Latest on Tofacitinib for Refractory Ulcerative Colitis

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From Gastroenterology & Endoscopy News July 2016: Tofacitinib Effective in Refractory and Severe UC

An excerpt:

Tofacitinib (Pfizer), an oral agent already approved for certain patients with rheumatoid arthritis, can induce clinical remission in up to 25% of individuals with moderate to severe, refractory ulcerative colitis (UC) and clinical response in as many as 60% of these patients.

The results, based on two placebo-controlled trials involving more than 1,100 patients, showed the drug also increased the risk for serum lipid elevations but was otherwise safe. Researchers presented the data at the 2016 annual meeting of the European Crohn’s and Colitis Organization (ECCO; oral presentation 019)…

The new data are from the OCTAVE Induction 1 and Induction 2 trials, identically designed, randomized, double-blind and placebo-controlled Phase III studies…In the OCTAVE 1 trial, 476 patients received 10 mg of tofacitinib orally twice daily for eight weeks and 122 received an oral placebo. In OCTAVE 2, 429 and 112 patients were randomized to receive the two regimens, respectively.

Screenshot from gastroendonews.com

Screenshot from gastroendonews.com

Also from Gastroenterology & Endoscopy News August 2016: Update on Diagnosis and Treatment for Ulcerative Colitis  This article provides a succinct summary regarding diagnosis and treatments of ulcerative colitis; treatments discussed include emerging therapies like tofacitinib.

 

Early Preview of Basic Science Review: Biliatresone

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Generally, one of the best lectures at our national meeting is the “Basic Science Year in Review.”  I would be surprised if a recent study (O Waisbourd-Zinman et al. Hepatology 2016; 64: 880-93) does not get some attention during this review.

Even though biliary atresia (BA) remains the leading cause of pediatric liver transplantation, the exact reasons for its development have not been elucidated.  There are data “implicating both immune dysregulation and genetic factors in human BA.  Toxin-induced BA is not inconsistent with these findings and may represent a primary injury, with immune dysregulation representing a secondary insult.”

One of the reasons for suspecting a toxin dates back to outbreaks of a BA-like disease in newborn lambs that occurred in New South Wales in 1964 and 1988. During both these periods, severe droughts led to pregnant livestock grazing on atypical flora.  Ultimately, a plant toxin termed “biliatresone” was isolated from Australian plants (Dysphania species).

Here’s how this study advanced the science on biliatresone:

  • The authors treated mouse cholangiocytes in 3D spheroid culture and neonatal extrahepatic duct exlplants with biliatresone and compounds that regluate glutathione (GSH)
  • The authors determined the effects of biliatresone on SOX17 levels and the effects of Sox17 knockdown on cholangiocytes in 3D culture

Key findings:

  • “Biliatresoe caused disrupton of cholangiocyte apical polarity and loss of monolayer integrity.”
  • “Neonatal bile duct explants treated with the toxin showed lumen obstruction with increased subepithelial staining for α-smooth muscle actin and collagen, consistent with fibrosis”
  • “Biliatresone caused a rapid and transient decrease in GSH…and caused a significant decrease in cholangiocyte SOX17, and Sox17 knockdown in cholangiocyte spheroids mimicked the effects of biliatresone.”
  • These findings are easiest to appreciate in their figures, particularly Figure 4 and 5.

While pregnant women are not likely exposed to biliatresone, the authors showed that the effects of the toxin on lowering GSH was sufficient for cholangiocyte injury.; in addition, they showed that “SOX17 is required to maintain the epithelial architecture of the gallbladder and the cystic duct.”  Thus, there are likely other exposures that could lead to similar outcomes

My take: I will let Dr. Barnard explain the elegant experiments.  This study strongly supports maternal dietary factors as a contributing role in the pathophysiology of BA.  Now identifying these teratogens is crucial.

Also noted: X Zhao et al. Hepatology 2016; 64: 894-907. This study “strongly support redox stress as a critical contributing factor in biliatresone-induced cholangioctye injury” in Zebrafish.  Specifically, the authors identified that gene transcripts involved in redox stress, particularly regarding glutathione were upregulated after exposure to biliatresone.

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Glacier Natl Park

Glacier Natl Park

What to Make of A Motility Study of Children with Orthostatic Intolerance

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While a recent study (A Darbari et al JPGN 2016; 63: 329-35) provides some interesting data regarding the potential origin of gastrointestinal symptoms in the setting of orthostatic intolerance, I cannot support their conclusion that antroduodenal manometry (ADM) “should” be part of the evaluation of these affected children.

Background:

  • Retrospective study which included only subjects with a positive tilt test

What’s interesting:

  • Among 35 children with orthostatic intolerance due to either neurally mediated hypotension (NMH) or postural orthostatic tachycardia syndrome (POTS), ADM was abnormal at baseline or during tilt table testing in 26 (75%).
  • ADM studies were more often abnormal than gastric emptying studies, which were normal in 12 or 25.
  • Specific findings included neurogenic intestinal dysmotility in 15, antral hypomotility in 4, visceral hyperalgesia in 2, and regurgitation in 5.
  • GI symptoms of nausea, abdominal pain or vomiting were reproduced during tilt testing in 31 of 35 patients (89%).

Based on the discussion, the authors imply that ADM testing could help determine if the symptoms are due to neurogastrointestinal pathology or if normal, could indicate a central origin for the GI symptoms.  Thus, they conclude that motility testing “should” be part of comprehensive” orthostatic intolerance evaluation.

I would argue that this study does not show that ADM testing can reliably distinguish whether symptoms are due to a neurogastroenterological pathology or central pathology. And, in fact, there are better tests to examine for central origin.  I wouldn’t be surprised if many of their subjects had brain imaging, though this is not reported.

In addition, the authors acknowledge that ADM testing may not influence therapeutic decisions.  “The clinical response to promotility agents in children with POTS is generally low.”

My take: This study provides a useful mechanistic explanation of symptoms associated with orthostatic intolerance.  However, “I’m not there yet” on supporting ADM for all children with OI.

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Avalanche Creek Lake, Glacier Natl Park

Avalanche Creek Lake, Glacier Natl Park

 

Cutting Edge for Endoscopic Control of Bleeding

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A recent review elaborates on the newest methods for endoscopic control of bleeding. Topics included caplock clips, endoscopic suturing, and hemostatic sprays.

Full text: New Endoscopic Technologies and Procedureal Advances for Endoscopic Hemostasis (from Clinical Gastroenterology and Hepatology)

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Many Glacier Hotel

Many Glacier Hotel

Latest Vaccine Recommendations

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As a pediatric specialist, I do not administer vaccines in our office; at times I wonder how the recommendations for immunizations may have changed.  Relatively new vaccines include HPV and MenB. For those who want an up-to-date guidance for 2016 from CDC/ACIP:

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HBV Vaccination Prevents Cancer

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In a Gastroenterology study from Taiwan, HBV vaccination has been shown to reduce the risk of Hepatocellular Carcinoma.

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Results

Of the 1509 patients with HCC, 1343 were born before, and 166 were born after, the HBV vaccination program began. HCC incidence per 105 person-years was 0.92 in the unvaccinated cohort and 0.23 in the vaccinated birth cohorts. The RRs for HCC in patients 6–9 years old, 10–14 years old, 15–19 years old, and 20–26 years old who were vaccinated vs unvaccinated were 0.26 (95% confidence interval [CI], 0.17–0.40), 0.34 (95% CI, 0.25–0.48), 0.37 (95% CI, 0.25–0.51), and 0.42 (95% CI, 0.32–0.56), respectively. The RR for HCC in 6- to 26-year-olds was lower in the later vs the earlier cohorts (born in 1992–2005 vs 1986–1992; P < .001 and 1986–1992 vs 1984–1986; P < .002). Transmission of HBV from highly infectious mothers and incomplete immunization were associated with development of HCC.

Celiac Hepatopathies 2016

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A recent study (GJ Lee et al. JPGN 2016; 63: 340-3) adds a little bit more information regarding hypertransaminasemia in newly diagnosed celiac disease.  Some previous information was summarized in a previous blog: Celiac Hepatopathies (2013)

In this retrospective, single center study, 185 children had transaminases obtained at the time of celiac diagnosis (185/388 = 47.7%).

Key findings:

  • Among this group, 28 (15.1%) had elevated transaminases, with an average of ALT 2.52 x ULN and AST 1.87 x ULN.
  • Patients with elevated liver transaminases tended to be younger (mean 6.3 yrs compared with 11.0 without elevation). Among those who had followup blood testing available, 15/21 (71.4%) normalized their values over an average of 210 days.
  • For the 6 who had persistent elevation of transaminases, 3 were suspected to have poor adherence, 1 was thought to have a fatty liver, 1 had only mild elevation, and 1 remained unexplained.

My take: This study indicates that elevated transaminases are common in children with celiac, particularly younger children.  As with other studies, the majority resolve on a gluten-free diet.  As there is a recognized association with autoimmune hepatitis, in those with elevated ALT, followup after institution of a gluten free diet seems prudent.

Iceberg Lake, Glacier Natl Park

Iceberg Lake, Glacier Natl Park

Hepatitis E Update

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Briefly noted:

B Fischler et al. JPGN 2016; 63: 288-94.  This position paper by ESPGHAN suggests testing children with increased transaminases for hepatitis E virus (HEV) and notes that immunocompromised children with HEV may require treatment (with ribavirin or lowering immunosuppression). Best tests: serology for IgM and IgG and HEV RNA PCR.

F Huang et al Hepatology 2016; 64: 350-59. This study from China showed frequent Hepatitis E excreted in milk from infected cows and that this milk is capable of transmit infection when given to rhesus macaques, even if pasteurized.  Also, the article notes that seroprevalence of HEV in recent years has been higher than prior estimates (21% from 1988-94 and 6% from 2009-2010).

Glacier Natl Park

Glacier Natl Park

Deceptive Research: When Sugar Leaves A Bitter Taste

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This study was covered widely including USA Today, NBC News and other outlets.

From NY Times, an excerpt:

The sugar industry paid scientists in the 1960s to play down the link between sugar and heart disease and promote saturated fat as the culprit instead, newly released historical documents show.

The internal sugar industry documents, recently discovered by a researcher at the University of California, San Francisco, and published Monday in JAMA Internal Medicine, suggest that five decades of research into the role of nutrition and heart disease, including many of today’s dietary recommendations, may have been largely shaped by the sugar industry…

he Sugar Association, paid three Harvard scientists the equivalent of about $50,000 in today’s dollars to publish a 1967 review of research on sugar, fat and heart disease. The studies used in the review were handpicked by the sugar group, and the article, which was published in the prestigious New England Journal of Medicine, minimized the link between sugar and heart health and cast aspersions on the role of saturated fat…

The New England Journal of Medicine did not begin to require financial disclosures until 1984.

Eosinophilic Disease in Children with Intestinal Failure

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Last week, this blog posted an abstract regarding the use of “real foods” for short gut kids.  This post looks into whether certain foods may provoke an allergic response.

A large (n=105) single center retrospective study (C Duggan et al. JPGN 2016; 63: 336-39) examined the histology from 208 endoscopic procedures to determine the frequency of eosinophilic disease in children with intestinal failure.

Key findings:

  • 37% of patients had evidence of eosinophilic inflammation in at least one section of the GI tract.
  • Most common sites for eosinophilic disease: colon/rectosigmoid 18/68 (26%), esophagus 17/83 (20%), ileum 9/54 (17%) and duodenum 4/83 (5%)
  • Both peripheral eosinophilia and hematochezia correlated with eosinophilic colitis
  • The authors state that “a strict elemental diet for 3 months before endoscopy was not associated with a decreased frequency of eosinophilic inflammation.”

While a strict elemental diet was not shown to be effective in this study, the limitations of the study design (eg. retrospective, small number on amino acid diet) preclude a definitive answer about the utility of these diets.  Other confounders, including ongoing parenteral nutrition support, also ‘muddy’ the picture.  A prospective study would be able to determine more conclusively how effective elemental diets are at minimizing eosinophilic inflammation and to allow for a more uniform definition of abnormal tissue eosinophilia.

Given the frequency of elemental diets early in life along with prior GI insults, the propensity to eosinophilic disease may have its origins well before this study period.  In healthy children, the LEAP, LEAP-ON, and EAT studies indicated that earlier exposure to allergens reduces the risk of allergic disease.

My take: This study shows a high prevalence of GI eosinophilic inflammation among children with intestinal failure.  Thus, in children with hematochezia and intestinal failure, eosinophilic colitis needs to be considered.

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Grinnell Glacier, Glacier Natl Park

Glacier Natl Park