Introduction
Psoriasis is a chronic inflammatory skin disease that affects approximately 2–3% of the world’s population. It not only causes physical discomfort and pain but also has a significant impact on health-related quality of life (HRQoL), leading to psychological distress and social isolation [
1,
2]. Despite the availability of various treatment options, including topical corticosteroids, phototherapy, and systemic medications, many patients with plaque psoriasis do not achieve satisfactory control of their symptoms [
3]. In recent years, biologic agents have revolutionized the treatment of plaque psoriasis by targeting specific components of the immune system involved in the pathogenesis of the disease [
4].
In psoriasis clinical trials for biologic agents, a 90% improvement in psoriasis area and severity index (PASI 90) is widely accepted as a technical treatment goal [
5]. However, in psoriasis patients who respond to treatment but without total skin clearance (TSC), the residual disease may continue to have negative impacts on HRQoL and increase the risk of comorbidities such as psoriatic arthritis (PsA). Multiple studies have indicated that patients with psoriasis who achieved PASI 100 experienced significantly greater improvements in HRQOL and reduced pruritus symptoms than those with almost skin clearance (PASI 90–100) [
6‐
8]. Therefore, achieving TSC represents a clinically meaningful treatment goal in daily practice, especially from the patient’s perspective.
Interleukin (IL)-17 A inhibitors, such as ixekizumab and secukinumab have emerged as an effective treatment option for plaque psoriasis. Clinical trials have demonstrated the remarkable efficacy of IL-17 inhibitors in the treatment of plaque psoriasis, with a significant proportion of patients achieving PASI100 after 12 weeks of treatment [
9]. However, not all patients respond equally to treatment, and predicting individual treatment outcomes remains a challenge [
10]. In order to optimize the effectiveness of anti-IL17 therapies, it is crucial for clinicians to identify predictive factors that can assist in determining the patients who are most likely to derive substantial benefits.
Identifying patients who are more likely to respond to IL-17 inhibitors has significant clinical implications. It enables personalized treatment decisions, ensuring optimal therapy selection and potentially reducing treatment failures, healthcare costs, and improving patient outcomes [
11,
12]. In this study, we will develop a nomogram based on the logistic regression model to provide a visual representation of the predictive factors and their corresponding probabilities of achieving TSC. The findings of this study hold significant implications for tailoring the management of psoriasis on an individualized basis, thereby potentially advancing the development of enhanced therapeutic approaches.
Methods
Study design and setting
This real-world prospective, multicenter observational cohort study included psoriasis patients in the dermatological centers and outpatient clinics of 26 general hospitals in China between September 2020 to May 2022. Inclusion criteria were listed as follows: (1) patients aged 18 years or older; (2) patients diagnosed with moderate to severe psoriasis, confirmed by a dermatologist; (3) patients who provide written informed consent to participate in the study; (4) patients who have completed 12 weeks of biologic treatment. Exclusion criteria: (1) patients who are currently participating in another clinical trial involving an investigational drug or therapy; (2) patients who have administered IL-17 inhibitors in the past; (3) patients with severe infections or immunodeficiency disorders.
A development cohort including 381 psoriasis patients treated with ixekizumab was used for identifying the independent predictive factors for TSC response and to develop a predictive model. Patients received ixekizumab 160 mg at week 0.80 mg at weeks 2 and 4, then 80 mg every 4 weeks up to and including week 12. A total of 229 patients with psoriasis receiving secukinumab were included in the development cohort. Patients received secukinumab 300 mg once a week from 0 to 4 weeks then 300 mg every 4 weeks up to and including week 12. The disease’s severity and treatment response were evaluated by body surface area (BSA), PASI, and dermatology quality of life index (DLQI) at baseline and after 4 and 12 weeks. Ethical approval for the study was approved by the Clinical Research Ethics Committee of the Shanghai Skin Disease Hospital (approval #2020-36), in compliance with the Declaration of Helsinki. All patients in the study provided informed consent for the review of their clinical data.
Data collection
To minimize bias, a standardized data collection protocol was implemented. The following demographic and clinical data were obtained: Age (years), Sex, Duration of psoriasis (year), Age at onset of psoriasis (year), Bodyweight (kg), Baseline PASI score, Baseline BSA score, Baseline DLQI score, History of comorbidities (hypertension, hyperlipidemia, diabetes mellitus, obesity), Prior treatment history (systemic non-biologic treatments, phototherapy, biologic agents) and Special areas involvement (joints, nails, scalp, palmoplantar area and genital area). All laboratory tests were performed at a central laboratory using standardized laboratory procedures.
Variables analyze and model development
Appropriate statistical methods were employed to minimize bias in the data analysis. Data collection involved the gathering and analysis of clinical and hematological parameters. Continuous variables were summarized using median and interquartile range (IQR) and compared using Wilcoxon rank-sum tests. Categorical variables were presented as counts and percentages, and their comparison was conducted using either Chi-square tests or Fisher’s exact tests, depending on the suitability of each test for the specific variable. Receiver operating characteristic (ROC) analysis was performed to assess the predictive power of early PASI response at week 4 for determining TSC at week 12. The value of PASI percentage improvement with the highest predictive value was determined by calculating the Youden Index (YI) at each percentage of PASI improvement (a), which is represented by the equation YI (a) = sensitivity (a) + specificity (a)– 1. Spearman r was calculated and P < 0.05 suggested a highly relevant association. Multivariable logistic regression and LASSO logistic regression were applied respectively for clinical variables and hematological parameters to identify meaningful candidate variables. Based on multivariate logistic regression analysis, the selected variables were developed into a prediction model that was presented as a nomogram.
Model assessment
The discriminative ability of the model was evaluated using the area under the ROC curve (AUC). Calibration was assessed by conducting a Hosmer-Lemeshow goodness-of-fit test after dividing the sample into quintiles. This test was employed to determine the extent to which the model accurately fits the observed data, with a p-value greater than 0.05 indicating no indication of poor fit. The calibration curves, aligning with the 45-degree line, demonstrated an exceptional calibration model wherein the predicted probabilities closely matched the actual outcomes. In order to assess the clinical efficacy of the nomogram model, decision curve analysis (DCA) was conducted by evaluating the net benefit within a specified range of threshold probabilities. The statistical analyses were conducted using R software (version 3.6.1). ROC curves were generated using the ‘pROC’ package, while nomograms and calibration curves were created using the ‘rms’ package. DCA was generated using the ‘rmda’ package.
Discussion
Currently, the therapeutic objective for individuals with psoriasis has progressed from achieving remission to attaining total skin clearance (TSC), which represents a more ambitious goal [
6,
13]. As a ‘treat-to-target’ strategy, TSC improves the quality of life and pruritus symptoms, prolongs drug survival, and decreases the risks of complications such as psoriatic arthritis [
14,
15]. In this multicenter real-world study, fewer than half of all patients could achieve a TSC response after 12 weeks of IL-17 inhibitors treatment. At present, no single index can be used to predict TSC response [
16]. Therefore, it is necessary to combine routine clinical data and laboratory parameters to predict the treatment response.
Previous studies have suggested that certain biomarkers may be associated with treatment response in psoriasis. For instance, female sex has been found to be associated with a better response to systemic therapy in psoriasis compared with males, it can be partly explained by weight, adherence to treatment and different lifestyle behavior [
17]. In the present data, we also observed that TSC responders had a higher proportion of females compared with non-TSC responders. Unfortunately, it was not influential enough to enter the final model through multivariable logistic regression analysis. Thus, physicians should not make decisions according to patient’s gender. Consistent with past studies, we found that experience of prior biologic treatment could affect response to ixekizumab [
18,
19]. This phenomenon can potentially be attributed to the prolonged inhibition of a specific cytokine, leading to the induction of other pro-inflammatory cytokines with overlapping functions. Manifestations of plaque psoriasis can occur in special areas, making it difficult to treat [
20,
21]. Our findings agree with others that involvement with joints and genital area affected were associated with reduced odds of achieving TSC response.
In randomized controlled trials (RCT) for IL-17 A inhibitors in psoriasis, the correlation between early improvements in disease activity and improved long-term clinical outcomes has been observed. This is demonstrated by pooled data from phase 3 studies of secukinumab, which indicate that an early onset of response, defined as a PASI 50 at week 4, is associated with sustained efficacy at week 16 [
22]. Similarly, in another post-hoc analysis of phase II study for ixekizumab, early PASI40 response at week 4 was predictive of PASI 75 response at week 12 [
23]. However, there is limited real-world evidence available in this particular area. Results of the current analysis confirm previous findings showing that early response could serve as a reliable indicator for later response. Furthermore, our results complement and extend previous studies that a 60% improvement in PASI from baseline to week 4 was the optimum value for predicting PASI 100 response at week 12.
The routine blood test, a widely available and fundamental examination, has long been advocated as an indispensable adjunct for disease assessment. The combination of clinical characteristics and laboratory parameters may make the prediction model more accurate and effective [
24,
25]. Among multiple routine blood indexes, baseline neutrophil counts and uric acid levels were found to be the best biomarkers for predicting TSC in our analysis. TNF-α accelerates the infiltration of neutrophils from the peripheral blood into the skin with dendritic cell activation [
26]. The severe psoriasis group exhibited elevated neutrophil activity in the bloodstream compared to the moderate psoriasis group, and this activation was inhibited by biologic therapy in the psoriasis patients [
27]. Recently, multiple studies have shown that the neutrophil-based index could serve as predictive biomarkers of treatment response to biologic agents in patients with psoriasis [
28,
29]. Additionally, psoriasis patients commonly present with high levels of uric acid, which have been shown to facilitate inflammatory pathways through the release of pro-inflammatory chemokines [
30]. Several studies have shown that serum uric acid concentration in psoriasis patients is positively associated with disease severity and extent of skin involvement [
31,
32]. During 52 weeks of treatment with secukinumab, uric acid levels decreased in psoriasis patients [
33]. A study by Pan et al. demonstrated that pre-treatment uric acid was effective in predicting the responses to biologic agents in patients with Crohn’s disease [
34]. The mechanisms underlying the association between neutrophil counts and uric acid levels with treatment response to biologic agents need to be further investigated.
Collectively, we have identified six factors that exhibit predictive capabilities for the TSC response, specifically, previous biologic treatment, joint involvement, genital area affected, early response, neutrophil counts, and uric acid levels. Our findings signify a significant advancement in the stratification of psoriasis patients during the initial stages of IL-17 inhibitors treatment, thereby facilitating a personalized approach to the prescription of IL-17 inhibitors. Furthermore, the development of a web-based online calculator enhances the accessibility and efficiency of the nomogram in clinical practice. Clinicians can easily input patient characteristics into the calculator to obtain individualized predictions of TSC response. This tool can aid treatment decision-making, facilitate patient counseling, and optimize the allocation of healthcare resources.
Our study has several strengths. Firstly, the involvement of six dermatology centers throughout China guarantees the external validity of the findings. The second is to take into consideration predictive factors from three different aspects: patient and disease characteristics (previous biologic treatment, joint involvement and genital area affected), early treatment response (achieving PASI60 at week 4) and serological biomarker (neutrophil counts and uric acid levels), which is a promising approach to improve the predictive accuracy of the combined model. Third, we included only routine clinical and laboratory data in our study, thereby obviating the need for additional physical examinations or genetic profiling of patients. Several limitations should be considered when interpreting the results of this study. The study is based on data collected in the daily routine and some data were missing. Unlike in RCT, selection bias and potential confounders are inevitable, and many patients did not strictly follow the visit schedule in the study. Second, the study focused on IL-17 inhibitors, and the generalizability of the nomogram to other biologic agents or systemic therapies requires further investigation. Further, only short intervention course (12 weeks) was examined.
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