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<p>Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease characterized by erythema, tense blisters, pruritus, and pain. The pathogenesis of BP involves antibodies targeting structural proteins at the dermal-epidermal junction. Prior studies have identified IL-17 as a potential therapeutic target in BP. We hypothesize IL-17 blockade with ixekizumab, an IL-17&#xa0;A inhibitor, may have a targeted, disease-modifying effect on BP. We conducted a single-center, exploratory, open-label, single-arm pilot study using ixekizumab treatment for 12 weeks. Treatment response was assessed by new blister formation, Bullous Pemphigoid Disease Area Index (BPDAI), and use of prednisone rescue. A total of 4 patients were recruited, with 3 withdrawing during the treatment phase with worsening disease. All 3 withdrawn patients required oral prednisone rescue therapy. One patient completed the study with a 60% improvement in blister/erosion BPDAI on ixekizumab and rescue oral prednisone. RNA levels in baseline disease tissue and control samples were analyzed using a NanoString<sup>®</sup> panel of 249 inflammatory genes. Cytokine analysis was performed on serum and blister fluid for interleukin (IL)-1b, -2, -4, -5, -6, -12p70, -17a, -18, -21, -22. Array-based ELISAs were used for transforming growth factor beta (TGF-β) and matrix-metalloprotease-2 (MMP-2), MMP-9, and MMP-13 expression. There were 24 statistically significant differentially expressed genes (DEGs) identified. Type I and II IFNs as well as the Th2 chemokine CCL13 were upregulated in BP. Serum pre-treatment IL-17&#xa0;A was elevated in 1 patient and was no longer detectable after week 12. Cytokine analysis demonstrated elevated serum IFN-γ, MMP-13, and Th2 cytokines in BP patients after receiving ixekizumab relative to pre-treatment levels, with a decrease in MMP-2. Our clinical data, RNA, and cytokine analysis suggest that IL-17&#xa0;A inhibition with ixekizumab may not target the critical pathways in BP and support Type I and II IFN and the Th2 pathway as potential future therapeutic targets. <i>Trial Registration</i>: NCT03099538.</p>

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The role of IL-17A and ixekizumab in the treatment of bullous pemphigoid: an exploratory pilot study

  • 期刊论文

  • 发表日期：

    2025年10月17日

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  • A. L. Stockard,
  • Z. Leibovit-Reiben,
  • B. W. Boudreaux,
  • A. Hughes,
  • C. M. Costello,
  • P. K. Bhullar,
  • P. Wang,
  • X. Li,
  • M. R. Pittelkow,
  • A. R. Mangold

摘要

Bullous pemphigoid (BP) is a subepidermal autoimmune blistering disease characterized by erythema, tense blisters, pruritus, and pain. The pathogenesis of BP involves antibodies targeting structural proteins at the dermal-epidermal junction. Prior studies have identified IL-17 as a potential therapeutic target in BP. We hypothesize IL-17 blockade with ixekizumab, an IL-17 A inhibitor, may have a targeted, disease-modifying effect on BP. We conducted a single-center, exploratory, open-label, single-arm pilot study using ixekizumab treatment for 12 weeks. Treatment response was assessed by new blister formation, Bullous Pemphigoid Disease Area Index (BPDAI), and use of prednisone rescue. A total of 4 patients were recruited, with 3 withdrawing during the treatment phase with worsening disease. All 3 withdrawn patients required oral prednisone rescue therapy. One patient completed the study with a 60% improvement in blister/erosion BPDAI on ixekizumab and rescue oral prednisone. RNA levels in baseline disease tissue and control samples were analyzed using a NanoString® panel of 249 inflammatory genes. Cytokine analysis was performed on serum and blister fluid for interleukin (IL)-1b, -2, -4, -5, -6, -12p70, -17a, -18, -21, -22. Array-based ELISAs were used for transforming growth factor beta (TGF-β) and matrix-metalloprotease-2 (MMP-2), MMP-9, and MMP-13 expression. There were 24 statistically significant differentially expressed genes (DEGs) identified. Type I and II IFNs as well as the Th2 chemokine CCL13 were upregulated in BP. Serum pre-treatment IL-17 A was elevated in 1 patient and was no longer detectable after week 12. Cytokine analysis demonstrated elevated serum IFN-γ, MMP-13, and Th2 cytokines in BP patients after receiving ixekizumab relative to pre-treatment levels, with a decrease in MMP-2. Our clinical data, RNA, and cytokine analysis suggest that IL-17 A inhibition with ixekizumab may not target the critical pathways in BP and support Type I and II IFN and the Th2 pathway as potential future therapeutic targets. Trial Registration: NCT03099538.