What is the pathophysiology of Sjogren's syndrome and how is it related to lymphoma?

Pathophysiology of Sjögren's Syndrome and Its Relationship to Lymphoma

Sjögren's syndrome is characterized by lymphocytic infiltration of the lacrimal and salivary glands with secondary compromise of gland function, leading to dry eyes and dry mouth, and carries approximately a 5% risk of developing lymphoid malignancy, with primary Sjögren's syndrome being the rheumatic disease most strongly associated with lymphoma development. 1

Core Pathophysiological Mechanisms

• Sjögren's syndrome is an autoimmune disorder defined by chronic inflammatory cellular infiltration of exocrine glands, particularly the lacrimal and salivary glands, resulting in diminished tear and saliva production 1

• The disease is characterized by a type I interferon signature that establishes a proinflammatory environment, facilitating disease propagation by activating T and B cell subsets 2

• Autoantibodies, particularly anti-Ro/SSA and anti-La/SSB, are key serological markers in the diagnostic criteria for Sjögren's syndrome 3

• The condition can present as primary Sjögren's syndrome or secondary to other autoimmune diseases such as rheumatoid arthritis, scleroderma, or systemic lupus erythematosus 1, 4

• Systemic manifestations beyond sicca symptoms include arthralgia, myalgia, fatigue, and potential involvement of multiple organs including the lungs, kidneys, liver, nervous system, and vasculature 1, 5

Lymphocytic Infiltration and Progression

• The histological hallmark is focal lymphocytic infiltration of exocrine glands, determined by minor labial salivary gland biopsy 1

• This infiltration leads to progressive destruction of the glandular tissue and subsequent loss of functional epithelium 2, 6

• Both innate and adaptive immune cells participate in the disease process, with innate immune cells establishing the initial inflammatory environment 2

• The chronic autoimmune inflammation can progress beyond exocrine glands to involve other organs and tissues 5, 7

Connection Between Sjögren's Syndrome and Lymphoma

• About 5% of patients with Sjögren syndrome will develop some form of lymphoid malignancy, representing a significant increase in risk compared to the general population 1

• A meta-analysis found that primary Sjögren's syndrome is the risk factor most strongly associated with lymphoid malignancy among rheumatic diseases, with an incidence rate of 18.9% (95% CI, 9.4–37.9) 1

• This translates to an increased incidence of 320 cases per 100,000 patient years 1

• Decreased C4 levels at the time of diagnosis of Sjögren's syndrome are associated with a higher risk of developing lymphoma 1, 5

• The majority of lymphomas in Sjögren's syndrome are B-cell non-Hodgkin lymphomas, though Hodgkin lymphoma can also occur, albeit more rarely 8, 9

• The relationship between Sjögren's syndrome and lymphoma highlights the disease's position between autoimmune rheumatic diseases and lymphoid B-cell malignancies 9

Pathophysiological Similarities with Lymphoma

• Both conditions involve abnormal lymphocyte proliferation and activation 9

• The chronic B-cell activation and proliferation in Sjögren's syndrome creates an environment conducive to potential malignant transformation 7, 8

• The persistent antigenic stimulation in Sjögren's syndrome may lead to clonal expansion of B cells, potentially progressing to lymphoma 2, 9

• Shared genetic and environmental factors may contribute to the development of both conditions 4

• The lymphocytic infiltrates in Sjögren's syndrome can evolve from benign polyclonal aggregates to malignant monoclonal proliferations 7, 9

Clinical Implications

• Ophthalmologists caring for patients with clinically significant dry eye should maintain a high index of suspicion for Sjögren's syndrome and have a low threshold for serological workup 1

• Patients with Sjögren's syndrome should be co-managed with a rheumatologist due to the many possible comorbid systemic conditions and the increased risk of lymphoma 1

• Regular monitoring for signs of lymphoma development is essential in the management of Sjögren's syndrome patients 1, 3

• Early diagnosis and treatment of underlying systemic immune disorders may decrease morbidity and may even be lifesaving 1