Blocking Tumor Necrosis Factor Paved the Way for Targeted Therapeutics in Inflammatory Diseases
Tumor necrosis factor (TNF) has become a cornerstone in the treatment of inflammatory diseases, largely due to the success of its antagonists in managing conditions such as rheumatoid arthritis (RA), Crohn’s disease (CD), and ankylosing spondylitis (AS). The discovery of TNF dates back to 1975 when Lloyd Old and colleagues identified a substance in the serum of mice that caused tumor necrosis in experimental models. This substance was later named TNF. Although initially explored for its potential in cancer therapy, TNF’s role in inflammation soon overshadowed its tumor-killing properties. The gene encoding TNF was cloned, and it was found to be identical to cachectin, a molecule associated with cachexia in cancer patients. TNF was subsequently recognized as a potent inflammatory cytokine, mediating a wide range of inflammatory activities in the body.
The therapeutic potential of TNF was initially explored in the context of sepsis and septic shock. However, early clinical trials with TNF inhibitors (TNFi) in these conditions were disappointing. Despite this setback, the role of TNF in chronic inflammatory diseases such as RA and CD became evident. TNF was found to be highly expressed in the synovial tissue of RA patients and in the submucosal tissue of CD patients. This discovery led to the development of TNFi as a targeted therapy for these conditions. The first TNFi, infliximab and etanercept, were initially tested in sepsis trials but later found their success in treating RA and CD.
TNFi have since become a mainstay in the treatment of various inflammatory diseases. Five TNFi—infliximab, golimumab, adalimumab, certolizumab pegol, and etanercept—along with their biosimilars, are widely used in clinical practice. These agents have demonstrated high efficacy in both clinical trials and real-world settings, significantly improving patient outcomes and reducing the need for surgical interventions in conditions like inflammatory bowel disease (IBD). TNFi are also effective in managing extra-intestinal manifestations of IBD.
The mechanism of action of TNFi involves neutralizing the activity of both soluble and transmembrane TNF. Etanercept, a fusion protein consisting of the extracellular domains of the type 2 TNF receptor and the human IgG1 Fc fragment, also binds to lymphotoxin (LT) and blocks its activity. Other TNFi, such as infliximab and adalimumab, are monoclonal antibodies that specifically target TNF. These agents can induce antibody-mediated cytotoxicity and complement-mediated cytotoxicity in cells bearing transmembrane TNF. Additionally, reverse signaling via transmembrane TNF may contribute to the killing of TNF-producing cells. Despite their similar therapeutic profiles, differences in the mechanisms of action among TNFi can influence their efficacy in specific diseases. For example, etanercept is ineffective in treating IBD or non-infective uveitis, whereas other TNFi are effective in these conditions.
The success of TNFi in treating RA and CD inspired their use in other inflammatory diseases, such as AS and spondyloarthritis (SpA). TNF is highly expressed in the sacroiliac joints of AS patients, suggesting its involvement in the pathogenesis of the disease. The first randomized controlled trial with infliximab in SpA patients was conducted in 2000, following promising results from open-label trials. Significant clinical improvement was observed as early as two weeks after the first dose of infliximab, accompanied by a reduction in C-reactive protein levels. Subsequent clinical trials confirmed the efficacy of TNFi in treating AS and SpA, demonstrating their ability to slow disease progression and protect patients from neo-ossification in long-term treatment. The structural protective effects of TNFi are particularly evident in patients who have been on continuous therapy for more than four years.
The therapeutic success of TNFi has set a high standard for the development of other targeted therapies in inflammatory diseases. For instance, interleukin-17 (IL-17) inhibitors (IL-17i) have been developed as a second class of biological therapeutics. While IL-17i have shown inferior efficacy compared to TNFi in RA, they have proven to be highly effective in treating psoriasis and SpA. Antibodies targeting IL-17A or dual-specific antibodies targeting both IL-17A and IL-17F have demonstrated superiority over placebo in SpA patients, including those who have previously failed TNFi therapy. Observational studies have shown that patients who fail TNFi respond similarly to IL-17i and alternative TNFi, suggesting that switching between these agents may be a viable strategy. However, head-to-head comparative trials are needed to determine the superiority of TNFi over IL-17i and vice versa.
The long-term effects of IL-17i on new bone formation in SpA patients remain to be fully understood, as syndesmophyte formation is a slow process. Enthesitis, an important comorbidity in SpA, has recently gained attention as a therapeutic target. IL-17i have shown effectiveness in treating enthesitis, particularly in patients with psoriatic arthritis. Interestingly, ustekinumab, a monoclonal antibody targeting the common subunit of IL-12 and IL-23, has demonstrated superiority over TNFi in treating peripheral enthesitis, although it is ineffective in treating axial SpA.
TNFi have also served as a benchmark for assessing the efficacy and safety of other targeted therapies, such as Janus kinase (JAK) inhibitors. The success of TNF blockade in inflammatory diseases has established a model for developing targeted therapies, with TNFi remaining the gold standard for comparison. The efficacy of novel therapeutic agents is often measured against that of TNFi, and their safety profiles are similarly evaluated in reference to TNFi.
In conclusion, the discovery and development of TNFi have revolutionized the treatment of inflammatory diseases, providing a targeted approach that has significantly improved patient outcomes. The success of TNFi has not only set a high standard for subsequent therapies but also paved the way for the development of other biological agents, such as IL-17i and JAK inhibitors. As research continues, the potential for synergistic effects between TNFi and other targeted therapies remains an exciting area of exploration. The ongoing evolution of targeted therapeutics in inflammatory diseases holds promise for further advancements in patient care and treatment outcomes.
doi.org/10.1097/CM9.0000000000001846
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