Drug survival of IL-12/23, IL-17 and IL-23 inhibitors for moderate-to-severe plaque psoriasis: a retrospective multicenter real-world experience on 5932 treatment courses – IL PSO (Italian landscape psoriasis)

Introduction The development of several effective biological drugs for moderate-to-severe plaque psoriasis has dramatically changed the lives of patients. Despite the wide use of interleukin (IL) inhibitors, limited data are available to date regarding long-term treatment persistence. Method This multicenter retrospective real-world study evaluated 5932 treatment courses across 5300 patients, all treated with interleukin inhibitors. Drug survival was expressed by using the Kaplan-Meier estimator for each biological drug at 6, 12, 24, 36 and 48 months. We also stratified by discontinuation associated with primary or secondary ineffectiveness. Results In our study, the most prescribed drugs were secukinumab (1412), ixekizumab (1183), and risankizumab (977). After four years of follow-up, risankizumab emerged as the treatment with the highest drug survival overall, as 91.6% of patients were still on treatment. The overall probability of drug survival at four years was comparable for tildrakizumab (83.5%), ixekizumab (82.6%), guselkumab (82.4%) and brodalumab (81.8%). When evaluating only patients who discontinued the treatment because of ineffectiveness, once again risankizumab was the molecule with the highest drug survival at 4 years (93.4%), this time followed by ixekizumab (87%). Our study, in which all IL inhibitors were adequately represented, confirmed a slightly better treatment persistence for IL-23 inhibitors, consistent with other real-world studies. Conclusion Our experience showed that IL-23 inhibitors, and risankizumab in particular, had a higher probability of drug survival overall during a 4-year follow-up. Risankizumab and ixekizumab were less likely to be discontinued because of ineffectiveness after four years.


Introduction:
The development of several effective biological drugs for moderate-to-severe plaque psoriasis has dramatically changed the lives of patients.Despite the wide use of interleukin (IL) inhibitors, limited data are available to date regarding long-term treatment persistence.
Method: This multicenter retrospective real-world study evaluated 5932 treatment courses across 5300 patients, all treated with interleukin inhibitors.Drug survival was expressed by using the Kaplan-Meier estimator for each biological drug at 6, 12, 24, 36 and 48 months.We also stratified by discontinuation associated with primary or secondary ineffectiveness.
Results: In our study, the most prescribed drugs were secukinumab (1412), ixekizumab (1183), and risankizumab (977).After four years of follow-up, risankizumab emerged as the treatment with the highest drug survival overall, as 91.6% of patients were still on treatment.The overall probability of drug survival at four years was comparable for tildrakizumab (83.5%), ixekizumab (82.6%), guselkumab (82.4%) and brodalumab (81.8%).When evaluating only patients who discontinued the treatment because of ineffectiveness, once again risankizumab was the molecule with the highest drug survival at 4 years (93.4%), this time followed by ixekizumab (87%).Our study, in which all IL inhibitors were adequately represented, confirmed a slightly better treatment persistence for IL-23 inhibitors, consistent with other real-world studies.

Conclusion:
Our experience showed that IL-23 inhibitors, and risankizumab in particular, had a higher probability of drug survival overall during a 4-year followup.Risankizumab and ixekizumab were less likely to be discontinued because of ineffectiveness after four years.

Introduction
Psoriasis is a chronic immune-mediated disease affecting up to 3% of the population worldwide (1).It is a condition that primarily affects the skin and joints and can severely impact patients' quality of life and their productivity.The development of different biological treatments has dramatically changed the lives of patients affected by moderate-to-severe plaque psoriasis (1).In Italy, several biological drugs are approved for the treatment of these patients.In particular, interleukin (IL) inhibitors include drugs targeting IL-12/23 (ustekinumab), IL-17 (secukinumab, ixekizumab, brodalumab and bimekizumab) and IL-23 (guselkumab, risankizumab and tildrakizumab).These molecules have shown high efficacy and safety profiles in both clinical trials and real-world experiences, supporting the wide use of biologics in wide cohorts of patients with moderate-to-severe plaque psoriasis (2).Currently, the switch among biologics is becoming more common due to several reasons, including ineffectiveness and adverse events.Patients' preferences also play a role in the decision to switch treatments.Because of that, it is crucial to evaluate the drug survival of these molecules since it seems to correlate with clinical response and tolerability in a real-world setting.This is particularly important if we consider that it has been shown that bio-naïve patients and those with a very short disease duration (less than two years) are more likely to have better clinical response to some molecules (3,4).Hence, it is crucial to choose the best possible drug for each patient in order to achieve better outcomes.Current Guidelines do not give any specific recommendations regarding which biological drug should be used as a first-line treatment for each type of patient in terms of disease severity, involvement of difficult-to-treat areas, or presence of cardiometabolic comorbidities (5).Italian Guidelines provide limited evidence for the use of specific classes of biologics for some patients' subpopulations.As a matter of fact, patients with concomitant psoriatic arthritis (PsA), should be treated with anti-TNF-alfa or anti-IL-17 drugs, while those with a diagnosis or medical history of inflammatory bowel disease should not receive IL-17 inhibitors.Regarding all other medical conditions, no strong recommendations are currently available (6).For all these reasons, during the last years, a few studies on treatment persistence have been published, showing a higher drug survival for patients treated with IL-23 inhibitors (7)(8)(9)(10).However, limited data are available in particular for the most recently approved treatments, such as tildrakizumab and risankizumab.More research is needed to evaluate these drugs' effectiveness and safety profiles in a realworld setting.

Method
We conducted a retrospective real-world study to assess the drug survival of IL-inhibitors in plaque psoriasis, across 5300 patients and 5932 treatment courses, with a 4-year follow-up.Patients were followed from 1 st January 2012 to 31 st December 2022 at 15 Italian Dermatology Units.Patients who discontinued a drug and started another treatment were included in the analysis as a new treatment course with a re-evaluation of all baseline characteristics.Drug survival was expressed by using the Kaplan-Meier estimator for each biological drug at 6, 12, 24, 36 and 48 months.We also stratified by discontinuation associated with primary or secondary ineffectiveness.The date of the event was defined as the date the patient discontinued the biologic for any reason.Time data was censored for patients who were still on treatment when the study was conducted.We also used the logranked test to assess the differences in drug survival between the subgroups.To describe demographic characteristics, we used mean and Standard Deviation (SD) for continuous variables and absolute frequency and percentage for categorical parameters.STATA/SE 17.0 software was used to conduct the data analysis and to generate graphs.For this retrospective study, institutional review board approval was waived as the study protocol did not deviate from routine clinical practice.In this study, we did not perform any procedure differently from routine clinical practice.All patients included in the study had provided written consent for retrospective analysis of anonymous data collected during routine clinical practice, including demographics and clinical severity scores.This study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments.

Results
The demographic characteristics of our cohort at the start of the treatment are available in Table 1.
Three thousand eight-hundred and ninety-eight patients were males (65.71%), with a mean age of 53.74 years (SD 14.85).The vast majority of our patients were Caucasians, and no other ethnicity was significantly represented in our cohort.A concomitant psoriatic arthritis (PsA) was diagnosed by rheumatologists in 1330 patients (22.42%), according to CASPAR (ClASsification of Psoriatic ARthritis) classification criteria (11).Two thousand nine hundred and nineteen patients (49.21%) presented with at least one cardiometabolic comorbidity (including obesity, arterial hypertension, hypercholesterolemia, type II diabetes mellitus and cardiovascular diseases).At baseline, our patients had a mean body mass index (BMI) of 27.31 (5.29).The mean Psoriasis Area and Severity Index (PASI) at the start of the biological treatment was 14.42 (7.08), comparable with other real-world experiences.Two thousand seven hundred and sixteen patients (45.79%) had the involvement of at least one difficult-to-treat area (including scalp, palms/soles, nails and genitalia).Slightly less than half of our patients were naïve to biological treatments (46.26%At 1-year, anti-IL 12/23 and anti-IL 23 drugs showed a higher drug survival overall, compared with IL-17 inhibitors (Figure 1).After four years of follow-up, risankizumab had the highest drug survival overall, as 91.6% of patients were still on treatment with a confidence interval (95% C.I.) of 89.3-93.4.The overall probability of drug survival at four years was comparable for tildrakizumab (83.5%, with a 95% C.I. of 78.1-87.7),ixekizumab (82.6%, 79.9-84.9),guselkumab (82.4%, 76.4-86.5)and brodalumab (81.8%, 75.6-86.6).Secukinumab had a probability of drug survival of 74.7% (72.1-77.0)and ustekinumab of 67.8% (62.6-72.5)(Figure 1).We then described the drug survival of all molecules evaluating only the     2).The log-rank test showed no difference in drug survival in patients with a concomitant PsA (p= 0.41), while bio-naive status was a predictor of better drug survival (p <0.001) compared to patients who had previously failed another biologic.

Discussion
Given the chronic nature of plaque psoriasis, the treatment persistence of a biological treatment is becoming more and more important in terms of both patients' quality of life and pharmacoeconomic.The drug survival of treatment represents a marker of both satisfying disease control and good tolerability.As the therapeutic landscape in plaque psoriasis continues to evolve, several drugs have become available to patients.This has allowed for a rapid switch between biologics, making it crucial to understand the treatment persistence of each drug.Our real-world experience, which included one of the largest populations to date, provides more knowledge on the probability of drug survival of different biological treatments for plaque psoriasis, including the most recently approved drugs (tildrakizumab and risankizumab), which were significantly under-represented in previously studies (7)(8)(9).In our study, we found higher overall rates of drug survival after four years for IL-23 inhibitors, confirming data from both clinical trials and real-life experiences on the efficacy and safety of this therapeutic class (7)(8)(9).In particular, risankizumab was the drug with the highest drug survival overall throughout the study period (Figure 1).When evaluating only discontinuation due to ineffectiveness, once again risankizumab emerged as the treatment with the highest drug survival, this time followed by ixekizumab.These findings are consistent with data from recent network meta-analyses that highlighted the high effectiveness profile of ixekizumab and risankizumab (12).In particular, risankizumab has shown high efficacy in clinical trials, with rates of PASI 90 at week 16 of 75.3% and 74.8% in the phase-3 studies UltIMMa 1 and UltIMMa 2, respectively (13).Other clinical trials confirmed the long-term efficacy of risankizumab, as PASI 90 was reached by 86.6% of patients at week 52 in the IMMerge study (14) and by 85.5% of patients in the open-label LIMMitless study after more than 3 years (15).Our findings align with the results of a recent study by Torres et al. (8), which described a higher probability of drug survival for anti-IL-23 treatments, despite a limited follow-up for patients receiving tildrakizumab and risankizumab.In particular, the authors found a cumulative probability of survival at 18 months of 96.4% for risankizumab.The baseline characteristics of our population, also categorized by biological drugs, are comparable with those of other real-world experiences (7)(8)(9).As expected in real-world retrospective studies, patients' populations were not homogeneous among all treatment courses in terms of comorbidities and previous exposure to biological treatments.In our study, consistent with other experiences (7), previous exposure to at least one biological drug had a significant impact on drug discontinuation.On the other hand, the concomitant diagnosis of PsA did not play a significant role in our study.
Nevertheless, our study has a few limitations, which are primarily due to its retrospective nature.Moreover, the different biological treatments were approved in different years, resulting in longer follow-up periods for drugs like ustekinumab and secukinumab and shorter ones for IL-23 inhibitors (in particular, risankizumab and tildrakizumab).In addition, the recent availability of different drugs may have resulted in a higher tendency towards therapeutical switches after a shorter period of treatment in the last couple of years.Being this a retrospective realworld study, different comorbidities were not equally represented among different treatment groups, which could interfere with our results.Also, different ethnicities were not significantly represented in our study, which could limit the generalization of our findings.Further studies should be conducted in the next years to evaluate the treatment persistence of bimekizumab, which was not included in this analysis due to its very recent approval (16).
In conclusion, our experience on more than 5900 treatment courses showed that IL-23 inhibitors, and risankizumab in particular, had a higher probability of drug survival overall during a 4-year follow-up.Risankizumab and ixekizumab were less likely to be discontinued because of ineffectiveness after four years of treatment.Secukinumab and ustekinumab emerged as the drugs with the lowest drug survival overall.

FIGURE 1
FIGURE 1 Overall probability of drug survival throughout the study period for interleukin (IL-)12/23, IL-17 and IL-23 inhibitors.Data are presented as probability with 95% C.I. (Confidence Interval).

FIGURE 2
FIGURE 2 Drug survival rates analyzing only treatment discontinuations due to ineffectiveness.Data are presented as probability with 95% C.I. (Confidence Interval).

TABLE 1
Characteristics of our population at the start of the start of the treatment.

TABLE 2
Baseline characteristics of our population separated by biological treatment.