• Sign Up



Article Author:
Adrianne Pan
Article Editor:
Valerie Gerriets
8/11/2020 11:48:36 PM
For CME on this topic:
Etanercept CME
PubMed Link:


Etanercept is a biologic TNF inhibitor commonly used to control ankylosing spondylitis, juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, and rheumatoid arthritis. Etanercept is a soluble receptor that binds both TNF-alpha and TNF-beta to inhibit the inflammatory response in joints and skin that is characteristic of these autoimmune disorders. The drug can be used as a monotherapy or taken with other immunosuppressants, such as methotrexate. 

FDA approved uses for etanercept[1][2][3][4][5][4][3][2][1]:

  • Ankylosing spondylitis
  • Juvenile idiopathic arthritis (2 years or older)
  • Plaque psoriasis (4 years or older)
  • Psoriatic arthritis
  • Rheumatoid arthritis

Off-label uses (not FDA approved):

  • Acute graft-versus-host disease (combined with methylprednisolone)
  • Behcet disease
  • Hidradenitis suppurativa 
  • Kawasaki disease 
  • Pemphigus vulgaris 
  • Pustular psoriasis 
  • Pyoderma gangrenosum 
  • Scleroderma/systemic sclerosis 
  • Still disease 

Mechanism of Action

Etanercept is a biologic tumor necrosis factor (TNF) inhibitor; the drug acts as a soluble TNF receptor and binds TNF-alpha and TNF-beta.[6] TNF is a cytokine that can bind to TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2) and is involved in inflammation and the immune response.[7] When TNF binds to TNFR1 or TNFR2, it activates important inflammatory pathways, such as NFkB and MAPK. The structure of Etanercept consists of two p75 TNF receptors fused to the Fc portion of human IgG.[6] Etanercept works by blocking the effects of TNF-alpha, a pro-inflammatory cytokine that becomes elevated in psoriasis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis.


Etanercept administration is via subcutaneous injection, usually on the thigh, lower abdomen, or upper arm. If given on the abdomen, the injection should not be within the 2-inch area around the navel. Injections should be administered at least 1 inch away from previous injection sites. The medication comes in a pre-filled syringe, automatic injection device, or multiple-dose vial. After the initial injection of Etanercept at the doctor’s office, the patient can self-inject at home.[8]

For the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, 50 mg of etanercept is injected once a week. For psoriasis, the dosage is 50 mg twice weekly for three months, followed by 50 mg once weekly. Children with juvenile idiopathic arthritis are administered 0.8 mg/kg once a week, up to 50 mg.

Adverse Effects

The most common adverse effects include[1]:

  • Infection (viral, bacterial, and fungal – mostly upper respiratory tract infections)
  • Injection site reaction (erythema, itching, pain, swelling, bleeding, bruising)

Rare adverse effects include (in alphabetical order):

  • Blood and lymph disorders: aplastic anemia, leukopenia, myelodysplastic syndrome, neutropenia, pancytopenia, thrombocytopenia[9]
  • Cancers: lymphoma [10], skin cancers
  • Cardiopulmonary problems: congestive heart failure, interstitial lung disease[11]
  • Gastrointestinal and liver problems: autoimmune hepatitis,[12] diarrhea,[13] elevated transaminases,[14] inflammatory bowel disease,[15] nausea[16] 
  • Immune and inflammatory conditions:  angioedema,[17] hypersensitivity reaction,[18] lupus-like syndrome,[11] non-neutralizing anti-Etanercept antibodies,[1] pyrexia,[16] sarcoidosis, uveitis, vasculitis
  • Infections: aspergillosis,[19] candidiasis,[19] coccidioidomycosis, cryptococcus,[19] herpes zoster, histoplasmosis,[19] legionella pneumonia,[20] listeriosis,[19] nocardiosis,[19] pneumocystis pneumonia, reactivation of Hepatitis B or TB,[21] salmonella infection,[19] septic arthritis 
  • Nervous system disorders: headache.[5] multiple sclerosis, optic neuritis, paresthesias, seizures, transverse myelitis
  • Skin disorders: cutaneous lupus erythematosus,[22] erythema multiforme,[22] new or worsening psoriasis, rash, Stevens-Johnson syndrome,[22] toxic epidermal necrolysis,[22] urticaria

US boxed warnings

Infections, including tuberculosis:

Patients using etanercept have an increased risk of acquiring serious and/or fatal infections, including the development of active tuberculosis or reactivation of latent tuberculosis. There are reports of various bacterial, viral, and fungal infections, including invasive fungal (aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and pneumocystosis) and opportunistic infections (legionellosis, listeriosis). 

Infections were more common in patients that received adjunct immunosuppressive medications, such as methotrexate or corticosteroids. Medical providers should exercise caution when prescribing etanercept to patients at higher risk for infections, including elderly patients, immunocompromised patients, patients with a history of recurrent/chronic/opportunistic infections, and patients exposed to tuberculosis or endemic mycoses. Physicians should consider empiric antifungal therapy for patients living in or traveling to endemic areas with an increased risk of invasive fungal infections.


Reports exist of malignancies in patients receiving etanercept, especially in children and adolescents. Lymphomas were most commonly reported, followed by melanoma and other skin cancers. Though the connection between etanercept and malignancies is not fully understood, clinical trials and case reports showed an increased rate of lymphoma and other malignancies in patients on etanercept compared to the general population. However, it is worth noting that rheumatoid arthritis alone has associations with increased rates of lymphoma and leukemia.


Etanercept contraindications include patients with sepsis. Patients should not start etanercept during active bacterial infections, including tuberculosis (active or latent), active herpes zoster infection, active or chronic untreated Hepatitis B or C infection, or active invasive fungal infections.[23] Patients should not use etanercept if they have a hypersensitivity reaction to the medication ingredients.


Before starting etanercept, patients should receive screening for any infections, including latent tuberculosis or hepatitis B. Patients on etanercept require monitoring for signs of infection and reactivation or development of tuberculosis and hepatitis B.[24] If a severe infection or sepsis develops during etanercept treatment, discontinue treatment. Also, patients should have monitoring for signs or symptoms of hypersensitivity reactions, malignancy, or lupus-like syndrome. Patients with a history of heart failure also require monitoring during etanercept treatment.[25]


There have not been any dose-limiting toxicities observed during clinical trials, in vivo, and in vitro studies. However, the long-term toxicity of etanercept treatment is unknown.

Enhancing Healthcare Team Outcomes

Etanercept is one of several different options for the treatment of plaque psoriasis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, and ankylosing spondylitis. The medical providers should weigh the risks and benefits of selecting etanercept as a treatment, such as drug cost, effectiveness, method of administration, and adverse effects. Because it is a biologic, etanercept usage comes with some serious side effects such as infections, malignancies, and autoimmune conditions.

An interprofessional team of physicians, nurses, and pharmacists must work together to ensure the safety and wellbeing of the patient. When deciding to treat with etanercept, physicians should know the treatment guidelines, which include monitoring the patient for signs of heart failure, tuberculosis, hepatitis B, and other infections before and during treatment. Clinicians and nurses will instruct the patient or the patient’s relative on how to properly give etanercept injections at home. Physicians and pharmacists must ensure that the patient is receiving the proper medication and dosage and that the patient receives on drug interactions and adverse effects. Nursing should keep the team informed regarding the appearance of these adverse reactions, as well as monitoring the success/failure of therapy. Also, biosimilars of etanercept have been emerging on the market, so healthcare providers need to be kept abreast regarding the different options that they have for treatment.[26][27] Without proper management, the quality of life in patients with these diseases is low. An interprofessional healthcare team can help achieve the best possible outcomes with minimal adverse events. [Level 5]


[1] Davis JC Jr,Van Der Heijde D,Braun J,Dougados M,Cush J,Clegg DO,Kivitz A,Fleischmann R,Inman R,Tsuji W, Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis and rheumatism. 2003 Nov;     [PubMed PMID: 14613288]
[2] Lovell DJ,Giannini EH,Reiff A,Cawkwell GD,Silverman ED,Nocton JJ,Stein LD,Gedalia A,Ilowite NT,Wallace CA,Whitmore J,Finck BK, Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group. The New England journal of medicine. 2000 Mar 16;     [PubMed PMID: 10717011]
[3] Papp KA,Tyring S,Lahfa M,Prinz J,Griffiths CE,Nakanishi AM,Zitnik R,van de Kerkhof PC,Melvin L, A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. The British journal of dermatology. 2005 Jun;     [PubMed PMID: 15948997]
[4] Mease PJ,Kivitz AJ,Burch FX,Siegel EL,Cohen SB,Ory P,Salonen D,Rubenstein J,Sharp JT,Tsuji W, Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis and rheumatism. 2004 Jul;     [PubMed PMID: 15248226]
[5] Moreland LW,Schiff MH,Baumgartner SW,Tindall EA,Fleischmann RM,Bulpitt KJ,Weaver AL,Keystone EC,Furst DE,Mease PJ,Ruderman EM,Horwitz DA,Arkfeld DG,Garrison L,Burge DJ,Blosch CM,Lange ML,McDonnell ND,Weinblatt ME, Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Annals of internal medicine. 1999 Mar 16;     [PubMed PMID: 10075615]
[6] Tracey D,Klareskog L,Sasso EH,Salfeld JG,Tak PP, Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacology     [PubMed PMID: 18155297]
[7] Mocci G,Marzo M,Papa A,Armuzzi A,Guidi L, Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease. Journal of Crohn's     [PubMed PMID: 23453887]
[8] van den Bemt BJF,Gettings L,Domańska B,Bruggraber R,Mountian I,Kristensen LE, A portfolio of biologic self-injection devices in rheumatology: how patient involvement in device design can improve treatment experience. Drug delivery. 2019 Dec;     [PubMed PMID: 30905213]
[9] Feltelius N,Fored CM,Blomqvist P,Bertilsson L,Geborek P,Jacobsson LT,Lindblad S,Lysholm J,Rantapää-Dahlqvist S,Saxne T,Klareskog L, Results from a nationwide postmarketing cohort study of patients in Sweden treated with etanercept. Annals of the rheumatic diseases. 2005 Feb;     [PubMed PMID: 15208177]
[10] Brown SL,Greene MH,Gershon SK,Edwards ET,Braun MM, Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis and rheumatism. 2002 Dec;     [PubMed PMID: 12483718]
[11] Ramos-Casals M,Brito-Zerón P,Muñoz S,Soria N,Galiana D,Bertolaccini L,Cuadrado MJ,Khamashta MA, Autoimmune diseases induced by TNF-targeted therapies: analysis of 233 cases. Medicine. 2007 Jul;     [PubMed PMID: 17632266]
[12] French JB,Bonacini M,Ghabril M,Foureau D,Bonkovsky HL, Hepatotoxicity Associated with the Use of Anti-TNF-α Agents. Drug safety. 2016 Mar;     [PubMed PMID: 26692395]
[13] van der Heijde D,Da Silva JC,Dougados M,Geher P,van der Horst-Bruinsma I,Juanola X,Olivieri I,Raeman F,Settas L,Sieper J,Szechinski J,Walker D,Boussuge MP,Wajdula JS,Paolozzi L,Fatenejad S, Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Annals of the rheumatic diseases. 2006 Dec;     [PubMed PMID: 16968715]
[14] Akhlaghi S,Sahebari M,Mahmoodi M,Yaseri M,Mansournia MA,Rafatpanah H,Zeraati H, Additional effect of etanercept or infliximab on the liver function tests of patients with rheumatoid arthritis: a cohort study. Therapeutics and clinical risk management. 2018;     [PubMed PMID: 30349273]
[15] O'Toole A,Lucci M,Korzenik J, Inflammatory Bowel Disease Provoked by Etanercept: Report of 443 Possible Cases Combined from an IBD Referral Center and the FDA. Digestive diseases and sciences. 2016 Jun;     [PubMed PMID: 26728477]
[16] Lovell DJ,Giannini EH,Reiff A,Jones OY,Schneider R,Olson JC,Stein LD,Gedalia A,Ilowite NT,Wallace CA,Lange M,Finck BK,Burge DJ, Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial. Arthritis and rheumatism. 2003 Jan;     [PubMed PMID: 12528122]
[17] Sendur OF,Turan Y,Berkit IK,Tastaban E, Angio-oedema in a patient treated with etanercept for rheumatoid arthritis. Basic     [PubMed PMID: 19371261]
[18] Puxeddu I,Caltran E,Rocchi V,Del Corso I,Tavoni A,Migliorini P, Hypersensitivity reactions during treatment with biological agents. Clinical and experimental rheumatology. 2016 Jan-Feb;     [PubMed PMID: 26751942]
[19] Wallis RS,Broder MS,Wong JY,Hanson ME,Beenhouwer DO, Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004 May 1;     [PubMed PMID: 15127338]
[20] Lanternier F,Tubach F,Ravaud P,Salmon D,Dellamonica P,Bretagne S,Couret M,Bouvard B,Debandt M,Gueit I,Gendre JP,Leone J,Nicolas N,Che D,Mariette X,Lortholary O, Incidence and risk factors of Legionella pneumophila pneumonia during anti-tumor necrosis factor therapy: a prospective French study. Chest. 2013 Sep;     [PubMed PMID: 23744173]
[21] Cantini F,Niccoli L,Goletti D, Adalimumab, etanercept, infliximab, and the risk of tuberculosis: data from clinical trials, national registries, and postmarketing surveillance. The Journal of rheumatology. Supplement. 2014 May;     [PubMed PMID: 24789000]
[22] Kerbleski JF,Gottlieb AB, Dermatological complications and safety of anti-TNF treatments. Gut. 2009 Aug;     [PubMed PMID: 19592682]
[23] Singh JA,Saag KG,Bridges SL Jr,Akl EA,Bannuru RR,Sullivan MC,Vaysbrot E,McNaughton C,Osani M,Shmerling RH,Curtis JR,Furst DE,Parks D,Kavanaugh A,O'Dell J,King C,Leong A,Matteson EL,Schousboe JT,Drevlow B,Ginsberg S,Grober J,St Clair EW,Tindall E,Miller AS,McAlindon T, 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis care     [PubMed PMID: 26545825]
[24] Thalayasingam N,Isaacs JD, Anti-TNF therapy. Best practice     [PubMed PMID: 22137924]
[25] Rosenblum H,Amital H, Anti-TNF therapy: safety aspects of taking the risk. Autoimmunity reviews. 2011 Jul;     [PubMed PMID: 21570495]
[26] Bae SC,Kim J,Choe JY,Park W,Lee SH,Park YB,Shim SC,Lee SS,Sung YK,Choi CB,Lee SR,Park H,Ahn Y, A phase III, multicentre, randomised, double-blind, active-controlled, parallel-group trial comparing safety and efficacy of HD203, with innovator etanercept, in combination with methotrexate, in patients with rheumatoid arthritis: the HERA study. Annals of the rheumatic diseases. 2017 Jan;     [PubMed PMID: 26905864]
[27] Matsuno H,Tomomitsu M,Hagino A,Shin S,Lee J,Song YW, Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate. Annals of the rheumatic diseases. 2018 Apr;     [PubMed PMID: 29259050]