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Most autoimmune diseases like RA (rheumatoid arthritis) are usually associated with lifelong treatment. The etiology of RA remains unclear, but it depends on a high-risk genetic background and an environmental trigger, which leads to autoimmune dysregulation and results in autoinflammation. This process preferentially affects joints but may spread to different organs and systems. Several studies have illustrated that patients with RA have an increased overall incidence of malignancy compared to the general population (risk of 5–10%). However, it remains unclear if biological agents like DMARDs (disease-modifying antirheumatic drugs) are associated with a potential increased risk of generating new neoplasms. Data indicate that it is unlikely that RA patients who have received biological agents have a much higher risk of developing lymphoproliferative disorder, other hematologic malignancies or solid tumors compared to MTX (methotrexate) users. In most cases, it also depends on the activity of the underlying rheumatic disease. Thus, clinical decision making must carefully weigh benefits and risks of both aspects of antirheumatic treatment and the risk of elevating the likelihood of developing cancer. The decision to treat with a DMARD must always be based on clinical features and reflect the risk pattern of the individual patient. Up to now, there is no clear evidence that proves the link between long-term DMARD or glucocorticoid use and the increased incidence of newly developed neoplasms. The pathophysiological context is still not well understood and the underlying link between RA and lymphoma still needs to be addressed.