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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 38  |  Issue : 3  |  Page : 166-171

Changes in metabolic parameters in psoriasis patients treated with interleukin-12/23 blockade (ustekinumab)


1 Department of Dermatology, College of Medicine, Chang Gung Memorial Hospital, Linkou Branch; School of Medicine, College of Medicine; Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan
2 Department of Dermatology, College of Medicine, Chang Gung Memorial Hospital, Linkou Branch; School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
3 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University; Department of Statistics, National Taipei University, Taipei, Taiwan
4 School of Medicine, College of Medicine, Chang Gung University; Department of Family Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan

Date of Submission03-Mar-2020
Date of Decision10-May-2020
Date of Acceptance27-May-2020
Date of Web Publication10-Sep-2020

Correspondence Address:
Dr. Ya-Ching Chang
Department of Dermatology, Chang Gung Memorial Hospital, Linkou Branch, No. 5, Fushin Street, Taoyuan
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ds.ds_27_20

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  Abstract 


Background: The associations between psoriasis, metabolic syndrome, and cardiovascular events are increasingly recognized. Studies have shown decreased cardiovascular events with the treatment of methotrexate and anti-tumor necrosis factor-α. However, effects of interleukin (IL)-12/23 blockade remain debatable. Objectives: Our study sought to investigate the effect of IL-12/23 blockade on the metabolic parameters in patients with psoriasis. Methods: We performed a retrospective cohort study to assess 93 consecutive patients with moderate-to-severe plaque-type psoriasis who received IL-12/23 blockade (ustekinumab) for 24 weeks between January 2012 and May 2016. Results: Metabolic parameters and disease activity (psoriasis area severity index score) at baseline and 24 weeks of treatment were collected. At week 24 (wk24), the disease activity improved significantly (mean: baseline, wk0: 21.35 ± 11.55 to wk24: 6.87 ± 6.81, P < 0.0001), with a significant reduction of erythrocyte sedimentation rate. Conversely, body mass index was significantly elevated in PASI-75 responders at wk24 of treatment and was independent of disease severity. Fasting sugar and triglyceride level were elevated at wk24. Cholesterol (Chol), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) remained unchanged. These metabolic parameters were not correlated with the improvement in disease severity after ustekinumab treatment. Nonetheless, the atherogenic index, LDL/HDL ratio, and Chol/HDL ratio remained unchanged. Male gender is a predictor of elevated plasma triglyceride level. Conclusion: Our results suggest that despite tremendous improvement in disease activity after ustekinumab treatment, obesity, fasting sugar, and hypertriglyceridemia are still present in these patients. Regular screening of lipid profile and obesity control is advised during the treatment of ustekinumab, especially in male psoriasis patients with predisposing cardiovascular risks.

Keywords: Metabolic parameters, psoriasis, ustekinumab


How to cite this article:
Ng CY, Huang YH, Tzeng IS, Liu SH, Chang YC. Changes in metabolic parameters in psoriasis patients treated with interleukin-12/23 blockade (ustekinumab). Dermatol Sin 2020;38:166-71

How to cite this URL:
Ng CY, Huang YH, Tzeng IS, Liu SH, Chang YC. Changes in metabolic parameters in psoriasis patients treated with interleukin-12/23 blockade (ustekinumab). Dermatol Sin [serial online] 2020 [cited 2020 Sep 19];38:166-71. Available from: http://www.dermsinica.org/text.asp?2020/38/3/166/294709




  Introduction Top


Psoriasis is a chronic inflammatory skin disorder that affects approximately 1%–3% of the general population.[1],[2] Patients with psoriasis vulgaris are known to have an increased mortality rates compared to the general population, and cardiovascular event is among the most important cause of death in patients with severe psoriasis.[3],[4],[5],[6] An increased risk of obesity and metabolic syndrome was found in psoriasis, and these were established risk factors for cardiovascular events.[5],[7] Severe psoriasis is correlated with metabolic syndrome.[8] Studies suggested that chronic systemic inflammation plays a key role in metabolic disorders and psoriasis.[9],[10] Psoriasis and atherosclerosis both share a common upregulation of Th1 and Th17 cytokine, systemic expression of adhesion molecules, and endothelins.[10] Through improvement in the disease activity, one would expect an improvement in the lipid profiles, atherosclerosis, and cardiovascular events. Disease activity suppression with methotrexate and antitumor necrosis factor was associated with reduced cardiovascular risk.[11] Interestingly, previous reports have shown an increased total cholesterol (Chol) and triglyceride following treatment of anti-tumor necrosis factor (TNF) therapy without affecting the atherogenic index.[12],[13],[14] To date, reports of anti-interleukin (IL)-12/23 to metabolic parameters and cardiovascular risk are still limited and were rather controversial.[15] Since obesity and dyslipidemia were reversible risk factors for cardiovascular events, our aim of this study was to ascertain the effects of IL-12/23 blockade on metabolic parameters and obesity by the disease activity and treatment responses in patients with psoriasis.


  Materials and Methods Top


A retrospective cohort study was carried out in a Chang Gung Memorial Hospital, Linkou, from January 2012 to May 2016. The study population comprised consecutive patients older than ≥18 years of age with the diagnosis of chronic plaque-type psoriasis vulgaris made by a certified dermatologist. All patients received three doses of IL-12/23 antagonist (ustekinumab) injection (45 mg subcutaneously [SC] for patients weighing <100 kg and 90 mg SC for patients weighing >100 kg) at week 0 (wk0), week 4, and week 16 of a treatment course. This study was approved by the Institutional Review Board of the Ethical Standards Committee of Chang Gung Memorial Hospital (approval no. 201600056B0) before study initiation and was conducted in accordance with the Declaration of Helsinki and all relevant local laws, regulations, and guidelines for the use of human subjects. Patient informed consent was not required by the Ethical Standards Committee due to retrospective nature.

Disease activity (Psoriasis Area Severity Index (PASI)) and body mass index (BMI) were assessed at baseline (wk0) and week 24 (wk24). Assessments of acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), fasting glucose, serum lipoprotein concentration including total Chol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglyceride at wk0 and wk24 were collected. Lipid protein ratios reflecting cardiovascular risks (atherogenic index of plasma [AIP], Chol/HDL ratio, and LDL/HDL ratio) were calculated. The changes of metabolic parameters in correlation to disease activity (PASI score, ESR, and CRP) at wk0 and wk24 of IL12/23 blockade (ustekinumab) treatment were assessed. Subsequently, we compared the differences of metabolic parameters and lipoprotein ratios in the PASI-75 responders (PASI score with more than 75% improvement [PASI-75+]) versus non-PASI-75 responders (PASI score with <75% improvements [PASI-75−]).

Results were expressed as mean ± standard deviation (SD) for normally distributed data and median (interquartile range [IQR]) for nonnormally distributed data. Descriptive statistics and comparative analysis were performed using the (SAS Institute Inc., Cary, NC, USA). Categorical variables were assessed using the Chi-squared test. Quantitative variables were analyzed using a t-test and paired t-test (for BMI). Wilcoxon signed-rank test was used to analyze the metabolic parameters of the patients before and after treatment. Multiple linear regression was later used for possible predictors of triglyceride increase after treatment found in the initial analyses. McNemar test was used to analyze the changes of lipoprotein ratios. The level of significance for all two-tailed analysis was at 0.05.


  Results Top


A roster of 93 consecutive patients with moderate-to-severe plaque-type psoriasis were included in this study. All patients had initially a high disease activity (PASI score >10) that justified the use of ustekinumab. The demographic characteristics of these patients at baseline including age, BMI, gender, pre/postmenopause, smoking, alcoholism, disease duration, and underlying comorbidities were described in [Table 1]. The mean age at treatment was 41.86 ± 10.56 years old, with an average disease duration of 15.21 ± 8.4 years. Males (71%) were slightly more than females (29%) (P = 0.77). The baseline age, disease duration, gender, comorbidities, and BMI were similar in both PASI-75 + and PASI-75− (P > 0.05). All patients tolerated ustekinumab infusions throughout the study with no adverse reactions. No significant changes in smoking/alcohol habit or dosage of background medications were registered during the study period.
Table 1: Demographic and clinical characteristics of 93 psoriasis patients receiving IL12/23 blockade (ustekinumab/ Stelara®)

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PASI score improved significantly over the study period from a wk0 mean of 21.35 ± 11.55–6.87 ± 6.81 at wk24 (P< 0.0001). ESR improved after treatment. Interestingly, BMI significantly elevated after treatment (mean [±SD]: w0: 26.95 [1.404] and wk24: 27.59 [±1.67], P < 0.0001). Uric acid was lower at wk24 compared to baseline (median wk0: 6.8 [IQR: 6.98, 8.3] and wk24: 6.7 [5.6, 7.7], P = 0.132). Fasting sugar and triglyceride both increased significantly after ustekinumab treatment (fasting sugar, median [IQR], wk0: 91.5 (85, 102) and wk24: 93 (88, 105), P < 0.0431; triglyceride, w0: 122.5 (86, 150.5) and wk24: 129 (96, 173), P < 0.0021). We further compared changes in disease activity, inflammatory markers, and metabolic parameters between PASI-75+ and PASI-75− groups, as shown in [Table 2]. Our results demonstrate that PASI and ESR were significantly improved in both the groups. BMI was significantly elevated at wk24 compared to wk0 in PASI-75+ (mean [±SD], wk0: 25.64 [±5.27] and wk24: 26.55 [±5.55], P < 0.0001) but not in PASI-75− patients. Triglyceride level was significantly elevated in both the groups. Nevertheless, the lipoprotein ratios including AIP, LDL/HDL ratio, and Chol/HDL ratio of both risk categories remained unchanged [Supplementary Table 1]. Subsequently, we performed a multiple linear regression to investigate the predictors of serum triglyceride level elevation in these patients, as shown in [Table 3]. Our results show that male gender alone is significantly correlated with the elevation of triglyceride level, whereas BMI, PASI-75 response, alcohol, and the presence of comorbidities were not.
Table 2: Changes of inflammatory markers and metabolic parameters between after receiving IL12/23 blockade (ustekinumab/Stelara®)

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Table 3: Predictors of serum triglyceride level difference at week 0 and week 24 of treatment with IL12/23 blockade (ustekinumab/Stelara®) in patients with psoriasis

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  Discussion Top


Psoriasis is a chronic inflammatory disease that is more than skin deep. Associations between psoriasis and metabolic comorbidities such as obesity, hyperlipidemia, diabetes, and cardiovascular events have been well demonstrated.[1],[16],[17],[18],[19],[20] “Psoriatic march” was proposed by Boehncke et al. to describe the evolution of metabolic syndrome to cardiovascular events in psoriatic disease.[18] The key mediators to the pathogenesis of psoriasis, obesity, metabolic syndrome, and cardiovascular events all lie in chronic Th-1 inflammation.[19] Through controlling psoriasis disease activity, one would expect to provide beneficial effects on these metabolic parameters and eventually lower the risk of cardiovascular events. However, only methotrexate and antitumor necrosis factor were found to reduced cardiovascular risk in psoriasis patients, whereas the effect of IL-12/23 antagonist to cardiovascular event remains debatable.[11],[20],[21] Tzellos et al.[20] systemically analyzed the major adverse cardiovascular events (MACEs) in patients with psoriasis after treatment of ustekinumab or briakinumab and found that the MACEs events increase in both treatment groups. The study was, however, contradictory to a previous study by Ryan et al.[21] which showed no increased risk of MACEs in the treatment arm of anti-IL12/23 antibodies. The discrepancy in both studies was caused by different Peto's meta-analysis methods and risk-difference methods, respectively. Lipid profile and BMI are metabolic parameters that are strong, yet reversible predictors of MACEs. Studies have shown that antitumor necrosis factor improved insulin sensitivity and alters lipid profile in psoriasis patients.[22] To our knowledge, there was no previous report regarding the effect of IL-12/23 antagonist (ustekinumab) on lipid profile and studies on the impact of BMI and correlation to disease severity were limited.[23],[24]

In this study, a significant improvement in disease activity was found at w24 of ustekinumab treatment. Interestingly, BMI, fasting sugar, and triglyceride were significantly elevated at w24 of treatment. The elevation of BMI and triglyceride was more prominent in the PASI-75+ patients. On subsequent multiple linear regression analysis, we found that serum triglyceride elevation was correlated to male gender. Nevertheless, the lipoprotein ratios including Chol/HDL ratio, LDL/HDL ratio, and AIP, which are good predictors for cardiovascular risks, did not change significantly during treatment period.[25]

Hypertriglyceridemia is a known independent risk factor of cardiovascular disease.[26] We observed a significant correlation between fasting triglyceride and male gender but not with other variables. The baseline triglyceride level of psoriasis patients who are smokers was not higher than of nonsmoker. However, after treatment, the level of triglyceride in psoriasis patients who are nonsmokers increased more than of psoriasis patients who are smokers. Previous studies have shown that cigarette smoking is associated with increased serum triglyceride that portends a higher risk for coronary artery diseases and secondary insulin resistance.[27] Studies have shown that smoking causes changes in the expression of triglyceride-rich lipoprotein causing hypercoagulability and reduced fibrinolysis.[27],[28] Conversely, an increased prevalence of smoking in psoriasis patients and an increased incidence of psoriasis among smokers have been reported, resulting in a vicious cycle.[29] Interestingly, a similar effect has not been observed in psoriasis patients who are nonsmokers. One possible explanation is that other contributing factors of triglyceridemia may exceed the effect of smoking. In this study, we have found that male psoriasis patients are more prone to triglyceride elevation. Studies have shown that only men but not women with hypertriglyceridemia are significantly associated with arterial stiffness that determines coronary artery disease; hence, we should closely monitor and treat these patients to prevent this notorious sequela.[30]

Although yet fully understood, the relationship of pro-inflammatory cytokines in psoriasis and metabolic parameters has been studied.[31],[32] In psoriasis skin, IL-12 and IL-23 induce the differentiation of naive CD4+ T-cells into highly pathogenic helper T-cells Th1 and Th17, respectively.[33],[34] These helper T-cells produce inflammatory cytokines such as tumor TNF-α, IL-17, IL-6, and IL-22.[34],[35] These pro-inflammatory cytokines that are heavily involved in the pathogenesis of psoriasis also play an important role in metabolic regulations. For instance, TNF-α is involved in insulin regulation and lipid metabolism and is overexpressed in obese patients.[35],[36] Furthermore, low levels of IL-10 in psoriasis patients were linked to metabolic syndrome, weight gain, and insulin resistance.[37],[38] One would expect an antagonist to these pro-inflammatory cytokines to have an opposite effect, however, studies have reported increased levels of triglycerides in mice treated with anti-TNF-α.[39],[40] Significant weight gain and increased BMI were also reported after anti-TNF-alpha treatment.[41] Furthermore, IL-17 deficiency increases diet-induced obesity and accelerates fatty tissue accumulation.[42] While the effects of IL-12/23 blockade on these metabolic parameters are largely unknown in psoriasis patients, Phase 2 study of ustekinumab has shown a paradoxically increased serum levels IL-12 up to 13-fold in the first 12 weeks of treatment with a gradual decrease to above baseline levels at week 32.[15],[42] IL-12 is a pro-atherogenic cytokine that induces the production of serum triglyceride and Chol and causes higher insulin resistance.[43],[44],[45],[46],[47] As opposed to our traditional understanding, this phenomenon suggests that anti-cytokine antibodies might produce agonists, rather than antagonist effect, especially in the induction period, which may explain findings of increased triglyceride level in this study.[46],[47] There are several limitations in this study. First, the study was a retrospective analysis of consecutive psoriasis patients under ustekinumab treatment. The results can only determine the association but not causation effect between metabolic parameters and the use of ustekinumab. Secondly, there is a possibility that other confounding factors such as diet and exercise habit that may affect the results.


  Conclusion Top


This study illustrates the effect of IL-12/23 blockade by ustekinumab on metabolic parameters in patients with psoriasis. The present study denotes that despite clinical improvement after ustekinumab treatment, the coronary artery risk factors of BMI and triglyceride level can still increase. Furthermore, male patients are the only predicting factors to the elevation of triglyceride. These findings suggest that when treating patients with ustekinumab, physicians should still regularly follow-up patients' metabolic profiles. Moreover, these patients should be strongly counseled to control obesity to minimize cardiovascular risks associated with psoriasis during the treatment period.

Financial support and sponsorship

This study was supported by CMRPG 1F0061, 1F0062, MOST 104-2314-B-182A-082.

Conflicts of interest

Yu-Huei Huang has conducted clinical trials or received honoraria as a consultant for Abbvie, Celgene, Janssen-Cilag Pharmaceuticals, Novartis, Pfizer Pharmaceuticals. All other authors have no conflict of interest.



 
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