Sjögren's syndrome (SS) is a chronic autoimmune disease that primarily affects exocrine glands such as the salivary and lacrimal glands. It is characterized by lymphocyte infiltration and inflammation in glandular tissue, as well as the presence of autoantibodies in the serum. Patients commonly present with symptoms of dry mouth and dry eyes. SS can also involve extraglandular organs and tissues, leading to systemic manifestations. SS is classified into two types: primary SS (pSS), with no identifiable underlying cause, and secondary SS, which occurs in association with other connective tissue diseases. This section focuses on primary SS.
Pathogenesis
The exact cause and mechanisms remain unclear. Studies indicate involvement of HLA genes, innate/adaptive immunity, and epigenetic factors. T and B lymphocytes infiltrate glandular tissues, often forming tertiary lymphoid organs (ectopic lymph node-like structures), which facilitate the differentiation of autoreactive B cells into plasma cells that produce autoantibodies, thereby damaging exocrine glands. Extraglandular manifestations include epithelial tissue inflammation (e.g., interstitial nephritis and cholangitis), vasculitis caused by immune complex deposition (e.g., IgA vasculitis and cryoglobulinemia), cell- or tissue-specific autoimmune damage (e.g., thrombocytopenia, ataxic sensory ganglionopathy, and neuromyelitis optica spectrum disorders), and lymphoproliferative conditions (e.g., lymphocytic interstitial pneumonia). Abnormal B cell proliferation and differentiation can result in hypergammaglobulinemia and increase the risk of lymphoma development.
Pathological Anatomy and Pathophysiology
The main pathological hallmark is dense lymphocytic infiltration in exocrine glands, most commonly observed in labial gland biopsy specimens. A lymphocytic focus is defined as an infiltration aggregate with more than 50 lymphocytes, forming focal lymphocytic sialadenitis. In pSS, lymphocytic foci are typically located around ducts and adjacent to normal mucinous acini. Elderly individuals may show glandular atrophy, fibrosis, and scattered lymphocyte infiltration in the salivary glands, indicative of nonspecific sialadenitis rather than pSS-specific changes. The focus score (index) refers to the number of lymphocytic foci per 4 mm2 of glandular section; a score of ≥1 is considered positive and is a pathological diagnostic criterion for pSS. Other exocrine glands, including sweat glands in the skin, respiratory tract, gastrointestinal tract, and vaginal mucosa, as well as exocrine glandular components in renal tubules, bile ducts, and pancreatic ducts, may exhibit similar pathological alterations.
Clinical Manifestations
Dryness-Related Symptoms
Xerostomia (Dry Mouth)
Salivary gland involvement results in the following symptoms:
- Reduced saliva production leads to dry mouth, frequent water drinking, and difficulty swallowing dry foods like crackers, often requiring water to aid ingestion.
- Severe dental caries, characterized by progressive tooth darkening, followed by fragmental chipping and root remnant formation, is a hallmark of the disease.
- Tongue pain, a dry and cracked tongue surface, atrophy of lingual papillae resembling a "mirror-like tongue," and potential oral ulcers or secondary infections may occur.
- Sialadenitis, most commonly affecting the parotid glands, can involve one or both sides and may resolve spontaneously.
Dry Eye Syndrome (Keratoconjunctivitis Sicca)
Reduced tear secretion causes sensations of eye dryness, burning, grittiness, or foreign body sensation. Thickened discharge may accumulate at the inner canthus, leading to eye fatigue and blurred vision. Tear deficiency may result in corneal epithelial damage or keratoconjunctivitis sicca.
Extraglandular Manifestations
Extraglandular features may include systemic symptoms such as fatigue and low-grade fever. Approximately two-thirds of patients display damage involving other exocrine glands or systemic organs.
Musculoskeletal System
Joint pain is common, and a small proportion of patients develop arthritis, which typically involves multiple joints symmetrically, without causing joint destruction.
Renal System
Renal involvement primarily manifests as interstitial nephritis and renal tubular acidosis (RTA). Clinical features include metabolic acidosis, hypokalemia, nephrogenic diabetes insipidus, renal osteodystrophy, urinary calculi, or nephrocalcinosis. pSS is a leading cause of RTA. Glomerular involvement is relatively rare, with membranous nephropathy or cryoglobulinemia-associated mesangial capillary glomerulonephritis being the most common patterns.
Respiratory System
Reduced mucosal secretion causes airway dryness. Pulmonary involvement mainly presents as interstitial pneumonia, most commonly nonspecific interstitial pneumonia (NSIP) and lymphocytic interstitial pneumonia (LIP). pSS is a leading cause of LIP, and CT imaging often reveals thin-walled cysts within the lung parenchyma.
Digestive System
Dryness of the pharynx and esophagus, or esophageal motility disorders, may result in difficulty swallowing, nausea, heartburn, and upper abdominal discomfort. Chronic atrophic gastritis, reduced gastric acid secretion, and symptoms of indigestion are also common. Liver involvement, such as primary biliary cholangitis and autoimmune hepatitis, may co-occur. The pancreas can also be affected, typically with subclinical manifestations.
Nervous System
Peripheral neuropathy may be present, commonly manifesting as symmetrical polyneuropathy. Sensory neuropathy is more prominent and presents with glove- or stocking-like sensory deficits in the extremities, accompanied by numbness or tingling sensations. Among cranial nerves, the trigeminal nerve is most commonly and characteristically affected, leading to trigeminal neuralgia or facial numbness. The central nervous system may also be involved, leading to conditions such as neuromyelitis optica spectrum disorders.
Hematological System
All three blood cell lineages (red cells, white cells, and platelets) may be affected. Patients with SS have a higher incidence of lymphoma compared to the general population, primarily non-Hodgkin lymphoma, with the most common subtype being mucosa-associated lymphoid tissue (MALT) lymphoma. Risk factors for lymphoma development include persistent glandular swelling, splenomegaly and/or lymphadenopathy, purpura, an EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) >5, positive rheumatoid factor (RF), cryoglobulinemia, low complement C4 levels, ectopic germinal center-like structures in labial gland pathology, and a focus score >3.
Thyroid Diseases
Thyroid abnormalities or autoimmune thyroiditis may be observed.
Vasculitis
Purpura is associated with IgA vasculitis and cryoglobulinemia. Involvement of larger vessels may present with livedo reticularis or limb ulcers.
Pregnancy-Related Manifestations
Pregnant women who test positive for anti-SSA (Ro) and anti-SSB (La) antibodies have an increased risk of neonatal lupus and fetal heart block in the newborn.
Auxiliary Examinations
Blood and Urine Tests
Immunological Tests
ANA is positive in approximately 85% of patients, with immunofluorescence patterns typically homogeneous or speckled. Anti-SSA (Ro) antibodies are positive in 60–80%, while anti-SSB (La) antibodies are positive in about 50%. These are hallmark autoantibodies for primary SS. Anti-SSA (Ro) antibodies serve as a primary diagnostic criterion, while anti-SSB (La) antibodies do not significantly increase diagnostic sensitivity and are thus not included in the classification criteria. Rheumatoid factor (RF) may be positive in some patients. CRP levels are often normal. Hypergammaglobulinemia, a common finding, is the primary cause of an elevated erythrocyte sedimentation rate (ESR). A minority of patients show cryoglobulinemia or monoclonal gammopathy of undetermined significance (MGUS).
Routine Tests
Findings may include anemia, leukopenia, or thrombocytopenia. Patients with renal tubular acidosis (RTA) exhibit hyperchloremic metabolic acidosis with paradoxical hypokalemia (acid-base disturbances usually cause hyperkalemia) and alkaline urine (acid-base disturbances typically result in acidic urine).
Oral Examination
Salivary Flow Rate
Salivary flow rate is a sensitive parameter for diagnosing xerostomia. It can be assessed under unstimulated conditions (resting salivary flow rate) or with stimulation (dynamic salivary flow rate). The unstimulated flow rate is determined by measuring the total amount of saliva pooled in the sublingual cavity over a specific time period under non-stimulated conditions. A rate of ≤0.1 ml/min is considered positive.
Labial Gland Biopsy
Labial gland biopsy is regarded as the "gold standard" for diagnosing primary SS. The characteristic pathological feature is focal lymphocytic sialadenitis. A biopsy should be considered when a definitive diagnosis cannot be made after comprehensive clinical and laboratory evaluations.
Ophthalmological Examination
Tear Secretion Test (Schirmer's Test)
This test evaluates tear production. A sterile filter paper strip (5 mm × 35 mm) is folded at one end and placed in the conjunctival sac at the junction of the outer and middle thirds of the lower eyelid. After gently closing the eyes, wetting of the strip is measured after 5 minutes. Without local anesthesia, a wetting length of ≤10 mm indicates reduced tear secretion, while ≤5 mm serves as a diagnostic criterion for primary SS.
Tear Film Break-Up Time (TBUT)
This test assesses tear film stability. A 1% fluorescein sodium solution (2 μl) is instilled into the conjunctival sac. After three to four blinks to spread the dye, the patient gazes forward. A slit lamp with cobalt blue filter is used to observe the cornea, and the time from the last blink to the appearance of the first black spot (indicating tear film break-up) is recorded. The average of three measurements is used. A TBUT of ≤10 seconds is considered positive and indicates tear film instability.
Corneal and Conjunctival Staining
Abnormalities in tear quantity or quality can lead to corneal and conjunctival damage. These can be detected using staining techniques. The Sjögren's International Clinical Collaborative Alliance (SICCA) introduced the ocular staining score (OSS), which uses fluorescein sodium and lissamine green to stain the cornea and conjunctiva. The score is based on the number, shape, and distribution of staining points. A severe staining score supports the diagnosis of SS.
Diagnosis and Differential Diagnosis
Diagnostic Criteria
The 2016 Classification Criteria for Primary Sjögren’s Syndrome by the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) is commonly used. Diagnosis requires the presence of at least one of the following symptoms of dryness:
- Daily intolerable eye dryness lasting for more than 3 months.
- A recurrent sensation of sand or grit in the eyes.
- The use of artificial tears ≥3 times daily for eye discomfort.
- Daily sensation of dry mouth lasting for more than 3 months.
- The need to use water to help swallow dry foods.
Alternatively, one item from the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) can replace dryness symptoms. Diagnosis requires a score of ≥4 points based on 5 defined criteria.
Table 1 2016 ACR/EULAR classification criteria for primary Sjögren’s syndrome
Note: Diagnosis requires the exclusion of the following: history of head and neck radiation, active hepatitis C virus infection (confirmed by PCR), HIV infection, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related disease. * Patients taking anticholinergic medications should undergo sufficient washout before assessment of dry mouth and dry eyes.
Differential Diagnosis
Given its varied manifestations, especially when extraglandular symptoms such as skin rash, joint pain, interstitial pneumonia, hypokalemic paralysis, renal tubular acidosis (RTA), biliary cholangitis, or peripheral neuropathy dominate the clinical presentation, primary Sjögren's syndrome should be considered. Other conditions causing similar dryness symptoms or glandular enlargement must be differentiated, including drug- or age-related dryness, IgG4-related disease, sarcoidosis, chronic graft-versus-host disease, salivary gland tumors, hepatitis C or HIV infection, diabetes, and anxiety disorders.
Disease Assessment
Disease activity is assessed using ESSDAI and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI). ESSDAI evaluates overall disease activity based on scores across 12 domains, including systemic symptoms, lymph nodes, glands, joints, skin, lungs, kidneys, muscles, peripheral nerves, central nervous system, hematological system, and serological findings. ESSPRI is a patient-reported index assessing the severity of dryness, pain, and fatigue using a visual analog scale. These tools are primarily used in clinical research due to their complexity.
Treatment
There is currently no curative treatment. Patients with only dryness symptoms receive symptomatic and supportive therapies, while those with visceral involvement or systemic vasculitis require glucocorticoids and/or immunosuppressants.
Treatment of Dry Mouth and Dry Eyes
General Measures
Avoid exposure to wind and dry environments. Frequent small sips of water can help alleviate symptoms of xerostomia. Sugar-free chewing gum may reduce dry mouth severity. Medications that exacerbate dryness, such as anticholinergics, should be avoided. Oral hygiene is essential in reducing dental caries and secondary infections.
Artificial Tears
Artificial tears can alleviate symptoms of dry eyes, prevent corneal damage, and reduce ocular complications. Nighttime use of eye ointments may further protect the cornea and conjunctiva. Artificial saliva is less commonly used in clinical practice.
Topical Immunosuppressive Eye Drops
Cyclosporine or tacrolimus eye drops can suppress ocular surface inflammation and improve tear secretion, thus relieving moderate to severe dry eye symptoms.
Stimulation of Salivary and Lacrimal Gland Function
Pilocarpine activates cholinergic receptors to promote exocrine gland secretion, with a dosage of 5 mg three to four times daily. Potential side effects include sweating, frequent urination, and gastrointestinal disturbances, and it is contraindicated in patients with peptic ulcers, asthma, or angle-closure glaucoma. Cevimeline targets M3 receptors in exocrine glands with higher specificity, administered at a dose of 30 mg three times daily.
Treatment of Extraglandular Manifestations
Glucocorticoids
Glucocorticoids are considered in cases of significant hypergammaglobulinemia, organ involvement, or high disease activity. The dosage of prednisone ranges from 10 to 60 mg/day, depending on disease severity, and severe cases may require short-term use of higher doses of methylprednisolone.
Immunomodulatory or Immunosuppressive Agents
Hydroxychloroquine is effective for joint and muscle pain, fatigue, skin rash, hypergammaglobulinemia, and glandular inflammation, typically administered at 5 mg/kg/day. Immunosuppressive agents include methotrexate, mycophenolate mofetil, azathioprine, cyclosporine, tacrolimus, leflunomide, iguratimod, and cyclophosphamide.
Biologic Agents
Rituximab can be considered for severe or refractory organ involvement, such as severe cryoglobulinemic vasculitis or refractory thrombocytopenia.
Other Therapies
Nonsteroidal anti-inflammatory drugs (NSAIDs) may help alleviate joint and muscle pain. Intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/day for 3 to 5 days may benefit patients with neurological involvement or severe immune-mediated thrombocytopenia. Additional organ-specific treatments should be initiated as required, such as potassium citrate or potassium citrate mixture for correcting renal tubular acidosis.
Prognosis
Patients without visceral involvement generally have a favorable prognosis. However, the presence of complications such as interstitial lung disease, central nervous system involvement, renal impairment, or malignant lymphoma is associated with poorer outcomes.