Debilitating diarrhoea and weight loss due to colitis in two RA patients treated with leflunomide

Diarrhoea and weight loss are frequently reported adverse events in rheumatoid arthritis (RA) patients receiving the disease-modifying antirheumatic drug (DMARD) leflunomide. According to the available literature these side effects occur mostly during the first 6 months of treatment, are rather mild and rarely lead to treatment withdrawal. In this report, we describe the clinical, endoscopic and histologic findings in two RA patients with severe diarrhoea and important weight loss more than 12 months after starting treatment with leflunomide. In both cases the symptoms were caused by colitis, but one had ulcerative and the other microscopic colitis. Despite treatment with budesonide the complaints only improved after withdrawal of leflunomide, making a causal relationship between this drug and the pathogenesis of colitis probable. The heterogeneous histopathological findings in these two patients, however, do not allow us to draw any definitive conclusions about the mechanism by which leflunomide causes diarrhoea and weight loss in RA patients. We conclude that persistent diarrhoea or weight loss in patients taking leflunomide can be more serious than what is previously reported in the literature. In such cases leflunomide treatment should be stopped and an endoscopic examination of the colon is recommended. Given the long half-life of this drug a washout procedure with cholestyramine should be considered whenever the problem is severe or persistent.     

Oral immune regulation using colitis extracted proteins for treatment of Crohn＇s disease： Results of a phase I clinical trial

AIM: To evaluate safety and possible efficacy of induction of oral immune regulation using colitis extracted proteins(CEP) in Crohn‘s disease (CD) subjects.METHODS: Ten CDs were treated orally with autologous CEP thrice weekly for 16 wk. Subjects were monitored for CDAI and IBDQ. Immune modulatory effect was assessed by T-lymphocyte FACS analysis, CEP-specific IFNγ ELISPOT assay and cytokine levels.RESULTS: Induction of oral immune regulation significantly ameliorated disease activity. All (10/10) subjects had clinical response (CDAI≤70) and 7/10 achieved clinical remission (CDAI≤150). Significant increase in mean IBDQ score was noted (134±9vs 164±12). No treatment-related adverse events were noted. High levels of CEP-specific IFNγ spot forming colonies were detected in five subjects prior to treatment and in all five, a marked decrease was observed. The CD4+/CDS+ lymphocyte ratio and peripheral NKT cell numbers increased significantly, in 7/10 and in 5/10 subjects, respectively. Significant increase in serum IL-10 and IL-4 levels was observed in 7/10 subjects during treatment period.CONCLUSION: Immune regulation via oral administration of CEP is a safe and possibly effective treatment for subjects with moderate CD and may provide means of antigen-specific immune modulation.     

Inflammatory bowel disease in rats： Bacterial and chemical interaction

AIM：To develop a novel model of colitis in rats, using a combination of iodoacetamide and enteropathogenic E. coli（EPEC）, and to elucidate the pathophysiologic processes implicated in the development of ulcerative colitis （UC）.
METHODS： Hale Sprague-Dawley rats （/7 = 158） were inoculated intrarectally on a weekly basis with 4 different combinations： （a） 1% methylcellulose （HC）, （b） 100 μL of 6% iodoacetamide （IA） in 1% HC, （c） 200 p.L containing 4×10^8 colony factor units （CFU） of EPEC, and （d） combined treatment of （IA） followed by bacteria （13） after 2 d. Thirty days post treatment, each of the four groups was divided into two subgroups; the inoculation was stopped for one subgroup and the other subgroup continued with biweekly inoculation until the end of the experiment. Colitis was evaluated by the clinical course of the disease, the macroscopic and microscopic alterations, activity of myeloperoxidase （HPO）, and by TNF-α gene expression. RESULTS： Findings indicative of UC were seen in the combined treatment （IA ＋ B） as well as the IA continued treatment groups： the animals showed slow rate of increase in body weight, diarrhea, bloody stools, high colonic ulcer score, as well as histological alterations characteristic of UC, with an extensive inflammatory reaction. During the course of the experiment, the MPO activity was consistently elevated and the TNF-α gene expression was upregulated compared to the control animals.
CONCLUSION： The experimental ulcerative colitis model used in the present study resembles, to a great extent, the human disease. It is reproducible with characteristics indicative of chronicity.     

辨证论治对溃疡性结肠炎相关细胞因子调节作用的研究进展

溃疡性结肠炎（ Ulcerative Colitis,UC）是一种病因尚不明确的慢性肠道炎性疾病,目前认为UC的发病主要涉及免疫异常、遗传、感染、黏膜屏障等因素。大量研究表明细胞因子与UC的发病有重要的关系,与UC相关的主要促炎细胞因子有IL－1、IL－2、IL－6、IL－8、IL－1β和肿瘤坏死因子（ TNF－α）,而主要的抗炎细胞因子有IL－4、IL－10、IL－13等。目前所知的西药存在不良反应多、复发率高、难于长期服用等缺点,而中医辨证论治治疗UC疗效好,副作用少。近年来,中医药治疗UC的分子生物学和免疫学研究也取得了一定进展,研究发现白头翁汤、黄芩汤、四逆汤、乌梅丸、参苓白术散等能够降低UC大鼠血清或结肠组织中促炎细胞因子IL－2、IL－6、IL－8、TNF－α、IL－1β含量,升高血清中抗炎细胞因子IL－4、IL－10、IL－13的含量。本文就近5年来UC中医分型的代表方剂在细胞因子的实验研究中所取得的进展进行了总结。     

Clinical relevance of intestinal barrier dysfunction in common gastrointestinal diseases

The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall. In this review, we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment, specifically the microbiome. The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens, luminal antigens, or other pro-inflammatory factors. Control over barrier function and the luminal milieu is maintained at the biochemical, cellular, and immunological level. However, disruption to this highly regulated environment can cause disease. Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology. There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences. The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases. This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.     

活动期溃疡性结肠炎患者血清vaspin水平及其临床意义

脂肪细胞因子与机体内能量稳定相关,并介导多种免疫应答和炎症反应。内脏脂肪特异性丝氨酸蛋白酶抑制剂vaspin是近年发现的一种与炎症反应有关的脂肪细胞因子。目的:检测活动期溃疡性结肠炎(UC)患者的血清vaspin水平并探讨其临床意义。方法:选取2008年1月~2013年4月苏州市立医院收治的150例活动期UC患者,以150名健康体检者作为正常对照组。采用ELISA法检测血清vaspin水平,并分析其与UC临床特征的相关性。结果:UC患者血清vaspin水平显著高于正常对照者[(1.86±0.38)μg/L对(0.96±0.43)μg/L,P0.01],并与血清CRP水平和疾病活动指数呈显著正相关(r=0.628,P0.01;r=0.514,P0.05),与血清ESR水平和病变部位无关(r=0.098,P0.05;r=0.124,P0.0)5)。结论:Vaspin可能在UC发生、发展的病理生理机制中发挥重要作用。