Pardi, Darrell S.

Abstract Background and Aims Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Introduction Hospitalizations, proton-pump inhibitors (PPI), and systemic antibiotics increase the risk of Clostridioides difficile infection (CDI) in cirrhosis. We compare the risk of CDI with hepatic encephalopathy (HE) medications, hypothesizing that rifaximin may decrease CDI risk. Materials and Methods A retrospective study of hospitalized HE patients treated with lactulose and/or rifaximin at Mayo Clinic Minnesota, Florida, and Arizona from 2008 to 2013 was conducted. Data on demographics, hospitalizations, antibiotics, and PPI use and CDI were gathered. Univariate and multivariable cox models were constructed. Results We found 1,112 hospitalizations in 1,055 unique patients (55 had 1 subsequent readmission, 1 patient had 2); 428 (40.6%) patients were women (median age: 58 years [interquartile range: 52–65]). CDI developed after 66/1,112 (5.9%) hospitalizations within 12 months post-discharge. Lactulose was administered in 21 (31.8%), rifaximin in 5 (7.6%), both in 40 (60.6%) hospitalizations. Systemic antibiotics were used in 28 (42.4%) patients and PPIs in 60 (90.9%) patients.Univariate analysis using medication (with lactulose alone as the reference group) showed rifaximin was not significantly associated with CDI compared with lactulose (hazard ratio [HR]: 1.57, 95% confidence interval [CI]: 0.57–4.33, p = 0.39). Use of both medications was not significant compared with lactulose (HR: 1.41, 95% CI: 0.84–2.38, p = 0.19). Results were similar after controlling for confounders. Multivariable analysis based on length of stay, age, and gender showed no differences between rifaximin versus lactulose and both versus lactulose. Conclusion There is no significant difference between lactulose and rifaximin on CDI development in HE patients. However, CDI should still be considered when managing diarrhea in HE patients.

Background Clostridioides difficile infection (CDI) is associated with frequent recurrences. The role of probiotics in preventing CDI remains unclear despite patients frequently using them. Methods We performed a systematic-review and meta-analysis to evaluate the role of Saccharomyces boulardii, a yeast probiotic, in preventing primary or recurrent CDI in patients on systemic antimicrobial therapy. We searched MEDLINE, Embase, and Web of Science up to December 2021 to identify studies (case-control, cohort, or clinical trial studies) reporting the use of systemic antimicrobials with or without S. boulardii and providing information on primary or recurrent CDI. Pooled odds ratios with 95% confidence intervals were calculated using a random effects model. Results Eight studies (six randomized control trials and two cohort studies) were included. Six studies with 9,712 patients evaluated primary prevention. The rate of CDI in patients who received S. boulardii was 0.73% (44/5977) compared to 1.09% (41/3735) in the control group. Meta-analysis showed no difference in the risk of CDI among the two groups (odds ratio [OR], 0.71; 95%CI, 0.46–1.10; p = 0.124) with no significant heterogeneity (I2 = 0%). In two studies with 292 patients evaluating secondary prevention, the rate of recurrent CDI was 36.73% (54/147) on S. boulardii compared to 46.20% (67/145) in controls, with no significant difference (p = 0.19). Subgroup analysis of studies using S. boulardii (250 mg twice daily) showed no difference in the CDI risk with or without S. boulardii. No serious adverse events from S. boulardii were noted. Conclusion The use of S. boulardii appears to have no benefit for preventing either primary or recurrent CDI in patients taking systemic antimicrobials.

Background The outcomes from fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (rCDI) in patients after complete or partial colectomy are not well-defined. Objectives We sought to report our experience with FMT for rCDI in patients who have undergone colectomy. Methods Descriptive analyses of FMT outcomes from 2014 to 2020 were performed in patients who previously had undergone complete or partial colectomy. Results Twenty-nine patients with prior colectomy for inflammatory bowel disease, malignancy, slow-transit constipation refractory to medical therapy, or fulminant CDI underwent FMT for rCDI. Two patients (6.9%) had rCDI within 8 weeks post-FMT. Seven had CDI beyond 8 weeks (median 10 months) with 71% related to antibiotic exposure post-FMT, suggesting a 69% overall success. Conclusion FMT resolves rCDI in most patients after colectomy with subsequent antibiotic exposure predicting CDI after FMT.

Background: Tumor necrosis factor (TNF-α) inhibitors and the α4β7 integrin antagonist, vedolizumab, have been investigated as treatment options for patients with steroid-refractory microscopic colitis. Aims: To evaluate the benefit of vedolizumab and TNF-α inhibitors in patients with steroid-refractory microscopic colitis. Methods: Retrospective studies and case series involving patients with steroid-refractory MC who either received vedolizumab, adalimumab, or infliximab were eligible for inclusion. Pooled proportional meta-analyses were used to calculate the rate of clinical remission at induction, clinical response, maintenance of remission, histologic remission, and overall medication related adverse effects. Statistical analysis was performed in R using the metafor and meta packages. Results: A total of 14 studies involving 164 patients were included. Pooled analysis showed a clinical remission rate of 63.5% [95% CI (0.483; 0.776), I 2 =43% P =0.08], 57.8% [95% CI (0.3895; 0.7571), I 2 =0%, P =0.7541], and 39.3% [95% CI (0.0814; 0.7492), I 2 =66%, P =0.02] for vedolizumab, infliximab, and adalimumab, respectively. The maintenance of remission rates were 65.9% [95% CI (0.389; 0.889), I 2 =67%, P =0.02], 45.3% [95% CI (0.1479; 0.7747), I 2 =0%, P =0.36] and 32.5% [95% CI (0.000; 0.8508), I 2 =53%, P =0.14] in patients who received vedolizumab, infliximab, and adalimumab, respectively. Rate of biological-related adverse events warranting discontinuation of therapy was 12.2%, 32.9%, and 23.0% for the vedolizumab, infliximab, and adalimumab groups, respectively. Conclusion: Vedolizumab and anti-TNF-α agents demonstrated a clinical benefit in the treatment of steroid-refractory microscopic colitis and with a tolerable safety profile. Future randomized controlled trials are needed to compare vedolizumab with TNF-α inhibitors and examine treatment effect on patients’ quality of life.

SummaryBackgroundMedication use has been implicated in the development of microscopic colitis (MC). However, studies have demonstrated inconsistent findings and there exist variations in design.AimTo measure the association between medication use and MC.MethodsPatients who underwent a colonoscopy over a 10‐year period at two academic medical centres (Columbia University Medical Centre and Mayo Clinic) were identified. Cases were patients with biopsy‐proven MC and controls were patients who underwent colonoscopy for evaluation of diarrhoea with biopsies negative for MC. Cases were matched by age, gender and calendar period with up to two controls. Demographics, medication use, smoking history and coeliac disease status were collected. Conditional logistic regression was used with and without adjustment for smoking.ResultsA total of 344 patients with MC were matched to 668 controls. After adjusting for smoking, there was an inverse association between MC and use of proton pump inhibitors (PPIs) (OR 0.64; 95% CI 0.47‐0.87), H2 blockers (OR 0.46; 95% CI 0.24‐0.88) and oral diabetes medications (OR 0.47; 95% CI 0.27‐0.81). There was a positive association with nonsteroidal anti‐inflammatory drug (NSAID) use and MC (OR 1.63; 95% CI 1.12‐2.38).ConclusionsNSAID use was associated with MC, while use of PPIs, H2 blockers and oral diabetes medications were inversely related to MC. Our use of a control group with diarrhoea, as opposed to healthy controls, may have contributed to these inverse associations. Future studies of drug‐induced microscopic colitis should include control groups with diarrhoea, and not only healthy controls.

Abstract Background Microscopic colitis (MC) is a common cause of chronic diarrhea. Randomized controlled trials (RCTs) have demonstrated the efficacy of budesonide treatment for MC. However, relapse is frequent after discontinuation of budesonide, and data on maintenance therapy are limited. We performed a systematic review and meta-analysis evaluating these outcomes in clinical trials and real-world settings. Methods A systematic search was performed on October 31, 2022, of Medline, Embase, Cochrane, and Scopus. Case series, case-control, cohort studies, and RCTs of adults with MC were included. Data were pooled using random effects models to calculate weighted pooled estimates and 95% confidence intervals. Heterogeneity was assessed using the I2 statistic. Results We included 35 studies (11 RCTs, 24 observational studies) with 1657 MC patients treated with budesonide induction and 146 for maintenance. The overall pooled clinical remission rate with budesonide treatment was similar between RCTs and observational studies. The pooled remission rate with budesonide maintenance therapy was 84% (95% CI, 0.60-1.00; I2 = 91%). After budesonide discontinuation, the pooled relapse rate was 53% (95% CI, 0.42-0.63; I2 = 76%). On maintenance therapy, no differences were noted in adverse events (eg, metabolic bone disease, hypertension, hyperglycemia, cataracts/glaucoma) in those on budesonide vs placebo or other noncorticosteroid medications for MC (P = .9). Conclusions Budesonide is an effective maintenance treatment for MC. There is a high risk of recurrence after budesonide discontinuation, but long-term use at the lowest effective dose appears to be relatively safe and have limited adverse effects.

Abstract Background Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter “VOS,” formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. Methods Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1–2, 3–4, ≥5); (ii) baseline creatinine clearance (<30, 30–50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. Results Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. Conclusions In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

AbstractBackground and AimAlthough fidaxomicin is an effective first‐line treatment for Clostridioides difficile infection, it has not been well studied in patients with inflammatory bowel disease. We aimed to assess the effectiveness of fidaxomicin for the treatment of C. difficile infection in patients with inflammatory bowel disease.MethodsThis was a multicenter retrospective study of adults with inflammatory bowel disease and C. difficile infection treated with fidaxomicin with at least 3 months of follow up. The primary outcomes were treatment response, defined as resolution of C. difficile infection‐attributed diarrhea and/or negative C. difficile infection stool test, and time to C. difficile infection recurrence after fidaxomicin.ResultsThirty‐three patients (median age 42 years; 60.6% female) were included. Most patients had ulcerative colitis (26, 78.8%), were receiving treatment with a biologic or small molecule medication (19, 57.6%), and had a prior episode of C. difficile infection (26, 78.8%, median 2 episodes, range 0–15). Fidaxomicin led to resolution of C. difficile infection in 20 (60.6%) patients, with 6/20 (30.0%) developing a recurrence at a median of 55 days. Most patients who failed to respond to fidaxomicin underwent fecal microbiota transplantation (10/13, 76.9%) with resolution.ConclusionsIn this cohort of patients with inflammatory bowel disease and C. difficile infection, 60.6% responded to treatment with fidaxomicin. Of those who did not respond, fecal microbiota transplantation was an effective therapy.

Background: Microbiota restoration is highly effective to treat recurrent Clostridioides difficile infection (CDI) in observational studies (cure rates >90%) but efficacy in controlled clinical trials appears to be lower. Objectives: To perform an updated meta-analysis to assess the efficacy of microbiota restoration for recurrent CDI in open-label registered prospective clinical trials compared to randomized controlled trials (RCTs). Design: A systematic review and meta-analysis was conducted. Data Sources and Methods: A systematic search of various databases was performed up to July 2022 to identify studies of interest. Clinical trials of microbiota restoration for recurrent CDI with clinical resolution with one dose were included. We calculated weighted pooled rates (WPRs) with 95% confidence intervals (CIs). Results: In all, 19 clinical trials with 1176 recurrent CDI patients were included. Of the patients treated with microbiota restoration, 897 experienced a clinical cure with a single microbiota restoration therapy (WPR, 78%; 95% CI, 71–85%). There was significant heterogeneity among studies with an I2 of 88%. Analysis of trials with a control arm (non-microbiota restoration) revealed CDI resolution in 373 of 523 patients (WPR, 72%; 95% CI, 60–82%) with microbiota restoration. Among the nine open-label clinical trials, CDI resolution was seen in 524 of 653 patients after initial microbiota restoration (WPR, 84%; 95% CI, 74–92%). Comparison of resolution rates between RCTs and open-label trials revealed a lower cure rate in RCTs compared to open-label trials (WPR, 73 versus 84%, p < 0.0001). Conclusions: Microbiota restoration in a randomized controlled setting leads to lower resolution rates compared to open label and observational settings, likely due to stricter definitions and inclusion criteria. Resolution rates in open-label studies were similar to observational studies.