Tag Archives: Crohn’s disease

More on Adalimumab (Humira) in Pediatrics

Posted on by

A recent ‘observational cohort’ study (Cozijnsen M, et al. JPGN 2015; 60: 205-10) provides more information regarding the use of adalimumab in pediatrics.  The authors attempted to identify all Dutch patients <18 years of age with Crohn’s disease who received adalimumab after infliximab therapy.  Excluded patients were those with “bad treatment adherence,” conflicting comorbidity, and previous participation in prospective study by Hyams et al Gastroenterol 2012; 143: 365-74 (Related blog post: Adalimumab for children with Crohn’s disease | gutsandgrowth).

Key findings:

  • 53 patients met the inclusion criteria.  12 received monotherapy with adalimumab; cotherapy in 21 with thiopurines, 11 with methotrexate, 7 with steroids, and 2 with enteral nutrition.
  • Median followup was only 12 months.
  • Remission noted in 34 (64%) patients based on either wPCDAI or PGA (physician global assessment) after a median of 3.3 months.  Remission was durable in 50% of these patients for 2 years.
  • Adalimumab failure was noted in 18 (34%).  Only 3 patients in this study were primary infliximab nonresponders and only 1/3 responded to adalimumab.
  • One serious adverse event (infection) was reported.

One weakness of this study (& many others) is its reliance on clinical disease activity indices rather than more precise measures of mucosal healing.

Take-home point: This small study provides some information about the utility of adalimumab in clinical practice in pediatrics.  As noted in other studies, those with a loss of response to infliximab, rather than primary nonresponders, appear to have a more favorable response to adalimumab. In addition, the glaring weakness in this study (i.e. small number of participants) validates the rationale behind efforts like ImproveCareNow which can generate information quickly from a large patient population.

Related study: “Levels of Drug and Antidrug Antibodies are Associated with Outcome of Interventions After Loss of Response to Infliximab or Adalimumab.” Yanai H, et al. Clin Gastroenterol Hepatol 2015; 13: 522-30. Retrospective study of 247 adult and pediatric patients. Key findings:

  • Patients with adequate trough levels (>4.5 mcg/mL for adalimumab, >3.8 mcg/mL for infliximab) “identified patients who failed to respond to an increase in dosage or a switch to another anti-TNF agent with 90% specificity.”
  • “Levels of antibody against adalimumab >4 mcg/mL-eq or antibodies against infliximab >9 mcg/mL-eq identified patients who did not respond to an increased drug dosage with 90% specificity.” These patients were likely to benefit by switching to an alternative anti-TNF.

Related study: Clin Gastroenterol Hepatol 2015; 13: 539-47.  Trough levels of infliximab (>3 mcg/mL) at week 30 was associated with improved outcomes, including mucosal healing and corticosteroid-free remission.

Briefly noted from ImproveCareNow: Dotson JL et al. “Feasibility and Validity of the Pediatric Ulcerative Colitis Activity Index in Routine Clinical Practice.” JPGN 2015; 60: 200-04.  This study, with 2503 patients, found that the PUCAI was completed in 96% if visits.  The PUCAI correlated with PGA chain scores.

Related blog posts:

Emigration -One Way to Acquire Inflammatory Bowel Disease

Posted on by

A recent study (Shitrit AB, et al. Inflamm Bowel Ds 2015; 21: 631-35) highlights the phenomenon of acquiring inflammatory bowel disease (IBD) by moving from a non-developed country to a developed country; the implication is that the changes in environment and diet predispose towards the development of IBD.

This study examined Ethiopian Jews who migrated to Israel.  Using a case-control study, the authors compared 32 Ethiopian immigrants to 33 Ashkenazi patients with IBD.

Key findings:

  • No Ethiopian immigrants had a positive family history compared with 42% of Ashkenazi group.
  • Crohn’s disease was more prevalent in the Ethiopian immigrants: 94% versus 73%.
  • The Ethiopian immigrants lived in Israel for at least 8 years before developing IBD an da median duration of 13 years.

The study discusses the difficulty of diagnosing IBD in rural Africa but speculates that rather than an underdiagnosis of IBD, it is likely to have a true low prevalence of IBD.

Take-home message: It takes many years for the environment exposures to allow for the development of IBD.  Additional work is needed to establish the clinical, genetic, and microbial factors that influence the acquisition of IBD in immigrants to developing countries.  Understanding the susceptibility of immigrants would have widespread application.

Related blog posts:

Withdrawing Therapy Leads To Relapse, Even if in Deep Remission

Posted on by

A recent study, presented as an oral abstract (thanks to Jeff Lewis for forwarding this reference), indicates that even in patients in deep remission, withdrawal of anti-TNF therapy leads to relapse in about 50% even when thiopurines are continued; this is in agreement with previous posts (see below).

Full abstract: OP007 Relapse after Deep Remission in Crohn’s disease. Here are the results and conclusion from the abstract:

Results

Sixty one patients were included and followed-up for a median of 28 months (range 7-47). After withdrawal of anti- TNFa therapy (44 infliximab and 17 adalimumab) 47 (77%) patients continued thiopurines. 32 (52.5%) patients relapsed until the end of follow-up with a median time to relapse of 8 months (range 1-25). The cumulative probability of maintaining remission was 82% at 6 months, 59% at 1 year and 51% at 2 years. Analysis of 28 patients who were in deep remission (endoscopic healing; faecal calprotectin <150mg/kg; CRP <5mg/l) revealed no better survival (82%, 64% and 40% at 6 months, 1 and 2 years, respectively). Four (8%) of relapsing CD patients required surgery 5 to 19 months after anti-TNFa cessation (2 for new stricture development, 1 for medically refractory flare and 1 for high grade dysplasia). In multivariate model only disease localization was risk factor of disease relapse (colonic vs. ileal/ileocolonic: OR 0.16, 95%CI: 0.03-0.72; p=0.02). Type of anti- TNFa preparation, smoking, disease behaviour, corticosteroid or thiopurine therapy, biological markers and anti-TNFa trough levels did not impact disease relapse.

Conclusion

Approximately half of CD patients relapsed within 2 years after anti- TNFa discontinuation despite being in endoscopic remission when anti-TNFa was stopped. The highest relapse rate was observed during the 1st year. Ileal disease increased the risk of disease flare, while no other risk factor was identified.

Related blog posts:

Bryce Canyon

Bryce Canyon

FMT for Crohn’s Disease -Small Study

Posted on by

A recent prospective open-label study (Suskind DL, et al. Inflamm Bowel Dis 2015; 21: 556-63) adds a bit more information on fecal microbial transplantation (FMT) for individuals with Crohn’s disease (CD). This study included 9 patients, ages 12-19, and 11 authors.

Study details:

  • Pretreated with rifaximin 200 mg TID x 3 days and Miralax 17 gm TID x 2 days prior, and omeprazole day before and morning of procedure
  • Patients continued on prior treatment: 4 on methotrexate, 2 on thiopurine, and 3 on mesalamine (1 mesalamine patient was receiving methotrexate also)
  • Stool donor was a screened parent
  • Stool administered via NG
  • Stool DNA studied –>metagenomic sequencing

Key findings:

  • FMT engraftment was demonstrated in 7 of 9 patients
  • Mean PCDAI improved –baseline 19.7 –>6.4 at 2 weeks–>8.6 at 6 weeks
  • 5 of 9 patients who did not receive additional medical therapy were in remission at 6 and 12 weeks.

One particular advance with this study was the correlation between microbial species before and after FMT.  One speculation from the authors was that “the more divergent a Crohn’s patient is from his donor the more the potential benefit of transplantation.”  Thus, this same study with unrelated donor stool (eg. OpenBiome) would be of interest as well.

My Take: While this study offers encouragement for bigger studies, we will not know if FMT is effective (& how to administer optimally) until we have studies with more patients than authors.

Related blog posts:

 

 

Short Takes on IBD Articles

Posted on by

Singh S, et al. Gastroenterol 2015; 148: 64-76.  In this study, the authors identified 21 trials with 2006 participants to examine the comparative efficacy of pharmacologic interventions to prevent relapse of Crohn’s disease (CD) after surgery.  Conclusion: “anti-TNF monotherapy appears to be the most effective strategy for postoperative prophylaxis for CD.” The relative risk of clinical relapse and endoscopic relapse with anti-TNF monotherapy was estimated to be between 0.02-0.20 and 0.005-0.04, respectively. Thus, those at highest risk for recurrence, including younger individuals, smokers, penetrating CD, perianal CD, and recurrent surgeries) are most likely to benefit.(Related blog post: More Lessons in TNF Therapy (Part 1) | gutsandgrowth)

Pariente B, et al. Gastroenterol 2015; 148: 52-63. The researchers in this cross-sectional study developed the Lémann Index which measures cumulative structural bowel damage in patients with CD.  My only complaint with this study was the associated editorial on pages 8-10, titled “The Holy Grail, or Only Half Way There?”  There are too many medical advances compared to ‘the holy grail’ and, in my opinion, this shouldn’t be one of them.

Zitomersky NL et al. Inflamm Bowel Dis 2015; 21: 307-14.  In this study the authors examine the relationship between the development of antibodies to infliximab (ATI) and the risk of surgery in a cross-sectional cohort of pediatric and young adult patients.  Not surprisingly, development of ATI, which was noted in 20% of cohort, correlated with reductions in infliximab levels and higher risk of surgery.  Interestingly, prior (but not current) immunomodulator therapy was associated with lower antibody levels (P=0.007).  Perhaps, “step-up” therapy may lower the risk of ATI. (This was a point noted by James Markowitz in a previous post: More NASPGHAN Meeting Notes: IBD Hot Topics | gutsandgrowth)

Rogler G, Vavricka S. Inflamm Bowel Dis 2015; 21: 400-08. This review article discusses the exposome in IBD.  Exposures include air pollution, diet, drugs, infections, water pollution, food additives, and smoking.  These exposures influence the gut microbiome and genetic susceptibility. “Only environmental influences…explain the rising incidence in IBD worldwide. The investigation of the exposome…is an enormous challenge…[but] of crucial importance.” (Related blog post: What do you know about the “exposome”? | gutsandgrowth)

Kalmon RS. Inflamm Bowel Dis 2015; 21: 428-35. Review article provides information when there is a prior personal or family history of malignancy (=avoid thiopurines).  Figure 2 is a suggested algorithm for those with IBD and a previous diagnosis of cancer.

  • In those in which the cancer is adequately controlled, the recommendations indicate that if it has been more than 2 years since completion of therapy to use a ‘step-up’ management and favor methotrexate over thiopurines
  • In those with less than 2 years since completion of cancer treatment and not responsive to 5-ASAs/antibiotics, then “consider monotherapy with biologic agents.”
  • In those still receiving chemotherapy, the authors suggest “hold immunosuppression and follow course of IBD.  If IBD not well controlled despite chemotherapy, 5-ASAs and antibiotics, treat flares with steroids, then consider biologic agents.”

An Oral Oligonucleotide in the Crohn’s Treatment Pipeline & Smart Patients

Posted on by

The preliminary data are in from a phase II study regarding Mongerson, a oral pill for Crohn’s disease.

Here’s the link: Oral oligonucledotide shows efficacy, safety in Crohn’s

Here’s an excerpt from GI & Hepatology News:

Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients…

Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.

Oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9).

From ImproveCareNow — Smart Patients Online Community -may be helpful resource for families:

There are many social networks and online communities for IBD, but we have chosen to partner with the Smart Patients team because their custom-built, disease-specific forums offer a truly safe, warm and engaging experience for users. Smart Patients also offers conversation tagging, and clearly defined community norms, which means community members are highly likely to find the answers they need and highly unlikely to be trolled. And because the conversations are arranged using tags and completely searchable, you can always find what you’re looking for.

The Smart Patients team and ImproveCareNow have partnered to create an online IBD community that is supportive and also powerful. The Smart Patients IBDcommunity has the power to improve health and health care systems through patient and family peer-to-peer learning.

 

Increased Narcotic Usage in Pediatric Patients with IBD

Posted on by

A summary from the AGA Journals Blog of a recent article highlights the increased use of chronic narcotics, not related to surgery, in pediatric patients with IBD.

Here’s a link:  Chronic Use of Narcotics in Children with IBD and here’s an excerpt:

Jessie P. Buckley et al used data from a large insurance claims database, collected from 2010 through 2011, to compare the prescription narcotic use among children (younger than 18 years old) with and without IBD who were not undergoing surgery. Buckley et al also searched for factors associated with narcotic treatment of pediatric patients with IBD.

Of 4344 children with IBD during the study period, 63% had Crohn’s disease, and 37% had ulcerative colitis.

Buckley et al found that 5.6% among children with IBD vs 2.3% in the general population received chronic narcotic therapy. Associations between IBD and narcotic use revealed a particularly high burden among children with concomitant anxiety or depression.

Cover of Clinical Gastroenterology & Hepatology

Cover of Clinical Gastroenterology & Hepatology –The pills look cool but wrong age depicted

Gut Microbiome, Crohn’s Disease and Effect of Diet

Posted on by

At this past year’s NASPGHAN conference, Bob Baldassano indicated that a low-residue diet probably does not makes sense for the majority of patients with Crohn’s disease because it would not promote a ‘healthy’ gut microbiome.  Another article (Walter SS, Quiros A, et al. SOJ Microbiol Infect Dis 2014; 2: 1-13) supporting this argument has been published. (Thanks to Ben Gold for giving me this reference.)

In this study, the authors examined the gut microbiome from two healthy volunteers and compared them to six patients with Crohn’s disease (CD) (ages 16-50).  The CD cohort were in clinical remission and were not receiving probiotics.  Subjects were randomized to either a low-residue diet (LRD) or a specific carbohydrate diet (SCD).

Besides having some cool figures to explain their results, the key points:

  • The complexity of the gut microbiome was lower in IBD patients compared to healthy controls
  • Bacteroides fragilis was increased in fecal samples of IBD positive patients
  • There was a temporal response of gut microbiome to SCD with increased microbial diversity while the LRD diet was associated with a reduced diversity of the microbiome in patients with CD

While the number of patients participating in this study are low, the affects of these diets can still be measured due to the trillions of microbes in the gut microbiome.

Also noted: Church PC, Turner D, et al. Aliment Phamacol There 2015; 41: 153-66. “Systematic review with meta-analysis: magnetic resonance enterography for the detection of inflammation and intestinal damage in Crohn’s disease.”

How the gut micro biome may affect other diseases including Multiple Sclerosis: Study Hints Gut Microbiome Plays a Role in Multiple Sclerosis (Link to Gastroenterology & Endoscopy News)

Related blog posts:

From NASPGHAN:  Introducing New Website for Teens with Inflammatory Bowel Diseases: JustLikeMeIBD.org  PRESS RELEASE

New York, NY- January 20, 2015 – The number of inflammatory bowel disease (IBD) patients in the U.S. has now increased to an estimated 1.6 million, with approximately 5 percent of that patient population under the age of 18. In response to the growing number of kids with IBD, the Crohn’s & Colitis Foundation of America (CCFA) along with the NASPGHAN Foundation for Children’s Digestive Health and Nutrition, has launched a new website called “Just Like Me” for teenagers with Crohn’s disease and ulcerative colitis.

The interactive site will feature stories and videos from teens with IBD as well as information on school, dating, stress, diet, and research.

 

 

What We Know Now: Therapeutic Drug Monitoring for Inflammatory Bowel Disease

Posted on by

This blog has discussed the utility of obtaining drug levels for both biologic agents and thiopurines.  A recent article (Inflamm Bowel Dis 2015; 21: 182-97) provides a concise up-to-date review.

Here are the key points:

  • Primary nonresponse to anti-TNF therapy (PNR) “is most commonly defined as lack of improvement of clinical signs and symptoms after the induction phase leading to discontinuation of the drug.”
  • “We think that patients who respond but fail to achieve remission…are likely almost all due to insufficient drug.”
  • Table 2 provides a list of predicting factors, both negative and positive, for PNR.  This list includes genetic mutations (e.g.. IL23R, NOD2/CARD15 variant), mucosal gene expression, clinical factors (e.g. young age, isolated colitis, smoking, nonstricturing disease, concomitant immunomodulators) and serologic (eg. CRP, hemoglobin, and presence of pANCA).
  • Patients with PNR to a TNF antagonist, “despite therapeutic concentrations of drug and no anti-drug antibodies (ADA), would likely benefit from a switch to an alternative drug with a different mechanism of action.”
  • “Patients with a high baseline inflammatory load…and increased clearance of drug because of a high turnover would likely benefit from higher induction doses.”  This hypothesis has been proven in rheumatoid arthritis patients in which patients with high TNF concentrations had a clinical response to 10 mg/kg that was “significantly better than the response to 3 and 6 mg/kg of infliximab.”
  • Patients (with ADA) with an “early immunogenic response against the TNF antagonist are unlikely to respond to dose escalation and thus should be switched to another TNF antagonist, and it should be considered to give higher induction doses in combination with an IMM [immunomodulator] to reduce the risk of immunogenicity.”

Take-home message: New definition of primary nonresponse to anti-TNF agent: “a lack of improvement of objectively assessed signs of active inflammation at baseline, after the induction phase despite the presence of adequate concentrations of drug and the absence of anti drug antibodies.”

Also noted: “Surgical management of ulcerative colitis in the era of biologicals” Inflamm Bowel Dis 2015; 21: 208-10. Key point: “Sacrificing the non responsive diseased colon is an underused or unnecessarily delayed chance to normalize ..health and life.”  “Deconditioning of patient with unreasonably long escalations of ineffective medications adds to the morbidity of surgical intervention.”

“Automimmune Features are Associated with Chronic Antibiotic-refractory Pouchitis”Inflamm Bowel Dis 2015; 21: 110-20. Key point: “Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors” for chronic antibiotic-refractory pouchitis.”

Update on MOC (recent blog:Resistance to Maintenance of Certification | gutsandgrowth) American Board of Internal Medicine “We Got It Wrong” “We launched programs that weren’t ready and we didn’t deliver an MOC program that physicians found meaningful. We want to change that.”

Related blog posts:

IBD Update January 2015 (Part 1)

Posted on by

1. From the recent Advances in IBD Conference, Healio Gastroenterology reports on Dr. Baldassano’s update on PLEASE study which examined enteral nutrition in comparison to anti-TNF therapy.  Here’s the link: Enteral Nutrition Outcomes (Thanks to Kipp Ellsworth for this reference)

Here’s an excerpt:

Citing the findings from the Pediatric Longitudinal Study of Semi-Elemental Diet and Stool Microbiome (PLEASE), Baldassano demonstrated that greater mucosal healing was achieved in CD patients on exclusive enteral nutrition compared with partial enteral nutrition therapy. In this prospective cohort study, 38 children received enteral therapy with defined formula diet and 52 controls received anti-TNF-alpha therapy. The enteral nutrition group was further stratified to evaluate mucosal healing on a more restrictive diet; one subgroup received 80% to 90% of total caloric needs from enteral therapy, of which 14% achieved induction of remission at 8 weeks, the other subgroup received 90% to 100% of total caloric needs from enteral therapy, of which 45% achieved remission, and 62% of controls achieved remission.

2. NEJM 2014; 371: 2418-27. This is a case report of a 9-year-old with Crohn’s Disease and pulmonary nodules.  This report serves as a useful review.

3. Standardized use of fecal calprotectin (here’s the link -from KT Park’s Twitter feed):

Fecal calprotectin -use for identifying IBD and for identifying relapse risk

4. Inflamm Bowel Dis 2014; 20: 2247-59. Study examined factors associated with infliximab clearance.  Higher clearance noted with low albumin, high body weight, and the presence of antibodies to infliximab (ATI).  The authors note that higher concentrations with dose escalation are more likely when the dose interval was shortened than by increasing the administered dose.

5. Inflamm Bowel Dis 2014; 20: 2260-65. “Natural History of Perianal Crohn’s Disease After Fecal Diversion.”  Despite greater use of biologics, only 15 of 49 patients reestablished intestinal continuity between 2000-2011.  In this group of 15, only 5 remained reconnected and 3 of these 5 patients had procedures to control sepsis.  The likelihood of sustained intestinal continuity remains low in patients who have required a diverting procedure.

Related blog posts:

Sandy Springs, Georgia

Sandy Springs, Georgia