Tumor Necrosis Factor (TNF) Inhibitors

Article Author:
Valerie Gerriets
Article Editor:
Karam Khaddour
Updated:
2/19/2019 4:53:32 PM
PubMed Link:
Tumor Necrosis Factor (TNF) Inhibitors

Indications

Tumor necrosis factor (TNF)-alpha inhibitors, including etanercept (E), infliximab (I), adalimumab (A), certolizumab pegol (C) and golimumab (G), are used to treat the following conditions [1][2][3][4]:

FDA-approved Indications (alphabetical list)

  • Ankylosing spondylitis (E, I, A, C, and G)
  • Crohn disease (I, A and C)
  • Hidradenitis suppurativa (A)
  • Juvenile idiopathic arthritis (A)
  • Plaque psoriasis (E, I and A)
  • Polyarticular juvenile idiopathic arthritis (E)
  • Psoriatic arthritis (E, I, A, C, and G)
  • Rheumatoid arthritis (E, I, A, C, and G)
  • Ulcerative colitis (I, A and G)
  • Uveitis (A)

Off-label Indications

  • Graft-vs-host disease
  • Juvenile idiopathic arthritis
  • Pustular psoriasis
  • Pyoderma gangrenosum

Mechanism of Action

The tumor necrosis factor (TNF)-alpha inhibitors, including etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab, all bind to the cytokine TNF and inhibit its interaction with the TNF receptors [5][6]. As a cytokine, TNF is involved with the inflammatory and immune response and can bind to TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2) [7].  It occurs in numerous forms, both monomeric and trimeric, as well as soluble and transmembrane. Upon binding, TNF triggers the activation of numerous pathways including the NFkB and MAPK pathways. This leads to the production of numerous inflammatory cytokines and can also lead to TNF-induced apoptotic pathway initiation. Etanercept is a fusion protein of two TNFR2 receptor extracellular domains and the Fc fragment of human IgG1 [8]. It inhibits the binding of both TNF-alpha and TNF-beta to cell surface TNFRs.  Infliximab is a chimeric monoclonal antibody that includes a murine variable region and constant human region [9]. It binds to the soluble and transmembrane forms of TNF-alpha and inhibits the binding of TNF-alpha to TNFR. Adalimumab and golimumab are fully human monoclonal antibodies against TNF-alpha and, like infliximab, these antibodies bind to TNF-alpha and inhibit its binding to TNFR. Certolizumab is a humanized Fab fragment conjugated to polyethylene glycol (PEG).

Administration

Etanercept is administered subcutaneously. The injection sites should be rotated and given at least one inch apart from previous injection sites. 

Infliximab is administered as an infusion. The infusion should occur over a period of 2 hours and should not be co-administered with other agents. Infusion-related reactions are possible, and if necessary, antihistamines, acetaminophen, and corticosteroids can be used to treat these reactions.

Adalimumab is administered by subcutaneous injection. The injection sites should be rotated and away from previous injection sites.

Certolizumab pegol is subcutaneously administered into the thigh or abdomen. 

Golimumab can be administered intravenously (IV) or subcutaneously. Infusions should occur over a period of 30 minutes and should not be co-administered with any other agents. Subcutaneous injections are administered using an autoinjector.

Adverse Effects

The following adverse effects (AEs) were observed in greater than 10% of patients receiving a TNF-alpha inhibitor, including etanercept, infliximab, adalimumab, certolizumab pegol and golimumab [10][11][4][12][8].

Central Nervous System-related AEs: Headache   

Dermatology-related AEs: Skin rash

Gastrointestinal-related AEs: Abdominal pain, nausea, diarrhea

Hematology-related AEs: Anemia

Hepatic-related AEs: Increased serum ALT

Immunology-related AEs: Increased ANA titer (~50%), antibody development

Infection-related AEs: Infection, including serious infection and abscess

Respiratory-related AEs: Upper respiratory tract infections, sinusitis, cough, pharyngitis

Miscellaneous AEs: Infusion-related reaction, injection site reactions

Other serious concerns related to AEs:  Anaphylaxis and hypersensitivity reactions, autoimmune disorders, demyelinating CNS disease, heart failure, aplastic anemia, pancytopenia, reactivation of hepatitis B, leukopenia, neutropenia

US boxed warnings (for all TNF-alpha inhibitors): 

Malignancy:  Malignancies, including lymphoma, have been reported in patients receiving TNF alpha inhibitors. The malignancies arose approximately 30 months (ranging from 1 month to 84 months) after the first dose of the TNF alpha inhibitor and many of the cases were in pediatric and young adult populations. Additionally, cases of hepatosplenic T-cell lymphoma have been reported in the postmarketing period for adolescent males with either ulcerative colitis or Crohn disease. 

Tuberculosis:  Active tuberculosis or the reactivation of latent tuberculosis has been reported in patients receiving TNF-alpha inhibitors. Patients should be evaluated for the presence of tuberculosis before the initiation of therapy with TNF alpha inhibitors and treatment with antimycobacterial therapy should be initiated if latent tuberculosis is found. In cases of reactivation of latent tuberculosis, the reactivation occurs within the first few months of treatment with TNF-alpha inhibitors.

Infection:  Patients receiving treatment with a TNF-alpha inhibitor are at heightened risk of developing serious or fatal infections. This occurred more commonly in patients that are receiving treatment with other immunosuppressive agents including methotrexate and corticosteroids. The types of infections include fungal infections, such as aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis and pneumocystosis, and bacterial and viral infections. In particular, legionellosis and listeriosis have been reported. Patients should be monitored for signs of infection and treatment with TNF-alpha inhibitors should be discontinued if serious infection or sepsis occurs. Empiric antifungal therapy should be considered in patients who are at increased risk of invasive fungal infections.

Contraindications

Etanercept: Do not administer to patients with sepsis.

Infliximab: Do not administer to patients with hypersensitivity to infliximab or murine proteins.

Adalimumab: None listed

Certolizumab pegol: None listed 

Golimumab: None listed

Monitoring

Monitoring of etanercept, infliximab, adalimumab, certolizumab pegol, and golimumab includes latent tuberculosis (TB) screening before initiating treatment and during therapy [12]. The patient should also be monitored for signs of infection before, during and after treatment [13].  Additionally, a CBC with differential and HBV screening should be performed. In certain patients, symptoms of heart failure, malignancy, hypersensitivity reactions, and lupus should be monitored. 

Toxicity

Etanercept: The toxicity profile of etanercept is unknown; long-term human or animal studies have not been conducted. It was not shown to be mutagenic in vitro or in vivo studies.

Infliximab: The toxicity profile of infliximab is unknown. It also is not known if infliximab impairs fertility in humans.

Adalimumab: The toxicity profile of adalimumab is unknown; long-term human or animal studies have not been conducted. It was not shown to be mutagenic in vitro or in vivo studies.

Certolizumab pegol: The toxicity profile of certolizumab is unknown; long-term human or animal studies have not been conducted. It did not impair fertility in an in vivo mouse study.

Golimumab: The toxicity profile of golimumab is unknown; long-term human or animal studies have not been conducted. It did not impair fertility in an in vivo mouse study. 

Enhancing Healthcare Team Outcomes

As with many medications, there must be interprofessional communication when it comes to the dispensing and monitoring of the various TNF alpha inhibitors.  With inflammatory bowel disease and other autoimmune disorders, physicians and pharmacists must be aware of the treatment guidelines when making the decision to treat with TNF alpha inhibitors as opposed to other treatment options [14].  Pharmacists, nurses and physicians must work together to ensure that proper dosing and dispensing protocols are in place and be aware of the possibility of adverse effects [15].  For example, infliximab requires an infusion over a specific period of time, cannot be combined with other medications and there is the possibility of infusion-related reactions.  Therefore, the healthcare team must work together to ensure patient safety, and the use of electronic medical records may be useful in this setting [16].  Additionally, the healthcare team should be aware of the evolving nature of biosimilars as they relate to prescribing TNF alpha inhibitors and keep up-to-date on the available prescribing options [17]


References

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