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Pre-treatment plasma retinol binding protein 4 level and its change after treatments predict systemic treatment response in psoriasis patients
BMC Immunology volume 25, Article number: 55 (2024)
Abstract
Background
Retinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients.
Methods
This prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients.
Results
RBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71–22.92) versus 9.59 (6.57–13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P < 0.001). Lower RBP4 at baseline predicted achieving PASI 75 at W12 (P = 0.038). Greater RBP4 change (baseline-W12) precited achieving PASI 75 (P = 0.036) and PASI 90 (P = 0.045) at W12. Receiver operating characteristic curves suggested that after adjustment for all clinical features, RBP4 at baseline and RBP4 change (baseline-W12) had an acceptable ability to predict PASI 75 and PASI 90 at W12 with all area under curve values > 0.7.
Conclusion
Plasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.
Introduction
Psoriasis is a chronic autoimmune skin disease characterized by abnormal skin cell proliferation, which typically manifests as a red and raised area of plaques on the skin covered with a silvery-white scale [1]. Globally, the incidence of psoriasis varies from 30.3 to 321.0 per 100,000 person-years, and the prevalence of psoriasis ranges from 0.14 to 1.99% [2]. Systemic treatments, including conventional systemic agents and biologic agents, are common treatment strategies for psoriasis patients [3,4,5]. However, the response to systemic treatments is still unsatisfactory in some psoriasis patients, and the Psoriasis Area and Severity Index (PASI) 90 response rate ranges from 12.2 to 72% after 10 to 16 weeks [6,7,8]. Subsequently, psoriasis patients who do not respond to systemic treatments would suffer from disease progression and reduced quality of life [5]. Therefore, investigating potential markers that estimate response to systemic treatments may help to improve the management of psoriasis patients.
Retinol binding protein 4 (RBP4), the specific transport protein of the lipophilic vitamin A with a molecular weight of about 21Â kDa, is primarily derived from hepatocytes and adipocytes [9,10,11,12]. Previous studies found that RBP4 might be related to psoriatic skin lesion formation and was a mediator of inflammation, suggesting a potential involvement of RBP4 in psoriasis pathology and progression [13, 14]. As reported by a previous study, RBP4 protein was accumulated in psoriatic skin lesions, and this study also proposed a physiological role of RBP4 in psoriasis: the demand for vitamin A in psoriatic skin lesions was elevated. In response, RBP4 transferred retinol to lesional skin. After that, retinol was metabolized into retinoic acid, which further activated downstream pathways that facilitated keratinocyte proliferation and aggravated psoriasis [14]. More importantly, some clinical studies have reported the variation of RBP4 after treatments in psoriasis patients [15,16,17,18]. For instance, a study discovered that RBP4 was reduced after 6 months of adalimumab treatment in psoriasis patients [18]. Another study disclosed that after 3 months of acitretin treatment, RBP4 was decreased in psoriasis patients [15]. However, RBP4 was not influenced by phototherapy or topical treatment in psoriasis patients [16, 17]. Based on the above evidence, we deduced that RBP4 might predict response to systemic treatments in psoriasis patients. However, relevant evidence is scarce.
Therefore, the current study aimed to investigate the longitudinal change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients.
Methods
Patients and healthy subjects
This prospective, observational cohort study enrolled 85 psoriasis patients who were in the active state of the disease (PASI score ≥ 8) and needed systemic treatment (conventional systemic agents or biologic agents). Patients who met all of the following criteria were included: (1) clinically diagnosed as psoriasis [19]; (2) PASI score ≥ 8; (3) needed systemic treatment (conventional systemic agents or biologic agents); (4) could be followed up for 12 weeks; (5) could provide the blood samples. Patients who met one of the following criteria were excluded: (1) concomitant infections; (2) concomitant hematological diseases; (3) pregnant or lactating women. The study enrolled 20 age-sex-matched healthy subjects during the same period. The inclusion criteria were: (1) physical examination results were normal; (2) could provide the blood samples. The exclusion criteria were the same as the psoriasis patients. This study was approved by the Ethics Committee of HanDan Central Hospital. Psoriatic patients and healthy subjects signed an informed consent form.
Clinical characteristics collection
Clinical characteristics of psoriasis patients such as age, gender, body mass index (BMI), psoriasis duration, disease involving arthritis, conventional systemic agents, and biologic agents were collected after enrollment. The clinical characteristics of healthy subjects such as age, gender, and BMI were also collected.
Blood sample collection and RBP4 detection
Blood samples were collected from patients at baseline (before the start of systemic treatment) and the 12th week (± 2 weeks) of follow-up (W12). Blood samples from healthy subjects were also collected after enrollment. All blood samples were centrifuged in a centrifuge at 1500 rpm for 10 min at 4 °C. The plasma was obtained and then stored at -80 °C until testing. In this study, RBP4 levels in plasma were detected using an Enzyme-linked immunosorbent assay (ELISA) kit purchased from R&D, USA. The experimental procedure was performed in strict accordance with the instructions.
PASI score evaluation
PASI scores were assessed at baseline (before the start of systemic treatment) and W12. PASI 75 and PASI 90 for the patients were calculated. The PASI score was evaluated in four sections: head, trunk, upper extremities, and lower extremities, which accounted for 10%, 30%, 20%, and 40% of the total score, respectively. The percentage of skin with psoriasis in that section was calculated and categorized on a scale of 0–6. The severity of psoriasis (erythema, induration, scale) was assessed separately for each section on a scale of 0–4. The total score ranging from 0 to 72. The higher the score, the more severe the psoriasis [20]. PASI 75/90 was defined as the PASI ≥ 75%/90% improvement from the baseline [21].
Statistical analysis
SPSS 26.0 (IBM, USA) was used for the data analysis. Patients who lacked blood samples or PASI score at W12 were excluded from this study analysis, and a total of 85 patients were finally included. The comparative analyses were performed through the student’s t, Mann-Whitney U, Chi-square, and Wilcoxon Signed Rank tests. The Correlation analysis was done using the Spearman test. The distinguishing efficiency of RBP4 at baseline between psoriasis and healthy subjects was analyzed by receiver operating characteristic (ROC). A logistic regression analysis model was used to find the factors associated with the PASI 75/90. The predictive efficacy of RBP4 at baseline and decreased RBP4 level for PASI 75/90 were analyzed by ROC. P values less than 0.05 were considered statistically different.
The study developed 4 logistic regression models. The logistic regression model 1 was an unadjusted logistic regression of RBP4 at baseline or decreased RBP4 level. In model 2, age and male were adjusted. In model 3, age, male, and BMI were adjusted. In model 4, all clinical characteristics in our study were adjusted.
Results
Clinical information of psoriasis patients and healthy subjects
The mean age was 41.7 ± 11.5 years in psoriasis patients and 38.1 ± 9.2 years in healthy subjects (P = 0.201). There were 45 (52.9%) male psoriasis patients and 10 (50.0%) male healthy subjects (P = 0.813). The BMI was increased in psoriasis patients compared to healthy subjects (P < 0.001) (Table 1).
In psoriasis patients, the mean psoriasis duration was 13.3 ± 6.7 years. The median [interquartile range (IQR)] PASI score was 12.9 (10.6–18.0). Sixteen (18.8%) psoriasis patients were found to have disease involving arthritis. Moreover, 58 (68.2%) patients received conventional systemic agents, and 39 (45.9%) patients received biologic agents. Regarding conventional systemic agents, 28 (32.9%), 19 (22.4%), and 11 (12.9%) patients received methotrexate (MTX), cyclosporin A (CyA), and acitretin, respectively. Regarding biologic agents, 28 (32.9%), 7 (8.2%), and 4 (4.7%) patients received tumor necrosis factor (TNF) inhibitor, interleukin (IL)-12/23 inhibitor, and IL-17 inhibitor, respectively (Table 1).
Comparison of RBP4 at baseline between psoriasis patients and healthy subjects
RBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (IQR): 13.39 (9.71–22.92) versus 9.59 (6.57–13.72) µg/mL] (P = 0.003) (Fig. 1A). The ROC curve suggested that RBP4 at baseline had an acceptable ability to discriminate psoriasis patients from healthy subjects with an area under curve (AUC) [95% confidence interval (CI)] of 0.717 (0.597–0.837) (Fig. 1B). After adjustment for age, gender, and BMI, RBP4 at baseline had a good ability to discriminate psoriasis patients from healthy subjects [AUC (95% CI): 0.794 (0.693–0.894)] (Fig. 1C).
Correlation of RBP4 at baseline with clinical features in psoriasis patients
RBP4 at baseline was positively correlated with disease involving arthritis in psoriasis patients (r = 0.234, P = 0.031). Meanwhile, RBP4 at baseline showed a trend to be positively correlated with BMI in psoriasis patients but did not achieve statistical significance (r = 0.194, P = 0.075). However, RBP4 at baseline was not correlated with other clinical features in psoriasis patients (all P > 0.05) (Table 2).
Relationship of RBP4 at baseline and RBP4 change (baseline-W12) with systemic treatment response at W12 in psoriasis patients
A total of 50 (58.8%) psoriasis patients achieved PASI 75 at W12, and 25 (29.4%) psoriasis patients achieved PASI 90 at W12 (Fig. 2A). RBP4 at W12 was lower than its level at baseline [median (IQR): 11.10 (6.88–16.28) versus 13.39 (9.71–22.93) µg/mL] (P < 0.001). The median (IQR) RBP4 change (baseline-W12) was 2.87 (0.47–7.82) µg/mL (Fig. 2B).
RBP4 at baseline was lower in psoriasis patients who achieved PASI 75 at W12 than those who did not achieve that (P = 0.038). However, RBP4 at baseline was not different between psoriasis patients who achieved PASI 90 at W12 and those who did not achieve that (P = 0.130) (Fig. 2C). RBP4 change (baseline-W12) was greater in psoriasis patients who achieved PASI 75 at W12 than those who did not achieve that (P = 0.036); it was also greater in patients who achieved PASI 90 at W12 than those who did not achieve that (P = 0.045) (Fig. 2D).
Comparison of RBP4 before and after treatments in psoriasis patients
RBP4 at W12 was lower than its level at baseline in patients receiving MTX (P < 0.001) and acitretin (P = 0.041). However, there was no difference in RBP4 at W12 and baseline in patients receiving CyA (P = 0.601). Regarding biologic agents, RBP4 at W12 was lower than its level at baseline in patients receiving TNF inhibitor (P < 0.001) and IL-12/23 inhibitor (P = 0.018). However, there was no difference in RBP4 at W12 and baseline in patients receiving IL-17 inhibitor (P = 0.144) (Supplementary Table 1).
Subgroup analysis of the prognostic value of RBP4 based on treatment regimens in psoriasis patients
Subgroup analysis revealed that RBP4 at baseline showed a decreasing trend in patients receiving MTX (P = 0.078) and TNF inhibitor (P = 0.084) who achieved PASI 75 at W12 compared to those who did not achieve it, but it did not reach statistical significance. Additionally, RBP4 at baseline was numerically decreased in patients receiving CyA who achieved PASI 90 at W12 compared to those who did not achieve it, but without statistical significance (P = 0.057). Moreover, the RBP4 change (baseline-W12) was greater in patients receiving CyA who achieved PASI 75 at W12 than those who did not achieve that, but it did not reach statistical significance (P = 0.099) (Supplementary Table 2).
ROC curves of RBP4 at baseline and RBP4 change (baseline-W12) for systemic treatment response at W12 in psoriasis patients
ROC curves were applied to analyze the abilities of RBP4 at baseline to predict PASI 75 (Fig. 3A-D) and PASI 90 (Fig. 3E-H) at W12 in psoriasis patients. After adjustment for all clinical characteristics, RBP4 at baseline had an acceptable ability to predict PASI 75 [AUC (95% CI): 0.762 (0.654–0.871)] (Fig. 3D) and PASI 90 [AUC (95% CI): 0.828 (0.721–0.935)] (Fig. 3H) at W12 in psoriasis patients.
The abilities of RBP4 change (baseline-W12) to predict PASI 75 (Fig. 3I-L) and PASI 90 (Fig. 3M-P) at W12 in psoriasis patients were also analyzed. After adjustment for all clinical characteristics, RBP4 change (baseline-W12) had a certain ability to predict PASI 75 [AUC (95% CI): 0.717 (0.600-0.834)] (Fig. 3L) and PASI 90 [AUC (95% CI): 0.785 (0.675–0.895)] (Fig. 3P) at W12 in psoriasis patients.
Logistic regression models for systemic treatment response at W12 in psoriasis patients
Model 1 (unadjusted) suggested that RBP4 at baseline was negatively associated with PASI 75 at W12 [odds ratio (OR) = 0.946, P = 0.039]. Model 4 (adjusted all clinical characteristics in our study) disclosed that RBP4 at baseline was negatively and independently associated with PASI 75 at W12 (OR = 0.923, P = 0.019). Meanwhile, only model 4 (adjusted all clinical characteristics in our study) revealed that RBP4 at baseline was negatively and independently associated with PASI 90 at W12 (OR = 0.920, P = 0.038) (Table 3).
Regarding RBP4 change (baseline-W12), models 1, 2, 3, and 4 suggested that RBP4 change (baseline-W12) was not associated with PASI 75 or PASI 90 at W12 in psoriasis patients (all P > 0.05) (Table 4).
Discussion
RBP4 is dysregulated in patients with autoimmune diseases according to previous studies [16, 22,23,24]. In terms of psoriasis, previous studies found that RBP4 was increased in psoriasis patients compared to healthy controls [16, 24, 25]. In line with these previous studies [16, 24, 25], we also discovered that RBP4 at baseline was higher in psoriasis patients compared to healthy subjects. The potential explanations would be that: (1) the increase in RBP4 might be related to psoriatic skin lesion formation [14]. (2) RBP4 could also regulate stimulated by retinoic acid (STRA)6, c-Jun N-terminal protein kinase (JNK), and toll-like receptor 4 (TLR4) to amplify inflammation, thereby inducing psoriasis [26,27,28]. Thus, an increase in RBP4 was discovered in psoriasis patients compared to healthy controls. Another finding was that, after adjustment for age, gender, and BMI, RBP4 at baseline had a good ability to estimate psoriasis risk. This finding suggested that the detection of RBP4 might assist in diagnosing psoriasis. It should be clarified that only 20 healthy subjects were enrolled in this study, which might affect the statistical power.
The current study also discovered that RBP4 at baseline showed a trend to be positively correlated with BMI in psoriasis patients, but it did not achieve statistical significance. We speculated that a potential reason would be that RBP4 could regulate adipogenesis, lipid accumulation, and insulin resistance, which might contribute to an increase in BMI [26, 29,30,31]. Therefore, RBP4 showed a trend of positive correlation with BMI in psoriasis patients. In addition, we also found that RBP4 was positively correlated with psoriasis involving arthritis. A possible explanation would be that RBP4 could induce an inflammatory response in chondrocytes and synoviocytes, which triggered joint destruction [32]. Thus, there was a positive correlation between RBP4 and psoriasis involving arthritis in psoriasis patients.
The change in RBP4 after treatments in psoriasis patients has been revealed by previous studies [15,16,17,18]. Some studies reported that RBP4 remained unchanged after phototherapy or topical treatment in psoriasis patients [16, 17]. However, after systemic treatments (acitretin treatment and anti-TNF-α treatment), RBP4 was decreased in psoriasis patients [15, 18]. In line with the two previous studies [15, 18], our study also found that RBP4 was decreased after systemic treatments in psoriasis patients. A possible reason behind this might be that RBP4 was predominantly secreted by adipocytes [33], and systemic treatments might influence the structure of adipocytes, thereby decreasing the production of RBP4 [15]. Moreover, it was discovered that lower RBP4 at baseline and its greater change after treatment were related to achieving response to systemic treatments in psoriasis patients, which was further validated by our ROC curves. A potential reason might be that decreased RBP4 might attenuate psoriatic skin lesion formation, which might promote the efficacy of systemic treatments [14].
Several limitations should be noted in this study. (1) The number of psoriasis patients and healthy subjects was unmatched. Thus, the level of RBP4 in psoriasis patients and healthy subjects should be further explored. (2) The follow-up duration should be prolonged to investigate the ability of RBP4 to predict long-term response to systemic treatments in psoriasis patients. (3) The number of psoriasis patients was small, which limited the statistical power. Further studies should consider enrolling more psoriasis patients. (4) The specific reason behind the decrease in RBP4 after systemic treatments should be investigated in cellular or animal experiments.
Conclusions
In conclusion, plasma RBP4 is reduced after systemic treatments, and its lower basal level and greater change after treatments predict satisfactory systemic treatment response in psoriasis patients. Our findings provide a reference that the detection of RBP4 predicts treatment response in psoriasis patients receiving systemic treatments, which helps to stratify these patients and improve their management.
Data availability
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
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RN: Conceptualization, Formal Analysis, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. ZL: Conceptualization, Formal Analysis, Resources, Supervision, Writing – original draft, Writing – review & editing. WJ: Data curation, Methodology, Resources, Supervision, Writing – original draft, Writing – review & editing. QY: Formal Analysis, Investigation, Resources, Supervision, Writing – review & editing. XD: Conceptualization, Formal Analysis, Investigation, Methodology, Supervision, Writing – review & editing. LS: Data curation, Investigation, Resources, Supervision, Writing – review & editing. ZC: Data curation, Investigation, Resources, Supervision, Writing – review & editing. JH: Formal Analysis, Investigation, Resources, Supervision, Writing – review & editing. LL: Data curation, Methodology, Resources, Writing – original draft, Writing – review & editing. JM: Data curation, Methodology, Resources, Writing – original draft, Writing – review & editing. TH: Data curation, Investigation, Resources, Supervision, Writing – review & editing. LZ: Data curation, Investigation, Resources, Supervision, Writing – review & editing. JD: Data curation, Methodology, Resources, Writing – original draft, Writing – review & editing. CW: Data curation, Methodology, Resources, Writing – original draft, Writing – review & editing. FL: Data curation, Investigation, Resources, Supervision, Writing – review & editing.
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Niu, R., Li, Z., Jiang, W. et al. Pre-treatment plasma retinol binding protein 4 level and its change after treatments predict systemic treatment response in psoriasis patients. BMC Immunol 25, 55 (2024). https://doi.org/10.1186/s12865-024-00647-7
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DOI: https://doi.org/10.1186/s12865-024-00647-7