Inextricable association of connective tissue disease with B‑cell lymphoma (Review)

Abstract

Connective tissue disease (CTD) is a kind of autoimmune disease with multisystem damage that mainly involves the bone, muscle and the vascular system. Patients with CTD have an increased incidence of malignant tumors, particularly hematological malignancies, compared to the general population. This association of autoimmune diseases with lymphoproliferative diseases is bidirectional. There is a heightened risk of B-cell lymphoma development among patients with CTD, and patients with autoimmune disease display a higher prevalence of non-Hodgkin lymphoma compared to the general population. More than 80% of malignant tumours occur after or at the same time as CTD develops. Among secondary lymphomas, the most common aggressive type of lymphoma is diffuse large B-cell lymphoma, while the most common indolent type is marginal zone lymphoma. Novel targets in patients with B-cell lymphoma are BCL2, the NF-κB pathway, components of the BCR activator of RhoGEF and GTPase signalling pathway and the PI3K-mTOR pathway. In this review, information is provided on the common types of B-cell lymphoma in CTD, the pathogenic factors implicated in lymphoma development and recent advancements in therapies effective for both autoimmune conditions and malignant lymphoproliferative diseases.

Keywords: B-cell lymphoma; antigen stimulation; classic treatment; connective tissue disease; risk factors.

Figure 1

Autoimmune disease-induced pathophysiologic mechanisms leading to lymphoma. The progression from autoimmune disease to lymphoma may involve various mechanisms, such as the dysregulation of B cells due to prolonged exposure to antigens, shared genetic or environmental factors, common viral infections and external influences. Overexpression of TNF-α can enhance the activity of antiapoptotic regulators and proinflammatory mediators through the NF-κB pathway, disrupting the balance between proapoptotic and antiapoptotic processes, promoting cell survival and potentially facilitating the development of lymphoma. Proinflammatory mediators like IL-6 and IL-10 interact with lymphocyte receptors to promote cell growth and differentiation while inhibiting apoptosis. These cytokine signals are transmitted through NF-κB, an essential intracellular transducer. Additionally, BAFF, a member of the TNF protein family, modulates the survival and proliferation of b lymphocytes by binding to the BR-3 receptor, potentially contributing to the pathogenic activation of b cells in systemic autoimmune diseases and lymphomas. Furthermore, the secretion of BAFF creates a positive feedback loop that stimulates B-cell activation. RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; DLBCL, diffuse large B-cell lymphoma; MZL, marginal zone lymphoma; FL, follicular lymphoma; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; EBV, Epstein-Barr virus; HBV, hepatitis B virus; BAFF, B-cell activating factor; IL-6R, IL-6 receptor; BCR, B-cell receptor; BR3, B-cell activating factor receptor 3; MHC II, major histocompatibility complex II; TCR, T-cell receptor.