Plasma metabolomic profiling reveals a novel circulating biomarker signature in chronic pruritus of unknown origin.

Chronic pruritus of unknown origin (CPUO) is characterized by chronic itch for 6 weeks or greater without an identifiable primary cause. Studies are needed to investigate circulating blood biomarkers to elucidate disease pathogenesis. The objective of this study was to investigate changes in circulating blood metabolites in CPUO patients and to identify potential therapeutic targets. Our cross-sectional study collected plasma from 11 CPUO patients and 11 matched control patients for mass-spectrometry based metabolite data analysis. 15 metabolites differed significantly in the blood of CPUO patients compared to controls, including nine amino acids (isoleucine, L-tyrosine, threonine, DL-tryptophan, L-valine, methionine, glycine, lysine, and L-phenylalanine), four amino acid derivatives (creatinine, DL-carnitine, acetyl-L-carnitine, and indole-3-acrylic acid), and two aromatic and fatty acid derivatives (2-hydroxycinnamic acid and oleamide). These metabolites were also correlated with itch severity. Metabolic set enrichment analysis (MSEA) identified downregulation of several pathways in CPUO: phenylalanine, tyrosine, tryptophan biosynthesis; catecholamine biosynthesis; and glycine, serine, and threonine metabolism. Our study identified decreases in several circulating plasma metabolites in CPUO patients and downregulation of pathways related to catecholamine biosynthesis and tryptophan biosynthesis, providing insight into the pathogenesis of CPUO.

Serum Concentration of IL-5 Receptor (IL-5R) and Associations with Disease Severity in Patients with Chronic Spontaneous Urticaria (CSU) and Atopic Dermatitis (AD).

The immunological pathogenesis of atopic dermatitis (AD) and chronic spontaneous urticaria (CSU) has not been fully elucidated yet. The aim of our research was to assess the serum concentration of interleukin-5 receptor (IL-5R) in relation to the disease activity and pruritus intensity in adult patients with AD and CSU. This pilot study included 45 participants (15 patients with AD, 15 patients with CSU, and 15 healthy controls). Blood samples were taken to examine the serum levels of IL-5R using the enzyme-linked immunosorbent assay (ELISA) test. The Scoring Atopic Dermatitis (SCORAD) index, the Urticaria Activity Score (UAS7), and the Visual Analogue Scale (VAS) were used to assess the disease activity and the pruritus intensity, respectively. Obtained results revealed that the IL-5R concentration was significantly higher in patients with CSU than in patients with AD and in the controls (p = 0.038). There was a positive correlation between the IL-5R level and the SCORAD index in patients with AD (r = -0.9, p = 0.047), which was not found for the CSU activity by UAS7 and with the pruritus severity by VAS in both examined groups of patients. Our findings underscore higher serum levels of IL-5R among CSU and AD patients, which may highlight its functional role in the pathogenesis of these diseases. In contrast, IL-5R might not be fully useful in reflecting the severity of symptoms. Although our results are promising, this study should be conducted on a larger cohort of patients.

Metabolites Associated With Uremic Symptoms in Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The toxins that contribute to uremic symptoms in patients with chronic kidney disease (CKD) are unknown. We sought to apply complementary statistical modeling approaches to data from untargeted plasma metabolomic profiling to identify solutes associated with uremic symptoms in patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 1,761 Chronic Renal Insufficiency Cohort (CRIC) participants with CKD not treated with dialysis. PREDICTORS: Measurement of 448 known plasma metabolites. OUTCOMES: The uremic symptoms of fatigue, anorexia, pruritus, nausea, paresthesia, and pain were assessed by single items on the Kidney Disease Quality of Life-36 instrument. ANALYTICAL APPROACH: Multivariable adjusted linear regression, least absolute shrinkage and selection operator linear regression, and random forest models were used to identify metabolites associated with symptom severity. After adjustment for multiple comparisons, metabolites selected in at least 2 of the 3 modeling approaches were deemed "overall significant." RESULTS: Participant mean estimated glomerular filtration rate was 43mL/min/1.73m2, with 44% self-identifying as female and 41% as non-Hispanic Black. The prevalence of uremic symptoms ranged from 22% to 55%. We identified 17 metabolites for which a higher level was associated with greater severity of at least one uremic symptom and 9 metabolites inversely associated with uremic symptom severity. Many of these metabolites exhibited at least a moderate correlation with estimated glomerular filtration rate (Pearson's r≥0.5), and some were also associated with the risk of developing kidney failure or death in multivariable adjusted Cox regression models. LIMITATIONS: Lack of a second independent cohort for external validation of our findings. CONCLUSIONS: Metabolomic profiling was used to identify multiple solutes associated with uremic symptoms in adults with CKD, but future validation and mechanistic studies are needed. PLAIN-LANGUAGE SUMMARY: Individuals living with chronic kidney disease (CKD) often experience symptoms related to CKD, traditionally called uremic symptoms. It is likely that CKD results in alterations in the levels of numerous circulating substances that, in turn, cause uremic symptoms; however, the identity of these solutes is not known. In this study, we used metabolomic profiling in patients with CKD to gain insights into the pathophysiology of uremic symptoms. We identified 26 metabolites whose levels were significantly associated with at least one of the symptoms of fatigue, anorexia, itchiness, nausea, paresthesia, and pain. The results of this study lay the groundwork for future research into the biological causes of symptoms in patients with CKD.

Seladelpar treatment reduces IL-31 and pruritus in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: Pruritus is a debilitating symptom for many people living with primary biliary cholangitis (PBC). In studies with seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, patients with PBC experienced significant improvement in pruritus and reduction of serum bile acids. Interleukin-31 (IL-31) is a cytokine known to mediate pruritus, and blocking IL-31 signaling provides relief in pruritic skin diseases. This study examined the connection between seladelpar's antipruritic effects and IL-31 and bile acid levels in patients with PBC. APPROACH AND RESULTS: IL-31 levels were quantified in serum samples from the ENHANCE study of patients with PBC receiving daily oral doses of placebo (n = 55), seladelpar 5 mg (n = 53) or 10 mg (n = 53) for 3 months, and for healthy volunteers (n = 55). IL-31 levels were compared with pruritus using a numerical rating scale (NRS, 0-10) and with bile acid levels. Baseline IL-31 levels closely correlated with pruritus NRS ( r = 0.54, p < 0.0001), and total ( r = 0.54, p < 0.0001) and conjugated bile acids (up to 0.64, p < 0.0001). Decreases in IL-31 were observed with seladelpar 5 mg (-30%, p = 0.0003) and 10 mg (-52%, p < 0.0001) versus placebo (+31%). Patients with clinically meaningful improvement in pruritus (NRS ≥ 2 decrease) demonstrated greater dose-dependent reductions in IL-31 compared to those without pruritus improvement (NRS < 2 decrease). Strong correlations were observed for the changes between levels of IL-31 and total bile acids ( r = 0.63, p < 0.0001) in the seladelpar 10 mg group. CONCLUSIONS: Seladelpar decreased serum IL-31 and bile acids in patients with PBC. The reductions of IL-31 and bile acids correlated closely with each other and pruritus improvement, suggesting a mechanism to explain seladelpar's antipruritic effects.

Serum thymus and activation-regulated chemokine level is associated with the severity of chronic kidney disease-associated pruritus in patients undergoing peritoneal dialysis.

BACKGROUND: Thymus and activation-regulated chemokine (TARC), which induces a Th2-dominated inflammation, is a well-known biomarker that reflects the severity of atopic dermatitis. The present study aimed to evaluate TARC as a Th2-associated marker with chronic kidney disease-associated pruritus (CKD-aP) in patients with peritoneal dialysis (PD). METHODS: This single-centre cross-sectional study included patients who underwent PD in our hospital between August 2020 and July 2021. The severity and impaired quality of life (QOL) of CKD-aP were assessed using the visual analogue scale (VAS) and Japanese version of the 5-D itch scale (5D-J), respectively. RESULTS: A total of 48 patients with PD were included in the present study. Age and dialysis vintage were (mean ± SD) 64.8 ± 12.0 year and (median (IQR)) 38.5 (11.5-91.5) month, respectively. VAS and 5D-J scores were 3.3 ± 2.0 and 10.5 (9.0-12.0), respectively. Serum TARC level was 481.5 (278.9-603.4) pg/mL (upper limits of normal 450 pg/mL) and significantly correlated with VAS (r = 0.39, p = 0.006) and 5D-J score (r = 0.37, p = 0.009). Multivariate linear analysis revealed that higher serum TARC level was significantly associated with VAS (p < 0.001) and 5D-J score (p < 0.001). Furthermore, the serum brain natriuretic peptide level tended to be associated with VAS (p = 0.060) and 5D-J score (p = 0.029). CONCLUSION: Serum TARC level is an independent predictor of the severity and impaired QOL of CKD-aP in patients with PD, and TARC might be involved in the pathogenesis of CKD-aP.

Effects of Uremic Clearance Granules in Uremic Pruritus: A Meta-Analysis.

Uremic pruritus is common among patients with advanced or end-stage renal disease, with an incidence of >40% among patients on dialysis. Uremic clearance granules (UCGs) are effective in managing uremic pruritus and delay the progression of chronic kidney disease. We conducted a systematic review and a meta-analysis to evaluate the efficacy of UCG in patients with uremic pruritus. Several electronic databases were searched systematically from their inceptions until 19 July 2021. Randomized control trials evaluating the efficacy of UCG in patients with uremic pruritus were selected. Eleven trials including 894 participants were published between 2011 and 2021. Patients administered UCGs had a significantly decreased visual analog scale score (mean difference [MD], -2.02; 95% confidence interval [CI], -2.17 to -1.88), serum levels of hsCRP (MD, -2.07 mg/dL; 95% CI, -2.89 to -1.25; p < 0.00001), TNF-α (MD, -15.23 mg/L; 95% CI, -20.00 to -10.47; p < 0.00001]), ß2-MG (MD, -10.18 mg/L; 95% CI, -15.43 to -4.93; p < 0.00001), and IL-6 (MD, -6.13 mg/L; 95% CI, -7.42 to -4.84; p < 0.00001). In addition, UCGs significantly reduced serum levels of creatinine, BUN, PTH, iPTH, phosphorus, and the overall effectiveness rate. UCGs could be an attractive complementary therapy for patients with uremic pruritus.

Inhibition of autotaxin by bile salts and bile salt-like molecules increases its expression by feedback regulation.

BACKGROUND: Autotaxin is an enzyme that converts lysophospholipid into lysophosphatidic acid (LPA), a highly potent signaling molecule through a range of LPA receptors. It is therefore important to investigate which factors play a role in regulating ATX expression. Since we have reported that ATX levels increase dramatically in patients with various forms of cholestasis, we embarked on a study to reveal factors that influence the enzyme activity ATX as well as its expression level in vitro and in vivo. METHODS: Bile from cholestatic patients was fractionated by HPLC and analyzed for modulation of ATX activity. ATX expression was measured in fibroblasts upon stimulation or inhibition of LPA signaling. RESULTS: Surprisingly, ATX activity was stimulated by most forms of its product LPA, but it was inhibited by bile salts and bile salt-like molecules, particularly by 3-OH sulfated bile salts and sulfated progesterone metabolites that are known to accumulate during chronic cholestasis and cholestasis of pregnancy, respectively. Activation of fibroblasts by LPA decreased ATX expression by 72%. Conversely, inhibition of LPA signaling increased ATX expression 3-fold, indicating strong feedback regulation by LPA signaling. In fibroblasts, we could verify that inhibition of ATX activity by bile salts induces its expression. Furthermore, induction of cholestasis in mice causes increased plasma ATX activity. CONCLUSIONS: Multiple biliary compounds that accumulate in the systemic circulation during cholestasis inhibit ATX activity and thereby increase ATX expression through feedback regulation. This mechanism may contribute to increased serum ATX activity in patients with cholestasis.

Chronic Itch of Unknown Origin Is Associated With an Enhanced Th2 Skin Immune Profile.

ABSTRACT: Chronic pruritus of unknown origin (CPUO) is described as chronic itch lasting longer than 6 weeks in the absence of a defined skin rash and any known causative disease process. A retrospective study was performed on biopsy samples from patients with CPUO and normal controls to compare the immune profiles of these patients with healthy individuals. We used dual CD3/T-bet and CD3/GATA3 immunohistochemical staining to assess for T-cells expressing Th1 versus Th2 transcription factors, respectively. Our data showed that CD3+ cells of patients with CPUO co-express significantly more GATA3 compared with normal controls. Meanwhile, the normal control skin showed a much more balanced T-bet/GATA3 ratio of co-expression. Our data suggest an enrichment of Th2 cells in CPUO skin by T cell/GATA3 co-staining, supporting that CPUO is increasingly considered a type 2/Th2 cell-associated disease. We thus speculate that type 2 cytokine blockade-based therapies may represent effective treatments for CPUO.

Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy / Relación entre el prurito y la autotaxina en la colestasis intrahepática del embarazo

Objective: Intrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy. Patients and methods: Sixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically. Results: The mean serum bile acid level (n=69; 38.74±35.92μmol/L) in patients with intrahepatic cholestasis of pregnancy (n=69) was detected to be higher than healthy pregnant women (n=20; 5.05±1.88μmol/L) (p<0.001). Weak correlation was detected between serum bile acid level and itch intensity (p=0.014, r=0.295), while no relation was detected between Autotaxin and itch intensity (p=0.446, r=0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10±424.42pg/mL, control: 535.16±256.47pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p=0.157). Conclusion: In our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.(AU)

Objetivo: La colestasis intrahepática del embarazo es una enfermedad temporal específica del embarazo caracterizada por picazón (prurito), niveles elevados de transaminasas y ácidos biliares séricos elevados en el tercer trimestre del embarazo que se resuelve con el parto. Debido a los efectos de la autotaxina en la fisiología del embarazo, nuestro objetivo fue investigar la actividad de la autotaxina en pacientes con colestasis intrahepática del embarazo. Pacientes y métodos: En el estudio se incluyeron 69 pacientes con diagnóstico de colestasis intrahepática del embarazo y 20 mujeres embarazadas sanas. Registramos los ácidos biliares séricos en ayunas, la intensidad del prurito, los parámetros séricos y la semana de gestación de las pacientes en el momento del diagnóstico, y controlamos la semana del parto y el peso al nacer. Los niveles séricos de autotaxina se midieron de forma enzimática. Resultados: Se observó que el nivel medio de ácidos biliares en suero era mayor en pacientes con colestasis intrahepática del embarazo (n=69; 38,74±35,92μmol/l) que en mujeres embarazadas sanas (n=20; 5,05±1,88μmol/l) (p<0,001). Se detectó una correlación débil entre el nivel de ácidos biliares en suero y la intensidad del prurito (p=0,014; r=0,295), mientras que no se observó ninguna relación entre la autotaxina y la intensidad del prurito (p=0,446; r=0,09). Aunque los niveles medios de autotaxina fueron altos en pacientes con colestasis intrahepática del embarazo (678,10±424,42 frente a 535,16±256,47pg/ml en los controles), la diferencia no fue estadísticamente significativa (p=0,157). Conclusión: Observamos que el nivel de autotaxina sérica no supuso una diferencia significativa en pacientes con colestasis intrahepática del embarazo en comparación con las mujeres embarazadas sanas. Estos hallazgos sugieren que se requieren estudios clínicos más amplios para determinar los efectos fisiopatológicos de la autotaxina en el embarazo.(AU)

Determinants of the intensity of uremic pruritus in patients receiving maintenance hemodialysis: A cross-sectional study.

BACKGROUND: Uremic pruritus (UP) is a common and frustrating symptom in patients receiving hemodialysis (HD). The majority of patients have mild to moderate itching of the skin, and a small percentage have severe itching, which seriously affects their quality of life and survival rate. However, little is known about factors that influence the intensity of itching in patients. METHODS: A cross-sectional study on uremic pruritus in male and female patients receiving HD was conducted in September 2019. This study included 148 eligible patients who received HD at the Blood Purification Center of Xinchang County People's Hospital, Zhejiang Province, China from March 2019 to June 2019. We collected general data consisted of age, sex, body mass index (BMI), place of residence, educational level, diabetes mellitus status and duration of HD; as well as clinical, biochemical indicators, including serum calcium (Ca), serum phosphorus (P), serum albumin (ALB), haemoglobin (Hb), serum intact parathyroid hormone (iPTH), pre-dialysis serum urea nitrogen (BUN), normalized protein catabolic rate (nPCR), urea nitrogen clearance index (KT/V), ferritin (FER) and pre-dialysis serum creatinine (sCR). We also assayed the inflammatory cytokine serum high sensitivity C-reactive protein (hs-CRP). The Five-Dimensional Itching Scale (5DIS) was used to evaluate the degree of skin itching (none, mild, moderate, or severe). We used multiple logistic regression to analyze influencing factors on the degree of skin itching in patients with UP. RESULTS: Of the 148 patients, 60 had uremic pruritus (incidence rate, 40.54%). These included 22 cases of mild skin itching (14.86%), 30 of moderate skin itching (20.27%), and 8 of severe skin itching (5.41%). Compared with uremia patients without skin pruritus, patients with UP had higher levels of iPTH, Hb, BUN, nPCR, and hs-CRP. The composition ratio showed significant differences between urban and rural patients with different degrees of skin itching (P = 0.017); moreover, the difference of iPTH and hs-CRP levels were statistically significant (P = 0.009 and < 0.001, respectively). Using no itching as a reference, multiple logistic regression analysis showed that as hs-CRP level increased, the patient's risks of mild skin itching (odds ratio [OR] = 1.740; 95% confidence interval [CI], 1.061-2.854; P = 0.028), moderate skin itching (OR = 2.8838 95% CI, 1.744-4.718; P < 0.001), and severe skin itching (OR = 9.440; 95% CI, 3.547-25.124; P < 0.001) all increased as well. Compared with urban residents, rural residents have a higher risk of moderate itching (OR = 3.869; 95% CI, 1.099-13.622; P = 0.035). CONCLUSION: Levels of hs-CRP were associated with the intensity of skin itching in patients with UP. Higher hs-CRP levels were closely related to severe skin itching. The relationship between the intensity of skin itching and the environment in maintenance hemodialysis patients needs further clarification.

The polymorphisms of IL-6/STAT3 signaling pathway may contribute to cutaneous T-cell lymphomas susceptibility.

IL-6/STAT3 signaling pathway has been suggested to play a role in CTCL pathogenesis. Polymorphisms in STAT3 signaling pathway-related genes might be a risk factor for CTCL. However, the exact role of inherited gene polymorphisms of IL-6 and STAT3 in the pathogenesis of CTCL is still not fully understood. The aim was to examine whether IL-6 cytokine and polymorphisms of IL-6 and STAT3 gene are associated with CTCL susceptibility, stage of disease and pruritus intensity. We compared the IL-6 serum level and the frequency of selected single nucleotide polymorphisms of IL-6 and STAT3 in 106 CTCL and 198 control group using polymerase chain reaction with sequence-specific primers method and ELISA. We have found that serum IL-6 level in CTCL patients was significantly higher than in healthy controls (p < 0.05). We also demonstrated that two genotypes, CC of IL-6 and GG of STAT3, were overexpressed in CTCL patients compared to healthy controls, and that they increase the risk of malignancy development (OR = 1.8, p = 0.04 for IL-6 and OR 2.53, p = 0.0064 for STAT3). Moreover, the GG genotype of STAT3 polymorphism seems to be associated with lack of pruritus or mild pruritus in CTCL patients. Our results indicate that IL-6 is involved in pathogenesis of CTCL but not pruritus. Moreover, CC of IL-6 and GG genotype of STAT3 genes might be considered as the risk factor for development of CTCL.

Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.

BACKGROUND: Pruritus is a common symptom that can significantly reduce quality of life through sleep disruption. OBJECTIVE: To examine features of disturbed sleep in patients with chronic pruritic dermatoses and test the hypothesis that systemic inflammation may serve as a biomarker for impaired sleep in these patients. METHODS: Cross-sectional analysis of the National Health and Nutrition Examination Survey investigating systemic inflammation using C-reactive protein (CRP) levels. Logistic regression was used to compare patients with and without sleep disturbances, adjusting for demographics (model 1) and medical comorbidities (model 2). RESULTS: Chronic pruritic dermatoses were associated with multiple sleep disturbances, including nighttime awakenings (model 1: odds ratio [OR], 1.646; 95% confidence interval [CI], 1.031-2.627; model 2: OR, 1.329; 95% CI, 0.888-1.989) and early morning awakening (model 1: OR, 1.669, 95% CI, 1.118-2.493; model 2: OR, 1.582; 95% CI, 1.008-2.481). Mean CRP levels were 52.8% higher among patients with pruritic dermatoses reporting trouble sleeping compared with those who did not (0.663 vs 0.434 mg/dL; P = .034). Trouble sleeping was also positively correlated with CRP levels (ß = 0.142, P = .025). LIMITATIONS: Potential recall bias among participants. CONCLUSIONS: In addition to confirming sleep disturbances with pruritic dermatoses, we found these disturbances are more likely to present with elevated CRP levels. Clinicians should consider the potential risk for sleep-related and cardiac comorbidities in patients diagnosed with itchy skin conditions.

Elevated interleukin 31 serum levels in hemodialysis patients are associated with uremic pruritus.

INTRODUCTION: Uremic pruritus is a multifactorial devastating complication of renal failure, which has a significant negative impact on patients' quality of life including medical, psychological, as well as social aspects. It is also associated with an increased mortality in dialysis patients. METHODS: A cross sectional study evaluating the traditional risk factors for uremic pruritus (UP) - using pruritus grading system (PGS) and visual analogue scale (VAS) - as well as measuring the serum levels of different inflammatory cytokines (ILs 13, 31 and 33) in chronic hemodialysis and healthy controls, in a tertiary referral hospital. RESULTS: 65 hemodialysis (HD) patients and 49 heathy controls were enrolled in the study. The mean age for the HD patients was 43.4 years (SD ± 21.3), and 31.5 years (SD ± 11.1) for the control group. The most common cause for End Stage Renal Disease (ESRD) was diabetes mellitus (DM) 27.7%. The mean PGS score in HD patients was 5.92 (SD ± 2.9); 50% had mild itch, 43.8% moderate itch and 6.2% had severe itch. The mean serum levels for IL-13 was 8674.3 pg/ml (SD ± 4353.9), serum levels of IL-31 were 150.7 pg/ml (SD ± 178.2) and for IL-33 it was 42850.5 pg/ml (SD ± 11370.7) in hemodialysis patients; in comparison to serum levels of 7913.4 pg/ml (SD ± 3454.1), 67.1 pg/ml (SD ± 71.9) and 44875.9 pg/ml (SD ± 12114.6), respectively in the control group. IL-31 level was significantly higher in HD patients than in the control group (P = 0.0001), while the difference in the levels of IL-13 and IL-33 between the two groups were not statistically significant (P = 0.41 and 0.18, respectively). IL-13 had a statistically significant relationship with the itch score (P = 0.014) and the severity of itch (P = 0.03), while IL-31 and IL-33 were not statistically significant. CONCLUSION: UP is a complex and multifactorial problem. In patients with UP the high levels of IL-31 indicates a possible role in pathogenesis. IL-13 serum level on the other hand may be related to the severity of itch in these patients. Optimizing dialysis and targeting these cytokines may provide a potential therapeutic option especially in refractory UP. Further studies addressing these cytokines and their levels in response to various treatments may provide additional information on UP.

Relationship between pruritus and autotaxin in intrahepatic cholestasis of pregnancy.

OBJECTIVE: Intrahepatic cholestasis of pregnancy is a temporary, pregnancy-specific disease that resolves with delivery, characterized by itching (pruritus), as well as high transaminase and serum bile acid levels in the third trimester of pregnancy. Due to the effects of Autotaxin on the physiology of pregnancy, we aimed to investigate Autotaxin activity in patients with intrahepatic cholestasis of pregnancy. PATIENTS AND METHODS: Sixty-nine patients diagnosed with intrahepatic cholestasis of pregnancy and 20 healthy pregnant women were enrolled in the study. Fasting serum bile acid, pruritus intensity, serum parameters, gestational week of the patients at the time of diagnosis were recorded, and birth week and birth weight were monitored. Autotaxin serum level was measured enzymatically. RESULTS: The mean serum bile acid level (n=69; 38.74±35.92µmol/L) in patients with intrahepatic cholestasis of pregnancy (n=69) was detected to be higher than healthy pregnant women (n=20; 5.05±1.88µmol/L) (p<0.001). Weak correlation was detected between serum bile acid level and itch intensity (p=0.014, r=0.295), while no relation was detected between Autotaxin and itch intensity (p=0.446, r=0.09). Although mean Autotaxin (intrahepatic cholestasis of pregnancy: 678.10±424.42pg/mL, control: 535.16±256.47pg/mL) levels were high in patients with intrahepatic cholestasis of pregnancy, it was not statistically significant (p=0.157). CONCLUSION: In our study, we observed that the serum Autotaxin level did not make a significant difference in patients with intrahepatic cholestasis of pregnancy compared to healthy pregnant women. These findings suggest that larger clinical studies are required to reveal the physio-pathological effects of Autotaxin on pregnancy.

Social defeat stress exacerbates atopic dermatitis through downregulation of DNA methyltransferase 1 and upregulation of C-C motif chemokine receptor 7 in skin dendritic cells.

DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.

Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis.

Untreated progressive familial intrahepatic cholestasis (PFIC) type 2, or bile salt exporter protein deficiency, frequently leads to severe pruritus, impaired growth and progressive liver fibrosis with risk of organ failure. We describe a 15-month-old male patient with severe pruritus diagnosed with PFIC type 2 enrolled in an open-label phase 2 study who received 4 weeks of treatment with odevixibat, an ileal bile acid transporter inhibitor under development for cholestatic liver disease treatment. The patient experienced reductions in serum bile acids and improvement in itching and sleep scores, and odevixibat was well tolerated. After the odevixibat study, symptoms returned and the patient underwent partial external biliary diversion (PEBD). Odevixibat treatment and PEBD produced similar normalisation of serum bile acid levels and improvements in pruritus and sleep disruptions. Thus, odevixibat appeared to be as effective as invasive PEBD in treating serum bile acids and cholestatic pruritus in this patient.

The Effect of Acupressure on the Severity of Pruritus and Laboratory Parameters in Patients Undergoing Hemodialysis: A Randomized Clinical Trial.

BACKGROUND: Uremic pruritus is a common boring complaint in patients suffering from chronic renal failure. Owing to cost and the side-effects of medications, complementary therapies are more attractive for pruritus treatment. OBJECTIVES: The aim of this study is to determine the effect of acupressure on the severity of pruritus and some laboratory parameters in patients undergoing hemodialysis. MATERIALS AND METHODS: The present clinical trial was conducted on 90 patients undergoing hemodialysis who were allocated in intervention, sham control, and negative control groups (30 in each group). Pressure was applied on SP6, SP10, ST36, and LI11 points in the intervention group and on ineffective points for the sham control group. The negative control group received routine care. The severity of pruritus was measured using the numeric rating scale before, two weeks, and five weeks after intervention. The laboratory parameters were measured before and after the intervention. RESULTS: There was a significant reduction in the severity of pruritus over the course of the study in the intervention and sham control groups (p = 0.001). In addition, significant differences were observed at the end of the intervention in terms of serum phosphorus (p = 0.045) and parathyroid hormone (p = 0.004) levels between groups. CONCLUSION: Acupressure can improve the severity of pruritus dramatically in hemodialysis patients. It can also reduce serum phosphorus and parathyroid hormone levels, which affect pruritus, significantly. Therefore, this simple and inexpensive intervention may be recommended for reducing uremic pruritus among patients undergoing hemodialysis.

Hemodialysis Patients with Pruritus and Insomnia Have Increased Risk of Death.

BACKGROUND: Pruritus and insomnia are common disorders in hemodialysis (HD) patients, with a major clinical impact as they are associated with poor quality of life and increased mortality. Their coexistence and impact on survival in HD patients have rarely been investigated. Our aim is to investigate the survival of HD patients presenting either none, one, or both disorders and to compare certain features between these groups. METHODS: After the inclusion/exclusion criteria, 170 patients treated by HD or online hemodiafiltration were assigned in 4 study groups depending on the presence of either, neither, or both pruritus and insomnia. We analyzed the survival difference between groups after 20 months, and we searched if there were significant differences in terms of clinical and laboratory features. RESULTS: Survival at 20 months was lower in patients with both pruritus and insomnia. Patients with pruritus alone had a lower Kt/V than those with no complaints or insomnia alone. Those with no complaints had lower C-reactive protein and higher albumin levels than patients with insomnia alone or both conditions. CONCLUSION: Pruritus and insomnia should be actively investigated and correlated with some clinical and laboratory features as they have a significant impact on survival in HD patients.