Taha Qazi, MD

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.

Articles

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.

AGA Clinical Guidelines on the Management of Pouchitis and Inflammatory Pouch Disorders

 remains the second most common cause of cancer-related death, despite preventative screening and detection strategies.

 Multiple strategies exist for the screening CRC, ranging from colonoscopy to stool-based testing. Prior studies have suggested that screening for early-stage cancers was curable with reduced mortality.

 Unfortunately, adherence to colon cancer screening continues to be below the rate of targeted recommendations.

Non-invasive screening tests have been developed for the evaluation of colon cancer using stool DNA molecular markers and is currently a part of the colon cancer screening guidelines. In the initial trials, however, the despite having a higher sensitivity than a comparator stool test, the specificity was lower. Recently, a newly developed, multi-target DNA test has been developed for the goal of improving specificity. In the BLUE-C study, the authors aimed to evaluate the test characteristics, sensitivity and specificity of this next-generation stool test for CRC and advanced neoplasia (colorectal cancer or advanced precancerous lesions).

The next generation test includes a new molecular panel, including the methylated DNA markers ceramide synthase 4 gene (LASS4), leucine-rich repeat containing protein 4 gene (LRRC4), serine–threonine protein phosphatase 2A 56-kDa regulatory subunit gamma isoform gene (PPP2R5C), and the reference marker zinc finger DHHC-type containing 1 gene (ZDHHC1), while retaining fecal hemoglobin.

Across 186 sites between 2019-2023, asymptomatic patients aged ≥40 years old undergoing screening colonoscopy were approached for inclusion. Patients with a prior history of CRC, advanced pre-cancerous lesions, a family history or personal history of polyposis conditions were excluded. Patients with a history of inflammatory bowel disease (IBD) or Cronkhite-Canada Syndrome were also excluded. Patient with a prior positive first generation multi-target stool DNA test, a positive fecal immunohistochemical test (FIT) or fecal occult blood test within the previous 6 months of inclusion were also excluded. Symptoms of rectal bleeding were also exclusionary as was a recent colonoscopy within nine years of inclusion.

Patients who were included had stool testing obtained for both FIT and the next-generation multi-target stool DNA test, prior to the provision of preparation. Screening colonoscopy was then performed as standard of care. The primary outcome was the sensitivity of the newer generation, multi-target stool DNA test for CRC, with sensitivity defined as proportion of patients with CRC with a positive test result.Additionally, specificity for advanced neoplasia was defined as the proportion of patients with a negative test result among patients without advanced neoplasia. Advanced precancerous lesions included adenomas and sessile serrated lesions (including large, hyperplastic polyps) that were at least 1 cm in the longest dimension, lesions with villous histologic features, and high-grade dysplasia.

A total of 20,176 participants were included in the study, of which 98 had CRC; 2144 had advanced precancerous lesions; 6973 had non-advanced adenomas; and 10,961 had non-neoplastic findings. The next-generation test had a sensitivity for CRC of 93.9% (95% CI, 87.1 - 97.7), a specificity of advanced neoplasia of 90.6% (95% CI, 90.1 - 91.0).

Sensitivity of advanced pre-cancerous lesions was 43.4% (95% CI, 41.3 - 45.6). Sensitivity for high-grade dysplasia was 74.6% (95% CI, 65.6 - 82.3). Specificity for non-neoplastic lesions or a negative colonoscopy was 92.7% (95% CI, 92.2 - 93.1). In comparison to the FIT testing, the multi-target DNA test had a better sensitivity for CRC and advanced pre-cancerous lesions; however, the specificity was lower for advanced neoplasia with the next-generation multi-target stool DNA test compared to FIT.

The reduction in false positives with the next-generation screening tool may play a pivotal role in appropriate resource and screening allocations. More importantly, this increased specificity did not result in a decreased sensitivity. When analyzing age-related cohorts, the specificity was highest in the next-generation stool testing, (97.3% among those 45 - 49 years old and 95.9% among those 50 - 54 years old). Considering this, the test may role in improving screening adherence, especially in this younger cohort of patients.

A major limitation of the study is the lack of comparison of the next generation multi-target stool DNA test to the current multi-target stool test. A direct comparison of the 2 tests may provide initial insight on the improvement of the next generation multi-target DNA test compared to the currently available multi-target stool test. Despite this fact, the next-generation multi-target stool DNA test provides another avenue for CRC screening which may improve adherence to CRC screening guidelines and improve detection of a preventable CRC and neoplastic lesions.

Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer JClin 2023; 73: 17-48.

Carethers JM. Screening for colorectal cancer in African Americas: Determinatns and Rationale for Earlier Age to Commence Screening. Dig Dis Sci 2015; 60:711-721

American Cancer Society. 80% in every community. National Colorectal Cancer Roundtable (https://nccrt .org/80-in-every-community-2/

Imperiale, T. F., et al. (2024). "Next-Generation Multitarget Stool DNA Test for Colorectal Cancer Screening." New England Journal of Medicine 390(11): 984-993.

As clinicians work to improve CRC screening rates, a promising new test has shown favorable accuracy in detecting cases.

BLUE-C: Next Generation Multi-Target Stool DNA Test for Colorectal Cancer and Advanced Neoplasia

It is my pleasure to introduce the final edition of the 

for the 2023 calendar year. In this edition, we hope to present research that is groundbreaking at recent meeting, highlighting the role of new therapies for both inflammatory bowel disease (IBD) as well as esophagitis. We also present an article of the recent Celiac disease guidelines, a helpful review for practitioners on the diagnosis and management of celiac disease.

Chiara Maruggi, MD, returns to discuss a recent article reviewing the role of vonoprazan for the management of erosive esophagitis. Vonoprazan, a potassium-competitive acid blocker (PCAB) is a novel therapy for the management of esophagitis. An aspect of PCABs which differentiates them from guideline-recommended proton pump inhibitors (PPIs) are the need for dosing around meals, particular to PPIs only. In a randomized, double-blind, parallel group, multicenter trial, vonoprazan was compared to lansoprazole in adults for the management of erosive esophagitis. A total of 1027 patients were included in the trial, and vonoprazan was found to be superior for the primary endpoint of endoscopic healing of erosive esophagitis at week 8, with a greater effect of healing in patients with severe esophagitis (LA Grade C/D). PCABs represent a novel mechanism for the management of erosive esophagitis and may hold promise for the management of other peptic conditions.

Shubha Bhat, PharmD, MS, BCACP, an IBD leader in clinical pharmacology at the Cleveland Clinic, also reports on the recent approval of a new agent for the management of ulcerative colitis, etrasimod. Etrasimod, a sphingosine 1-phosphate receptor modulator (S1PR), represents a novel, oral therapy for the management of ulcerative colitis. Sharing the data from the phase 3, double-blind randomized controlled trials, ELEVATE UC-12 and ELEVATE UC-52, a higher proportion of patients on the study drug met the outcomes of clinical remission and sustained clinical remission at week 12 and 52. Interestingly, the trial design did feature patients with proctitis and left-sided disease, suggesting another option for advanced therapies in these populations.

Katherine Falloon, MD, returns to discuss the results of the SEQUENCE trial, which represents the third trial comparing biological efficacy for the management of Crohn’s disease. Risankizumab, a selective anti-IL-23 therapy, is compared to ustekinumab, which blocks the activity of both IL-12 and IL-23. Patients in the trial had moderate to severe Crohn’s disease with endoscopic disease activity. Patients were randomized to receive either Ustekinumab or Risankizumab. The results of the study demonstrate the non-inferiority of risankizumab to ustekinumab in the endpoint of clinical remission at week 24, and the superiority of risankizumab to ustekinumab for endoscopic remission at week 48. The trial demonstrates additional evidence of the potential positioning of medications as we enter a world of multiple medical therapies for Crohn’s disease.

Lastly, Lady Katherine Mejía Pérez, MD, presents the most recent guideline update for the diagnosis and management of Celiac disease, by the American College of Gastroenterology (ACG). The article provides a summary of the major recommendations in diagnosis, including the role of serological testing for diagnosis combined with endoscopic evaluation with duodenal biopsies. In situations of discordance, HLA haplotyping can aid in eliminating the diagnosis of celiac disease. In children, diagnosis is often established only through serological testing. Serologic testing can confirm adherence to a gluten free diet as endoscopic healing can take time, especially in adults.

I hope you enjoy the most recent version of HCPLive’s Qazi Corner!

The final quarterly issue of the year touches on head-to-head trial data, a new treatment for erosive esophagitis, an ulcerative colitis agent, and the latest ACG recommendations for Celiac disease.e.