Anti-TNF-α Biological Therapies: Adalimumab and Infliximab

Mechanism

Pharmacological Class and Group

Immunobiological antagonists of Tumor Necrosis Factor alpha (TNF-α). Adalimumab is a fully human recombinant IgG1 monoclonal antibody; Infliximab is a chimeric (mouse/human) IgG1 monoclonal antibody.

Mechanism of Action

TNF-α is a key proinflammatory cytokine secreted by activated macrophages, keratinocytes and T lymphocytes, which acts by stimulating the expression of vascular adhesion molecules (ICAM-1, VCAM-1) on dermal endothelial cells and promoting the secretion of synergistic inflammatory cytokines.

Neutralization Mechanism of Soluble and Transmembrane TNF-α

1. Ligand Binding and Inactivation: Adalimumab and Infliximab bind with extreme affinity and specificity to the soluble (sTNF-α) and transmembrane (tmTNF-α) forms of the TNF-α homotrimer.

2. Receptor Docking Blockage: Antibody binding physically prevents the coupling of TNF-α to its cognate cellular receptors TNFR1 (p55) and TNFR2 (p75):

Anti-TNF Antibody + TNF-α Blocking TNFR1/2 Stopping the NF-κB Pathway

3. Antibody-Dependent Cell-mediated Cytotoxicity (ADCC): By binding to the transmembrane form expressed on active inflammatory cells, the Fc portion of the antibody recruits NK cells and the complement system, inducing direct cell lysis and stopping the local inflammatory cascade.

Pharmacokinetics

High Resolution Pharmacokinetics

• Routes and Bioavailability: Adalimumab is administered subcutaneously (SC) with a bioavailability of 64%, reaching the peak of maximum serum concentration (C_max) between 4 and 6 days post-injection. Infliximab is administered exclusively by slow intravenous (IV) infusion, ensuring 100% immediate bioavailability.
• Distribution: Reduced apparent volume of distribution, limited mainly to the peripheral vascular and cellular interstitial space.
• Metabolism: Elimination by nonspecific proteolytic degradation mediated by the reticulocyte mononuclear phagocytic system. It does not undergo hepatic clearance or degradation by cytochromes.
• Half-life (t_1/2): Adalimumab has a plasma half-life of 10 to 20 days. Infliximab has a terminal elimination half-life of approximately 9.5 days.

Indicators and dose

Clinical Indications and Off-Label Uses

• Moderate to Severe Plaque Psoriasis: Standard indication in adults and pediatrics refractory to classic immunosuppressants.
• Hidradenitis Suppurativa (Acne Inversa): Adalimumab is the first biologic approved for the control of nodules, abscesses and suppurative tunnels of moderate-severe hidradenitis (Hurley scale II or III).
• Psoriatic Arthritis: Priority treatment that stops progressive erosive joint damage.
• Refractory Pyoderma Gangrenosum (off-label): Especially effective in the subtype associated with inflammatory bowel disease.

Dosage and Clinical Adjustment

Adalimumab (Psoriasis):

• Initial Loading Dose: 80 mg subcutaneously administered at week 0.
• Maintenance Dose: 40 mg subcutaneously administered once every two weeks (starting one week after the loading dose).
• Adjustment in Hidradenitis Suppurativa: Requires higher loading doses: 160 mg in week 0 (on one day or divided into two consecutive days), 80 mg in week 2 and maintenance dose of 40 mg weekly or 80 mg every 2 weeks starting from week 4.

Infliximab (Psoriasis):

• Intravenous Infusion: 5 mg/kg by slow intravenous infusion (duration of 2 hours) administered in weeks 0, 2 and 6 (induction phase), followed by maintenance infusions every 8 weeks indefinitely.

Adjustment in Renal and Hepatic Insufficiency: No dose adjustment is required in patients with renal or hepatic insufficiency, since the clearance of immunoglobulins does not depend on renal excretory or hepatic metabolic mechanisms of CYP450.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the active substance or proteins of murine origin (for infliximab).
• Active tuberculosis or other severe opportunistic infections (listeriosis, legionellosis, deep mycoses).
• Moderate to severe congestive heart failure (NYHA class III or IV) (due to reported risk of severe worsening and death).

Relative Contraindications

• Personal history of demyelinating disease (Multiple Sclerosis, Guillain-Barré Syndrome).
• Chronic active hepatitis B (risk of acute massive viral reactivation).

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Reactions at the injection site (erythema, local pain), superficial nasopharyngitis, headache.
• Common (1%-10%): Upper respiratory tract infections, transient elevation of transaminases, development of autoantibodies (ANA, anti-dsDNA) that rarely cause drug-induced Lupus Syndrome, acute infusion reactions (Infliximab).
• Uncommon (0.1%-1%): Paradoxical psoriasis (appearance of new psoriatic lesions or plantar pustular forms paradoxically induced by the drug due to local interferon-alpha imbalance), reactivation of Latent Tuberculosis.

Critical Toxicity: Reactivation of Latent Tuberculosis and Mandatory Screening

TNF-α plays an indispensable physiological biological role in the formation and structural maintenance of immune granulomas containing Mycobacterium tuberculosis within alveolar macrophages. The administration of an anti-TNF agent destroys this granulomatous structure:

Anti-TNF Disintegration of Alveolar Granuloma Dissemination of Bacillus Miliary / Extrapulmonary Severe TB

It causes immediate reactivation of latent tuberculosis and destructive hematogenous dissemination (extrapulmonary, bone or miliary tuberculosis). It is mandatory to perform for all patients, prior to starting the biological drug: an AP chest x-ray and a Mantoux intradermoreaction test (PPD) or Interferon Gamma release test (IGRA - QuantiFERON). If latent tuberculosis is diagnosed, complete preventive treatment with Isoniazid should be instituted for 6-9 months, and the biological drug can be started after completing the first month of anti-tuberculosis therapy.

Drug Interactions of Clinical Relevance

• Anakinra or Abatacept: Concomitant use of multiple immunobiological agents in the same time window unacceptably multiplies the risk of neutropenia and serious opportunistic infections without adding measurable clinical efficacy.
• Live Attenuated Vaccines (Yellow Fever, Triple Viral, Chicken Pox): Absolute contraindication due to the risk of generalized infection spread by uncontrolled replication of the vaccine virus.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Compatible with precautions. The transplacental passage of IgG1 antibodies is negligible during the first gestational trimester, but increases massively during the third trimester through active transport mediated by the neonatal Fc receptor (FcRn). Although teratogenicity has not been demonstrated, it is advisable, if the stability of the disease allows it, to suspend the biological in week 30-32 of gestation to avoid neonatal immunosuppression at birth (which would contraindicate live vaccines in the newborn during the first 6 months of life).
• Breastfeeding: Absolutely compatible. The concentration in human milk is negligible and any ingested remains are disintegrated by acid proteolytic digestion in the infant's gastrointestinal tract.