Real‐world effectiveness and safety of bimekizumab in Japanese patients with psoriasis: A single‐center retrospective study

Bimekizumab, which suppresses both interleukin (IL)‐17A and IL‐17F, has recently been approved as a biologic for psoriasis. We aimed to evaluate the real‐world effectiveness and safety of bimekizumab for psoriasis and to identify predictive factors for its treatment responsiveness. We analyzed 36 Japanese patients with psoriasis (19 with psoriasis vulgaris and 17 with psoriatic arthritis) from May 2022 to September 2023. All patients received bimekizumab (320 mg every 4 weeks) until week 16. Seventeen patients (43.2%) had experienced bio‐switch. The median (interquartile range) baseline total psoriasis area and severity index (PASI) was 6 (3.2–20.0). Total PASI rapidly and significantly decreased at week 4 by a median 79.8% from baseline, and gradually decreased thereafter. The PASI on the trunk, and upper and lower limbs rapidly and significantly decreased at week 4 compared to baseline and plateaued thereafter. The neutrophil‐to‐lymphocyte ratio and neutrophil number significantly decreased at week 16 compared to baseline. At weeks 4, 8, 12, and 16, the achievement rate of absolute PASI ≤2 was 72.2%, 80.6%, 92.9%, and 96.4%, respectively; that of absolute PASI ≤1 was 41.7%, 61.3%, 85.7%, and 82.1%; that of PASI 75 was 55.5%, 52.9%, 69.7%, and 75.8%; that of PASI 90 was 36.1%, 50.0%, 57.6%, and 62.9%; and that of PASI 100 was 19.4%, 38.2%, 51.5%, or 57.6%, respectively. Linear multivariate regression analysis revealed that younger age was associated with a higher percentage reduction of total PASI at weeks 4 and 8. There were no serious or fatal adverse events during treatment. In conclusion, bimekizumab rapidly and remarkably reduced the total PASI together with high achievement rates of absolute PASI ≤1 and ≤2, and with favorable safety in real‐world clinical practice. Younger age may be a predictive factor for a good treatment response to bimekizumab.

tildrakizumab, and spesolimab) are currently approved for psoriasis treatment in Japan.In May 2022, bimekizumab, a humanized monoclonal antibody that binds both IL-17A and IL-17F, was approved in Japan for the treatment of patients with moderateto-severe psoriasis aged ≥15 years.The clinical trials have demonstrated the efficacy and safety of bimekizumab, 2 3 4 however, reports on its effectiveness and safety in real-world clinical practice are limited. 5 particular, background factors of patients to predict treatment responses to bimekizumab, such as age, sex, body mass index (BMI), disease duration, baseline psoriasis area and severity index (PASI), presence or absence of bio-switch, and arthritis, have not been precisely examined.In addition, laboratory parameters that reflect the therapeutic effects of bimekizumab are unknown.][8][9][10] Thus, these laboratory parameters may act as biomarkers reflecting the therapeutic effects of bimekizumab.
In this study we aimed to assess the effectiveness and safety of bimekizumab in real-world clinical practice and to detect predictive factors for treatment responses to bimekizumab in psoriasis patients.

| Study design and data collection
We analyzed the effectiveness and safety of bimekizumab in 36 adult Japanese psoriasis patients ( The achievement rates of PASI 75, 90, or 100 (i.e., the improvement of PASI from baseline ≥75%, ≥90%, or 100% respectively), of absolute PASI ≤2 or absolute PASI ≤1, and percentage reductions of PASI were calculated at weeks 4, 8, 12 and 16.
Safety was assessed by the occurrence of treatment-emergent adverse events (TEAEs) during bimekizumab treatment, until 30 days after the last dose.A TEAE was defined as any adverse event (AE) that began or worsened after the initiation of treatment.

| Statistical analysis
Results are expressed as the mean ± standard deviation for variables with a normal distribution, or as the median and interquartile range for variables with a non-parametric distribution.Differences between weeks 0, 4, 8, 12, and 16 were analyzed using Friedman's test for variables with non-parametric distribution.Bonferroni correction was used for post-hoc analysis.
A comparison between two independent groups was performed using the Mann-Whitney U test for variables with non-parametric distribution.A comparison between two groups was performed using Wilcoxon rank sum test for variables with non-parametric distribution.The correlations of the variables with each other were analyzed using Spearman's correlation coefficients.Statistical significance was set at p < 0.05.
A linear multivariate regression analysis was performed to determine the predictive factors for a high percentage reduction of PASI at weeks 4, 8, 12, and 16 of bimekizumab treatment.The analysis included only the variables with a p value of <0.05 in univariate analyses and was adjusted for age, sex, and BMI.Variables with a variance inflation factor of >10 were excluded to avoid multicollinearity.
All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical School).

| Patient demographics and baseline characteristics
Thirty-six Japanese patients with psoriasis were enrolled in the study (Table 1).Baseline (week 0) values of the total PASI, PASI on four anatomical sites, NLR, MLR, PLR, CRP, neutrophil, lymphocyte, monocyte, and platelet numbers are shown in Table 1.The majority of patients were male (75.0%).The baseline total PASI was median (interquartile range) 6.0 (3.4-12.3).The low baseline PASI might be attributable to the high rate of pretreatment with other biologics, which might have reduced PASI scores before initiation of bimekizumab treatment.Seventeen patients (47.2%) had experienced bio-switch; one patient was pretreated with adalimumab, two with infliximab, one with certolizumab pegol, one with ixekizumab, six with secukinumab, two with ustekinumab, five with guselkumab, one with risankizumab, and two patients with tildrakizumab.

| Transition of total PASI and PASI on individual anatomical sites during treatment with bimekizumab
Total PASI rapidly and significantly reduced at week 4 by a median 79.8% of baseline, and gradually reduced thereafter (Figure 1a).The total PASI score at week 12 was significantly lower than that at week 4, and that at week 16 was significantly lower than those at weeks 4 and 8.The PASI score on the trunk and upper and/or lower limbs rapidly and significantly reduced at week 4 by a median 86.7%, 80.0%, or 66.7% of baseline respectively, and plateaued thereafter (Figure 1c-e).PASI on the head and neck appeared to decrease at week 4 by a median 73.2% of baseline, however, the difference from baseline was not significant (Figure 1b).

| Changes of laboratory parameters after bimekizumab treatment, and correlations between percentage reductions of those parameters versus that of total PASI
The neutrophil-to-lymphocyte ratio and number of neutrophils at week 16 were significantly lower than those at week 0, while MLR, PLR, numbers of lymphocytes, monocytes, and platelets and CRP at week 16 were not significantly different from those at week 0 (Table 2).These results suggest that the reduction of NLR after bimekizumab treatment may be attributable to that of the number of neutrophils in the blood.
We then analyzed if the percentage reductions of laboratory parameters at week 16 might be correlated with that of the total PASI score (Table 3).There were no significant correlations between the percentage reduction of total PASI with those of laboratory parameters except for a positive correlation with that of lymphocyte number.However, that correlation appeared non-specific since the lymphocyte number at week 16 was not significantly reduced compared to baseline (Table 2).

| Background factors predicting treatment response to bimekizumab in patients with psoriasis
We tried to detect background factors that may predict a high treatment response to bimekizumab, as evaluated by the percentage reduction of the total PASI score.We first analyzed whether sex, presence or absence of bio-switch, arthritis, scalp, nail, or genital lesions, diabetes, or current smoking affected the treatment response to bimekizumab.There were no differences in percentage reductions of total PASI between males and females, or between groups TA B L E 1 Baseline characteristics of psoriasis patients treated with bimekizumab (n = 36).

| Safety profile
The safety profile for bimekizumab in this real-world study (Table 7) was similar to that in the previous clinical trial. 11No new AEs were observed with bimekiuzmab.TEAEs occurred in 12 patients (33.3%).
There were no serious AEs or AEs that resulted in death.Major AEs were pruritus in three patients (8.3%) and oral candidiasis in three patients (8.3%), which was reported as a frequent AE during bimekizumab treatment.synoviocytes 12 and keratinocytes, 13 and neutrophil chemotaxis induced by T helper 17 (Th17) cell supernatants. 12Bimekizumab treatment completely reversed the levels of cytokines/chemokines, anti-microbial peptides, or proliferation-related molecules, such as CXCL8, CCL20, IL-17A, IL-17F, IL-17C, keratin 16, IL-36γ, DEFB4, or S100A7, in psoriasis lesional skin to the levels of non-lesional skin. 13ose in vitro and in vivo effects of bimekizumab may be reflected  The lack of a significant difference in PASI scores on the head and neck between, before, and after treatment (Figure 1b) may be due to the very low baseline scores of PASI on these regions.
3][4] The achievement rates at week 16  all other biologics in a network meta-analysis. 15Clinicians might hesitate to select bimekizumab as a first biologic and tend to hold it as a second or third biologic, considering that patients who have experienced extremely high therapeutic effects of bimekizumab might be dissatisfied with the other biologics.This might be the possible reason for the low rate of bio-naive patients, namely the high rate of bio-switched patients in bimekizumab-treated cohort in this realworld study.The safety profile of bimekizumab in this real-world study was akin to that in a previous clinical trial. 11In this study, there were three cases of oral candidiasis (8.3%), which appeared to be lower than the frequency in the clinical trial (15.6% or 19.3%) Note: Correlations between variables were examined using Spearman's correlation coefficient.
This study has several limitations.First, the baseline scores of total PASI were low.This might influence the achievement rates of PASI 75, 90, or 100.Second, the sample size was small.Third, medications for comorbidities or previous treatments for psoriasis were not included in the analysis.Fourth, we used the conventional method for the measurement of CRP.High-sensitivity CRP quantification might be preferable.
In conclusion, this study demonstrated that bimekizumab rapidly and remarkably reduced total PASI scores at week 4, with high achievement rates of absolute PASI ≤2 and absolute PASI ≤1, and a favorable safety profile.Younger age might be a predictive factor for high treatment responses to bimekizumab.

ACK N OWLED G M ENTS
Hidehisa Saeki is a co-author of this article.To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication.

CO N FLI C T O F I NTE R E S T S TATE M E NT
19 with psoriasis vulgaris and 17 with psoriatic arthritis) treated with bimekizumab at the Department of Dermatology in Nippon Medical School Chiba Hokusoh Hospital from May 2022 to September 2023.All the patients received bimekizumab (320 mg every 4 weeks) until week 16.This study was conducted in accordance with the Declaration of Helsinki (2004) and was approved by the Ethics Committee of Nippon Medical School Chiba Hokusoh Hospital.Medical records of patients were analyzed retrospectively.The diagnosis of psoriasis was made clinically.Before treatment, we recorded the patients' sex, age, BMI, disease duration, presence or absence of bio-switch and the number of occurrences, presence or absence of arthritis, scalp, nail or genital lesions, diabetes mellitus, and current smoking.Total (whole body) PASI, PASI on the head and neck, trunk, and upper and lower limbs were analyzed at weeks 0, 4, 8, 12, and 16 of treatment.The values of NLR, MLR, PLR and CRP, numbers of neutrophils, lymphocytes, monocytes, and platelets were analyzed at weeks 0 and 16.

F
I G U R E 1 (a) The reduction of total psoriasis area and severity index (PASI) scores.(b) PASI scores on head and neck (c), trunk, (d) upper limbs, and (e) lower limbs during bimekizumab treatment in patients with psoriasis (n = 36).Data are provided as the median (interquartile range).*, p < 0.05, ** p < 0.01 versus values of week 0; †, p < 0.05, † †, p < 0.01 versus values of week 4; §, p < 0.05 versus values of week 8, assessed by Friedman's test with the Bonferonni post-hoc test.factors beyond those captured in the study.These results emphasize the complexity of predicting treatment response and highlight the need for further, large-scale studies to identify more nuanced predictive factors, particularly in specific subgroups such as the elderly.

4 |
DISCUSS IONIn this study, whole body rash of psoriasis, as evaluated by total PASI, rapidly and remarkably improved by 79.8% of baseline at week 4 of bimekizumab treatment and almost completely disappeared at weeks 12 or 16.The high therapeutic effectiveness at an early time-point might be attributable to the dual inhibition of IL-17A and IL-17F by bimekizumab.By selectively binding to IL-17F as well as IL-17A and IL-17A/F, bimekizumab suppresses the activation of receptor complex IL-17RA/RC by these cytokines and the subsequent signaling cascade.The dual blockade of IL-17A and IL-17F may be more effective than IL-17A blockade alone.IL-17F induced qualitatively similar inflammatory responses to IL-17A in dermal fibroblasts and synoviocytes, such as secretion of IL-6 and IL-8, though they were quantitatively less potent.12Compared to selective inhibition of IL-17A or IL-17F alone, neutralization of IL-17A and IL-17F with bimekizumab more effectively suppressed in vitro production of cytokines/chemokines, such as IL-6 or the chemokine (C-X-C motif) ligand 1 (CXCL1)/2/8 in fibroblasts/ by the almost complete disappearance of eruptions at weeks 12 or 16 of bimekizumab treatment in this study.In parallel with whole body rash, rash on individual anatomical sites, as evaluated by PASI, rapidly and remarkably improved at week 4 of bimekizumab treatment.These results indicate that bimekizumab might equally improve the rash on individual anatomical sites.
After 16 weeks of bimekizumab treatment, NLR and the blood neutrophil number significantly reduced, indicating that bimekizumab might suppress neutrophilia.IL-17A and IL-17F promote neutrophilia.Both cytokines induce granulopoiesis in bone marrow via induction of granulocyte-colony stimulating factor secretion in bone marrow stromal cells.16,17IL-17A also increases viability of blood neutrophils by suppressing their apoptosis.18The reduction of the neutrophil number and NLR after bimekizumab treatment might be mediated by suppressing the above effects of IL-17A and IL-17F.These effects of bimekizumab might warn of the occurrence of neutropenia during the treatment.In this study, serious neutropenia (neutrophil number <1000/mm 3 ) did not occur.However, clinicians should monitor the occurrence of neutropenia with regular blood tests during bimekizumab treatment.The percentage reductions of NLR and neutrophil number were not significantly correlated with that of total PASI at week 16.The correlation should be further investigated by a large-scale study with more frequent examination during bimekizumab treatment to see if NLR and/or neutrophil number can function as a biomarker reflecting the therapeutic effects of bimekizumab.Multivariate regression analysis showed that high percentage reductions of PASI by bimekizumab treatment at weeks 4 and 8 were associated with younger age, indicating that younger age might predict a better treatment response to bimekizumab.It is reported that healthy elderly people (aged ≥65 years) have increased Th17 frequency and retinoic acid receptor-related orphan receptor γt expression in peripheral blood mononuclear cells and increased serum levels of IL-17A and IL-6 compared to healthy middle-aged (aged 45-64 years) and young people (aged ≤44 years), indicating that IL-17-related immune response is enhanced with aging. 19It is thus hypothesized that younger psoriasis patients may have lower IL-17A, IL-17A/F, or IL-17F-mediated immune responses, which may be more susceptible to bimekizumab treatment compared to elderly patients.Other than age, patients' sex, BMI, presence of arthritis, scalp, nail, or genital lesions, diabetes, current smoking, or prior bio-switch did not F I G U R E 2 Achievement rates of psoriasis area and severity index (PASI) 75, PASI 90, PASI 100, absolute PASI ≤2, and absolute PASI ≤1 during bimekizumab treatment in patients with psoriasis (n = 36).TA B L E 4 The comparisons of percentage reductions of total PASI between two independent groups based on the background factors at weeks 4, 8, 12, or 16 of bimekizumab treatment in patients with psoriasis (n = 36).64.0-100.0)79.8 (66.9-100.0)0.91 100.0 (80.6-100.0)100.0 (86.7-100.0)0.90 100.0 (93.7-100.Data are shown as the median (interquartile range), assessed by Mann-Whitney U test.Abbreviation: PASI, Psoriasis Area and Severity Index.appear to influence the treatment responses to bimekizumab as evaluated by the percentage reduction of total PASI.The results indicate that bimekizumab might be universally effective for psoriasis patients, independently of various background factors, except for age.
Correlations of percent reduction of total PASI with those of laboratory parameters at week 16 of bimekizumab treatment in patients with psoriasis (n = 36).
2,4possibly due to the small sample size and/or short duration of observation in this study.IL-17A is necessary for defense against Candid albicans by promoting recruitment of neutrophils via IL-8 production in epithe-The predictive factors for the percentage reduction of total PASI scores at weeks 4 or 8 of bimekizumab treatment assessed by linear multivariate regression analysis in patients with psoriasis (n = 36).The correlations of baseline values of background factors with the percent reduction of total PASI at week 4, 8, 12, and 16 of bimekizumab treatment in patients with psoriasis (n = 36).
21al cells.IL-17F is produced by oral γδT cells during oropharyngeal candidiasis, and might contribute to defense against Candid albi-21 while IL-17F-neutralizing antibody does not alter the susceptibility; however, dual blockade of IL-17A and IL-17F increases susceptibility to oropharyngeal candidiasis over blockade of IL-17A alone.21Similarmechanismsmightbeanticipated for the higher frequency of oral candidiasis during treatment with bimekizumab compared to the other antibodies specific to IL-17A alone.TA B L E 6*Statistically significant at p < 0.05.**Atp < 0.01.TA B L E 5 Teppei Hagino, Hidehisa Saeki, and Naoko Kanda received lecture fees from UCB Japan.The other authors have conflicts of interest to declare.Treatment-emergent adverse events (TEAEs) until week 16 of treatment with bimekizumab in patients with psoriasis (n = 36).