Combination therapy of mycophenolate mofetil and ursodeoxycholic acid for the treatment of patients with incomplete response to ursodeoxycholic acid in primary biliary cirrhosis / 中华风湿病学杂志

Objective:To observe the efficacy of mycophenolate mofetil (MMF) combined with ursodeoxycholic acid (UDCA) for the treatment of primary biliary cholangitis (PBC) with incomplete response to UDCA monotherapy.Methods:This is an open label study. Combination therapy of MMF (0.75-1.5 g/d) and UDCA (13-15 mg·kg -1·d -1) were applied to PBC patients with incomplete response to UDCA alone according to Barcelona Criteria. The expected observation duration of treatment were at least 12 months. The levels of serum alanine amiotransferase (ALT), aspartate transaminase (AST), total bilirubin (TBil), albumin (Alb), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (GGT), immunoglobulin (Ig)M, IgG, IgA were mea-sured at different time points before and after treatment. The biochemical response rates were evaluated with reference to formerly reported criteria including Barcelona criteria and so on. Paired student's t-test and wilcoxon matched-pairs signed rank test were used to compare differences between groups before and after treatment. Mann-Whitney U test was used to compare differences between the two independent groups with abnormal distribution. A two-sided P<0.05 was considered statistically significant. Results:Seventeen of 29 patients included were treated with combination therapy for at least 1 year. The levels of serum ALP were significantly decreased after 3 months [(369±184) U/L vs (309±148) U/L, t=2.149, P=0.045] but not afterwards. GGT levels were significantly decreased at 6 months [266.5(205.5, 414.0) U/L vs 217.5(173.8, 391.8) U/L, Z=-2.334, P=0.018] and the significance continued to 1 year. IgM, IgG and IgA levels had a significant decrease at 3, 6 and 12 months but not AST, Tbil or Alb levels. The biochemical response rates were between 9.5%-23.5%. Conclusion:Overall, the biochemical response rate of combination therapy of MMF and UDCA is low in incomplete responders to UDCA alone. Early recognition of incomplete responders is of great im-portance and high quality researches are needed to confirm the effectiveness of the combined therapies.

Clinical features of dyslipidemia in patients with primary biliary cholangitis / 中华全科医师杂志

Objective@#To analyze the clinical features of dyslipidemia in patients with primary biliary cholangitis (PBC).@*Methods@#The clinical and laboratory data of 136 PBC patients in Peking Union Medical College Hospital from 2010 to 2016 were retrospectively analyzed.The liver function was compared between patients with normal and abnormal blood lipids.@*Results@#Among 136 PBC patients, 100(74%)had abnormal serum lipids. The incidence of increased cholesterol, low-density lipoprotein and triglyceride was 61%(59/96), 58%(48/83) and 47%(46/97), respectively; while that of reduced HDL-C was 26%(21/82). The incidences of pruritus [26%(26/100) vs. 8%(3/36), χ2=4.93, P=0.032], serum total bilirubin (TBIL) [17.3(12.2, 28.2) μmol/L vs. 14.5 (9.4, 21.1) μmol/L, Z=2.25, P=0.024], direct bilirubin (DBIL)[5. 5 (3.4, 12.4) μmol/L vs. 4.4(2.9, 7.1) μmol/L, Z=2.00, P=0.045], and glutamyl aminotransferase (GGT)[193.0(64.3, 454.8)U/L vs. 105.5(53.5, 179.5)U/L, Z=2.02, P=0.043], alkaline phosphatase(ALP)[183(86, 351)U/L vs. 135(85, 188) U/L, Z=1.98, P=0.048] in PBC patients with dyslipidemia were significantly higher than thosein patients with normal serum lipids.Pearson regression analysis showed that in PBC patients with dyslipidemia, the ALT was positively corrected with TG and TC(r=0.248 and 0.272, P=0.015 and 0.008); ALB was positively correlated with LDL-C(r=0.335, P=0.002); DBIL was positively corrected with HDL-C(r=0.252, P=0.022); TC was positively correlated with ALP and GGT(r=0.313 and 0.346, P=0.002 and 0.001); GGT was positively correlated with LDL-C(r=0.251, P=0.022).@*Conslusion@#Increased TC and LDL-C were more common in PBC patients. PBC patients with dyslipidemia have more severe liver damage than the patients with normal serum lipids.

In vitro-engineered non-antibody protein therapeutics

Antibodies have proved to be a valuable mode of therapy for numerous diseases, mainly owing to their high target binding affinity and specificity. Unfortunately, antibodies are also limited in several respects, chief amongst those being the extremely high cost of manufacture. Therefore, non-antibody binding proteins have long been sought after as alternative therapies. New binding protein scaffolds are constantly being designed or discovered with some already approved for human use by the FDA. This review focuses on protein scaffolds that are either already being used in humans or are currently being evaluated in clinical trials. Although not all are expected to be approved, the significant benefits ensure that these molecules will continue to be investigated and developed as therapeutic alternatives to antibodies. Based on the location of the amino acids that mediate ligand binding, we place all the protein scaffolds under clinical development into two general categories: scaffolds with ligand-binding residues located in exposed flexible loops, and those with the binding residues located in protein secondary structures, such as α-helices. Scaffolds that fall under the first category include adnectins, anticalins, avimers, Fynomers, Kunitz domains, and knottins, while those belonging to the second category include affibodies, β-hairpin mimetics, and designed ankyrin repeat proteins (DARPins). Most of these scaffolds are thermostable and can be easily produced in microorganisms or completely synthesized chemically. In addition, many of these scaffolds derive from human proteins and thus possess very low immunogenic potential. Additional advantages and limitations of these protein scaffolds as therapeutics compared to antibodies will be discussed.

Expression of programmed death-1 in CD8+T lymphocyte and Treg lymphocyte in patients with primary biliary cholangitis / 中华风湿病学杂志

Objective To investigate the expression of programmed death receptor-1 (PD-1) in CD8+ T cells and FoxP3+CD4+ cells in patients with primary biliary cholangitis (PBC).Methods The peripheral blood and clinical data of 69 PBC patients in Peking Union Medical College Hospital and 58 health controls (HC) were collected.They were divided into initial treatment group and follow-up group according to whether they were treated or not.Patients in the treatment group were further divided into the refractory group and stable group according to treatment response.Flow cytometry was used to detect the expression of PD-1 in CDS+T cells and FoxP3+CD4+ cells.T-test and Person correlation analysis were used for data analysis.Results The PD-1 expression in peripheral blood mononuclear cells (PBMCs) of 69 PBC patients (12±9)％ was lower than that of HC (20±12)％ (t=-3.687,P＜0.01).The percentage of PD-1+ in FoxP3+ CD4+T cells was significantly increased in PBC (5.6±3.7)％ than HC (7.4±2.4)％ (t=2.048,P＜0.01).The proportion of CD8+T cells,PD-1 expression in CD8+T cells and the proportion of FoxP3+CD4+ cells weren't correlated with clinical parameters (P＞0.05).There was a negative correlation between the expression of PD-1 cells in FoxP3+CD4+ cells and GLOBE score (r=-0.307,P＜0.05).Conclusion The expression of PD-1 in peripheral CD8+T lymphocytes of PBC patients is lower than that of HC,and decreases more significantly in the refractory group.The expression of PD-1 on FoxP3+CD4+T cells is higher than that in HC,and is negatively correlated with the prognostic GLOBE score.It suggests that PD-1/PD-L1 pathway participates in the immune mechanism of PBC.

Analysis of the relationship between health-related quality of life (primary biliary cholangitis-40) and clinical presentations of patients with primary biliary cholangitis / 中华风湿病学杂志

Objective To investigate the health related quality of life score [primary biliary cholangitis (PBC)-40] in patients with PBC,and the relationship between PBC-40 and clinical presentations.Methods The PBC-40 score and clinical presentations in PBC patients (n=65) were adapted in this study.Patients were divided into the untreated group and the treated group,and the treated group was further divided into ursodesoxycholic acid (UDCA) response group and UDCA non-response group.PBC-40 scores of different groups were analyzed by t-test and the relationship between PBC-40 and clinical presentations were analyzed with Pearson's test.Results Dimensions of PBC-40 scores of this group of patients were as follows:symptoms were (15.8±4.1) points,itch was (4.9±2.8) points,atigue was (23.8±8.9) points,cognitive dysfunction score was (11.4±4.7) points,social activity score was (17.0±7.5) points,and the emotion score was (6.5±3.1) points.The untreated group had higher emotion scores than the treated group (t=2.024,P=0.045).Compared with the UDCA response group,UDCA non-response group had higher scores in cognitive,social and emotion dimension (t =2.126,2.309,2.062,respectively,P=0.039,0.025,0.045,respectively).Itch score was significantly correlated with total bilirubin (TBil),direct bilirubin (DBil),alkaline phosphatase (ALP) and total bile acid (TBA) (r=0.349,0.345,0.324,0.427,respectively,P＜0.01),while the social scores were correlated with TBil,DBil,aspartate aminotransferase (AST) and TBA (r=0.361,0.383,0.316,0.331,P＜0.01) and emotion scores were associated with ALT,TBil,GGT,ALP,AST and TBA (r=0.332,0.430,0.265,0.326,0.297,0.353,P＜0.05).ConclusionPBC-40 can be used as a health-related quality of life assessment for PBC patients inChinese population.Itch,social and emotion dimensions are correlated with clinical activity indicators.Hyperbilirubin,ALP and TBA can predict low health quality of life in PBC patients.Conclusion PBC-40 can be used as a health-related quality of life assessment for PBC patients in Chinese population.Itch,social and emotion dimensions are correlated with clinical activity indicators.Hyperbilirubin,ALP and TBA can predict low health related quality of life in PBC patients.

Regulatory effect of Astragalus Polysaccharides on immune function of mice infected by Brucella suis S2 / 中国免疫学杂志

To study the regulating effect of Astragalus Polysaccharides ( APS) to the mice infected by Brucella suis S2.Methods:120 BALB/c mice were randomly divided into 4 groups:experimental mice were injected APS 1 ml ( 0.4,1.2,3 mg/ml) via peritoneal cavity respectively once a day and the control group was injected with the same volume of saline for 3 days,then infected with Brucella suis S2 1 ml (1×107 L-1 ) by ip.Five mice of each group were killed through eye bloodletting at 1,6,12,24,48, 72 h respectively post-infection with Brucella suis S 2 and the peritoneal macrophage were obtained respectively to make smear.Phagocytic rate and phagocytic index were calculated by the Wright Giemsa staining after infected 1 h.TNF-α,IL-12 and IFN-γlevels of serum at different time points were measured by ELISA.The bacterial load of MΦand spleen were measured by coating method.Results:The phagocytic rate and phagocytic index of MΦin APS 3 dose groups were higher than those of the control group ( P<0.05 ).The microbial load of MΦin APS 3 dose groups at 1 h infected by Brucella suis S 2 were significantly higher than those of control,but significantly lower than those of control at 6,12,24,48,72 h after infected by Brucella suis S2.The microbial load of spleen in APS 3 dose groups at 6 h infected by Brucella suis S 2 were significantly higher than those of control ,but significantly lower than those of control at 12,24,48,72h after infected by Brucella suis S2.The concentrations of TNF-α,IL-12 and IFN-γin the serum of APS groups had significantly been improved ( P<0.05 ).Conclusion: APS can promote the activation of MΦin vivo and strengthen the activity of phagocytosis and killing to Brucella suis S 2.APS can promote the secretion of TNF-α,IL-12 and IFN-γof mice,strengthen the cellular immune response of mice to Brucella suis S 2.