What are examples of tumor necrosis factor (TNF) inhibitors?

Tumor Necrosis Factor (TNF) Inhibitors: Examples and Clinical Applications

The five FDA-approved tumor necrosis factor inhibitors are infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol, which are used to treat various inflammatory conditions including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and inflammatory bowel disease. 1, 2

Types and Structures of TNF Inhibitors

• Infliximab: A chimeric mouse/human anti-TNFα monoclonal antibody consisting of a variable murine region and a constant human IgG1 region, administered intravenously 1, 3
• Adalimumab: A fully humanized anti-TNFα monoclonal antibody that cannot be distinguished from normal human IgG1, administered subcutaneously 1, 4
• Golimumab: A fully humanized anti-TNFα monoclonal antibody similar to adalimumab, administered subcutaneously 1, 2
• Etanercept: A fusion protein consisting of two extracellular portions of human TNF receptor 2 (p75 TNF receptor) and the Fc portion of human IgG1, administered subcutaneously 1
• Certolizumab pegol: A Fab' fragment of an anti-TNFα monoclonal antibody lacking the Fc portion, with its hinge region covalently linked to polyethylene glycol chains, administered subcutaneously 1, 2

Approved Indications

TNF inhibitors have been approved for multiple inflammatory conditions:

• Rheumatoid Arthritis (RA): All five TNF inhibitors are effective 1
• Psoriatic Arthritis (PsA): All five TNF inhibitors are approved 1
• Ankylosing Spondylitis (AS): All five TNF inhibitors are effective 1
• Inflammatory Bowel Disease (IBD): Only infliximab, adalimumab, and golimumab are effective for Crohn's disease and ulcerative colitis 1
• Plaque Psoriasis: All TNF inhibitors are effective, though with varying degrees of efficacy 1, 5
• Juvenile Idiopathic Arthritis: Adalimumab and etanercept are approved 4, 6
• Hidradenitis Suppurativa: Adalimumab is approved 4
• Uveitis: Adalimumab is approved 4

Differential Efficacy Among TNF Inhibitors

• While all TNF inhibitors are effective for joint diseases (RA, PsA, AS), they differ in their efficacy for other conditions 1, 2
• Infliximab, adalimumab, and golimumab can induce clinical and endoscopic remission of IBD, which is not true of etanercept 1, 7
• The structural differences between these agents may explain their varying efficacy in different conditions 7, 6

Mechanism of Action

• TNF-α is a proinflammatory cytokine that mediates inflammatory and immunoregulatory activities 2
• TNF-α levels are elevated in affected tissues and fluids of patients with inflammatory conditions, with levels correlating with disease severity 2
• TNF inhibitors work by binding to TNF-α, preventing its interaction with cell surface TNF receptors and thereby inhibiting its inflammatory effects 2, 6

Safety Considerations

• TNF inhibitors have been proven safe when correctly prescribed and monitored 1, 2
• Important safety concerns include:
  • Increased risk of serious infections, including tuberculosis reactivation 2, 4
  • Risk of lymphoma and other malignancies, particularly in children and adolescents 4, 3
  • Contraindication in multiple sclerosis and other demyelinating diseases 2
  • Caution in patients with congestive heart failure 2, 3

Treatment Failure and Alternatives

• Primary and secondary failures of TNF inhibitor therapy affect 30-50% of patients in clinical practice, particularly those with long-standing diseases 1, 2
• In cases of TNF inhibitor failure, options include:
  • Switching to another TNF inhibitor 1
  • Switching to a different class of biologic DMARDs 1, 2
  • Considering JAK inhibitors or other targeted synthetic DMARDs 1, 2

Clinical Pearls

• Always screen for latent tuberculosis before initiating TNF inhibitor therapy 2, 4
• Consider combination therapy with methotrexate to enhance efficacy, particularly with infliximab 1, 8
• For pregnant patients, certolizumab may be preferred due to minimal placental transfer 2
• Regular monitoring for infections and other adverse effects is essential 2, 3
• Biosimilars of TNF inhibitors are becoming increasingly available, offering cost-effective alternatives 1