Category Archives: Pediatric Gastroenterology Intestinal Disorder

Monotherapy or Combination Therapy with Adalimumab?

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Since the introduction of anti-tumor necrosis factor therapies (anti-TNFs), the benefit of using these agents in combination with immunomodulators or as monotherapy has shifted a few times based on the latest studies.  The most influential recent studies had been SONIC and UC Success which indicated that combination therapy for Crohn’s and Ulcerative Colitis, respectively, was more effective and without more adverse effects than monotherapy. A recent study may create some additional uncertainty in this line of thought (Gastroenterol 2014; 146: 941-49).

The author performed a pooled analysis of data from 1594 patients with Crohn’s disease (CD).  Studies included CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE.  In total, these studies provided 3050 patient-years of exposure. For individual patients, the median followup period was 1.5 years.

Key findings:

  • “Those patients receiving combination therapy had an increased risk of malignancy (other than non melanoma skin cancer [NMSC])” with a relative risk of 2.82.
  • Adalimumab monotherapy was not associated with an increased risk of malignancy other than NMSC
  • Combination therapy was associated with relative risk of NMSC of 3.46

In the discussion, the authors state “the data suggest that the increased risk likely is attributed to the immunomodulator therapy.”

A related editorial (884-86) helps dissect the articles strengths/limitations as well as implications.

Strengths:

  • the study captured data from randomized controlled trials.

Limitations:

  • median followup of 1.5 years –may not be long enough to detect a malignancy signal from anti-TNF therapy
  • unclear how many adalimumab monotherapy patients had been on a thiopurine previously

Implications:

  • “Even if Osterman et al are correct, is this information clinically meaningful enough to swing the mono-combo pendulum back to mono therapy?”
  • “The clinical relevance of the increase in absolute cancer risk from 4 in 1000 with adalimumab monotherapy to 10 in 1000 with combination therapy for cancers other than NMSC is unclear”
  • This difference of 6 in 1000 “translates to 167 patients who are treated before seeing 1 excess cancer”
  • “Most (if not all) of the cancer risk is associated with thiopurine exposure…induction therapy is more effective with combination treatment–>”we propose that we should induce patients into remission with combination therapy, and then consider withdrawing thiopurines at some point.“
  • “Consider treating younger males with thiopurines short term, or alternatively with methotrexate.”  Though the authors note that data from rheumatology brings some concern to methotrexate cancer risk (Semin Arthritis Rheum 2014; 43: 489-97). Source Article: Methotrexate Safety | gutsandgrowth
  • “Consider treating elderly patients with anti-TNF monotherapy to decrease their risk of serious infections”

Also noted: “Risk of Cancer in Patients with Inflammatory Bowel Diseases: A Nationwide Population-based Cohort Study with 30 Years of Follow-up Evaluation” (Clin Gastroenterol Hepatol 2014; 13: 265-73). n=13,756 patients with CD and 35,152 with UC. Key findings –among CD patients, the excess risk was largely due to extra-intestinal cancers such as hematological malignancies (SIR 1.9) and smoking-related malignancies (SIR 1.5).  Associations between UC and gastrointestinal/extraintestinal cancers were weaker (both SIRs were 1.1); the risk of gastrointestinal cancers decreased over the course of the study.

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Don’t Forget to Check Urine Sodium

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In patients with short bowel syndrome and excessive ostomy losses, salt depletion is associated with failure to thrive.  An easy way to screen for this is checking a “spot” urine sodium level; a urine sodium <10 mmol/L is too low.  While this has been recognized in infants for a long time, a recent case report shows that this can be an issue for older children (up to 19 years) as well (Nutr Clin Pract 2014 vol. 29 no. 397-401 -thanks to Kipp Ellsworth’s twitter feed for this reference & link: http://goo.gl/TkjKyd).

The authors conclusion: “We advise that patients of all ages with high stoma output have routine urine sodium levels checked, particularly in the setting of weight loss or poor gain. Furthermore, instances of TBSD [total body salt depletion] should be treated with sodium supplementation.”

Sticky Decisions with IBD Therapy – When an Infection or Malignancy Develops

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A recent review article provides advice for management of biologics and immunomodulators when an infection or malignancy develops (Inflamm Bowel Dis 2014; 20: 926-35).  Serious infections are noted in 3-5% of adults receiving either thiopurines or anti-tumor necrosis factor agents (anti-TNFs); less than 0.1% of adults develop treatment-related lymphoma.  The recommendations are provided in 5 separate tables.

Table 1 addresses the issue of bacterial infections.  For mild infections, the authors recommend that thiopurines (azathiopurine, 6-mercaptopurine) as well as anti-tumor necrosis factor agents (infliximab, adalimumab, certolizumab, golimumab) be continued.  Examples of these ‘mild’ infectious included E. coli UTI and strep pharyngitis.  For severe bacterial infections (eg. pneumococcal pneumonia), for both these therapies, the authors recommend: “stop, but may restart once treated.”  For bacterial opportunistic infections (eg. mycobacterium), for latent infections, “do not start until 2 to 4 wk INH” whereas for active infections, the authors recommend (for anti-TNFs) “stop, only restart after full treatment, and if IBD is severe.”

  • Table 2 addresses fungal infections.
  • Table 3 addresses viral infections (eg. CMV, EBV).  For EBV, the authors recommend stopping thiopurines and not restarting in male patients.
  • Table 4 addresses malignancy: solid tumors, hepatosplenic T-cell, EBV-associated lymphoma, and lymphoproliferative lymphoma.
  • Table 5 addresses skin cancers.

Towards the end of the review, the authors provide some context for the risks with thiopurines and anti-TNFs.  “The majority of side effects associated with thiopurines and anti-TNFs are mild, self-limited and reversible…the risk of a lymphoma developing on AZA/6-MP (4/10,000 patient-years) is comparable with the lifetime risk of dying from drowning (1/1112) or dying in a bicycle accident (1/5000).  The risk is much less than the risk of dying in an automobile accident (1/108).  Patients are willing to accept risks..if their disease is severe and the chance of a clinical response outweighs the risk.”

With regard to dual therapy, the authors note, “it has been our practice to lower the concomitant AZA/6-MP in patients on combination therapy with anti-TNF and then to stop the thiopurine in patients in deep remission for 3 years. However, this decision must be individualized, and for patients with severe, disabling disease, we generally do not alter treatment.”

Bottomline: This is a useful advice/handy reference for the sticky situation of managing IBD in the face of infections and malignancy.

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.

 

Connecting the Dots: Selenium and Keshan Disease

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With the recent concerns regard micronutrient deficiencies (see links below), I was intrigued with a recent article on Keshan Disease and how it was determined that the cause was selenium deficiency (NEJM 2014; 370: 1756-60).

Here’s the background:  “In 1958, Muth and colleagues demonstrated that the addition of selenium to the diet provides protection against the development of white muscle disease in sheep” (Science 1958; 128: 1090).  Prior to this, in 1935, there had been “an outbreak of rapidly progressive and fatal cardiomyopathy” in Keshan (northeastern China).  So, when the disease reappeared in the 1960s in the Sichuan and Yunnan provinces in southwestern China, at autopsy, heart tissue showed myocardial pallor.  “For this reason, Zheng concluded in 1962 that there were morphologic similarities between Keshan disease and white muscle disease.”  Subsequently, “oral selenium supplementation…virtually eliminated Keshan disease in areas where it was endemic.”

The referenced NEJM article goes on to discuss the mechanisms of action of selenium and its important role in preventing oxidant stress and injury through many selenoproteins.

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Are Biopsies Needed with a Normal-appearing Colonoscopy?

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“Colonoscopy in children routinely includes the practice of obtaining multiple biopsy samples even in the absence of gross mucosal abnormalities.”  This is the beginning of a recent report (JPGN 2014; 58: 773-78) which shows good agreement between endoscopic and histologic findings in a retrospective study of 390 colonoscopies.

Key findings:

  • “A known diagnosis of inflammatory bowel disease was a strong predictor of abnormal histology (OR 6.4 P<0.0001)”
  • 20 of 172 patients with a reportedly normal-appearing colonic mucosa had abnormal histology.  8 had a known diagnosis of IBD, 4 had symptoms/bloodwork highly suspicious for IBD, and another 3 were immunosuppressed.
  • The agreement rate (normal vs. abnormal) between pathologist and endoscopist was 84% with most of the disagreement when the endoscopist reported an abnormal finding whereas the pathologist reported normal histology.  This occurred in 11% of colonoscopies.

The authors “believe our data support the use of a combination of endoscopic appearance and evidence-based risk stratification to…reduce the number of biopsies obtained.”  “The symptom of abdominal pain as a primary indication for performing the procedure was an extremely strong negative predictor of histopathology. ”

Take-home message: If the colon appears normal and there is no prior evidence of IBD/along with reassuring laboratory studies, taking fewer biopsies is appropriate with colonoscopy in children.

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.  Endoscopy decisions should be determined by your 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.

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.

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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.

Gastric Emphysema -A Quick Pic

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A recent image (available online only N Engl J Med 2014; 370:e33) shows a clearcut case of gastric emphysema and the narrative explains the differential diagnosis:

“The differential diagnosis included infection, ischemia, and gastric-outlet obstruction due to volvulus, annular pancreas, intestinal malrotation, and duodenal hematoma or stenosis. Laparotomy revealed diffuse gastric and omental emphysema resulting from duodenal stenosis.”

ESPGHAN IBD Diagnostic Practice Recommendations -Revised Porto Criteria

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Recently ESPGHAN assembled an international group of European experts in pediatric inflammatory bowel disease (PIBD) to establish practice recommendations (JPGN 2014; 58: 795-806).  Their aim was “to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD.”

Before detailing some of their recommendations, I want to state my main criticism: these recommendations do not consider cost or cost-effectiveness. This is important since we do not live in a world where costs are irrelevant.

Some specific recommendations/observations:

1. “We recommend performing small bowel imaging in all suspected cases of IBD at diagnosis; this may be deferred in typical UC.”  In addition, all suspected cases of IBD should undergo esophagogastroduodenoscopy (EGD) and ileocolonoscopy.  “The diagnostic yield of an EGD to diagnose Crohn’s disease (CD) in patients with an otherwise normal workup [ileocolonoscopy/small bowel imaging] is ~7.5%. ”

2. The authors clarify the use of IBD-unclassified (IBD-U). “IBD-U should be …for patients with colitis and highly atypical findings.” Atypical findings for ulcerative colitis: include rectal sparing, and cecal patch (present in 2% of pediatric patients with left-sided colitis).  Table 3 suggests that if at least one “class 2” (rare feature) exists or at least 2 “class 3” (uncommon) feature exists, then labeling IBD-U is appropriate.

Rare (Class 2):

  • significant growth delay
  • histologic and gross sparing of rectum
  • transmural inflammation in the absence of severe colitis
  • duodenal or esophageal ulcers (not due to other causes)
  • multiple aphthous ulcerations in the stomach (not due to other causes)
  • positive ASCA in the presence of negative pANCA
  • mucosal inflammation more severe in proximal colon

Uncommon (Class 3):

  • severe scalloping of stomach or duodenum (not due to other causes)
  • focal chronic duodenitis (not due to other causes)
  • aphthous ulcerations in the colon

3. Crohn’s disease, according to Table 3, should be diagnosed with any of the following:

  • well-formed granulomas anywhere in the GI tract, remote from a ruptured crypt
  • deep serpentine ulcerations, cobblestoning or stenosis anywhere in the small bowel
  • fistulizing disease
  • ileal inflammation in the presence of normal cecum

4. “Normal blood tests do not exclude the diagnosis of IBD”… Fecal markers (eg. calprotectin) are “extremely sensitive in the detection of mucosal inflammation but are not specific for IBD.”

5.”Although small bowel imaging is encouraged in all of the patients with suspected IBD, it is essential in pediatric patients with CD, IBD-U, or atypical UC.”  Magnetic resonance enterography (MRE) is currently the imaging modality of choice in PIBD.  Wireless capsule endoscopy (WCE) is a “useful alternative.”  The authors advocate for imaging because it may “detect small intestinal involvement…and identify disease complications.”

6. Evaluation for primary immune deficiency should be performed in all cases of PIBD  diagnosed <2 years of age.

While the authors acknowledge that “clinical considerations may require taking a course of action that varies from these criteria,” nevertheless, they are likely to influence clinical practice.  My personal belief is that there are many situations in which small bowel imaging will not result in changes in clinical care.  Furthermore, many patients, especially younger patients, would require anesthesia in order to complete a MRE which is an added burden.  In addition, with the added emphasis on assessing response to therapy, one could envision that some patients would be better served with imaging after implementing treatment.

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Another Study Supporting Enteral Therapy for Crohn’s Disease

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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.

 

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Change the Name: “Functional” is Lousy

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A recent commentary explains why “functional” pain is such a lousy term (JAMA Pediatr. Published online June 02, 2014. doi:10.1001/jamapediatrics.2014.530 –thanks to Ben Gold for this reference).  In pediatric GI practice, functional gastrointestinal disorders (FGIDs) constitute a large part of clinical work.

The author, Neil Schechter from the Chronic Pain Program in Boston, makes several important observations:

  • “There is general dissatisfaction with the terminology.”  This stems from the fact that “in common parlance today, functional disorders are typically assumed to be a product of psychological distress.” Yet, parents/patients are “not ready to accept a strictly psychological explanation.”
  • The idea that functional pain is solely a psychological disturbance is inaccurate.  Though, anxiety and depression are common associated problems which often contribute to symptoms.  He states that “hyperexcitability” of the nervous system is “the core biological link and final common pathway for the creation of functional pain disorders.”
  • This category should be labeled dysfunctional pain.  “In effect, calling pain ‘functional’ is like calling disease, ‘ease.'”
  • These disorders frequently respond to centrally acting therapies including antidepressants, anticonvulsants, exercise, cognitive behavioral therapy, and acupuncture.
  • “The search for an appropriate term for these pain problems is far more than semantic…[a patient’s] understanding of their illness is clearly linked to their compliance with medical advice…it may stem their desire for additional costly investigation.”
  • Dr. Schechter proposes the term “primary pain disorder.”  “Unlike Shakespeare’s rose, functional pain would benefit from a new name.”

Take-home message: I wish I had written this commentary.  Explaining “functional” pain and “irritable bowel syndrome” are Sisyphean tasks.  Better nomenclature could ease the burden.  Join me in abandoning the use of the word “functional.”

In the same issue, an editorial on the “Role of Celiac Disease Screening for Children with Functional Gastrointestinal Disorders” (JAMA Pediatr. 2014;168(6):514-515. doi:10.1001/jamapediatrics.2013.5418) comments on a study (JAMA Pediatr. 2014; 168(6):555-60) in the same issue which reports a 4-fold higher prevalence of celiac disease among children who meet clinical criteria for irritable bowel syndrome.  The study reports the results from a cohort of 992 children identified with recurrent abdominal pain in a primary care setting.  In the editorial, the authors note:  “When grouped together, the prevalence rate of celiac disease among all children with FGIDs (IBS included) approaches 2%.  Celiac disease screening in this population would result in a positive tTG-IgA test result in 4%…However, 53% of all positive test results would be falsely elevated.”  As such the editorial advocates in favor of screening for celiac disease in children with IBS but not all FGIDs.

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