Makindo Medical Notes

🔥 TNF: A Pivotal Cytokine Mediator

• 🧬 Tumour Necrosis Factor (TNF) is a master regulator of inflammation, central to many immune-mediated diseases.
• Exists in both soluble and transmembrane forms.
• Binds to TNFR1 and TNFR2 → driving inflammation, apoptosis, and cell survival pathways.

💉 TNF Blockade: A Revolutionary Therapy

• First modern biological therapy introduced at the turn of the 21st century.
• Now licensed for both adults and children across several immune-mediated diseases:
• 🤲 Rheumatoid arthritis
• 🦴 Ankylosing spondylitis
• 🧩 Psoriatic arthritis
• 👶 Juvenile idiopathic arthritis
• 🩸 Psoriasis
• 🌿 Crohn’s disease
• 🧻 Ulcerative colitis
• 👁 Uveitis
• 💥 Hidradenitis suppurativa

💊 Licensed Anti-TNF Agents

• Currently 5 licensed anti-TNF drugs:
• 🧬 Fully human monoclonal antibodies (e.g., adalimumab, golimumab)
• 🧪 Chimeric monoclonal antibody (infliximab)
• ⚗️ Certolizumab – PEGylated Fab fragment, produced in E. coli
• 🔗 Etanercept – soluble receptor (also blocks lymphotoxin-α3)

🤲 Impact on Rheumatoid Arthritis

• 📈 Licensed in early 2000s → transformed management.
• Marked improvements in pain, stiffness, fatigue → reduced disability and need for surgery.
• Registry data: ↑ risk of serious infection, but no increase in malignancy overall.
• 💡 Teaching pearl: Anti-TNFs often combined with methotrexate for durability and to reduce antibody formation against biologics.

⚠️ Unexpected Complications

• 🧫 Tuberculosis (TB) reactivation:
  • Disruption of granulomas → extrapulmonary/miliary TB.
  • Now standard: TB screening (IGRA or Mantoux + CXR) before therapy.
  • Etanercept less likely to reactivate TB compared to infliximab/adalimumab.
• ⬆️ Susceptibility to intracellular pathogens: listeria, salmonella, fungi.

🌿 Crohn’s Disease & Ulcerative Colitis

• Highly effective in severe Crohn’s (esp. fistulising or perianal disease).
• ~50% achieve remission & mucosal healing within 2 years.
• Etanercept ❌ ineffective in Crohn’s → reflects granulomatous nature of disease.
• Effective in ulcerative colitis too.

🩸 Psoriasis & Psoriatic Arthritis

• Clear benefit in moderate-severe psoriasis: infliximab → >80% achieve PASI 75 improvement.
• Also effective in psoriatic arthritis & ankylosing spondylitis → ↓ joint inflammation and improved spinal mobility.

🚫 Limitations of TNF Blockade

• Not effective in all conditions → can worsen:
  • 🧠 Multiple sclerosis
  • ❤️ Congestive heart failure
• Trials in these diseases stopped due to adverse outcomes.

💥 Adverse Effects of TNF Blockade

• In addition to infections, rare but important side effects include:
• 🩸 Neutropenia
• 🩻 Vasculitis
• 🩺 Paradoxical psoriasis (new onset)
• 🌙 Drug-induced lupus (including renal & CNS disease)

💡 Clinical pearl: Anti-TNF agents have redefined outcomes in chronic inflammatory diseases, but require pre-treatment screening (TB, hepatitis B/C, HIV) and ongoing vigilance for infections and autoimmune complications.