Psoriasis is a chronic immune-mediated inflammatory multisystem disease primarily characterized by cutaneous manifestations, with chronic plaque psoriasis accounting for approximately 90% of cases. Beyond skin lesions, psoriasis is often associated with-comorbidities such as cardiometabolic disease and psoriatic arthritis [ 1 , 2 ] . Over the past decade, the advent of biologic therapies for chronic plaque psoriasis and psoriatic arthritis have represented a groundbreaking advancement in treatment. Recently, new therapeutic options for moderate-to-severe psoriasis have emerged, including IL-17 inhibitors (IL-17i) (secukinumab, ixekizumab, brodalumab, and bimekizumab) and IL-23 inhibitors (IL-23i) (guselkumab, risankizumab, and tildrakizumab), which have demonstrated remarkable efficacy [ 1 , 2 ] . However, their high cost imposes a significant burden on the national health care system, necessitating the exploration of strategies to reduce economic strain without compromising treatment outcomes.

Currently, the main guidelines for the management of psoriasis [ 1 , 2 ] do not include a flexible therapeutic window based on patients’ clinical response, and biologic therapies are typically prescribed in fixed doses, but “long-term responder” patients, achieving excellent and sustained responses, may not require the standard regimen, which could lead to overtreatment. This underscores the importance of studies focusing on dose reduction (DR) to ensure cost-efficiency while maintaining high effectiveness. Previous research has demonstrated the effectiveness and safety of a reduced dose compared to the standard dose (StD) in psoriasis treatment, with a slightly increased Psoriasis Area and Severity Index (PASI) while maintaining a stable Dermatology Life and Quality Index (DLQI) [ 3 – 7 ] . Consequently, dose reduction (DR), also referred to as dose tapering, appears to be a promising strategy. However, extending the therapeutic window should be guided by patient profiling and tailored therapeutic choices to ensure optimal outcomes. In this regard, these inhibitors have demonstrated significant efficacy in reducing disease severity; however, their pharmacodynamics differ, making one drug class potentially more suitable than the other for dose spacing. IL-23i provide longer-lasting effects by targeting the root of the inflammatory cascade, whereas IL-17i act more immediately on downstream inflammation [ 8 ] . The aims of this study were to contribute to the understanding of the DR outcomes in real-life settings and to investigate whether disease activity-guided DR of Il-17i and IL-23i could be a suitable option for selected psoriasis patients. The secondary aim was to analyse potential differences in effectiveness and safety between IL-17i and IL-23i during DR.

Based on our experience, implementing DR through extended dosing intervals for IL-17 and IL-23 inhibitors appears to be an effective therapeutic strategy for many patients with stable plaque psoriasis. At both 26 and 52 weeks, most patients maintained disease control indicated by PASI and DLQI scores ≤ 3, while only a small percentage experienced flare-ups requiring a return to the standard dose (StD) or a change in therapy. The feasibility of administering reduced or spaced doses or DS was already explored with these therapies, with good results. Notably, the IL-23i risankizumab has shown the capacity to sustain clinical improvement for up to 66 weeks following a single intravenous administration [ 14 ] . Furthermore, an asneeded dosing approach has proven viable in maintaining response, as evidenced by a successive study of 64 patients that progressively extended dosing intervals to an average of over 38 weeks [ 11 ] . The GUIDE randomized clinical trial demonstrated noninferiority of treatment with guselkumab every 16 weeks vs 8-weeks in super-responder patients (those who achieved and maintained PASI 0 at both Week 20 and Week 28) [ 12 ] . In the OPTIMISE study [ 13 ] , the IL-17 inhibitor secukinumab was prescribed every six weeks during the maintenance phase, although the final results favored the superiority of the standard four-week dosing schedule. In contrast, a recent study by Daudén et al. proposed a DR strategy for patients who had achieved prolonged remission with secukinumab [ 9 ] . Most patients in that study simply extended the interval between administrations—some also halved the dose—and 77.8% maintained therapeutic success without compromising safety. Meanwhile, the phase II OLE study evaluated the efficacy and safety of brodalumab in patients with moderate-severe plaque psoriasis, revealing that individuals weighing ≤ 100 Kg who received brodalumab 140 mg Q2W achieved comparable response to those receiving 210 mg [ 15 ] .

A cohort of “long term responders” was selected to initiate the reduced dose in our study. To the best of our knowledge, this is the first multicenter study evaluating the effectiveness of DS in maintaining the clinical response achieved with IL-17/IL-23 inhibitors in patients affected by moderate/ severe psoriasis. The rationale for the off-label use of spaced doses of IL-17/IL-23 inhibitors in treating moderate-to-severe psoriasis lies in identifying the minimal effective dose needed to sustain response, thereby preserving the treatment’s safety profile while alleviating healthcare costs. This cost-saving objective is particularly pertinent given psoriasis’s high prevalence and associated economic and social impact [ 16 – 18 ] . Consistent with prior research [ 6 ] , our finding indicates potential cost savings of up to 30%, although further tailoring of individual dosing schedules may enhance the long-term sustainability of this approach; a more comprehensive and accurate pharmacoeconomic analysis has been planned for an upcoming dedicated article. Both IL-17i and IL-23i showed sustained efficacy after one year of follow-up; however, a comparison of the two cohorts revealed a difference in therapeutic maintenance showed a trend favoring IL-23i. This difference may be linked to the superior drug survival of the IL-23i [ 19 ] , to IL-23i’s sustained suppression of CD8-positive tissue-resident memory T cells in lesional skin that play a crucial role in psoriasis recurrence [ 12 ] , to the difference in patient selection (slightly higher DLQI), and/ or to the mechanism of action of treatments. In particular, brodalumab, by its unique mechanism - IL-17 receptor A blockade, provides fast onset of action but may also simultaneously correlate with a greater secondary loss of efficacy in dose spacing regime. Most patients who reverted to StD regained complete control of the disease, with only 2.56% (0.64% compared to the total of DR) requiring a therapy switch, indicating that DR is both a reversible and manageable strategy. However, interval prolongation might increase the production of anti-drug antibodies (ADA), thus reducing the drug’s effectiveness [ 5 ] . Moreover, excessive prolongation between administrations, e.g., doubling the therapeutic window, could likely lead to a significant reduction in therapeutic response, as already highlighted in the study conducted by Blauvelt et al. [ 20 ] . Hence, careful patient selection is essential to optimizing outcomes. Factors such as biologic treatment history, speed of response to treatment, disease duration, baseline PASI/DLQI scores, BMI, or type of biologic agent used should be considered prior to initiating DR. Further studies are needed to identify potential predictive markers that can more accurately forecast successful outcomes.

The primary clinical implication of our study is represented by the potential benefits of DR in reducing the economic burden on healthcare systems without compromising treatment efficacy. In fact, DR could lead to more sustainable long-term management of psoriasis, especially in healthcare settings with limited resources, and aligns with the principles of personalized medicine. The future of biologic treatments for psoriasis is promising in this regard. Continuous therapy with the minimal effective dose, based on the clinical situation, has been considered for other psoriasis treatments, such as cyclosporin and acitretin, and could represent the future of biologic treatment [ 21 ] . To optimize drug efficacy and minimize toxicity, measuring drug concentrations in a patient’s blood could be a possibility. Therapeutic drug monitoring (TDM) is a clinical practice that helps achieve this goal by ensuring appropriate dosing based on individual pharmacokinetics. Particularly valuable for medications with a narrow therapeutic index, TDM could also guide personalized treatment decisions in biologic treatment, enhancing patient safety and therapeutic outcomes.

Nevertheless, our study suffers from several limitations. The data are preliminary, the sample size is relatively small, and the observational design introduces potential biases, including selection bias from the inclusion criteria and a lack of randomization. These factors limit the generalizability of our findings, underscoring the need for additional research. Future research direction can be represented by larger randomized controlled trials to confirm the efficacy and safety of DR strategies and by longitudinal studies to assess the long-term outcomes and sustainability of DR. Moreover, biologic mechanisms underlying successful DR must be explored in depth to identify appropriate biomarkers useful for patient selection. Currently, prolonged remission is the main criterion for dose reduction eligibility [ 22 ] , but the identification of more specific criteria could further improve the results obtained through this strategy.

The disease activity-guided DR of IL-17 and IL-23 inhibitors appears to be a feasible and effective strategy for selected patients with plaque psoriasis. It allows for the optimization of treatment regimens, improving patient quality of life and reducing healthcare costs. Based on our experience, we encourage clinicians to consider DR for patients who have maintained low disease activity over an extended period, while emphasizing the importance of regular monitoring for early detection of flare-ups. Future studies should include randomized controlled trials and long-term follow-up to confirm these results and assess their implications for clinical practice. Finally, clear communication and patient education are essential to ensuring that patients are actively involved in the decision-making process of a valuable yet off-label protocol and to knowing when to report any concerning symptoms.