Why does psoriasis relapse after the withdrawal of biological drugs? 为何在停止使用生物制剂后，银屑病会复发？

Biological drugs, such as TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors, target specific components of the immune system that are involved in the pathogenesis of psoriasis. These drugs suppress the overactive immune response that causes the rapid skin cell turnover characteristic of the disease.

When biological drugs are withdrawn, the immune system gradually returns to its pre-treatment state, including the reactivation of pro-inflammatory pathways. This can lead to a resurgence of psoriasis symptoms, as the inflammatory processes responsible for the skin lesions resume. Furthermore, the long-term effects of biological therapies may also influence the skin’s immune tolerance, and once the suppression is lifted, the disease may return more aggressively. In some cases, withdrawal can even lead to withdrawal flare-ups, where the disease worsens temporarily before stabilizing.

1.Incomplete Targeting of Pathogenic Cells:

  • tissue-resident memory T (TRM) cells persist in resolved psoriasis skin, retaining the ability to produce cytokines like IL-17A and IL-22 upon reactivation.
  • Antigen-presenting cells in the epidermis and dermis continue to support inflammation, even after biologic treatment.

2.Residual Molecular Scars:

  • Epigenetic modifications, such as increased chromatin accessibility in inflammatory genes, are not reversed by current therapies.
  • These molecular changes create a tissue environment primed for rapid inflammatory responses.

3.Poor Drug Penetration:

  • Biologics often have limited bioavailability in epidermal layers, allowing pathogenic TRM cells to evade treatment.

Why Relapse After Biological Drug Withdrawal

“The routine use of targeted systemic immunomodulatory therapies has transformed outcomes for people with severe psoriasis, with skin clearance (clinical remission) rates up to 60% at 1 year of biologic treatment. However, psoriasis may recur following drug withdrawal, and as a result, patients tend to continue receiving costly treatment indefinitely.”

 

—- Francis L, Capon F, Smith CH, Haniffa M, Mahil SK. Inflammatory memory in psoriasis: From remission to recurrence. J Allergy Clin Immunol. 2024 Jul;154(1):42-50. doi: 10.1016/j.jaci.2024.05.008. Epub 2024 May 17. PMID: 38761994.

Francis et al paper delves into the concept of inflammatory memory in psoriasis, where molecular and cellular alterations persist in clinically resolved skin, leading to disease recurrence after treatment withdrawal. Key contributors include tissue-resident memory T (TRM) cells, antigen-presenting cells (Langerhans and dendritic cells), epithelial stem cells, and fibroblasts. These cells maintain inflammatory potential through mechanisms such as epigenetic modifications and tissue remodeling.

1.Inflammatory Memory Mechanisms:

  • TRM cells are the primary drivers of recurrence, capable of producing IL-17 and IL-22 even after clinical remission.
  • Antigen-presenting cells, such as Langerhans cells and dendritic cells, upregulate psoriasis-related cytokines.
  • Epithelial stem cells and fibroblasts retain inflammatory memory through epigenetic changes, sensitizing skin to future insults.

2.Molecular Basis:

  • Persistent chromatin accessibility and histone modifications lead to a “molecular scar.”
  • Pro-inflammatory pathways, such as those involving IL-23 and IL-17, remain active in resolved psoriasis skin.

3.Role of Single-Cell Technologies:

  • scRNA-seq and scATAC-seq enable high-resolution, hypothesis-free analysis of transcriptomic and epigenomic changes.
  • Spatial transcriptomics and protein imaging offer additional insights into tissue-specific inflammatory memory.

4.Challenges and Research Gaps:

  • Targeting TRM cells or antigen-presenting cells without compromising skin immunity is difficult.
  • Improved understanding of somatic mutations, epigenetic changes, and cell-type-specific contributions is needed.

银屑病在停止使用生物制剂后复发的原因与这些治疗的机制有关。生物制剂，如TNF抑制剂、IL-17抑制剂和IL-23抑制剂，针对参与银屑病发病机制的免疫系统特定成分。这些药物通过抑制免疫系统过度活跃的反应，减少了导致皮肤细胞过快更新的原因。

1.靶向病理性细胞的不完全性：

  • 驻留组织的记忆T细胞（tissue-resident memory T cells, TRM）在已缓解的银屑病皮肤中持续存在，并在重新激活后仍能产生如IL-17A和IL-22等细胞因子。
  • 即使经过生物制剂治疗，表皮和真皮中的抗原呈递细胞仍可支持炎症反应。

2.残余分子痕迹：

  • 表观遗传修饰（如炎症基因的染色质可及性增加）未被现有疗法逆转。
  • 这些分子改变使组织环境处于易于迅速引发炎症反应的状态。

3.药物渗透性差：

  • 生物制剂通常在表皮层中的生物利用度有限，使病理性TRM细胞能够逃避治疗。

Reference:

Francis L, Capon F, Smith CH, Haniffa M, Mahil SK. Inflammatory memory in psoriasis: From remission to recurrence. J Allergy Clin Immunol. 2024 Jul;154(1):42-50. doi: 10.1016/j.jaci.2024.05.008. Epub 2024 May 17. PMID: 38761994.