Early Results with Upadacitinib -a JAK1 Inhibitor for Crohn’s Disease

From Gastroenterology & Endoscopy News: New JAK1 Inhibitor Treats Most Challenging Crohn’s Patients

An excerpt:

An experimental oral JAK1 inhibitor, upadacitinib (AbbVie), has been tested in the most clinically challenging patients with Crohn’s and yielded impressive results. The drug led to a clinical response in 61% of these patients and remission in 22%, the new data show…

William Sandborn, MD, chief of gastroenterology at the University of California, San Diego, who led the study. “It seems to be a really effective drug in a very difficult-to-treat patient population, and the oral route of administration is attractive.”

Dr. Sandborn’s group presented the findings at the 2017 Digestive Disease Week (abstract 974h).

The CELEST trial enrolled 220 patients with active, moderate to severe Crohn’s disease. Patients received 16 weeks of induction therapy with one of five dosing regimens of upadacitinib or a placebo…

Dr. Sandborn called the findings particularly impressive given that the study participants are the most refractory patient population ever recruited in a trial for Crohn’s disease. “And this is also one of the first trials to meet new FDA requirements for demonstrating clinical remission using patient-reported outcomes as well as endoscopic improvement,” he noted.

My take: It is exciting that another oral agent may be helpful. Tofacitinib, a different JAK1 inhibitor, has data supporting its use in ulcerative colitis but not with Crohn’s disease.

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ACG World Congress -Useful Tweets

I wanted to share several tweets from this year’s ACG World Congress that looked helpful.

Topic: SBBO and IBS-D

A positive breath test is the ONLY variable that can predict response to Rifaximin in IBS-D: ACG and Mark Pimenthal. tweet from @AllRezale, MD

Topic: Polyps -slides recommend cold forceps for polyps 1-3 mm and cold snare for 4-5  mm polyps.

Topic: Hereditary Colorectal Cancer Syndromes

Topic: Aggressive fluids for pancreatitis

Rising BUN is Associated with mortality with pancreatitis. Tauseef, Ali @ibdtweets: “Pancreatitis pearls: aggressive fluid hydration 250-500 cc lactated ringer’s (my personal favorite also) and ensure BUN dropping #WCOGatACG2017”

Drug Development for Eosinophilic Esophagitis

Full text link: White Paper AGA: Drug Development for Eosinophilic Esophagitis (EoE)

I Hirano et al. Clin Gastroenterol Hepatol 2017; 15: 1173-83. This article reviews diagnostic criteria for EoE, clinical endpoints, and current/emerging treatments.

From AGA website-an excerpt:

Four important points from the white paper:

1. There is a complex inter-relationship between EoE, gastroesophageal reflux disease (GERD) and proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). A substantial proportion of patients with esophageal eosinophilia will improve with PPI treatment.

2. The clinical features and presentation of EoE differ between children and adults. Poor symptom specificity among children has limited the ability to identify appropriate candidates for enrollment into clinical trials and has impeded the development of pediatric patient-reported outcome instruments.

3. Aside from pharmacologic approaches, EoE can be addressed with dietary modifications and/or endoscopic dilation.

4. We should remember that the diagnosis of EoE carries a potentially major financial burden on patients’ families, making identifying new, effective and affordable treatment options a priority.

FDA Warning for Obeticholic Acid

Obeticholic acid was approved last year as a treatment for primary biliary cholangitis (PBC). Now (9/21/17), the FDA warns of 19 deaths associated with Obeticholic Acid, particularly when the medication has been used at higher than recommended dosing.

Link: FDA Warning on Obeticholic Acid

An excerpt:

Nineteen cases of death were identified, of which eight provided information about the patient’s cause of death. The cause of death was reported to be worsening of PBC disease in seven cases, with cardiovascular disease cited in the other case. Seven of these eight cases described patients with moderate to severe decreased liver function who received Ocaliva 5 mg daily, instead of a dose no greater than 10 mg twice weekly as recommended in the label prescribing information for patients with this extent of decreased liver function.

Somewhat Funny Flatulent Research

A recent study (CV Almario et al. Clin Gastroenterol Hepatol 2017; 15: 1308-10) was titled: “Old Farts -Fact or Fiction?  Results from a Population-Based Survey of 16,000 Americans Examining the Association Between Age and Flatus.” I was surprised that this was not in an April Fools edition, though I had to read the article because of the intriguing title. The authors premise was to determine if the elderly pass more flatus.

Key findings:

  • Based on self-reporting using a mobile app (MyGiHealth), the authors found that individuals ≥65 years passed flatus less often than the younger age groups. Among those reporting flatulence every 1-2 hours, only 22.6% of those ≥65 years had this frequency; this compared to at least 33% in all other age groups.
  • Most commonly, individuals in all age groups reported passing flatus about every 3-4 hours (36-41%); the next most common frequency was about every 1-2 hours (23-38%) across all age groups. The other frequent category was passing flatus once or twice a day which was reported between 24-29% across all age groups.

The authors indicate that limitations of their study include “social desirability bias” and “information bias.”  In addition, while the entire cohort was >16,000, there were only 296 who were ≥65 years of age.

While I’m not an expert in this field, other limitations could include worsened ability to detect/record flatus with age and/or worsened memory about frequency of passing flatus.

My take: This study shows that almost any study could find a home in some medical journals. In my view, self-reported frequency of passing flatus may not be accurate (the dog did it!).

Pitt Street Bridge, Charleston, SC

Northern Latitudes -Higher Prevalence of Celiac Disease and Gluten Avoidance

A recent study (A Unalp-Arida et al. Gastroenterol 2017; 152: 1922-32) examines the relationship of latitude and the prevalence of celiac disease and gluten avoidance.

Using the NHANES 2009-2014 survey with 22,277 participants (6 years and older), the authors identified persons with celiac disease (based on serology) along with those who avoided gluten without a diagnosis of celiac disease.

Key findings:

  • 0.7% of participants had celiac disease and 1.1% avoided gluten without celiac disease
  • Celiac disease was more common among individuals who lived at latitudes of above 35 degrees and more common with higher socioeconomic status. Figure 2 map provides latitude lines. In the eastern U.S. the Georgia-Tennessee border corresponds to this latitude line and in the western U.S. the southern tip of Nevada lies on this line.
  • From 35 degrees to 39 degrees the odds ratio was 3.2, whereas the odds ratio was 5.4 for those above 40 degrees.  These odds ratios were independent of race, ethnicity, socioeconomic status and body mass index.
  • Similarly, the prevalence of gluten avoidance without celiac disease was twice as common among persons living north of 40 degrees compared with those residing at latitudes <35 degrees.
  • The findings on latitude were heavily influenced by the increased rate of celiac and gluten avoidance in the Northeast region (more so than in the West)

In their discussion, the authors note that “a North-South gradient in disease occurrence in genetically similar populations has been shown in studies of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis.” Potential environmental factors could include lack of sunshine/vitamin D deficiency, hygiene, and infections.  A study comparing similar populations in Finland and Russia suggested a lower economic status/less hygiene increased the risk of celiac disease despite similar gluten exposure.  The authors note that there was NOT an increased risk in Northern Sweden compared to Southern Sweden.  In fact, this study of children found a higher rate of celiac disease in Southern Sweden (Arch Dis Child 2016; 101: 1114-18).

My take: This is another intriguing study regarding celiac disease epidemiology which strongly points to environmental factors accounting for marked variation in celiac disease prevalence.

More information on this topic from AGA Blog: Do More People Have Celiac Disease in the North vs the South?

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Big Study of Primary Sclerosing Cholangitis

This blog has reviewed multiple publications on primary sclerosing cholangitis (see blog posts below). Now, a study from 37 centers with 7121 patients with PSC has been published: TJ Weismuller et al. Gastroenterol 2017; 152: 1975-84. Given the relative infrequency of PSC, this retrospective report offers more insight into the predictors of the clinical course of PSC.

Key points:

  • Most of the patients in the study had large duct PSC (89.8%); 3.6% had small duct disease and 6.6% had overlapping PSC/autoimmune hepatitis.
  • Mean age of cohort at diagnosis was 38.5 yrs.
  • 70% of PSC patients developed IBD with ulcerative colitis (UC) about 5-times more common than Crohn’s disease.
  • 37% of patients met the primary endpoint of either liver transplantation or death
  • Individuals with small duct PSC had a favorable outcome; only one of 254 (0.4%) developed cholangiocarcinoma (CCA). Risk of primary endpoint was much lower in small duct PSC compared with classical PSC with an adjusted hazard ratio of 0.23.
  • Individuals with PSC/AIH variant also had a reduced risk of primary endpoint compared with classical PSC with an adjusted hazard ratio of 0.73.
  • Overall, CCA occurred in 594 patients (8.3%); the incidence of CCA changed markedly with the age of the patient.  In the youngest group (<20 years), the rate was 1.2 per 100 patient-years, it was 6.0 in 21-30 yr-olds, 9.0 for 31-40 yr-olds, 14.0 fr 41-50 year olds, 15.2 for 51-60 yr-olds, and 21.0 per 100 patient-years in those older than 60 years.
  • The absence of IBD, particularly UC, was associated with a lower risk PSC clinical course. Patients with UC had increased liver disease progression compared with patient’s with Crohn’s disease, with a HR of 1.56.
  • The median transplant-free survival time was 14.5 years; the estimated survival was approximately 21 years in the entire cohort

It is noted that an important limitation is that the cohort is from specialist centers and may not reflect a more typical population-based cohort; that is, this patient population is likely to be severely affected.

My take: Patients with small-duct PSC have a much lower risk of disease progression.

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