Category Archives: Pediatric Gastroenterology Intestinal Disorder

Anti-TNF Agents in Pediatrics Have NOT Been Shown to Cause Lymphoma

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This blog title is supported by a recent publication (Clinical Gastroenterology and Hepatology: http://dx.doi.org/10.1016/j.cgh.2014.01.021)

Here’s the abstract -(I emphasize a key point with bold) or check out the link above:

Background & Aims

Many physicians hesitate to recommend anti–tumor necrosis factor (TNF) therapy for pediatric patients with inflammatory bowel disease (IBD) because of concerns about risk of infection and cancer. We performed a systematic review to quantify the incidence of serious infection, lymphoma, and death among pediatric patients with IBD who received anti-TNF therapy. These values were compared with those expected from other treatments, from adults with IBD, and from the general pediatric population.

Methods

We searched MEDLINE, EMBASE, the Cochrane Collaboration, and Web of Knowledge for studies of infliximab therapy for children with ulcerative colitis or Crohn’s disease, or adalimumab therapy for children with Crohn’s disease. Standardized incidence ratios (SIRs) were calculated, comparing rates of infection and cancer among pediatric patients exposed to anti-TNF agents vs expected rates from pediatric patients not exposed to anti-TNF therapies or adult patients exposed to anti-TNF agents. Our analysis included 5528 patients with 9516 patient-years of follow-up evaluation (PYF).

Results

The rate of serious infections among pediatric patients treated with anti-TNF agents (352/10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR, 1.06; 95% confidence interval [CI], 0.83–1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR, 0.48; 95% CI, 0.40–0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR, 0.54; 95% CI, 0.43–0.67). Five treatment-related deaths occurred (4 from sepsis and 1 from arrhythmia). Two patients developed lymphoma (2.1/10,000 PYF). This value was similar to the expected rate of lymphoid neoplasia in the entire pediatric population (5.8/100,000 PYF; SIR, 3.5; 95% CI, 0.35–19.6), and lower than the population of pediatric patients receiving thiopurine monotherapy (4.5/10,000 PYF; SIR, 0.47; 95% CI, 0.03–6.44), and among adults treated with anti-TNF agents (6.1/10,000 PYF; SIR, 0.34; 95% CI, 0.04–1.51).

Conclusions

Based on a systematic review, the risk of lymphoma was no greater among children with IBD who received anti-TNF therapy than those treated with other IBD therapies or adults treated with anti-TNF agents. The rate of serious infection was significantly lower among pediatric patients with IBD treated with anti-TNF agents than those treated with steroids, or adults with IBD who received anti-TNF therapy.

My take: This study shows that the concern for malignancy with anti-TNF agents (monotherapy) is often disproportionate to the true risk.  At the same time, much longer followup will be needed to assess the benefit and harm of these agents over decades.

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Celiac Disease Risk -TEDDY Study

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“The Environmental Determinants of Diabetes in the Young (TEDDY) is a multinational study that follows children at high genetic risk for type 1 diabetes, with the development of celiac disease as a secondary outcome.”  A recent publication provides excellent data with regard to the longitudinal risk of developing celiac disease (CD) (NEJM 2014; 371: 42-9).

Methods: 424,788 newborns were screened for at-risk HLA genotypes (from 2004 to 2010) in four countries (U.S, Finland, Germany, and Sweden).  21,589 had one of nine HLA genotypes of interest to the investigators –>8677 infants were enrolled in the study; 6403 of this group had one of the four HLA genotypes reported in this study:

  1. DR3-DQ2 homozygotes
  2. DR3-DQ2/DR4-DQ8
  3. DR4-DQ8 homozygotes
  4. DR4-DQ8/DR8-DQ4

Median follow-up: 60 months

Definitions for study:

  • Celiac autoimmunity: presence of tTG antibodies on two consecutive tests at least 3 months apart
  • Celiac disease: CD diagnosis based on biopsy (Marsh 2 or higher) or persistently high tTG (≥100 units) on at least two tests at least 3 months apart

Key findings:

  • Overall 786 children developed celiac autoimmunity (12%) and 291 had confirmed CD.
  • Children with DR3-DQ2 homozygosity had more than 5 times the risk of CD than the lowest-risk groups; in addition, the risk was 2.5 times more than the risk for a heterozygote (single DR3-DQ2) haplotype.
  • By 5 years of age, celiac autoimmunity developed in 26% and 12% respectively among children with DR3-DQ2 homozygosity  and in 11% and 3% of those children with DR3-DQ2 heterozygosity.
  • Residence in Sweden increased risk for CD with hazard ratio of 1.9.  The fact that residents with same genetic haplotypes had increased risk suggests that an environmental factor is playing a role.  It was noted that these children were given gluten-containing cereals at the earliest age.
  • CD was more common in females with HR of 2.16 (P<0.001) and in those with family history of CD HR 2.95 (P<0.001)

Take-home message: This prospective TEDDY study is providing useful information about how likely an individual with a genetic predisposition will develop CD and how quickly this develops.

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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.”

No Habla Appendicitis

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Before today’s blog, I wanted to state that our physicians now can treat Clostridium difficile with fecal microbiota transplant (would have been more relevant to yesterday’s blog: “Gut Microbiome”) :

GI Care for Kids is one of the few places in the region to offer this capability for children (thanks to Jeff Lewis for working to navigate the logistics/regulatory burdens).

Today’s blog: Though physicians make efforts to combat language barriers with translators, the personal connection between physicians and patients is undoubtedly weakened in those with limited English proficiency LEP).  Recently, one of my emergency room colleagues explained that he had ordered a CT scan on a young man in part due to his hispanic ethnicity and concern that this would lead him to overlook a diagnosis of appendicitis.  According to a recent study, my emergency room colleague was right –hispanic ethnicity and language barriers increased the risk for appendiceal perforation (J Pediatr 2014; 164: 1286-91).

The researchers performed a secondary analysis of a prospective, cross-sectional, multi center study of children aged 3-18 years who presented with abdominal pain/possible appendicitis (2009-2010) at 10 tertiary care pediatric emergency departments in the U.S.

Results:

  • Of the 2590 patients enrolled, 1001 (38%) had appendicitis.
  • Hispanics with LEP had an odds ratio of 1.44 of having appendiceal perforation.  In addition, these patients were less likely to undergo advanced imaging (OR 0.64)

Bottomline: Patients/families who speak English are more likely to communicate the severity of their medical problem.  Those with limited English proficiency are at increased risk for complications and this extends beyond perforation with appendicitis.

Related blog post: How much radiation from your CT scanner? | gutsandgrowth

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.

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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.