Mechanism of Action of Etanercept (Enbrel)

Introduction

Etanercept is a biologic fusion protein that functions as a soluble tumor necrosis factor (TNF) receptor. By binding TNF-α and TNF-β in circulation, it blocks their interaction with cell surface receptors, reducing systemic inflammation. It is approved for rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), juvenile idiopathic arthritis (JIA), and plaque psoriasis.

---

Step-by-Step Mechanism of Action

1. Fusion receptor structure
   Etanercept is composed of the extracellular portion of the p75 TNF receptor fused to the Fc portion of IgG1.
2. Decoy receptor activity
   It binds to TNF-α and TNF-β trimers in the bloodstream, preventing them from activating cell-associated TNF receptors.
3. Inhibition of downstream signaling
   Prevention of TNF binding blocks cellular NF-κB and MAPK pathway activation, reducing cytokine release and inflammatory cell recruitment.
4. Modulation of immune cell balance
   It can inhibit overactive Th17 responses, restore Th17/Treg balance, and promote anti-inflammatory macrophage (M2) polarization.
5. Decrease in inflammatory mediators
   Reduces levels of adhesion molecules, matrix metalloproteinases, and acute-phase proteins responsible for tissue damage.

---

Pharmacokinetic Parameters

Parameter	Value
Route	Subcutaneous injection
Bioavailability	~60–76%
Half-life	~70–132 hours (3–5 days)
Distribution	~12 L
Excretion	Proteolytic degradation—no renal elimination

---

Clinical Uses

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Juvenile idiopathic arthritis
• Plaque psoriasis

---

Adverse Effects

• Increased risk of serious infections (e.g., TB reactivation)
• Injection-site reactions
• Possible demyelination and lupus-like syndrome
• Rare hematologic abnormalities and malignancy

---

Comparative Analysis

Agent	Type	Mechanism	Indications
Etanercept	Fusion receptor	Soluble TNF decoy receptor	RA, PsA, AS, JIA, Psoriasis
Infliximab	Monoclonal antibody	Binds TNF-α	RA, PsA, IBD, AS
Adalimumab	Monoclonal antibody	Binds TNF-α	RA, PsA, Psoriasis, IBD

---

MCQs

1. Etanercept is constructed as:
   a) Monoclonal antibody b) Soluble TNF receptor–Fc fusion c) Receptor antagonist d) Small-molecule inhibitor
   Answer: b) Soluble TNF receptor–Fc fusion
2. It binds primarily to:
   a) IL‑6 b) TNF‑α & TNF‑β c) IL‑17 d) Interferon-γ
   Answer: b) TNF‑α & TNF‑β
3. Main downstream pathway inhibited is:
   a) JAK-STAT b) NF-κB & MAPK c) cAMP d) PI3K-AKT
   Answer: b) NF-κB & MAPK
4. Common pharmacokinetic half-life is:
   a) 12 hours b) 3–5 days c) 1 week d) 12 days
   Answer: b) 3–5 days
5. Key safety concern before initiating is:
   a) Hepatitis C b) Latent tuberculosis c) Venous thromboembolism d) G6PD deficiency
   Answer: b) Latent tuberculosis
6. Compared to infliximab, etanercept:
   a) Is a monoclonal antibody b) Is a decoy receptor c) Targets IL‑17 d) Is orally administered
   Answer: b) Is a decoy receptor
7. Etanercept may modulate autoimmune balance by:
   a) Enhancing Th17 b) Reducing Th17/Treg ratio c) Promoting Th1 d) Blocking IL‑2
   Answer: b) Reducing Th17/Treg ratio
8. Injection-site reactions occur in about:
   a) 1% b) 10% c) 25% d) 50%
   Answer: b) 10%
9. Proteolytic degradation signifies:
   a) Hepatic metabolism b) Small-molecule renal excretion c) Enzymatic protein breakdown d) Bile secretion
   Answer: c) Enzymatic protein breakdown
10. Etanercept is contraindicated in patients with:
    a) History of MS b) Mild hypertension c) Controlled DM d) Osteoarthritis
    Answer: a) History of MS

---

FAQs

1. Why test for TB before prescribing etanercept?
TNF inhibition impairs granuloma formation, increasing TB reactivation risk.

2. Can etanercept be used during pregnancy?
It is classified as Category D—used only if benefits outweigh risks.

3. Should live vaccines be avoided?
Yes—live vaccines are contraindicated during therapy.

4. How soon are clinical benefits seen?
Improvements usually begin within 1–2 weeks of initiating treatment.

5. Is etanercept safe long-term?
Long-term use is common, but periodic monitoring for infection and malignancy is essential.

---

References

• StatPearls: Etanercept Mechanism and Use
• DrugBank: Etanercept Summary
• PMC Research: Etanercept Reduces Th17/Treg Ratio
• ScienceDirect: Etanercept Binds TNF-α/β
• Medscape: Etanercept Mechanism of Action

---