{{Short description|Class of immunosuppressive drug}}
thumb | right | alt=A diagram of a cell wall that shows the function of TNF-α and TNF- α inhibitor. With a TNF- α inhibitor in the TNF receptor, a TNF- α protein cannot bind to the receptor, which prevents the inflammatory response. | The function of TNF-α and TNF- α inhibitor A '''TNF inhibitor''' is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections (especially reactivation of latent tuberculosis), congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.<ref>{{cite journal | vauthors = Scheinfeld N | title = A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab | journal = The Journal of Dermatological Treatment | volume = 15 | issue = 5 | pages = 280–294 | date = September 2004 | pmid = 15370396 | doi = 10.1080/09546630410017275 | s2cid = 43332215 }}</ref>
The global market for TNF inhibitors in 2008 was {{US$|13.5 billion}},<ref>{{cite journal | vauthors = Pappas DA, Bathon JM, Hanicq D, Yasothan U, Kirkpatrick P | title = Golimumab | journal = Nature Reviews. Drug Discovery | volume = 8 | issue = 9 | pages = 695–696 | date = September 2009 | pmid = 19721444 | doi = 10.1038/nrd2982 }}</ref> in 2009 {{US$|22 billion}},<ref>{{cite web|url=http://knol.google.com/k/top-ten-twenty-best-selling-drugs-2009#Best_selling_therapeutic_categoriesBest_selling_therapeutic_categoriesef |title=Top Ten/Twenty Best Selling Drugs 2009 |access-date=2011-09-08 |archive-url=https://web.archive.org/web/20110917104658/http://knol.google.com/k/top-ten-twenty-best-selling-drugs-2009 |archive-date=2011-09-17 }}</ref> and in 2024 {{US$|44 billion}}.<ref>{{cite web|url=https://www.factmr.com/report/tumor-necrosis-factor-tnf-inhibitors-market#:~:text=The%20global%20tumor%20necrosis%20factor,USD%2050.3%20billion%20by%202035 | title=Tumor Necrosis Factor Inhibitors Market Statistics - 2035 }}</ref>
==Examples== Inhibition of TNF effects can be achieved with a monoclonal antibody such as infliximab,<ref>{{cite journal | vauthors = Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C | title = Binding and functional comparisons of two types of tumor necrosis factor antagonists | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 301 | issue = 2 | pages = 418–426 | date = May 2002 | pmid = 11961039 | doi = 10.1124/jpet.301.2.418 | s2cid = 43021140 }}</ref> adalimumab, certolizumab pegol, and golimumab, or with a circulating receptor fusion protein such as etanercept.
While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such as xanthine derivatives<ref name="pmid11692087">{{cite journal | vauthors = Essayan DM | title = Cyclic nucleotide phosphodiesterases | journal = The Journal of Allergy and Clinical Immunology | volume = 108 | issue = 5 | pages = 671–680 | date = November 2001 | pmid = 11692087 | doi = 10.1067/mai.2001.119555 | s2cid = 21528985 | doi-access = free }}</ref> (e.g. pentoxifylline)<ref name="pmid9927365">{{cite journal | vauthors = Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U | title = Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages | journal = American Journal of Respiratory and Critical Care Medicine | volume = 159 | issue = 2 | pages = 508–511 | date = February 1999 | pmid = 9927365 | doi = 10.1164/ajrccm.159.2.9804085 }}</ref> and bupropion.<ref name="pmid16644475">{{cite journal | vauthors = Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB | title = A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice | journal = International Immunopharmacology | volume = 6 | issue = 6 | pages = 903–907 | date = June 2006 | pmid = 16644475 | doi = 10.1016/j.intimp.2005.12.007 | url = https://www.arca.fiocruz.br/handle/icict/2741 }}</ref>
Thalidomide and its derivatives lenalidomide and pomalidomide are also active against TNF.
Several 5-HT<sub>2A</sub> 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.<ref name="pmid9928254">{{cite journal | vauthors = Miller KJ, Gonzalez HA | title = Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells | journal = Annals of the New York Academy of Sciences | volume = 861 | issue = 1 | pages = 169–173 | date = December 1998 | pmid = 9928254 | doi = 10.1111/j.1749-6632.1998.tb10188.x | s2cid = 23264746 | bibcode = 1998NYASA.861..169M }}</ref><ref name="pmid18708586">{{cite journal | vauthors = Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD | title = Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 327 | issue = 2 | pages = 316–323 | date = November 2008 | pmid = 18708586 | doi = 10.1124/jpet.108.143461 | s2cid = 25374241 }}</ref><ref name="pmid20048135">{{cite journal | vauthors = Pelletier M, Siegel RM | title = Wishing away inflammation? New links between serotonin and TNF signaling | journal = Molecular Interventions | volume = 9 | issue = 6 | pages = 299–301 | date = December 2009 | pmid = 20048135 | pmc = 2861806 | doi = 10.1124/mi.9.6.5 }}</ref> Similarly, many sigma-1 agonist psychoactive drugs including dextromethorphan, fluoxetine, and cocaine have also been found to inhibit TNF to varying degrees.<ref>{{Cite journal |last1=Chen |first1=Der-Yuan |last2=Song |first2=Pei-Shan |last3=Hong |first3=Jau-Shyong |last4=Chu |first4=Ching-Liang |last5=Pan |first5=I.-Horng |last6=Chen |first6=Yi-Ming |last7=Lin |first7=Ching-Hsiung |last8=Lin |first8=Sheng-Hao |last9=Lin |first9=Chi-Chen |date=2013 |title=Dextromethorphan inhibits activations and functions in dendritic cells |journal=Clinical & Developmental Immunology |volume=2013 |article-number=125643 |doi=10.1155/2013/125643 |doi-access=free |issn=1740-2530 |pmc=3679715 |pmid=23781253}}</ref><ref>{{Cite journal |last1=Almeida |first1=Isabella Barros |last2=Gomes |first2=Isla Alcântara |last3=Shanmugam |first3=Saravanan |last4=de Moura |first4=Tatiana Rodrigues |last5=Magalhães |first5=Lucas Sousa |last6=de Aquino |first6=Luana Aline Gonçalves |last7=de Souza Araújo |first7=Adriano Antunes |last8=Oliveira |first8=Pedro Dantas |last9=Santos |first9=Márcio Roberto Viana |date=July 2020 |title=Inflammatory modulation of fluoxetine use in patients with depression: A systematic review and meta-analysis |journal=Cytokine |volume=131 |article-number=155100 |doi=10.1016/j.cyto.2020.155100 |issn=1096-0023 |pmid=32315957}}</ref><ref>{{Cite journal |last1=Fu |first1=Xiaoyu |last2=Bian |first2=Chuanxiu |last3=Kruyer |first3=Anna |last4=Zhou |first4=Zejun |last5=Luo |first5=Zhenwu |last6=Haque |first6=Azizul |last7=Wagner |first7=Amanda |last8=Lang |first8=Ren |last9=Fitting |first9=Sylvia |last10=Robinson |first10=Catrina |last11=McRae-Clark |first11=Aimee |last12=Amato |first12=Davide |last13=Jiang |first13=Wei |date=2022 |title=Cocaine administration protects gut mucosa barrier and reduces plasma level of TNF-α |journal=Current Psychopharmacology |volume=11 |issue=2 |pages=1–8 |article-number=e180822207620 |doi=10.2174/2211556011666220818091709 |issn=2211-5560 |pmc=9974179 |pmid=36860288}}</ref>
== Medical uses ==
=== Rheumatoid arthritis === The role of TNF as a key player in the development of rheumatoid arthritis was originally demonstrated by Greek biologist George Kollias and colleagues in proof of principle studies in transgenic animal models.<ref name="pmid1721867">{{cite journal | vauthors = Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G | title = Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis | journal = The EMBO Journal | volume = 10 | issue = 13 | pages = 4025–4031 | date = December 1991 | pmid = 1721867 | pmc = 453150 | doi = 10.1002/j.1460-2075.1991.tb04978.x }}</ref><ref name="pmid26008591">{{cite journal | vauthors = Brenner D, Blaser H, Mak TW | title = Regulation of tumour necrosis factor signalling: live or let die | journal = Nature Reviews. Immunology | volume = 15 | issue = 6 | pages = 362–374 | date = June 2015 | pmid = 26008591 | doi = 10.1038/nri3834 | s2cid = 1550839 | url = https://orbilu.uni.lu/bitstream/10993/58011/1/Brenner%20and%20Blaser%20et%20al_Nature%20Reviews%20Immunol%202015.pdf }}</ref>
TNF levels have been shown to be raised in both the synovial fluid and synovium of patients with rheumatoid arthritis. This leads to local inflammation through the signalling of synovial cells to produce metalloproteinases and collagenase.<ref name="PMC3956207">{{cite journal | vauthors = Ma X, Xu S | title = TNF inhibitor therapy for rheumatoid arthritis | journal = Biomedical Reports | volume = 1 | issue = 2 | pages = 177–184 | date = March 2013 | pmid = 24648915 | pmc = 3956207 | doi = 10.3892/br.2012.42 }}</ref>
Clinical application of anti-TNF drugs in rheumatoid arthritis was demonstrated by Marc Feldmann and Ravinder N. Maini, who won the 2003 Lasker Award for their work.<ref name="pmid14520364">{{cite journal | vauthors = Feldmann M, Maini RN | title = Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases | journal = Nature Medicine | volume = 9 | issue = 10 | pages = 1245–1250 | date = October 2003 | pmid = 14520364 | doi = 10.1038/nm939 | s2cid = 52860838 }}</ref> Anti-TNF compounds help eliminate abnormal B cell activity.<ref name="pmid18178805">{{cite journal | vauthors = Anolik JH, Ravikumar R, Barnard J, Owen T, Almudevar A, Milner EC, Miller CH, Dutcher PO, Hadley JA, Sanz I | display-authors = 6 | title = Cutting edge: anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effects on lymphoid germinal centers and follicular dendritic cell networks | journal = Journal of Immunology | volume = 180 | issue = 2 | pages = 688–692 | date = January 2008 | pmid = 18178805 | doi = 10.4049/jimmunol.180.2.688 | s2cid = 45744340 | doi-access = free }}</ref><ref>{{cite web|url=http://medicineworld.org/cancer/lead/1-2008/drugs-used-to-treat-rheumatoid-arthritis.html|title=A new view of drugs used to treat rheumatoid arthritis from medicineworld.org|website=medicineworld.org|access-date=16 April 2018}}</ref>
Therapy which combines certain anti-TNF agents such as etanercept with DMARDs such as methotrexate has been shown to be more effective at restoring quality of life to sufferers of rheumatoid arthritis than using either drug alone.<ref name="PMC3956207"/>
=== Skin disease === Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are ongoing.<ref name="pmid19997689">{{cite journal | vauthors = Haslund P, Lee RA, Jemec GB | title = Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors | journal = Acta Dermato-Venereologica | volume = 89 | issue = 6 | pages = 595–600 | date = November 2009 | pmid = 19997689 | doi = 10.2340/00015555-0747 | doi-access = free }}</ref>
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 treatment ustekinumab. In cases where more conventional systemic treatments such as psoralen combined with ultraviolet A treatment (PUVA), methotrexate, and ciclosporin 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.<ref>{{cite web|url=https://www.psoriasis-association.org.uk|title=Psoriasis Association|website=psoriasis-association.org.uk|access-date=16 April 2018}}</ref>
=== Gastrointestinal disease === In 2010 The National Institute of Clinical Excellence (NICE) in the UK issued guidelines for the treatment of severe Crohn's Disease with infliximab and adalimumab.<ref>{{Cite web|url=https://www.nice.org.uk/guidance/TA187/chapter/1-Guidance|title=Infliximab and adalimumab for the treatment of Crohn's disease {{!}} 1-guidance {{!}} Guidance and guidelines {{!}} NICE|website=www.nice.org.uk|date=19 May 2010 |access-date=2016-12-04}}</ref>
=== Cancer === Anti-TNF therapy has shown only modest effects in cancer therapy. Treatment of renal cell carcinoma with infliximab resulted in prolonged disease stabilization in certain patients. Etanercept was tested for treating patients with breast cancer and ovarian cancer showing prolonged disease stabilization in certain patients via downregulation of IL-6 and CCL2. On the other hand, adding infliximab or etanercept to gemcitabine for treating patients with advanced pancreatic cancer was not associated with differences in efficacy when compared with placebo.<ref>{{cite journal | vauthors = Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA | title = TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis | journal = Cytokine | volume = 89 | pages = 127–135 | date = January 2017 | pmid = 26854213 | doi = 10.1016/j.cyto.2016.01.021 }}</ref>
==Side effects==
===Cancer=== The U.S. Food and Drug Administration 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 TNF blockers, as well as with azathioprine, and/or mercaptopurine.<ref>{{cite web|url=https://www.drugs.com/fda/tumor-necrosis-factor-tnf-blockers-azathioprine-mercaptopurine-update-reports-hepatosplenic-t-cell-12945.html|title=FDA Alert: Tumor Necrosis Factor (TNF) blockers, Azathioprine and/or Mercaptopurine: Update on Reports of Hepatosplenic T-Cell Lymphoma in Adolescents and Young Adults|website=drugs.com|access-date=16 April 2018}}</ref>
===Opportunistic infections=== 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'' and ''Listeria''. 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.<ref>{{cite web|url=https://www.drugs.com/fda/tumor-necrosis-factor-alpha-tnf-alpha-blockers-label-change-boxed-warning-updated-risk-infection-13023.html|title=FDA Alert: Tumor Necrosis Factor-alpha (TNFα) Blockers: Label Change - Boxed Warning Updated for Risk of Infection from Legionella and Listeria|website=drugs.com|access-date=16 April 2018}}</ref>
==== Tuberculosis ==== In patients with latent ''Mycobacterium tuberculosis'' infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab.<ref name="pmid11596589">{{cite journal | vauthors = Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM | display-authors = 6 | title = Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent | journal = The New England Journal of Medicine | volume = 345 | issue = 15 | pages = 1098–1104 | date = October 2001 | pmid = 11596589 | doi = 10.1056/NEJMoa011110 | doi-access = free }}</ref> Before prescribing a TNF inhibitor, physicians should screen patients for latent tuberculosis. The anti-TNF monoclonal antibody biologics infliximab, golimumab, certolizumab and adalimumab, and the fusion protein etanercept, 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.
==== Fungal infections ==== 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 disseminated histoplasmosis, coccidioidomycosis, and blastomycosis. They encourage clinicians to consider empiric antifungal therapy in certain circumstances to all patients at risk until the pathogen is identified.<ref>{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116942.htm | archive-url = https://web.archive.org/web/20090710095910/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116942.htm | archive-date = July 10, 2009 | title = FDA: Manufacturers of TNF-Blocker Drugs Must Highlight Risk of Fungal Infections | publisher = U.S. Food and Drug Administration (FDA) | date = September 4, 2008 | access-date = 2009-11-15}}</ref> 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.<ref>{{cite journal | vauthors = Tragiannidis A, Kyriakidis I, Zündorf I, Groll AH | title = Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors | journal = Mycoses | volume = 60 | issue = 4 | pages = 222–229 | date = April 2017 | pmid = 27766695 | doi = 10.1111/myc.12576 | s2cid = 23722641 }}</ref>
=== Multiple sclerosis and demyelinating disorders === In 1999 a randomized control trial was conducted testing a TNF-alpha inhibitor prototype, Lenercept, for the treatment of multiple 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.<ref>{{cite journal | vauthors = | title = TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group | journal = Neurology | volume = 53 | issue = 3 | pages = 457–465 | date = August 1999 | pmid = 10449104 | doi = 10.1212/WNL.53.3.457 | s2cid = 26126291 | doi-access = free }}</ref><ref name=":0" />
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 other demyelinating disorders in some patients.<ref name=":0">{{cite journal | vauthors = Kemanetzoglou E, Andreadou E | title = CNS Demyelination with TNF-α Blockers | journal = Current Neurology and Neuroscience Reports | volume = 17 | issue = 4 | article-number = 36 | date = April 2017 | pmid = 28337644 | pmc = 5364240 | doi = 10.1007/s11910-017-0742-1 }}</ref> 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.<ref>{{cite journal | vauthors = Napolitano M, Balato N, Ayala F, Cirillo T, Balato A | title = Multiple sclerosis following anti-tumor necrosis factor-alpha therapy for psoriasis: first case in Italy? | journal = Giornale Italiano di Dermatologia e Venereologia | volume = 153 | issue = 4 | pages = 567–572 | date = August 2018 | pmid = 25692775 | doi = 10.23736/S0392-0488.17.04992-6 }}</ref> 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.<ref>{{cite journal | vauthors = Mansouri B, Horner ME, Menter A | title = Tumor Necrosis Factor-α Inhibitor Use in Psoriasis Patients With a First-degree Relative With Multiple Sclerosis | journal = Journal of Drugs in Dermatology | volume = 14 | issue = 8 | pages = 876–878 | date = August 2015 | pmid = 26267733 }}</ref><ref name=":0" />
Several other monoclonal antibodies like adalimumab,<ref name="doi.org">{{cite journal | vauthors = Engel S, Luessi F, Mueller A, Schopf RE, Zipp F, Bittner S | title = PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders | journal = Therapeutic Advances in Neurological Disorders | volume = 13 | article-number = 1756286419895155 | date = 2 January 2020 | pmid = 31921355 | pmc = 6940603 | doi = 10.1177/1756286419895155 }}</ref><ref name="dx.doi.org">{{cite journal | vauthors = Alnasser Alsukhni R, Jriekh Z, Aboras Y | title = Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature | journal = Case Reports in Medicine | volume = 2016 | article-number = 1423131 | date = 2016-10-20 | pmid = 27840642 | pmc = 5093248 | doi = 10.1155/2016/1423131 | doi-access = free }}</ref> pembrolizumab,<ref name="Marzia Anita Lucia Romeo pp 1">{{cite journal | vauthors = Romeo MA, Garassino MC, Moiola L, Galli G, Comi G, Martinelli V, Filippi M | title = Multiple sclerosis associated with pembrolizumab in a patient with non-small cell lung cancer | journal = Journal of Neurology | volume = 266 | issue = 12 | pages = 3163–3166 | date = December 2019 | pmid = 31586260 | doi = 10.1007/s00415-019-09562-z | s2cid = 203654410 }}</ref> nivolumab, and infliximab<ref name="ReferenceC">{{cite journal | vauthors = Kalinowska-Lyszczarz A, Fereidan-Esfahani M, Guo Y, Lucchinetti CF, Tobin WO | title = Pathological findings in central nervous system demyelination associated with infliximab | journal = Multiple Sclerosis | volume = 26 | issue = 9 | pages = 1124–1129 | date = August 2020 | pmid = 31845616 | pmc = 7297659 | doi = 10.1177/1352458519894710 }}</ref> have been reported to trigger MS as an adverse event.<ref>{{cite journal | vauthors = Garcia CR, Jayswal R, Adams V, Anthony LB, Villano JL | title = Multiple sclerosis outcomes after cancer immunotherapy | journal = Clinical & Translational Oncology | volume = 21 | issue = 10 | pages = 1336–1342 | date = October 2019 | pmid = 30788836 | pmc = 6702101 | doi = 10.1007/s12094-019-02060-8 }}</ref><ref name=":0" />
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.<ref>{{cite journal | vauthors = Williams I, Uhlig HH | title = Demyelination After Anti-TNF Therapy: Who is at Risk? | journal = Journal of Crohn's & Colitis | volume = 14 | issue = 12 | pages = 1651–1652 | date = December 2020 | pmid = 33026456 | doi = 10.1093/ecco-jcc/jjaa144 | doi-access = free }}</ref>
===Paradoxical psoriasis===
Despite their good safety profile, one of the reported side effects of TNF-α inhibitors is the occurrence of paradoxical psoriasis; defined as the development of psoriatic lesions or as an exacerbation of pre-existent lesions, in patients with or without a prior history of psoriasis, while undergoing treatment with TNF-α inhibitors, such as infliximab, adalimumab, and etanercept for their underlying inflammatory disease.<ref name=":1">{{Cite journal |last1=Bucalo |first1=Agostino |last2=Rega |first2=Federica |last3=Zangrilli |first3=Arianna |last4=Silvestri |first4=Valentina |last5=Valentini |first5=Virginia |last6=Scafetta |first6=Giorgia |last7=Marraffa |first7=Federica |last8=Grassi |first8=Sara |last9=Rogante |first9=Elena |last10=Piccolo |first10=Arianna |last11=Cucchiara |first11=Salvatore |last12=Viola |first12=Franca |last13=Bianchi |first13=Luca |last14=Ottini |first14=Laura |last15=Richetta |first15=Antonio |date=January 2020 |title=Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers |journal=International Journal of Molecular Sciences |language=en |volume=21 |issue=21 |page=7873 |doi=10.3390/ijms21217873 |pmid=33114187 |pmc=7660646 |issn=1422-0067 |doi-access=free }}{{Creative Commons text attribution notice|cc=by4|from this source=yes}}</ref><ref name=":2">{{Cite journal |last1=Vasconcellos |first1=Jaqueline Barbeito de |last2=Pereira |first2=Daniele do Nascimento |last3=Vargas |first3=Thiago Jeunon de Sousa |last4=Levy |first4=Roger Abramino |last5=Pinheiro |first5=Geraldo da Rocha Castelar |last6=Cursi |first6=Ígor Brum |date=September–October 2016 |title=Paradoxical psoriasis after the use of anti-TNF in a patient with rheumatoid arthritis |journal=Anais Brasileiros de Dermatologia |language=en |volume=91 |issue=5 suppl 1 |pages=137–139 |doi=10.1590/abd1806-4841.20164456 |pmid=28300922 |pmc=5325021 |issn=0365-0596}}</ref><ref name=":3">{{Cite journal |last1=Toussirot |first1=Éric |last2=Aubin |first2=François |date=2016-07-01 |title=Paradoxical reactions under TNF-α blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview |url=https://rmdopen.bmj.com/content/2/2/e000239 |journal=RMD Open |language=en |volume=2 |issue=2 |article-number=e000239 |doi=10.1136/rmdopen-2015-000239 |issn=2056-5933 |pmid=27493788|pmc=4964220 }}</ref> The first case of paradoxical psoriasis induced by TNF-α inhibitors was reported in a patient with inflammatory bowel disease.<ref name=":1" /><ref name=":2" /><ref name=":3" /> Since then, an increasing number of cases have been reported in IBD cohorts and in patients suffering from other chronic immune-mediated inflammatory diseases such as rheumatoid arthritis.<ref name=":1" /><ref name=":2" /><ref name=":3" /> This increase is positively correlated with the increasing use of TNF-α inhibitors.<ref name=":1" /><ref name=":2" /><ref name=":3" /> The rates of paradoxical psoriasis reported across observational studies range from 2% to 5%, with higher rates observed in female patients.<ref name=":1" /><ref name=":2" /><ref name=":3" /> The time to onset from induction can range anywhere from a few days to a few months.<ref name=":1" /><ref name=":2" /><ref name=":3" /> The most common clinical presentations being pustular psoriasis, plaque psoriasis and guttate psoriasis, with nail and scalp involvement.<ref name=":1" /><ref name=":2" /><ref name=":3" /> Some patients may experience more than one type of lesion and/or have lesions across multiple locations.<ref name=":1" /><ref name=":2" /><ref name=":3" />
== Anti-TNF agents in nature == TNF or its effects are inhibited by several natural compounds, including curcumin<ref name="pmid16715036">{{cite journal | vauthors = Siddiqui AM, Cui X, Wu R, Dong W, Zhou M, Hu M, Simms HH, Wang P | display-authors = 6 | title = The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma | journal = Critical Care Medicine | volume = 34 | issue = 7 | pages = 1874–1882 | date = July 2006 | pmid = 16715036 | doi = 10.1097/01.CCM.0000221921.71300.BF | s2cid = 71135736 }}</ref><ref name="pmid16751071">{{cite journal | vauthors = Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, Pentland A, Ryan JL, Ding I | display-authors = 6 | title = Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines | journal = International Journal of Radiation Oncology, Biology, Physics | volume = 65 | issue = 3 | pages = 890–898 | date = July 2006 | pmid = 16751071 | doi = 10.1016/j.ijrobp.2006.03.025 }}</ref><ref name="pmid16411910">{{cite journal | vauthors = Gulcubuk A, Altunatmaz K, Sonmez K, Haktanir-Yatkin D, Uzun H, Gurel A, Aydin S | title = Effects of curcumin on tumour necrosis factor-alpha and interleukin-6 in the late phase of experimental acute pancreatitis | journal = Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine | volume = 53 | issue = 1 | pages = 49–54 | date = February 2006 | pmid = 16411910 | doi = 10.1111/j.1439-0442.2006.00786.x }}</ref><ref name="pmid16008121">{{cite journal | vauthors = Lantz RC, Chen GJ, Solyom AM, Jolad SD, Timmermann BN | title = The effect of turmeric extracts on inflammatory mediator production | journal = Phytomedicine | volume = 12 | issue = 6–7 | pages = 445–452 | date = June 2005 | pmid = 16008121 | doi = 10.1016/j.phymed.2003.12.011 }}</ref> (a compound present in turmeric), and catechins (in green tea). Cannabidiol<ref>{{cite journal | vauthors = Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO | title = Cannabidiol--recent advances | journal = Chemistry & Biodiversity | volume = 4 | issue = 8 | pages = 1678–1692 | date = August 2007 | pmid = 17712814 | doi = 10.1002/cbdv.200790147 | s2cid = 3689072 }}</ref> and ''Echinacea purpurea'' also seem to have anti-inflammatory properties through inhibition of TNF-α production, although this effect may be mediated through cannabinoid CB<sub>1</sub> or CB<sub>2</sub> receptor-independent effects.<ref name="pmid16547349">{{cite journal | vauthors = Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J | display-authors = 6 | title = Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects | journal = The Journal of Biological Chemistry | volume = 281 | issue = 20 | pages = 14192–14206 | date = May 2006 | pmid = 16547349 | doi = 10.1074/jbc.M601074200 | s2cid = 1570400 | doi-access = free }}</ref>
5-HT<sub>2A</sub> receptor agonists as well as sigma-1 receptor agonists have also been shown to have potent inhibitory effects on TNF-α, including psilocybin found in many species of mushrooms and DMT found in a wide variety of plants.<ref>{{cite journal | vauthors = Nkadimeng SM, Steinmann CM, Eloff JN | title = Anti-Inflammatory Effects of Four Psilocybin-Containing Magic Mushroom Water Extracts in vitro on 15-Lipoxygenase Activity and on Lipopolysaccharide-Induced Cyclooxygenase-2 and Inflammatory Cytokines in Human U937 Macrophage Cells | journal = Journal of Inflammation Research | volume = 14 | pages = 3729–3738 | date = 2021 | pmid = 34385833 | pmc = 8352634 | doi = 10.2147/JIR.S317182 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Nau F, Yu B, Martin D, Nichols CD | title = Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo | journal = PLOS ONE | volume = 8 | issue = 10 | article-number = e75426 | date = 2013-10-02 | pmid = 24098382 | pmc = 3788795 | doi = 10.1371/journal.pone.0075426 | doi-access = free | bibcode = 2013PLoSO...875426N }}</ref><ref>{{Cite journal |last1=Szabo |first1=Attila |last2=Kovacs |first2=Attila |last3=Frecska |first3=Ede |last4=Rajnavolgyi |first4=Eva |date=2014 |title=Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells |journal=PLOS ONE |volume=9 |issue=8 |article-number=e106533 |doi=10.1371/journal.pone.0106533 |doi-access=free |issn=1932-6203 |pmc=4149582 |pmid=25171370 |bibcode=2014PLoSO...9j6533S }}</ref>
Thymoquinone, a compound found in the flower ''Nigella sativa'', has been studied for possible TNF-α inhibition and related benefits for autoimmune disorder treatment.<ref name="pmid26134265">{{cite journal | vauthors = Umar S, Hedaya O, Singh AK, Ahmed S | title = Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation | journal = Toxicology and Applied Pharmacology | volume = 287 | issue = 3 | pages = 299–305 | date = September 2015 | pmid = 26134265 | pmc = 4549173 | doi = 10.1016/j.taap.2015.06.017 | bibcode = 2015ToxAP.287..299U }}</ref><ref name="pmid29662431">{{cite journal | vauthors = Farkhondeh T, Samarghandian S, Shahri AM, Samini F | title = The Neuroprotective Effects of Thymoquinone: A Review | journal = Dose-Response | volume = 16 | issue = 2 | article-number = 1559325818761455 | date = 2018 | pmid = 29662431 | pmc = 5898665 | doi = 10.1177/1559325818761455 }}</ref><ref name="pmid33370631">{{cite journal | vauthors = Ali MY, Akter Z, Mei Z, Zheng M, Tania M, Khan MA | title = Thymoquinone in autoimmune diseases: Therapeutic potential and molecular mechanisms | journal = Biomedicine & Pharmacotherapy | volume = 134 | issue = | article-number = 111157 | date = February 2021 | pmid = 33370631 | doi = 10.1016/j.biopha.2020.111157 | s2cid = 229714190 | doi-access = free }}</ref><ref name="pmid34303824">{{cite journal | vauthors = Malik S, Singh A, Negi P, Kapoor VK | title = Thymoquinone: A small molecule from nature with high therapeutic potential | journal = Drug Discovery Today | volume = 26 | issue = 11 | pages = 2716–2725 | date = November 2021 | pmid = 34303824 | doi = 10.1016/j.drudis.2021.07.013 | s2cid = 236431672 }}</ref>
==History== Early experiments associated TNF with the pathogenesis of bacterial sepsis. Thus, the first preclinical studies using polyclonal antibodies against TNF-alpha were performed in animal models of sepsis in 1985 and showed that anti-TNF antibodies protected mice from sepsis.<ref>{{cite journal | vauthors = Vilcek J | title = First demonstration of the role of TNF in the pathogenesis of disease | journal = Journal of Immunology | volume = 181 | issue = 1 | pages = 5–6 | date = July 2008 | pmid = 18566362 | doi = 10.4049/jimmunol.181.1.5 | s2cid = 44529219 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Beutler B, Milsark IW, Cerami AC | title = Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science, 1985, 229(4716):869-871. Classical article | journal = Journal of Immunology | volume = 181 | issue = 1 | pages = 7–9 | date = July 2008 | doi = 10.1126/science.3895437 | pmid = 18566363 | url = https://www.science.org/doi/pdf/10.1126/science.3895437 | url-access = subscription }}</ref> 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.<ref name="pmid1721867"/> This was later confirmed in clinical trials<ref>{{cite journal | vauthors = Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H | display-authors = 6 | title = Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis | journal = Lancet | volume = 344 | issue = 8930 | pages = 1105–1110 | date = October 1994 | pmid = 7934491 | doi = 10.1016/S0140-6736(94)90628-9 | s2cid = 22776233 }}</ref> and led to the development of the first biological therapies for rheumatoid arthritis.
== References == {{reflist|32em}}
{{Immunosuppressants}} {{Cytokine receptor modulators}}
{{DEFAULTSORT:Tnf Inhibitor}} Category:TNF inhibitors Category:Immunology Category:Biotechnology Category:Immune system Category:Monoclonal antibodies