The Biologic Revolution II: IL-17, IL-23 and the New Oral Small Molecules
The first biologics proved a point: block the right cytokine and psoriasis melts away. But TNF and ustekinumab left a gap — plenty of patients cleared partly, not completely. The next generation closed it. By aiming at the exact axis that drives the disease — IL-23 up top, IL-17 at the skin — the newer drugs pushed the goalposts from "much better" to "clear or almost clear." And for the first time, a pill could rival an injection. This is the story of how psoriasis therapy went from smearing tar to switching off single cytokines by name.
A 34-year-old man has lived with thick, scaling plaques over his elbows, knees and scalp since his twenties. He has been through coal tar, potent topical steroids, phototherapy, methotrexate and, more recently, a TNF inhibitor that helped — his skin went from awful to tolerable, but never clear. He still avoids short sleeves. His dermatologist switches him to an IL-23 inhibitor given as an injection just a few times a year. Twelve weeks later he is, for the first time in a decade, essentially clear — no visible plaques, no daily creams, no thinking about it. The disease that shaped how he dressed and who he dated has been quietened by blocking a single cytokine at the top of its cascade. That leap — from "better" to "clear," and from monthly to seasonal dosing — is what this second generation of psoriasis drugs is about.
A quick recap of the axis
Everything here builds on one signalling chain, laid out in full in Psoriasis Biologics I. Psoriasis is driven by a specific immune circuit: dendritic cells release IL-23, IL-23 sustains a population of T-helper-17 cells, and those cells pour out IL-17, the cytokine that actually tells skin keratinocytes to divide too fast and inflame. TNF feeds into the loop as a more general amplifier. The first-generation biologics — the TNF inhibitors (etanercept, adalimumab, infliximab) and ustekinumab, which blocks the shared p40 subunit of both IL-12 and IL-23 — are covered in Biologics I along with the axis figure. The second generation is defined by a simple insight: hit the axis more precisely, and lower down or higher up, and you get cleaner skin with, in many cases, a cleaner safety profile.
IL-17 inhibitors: hit the disease at the skin
IL-17 is the business end of the cascade — the cytokine sitting closest to the keratinocyte. Block it and the effect is fast and dramatic; IL-17 inhibitors are among the quickest of all psoriasis drugs to clear skin. There are several ways to hit it. Secukinumab and ixekizumab are monoclonal antibodies against the cytokine IL-17A itself. Brodalumab takes a different angle: instead of mopping up the cytokine, it blocks the IL-17 receptor, so it shuts down signalling from IL-17A, IL-17F and their combinations at once. The newest, bimekizumab, is a dual antibody that neutralises both IL-17A and IL-17F — and by catching that second ligand it produces some of the highest complete-clearance rates recorded, though at the cost of more of the class's signature side effect.
The class caution follows directly from what IL-17 normally does. IL-17 is not just a psoriasis molecule; in health it defends mucosal surfaces against fungi. Take it away and you get the class's signature adverse effect: mucocutaneous candidiasis — oral thrush and genital or skin-fold yeast infection. It is usually mild and easily treated (linking to the Antimicrobials chapter, where topical and oral antifungals such as the azoles are covered), but it is the predictable price of blocking an antifungal cytokine. Second, IL-17 blockade can unmask or worsen inflammatory bowel disease — the reverse of what you might expect, because IL-17 appears to be protective in the gut. So IL-17 inhibitors are avoided, or used with real caution, in a patient with Crohn's disease or ulcerative colitis; this connects to the Gastrointestinal section, where the IL-23/IL-17 axis behaves very differently in the bowel than in the skin. Third, and specific to one drug: brodalumab carries a boxed warning about suicidal ideation and behaviour, which is why it is prescribed under extra counselling and monitoring even though a clear causal link was never firmly established.
Think of the disease cascade as a factory with a foreman (IL-23) upstairs and workers (IL-17) on the shop floor. TNF drugs cut general power to the building. IL-17 inhibitors walk onto the floor and stop the workers directly — fast, visible, but you lose the useful work those same workers did guarding the mucosal doors, so fungi slip in. IL-23 inhibitors take the elevator up and quietly send the foreman home; without instructions the workers drift off over the following weeks — slower to start, but the floor stays empty for a long time and the mucosal doors keep their guards.
IL-23 (p19) inhibitors: cut the disease off at the top
If IL-17 is the worker, IL-23 is the master switch that keeps the whole Th17 program running. The newest antibodies — guselkumab, risankizumab and tildrakizumab — target the p19 subunit that is unique to IL-23. This is the crucial refinement over ustekinumab: ustekinumab blocked p40, the subunit shared by IL-12 and IL-23, so it hit both. The p19 drugs spare IL-12 and shut down only IL-23, which turns out to be exactly the pathway psoriasis needs. The clinical payoff is threefold: excellent, high-level clearance; remarkable durability — remissions that hold for months; and infrequent dosing, often just once every eight to twelve weeks after loading, i.e. four or fewer injections a year. Their safety record has been notably clean, without a signal for the candidiasis or IBD problems that shadow the IL-17 class. For many patients and prescribers, the IL-23 inhibitors now represent the best overall benefit-to-risk balance in psoriasis.
The whole second generation is a lesson in precision. Ustekinumab hit p40 (IL-12 + IL-23); the p19 drugs realised only the IL-23 half mattered and dropped the rest. IL-17 blockade is faster but pays a mucosal-immunity tax; IL-23 blockade is slower to peak but more durable and cleaner. The trend across three generations — TNF → p40 → p19/IL-17 — is the same direction of travel that runs through all of modern immunology: from blunt, broad suppression toward hitting one named node in one pathway.
Anti-IL-17A: secukinumab (Cosentyx), ixekizumab (Taltz). Anti-IL-17 receptor: brodalumab (Siliq/Lumicef) — boxed warning for suicidality. Dual anti-IL-17A/F: bimekizumab (Bimzelx) — highest complete-clearance rates, more candidiasis. Anti-IL-23 (p19): guselkumab (Tremfya), risankizumab (Skyrizi), tildrakizumab (Ilumya) — durable, few-times-a-year dosing, clean safety. Several IL-17 and IL-23 agents also carry approvals for psoriatic arthritis, which becomes decisive when a patient has joint disease as well as skin.
- IL-17 inhibitors act at the bottom of the cascade (nearest the skin): fastest, most dramatic clearance.
- Anti-IL-17A: secukinumab, ixekizumab. Anti-IL-17-receptor: brodalumab. Dual IL-17A/F: bimekizumab.
- IL-17 class cautions: mucocutaneous candidiasis, worsening of IBD, and brodalumab's suicidality warning.
- IL-23 (p19) inhibitors act at the top: guselkumab, risankizumab, tildrakizumab — slower to peak, very durable.
- p19 blockade spares IL-12 (unlike ustekinumab's p40) and has a notably clean safety profile.
- IL-23 inhibitors offer among the best benefit-to-risk balance and the least frequent dosing.
How to choose among the biologics
With so many highly effective options, the choice is driven less by "which clears best" and more by the patient's other facts. A short mental checklist decides most cases. Inflammatory bowel disease: avoid IL-17 inhibitors (they can worsen it) and favour an IL-23 inhibitor or a TNF inhibitor, several of which treat the bowel too. Psoriatic arthritis: pick an agent with a strong joint indication — IL-17 inhibitors and some IL-23 inhibitors, as well as the TNF class from Biologics I, all qualify. Recurrent candidiasis or a job/lifestyle where thrush would be a real problem: lean away from IL-17 blockade. Dosing burden and adherence: if a patient wants the fewest injections, the IL-23 (p19) drugs win, with dosing only a few times a year. Pregnancy: no biologic is proven safe, and most are avoided; where treatment is unavoidable, certolizumab pegol (a TNF inhibitor detailed in Biologics I) is often preferred because its structure limits placental transfer. Speed matters too — if a patient needs to clear fast for an imminent event, the rapid IL-17 agents have the edge.
Oral small molecules: pills that finally compete
Biologics are injected proteins; many patients would rather take a pill. Two oral small molecules serve that wish, and they sit at very different points on the effectiveness scale. Apremilast is a phosphodiesterase-4 (PDE4) inhibitor. PDE4 normally breaks down cyclic AMP inside immune cells; block it and cAMP rises, which broadly dials down the output of inflammatory cytokines. Its appeal is convenience and safety more than raw power: efficacy is modest — better than placebo, well short of the biologics — but it needs no laboratory monitoring at all, which makes it an easy, low-hassle oral option for milder disease or for patients who refuse injections. Its characteristic downsides are gastrointestinal — diarrhoea and nausea, usually early and self-limiting — some weight loss, and a warning about depression and low mood that is worth asking about at follow-up.
The second oral drug is the one that changed expectations. Deucravacitinib is an allosteric TYK2 inhibitor, and it deserves careful placement because students routinely file it under "JAK inhibitor" and get the safety story wrong. TYK2 is a member of the JAK family, and it sits in the signalling relay for IL-23 (and type I interferons) — so blocking it turns down exactly the psoriasis axis. But deucravacitinib does not bind the active (ATP) site the way classic JAK inhibitors do. It binds a separate regulatory (allosteric) pocket unique to TYK2, which makes it far more selective and avoids the broad JAK1/2/3 blockade responsible for much of the class toxicity. The clinical result is an oral drug whose efficacy genuinely rivals some injectable biologics — a first for a pill in psoriasis — with a much lighter monitoring burden than the older JAK inhibitors. This connects to the Topical therapy chapter, where the JAK/STAT pathway also appears: topical ruxolitinib (a JAK inhibitor cream) and tapinarof (an aryl-hydrocarbon-receptor agonist) work on related inflammatory signalling at the skin surface, while deucravacitinib acts systemically but with the TYK2 selectivity that sets it apart from the classic oral JAK inhibitors.
- Apremilast = oral PDE4 inhibitor → ↑cAMP → broad cytokine dampening; modest efficacy, no lab monitoring.
- Apremilast side effects: diarrhoea/nausea (early, self-limiting), weight loss, and a depression/mood warning.
- Deucravacitinib = allosteric TYK2 inhibitor; TYK2 relays IL-23 signalling, so it hits the psoriasis axis.
- It binds a regulatory pocket unique to TYK2 — far more selective than classic ATP-site JAK inhibitors.
- Deucravacitinib is an oral whose efficacy rivals biologics, with lighter monitoring than older JAK inhibitors.
Biosimilars, cost and access
All of this precision is expensive. Biologics are large, complex proteins, and their list prices put them among the costliest drugs a dermatologist prescribes — which is why access is gated by step therapy (try a cheaper agent first) and prior authorisation in most health systems. Two forces push back on cost. First, biosimilars: as the original patents expire, near-identical follow-on versions of the older biologics (notably the TNF inhibitors like adalimumab, and ustekinumab) enter the market at lower prices. A biosimilar is not a generic — proteins can't be copied atom-for-atom the way a small molecule can — but it is rigorously shown to have no clinically meaningful difference in efficacy or safety. Second, the oral small molecules: apremilast and deucravacitinib offer a pill without the cold-chain storage, injection training and, often, the same acquisition cost as an infused or injected biologic. Cost and route, as much as raw efficacy, shape what a given patient actually receives.
- Calling deucravacitinib "a JAK inhibitor" and applying classic JAK-class warnings. It is an allosteric TYK2 inhibitor — far more selective, with a distinct, lighter safety profile.
- Reaching for an IL-17 inhibitor in a psoriasis patient who also has inflammatory bowel disease — it can worsen the gut disease; favour an IL-23 or TNF inhibitor instead.
- Expecting apremilast to match a biologic. It is a convenient, monitoring-free oral with modest efficacy — not an equal to IL-23/IL-17 blockade for severe disease.
A 40-year-old with severe plaque psoriasis and long-standing Crohn's disease needs a systemic agent. Which choice is the most appropriate, and why?
- The second generation targets the psoriasis axis precisely — IL-17 at the skin (fast, dramatic) and IL-23/p19 at the top (durable, clean) — raising the bar to near-clear skin.
- IL-17 inhibitors (secukinumab, ixekizumab; brodalumab at the receptor; bimekizumab dual A/F) carry class cautions: candidiasis, IBD worsening, and brodalumab's suicidality warning.
- IL-23 (p19) inhibitors (guselkumab, risankizumab, tildrakizumab) spare IL-12, dose only a few times a year, and arguably offer the best benefit-to-risk balance.
- Two orals: apremilast (PDE4 → ↑cAMP; modest, no monitoring) and deucravacitinib (allosteric TYK2, distinct from classic JAK inhibitors, rivals biologics). Biosimilars and route are pushing cost down. Psoriasis moved from tar to cytokine-precision therapy.
- Rook's Textbook of Dermatology — Psoriasis: biologic and systemic therapy.
- Wolverton SE. Comprehensive Dermatologic Drug Therapy — biologics, IL-17/IL-23 inhibitors, and oral small molecules.
- American Academy of Dermatology–National Psoriasis Foundation (AAD-NPF) Guidelines of Care for the Management of Psoriasis with Biologics.
- British Association of Dermatologists (BAD) guidelines for biologic therapy for psoriasis.
- Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. Lancet (Seminar).
- Armstrong AW, Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review. JAMA.
