Author Archives: gutsandgrowth

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About gutsandgrowth

I am a pediatric gastroenterologist at GI Care for Kids (previously called CCDHC) in Atlanta, Georgia. The goal of my blog is to share some of my reading in my field more broadly. In addition, I wanted to provide my voice to a wide range of topics that often have inaccurate or incomplete information. Before starting this blog in 2011, I would tear out articles from journals and/or keep notes in a palm pilot. This blog helps provide an updated source of information that is easy to access and search, along with links to useful multimedia sources. I was born and raised in Chattanooga. After graduating from the University of Virginia, I attended Baylor College of Medicine. I completed residency and fellowship training at the University of Cincinnati at the Children’s Hospital Medical Center. I received funding from the National Institutes of Health for molecular biology research of the gastrointestinal tract. During my fellowship, I had the opportunity to work with some of the most amazing pediatric gastroenterologists and mentors. Some of these individuals included Mitchell Cohen, William Balistreri, James Heubi, Jorge Bezerra, Colin Rudolph, John Bucuvalas, and Michael Farrell. I am grateful for their teaching and their friendship. During my training with their help, I received a nationwide award for the best research by a GI fellow. I have authored numerous publications/presentations including original research, case reports, review articles, and textbook chapters on various pediatric gastrointestinal problems. In addition, I have been recognized by Atlanta Magazine as a "Top Doctor" in my field multiple times. Currently, I am the vice chair of the section of nutrition for the Georgia Chapter of the American Academy of Pediatrics. In addition, I am an adjunct Associate Clinical Professor of Pediatrics at Emory University School of Medicine. Other society memberships have included the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN), American Academy of Pediatrics, the Food Allergy Network, the American Gastroenterology Association, the American Association for the Study of Liver Diseases, and the Crohn’s and Colitis Foundation. As part of a national pediatric GI organization called NASPGHAN (and its affiliated website GIKids), I have helped develop educational materials on a wide-range of gastrointestinal and liver diseases which are used across the country. Also, I have been an invited speaker for national campaigns to improve the evaluation and treatment of gastroesophageal reflux disease, celiac disease, eosinophilic esophagitis, hepatitis C, and inflammatory bowel disease (IBD). Some information on these topics has been posted at my work website, www.gicareforkids.com, which has links to multiple other useful resources. I am fortunate to work at GI Care For Kids. Our group has 17 terrific physicians with a wide range of subspecialization, including liver diseases, feeding disorders, eosinophilic diseases, inflammatory bowel disease, cystic fibrosis, DiGeorge/22q, celiac disease, and motility disorders. Many of our physicians are recognized nationally for their achievements. Our group of physicians have worked closely together for many years. None of the physicians in our group have ever left to join other groups. I have also worked with the same nurse (Bernadette) since I moved to Atlanta in 1997. For many families, more practical matters about our office include the following: – 14 office/satellite locations – physicians who speak Spanish – cutting edge research – on-site nutritionists – on-site psychology support for abdominal pain and feeding disorders – participation in ImproveCareNow to better the outcomes for children with inflammatory bowel disease – office endoscopy suite (lower costs and easier scheduling) – office infusion center (lower costs and easier for families) – easy access to nursing advice (each physician has at least one nurse) I am married and have two sons (both adults). I like to read, walk/hike, bike, swim, and play tennis with my free time. I do not have any financial relationships with pharmaceutical companies or other financial relationships to disclose. I have helped enroll patients in industry-sponsored research studies.

Are you familiar with CMMR-D?

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In a recent review, CMMR-D and Lynch syndrome are reviewed (JPGN 2014; 58: 144-52). The term CMMR-D refers to constitutional mismatch repair deficiency.  This occurs when an individual inherits two MMR gene defects (rather than one gene defect in Lynch syndrome). CMMR-D can occur when a different mutation is inherited from each parent. MMR genes include MLH1, MSH2, MSH6 and PMS2.

Unlike Lynch syndrome when screening for colorectal cancer (CRC) usually starts at age 20 years or 5 years before first CRC in family, with CMMR-D screening recommendations include yearly endoscopic evaluation beginning at age 3 years or at diagnosis.  Complete management guidelines are listed in Table 4.

Digging into the COMMIT Study

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“Lies, damned lies, and statistics” –Mark Twain (who attributed this quote to Benjamin Disraeli)

Using statistics, the recent COMMIT study (Gastroenterol 2014; 146: 681-88) showed that the combination therapy of methotrexate (MTX) and infliximab (IFX) was not more effective than IFX alone. Does this result makes sense? No.

Before getting back to that question, here’s the background: this 50-week study was a randomized, double-blind, placebo-controlled trial with patients assigned to either methotrexate at dose escalated gradually to 25 mg/week (n=63) or placebo (n=62); both groups received a prednisone induction (with tapering starting at week 1) along with IFX (5 mg/kg) at weeks 1, 3, 7, 14, 22, 30, 38, and 46.  Remission was considered to be a CD Activity Index (CDAI) of <150 in individuals off prednisone.  The patients enrolled in this study were on average about 40 years of age and had similar baseline characteristics, including disease duration of more 9 years.

Amazing to me was the fact that nearly 40% of both the treatment and control group included current smokers (since smoking clearly worsens CD).

Key Results:

  • Combination therapy resulted in fewer antibodies to IFX (ATIs): 4% vs. 20% (P=.01)
  • Combination therapy resulted in higher IFX trough levels: 6.35 mcg/mL vs. 3.75 mcg/mL (P=.08); the proportion with detectable trough levels was also higher in the combination group: 52% compared with 46%.
  • Safety was similar.  “No clinically relevant hepatotoxicity was identified.” However, 14 patients did experience an increase in liver enzymes. Infusion-related reactions were infrequent: 1 in combination group, and 3 in IFX monotherapy.
  • At week 14, 76% of combination group achieved prednisone-free remission and 78% of IFX monotherapy.  At week 50, these numbers were 56% and 57% respectively.

Getting back to the question about why this does not add up as a negative study –the combination group had lower ATIs and better IFX drug levels, this usually translates into better response.  As such, the limitations of this study deserve to be scrutinized:

  • Relatively small numbers of patients
  • Objective markers like colonoscopy were not included
  • Short duration of study period.  While a 1 year study is not really all that short, some benefits of medications can take a longer time to appreciate
  • Prednisone induction may have obscured MTX benefit
  • Treatment group had long duration of disease.  Those with shorter disease duration may have a more inflammatory component to their disease and respond more favorably.

Bottomline: this study showed that the combination of MTX/IFX was not statistically-superior to IFX alone.  Given the favorable benefit on ATIs and IFX drug levels, MTX combination may still be useful, particularly in those with more recent onset of IBD.

Plus One More Reference:

Clin Gastroenterol Hepatol 2014; 12: 434-42.  This retrospective study of 425 patients (1975-2012) examined features associated with failure of medical treatment. “Patients prescribed thiopurine or anti-TNF therapy when they have a complicated stage of CD are more likely to require surgery.  Better patient outcomes are achieved by treating CD at early inflammation stages.”

Related blog entries:

 

 

Only in Kids: Allergies Vary by Region

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From the NIH:  link to full article: http://t.co/QuVzGFPTDb

An excerpt (highlighted for emphasis):

In the largest, most comprehensive, nationwide study to  examine the prevalence of allergies from early childhood to old age, scientists  from the National Institutes of Health report that allergy prevalence is the  same across different regions of the United States, except in children 5 years  and younger.

“Before this study, if you would have asked 10 allergy  specialists if allergy prevalence varied depending on where people live, all 10 of them would have said yes, because allergen  exposures tend to be more common in certain regions of the U.S.,” said Darryl  Zeldin, M.D., scientific director of the National Institute of Environmental  Health Sciences (NIEHS), part of NIH. “This study suggests that people prone to  developing allergies are going to develop an allergy to whatever is in their  environment. It’s what people become allergic to that differs.”

The research appeared online in February in the Journal of  Allergy and Clinical Immunology, and is the result of analyses performed on  blood serum data compiled from approximately 10,000 Americans in the National  Health and Nutrition Examination Survey (NHANES) 2005-2006.

… Among children  aged 1-5, those from the southern U.S. displayed a higher prevalence of  allergies than their peers living in other U.S. regions. ..

“The higher allergy prevalence among the youngest children  in southern states seemed to be attributable to dust mites and cockroaches,”  explained Paivi Salo, Ph.D., an epidemiologist in Zeldin’s research group and  lead author on the paper. “As children get older, both indoor and outdoor  allergies become more common, and the difference in the overall prevalence of  allergies fades away.”

The NHANES 2005-2006 not only tested a greater number of  allergens across a wider age range than prior NHANES studies, but also provided  quantitative information on the extent of allergic sensitization. The survey  analyzed serum for nine different antibodies in children aged 1-5, and nineteen  different antibodies in subjects 6 years and older. Previous NHANES studies used skin prick tests to test for allergies.

The scientists determined risk factors that made a person  more likely to be allergic. The study found that in the 6 years and older  group, males, non-Hispanic blacks, and those who avoided pets had an increased  chance of having allergen-specific IgE antibodies, the common hallmark of  allergies.

Socioeconomic status (SES) did not predict allergies, but  people in higher SES groups were more commonly allergic to dogs and cats,  whereas those in lower SES groups were more commonly allergic to shrimp and  cockroaches.

Briefly Noted…Paracentesis, Hyperinsulinemic Hypoglcemia, and Hepatitis E

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Paracentesis is associated with reduced mortality in patients hospitalized with cirrhosis and ascites (Clin Gastroenterol Hepatol 2014: 496-503).  This study relied on a 2009 Nationwide Inpatient Sample database with about 8 million discharges per year.  Of the 17,771 eligible admissions, 61% underwent paracentesis, most (66%) within 1 day of admission.  “In-hospital mortality was reduced by 24% among patients who underwent paracentesis.”  The authors note that some providers may overestimate the risk of bleeding and that many have developed an increased reliance on interventional radiology. While the authors were not certain why this mortality benefit occurred, they note that patients who underwent paracentesis were probably at least as sick as those who did not.  “Patients who underwent paracentesis were actually more likely to have sepsis or acute renal failure, both markers of illness severity.”

Sirolimus helps with hyperinsulinemic hypoglycemia (NEJM 2014; 370: 1131-37).  This brief report showed that sirolimus can be an alternative to subtotal pancreatectomy.  It enabled the authors “to discontinue intravenous infusions of dextrose and glucagon in all four patients and to halt octreotide in three of four.  At 1 year of age, the four patients were continuing to receive sirolimus and were normoglycemic, without any apparent major adverse events.”  Of interest, these findings parallel the findings in adults with insulinoma who were treated with mTOR inhibitors.

Ribavirin treatment for chronic hepatitis E infection in transplant recipients (NEJM 2014; 370: 1111-20).  Retrospective uncontrolled study of 59 patients who had undergone solid-organ transplant had been treated with ribavirin at a mean dose of 600 mg for median of three months.  Median time for HEV infection prior to therapy was nine months. HEV RNA level was undetectable in 46 of 59 patients (78%) after cessation of ribavirin.

Related blog posts:

Cannabis: Feel better, Worse Crohn Disease

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To my amazement, the Georgia legislature has voted to eliminate all speed limits for those individuals with a gun permit.  After all, if you need a gun for self-defense, you might need to get somewhere quick to use it.  In addition, they have mandated that all dictionaries sold in the state to list “Obamacare” as an official synonym for the word “evil.”

The first part of this post is in jest. Today’s post is not all fiction:

While cannabis is not a frequent pediatric GI issue, it has received a lot of press of late.    A recent article has shown that cannabis is associated with worse disease prognosis in Crohn disease despite symptom relief (Inflamm Bowel Dis 2014; 20: 472-80).

Design: 313 consecutive patients (69% response of initial 461 distributed questionnaires) seen in Calgary (2008-2009) completed a structured anonymous questionnaire.  Subjects who had taken cannabis for IBD symptom relief were compared with those who had not.  Cannabis user had a mean age of 36.6 yrs compared with 40.2 yrs for nonusers.

Key findings:

  • Cannabis had been used by 17.6% of respondents to relieve IBD symptoms, mostly by inhalation (96%).  It reportedly improved abdominal pain, joint pain, and diarrhea.
  • The use of cannabis for more than 6 months at any time for IBD symptoms was a strong predictor of requiring surgery (odds ratio =5.03) after controlling for other demographic factors including tobacco smoking.

Limitations:

  1. Questionnaire honesty, though authors indicate several reasons why the number of cannabis users is likely fairly accurate.
  2. Previous surgery was higher in the cannabis users.  It is possible that patients with greater disease severity take cannabis more frequently; in this situation, cannabis would be a marker of disease severity rather than a potentially causative factor.
  3. The average patient had long-standing disease, >13 years.  Cannabis could potentially be more helpful (or less harmful) at an earlier inflammatory stage.

The study findings are in contrast to a small study previously reviewed on this blog which indicated that cannabis may improve Crohn disease: Crohn’s Research: Going to Pot | gutsandgrowth.

Take home message: For those of you planning to move to Colorado, cannabis does not cure all ills.  In this single center, tertiary care study, it was associated with a worse prognosis in adults with Crohn disease.

Applying New Techniques in Pediatric GI: Double-Ballon Enteroscopy

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A recent prospective study documented the utility of double-balloon enteroscopy (DBE) in the pediatric population (JPGN 2014; 58: 204-12).

Key stats/findings:

  • 113 DBE procedures were performed in 58 children with a median age of 12.7 years (range 1-18 years) during the years 2008-2012.  54 of these children had undergone wireless capsule endoscopy.
  • Procedural time: 92.5 minutes
  • Median estimated insertion length of SB distal to pylorus was 230 cm and proximal to ileocecal valve was 80 cm. The DBE approach (oral, anal, or both) was at the discretion of the gastroenterologist.  In cases where both approaches were used, the authors used a methylene blue “tattoo” at the most distal portion of the oral approach to help ascertain whether the entire bowel was visualized.
  • Indications: polyposis syndromes (n=21), obscure GI bleeding (n=16)
  • Findings: polyps (n=19), ulcers/erosions (n=8), submucosal elevations with white nodules (n=4), angioma/angiodysplasia (n=2)
  • Overall diagnostic yield for SB lesions was 70.7% and for WCE 77.7%; endscopic therapy intervention was successfully used in 46.5% (27/58)
  • Three complications (5.2%) were noted with uneventful recovery.  One perforation in a SB transplant patient, one had hypotension requiring fluid resuscitation, and one (who had laparascopic assistance) developed a pelvic abscess (no perforation identified).

Take-home message: DBE has developed as a useful procedure in highly selected cases.  A small number of highly qualified, procedurely-oriented pediatric gastroenterologists are likely to fill this niche.

Related blog post: Pediatric capsule endoscopy experience | gutsandgrowth

For Increased Longevity: More Greens are Good

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From NPR, link:http://t.co/07NyZaXqzE

 Excerpt:

A new study linking animal protein-rich diets to increased mortality in middle age adds fuel to the controversy over how much protein — and from what sources — is ideal for health. One thing that seems pretty clear: It doesn’t hurt to go heavy on the greens.

Americans who ate a diet rich in animal protein during middle age were significantly more likely to die from cancer and other causes, compared with people who reported going easy on foods such as red meat and cheese, fresh research suggests.

The study, published Tuesday in the journal Cell Metabolism, was based on an analysis of data from NHANES, an ongoing federally funded study that surveys Americans about their eating habits and behaviors.

In this particular study, researchers tracked about 6,000 older adults included in the survey to find connections between dietary patterns, death and disease.

“The research shows that a low-protein diet in middle age is useful for preventing cancer and overall mortality,” wrote co-author Eileen Crimmins, the AARP Chair in Gerontology at the University of Southern California, in a release about the paper.

But here’s the catch: The researchers also found that for older people, ages 65 and up, there may be a benefit to eating more protein. In this age group, higher levels of protein seemed to be protective against cancer and premature death…

When we’re young, IGF-1 help promotes growth, which is good. But as we age, too much protein in our diets may lead to overly high levels of IGF-1, which may contribute to aging and DNA damage, Longo explains.

Then, after 65, when IGF-I levels trail off, our bodies may benefit from more protein in the diet to help fend of frailty and decline…

In the new study, Longo and his colleagues found that high-protein foods derived from plants, such as beans and nuts, did not have the same effect on mortality as did high-protein foods from animals.

Singling out the effects of protein in the diet is hard to do. For starters, our diets are complex, and sussing out the independent effect of any one component is tough. What’s more, surveying people on what they have eaten, as NHANES does, and then trying to figure out how that influences their health years later is a tricky business. So there are still lots of questions about how to interpret these findings.

In an age when advocates of the Paleo Diet and other low-carb eating plans such as Atkins talk up the virtues of protein because of its satiating effects, expect plenty of people to be skeptical of the new findings.

That said, as we’ve previously reported, several other studies have found a link between a high intake of red meat — especially processed meats like bacon and salami — and other animal proteins and an increased risk of mortality…

according to Dr. Frank Hu, a researcher at the Harvard School of Public Health who studies the links between health, diet and lifestyle.

“The harmful effects of smoking on cancer and mortality are well-established to be substantial, while the harmful effects of red meat consumption are modest in comparison,” Hu wrote to us in an email.

For instance, in a study Hu authored, people who ate a serving of red meat every day had a 13 percent increased risk of mortality, compared with those who ate little meat… Choosing chicken and other poultry decreased the risk by 14 percent, fish decreased the risk by 7 percent and legumes decreased the risk by 10 percent….In the meantime, if you’re feeling confused, consider the one strategy that almost all experts agree on: moderation.

The simplest way to maintain a healthy body weight and cut the risk of so many weight-related diseases is to limit calories.

So eat what you enjoy. Upsize servings of greens and other vegetables. And downsize servings of meat, cheese and other high-calorie foods.

Second-Guessing Aggressive Medical Treatment in Pediatrics

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An excerpt of a review of a recent study (Inflamm Bowel Dis. 2014;20:291-300.) from Healio Gastro, http://bit.ly/1njexRZ.  This study was briefly referenced at the bottom of a previous blog post (UC SUCCESS | gutsandgrowth).

Mortality and malignancy, the most serious complications of pediatric inflammatory bowel disease, were relatively rare and linked most commonly with aggressive treatment rather than the condition itself, according to recent study data.

In a multinational retrospective study, researchers surveyed all pediatric gastroenterologists in 20 European countries and Israel on cancer and/or mortality among their pediatric patients with inflammatory bowel disease (PIBD) from 2006 to 2011.

Among 44 children diagnosed with IBD (median age at diagnosis, 10 years; 26 boys), 18 cases of cancer were identified and/or 31 patients died. Twelve cancer patients had Crohn’s disease, and 19 patients who died had ulcerative colitis (UC). The most common cancers were hematopoietic tumors (n=11). Mortality was attributed to infections (n=14) and other causes, including cancer (n=5), uncontrollable disease activity related to IBD (n=4) and procedural complications (n=3).

“Cancer and mortality in PIBD are rare, but cumulative rates are not insignificant,” the researchers wrote. “…. At least six lymphomas were likely treatment-associated by virtue of their phenotype.”

Researchers said that aggressive therapy with immunosuppressants and biologics has become common among PIBD patients because their disease is often more severe than that found in adults with IBD…

“Nine out of 19 patients with UC died because of an infectious complication. These fatalities may have been prevented by earlier surgical intervention when intensified medical treatment is ineffective.”

Bottomline: Making a colectomy decision is quite difficult when medical therapies may be effective.  Recent guidelines using PUCAI scores may assist physicians in identifying medical failures more quickly.

 

CCFA Conference Notes 2014 (part 2)

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Yesterday’s notes highlighted the most useful discussion at this year’s meeting regarding mucosal healing (MH) in inflammatory bowel disease.

Many points were intriguing but often at odds. For example, the speakers noted that symptoms and scoring systems like CDAI are unreliable in establishing remission.  It was noted that the FDA is mandating more objective measures (like endoscopic improvement) in future studies. Yet, the studies cited for their arguments often were derived from studies which did not use objective endpoints. Similarly, some of the arguments were based on small studies and yet experts often caution to use evidence-based medicine.

Bo Shen (Cleveland Clinic) “Surgerical Options in IBD”

  • 50-71% of CD patients require some type of surgery within 10 years of diagnosis
  • End-ileostomy may be a cure for some CD patients,  For UC, end-ileostomy 98% are cured.  2% develop enteritis.
  • Can use infliximab after surgery.  Immune system different after surgery and may work even
  • ‘Don’t operate until a CD patient develops a complication. But, don’t wait until further complications develop.’

Different type strictures –web-like strictures are suitable for dilatation, others are more difficult: spindle-like (longer) , ulcerated stricture, and anastomotic.

  • Classification: Gast Endosc 2013; 78: 8181-35.
  • Etiology: primary, secondary (anastomotic), benign, malignant
  • Short-long: Length (<4cm) if dilating
  • Degree: high-grade, low-grade
  • Number: single, multiple
  • Associated conditions: abscess, others

Determining resection margin –does not depends on absence of histologic activity (Ann Surg 1996; 224: 563-71).  Try to save as much bowel as possible, often based on how thick bowel is rather than histologic margins.

Save the gut –stricturoplasty.  1st surgery –usually is a resection rather than stricture plasty.  Heineke-Mikulicz (most common) <10 cm for short , Finney for strictures 10-20 cm, Michelassi >20 cm (sid-to-side isoperistaltic). (Dis Colon Rectum 2007) Stricturoplasty –best for mid small bowel, minimum inflammation, no fistula

Fistula –Hollow-organ to hollow-organ fistula –treat surgically. Whereas if fistula is perianal, start with medical treatment. Perianal fistulas often treated with seton; seton often kept in place for a long time (“forever if not bothering patient”).

Abscess—avoid surgical drainage if possible.  Delineate anatomy and consider elective surgery later.  If less than 3 cm, could aspirate and not leave in drain. If >3 cm, start with interventional radiology

Post-op management –Ruttgerts score.  Rescope 6 months post-op to determine if needs more aggressive treatment.

UC Surgery: issues: preoperative biologics, 2- or 3-stage operations, what type of pouch

  • There may be increased risk with biologics (studies have not shown this consistently) –depends on type of surgery.  If very sick, use 3-stage rather than 2-stage operation.  Don’t do pouch at time of 1st operation if very sick DCR 2013; 56: 1243-52).
  • J-pouch now standard.  Kock pouch –catheterize pouch/no ostomy.  S-pouch –problemswith mechanical obstruction.
  • Even with mucosectomy (vs. stapler/no mucosectomy)–can still develop cuffitis and malignancy.  Mucosectomy may increase risk of incontinence.

Edward Loftus (Mayo Clinic) “Optimizing Biologic Therapy: Maximizing Benefit and Minimizing Risk”

Is azathioprine an effective drug? Should we be using biologics sooner?

Key points:

  • ACT1 and ACT2 were pivotal studies for infliximab approval for UC.  1/3rd chance of going into full remission, 1/3rd chance of response, 1/3rd chance of not responding.  Infliximab lowers risk of colectomy.  Favorable studies of other anti-TNFs as well: adalimumab (Gastroenterol 2012; 142: 257-65) and golimumab (Gastroenterol 2014; 46: 85-95 & 96-109). No head-to-head anti-TNF trials.
  • Crohn disease:  5-ASA products don’t work for Crohn disease.  Reviewed pivotal trials of anti-TNF agents (infliximab, adalimumab, certolizumab)-30% in remission.
  • Natalizumab (anti-alpha 4 integrin) for refractory disease was discussed (NEJM 2005; 353: 1912-25).  Takes longer to work then anti-TNFs but maintenance data look good. PML risk: 395 cases among 118,100 patients treated as of August 2013.  Lots of paperwork and physicians have to be certified.  If you are JC virus serology is negative, “your risk is about 1 in one million in the next year. If you are positive, about a 1% risk in the following year.”
  • Azathioprine (AZA) not very effective (Gastroenterol 2013; 145: 766-74 & 758-65).  Prospective double-blind Spanish study (n=131) –no statitistical benefit.  2nd reference is French study. N=132. No significant difference at 36 months in patients with added AZA.  In U.S., most “thought leaders” going straight to anti-TNFs.
  • Combination therapy works best in adults (SONIC study for Crohn disease, UC Success for UC).  UC Success only studied 16 weeks, no maintenance therapy trial.  However, methotrexate (MTX) with anti-TNFs combination has not been proven to be effective (Gastroenterol 2014; 146: 681-8).  Reason this was a negative study, per lead author, may have been related to steroid use.

Other pointers:

  • Don’t rely on symptoms alone.  Symptoms/CDAI do not correlate with CDEIS (endoscopic improvement).  FDA mandating all future trials have an endoscopic endpoint and not rely on use of CDAI alone. Other factors cause symptoms including IBS, infections, and bacterial overgrowth. Take-home point: Need to look (endoscopy) if someone is not doing well.
  • In the SONIC trial –if there was inflammation on endoscopy, there was an impressive 30% delta in response to treatment (with combination therapy compared with AZA monotherapy). Whereas if you have no lesions, combination therapy no more effective than either monotherapy agent.  Patients whose complaints are due to irritable bowel rather than inflammation do not respond well to treatment.
  • OLD paradigm –treat based on symptoms.  NEW paradigm–treat based on biologic/radiographic markers or endoscopic findings.  “Treat to target” has been approach used by Dr. Sandborn. Target mucosal healing and then assess mucosal healing every 6 months until target achieved, then less frequently.  Yet mucosal healing cannot be achieved in many/most patients.
  • Therapeutic drug monitoring.  For example, 6-TGN >235 associated with better response to AZA (OR 5.0)
  • Pharmacokinetics of anti-TNFs: lower clearance if concomitant use of immunomodulators, increased clearance if high CRP, higher BMI
  • New drugs: Ustekinumab –three phase 3 trials underway.  Should be available in about 2 yrs for Crohn disease. Vedolizumab –under FDA review (NEJM 2013; 369: 699-710).  Infusion (similar to remicade frequency). Blocks lymphocyte homing in the gut. UC data much more robust than with CD, but probably will be approved for both.  Rate of adverse events were low. Etrolizumab—similar to Vedolizumab, but SC administered. Currently, this drug is in phase 2 studies.

Eva Szigethy (Pittsburgh Pediatrics) “Psychological evaluation and assessment in IBD”

Key points:

  • Anxiety/depression ~25-40% of pediatric IBD.  Occurs in both active and inactive disease.
  • IBD effects on brain: inflammation, drugs (steroids, biologics)–both have direct effects on brain.
  • 15% of kids and 25% of adults are having thoughts of death on screening tools. Pain is frequent trigger for suicidal thoughts.
  • Simple depression screen: Mood, Energy, Sleep, Suicide/Self-esteem, Anhedonia (lack of pleaure), Guilt, Eating (change in appetite)
  • We should not ignore adjustment disorders.  We may be able to prevent a full-blown psychiatric disorder.  Each time we let problems like anxiety or depression go untreated, this can leave long-term changes in brain.
  • Anxiety screen: Tense, Tired, Recurrent worries/fear, Restless, Avoidance, Poor sleep/nightmares, Poor concentration
  • Important to look at patient perspective of their disease: identity (what they see as their symptoms), cause/etiology, timeline (how long the patient believes that the illness will last), consequences, cure/control.
  • Catastrophizing –more persistent pain and increased visceral hyperalgesia.  Abnormal brain activation. Poor coping drives development of depression and anxiety.
  • With adult IBD, 20% of patients consume up to 80% of medical costs.  Chronic pain and depression are key factors (Binion et al 2010).
  • Management of anxiety/depression: Cognitive Behavioral therapy –changing behaviors and thinking, problem-solving. ACT –activities, calm (relaxation, guided imagery, hypnosis), think positive (cognitive reframing). Antidepressants: TCA, SSRI, SNRI.  SSRI/SNRI –few side effects or drug interactions.  Overdose risk is highest with TCA (but typically using low doses of these agents).  No pediatric studies in IBD and only small studies in adults. If inactive IBD, SSRI often 1st line. If active IBD, Bupropion often used as 1st line.
  • For anxiety, most likely use SSRI if comorbid anxiety
  • For pain, most likely use SNRI  or low dose TCA
  • Opiates are problematic due to psychological/physical dependence, increased mortality/infection risk, narcotic bowel
  • Sleep –don’t go to bed if not tired, aim for consistency, if not asleep in 20 minutes, then do something else.  1st line pharmacology: consider antihistamines or melatonin.

Sachin Kunde (Michigan State University, Helen DeVos Children’s Hospital) “FMT for IBD”

Key points:

  • Microbial diversity altered in IBD –can we modulate dysbiosis to treat IBD?
  • Issues with cause and effect.  Is dysbiosis due to IBD or causing IBD.
  • FMT –“the ultimate probiotic.” Application of FMT.  For recurrent C difficile, cure rate nearly 90% –?better with lower GI route. For any indication besides C difficile infection (CDI), can only be given through clinical trials (FDA IND).  Currently 9 ongoing trials for IBD (1 pediatric, 3 in U.S).

FMT in IBD: Studies:

  1. -Anderson et al.  Aliment Phar Ther 2012: 13/18 without CDI had some resolution of IBD symptoms.
  2. -Kunde et al JPGN 2013: n=10. PUCAI decrease by 15 indicated response found in 78% (7/9) at 1 week, and 67% (6/9) at 1 month, 3 (33%) went into remission.
  3. -Kump et al IBD 2013: n=6. FMT for UC was not effective.  Transient improvement in 2/6 patients, 1/6 improved on Mayo sub score.

Bottomline for FMT & IBD: More questions than answers: efficacy, route of administration, # of infusions needed, fresh vs. frozen, adverse effects, best donor, etc.

For today’s post today and yesterday’s post, I may have made some transcription errors and these notes were not reviewed with the speakers.  Also, due to brevity, some useful information was not included.  Thus, the disclaimer with these posts is particularly important.

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.

Related blog posts:

CCFA Conference Notes 2014 (part 1)

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Each year our local CCFA chapter holds a one day seminar with separate lectures for health care providers and families.  Overall, it is a good opportunity to hear ‘cutting edge’ material.  I did not pick up as much at this year’s seminar as in previous years, but will highlight what I thought was most important.

Key points:

  1. Symptoms are not accurate at determining effectiveness of IBD therapy.
  2. More frequent use of objective markers are needed to optimize treatment.  Mucosal healing is starting to be a target in clinical practice, but limited by number of medications available.
  3. Stricture classification and operative techniques were reviewed.
  4. IBD frequently results in psychological problems: anxiety, depression, pain, sleep. 15% of kids and 25% of adults are having thoughts of death on screening tool intake.
  5. Fecal microbiota transplantation (FMT) –not enough data to recommend for IBD.  Clinical trials ongoing.

Debate: What should be the End Points in Therapy? 

  • Tanvi Dhere (Emory): Goal: clinical symptoms
  • Cary Sauer (Emory Pediatrics): Goal: mucosal healing and normal bloodwork

In my opinion, this was the most thought-provoking and best presentation

Mucosal healing (MH) consensus definition –normal mucosa after previously abnormal with complete absence of ulceration, macroscopic and histologic signs of inflammation.  In practice MH = absence of ulcerations.

Reasons why mucosal healing as a target is problematic:

  • Problems with MH –not validated.  No long-term data utilizing endoscopic scoring indices of MH.
  • MH relies on a binomial endpoint –Yes or no, but there may be intermediate endpoints.
  • How likely is MH (different definitions in these studies)?  SONIC –MH in 43.9% of combination Rx (30.1% in those with infliximab monotherapy); EXTEND (Adalimumab) 27% and 24.2% 12/52 weeks; MUSIC (certolizumab at 10/54 weeks) 11.5% and 18.9%.

In practice, Mayo Score 0-1 both considered to have MH.

MayoScore Visual

Images above online at www.nature.com

In small study, MH at 1 year were not associated with improved outcomes at 5 years.  Risks of MH: more procedures, more costs of treatment, and potential for more complications.

Dr. Sauer’s reply.  Three simple questions –why should I try to target MH, is it possible, what is needed to get this done?

  1. If the goal were only an asymptomatic patient – why do screening colonoscopy in the general population, much less in IBD?
  2. In IBD, long-term evolution of IBD (Cosnes J et al. Inflamm Bowel Dis. 2002 Jul;8(4):244-50) is toward structuring and penetrating disease. CD Evolution This needs to be modified if possible.

Why MH? Improved symptoms, better quality of life, less likely to develop colon cancer, and it is an objective measure of treatment response.

  • In MH patients, less steroids and fewer flares over 2 year period.
  • MH healing patients have sustained clinical benefit over 96 months.
  • With MH, there is a decreased colectomy in UC.  In one study, there was a lower  colectomy rate at 8 years if colonic CD (62% vs 8%), decreased steroids in CD, decreased hospitalizations, & decreased fistulae.

Is MH possible in clinical practice?  The accuracy of CDAI to detect endoscopic healing is low in patients with CD. (Bouguen G et al Clin Gastrohep 2014).  More frequent adjustments in medical therapy –could lead to MH in up to 80% over 80 week study period.  Same story in UC (Bouguen G et al IBD 2014).

What do I need to do to obtain MH? Endoscopy (or MRE), maximize medications (checking levels), change medications, and most important –set a target. “Adjusting infliximab dose alone could lead to MH in up to 60%.”

When to assess for MH?  Consider endoscopy at 6 months into treatment if symptoms and at 12 months if in clinical remission.

Other viewpoints on MH from panel:

Dr. Loftus –“I think of this like oncology.” He agreed with using the best evaluating tool 6 months into treatment.  Cross-sectional imaging is often more helpful, but may need more than one tool.

Dr. Long—“Are we going to check every 6 months?” No.  She stated that she does not do this and tries to avoid repeated endoscopic procedures if this will not change treatment.  Goal is to make sure patient is headed in right direction, often after starting therapy.  Dr. Long stated that stool biomarkers most useful for colonic disease.

Dr. Dhere—documenting MH is important for deescalating treatment.

Millie Long  “Quality of Care in IBD”

  • 75% of Crohn disease patients will need surgery, 10% in 1st year
  • “One way to gauge quality of care is to examine the degree of consistency in care”
  • High variability in care in IBD (Aliment Pham Ther 2007; 26: 1005-18)
  • “Over half of institutions with worst quality have mortality in normal range.” Outcomes may not occur until several years after treatment, thus more useful to measure process measures

PQRS IBD Quality Measures in Adults: 10 Measures

  • #1 Establishing/documenting IBD type, anatomic location, and activity
  • #2 Preventive care: corticosteroid sparing.  Steroids associated with mortality (OR 2.1 in TREAT registry)
  • #3 Preventive care:  Preventing bone loss.  Limiting steroid use.  Recommend weight-bearing exercise, Quit Smoking, Measure DEXA, added Calicum/Vit D/Bisphosphonates
  • #4: Vaccination –pneumococcal vaccine.  Avoid live virus vaccines
  • #5 Vaccination –influenza vaccine, zoster vaccine
  • #6 Testing for latent TB prior to anti-TNF
  • #7 Testing for hepatitis B virus
  • #8 Testing for C diff with patients hospitalized with IBD
  • #9 VTE prophylaxis in adult IBD patients.  Risk assessment on admission to hospital is recommended.  IBD patients have 1.5-3.5-fold higher risk of VTE àwhich can increase mortality risk
  • #10 Screening for tobacco.  Tobacco use after surgery increases recurrence by 2.5-fold.  It also increases risk for reoperation.

Last year’s notes:

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.