Interleukin 12 and 23 Pathway Inhibitors

Interleukin 12 and 23 (IL-12/23) inhibitors block cytokines that drive T helper 1 and 17 cell responses. Ustekinumab blocks both cytokines through their shared p40 subunit; guselkumab, risankizumab and tildrakizumab block IL-23 alone through its p19 subunit. They treat plaque psoriasis, psoriatic arthritis, Crohn disease and ulcerative colitis, with infrequent dosing and a low rate of serious infection.

Mechanism. Inhibiting IL-23 stops the maintenance of T helper 17 cells and their production of IL-17 and IL-22. Ustekinumab also blocks IL-12-driven T helper 1 responses, which may matter in bowel disease.

Pharmacokinetics. Half-lives about 3 to 4 weeks (ustekinumab 21 days; risankizumab 28 days). Doses are given every 8 to 12 weeks after induction.

Biosimilars. Ustekinumab biosimilars are now available in many regions and reduce cost.

Response. Skin response is slower than with IL-17 inhibitors, usually clear by 12 to 16 weeks. Review at 16 weeks.

• First-line. Moderate to severe plaque psoriasis; Crohn disease and ulcerative colitis in patients failing conventional therapy.
• Alternative. Psoriatic arthritis (especially skin predominant); after TNF inhibitor failure.
• Specialist. Biologic-experienced inflammatory bowel disease; generalised pustular psoriasis (selected agents).
• Emergency. None.

Selection. Choose for combined psoriasis and inflammatory bowel disease, patients who prefer infrequent injections, and patients with recurrent infection or candidiasis on other biologics. Choose IL-17 inhibitors for axial disease and faster skin clearance.

Contraindications. Active serious infection including untreated tuberculosis; hypersensitivity; active clinically important infection.

Serious adverse effects.

• Upper respiratory infection, headache, injection-site reactions, fatigue.
• Serious infection (rare); tuberculosis reactivation (screen first).
• Hypersensitivity; rare reversible posterior leukoencephalopathy (ustekinumab).
• Raised liver enzymes with risankizumab in inflammatory bowel disease induction.

Major interactions. Live vaccines; other biologics; CYP substrates with narrow range may be altered as inflammation settles.

Common prescribing errors.

• Wrong dose by weight (ustekinumab over or under 100 kg).
• Missing induction doses for Crohn disease.
• Stopping at 12 weeks because of slow response.
• Using in axial spondyloarthritis (ineffective).
• No tuberculosis screening.

Special groups.

• Pregnancy: limited data; ustekinumab crosses the placenta, so avoid live vaccines for the infant for 12 months.
• Breastfeeding: low transfer; generally acceptable.
• Children: ustekinumab licensed for paediatric psoriasis and Crohn disease in some regions.
• Older adults: no adjustment.
• Kidney and liver: no adjustment; monitor liver tests with risankizumab.
• East Africa: HIV, tuberculosis and hepatitis B testing before treatment; IL-23 agents have a good infection profile, but supply and cost are the main limits; ustekinumab biosimilars may widen access.

Monitoring. Infection symptoms; skin and bowel disease scores at 16 weeks; liver tests at baseline and during Crohn induction (risankizumab); tuberculosis symptoms yearly.

Referral and escalation. Serious infection; failure at 16 weeks; severe neurological or hepatic symptoms; pregnancy.

Comparison with alternative classes. IL-12/23 and IL-23 inhibitors have infrequent dosing and the best infection and candidiasis profile of the newer classes. They are slower than IL-17 inhibitors in skin disease and do not treat axial spondyloarthritis.