What is the pathophysiology of Sjögren's (Sjögren's syndrome)?

From the Guidelines

Sjögren's syndrome is an autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, particularly the salivary and lacrimal glands, leading to their destruction and dysfunction, as supported by the most recent evidence from 1 and 1. The pathophysiology of Sjögren's syndrome begins with genetic predisposition combined with environmental triggers such as viral infections or hormonal factors that initiate an abnormal immune response.

• B and T lymphocytes target self-antigens, particularly the ribonucleoproteins SS-A (Ro) and SS-B (La), resulting in inflammation and progressive damage to glandular tissue.
• This immune dysregulation involves overproduction of proinflammatory cytokines like interferon-alpha, interleukin-6, and B-cell activating factor (BAFF). As the disease progresses, lymphocytic infiltration extends beyond the exocrine glands, potentially affecting multiple organ systems including joints, lungs, kidneys, and the nervous system.
• The destruction of salivary and lacrimal glands leads to the hallmark symptoms of dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). Additionally, B-cell hyperactivity results in hypergammaglobulinemia and production of various autoantibodies, which contribute to systemic manifestations and increase the risk of developing lymphoma, particularly mucosa-associated lymphoid tissue (MALT) lymphoma, as noted in 1, 1, 1, 1, and 1.

The management of Sjögren's syndrome involves a multidisciplinary approach, including the use of topical and systemic therapies, as recommended by the European League Against Rheumatism (EULAR) in 1.

• Topical therapies, such as artificial tears and saliva substitutes, can help alleviate symptoms of dry eyes and mouth.
• Systemic therapies, such as glucocorticoids and immunosuppressive agents, may be necessary to manage systemic disease and prevent organ damage. It is essential to carefully evaluate the severity and organ damage of systemic disease before initiating systemic therapy, as noted in 1.

In terms of specific treatments, the use of antifibrotic therapy, such as nintedanib, may be considered for patients with progressive fibrotic interstitial lung disease (ILD), as recommended in 1.

• Rituximab, a biologic therapy, may also be considered for patients with refractory or rapidly progressive ILD, but its use should be cautious due to potential risks and side effects, as noted in 1.

Overall, the management of Sjögren's syndrome requires a comprehensive and individualized approach, taking into account the severity and extent of disease, as well as the patient's overall health and quality of life, as supported by the evidence from 1, 1, 1, 1, 1, 1, and 1.

From the Research

Pathophysiology of Sjögren's Syndrome

• Sjögren's syndrome is a chronic autoimmune disorder characterized by lymphocytic infiltration and malfunction of the exocrine glands, resulting in dry mouth and eyes 2, 3, 4, 5, 6.
• The syndrome can present either alone (primary Sjögren's syndrome) or in the context of an underlying connective tissue disease (secondary Sjögren's syndrome) 2, 3, 4, 6.
• The pathogenesis of Sjögren's syndrome is still elusive, but different models involving genetic and environmental factors have been proposed to explain its development 4, 6.
• The emergence of aberrant autoreactive B-lymphocytes, conducting to autoantibody production and immune complex formation, seems to be crucial in the development of the disease 4, 6.

Immunological Parameters

• In Sjögren's syndrome, lymphocytic infiltration of salivary and lacrimal glands, and deposition of several types of autoantibodies, mainly anti-SS-A (anti-Ro) and anti-SS-B (anti-La), lead to chronic inflammation, with xerostomia and keratoconjunctivitis sicca 6.
• T cells predominate in mild lesions, whereas B cells predominate in advanced lesions 6.
• Th1, Th2, Th17, follicular helper T (Tfh) cells and regulatory cells (Tregs/Bregs), with their characteristic cytokine profiles, have been implicated in the pathogenesis of Sjögren's syndrome 6.

Clinical Manifestations

• Sjögren's syndrome is characterized by pleomorphic clinical manifestations whose characteristics and severity may vary greatly from one patient to another 4.
• The disease can involve virtually any organ system, resulting in a variety of systemic manifestations 4.
• Ocular involvement, manifested as keratoconjunctivitis sicca, is managed with local and systemic stimulators of tear secretion and supportive surgical procedures 2, 3.
• Treatment of oral manifestations includes intense oral hygiene, prevention and treatment of oral infections, use of saliva substitutes, and local and systematic stimulation of salivary secretion 3.