Tag Archives: Crohn’s disease

More Data on Early-Onset Pediatric Inflammatory Bowel Disease

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In 2009, a large prospective database involving Italian Pediatric Gastroenterologists was established.  A recent study describes the classification (Paris) and phenotype of early-onset pediatric inflammatory bowel disease (EO-IBD) (Inflamm Bowel Dis 2014; 20: 597-605).

In 506 consecutive patients, 224 had Crohn’s disease (CD), 245 ulcerative colitis (UC) and 37 IBD-unclassified.

Key findings:

  • 11% were aged 0-5 years, 39% 6-11 years, 50% were 12-18 years.
  • UC was more frequently diagnosed in 0-11 years of age whereas as CD was more common in 12-18 years.
  • EO-Crohn’s showed more frequent isolated colonic disease
  • EO-UC noted 62% with pancolitis compared with 38% in 6-11 years and 31% in 12-18 year group

Take-home message: The authors conclude that “EO-IBD exhibits an extensive phenotype and benefit from aggressive treatment strategies, although surgical risk is similar to later-onset disease. A family history for IBD is not common in EO disease.”

New Biomarker for Crohn’s Disease (Plus Two)

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A recent study identifies a new biomarker for Crohn’s disease (CD) (Inflamm Bowel Dis 2014; 20: 1037-48).

The authors examined a cohort of 208 newly diagnosed pediatric CD and 43 non-IBD controls for ileal/rectal expression of FcγRIA mRNA.  In addition, in a smaller cohort of 26 newly diagnosed CD patients, 83 established CD patients and 30 non-IBD controls the authors measured peripheral blood polymorphonuclear neutrophil (PMN) CD64 index.

Key findings:

  • Ileal FcγRIA mRNA expression was significantly elevated in CD compared with non-IBD controls
  • PMN CD64 was significantly elevated in CD compared with non-IBD controls and correlated with mucosal injury as measured by the simple endoscopic score for CD.
  • Patients in clinical remission with a PMN CD64 <1 had a high rate of sustained remission (95%) whereas only 56% had sustained remission if PMN CD64 was >1.

Take-home point: This study shows in pediatrics, as in adults IBD patients, that PMN CD64 index is associated with mucosal inflammation; high levels are associated with clinical relapse.  Serum biomarkers are likely to complement stool biomarkers like fecal calprotectin.

One other point the authors make: “studies have found that 57% to 59% of CD have concurrent IBS.”  Thus, there is a need for biomarkers to distinguish whether patients with clinical symptoms are experiencing an inflammatory relapse.

Related blog post: Calprotectin: Part of diagnostic algorithm for IBD …

Two other studies in same issue:

“Alterations in the Intestinal Microbiome (Dysbiosis) as a Predictor of Relapse After Infliximab Withdrawal in Crohn’s disease” pages 978-86.  N=33 CD patients. Key finding: “CD-associated dysbiosis, characterized by a decrease in Firmicutes, correlates with the time-to-relapse after infliximab withdrawal.”

“Tissue Studies in Screened First-degree Relatives Reveal a Distinct Crohn’s Disease Phenotype” pages 1049-56. N=38 asymptomatic relatives. Key finding: based on histologic scoring 61% were normal, 26% had minor lesions, and 13% had evidence of active disease. This study indicates that screening relatives may identify a subset with early biologic disease.

What I Didn’t Know About Vitamin B12 and Crohn’s Disease

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This month I learned from a recent publication (Inflamm Bowel Dis 2014; 20: 1120-23) that Crohn’s disease without ileal resection does not seem to increase the risk of Vitamin B12 (cobalamin) deficiency.  To reach this conclusion, the authors did an extensive literature search and identified 42 relevant articles with 3732 IBD patients.

Key findings:

  • Ileal resections >30 cm were associated with B12 deficiency.
  • Resections <20 cm were not associated with B12 deficiency; whereas the findings were inconsistent when resections were 20-30 cm.

Take home message:  Crohn’s disease, regardless of disease location, did not increase the risk of B12 deficiency in the absence of ileal resections >20 cm.

Related blog posts:

Another Reason for Inflammatory Bowel Disease Patients to Take Vitamin D

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According to a recent study (Clin Gastroenterol Hepatol 2014; 12: 821-27), “in a large mulit-institutional IBD cohort, a low plasma level of 25(OH)D was associated with an increased risk of cancer, especially colorectal cancer.”  The study reviewed data from 2809 patients who vitamin D levels check (total cohort 11,028 persons with IBD); nearly a third had vitamin [25(OH)D] levels less than 20 ng/mL.  The median followup was 11 years.  During this period, 7% developed cancer (excluding nonmelanoma skin cancer).  Vitamin D deficiency was associated with an adjusted odds ratio of 1.82 of increased cancer risk.

Like so many other studies, this study is another reason for vitamin D manufacturers to feel pretty good.  The associated editorial provides some helpful context (pgs 828-30). The evidence regarding vitamin D dates back to at least 1980 when there was an observed higher incidence of colorectal cancer (CRC) mortality in regions with low solar radiation levels.  Similar findings were noted with breast cancer.

There is biologic plausibility to the importance of vitamin D with regard to cancer as it is involved in “cell signaling, cell proliferation, cell apoptosis, cell adhesion, angiogenesis and it can up-regulate tumor suppressor genes.” A number of reviews have shown an inverse relationship to vitamin D levels and CRC risk.

The editorial points out a number of potential flaws.  “For instance, those who had vitamin D measured may have been among the more ill patients…they may have been the most malnourished.”  “Whether patients had concurrent …primary sclerosing cholangitis was also omitted.”

Take-home message (from editorial): “Although the authors have identified an association, for several reasons it may be spurious…the jury is still out as to what impact maintaining normal vitamin D levels may have on reducing inflammation and modulating cancer risk in chronic inflammatory diseases. However, it is healthful to have adequate vitamin D.” In Manitoba, the authors recommend that all of their patients receive vitamin D supplementation.  In areas with more sun, checking levels may be worthwhile.

Related posts:

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.

Treating to Target

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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 post: EXTEND & 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.

Specific Carbohydrate Diet in Children -Ahead of Print

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Here is a link, bit.ly/1xb1kk8, (from JPGN) and the abstract to an article on the Specific Carbohydrate Diet in Children.  This study shows clinical improvement and mucosal healing, confirmed by capsule endoscopy, in response to the specific carbohydrate diet (SCN). Congratulations to my colleagues/partners from GI Care for Kids who published this study in JPGN:

Objective: To prospectively evaluate clinical and mucosal responses to the specific carbohydrate diet (SCD) in children with Crohn’s disease (CD).

Methods: Eligible patients with active CD (Pediatric Crohn’s Disease Activity Index, PCDAI >= 15) underwent a patency capsule and if passed intact, capsule endoscopy (CE) was performed. Patients were monitored on SCD for 52 weeks while maintaining all prescribed medications. Demographic, dietary and clinical information, PCDAI, Harvey Bradshaw (HB) and Lewis score (LS) were collected at 0, 12 and 52 weeks. CE’s were evaluated by an experienced reader blinded to patient clinical information and timing.

Results: Sixteen patients were screened; 10 enrolled; and 9 completed the initial 12 week trial; receiving 85 % of estimated caloric needs prior to, and 101%, on the SCD. HB significantly decreased from 3.3 + 2.0 to 0.6 + 1.3 (p = 0.007) as did PCDAI (21.1 + 5.9 to 7.8 + 7.1; p = 0.011). LS declined significantly from 2153 + 732 to 960 + 433 (p = 0.012). Seven patients continued the SCD to 52 weeks with HB (0.1 + 0.4) and PCDAI (5.4 + 5.5) remaining improved (p = 0.016 and 0.027 compared to baseline) with mean LS at 1046 + 372 and 2 patients showing sustained mucosal healing.

Impressions: Clinical and mucosal improvements were seen in children with CD using the SCD over 12 and 52 weeks. Additionally, CE can monitor mucosal improvement in treatment trials for pediatric CD. Further studies are critically needed to understand the mechanisms underlying SCD’s effectiveness in children with CD.

Related Blog Posts:

Infliximab Compared to Adalimumab -Which is Better?

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Pharmaceutical companies are not motivated to provide a definitive answer on the title question.  A recent study (Clin Gastroenterol Hepatol 2014; 12: 811-17) states that “head-to-head clinical trials of anti-TNF therapies are unlikely to ever be undertaken because of the extreme cost to conduct such studies and the financial risk that such trials would entail for the manufacturers.”  The two most popular biologics, infliximab (IFX) and adalimumab (ADA), for inflammatory bowel disease have been incredibly successful (Multi-billion dollar biologics | gutsandgrowth).

The current study is “one of the first to directly compare the effectiveness” of IFX and ADA for Crohn’s disease.  The authors retrospectively examined a U.S. Medicare data cohort from 2006-2010 and identified new users with 1459 IFX and 871 ADA patients.  While 94% of Medicare enrollees are >65 years, this study had a range of patient ages due to those who received Medicare due to disability.  In fact, in the ADA group, ~60% were between 30-60 years and in the IFX group, ~44% were in this age group.

Key result:

  • After 26 weeks of treatment, 49% of patients receiving IFX remained on drug compared with 47% of those receiving ADA.
  • Fewer patients with IFX underwent surgery (5.5 vs 6.9 surgeries per 100 person-years) but this did not reach statistical significance.
  • Rates of hospitalization did not differ among the two groups

While persistence is an imperfect measure of effectiveness, the fact that surgeries and hospitalizations were similar indicates that the medications are likely to have similar clinical effectiveness, at least in this population.  Data on mucosal healing, more direct measures of effectiveness, and longer followup certainly would strengthen this conclusion.

Marriage, Divorce and Separation with Anti-TNF Therapy

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This review article (Inflamm Bowel Dis 2014; 20: 757-66) examines the question of whether and when anti-tumor necrosis factor (anti-TNF) agents can be stopped in Crohn’s disease (CD) patients in remission.  This topic is particularly helpful since this comes up frequently in clinical practice.

As recently as a few years ago, one expert advised me that starting an anti-TNF agent (like infliximab or adalimumab) was like getting married.  Once you committed, you stayed in that relationship indefinitely.  Of course, it is well-known that individuals get divorced.  In medical terms, I guess that would be the equivalent of developing antibodies to the anti-TNF agent or other adverse reactions.  Switching from one anti-TNF to another would be equivalent to marital infidelity.

So what does this review article say about all of this?  The article examines nine studies with a little more than 500 patients.  “Current evidence suggests that a group of CD patients, possibly 30% to 40% in clinical remission while on IM (immunomodulators) and infliximab can stop the latter and maintain clinical remission for a relatively long interval.  It seems that, if followed long enough, virtually all patients (including those on IM) will eventually develop clinical recurrence.”

If tempted to separate but not divorce anti-TNF therapy, the authors recommend, in addition to clinical remission, “normal colonoscopy (and/or normal surrogate markers of disease activity) should be adopted as a criterion when stopping therapy and during follow-up….As of today, many authors do not recommend to routinely stop anti-TNF agents in patients responding to this therapy and in the absence of other issues.  Others propose to stop them after a minimum of 2 years of clinical and endoscopic remission or longer if only clinical remission can be documented…

If costs or other issues are present, we suggest to cautiously stop anti-TNF agents only in patients on combination therapy with profound (clinical, biochemical, and endoscopic) and long lasting (>1 year) remission and continuing the IM.  Such patients should be closely followed by serial determinations of fecal calprotectin and inflammatory indices, and the medication immediately restarted in the presence of a flare. When in doubt, colonoscopy should be performed.”

Take-home message: Most patients are better off staying married to their anti-TNF therapy.

Also noted: Inflamm Bowel Dis 2014; 20: 742-56.  Clinical Utility of Fecal Biomarkers for the Diagnosis and Management of Inflammatory Bowel Disease.  This is a useful review with 103 references.

Superiority of Anti-TNF Therapy (Part 2)

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A recent blog (Superiority of Anti-TNF Therapy in Children | gutsandgrowth) described a recent article showing that kids treated with anti-TNF therapy at the time of diagnosis had improved outcomes compared to children who were treated with other medications.  In this day of multimedia, there is a video explaining the study which may be helpful for families and clinicians alike –here’s the link:  Dr. Michael Stephens discusses the research findings: .

An excerpt from the explanation with the video:

The current research study looks at outcomes and compares three different types of treatments. The first group receives anti-TNF therapy. The second group received immune modulating therapy. The third group received no treatment within the first three months. This study was an observational study and the choice of treatment was at the discretion of the physician. In order to correct for this factor, a statistical technique was used. Patients with similar characteristics were paired within the three groups . The results showed that patients who received the anti-TNF therapy had an improved outcome, such as a higher remission rate and some indications of improved growth, at one year. All three groups had improvements in weight and body mass index but only the anti-TNF group had improvements in linear growth.

How Long Will Infliximab Work?

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Given the limited therapeutic options, the question of infliximab (IFX) durability in pediatrics is quite important.  One center has published its 10-year retrospective experience (Inflamm Bowel Dis 2014; 20: 606-13).

Inclusion criteria for the 188 patients included initiating IFX prior to age 21 years and patients who had a minimum of 1-year followup.

Demographics: Median age at diagnosis was 11 years for Crohn’s disease (CD) and 12 years for ulcerative colitis (UC). Indication for IFX due to steroid refractory disease was present in 42% of UC patients compared with 14% of CD patients.  Monotherapy was more common in UC patients, 65%, compared to 35% of CD patients.

Methotrexate was administered in 69 (44%) of CD patients at time of IFX with the majority (n=56) as oral treatment (low-dose <10 mg every week).  In addition, MTX was initiated after IFX induction in another 38 (24%).  Only 36 (23%) remained on IFX mono therapy throughout the duration of treatment in CD patients.

Key findings:

  • 88% of CD patients remained on IFX at 1 year, 80% at 2 years, and 72% at 5 years.
  • Only 7 of 157 CD patients were primary nonresponders.
  • 65 of 89 CD patients who did not achieve a sustained durable remission underwent dose escalation. 40 of 65 responded to dose escalation.
  • Of those who lost response to IFX, the majority were transitioned to adalimumab (ADA) and among this group, 82% remained on ADA treatment at last followup.
  • Among UC patients (n=31), 9 were primary nonresponders. At last followup, 41% (9) remained in a durable sustained response at last followup.
  • While the authors used MTX due to favorable effects on IFX pharmacokinetics (Arthritis Rheum 1998; 41: 1552-63), there was “not a significant difference in IFX durability or efficacy between this group and patients with CD on IFX monotherapy”
  • Availability of antibodies to infliximab (ATIs) and IFX trough levels were only assessed in a subset.  However, “we did see a significant difference in those that responded to dose intensification when ATIs were undetectable.”

Bottomline: The majority of CD patients can remain on IFX for >5 years.  Among those who lose response, adalimumab was a durable alternative.  A much lower durable response was evident with the subset of patients with UC.

Related blog post:

Also noted:

Inflamm Bowel Dis 2014; 20: 614-21. In this study of 78 youth with IBD, depressive symptoms warranting additional evaluation were present in 13% which was lower than in the community comparison group.  Disease severity was noted to be inactive in 63% and mild in another 18%.

Inflamm Bowel Dis 2014; 20: 495-501. This study showed that 25 children exposed to anti-TNFs prenatally for maternal IBD seemed to show good safety.  Immunologic investigation undertaken in 17 of the children was normal.  No control group limited the ability to determine if increased infections were present.

And, here’s a link to Mar-April Circle Newsletter from ImproveCareNow -topics include group medical appointments, parent working group, dieting with IBD, and includes link to self management handbook.