IL-12 and IL-23 pathway inhibition in inflammatory bowel disease

Summary


Acute maternal infection with Toxoplasma gondii during pregnancy is associated with adverse pregnancy outcomes. Although previous reports have indicated that T. gondii may result in abortion without direct transmission of the parasite to the foetus, the molecular mechanism remains unclear. CD4+CD25+-regulatory T cells are known to be involved in maternal tolerance toward the foetus-bearing alloantigens. With a model of pregnant mice infected with T. gondii, we found that Foxp3 mRNA expression levels in both splenocytes and placenta were reduced markedly during the process of infection. Furthermore, the numbers of splenic CD4+CD25+-regulatory T cells and placental Foxp3+ cells decreased synchronously in the infected mice, and the reduction of splenic CD4+CD25+-regulatory T cells were associated with apoptosis induced by the infection. Additionally, injection of pregnant mice with excretory–secretory antigens (ESA) of T. gondii also resulted in foetal loss, which could be partly prevented by adoptive transfer of CD4+CD25+-regulatory T cells from normal pregnant mice. These data suggest that foetal loss caused by T. gondii can be independent of vertical infection and that the decrease of CD4+CD25+-regulatory T cells during infection may represent a previously unrecognized mechanism for the pathogenesis of abortion caused by this parasite.

In pregnant mice, the infection of Toxoplasma gondii causes the decrease of CD4+CD25+‐regulatory T cells

Key studies published in 2022 highlight the emergence of several novel drugs for inflammatory bowel disease. Head-to-head trials and network meta-analyses have also been conducted to identify the sequencing of these treatments, but we still have a long way to go to achieve personalized medicine. 

/pdf/improving-ibd-outcomes-in-the-era-of-many-treatment-options-3ejn3wv8.pdf

Improving IBD outcomes in the era of many treatment options

The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. 

Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study

Abstract Background Bowel urgency reduces ulcerative colitis patients' quality of life. Mirikizumab, a p19-directed anti-IL-23 antibody, demonstrates ulcerative colitis efficacy. Mirikizumab efficacy to reduce bowel urgency and bowel urgency association with other endpoints were analyzed in 2 Phase 3 trials. Methods LUCENT-1 (Induction): 1162 patients randomized 3:1 to intravenous 300 mg mirikizumab or placebo every 4 weeks for 12 weeks. LUCENT-2 (Maintenance): 544 mirikizumab responders during induction were re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo every 4 weeks for 40 weeks (52 weeks of continuous treatment). Bowel urgency was measured using the Urgency Numeric Rating Scale (0–10); for patients with LUCENT-1 baseline score ≥3, bowel urgency clinically meaningful improvement (≥3-point decrease) and remission (score ≤1) rates in mirikizumab versus placebo groups were compared at Weeks 12 and 52. Associations between bowel urgency and other efficacy endpoints were assessed at Weeks 12 and 52. Results A significantly higher proportion of mirikizumab patients versus placebo achieved clinically meaningful improvement in bowel urgency and remission at Weeks 12 and 52. Significantly higher percentages of patients achieving bowel urgency clinically meaningful improvement or remission, compared with those who did not, also achieved endpoints for clinical, corticosteroid-free, endoscopic, and symptomatic remission; clinical response; normalized fecal calprotectin and C-reactive protein; and improved quality of life. Conclusions In patients with ulcerative colitis, bowel urgency improvement was associated with better clinical outcomes than in patients without improvement during induction and maintenance. A greater proportion of mirikizumab patients achieved sustainable bowel urgency improvement and remission compared to placebo patients.

/pdf/clinical-effect-of-mirikizumab-treatment-on-bowel-urgency-in-by8q928k.pdf

Clinical Effect of Mirikizumab Treatment on Bowel Urgency in Patients with Moderately to Severely Active Ulcerative Colitis and the Clinical Relevance of Bowel Urgency Improvement for Disease Remission

/pdf/efficacy-and-safety-of-mirikizumab-as-induction-therapy-in-18tzvuge.pdf

Efficacy and Safety of Mirikizumab as Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 LUCENT-1 Study.

Toxoplasma antibody levels in females with habitual or sporadic abortions and normal pregnancies.

/pdf/p469-effect-of-mirikizumab-on-clinical-and-endoscopic-1vki7p3l.pdf

P469 Effect of mirikizumab on clinical and endoscopic outcomes based on prior advanced therapy failure in patients with moderately to severely active ulcerative colitis

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Efficacy and Safety of Mirikizumab as Induction Therapy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 LUCENT-1 Study.

Toxoplasma antibody levels in females with habitual or sporadic abortions and normal pregnancies.

P469 Effect of mirikizumab on clinical and endoscopic outcomes based on prior advanced therapy failure in patients with moderately to severely active ulcerative colitis