TNF alfa inhibitors

Definition and Therapeutic Scope

Tumor necrosis factor-alpha (TNF-α) inhibitors are a class of immunomodulatory biologic agents that neutralize the activity of TNF-α, a pro-inflammatory cytokine implicated in the pathogenesis of various autoimmune and inflammatory disorders. These agents have transformed the management of chronic immune-mediated diseases by targeting the underlying inflammatory cascade rather than merely suppressing symptoms. TNF-α inhibitors are primarily used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, and plaque psoriasis, among other conditions.

TNF-α plays a central role in systemic inflammation, immune cell recruitment, and cytokine network amplification. Overexpression of TNF-α contributes to tissue damage, joint destruction, mucosal erosion, and skin pathology in affected patients.

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Mechanism of Action

TNF-α inhibitors work by:

• Binding to and neutralizing soluble and/or membrane-bound TNF-α

• Preventing TNF-α from interacting with its receptors (TNFR1 and TNFR2) on cell surfaces

• Inhibiting downstream pro-inflammatory signaling pathways including:

  • NF-κB activation

  • MAPK cascades

  • Cell adhesion molecule expression

• Reducing production of other inflammatory cytokines like IL-1, IL-6, and interferon-gamma

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Approved TNF-α Inhibitors

There are five primary agents approved for clinical use:

1. Infliximab (Remicade)

   • Structure: Chimeric monoclonal IgG1 antibody (human-mouse)

   • Administration: Intravenous infusion

   • Indications: RA, Crohn’s disease, ulcerative colitis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis

   • Dosing: Initial IV infusion followed by maintenance every 6–8 weeks

   • Notes: Often combined with methotrexate to reduce immunogenicity

2. Etanercept (Enbrel)

   • Structure: Fusion protein (two soluble TNF receptors fused to human IgG1 Fc region)

   • Administration: Subcutaneous injection

   • Indications: RA, JIA, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis

   • Dosing: Weekly or biweekly SC injection

   • Notes: Binds only soluble TNF-α (not membrane-bound)

3. Adalimumab (Humira)

   • Structure: Fully human monoclonal IgG1 antibody

   • Administration: Subcutaneous injection

   • Indications: Broadest approval—RA, JIA, psoriasis, IBD (Crohn’s, UC), uveitis

   • Dosing: Every 1–2 weeks

   • Notes: First SC biologic approved for IBD

4. Certolizumab pegol (Cimzia)

   • Structure: PEGylated humanized Fab fragment (lacks Fc region)

   • Administration: Subcutaneous injection

   • Indications: RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease

   • Dosing: Loading doses, followed by biweekly or monthly

   • Notes: PEGylation extends half-life; does not induce complement activation

5. Golimumab (Simponi, Simponi Aria)

   • Structure: Fully human monoclonal IgG1 antibody

   • Administration: SC (Simponi) and IV (Simponi Aria)

   • Indications: RA, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis

   • Dosing: SC monthly; IV every 8 weeks

   • Notes: Combined with methotrexate in RA for enhanced efficacy

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Therapeutic Indications (FDA/EMA Approved)

Disease	TNF Inhibitors Indicated
Rheumatoid arthritis (RA)	All 5 agents
Psoriatic arthritis (PsA)	All 5 agents
Ankylosing spondylitis (AS)	All 5 agents
Juvenile idiopathic arthritis	Etanercept, adalimumab, infliximab (off-label)
Crohn’s disease	Infliximab, adalimumab, certolizumab
Ulcerative colitis	Infliximab, adalimumab, golimumab
Plaque psoriasis	Etanercept, adalimumab, infliximab
Uveitis	Adalimumab (approved), infliximab (off-label)
Hidradenitis suppurativa	Adalimumab

Onset and Duration of Action

• Onset: Varies; typically 1–4 weeks for symptom relief

• Maximal efficacy: 8–12 weeks

• Half-life: Ranges from 4–20 days depending on agent

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Administration Routes and Dosing Frequencies

Agent	Route	Dosing Frequency
Infliximab	IV	Every 6–8 weeks (after loading)
Etanercept	SC	Weekly or twice weekly
Adalimumab	SC	Every 1–2 weeks
Certolizumab	SC	Every 2–4 weeks
Golimumab	SC/IV	Monthly (SC) / Every 8 weeks (IV)

Adverse Effects

1. Common:

   • Injection site reactions

   • Headache

   • Rash

   • Upper respiratory infections

2. Serious:

   • Infections: Tuberculosis (latent/reactivation), fungal (histoplasmosis), bacterial, viral

   • Malignancies: Lymphoma (esp. in young males with IBD), skin cancers

   • Autoimmune phenomena: Drug-induced lupus, demyelinating disorders

   • Hematologic toxicity: Pancytopenia, aplastic anemia (rare)

   • Congestive heart failure: May worsen symptoms (black box warning)

   • Anaphylaxis and infusion reactions: Especially with infliximab

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Monitoring Requirements

• Before initiation:

  • Tuberculosis screening (TST or IGRA)

  • Hepatitis B and C serology

  • Full blood count, liver function tests

• During therapy:

  • Regular infection surveillance

  • Periodic CBC, LFTs

  • Clinical monitoring for signs of demyelination or autoimmunity

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Contraindications and Precautions

• Active or chronic infections

• Untreated latent TB

• Severe heart failure (NYHA class III–IV)

• Demyelinating disease (e.g., multiple sclerosis)

• Hypersensitivity to monoclonal antibodies

• Pregnancy (risk-benefit analysis required; certolizumab preferred due to lack of Fc fragment)

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Drug Interactions

• Immunosuppressants: Increased risk of infections (e.g., methotrexate, corticosteroids)

• Live vaccines: Contraindicated during treatment

• Other biologics: Combining TNF inhibitors with other biologics (e.g., IL inhibitors, JAK inhibitors) is not recommended due to additive immunosuppression

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Comparative Considerations

Parameter	Infliximab	Etanercept	Adalimumab	Certolizumab	Golimumab
Structure	Chimeric mAb	Fusion protein	Human mAb	PEGylated Fab	Human mAb
Route	IV	SC	SC	SC	SC/IV
Anti-TNF Binding	Soluble + membrane	Soluble only	Soluble + membrane	Soluble + membrane	Soluble + membrane
Immunogenicity	High (w/o MTX)	Low	Moderate	Low	Low

Biosimilars

• Approved biosimilars for infliximab (e.g., Inflectra, Renflexis) and adalimumab (e.g., Amjevita, Cyltezo) offer more affordable alternatives with equivalent efficacy and safety.

• Switching from originators to biosimilars is considered safe in most settings but should be guided by clinician and patient preference