Simon Campbell

Ciclosporin use in acute ulcerative colitis: a long-term experience.

Background Within a lifetime, approximately 15% of ulcerative colitis (UC) patients will have a severe relapse necessitating admission to hospital. Despite intravenous steroid treatment, approximately 25% will require either surgery or ciclosporin (CsA) rescue therapy. Initial response rates to CsA have been encouraging, but remission rates have been disappointing. There is a paucity of long-term data on UC patients who have been brought into remission with CsA. Objectives To report our 7 year experience on the use of CsA in acute UC and to highlight long-term follow-up data on these patients. Patients and methods A retrospective database of 76 UC patients requiring CsA between 1996 and 2003 was constructed. CsA was started on the basis of their C-reactive protein (CRP) and/or stool frequency after 3 days or after 5-7 days of i.v. hydrocortisone. The patients (33 female, 43 male, mean age 44.5 years) were followed up for a median 2.9 years (range 0.2-7.0 years). Fifty-four patients received i.v. CsA (4 mg/kg), while 22 received oral CsA (5 mg/kg). Long-term outcome was evaluated by Kaplan-Meier survival analysis: time to first relapse and time to surgery. Results Median disease duration was 6.6 years. Median CRP and stool frequency at day 3 was 20 mg/l and 6 per day, respectively. Fifty-six patients (74%) achieved initial remission. CsA was discontinued in only four patients due to side effects. Duration of i.v. steroids or the addition of AZA did not improve time to first relapse or time to surgery. Comparison between i.v. CsA and oral CsA revealed a statistically significant difference in time to first relapse (P< 0.01) and time to surgery (P< 0.05) in favour of oral CsA. Conclusions These data describe the long-term outcome of the largest series of patients so far reported that have had treatment with CsA for severe refractory UC. If patients achieved initial remission with CsA, after 1 year, 65% had relapsed and after 3 years 90% had relapsed. After 7 years, 58% had come to colectomy. Minor side effects were frequent, but none were life threatening. There was no increase in post-operative complications in those who came to colectomy.

Clinical guidelines for the management of pouchitis

Abstract: When surgery is necessary in patients with ulcerative colitis, total proctocolectomy with ileal pouch–anal anastomosis (IPAA) is the procedure of choice. Several inflammatory and noninflammatory complications can occur after IPAA. Pouchitis is the most common, occurring in ≈50% of patients. Whereas “acute” pouchitis can be treated rapidly and successfully in the majority of patients, “refractory” and “chronic pouchitis” remain therapeutic challenges to patients and physicians. This article reviews the literature and offers consensus guidelines on issues related to the epidemiology, diagnosis, pathogenesis, risk factors, and treatment of pouchitis. Inflamm Bowel Dis

Infliximab therapy for Crohn's disease in the presence of chronic hepatitis C infection

Treatment of Crohns disease with infliximab is an important drug therapy for patients with refractory and fistulating disease. There are concerns over its use in a proportion of Crohns patients with concurrent hepatitis C infection, since there are theoretical risks of accelerated hepatic decompensation due to the immunomodulatory impact of infliximab. We report a patient with both Crohns disease and ongoing active hepatitis C infection who underwent infliximab therapy, with no worsening of his liver function or PCR status.

Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation

Summary Regulatory T (Treg) cells play a pivotal role in suppressing self-harmful T cell responses, but how Treg cells mediate suppression to maintain immune homeostasis and limit responses during inflammation is unclear. Here we show that effector Treg cells express high amounts of the integrin αvβ8, which enables them to activate latent transforming growth factor-β (TGF-β). Treg-cell-specific deletion of integrin αvβ8 did not result in a spontaneous inflammatory phenotype, suggesting that this pathway is not important in Treg-cell-mediated maintenance of immune homeostasis. However, Treg cells lacking expression of integrin αvβ8 were unable to suppress pathogenic T cell responses during active inflammation. Thus, our results identify a mechanism by which Treg cells suppress exuberant immune responses, highlighting a key role for effector Treg-cell-mediated activation of latent TGF-β in suppression of self-harmful T cell responses during active inflammation.

Effective maintenance of inflammatory bowel disease remission by azathioprine does not require concurrent 5-aminosalicylate therapy

Objectives To assess the effect of 5-aminosalicylate treatment in conjunction with azathioprine on remission maintenance in inflammatory bowel disease patients. Method This retrospective study was based on a total of 186 inflammatory bowel disease patients (104 with Crohns disease; 82 with ulcerative colitis), who were stable on azathioprine for a minimum of 6 months. The median duration of follow-up was 4.3 years (range 0.6–15.5 years). Relapse rates per year of follow-up were compared in an azathioprine + 5-aminosalicylate group (n = 103) and an azathioprine alone group (n = 83); survival curves for cumulative remission rates were compared by log-rank test. Discontinuation of azathioprine in both groups was also recorded, as was the incidence of malignancy. Results In ulcerative colitis patients (n = 82), mean relapse rates for the azathioprine + 5-aminosalicylate group were 0.21/year compared with 0.19/year for the azathioprine alone group (P = not significant). In Crohns disease patients (n = 104), mean relapse rates for the azathioprine + 5-aminosalicylate group were 0.27/year compared with 0.3/year for the azathioprine alone group (P = not significant). The cumulative remission percentage (determined from time to first relapse) was used in Kaplan–Meier survival analysis and showed no difference between the azathioprine + 5-aminosalicylate group and the azathioprine alone group by log-rank analysis, for ulcerative colitis and Crohns disease as well as for all inflammatory bowel disease patients. Concurrent use of 5-aminosalicylates was no more frequent in patients who discontinued azathioprine due to adverse events. The only malignancy recorded was Waldenströms macroglobulinaemia after 7 years of azathioprine therapy. Conclusion Concurrent use of 5-aminosalicylate drugs did not reduce the relapse rates of inflammatory bowel disease patients who were established on azathioprine therapy. The use of 5-aminosalicylate drugs did not lead to any increase in discontinuation of azathioprine due to adverse events.

Experience of maintenance infliximab therapy for refractory ulcerative colitis from six centres in England.

Background  Infliximab is used for treatment of Crohn’s disease and, following the Active Ulcerative Colitis Trials (ACT) 1 and 2, it has been used as rescue and maintenance therapy in moderate and severe ulcerative colitis (UC).

Does weight-adjusted anti-tumour necrosis factor treatment favour obese patients with Crohn's disease?

Background Adalimumab (ADA) is a subcutaneous anti-tumour necrosis factor (anti-TNF) agent, effective in inducing and maintaining remission in Crohn’s disease (CD). Unlike Infliximab (IFX), ADA dosing is not weight adjusted and dose frequency is based on clinical response. Aim To determine whether obesity is a risk factor for early loss of response (LOR) to anti-TNF treatment and whether weight-adjusted anti-TNF treatment is favourable. Materials and methods A hospital database of CD patients receiving anti-TNF treatment was analyzed retrospectively. The relationship between time to LOR and BMI was examined by Kaplan–Meier (KM) survival curves and a Cox proportional hazards model. Results ADA patients: Of the 54 patients (46 BMI<30 and 8 BMI≥30), KM estimation indicated a significantly shorter time to dose escalation in the BMI of at least 30 (&khgr;2=6.117, P=0.01). The Cox proportional hazards model showed that an increased hazard of LOR to ADA is related to increases in BMI (P=0.04). IFX patients: Of the 76 patients (62 BMI<30 and 14 BMI≥30), KM estimation showed that the differences in survival curves were not significant (&khgr;2=1.933, P=0.16) for the BMI groups. This was supported by the Cox proportional hazard model (P=0.36). Conclusion BMI appears to be important in predicting ADA efficacy (LOR) in CD. IFX appears to overcome this reduction of efficacy in obese patients. A prospective study evaluating the effect of weight on anti-TNF drug response and serum drug levels is warranted.

Is neutropenia required for effective maintenance of remission during azathioprine therapy in inflammatory bowel disease

Background Azathioprine is an effective treatment for maintaining remission in inflammatory bowel disease (IBD). It is a matter of debate as to whether neutropenia is required during azathioprine therapy to achieve more effective disease remission. We evaluated whether neutropenia during azathioprine therapy reduced relapse rates in IBD patients. Patients and methods This retrospective study was based on a total of 173 IBD (96 Crohn’s disease (CD), 77 ulcerative colitis (UC)) patients who were stable on azathioprine for a minimum of 6 months. Median duration of follow-up was 4.0 years (range 0.6–21 years). The lowest neutrophil counts during treatment for these patients were recorded. Relapse rates per year of follow-up were compared in non-neutropenic patients (neutrophil count > 2.5 × 109, n = 129) and neutropenic patients (neutrophil count ⩽ 2.5 × 109, n = 44) groups, and survival curves for cumulative remission rates compared by log-rank test. Results Mean relapse rate per year of follow-up for the non-neutropenic group was 0.19/year (SD = 0.37/year) compared with the neutropenic group 0.28/year (SD = 0.43/year) (P = NS). Analysis was performed on UC and CD subgroups, and relapse rates were not significantly different. The cumulative remission per cent determined by Kaplan–Meier survival analysis showed no difference between non-neutropenic and neutropenic groups by log-rank analysis, for UC and CD as well as for all IBD patients. Conclusion Neutropenia ⩽ 2.5 × 109 while on azathioprine does not reduce the relapse rates of IBD patients who were established on azathioprine therapy compared with neutrophil counts > 2.5 × 109.

Replication and meta-analysis of 13,000 cases defines the risk for interleukin-23 receptor and autophagy-related 16-like 1 variants in Crohn's disease.

BACKGROUND/OBJECTIVE Variants in the interleukin-23 receptor (IL23R) and the autophagy-related 16-like 1 (ATG16L1) genes have been associated with an increased risk of Crohns disease (CD). Both genes were identified through genome-wide association scans and subsequent studies have validated these associations. To assess the effect size of these variants, an independent case-control association study and meta-analysis were performed. METHODS British Caucasian subjects with inflammatory bowel disease (n=500) and 877 ethnically matched controls were genotyped for the disease-associated variants in IL23R and ATG16L1. In addition, meta-analyses of 12,991 patients and 14,598 controls, and 11,909 patients and 15,798 controls, were conducted on independently published data for the associations between IL23R and ATG16L1 variants and CD, respectively. RESULTS In the present cohort, both susceptibility variants showed highly significant associations, including IL23R (rs11209026, P=0.0006; OR 0.37; 95% CI 0.21 to 0.67) and ATG16L1 (rs2241880, P=0.0017; OR 1.36; 95% CI 1.12 to 1.66). The meta-analysis based on the random effects model showed similar combined effects for rs11209026 (n=26, OR 0.41; 95% CI 0.37 to 0.46) and rs2241880 (n=25, OR 1.33; 95% CI 1.28 to 1.39). There was no statistically significant gene-gene interaction between caspase recruitment domain (CARD15) variants and the IL23R or ATG16L1 polymorphisms (P=0.44 and P=0.24, respectively). CONCLUSION The present cohort and meta-analysis provides strong evidence that, in addition to CARD15, polymorphisms in both IL23R and ATG16L1 alter susceptibility to CD and that these effects are consistent across all populations of European ancestry; however, only ATG16L1 is relevant to inflammatory bowel disease in the Asian population.

Inflammatory cues enhance TGFβ activation by distinct subsets of human intestinal dendritic cells via integrin αvβ8

Regulation of intestinal T-cell responses is crucial for immune homeostasis and prevention of inflammatory bowel disease (IBD). A vital cytokine in regulating intestinal T cells is transforming growth factor-β (TGFβ), which is secreted by cells as a latent complex that requires activation to function. However, how TGFβ activation is regulated in the human intestine, and how such pathways are altered in IBD is completely unknown. Here we show that a key activator of TGFβ, integrin αvβ8, is highly expressed on human intestinal dendritic cells (DCs), specifically on the CD1c+ but not the CD141+ intestinal DC subset. Expression was significantly upregulated on intestinal DC from IBD patients, indicating that inflammatory signals may upregulate expression of this key TGFβ-activating molecule. Indeed, we found that the Toll-like receptor 4 ligand lipopolysaccharide upregulates integrin αvβ8 expression and TGFβ activation by human DC. We also show that DC expression of integrin αvβ8 enhanced induction of FOXP3 in CD4+ T cells, suggesting functional importance of integrin αvβ8 expression by human DC. These results show that microbial signals enhance the TGFβ-activating ability of human DC via regulation of integrin αvβ8 expression, and that intestinal inflammation may drive this pathway in patients with IBD.