IBD Shorts: September 2019

S Olivia et al (including Stanley Cohen from GI Care for Kids) Clin Gastroenterol Hepatol 2019; 17: 2060-7.A Treat to Target Strategy Using Panenteric Capsule Endoscopy in Pediatric Patients with Crohn’s Disease”  In this prospective study with 48 children with Crohn’s disease, pan-enteric capsule endoscopy (PCE) detected inflammation in 34 (71%) at baseline, 22 (46%) at week 24, and 18 (39%) at week 52.  PCE results were used to manage treatment and resulted in change in therapy in 71% at baseline and 23% at week 24.  Furthermore, PCE increased the proportions of patients in deep remission, up to 58% at week 52.

M Wright, et al. J Pediatr 2019; 210: 220-5. This case report of a 4 year-old boy with a perianal abscess and granulomatous colitis identified a NCF4 mutation causing severe neutrophil dysfunction.  He developed osteomyelitis with anti-TNF therapy and did not respond to vedolizumab. He had an excellent outcome following a hematopoietic stem cell transplantation. This study reinforces the potential benefit of investigating VEO-IBD which could allow more targeted therapy. Related blog post:

P Zapater et al. Inflamm Bowel Dis 2019; 25: 1357-66. This study with 112 patients with Crohn’s disease showed that serum interleukin-10 levels were directly related to infliximab and adalimumab levels.  This suggests that serum anti-TNF levels are significantly influenced by immunological activation.

JE Axelrad et al. Clin Gastroenterol Hepatol 2019; 17: 1311-22.  This study, using the Swedish National Patient Register, showed that gastrointestinal infection increased the odds of developing IBD in a nationwide case-control study.  “Of the patients with IBD, 3105 (7%) had a record of previous gastroenteritis compared with 17,685 control subjects (4.1%). IBD cases had higher odds for an antecedent episode of gastrointestinal infection (aOR 1.64), bacterial gastrointestinal infection (aOR 2.02) and viral gastrointestinal infection (aOR 1.55)…a previous episode of gastroenteriitis remained associated with odds for IBD more than 10 years later (aOR 1.26).”  The authors note that they cannot formally exclude misclassification bias, but it appears that enteric infections contribute to the development of IBD in susceptible individuals.

#NASPGHAN18 Highlights (Part 2)

I did not make it to this year’s meeting but did get a chance to catch up on a lot information via the PG 2018 Syllabus and based on information posted online.

Here are a couple of highlights for me:

My favorite slide from postgraduate course -Dr. Robert Kramer

Slides regarding the topic of Treat-toTarget Dr. Eric Benchimol:

Slides regarding GI symptoms and autism from Dr. Kara Margolis:

Slide regarding the frequency of bariatric surgery: Dr. Rohit Kohli:

Slides regarding intestinal failure population from Dr. Conrad Cole:

From Dr. Miranda van Tilburg regarding psychological therapies for functional GI disorders:

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.

#NASPGHAN17 IBD Treat to Target and Tight Control

More information from this year’s annual NASPGHAN meeting.

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

IBD Treat to Target: Treat the Patient or Treat the Disease

Robert Baldassano  Children’s Hospital of Philadelphia

I missed the first few minutes of this presentation, even though I had highlighted this as one of my top priorities.  So, if anyone reading this post has some additional comments, they are certainly welcome.

Key points:

  • Do not rely on symptoms alone to assess patient improvement.
  • Best surrogate marker: calprotectin.  Frequent calprotectin levels can help determine objective improvement; it is much more helpful than CRP as ~25% of patients do not elevate their CRP levels
  • Therapeutic drug monitoring is important in improving outcomes. Dose optimization improves response rate and durability of infliximab response.
  • Evolving targets in ulcerative colitis.  Even histologic activity, in the absence of endoscopic activity, is associated with relapsing disease
  • Dr. Baldassano indicated that he no longer is starting patients on thiopurine therapy. There are “36 phase 3 trials underway.” Thus, many promising options for those who may burn through current treatments
  • This lecture reviewed data from the RISK study showing that early (1st 90 days w/in diagnosis) TNF therapy helps prevent penetrating disease (related post: CCFA Update 2017/RISK study)

Another presentation by Philip Minar et al (Cincinnati Children’s Hospital Medical Center) shows that CD64 suppression is an early biomarker of response to infliximab therapy.

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.”

 

 

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

 

 

NASPGHAN Notes –Last Word for this Year

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

IBD Treatment: Targets for the Modern Age –Eric Benchimol (Children’s Hospital of Eastern Ontario)

Goal: Review mucosal healing and best targets to measure to predict prognosis

Treat-to-target:

  • Regular assessment of disease activity using objective outcome measures.
  • Adjust treatment if not accomplishing goal.
  • Proven helpful in rheumatoid arthritis, hypertension, diabetes, and hypercholesterolemia.

Old targets:

  • “Clinical remission”
  • “Feeling better”
  • Indices: PCDAI, CDAI, Harvey-Bradshaw
  • Problem: Active disease is not well-predicted by symptoms or laboratory markers
  • 2nd Problem: Active symptoms not always due to active IBD (could be due to functional complaints)
  • PUCAI score in ulcerative colitis does reflect ulcerative colitis severity fairly well

New Targets

  • High correlation with outcomes
  • Cost-effective
  • Available

Is mucosal healing achievable?   If you were scoped and adjustments made in therapy, then much higher rate (HR >4) of remission. Bougen, Clin Gastroenterol Hepatol 12: 978.  Endoscopy may be best way to assess mucosal healing.  Since it is invasive, efforts have been made to identify surrogate markers.

Treat-to-Target Algorithm

Treat-to-Target Algorithm

Surrogate Markers

  • Ultrasound –can be useful but operator-dependent
  • MRE had 83% accuracy for endoscopic remission: Gastroenterol 2014; 146: 374.
  • Calprotectin not as accurate in children? Am J Gastroenterol 2014; 109: 637. Sensitivity high 97%, specificity for remission 68%
  • CRP –if elevated, higher risk of complications or surgery. However, sensitivity is much lower for disease activity than calprotectin/imaging studies for active disease
  • Drug levels. Therapeutic IFX trough levels (and adalimumab) are highly predictive of mucosal healing.

Bottomline (my interpretation): Resolution of clinical symptoms and improvement in bloodwork is not good enough.  When/timing to assess with sensitive surrogate markers is still uncertain.  In many patients, endoscopy is needed to assure adequate improvement; however, in others, a followup imaging study (eg. MRE) or sensitive stool assays may be the best approach.

A related story (from AGA’s Today in Medicine email feed & pointed out to me by Ben Gold) indicates that estimation of clinical symptoms is not accurate:

Survey Suggests Severity Of IBD Is Underestimated By Gastroenterologists.

MedPage Today (10/31, Walsh, 186K) reports that survey results presented at a medical conference indicate that “the severity of inflammatory bowel disease is significantly underestimated by gastroenterologists.” Researchers found that “a total of 55% and 67% of physicians who participated in a web-based survey rated cases of Crohn’s disease and ulcerative colitis as being mild when they were actually moderate.” Meanwhile, “for case studies that represented severe disease, 76% and 81% of the physicians gave ratings of either moderate or mild for Crohn’s disease and ulcerative colitis, respectively.”

 

Related blog posts:

Risk Stratification in Pediatric IBD: Are we there yet? Jeffrey Hyams (Connecticut Children’s

Initially, Dr. Hyams described the exploding head syndrome; many attendees might have thought they had this due to information/”big data” overload, but this syndrome is a sleep disorder/parasomnia event.  Here’s a link to the image from his talk.  Then, Dr. Hyams reviewed data on risk stratification:

  • Mutations: Some genetic mutations are associated with disease severity
  • Still needed: specific pediatric data
  • Microbiome: Some profiles associated as prognostic factors in pediatric RISK study
  • Early anti-TNF associated with improved outcomes (using propensity analysis) Gastroenterol 2014; 146: 383.

Bottomline: Not there yet with risk stratification. Many factors environmental, genetic susceptibility, immune response, and treatment need to be sorted out with “big data.”

Key Clinical Questions for your practice at this time:

  • Does this patient have known risk factors for doing poorly?
  • Am I using current therapies properly?
  • What is the risk of undertreated disease? This needs to be considered with discussion of safety of IBD meds.

Cross Examination of Cross-Sectional Imaging in IBD –Sudha Anupindi (Radiology/CHOP)

  • For the most part, barium studies discouraged (eg. UGI/SBFT) by speaker; radiation ~1 mSv.
  • CT (conventional) widely available and easy –if needed urgently/middle of night.

Initial presentation: imaging of choice

  • MR enterography –no radiation, better contrast resolution, best for perianal disease, able to evaluated peristalsis. Two limitations: cost, interpretation
  • CT enterography –fewer motion artifacts (0.6 seconds), lower cost, increased availability, better spatial resolution radiation reduced with current technology at most Children’s hospitals: 1-2 mSv

Abdominal ultrasound holds promise as alternative imaging with lower cost.

 

Treating to Target

As alluded to in a previous post (CCFA Conference Notes 2014 (part 2) | gutsandgrowth), there has been increasing discussion and efforts aimed at mucosal healing (MH) because it is associated with improved clinical outcomes in patient’s with Crohn’s disease (CD).  Even before its print publication, this study (Clin Gastroenterol Hepatol 2014; 12: 978-85) by William Sandborn’s group has influenced the discussion.

This retrospective study analyzed 67 patients with CD (2011-2012).  These 67 were selected from a population of 510 patients seen at UCSD who had at least several endoscopies and ulcers  seen at the initial procedure.  In this cohort of 67 patients, the median disease duration was 9.8 years.  Only 26 (38.8%) were naive to both immunosuppressives and biologics at referral.

Key findings:

  • 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.

The authors conclude that “serial endoscopic procedures to guide treatment to the goal of MH is feasible in clinical practice.” Ultimately the goal is to influence the natural history of Crohn’s disease.

Study limitations:

  • retrospective study
  • small number of highly-selected patients
  • lack of randomization
  • definition of MH remains debated
  • no cost data
  • lack of data on stool biomarkers (e.g. calprotectin) which could serve as alternative
  • no answer to the question of what to do for the patient without MH who is receiving ‘maximal medical treatment’

From Dr. Sandborn: (from Healio Gastro summary):

Evidence has accumulated that the complications of Crohn’s disease [CD] … are due to chronic inflammation that has not been fully treated,” William J. Sandborn, MD, chief of the gastroenterology division and director at the University of California, San Diego, IBD Center, told Healio.com. “This in turn has led to the concept of ‘treat to target’ in which patients are assessed with endoscopy for active inflammation prior to making important changes in therapy, and then reassessed with endoscopy within 4 to 6 months to ensure that the therapy change healed the bowel and resolved the inflammation.

“If active disease persists at endoscopy, even in the absence of clinical symptoms, then therapy is intensified and this cycle is repeated until mucosal healing (MH) is achieved.”

Take-home message: This study is one of many that are likely to influence the practice of clinicians to prove that the treatment is exerting a biologic effect and not solely improvement in clinical scoring indices.  With the emergence of multiple modalities to assess improvement, including biomarkers and imaging, it is not clear that repeated endoscopy will be the best assessment tool.

Related blog postEXTEND & MUSIC: Optimizing Crohn Disease Care …

Also noted:

Clin Gastroenterol Hepatol 2014; 12: 986-94.  “Association Between Telephone Activity and Features of Patients with Inflammatory Bowel Disease.”  The authors found that 15% of patients were responsible for half of all telephone calls.  These patients were more likely to be seen in ED and hospitalized.

Clin Gastroenterol Hepatol 2014; 12: 929-34. “Histologic Remission: The Ultimate Therapeutic Goal in Ulcerative Colitis?” This article reviews definitions for histologic remission and highlights questions that need to be addressed before histologic remission is used more widely as a clinical endpoint in trials and in practice.