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.
Inhibition of TNF effects can be achieved with a monoclonal antibody such as infliximab, adalimumab, certolizumab pegol, and golimumab, or with a circulating receptor fusion protein such as etanercept.
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.
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.
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. Anti-TNF compounds help eliminate abnormal B cell activity.
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.
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.
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.
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.
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.
In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab. 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.
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. 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.
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.
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. 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. 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.
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.
Anti-TNF agents in nature
TNF or its effects are inhibited by several natural compounds, including curcumin (a compound present in turmeric), and catechins (in green tea). Cannabidiol and Echinacea purpurea also seem to have anti-inflammatory properties through inhibition of TNF-α production, although this effect may be mediated through cannabinoid CB1 or CB2 receptor-independent effects.
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. 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. This was later confirmed in clinical trials and led to the development of the first biological therapies for rheumatoid arthritis.
- Scheinfeld N (September 2004). "A comprehensive review and evaluation of the side effects of the tumor necrosis factor alpha blockers etanercept, infliximab and adalimumab". The Journal of Dermatological Treatment. 15 (5): 280–294. doi:10.1080/09546630410017275. PMID 15370396. S2CID 43332215.
- Pappas DA, Bathon JM, Hanicq D, Yasothan U, Kirkpatrick P (September 2009). "Golimumab". Nature Reviews. Drug Discovery. 8 (9): 695–696. doi:10.1038/nrd2982. PMID 19721444.
- "Top Ten/Twenty Best Selling Drugs 2009". Archived from the original on 2011-09-17. Retrieved 2011-09-08.
- Scallon B, Cai A, Solowski N, Rosenberg A, Song XY, Shealy D, Wagner C (May 2002). "Binding and functional comparisons of two types of tumor necrosis factor antagonists". The Journal of Pharmacology and Experimental Therapeutics. 301 (2): 418–426. doi:10.1124/jpet.301.2.418. PMID 11961039. S2CID 43021140.
- Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology. 108 (5): 671–680. doi:10.1067/mai.2001.119555. PMID 11692087. S2CID 21528985.
- Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine. 159 (2): 508–511. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
- Brustolim D, Ribeiro-dos-Santos R, Kast RE, Altschuler EL, Soares MB (June 2006). "A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice". International Immunopharmacology. 6 (6): 903–907. doi:10.1016/j.intimp.2005.12.007. PMID 16644475.
- Miller KJ, Gonzalez HA (December 1998). "Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells". Annals of the New York Academy of Sciences. 861 (1): 169–173. Bibcode:1998NYASA.861..169M. doi:10.1111/j.1749-6632.1998.tb10188.x. PMID 9928254. S2CID 23264746.
- Yu B, Becnel J, Zerfaoui M, Rohatgi R, Boulares AH, Nichols CD (November 2008). "Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-alpha-induced inflammation with extraordinary potency". The Journal of Pharmacology and Experimental Therapeutics. 327 (2): 316–323. doi:10.1124/jpet.108.143461. PMID 18708586. S2CID 25374241.
- Pelletier M, Siegel RM (December 2009). "Wishing away inflammation? New links between serotonin and TNF signaling". Molecular Interventions. 9 (6): 299–301. doi:10.1124/mi.9.6.5. PMC 2861806. PMID 20048135.
- Keffer J, Probert L, Cazlaris H, Georgopoulos S, Kaslaris E, Kioussis D, Kollias G (December 1991). "Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis". The EMBO Journal. 10 (13): 4025–4031. doi:10.1002/j.1460-2075.1991.tb04978.x. PMC 453150. PMID 1721867.
- Brenner D, Blaser H, Mak TW (June 2015). "Regulation of tumour necrosis factor signalling: live or let die". Nature Reviews. Immunology. 15 (6): 362–374. doi:10.1038/nri3834. PMID 26008591. S2CID 1550839.
- Ma X, Xu S (March 2013). "TNF inhibitor therapy for rheumatoid arthritis". Biomedical Reports. 1 (2): 177–184. doi:10.3892/br.2012.42. PMC 3956207. PMID 24648915.
- Feldmann M, Maini RN (October 2003). "Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases". Nature Medicine. 9 (10): 1245–1250. doi:10.1038/nm939. PMID 14520364. S2CID 52860838.
- Anolik JH, Ravikumar R, Barnard J, Owen T, Almudevar A, Milner EC, et al. (January 2008). "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 of Immunology. 180 (2): 688–692. doi:10.4049/jimmunol.180.2.688. PMID 18178805. S2CID 45744340.
- "A new view of drugs used to treat rheumatoid arthritis from medicineworld.org". medicineworld.org. Retrieved 16 April 2018.
- Haslund P, Lee RA, Jemec GB (November 2009). "Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors". Acta Dermato-Venereologica. 89 (6): 595–600. doi:10.2340/00015555-0747. PMID 19997689.
- "Psoriasis Association". psoriasis-association.org.uk. Retrieved 16 April 2018.
- "Infliximab and adalimumab for the treatment of Crohn's disease | 1-guidance | Guidance and guidelines | NICE". www.nice.org.uk. Retrieved 2016-12-04.
- Korneev KV, Atretkhany KN, Drutskaya MS, Grivennikov SI, Kuprash DV, Nedospasov SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine. 89: 127–135. doi:10.1016/j.cyto.2016.01.021. PMID 26854213.
- "FDA Alert: Tumor Necrosis Factor (TNF) blockers, Azathioprine and/or Mercaptopurine: Update on Reports of Hepatosplenic T-Cell Lymphoma in Adolescents and Young Adults". drugs.com. Retrieved 16 April 2018.
- "FDA Alert: Tumor Necrosis Factor-alpha (TNFα) Blockers: Label Change - Boxed Warning Updated for Risk of Infection from Legionella and Listeria". drugs.com. Retrieved 16 April 2018.
- Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. (October 2001). "Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent". The New England Journal of Medicine. 345 (15): 1098–1104. doi:10.1056/NEJMoa011110. PMID 11596589.
- "FDA: Manufacturers of TNF-Blocker Drugs Must Highlight Risk of Fungal Infections" (Press release). U.S. Food and Drug Administration (FDA). September 4, 2008. Retrieved 2009-11-15.
- Tragiannidis A, Kyriakidis I, Zündorf I, Groll AH (April 2017). "Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors". Mycoses. 60 (4): 222–229. doi:10.1111/myc.12576. PMID 27766695. S2CID 23722641.
- "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". Neurology. 53 (3): 457–465. August 1999. doi:10.1212/WNL.53.3.457. PMID 10449104. S2CID 26126291.
- Kemanetzoglou E, Andreadou E (April 2017). "CNS Demyelination with TNF-α Blockers". Current Neurology and Neuroscience Reports. 17 (4): 36. doi:10.1007/s11910-017-0742-1. PMC 5364240. PMID 28337644.
- Napolitano M, Balato N, Ayala F, Cirillo T, Balato A (August 2018). "Multiple sclerosis following anti-tumor necrosis factor-alpha therapy for psoriasis: first case in Italy?". Giornale Italiano di Dermatologia e Venereologia. 153 (4): 567–572. doi:10.23736/S0392-0488.17.04992-6. PMID 25692775.
- Mansouri B, Horner ME, Menter A (August 2015). "Tumor Necrosis Factor-α Inhibitor Use in Psoriasis Patients With a First-degree Relative With Multiple Sclerosis". Journal of Drugs in Dermatology. 14 (8): 876–878. PMID 26267733.
- Engel S, Luessi F, Mueller A, Schopf RE, Zipp F, Bittner S (2 January 2020). "PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders". Therapeutic Advances in Neurological Disorders. 13: 1756286419895155. doi:10.1177/1756286419895155. PMC 6940603. PMID 31921355.
- Alnasser Alsukhni R, Jriekh Z, Aboras Y (2016-10-20). "Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature". Case Reports in Medicine. 2016: 1423131. doi:10.1155/2016/1423131. PMC 5093248. PMID 27840642.
- Romeo MA, Garassino MC, Moiola L, Galli G, Comi G, Martinelli V, Filippi M (December 2019). "Multiple sclerosis associated with pembrolizumab in a patient with non-small cell lung cancer". Journal of Neurology. 266 (12): 3163–3166. doi:10.1007/s00415-019-09562-z. PMID 31586260. S2CID 203654410.
- Kalinowska-Lyszczarz A, Fereidan-Esfahani M, Guo Y, Lucchinetti CF, Tobin WO (August 2020). "Pathological findings in central nervous system demyelination associated with infliximab". Multiple Sclerosis. 26 (9): 1124–1129. doi:10.1177/1352458519894710. PMC 7297659. PMID 31845616.
- Garcia CR, Jayswal R, Adams V, Anthony LB, Villano JL (October 2019). "Multiple sclerosis outcomes after cancer immunotherapy". Clinical & Translational Oncology. 21 (10): 1336–1342. doi:10.1007/s12094-019-02060-8. PMC 6702101. PMID 30788836.
- Williams I, Uhlig HH (December 2020). "Demyelination After Anti-TNF Therapy: Who is at Risk?". Journal of Crohn's & Colitis. 14 (12): 1651–1652. doi:10.1093/ecco-jcc/jjaa144. PMID 33026456.
- Siddiqui AM, Cui X, Wu R, Dong W, Zhou M, Hu M, et al. (July 2006). "The anti-inflammatory effect of curcumin in an experimental model of sepsis is mediated by up-regulation of peroxisome proliferator-activated receptor-gamma". Critical Care Medicine. 34 (7): 1874–1882. doi:10.1097/01.CCM.0000221921.71300.BF. PMID 16715036. S2CID 71135736.
- Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, et al. (July 2006). "Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines". International Journal of Radiation Oncology, Biology, Physics. 65 (3): 890–898. doi:10.1016/j.ijrobp.2006.03.025. PMID 16751071.
- Gulcubuk A, Altunatmaz K, Sonmez K, Haktanir-Yatkin D, Uzun H, Gurel A, Aydin S (February 2006). "Effects of curcumin on tumour necrosis factor-alpha and interleukin-6 in the late phase of experimental acute pancreatitis". Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine. 53 (1): 49–54. doi:10.1111/j.1439-0442.2006.00786.x. PMID 16411910.
- Lantz RC, Chen GJ, Solyom AM, Jolad SD, Timmermann BN (June 2005). "The effect of turmeric extracts on inflammatory mediator production". Phytomedicine. 12 (6–7): 445–452. doi:10.1016/j.phymed.2003.12.011. PMID 16008121.
- Mechoulam R, Peters M, Murillo-Rodriguez E, Hanus LO (August 2007). "Cannabidiol--recent advances". Chemistry & Biodiversity. 4 (8): 1678–1692. doi:10.1002/cbdv.200790147. PMID 17712814. S2CID 3689072.
- Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, et al. (May 2006). "Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects". The Journal of Biological Chemistry. 281 (20): 14192–14206. doi:10.1074/jbc.M601074200. PMID 16547349. S2CID 1570400.
- Nkadimeng SM, Steinmann CM, Eloff JN (2021). "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 of Inflammation Research. 14: 3729–3738. doi:10.2147/JIR.S317182. PMC 8352634. PMID 34385833.
- Nau F, Yu B, Martin D, Nichols CD (2013-10-02). "Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo". PLOS ONE. 8 (10): e75426. Bibcode:2013PLoSO...875426N. doi:10.1371/journal.pone.0075426. PMC 3788795. PMID 24098382.
- Umar S, Hedaya O, Singh AK, Ahmed S (September 2015). "Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation". Toxicology and Applied Pharmacology. 287 (3): 299–305. doi:10.1016/j.taap.2015.06.017. PMC 4549173. PMID 26134265.
- Farkhondeh T, Samarghandian S, Shahri AM, Samini F (2018). "The Neuroprotective Effects of Thymoquinone: A Review". Dose-Response. 16 (2): 1559325818761455. doi:10.1177/1559325818761455. PMC 5898665. PMID 29662431.
- Ali MY, Akter Z, Mei Z, Zheng M, Tania M, Khan MA (February 2021). "Thymoquinone in autoimmune diseases: Therapeutic potential and molecular mechanisms". Biomedicine & Pharmacotherapy. 134: 111157. doi:10.1016/j.biopha.2020.111157. PMID 33370631. S2CID 229714190.
- Malik S, Singh A, Negi P, Kapoor VK (November 2021). "Thymoquinone: A small molecule from nature with high therapeutic potential". Drug Discovery Today. 26 (11): 2716–2725. doi:10.1016/j.drudis.2021.07.013. PMID 34303824. S2CID 236431672.
- Vilcek J (July 2008). "First demonstration of the role of TNF in the pathogenesis of disease". Journal of Immunology. 181 (1): 5–6. doi:10.4049/jimmunol.181.1.5. PMID 18566362. S2CID 44529219.
- Beutler B, Milsark IW, Cerami AC (July 2008). "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science, 1985, 229(4716):869-871. Classical article". Journal of Immunology. 181 (1): 7–9. doi:10.1126/science.3895437. PMID 18566363.
- Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, et al. (October 1994). "Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis". Lancet. 344 (8930): 1105–1110. doi:10.1016/S0140-6736(94)90628-9. PMID 7934491. S2CID 22776233.