Is Rheumatoid Arthritis (RA) associated with an increased risk of developing Lymphoma?

From the Guidelines

Rheumatoid arthritis (RA) is associated with an increased risk of developing lymphoma, particularly non-Hodgkin lymphoma, with a two to four times higher risk compared to the general population. This increased risk is primarily related to the chronic inflammation associated with RA, as persistent inflammatory activity can lead to abnormal immune cell proliferation and potential malignant transformation 1. The severity and duration of RA inflammation appear to be important factors - those with more severe, long-standing disease typically face higher lymphoma risk. Some medications used to treat RA may also influence this risk, though the relationship is complex. TNF inhibitors like adalimumab, etanercept, and infliximab have been studied extensively, with current evidence suggesting their benefits in controlling inflammation generally outweigh potential lymphoma risks 1.

Key Factors Influencing Lymphoma Risk in RA

• Chronic inflammation associated with RA
• Severity and duration of RA inflammation
• Medications used to treat RA, such as TNF inhibitors

Important Considerations for RA Patients

• Regular monitoring by healthcare providers is crucial for early detection of lymphoma
• Watching for symptoms like persistent swollen lymph nodes, unexplained weight loss, night sweats, or fever, which could warrant further investigation for lymphoma
• Weighing the benefits and risks of medications, including TNF inhibitors, in the context of individual patient factors and disease severity.

From the Research

Association between Rheumatoid Arthritis and Lymphoma

• Rheumatoid Arthritis (RA) is associated with an increased risk of developing lymphoma, particularly non-Hodgkin lymphoma (NHL) and diffuse large B cell lymphoma (DLBCL) 2, 3, 4.
• The clinical course of lymphoma in RA patients is often aggressive, but the prognosis is similar to that of lymphoma in the general population 2.
• The exact mechanisms linking RA and lymphoma are unclear, but possible factors include genetic predisposition, persistence of long-standing disease activity with continued immune stimulation, and the role of anti-RA therapy 2, 5.

Lymphoma Subtypes in RA Patients

• RA patients have an increased proportion of DLBCL, with 67% of NHL patients having DLBCL, compared to 30-40% in the general population 4.
• DLBCL is the most frequent subtype observed in RA patients, and it is often associated with medium or high inflammatory activity 4.
• Epstein-Barr virus (EBV) is detected in a subset of lymphomas from RA patients, but its role in lymphomagenesis is unclear 4.

Inflammatory Profiles in RA-DLBCL Patients

• RA-DLBCL patients have significantly higher levels of pro-inflammatory markers, including TNF, IL-8, CXCL9, APRIL, and CXCL13, compared to RA controls 6.
• CXCL13 is particularly elevated in RA-DLBCL patients, with a median level of 796 pg/mL, compared to 206 pg/mL in RA controls 6.
• RA-DLBCL patients are often autoantibody seropositive, but they do not display significantly different autoantibody signatures compared to RA controls 6.

Risk Factors and Disease Activity

• The risk of lymphoma in RA patients increases with time since RA diagnosis, particularly within the first decade 5.
• Continuing disease activity and immune stimulation appear to be the most significant factors in lymphomagenesis in RA patients 2, 5.
• The role of anti-RA therapy, including immunosuppressive drugs, is unclear, but it does not appear to be associated with a higher risk of lymphoma in RA patients 2, 5.