Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford.

BACKGROUND: Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients. AIM: To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission. METHODS: A retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded. RESULTS: Three hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% n = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% vs 70% P = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% vs 40% P < 0.001, 6 mo 73% vs 46% P < 0.001, 12 mo 66% vs 51% P = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% vs 43% P = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed (P < 0.001). 32 patients (11%) had colectomy by 12 mo. CONCLUSION: VDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.

Modifying T-cell trafficking to the intestinal as a potential management for inflammatory bowel disease.

INTRODUCTION: The Inflammatory Bowel Diseases (IBDs) are life-long chronic relapsing incurable inflammatory conditions that usually appear in the first few decades of life. There have been marked advances in the management of these conditions, but none of the currently available therapies are a panacea as they are neither universally efficacious nor will their efficacy necessarily last. There is a desperate need for new therapies that target the immunological deficits within the immune system with low side effects and long-term efficacy. AREAS COVERED: Leukocyte trafficking into the intestinal mucosa is central to the inflammatory pathogenesis in both Crohn's disease (CD) and ulcerative colitis (UC) and modification of this trafficking has the ability to reduce the level of inflammation. The α4ß7 integrin heterodimer is highly expressed on the CD4(+)CD45RA-memory T-cell subpopulation located within the intestine, and these play a critical part in the pathogenesis of IBD. EXPERT OPINION: By modifying the integrin and chemokine interactions with their specific receptors, inhibition of α4(+) and α4ß7(+) T-cell trafficking to the sites of intestinal inflammation is possible with promising outcomes in the management of IBD.

Mesenchymal cell proliferation and programmed cell death: key players in fibrogenesis and new targets for therapeutic intervention.

An exquisite equilibrium between cell proliferation and programmed cell death is required to maintain physiological homeostasis. In inflammatory bowel disease, and especially in Crohn's disease, enhanced proliferation along with defective apoptosis of immune cells are considered key elements of pathogenesis. Despite the relatively limited attention that has been given to research efforts devoted to intestinal fibrosis to date, there is evidence suggesting that enhanced proliferation along with defective programmed cell death of mesenchymal cells can significantly contribute to the development of excessive fibrogenesis in many different tissues. Moreover, some therapies have demonstrated potential antifibrogenic efficacy through the regulation of mesenchymal cell proliferation and programmed cell death. Further understanding of the pathways involved in the regulation of mesenchymal cell proliferation and apoptosis is, however, required.

Topical agents for idiopathic distal colitis and proctitis.

Rectally administered topical agents have demonstrated efficacy in the maintenance of distal colitis (DC) and proctitis and as they are rarely associated with significant blood drug levels, side effects are infrequent. The topical 5-aminosalicylic acid (5-ASA) suppositories and enemas target different regions of the distal colon and are effective for proctitis and DC, respectively. They demonstrate clinical results that are better than oral 5-ASAs and are preferred to topical steroids with better clinical, endoscopic and histological outcomes, without the risk of adrenal suppression. Disease resistant to topical agents, however, can be extremely difficult to manage. The addition of oral 5ASAs, steroids, immunosuppressants and the anti-tumor necrosis factor-α agents may be effective, but can result in significant side effects and not all patients will respond to the therapies. It is for these patients that new and novel therapies are required. Novel topical agents have been proposed for the management of resistant DC. These agents included butyrate, cyclosporine, and nicotine enemas, as well as tacrolimus suppositories, and tacrolimus, ecabet sodium, arsenic, lidocaine, bismuth, rebamipide and thromboxane enemas. While some of these agents appear to demonstrate impressive outcomes, the majority have only been examined in small open-labeled studies. There is thus a desperate need for more randomized double-blinded placebo controlled studies to investigate the clinical utility of these topical therapies. This review summarizes the efficacy of the established topical therapies, and explores the available data on the new and novel topical agents for the management of DC and proctitis.

Novel topical therapies for distal colitis.

Distal colitis (DC) can be effectively treated with topical 5ASA agents. Suppositories target the rectum while enemas can reliably reach the splenic flexure. Used in combination with oral 5ASAs, the control of the inflammation is even more effective. Unfortunately, resistant DC does occur and can be extremely challenging to manage. In these patients, the use of steroids, immunosuppressants and the anti-tumor necrosis factor α agents are often required. These, however, can be associated with systemic side effects and are not always effective. The investigation of new topical therapeutic agents is thus required as they are rarely associated with significant blood drug levels and side effects are infrequent. Some of the agents that have been proposed for use in resistant distal colitis include butyrate, cyclosporine and nicotine enemas as well as tacrolimus suppositories and tacrolimus, ecabet sodium, arsenic, lidocaine, rebamipide and Ridogrel(®) enemas. Some of these agents have demonstrated impressive results but the majority of the agents have only been assessed in small open-labelled patient cohorts. Further work is thus required with the investigation of promising agents in the context of randomized double-blinded placebo controlled trials. This review aims to highlight those potentially effective therapies in the management of resistant distal colitis and to promote interest in furthering their investigation.

Stevens-Johnson syndrome complicating adalimumab therapy in Crohn's disease.

The anti-tumor necrosis factor (TNF)alpha medications demonstrate efficacy in the induction of remission and its maintenance in numerous chronic inflammatory conditions. With the increasing number of patients receiving anti-TNFalpha agents, however, less common adverse reactions will occur. Cutaneous eruptions complicating treatment with an anti-TNFalpha agent are not uncommon, occurring in around 20% of patients. Adalimumab, a fully humanized antibody against TNFalpha, may be expected to cause minimal immune-mediated skin reactions compared to the chimeric monoclonal antibody, infliximab. We, however, report a case of Stevens-Johnson syndrome that required hospitalization and cessation of adalimumab in a patient with Crohn's disease (CD). In this case report, a 29-year-old male with colonic and perianal CD with associated erythema nodosum and large joint arthropathy developed severe mucositis, peripheral rash and desquamation, fevers and respiratory symptoms concomitant with a second dose of 40 mg adalimumab after a 2 mo break from adalimumab therapy. Skin biopsies of the abdominal wall confirmed erythema multiforme and the patient was on no other drugs and infective etiologies were excluded. The patient responded rapidly to IV hydrocortisone and was able to be commenced on infliximab without recurrence of the Stevens-Johnson syndrome. Desquamating skin reactions have now been described in three of the TNFalpha antagonists (infliximab, etanercept and adalimumab). These reactions can be serious and prescribers need to be aware of the potential mucocutaneous side effects of these agents, especially as Stevens-Johnson syndrome is associated with significant morbidity and mortality.

Correlation of MRI-determined small bowel Crohn's disease categories with medical response and surgical pathology.

AIM: To determine whether magnetic resonance imaging (MRI) can be used to categorize small bowel Crohn's disease (SB CD) into groups that correlate with response to medical therapy and surgical pathology. METHODS: Data was collected from all patients with MRI evidence of SB CD without significant colonic disease over a 32-mo period. Two radiologists, blinded to clinical findings, evaluated each MRI and grouped them based on bowel wall thickness and wall enhancement. These categories were: (1) "fibrosis", (2) "mild segmental hyper-enhancement and mild wall thickening", (3) "mild segmental hyper-enhancement and marked wall thickening", (4) "marked segmental transmural hyper-enhancement". Patient response to additional medical therapy post-MRI was prospectively determined at 8-wk. Non-responders underwent endoscopy and were offered therapeutic endoscopy or surgery. Surgical pathology was assessed against the MRI category. RESULTS: Fifty-five patients were included. Females and category "2" patients were more likely, and patients with luminal narrowing and hold-up less likely, to respond to medical therapy (P < 0.05). Seventeen patients underwent surgery. The surgical pathological findings of fibrosis and the severity of inflammation correlated with the MRI category in all cases. CONCLUSION: Our findings suggest that SB CD can be grouped by the MRI findings and that these groups are associated with patients more likely to respond to continued medical therapy. The MRI categories also correlated with the presence and level of intestinal inflammation and fibrosis on surgical pathology, and may be of prognostic use in the management of CD patients.

Use of mycophenolate mofetil in inflammatory bowel disease.

AIM: To assess the efficacy and safety of mycophenolate mofetil (MMF) prospectively in inflammatory bowel disease (IBD) patients intolerant or refractory to conventional medical therapy. METHODS: Crohn's disease (CD) or ulcerative colitis/IBD unclassified (UC/IBDU) patients intolerant or refractory to conventional medical therapy received MMF (500-2000 mg bid). Clinical response was assessed by the Harvey Bradshaw index (HBI) or colitis activity index (CAI) after 2, 6 and 12 mo of therapy, as were steroid usage and adverse effects. RESULTS: Fourteen patients (9 CD/5 UC/IBDU; 8M/6F; mean age 50.4 years, range 28-67 years) were treated and prospectively assessed for their response to oral MMF. Of the 11 patients who were not in remission on commencing MMF, 7/11 (63.6%) achieved remission by 8 wk. All 3 patients in remission on commencing MMF maintained their remission. Ten patients were still on MMF at 6 mo with 9/14 (64.3%) in remission, while of 12 patients followed for 12 mo, 8 were in remission without dose escalation (66.7%). Three patients were withdrawn from the MMF due to drug intolerance. There were no serious adverse events attributed due to the medication. CONCLUSION: MMF demonstrated efficacy in the management of difficult IBD. MMF appeared safe, well tolerated and efficacious for both short and long-term therapy, without the need for dose escalation. Further evaluation of MMF comparing it to conventional immunosuppressants is required.

Use of infliximab in the prevention and delay of colectomy in severe steroid dependant and refractory ulcerative colitis.

AIM: To determine if infliximab can prevent or delay surgery in refractory ulcerative colitis (UC). METHODS: UC patients who failed to have their disease controlled with conventional therapies and were to undergo colectomy if infliximab failed to induce a clinical improvement were reviewed. Patients were primarily treated with a single 5 mg/kg infliximab dose. The Colitis Activity Index (CAI) was used to determine response and remission. Data of 8 wk response and colectomy rates at 6 mo and 12 mo were collected. RESULTS: Fifteen patients were included, 7 with UC unresponsive or intolerant to i.v. hydrocortisone, and 8 with active disease despite oral steroids (all but one with therapeutic dosage and duration of immunomodulation). All the i.v. hydrocortisone-resistant/intolerant patients had been on azathioprine/6-MP < 8 wk. At 8 wk, infliximab induced a response in 86.7% (13/15) with 40% in remission (6/15). Within 6 mo of treatment 26.7% (4/15) had undergone colectomy and surgery was avoided in 46.6% (7/15) at 12 mo. The colectomy rate at 12 mo in those on immunomodulatory therapy < 8 wk at time of infliximab was 12.5% (1/8) compared with 100% (7/7) in patients who were on long-term maintenance immunomodulators (P < 0.02). CONCLUSION: Infliximab prevented colectomy due to active disease in immunomodulatory-naive, refractory UC patients comparable to the use of Cyclosporine. In patients, however, on effective dosage and duration of immunomodulation at time of infliximab therapy colectomy was not avoided.

Indomethacin and retinoic acid modify mouse intestinal inflammation and fibrosis: a role for SPARC.

The mouse model of 2,4,6-Trinitrobenzene Sulfonic Acid (TNBS)-induced intestinal fibrosis allows for detailed study of the extracellular matrix changes that complicate Crohn's disease. Indomethacin induces intestinal fibrosis, while retinoic acid (RA) reduces liver fibrosis. Secreted protein acidic and rich in cysteine (SPARC), an extracellular matrix-modifying agent, may potentially link these opposing effects. Our aim was to determine the effects of indomethacin and RA and to evaluate their correlation to SPARC expression in the TNBS mouse model. CD-1 mice were randomised to TNBS enemas weekly for 2 or 8 weeks with or without indomethacin (0.2 mg/kg per day) or RA (100 microg/kg per day). At 2 weeks, indomethacin/TNBS enhanced and RA reduced inflammation, tissue destruction and fibrosis. The expression of SPARC was inversely related to fibrosis, but not to inflammation, in the TNBS-alone groups at 2 weeks; these differences were lost by 8 weeks. The results demonstrate that indomethacin increases TNBS-induced fibrosis in mice, while RA reduces it, and that SPARC may link these opposing effects.

Poor correlation between clinical impression, the small colonic polyp and their neoplastic risk.

BACKGROUND AND OBJECTIVES: Significance of the small colonic polyp is unclear and its removal is frequently determined by the proceduralist's clinical impression. Our aims were to determine if clinical discernment is accurate, and the likelihood that lesions < 10 mm are histologically advanced. METHOD: We prospectively collected 1988 lesions from 854 subjects (2215 consecutive colonoscopies). Lesion size, location, patient age, sex and the colonoscopist's clinical impression was recorded. RESULTS: Clinical assessment for neoplasia had a sensitivity of 87.4%, specificity of 65.0%, positive predictive value of 76.0% and negative predictive value of 80.2%, resulting in an accuracy of 73.4%. Factors predictive of correct clinical impression were polyp size, location in the rectum and being pedunculated, but not the patient's age, sex or the endoscopist's experience. Of the 1434 lesions < or = 5 mm in size, 44.5% were neoplastic and 3.5% were histologically advanced. Of the 266 lesions 6-9 mm, 79.3% were neoplastic, 19.9% were histologically advanced, five demonstrated high-grade dysplasia and three were malignant. Only two patients with an adenocarcinoma or high-grade dysplasia in a polyp <10 mm had a lesion > or =10 mm elsewhere in the colon. Of the 288 lesions > or =10 mm in size, 92.7% were neoplastic, 29.5% had a villous component, 6.9% demonstrated high-grade dysplasia and 29.2% were malignant. Factors predictive of neoplasia were patient age, polyp size and sessile nature of the lesion. CONCLUSION: Polyps < 10 mm had a significant risk of neoplasia and advanced histology and, in general, clinical impression correlated poorly with neoplasia. Removal of all lesions proximal to the rectum, regardless of size, should therefore be considered.

A comparative study of goblet cell and pancreatic exocine autoantibodies combined with ASCA and pANCA in Chinese and Caucasian patients with IBD.

BACKGROUND: The incidence of Crohn's disease (CD) and ulcerative colitis (UC) is increasing, but differentiating between them is often extremely difficult. Pancreatic (PAB) and goblet cell autoantibodies (GAB) are specific for CD and UC, respectively, but with low sensitivity. In combination with anti-Saccharomyces cerevisiae (ASCA) and anti-neutrophil cytoplasmic antibodies (pANCA) testing, these antibodies may improve differentiation between the diseases. This study determined the sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of PAB and GAB +/- ASCA and pANCA testing in Chinese and Caucasian IBD populations. RESULTS: Patients were recruited from Caucasian and Chinese populations (CD, n = 100; UC, n = 99; controls, n = 100). PAB was highly specific for CD, and detection was greater in patients less than 35 years old and in Chinese compared with Caucasian patients with CD (CD, 46% versus 22%, P = 0.018; UC, 2% versus 6%; controls, 0% versus 2%). GAB detection was poor in all groups (<2%). PAB showed a PPV of 93% to differentiate all patients with CD from patients with UC, but only 62% for those with isolated colonic disease. The PPV of PAB increased to 100%, specificity was 100%, and sensitivity was 21% for isolated colonic disease when combined with pANCA and ASCA. PAB expression was not associated with stricturing or perforating CD. CONCLUSIONS: This study identified that GAB was not useful in our patients with IBD. PAB expression was highly specific for CD and more sensitive in Chinese than Caucasian patients with CD. The combination of PAB, pANCA, and ASCA testing improved the differentiation between UC and CD, particularly in isolated colonic disease, compared with pANCA and ASCA testing alone.

A prospective comparative study of ASCA and pANCA in Chinese and Caucasian IBD patients.

BACKGROUND: Inflammatory bowel disease manifests throughout all ethnic groups. Antisaccharomyces cerevisiae (ASCA) and antineutrophil cytoplasmic antibodies (pANCA) can aid in the differentiation between Crohn's disease (CD) and ulcerative colitis (UC), but their sensitivity may vary between races. OBJECTIVES: This study compared the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of pANCA and ASCA between Chinese and Caucasian IBD populations and identified disease subtype associations. RESULTS: Three hundred patients were prospectively recruited from Caucasian and Chinese populations (CD, n = 50, UC, n = 50, controls, n = 50 each). pANCA detection was greater in Caucasian than Chinese UC patients (p= 0.046). ASCA IgG detection was similar, but IgA was lower in Chinese CD patients (p < 0.001). Differentiation between UC and CD (+ve pANCA/-ve ASCA) demonstrated a PPV of 92% in isolated colonic disease. Logistic regression in CD identified positive pANCA had a lower association with ileal (OR = 6.8, p= 0.0067) and complicated disease (OR = 5.5, p= 0.015). Caucasian CD patients with positive ASCA IgA/IgG had a greater association with ileal (OR = 6.7, p= 0.022) or complicated disease (OR = 9.4, p= 0.0073) and in Chinese CD patients positive ASCA IgA/IgG was associated with isolated ileal disease (OR = 16.8, p= 0.032). Linear regression demonstrated that higher ASCA titers predicted complicated CD and isolated ileal disease. CONCLUSIONS: This study identified that pANCA is more sensitive in Caucasian than Chinese UC and that ASCA IgA has a low yield in Chinese CD. pANCA and ASCA are useful for differentiating between UC and CD in both populations, and ASCA IgG and IgA titers have potential use in determining the risk of developing complicated CD.