Taha Qazi, MD

It's my pleasure to present the third iteration of Qazi Corner for the 2024 year. In this installment, we highlight research from our fellows and from our team, as well as poignant topics in gastroenterology that we believe are very important and relevant for clinicians.

 is written by Rajat Garg, MD, who reviewed a retrospective cohort study looking at early versus late complications in patients who have liver transplantation and are sent to ERCP. It's a very poignant article looking at what the risk factors are and the complication rates in these patients who have an ERCP earlier versus later. What he came up with through this review of the coronary center at the Cleveland Clinic is that patients who have an earlier ERCP, ideally within 30 days of their liver transplantation, have a higher risk for bleeding compared to patients who have ERCP later than 30 days post-transplant, and without any change in technical success or clinical success for the procedure itself.

This provides a little bit of a pause as we're sort of rushing into our procedures and evaluating. Obviously, there are reasons why we sometimes have to do our procedures in a more timely fashion, but I think it does provide that situation where a patient may be able to wait for a delay prior to that procedure without necessarily changing your technical level of success or clinical success.

 is by David Long, DO, a current second-year GI fellow at Cleveland Clinic, who summarizes the use of GLP-1 receptor agonists in the context of endoscopic management and how we evaluate these new medications with their ubiquitous use and gaining popularity, as well as how we sort of try and utilize techniques that can minimize complications with these agents that are designed to delay gastric emptying, delay gastric utility, impair peristalsis, and actually potentially result in poor preps and higher risk for aspirations. I think he provides a very good summary of the data that is out there, but also the current updates and practice guidelines.

 is by Chiara Maruggi, MD, a graduated third-year GI fellow, currently in practice at Scripps in San Diego, and she provides her research on the diagnosis of seronegative celiac disease in patients with villous atrophy found on endoscopy. I think the bigger thing that we need to sort of realize is that in most of these situations where we look and we find patients who have villous atrophy on endoscopy, the more common things that we're often finding is the patient does have seronegative celiac disease. The blood testing can be negative, but they do have evidence suggesting that they have celiac disease, and the differential can be wide, potentially including things like HIV, CVID, Crohn's disease, and medication-induced. So I think the big sort of telltale sign is to keep the differential broad, always review whether it truly is celiac disease by implementing a gluten challenge, but really evaluate what we can do to address this sort of condition and really come with a good diagnosis or a diagnostic skill to create the best differential possible.

Articles

The third quarterly issue of 2024 reviews early versus late ERCP outcomes post-transplant, the impact of GLP-1RA use on endoscopic management, and the differential diagnosis of seronegative villous atrophy.

Qazi Corner, Edition 7: ERCP Timing, GLP-1 RA Considerations, Seronegative Villous Atrophy

In this issue of Qazi Corner, we have 3 amazing articles looking at a variety of issues in IBD, as well as GI care and liver care.

 is by a fellow named Dr. Steven Firkins who is interested in bariatric endoscopy. He looked at the National Inpatient Sample and evaluated whether patients with cirrhosis who have a common condition called metabolic-associated liver disease do better when they have bariatric surgery or not. This is a large retrospective study suggesting that overall, patients who get bariatric surgery for cirrhosis in the context of MASLD actually did very, very well. The implications of this study suggest that not only bariatric surgery, but basically bariatric endoscopy and bariatric procedures, are very beneficial for these patients, not only from a hepatology perspective, but from a mortality perspective as well.

 is by a colleague of mine, Dr. Roma Patel, one of our fantastic fellows at the Cleveland Clinic, who is reviewing the role of glucagon in the context of esophageal impactions. Esophageal impactions are very common. They normally happen around 5 o'clock in the morning or 5 o'clock in the evening, when people are eating and all of a sudden food gets stuck. A common noninterventional strategy is to use glucagon, which is an agent for the management of these esophageal impactions. Unfortunately, this study, which was done very recently, showed that glucagon had no impact on esophageal impactions. This tells us that we should be coming in sooner and getting these endoscopic procedures in and making sure that we are able to get these areas alleviated from this impaction movement and moving forward with that.

, I want to highlight the work of a medical student, Dr. Carter Powers, who's doing a lot of amazing work with me in the pouch and the cuff. He was able to evaluate whether patients who have pouches and also have a condition called cuffitis have long-term complications related to the disease. He found that patient with cuffitis had higher rates of pouch surgeries and higher rates of ileostomy creation and pouch failure. What he determined is that in patients who have severe cuff inflammation, they also have higher rates of fistula formation and higher rates of stricture formation. It’s a really interesting idea. How do we change that? Do we trend toward treating these patients sooner with medications for cuffitis? I think it still needs to be seen, but I think this provides a great deal of context as to how we manage this really complicated cohort of patients as we move forward.

The second quarterly issue of 2024 reviews outcomes in liver disease after bariatric surgery, glucagon’s role in esophageal impaction management, and outcomes after cuffitis following pouch creation.

Qazi Corner, Edition 6: Bariatric Surgery in Liver Disease, Glucagon, and Cuffitis Outcomes

It is my pleasure to present the first issue Qazi’s Corner of 2024. Over the course of the year, we will continue to highlight important research in 

, presented at major meeting and conferences, as well as any clinically relevant research publications that can be directly applied to the management of patients in gastroenterology. 

In the current version of the publication, we present recent data on the new guidelines for the management of inflammatory conditions of the pouch and pouchitis. In recognition of Colorectal Cancer Awareness month, we also present the result of a new generation multi-DNA target stool test for colon cancer and advanced neoplasia (BLUE-C), initially presented at the American College of Gastroenterology (ACG) 2023 Annual Meeting, but recently published in 

. Ravi Shah, MD, returns to present the results of tofacitinib in the management of acute severe ulcerative colitis (ASUC), and Jeffrey Schwartz, MD, presents on the use of fenfibrates for the management of primary biliary cholangitis (PBC).

describes new evidence for the use of tofacitnib for the management of ASUC

. There are limited data on the medical management of acute severe colitis, with the commonly used agents being cyclosporine, infliximab and intravenous corticosteroids. Tofacitinib, an oral non-selective Janus-kinase (JAK) inhibitor, presents a novel means to manage hospitalized patients with severe colitis.

Schwartz, a second-year clinical fellow, 

reports on a recent trial on the use of fenofibrates in PBC

, a chronic autoimmune condition that presents as non-suppurative bile duct injury resulting in eventual fibrosis. In comparing fenofibrates combination therapy with ursodiol to ursodiol alone, the authors of the study reported a higher proportion of biochemical response in patients treated in the combination arm. Fenofibrates appear to show promise as a potential therapeutic agent alongside ursodiol for the management of PBC.

The management of inflammatory conditions of the pouch or ileal-pouch anal anastomosis (IPAA) are complicated by increased variability in practice.

 In synthesizing the guidelines for management of IPAA inflammatory conditions

, the authors of the guidelines hoped to standardize definitions of these conditions and provide a better understanding on the management of inflammatory pouch diseases.

Lastly, despite being the second leading of cause of cancer deaths, colorectal cancer screening adherence continues to not reach targets instructed but our national societies. In the last study presented, 

 reviewing the role of a next generation multi-target DNA stool test for the sensitivity and specificity of detecting colorectal cancer, advance neoplasia, and dysplasia. Without sacrificing sensitivity, the newer generation stool tests was highly specific in the evaluation of CRC and advanced neoplasia, especially in a younger cohort of patients, representing another non-invasive strategy for CRC screening.

The first quarterly issue of 2024 reviews a promising JAK inhibitor for acute severe ulcerative colitis, fenofibrates in PBC, new recommendations from the AGA, and a next generation multi-target DNA stool test for detecting colorectal cancer.

Qazi Corner, Edition 5: Tofacitinib, Fenofibrates, Pouchitis Guidelines and BLUE-C

Despite the advent of biologics, nearly 20-30% of patients with 

 will require colectomy. Total proctocolectomy with IPAA remains the surgical choice of management for ulcerative colitis and complications related to the disease. The procedure is typically multi-staged, and there are both procedure associated and patient-specific considerations that are important in the ultimate success of the surgery.

Following surgery, most patients experience great functional outcomes, with a gradual improvement in stool frequency and consistency. Most patients average between 4-8 bowel movements daily, and 1-2 nocturnal bowel movements with semi-liquid consistency. Fecal incontinence and seepage can occur in the long term and should be discussed with patients.

Despite most patients having good long-term functional outcomes, complications can occur; the most common complication is the inflammatory complication of pouchitis, which may a significant burden in terms of both quality of life and care costs. Studies suggests that nearly half of patients develop pouchitis within the first 2 years after colectomy, and roughly 80% develop pouchitis at some point during their post-operative course.

Symptoms suggestive of pouchitis or an inflammatory pouch disorder and the need for additional workup include increased bowel movement frequency and urgency, abdominal pain/cramping, blood in stool, and perianal disease. This additional workup generally involves an endoscopic evaluation of the pouch. Additional workup may include imaging evaluations, such as MRI, defocography, or an exam under anesthesia to assess other sources/causes of pouch dysfunction.

In order to provide guidance on the management of inflammatory pouch complications, the authors of the American Gastroenterological Association (AGA) guidelines aimed to provide standardized definitions for the treatment of inflammatory pouch conditions.

 Moreover, by compiling the data from the studies provided, the authors hoped to provide a better treatment paradigm in treating pouch inflammatory disorders.

A crucial aspect of the guidelines are the standardized definitions of pouchitis and inflammatory conditions of the pouch that the authors propose. These pragmatic definitions are not defined on the basis of specific number of episodes or requirement of antibiotics, as this likely represents a continuum.

: Isolated and infrequent episodes of typical symptoms that resolve with therapy (antibiotics)

Chronic Antibiotic-Dependent Pouchitis (CADP)

: Recurrent episodes of pouchitis that respond to antibiotics but relapses thereafter, requiring recurrent or continuous antibiotics or advanced therapies

Chronic Antibiotic Refractory Pouchitis (CARP)

: Relapsing-remitting or continuous symptoms of pouchitis with 

response to typical antibiotics, requiring escalation of therapies

Crohn’s-like Disease of the Pouch (CLDP):

Presence of perianal and other fistulizing disease 12 months from final stage

Stricture of the pouch body or pre-pouch ileum

Lastly, the authors posed that the treatment goals and targets are clinical remission, and recommendations for endoscopic and/or histologic remission were not considered a critical target.

For primary prevention, the authors of the guideline provide no recommendation on the use of probiotics against primary prevention of pouchitis. The authors reported a knowledge gap, with very low-quality evidence. In current practice, most patients undergoing pouch creation do not use of a primary preventative strategy and respond rapidly to an initial course of antibiotics. A daily preventative strategy may not be useful in this setting. Although there is low risk of adverse events, cost of probiotics can be an issue and data on the strains of probiotics that are most helpful has not been studied.

The guideline authors also recommended against the use of antibiotics for primary prevention for similar reasons. Although the authors cited a single study using oral tinidazole with possible benefit, the risk of adverse effects of indefinite antibiotic therapy for the prevention in an asymptomatic patient may be higher compared to sporadic use in setting of acute pouchitis.

The authors do recommend the use of antibiotics for the management of acute, intermittent pouchitis, based on 4 randomized controlled trials as well as 8 observational studies. The pooled response rate in these studies was 65%. The most well-studied agents were ciprofloxacin and/ or metronidazole, singularly or in combination. Additional agents included vancomycin, which was shown to have clinical benefit, as well as rifximin. The typical antibiotic course was 2-4 weeks.

The authors provided no recommendation on the use of probiotics for the treatment of acute intermittent pouchitis, reporting a knowledge gap with low-quality data. Three studies were cited using varying formulations of probiotics with benefit, and although adverse effects are infrequent, cost considerations were significant. Moreover, recommendations regarding benefits of un-studied formulations of probiotics cannot be made. Probiotics may delay effective therapy with antibiotics, which have a greater body of evidence and known clinical efficacy.

However, the authors of the guidelines did suggest that probiotics can be used for the secondary prevention of pouchitis. This is based on the data from 3 randomized, with an 87% lower risk of relapse over 12 months in patients treated with probiotics, specifically the De Simone formulation. The authors of the guidelines did state personal experience temper the use of probiotics, as the reduction reported in the RCTs has not been borne out in real-world practice.

The authors of the guidelines did recommend for the use of chronic antibiotics in the treatment of Chronic Antibiotic Dependent Pouchitis. There is limited evidence and the basis of this recommendation is based on real-world efficacy in the collective experience of the guideline writers. Multiple antibiotic therapies may be effective in this setting, and the authors suggests cycling antibiotics and/or potentially de-escalating to the lowest dose possible with intermittent gaps to minimize adverse events.

The guidelines also suggest for the use of advanced therapies in chronic antibiotic dependent pouchitis (CADP) and chronic antibiotic refractory pouchitis (CARP.) Although much of this is based on the results of cohort studies, it is also based on the recently published EARNEST trial, featuring 102 patients with chronic pouchitis (both CADP and CARP) who were treated with placebo or vedolizumab. Vedolizumab was more effective than placebo in inducing clinical remission (35%) versus placebo (18%). It is important to note that 21% of patients continued to require antibiotics after week 34, and more patients in the vedolizumab treatment arm required antibiotics than in the placebo group, suggesting the ongoing role of anti-microbials in this patient population.

The use of corticosteroids, namely ileal-released budesonide, was suggested by the authors for the management of CARP. This was based on both expert opinion as well as the results of 2 case series, reporting an endoscopic and clinical benefit of ileal-released corticosteroid preparation. The pooled response rates in these case series were 77%. The authors recommended limiting duration to 8-12 weeks with a consideration for steroid-sparing agents.

The authors offered no recommendation regarding the use of Mesalamine for the treatment of CARP. The guidelines did cite 1 study on the use of sulfasalazine in 11 patients with benefit, which may be unique to the use of sulfasalazine due to its known anti-microbial effect.

The authors do recommend the use of ileal-released budesonide for Crohn’s-like disease of the pouch based on no studies, but with indirect data based on expert experience. The goal, once again, is to minimize duration to 8-12 weeks with a consideration for steroid-sparing agents.

Based on 10 cohort studies or case series, the authors also suggested for the use of advanced therapies for Crohn’s-like disease of the pouch, with a pooled response rate of 74%. Pre-colectomy therapies can be recycled. The majority of the studied therapies were anti-tumor necrosis factor (TNF), with smaller number of studies for vedolizumab and ustekinumab.

For the management of cuffitis, the authors suggested therapies that have been approved for the treatment of UC. Topical agents were recommended as first lines, with a suggestion of advanced IST in refractory cases. Data extrapolated from prior AGA guidelines for the management of mild-to-moderate and severe UC, considering that the cuff is a remnant of the rectal mucosa.

A friendly table for the guideline recommendation is provided above. Overall, I want to highlight that the nearly all of these recommendations are conditional and based on low/very low certainty of evidence, from studies of a few patients. This is likely due to the fact that although there is a rising incidence of pouchitis, definitions of disease, outcomes as well as recruitment has been a major issues in clinical trials and studies, including the EARNEST Study.

One of the biggest values of these guidelines is the push to standardize our definitions of inflammatory conditions of the pouch and provide guidance on clear treatment goals, which will aid in future research in this area—a clear unmet need for our patients.

Lightner AL, Mathis KL, Dozois EJ, et al. Results at Up to 30 Years After Ileal Pouch-Anal Anastomosis for Chronic Ulcerative Colitis. Inflamm Bowel Dis 2017;23:781-790.

Barnes EL, Herfarth HH, Sandler RS, et al. Pouch-Related Symptoms and Quality of Life in Patients with Ileal Pouch-Anal Anastomosis. Inflamm Bowel Dis 2017;23:1218-1224.

Barnes EL, Agrawal M, Syal G, Ananthakrishnan AN, Cohen BL, Haydek JP, Al Kazzi ES, Eisenstein S, Hashash JG, Sultan SS, Raffals LE, Singh S; AGA Clinical Guidelines Committee. Electronic address: clinicalpractice@gastro.org. AGA Clinical Practice Guideline on the Management of Pouchitis and Inflammatory Pouch Disorders. Gastroenterology. 2024 Jan;166(1):59-85. doi: 10.1053/j.gastro.2023.10.015. PMID: 38128971.

Recent recommendations from the AGA may help gastroenterologists manage the rising rate of pouchitis with the aid of clinical evidence.