Biologics have revolutionized the treatment of inflammatory skin diseases but can trigger immune drift, shifting CD4+ T-cell polarization and causing adverse skin reactions.

Researchers reviewed CD4⁺ T Cell-mediated immune drift and mechanisms in the treatment of immune inflammatory skin diseases with biological agents in Future Integrative Medicine.

Here’s what they found:

Mechanisms of Immune Drift by Biologic Class

1. TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

• Mechanism: Blocking Th1 pathway → Loss of Th1-mediated suppression of Th2 → Th2 dominance
• Clinical Manifestations: Eczema-like lesions (2%–20% incidence in non-dermatologic diseases; 1%–6% in psoriasis)
• Evidence: Elevated interleukin (IL)-5/IL-13 in lesions; exacerbated atopic dermatitis in Crohn’s disease patients

2. IL-17 Inhibitors: Secukinumab (Cosentyx, Novartis), Ixekizumab (Taltz, Lilly)

• Mechanism:
  • Suppression of Th17 → Th2/Th22 imbalance (elevated IL-22)
  • Reduced antimicrobial peptides → Staphylococcus aureus colonization → Barrier disruption
  • Overexpression of IL-17C (linked to Th2 inflammation)
• Clinical Manifestations: Eczema (2.2%–12.1%), bullous pemphigoid (Th2-driven)

3. IL-12/23 Inhibitors: Ustekinumab, Guselkumab (Tremfya, Janssen Biotech, Inc)

Mechanism: Blocking p40 subunit → Impaired Th1/Th17 differentiation → Compensatory Th2 activation

• Clinical Manifestations: Atopic dermatitis flare (especially in patients with a history of atopy/elevated IgE)

4. IL-4/13 Inhibitors: Dupilumab (Dupixent, Sanofi & Regeneron)

• Mechanism: Blocking IL-4Rα → Suppressed Th2 → Unchecked Th1/Th17 expansion
• Clinical Manifestations: Psoriasiform lesions (3%–5%), polymyalgia rheumatica (Th17-mediated), ulcerative colitis (Th1-driven)

5. PD-1/PD-L1 Inhibitors

• Mechanism:
  • T-cell activation → IFN-γ release → Epidermal dyshomeostasis
  • Shift from M2 to M1 macrophages → TNF-α/IL-12 release → Th17 expansion
• Clinical Manifestations: Psoriasiform eruptions (high prevalence in cancer patients)

Clinical Management of Immune Drift

Risk Identification

• High-risk patients: History of atopy, asthma, psoriasis, or elevated serum IgE
• Monitoring: Regular assessment of cytokine profiles (e.g., Th2 cytokines for TNF-α inhibitor users)

Therapeutic Strategies

1. Mild Reactions: Topical glucocorticoids or antimicrobial ointments
2. Persistent Reactions:
   • Biologic suspension/switching (e.g., dupilumab for IL-17-induced eczema)
   • Immunomodulators: Methotrexate, cyclosporine
   • Phototherapy for psoriasiform lesions
3. Emerging Approaches:
   • Natural Compounds: Curcumin/resveratrol activate aryl hydrocarbon receptor (AhR), restoring barrier function and suppressing Th2 cytokines
   • Nanotechnology: Epidermal-targeted carriers enhance drug delivery, minimizing systemic immune drift
   • Platelet-Rich Plasma (PRGF): Anti-inflammatory modulation in atopic dermatitis/psoriasis

Limitations and Future Directions

• Knowledge Gaps: Non-classical pathways (e.g., Th9, Th22) underexplored
• Precision Medicine Goals:
  • Biomarker development (e.g., IgE, cytokine panels) for risk stratification
  • Dual-target biologics to prevent compensatory pathway activation
  • Dynamic immune monitoring via liquid biopsies