Are IL-23 (Interleukin-23) inhibitors, such as risankizumab (Risankizumab) and ustekinumab (Ustekinumab), effective in treating ankylosing spondylitis?

IL-23 Inhibitors Lack Efficacy in Ankylosing Spondylitis

IL-23 inhibitors have not demonstrated efficacy in ankylosing spondylitis and cannot be recommended for this condition, despite their effectiveness in other inflammatory conditions like psoriatic arthritis and psoriasis. 1

Evidence Against IL-23 Inhibitor Use in Ankylosing Spondylitis

• Multiple clinical trials have shown that IL-23 inhibitors (including risankizumab and ustekinumab) lack efficacy in ankylosing spondylitis, suggesting that IL-23 may not be a relevant driver of disease pathogenesis in axial spondyloarthritis 1, 2
• The 2022 GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) guidelines specifically state that "IL-12/23 inhibitors and IL-23 inhibitors have not demonstrated efficacy in ankylosing spondylitis" 1
• A randomized controlled trial of risankizumab in ankylosing spondylitis failed to meet its primary endpoint, with no evidence of clinically meaningful improvements compared to placebo 2
• A systematic review informing the 2023 EULAR recommendations confirmed that inhibitors of IL-23 and IL-12/23 demonstrated no efficacy in axial spondyloarthritis 1

Contrasting Evidence in Other Conditions

• IL-23 inhibitors have shown efficacy in other inflammatory conditions:
  • Risankizumab, guselkumab, and tildrakizumab have demonstrated effectiveness for psoriatic arthritis, particularly for dactylitis 1
  • These agents are strongly recommended for skin psoriasis 1
  • Risankizumab has been approved for Crohn's disease, and mirikizumab for ulcerative colitis 1

Conflicting Evidence from Post-hoc Analyses

• Some post-hoc analyses from trials of ustekinumab and guselkumab in patients with psoriatic arthritis who had axial symptoms suggest these agents might improve back pain 1, 3
• However, these improvements could reflect changes in other disease domains rather than true axial disease improvement 1, 3
• The evidence is considered "too limited and conflicting" to recommend IL-23 inhibitors for axial disease even in psoriatic arthritis 1

Recommended Treatments for Ankylosing Spondylitis

• For patients with ankylosing spondylitis who have had an inadequate response to NSAIDs, the following therapies have demonstrated efficacy:
  • TNF inhibitors (including golimumab, adalimumab, infliximab) are strongly recommended 1, 4
  • IL-17 inhibitors (secukinumab, ixekizumab, bimekizumab) have shown efficacy and are approved for axial spondyloarthritis 1
  • JAK inhibitors (tofacitinib, upadacitinib, filgotinib) have demonstrated efficacy in phase II and III trials 1

Clinical Implications and Management Algorithm

For patients with ankylosing spondylitis:

1. First-line: NSAIDs, physiotherapy, and/or sacroiliac joint glucocorticoid injections when appropriate 1
2. If inadequate response to first-line therapy:
   • TNF inhibitors or IL-17 inhibitors should be the preferred biologic agents 1
   • JAK inhibitors can be considered as alternative options 1
3. Do not use IL-23 inhibitors for ankylosing spondylitis due to lack of efficacy 1, 2, 3

Special Considerations

• In patients with both Crohn's disease and ankylosing spondylitis, a dual-targeted approach might be necessary (e.g., an IL-23 inhibitor for intestinal disease and a TNF inhibitor for axial disease) 5
• The lack of efficacy of IL-23 inhibitors in ankylosing spondylitis, despite their effectiveness in psoriatic arthritis, highlights the distinct pathophysiological mechanisms underlying these related but different conditions 3