Biology:TNF inhibitor

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Short description: Immunosuppressive drug

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.[1]

The global market for TNF inhibitors in 2008 was $13.5 billion[2] and $22 billion in 2009.[3]

Examples

Inhibition of TNF effects can be achieved with a monoclonal antibody such as infliximab,[4] adalimumab, certolizumab pegol, and golimumab, or with a circulating receptor fusion protein such as etanercept.

Thalidomide and its derivatives lenalidomide and pomalidomide are also active against TNF.

While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such as xanthine derivatives[5] (e.g. pentoxifylline)[6] and bupropion.[7]

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.[8][9][10]

Medical uses

Rheumatoid arthritis

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.[11][12]

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.[13]

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.[14] Anti-TNF compounds help eliminate abnormal B cell activity.[15][16]

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.[13]

Skin disease

Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are ongoing.[17]

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.[18]

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.[19]

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.[20]

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.[21]

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.[22]

Tuberculosis

In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab.[23] 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.[24] 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.[25]

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.[26][27]

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.[27] 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.[28] 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.[29][27]

Several other monoclonal antibodies like adalimumab,[30][31] pembrolizumab,[32] nivolumab, and infliximab[33] have been reported to trigger MS as an adverse event.[34][27]

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.[35]

Paradoxical Psoriasis

Despite their good safety profile, one of the common adverse events and side effects associated with TNF-α inhibitors is the occurrence of Paradoxical Psoriasis.[36][37][38] Paradoxical Psoriasis 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 of psoriasis, while undergoing treatment with TNF-α inhibitors, such as Infliximab, Adalimumab, and Etanercept for their underlying inflammatory disease.[36][37][38] The first case of paradoxical psoriasis induced by TNF-α inhibitors was reported in a patient suffering from Inflammatory Bowel Disease.[36][37][38] Subsequently, an increasing number of cases were reported in IBD cohorts and in patients suffering from other chronic immune-mediated inflammatory diseases such as rheumatoid arthritis.[36][37][38] This increase was positively correlated with the increasing use of TNF-α inhibitors across different patient populations.[36][37][38] The rates of paradoxical psoriasis reported across observational studies (prospective and retrospective) range from 2–5%; with higher rates observed in female patients.[36][37][38] The time to onset from induction therapy to development of psoriatic lesions can range from anywhere from a few days to a few months.[36][37][38] The most common clinical presentations are pustular psoriasis, plaque psoriasis and guttate psoriasis, with nail and scalp involvement.[36][37][38] Moreover, some patients may experience more than one type of psoriatic lesion and/or have lesions across multiple locations.[36][37][38]

Anti-TNF agents in nature

TNF or its effects are inhibited by several natural compounds, including curcumin[39][40][41][42] (a compound present in turmeric), and catechins (in green tea). Cannabidiol[43] 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.[44]

5-HT2A receptor agonists have also been shown to have potent inhibitory effects on TNF-α, including psilocybin found in many species of mushrooms.[45][46]

Thymoquinone, a compound found in the flower Nigella sativa, has been studied for possible TNF-α inhibition and related benefits for autoimmune disorder treatment.[47][48][49][50]

Isomyosamine, an isomer of myosmine, known by the brand name MYMD-1®, is a synthetic alkaloid derived from tobacco plant with potential lifespan extending properties that markedly outperformed rapamycin in a mouse longevity study.[51] MyMD-1 targets the root causes of inflammation and regulates the immuno-metabolic system through the modulation of numerous pro-inflammatory cytokines, including TNF-α, IL-6 and IL17A.[52]

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.[53][54] 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.[11] This was later confirmed in clinical trials[55] and led to the development of the first biological therapies for rheumatoid arthritis.

References

  1. ↑ "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. September 2004. doi:10.1080/09546630410017275. PMID 15370396. 
  2. ↑ "Golimumab". Nature Reviews. Drug Discovery 8 (9): 695–696. September 2009. doi:10.1038/nrd2982. PMID 19721444. 
  3. ↑ "Top Ten/Twenty Best Selling Drugs 2009". http://knol.google.com/k/top-ten-twenty-best-selling-drugs-2009#Best_selling_therapeutic_categoriesBest_selling_therapeutic_categoriesef. 
  4. ↑ "Binding and functional comparisons of two types of tumor necrosis factor antagonists". The Journal of Pharmacology and Experimental Therapeutics 301 (2): 418–426. May 2002. doi:10.1124/jpet.301.2.418. PMID 11961039. 
  5. ↑ "Cyclic nucleotide phosphodiesterases". The Journal of Allergy and Clinical Immunology 108 (5): 671–680. November 2001. doi:10.1067/mai.2001.119555. PMID 11692087. 
  6. ↑ "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". American Journal of Respiratory and Critical Care Medicine 159 (2): 508–511. February 1999. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365. 
  7. ↑ "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. June 2006. doi:10.1016/j.intimp.2005.12.007. PMID 16644475. https://www.arca.fiocruz.br/handle/icict/2741. 
  8. ↑ "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. December 1998. doi:10.1111/j.1749-6632.1998.tb10188.x. PMID 9928254. Bibcode: 1998NYASA.861..169M. 
  9. ↑ "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. November 2008. doi:10.1124/jpet.108.143461. PMID 18708586. 
  10. ↑ "Wishing away inflammation? New links between serotonin and TNF signaling". Molecular Interventions 9 (6): 299–301. December 2009. doi:10.1124/mi.9.6.5. PMID 20048135. 
  11. ↑ 11.0 11.1 "Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis". The EMBO Journal 10 (13): 4025–4031. December 1991. doi:10.1002/j.1460-2075.1991.tb04978.x. PMID 1721867. 
  12. ↑ "Regulation of tumour necrosis factor signalling: live or let die". Nature Reviews. Immunology 15 (6): 362–374. June 2015. doi:10.1038/nri3834. PMID 26008591. 
  13. ↑ 13.0 13.1 "TNF inhibitor therapy for rheumatoid arthritis". Biomedical Reports 1 (2): 177–184. March 2013. doi:10.3892/br.2012.42. PMID 24648915. 
  14. ↑ "Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases". Nature Medicine 9 (10): 1245–1250. October 2003. doi:10.1038/nm939. PMID 14520364. 
  15. ↑ "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. January 2008. doi:10.4049/jimmunol.180.2.688. PMID 18178805. 
  16. ↑ "A new view of drugs used to treat rheumatoid arthritis from medicineworld.org". http://medicineworld.org/cancer/lead/1-2008/drugs-used-to-treat-rheumatoid-arthritis.html. 
  17. ↑ "Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors". Acta Dermato-Venereologica 89 (6): 595–600. November 2009. doi:10.2340/00015555-0747. PMID 19997689. 
  18. ↑ "Psoriasis Association". https://www.psoriasis-association.org.uk. 
  19. ↑ "Infliximab and adalimumab for the treatment of Crohn's disease | 1-guidance | Guidance and guidelines | NICE". 19 May 2010. https://www.nice.org.uk/guidance/TA187/chapter/1-Guidance. 
  20. ↑ "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine 89: 127–135. January 2017. doi:10.1016/j.cyto.2016.01.021. PMID 26854213. 
  21. ↑ "FDA Alert: Tumor Necrosis Factor (TNF) blockers, Azathioprine and/or Mercaptopurine: Update on Reports of Hepatosplenic T-Cell Lymphoma in Adolescents and Young Adults". https://www.drugs.com/fda/tumor-necrosis-factor-tnf-blockers-azathioprine-mercaptopurine-update-reports-hepatosplenic-t-cell-12945.html. 
  22. ↑ "FDA Alert: Tumor Necrosis Factor-alpha (TNFα) Blockers: Label Change - Boxed Warning Updated for Risk of Infection from Legionella and Listeria". https://www.drugs.com/fda/tumor-necrosis-factor-alpha-tnf-alpha-blockers-label-change-boxed-warning-updated-risk-infection-13023.html. 
  23. ↑ "Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent". The New England Journal of Medicine 345 (15): 1098–1104. October 2001. doi:10.1056/NEJMoa011110. PMID 11596589. 
  24. ↑ "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.
  25. ↑ "Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors". Mycoses 60 (4): 222–229. April 2017. doi:10.1111/myc.12576. PMID 27766695. 
  26. ↑ "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. 
  27. ↑ 27.0 27.1 27.2 27.3 "CNS Demyelination with TNF-α Blockers". Current Neurology and Neuroscience Reports 17 (4): 36. April 2017. doi:10.1007/s11910-017-0742-1. PMID 28337644. 
  28. ↑ "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. August 2018. doi:10.23736/S0392-0488.17.04992-6. PMID 25692775. 
  29. ↑ "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. August 2015. PMID 26267733. 
  30. ↑ "PPMS onset upon adalimumab treatment extends the spectrum of anti-TNF-α therapy-associated demyelinating disorders". Therapeutic Advances in Neurological Disorders 13: 1756286419895155. 2 January 2020. doi:10.1177/1756286419895155. PMID 31921355. 
  31. ↑ "Adalimumab Induced or Provoked MS in Patient with Autoimmune Uveitis: A Case Report and Review of the Literature". Case Reports in Medicine 2016: 1423131. 2016-10-20. doi:10.1155/2016/1423131. PMID 27840642. 
  32. ↑ "Multiple sclerosis associated with pembrolizumab in a patient with non-small cell lung cancer". Journal of Neurology 266 (12): 3163–3166. December 2019. doi:10.1007/s00415-019-09562-z. PMID 31586260. 
  33. ↑ "Pathological findings in central nervous system demyelination associated with infliximab". Multiple Sclerosis 26 (9): 1124–1129. August 2020. doi:10.1177/1352458519894710. PMID 31845616. 
  34. ↑ "Multiple sclerosis outcomes after cancer immunotherapy". Clinical & Translational Oncology 21 (10): 1336–1342. October 2019. doi:10.1007/s12094-019-02060-8. PMID 30788836. 
  35. ↑ "Demyelination After Anti-TNF Therapy: Who is at Risk?". Journal of Crohn's & Colitis 14 (12): 1651–1652. December 2020. doi:10.1093/ecco-jcc/jjaa144. PMID 33026456. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 36.7 36.8 Bucalo, Agostino; Rega, Federica; Zangrilli, Arianna; Silvestri, Valentina; Valentini, Virginia; Scafetta, Giorgia; Marraffa, Federica; Grassi, Sara et al. (January 2020). "Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers" (in en). International Journal of Molecular Sciences 21 (21): 7873. doi:10.3390/ijms21217873. ISSN 1422-0067. PMID 33114187.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  37. ↑ 37.0 37.1 37.2 37.3 37.4 37.5 37.6 37.7 37.8 Vasconcellos, Jaqueline Barbeito de; Pereira, Daniele do Nascimento; Vargas, Thiago Jeunon de Sousa; Levy, Roger Abramino; Pinheiro, Geraldo da Rocha Castelar; Cursi, Ígor Brum (September–October 2016). "Paradoxical psoriasis after the use of anti-TNF in a patient with rheumatoid arthritis" (in en). Anais Brasileiros de Dermatologia 91 (5 suppl 1): 137–139. doi:10.1590/abd1806-4841.20164456. ISSN 0365-0596. PMID 28300922. 
  38. ↑ 38.0 38.1 38.2 38.3 38.4 38.5 38.6 38.7 38.8 Toussirot, Éric; Aubin, François (2016-07-01). "Paradoxical reactions under TNF-α blocking agents and other biological agents given for chronic immune-mediated diseases: an analytical and comprehensive overview" (in en). RMD Open 2 (2): e000239. doi:10.1136/rmdopen-2015-000239. ISSN 2056-5933. PMID 27493788. PMC 4964220. https://rmdopen.bmj.com/content/2/2/e000239. 
  39. ↑ "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. July 2006. doi:10.1097/01.CCM.0000221921.71300.BF. PMID 16715036. 
  40. ↑ "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. July 2006. doi:10.1016/j.ijrobp.2006.03.025. PMID 16751071. 
  41. ↑ "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. February 2006. doi:10.1111/j.1439-0442.2006.00786.x. PMID 16411910. 
  42. ↑ "The effect of turmeric extracts on inflammatory mediator production". Phytomedicine 12 (6–7): 445–452. June 2005. doi:10.1016/j.phymed.2003.12.011. PMID 16008121. 
  43. ↑ "Cannabidiol--recent advances". Chemistry & Biodiversity 4 (8): 1678–1692. August 2007. doi:10.1002/cbdv.200790147. PMID 17712814. 
  44. ↑ "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. May 2006. doi:10.1074/jbc.M601074200. PMID 16547349. 
  45. ↑ "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. 2021. doi:10.2147/JIR.S317182. PMID 34385833. 
  46. ↑ "Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo". PLOS ONE 8 (10): e75426. 2013-10-02. doi:10.1371/journal.pone.0075426. PMID 24098382. Bibcode: 2013PLoSO...875426N. 
  47. ↑ "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. September 2015. doi:10.1016/j.taap.2015.06.017. PMID 26134265. 
  48. ↑ "The Neuroprotective Effects of Thymoquinone: A Review". Dose-Response 16 (2): 1559325818761455. 2018. doi:10.1177/1559325818761455. PMID 29662431. 
  49. ↑ "Thymoquinone in autoimmune diseases: Therapeutic potential and molecular mechanisms". Biomedicine & Pharmacotherapy 134: 111157. February 2021. doi:10.1016/j.biopha.2020.111157. PMID 33370631. 
  50. ↑ "Thymoquinone: A small molecule from nature with high therapeutic potential". Drug Discovery Today 26 (11): 2716–2725. November 2021. doi:10.1016/j.drudis.2021.07.013. PMID 34303824. 
  51. ↑ Sabini, E., O’Mahony, A., & Caturegli, P. (2022). MyMD-1 Improves Health Span and Prolongs Life Span in Old Mice: A Noninferiority Study to Rapamycin. The Journals of Gerontology: Series A. PMID 35914953 doi:10.1093/gerona/glac142
  52. ↑ Di Dalmazi, G., Chalan, P., & Caturegli, P. (2019). MYMD-1, a novel immunometabolic regulator, ameliorates autoimmune thyroiditis via suppression of Th1 responses and TNF-α release. The Journal of Immunology, 202(5), 1350-1362. PMID 30674573 doi:10.4049/jimmunol.1801238
  53. ↑ "First demonstration of the role of TNF in the pathogenesis of disease". Journal of Immunology 181 (1): 5–6. July 2008. doi:10.4049/jimmunol.181.1.5. PMID 18566362. 
  54. ↑ "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. July 2008. doi:10.1126/science.3895437. PMID 18566363. https://www.science.org/doi/pdf/10.1126/science.3895437. 
  55. ↑ "Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis". Lancet 344 (8930): 1105–1110. October 1994. doi:10.1016/S0140-6736(94)90628-9. PMID 7934491. 



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