Understanding immune drift in biologic therapy for inflammatory skin diseases

Immune-inflammatory skin diseases (e.g., psoriasis, atopic dermatitis) involve dysregulation of CD4+ T-cell subsets (Th1/Th2/Th17/Treg) and cytokine networks (IL-17/IL-23/IL-4). Biologics targeting specific pathways-TNF-α, IL-17, IL-12/23, IL-4/13, PD-1/PD-L1-revolutionize treatment but trigger immune drift, shifting CD4+ T-cell polarization and causing adverse skin reactions. This review synthesizes mechanisms, clinical manifestations, and management strategies.

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 IL-5/IL-13 in lesions; exacerbated atopic dermatitis in Crohn's disease patients.

2. IL-17 inhibitors (Secukinumab, Ixekizumab)

• 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)

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

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

4. IL-4/13 inhibitors (Dupilumab)

• 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.

Conclusion

Skin adverse reactions due to immune drift not only exacerbate patient suffering and increase treatment costs but also place pressure on social healthcare resources and economic productivity. The underlying mechanisms may involve immune imbalances between Th1/Th2 cells, as well as imbalances between IL-17 isoforms, decreased expression of antimicrobial peptides leading to Staphylococcus aureus infections, and disruption of the skin barrier function, among other factors. By reviewing these phenomena and revealing the dual effects of biologic therapies, we can provide a theoretical basis for optimizing treatment strategies and strengthening risk management in the future through mechanism-based research. In the future, interdisciplinary cooperation will be essential to promote the development of safer immunotherapies. It is expected to achieve the therapeutic goal of "maximizing efficacy and minimizing toxicity" and to reshape the landscape of immunotherapy.