicity or the production of cytotoxic antibodies, which, through lymphocyte chemotactic factors, lead to T-cell accumulation at the site of the abdominal mass.

bubble_chart Clinical Manifestations

The onset of the disease is mostly insidious and chronic, with a minority of cases being acute and rapidly progressive. This is a systemic disease involving multiple systems:

1. **Oral cavity**: Grade I lesions are often overlooked by patients. In more severe cases, saliva production is reduced, and food stimulation or chewing fails to increase salivary secretion. The tongue appears red, dry, or ulcerated, with limited mobility. No salivary abdominal mass is observed at the base of the lingual frenulum. Difficulty in chewing and swallowing is common. Dental caries and gingivitis are frequent, with teeth crumbling into powder or small fragments. The lips and corners of the mouth become dry and fissured (rhagade), accompanied by fetid mouth odor. About half of the patients experience recurrent parotid gland swelling, leading to a "squirrel-like" face in Grade III cases. The submandibular glands may also enlarge.
2. **Eyes**: Dry keratoconjunctivitis is present, with symptoms including dryness, itching, pain, foreign body or burning sensations, blurred vision, a "curtain-like" obstruction, and photophobia. The cornea may become cloudy, eroded, or ulcerated, with small blood vessel proliferation. Severe cases may lead to perforation. Associated conditions include iridocyclitis and chorioretinitis; conjunctival inflammation with dilation of bulbar conjunctival vessels; reduced tear production, and occasional lacrimal gland enlargement, predisposing to bacterial, fungal, or viral infections. Rarely, proptosis may be the initial symptom.
3. **Respiratory tract**: Nasal mucosal gland involvement leads to dryness, crust formation, frequent epistaxis, and nasal septitis. Eustachian tube obstruction may cause serous otitis media and conductive deafness. Throat dryness, hoarseness, and thick sputum are common, with complications including tracheitis, bronchitis, pleuritis, interstitial pneumonia, and atelectasis. Even patients without obvious clinical lung lesions may exhibit restrictive ventilation impairment and reduced gas diffusion capacity.
4. **Digestive tract**: Pharyngeal and esophageal dryness can cause dysphagia, with occasional post-cricoid esophageal stricture. Gastric mucosal hypertrophy due to glandular lymphocyte infiltration results in coarse gastric folds and reduced acid secretion, forming a cobblestone-like pseudocancer. The incidence of accompanying atrophic gastritis can reach 70.5%. Small intestine absorption may be impaired, with abnormal responses to gastrin and pancreozymin, suggesting subclinical pancreatitis is common. Hepatosplenomegaly occurs in 1/5 of cases.
5. **Urinary tract**: Renal involvement occurs in 1/3 of cases, commonly manifesting as interstitial nephritis with tubular dysfunction, including renal tubular acidosis, renal glycosuria, aminoaciduria, and reduced uric acid reabsorption. Glomerulonephritis may also occur due to IgM and complement deposition in the glomeruli.
6. **Nervous system**: Neural tissue at various levels may be affected, with central nervous system involvement in 25% and peripheral nerves in 10–43% of cases. Central lesions can range from meninges to brain parenchyma and spinal cord at all levels. Peripheral nerve involvement is widespread, including roots, axons, myelin sheaths, and sensory or motor branches. Clinical manifestations vary, including psychiatric disorders, spasms, hemianopia, aphasia, hemiplegia, paraplegia, and ataxia. The mechanism involves inflammatory vascular changes leading to ischemia or blood loss, or mononuclear cell infiltration.
7. **Muscles**: Involvement occurs in about 2% of cases, presenting as myalgia and weakness due to interstitial myitis, with perivascular lymphocyte and mononuclear cell infiltration. Periodic paralysis may also occur secondary to renal tubular acidosis or hypokalemia.
8. **Joints**: Approximately 10% of cases involve joints, presenting with swelling and pain, typically non-erosive arthritis.
9. **Skin and mucous membranes**: Dryness resembling ichthyosis, with nodular erythema, purpura, Raynaud's phenomenon, and ulcers. Vaginal mucosa may also become dry and atrophic.
10. **Lymph nodes**: Local or systemic lymphadenopathy may occur.

**Secondary SS**: Most commonly associated with connective tissue diseases, particularly rheumatoid arthritis (35–55%). Other associations include SLE, PSS, MCTD, polyarteritis nodosa, Hashimoto's thyroiditis, primary biliary cirrhosis, and chronic active hepatitis.

Pseudolymphoma: In SS, lymphocyte infiltration is typically confined to the salivary and lacrimal glands, presenting as a benign progressive process of dry mouth and eyes. However, there may also be significant extraglandular lymphoid cell infiltration, clinically manifesting as lymphadenopathy with involvement of the lungs, kidneys, liver, spleen, muscles, etc. Blood tests show leukopenia, elevated gamma globulin, and macroglobulinemia. Histopathology reveals polymorphic infiltrates in the affected tissues, including small and large lymphocytes, plasma cells, and reticular cells. This condition persists for several years with a benign course and is termed pseudolymphoma. Some of these cases may transform into cervical malignancy with cachexia, where the infiltrating cells are highly undifferentiated, tissue structure is disrupted, and infiltration extends beyond the membrane. The prevalence of cervical malignancy with cachexia in SS patients is significantly higher compared to the general population.

bubble_chart Auxiliary Examination

Grade I normocytic normochromic anemia (25%), leukopenia (6–33%), eosinophilia (5–25%), and Grade I thrombocytopenia may also occur. Increased erythrocyte sedimentation rate (80–94%). Approximately half of the cases show decreased albumin and elevated polyclonal globulins, primarily in the γ-globulin fraction, with possible increases in α- and β-globulins as well. Immunoglobulins, mainly IgG and IgM, are elevated. About 3/4 of patients test positive for rheumatoid factor, often of the IgM type; antinuclear antibodies are positive (17–68%), while anti-dsDNA antibodies are rare. Macroglobulins and cryoglobulins may be positive, accompanied by hyperviscosity syndrome. Anti-thyroglobulin and anti-gastric parietal cell antibodies are positive (30% each), and anti-human globulin tests and anti-mitochondrial antibodies are positive (10% each). In primary Sjögren’s syndrome (SS), anti-SS-A antibodies are positive in 70–75% of cases, and anti-SS-B antibodies in 48–60%, whereas in SS combined with rheumatoid arthritis, these rates are 9% and 3%, respectively. Anti-salivary duct epithelial cell antibodies (ASDA) are positive in 25% of primary SS cases but rise to 70–80% in SS with rheumatoid arthritis. Serum and salivary β₂

-microglobulin (β₂-M) levels are elevated, with serum concentration serving as an indicator of disease activity. Salivary IgG levels increase, with high levels of IgA and IgM rheumatoid factor (RF). Direct immunofluorescence (DIF) shows IgG deposition in the epidermal basal layer and adjacent areas. Peripheral blood T lymphocytes are reduced, particularly Ts cells, while Ia-positive T lymphocyte populations increase. Lymphocyte transformation tests and active rosette formation tests show reduced activity. Circulating immune complexes are elevated; CH₅₀ and C₃ levels are increased or normal but may decrease during vasculitis. Approximately 2/3 of patients exhibit defects in Fc receptor function of the reticuloendothelial system. When benign lymphoproliferation in SS progresses to cervical malignancy with cachexia, hypergammaglobulinemia may transition to hypogammaglobulinemia, and autoantibody titers may decline or become negative.

(1) Lacrimal gland function tests: - Schirmer’s test (measuring tear flow using filter paper: a 35mm strip is folded 5mm from the end and placed in the lower conjunctival sac; after 5 minutes, the length of wetting is observed). <10mm為低於正常）；淚膜破碎時間（BUT試驗，<10〃為不正常），角膜2%螢光素或1%剛果紅或1%孟加拉玫瑰紅活體染色（染色點<10個正常）。以上現代兩項陽性符合乾燥性角結膜炎。

(2) Salivary gland tests: - Salivary secretion measurement (sugar tablet test: an 800mg sucrose tablet is placed on the central tongue, and the time to complete dissolution is recorded; <30 minutes is normal). - Salivary flow rate measurement: a small suction cup connected to a hollow tube is placed with negative pressure over the opening of a unilateral parotid duct to collect saliva; normal secretion is >0.5ml/min. - Parotid sialography: 40% iodized oil contrast is used to assess gland morphology, destruction, atrophy, retention time of the contrast agent, and duct stenosis or dilation. - Parotid gland scintigraphy using ¹³¹iodine or ^99mtechnetium to observe radiotracer distribution, excretion, and concentration delays or reductions, reflecting secretory function. - Lip or nasal mucosal biopsy to examine gland pathology. A positive result in either of the above two tests confirms xerosis.

(3) Histopathology There is extensive lymphocyte infiltration in glands such as the lacrimal, parotid, and submandibular glands, predominantly composed of β cells. In severe cases, β cell infiltration may resemble the germinal centers of lymph nodes, accompanied by glandular atrophy. The epithelial cells of the ducts proliferate, forming epithelial-myoepithelial cell islands, and the glandular ducts become narrowed or dilated. In the late stage [third stage], the glands are replaced by connective tissue. Extraglandular lymphoid infiltration may involve organs such as the lungs, kidneys, or skeletal muscles, leading to functional impairment.

bubble_chart Diagnosis

The international literature proposes five diagnostic criteria such as the Copenhagen criteria and Fox criteria, which are rarely used today due to their poor sensitivity. Another example is the Manthorpe diagnostic criteria (1981):

1. ocular xerosis;
2. oral xerosis;
3. another connective tissue disease.

Those who meet criteria 1 and/or 2 along with 3 are diagnosed with secondary SS. During its trial period, this standard was found to have poor specificity.

In 1992, Dong Yi et al. proposed diagnostic criteria:

1. dry keratoconjunctivitis;
2. oral xerosis;
3. presence of one of the following antibodies in the serum: anti-SS-A, anti-SS-B, ANA >1:20, RF >1:20.

Patients who meet all three criteria and have excluded other connective tissue diseases, lymphoma, AIDS, and GVH can be definitively diagnosed. Those who meet only two of the criteria and have excluded other diseases are considered probable cases. The specificity and sensitivity of this standard were found to be relatively high in clinical trials.

bubble_chart Treatment Measures

There is no specific treatment. Maintain oral and eye hygiene by using 0.5% methylcellulose eye drops; frequently rinse the mouth with a citric acid solution to stimulate salivary gland secretion and partially substitute saliva. Applying 2% methylcellulose to the oral cavity before meals may occasionally alleviate symptoms. In cases of severe functional impairment, extensive systemic involvement, or concurrent connective tissue diseases, corticosteroids, immunosuppressants, or Root Leaf or Flower of Common Threewingnut preparations may be used. Plasma exchange therapy can help suppress parotid gland swelling and improve exocrine function.

bubble_chart Prognosis

The disease progresses slowly, depending on the extent of the lesions and any accompanying conditions. Cases of pseudolymphoma require close monitoring for outcomes, and those developing cervical malignancy with cachexia have a poor prognosis.