Effectiveness of ixekizumab for the treatment of moderate‐to‐severe plaque psoriasis with involvement of difficult‐to‐treat areas: A 52‐week multicenter retrospective study

Biological drugs have dramatically changed the approach to treating moderate‐to‐severe plaque psoriasis, achieving excellent skin clearance and safety outcomes. However, the management of difficult‐to‐treat areas (e.g., scalp, palms/soles, nails, and genitalia) still represents a challenge in psoriasis treatment. Data in the literature on difficult‐to‐treat sites are limited and, frequently, no specific analysis is performed during clinical trials. We conducted a 52‐week, retrospective study to evaluate the effectiveness of ixekizumab in 120 patients with moderate‐to‐severe plaque psoriasis of at least one difficult‐to‐treat area (scalp, palmoplantar surfaces, nails, and genitalia). Ninety‐nine patients had scalp psoriasis, 35 had involvement of the palms or soles, 27 were affected by genital psoriasis, and 22 patients reported involvement of the nails. After 1 year of treatment, 96% of patients with scalp involvement, 95.6% of patients with palmoplantar psoriasis, 95.2% of patients with genital psoriasis, and 85% of patients with nail involvement achieved a site‐specific Physician's Global Assessment of 0 or 1 (clear or almost clear). No serious adverse events were observed during the study. Our study supports the effectiveness of ixekizumab in plaque psoriasis involving difficult‐to‐treat sites.

area (BSA) affected and the predominant involvement of difficultto-treat areas. 4,5This is primarily due to the strict inclusion criteria of clinical trials, which usually enroll patients with a Psoriasis Area and Severity Index (PASI) a score of at least 10.Among the biological drugs approved for plaque psoriasis, ixekizumab is an inhibitor of interleukin (IL)-17A that has been evaluated in several clinical trials demonstrating effectiveness in difficult-to-treat areas.
This multicenter study aimed to assess the effectiveness and safety of ixekizumab in patients affected by plaque psoriasis involving difficult sites.

| ME THODS
We enrolled 120 adult patients affected by plaque psoriasis with moderate-to-severe involvement of at least one difficult-to-treat area (defined by a site-specific Physician's Global Assessment [PGA] ≥ 3), all treated with ixekizumab.Patients' demographic characteristics were retrospectively retrieved from the database of three Italian dermatology units.Ixekizumab was administered according to the Summary of Product Characteristics. 6Scalp-specific PGA (sc-PGA), palmoplantar PGA (ppPGA), static PGA of the genitalia (sPGA-G), fingernail PGA (f-PGA), and PASI were recorded at each dermatological examination.For each area, the severity of psoriasis was evaluated clinically on a scale from 0 (absence of lesions) to 4 (severe involvement of the area).The possible occurrence of any adverse events (AEs) was also evaluated throughout the study period.
The primary endpoints were the proportion of patients achieving a site-specific PGA of 0/1 (clear or almost clear) at weeks 16, 28, and 52.Continuous data were reported as mean and standard deviation (SD), while categorical variables were presented as absolute numbers and percentages.The within-group comparison of mean PGA (between baseline and weeks 16, 28, and 52) was performed using the Student's t-test.
The procedures for this study adhered to clinical standards and did not necessitate approval from the institutional review board.All patients provided written consent for their anonymous data to be retrieved retrospectively.The research complied with the Helsinki Declaration of 1964 and its later amendments.
Finally, for the 24 patients with nail involvement, an f-PGA of clear or almost clear was reached by 42% at week 16, 74% at week 28, and 85% at week 52 (Figure 1d).Mean site-specific PGA improved in each difficult-to-treat area during the study.At baseline, the mean sc-PGA was 3.43 and decreased to 0.48 at week 16, 0.27 at week 28, and 0.15 after 1 year of treatment (Figure 2a).Mean pp-PGA decreased from a mean of 3.32 at baseline to 1.21 at week 16, 0.68 at week 28, and 0.37 at week 52 (Figure 2b).Mean sPGA-G decreased from a mean of 3.27 at baseline to 0.57, 0.31, and 0.19 at 16, 28 and 52 weeks (Figure 2c).Mean f-PGA was 3.23 at baseline and decreased to 1.52 at week 16, 1.02 at week 28, and 0.58 after 52 weeks of treatment (Figure 2d).At baseline, the mean (SD) PASI of our cohort was 12.48 (7.81).During the study, it decreased to 1.53 (1.80) at week 16, 0.58 (1.45) at week 28, and 0.38 (1.39) at week 52.
No significant safety findings were reported during the study, as no patient had to discontinue the drug because of treatmentemergent AEs or serious AEs.

| DISCUSS ION
Phase-3 clinical trials have demonstrated that ixekizumab is an efficacious option for the treatment of difficult sites.In our real-world experience, we observed similar responses compared with those from clinical trials.Regarding scalp psoriasis, an analysis of the UNCOVER-1, UNCOVER-2, UNCOVER-3 studies showed a reduction of 90% and 100% on the Psoriasis Scalp Severity Index in 75.6% and 65.9% of patients respectively at week 12. 7 Narcisi et al., 4 observed an s-PGA of 0 or 1 in 93.1% and 91.6% of patients treated with ixekizumab after 16 and 24 weeks, respectively.A subpopulation analysis of the UNCOVER studies also supports the use of ixekizumab in non-pustular palmoplantar psoriasis as approximately half of the patients achieved complete skin clearance of the palms and soles after 12 weeks of treatment. 8specific clinical trial was conducted to evaluate the role of ixekizumab in the treatment of genital psoriasis (IXORA-Q).9 In this study, clear or almost clear genital skin was achieved by 73% of patients at week 12 and 75% after 1 year of treatment.A site-specific PGA of 0 was observed in 56% of patients after 12 weeks.
Regarding nail psoriasis, the IXORA-S clinical trial, compared the efficacy of ixekizumab with ustekinumab after 52 weeks in terms of the Nail Psoriasis Severity Index (NAPSI). 10In particular, a NAPSI score of 0 was reached by 61.9% of patients with a mean decrease from baseline of 22.4 points after 52 weeks of treatment with ixekizumab.In comparison, patients treated with ustekinumab in this study experienced a mean NAPSI decrease of 15.6 points from baseline with just 28.6% of them achieving complete nail clearance. 10ese findings were consistent with those from a subpopulation analysis of the UNCOVER-3 clinical trial, which reported a NAPSI of 0 in more than half of patients after 60 weeks of treatment with ixekizumab. 11In addition, a recent network meta-analysis showed that ixekizumab had the greatest likelihood among approved biologics of achieving complete resolution of nail psoriasis at week 24. 12[11][12][13] The safety profile of ixekizumab in our study was very high as no serious AEs or AEs leading to discontinuation were observed, consistent with the results of a 5-year analysis of the UNCOVER-3 study. 14e main limitations of this study include are the retrospective nature and the absence of a control group, which do not allow the generalization of our findings.
Our experience supports data from clinical trials and metaanalyses regarding the high efficacy of ixekizumab in plaque psoriasis with the predominant involvement of difficult-to-treat areas.
Therefore, ixekizumab could be considered as a first-line biological drug when treating this subset of patients.However, larger and longer studies are needed to further investigate the effectiveness and safety of ixekizumab in psoriasis patients with moderate-to-severe involvement of difficult sites.

ACK N OWLED G M ENTS
Open access funding provided by BIBLIOSAN.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Mario Valenti has been a consultant and/or speaker for Sanofi, Leo Pharma, Eli Lilly, Novartis, Janssen, AbbVie, and Boehringer Ingelheim.
Luigi Gargiulo has been a consultant for Almirall.Antonio Costanzo has served as an advisory board member, consultant, and has received fees and speaker's honoraria or has participated in clinical trials for Abbvie, Almirall, Biogen, LEO Pharma, Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme, and UCB-Pharma.Alessandra Narcisi has served on advisory boards, received honoraria for lectures and research grants from Almirall, Abbvie, Leo Pharma, Celgene, Eli Lilly, Janssen, Novartis, Sanofi-Genzyme, Amgen and Boehringer Ingelheim.The other authors have no conflicts of interest to disclose.

F I G U R E 1
Percentages of patients achieving a site-specific Physician's Global Assessment (PGA) score of 0/1 (clear or almost clear) throughout the study period regarding involvement of (a) the scalp (sc-PGA), (b) palmar and/or plantar regions (pp-PGA), (c) genitalia (s-PGA-g), and (d) fingernails.F I G U R E 2 Reduction of mean (standard deviation) site-specific Physician's Global Assessment (PGA) during 52 weeks concerning each difficult-to-treat area.(a) scalp (sc-PGA), (b) palmar and/or plantar regions (pp-PGA), (c) genitalia (s-PGA-g), and (d) fingernails (fn-PGA).
Demographic and clinical characteristics of the study population at baseline.
TA B L E 1