Abstract
Background:
Ustekinumab, as a monoclonal antibody against interleukin (IL)-12 and IL-23, gets approved in China since 2019, therefore fewstudies report the application of ustekinumab in treating Chinese psoriasis patients in the real clinical settings until now.
Aims:
Thus, this study aimed to evaluate treatment efficacy, treatment response–related factors, and safety of ustekinumab in treating Chinese psoriasis patients.
Materials and Methods:
Totally, 72 moderate-to-severe plaque psoriasis patients who underwent ustekinumab treatment were analyzed. Their clinical data were recorded. Furthermore, improvement of psoriasis area severity index (PASI) score more than 75% (PASI75) and improvement of PASI score more than 90% (PASI90) at week 12 and week 24 were retrieved. Besides, the adverse events were reviewed.
Results:
There were 72.2% and 37.5% psoriasis patients who achieved PASI75 response and PASI90 response at week 12. Meanwhile, 86.7% and 46.7% psoriasis patients realized PASI75 response and PASI90 response at week 24. Besides, multivariant logistic regression analyses revealed that body mass index (BMI), disease duration, and history of tumor necrosis factor (TNF) inhibitors could independently predict reduced ustekinumab response in psoriasis patients. Additionally, the most common adverse events of ustekinumab treatment in psoriasis patients were infection (12.5%) and nasopharyngitis (9.7%), followed by headache (4.2%), cough (4.2%), abnormal hepatic function (4.2%), injection site reactions (2.8%), and eosinophilia (1.4%), which were all mild and manageable.
Conclusions:
Ustekinumab is an effective and safe immunotherapy drug for treating Chinese psoriasis patients. Furthermore, BMI, disease duration, and history of TNF inhibitors are predictors of poor ustekinumab response.
KEY WORDS: PASI75, PASI90, psoriasis, safety, ustekinumab
Introduction
Psoriasis is a chronic, inflammatory skin disease characterized by skin barrier disruption and immune dysfunction.[1] Notably, most psoriasis patients experience multiple recurrence and psychological issues that impact their daily life and long-term mental health.[1,2,3] Regarding disease management, topical therapy (such as Vitamin D analogues and corticosteroids) is usually applied in mild psoriasis patients, then systemic therapy (including biologics and nonbiological therapy), and phototherapy are recommended to treat moderate-to-severe psoriasis patients.[2,3] Although systematic biologic therapy displays promising efficacy to treat moderate-to-severe psoriasis patients (such as tumor necrosis factor (TNF) inhibitor), parts of them may experience low response and adverse events, which decreases their long-term outcomes and quality of life.[4] Therefore, discovering novel therapy options for psoriasis patients is needed.
Ustekinumab, as a monoclonal antibody against p40 subunits of IL-12 and IL-23, has been approved by the US Food and Drug Administration (FDA) to treat adult moderate-to-severe psoriasis patients since 2009.[5] Ustekinumab exhibits a higher response rate compared to TNF-inhibitors (such as etanercept) in psoriasis patients based on European populations.[6] Besides, ustekinumab displays a prolonged response duration for psoriasis patients up to 76 weeks based on the American population.[7] Regarding the safety issues, ustekinumab induces less unadjusted serious infection rates compared to other types of biologics in psoriasis patients based on Canada and American populations.[8] As in China, ustekinumab gets approved since 2019, thus little studies report the application of ustekinumab in treating Chinese psoriasis patients until now. Only one phase III, double-blinded, placebo-controlled clinical trial (LOTUS) reports that ustekinumab increases clinical response and quality of life, whereas it induces similar adverse events compared to placebo in Chinese moderate-to-serve psoriasis patients.[9] However, no real-world study has been conducted. Therefore, we performed this study and aimed to explore the treatment efficacy, treatment response–related factors, and safety of ustekinumab in Chinese psoriasis patients.
Materials and Methods
Participants
Between November 2018 and March 2020, 72 moderate-to-severe plaque psoriasis patients who underwent ustekinumab treatment in our hospital were analyzed in this retrospective study. The inclusion criteria were as follows: Patients with (1) diagnosis as plaque psoriasis; (2) psoriatic body-surface area (BSA) >10%; (3) Psoriasis Area Severity Index (PASI) score ≥ 12; (4) who underwent ustekinumab treatment; (5) had efficacy assessment data at week 12, at least. Exclusion criteria were as follows: Patients (1) companied with other serious skin diseases; (2) had a history of infectious disease or malignancy; (3) previously treated by interleukin (IL)-12/23 inhibitor or IL-17 inhibitor. All participants signed the informed consent. This study has been approved by the ethics committee of Renmin Hospital, Hubei University of Medicine on 2020/09/01.
Collection of data
Characteristics of plaque psoriasis patients were collected from electronic medical records, including age, gender, body mass index (BMI), disease duration, psoriatic BSA, PASI score, history of topical therapy, phototherapy, systemic nonbiologic treatment, and tumor necrosis factor (TNF) inhibitor, as well as combined therapy (topical therapy and phototherapy). Moreover, treatment efficacy data at week 12 and week 24, and adverse events were also collected.
Treatment
The patients received 45 mg ustekinumab by subcutaneous injection at week 0 and week 4, then 45 mg ustekinumab was administered by subcutaneous injection every 12 weeks.
Evaluation of efficacy
Efficacy evaluation included PASI75 and PASI90, which were based on PASI score (ranging from 0 (no psoriasis) to 72 (severe psoriasis)[10]). PASI75 was defined as the improvement of PASI score more than 75% from the initiation of ustekinumab treatment; PASI90 was defined as the improvement of PASI score more than 90% from the initiation of ustekinumab treatment.[11]
Statistical analysis
Statistical analysis was performed using the SPSS 22.0 program (IBM, Chicago, Illinois, USA). Graphs were made using the GraphPad Prism 7.01 software (GraphPad Software Inc., San Diego, California, USA). The continuous normally distributed data were expressed as mean ± standard deviation (SD). The continuous non-normal data were expressed as median and interquartile range (IQR). The categorical data were expressed as count and percentage. Characteristics, treatment efficacy, and adverse events of plaque psoriasis patients were analyzed by descriptive statistics. Factors affecting PASI75 and PASI90 response were analyzed by univariate and forward stepwise multivariate logistic regression. P value <0.05 was considered statistically significant.
Results
The mean age of recruited psoriasis patients was 51.6 ± 11.4 years, and there were 43 (59.7%) males and 29 (40.3%) females [Table 1]. Besides, the mean psoriatic BSA and mean PASI scores were 18.5 (15.3–23.8)% and 18.6 ± 5.7, respectively. Furthermore, the information regarding the history of treatment in recruited psoriasis patients is listed in Table 1.
Table 1.
Characteristics of psoriasis patients
| Items | Psoriasis patients (n=72) |
|---|---|
| Age (years), mean±SD | 51.6±11.4 |
| Gender, No. (%) | |
| Male | 43 (59.7) |
| Female | 29 (40.3) |
| BMI (kg/m2), mean±SD | 23.7±2.9 |
| Disease duration (years), median (IQR) | 8.5 (2.0-13.0) |
| Psoriatic BSA (%), median (IQR) | 18.5 (15.3-23.8) |
| PASI score, mean±SD | 18.6±5.7 |
| History of topical therapy, No. (%) | 65 (90.3) |
| History of phototherapy, No. (%) | 61 (84.7) |
| History of systemic nonbiologic treatment, No. (%) | 52 (72.2) |
| History of TNF inhibitor, No. (%) | 15 (20.8) |
| Combined topical therapy, No. (%) | 55 (76.4) |
| Combined phototherapy, No. (%) | 30 (41.7) |
SD, standard deviation; BMI, body mass index; IQR, interquartile range; BSA, body surface area; PASI, Psoriasis Area and Severity Index; TNF, tumor necrosis factor.
The efficacy of ustekinumab in psoriasis patients was determined by PASI75 and PASI90. There were 72 psoriasis patients assessed at week 12, among which 52 (72.2%) patients achieved PASI75 response and 27 (37.5%) patients achieved PASI90 response. [Figure 1a]. Whereas 60 psoriasis patients were assessed at week 24, among which 52 (86.7%) of them realized PASI75 response and 28 (46.7%) psoriasis patients realized PASI90 response [Figure 1b].
Figure 1.
The treatment response of ustekinumab in psoriasis patients. The treatment response at week 12 (a) and at week 24 (b) in psoriasis patients. PASI: Psoriasis Area Severity Index, PASI75: improvement of PASI score more than 75%, PASI90: improvement of PASI score more than 90%
In order to determine the factors related to PASI75 response to ustekinumab in psoriasis patients, multivariant logistic regression analyses were performed. It showed that BMI was independently correlated with reduced PASI75 response to ustekinumab treatment at week 12 (P = 0.017, OR: 0.793, (95% CI: 0.657–0.959)) [Table 2]. Meanwhile, BMI could be an independent predictive factor for declined PASI75 response to ustekinumab treatment at week 24 (P = 0.014, OR: 0.712, (95% CI: 0.543–0.934)).
Table 2.
Factors affecting PASI75 response by logistic regression model analysis
| Parameters | PASI75 response at week 12 | PASI75 response at week 24 | ||||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||
| P | OR | 95% CI | P | OR | 95% CI | |||
|
|
|
|||||||
| Lower | Higher | Lower | Higher | |||||
| Univariate logistic regression | ||||||||
| Age (years) | 0.154 | 0.966 | 0.921 | 1.013 | 0.817 | 0.993 | 0.931 | 1.058 |
| Gender (male vs. female) | 0.572 | 0.734 | 0.252 | 2.143 | 0.648 | 0.700 | 0.151 | 3.238 |
| BMI (kg/m2) | 0.017 | 0.793 | 0.657 | 0.959 | 0.014 | 0.712 | 0.543 | 0.934 |
| Disease duration (years) | 0.125 | 0.934 | 0.856 | 1.019 | 0.050 | 0.861 | 0.742 | 1.000 |
| Psoriatic BSA (%) | 0.371 | 1.040 | 0.955 | 1.132 | 0.836 | 0.050 | 0.861 | 0.742 |
| PASI score | 0.611 | 1.025 | 0.933 | 1.126 | 0.640 | 0.970 | 0.852 | 1.103 |
| History of topical therapy | 0.415 | 0.404 | 0.045 | 3.582 | 0.999 | 0.000 | 0.000 | - |
| History of phototherapy | 0.968 | 0.971 | 0.230 | 4.097 | 0.832 | 0.786 | 0.085 | 7.282 |
| History of systemic nonbiologic treatment | 0.744 | 0.822 | 0.254 | 2.667 | 0.822 | 0.822 | 0.149 | 4.542 |
| History of TNF inhibitor | 0.073 | 0.338 | 0.103 | 1.108 | 0.148 | 0.303 | 0.060 | 1.527 |
| Combined topical therapy | 0.431 | 1.597 | 0.498 | 5.122 | 0.705 | 1.400 | 0.245 | 7.997 |
| Combined phototherapy | 0.081 | 2.778 | 0.880 | 8.764 | 0.236 | 2.778 | 0.512 | 15.058 |
| Forward stepwise multivariate logistic regression | ||||||||
| BMI (kg/m2) | 0.017 | 0.793 | 0.657 | 0.959 | 0.014 | 0.712 | 0.543 | 0.934 |
PASI, Psoriasis Area and Severity Index; CI, confidence interval; OR, odd ratio; BMI, body mass index; BSA, body surface area; TNF, tumor necrosis factor.
Additionally, multivariant logistic regression analysis showed that disease duration (P = 0.015, OR: 0.882, (95% CI: 0.798–0.976)) and history of TNF inhibitors (P = 0.036, OR: 0.167, (95% CI: 0.031–0.891)) could independently predict declined PASI90 response to ustekinumab treatment at week 12 in psoriasis patients [Table 3]. Furthermore, multivariant logistic regression analysis implied that disease duration (P = 0.026, OR: 0.892, (95% CI: 0.806–0.986)) could independently predict declined PASI90 response to ustekinumab treatment at week 24 in psoriasis patients.
Table 3.
Factors affecting PASI90 response by logistic regression model analysis
| Parameters | PASI90 response at week 12 | PASI90 response at week 24 | ||||||
|---|---|---|---|---|---|---|---|---|
|
|
|
|||||||
| P | OR | 95% CI | P | OR | 95% CI | |||
|
|
|
|||||||
| Lower | Higher | Lower | Higher | |||||
| Univariate logistic regression | ||||||||
| Age (years) | 0.596 | 0.989 | 0.948 | 1.031 | 0.765 | 0.993 | 0.951 | 1.037 |
| Gender (male vs. female) | 0.577 | 0.759 | 0.288 | 2.000 | 0.835 | 0.897 | 0.324 | 2.488 |
| BMI (kg/m2) | 0.040 | 0.824 | 0.685 | 0.991 | 0.207 | 0.892 | 0.747 | 1.065 |
| Disease duration (years) | 0.022 | 0.903 | 0.827 | 0.985 | 0.026 | 0.892 | 0.806 | 0.986 |
| Psoriatic BSA (%) | 0.511 | 1.025 | 0.953 | 1.102 | 0.496 | 1.028 | 0.950 | 1.112 |
| PASI score | 0.398 | 0.963 | 0.882 | 1.051 | 0.616 | 0.977 | 0.892 | 1.070 |
| History of topical therapy | 0.610 | 1.562 | 0.281 | 8.676 | 0.386 | 2.793 | 0.274 | 28.509 |
| History of phototherapy | 0.212 | 0.438 | 0.119 | 1.604 | 0.203 | 0.379 | 0.085 | 1.687 |
| History of systemic nonbiologic treatment | 0.786 | 0.864 | 0.300 | 2.487 | 0.969 | 0.978 | 0.318 | 3.014 |
| History of TNF inhibitor | 0.044 | 0.197 | 0.041 | 0.954 | 0.051 | 0.197 | 0.038 | 1.005 |
| Combined topical therapy | 0.830 | 1.132 | 0.364 | 3.519 | 0.306 | 2.000 | 0.531 | 7.539 |
| Combined phototherapy | 0.177 | 1.952 | 0.739 | 5.153 | 0.080 | 2.545 | 0.895 | 7.239 |
| Forward stepwise multivariate logistic regression | ||||||||
| Disease duration (years) | 0.015 | 0.882 | 0.798 | 0.976 | 0.026 | 0.892 | 0.806 | 0.986 |
| History of TNF inhibitor | 0.036 | 0.167 | 0.031 | 0.891 | - | - | - | - |
PASI, Psoriasis Area and Severity Index; CI, confidence interval; OR, odd ratio; BMI, body mass index; BSA, body surface area; TNF, tumor necrosis factor.
In order to explore the safety profile of ustekinumab in psoriasis patients, adverse events were recorded. The most commonly found adverse events of ustekinumab treatment in psoriasis patients were infection (12.5%) and nasopharyngitis (9.7%) [Table 4]. Besides, 3 (4.2%), 3 (4.2%), 3 (4.2%), 2 (2.8%), and 1 (1.4%) psoriasis patients experienced headache, cough, abnormal hepatic function, injection site reactions, and eosinophilia, respectively. Notably, all these mentioned adverse events were mild and manageable.
Table 4.
Adverse events
| Parameters | Psoriasis patients (n=72) |
|---|---|
| Infection, No. (%) | 9 (12.5) |
| Nasopharyngitis, No. (%) | 7 (9.7) |
| Headache, No. (%) | 3 (4.2) |
| Cough, No. (%) | 3 (4.2) |
| Abnormal hepatic function, No. (%) | 3 (4.2) |
| Injection site reactions, No. (%) | 2 (2.8) |
| Eosinophilia, No. (%) | 1 (1.4) |
Discussion
Ustekinumab, as an immunotherapy drug approved by FDA to treat moderate-to-severe psoriasis, shows improvement of treatment response in psoriasis patients. For example, one phase II randomized controlled trial carried by Papp et al. (2017) discovered that around 40% of the psoriasis patients realize PAPSI90 response to ustekinumab treatment at week 12 based on Canadian and European populations.[12] Moreover, two phase III, multi-center, randomized, double-blinded, placebo-controlled clinical trials (PHOENIX 1) display that the percentages of psoriasis patients who achieve PASI75 response to ustekinumab treatment at week 12 were 67.1% (PHOENIX 1) and 66.7% (PHOENIX 2) based on the American population.[7,13] As ustekinumab gets approved in China from 2019, thus few studies report the application of ustekinumab for treating Chinese psoriasis patients, especially in real clinical settings. Therefore, we perform this study and discover that ustekinumab displays promising efficacy in treating Chinese psoriasis patients. The possible reasons to explain these are: (a) ustekinumab suppresses the p40 subunits of IL-12/23, which further leads to inhibition of Th1/17 cell differentiation, and reduction of immune reaction, thus results in good ustekinumab response in psoriasis patients.[5] (b) ustekinumab inhibits IL-12 expression, thus leads to a decreased chance of B-cell apoptosis and elevated antibody secretion, which results in good ustekinumab response in psoriasis patients as well.[14] Taken together, ustekinumab displays its satisfied efficacy in Chinese psoriasis patients.
In addition, we further performed the multivariate logistic regression analysis to explore the factors related to ustekinumab response in psoriasis patients, and we found that BMI, disease duration, and history of TNF inhibitors are independently correlated with lower ustekinumab response in psoriasis patients. The possible reasons to explain these are as follows: (a) As for BMI, higher BMI suggests a reduced circulatory adiponectin level (a cytokine secreted from adipocytes) in these patients, which further reduces the expression of anti-inflammatory cytokines through its receptor AdipoR1 and AdipoR2 signaling cascade and eventually leads to dysregulation of immune response and reduced ustekinumab response in psoriasis patients.[15,16] Also, ustekinumab therapy displays a dose-dependent manner, which means that psoriasis patients with higher BMI may need a higher dose of ustekinumab to achieve response, thus the same dose causes reduced ustekinumab response in psoriasis patients with higher BMI. (b) Regarding disease duration, a longer disease duration suggests reactive oxygen species activation and an increased chance of inflammation, which further results in declined ustekinumab response in psoriasis patients.[17] (c) As for the history of TNF inhibitors is concerned, the usage of TNF inhibitors before ustekinumab treatment increases the risk of developing resistance, thus leads to a decreased response rate in psoriasis patients. Taken together, all these mentioned factors (including BMI, disease duration, and history of TNF inhibitors) may serve as predictive factors for declined ustekinumab response in psoriasis patients.
The safety of ustekinumab therapy is also an important issue. The data from 2014 psoriasis longitudinal assessment and registry (PSOLAR) illustrate that ustekinumab shows a reduction in serious infection rates than other types of biologics (such as TNF-inhibitors) in psoriasis patients based on the Canada and American populations.[8] Besides, a meta-analysis study discovered that there is no difference in serious adverse events occurrence among ustekinumab, other biologics, and placebo in treating active psoriatic arthritis patients, indicating that ustekinumab is a relative safe immunotherapy drug.[18] In our study, we discover that infection and nasopharyngitis are the most common adverse events of ustekinumab treatment in Chinese psoriasis patients; however, they are mild and manageable. The reason to explain this is described as follows: ustekinumab, as a targeted immunotherapy drug, inhibits immune cell proliferation and further suppresses their function, thus leads to immunosuppressed state and those mentioned adverse events (such as infection and nasopharyngitis) in psoriasis patients. Taken together, ustekinumab therapy induces low adverse events in psoriasis patients, indicating its well-tolerant property.
Limitations of the study
Firstly, the sample size in our study is relatively small, which may reduce the statistical power, thus further studies with a larger sample size are needed. Moreover, the follow-up period in our study was relatively short, thus further studies with a longer follow-up period to explore the ustekinumab long-term efficacy in Chinese psoriasis patients are also warranted. Furthermore, as a single-arm retrospective study, we do not set up the controlgroup in our study, thus further prospective, parallel, controlled studies are necessary.
Conclusion
Ustekinumab is effective and safe for treating Chinese psoriasis patients. Furthermore, BMI, disease duration, and history of TNF inhibitors are predictors of poor ustekinumab response.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This study was supported by Guidance Project of Health Commission of Hubei Province (No. WJ2019F048).
Conflicts of interest
There are no conflicts of interest.
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