ATNF inhibitor is apharmaceutical drug that suppresses the physiologic response totumor necrosis factor (TNF), which is part of theinflammatory response. TNF is involved in autoimmune and immune-mediated disorders such asrheumatoid arthritis,ankylosing spondylitis,inflammatory bowel disease,psoriasis,hidradenitis suppurativa and refractoryasthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections (especially reactivation of latenttuberculosis),congestive heart failure,demyelinating disease, a lupus-like syndrome, induction ofauto-antibodies,injection site reactions, and systemic side effects.^[1]

The global market for TNF inhibitors in 2008 wasUS$13.5 billion,^[2] in 2009US$22 billion,^[3] and in 2024US$44 billion.^[4]

Inhibition of TNF effects can be achieved with amonoclonal antibody such asinfliximab,^[5]adalimumab,certolizumab pegol, andgolimumab, or with a circulating receptorfusion protein such asetanercept.

While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such asxanthine derivatives^[6] (e.g.pentoxifylline)^[7] andbupropion.^[8]

Thalidomide and its derivativeslenalidomide andpomalidomide are also active against TNF.

Several5-HT_2A agonisthallucinogens including (R)-DOI,TCB-2,LSD andLA-SS-Az have unexpectedly also been found to act as potent inhibitors of TNF, with DOI being the most active, showing TNF inhibition in thepicomolar range, an order of magnitude more potent than its action as a hallucinogen.^[9][10][11]

The role of TNF as a key player in the development ofrheumatoid arthritis was originally demonstrated byKollias and colleagues in proof of principle studies in transgenic animal models.^[12][13]

TNF levels have been shown to be raised in both thesynovial fluid andsynovium of patients with rheumatoid arthritis. This leads to local inflammation through the signalling of synovial cells to producemetalloproteinases andcollagenase.^[14]

Clinical application of anti-TNF drugs in rheumatoid arthritis was demonstrated byMarc Feldmann andRavinder N. Maini, who won the 2003Lasker Award for their work.^[15] Anti-TNF compounds help eliminate abnormal B cell activity.^[16][17]

Therapy which combines certain anti-TNF agents such asetanercept withDMARDs such asmethotrexate has been shown to be more effective at restoring quality of life to sufferers of rheumatoid arthritis than using either drug alone.^[14]

Clinical trials regarding the effectiveness of these drugs onhidradenitis suppurativa are ongoing.^[18]

The National Institute of Clinical Excellence (NICE) has issued guidelines for the treatment of severe psoriasis using the anti-TNF drugs etanercept and adalimumab as well as the anti-IL12/23 biological treatmentustekinumab. In cases where more conventional systemic treatments such as psoralen combined with ultraviolet A treatment (PUVA),methotrexate, andciclosporin have failed or can not be tolerated, these newer biological agents may be prescribed. Infliximab may be used to treat severe plaque psoriasis if aforementioned treatments fail or can not be tolerated.^[19]

In 2010 The National Institute of Clinical Excellence (NICE) in the UK issued guidelines for the treatment of severeCrohn's Disease with infliximab and adalimumab.^[20]

Anti-TNF therapy has shown only modest effects in cancer therapy. Treatment ofrenal cell carcinoma withinfliximab resulted in prolonged disease stabilization in certain patients.Etanercept was tested for treating patients withbreast cancer andovarian cancer showing prolonged disease stabilization in certain patients via downregulation ofIL-6 andCCL2. On the other hand, addinginfliximab oretanercept togemcitabine for treating patients with advancedpancreatic cancer was not associated with differences in efficacy when compared with placebo.^[21]

TheU.S. Food and Drug Administration continues to receive reports of a rare cancer of white blood cells (known ashepatosplenic T-cell lymphoma or HSTCL), primarily in adolescents and young adults being treated forCrohn's disease andulcerative colitis with TNF blockers, as well as withazathioprine, and/ormercaptopurine.^[22]

TNF inhibitors put patients at increased risk of certain opportunistic infections. The FDA has warned about the risk of infection from two bacterial pathogens,Legionella andListeria. People taking TNF blockers are at increased risk for developing serious infections that may lead to hospitalization or death due to certain bacterial,mycobacterial, fungal, viral, and parasitic opportunistic pathogens.^[23]

In patients with latentMycobacterium tuberculosis infection, activetuberculosis (TB) may develop soon after the initiation of treatment with infliximab.^[24] Before prescribing a TNF inhibitor, physicians should screen patients for latent tuberculosis. The anti-TNF monoclonal antibody biologics infliximab, golimumab, certolizumab and adalimumab, and thefusion proteinetanercept, which are all currently approved by the FDA for human use, have warnings which state that patients should be evaluated for latent TB infection, and if it is detected, preventive treatment should be initiated prior to starting therapy with these medications.

The 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 disseminatedhistoplasmosis,coccidioidomycosis, andblastomycosis. They encourage clinicians to consider empiric antifungal therapy in certain circumstances to all patients at risk until the pathogen is identified.^[25] A recent review showed that anti-TNFα agents associate with increased infection risks for both endemic and opportunistic invasive fungal infections, particularly when given late in the overall course of treatment of the underlying disease, and in young patients receiving concomitant cytotoxic or augmented immunosuppressive therapy.^[26]

In 1999 a randomized control trial was conducted testing a TNF-alpha inhibitor prototype, Lenercept, for the treatment ofmultiple sclerosis (MS). However, the patients in the study who received the drug had significantly more exacerbations and earlier exacerbations of their disease than those who did not.^[27][28]

Case reports have also come out suggesting the possibility that anti-TNF-alpha agents not only may worsen, but may cause new-onset Multiple Sclerosis or otherdemyelinating disorders in some patients.^[28] A 2018 case report described an Italian man with plaque psoriasis who developed MS after starting entanercept. Their literature review at that time identified 34 other cases of demyelinating disease developing after the initiation of an anti-TNF drug.^[29] Thus, anti-TNF-alpha drugs are contraindicated in patients with MS, and the American Academy of Dermatology recommends avoiding their use in those with a first degree relative with MS.^[30][28]

Several other monoclonal antibodies likeadalimumab,^[31][32]pembrolizumab,^[33]nivolumab, andinfliximab^[34] have been reported to trigger MS as an adverse event.^[35][28]

The risk of anti-TNF-associated demyelination is not associated with genetic variants of multiple sclerosis. In some studies, there were clinical differences to multiple sclerosis as 70% of the patients with anti-TNF-induced demyelination. The symptoms of demyelination do not resolve with corticosteroids, intravenous immunoglobulin or plasma exchange, and is not clear whether MS therapies are effective in anti-TNF-induced demyelination.^[36]

Despite their good safety profile, one of the common adverse events and side effects associated with TNF-α inhibitors is the occurrence of paradoxicalpsoriasis.^[37][38][39] Paradoxicalpsoriasis is defined as the development of psoriatic lesions or as an exacerbation of pre-existent psoriatic lesions, in patients with or without a prior history ofpsoriasis, while undergoing treatment with TNF-α inhibitors, such asinfliximab,adalimumab, andetanercept for their underlying inflammatory disease.^[37][38][39] The first case of paradoxicalpsoriasis induced by TNF-α inhibitors was reported in a patient suffering frominflammatory bowel disease.^[37][38][39] Subsequently, an increasing number of cases were reported in IBD cohorts and in patients suffering from other chronic immune-mediated inflammatory diseases such asrheumatoid arthritis.^[37][38][39] This increase was positively correlated with the increasing use of TNF-α inhibitors.^[37][38][39] The rates of paradoxicalpsoriasis reported across observational studies range from 2% to 5%, with higher rates observed in female patients.^[37][38][39] The time to onset from induction therapy can range anywhere from a few days to a few months; with the most common clinical presentations being pustular psoriasis, plaque psoriasis and guttate psoriasis, with nail and scalp involvement.^[37][38][39] Moreover, some patients may experience more than one type of lesion and/or have lesions across multiple locations.^[37][38][39]

TNF or its effects are inhibited by several natural compounds, includingcurcumin^{[40][41][42][43]} (a compound present inturmeric), andcatechins (ingreen tea).Cannabidiol^[44] andEchinacea purpurea also seem to have anti-inflammatory properties through inhibition of TNF-α production, although this effect may be mediated through cannabinoidCB₁ orCB₂ receptor-independent effects.^[45]

5-HT_2A receptor agonists have also been shown to have potent inhibitory effects on TNF-α, includingpsilocybin found in many species of mushrooms.^[46][47]

Thymoquinone, a compound found in the flowerNigella sativa, has been studied for possible TNF-α inhibition and related benefits for autoimmune disorder treatment.^{[48][49][50][51]}

Early experiments associated TNF with the pathogenesis of bacterial sepsis. Thus, the first preclinical studies usingpolyclonal antibodies against TNF-alpha were performed in animal models of sepsis in 1985 and showed that anti-TNF antibodies protected mice from sepsis.^[52][53] However, subsequent clinical trials in patients with sepsis showed no significant benefit. It wasn't until 1991 that studies in a transgenic mouse model of overexpressed human TNF provided the pre-clinical rationale for a causal role of TNF in the development of polyarthritis and that anti-TNF treatments could be effective against human arthritides.^[12] This was later confirmed in clinical trials^[54] and led to the development of the first biological therapies for rheumatoid arthritis.

• TNF inhibitors
• Immunology
• Biotechnology
• Immune system
• Monoclonal antibodies

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