Why are IL-23 (Interleukin-23) inhibitors preferred over TNF (Tumor Necrosis Factor) inhibitors in patients with moderate to severe Inflammatory Bowel Disease (IBD)?

IL-23 Inhibitors Are NOT Preferred Over TNF Inhibitors as First-Line Therapy in IBD

TNF antagonists, particularly infliximab, remain the preferred first-line biologic therapy for most patients with moderate-to-severe IBD, with IL-23 inhibitors reserved for specific clinical scenarios including TNF-failure, older patients at high infection/malignancy risk, or when avoiding immunosuppression is prioritized. 1, 2, 3

First-Line Therapy Hierarchy in Biologic-Naïve Patients

Ulcerative Colitis

• Infliximab demonstrates superior efficacy over adalimumab and other biologics in biologic-naïve patients with moderate-to-severe UC 4, 1, 3
• Network meta-analysis shows infliximab is superior to vedolizumab, adalimumab, ustekinumab (IL-12/23 inhibitor), and ozanimod in treatment-naïve patients 1
• The 2024 AGA guidelines recommend infliximab, vedolizumab, risankizumab, and ozanimod over adalimumab for biologic-naïve patients 1
• IL-23 inhibitors (risankizumab, mirikizumab, guselkumab) are recommended options but not positioned above TNF antagonists for first-line use 1, 2

Crohn's Disease

• Anti-TNF therapy (infliximab, adalimumab) remains the biologic of choice for the majority of patients with moderate-to-severe CD 5, 6
• Thiopurines as monotherapy have fallen out of favor specifically because anti-TNF therapy has been shown superior to azathioprine in head-to-head trials 5

When IL-23/IL-12/23 Inhibitors ARE Preferred

After TNF Antagonist Failure

• In patients with prior infliximab exposure (especially primary non-response), ustekinumab (IL-12/23 inhibitor) or tofacitinib are preferred over vedolizumab or switching to another TNF antagonist like adalimumab 4
• Network meta-analysis demonstrates ustekinumab superiority over adalimumab (OR 10.71,95% CI 2.01-57.20) and vedolizumab (OR 5.99,95% CI 1.13-31.76) in TNF-exposed patients 4
• In biologic-exposed patients, upadacitinib shows the highest efficacy, followed by ustekinumab and tofacitinib, which outperform vedolizumab 1, 3

Safety-Prioritized Populations

• IL-12/23 and IL-23 antagonists should be considered preferentially in older patients at increased risk for infections and malignancy compared to anti-TNF therapy 6
• Ustekinumab demonstrates 51% lower risk of serious infections compared to TNF antagonists in Crohn's disease 7
• Concurrent immunosuppression is likely unnecessary with IL-12/23 and IL-23 antagonists due to low immunogenicity rates, providing additional safety advantages over TNF antagonists which benefit from combination therapy 4, 6

Specific Clinical Scenarios Favoring TNF Antagonists

• When mucosal healing is the primary goal, anti-TNF agents are positioned first due to robust evidence, whereas vedolizumab and ustekinumab lack equivalent mucosal healing data 5
• When rapid onset of action is desired, anti-TNF therapy is favored over vedolizumab (which has slower onset), though ustekinumab has comparable onset to TNF antagonists 5
• For patients with significant extraintestinal manifestations (uveitis, ankylosing spondylitis, pyoderma gangrenosum), anti-TNF therapies are strongly preferred 5, 8

Regulatory and Practical Considerations

JAK Inhibitor Restrictions

• The FDA recommends JAK inhibitors (tofacitinib, upadacitinib, filgotinib) only after prior failure or intolerance to TNF antagonists, not as first-line therapy 1, 2
• This restriction stems from cardiovascular and malignancy safety concerns identified in rheumatoid arthritis populations, particularly in patients ≥50 years with cardiovascular risk factors 1

IL-23 Inhibitor Positioning

• Risankizumab, mirikizumab, and guselkumab are approved for moderate-to-severe UC with strong to conditional recommendations 2
• These agents appear more effective than ustekinumab for Crohn's disease, representing an evolution within the IL-23 pathway targeting class 9
• Clinical remission rates for risankizumab in UC are 18.5% vs 6.2% placebo, and for mirikizumab 24.1% vs 11.8% placebo 7

Critical Pitfalls to Avoid

• Do not assume all biologics have equivalent efficacy in biologic-naïve patients—infliximab demonstrates superior efficacy over adalimumab and should be preferentially selected when both are options 4, 1
• Do not position IL-23 inhibitors as first-line therapy based solely on safety profile—efficacy data and treatment history must guide initial biologic selection 1, 2
• Do not extrapolate TNF-failure data to suggest IL-23 inhibitors are superior in treatment-naïve patients—the evidence clearly shows TNF antagonists, particularly infliximab, maintain superior first-line efficacy 4, 1, 3
• Recognize that "prior biologic exposure" is a critical effect modifier—treatment sequencing recommendations differ dramatically between biologic-naïve and biologic-experienced populations 4