Highlights in IBD from Two 2019 Meetings: American College of Gastroenterology and United European Gastroenterology Week

Gastroenterology & Hepatology. December 2019 – Volume 15, Issue 12, Supplement 5

Excerpts from William Sandborn Commentary which are at the end of this supplement along with references:

Vedolizumab

In the VARSITY study (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis), 769 patients with ulcerative colitis were randomized to a year of therapy with either adalimumab at the US Food and Drug Administration (FDA)-approved dose or vedolizumab at the FDA-approved dose…This shows that the idea that vedolizumab (and anti-integrin therapy) is slower-acting than anti-TNF therapy is not correct, and that both of these classes of drugs can work fairly quickly in a number of patients.

Dr Brian Bressler and colleagues looked at the effectiveness of anti-TNF therapy in the real world when used second line after failing first-line biologic therapy with vedolizumab…The study conducted by Dr Bressler and colleagues, which included both Crohn’s disease patients and ulcerative colitis patients, found that the results were fairly similar whether patients received first-line biologic therapy with an anti-TNF agent or whether patients received first-line therapy with vedolizumab… It is generally thought that vedolizumab is a safer therapy than anti-TNF therapy, so with the finding from this study, a reasonable treatment approach could be to start with vedolizumab and see if it works

Dr Christina Chambers and colleagues identified outcomes for pregnancy in 223 women, 53 of whom received vedolizumab. The researchers found that there were no major structural birth defects reported in the vedolizumab group, compared to 5.7% and 5.3% in the disease-matched group and healthy control group, respectively. Thus, there seemed to be no signal for an increased malformation risk in patients who were undergoing treatment with vedolizumab and became pregnant.

Adalimumab

The SERENE trials are a set of head-to-head trials, one for ulcerative colitis and one for Crohn’s disease, comparing standard-dose adalimumab to a more intensive induction regimen of adalimumab…

For both ulcerative colitis and Crohn’s disease, the SERENE trials showed that the current FDA-approved dosing regimen is effective and that more intensive induction therapy does not improve outcomes over time. Thus, there is no utility in giving high induction doses. 

Tofacitinib

Over 1000 patients who had been treated with tofacitinib were examined…during induction and maintenance of the placebo-controlled portion of the tofacitinib clinical trials, there were a total of 5 deep vein thrombosis and pulmonary emboli events. All 5 occurred in patients who were receiving placebo; none of these events occurred in patients who were receiving tofacitinib…[And] There was a total of 5 deep vein thrombosis and pulmonary emboli events during this long-term extension…Looking at the ulcerative colitis clinical trial data that I presented, it is somewhat reassuring that we did not see the same elevation in risk for deep vein thrombosis and pulmonary emboli that was seen in the high-risk rheumatoid arthritis patient population.

Mont Royal (Montreal)

More Good News for PPIs: NO Increased Risk of Dementia

From ACG SmartBrief (thanks to Ben Gold for this):

A study published in The American Journal of Gastroenterology found no link between the use of proton-pump inhibitors and increased dementia risk. The study, led by Muhammad Ali Khan, MD, examined 11 studies with a combined 642,949 participants, and researchers said “PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.”

The American Journal of Gastroenterology: January 2, 2020 – Volume Publish Ahead of Print – Issue – p doi: 10.14309/ajg.0000000000000500

Abstract

INTRODUCTION:

Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support.

METHODS:

We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach.

RESULTS:

We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88–1.37); for Alzheimer dementia only, it was 1.06 (0.72–1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84–1.25) and for Alzheimer dementia only 0.96 (0.82–1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low.

DISCUSSION:

We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.

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P’tit Train du Nord Linear Park

 

POEM vs Surgical Myotomy for Achalasia -Randomized Trial

A recent randomized trial (YB Werner et al. NEJM 2019; 381: 2219-29) compared peroral endoscopic myotomy (POEM) and laparoscopic Heller’s myotomy (LHM) for idiopathic achalasia in 221 patients.

Key findings:

  • Clinical success at 2-year followup was observed in 83% in the POEM group and 82% in the LHM group. Clinical success was defined as Eckardt score of 3 or less without the use of additional treatments.
  • Serious adverse events occurred in 2.7% of POEM group and 7.3% of LHM group
  • At 3 months following procedure, 57% of the POEM group and 20% of LHM group had reflux esophagitis; the rates were 44% and 29% at 2 years, respectively.

My take: This study demonstrates similar outcomes between POEM and LHM.  As a practical matter, local expertise is likely a crucial component in choosing between these options.

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More Details on Drug-Resistant E coli Transmitted by Fecal Microbiota Transplant

In June 2019, the FDA delivered a warning about the potential danger of transmitting drug-resistant E coli with fecal microbiota tranplantaion (FMT).  (FDA Warning for FMT)

A report on this issue has now been published: Z DeFilipp et al. NEJM 381: 2043-50, editorial M Blaser pgs 264-6.

The authors describe two patients, a 69 year-old with cirrhosis and a 73 year-old sp stem cell transplantation, who developed bacteremia due to transmission of a drug-resistant (extended-spectrum beta-lactamase [ESBL]) E coli following FMT which was delivered by oral capsules. The latter patient died from sepsis. The two patients had a genomicly-identical strain isolated that was also found in the donated aliquot.

In the commentary, a couple of important points:

  • “Up to now, the complications have been infrequent [from FMT], and for recurrent C difficile infection, the benefits of FMT clearly outweigh the risks; however, as the use of FMT is broadened and more compromised patients are treated, complications may be more frequently observed.”
  • “In the short term, improved and uniform screening of FMT material is needed to reduce the risks.”

My take: Both of these patients who became developed bacteremia were at risk for more severe infections.  However, we need to remain aware that severe complications can and do occur with FMT.  In context, though, there are risks of severe complications from routine use of antibiotics as well.

Frontenac Hotel, Quebec City

Only 3% Make It Through the Donor Screening Process for Fecal Microbiota Transplantation

A recent letter (Z Kassam et al. NEJM 2019; 381: 2070-2) describes the arduous process involved in being selected as a stool donor for fecal microbiota transplantation (FMT).

In a previous blog (2015), it appeared that 17% of donors were accepted for FMT: Rejected! Most Stool is Not Good Enough for FMT This current review of the donor program from a stool bank (OpenBiome) prospectively evaluated 15,317 donor candidates from 2014-2018.

Key finding:

  • Only 3% (n=386) made it through all the steps to become donors

Reasons for exclusion:

Stage 1: common reasons for exclusion:

  • geographical -living too far away to donate regularly
  • BMI >30
  • social history
  • travel history
  • not in age range

Stage 2: “failing” the 200-item clinical assessment –common reasons for exclusion:

  • lost to followup
  • allergic disorders/asthma
  • receiving medications/supplements
  • mental health concerns
  • infectious disease history
  • social history/sexual history/other reasons

Stage 3: “failing” the stool and nasal screening which included (in 2016) carbapenem-resistant Enterobacteriacea (CRE), extended-spectrum beta-lactamase-producing organisms (ESBL) and MRSA. –common reasons for exclusion:

  • lost to followup
  • infectious disorders (including C diff in 7 patients)

Stage 4: “failing” serological screening

  • lost to followup
  • abnormal LFTs, CBC or infection

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Island Ford, Sandy Springs, GA

Surprising Genetic Mutations in Polyposis Study

A recent cross-sectional study (PP Stanich et al. Clin Gastroenterol Hepatol 2019; 17: 2008-15, editorial 1942-44) identified a high frequency of genetic mutations among adults with at least 10 colonic polyps (cumulative burden of either adenomatous or hamartomatous).

This study had 3789 subjects who underwent multigene panel testing (MGPT) from 2012-16.

  • All subjects had at least 14 CRC-associated genes tested: APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
  • A subset had 3 more newly recognized polyposis genes: GREM1, POLD1, and POLE

Key findings:

  • A mutation in at least 1 gene was found in 13.7%
  • In those with fewer than 20 cumulative adenomas, 7.6% had a disease-associated genetic mutation with the majority (5.3%) being nonpolyposis CRC genes
  • Younger patients, 18-29, were more likely to have mutations in any gene.  For example, among patients with 10-19 polyps, these younger patients had a mutation in one of these genes in 27.8%; this is more than double the rate in any other age group.
  • Hamartomatous polyps, regardless of number, had a very high yield with genetic testing: 40% with 10-19 polyps and 72% with 20-99 polyps.

Limitations:

  • There is a referral bias in that the population was derived from a testing laboratory (Ambry)
  • In clinical practice, genetic testing frequently results in variants of unknown significance

My take: This study shows that genetic mutations are fairly frequent in patients with cumulative polyp burden of 10 or more, especially in younger age groups.  The surprising finding is the high frequency of nonpolyposis CRC genes.  Thus, in patients with adenomatous polyposis, testing beyond APC and MUTYH may be needed.

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Atlanta Botanical Garden