Role of conventional therapies in the era of biological treatment in Crohn’s disease

Outstanding progress regarding the pathophysiology of Crohn’s disease (CD) has led to the development of innovative therapeutic concepts. Numerous controlled trials have been performed in CD. This review concentrates on the results of randomized,placebo-controlled trials,and meta-analyses when available,that provide the highest degree of evidence. Current guidelines on the management of CD recommend a step-up approach to treatment involving the addition of more powerful therapies as the severity of disease ...     

Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn’s disease patients

AIM:To investigate the correlation between the appearance of skin lesions and concentration of interleukin(IL)-17A,IL-23 and interferon-γ(IFN-γ)in Crohn’s disease(CD)patients during anti-tumor necrosis factor-α(TNF-α)therapy METHODS:A prospective study included 30 adult patients with CD of Caucasian origin(19 men and 11women;mean age±SD 32.0±8.6 years)during biological therapy with anti-TNF-αantibodies from January2012 to March 2013.Eighteen patients were treated with infliximab,seven with adalimumab and five withcertolizumab.Inclusion criteria were exacerbation of the underlying disease,Crohn’s Disease Activity Index over 300 and the ineffectiveness of previously used non-biological therapies.Patients with a history of psoriasis,atopic dermatitis and other autoimmune skin lesions were excluded from the study.The control group consisted of 12 healthy subjects.A diagnostic survey was carried out,blood tests and careful skin examination were performed,and the serum levels of IL-17,IL-23 and IFN-γwere measured using an enzyme-linked immunosorbent assays technique.Dermatoses that have developed in the course of biological therapy in patients who had no pre-existing skin lesions of similar character were qualified as skin lesions induced by antiTNF-αtherapy.RESULTS:Skin manifestations occurred in 18 of CD patients during the anti-TNF-αtherapy(60%),in the average time of 10.16±3.42 mo following the beginning of the 52-wk treatment cycle.Skin lesions observed in CD patients during biological therapy included psoriasiform lesions(44.4%),and eczema forms lesions(22.2%).In CD patients with drug induced skin lesions significantly higher levels of hemoglobin(13.3±1.5 g/dL vs 10.8±1.9 g/dL,P=0.018)and hematocrit(39.9%±4.5%vs 34.3%±5.4%,P=0.01),as well as a significantly lower level of platelets(268±62×103/μL vs 408±239×103/μL,P=0.046)was observed compared with CD patients without skin manifestations.The concentrations of IL-17A and IL-23in CD patients with skin lesions developed under antiTNF-αtherapy were significantly higher compared to those in patients without lesions(IL-17A:39.01±7.03pg/mL vs 25.71±4.90 pg/mL,P=0.00004;IL-23:408.78±94.13 pg/mL vs 312.15±76.24 pg/mL,P=0.00556).CONCLUSION:Skin lesions in CD patients during bio-logical therapy may result from significantly increased concentrations of IL-17A and IL-23,which are strongly associated with TNF-α/Th1 immune pathways.     

Treatment of pediatric refractory Crohn’s disease with thalidomide

AIM: To assess the efficacy and tolerability of thalidomide in pediatric Crohn’s disease (CD). METHODS: Six patients with refractory CD received thalidomide at an initial dose of 2 mg/kg per day for one month, then increased to 3 mg/kg per day or decreased to 1 mg/kg per day, and again further reduced to 0.5 mg/kg per day, according to the individual patient’s response to the drug. RESULTS: Remission was achieved within three months. Dramatic clinical improvement was demonstrated after thalidomide treatment...     

Adalimumab-induced interstitial pneumonia in a patient with Crohn’s disease

There are several reports of anti-tumor necrosis factor(TNF)-induced lung disease,especially in patients with rheumatologic diseases.Adalimumab is an antiTNF drug used to induce and maintain remission in patients with immune-mediated diseases,such as Crohn’s disease.Although pulmonary disorders could be an extra-intestinal manifestation of inflammatory bowel disease,biologic therapy could also be a cause of lung injury.Only few cases of adalimumab-induced lung toxicity have been reported,and the majority of them were in patients with rheumatologic diseases.Lung injury secondary to anti-TNF therapy should,after ruling out other etiologies,be considered in patients who have a temporal association between the onset of respiratory symptoms and the exposure to these drugs.A compatible pattern in the biopsy and the clinical improvement after discontinuation of the anti-TNF drug would strongly support the diagnosis.     

Pulmonary manifestations of Crohn’s disease

Crohn’s disease(CD)is a systemic illness with a constellation of extraintestinal manifestations affecting various organs.Of these extraintestinal manifestations of CD,those involving the lung are relatively rare.However,there is a wide array of lung manifestations,ranging from subclinical alterations,airway diseases and lung parenchymal diseases to pleural diseases and drug-related diseases.The most frequent manifestation is bronchial inflammation and suppuration with or without bronchiectasis.Bronchoalveolar lavage findings show an increased percentage of neutrophils.Drug-related pulmonary abnormalities include disorders which are directly induced by sulfasalazine,mesalamine and methotrexate,and opportunistic lung infections due to immunosuppressive treatment.In most patients,the development of pulmonary disease parallels that of intestinal disease activity.Although infrequent,clinicians dealing with CD must be aware of these,sometimes life-threatening,conditions to avoid further impairment of health status and to alleviate patient symptoms by prompt recognition and treatment.The treatment of CD-related respiratory disorders depends on the specific pattern of involvement,and in most patients,steroids are required in the initial management.     

Role of Salmonella enterica exposure in Chilean Crohn’s disease patients

AIM:To study the association between exposure toSalmonella enterica(SE)and Crohn’s disease(CD)and its clinical implications in Chilean patients.METHODS:Ninety-four unrelated Chilean CD patients from CAREI(Active Cohort Registry of Inflammatory Bowel Disease)presenting to a single inflammatory bowel disease(IBD)unit of a University Hospital were prospectively included in this study.A complete clinical evaluation,including smoking history,was performed at the initial visit,and all the important data of clinical evolution of CD were obtained.Blood samples from these CD patients and 88 healthy sex-and agematched control subjects were analyzed for exposure to SE and for their NOD2/CARD15 gene status using the presence of anti-Salmonella lipopolysaccharide antibodies[immunoglobulin-G type(IgG)]and polymerase chain reaction(PCR),respectively.We also evaluated exposure to SE in 90 sex-and age-matched patients without CD,but with known smoking status(30 smokers,30 non-smokers,and 30 former smokers).RESULTS:CD patients comprised 54 females and 40males,aged 35.5±15.2 years at diagnosis with a mean follow-up of 9.0±6.8 years.CD was inflammatory in 59 patients(62.7%),stricturing in 24(25.5%)and penetrating in 15(15.5%).Thirty cases(31.9%)had lesions in the ileum,29(30.8%)had ileocolonic lesions,32(34.0%)had colonic lesions and 23(24.4%)had perianal disease.Sixteen CD patients(17%)were exposed to SE compared to 15(17%)of 88 healthy control subjects(P=0.8).Thirty-one CD patients(32.9%)were smokers,and 7(7.4%)were former smokers at diagnosis.In the group exposed to SE,10 of 16 patients(62.5%)were active smokers compared to 21 of 78 patients(26.9%)in the unexposed group(P=0.01).On the other hand,10 of 31 smoking patients(32%)were exposed to SE compared to 5 of 56 nonsmoking patients(9%),and one of the seven former smokers(14%)(P=0.01).In the group of 90 patients without CD,but whose smoking status was known,there was no differ-ence in exposure to SE[3 of 30 smokers(10%),5 of30 non-smokers(16%),and 5 of 30 former smokers(16%)     

Time of infliximab therapy initiation and dose escalation in Crohn’s disease

AIM:To determine if early initiation of anti-tumor necrosis factor therapy affects the need for dose escalation.METHODS:This was a retrospective review of patients receiving infliximab therapy for Crohn’s disease(CD)at two outpatient gastroenterology clinics during July2009 to October 2010.All patients included in the study were biologic agent na?ve and had moderate to severe CD(Harvey Bradshaw index>8).Patients were divided into groups based on length of time between diagnosis to therapy initiation and concurrent immunosuppressant therapy.Kaplan-Meier survival analysis was used to compare the time to dose escalation for the four groups.RESULTS:There were 68 patients,51% female and 49% male,with an average age at diagnosis of 24.7±11.9 years.The average age at infliximab initiation was 34.8±14.8 years.Of the 68 patients,19%initiated inflixiamb within 2 years of diagnosis,and 51%had concurrent immunosuppressant therapy at the time of therapy initiation.Fifty percent of patients required dose escalation and the median time from therapy initiation to dose escalation was 10 mo(interquartile range:5.3-14.8).There was a statistically significant higher probability of requiring dose esclataion in patients who initiated biologic therapy within 2 years of diagnosis,without concurrent immunosuppressant therapy(P<0.01).CONCLUSION:Those who receive infliximab within 2years of CD diagnosis require more intense immunosuppressant therapy than those who received infliximab later.     

Current therapy of pediatric Crohn’s disease

Inflammatory bowel diseases(IBD), including Crohn's disease(CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate,antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor(TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy- induction and maintenance of remission while improving the patient's growth and overall well-being.     

Effect of tumor necrosis factor-α antagonists on oxidative stress in patients with Crohn's disease

AIM: To investigate changes in oxidative stress in Crohn's disease(CD) before and after anti-tumor necrosis factor(TNF)-α treatment.METHODS: A total of 42 patients with active CD, who were scheduled to be treated by anti-TNF-α antibodies, were enrolled. Serum levels of diacron-reactive oxygen metabolites(d-ROM), biological antioxidant potential(BAP), and modified ratio of oxidative stress and antioxidant capacity(m-OA) were measured using the Free Radical Analytical System before and 8 wk after induction of therapy with infliximab or adalimumab. The values for oxidative stress were correlated with disease activity and clinical response as determined by the CD activity index(CDAI) at 8 and 54 wk after the therapy.RESULTS: Prior to treatment, d-ROM showed significant correlations with CDAI(r = 0.42, P 0.01). There was a significant negative correlation between m-OA and CDAI before and after treatment(r =-0.48 vs r =-0.42, P 0.01). CDAI and d-ROM had decreased significantly by 8 wk after treatment(CDAI; 223.3 ± 113.2 vs 158.3 ± 73.4, P 0.01, d-ROM; 373 ± 133 vs 312 ± 101, P 0.05). However, neither BAP nor m-OA had changed significantly. In patients who had responded to the treatment at 8 wk, d-ROM, BAP, and m-OA levels before treatment did not differ significantly between patients with and without loss of response.CONCLUSION: Anti-TNF-α therapy decreases oxi-dative stress in patients with CD, but does not alter the production of antioxidants. Dysregulation of antioxidants may be associated with the disease.     

Role of the receptor for advanced glycation end products in hepatic fibrosis

AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE) in the pathogenesis of liver fibrogenesis. METHODS: In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells (HSC) were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin (AGEBSA) and Nε-(carboxymethyl) lysine (CML)-BSA, or with tumor necrosis factor-α (TNF-α). In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS: In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α. RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1(Ⅰ) mRNA by AGE-BSA. CONCLUSION: Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.     

Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis

Objectives Generation of advanced glycation end products (AGE) is an inevitable process in vivo and can be accelerated under pathologic conditions such as oxidative stress, e.g. in rheumatoid arthritis (RA). This process is mediated by the AGE-specific receptor (RAGE). In this study we analysed the presence of RAGE in RA and osteoarthritic (OA) synovial tissue using immunohistology.Methods Frozen synovial tissue samples from 11 RA patients and 12 OA patients were treated with goat anti-RAGE immunoglobulin G (IgG) and rabbit antigoat IgG. Immunostaining was visualised with streptavidin horse radish peroxidase (chromogen amino-ethyl-carbazole). Cell differentiation was performed with antibodies against CD68, CD45RO, and CD20.Results In 9/11 RA and 8/12 OA synovial specimens, RAGE was detected in synovial lining, sublining, and stroma. In RA, many T cells (CD45RO⁺) and some macrophages (CD68⁺) showed positive immunostaining for RAGE, whereas B cells were mostly negative. We found no difference in staining patterns between the RA and OA samples.Conclusions We detected RAGE in RA and OA synovial tissue. The presence of RAGE on macrophages, T cells, and some B cells suggests its role in the pathogenesis of inflammatory joint disease.     

Controlling the receptor for advanced glycation end‐products to conquer diabetic vascular complications

Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long‐term diabetes. Extensive intracellular and extracellular formation of advanced glycation end‐products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor‐dependent mechanisms are involved in AGE‐induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE‐binding receptor, is now recognized as a member of pattern‐recognition receptors and a pro‐inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00191.x, 2012)     

晚期糖基化终末产物受体在急性肺损伤中作用的研究进展

晚期糖基化终末产物受体是细胞表面模式识别受体,在Ⅰ型肺泡上皮细胞有丰富表达.近年研究表明急性肺损伤时,支气管肺泡灌洗液及血浆中晚期糖基化终末产物受体含量明显升高,且与肺损伤程度密切相关.另一方面,它与相应配体结合激活细胞内信号通路,参与急性肺损伤的炎症激活和放大过程.晚期糖基化终末产物受体将在判断急性肺损伤患者病情、预...     

Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes

Aims/hypothesis Activation of the receptor for advanced glycation end products (RAGE, also known as AGE-specific receptor [AGER]) has been implicated in the development of diabetic vascular complications. Blockade of RAGE using a soluble form of the receptor (sRAGE) suppressed vascular hyperpermeability and atherosclerosis in animal models. Since little is known about the regulation of endogenous sRAGE levels, we determined whether serum sRAGE is influenced by circulating AGEs and the severity of nephropathy in type 2 diabetic patients.Materials and methods We recruited 150 healthy control and 318 diabetic subjects. Diabetic subjects were subdivided into those with proteinuria, microalbuminuria or normoalbuminuria. Serum sRAGE was assayed by ELISA and serum AGEs by competitive ELISA using a polyclonal rabbit antiserum raised against AGE-RNase.Results Diabetic subjects had higher sRAGE (1,029.5 pg/ml [766.1–1,423.0] interquartile range vs 1,002.6 [726.5–1,345.3], p<0.05) and AGEs (4.07±1.13, SD, unit/ml vs 3.39±1.05, p<0.01) than controls. Proteinuric subjects had the highest sRAGE levels and there was a significant trend between the severity of nephropathy and sRAGE (p=0.01). In diabetic subjects, serum log(sRAGE) correlated with AGEs (r=0.27, p<0.001), log(plasma creatinine) (r=0.31, p<0.001), log(urine AER) (r=0.24, p<0.01) and log(triglycerides) (r=0.15, p<0.01). On stepwise linear regression analysis, AGEs and creatinine levels were the main independent determinants of sRAGE concentration.Conclusions/interpretation Serum sRAGE levels and circulating AGEs are associated with the severity of nephropathy in type 2 diabetic patients. Prospective studies are required to determine whether endogenous sRAGE potentially influences the development of diabetic vascular complications.     

Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients

BACKGROUND:

Interaction of the receptors for advanced glycation end products (RAGEs) with advanced glycation end products (AGEs) results in expression of inflammatory mediators (tumor necrosis factor-alpha [TNF-α] and soluble vascular cell adhesion molecule-1 [sVCAM-1]), activation of nuclear factor-kappa B and induction of oxidative stress – all of which have been implicated in atherosclerosis. Soluble RAGE (sRAGE) acts as a decoy for the RAGE ligand and is protective against atherosclerosis.

OBJECTIVES:

To determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs, TNF-α and sVCAM-1 are higher in non-ST elevation myocardial infarction (NSTEMI) patients than in healthy control subjects; and whether sRAGE or the ratio of AGEs to sRAGE (AGEs/sRAGE) is a predictor/biomarker of NSTEMI.

METHODS:

Serum levels of sRAGE, AGEs, TNF-α and sVCAM-1 were measured in 46 men with NSTEMI and 28 age- and sex-matched control subjects. Angiography was performed in the NSTEMI patients.

RESULTS:

sRAGE levels were lower, and levels of AGEs, TNF-α, sVCAM-1 and AGEs/sRAGE were higher in NSTEMI patients than in control subjects. sRAGE levels were negatively correlated with the number of diseased coronary vessels, serum AGEs, AGEs/sRAGE, TNF-α and sVCAM-1. The sensitivity of the AGEs/sRAGE test is greater than that of the sRAGE test, while the specificity and predictive values of the sRAGE test are greater than those of the AGEs/sRAGE test for identifying NSTEMI patients.

CONCLUSIONS:

Serum levels of sRAGE were low in NSTEMI patients, and were negatively correlated with extent of lesion, inflammatory mediators, AGEs and AGEs/sRAGE. Both sRAGE and AGEs/sRAGE may serve as biomarkers/predictors for identifying NSTEMI patients.     

晚期糖基化终末产物受体在心血管疾病中的研究进展

晚期糖基化终末产物受体(RAGE)属于细胞表面免疫球蛋白超家族中的一员,广泛表达于人体内皮细胞、平滑肌细胞、系膜细胞、心肌细胞、单核巨噬细胞和神经元细胞等。RAGE不仅参与炎症反应,还与糖尿病慢性并发症的发生、发展,类风湿性关节炎,肿瘤的侵袭和转移,阿尔茨海默病,慢性肾病等有关。现主要论述其在心血管疾病中的作用。