#NASPGHAN17 Celiac Disease and Mucosal Healing

This blog entry has abbreviated/summarized this presentation. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

Celiac disease: treat to target! Where should we aim and how do we get there?

Ivor Hill  Nationwide Children’s Hospital

Key point:

  • Dr. Hill asserted that long-term outcomes are related to ongoing intestinal inflammation and thus our goal should be mucosal healing rather than normalized symptoms/normalized serology

At this lecture, I asked Dr. Hill what he would recommend for an asymptomatic pediatric patient with ongoing intestinal inflammation who was strictly adherent to a gluten-free diet, who had no other recognizable diseases, and who had normalized their serology on treatment.  His response was that in adults that ~50% of patients improve with better attention to diet.  Thus, currently besides further dietary scrutiny, it is unclear what should be done in the pediatric population should one find ongoing mucosal disease in an asymptomatic adherent patient.

My take: Until prospective pediatric studies are published to determine the frequency of ongoing intestinal inflammation in those on a strictly GFD in asymptomatic patients and until we have additional management options, it does not make sense to look for mucosal healing.  “Don’t hunt what you cannot kill.”

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.

 

Abstract Only: Mucosal Healing in Pediatric Inflammatory Bowel Disease

This post provides the full abstract from today’s earlier post.

 

A retrospective study (Inflamm Bowel Dis 2017; 23: 1447-53) describes assessment of mucosal healing in pediatric patients with inflammatory bowel disease.

Here is abstract:

Background: Mucosal healing (MH) is associated with improved clinical outcomes in patients with Crohn’s disease (CD) and ulcerative colitis (UC). MH as a target for treatment has been suggested, although there is little pediatric data. The goal of this study was to evaluate MH in clinical practice in pediatric patients with inflammatory bowel disease in clinical remission.

Methods: A retrospective review of electronic health record data was performed on all patients with CD or UC who underwent at least 2 colonoscopies from 2010 through 2016. Only patients in clinical remission undergoing a scope for MH were included in our study. The incidence of MH and histologic healing (HH) was analyzed, along with cumulative rates of MH in each group. MH was defined by both physician assessment of MH and an endoscopic score of zero for CD and UC.

Results: A total of 76 patients with CD and 28 patients with UC underwent at least one MH scope while in clinical remission. Of the 76 patients with CD, 51 patients (67%) demonstrated MH by physician assessment, 34 patients (45%) demonstrated MH by a simple endoscopic score for CD of zero, and 35 patients (46%) demonstrated HH. Of the 28 patients with UC, 20 patients (71%) demonstrated MH by physician assessment, 10 patients (36%) demonstrated MH by a Mayo score of zero, and 10 patients (36%) demonstrated HH. Nineteen patients underwent a second MH scope and 11 (58%) demonstrated MH by physician assessment, 7 patients (37%) demonstrated MH by simple endoscopic score for CD or Mayo scores of zero, and 5 patients (26%) demonstrated HH. Of those patients with active disease, 21 of 25 patients with CD underwent escalation of therapy, whereas 8 of 8 patients with UC underwent escalation of therapy. Cumulative rates of MH when defined by physician assessment were 79% (60 of 76 patients) in CD and 79% (22 of 28 patients) in UC.

Conclusions: MH is feasible in pediatric CD and UC, and rates of cumulative MH in pediatric patients are similar to previously published adult data. In children with inflammatory bowel disease in clinical remission, approximately one-third demonstrate active disease at endoscopy.

Pediatric IBD: Treating to Target

In 2014, an influential study by Sandborn et al (Clin Gastroenterol Hepatol 2014; 12: 978-85) described the importance of mucosal healing in a strategy termed “treating to target.”  The main findings (reviewed in a previous post Treating to Target) were the following:

  • Only half of the patients achieved MH.  “After a median follow-up of 62 weeks, 50.7% had MH and 61.1% had endoscopic improvement.”  79% of those who underwent adjustments achieved MH.
  • Clinical symptoms do not correlate with MH. “40.9% of patients experienced clinical symptoms despite MH and 18.8% of patients without clinical symptoms had significant endoscopic lesions.”
  • Biomarkers may be effective at predicting MH. “None of the patients with MH had an increased concentration of CRP.”
  • Adjusting treatment is needed if abnormal endoscopy; this is inherent in the philosophy of treating-to-target.

Now, my colleagues at Emory have published a single-center experience on mucosal healing (MH) (SL Santha, PR Shankar, A Pan, B Schoen, S Kugasthasan, CG Sauer. Inflamm Bowel Dis 2017; 23: 1447-53).  While this study has the typical limitations of a retrospective study, it makes several useful points.  It takes a little extra effort to interpret their findings as they describe their results based only on the 104 patients with clinical remission rather than based on the total of 182 patients who had at least two colonoscopies.  78 were excluded due to ‘acute GI symptoms.’

Of the 104 patients considered to be in clinical remission, 76 had Crohn’s disease and 28 patients had ulcerative colitis.

Key findings:

  • For patients with ulcerative colitis (UC) who were in clinical remission, 20 (71%) had MH per physician assessment, though only 10 patients (36%) had MH based on Mayo score of zero.  10 patients (36%) demonstrated histologic healing.
  • For patients with Crohn’s disease (CD) who were in clinical remission, 51 (67%) had MH per physician assessment, 34 (45%) had MH base on simple endoscopic score for CD, and 35 (46%) had histologic healing.
  • 21 of 25 CD patients and 8 of 8 patients with UC underwent escalation of therapy based on endoscopic evaluation. 9 patients underwent dose optimization of their biologic as the modification in their therapy; this step is now routinely done in pediatrics without followup endoscopy.

The discrepancy in MH rates based on physician assessment, endoscopic scores, and histologic healing is explained.  Generally, MH based on physician assessment would include normal and those with very mild mucosal disease.  “For CD, this included small and rare aphthous ulcers, and for UC, this included mild Mayo 1 erythema in only one segment of bowel.”

Questions about the approach to ‘treating to target:’

  • This study does not describe other alternative modalities to assess for mucosal healing. Is it feasible to use a biomarker like an abnormal calprotectin to target those in need of further evaluation? In those with abnormal biomarkers, dose escalation would not require a repeat scope.
  • The Emory group has used MRE extensively, but does not report MRE findings in this population.  Would MRE (which does not require sedation) be more useful in some patients?

As in adult patients, this study does show the need for objective markers in pediatric inflammatory bowel disease; 30% of patients who were considered to be in clinical remission had active disease with further investigation.  This finding has implications for ImproveCareNow which uses physician global assessment in tracking remission rates for pediatric IBD.

In their discussion, the authors state that “changes in medical therapy can increase the MH rate to nearly 80%, which could be even higher with additional changes in those who did not demonstrate MH on a second endoscopy.”  This sentence needs to be carefully interpreted.  The authors were able to show MH based on physician assessment in 82 of 104 patients (79%) who were in clinical remission.  This rate would be MUCH lower if the entire cohort of 182 were included, possibly no greater than 50%.

The authors conclude with “endoscopy should be considered in pediatric patients with IBD in clinical remission to identify those without MH who may require medication escalation despite the absence of clinical symptoms.”

My take: I agree with the authors that objective markers of clinical remission need to be obtained to assess the effectiveness of therapy.  However, I am not convinced that endoscopy is needed in every patient who is doing well on therapy; other biomarkers and imaging may be more beneficial.

Related blog posts:

Sign at Pisgah Fish Camp Restaurant: “On this site in 1897 nothing happened.”

 

 

Are Followup Biopsies Necessary for Celiac Disease? Look Beyond the Headline

A retrospective study from Boston has gained attention for suggesting that repeat biopsies may be needed for celiac disease (published online, MM Leonard et al JPGN, doi: 10.1097/MPG.0000000000001460).  In my view, this may be a little early for that recommendation for asymptomatic patients with normal serology.

Full Abstract:

Value of IgA tTG in Predicting Mucosal Recovery in Children with Celiac Disease on a Gluten Free Diet.

Objective: Our objective was to determine the rate of mucosal recovery in pediatric patients with celiac disease on a gluten free diet. We also sought to determine whether IgA tissue transglutaminase (tTG) correlates with mucosal damage at the time of a repeat endoscopy with duodenal biopsy in these patients.

Methods: We performed a retrospective chart review of one-hundred and three pediatric patients, under 21 years of age, with a diagnosis of celiac disease defined as Marsh 3 histology, and who underwent a repeat endoscopy with duodenal biopsy at least twelve months after initiating a gluten free diet.

Results: We found that 19% of pediatric patients treated with a gluten free diet had persistent enteropathy. At the time of the repeat biopsy, tTG was elevated in 43% of cases with persistent enteropathy and 32% of cases in which there was mucosal recovery. Overall the positive predictive value of the autoantibody tissue transglutaminase was 25% and the negative predictive value was 83% in patients on a gluten free diet for a median of 2.4 years.

Conclusions: Nearly one in five children with celiac disease in our population had persistent enteropathy despite maintaining a gluten free diet and IgA tTG was not an accurate marker of mucosal recovery. Neither the presence of symptoms nor positive serology were predictive of a patient’s histology at the time of repeat biopsy. These findings suggest a revisitation of monitoring and management criteria of celiac disease in childhood.

Link to full text: A few other key points:

  • The most common indications for repeat endoscopy were due to persistent symptoms (43%) and new gastrointestinal symptoms (27%). Twenty-four subjects (34%) had persistently elevated serology at the time of the repeat biopsy.
  • 19% exhibited persistent enteropathy consistent with a Marsh 3 lesion at the time of the repeat endoscopy.
  • Only 71 patients had serology within 4 months of repeat endoscopy, limiting the interpretation of the concordance of tTG value to histology

My take: I think it is premature to recommend routine followup biopsies in asymptomatic patients with normal serology.  I think a prospective study will be helpful; the majority of patients in this study who underwent repeat biopsy were symptomatic and 9% were not adherent to their diet.  Thus, this may not reflect a typical patient with celiac disease at followup.  In addition, it would be helpful with regard to whether persistent histological findings have clinical significance.

Despite these limitations –this is how this article is being reported (from news-medical.net), here’s an excerpt from a recent summary:

Study finds 1 in 5 pediatric celiac disease patients on gluten-free diet sustain persistent intestinal damage

Alessio Fasano, MD, director of the MGHfC center and co-senior author of the study, was also surprised by the results, which were based on a retrospective examination of the biopsy and medical records of 103 children with celiac disease treated at MGHfC or BCH. The children had been on the gluten-free diet for at least one year and were determined by dietitians and other hospital health care practitioners to have complied well with the diet. But repeat biopsies found persistent intestinal damage in 19 percent of them. “The number of children who don’t heal on the gluten-free diet was much higher than what I expected,” Fasano says.

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Final Tweets from #NASPGHAN15

BG

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From debate regarding importance of mucosal healing:

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Related blog posts:

Stopping Infliximab –What Happens Next?

A recent retrospective single-center study (Papmichael K et al. Clin Gastroenterol Hepatol 2015; 13: 1103-10) of 100 patients with Crohn’s disease examined what happens to patients who discontinued infliximab therapy upon clinical remission.  The study used a medical database in Belgium.  The authors defined sustained clinical remission (SCR) as “maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period, which was a median period of approximately 10 years.” 84 patients continued on immunomodulator therapy.

Key findings:

  • 52 (52%) had SCR.
  • Complete mucosal healing, lower infliximab trough concentrations, and serum positivity for vascular cell adhesion molecule-1 were factors associated with SCR.

Limitations: SCR was based on physician global assessment which may underestimate relapse rates and endoscopic data at the time of infliximab discontinuation was available in only a small subgroup.

Bottomline: In this small study, half of the patients did well clinically for a long time after stopping infliximab (most remained on immunomodulator therapy).  However, given the insidious nature of Crohn’s disease, careful monitoring before and after stopping infliximab is worthwhile.  In addition, other studies have demonstrated higher relapse rates.

Related blog posts:

 

What “Treat-to-Target” Could Look Like in Crohn’s Management

A recent study (treat to target full text -Bouguen G et al. Clin Gastroenterol Hepatol 2015; 13: 1042-50) proposes  a “new paradigm for the management of Crohn’s disease.”  The concept of treating-to-target has been discussed in several previous blogs:

The concern with the traditional management has been ongoing damage to the bowel in many patients and lack of optimizing long-term outcomes.  The authors in the report make the following points:

  • Only 10% of Crohn’s disease (CD) patients experience prolonged remission of symptoms
  • Even asymptomatic patients often have evidence of active inflammation on endoscopy
  • The majority of patients will require surgery
  • Two big obstacles: delay in initiation of highly effective therapy (eg. combined biologic/immunosuppressant) and underestimation of disease activity due to poor correlation of symptoms to actual disease activity

While the fact that the majority of patients are at risk, some populations are at increased risk including the following:

  • those who smoke cigarettes
  • patients younger than 40 years at diagnosis
  • stricturing or penetrating disease
  • need for surgery
  • inability to wean corticosteroids
  • deep ulcerations on endoscopy

However, the authors note that “the lack of adequate data in this area of research makes risk stratification very difficult in clinical practice.” The authors review several studies:

  • ACCENT-I
  • Step-Up Top-Down trial
  • IBSEN population-based cohort study
  • SONIC
  • The Leuven cohort study
  • EXTEND trial

The data from these studies is used to base their argument of pursuing mucosal healing/more aggressive treatment, though they acknowledge that one risk is potentially subjecting some patients to overtreatment.  The review indicates that mucosal healing (MH) is defined endoscopically as “the disappearance of ulceration” and that endoscopy is the tool for testing for MH for the near-term, but that other markers including MRE and surrogate biomarkers may be useful alternatives.

The authors’ Table 1 list their proposed recommendations for CD, modeled after similar recommendations for Rheumatoid Arthritis.  The Four Key points:

  1. The physician and patient need to agree on the treatment target strategy
  2. The primary target for treatment of CD should be absence of endoscopic ulceration
  3. The use of both clinical symptoms and objective measures of inflammation (endoscopic or imaging) is required in routine clinical practice to guide treatment decisions
  4. Until the desired treatment target is reached, MH should be assessed every 6 months until the disappearance of ulceration and every 1-2 years thereafter.  Drug therapy should be adjusted accordingly.

Limitations on this strategy:

  • Cost of assessment–both endoscopy and MRE are expensive
  • Cost of therapies
  • While MH can be achieved in a higher percentage of patients, there are some patients who will not respond to any of the currently available therapies
  • Risk of therapies.  Some patients will develop adverse effects from the available therapies which will limit their therapeutic options.
  • This proposed strategy has very limited data in clinical practice

Take-home message from the authors: The “natural history” is not likely to improve unless the overall, symptom-based, therapeutic strategy for CD is changed.

Atlanta Zoo, Wreathed Hornbill

Atlanta Zoo, Wreathed Hornbill