Category Archives: inflammatory bowel disease

An Overlooked Finding in a Recent Acute Severe Ulcerative Colitis Study

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A recent study (S Choshen et al. JPGN 2016; 63: 58-64) examined 283 children who were treated with IV steroids for acute severe ulcerative colitis.  This study focused on steroid dosing.  Their conclusion: “there does not seem to be a consistent superiority of high dose (>2 mg/kg/day) versus standard (1.25 mg/kg/day) or low-dose (1 mg/kg/day) methylprednisolone in pediatric acute severe colitis.”

Before looking into the details a little closer, one finding that was not even discussed in the abstract or discussion was the colectomy rate of 31%.  Previous pediatric studies of patients with ulcerative colitis had found rates generally half that rate but notably included patients with milder presentations of ulcerative colitis.  Thus, this rate of 31% (by 1 year after discharge) is useful information to reference when considering pediatric patients with acute severe colitis (ACS).

This study used datasets from the prospective Outcome of Steroid therapy in Colitis Individuals (OSCI) (n=128) and from the retrospective OSCI study (n=99).

Other results:

  • By day 5 of steroids, 45% had at most mild disease (ie PUCAI <35)
  • 31% had failed IV steroids and required salvage therapy (biologic or calcineurin inhibitor)
  • 20% had colectomy by discharge
  • When examining steroid dosage and outcomes, the authors could not discern any differences in need for salvage therapy, PUCAI <35 at day 5, or need for salvage therapy within 1 year. There was a mild difference in length of stay with 9 days in the low-dose group and 10-days in the high dose group.

My take: This large cohort provides some reassurance that current steroid dosing recommendations are probably right, in that there was no discernible improvement with higher doses.  This is in agreement with previous studies in adults which have not shown advantages of methylprednisolone >60 mg/day.  The high colectomy rate of 31% is worth keeping in mind in this population.

Related blog posts:

NewAbxDiscovered

 

Expanding VEO Variants

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A recent study (Q Li, CH Lee, LA Peters, et al. Gastroenterol 2016; 150: 1196-1207) provides a description of a new genetic variant causing very early onset inflammatory bowel disease (VEOIBD), which designates cases of IBD which presents <6 years of age.

Using whole exome sequencing, the authors identified TRIM22 mutations in 3 infants with fistulizing perianal disease and granulomatous colitis.  The authors further characterized the defect using functional studies that showed TRIM22 is important in the regulation of nucleotide binding oligomerization domain containing 2 (NOD2)–dependednt activation of interferon-beta signaling and nuclear factor (NF)-κB.

“NOD2 has long been recognized as a critical player in Crohn’s disease pathogenesis, where it is proposed to regulate innate immunity through NF-κB induced proinflammatory responses triggered by peptidoglycan…Simarlarly, mutations in XIAP..are associate with loss of NOD-2-dependent mediated NF-κB signaling” and has a similar phenotype.

My take: Identification of the numerous mutations that lead to VEOIBD is likely to help understand the pathogenesis and ultimately to better therapies.

Related blog posts:

How Much Lower Would The Braves Be Without the Marlins?

How Much Lower Would The Braves Be Without the Marlins?

What to Make of Post-op Treatment for Crohn’s Disease

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In 2009, Regueiro and colleagues published an influential paper “Infliximab prevents Crohn’s disease recurrence after ill resection” (Gastroenterol 2009; 136: 441-50). However, this was a small study with only 24 patients.  In this study, only 1 of 11 patients on infliximab had endoscopic recurrence compared with 11 of 13 of placebo patients at 1 year.  Besides the promising result that infliximab may prevent recurrent Crohn’s disease, this study confirmed that there is poor correlation between endoscopic recurrence and clinical activity scores.  In addition, the implication was that early treatment could be very important.

Now, a much larger study has been published (M Regueiro et al. Gastroenterol 2016; 150: 1568-78) and has cast some doubt on these earlier findings. It may have “muddied the waters” regarding the optimal approach.  The authors conclude that infliximab reduces postoperative endoscopic, but not clinical, recurrence of Crohn’s disease. Furthermore, they recommend in their discussion: “it may be reasonable to approach low-risk patients undergoing their first resection for CD conservatively and initiate treatment only if there is endoscopic recurrence at 6 months” [post-op].  The associated editorial (1521-24), after highlighting some of the important clinical findings, also says, that it may be “difficult to convince payers and patients that >2-4 years of treating an asymptomatic patient with TNFi, with its potential risks of long-term adverse effects, will be required to prevent clinically meaningful endpoints.”

Before accepting these conclusions, a closer look at the study is important.  This randomized study evaluated 297 patients at 104 sites. The study was intended to stop at 200 weeks, but was prematurely terminated at 104 weeks. Infliximab dosing was 5 mg/kg every 8 weeks.  This study was called the PREVENT study:  Prospective, Multicenter, Randomized, Double-blind, Placebo-Controlled Trial Comparing Remade and Placebo in the Prevention of Surgical Resection Who Are at an Increased Risk of Recurrence.

Key findings:

  • At week 76, clinical recurrence was not statistically different, though favored infliximab group: 12.9% vs. 20.0%
  • At week 76, endoscopic recurrence was less in infliximab-treated: 30.6% vs 60.0%
  • Also, more severe endoscopic recurrence  (Rutgeerts scores of i3 or i4) was markedly lower: 22.4% vs 51.3%

Other points:

  • Infliximab effectiveness could have been even higher if there had been an opportunity to escalate dosing; this occurs in about half of patients in typical clinical care.
  • This study’s focus on the primary outcome of clinical recurrence winds up overshadowing the much improved endoscopic results.

My take: I think that most well-informed patients and physicians would prefer to be treated post-operatively if they look at the results of this study closely.

From AGA twitter feed

From AGA twitter feed

Best Fecal Marker for Crohn’s Disease: Calprotectin

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A recent study (EK Wright et al. Inflamm Bowel Dis 2016; 22: 1086-94) collected data from 135 participants in a prospective, randomized, controlled trial aimed at preventing postoperative Crohn’s disease (CD) recurrence.  As part of this study, serial stool collections enabled comparison of fecal markers: calprotectin (FC), lactoferrin (FL) and S100A12 (FS).

FC was the optimal marker and was superior to CRP and CDAI. Table 4 provides a list of sensitivity, specificity, PPV, and NPV for each of the fecal markers at various cutoffs.

For FC, using the optimal cutoff of 135 mcg/g, the sensitivity was 0.87, specificity was 0.66, PPV was 56%, and NPV 91%.  A lower cutoff (50 mcg/g) improved sensitivity to 0.96 and NPV to 94%; whereas a higher cutoff (200 mcg/g) lowered the sensitivity to 71% but improved the specificity to 0.74 along with raising the PPV% to 59%.

My take: While the yield of a test changes based on the population examined, this report indicates that it is likely that calprotectin would outperform the other fecal inflammatory markers in most settings.

Related blog posts:

Briefly noted: G Gale et al. Inflamm Bowel Dis 2016; 22: 1071-77.  This report describes more extensive disease when there is concomitant orofacial granulomatosis with Crohn’s disease.

Paris from Postcards

Paris from Postcards, Vik Muniz

ParisCaption

Identifying IBD Years Before Symptoms

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A while back there was a movie called “Minority Report.”  The movie’s premise was that crimes could be predicted and stopped before they occurred.  A recent study (P Lochhead et al. Clin Gastroenterol Hepatol 2016; 14: 818-24) presents intriguing data suggesting a similar scenario for inflammatory bowel disease (IBD).

The authors used a prospective, nested case control study of participants in the Nurses’ Health Study I and II. Median age of patients with Crohn’s disease (CD) (n=83) and ulcerative colitis (UC) (n=90) was 52.7 years and 50.4 years respectively. Key findings:

  • Median prediagnostic hsCRP levels (mg/L) were 2.3 in CD, 2.2 in UC and 1.5 in controls (n=344).
  • Median prediagnostic IL6 levels (pg/mL) were 1.7 in CD, 1.2 in UC, and 1.0 in controls.
  • Median time interval between blood collection and diagnosis was 6.6 years for CD and 6.8 years for UC.
  • There was increased odds for developing disease even after adjustment for potentially confounding variables like smoking.  This analysis held up even when excluding disease that developed within 2 years of sampling.

Overall, this study suggests that there is a significant population of patients with subclinical IBD which precedes the diagnosis by several years.  This report adds to a number of other studies showing potential “preclinical phase” of many diseases including rheumatoid arthritis and type 1 diabetes.

My take: It is fascinating that bloodwork can be abnormal years before clinical symptoms. However, as in “Minority Report” the problem will be with identifying a crime/disease that might never occur.

Unrelated –Chart Depicting Car Temps:

car temp

IBD School Videos for Patients and Families

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While these “IBD School” YouTube videos have been around for several years, I only became aware of them in the past few months.  I think they are good patient education resources.

Here are some links to a few of them:

There are a lot of these videos including the following:

My take: these videos are generally ~4 minutes and a good way to get a lot of information on IBD pretty quickly.

Screen Shot 2016-05-31 at 4.48.09 PM

Ozanimod for Ulcerative Colitis

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The results of a phase 2 trial for Ozanimod have been published: WJ Sandborn et al. NEJM 2016; 374; 1754-62.

Ozanimod (RPC1063) is “an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract.”

From the abstract:

METHODS

We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks.

RESULTS

The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache.

CONCLUSIONS

In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.)

Ozanimod

Related blog post: CCFA Conference Notes 2016 (part 5) -Emerging Therapies …

 

Extent of Disease: Microscopic or Endoscopic Classification?

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Several recent articles highlight the divergence between microscopic and endoscopic classification of disease.

  • Verstraete et al. JPGN 2016; 62: 242-5.
  • Asthon et al. JPGN 2016; 62: 246-51.
  • Pashankar et al. JPGN 2016; 62: 314-16.

The first two references describe histology in comparison to endoscopic extent of disease in pediatric Crohn’s and the 3rd reference provides information on the finding of “duodenitis.”

Verstraete et al selected 60 patients  randomly from their cohort for retrospective review.  Two physicians independently reviewed the patients.  In describing extent of disease, the extent of disease (Paris Classification) was discordant in 34 (56.6%) when comparing  macroscopic disease (imaging and endoscopy) to macroscopic/microscopic combined.  In addition, there was high interobserver variability of the physicians when the physicians reviewed just macroscopic findings (κ= 0.53).

Asthton et al examined data from 172 pediatric patients with inflammatory bowel disease.  They found that histologic disease was more extensive than endoscopic findings.  For example, among those with ileal biopsies, 49% had endoscopic findings compared with 71.3% having histologic disease.

Currently, the Paris classification relies on endoscopic findings; however, together these two studies suggest that the microscopic findings need to be considered as well. How often areas with microscopic disease will eventually develop endoscopic lesions is not clear.

Pashankar et al, reviewed pathology reports over a 5-year periods with 2772 children (mean age 10.6 years).  They identified duodenitis in 352 with a prevalence rate of 12.7%. Gastritis was seen in 64% of children with duodenitis. Interestingly, 63% of the cases with histologic duodenitis had normal endoscopic appearance. Reported reasons for duodenitis:

  • Celiac disease 32%
  • Crohn’s disease 13%
  • Ulcerative colitis 3%
  • Helicobacter pylori infection 6%
  • Functional dyspepsia 7%

The remaining children (36%) were considered to have nonspecific duodenitis.  The authors state: “this finding is similar to the high percentage of nonspecific duodenitis (60%) in adults.”

My take: It is difficult to know how important microscopic findings are in many cases.  With inflammatory bowel disease, whether/how to incorporate microscopic findings in classification is unclear.  With regard to the finding of microscopic duodenitis, when a specific etiology has not been identified, this leads to lots of questions:

  • How important is this finding?
  • How should this be treated?
  • How much additional workup and followup is needed?
  • How helpful is your pathologist –is the threshold for abnormality too low histologically?

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marriage colonoscopy

More on Anti-TNF Drug Levels (part 2) and a Few Mentions

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Another study (K Papamichael et al. Clin Gastroenterol Hepatol 2016; 14: 543-9) examined therapeutic drug levels with regard to infliximab induction and mucosal healing.

In this retrospective study with 101 patients with ulcerative colitis, 54 (53.4%) achieved mucosal healing between weeks 10-14, defined by a Mayo endoscopic score of 0 or 1.  97% of patients were treated with 5 mg/kg infusions.

Key finding:

  • Infliximab threshold concentrations of 28.3 mcg/mL at week 2, 15 mcg/mL at week 6, and 2.1 mcg/mL at week 14 were associated with mucosal healing.

My take: While this study provides information on what type of levels to expect at 2, 6, and 14 weeks, what is really important is figuring out which patients need higher doses of infusions from the start.

Unrelated, briefly noted:

R Yadlapati et al. Clin Gastroenterol Hepatol 2016; 14: 535-42. In this prospective blinded cohort study of 59 subjects, oropharyngeal pH testing (Restech Dx-pH) and salivary pepsin analysis was not able to distinguish between healthy volunteers and subjects with a combination of laryngeal and reflux symptoms.

M Moris et al. Clin Gastroenterol Hepatol 2016; 14: 585-93. This study reports increasing findings of small pancreatic cysts with more (and better) MRI imaging.

Y Kawamura et al. Clin Gastroenterol Hepatol 2016; 14: 597-605. This retrospective study shows, among almost 10,000 patients with fatty liver disease, that alcohol consumption of ≥40 g/day is an independent risk factor for hepatocellular carcinoma.

Strongloides

More on Anti-TNF Drug Levels

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B Ungar et al (Clin Gastroenterol Hepatol 2016; 14: 550-7) report median serum levels of infliximab (n=78) or adalimumab (n=67) in correlation with mucosal healing.

In this retrospective cross-sectional study of adult patients with IBD (median age ~35 years), the authors found a correlation with higher drug troughs and mucosal healing.

“Levels of infliximab above 5 mcg/mL…and levels of adalimumab above 7.1 mcg/mL identified patients with mucosal healing with 85% specificity. Increasing levels of infliximab above 8 mcg/mL produced only minimal increases in the rate of mucosal healing, whereas the association between higher level of adalimumab and increased rate of mucosal healing reached a plateau at 12 mcg/mL”

The authors propose a “therapeutic window” of 6-10 for infliximab and 8-12 for adalimumab.

Clin Gastro Trough Levels

Remarks from DDW

Remarks from DDW