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tumor necrosis factor (TNF) inhibitor

Includes: 1) infliximab (Remicade) 2) etanercept (Enbrel) 3) adalimumab (Humira) 4) certolizumab (Cimzia) 5) golimumab (Simponi) Indications: - autoimmune disease or connective tissue disorders - rheumatoid arthritis - spondyloarthropathies - inflammatory bowel disease (IBD) (ulcerative colitis, Crohn's disease) - reduce risk of Parkinson disease in patients with IBD [20] - poriasis - may mitigate risk for Alzheimer's disese in inflammatory disorders [22] Contraindications: - concurrent use of other biologic agent (abatacept, rituximab, anakinra) - active infection Caution: screening for tuberculosis, hepatitis B & hepatitis C prior to initiation of therapy [4] * treatment of active or latent tuberculosis prior to administration of TNF-alpha inhibitor * if patient develops signs & symptoms of tuberculosis while on a TNF-alpha inhibitor, obtain induced sputum acid-fast bacilli & culture (bronchoscopy & bronchoalveolar lavage is too invasive) [22] Pregnancy category: B [4] - use in 3rd trimester for inflammatory bowel disease not associated with adverse birth outcomes [18] Adverse effects: 1) pancytopenia 2) 2-fold increased risk of infections [5] a) increased risk of soft tissue & skin infection b) increased risk of intracellular bacterial infection 1] tuberculosis - increased risk of reactivation & death from disseminated disease [4] 2] Listeria [7] 3] Salmonella ? 4] Legionella [7] c) increased risk of Herpes zoster - about the same risk as non-biologic DMARDs [9] 3) pulmonary & disseminated histoplasmosis, coccidioidomycosis, blastomycosis & other opportunistic infections are not consistently recognized in patients taking TNF-alpha blockers; this has resulted in delays in appropriate treatment, & death; empiric antifungal treatment indicated for suspected disseminated mycosis in patients taking TNF-alpha blocker 4) increased risk of cancer a) increased risk of lymphoma & other cancers associated with use in children & adolescents [3] b) not associated with an increase in overall cancer risk [6] c) higher risk of lymphoma risk than the general population, but not higher than those taking traditional DMARDs d) increased risk for nonmelanoma skin cancer e) increased risk of melanoma in patients with rheumatoid arthritis (RR=1.5) [10] f) low risk of cancers [15] g) TNF inhibitors do not increase risk of cancer recurrence in cancer survivors [21] 5) autoantibodies - ANA, anti-dsDNA Ab, anti-Sm Ab common - drug-induced lupus uncommon [4] 6) cutaneous reactions common [14,17] - psoriasiform dermatitis (most common) [17] - cutaneous autoimmune disease - subacute cutaneous lupus erythematosus [4] - referral to a dermatologist can help keep patients on treatment [17] 7) heart failure [4] 8) demyelinating disorders [4] 9) increased risk of inflammatory CNS diseases, especially demyelinating diseases [23] Mechanism of action: - TNF-alpha inhibition

Interactions

drug interactions drug adverse effects (more general classes) monitor with immunosuppressive agents

Related

tumor necrosis factor [TNF]-alpha; tumor necrosis factor ligand superfamily member 2; cachectin (TNF, TNFA, TNFSF2)

Specific

adalimumab (Humira, Idacio, Yusimry, Yuflyma) certolizumab pegol (Cimzia) etanercept (Enbrel) golimumab (Simponi) infliximab (Remicade)

General

biologic immunosuppressive agent (biologic agent, biologic immune modulator)

References

  1. Dixon WG et al, Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy. Arthritis Rheum 2006, 54:2368 PMID: 16868999 - Mohan AK, Cote TR, Block JA, Manadan AM, Siegel JN, Braun MM. Tuberculosis following the use of etanercept, a tumor necrosis factor inhibitor. Clin Infect Dis. 2004 Aug 1;39(3):295-9. Epub 2004 Jul 16. PMID: 15306993 - Costamagna P et al, tuyberculosis associated with blocking agents against tumor necrosis factor-alpha - California, 2002-2003, MMWR Morb Mortal Wkly Rep 2004, Aug 6; 53:683-86 - Keane J. Tumor necrosis factor blockers and reactivation of latent tuberculosis. Clin Infect Dis. 2004 Aug 1;39(3):300-2. Epub 2004 Jul 16. No abstract available. PMID: 15306994 - Singh JA et al Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. Lancet. May 11, 2015 PMID: 25975452 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961704-9/abstract - Dixon WG. Rheumatoid arthritis: Biological drugs and risk of infection. Lancet 2015 May 11 PMID: 25975453 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2961907-3/abstract
  2. FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#TNF2
  3. FDA MedWatch Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi) August 2009 http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm175843.htm
  4. Medical Knowledge Self Assessment Program (MKSAP) 14, 16, 17, 18, 19. American College of Physicians, Philadelphia 2006, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. Komano Y et al. Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: A report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety. J Rheumatol 2011 Jul; 38:1258. PMID: 21498482
  6. Mariette X et al Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis Ann Rheum Dis doi:10.1136/ard.2010.149419 PMID: 21885875 http://ard.bmj.com/content/early/2011/07/29/ard.2010.149419.abstract
  7. FDA MedWatch 09-09-11 Tumor Necrosis Factor-alpha (TNF-alpha) Blockers: Label Change - Boxed Warning Updated for Risk of Infection from Legionella and Listeria including Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol), and Simponi (golimumab) http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm270977.htm
  8. Grijalva CG et al Initiation of tumor necrosis factor-alpha antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA 2011 Nov 6 PMID: 22056398 http://jama.ama-assn.org/content/306/21/2331 - Dixon W and Felson DT. Is anti-TNF therapy safer than previously thought? JAMA 2011 Nov 6 PMID: 22056396 http://jama.ama-assn.org/content/306/21/2380
  9. Winthrop KL et al Association Between the Initiation of Anti-Tumor Necrosis Factor Therapy and the Risk of Herpes Zoster. JAMA. 2013;309(9):887-895 PMID: 23462785 http://jama.jamanetwork.com/article.aspx?articleid=1660380
  10. Raaschou P et al. Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: Nationwide population based prospective cohort study from Sweden. BMJ 2013 Apr 8; 346:f1939 PMID: 23568792
  11. Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum. 2008 Jun;37(6):381-7 PMID: 17977585
  12. Askling J, van Vollenhoven RF, Granath F et al Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment? Arthritis Rheum. 2009 Nov;60(11):3180-9. PMID: 19877027
  13. Listing J, Strangfeld A, Kekow J et al Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 2008 Mar;58(3):667-77 PMID: 18311816
  14. Hernandez MV et al. Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumor necrosis factor antagonists: Study using the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases. Arthritis Care Res (Hoboken) 2013 Dec; 65:2024 PMID: 23926075
  15. Andersen NN et al. Association between tumor necrosis factor- alpha antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 2014 Jun 18; 311:2406 PMID: 24938563
  16. Dixon WG, Watson KD, Lunt M et al Influence of anti-tumor necrosis factor therapy on cancer incidence in patients with rheumatoid arthritis who have had a prior malignancy: results from the British Society for Rheumatology Biologics Register. Arthritis Care Res (Hoboken). 2010 Jun;62(6):755-63. PMID: 20535785
  17. Cleynen I et al Characteristics of Skin Lesions Associated With Anti-Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study. Ann Intern Med. Published online 8 December 2015 PMID: 26641955 http://annals.org/article.aspx?articleid=2474360
  18. Bachert A Anti-TNF Therapy Seems Safe in Pregnant Women with IBD. - Use in third trimester not tied to adverse birth outcomes. MedPage Today Dec 11, 2016 http://www.medpagetoday.com/MeetingCoverage/AIBD/61998
  19. Centers for Disease Control and Prevention (CDC). Tuberculosis associated with blocking agents against tumor necrosis factor-alpha--California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004 Aug 6; 53:683. PMID: 15295313 Free full text
  20. Peter I,Dubinsky M, Bressman S et al Anti-Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease. JAMA Neurol. Published online April 23, 2018 PMID: 29710331 https://jamanetwork.com/journals/jamaneurology/article-abstract/2679038 - Olsen AL, Riise T, Scherzer CR. Discovering New Benefits From Old Drugs With Big Data-Promise for Parkinson Disease. JAMA Neurol. Published online April 23, 2018 PMID: 29710184 https://jamanetwork.com/journals/jamaneurology/article-abstract/2679036
  21. Raaschou P, Soderling J, Turesson C, Askling J; ARTIS Study Group. Tumor necrosis factor inhibitors and cancer recurrence in Swedish patients with rheumatoid arthritis: A nationwide population-based cohort study. Ann Intern Med 2018 Sep 4; 169:291 PMID: 30105374 http://annals.org/aim/article-abstract/2697083/tumor-necrosis-factor-inhibitors-cancer-recurrence-swedish-patients-rheumatoid-arthritis
  22. Godfrey MS, Friedman LN Tuberculosis and Biologic Therapies: Anti-Tumor Necrosis Factor-alpha and Beyond. Clin Chest Med. 2019 Dec;40(4):721-739 PMID: 31731980
  23. Xie W, Sun Y, Zhang W, Zhu N, Xiao S et al Risk of Inflammatory Central Nervous System Diseases After Tumor Necrosis Factor-Inhibitor Treatment for Autoimmune Diseases: A Systematic Review and Meta-Analysis. JAMA Neurol. 2024 Oct 21. PMID: 39432288