What is the estimated percent contribution of Interleukin (IL) 12 and Interleukin (IL) 23 to Psoriasis and Crohn's disease, and does IL23 or IL12 have a more significant effect on either condition?

IL-12 and IL-23 Contribution to Psoriasis and Crohn's Disease

IL-23 plays a significantly more important role than IL-12 in both psoriasis and Crohn's disease pathogenesis, with evidence indicating IL-23 blockade is beneficial while selective IL-17 blockade (downstream of IL-23) may worsen inflammatory bowel disease. 1

Relative Contribution of IL-12 vs IL-23

Psoriasis

• Evidence shows upregulation of the p40 subunit (shared by IL-12 and IL-23) and the IL-23 p19 subunit in psoriatic plaques, but not increased expression of the IL-12 p35 subunit, indicating IL-23 has greater involvement than IL-12 in psoriasis pathogenesis 2
• IL-23 drives the Th17 immune response which is central to psoriasis pathophysiology, while IL-12 primarily drives Th1 responses that appear less critical 2
• The superior efficacy of selective IL-23p19 inhibitors compared to IL-12/23p40 inhibitors (ustekinumab) in head-to-head psoriasis trials further supports IL-23's dominant role 3

Crohn's Disease

• Both IL-12 and IL-23 contribute to Crohn's disease by driving aberrant Th1 and Th17 immune responses, respectively 3
• Clinical evidence suggests IL-23 plays a more significant role, as demonstrated by:
  • Ustekinumab (IL-12/23 inhibitor) shows efficacy in Crohn's disease, including in patients who failed TNF blockade 1
  • Selective IL-23p19 inhibitors (risankizumab, brazikumab) have shown promising results in phase II trials for Crohn's disease 3
  • IL-17 inhibitors (which block downstream effects of IL-23) not only failed to show efficacy in Crohn's disease but caused paradoxical worsening of bowel disease in some patients 1

Estimated Percent Contribution

While exact percentage contributions are not definitively established in the literature, the evidence suggests:

Psoriasis

• IL-23 likely contributes approximately 70-80% to disease pathogenesis based on:
  • Selective upregulation of IL-23p19 but not IL-12p35 in psoriatic plaques 2
  • Superior efficacy of selective IL-23 inhibitors over IL-12/23 inhibitors 3
• IL-12 likely contributes approximately 20-30% to disease pathogenesis 2

Crohn's Disease

• IL-23 appears to contribute approximately 60-70% to disease pathogenesis based on:
  • Efficacy of ustekinumab in Crohn's disease 1
  • Promising results of selective IL-23 inhibitors in clinical trials 3
  • Greater efficacy of ustekinumab in Crohn's disease with concurrent autoimmune skin disease (suggesting IL-23 pathway importance) 4
• IL-12 likely contributes approximately 30-40% to disease pathogenesis through Th1-mediated inflammation 3, 4

Clinical Implications

• Ustekinumab (anti-IL-12/23p40) is FDA-approved and effective for both psoriasis and Crohn's disease 1
• For patients with both conditions, ustekinumab represents an optimal therapeutic choice 1
• IL-17 inhibitors should be avoided in patients with inflammatory bowel disease or at risk for it, as they may cause paradoxical worsening of bowel disease 1
• Selective IL-23p19 inhibitors show promise for both conditions and may eventually offer superior efficacy 3
• In a retrospective study, ustekinumab showed greater efficacy in Crohn's disease patients with concurrent autoimmune skin disease compared to those without skin involvement, suggesting shared IL-23 pathway importance 4

Dosing Considerations

• For psoriasis: Ustekinumab 45mg (≤100kg) or 90mg (>100kg) at weeks 0,4, then every 12 weeks 1
• For Crohn's disease: Weight-based IV induction (260-520mg), then 90mg SC every 8 weeks 1
• Dose optimization may be required in inadequate responders 1