Dose Reduction of IL-17 and IL-23 Inhibitors: Are We Ready for Tailored Dosing in the Era of Disease Modification?

In this pragmatic, open-label, non-inferiority trial, van den Reek and colleagues randomized 244 patients (2:1) with stable low disease activity (PASI ≤5 and DLQI ≤5 for at least six months) on any marketed IL-17 or IL-23 inhibitor to stepwise interval prolongation versus usual care.³ Injection intervals were extended to 67% and then 50% of the standard dose when maintenance of low disease activity allowed. Persistent flares (PASI >5 for at least three months) at 18 months occurred in 4.0% vs 1.6% (difference 2.4%; 95% CI −2.0% to 6.8%; non-inferiority margin 15%), a generous margin given that persistent flares occurred in fewer than 5% of patients in either arm. The margin was prespecified based on earlier dose-reduction trials of TNF inhibitors in psoriasis and rheumatology, and the authors also report post hoc sensitivity analyses using 10% and 5% margins. At 18 months, 73% of patients remained on a reduced dose, half of them at 50%.

Reducing exposure may, in theory, translate into a safety gain. However, for drugs with a long-term safety and tolerability profile that is already favorable, this benefit is likely to be modest. However, at a time of rising healthcare costs, the most tangible gain is likely economic: in a class of high-cost drugs, maintaining control with half the dose in a substantial proportion of patients represents a relevant saving for healthcare systems and could allow more patients to gain access to therapeutic innovation, although true cost-effectiveness must also account for flare management, re-escalation, additional monitoring, and quality of life.

The trade-off, however, is not negligible. Short flares (PASI >5 at a single visit) were more than twice as frequent with dose reduction as with standard dosing (15.9% vs 6.3%), a difference that may seem modest in a table but can feel considerably less so in the consultation room. Comorbidities that are themselves treatment targets also warrant attention: four of 164 patients (2.4%) in the dose-reduction arm developed new-onset psoriatic arthritis (1.7 per 100 observation years), compared with none of 80 under usual care. Conversely, worsening of pre-existing psoriatic arthritis was less frequent with dose reduction (3.0% vs 5.0%; RR 0.6, 95% CI 0.2–2.2). The numbers are small and consistent with background incidence, but they should not be dismissed as irrelevant. Finally, immunogenicity data have not yet been reported. While immunogenicity is expected to be low with most IL-17 and IL-23 inhibitors, whether prolonged dose intervals might alter this risk remains an open question that warrants investigation rather than assumption.⁴

The trial also raises controversies that go beyond its endpoints. We are entering a period in which psoriatic disease is approached as something to be modified rather than merely suppressed: early intervention with high-efficacy drugs aimed at control beyond clinical clearance by acting on the molecular memory of the lesion, interception of psoriatic arthritis in at-risk patients, and a potential effect on cardiometabolic comorbidity.⁵⁻⁷ In this context, dose reduction implicitly reintroduces the premise that the only thing that matters is what we see, rather than what is actually happening in the patient or in the apparently resolved plaque.

A second controversy concerns what we accept as adequate control. The trial adopted PASI ≤5, the prevailing target when it was designed in 2018, and one that the authors themselves acknowledge would be set lower today. In the era of absolute PASI ≤2, a threshold of 5 may already be outdated.⁸ Three-quarters of the BeNeBio study population had a PASI ≤1 at baseline; for these patients, a flare may mean giving back much of the ground already gained. The Latin American consensus recommends considering dose reduction only after complete or near-complete clearance has been sustained for at least one year and defines failure as an absolute PASI >3.⁹ Real-world practice appears to follow the same experience-based clinical judgment: Portuguese dermatologists mostly require PASI ≤1 and more than 12 months of control before spacing doses.¹⁰

Finally, the heterogeneity in half-life, dosing schedule, and mechanism of action across drugs makes it difficult to establish standardized schemes for treatment individualization. Extending an interval by 50% does not mean the same for a drug given every four weeks as for one given every twelve. Nor should the effects be assumed to be equivalent across mechanisms of action: neutralizing an effector cytokine is fundamentally different from targeting the IL-23 axis upstream, where modulation of the inflammatory pathway may result in greater persistence of therapeutic effects (namely, greater hysteresis). The difference in success between IL-23 and IL-17 inhibitors in BeNeBio (83.9% vs 61.0% of patients, respectively) is consistent with this.

More sensitive biomarkers for psoriatic disease may help. A population pharmacokinetic-pharmacodynamic model for secukinumab, built in part on BeNeBio data, has identified trough concentration targets of 14.5 and 35.5 µg/mL, associated with a 90% probability of maintaining PASI ≤2 and ≤1, respectively.¹¹ Model-informed precision dosing dashboards have already been developed for risankizumab and are being evaluated in clinical trials.¹² The eventual shift from a fixed, one-size-fits-all reduction to truly individualized dosing could become a reality in the not-too-distant future. However, as biosimilars drive prices down, the cost of monitoring drug levels may eventually outweigh the savings they are meant to generate.

BeNeBio confirms, with randomized (albeit open-label) evidence, what many of us have been doing for years and provides a solid argument for those who still hesitate. It does not settle the debate but reopens it on firmer ground. Paradoxically, a sustained reduction in therapeutic needs may itself be one of the best markers of disease modification, provided we distinguish suppression from remission: psoriasis in a patient who remains clear only while on treatment is controlled, not in remission. The question is no longer whether we can reduce the dose, but whether we are adjusting it to the visible skin or to the disease that persists beneath it.