Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that mainly affects the joints, therefore, may cause deformities and disability if untreated. The first line of treatment is disease-modifying antirheumatic drugs (DMARDs). When the patient fails to respond to DMARDs, mainly methotrexate, then second-line therapy is required. Tumor necrosis factor α (TNFα) plays an important role in the pathogenesis of RA; however, the treatment with anti-TNFα medications is challenging. It may trigger the autoimmune system and result in producing antibodies that induce symptoms and signs mimic to systemic lupus erythematosus (SLE), and in rare situations can affect vital organs with severe and life-threatening complications. We report on a 38-year-old Saudi woman with longstanding erosive RA, who was diagnosed based on the 1987 classification criteria. She developed life-threatening SLE, and seroconversion of antinuclear antibodies (ANA), anti-double-stranded DNA, with severe systemic involvement (cerebritis, nephritis, myositis, and polyneuropathy), shortly after treatment with adalimumab. Adalimumab was started as anti TNFa therapy (after the failure of traditional therapy), SLE and other autoimmune diseases were ruled out by clinical history, examination, and laboratory investigations, including negative ANAs and anti-double-stranded DNA. When both tests turned out persistently positive even after stopping adalimumab, specific diagnostic and therapeutic modalities were required during her acute illness.