TNF 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.[1]

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

History of anti-TNF treatments

Early experiments associated TNF with the pathogenesis of bacterial sepsis. Thus, the first preclinical studies using anti-TNF antibodies were performed in animal models of sepsis[4] 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.[5] This was later confirmed in clinical trials[6] and led to the development of the first biological therapies for rheumatoid arthritis.

Examples

Inhibition of TNF effects can be achieved with a monoclonal antibody such as infliximab[7] (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or with a circulating receptor fusion protein such as etanercept (Enbrel).

Thalidomide (Immunoprin) and its derivatives lenalidomide (Revlimid) and pomalidomide (Pomalyst, Imnovid) are also active against TNF.

While most clinically useful TNF inhibitors are monoclonal antibodies, some are simple molecules such as xanthine derivatives[8] (e.g. pentoxifylline)[9] and bupropion.[10] Bupropion is the active ingredient in the smoking cessation aid Zyban and the antidepressants Wellbutrin and Aplenzin.

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.[11][12][13]

Therapeutic applications

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.[14][15]

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[16]

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.[17] Anti-TNF compounds help eliminate abnormal B cell activity.[18][19]

Therapy which combines certain anti-TNF agents such as ertanercept 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.[16]

Skin disease

Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are ongoing.[20]

The National Institute of Clinical Excellence (NICE) has issued guidelines for the treatment of severe psoriasis using the anti-TNF drugs etanercept (Enbrel) and adalimumab (Humira) as well as the anti-IL12/23 biological treatment ustekinumab (Stelara). 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 (Remicade) may be used to treat severe plaque psoriasis if aforementioned treatments fail or can not be tolerated.[21]

Gastrointestinal Disease

In 2010 The National Institute of Clinical Excellence (NICE) in the UK issues guidelines for the treatment of severe Crohn's Disease with Infliximab and adalimumab. [22]

Other uses

It's worth noting that TNF-Alpha inhibitors are being considered for more and more disease, particularly those affecting the immune system and inflammation. [23]

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.[24]

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.[25]

Tuberculosis

In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab.[26] 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.[27] 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.[28]

Anti-TNF agents in nature

TNF or its effects are inhibited by several natural compounds, including curcumin[29][30][31][32] (a compound present in turmeric), and catechins (in green tea). Activation of cannabinoid CB1 or CB2 receptors by cannabis or Echinacea purpurea also seems to have anti-inflammatory properties through TNF inhibition.[33]

References

  1. ↑ Scheinfeld N (September 2004). "A comprehensive review and evaluation of the side effects of the tumor necrosis factor blockers etanercept, infliximab and adalimumab". J Dermatolog Treat. 15 (5): 280–94. doi:10.1080/09546630410017275. PMID 15370396.
  2. ↑ Pappas DA, Bathon JM, Hanicq D, Yasothan U, Kirkpatrick P (September 2009). "Golimumab". Nat Rev Drug Discov. 8 (9): 695–6. doi:10.1038/nrd2982. PMID 19721444.
  3. ↑ http://knol.google.com/k/top-ten-twenty-best-selling-drugs-2009#Best_selling_therapeutic_categoriesBest_selling_therapeutic_categoriesef[]
  4. ↑ Beutler B, Milsark IW, Cerami AC (August 1985). "Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin.". Science. 229 (4716): 869–71. doi:10.1126/science.3895437. PMID 3895437.
  5. ↑ 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.". EMBO J. 10 (13): 4025–31. PMC 453150Freely accessible. PMID 1721867.
  6. ↑ Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, et al. (October 1994). "Randomized double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis.". Lancet. 344 (8930): 1105–10. doi:10.1016/S0140-6736(94)90628-9. PMID 7934491.
  7. ↑ doi: 10.1124/jpet.301.2.418 JPET May 1, 2002 vol. 301 no. 2 418-426
  8. ↑ Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". J. Allergy Clin. Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.
  9. ↑ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
  10. ↑ 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". Int. Immunopharmacol. 6 (6): 903–7. doi:10.1016/j.intimp.2005.12.007. PMID 16644475.
  11. ↑ Miller KJ, Gonzalez HA (December 1998). "Serotonin 5-HT2A receptor activation inhibits cytokine-stimulated inducible nitric oxide synthase in C6 glioma cells". Ann. N. Y. Acad. Sci. 861: 169–73. Bibcode:1998NYASA.861..169M. doi:10.1111/j.1749-6632.1998.tb10188.x. PMID 9928254.
  12. ↑ 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". J. Pharmacol. Exp. Ther. 327 (2): 316–23. doi:10.1124/jpet.108.143461. PMID 18708586.
  13. ↑ Pelletier M, Siegel RM (December 2009). "Wishing away inflammation? New links between serotonin and TNF signaling". Mol. Interv. 9 (6): 299–301. doi:10.1124/mi.9.6.5. PMC 2861806Freely accessible. PMID 20048135.
  14. ↑ 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): 4025–31. PMC 453150Freely accessible. PMID 1721867.
  15. ↑ Brenner D, Blaser H, Mak TW (May 2015). "Regulation of tumour necrosis factor signalling: live or let die.". Nat Rev Immunol. 15 (6): 362–74. doi:10.1038/nri3834. PMID 26008591.
  16. 1 2 Ma X, Xu S (March 2012). "TNF inhibitor therapy for rheumatoid arthritis". Biomed Rep. 1 (2): 177–184. doi:10.3892/br.2012.42. PMC 3956207Freely accessible.
  17. ↑ Feldmann M, Maini RN (October 2003). "Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases". Nat. Med. 9 (10): 1245–50. doi:10.1038/nm939. PMID 14520364.
  18. ↑ Anolik JH, Ravikumar R, Barnard J, Owen T, Almudevar A, Milner EC, Miller CH, Dutcher PO, Hadley JA, Sanz I (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". J. Immunol. 180 (2): 688–92. doi:10.4049/jimmunol.180.2.688. PMID 18178805.
  19. ↑ A new view of drugs used to treat rheumatoid arthritis
  20. ↑ Haslund P, Lee RA, Jemec GB (November 2009). "Treatment of hidradenitis suppurativa with tumour necrosis factor-alpha inhibitors". Acta Derm. Venereol. 89 (6): 595–600. doi:10.2340/00015555-0747. PMID 19997689.
  21. ↑ https://www.psoriasis-association.org.uk
  22. ↑ "Infliximab and adalimumab for the treatment of Crohn's disease | 1-guidance | Guidance and guidelines | NICE". www.nice.org.uk. Retrieved 2016-12-04.
  23. ↑ Ali, Tauseef; Kaitha, Sindhu; Mahmood, Sultan; Ftesi, Abdul; Stone, Jordan; Bronze, Michael S (2013-03-28). "Clinical use of anti-TNF therapy and increased risk of infections". Drug, Healthcare and Patient Safety. 5: 79–99. doi:10.2147/DHPS.S28801. ISSN 1179-1365. PMC 3615849Freely accessible. PMID 23569399.
  24. ↑ http://www.drugs.com/fda/tumor-necrosis-factor-tnf-blockers-azathioprine-mercaptopurine-update-reports-hepatosplenic-t-cell-12945.html
  25. ↑ http://www.drugs.com/fda/tumor-necrosis-factor-alpha-tnf-alpha-blockers-label-change-boxed-warning-updated-risk-infection-13023.html
  26. ↑ Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun MM (October 2001). "Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent". N. Engl. J. Med. 345 (15): 1098–104. doi:10.1056/NEJMoa011110. PMID 11596589.
  27. ↑ "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.
  28. ↑ Tragiannidis A, Kyriakidis I, Zündorf I, Groll AH (October 2016). "Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors". Mycoses. doi:10.1111/myc.12576.
  29. ↑ Siddiqui AM, Cui X, Wu R, Dong W, Zhou M, Hu M, Simms HH, Wang P (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): 1874–82. doi:10.1097/01.CCM.0000221921.71300.BF. PMID 16715036.
  30. ↑ Okunieff P, Xu J, Hu D, Liu W, Zhang L, Morrow G, Pentland A, Ryan JL, Ding I (July 2006). "Curcumin protects against radiation-induced acute and chronic cutaneous toxicity in mice and decreases mRNA expression of inflammatory and fibrogenic cytokines". Int. J. Radiat. Oncol. Biol. Phys. 65 (3): 890–8. doi:10.1016/j.ijrobp.2006.03.025. PMID 16751071.
  31. ↑ 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". J Vet Med a Physiol Pathol Clin Med. 53 (1): 49–54. doi:10.1111/j.1439-0442.2006.00786.x. PMID 16411910.
  32. ↑ 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): 445–52. doi:10.1016/j.phymed.2003.12.011. PMID 16008121.
  33. ↑ Raduner S, Majewska A, Chen JZ, Xie XQ, Hamon J, Faller B, Altmann KH, Gertsch J (May 2006). "Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects". J. Biol. Chem. 281 (20): 14192–206. doi:10.1074/jbc.M601074200. PMID 16547349.
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