Another Study Supporting Enteral Therapy for Crohn’s Disease

Here’s the link (Enteral Nutrition Study) from a summary of the study in Healio Gastroenterology (from their twitter feed) and an excerpt:

Frivolt K. Aliment Pharmacol Ther. 2014;39:1398-1407.

A retrospective study of all pediatric Crohn’s disease (CD) patients treated with exclusive enteral nutrition (EEN) at a children’s hospital in Munich between January 2004 and June 2011. Fifty-two included patients (mean age, 13.2 years; 59.6% male) had newly diagnosed CD (n=40) or had relapsed (n=12) while maintaining treatment for at least 3 months….The first course of EEN showed a higher median starting wPCDAI score compared with the second (59 vs. 40; P<.0001), as well as higher remission rates after 3 months (92% vs. 77%). Relapse rates after 1 year were comparable (67% vs. 70%), but fewer relapses occurred in the first 120 days after the first EEN course compared with the second (25% vs. 45%).

Of 48 patients with NOD2 genotype, 44 went into remission with EEN; 11 of 12 patients carrying R702W or G908R genotype relapsed within 1 year; and there were significantly lower rates of relapse in patients with wild-type (60%) or 1007fs (50%) mutations.

 

Related blog posts:

 

 

The Search for a Dietary Culprit in IBD

Uniformly, patients diagnosed with inflammatory bowel disease (IBD), both ulcerative colitis and Crohn disease, are interested in whether there is a dietary culprit which triggered their IBD and what modifications in their diet can help improve their IBD.  A really good summary of what we know has been published (Inflamm Bowel Dis 2014; 20: 732-41).

A summary of the key points:

Traditional dietary recommendations:  These diets may help decrease symptoms but are not thought to improve disease control.

  • Low-residue: <10-15 g/d of fiver. Potential deficiencies: folate, vitamin A, vitamin C, and potassium.  Overall, this diet is poorly studied.  “One small randomized controlled trial showed that low-residue diet made no difference in symptoms, need for hospitalization, need for surgery…when compared with an unrestricted diet.”
  • Lactose-free: potential deficiencies: calcium, vitamin D

Carbohydrate-restrictive:  Potential deficiencies with all carbohydrate restriction: folate, thiamine, vitamin B6

  • Specific carbodydrate diet: allows only monosaccharides.  Restricts complex sugars, starches, grains and legumes.  This diet was popularized by Elaine Gottschall in 1994 (Breaking the Vicious Cycle) but was developed by Dr. Sidney Haas in 1924.  The premise of SCD is that “complex carbohydrates and legumes are poorly absorbed in gastrointestinal disease…they promote bacterial overgrowth and fermentation.  By-products from bacterial dysbiossis are postulated to contribute to gut inflammation.”  Nevertheless, it “has been poorly studied.”
  • Low FODMAPs (see numerous previous posts).  “A small restrospective study…showed that the low FODMAPs diet resulted in improvement in functional symptoms present in patients with IBD who were in remission.”  This diet is difficult for long-term adherence.
  • Gluten-free: not truly a carbohydrate-restrictive diet, but breads/cereals contain large amounts of carbs. “No evidence that a gluten-free diet has any effect on disease activity in IBD.”

Fat-modified diets

  • Fat-restrictive diets: “On a cellular level, multiple animal studies have shown that prolonged feeding of a high-fat diet seems to promote colitis/ileitis and to perturb barrier function…shifts in microbiome composition…Despite some biologic plausibility, there is a paucity of data evaluating efficacy of fat-restrictive diet for IBD management.”
  • Vegetarian/semi-vegetarian: Potential deficiencies: iron, vitamin B12 (vegans), calcium, vitamin D, ω-3 fatty acids.   A small study of 22 patients with Crohn’s disease who adhered to a semi-vegetarian diet, had lower rate of relapse.  “There does not seem to be sufficient evidence at this time to recommend eliminating meat to patients with IBD as a means to control their disease.”
  • Modified ratio of ω-3/ω-6 polyunsaturated fat: “The efficacy of dietary interventions with ω-3 PUFA has been disappointing..recently, 2 large multicenter clinical trials demonstrated that ω-3 PUFA (fish oil) at a dose of 4 g/day was not significantly better than placebo at maintaining remission in CD.”

Restriction of Multiple food groups

  • Paleolithic: based on the “premise that human genetics have scarcely changed over the past 3000 years, and thus modern humans are genetically adapted to the diet of their Paleolithic ancestors (i.e. Stone Age)…daily calories should come from plant sources (50-65%) and from animal sources (35-45%) with fish preferred over meat.  Most of the restricted foods are carbohydrates..refined salt, and refined oils as well as any “processed foods.”  However, there are “no data that this diet has any effect in IBD.”  Previous reports of improvement in IBD are mainly testimonials (anecdotal evidence).
  • Exclusive enteral nutrition (EEN)/Elemental/Semielemental: In pediatric CD, “EEN has been shown to be as effective as corticosteroids in inducing remission (70-90%)..EEN does not seem to be effective in UC.”  High rate of relapse when diet is stopped.  Formula type does not seem to be very important.

Take-home message: “Clinical trials in all dietary strategies (with possible exception of EEN in pediatric patients) are lacking and further study is needed.” “From the current evidence available, a low FODMAPS or gluten-free diet may be the most helpful in controlling diarrheal and bloating symptoms…However, …symptom improvement does not equate to remission or objective evidence of disease regression.”

Related Blog Posts:

ImproveCareNow has published information on IBD and Nutrition as well.  Here’s an excerpt from their Circle eNewsletter:(initially published April 2013, Stacie Townsend, MS, RD, LDN, CSP)

Diet is an important part of your IBD treatment plan and should be used in conjunction with medications. Proper nutrition plays a critical role in managing IBD. Eating healthfully and in appropriate amounts will improve IBD symptoms, contribute to age-appropriate growth, and decrease risk of anemia, poor bone density, and vitamin/mineral deficiencies. It can also increase effectiveness of IBD medications.

No one diet has been proven to prevent IBD or to prevent flare ups, although several diet books and plans have claimed to “cure IBD”. Unfortunately, there is little scientific evidence to prove that these diet plans, such as the Specific Carbohydrate Diet (still being studied) and the Guts and Glory Program, are effective, and most of these plans avoid entire food groups, which can then lead to vitamin and mineral deficiencies and poor weight gain.

Nutritionists frequently get asked what foods are safe for people with IBD, and creating a diet plan for you is often trial and error… The best diet plan is one that includes all food groups (proteins, grains, fruits, vegetables, dairy, and oils) and in appropriate portions for your age, weight, and physical activity level… If gas, bloating, and diarrhea are among your symptoms, lactose free dairy products may be better tolerated.

So what IS the most appropriate diet for IBD? The United States Department of Agriculture’s food guidance system, MyPlate, is the appropriate diet plan for you… and the SuperTracker within the MyPlate website can help you track what you eat each day, and how your diet measures up to the recommended diet plan for you.

General nutrition guidelines for individuals with IBD include:

  • choose foods from all food groups
  • limit fried/fatty foods, caffeine and spicy foods, especially if these foods worsen symptoms of IBD
  • drink fluids at each meal to maintain hydration
  • consume a multivitamin daily to aid nutrient absorption
  • consume small frequent meals (eat every 2-3 hours while awake) if volume of foods at a meal is an issue

…If you want additional help with your diet, make an appointment to see our nutritionist.

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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.

 

EXTEND & MUSIC: Optimizing Crohn Disease Care

As noted in recent posts (see links below), there is increased interest in showing direct mucosal healing and achieving optimal drug levels in controlling Crohn disease (CD).

  1. Clin Gastroenterol Hepatol 2014: 12: 414-422.
  2. Clin Gastroenterol Hepatol 2014: 12: 423-431.

The first study examines the rates of deep remission induced by adalimumab.  Deep remission is “defined as the absence of mucosal ulceration and CD Activity Index scores less than 150.”

Design: The data is derived from the EXTEND (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing) trial.  EXTEND was a 52-week randomized, double-blind, placebo-controlled trial of adalimumab (ADA) for adults (n=135) with moderate to severe ileocolonic CD.  All patients received open-label induction with ADA (160/80 mg at weeks 0/2), then were randomized to ongoing ADA 40 mg every other week or placebo.

Results: Rates of DR were 16% in ADA patients compared with 10% of placebo-treated patients at week 12.  By week 52, 19% of ADA patients were in DR compared with 0% of placebo-treated patients.

Key findings:

  • Analysis showed that shorter disease duration was associated with DR.  One-third of patients with CD for <2 years achieved DR.
  • Patients with DR had better outcomes than those with only mucosal healing (n=8); those with isolated clinical remission (n=19, no mucosal healing), but not DR, had similar outcomes to those with DR.  The associated editorial (pg 432) notes “symptoms will still make patients go to the emergency department, or miss work, or feel miserable, regardless of how good their mucosa looks.”
  • The authors state that during the 40 weeks after early CR, “estimated savings were $6117 for direct medical costs and $4243 for indirect costs” (total $10,360).  This monetary savings may not be offset in clinical practice by ileocolonoscopy which is not only invasive but also expensive.

Conclusion (from the authors): “Before any recommendation to adopt DR as a treatment target, establishing a clear association between achievement of DR and better long-term prognosis is necessary.”  The editorial advises against adopting DR as a treatment goal: “combining symptoms and mucosal healing into 1 end-point should be reconsidered as a measure of response to anti-inflammatory therapies.”

The second study, referenced above, examined plasma concentrations of certolizumab pegol (CZP) and endoscopic outcomes of patients with Crohn disease.

Design: The authors analyzed data (post hoc analysis) from the MUSIC (The Endoscopic MUcoSal Improvement in Patients with Active CD Treated with CZP) study. Adult patients received subcutaneous CZP (400 mg) at weeks 0, 2, and 4 followed by every 4 week treatment for 52 weeks.  Endoscopic evaluation took place at weeks 0, 10, and 54 and CZP concentrations were measured at weeks 8 and 54. At week 10, there were 45 patients analyzed and at week 54, 18 patients.

Key findings:

  • Mean CZP concentrations: 11.1 mcg/mL at week 8 (4 weeks after previous dosing) and 14.9 mcg/mL at week 54 (2 weeks after previous dosing).
  • Higher CZP concentration (by quartile values) correlated with endoscopic response (P=.0016) and remission (P=.0302) at week 10.
  • Among those with the highest CZP values, their 8-week CDEIS (CD Endoscopic Index of Severity) remission rate was 75% (12/16).  Overall, CDEIS remission was noted in 56% (25/45) at week 8.
  • At week 54, endoscopic remission correlated with plasma CZP values (P=.0206).
  • Both high CRP and high body weight inversely correlated with CZP concentrations.

Conclusion from this study: As with other anti-TNF agents, higher serum levels were associated with mucosal healing.  However, the data do not prove causality.  “It is possible that higher trough concentrations at week 8 may be a consequence of mucosal healing” rather than the reverse.

Bottomline: These two studies together show that achieving optimal long-term response correlates with therapeutic drug levels and mucosal healing.  At the same time, these studies along with many other indicate that we have along way to go in order for us to achieve these objectives consistently.

Related blog posts:

 

Digging into the COMMIT Study

“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:

 

 

Cannabis: Feel better, Worse Crohn Disease

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.

Briefly Noted…Scoliosis, Cystic Fibrosis, Specific Carbohydrate Diet, GGT, Surgeon General

“Net effect of scoliosis surgery on gastric emptying, upper gastrointestinal symptoms, and clinical nutritional status was minimal”  according to this prospective study of 31 children: JPGN 2014; 58: 38-45.

Lactobacillus reuteri ATCC55730 was associated with reduced pulmonary exacerbations (but not improved FEV1) in 61 patients with cystic fibrosis who were enrolled in a prospective randomized, double-blind, placebo-controlled study over 6 months between 2007-2009 (JPGN 2014; 58: 81-86).

A retrospective chart review of seven children with Crohn disease who were treated with the specific carbohydrate diet with an average diet duration of 14.6 months showed that all symptoms resolved and laboratory studies improved or normalized.  (JPGN 2014; 58: 87-91). More studies on this diet are expected to be published soon.

Data from 200 preterm infants and 383 term infants help provide updated GGT (gamma-glutamyl transferase) reference values.  In preterm infants during 1st 7 days: 141 ± 89 U/L, then between days 8-28: 131 ± 85 U/L.  In term infants the values were similar 140 ±86 U/L and 145 ± 87 U/L respectively. (JPGN 2014; 58: 99-101).

And from NEJM twitter feed, Congress may allow the NRA veto power in the selection the next surgeon general: http://nej.md/1nECFlM.

More on Gut Microbiome and Crohn Disease

Earlier this week on NPR there was a story summarizing the altered microbiome in Crohn disease and a related recent paper; here’s the link: Mix Of Gut Microbes May Play Role In Crohn’s Disease.  Other media outlets covered the story too:

The graphical abstract (Cell Host & Microbe, Volume 15, Issue 3, 382-392, 12 March 2014) is noted below:

Graphical Abstract

The link to the full study is listed below if you want to see the source article.  The amount of data that is presented is impressive but easy to follow with the figures:

Full link to article (from Kipp Ellsworth twitter feed): http://goo.gl/603Rbz 

Related blog posts:

Sanjay Gupta is Wrong… about Stem Cell Therapy

According to a 3 min video (and article) publicized on twitter by Dr. Sanjay Gupta, Stem Cell therapy for Crohn disease is 97% effective. ow.ly/smrJM I sent him a tweet asking for data to support this figure but have not heard back.  That being said, there are very few treatments that work in 97% of patients with any chronic disease.

The context of the video regards a model who has had 75 hospitalizations for Crohn disease and is unable to tolerate standard treatment.  “Thus far, there is a 97 percent success rate with this procedure, but it’s not fully covered by insurance, so Jocelyn must find the money for the procedure, her travel, and the long recovery.”

To my knowledge, stem cell therapy, while promising, for Crohn disease remains an experimental treatment without any large studies proving its effectiveness. 

An abstract at DDW last year (Stem Cell Transplantation Halts Crohn’s Disease – Medscape) reported that among the 22 patients in the stem cell treatment group (who were refractory to multiple other medications), 40% had mucosal healing and 58% had segmental healing. The presenting physician, Dr. Christopher Hawkey, noted ‘there were serious adverse events and many patients were not cured…. We need controlled trials showing a long-term risk/benefit ratio.’

Another study (Blood. 2010;116:6123-6132) with 24 patients, reported that “the percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years.”

Bottomline: I think the information in the video is not accurate.  Inevitably, it will lead to a lot of ill-informed questions by families.  When a respected physician posts this type of unsupported information, it has the potential to undermine not just his credibility but other physicians as well. Perhaps, Dr. Gupta will consider revising this information.

Related article:

Clin Gastroenterol Hepatol 2014; 12: 64-71: “A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy.” Results: among the 15 patients (of 16) who completed the study, the mean CDAI score was reduced from 370 to 203.  Twelve patients had a clinical response and eight had clinical remission.  All patients received 4 weekly infusions of mesenchymal stromal cells.  One patient had a stage 1 adenocarcinoma (colon) but the authors think that this was likely present prior to the infusions. Why this study is important? If shown effective in larger studies, mesenchymal stromal cells  are much safer than allogeneic stem cells as donor to recipient matching is not needed nor chemotherapeutic marrow conditioning.

What you might not know about anti-TNF monitoring…

At a recent group dinner meeting, we had the opportunity to review therapeutic anti-TNF monitoring. In addition, we discussed emerging treatments for inflammatory bowel disease, like golimumab, tofacintinib and vedolizumab.

As noted in previous blog entries (see below), therapeutic anti-TNF monitoring can help adjust treatment.  Namely, if a patient loses response to therapy and has low trough levels of anti-TNF (Infliximab ❤ μg/mL, Adalimumab <8 μg/mL, or certolizumab <27.5 μg/mL) without antidrug antibodies (ADAs), then increasing the dose is likely to be effective.  However, if a patient has a therapeutic level and is not responding, changing to another agent and/or further investigation is worthwhile.

So, what information is new?

  • Only about 20% of patients who lose clinical response develop ADAs.  So, drug level, rather than ADAs, is most helpful.
  • For infliximab, adjusting dose 14 weeks into therapy to achieve a target trough level between 3-7 mcg/mL may be helpful.
  • Severe colitis patients may need higher initial doses (?as high as 20 mg/kg) due to potential for ‘antigen sink.’  This is due to notably higher clearance in the presence of low albumin, and high CRP.  Other factors that increase clearance include higher BMI and male gender.
  • About 1/2 of patients who receive higher doses due to severe disease may be able to deescalate dosage when improved. (?which half)
  • Currently, a reactive approach to checking levels is common in U.S. in part due to costs associated with checking trough levels and ADAs (as much as $2500).  That is, most commonly checking levels is undertaken in patients with suboptimal clinical response.  A proactive approach to achieve target levels may be shown to be helpful.
  • While studies have not shown higher adverse reactions with higher trough levels, there are a few clinical situations in which lower trough levels can be important.  In patients with psoriatic skin lesions and arthralgias, if trough levels are elevated, lowering the dose may be helpful.

Outstanding questions?

  • Should patients have drug levels checked when they are asymptomatic?
  • How does a practitioner account for variability among different laboratory assays?
  • What is the optimal target level for each anti-TNF agent? Is this different in Crohn disease compared with ulcerative colitis? Is the trough target level different in adults than children?
  • Is there a toxic level?
  • If a rapid test response were available, would checking drug levels be needed for hospitalized patients to assess anti-TNF rescue therapy?

Related blog links:

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