What are Tumor Necrosis Factor (TNF) inhibitors?

Tumor Necrosis Factor (TNF) Inhibitors

TNF inhibitors are a class of biologic medications that block the inflammatory effects of tumor necrosis factor alpha (TNF-α), a key cytokine involved in inflammatory processes across multiple immune-mediated inflammatory diseases.

What are TNF Inhibitors?

TNF inhibitors are biological agents designed to target and neutralize tumor necrosis factor alpha (TNF-α), which plays a central role in the inflammatory processes of various autoimmune conditions 1, 2.

• TNF-α is a proinflammatory cytokine produced by various cell types including keratinocytes that mediates inflammatory and immunoregulatory activities 1
• TNF-α levels are elevated in affected tissues and fluids of patients with inflammatory conditions, with levels correlating with disease severity 1
• TNF inhibitors work by binding to TNF-α, preventing its interaction with cell surface TNF receptors and thereby inhibiting its inflammatory effects 1, 3

Types of TNF Inhibitors

There are currently five FDA-approved TNF inhibitors, each with a unique structure and mechanism of TNF neutralization 1, 4:

• Infliximab: A chimeric mouse/human anti-TNF-α monoclonal antibody consisting of a variable murine region and a constant human IgG1 region; administered intravenously 1
• Adalimumab: A fully humanized anti-TNF-α monoclonal antibody; administered subcutaneously 1, 5
• Etanercept: A fusion protein consisting of two extracellular portions of human TNF receptor 2 (p75 TNF receptor) linked to the Fc portion of human IgG1; administered subcutaneously 1, 3
• Golimumab: A fully humanized anti-TNF-α monoclonal antibody; administered subcutaneously 1
• Certolizumab pegol: A Fab' fragment of an anti-TNF-α monoclonal antibody lacking the Fc portion, with its hinge region covalently linked to polyethylene glycol; administered subcutaneously 1

Approved Indications

TNF inhibitors have been approved for the treatment of multiple inflammatory conditions 1, 5:

• Rheumatoid arthritis (RA)
• Juvenile idiopathic arthritis (JIA)
• Psoriatic arthritis (PsA)
• Ankylosing spondylitis (AS)
• Plaque psoriasis (PsO)
• Crohn's disease (CD)
• Ulcerative colitis (UC)
• Hidradenitis suppurativa (adalimumab) 5
• Uveitis (adalimumab) 5
• Behçet's disease 1

Efficacy Differences Between TNF Inhibitors

While all TNF inhibitors are effective for rheumatologic conditions, there are important differences in their efficacy for certain conditions 1, 6:

• All five agents are effective in RA, PsA, and AS 1
• Only infliximab, adalimumab, and golimumab are effective for inflammatory bowel disease (IBD), while etanercept is not effective for IBD 1
• The differences in efficacy may be related to their unique pharmacological properties, including binding to transmembrane TNF, Fc function, and ability to form complexes 6

Safety Considerations and Contraindications

TNF inhibitors have several important safety considerations 1:

• Infections: Increased risk of serious infections, including tuberculosis reactivation; tuberculosis testing is required before starting therapy 1
• Malignancy: Potential increased risk, particularly in pediatric patients 3
• Demyelinating disorders: Should not be used in patients with multiple sclerosis (MS) or other demyelinating diseases, or in first-degree relatives of patients with MS 1
• Congestive heart failure (CHF): Reports of new onset and worsening of CHF; caution in patients with CHF; not recommended in New York Heart Association class III or IV CHF 1
• Hepatitis B reactivation: Screening recommended in appropriate clinical settings 1
• Live vaccines: Should not be administered concurrently with TNF inhibitors 1

Use in Special Populations

Pregnancy and Breastfeeding

• TNF inhibitors with an IgG1 Fc construct (infliximab, etanercept, adalimumab, golimumab) can cross the placenta, especially in the third trimester 1
• Certolizumab has minimal placental transfer due to lack of an Fc chain 1
• For women with well-controlled disease, TNF inhibitors containing an IgG1 Fc construct may be discontinued in the third trimester to minimize fetal exposure 1
• Certolizumab can be continued throughout pregnancy 1

Pediatric Patients

• Several TNF inhibitors are approved for use in pediatric patients with JIA, pediatric Crohn's disease, and pediatric plaque psoriasis 3, 5
• Caution is advised due to reports of malignancies in pediatric patients receiving TNF inhibitors 3

Elderly Patients

• No overall differences in safety or effectiveness have been observed in elderly patients, but caution is advised due to higher infection risk in this population 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 disease 1
• Alternative biologic DMARDs or JAK inhibitors may be considered in patients who fail TNF inhibitor therapy 1

Monitoring During Treatment

• Regular monitoring for infections, particularly tuberculosis
• Periodic laboratory assessments
• Vigilance for potential adverse effects, including injection site reactions, infusion reactions, and development of autoantibodies 1

TNF inhibitors have revolutionized the treatment of immune-mediated inflammatory diseases, offering significant improvements in outcomes for patients with conditions that were previously difficult to manage effectively 4, 7.