Douglas Samuel

Multidonor intensive faecal microbiota transplantation for active ulcerative colitis: a randomised placebo-controlled trial

BACKGROUND The intestinal microbiota is implicated in the pathogenesis of ulcerative colitis. Faecal microbiota transplantation is a novel form of therapeutic microbial manipulation, but its efficacy in ulcerative colitis is uncertain. We aimed to establish the efficacy of intensive-dosing, multidonor, faecal microbiota transplantation in active ulcerative colitis. METHODS We conducted a multicentre, double-blind, randomised, placebo-controlled trial at three hospitals in Australia. We randomly allocated patients with active ulcerative colitis (Mayo score 4-10) in a 1:1 ratio, using a pre-established randomisation list, to either faecal microbiota transplantation or placebo colonoscopic infusion, followed by enemas 5 days per week for 8 weeks. Patients, treating clinicians, and other study staff were unaware of the assigned treatment. Faecal microbiota transplantation enemas were each derived from between three and seven unrelated donors. The primary outcome was steroid-free clinical remission with endoscopic remission or response (Mayo score ≤2, all subscores ≤1, and ≥1 point reduction in endoscopy subscore) at week 8. Analysis was by modified intention-to-treat and included all patients receiving one study dose. We performed 16S rRNA stool analysis to assess associated microbial changes. This trial is registered with ClinicalTrials.gov, number NCT01896635. The trial has ended; this report presents the final analysis. FINDINGS From November, 2013, to May, 2015, 85 patients were enrolled to our trial, of whom 42 were randomly assigned faecal microbiota transplantation and 43 were allocated placebo. One patient assigned faecal microbiota transplantation and three allocated placebo did not receive study treatment and were excluded from the analysis. The primary outcome was achieved in 11 (27%) of 41 patients allocated faecal microbiota transplantation versus three (8%) of 40 who were assigned placebo (risk ratio 3·6, 95% CI 1·1-11·9; p=0·021). Adverse events were reported by 32 (78%) of 41 patients allocated faecal microbiota transplantation and 33 (83%) of 40 who were assigned placebo; most were self-limiting gastrointestinal complaints, with no significant difference in number or type of adverse events between treatment groups. Serious adverse events occurred in two patients assigned faecal microbiota transplantation and in one allocated placebo. Microbial diversity increased with and persisted after faecal microbiota transplantation. Several bacterial taxa were associated with clinical outcome; in particular, the presence of Fusobacterium spp was associated with lack of remission. INTERPRETATION Intensive-dosing, multidonor, faecal microbiota transplantation induces clinical remission and endoscopic improvement in active ulcerative colitis and is associated with distinct microbial changes that relate to outcome. Faecal microbiota transplantation is, thus, a promising new therapeutic option for ulcerative colitis. Future work should focus on precisely defining the optimum treatment intensity and the role of donor-recipient matching based on microbial profiles. FUNDING Broad Medical Research Program, Gastroenterological Society of Australia, Mount Sinai (New York) SUCCESS fund, University of New South Wales.

Donor Recruitment for Fecal Microbiota Transplantation.

Background:Increasing demand for fecal microbiota transplantation (FMT) has created a need for stool banks sourced from long-term healthy donors. Here, we describe our experience in recruiting and screening fecal donors. Methods:Mailbox, newspaper, and online advertisements were used. Potential donors were required to satisfy a prescreen telephone conversation, pass blood and stool investigations, then undertake a screening interview including medical history, physical examination, and evaluation of donor selection criteria. Results:One hundred sixteen potential donors were prescreened of whom 74 failed—47 declined based on study donation requirements (primarily related to frequency and duration of donations), 13 had medical comorbidities, 6 variant Creutzfeldt–Jakob disease risk factors, 8 for other reasons. Thirty-eight completed stool and blood testing—1 failed blood testing (indeterminate hepatitis C serology), whereas 15 failed stool investigations (5 Dientamoeba fragilis, 5 Blastocystis hominis, 1 B. hominis and D. fragilis, 1 Giardia intestinalis plus D. fragilis, 1 Norovirus plus Clostridium difficile toxin positive, and 2 leucocytes or erythrocytes on stool microscopy). Of the 18 potential donors proceeding to screening interview, 6 were excluded (3 body mass index >30, 1 illicit drug use, 1 uncontrolled anxiety and concerns regarding compliance, 1 irregular bowel movements after new medication commencement). In total, only 12 of 116 (10%) potential donors were enrolled as study donors. Conclusions:Recruitment of fecal donors for FMT is challenging with only a small percentage ultimately serving as donors. Many were unable or unwilling to meet the donor commitment requirements. A surprisingly large proportion of healthy asymptomatic donors failed stool testing, primarily due to gastrointestinal parasites.

Inflammatory Bowel Disease Environmental Risk Factors: A Population-Based Case–Control Study of Middle Eastern Migration to Australia

BACKGROUND & AIMS The incidences of the inflammatory bowel diseases (IBDs) Crohns disease (CD) and ulcerative colitis (UC) are increasing, indicating gene-environment interactions. Migrants from low-IBD-prevalence countries to a high-prevalence country may help identify the relative contribution of environmental risk factors compared with native Caucasians. METHODS This prospective case-control study evaluated IBD environmental risk factors of Middle Eastern migrants (MEM) in Australia compared with matched Caucasian IBD subjects, MEM controls, Caucasian controls, and controls in the Middle East using adjusted odds ratios (aOR). RESULTS A total of 795 subjects were recruited: 154 MEM cases (75 CD; 79 UC), 153 MEM controls, 162 Caucasian cases (85 CD; 77 UC), 173 Caucasian controls, and 153 controls in Lebanon. Smoking increased CD risk in MEM and Caucasians and reduced UC risk in Caucasians (aOR, 0.77; 95% CI, 0.41-0.98) but not MEM (aOR, 1.45; 95% CI, 0.80-2.62). Antibiotic use reduced the risk of MEM CD (aOR, 0.27; 95% CI, 0.11-0.67) and UC (aOR, 0.38; 95% CI, 0.18-0.80), but increased the risk in Caucasians (CD: aOR, 5.24; 95% CI, 2.13-12.90; and UC: aOR, 6.82; 95% CI, 2.67-17.38). Most hygiene markers (rural dwelling, pet ownership, pet feeding, and farm animal contact) reduced CD and UC risk in MEM (P < .05). In contrast, in Caucasians these hygiene markers lacked significance. Other significant risk factors include IBD family history, appendectomy, tonsillectomy, and breastfeeding. CONCLUSIONS Differential IBD environmental risk factors exist between migrants and native Caucasians, indicating a dynamic interplay between environmental factors and IBD risk for immigrants that is distinct to those factors most relevant in native Caucasians.

Severe autoimmune hepatitis first presenting in the early post partum period

BACKGROUND & AIMS Autoimmune hepatitis (AIH) may run an aggressive clinical course if untreated. The influence of pregnancy on AIH is variable. Both flares in disease activity and remissions, often followed by a post partum flare, are well recognized. In contrast, definite AIH first presenting in the early post partum period has not been reported. METHODS We discuss a case series of 5 patients who developed severe AIH within 4 months post partum. RESULTS The diagnosis of AIH was definite based on internationally accepted criteria. Liver injury responded to conventional immunosuppressive therapy in all patients. Immune reactivation in the early post partum period may contribute to this entity. CONCLUSIONS AIH should be considered in the differential diagnosis of liver dysfunction first presenting in the early post partum period.

Anti-TNF Therapeutic Drug Monitoring in Postoperative Crohn’s Disease

Background Anti-TNF prevents postoperative Crohns disease recurrence in most patients but not all. This study aimed to define the relationship between adalimumab pharmacokinetics, maintenance of remission and recurrence. Methods As part of a study of postoperative Crohns disease management, some patients undergoing resection received prophylactic postoperative adalimumab. In these patients, serum and fecal adalimumab concentration and serum anti-adalimumab antibodies [AAAs] were measured at 6, 12 and 18 months postoperatively. Levels of Crohns disease activity index [CDAI], C-reactive protein [CRP] and fecal calprotectin [FC] were assessed at 6 and 18 months postoperatively. Body mass index and smoking status were recorded. A colonoscopy was performed at 6 and/or 18 months. Results Fifty-two patients [32 on monotherapy and 20 on combination therapy with thiopurine] were studied. Adalimumab concentration did not differ significantly between patients in endoscopic remission vs recurrence [Rutgeerts ≥ i2] [9.98µg/mL vs 8.43 µg/mL, p = 0.387]. Patients on adalimumab monotherapy had a significantly lower adalimumab concentration [7.89 µg/mL] than patients on combination therapy [11.725 µg/mL] [p = 0.001], and were significantly more likely to have measurable AAA [31% vs 17%, p = 0.001]. Adalimumab concentrations were lower in patients with detectable AAA compared with those without [3.59 µg/mL vs 12.0 µg/mL, p < 0.001]. Adalimumab was not detected in fecal samples. Adalimumab serum concentrations were lower in obese patients compared with in non-obese patients [p = 0.046]. Conclusion Adalimumab concentration in patients treated with adalimumab to prevent symptomatic endoscopic recurrence postoperatively is, for most patients, well within the therapeutic window, and is not significantly lower in patients who develop recurrence compared with in those who remain in remission. Mechanisms of anti-TNF failure to prevent postoperative recurrence remain to be determined in these patients.

Tu1289 Preventing Crohn's Disease Recurrence After Resection With Adalimumab: Role of Drug and Anti-Drug Antibody Levels

remission at 3 months did not then undergo colectomy, yet 3/6 (50%) not in remission did (p=0.07). Bivariate comparisons for primary and secondary endpoints are tabulated below. Also, ROC analysis showed that the area under curve (AUC) of consecutive day 1 to 3 levels for serum IFX (cutoff ≤158 μg/ml), CRP (≤33 mg/L) and FC (≤4910 μg/ml) each predicted the primary endpoint (6w) with a sensitivity & specificity of 83% & 71% (AUC 0.81 [95% CI 0.57, 1.0]), 83% & 57% (AUC 0.75 [0.41, 1.0]) and 83% & 100% (AUC 0.88 [0.66, 1.0] respectively. Conclusions: Post-first IFX dose in ASUC early higher CRP and FC levels predicted poorer week 6 outcomes. Yet unexpectedly, an early decrement in IFX levels from day 1 through day 3 appeared to confer better outcomes; this might reflect appropriate IFX binding/utilization in early responders compared to static levels in potential non-responders (e.g. where a non-TNF pathway predominates). Further prospective evaluation of the predictive value of Day 1-3 biomarkers in ASUC is warranted given these findings.