Mechanism of Action of Adalimumab (Humira)

Introduction

Adalimumab is a fully human monoclonal IgG1 antibody that specifically targets tumor necrosis factor‑α (TNF‑α). By neutralizing TNF‑α, it reduces inflammation across a variety of autoimmune conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease, ulcerative colitis, and plaque psoriasis.

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Step-by-Step Mechanism of Action

1. Specific binding to TNF‑α
   Adalimumab attaches with high affinity to both soluble and membrane-bound TNF‑α.
2. Neutralization of TNF‑α activity
   Binding prevents TNF‑α from interacting with TNF receptors (TNFR1 and TNFR2) on target cells.
3. Inhibition of downstream signaling
   By blocking TNF‑α, activation of the NF‑κB and MAPK pathways is reduced.
4. Reduction of inflammatory mediator production
   This leads to decreased production of cytokines (IL‑1, IL‑6), adhesion molecules, and MMPs, lowering immune cell recruitment.
5. Modulation of immune functions
   Results in decreased infiltration of inflammatory cells into tissue and improved clinical outcomes in autoimmune diseases.

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Pharmacokinetic Parameters

Parameter	Value
Route	Subcutaneous injection
Bioavailability	~64%
Half-life	~10–20 days
Distribution	~5–6 L
Metabolism	Proteolytic catabolism
Excretion	Degraded to peptides and amino acids

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Clinical Uses

• Rheumatoid arthritis
• Psoriatic arthritis
• Ankylosing spondylitis
• Crohn’s disease
• Ulcerative colitis
• Plaque psoriasis
• Juvenile idiopathic arthritis
• Hidradenitis suppurativa

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Adverse Effects

• Increased risk of serious infections (e.g., TB, fungal infections)
• Injection-site and infusion reactions
• Rare lupus-like syndromes or demyelinating disorders
• Increased risk of certain malignancies (e.g., lymphoma)
• Possible development of antidrug antibodies reducing efficacy

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Comparative Analysis

Agent	Type	TNF Target	Indications
Adalimumab	Human monoclonal IgG1	TNF‑α	Comprehensive autoimmune coverage
Infliximab	Chimeric mAb	TNF‑α	Similar but IV infusion route
Etanercept	Receptor fusion protein	TNF‑α/β	Soluble receptor decoy

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MCQs

1. Adalimumab specifically targets:
   a) TNF‑α b) IL‑17 c) IL‑6 d) JAK
   Answer: a) TNF‑α
2. It neutralizes TNF‑α by:
   a) Binding to TNFR b) Binding TNF‑α directly c) Inhibiting TNF synthesis d) Activating TNF receptors
   Answer: b) Binding TNF‑α directly
3. Main downstream pathways inhibited include:
   a) cAMP b) NF‑κB and MAPK c) PI3K d) JAK‑STAT
   Answer: b) NF‑κB and MAPK
4. Half-life of adalimumab is:
   a) 1–2 hours b) 10–20 days c) 3–5 days d) 4–8 hours
   Answer: b) 10–20 days
5. A major safety concern prior to initiation is:
   a) Hypertension b) Latent TB c) Hyperthyroidism d) Diabetes
   Answer: b) Latent TB
6. Compared to infliximab, adalimumab is:
   a) Chimeric b) Fully human c) Small molecule d) Receptor decoy
   Answer: b) Fully human
7. Risk of antidrug antibodies is:
   a) Higher than etanercept b) Lower than infliximab c) Not present d) Highest among all biologics
   Answer: a) Higher than etanercept
8. Common adverse effect is:
   a) Hypoglycemia b) Infection c) Renal failure d) Hair loss
   Answer: b) Infection
9. Mechanism involves reduction of:
   a) IL‑1 and IL‑6 b) Dopamine release c) Glucagon secretion d) Histamine production
   Answer: a) IL‑1 and IL‑6
10. Route of elimination is mainly:
    a) Renal excretion b) Proteolytic degradation c) Hepatic metabolism d) Fecal unchanged
    Answer: b) Proteolytic degradation

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FAQs

1. Do I need TB testing before starting?
Yes—tuberculosis screening is mandatory due to increased reactivation risk.

2. Can it be tapered or stopped during remission?
Possibly—with careful monitoring, but disease relapse may require dose adjustment.

3. Are live vaccines allowed?
No—live vaccines are contraindicated during therapy.

4. How often is injection administered?
Frequently every 1 or 2 weeks, depending on indication and dose.

5. What monitoring is needed?
Check for infections, CBC, and consider imaging if demyelination is suspected.

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References

• FDA Label: Adalimumab (Humira)
• DrugBank: Adalimumab Summary
• StatPearls: Adalimumab Clinical Pharmacology
• PubMed: Adalimumab mechanism and immunogenicity
• PubMed Central: Anti-TNF therapy effects