Despite the desire of physicians to use scientific evidence to understand disease and its management, often, the experience with a single patient frames our perspective and influences our practice and research. Regarding tumor necrosis factor (TNF) blockade in systemic lupus erythematosus (SLE)—a topic of great controversy and confusion—consider the following case history and its implication for this modality of targeted therapy.
The Case
A middle-aged woman with lupus nephritis had suffered from serious disease manifestations for more than half a year. Almost 10 years prior to the recent period of intense disease activity, she had received the National Institutes of Health regimen for treatment of her lupus nephritis; she also underwent curative resection of a bladder carcinoma. Now, 10 years later, renal biopsy confirmed recurrent active class IV nephritis. Mycophenolate mofetil (MMF) was not an available option at that time. Thus, cyclophosphamide was started, and particular care was taken to protect her bladder as much as possible.
Unlike the situation with her first episode of active disease, the patient’s nephritis did not respond. Rather, her proteinuria increased to approximately 6 grams per day, and she developed nephrotic syndrome, suffering severely from edema of her legs. She also developed allergic reactions to mesna, first mild, then severe. Even though the mode of application of mesna was changed to instillation into the bladder, she suffered an anaphylactic reaction with subsequent treatment. Immunoabsorption using Therasorb immunoglobulin (Ig) G columns was the next attempt to treat her ongoing lupus nephritis. In contrast to other patients who responded to this intervention, she again had no or minimal benefit.
This experience placed her on the list for the first open-label trial of infliximab in SLE. Azathioprine was started in parallel with the infliximab in accordance with the protocol. One week after the first infusion of infliximab, her leg edema resolved completely. A few weeks later, her proteinuria fell to less than 1.5 grams per day and her serum albumin rose steadily. Despite some problems with azathioprine, which had to be stopped, she did well for more than one year. Although she encountered other problems, her good response to infliximab, along with that of other patients, laid the foundation for controlled clinical trials of anti-TNF for the treatment of lupus nephritis.1
Effects of TNF Blockade in SLE
Before contemplating the role of TNF blockade in SLE, it is important to highlight the major issues underlying our current knowledge of the role of TNF in lupus. In essence, this cytokine has two major effects: 1) TNF can downregulate the specific immune response and may also help control production of autoantibodies; and 2) TNF is a strong proinflammatory mediator with direct effects on blood vessels as well as lymphoid and myeloid cells. Both actions may play a role in the pathogenesis of human SLE and the role of TNF in mediating severe disease ma1nifestations.
