Briefly: Notable Recent IBD Publications

Vermeire S et al. Lancet 2017; 389: 266-75.  The “FITZROY ” study examined clinical remission in patients with moderate-to-severe Crohn’s disease treated with filgotinib, a orally administered selective JAK inhibitor.  This agent is 30 times more selective fo rJAK1 over JAK3. This study enrolled 174 patients in a phase II study. Key findings:

  • Among patients naive to anti-TNF agents, clinical remission (based on CDAI <150 at week 10) noted in 47% of filgotinib-treated compared with 23% of placebo group (P=.0077)
  • Among patients naive to anti-TNF agents, clinical response was noted in 67% of filgotinib-treated compared with 44% in the placebo group.

H Singh et al. Gastroenterol 2017; 153: 430-8.  Using the large Manitoba Epidemiology Database with 1.3 million population (2005-2014), the authors found that individuals with IBD had a 4.8 fold increase risk of Clostridium difficile infection.

T-D Kanneganti. NEJM 2017; 377: 694-6. This review examined the NLRP3 Inflammasome.  Neudecker et al (J Exp Med 2017; 214: 1737-52) identified microRNA miR-223 which functions “to suppress the Nlrp3 inflammasone during acute colitis.” Other useful points in this review of basic research:

  • “The majority of the immune cells in the body are located in the intestine, where they are spatially separated from more than 10 trillion microorganisms by a layer of mucus and a layer of epithelial cells.  Deterioration of this physical barrier …underlies inflammatory bowel disease.”
  • miR-223 is increased in the inflamed colon. “During inflammation, the expression of miR-223 is also upregulated..and the molecule binds to its complementary sequence in a regulatory part of Nlrp3 mRNA…lead[ing] to decreased Nlrp3 expression and the consequent dampening of interleukin-1β maturation and associated inflammation.”


Clostridium difficile Risk Factors in Children

From J Pediatr -full text: Risk Factors for Community-Associated Clostridium difficile Infection in Children  (DJ Adams J Pediatr 2017; 186: 105-9)

Methods: We performed a case-control study using billing records from the US military health system database

Results (from abstract):

A total of 1331 children with CA-CDI were identified and 3993 controls were matched successfully. Recent exposure to fluoroquinolones, clindamycin (OR 73.00; 95% CI 13.85-384.68), third-generation cephalosporins (OR 16.32; 95% CI 9.11-29.26), proton pump inhibitors (OR 8.17; 95% CI 2.35-28.38), and to multiple classes of antibiotics, each was associated strongly the subsequent diagnosis of CA-CDI. Recent exposure to outpatient healthcare clinics (OR 1.35; 95% CI 1.31-1.39) or to a family member with CDI also was associated with CA-CDI.

Table 2 lists other medications and their risks; for example, corticosteroids had adjusted OR of 1.22 and H2-receptor antagonists had adjusted OR of 3.33.  The OR of fluoroquinolone could not be calculated as 51 cases were exposed compared with 0 controls

In their discussion, the authors note the following:

Our study supports the occurrence of CDI among a population of children who were never hospitalized previously and provides a broad characterization of the medication and epidemiologic exposures associated with pediatric CA-CDI cases. Recent exposure to fluoroquinolones, clindamycin, third-generation cephalosporins, and to multiple classes of antibiotics was associated strongly with the subsequent diagnosis of CA-CDI in children; however, a sizeable minority had no preceding antibiotic exposure.

My take: This large study shows that CDI is more frequent after antibiotic usage and after usage of acid suppression (particularly with proton pump inhibitor) therapy.

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One Way Fecal Microbiota Transplant May Work: Changing Bile Acids

Breifly Noted:

From MedPage Today: Fecal transplant success may depend on bile acid metabolism

An excerpt:

the transplants change patterns of bile acid metabolism in the gut, making the environment inhospitable to C. diff colonization.

In three studies reported at Digestive Disease Week (DDW) 2017, it was demonstrated that individuals with C. diff who respond to fecal transplant showed a different pattern of microbiota species composition compared with baseline and/or with those who fail to respond. But that’s not all: the responders also showed distinct, altered profiles of those elements involved in bile acid metabolism.

Vincent Van Gogh; Hopital Saint-Paul (1889)


Another Shady Pharmaceutical Business Practice: Citizen’s Pathway to Delay Competition

First, a comment regarding yesterday’s post: The Truth About Probiotics: Constipation Version

Some readers took issue with my pessimism with probiotics in terms of their effectiveness for several conditions, their safety and the number needed to treat (NNT). It is noted that the number needed to treat (NNT) with probiotics is better than with many other conditions.  For example, the NNT for benefit with the influenza vaccine, Tamiflu for influenza, and mammography for preventing breast cancer are much worse than the NNT for benefit with probiotics for conditions like NEC, antibiotic-associated diarrhea, Clostridium difficile infection, and ulcerative colitis (with VSL#3). If one looks at multiple posts from this blog, there are plenty of posts supporting the use of probiotics (see some of the links yesterday or search “probiotics” on this blog.  Thus, it is important to not overlook the benefits of probiotics for many conditions and to not take a single study and extrapolate too much.

Now for today’s post -perhaps it will stir as much interest:

I must admit I’m fascinated with the way pharmaceutical companies operate and the creative ways they find to magnify their profits.  In previous posts, I’ve detailed how pharmaceutical companies will try to corner the generic market, increase the cost of liquid medicines, and package drugs in a way to force the purchase of additional vials of medicine among other tactics.  Now, a commentary (R Feldman, C Wang. NEJM 2017; 376: 1499-1501) details how pharmaceutical companies have increasingly used “the citizen-petition process that the Food and Drug Administration (FDA) implemented in the 1970s.”  This process was designed as “a way to voice concerns” by individual citizens.

Yet, this pathway is now being used to delay competition/entrance of generic drugs, mainly with frivolous claims.  In most cases, companies file these claims at the end of the approval process, almost always as a delaying tactic.  Approximately 80% of these actions by competitor drug companies are denied by the FDA.

Ultimately, these actions could be countered with antitrust actions; this, in fact, has occurred with Shire ViroPharma.  On February 7, 2017, the Federal Trade Commission filed an antitrust action “alleging that the company abused regulatory processes by filing 43 submissions with the FDA (including 24 meritless citizen-petition filings within one docket) in an effort to hold off generic competition for its gastrointestinal drug Vancocin (vancomycin).”  However, antitrust actions are typically difficult to pursue and expensive.

My take: I think these tactics (and others) will undermine the relationship of pharmaceutical companies with consumers. While their stock holders may see benefits in the short term, I expect that other stake holders will fight back.  There are several targets in that endeavor, including ending limits on Medicare negotiating for better prices.

Related blog posts:

Two for the PPI Team

Medicine safety is not nearly as straight-forward as most people would expect.  Virtually all medicines have the potential for adverse reactions.  In addition, there are often conflicting reports on how frequent adverse reactions occur; furthermore, negative studies demonstrating safety may be published less frequently due to publication bias.

This problem is compounded by the frequent misunderstanding of statistics.  Frequently, risks of medications are expressed as an odds ratio.  So, if an adverse reaction occurs twice as often with the medication than without the medication, the odds ratio would 2.0.  Yet, if the adverse reaction is rare (eg. one in a million), then the absolute increase in risk remains minuscule.

Proton pump inhibitors have received a lot of press, often about rare increases in adverse reactions. But, there are many potential benefits to these medications and numerous studies demonstrating fairly good safety profiles.  A few more studies (thanks to Ben Gold for these references) on their safety have recently been published:

  • 1. “Long-term Proton Pump Inhibitor Use is Not Associated with Changes in Bone Strength and Structure” LE Targownik et al. Am J Gastroenterol 2017; 112: 95: 101.
  • 2. “Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.” DM Faleck et al. Am J Gastroenterol 2016; 111: 1641-8.

In the first study, the authors examined 52 PPI-users (>5 yrs) and 52 non-PPI users with mean age of 65 years.  They underwent quantitative CT , DXA, and markers of bone metabolism. “There were no differences detected..between the two groups.”  The conclude that PPIs were not associated with changes that increase a risk of fracture and “provide further evidence that the association between PPI use and fracture is not causal.”

In the second study, the authors analyzed data from 14 ICUs 2010-2013 and identified 18,134 patients (mean age 66-67 yrs) who met inclusion criteria.  271 (1.5%) developed Clostridium difficile infection (CDI) in the ICU.  The main risk factor for CDI was antibiotics with adjusted Hazard Ratio (aHR) of 2.79.  “There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72-3.35).”  “PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI 0.48-0.83).”  The authors also noted that even those who received the highest doses of PPIs, “there was no risk for health-care facility-onset CDI.”

My take: PPIs can be life-saving medications and can alleviate a lot of suffering.  These studies pushback on some of the concerns about PPI risk.

Related blog posts:

The Coronation of Napoleon (Louvre); Jacques-Louise David

How Much Do We Really Know About Fecal Microbiota Transplantation?

A recent study (SJ Ott et al. Gastroenterol 2017; 152: 799-811) followed 5 patients who were treated with a sterile fecal filtrate (via nasojejunal tube) for recurrent Clostridium difficile infection (CDI) for a minimum of 6 months.  This open-label study noted that this fecal filtrate transfer eliminated the symptoms of CDI in all 5 patients.

A summary of this important study is available in the AGA blog:

Here’s an excerpt: What is the Active Ingredient in FMT for CDI?

Stool was collected from 5 donors selected by the patients and fully characterized according to FMT standards. The stool was then sterile filtered to remove small particles and bacteria, and the filtrate was transferred to patients in a single administration via nasojejunal tube.

Fecal samples were collected from patients before and at 1 week and 6 weeks after FFT. Microbiome, virome, and proteome profiles of donors and patients were compared….

They identified about 300 different proteins in each of the filtrates they analyzed—most proteins were of human origin, but the filtrates also contained 20–60 bacterial and fungal proteins. The major human proteins in the filtrate proteome were human enzymes such as intestinal-type alkaline phosphatase, chymotrypsin-like elastases, and α amylases. Bacterial proteins included metabolic enzymes and redox proteins without obvious microbiome-modifying properties, such as glyceraldehyde-3-phosphate dehydrogenase, phosphoenolpyruvate carboxykinase, glutaredoxin-1, or thioredoxin-1…

Ott et al propose that the active component of FMT therapy might not be living bacteria, but bacterial components, antimicrobial compounds of bacterial origin (bacteriocins), or bacteriophages that contribute to a healthy intestinal microenvironment. These could be common to all successful FMT therapies and even rather unspecific regarding the bacterial strain(s) used for therapies. They propose that bacteriophages affect community dynamics of gut microbiota to resolve dysbiosis.

My take: This is a provocative study that challenges us to rethink how FMT works. Ultimately, treating CDI needs to be more precise.

Related blog posts:


Clostridium difficile Infection in Inflammatory Bowel Disease: Expert Updates

A recent clinical practice update (S Khanna et al. Clin Gastroenterol Hepatol; 2017; 15: 166-74) provides some succinct recommendations regarding Clostridium difficile infection (CDI) in Inflammatory Bowel Disease (IBD).

Background: In 2011, the authors note that CDI was associated with 29,000 deaths and is now the most lethal enteric pathogen in the U.S.

Differences in pathogenesis of C diff in IBD compared to those without IBD:

  • Younger age
  • Less frequent antibiotic exposure
  • More often community onset (rather than hospital onset)
  • Higher recurrence (may be related to dysbiosis)

Key recommendations:

  • In patients with IBD flare, test for CDI
  • In patients with CDI and IBD, clinicians should consider “using vancomycin instead of metronidazole.”
  • In patients with recurrent CDI and IBD, consider fecal microbiota transplantation

Figure 4 proposes a management algorithm (for adults).  If uncomplicated CDI, recommended dose of vancomycin was 125 mg q6h. If no improvement in 3-4 days, then “consider escalation of immunosuppression.” For complicated CDI, consider oral vancomycin at 500 mg q6h and IV metronidazole 500 mg q8.  In addition, consider rectal vancomycin and surgery consult.

Complicated CDI includes ICU admission, hypotension, T >38.5, ileus/megacolon, mental status changes, leukocyte count >35,000  or < 2000, or lactate >2.2 mmol/L

Another review article (Y Chen et al. Inflamm Bowel Dis 2017; 23: 200-07) is a meta-analysis that identified six studies.  One of these studies was a case-control study with nearly 400,000 patients (and about 7000 cases of C diff). Key finding: CDI results in nearly a doubling of the risk of colectomy (OR 1.90), mainly in patients with ulcerative colitis.

Related blog posts

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.