• biologic treatment
• immunohistochemical parameters
• inflammatory bowel disease

• management
• monogenic IBD
• pharmacotherapy
• very early onset inflammatory bowel disease (VEO-IBD)

• Crohn’s disease
• Fistulising disease
• Infliximab
• Perianal
• Surgery

Infliximab (IFX), as a drug of first-line therapy, can alter the natural progression of Crohn’s disease (CD), promote mucosal healing and reduce complications, hospitalizations, and the incidence of surgery. Perianal fistulas are responsible for the refractoriness of CD and represent a more aggressive disease. IFX has been demonstrated as the most effective drug for the treatment of perianal fistulizing CD. Unfortunately, a significant proportion of patients only partially respond to IFX, and optimization of the therapeutic strategy may increase clinical remission. There is a significant association between serum drug concentrations and the rates of fistula healing. Higher IFX levels during induction are associated with a complete fistula response in these patients. Given the apparent relapse of perianal fistulizing CD, maintenance therapy with IFX over a longer period seems to be more beneficial. It appears that patients without deep remission are at an increased risk of relapse after stopping anti-tumor necrosis factor agents. Thus, only patients in prolonged clinical remission should be considered for withdrawal of IFX treatment when biomarker and endoscopic remission is demonstrated, especially when the hyperintense signals of fistulas on T2-weighed images have disappeared on magnetic resonance imaging. Fundamentally, the optimal timing of IFX use is highly individualized and should be determined by a multidisciplinary team.

• Infliximab
• Crohn’s disease
• Perianal fistula
• Optimization
• Trough level
• Deep remission

• Crohn Disease/complications
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Drug Administration Schedule
• Humans
• Infliximab/administration & dosage
• Magnetic Resonance Imaging
• Proctoscopy
• Rectal Fistula/diagnosis
• Rectal Fistula/drug therapy
• Rectal Fistula/etiology
• Recurrence
• Remission Induction/methods
• Secondary Prevention/methods
• Time Factors
• Treatment Outcome
• Wound Healing/drug effects

• Biologics
• Clinical pharmacology
• Crohn’s disease
• Inflammatory bowel disease
• Nutrition
• Thiopurines
• Ulcerative colitis

• Administration, Intravenous
• Administration, Oral
• Colitis, Ulcerative/therapy
• Crohn Disease/therapy
• Dose-Response Relationship, Drug
• Enteral Nutrition/methods
• Gastrointestinal Agents/therapeutic use
• Humans
• Patient Education as Topic
• Time Factors
• Treatment Outcome

• Hidradenitis suppurativa
• Keratinocytes
• MMP
• Macrophages
• NLRP3
• Pro-inflammatory cytokines

• Chitosan
• Macrophage
• N-(2-hydroxy)propyl-3-trimethyl ammonium chitosan chloride
• Nanoparticle
• RNA interference
• Tripolyphosphate

• Animals
• Chitosan/analogs & derivatives
• Chitosan/chemistry
• Macrophages/cytology
• Macrophages/metabolism
• Mice
• Nanoparticles/chemistry
• Polyphosphates/chemistry
• Quaternary Ammonium Compounds/chemistry
• RAW 264.7 Cells
• RNA Interference
• RNA, Small Interfering/administration & dosage
• RNA, Small Interfering/genetics
• RNA, Small Interfering/pharmacokinetics
• Tumor Necrosis Factor-alpha/genetics

• I01 BX002526 BLRD VA
• R01 DK071594 NIDDK NIH HHS

• Johne's disease
• TNF-α
• Thalidomide
• pharmacokinetics
• sheep
• tumour necrosis factor alpha

IBD (inflammatory bowel disease), where CD (Crohn's disease) and UC (ulcerative colitis) represent the two main forms, are chronic inflammatory conditions of the intestine. Macrophages play a central role in IBD pathogenesis and are regulated by major differentiation factors such as CSF-1 (colony-stimulating factor 1) in homoeostasis and inflammation. IL (interleukin)-34 has recently been discovered as a second ligand for CSF-1R (CSF-1 receptor). However, expression and involvement of IL-34 in IBD remain unknown. In the present paper, we investigated the expression of IL34, CSF1 and their shared receptor CSF1R in normal human ileum and colon, in inflamed and non-inflamed tissues of CD and UC patients, and in a mouse model of experimental colitis. We found distinct expression patterns of IL34 and CSF1 in ileum and colon, with higher IL34 in ileum and, in contrast, higher CSF1 in colon. Furthermore, IL34 and CSF1 expression was increased with inflammation in IBD patients and in experimental colitis. In humans, infiltrating cells of the lamina propria and intestinal epithelial cells expressed IL-34, and TNF-α (tumour necrosis factor α) regulated IL-34 expression in intestinal epithelial cells through the NF-κB (nuclear factor κB) pathway. These data demonstrate the expression pattern of IL-34 in ileum and colon and suggest IL-34 as a new modulator of inflammation in IBD.

The macrophage differentiation factor interleukin-34, produced by intestinal epithelial cells, is up-regulated in patients with inflammatory bowel disease, and may be a novel modulator of intestinal inflammation.

This study was undertaken to evaluate the efficacy of infliximab (IFX) in treatment of Crohn's disease (CD) patients. 106 CD patients were undergoing treatment with IFX from five hospitals in Shanghai, China. Clinical remission to IFX induction therapy was defined as Crohn's disease activity index (CDAI) < 150. Clinical response was assessed by a decrease in CDAI ≥ 70, and the failure as a CDAI was not significantly changed or increased. Ten weeks after therapy, 61 (57.5%) patients achieved clinical remission, 17 (16.0%) had clinical response, and the remaining 28 (26.4%) were failed. In remission group, significant changes were observed in CDAI, the Simple Endoscopic Score for Crohn's Disease (SES-CD), and serum indexes. Patients with short disease duration (22.2 ± 23.2 months) and luminal lesions showed better effects compared to those with long disease duration (71.0 ± 58.2 months) or stricturing and penetrating lesions. IFX markedly downregulated Th1/Th17-mediated immune response but promoted IL-25 production in intestinal mucosa from remission group. No serious adverse events occurred to terminate treatment. Taken together, our studies demonstrated that IFX is efficacious and safe in inducing clinical remission, promoting mucosal healing, and downregulating Th1/Th17-mediated immune response in short course CD patients with luminal lesions.

• Humans
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Antibodies, Anti-Idiotypic/blood
• Antibodies, Monoclonal/adverse effects
• Clinical Trials as Topic
• Drug Hypersensitivity/immunology
• Inflammatory Bowel Diseases/blood
• Inflammatory Bowel Diseases/drug therapy
• Infliximab
• Infusions, Intravenous
• Prognosis
• Risk Factors

• K23DK084338 NIDDK NIH HHS

• Bioreducible polymer
• IBD therapy
• Macrophage-targeted delivery
• Mannosylation
• RNA interference

Biological therapies have been introduced for the treatment of chronic inflammatory diseases including rheumatoid arthritis (RA) and Crohn's disease (CD). The efficacy of biologics differs from patient to patient. Moreover these therapies are rather expensive, therefore treatment of primary non-responders should be avoided.

We addressed this issue by combining gene expression profiling and biostatistical approaches. We performed peripheral blood global gene expression profiling in order to filter the genome for target genes in cohorts of 20 CD and 19 RA patients. Then RT-quantitative PCR validation was performed, followed by multivariate analyses of genes in independent cohorts of 20 CD and 15 RA patients, in order to identify sets ofinterrelated genes that can separate responders from non-responders to the humanized chimeric anti-TNFalpha antibody infliximab at baseline.

Gene panels separating responders from non-responders were identified using leave-one-out cross-validation test, and a pool of genes that should be tested on larger cohorts was created in both conditions.

Our data show that peripheral blood gene expression profiles are suitable for determining gene panels with high discriminatory power to differentiate responders from non-responders in infliximab therapy at baseline in CD and RA, which could be cross-validated successfully. Biostatistical analysis of peripheral blood gene expression data leads to the identification of gene panels that can help predict responsiveness of therapy and support the clinical decision-making process.

Despite significant improvements in medical management of inflammatory bowel disease, many of these patients still require surgery at some point in the course of their disease. Their young age and poor general conditions, worsened by the aggressive medical treatments, make minimally invasive approaches particularly enticing to this patient population. However, the typical inflammatory changes that characterize these diseases have hindered wide diffusion of laparoscopy in this setting, currently mostly pursued in high-volume referral centers, despite accumulating evidences in the literature supporting the benefits of minimally invasive surgery. The largest body of evidence currently available for terminal ileal Crohn’s disease shows improved short term outcomes after laparoscopic surgery, with prolonged operative times. For Crohn’s colitis, high quality evidence supporting laparoscopic surgery is lacking. Encouraging preliminary results have been obtained with the adoption of laparoscopic restorative total proctocolectomy for the treatment of ulcerative colitis. A consensus about patients’ selection and the need for staging has not been reached yet. Despite the lack of conclusive evidence, a wave of enthusiasm is pushing towards less invasive strategies, to further minimize surgical trauma, with single incision laparoscopic surgery being the most realistic future development.

• Laparoscopic surgery
• Inflammatory bowel disease
• Ulcerative colitis
• Crohn’s disease

Dendritic cells (DC) are antigen-presenting cells that play a pivotal role in regulating innate and adaptive immune responses. In autoimmunity, DC act as a double-edged sword since on one hand they initiate adaptive self-reactive responses and on the other they play a pivotal role in promoting and maintaining tolerance. Thus, DC are the most important cells in either triggering self-specific responses or in negatively regulating auto-reactive responses. The latter function is mediated by DC in the steady-state or specialized subsets of DC, named tolerogenic DC. Clinical and experimental evidence indicate that prolonged presentation of self-antigens by DC is crucial for the development of destructive autoimmune diseases, and defects in tolerogenic DC functions contribute to eradication of self-tolerance. In recent years, DC have emerged as therapeutic targets for limiting their immunogenicity against self-antigens, while tolerogenic DC have been conceived as therapeutic tools to restore tolerance. The purpose of this review is to give a general overview of the current knowledge on the pathogenic role of DC in patients affected by autoimmune diseases. In addition, the protective role of tolerogenic DC will be addressed. The currently applied strategies to block immune activation or to exploit the tolerogenic potential of DC will be discussed.

• autoimmune diseases
• dendritic cells
• tolerance

Ischaemia/reperfusion (I/R) injury is an underlying complex interrelated patho-physiological process which effects the outcome of many clinical situations, in particular transplantation. Tumor necrosis factor (TNF)-α is a pleiotropic inflammatory cytokine; a trimeric protein encoded within the major histocompatibility complex which plays a pivotal role in this disease process. This review is based at looking into an update, particularly the new insights in the mechanisms of action of TNF antagonist such as infliximab. Infliximab may thus play a dual role in the field of transplantation where it might not only down regulate the I/R injury, it may also have a beneficial role in the reduction of acute rejection.

• Infliximab
• Ischaemia/reperfusion injury
• Tumor necrosis factor-α

There have been increasing concerns regarding the safety of perioperative anti-tumour necrosis factor (anti-TNF) α agents. We performed a literature review to evaluate the post-operative complications associated with perioperative anti-TNF use in patients with inflammatory bowel disease. A comprehensive review was performed with a literature search utilizing Pub Med, Cochrane, OVID and EMBASE databases according to published guidelines. To date, there are only data for infliximab. There are three published studies which have assessed post-operative complications with perioperative infliximab use in patients with Crohn’s disease (CD), four studies in ulcerative colitis (UC) patients, and one study on both CD and UC patients. Two out of the three studies in CD patients showed no increased post-operative complications associated with perioperative infliximab. Two out of four studies in UC patients also did not show an increase in post-operative complications, and the combined study with CD and UC patients did not show an increased risk as well. Study results could not be combined secondary to significant differences in study designs, patient population and definition of their endpoints. There appears to be a risk of post-operative complications associated with TNF therapy in some patients. Based on these data, careful patient selection and prospective data collection should be performed.

• Crohn’s disease
• Ulcerative colitis
• Colectomy
• Post-operative complications

• Crohn Disease/surgery
• Humans
• Laparoscopy

Crohn’s disease (CD) is a chronic inflammatory disease of the gastrointestinal tract characterized by recurring flares followed by periods of inactive disease and remission. The etiology is unknown, although the common opinion is that the disease arises from a disordered immune response to the gut contents in genetically predisposed individuals. Infliximab (IFX), a chimeric immunoglobulin G1 monoclonal antibody to tumor necrosis factor, has dramatically changed the approach to managing patients with CD and improving their treatment, by achieving treatment goals, such as mucosal healing, and decreasing the need for hospitalizations and surgeries. This review provides an update on existing evidence for the use of IFX in CD, taking into account the safety profile in clinical practice and special situations such as pregnancy. Antitumor necrosis factor therapy has been evaluated as an induction and maintenance therapy in CD in several randomized controlled trials and meta-analyses, showing efficacy in both clinical settings. Early use of biologics may improve patient outcomes in active CD. However, a widespread use of a “top-down” approach in all CD patients cannot be recommended. Clinical factors at diagnosis may predict poor outcome in CD, and should be taken into account when determining the initial therapeutic approach.

• Crohn’s disease
• adult
• infliximab

Patients with IBD and chronic inflammation refractory to conventional therapy often demonstrate higher risk of serious complications. Combinations of immunosuppression and biological treatment as well as surgical intervention are often used in this patient group. Hence, there is need for additional treatment options. In this observational study, focused on re-treatment and long-term results, Granulocyte/Monocyte Adsorption (GMA, Adacolumn^®) treatment has been investigated to study efficacy, safety and quality of life in IBD-patients with chronic activity.

Fifteen patients with ulcerative colitis and 25 patients with Crohn's disease, both groups with chronically active inflammation refractory to conventional medication were included in this observational study. The patients received 5-10 GMA sessions, and the clinical activity was assessed at baseline, after each completed course, and at week 10 and 20 by disease activity index, endoscopy and quality of life evaluation. Relapsed patients were re-treated by GMA in this follow-up study up to 58 months.

Clinical response was seen in 85% and complete remission in 65% of the patients. Ten patients in the UC-group (66%) and 16 patients in the CD-group (64%) maintained clinical and endoscopic remission for an average of 14 months. Fourteen patients who relapsed after showing initial remission were re-treated with GMA and 13 (93%) went into a second remission. Following further relapses, all of seven patients were successfully re-treated for the third time, all of three patients for the fourth time and one for a fifth time.

IBD-patients with chronic inflammation despite conventional therapy seem to benefit from GMA. Re-treatment of relapsing remission patients seems to be effective.

• Age Factors
• Biological Products/therapeutic use
• Biomarkers
• C-Reactive Protein/analysis
• Drug Monitoring
• Endoscopy, Digestive System
• Feces/chemistry
• Humans
• Immunologic Factors/therapeutic use
• Immunosuppressive Agents/therapeutic use
• Inflammatory Bowel Diseases/blood
• Inflammatory Bowel Diseases/diagnostic imaging
• Inflammatory Bowel Diseases/epidemiology
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/pathology
• Inflammatory Bowel Diseases/therapy
• Intestinal Fistula/etiology
• Intestinal Mucosa/pathology
• Radiography
• Risk Factors
• Smoking/adverse effects

• Acute Disease
• Adult
• Anti-Inflammatory Agents/therapeutic use
• Antibodies, Monoclonal/therapeutic use
• Colonic Diseases/complications
• Colonic Diseases/drug therapy
• Colonic Diseases/pathology
• Colonoscopy
• Crohn Disease/complications
• Crohn Disease/drug therapy
• Crohn Disease/pathology
• Female
• Gastrointestinal Hemorrhage/complications
• Gastrointestinal Hemorrhage/drug therapy
• Gastrointestinal Hemorrhage/pathology
• Humans
• Infliximab
• Young Adult

• Adult
• Colitis, Ulcerative/physiopathology
• Crohn Disease/physiopathology
• Female
• Follow-Up Studies
• Hospitalization
• Humans
• Male
• Prognosis
• Retrospective Studies
• Risk Factors
• Smoking/physiopathology
• Surveys and Questionnaires
• Tobacco Smoke Pollution
• Young Adult