银屑胶囊对小鼠免疫功能的影响

目的研究银屑胶囊对小鼠免疫功能的影响.方法昆明种小鼠,体重18～22g,♂♀各半,随机分为6组,即对照组、环磷酰胺组(25 mg/kg)、左旋咪唑组(32 mg/kg)和银屑胶囊3个剂量组(0.47、0.95、1.89 g/kg).环磷酰胺组腹腔注射给药,隔日1次,其余各组均灌胃给药,每日1次,连续21 d,观察预定指标.结果银屑胶囊低、中剂量组均可明显提高小鼠腹腔巨噬细胞吞噬功能,提高淋巴细胞转化率,增加小鼠淋巴细胞非特异性酯酶染色阳性率,促进小鼠溶血素的产生,增加小鼠血清血凝抗体的形成.结论银屑胶囊有增强细胞免疫和体液免疫的作用,有益于银屑病的治疗.     

Chemerin/chemR23对银屑病患者外周血Th9/Treg细胞平衡的影响

目的：探究chemerin对银屑病患者外周血辅助性T淋巴细胞9(helper T cells 9,Th9)/调节性T淋巴细胞 (regulatory T cells,Treg)免疫平衡的调节作用及其潜在的机制。方法：选取25例银屑病患者和20例健康志愿者,采用 磁珠分离法分离出受试者外周血中CD4+ T细胞,行实时RT-PCR和ELISA检测细胞中chemerin和其受体chemR23的表 达;用不同浓度的chemerin(50,100,150,200 ng/mL)分别处理从健康志愿者外周血分离得到的CD4+ T细胞,行MTT 比色法检测细胞活力以筛选最适浓度;采用ELISA检测炎性细胞因子水平;行流式细胞术检测Th9和Treg细胞数。 结果：与对照相比,银屑病患者外周血中chemerin和chemR23的表达均显著增加,Th 9/Treg比例明显上升(均P<0.05); 选取最适浓度150 ng/mL的chemerin处理CD4+ T细胞后,细胞中白细胞介素(IL)-6,IL-9和IL-17的水平均显著增加, Th9/Treg比例明显上升(均P<0.05),而chemR23沉默可反转chemerin对CD4+ T细胞的上述作用(均P<0.05)。结论： Chemerin通过chemR23调节银屑病患者外周血CD4+ T淋巴细胞中的Th 9/Treg细胞免疫平衡。     

Psoriasis: to treat or to manage?

The recognition of psoriasis as a systemic disorder with characteristic skin symptoms and associated diseases has changed treatment concepts substantially. The complexity of psoriasis disease not only requires appropriate therapy but also weight‐loss and smoking cessation programmes as well as trigger factor elimination. The term ‘management’ may better reflect the aim for a holistic approach of disease control. Comorbidity and the presence of psoriatic arthritis are important denominators for drug selection. However, there is a lack of prospective data substantiating a benefit of associated diseases by antipsoriatic therapy. Securing success using treatment goals helps to establish an efficacious therapy and to control inflammation. A regular scoring of disease severity, patients’ quality of life and assessment of other clinically relevant conditions are mandatory to closely follow the disease course. There is debate whether an early treatment may modulate the future course of psoriasis. Concepts of minimal disease activity have not been implemented in psoriasis yet. There is a lack of evidence how long any treatment should be given and when and how to terminate. Finally, outcome tools should specifically be tailored for psoriasis to evaluate disease‐related items as well as the benefit of management from the patient's perspective.     

Anti-drug antibodies in psoriasis: a critical evaluation of clinical significance and impact on treatment response

TNF inhibitors and anti-p40IL12/23 monoclonal antibodies are efficacious treatments for moderate-to-severe psoriasis. However, the formation of anti-drug antibodies (ADA) with biologics may prevent patients from achieving a full clinical response. ADA have been reported in patients treated with etanercept, infliximab, adalimumab or ustekinumab at rates of 0–18.3%, 5.4–43.6%, 8.8–44.8% and 3.8–5.4%, respectively. Antibodies against etanercept have no apparent effects on clinical response, whereas antibodies against infliximab or adalimumab have been associated with diminished clinical response. The significance of ADA against ustekinumab is yet to be determined. Data regarding management strategies to counteract ADA formation and their effects are limited in psoriasis patients. However, some evidence suggests that concomitant immunomodulators such as methotrexate may suppress ADA development in psoriasis. ADA specific to one biologic do not appear to carry cross-linking potential with other biologic agents. ADA formation needs to be considered as a possible factor contributing to diminished response from biologic agents.     

Celiac disease: from gluten to skin

Celiac disease (CD) is an autoimmune gluten-dependent enteropathy characterized by atrophy of the intestinal villi that improves after a gluten-free diet. CD is often associated with extraintestinal manifestations. In the past few years, growing evidence has documented the involvement of skin diseases among the extraintestinal manifestations of CD. This association could be related to the impairment of intestinal absorption and motility, other than to immunological and hormonal changes. The aim of this review is to report all CD-associated skin manifestations described in the literature and to analyze the possible mechanisms involved in this association. The opportunity to evaluate the possible presence of CD in patients affected by skin disorders is discussed.     

Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility

NACHT leucine‐rich repeat‐ and PYD‐containing (NLRP)3 protein controls the inflammasome by regulating caspase‐1 activity and interleukin (IL)‐1β processing. The contribution of IL‐1β in the pathogenesis of psoriasis is well recognized. Polymorphisms in NLRP3 and caspase recruitment domain–containing protein (CARD)8, a negative regulator of caspase‐1 activity, have been associated with susceptibility to common inflammatory diseases, such as Crohn's disease and rheumatoid arthritis. To investigate the role for genetic variants in the NLRP3 inflammasome in psoriasis susceptibility. In a patient sample comprising 1988 individuals from 491 families and 1002 healthy controls, genotypes for four selected single‐nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and CARD8 (one SNP) were determined by TaqMan^® Allelic Discrimination. Using the transmission disequilibrium test (TDT), a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis was demonstrated (P = 0.015). Using logistic regression analysis in 741 patients with psoriasis and 1002 controls, the CARD8 rs2043211 genotype was significantly different in cases and controls in overall terms [OR 1.3 (1.1–1.5), P = 0.004] and for both genders. Our data support the hypothesis that the inflammasome plays a role in psoriasis susceptibility.     

Reduction of inflammatory slan (6‐sulfo LacNAc) dendritic cells in psoriatic skin of patients treated with etanercept

Dermal dendritic cells (DCs) play a central role in the immunopathology of psoriasis. We previously identified slanDCs as pro‐inflammatory TNF‐α, IL‐23‐ and IL‐12‐producing DCs in human blood and as prominent inflammatory dermal TNF‐α secreting and CD11c‐positive DC subset in psoriasis. Here, we ask for the effects of TNF‐α‐inhibition on inflammatory slanDCs in skin and blood of 10 patients with psoriasis during 24 weeks of treatment with etanercept. Treatment with etanercept reduced the frequency of dermal slanDCs but did not induce apoptosis as determined by lack of increased active caspase‐3‐expression. In parallel, we found increased frequencies of slanDCs in blood which expressed lower levels of HLA‐DR. Stimulating slanDCs isolated from the blood of healthy donors in vitro induced a strong production of IL‐1β, IL‐6, IL‐23 and IL‐12p70. This capacity was efficiently reduced in the presence of etanercept, thereby indicating that TNF‐α is an autocrine stimulus for maturation and pro‐inflammatory cytokine production of slanDCs. In vivo, we noticed that treatment with etanercept did reduce the number of dermal slanDCs in parallel to the overall expression of TNF‐α and IL‐23p19. However, successful treatment did not down‐regulated the percentage of dermal slanDCs that stained positive for TNF‐α and IL‐23p19 indicating that remaining slanDCs kept their pro‐inflammatory capacity. This study provides novel insights into the immune regulatory properties of etanercept at the level of inflammatory slanDCs in vivo in skin and blood as well as in vitro.     

Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases

ABSTRACT

Introduction: Biologic therapy has revolutionized the treatment of immune mediated inflammatory diseases (IMID), such as inflammatory bowel disease (IBD), rheumatoid and psoriatic arthritis, ankylosing spondylitis and psoriasis. Nevertheless, some patients exhibit primary nonresponse (PNR) or secondary loss of response (SLR) to biologics.

Areas covered: This collaborative review provides data on the role of therapeutic drug monitoring (TDM) in IMID for optimizing biologic therapy including infliximab, adalimumab, certolizumab pegol etanercept and golimumab vedolizumab, secukinumab and ustekinumab.

Expert opinion: Most exposure-response relationship studies show a positive correlation between biologic drug concentrations and favorable therapeutic outcomes in IMID with higher drug concentrations typically associated with more objective outcomes. Clinically, reactive TDM rationalizes the management of PNR and SLR to anti-tumor necrosis factor therapy and is emerging as the new standard of care in IBD as it is also more cost-effective than empiric dose escalation. Preliminary data suggest that proactive TDM with the goal to achieve a threshold drug concentration is associated with better therapeutic outcomes when compared to empiric drug optimization and/or reactive TDM of infliximab and adalimumab in IBD. However, more data from well-designed prospective studies are needed to prove the benefit of TDM-based algorithms in real life clinical practice in IMID.