Early experiments associated TNF function with the pathogenesis of bacterial sepsis, thus the first preclinical studies using anti-TNF antibodies were performed in animal models of sepsis  and showed that anti-TNF antibodies protected mice from sepsis. However, subsequent clinical trials in sepsis patients showed no significant benefit upon anti-TNF treatment. It wasn't until 1991 that studies in more physiological animal models of TNF overexpression, namely the human TNF transgenic mouse model, provided the pre-clinical rational for a unique role of TNF in the development of polyarthritis and that anti-TNF treatments could be effective against human arthritides. This was later confirmed in clinical trials  and led to the development of the highly successful first biological therapies for RA.
Several 5-HT2A agonist hallucinogens including (R)-DOI, TCB-2, LSD and LA-SS-Az have unexpectedly also been found to act as potent inhibitors of TNF, with DOI being the most active, showing TNF inhibition in the picomolar range, an order of magnitude more potent than its action as a hallucinogen.
The role of TNF as a key player in the development of rheumatoid arthritis was originally demonstrated by Kollias and colleagues in proof of principle studies in transgenic animal models.
The FDA continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factors (TNF) blockers, as well as with azathioprine, and/or mercaptopurine.
Starting TNF inhibition puts patients at increased risk of opportunistic infections. FDA has warned about the risk of infection from two bacterial pathogens, Legionella and Listeria. People taking TNF blockers are at increased risk for developing serious infections that may lead to hospitalization or death due to bacterial, mycobacterial, fungal, viral, parasitic, and other opportunistic pathogens.
In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent TB infection or disease. The anti-TNF monoclonal antibody biologics, Infliximab and adalimumab, and the fusion proteinetanercept which are all currently approved by the U.S. Food and Drug Administration (FDA) for human use, have label warnings which state that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with these medications.
The U.S. Food and Drug Administration (FDA) issued a warning on September 4, 2008, that patients on TNF inhibitors are at increased risk of opportunistic fungal infections, such as pulmonary and disseminated histoplasmosis, coccidioidomycosis, and blastomycosis. They encourage clinicians to consider empiric antifungal therapy in all patients at risk until the pathogen is identified.
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