1 CORRESPONDENCE

Crohn's disease (CD) is an inflammatory bowel disorder known for its chronic and progressive nature, characterized by persistent inflammation throughout various regions of the gastrointestinal tract. This ailment has exhibited a rising incidence on a global scale. It presents as a distinctive pattern of noncontiguous lesions, commonly referred to as “skip lesions,” affecting multiple parts of the gastrointestinal tract, spanning from the oral cavity to the anus. The etiology of CD is multifactorial and arises from a complex interplay involving genetic susceptibility, environmental elements, and the composition of the intestinal microbiota. These factors collectively contribute to an abnormal mucosal immune response and compromised epithelial barrier function.¹

This condition is most prevalent in Western Europe and North America, with an estimated prevalence of 100–300 cases per 100,000 individuals.² CD patients typically present with several clinical symptoms, including abdominal pain localized predominantly in the right lower quadrant, often accompanied by concomitant flatulence, bloating, and diarrhea. The symptoms are further characterized by the presence of fever, progressive weight loss, and anemia. In severe cases, patients may exhibit complications such as perianal abscesses and the formation of cutaneous fistulas. Furthermore, CD is associated with a spectrum of extraintestinal manifestations, such as episcleritis, uveitis, stomatitis, and the presence of aphthous ulcers. Hepatic involvement may manifest as hepatic steatosis, while gallstones, nephrolithiasis, hydronephrosis, and urinary tract infections represent urological manifestations. Joint-related pathologies, including arthritis and ankylosing spondylitis, are also encountered in association with CD. It is noteworthy that the majority of cases are diagnosed in individuals aged between their 20s and 40s.^{3, 4}

Current treatment strategies for CD include pharmaceutical interventions, measures to provide the bowel with essential rest, and, in certain cases, surgical intervention. Pharmaceutical interventions involve administering a range of medications, including corticosteroids, aminosalicylates, immunomodulators, and biological therapies. Notably, biological therapies targeting specific components of the immune system, such as anti-interleukin-12 (IL-12) and interleukin-23 (IL-23) therapy (e.g., ustekinumab), have gained prominence in the management of CD.⁵ Over time, there has been an immense increase in the utilization of biological therapies,⁶ reflecting their efficacy and the evolving landscape of treatment options for this inflammatory disorder. Ustekinumab is a monoclonal antibody therapy designed to treat various immune-mediated conditions, primarily psoriasis and psoriatic arthritis. It works by targeting the p40 subunit of IL-12 and IL-23 and has been indicated for use in the treatment of moderate to severe CD.

On the other hand, Mirikizumab, another biological therapy, is a humanized immunoglobulin G4 anti-human IL-23p19 monoclonal antibody. This particular monoclonal antibody targets the p19 subunit of IL-23, a cytokine that plays an important role in the pathogenesis of ulcerative colitis (UC) and CD. IL-23 is known to promote a Th-17 cell-related immune response, which, in turn, produces a pro-inflammatory effect.⁷ Other p19 inhibitors such as tildrakizumab, guselkumab, and risankizumab have been examined for other inflammatory diseases such as psoriasis and rheumatoid arthritis, showcasing favorable safety profile.⁸ By targeting IL-23, both mirikizumab and ustekinumab have the potential to modulate and mitigate these inflammatory responses, making them promising options for the treatment of both CD and UC. Hence, further head-to-head trials comparing the safety and efficacy of these two drugs must be planned.

In the VIVID-1 trial, mirikizumab demonstrated robust efficacy in patients with moderately to severely active CD. By Week 12, significantly more patients achieved clinical response with mirikizumab compared to placebo (45.4% vs. 19.6%, p < 0.000001). By Week 52, mirikizumab also showed substantial clinical remission rates (54.1% vs. 19.6% with placebo) and displayed noninferiority to ustekinumab for clinical remission, though it did not achieve superior endoscopic response (p = 0.51). Moreover, a higher proportion of patients on mirikizumab achieved combined clinical and endoscopic responses at Week 52 compared to placebo (38% vs. 9%, p < 0.000001). The safety profile was consistent with known effects, including common adverse events like COVID-19, anemia, and headache. In contrast, the SEQUENCE study compared risankizumab to ustekinumab in CD management. Risankizumab demonstrated superior efficacy in reducing inflammatory markers over ustekinumab. By Week 8, risankizumab achieved greater reductions in fecal calprotectin (−1014.0 vs. −650.2) and high sensitivity C-reactive protein (−10.6 vs. −5.5) compared to ustekinumab. Furthermore, a higher proportion of patients achieved biologic remission with risankizumab at Week 8 (26.3% vs. 21.9%), Week 24 (42.8% vs. 24.9%, p < 0.0001), and Week 48 (46.3% vs. 27.5%, p < 0.0001) compared to ustekinumab.⁹

The safety profiles for both treatments were similar, with no new safety concerns reported. In comparison, while mirikizumab demonstrated superior clinical response rates and a noninferiority to ustekinumab in clinical remission, risankizumab showed stronger efficacy in reducing inflammatory markers and achieving biological remission. Both therapies underline promising avenues for managing CD, each with distinct strengths in clinical endpoints and safety profiles. Mirikizumab not only met the predetermined co-primary endpoints but also exhibited favorable results across all secondary outcomes at the 52-week time point in contrast to the placebo-treated group. Among patients administered mirikizumab, the most frequently observed treatment-emergent adverse events encompassed COVID-19, anemia, headache, arthralgia, and infections of the respiratory tract.¹⁰

Based on the positive outcomes observed in the Phase 3 VIVID-1 trial, mirikizumab emerges as a promising addition to the therapeutic landscape for CD. Further research is imperative to assess its long-term efficacy and safety, while patient education, individualized treatment plans, and a multidisciplinary approach should guide its use. Rigorous monitoring and comparative studies are essential, and professional guidelines should be updated to incorporate mirikizumab, ensuring equitable access. Efforts to address affordability will facilitate widespread adoption of this innovative therapy, ultimately enhancing the management of CD and the well-being of affected individuals.

AUTHOR CONTRIBUTIONS

Muaaz Aslam: Conceptualization; writing—original draft; writing—review and editing; validation; project administration; supervision; data curation; resources. Mohammad Haris Ali: Conceptualization; writing—review and editing; writing—original draft; project administration; visualization; validation; data curation; methodology. Hamza Irfan: Conceptualization; writing—original draft; writing—review and editing; validation; project administration; data curation; supervision; resources.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

TRANSPARENCY STATEMENT

The lead author Hamza Irfan affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.