Dysregulation of innate immunity in ulcerative colitis patients who fail anti-tumor necrosis factor therapy

AIM To study the innate immune function in ulcerative colitis(UC) patients who fail to respond to anti-tumor necrosis factor(TNF) therapy.METHODS Effects of anti-TNF therapy, inflammation and medications on innate immune function were assessed by measuring peripheral blood mononuclear cell(PBMC) cytokine expression from 18 inflammatory bowel disease patients pre- and 3 mo post-anti-TNF therapy. Toll-like receptor(TLR) expression and cytokine production post TLR stimulation was assessed in UC "responders"(n = 12) and "non-responders"(n = 12) and compared to healthy controls(n = 12). Erythrocyte sedimentation rate(ESR) and C-reactive protein(CRP) levels were measured in blood to assess disease severity/activity and inflammation. Pro-inflammatory(TNF, IL-1β, IL-6), immuno-regulatory(IL-10), Th1(IL-12, IFNγ) and Th2(IL-9, IL-13, IL-17A) cytokine expression was measured with enzyme-linked immunosorbent assay while TLR cellular composition and intracellular signalling was assessed with FACS.RESULTS Prior to anti-TNF therapy, responders and nonresponders had similar level of disease severity and activity. PBMC's ability to respond to TLR stimulation was not affected by TNF therapy, patient's severity of the disease and inflammation or their medication use. At baseline, non-responders had elevated innate but not adaptive immune responses compared to responders(P < 0.05). Following TLR stimulation, nonresponders had consistently reduced innate cytokine responses to all TLRs compared to healthy controls(P < 0.01) and diminished TNF(P < 0.001) and IL-1β(P < 0.01) production compared to responders. This innate immune dysfunction was associated with reduced number of circulating plasmacytoid dendritic cells(p DCs)(P < 0.01) but increased number of CD4+ regulatory T cells(Tregs)(P = 0.03) as well as intracellular accumulation of IRAK4 in non-responders following TLR-2,-4 and-7 activation(P < 0.001). CONCLUSION Reduced innate immunity in non-responders may explain reduced efficacy to anti-TNF therapy. These serological markers may prove useful in predicting the outcome of costly anti-TNF therapy.

Small bowel MRI enteroclysis or follow through:Which is optimal?

AIM： TO determine if a nasojejunal tube （NJT） is required for optimal examination of enteroclysis and if patients can be examined only in the supine position. METHODS： Data were collected from all patients undergoing small bowel （SB） magnetic resonance imaging （MRI） examination over a 32-mo period. Patients either underwent a magnetic resonance （MR） follow-through （MRFT） or a MR enteroclysis （MRE） in the supine position. The quality of proximal and distal SB distension as well as the presence of motion artefact and image quality were assessed by 2 radiologists. RESULTS： One hundred and fourteen MR studies were undertaken （MRFT-49, MRE-65） in 108 patients in the supine position only. Image artefact was more frequent in MRE than in MRFT （29.2% vs 18.4%）, but was not statistically significant （P = 0.30）. Adequate distension of the distal SB was obtained in 97.8% of MRFT examinations and in 95.4% of MRE examinations, respectively. Proximal SB distension was, however, less frequently optimal in MRFT than in MRE （P = 0.0036）, particularly in patients over the age of 50 years （P = 0.0099）. Image quality was good in all examinations. CONCLUSION： All patients could be successfully iraaged in the supine position. MRE and MRFT are equivalent for distal SB distension and artefact effects. Proximal SB distension is frequently less optimal in MRFT than in MRE. MRE is, therefore, the preferred MR examination method of the SB.

Preventing infective complications in inflammatory bowel disease

Over the past decade there has been a dramatic change in the treatment of patients with Crohn&#x02019;s disease and ulcerative colitis, which comprise the inflammatory bowel diseases (IBD). This is due to the increasing use of immunosuppressives and in particular the biological agents, which are being used earlier in the course of disease, and for longer durations, as these therapies result in better clinical outcomes for patients. This, however, has the potential to increase the risk of opportunistic and serious infections in these patients, most of which are preventable. Much like the risk for potential malignancy resulting from the use of these therapies long-term, a balance needs to be struck between medication use to control the disease with minimization of the risk of an opportunistic infection. This outcome is achieved by the physician&#x02019;s tailored use of justified therapies, and the patients&#x02019; education and actions to minimize infection risk. The purpose of this review is to explore the evidence and guidelines available to all physicians managing patients with IBD using immunomodulating agents and to aid in the prevention of opportunistic infections.

Iron:An emerging factor in colorectal carcinogenesis

The carcinogenic potential of iron in colorectal cancer(CRC) is not fully understood.Iron is able to undergo reduction and oxidation,making it important in many physiological processes.This inherent redox property of iron,however,also renders it toxic when it is present in excess.Iron-mediated generation of reactive oxygen species via the Fenton reaction,if uncontrolled,may lead to cell damage as a result of lipid peroxidation and oxidative DNA and protein damage.This may promote carcinogenesis through increased genomic instability,chromosomal rearrangements as well as mutations of proto-oncogenes and tumour suppressor genes. Carcinogenesis is also affected by inflammation which is exacerbated by iron.Population studies indicate an association between high dietary iron intake and CRC risk.In this editorial,we examine the link betweeniron-induced oxidative stress and inflammation on the pathogenesis of CRC.

What is left when anti-tumour necrosis factor therapy in inflammatory bowel diseases fails?

The inflammatory bowel diseases (IBDs) are chronic incurable conditions that primarily present in young patients. Being incurable, the IBDs may be part of the patient&#x02019;s life for many years and these conditions require therapies that will be effective over the long-term. Surgery in Crohn&#x02019;s disease does not cure the disease with endoscopic recurrent in up to 70% of patients 1 year post resection. This means that, the patient will require many years of medications and the goal of the treating physician is to induce and maintain long-term remission without side effects. The development of the anti-tumour necrosis factor alpha (TNF&#x003b1;) agents has been a magnificent clinical advance in IBD, but they are not always effective, with loss of response overtime and, at times, discontinuation is required secondary to side effects. So what options are available if of the anti-TNF&#x003b1; agents can no longer be used? This review aims to provide other options for the physician, to remind them of the older established medications like azathioprine/6-mercaptopurine and methotrexate, the less established medications like mycophenolate mofetil and tacrolimus as well as newer therapeutic options like the anti-integins, which block the trafficking of leukocytes into the intestinal mucosa. The location of the intestinal inflammation must also be considered, as topical therapeutic agents may also be worthwhile to consider in the long-term management of the more challenging IBD patient. The more options that are available the more likely the patient will be able to have tailored therapy to treat their disease and a better long-term outcome.