Anita Afzali

Fecal Microbiota Transplant for Treatment of Clostridium difficile Infection in Immunocompromised Patients

OBJECTIVES:Patients who are immunocompromised (IC) are at increased risk of Clostridium difficile infection (CDI), which has increased to epidemic proportions over the past decade. Fecal microbiota transplantation (FMT) appears effective for the treatment of CDI, although there is concern that IC patients may be at increased risk of having adverse events (AEs) related to FMT. This study describes the multicenter experience of FMT in IC patients.METHODS:A multicenter retrospective series was performed on the use of FMT in IC patients with CDI that was recurrent, refractory, or severe. We aimed to describe rates of CDI cure after FMT as well as AEs experienced by IC patients after FMT. A 32-item questionnaire soliciting demographic and pre- and post-FMT data was completed for 99 patients at 16 centers, of whom 80 were eligible for inclusion. Outcomes included (i) rates of CDI cure after FMT, (ii) serious adverse events (SAEs) such as death or hospitalization within 12 weeks of FMT, (iii) infection within 12 weeks of FMT, and (iv) AEs (related and unrelated) to FMT.RESULTS:Cases included adult (75) and pediatric (5) patients treated with FMT for recurrent (55%), refractory (11%), and severe and/or overlap of recurrent/refractory and severe CDI (34%). In all, 79% were outpatients at the time of FMT. The mean follow-up period between FMT and data collection was 11 months (range 3–46 months). Reasons for IC included: HIV/AIDS (3), solid organ transplant (19), oncologic condition (7), immunosuppressive therapy for inflammatory bowel disease (IBD; 36), and other medical conditions/medications (15). The CDI cure rate after a single FMT was 78%, with 62 patients suffering no recurrence at least 12 weeks post FMT. Twelve patients underwent repeat FMT, of whom eight had no further CDI. Thus, the overall cure rate was 89%. Twelve (15%) had any SAE within 12 weeks post FMT, of which 10 were hospitalizations. Two deaths occurred within 12 weeks of FMT, one of which was the result of aspiration during sedation for FMT administered via colonoscopy; the other was unrelated to FMT. None suffered infections definitely related to FMT, but two patients developed unrelated infections and five had self-limited diarrheal illness in which no causal organism was identified. One patient had a superficial mucosal tear caused by the colonoscopy performed for the FMT, and three patients reported mild, self-limited abdominal discomfort post FMT. Five (14% of IBD patients) experienced disease flare post FMT. Three ulcerative colitis (UC) patients underwent colectomy related to course of UC >100 days after FMT.CONCLUSIONS:This series demonstrates the effective use of FMT for CDI in IC patients with few SAEs or related AEs. Importantly, there were no related infectious complications in these high-risk patients.

Excellent posttransplant survival for patients with nonalcoholic steatohepatitis in the United States

Because of the ongoing epidemics of obesity and diabetes, nonalcoholic steatohepatitis (NASH) may become a leading indication for liver transplantation. There are concerns about the posttransplant survival of patients with NASH because of associated cardiovascular and metabolic risk factors. We aimed to determine recent trends in the proportion of patients undergoing transplantation for NASH‐related cirrhosis in the United States and to estimate their posttransplant survival. We used data provided by the United Network for Organ Sharing for first‐time adult cadaveric liver transplants performed in the United States between January 1, 1997 and October 31, 2010 (n = 53,738). The proportion of liver transplants performed for NASH‐related cirrhosis increased dramatically from 1.2% in 1997‐2003 to 7.4% in 2010 when NASH was the fourth most common indication for transplantation. The posttransplant survival of patients with NASH (n = 1810) at 1 (87.6%), 3 (82.2%), and 5 years (76.7%) was superior to the survival of patients with hepatocellular carcinoma, hepatitis C virus, alcoholic liver disease, acute hepatic necrosis, hemochromatosis, or cryptogenic liver disease and was inferior to the survival of only 4 groups of patients (those with primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, or hepatitis B virus). In conclusion, NASH‐related cirrhosis is increasing rapidly as an indication for liver transplantation in the United States and is associated with excellent posttransplant survival. Liver Transpl 18:29–37, 2012.

Association between serum uric acid level and chronic liver disease in the United States

Elevated serum uric acid (UA) levels strongly reflect and may even cause oxidative stress, insulin resistance, and metabolic syndrome, which are risk factors for the progression of liver disease. We sought to determine whether serum UA levels are associated with the development of cirrhosis or the presence of elevated serum liver enzymes. We used cohort data from the first National Health and Nutrition Examination Survey (NHANES I) to determine whether the baseline serum UA level was associated with the incidence of hospitalization or death due to cirrhosis among 5518 participants during a mean follow‐up of 12.9 years (range = 4‐21 years) after the exclusion of the first 4 years of follow‐up. We also used cross‐sectional data from NHANES 1988‐1994 (n = 10,993) and NHANES 1999‐2006 (n = 6186) to determine whether the serum UA level was associated with elevated serum alanine aminotransferase (ALT) or γ‐glutamyl transferase (GGT), two markers of hepatic necroinflammation. Compared to persons in the lower third of the distribution of serum UA (<4.8 mg/dL), those in the top third (>6 mg/dL) had a higher risk of cirrhosis‐related hospitalization or death [adjusted hazard ratio (AHR) = 2.8, 95% confidence interval (CI) =1.3‐5.7], whereas the risk was not substantially increased in persons within the middle third (serum UA level = 2.6‐4.8 mg/dL, AHR = 1.3, 95% CI = 0.6‐2.7). A higher serum UA level was associated with greater mean serum ALT and GGT levels and a greater probability of elevated serum ALT and GGT. Conclusion: The serum UA level is associated with the development of cirrhosis and the presence of elevated serum liver enzymes after adjustments for important causes and risk factors of chronic liver disease. (HEPATOLOGY 2010;)

The association of psoriasiform rash with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease: A single academic center case series

BACKGROUND & AIMS Anti-tumor necrosis factors (anti-TNF) including infliximab, adalimumab and certolizumab pegol are used to treat Crohns disease (CD) and ulcerative colitis (UC). Paradoxically, while also indicated for the treatment of psoriasis, anti-TNF therapy has been associated with development of psoriasiform lesions in IBD patients and can compel discontinuation of therapy. We aim to investigate IBD patient, clinical characteristics, and frequency for the development of and outcomes associated with anti-TNF induced psoriasiform rash. METHODS We identify IBD patients on anti-TNFs with an onset of a psoriasiform rash. Patient characteristics, duration of anti-TNF, concomitant immunosuppressants, lesion distribution, and outcomes of rash are described. RESULTS Of 1004 IBD patients with exposure to anti-TNF therapy, 27 patients (2.7%) developed psoriasiform lesions. Psoriasiform rash cases stratified by biologic use were 1.3% for infliximab, 4.1% for adalimumab, and 6.4% for certolizumab. Average time on treatment (206.3weeks) and time on treatment until onset of psoriasiform lesions (126.9weeks) was significantly higher in the infliximab group. The adalimumab group had the highest need for treatment discontinuation (60%). The majority (59.3%) of patients were able to maintain on anti-TNFs despite rash onset. Among patients that required discontinuation (40.7%), the majority experienced improvement with a subsequent anti-TNF (66.7%). CONCLUSION 27 cases of anti-TNF associated psoriasiform lesions are reported. Discontinuation of anti-TNF treatment is unnecessary in the majority. Dermatologic improvement was achieved in the majority with a subsequent anti-TNF, suggesting anti-TNF induced psoriasiform rash is not necessarily a class effect.

Biologics in the management of ulcerative colitis – comparative safety and efficacy of TNF-α antagonists

Ulcerative colitis can cause debilitating symptoms and complications such as colonic strictures, colonic dysplasia, colorectal cancer, and toxic megacolon or perforation. Goals of treatment in ulcerative colitis include resolution of gastrointestinal symptoms, healing of colonic mucosa, and prevention of disease complications. Our treatment armamentarium has expanded dramatically over the past 10 years, and we now have multiple biologic agents approved for the treatment of moderate-severe disease, in addition to conventional therapies such as 5-aminosalicylates, thiopurines, and corticosteroids. In this review, we will provide a detailed discussion of the three tumor necrosis factor-alpha (TNF-α) inhibitors currently approved for treatment of ulcerative colitis: infliximab, adalimumab, and golimumab. All three agents are effective for inducing and maintaining clinical response and remission in patients with ulcerative colitis, and they have comparable safety profiles. There are no head-to-head trials comparing their efficacy, and the choice of agent is most often based on insurance coverage, route of administration, and patient preference. Combination therapy with an immunomodulator is proven to be more effective than anti-TNF monotherapy, and patients who lose response to an anti-TNF agent should undergo dose intensification in order to regain clinical response. Despite therapeutic optimization, a significant percentage of patients will not achieve clinical remission with anti-TNF agents, and so newer therapies are on the horizon.

Racial and Ethnic Minorities with Inflammatory Bowel Disease in the United States: A Systematic Review of Disease Characteristics and Differences.

Background:Inflammatory bowel disease (IBD) has predominantly affected whites, particularly Ashkenazi Jews. Over the last 2 decades, IBD has “emerged” in minorities. Differences in natural history and disease characteristics have been suggested. The objective of this systematic review is to summarize these differences in studies from the United States. Methods:A structured search was performed within the Medline database through PubMed, EMBASE, and Cochrane databases. Published studies of genetics, pathogenesis, prevalence or incidence, disease location and behavior, extraintestinal manifestations, disparities and access to care in patients with IBD who are of African American, Asian, and Hispanic descent living in the United States were eligible. Results:A total of 47 studies were included for African Americans (n = 20,054), Hispanics (n = 10,762), and Asians (n = 2668). The incidence and prevalence of IBD is increasing among minorities. There is less of a genetic influence in the pathogenesis of IBD among African Americans; however, novel variants have been identified. There is a predilection for pancolonic ulcerative colitis among Hispanics and Asians. Crohns disease-related hospitalizations are increasing in Asians, whereas African Americans are more likely to use the emergency department. No major differences are seen in disease location and behavior, upper gastrointestinal tract, and perianal involvement and extraintestinal manifestations among races and ethnic groups. Medication utilization seems to be similar. Differences in surgery are likely explained by health insurance status. Conclusions:Future prospective studies are needed to fully characterize disease characteristics and treatment response among minorities. With novel IBD therapies in the pipeline, enrollment in clinical trials should emphasize increased representation of all races and ethnic groups.

Preoperative Use of Methotrexate and the Risk of Early Postoperative Complications in Patients with Inflammatory Bowel Disease

Background:Preoperative immunosuppressive use among patients with Crohns disease or ulcerative colitis may lead to an increased risk of postoperative complications. There is limited information on the preoperative safety profile of methotrexate (MTX) in inflammatory bowel disease (IBD). Methods:A retrospective study of patients who underwent abdominal surgery for IBD between 1993 and 2012 was performed and records abstracted, including preoperative use of MTX, azathioprine/6-mercaptopurine, antitumor necrosis factor, and corticosteroids. Early postoperative complications, including death, septic, and nonseptic complications were identified. A meta-analysis was also performed on the use of preoperative MTX in patients with IBD or rheumatoid arthritis. Results:A total of 180 patients with IBD underwent abdominal surgery. A total of 15 patients received MTX either monotherapy or in combination therapy. Total early postoperative complications were identified in 71 (39%) patients, specifically 5 patients on oral MTX. A total of 51 cases (28%) of septic complications and 20 (11%) nonseptic. No significant association between the use of MTX and early postoperative complications was found. The odds ratio (OR) of complications versus no complications associated with MTX was 0.75 (95% CI, 0.25–2.29) and with azathioprine/6-mercaptopurine, OR 1.48 (95% CI, 0.77–2.84). The odds of a septic complication associated with MTX were 0.58 (95% CI, 0.09–3.73), and higher in azathioprine/6-mercaptopurine, OR 3.97 (95% CI, 1.03–15.3). Our meta-analysis also did not reveal an increased risk of postoperative complications in IBD or rheumatoid arthritis on preoperative MTX (OR 0.62, 95% CI, 0.34–1.15). Conclusions:Preoperative MTX use does not seem to be associated with early postoperative complications in IBD.

Effects of Transient and Persistent Anti-drug Antibodies to Certolizumab Pegol: Longitudinal Data from a 7-Year Study in Crohn's Disease

Background: Anti-drug antibodies (ADAbs) may decrease the efficacy of biologics and increase the risk of adverse events. A single positive test may not preclude further treatment because of variations in assays used, test timing, and patient variables. We evaluated the longitudinal patterns of immunogenicity during 7 years of antitumor necrosis factor-alpha drug certolizumab pegol (CZP) treatment for moderate-to-severe Crohns disease. Methods: PRECiSE 3 patients (n = 595) received open-label CZP 400 mg every 4 weeks up to 7 years. CZP–ADAb expression, plasma CZP concentration, Harvey-Bradshaw Index, C-reactive protein, and fecal calprotectin concentrations were measured multiple times. Longitudinal data, examined for CZP–ADAb positivity and categorized as transient (with temporary/no effect on CZP concentration), persistent, or negative, were correlated with clinical and biological variables. Results: Of the CZP–ADAb–positive patients, 40 (22.6%) had transient CZP–ADAbs and 94 (77.4%) had persistent CZP–ADAbs. Demographic characteristics were similar between groups. Median C-reactive protein and fecal calprotectin were higher (P < 0.05 at some visits) and plasma CZP concentrations were significantly lower (P < 0.0001 at all visits) in the persistent CZP–ADAb–positive group relative to the CZP–ADAb–negative group. Transient CZP–ADAb–positive and CZP–ADAb–negative patients had similar plasma CZP, C-reactive protein, and fecal calprotectin concentrations. Median Harvey-Bradshaw Index scores and rates of adverse events were similar among groups. Conclusions: This analysis demonstrates that persistent CZP–ADAb has negative effects on drug levels and efficacy, whereas transient expression may not. Serial measurements may be needed to characterize ADAb positivity. www.clinicaltrials.gov, Number NCT00160524.

Update on MR Enterography: Potentials and Pitfalls

Purpose of ReviewThis article serves to review the role of MR Enterography (MRE) in current clinical practice. Optimal technique is described based on recent consensus guidelines, as well as the potential role of optional and emerging sequences. The value of MRE for assessing patients with inflammatory bowel disease (IBD) is highlighted, including diagnosis, disease subtyping, detecting extraintestinal findings, and identifying complications, including particular attention to how these findings may be used for treatment decision-making. We specifically address the advantages and disadvantages of MRE compared to CT Enterography, including recently updated American College of Radiology Appropriateness Criteria for Crohn disease. Although less well established, we also discuss the utility of MRE in evaluating noninflammatory small bowel pathologies.Recent FindingsBeyond initial diagnosis and disease phenotype characterization, MRE is increasingly incorporated into clinical indices used for treatment decision-making and assessing bowel damage longitudinally. Detecting and quantifying fibrosis remains a challenge in imaging for IBD, but some MRE sequences, such as magnetization transfer (MT) imaging, or fusion modalities, such as PET/MRE, have shown promise in providing functional information and offering meaningful biomarkers. MRE is also increasingly utilized for applications outside of IBD, such as screening for or assessing small bowel neoplasms.SummaryMRE is a valuable noninvasive technique for imaging the entire gastrointestinal tract and extraintestinal organs in a single examination without ionizing radiation. In IBD, MRE allows for accurate initial diagnosis and subtyping by assessing the bowel lumen, bowel wall, and surrounding structures simultaneously. Reliably predicting and quantifying fibrosis remains a challenge, but novel techniques, including fusion PET/MRE and MT imaging, offer promise. Quantitative MRE indices have also been developed and validated for assessing treatment response in patients with IBD, which can help guide treatment toward mucosal healing.

Oral and Parenteral Corticosteroid Therapy in Ulcerative Colitis

Over the past 50 years, the widespread use of corticosteroids in the management of active ulcerative colitis (UC) has resulted in a dramatic mortality reduction. In the 1930s, mortality from UC was estimated to be up to 75 %, and this has decreased to less than 1 % in the twenty-first century. Similarly to other drugs used to treat autoimmune inflammatory disorders, corticosteroids were first used in the treatment of rheumatoid arthritis and then applied to inflammatory bowel disease.