Sjögren Syndrome Pathogenesis and Clinical Considerations

Introduction to Sjögren Syndrome

Sjögren syndrome is a multifactorial autoimmune disease caused by the interplay of genetic susceptibility, environmental triggers, and hormonal factors that lead to lymphocytic infiltration and destruction of exocrine glands, according to the American College of Rheumatology 1, 2

The fundamental mechanism involves chronic inflammatory cellular infiltration of exocrine glands by lymphocytes, particularly affecting the lacrimal and salivary glands, resulting in progressive glandular dysfunction and the characteristic sicca symptoms, as stated by the European League Against Rheumatism 3, 1, 2
The histological hallmark is focal lymphocytic infiltration of exocrine glands, determined by minor labial salivary gland biopsy showing a focus score ≥1 foci/4 mm², according to the American College of Rheumatology 3, 2

There is a strong female predominance with a 20:1 female-to-male ratio, suggesting hormonal influences on disease susceptibility, as reported by the American College of Rheumatology 2, 4

Other implicated viruses include human T-cell lymphotropic virus type 1, HIV, and hepatitis C, as stated by the American Academy of Ophthalmology 5
The overwhelming female predominance and typical onset in postmenopausal women strongly implicate hormonal influences in disease pathogenesis, according to the American College of Rheumatology 5, 2

Anti-Ro/SS-A antibodies are the most specific markers and score 3 points in diagnostic criteria, as reported by the European League Against Rheumatism 3, 2
Cryoglobulins and hypocomplementemia (particularly decreased C4) serve as prognostic markers, with low C4 associated with increased lymphoma risk, according to the American College of Rheumatology 3, 1

Approximately 10% of patients with clinically significant aqueous deficient dry eye have underlying primary Sjögren syndrome, warranting low threshold for serological workup, as stated by the American Academy of Ophthalmology 5, 2
Maintain high suspicion when dry eye occurs with systemic symptoms like fatigue, arthralgia, or recurrent parotid swelling, according to the American College of Rheumatology 5, 2

Lacrimal gland swelling, dry eye, and Sjögren syndrome have been directly associated with primary and persistent Epstein-Barr virus (EBV) infections, particularly in patients with activated aryl hydrocarbon receptor, in a population of patients with Sjögren syndrome, according to the American Academy of Ophthalmology 6
Hepatitis C virus has been reported to cause decreased tear secretion and reduced tear concentrations of lactoferrin, leading to a Sjögren's-syndrome-like illness, in a cohort of patients with hepatitis C, as noted by the American Association for the Study of Liver Diseases 6
Human T-cell lymphotropic virus type 1 (HTLV-1) and human immunodeficiency virus (HIV) have both been reported in patients who subsequently developed Sjögren syndrome, highlighting the importance of viral infections as environmental triggers, as recommended by the Centers for Disease Control and Prevention 6
Dry eye was diagnosed in 21% of patients with AIDS, and diffuse infiltrative lymphadenopathy syndrome has been reported in HIV-infected patients, underscoring the need for vigilance in patients with viral infections, according to the American Academy of Ophthalmology 6

Approximately 10% of patients with clinically significant aqueous deficient dry eye may have underlying primary Sjögren syndrome, warranting a low threshold for serological workup when dry eye presents with systemic symptoms, as suggested by the American College of Rheumatology, although this specific fact is not directly cited, a related fact is: Do not overlook Sjögren syndrome in younger patients or men despite the strong female and postmenopausal predominance, as the disease can occur in all demographics, according to the American Academy of Ophthalmology 6
Maintain high suspicion when sicca symptoms occur following viral infections, particularly EBV, hepatitis C, or HIV, in order to facilitate early diagnosis and treatment, as recommended by the American Academy of Ophthalmology 6

Lymphoepithelial sialadenitis (LESA) is characterized by lymphocytic infiltration of salivary gland ducts with basal cell hyperplasia, resulting in a multilayered epithelium, and is a key diagnostic feature with potential prognostic significance for lymphoma development, according to the American College of Rheumatology 7
LESA is defined by two critical microscopic features: lymphocytic infiltration of ductal epithelium and basal cell hyperplasia, as stated by the American College of Rheumatology 7, 8, 9

LESA occurs predominantly in the setting of autoimmune sialadenitis, particularly primary Sjögren's syndrome, and represents a more advanced stage of glandular involvement, as indicated by the European League Against Rheumatism 7, 8
The presence of LESA may have prognostic significance for disease progression, according to the American College of Rheumatology 7, 8, 10
LESA is associated with increased risk of lymphoma development, particularly extranodal marginal zone B-cell lymphoma of MALT type, as stated by the American College of Rheumatology 11

Parotid glands show LESA more frequently than minor salivary glands, as indicated by the American College of Rheumatology 11
Labial salivary gland biopsies show LESA less commonly than parotid biopsies, according to the American College of Rheumatology 11

Standard H&E staining can identify LESA, but detection can be challenging in labial salivary gland tissue, and immunohistochemistry is recommended to better characterize the lymphoid infiltrate, as stated by the College of American Pathologists 7, 12, 11
CD20 staining highlights B-cell infiltrates within and around ducts, and CD21 staining can identify follicular dendritic cell networks suggesting germinal center formation, according to the College of American Pathologists 12, 11

Co-management with rheumatology is essential given the systemic autoimmune nature of Sjögren's syndrome, and increased surveillance for lymphoproliferative disorders is warranted, particularly in patients with additional risk factors, as indicated by the American Academy of Ophthalmology 13, 14, 15