Exploration of circulating metabolic signature of erythrodermic psoriasis based on LC-MS metabolomics.

Erythrodermic psoriasis (EP) is a rare and life-threatening disease, the pathogenesis of which remains to be largely unknown. Metabolomics analysis can provide global information on disease pathophysiology, candidate biomarkers, and potential intervention strategies. To gain a better understanding of the mechanisms of EP and explore the serum metabolic signature of EP, we conducted an untargeted metabolomics analysis from 20 EP patients and 20 healthy controls. Furthermore, targeted metabolomics for focused metabolites were identified in the serum samples of 30 EP patients and 30 psoriasis vulgaris (PsV) patients. In the untargeted analysis, a total of 2992 molecular features were extracted from each sample, and the peak intensity of each feature was obtained. Principal component analysis (PCA), orthogonal partial least squares-discriminant analysis (OPLS-DA) revealed significant difference between groups. After screening, 98 metabolites were found to be significantly dysregulated in EP, including 67 down-regulated and 31 up-regulated. EP patients had lower levels of L-tryptophan, L-isoleucine, retinol, lysophosphatidylcholine (LPC), and higher levels of betaine and uric acid. KEGG analysis showed differential metabolites were enriched in amino acid metabolism and glycerophospholipid metabolism. The targeted metabolomics showed lower L-tryptophan in EP than PsV with significant difference and L-tryptophan levels were negatively correlated with the PASI scores. The serum metabolic signature of EP was discovered. Amino acid and glycerophospholipid metabolism were dysregulated in EP. The metabolite differences provide clues for pathogenesis of EP and they may provide insights for therapeutic interventions.

Evaluation of the inflammatory parameters as potential biomarkers of systemic inflammation extent and the disease severity in psoriasis patients.

The disease severity of psoriasis is mainly assessed subjectively via  psoriasis area and severity index (PASI) and body surface area (BSA), while an optimal measure of cutaneous response, may overlook systemic inflammation in psoriasis patients. The neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), monocyte to high density lipoprotein ratio (MHR), and systemic immune-inflammation index (SII) exhibit notable associations with the inflammation severity in multiple diseases. The aim of this retrospective study was to explore the associations between inflammatory parameters and the skin lesions' severity of psoriasis. After analysis, we found that patients with psoriasis had higher NLR, MLR, PLR, MHR, and SII levels compared to the control group. At baseline, the parameters of NLR (r = 0.124, P = 0.003), MLR (r = 0.153, P < 0.001), MHR (r = 0.217, P < 0.001) and SII (r = 0.141, P = 0.001) had a positive correlation with PASI in psoriasis patients. At the same time, we analyzed the patients who received different systemic therapy. We observed a significant decrease in NLR, PLR, MLR, and SII in psoriasis patients after treatment. Notably, TNF-α inhibitors and IL-17A inhibitors subgroups showed a more significant reduction than IL-23/IL-12/23 inhibitors and MTX medication. Additionally, we found the change of NLR (r = 0.194, P < 0.001), PLR (r = 0.104, P = 0.014), MLR (r = 0.191, P < 0.001), MHR (r = 0.106, P = 0.012), and SII (r = 0.228, P < 0.001) had a positive correlation with the change of PASI in psoriasis patients. In conclusion, this study suggests that NLR, MLR, and SII may serve as useful biomarkers for assessing systemic inflammation extent and disease severity in psoriasis patients.

Associations of novel complete blood count-derived inflammatory markers with psoriasis: a systematic review and meta-analysis.

Psoriasis is an immune-mediated disorder which primarily affects skin and has systemic inflammatory involvement. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and monocyte-to-lymphocyte ratio (MLR) are novel complete blood count (CBC)-derived markers which can reflect systemic inflammation. This study aimed to systematically investigate the associations of NLR, PLR, SII, and MLR with psoriasis. This study was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. A comprehensive search of Pubmed, Embase, Scopus, and Google Scholar was conducted for relevant studies. Observational studies evaluating the correlations of NLR, PLR, SII, or MLR with psoriasis were included. The primary outcomes were the associations of these inflammatory markers with the presence and severity of psoriasis. The random-effect model was applied for meta-analysis. 36 studies comprising 4794 psoriasis patients and 55,121 individuals in total were included in the meta-analysis. All inflammatory markers were significantly increased in psoriasis groups compared to healthy controls (NLR: MD = 0.59, 95% CI: 0.47-0.7; PLR: MD = 15.53, 95% CI: 8.48-22.58; SII: MD = 111.58, 95% CI: 61.49-161.68; MLR: MD = 0.034, 95% CI: 0.021-0.048; all p < 0.001). Between-group mean differences in NLR and PLR were positively correlated with the mean scores of Psoriasis Area Severity Index (NLR: p = 0.041; PLR: p = 0.021). NLR, PLR, SII, and MLR are associated with the presence of psoriasis. NLR and PLR serve as significant indicators of psoriasis severity. These novel CBC-derived markers constitute potential targets in the screening and monitoring of psoriasis.

Metabolomic Alterations in Methotrexate Treatment of Moderate-to-Severe Psoriasis.

BACKGROUND Aberrant lipid metabolism alterations in skin tissue, blood, or urine have been implicated in psoriasis. Here, we examined lipid metabolites related to psoriasis and their association with the age of disease onset. MATERIAL AND METHODS Differences in lipid metabolites before and after methotrexate (MTX) treatment were evaluated. The discovery cohort and validation cohort consisted of 50 and 46 patients, respectively, with moderate-to-severe psoriasis. After MTX treatment, the patients were divided into response (Psoriasis Area and Severity Index [PASI] 75 and above) and non-response (PASI below 75) groups, blood was collected for serum metabolomics, and multivariate statistical analysis was performed. RESULTS We detected 1546 lipid metabolites. The proportion of the top 3 metabolites was as follows: triglycerides (TG, 34.8%), phospholipids (PE, 14.5%), phosphatidylcholine (PC, 12.4%); diglycerides (DG) (16: 1/18: 1), and DG (18: 1/18: 1) showed strong positive correlations with onset age. There were marked changes in TG (16: 0/18: 0/20: 0), TG (18: 0/18: 0/22: 0), TG (14: 0/18: 0/22: 0), TG (14: 0/20: 0/20: 0), lysophosphatidylcholine (LPC) (16: 0/0: 0), LPC (18: 0/0: 0), LPC (14: 0/0: 0), and LPC (18: 1/0: 0) levels before and after 12 weeks of MTX treatment. The glycerophospholipid metabolic pathway was implicated in psoriasis development. Of the 96 recruited patients, 35% were MTX responders and 65% non-responders. PE (34: 4) and PE (38: 1) levels were significantly different between the groups. Obvious differences in lipid metabolism were found between early-onset (<40 years) and late-onset (≥40 years) psoriasis. Significant changes in serum lipid profile before and after MTX treatment were observed. CONCLUSIONS The specific lipid level changes in responders may serve as an index for MTX treatment efficacy evaluation.

Positive association between insulin resistance and fatty liver disease in psoriasis: evidence from a cross-sectional study.

Background: Fatty liver disease (FLD) is a common comorbidity of psoriasis and is often referred to as non-alcoholic fatty liver disease (NAFLD). However, the role of inflammation or insulin resistance (IR) in FLD is inconclusive. The study aims to explore whether FLD in psoriasis patients is more related to insulin resistance or systemic inflammation level. Methods: Data for this study were collected from the Shanghai Psoriasis Effectiveness Evaluation Cohort, a prospective cohort that examines psoriasis characteristics in the Chinese population. IR was assessed using the triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) indicators. Systemic non-specific inflammation was assessed using the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), and systemic immune inflammation index (SII). Results: The analysis included a total of 647 patients. Subsequent logistic regression analysis revealed that NLR, dNLR, and SII were not significantly associated with FLD in psoriasis patients, while TyG and TyG-BMI showed significant associations with FLD. Subgroup analysis indicated that in the majority of subgroups, TyG and TyG-BMI were significantly associated with FLD, particularly TyG-BMI. Excluding individuals with methotrexate and acitretin resulted in consistent findings with the main analysis. Further analysis revealed a significantly higher diagnosis rate of metabolic-associated fatty liver disease (MAFLD) compared to NAFLD. Conclusions: Metabolic factors play a crucial role in FLD in patients with psoriasis, and TyG and TyG-BMI are potential predictors of FLD. Therefore, MAFLD can be recommend as a term to describe FLD in psoriasis patients. Trial registration: https://www.chictr.org.cn/showproj.html?proj=58256, identifier ChiCTR2000036186. A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population. Registered 31 August 2020.

Proteomics in Psoriasis: Recent Advances.

Psoriasis continues to affect a large percentage of patients worldwide and strongly appears to be a systematic disease. Efforts are being made to understand its etiology, which have led to research extended to genomic analysis with a focus on the role of pro-inflammatory cytokines, which play a major role in the pathogenesis of the disease. Plasma proteomic analysis in various diseases has provided promising results for choosing the right treatment for psoriasis, suggesting that it could play a key role in the prevention, prognosis, and treatment of the disease by individualizing treatment choices based on the proteomic profile of each patient. In this review, we focus on existing data in the bibliography on proteomic analysis in psoriasis and relevant approaches to future targeted therapies.

TWEAK levels in psoriatic patients treated with narrowband ultraviolet B and methotrexate.

BACKGROUND: Psoriasis is an autoimmune disease which has an effect on the joints and skin. Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TWEAK) is a multi-functional cytokine which regulates the cellular processes and has been related to a variation of conditions. OBJECTIVES: To measure the level of serum TWEAK in psoriatic diseased persons and its relationship to the PASI score pre- and post-therapy with narrowband ultraviolet B phototherapy (NB-UVB) and methotrexate (MTX). METHODS: This randomized controlled trial was conducted on 40 patients and 20 healthy persons as controls. Patient Group was randomly subdivided to two groups. The 1st group consisted of 20 patients who received NB-UVB treatment. The 2nd group included 20 MTX-treated candidates. Blood samples were drawn from patients in order to detect serum TWEAK levels using ELISA. The research was registered on Clinical Trials Registration: RCT approval numbers: NCT0481191. RESULTS: The mean PASI score percent improvement after 12 weeks of treatment was higher in the MTX group (90%) than NB-UVB group (60%). The serum TWEAK level at baseline was 60.47 ± 12.6 pg/mL in NB-UVB group and 54.69 ± 21.7 pg/mL in MTX group which reduced to 24.93 ± 17.6 pg/mL and 32.13 ± 23.6 pg/mL, respectively (p < 0.001), after 12 weeks of treatment. There was a positive correlation between the serum levels of TWEAK and severity of PASI score (r = 0.399, p = 0.014). CONCLUSION: TWEAK grades in psoriasis are substantially higher than in controls. TWEAK levels were dramatically reduced during NB-UVB and MTX treatment. TWEAK may have a potential sign for psoriasis diagnosis and prognosis.

DiGeorge syndrome presenting with palmoplantar pustules: Comparative analysis of serum IL-22, NETs and IL-8 with usual palmoplantar pustulosis.

DiGeorge syndrome, also known as 22q11.2 deletion syndrome, shows cellular immunodeficiency due to by thymic hypoplasia and hypocalcemia caused by hypoparathyroidism. It was reported that erythrodermic psoriasis occurred in a patient with 22q11 deletion syndrome. Here, we report the first case of DiGeorge syndrome presenting with a severe palmoplantar pustulosis (PPP)-like eruption with extra-palmoplantar lesions on the distal limbs. Given that PPP is a subtype of pustular psoriasis, the pustular eruption may be associated with DiGeorge syndrome. We measured serum levels of citrullinated histone H3 (CitH3), a representative marker of neutrophil extracellular traps, interleukin (IL)-8, and IL-22 and compared them with nine cases of typical PPP. In the PPP patients, the three markers were higher than in healthy subjects with significant correlations between CitH3 and IL-8/IL-22. In our patient, CitH3, IL-8, and IL-22 were also high, and IL-22 was remarkably elevated compared with the PPP patients. Our case suggests that a certain T cell abnormality associated with DiGeorge syndrome induces IL-22 overproduction, leading to the PPP-like eruption with extra- palmoplantar lesions.

Longitudinal change in CDC42 in psoriasis: correlation with disease activity and treatment response.

Objective: To investigate longitudinal CDC42 change and its correlation with disease activity and treatment response in patients with psoriasis. Methods: This prospective study detected serum CDC42 at months (M) 0, M1, M3 and M6 in 150 patients with psoriasis with current initiation of topical therapy/phototherapy/systemic therapy. Results: CDC42 was positively related to systemic biologic treatment history (p = 0.025) but negatively associated with psoriatic area (p = 0.010) and Psoriasis Area Severity Index (PASI; p < 0.001). CDC42 continuously elevated from M0 to M6 (p < 0.001). CDC42 at M1/M3/M6 was enhanced in patients with current systemic biologic therapy and PASI 75 or 90 response at M6 versus those without (all p < 0.050). Conclusion: Increased serum CDC42 level reflects reduced disease severity and better treatment response in patients with psoriasis.

CDC42 is a protein that plays a role in inflammation and immune regulation in autoimmune diseases. CDC42 levels were detected in 150 patients with psoriasis at different time points and 150 healthy people at enrollment. The results showed that patients with psoriasis had lower CDC42 levels versus healthy people. Patients with psoriasis who received previous biologic treatments and those with smaller affected skin areas had higher CDC42 levels. Over time, CDC42 levels increased in patients with psoriasis. Patients who started biologic treatments (versus those who did not) and patients who responded better to treatment had higher CDC42 levels. The increase in CDC42 levels reflects better treatment outcomes in patients with psoriasis.

An optical system for noninvasive microscopy of psoriatic mice in vivo.

Psoriasis is a chronic inflammatory skin disease involved with both complex morphological changes of skin and immune processes. The clinical diagnostics and research of psoriasis often require invasive biopsy which lacks their real-time dynamics in vivo. Here we report a noninvasive microscopic system developed by combining in vivo fluorescent microscopy, optical clearing, and immunolabeling to enable real-time imaging of immune cells and cytokines in blood flow in psoriatic animal models. The vascular morphology and time-lapse kinetics of interleukin (IL)-23, IL-17, tumor necrosis factor-α, and CD4+ cells in blood are captured at submicron resolution through the thickening epidermis and opaque scales during the development of psoriasis in vivo. Our data suggest IL-23 recruits CD4+ cells to release IL-17 in blood that further leaks out in the psoriatic skin area. This optical system enables noninvasive and real-time assessment of immune molecules and cells in vivo, providing good potential for medical researches on psoriasis.

Concentrations of N6-Carboxymethyllysine (CML), N6-Carboxyethyllysine (CEL), and Soluble Receptor for Advanced Glycation End-Products (sRAGE) Are Increased in Psoriatic Patients.

Psoriasis is a chronic, recurrent, and often severe skin disease which is frequently associated with metabolic disorders and increased risk of cardiovascular complications. One of the postulated links is an intensified process of advanced protein glycation and/or glycoxidation. Therefore, the aim of the study was to assess concentrations of N6-carboxymethyllysine (CML), N6-carboxyethyllysine (CEL), and soluble form of receptor for advanced glycation end-products (sRAGE) in psoriasis patients at different phases of the disease activity, in comparison to healthy individuals. The study material consisted of sera from psoriasis patients in active phase, in the remission phase, and healthy controls. Concentrations of CML, CEL, and sRAGE were determined using ELISA technique. In the patients with psoriasis (in both phases of the disease), concentrations of CML, CEL and sRAGE were significantly higher than in healthy individuals but they did not correlate with psoriasis area severity index (PASI) values. The remission of the disease was followed by a significant decrease in CML, CEL, and sRAGE concentrations when compared to active patients; however, these concentrations were still significantly higher than in the controls. Our data suggest that psoriasis is accompanied by an intense glycoxidation process and that high sRAGE levels seem to reflect permanent RAGE overstimulation.

Dual specificity phosphatase 22 relates to skin lesion degree and biologics history, while its longitudinal elevation during treatment reflects better outcome in psoriasis patients.

BACKGROUND: Dual specificity phosphatase 22 (DUSP22) plays an important role in the regulation of immune and inflammation, but its correlation with clinical features and treatment outcome in psoriasis patients is still unclear. This study was to investigate the longitudinal change of DUSP22 with time, as well as its association with disease activity and treatment response in psoriasis patients. METHODS: Totally, 120 psoriasis patients, 50 patients with other skin inflammations as disease controls (DCs), and 50 health controls (HCs) were recruited. Serum samples were collected from psoriasis patients at baseline, month (M)1, M3, and M6 after initiation of etanercept-based treatment as well as from DCs and HCs after enrollment to assess DUSP22 level by enzyme-linked immunosorbent assay. RESULTS: DUSP22 was lower in psoriasis patients than in HCs and DCs (both p < 0.001). Besides, in psoriasis patients, DUSP22 was associated with lower psoriasis area severity index (PASI) score (p = 0.001) and systemic biological treatment history (p = 0.023), but not with other demographics, disease characteristics, or treatment history (all p>0.05). In addition, DUSP22 was increased with time (p < 0.001) in total patients. Moreover, DUSP22 at M3 (p = 0.004) and M6 (p < 0.001) was higher in response patients than in non-response patients evaluated by PASI 75. Additionally, DUSP22 at M3 (p < 0.001) and M6 (p = 0.003) was also increased in response patients compared with non-response patients evaluated by PASI 90. CONCLUSION: DUSP22 decreases and negatively correlates with disease activity, while its longitudinal elevation with time reflects satisfactory treatment response in psoriasis patients.

Serum tryptase levels in patients with psoriasis: a pilot study for a possible useful biomarker.

In psoriasis, biomarkers for disease prognosis and response to treatment may help clinicians to improve patient management. Hence, we decided to evaluate the role of serum tryptase (ST) in a sample of patients with psoriasis. We found higher levels of ST in patients with scalp psoriasis than in those without (6.1 vs. 4.6 ng/mL), in those with palmoplantar psoriasis than in those without (5.3 vs. 5 ng/mL) and, with less significance, in those with psoriatic arthritis than in those without (6.1 vs. 5.1 ng/mL).

Platelet-associated parameters in patients with psoriasis: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: The relationship between platelet-associated parameters and psoriasis has been controversial. The purpose of our meta-analysis was to assess whether platelet count, platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), and platelet distribution width (PDW) are associated with psoriasis. METHODS: We performed a thorough documentation retrieval via PubMed, EMBASE, and Web of Science until June 2021. Pooled standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated using a random-effects model. RESULTS: Overall, 22 studies involving 1749 patients with psoriasis and 1538 healthy controls were selected for the meta-analysis. The outcomes showed that platelet count presented non-significant differences between psoriatic patients and normal individuals (SMD = 0.12, 95% CI =  -0.07 to 0.32, P = .210), while PLR (SMD = 0.28, 95% CI = 0.03-0.53, P = .031), MPV (SMD = 0.55, 95% CI = 0.30-0.79, P < .001), and PDW (SMD = 0.29, 95% CI = 0.03-0.55, P = .027) were remarkably greater in the psoriatic patients than in the healthy individuals, and similar results were found in subgroup analyses. The analytical results of susceptibility revealed that the outcomes were robust, and no evidence of substantial publication bias was identified. CONCLUSION: Patients with psoriasis present significantly higher PLR, MPV, and PDW than healthy individuals, suggesting that psoriasis is accompanied by low-grade systemic inflammation and platelet activation.

The Effect of Three-Month Vitamin D Supplementation on the Levels of Homocysteine Metabolism Markers and Inflammatory Cytokines in Sera of Psoriatic Patients.

Psoriasis is an autoimmune and inflammatory skin disease. Psoriatic patients express higher levels of plasma homocysteine (Hcy) concentration and pro-inflammatory mediators than healthy people; this is frequently associated with vitamin D deficiency. The aim of this clinical study was to investigate the effects of high doses of vitamin D supplementation on the parameters of Hcy metabolism and cytokines in sera of psoriatic patients. This prospective study was conducted on 40 psoriatic patients who had the vitamin D deficiency. All patients received vitamin D 5000 IU/day for three months. Clinical and biochemical measurements were taken at baseline and at follow up (3 months). The results showed that the severity of clinical features, measured by the psoriasis area severity index (PASI) score, were considerably improved in patients after vitamin D supplementation. After vitamin D supplementation, most of the patients (n = 25 or 62.5%) had mild clinical form (p < 0.001). After twelve weeks of intervention period, there were significant increases in vitamin D and B12 serum levels in comparison to the levels that had been measured at the beginning of the study (56.77 ± 14.66 nmol/L and 301.08 ± 95.02 pg/mL vs. 103.85 ± 32.20 nmol/L and 362.81 ± 118.56 pg/mL, respectively; p < 0.001). Moreover, serum levels of Hcy and folate were significantly lower at the end of the study in comparison with the initial levels (12.45 ± 1.92 µmol/L and 8.01 ± 3.88 mg/mL vs. 10.38 ± 1.66 µmol/L and 6.27 ± 2.60 mg/mL, respectively). High doses of vitamin D supplementation led to a significant decrease in pro-inflammatory cytokines (IFN-ɤ, TNF-α, IL-1ß, IL-6, IL-8, and IL-17) and high-sensitivity C-reactive protein (hsCRP), whereas the production of anti-inflammatory cytokines (IL-10, IL-5) was up-regulated. In conclusion, supplementation with high doses of vitamin D could be one of the possible preventive and therapeutic measures to reduce systemic inflammation in psoriatic patients.