Infliximab Not Associated with Malignancy

Posted on March 23, 2017 by gutsandgrowth

JS Hyams et al. Gastroenterology http://dx.doi.org/10.1053/j.gastro.2017.02.004

Using the DEVELOP registry, a prospective study showed no increased risk of malignancy among 5766 pediatric participants with inflammatory bowel disease.

Link: Full Abstract

Immunosuppressive therapy for inflammatory bowel disease (IBD) in pediatric patients is thought to increase risk of malignancy and lymphoproliferative disorders, including hemophagocytic lymphohistiocytosis (HLH). We compared unadjusted incidence rates and of malignancy and HLH in pediatric patients with IBD exposed to infliximab compared with patients not exposed to biologics and calculated standardized incidence ratios (SIRs).

Methods

We collected and analyzed data from 5766 participants in a prospective study of long-term outcomes of pediatric patients with IBD (NCT00606346), from 2007 through 30 June 2016. Patients were 17 years old or younger and had Crohn’s disease, ulcerative colitis, or IBD unclassified with 24,543.0 patient-years of follow-up. We estimated incidence rates for malignancy and HLH as events/1000 patient-years of follow-up. We calculated age-, sex-, and race-adjusted SIRs, with 95% CIs, using the Surveillance, Epidemiology, and End Results Program (SEER) database.

Results

Thirteen of the 15 patients who developed a malignancy and all 5 of the patients who developed HLH had been exposed to thiopurine; 10 patients with malignancy patients had also been exposed to a biologic agent. Unadjusted incidence rates showed no increased risk of malignancy (0.46/1000 patient-years) or HLH (0.0/1000 patient-years) in patients exposed to infliximab as the only biologic vs those unexposed to biologics (malignancy: 1.12/1000 patient-years; HLH: 0.56/1000 patient-years). SIRs did not demonstrate an increased risk of malignancy among patients exposed to infliximab (SIR; 1.69; 95% CI, 0.46–4.32) vs patients not exposed to a biologic agent (SIR, 2.17; 95% CI, 0.59–5.56), even when patients were stratified by thiopurine exposure.

Conclusions

In determination of age-, sex- and race-adjusted SIRs using data from a large clinical trial and the SEER database, we found that infliximab exposure did not associate with increased risk of malignancy or HLH in pediatric patients with IBD. Thiopurine exposure is an important precedent event for the development of malignancy or HLH in pediatric patients with IBD.

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Turning Liquid into Gold: A Pharmaceutical Rumpelstiltskin Story

Posted on March 22, 2017 by gutsandgrowth

A recent letter to the editor (LA Probst, TR Welch. NEJM 2017; 376: 795-6) provides a sad tale of how well-intended legislation to promote safety and efficacy of pediatric liquid medications has led to both an increased number of liquid formulations approved by the FDA but with a much higher cost than previous extemporaneously compounded formulations.

The liquid version of lisinopril is priced 775 times the cost of the equivalent tablet. Other medications with high liquid to tablet cost ratios include enalapril (21 times), indomethacin (49 times), glycopyrrolate (14 times), and pyridostigmine (11 times).

The authors note that there are additional costs for developing/manufacturing these liquid formulations.

My take (borrowed from the authors): “there must be a better way to support the costs of developing the drug formulations that many children and some severely impaired adults desperately need.”

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Chattahoochee near Azalea drive

Pediatric NAFLD Guidelines 2017

Posted on March 21, 2017 by gutsandgrowth

The concise recommendations (M Vos et al. JPGN 2017; 64: 319-34) from the Expert Committee on NAFLD (ECON)/NASPGHAN provide helpful advice on this increasingly common disorder. Link to full text: NASPGHAN Clinical Practice Guideline for NAFLD

The recommendations are graded on strength of recommendation and quality of the evidence.

Some key points:

Use ALT as a screening tool (despite its imperfections). Persistently elevations (>2xULN) should be evaluated for liver disease, including NAFLD. (Norms: 22 U/L for girls, 26 U/L for boys). Values above 80 U/L “warrants increased clinical concern.”
Screening should be considered between ages 9 and 11 years for all obese children and for overweight children with additional risk factors.
Ultrasound and CT scans are NOT recommended.
Liver biopsy should be considered for the assessment of NAFLD in children who have increased risk of NASH and/or advanced fibrosis. This could include those with splenomegaly, AST/ALT>1, higher ALT (>80 U/L), panhypopituitarism, and type 2 diabetes.
Treatment: Lifestyle modifications recommended. No currently avaiable medications or supplements are recommended.
Look for & avoid comorbidities: dyslipidemias, hypertension, and diabetes. Assure vaccinations against Hep A/Hep B and counsel against binge drinking and against smoking.

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A Better Budesonide for Eosinophilic Esophagitis

Posted on March 20, 2017 by gutsandgrowth

A recent study (S Olivia et al. JPGN 2017; 64: 218-24) examines a preprepared viscous budesonide (PVB) for eosinophilic esophagitis (EoE).

The authors used higher doses than in previous studies: 1 mg twice a day if height <150 cm and 2 mg twice a day if height >150 cm. Treatment period was 12 weeks.

Key findings:

32 of 36 (89%) showed macroscopic remission at 12 weeks and median eosinophils count in histology dropped from 42.2 to 2.9 cells/hpf. 46.7% maintained remission (off therapy) at 36 weeks.
89% achieved eosinophil count <20 cells/hpf at 12 weeks.
In this short study, the authors did not identify any changes in cortisol levels.

My take: A reliable composition from a manufacturer, if not too expensive, would be a big improvement for many kids with EoE. Higher doses of budesonide may be warranted in some cases of EoE.

Related article: “How I Approach the Management of Eosinophilic Esophagitis in Adults” I Hirano. Am J Gastroenterol 2017; 112: 197-99. (Thanks to Seth Marcus for this reference). The author states that he prefers to perform a baseline assessment prior to PPI initiation. After diagnosis, he will use PPI and if no response, advance to either a dietary approach or topical steroids (he prefers fluticasone using the diskus formulations). His goals for therapy include: elimination of esophageal eosinophilia (<5-15 eos/hpf), resolution of dysphagia, and maintenance of esophageal diameter ≥16 mm. He does advocate annual testing for adrenal insufficiency for those taking long-term topical steroids.

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Protecting Animals in Medical Schools

Posted on March 19, 2017 by gutsandgrowth

An interesting development has been the abandonment of live animals to train surgical skills (DJ Simkin et al. NEJM 2017; 376: 713-15). Last year, the last two medical schools, who used live (anesthetized) animals, dropped this part of a core curriculum for training in surgery.

While the use of animals for medical education had “been used in medical education for millennia, the practice has now been abolished from the standard curriculum of every U.S. medical school.” While some alternative methods for training, like more sophisticated simulation, had been developed, clearly the change was driven by groups like “The Physicians Committee for Responsible Medicine” (8% of whose members are physicians).

While the goal of humane care for animals is laudable, it is worthwhile to contemplate that now “the brunt of the risks associated with learning tends to be borne by patients who are uninsured, undocumented, members of minority groups or otherwise marginalized.”

My take (borrowed from authors): “The underlying moral question –On whose bodies will clinical medicine first be practiced?–continues to require close attention.”

Vitamin D and Ulcerative Colitis Remission

Posted on March 18, 2017 by gutsandgrowth

A recent study (J Gubatan et al. Clin Gastroenterol Hepatol 2017; 15: 240-6) examined a prospective study of 70 patients with ulcerative colitis (UC). These patients (average age 48.6 yrs) were initially in clinical remission. Key findings:

Mean baseline vitamin D (25-OH) level was lower among patients with subsequent relapse (29.5 ng/mL) than those without relapse (50.3 ng/mL)
Over 12 months, a 25-OH D value <35, was associated with a small increased risk of relapse (odds ratio1.25). 20% of patients with a value <35 had clinical relapse compared with 9% (P= .003) who had values >35.

Because vitamin D levels are inversely related to UC disease activity, this study is particularly intriguing. By enrolling patients prospectively while in remission, this study suggests that good vitamin D levels may directly have immunoprotective and anti-inflammatory properties.

The AGA Journals blog provides an excellent summary of this study: Can Vitamin D Affect Risk of Ulcerative Colitis Relapse?

“In an editorial that accompanies the article, Stephen Hanauer reminds readers that the mean vitamin D level in the entire cohort was 44 ng/mL, and 60% of the subjects were taking vitamin D supplements. A normal vitamin D level is considered to be 20–40 ng/mL in healthy individuals, and the 35 ng/mL cut-off level used in the study was within this range.

Hanauer also mentions that in assessing the confidence intervals for risk of relapse at lower or higher vitamin D levels, there does not appear to be a dose–response effect in the odds ratios according to levels. Based on these findings, Hanauer says it would be premature to target a level of 35 ng/mL. He states that the best predictors of clinical relapse are still endoscopic and histologic markers of inflammation.”

My take: At this time, trying to maintain a normal vitamin D level is likely to be worthwhile; though, values obtained during acute flares remain unreliable.

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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.

Do antibiotics contribute to obesity? Not in recent study

Posted on March 16, 2017 by gutsandgrowth

There have been studies suggesting that antibiotics at a young age promote obesity and other studies that have NOT found an association. A recent study (JAMA Pediatr. 2017;171(2):150-156. doi:10.1001/jamapediatrics.2016.3349) could not find an effect of chronic prophylactic antibiotics.

Link: Weight Gain and Obesity in Infants and Young Children Exposed to Prolonged Antibiotic Prophylaxis

From Abstract:

Design, Setting, and Participants Secondary analysis of data from the Randomized Intervention for Children With Vesicoureteral Reflux Study, a 2-year randomized clinical trial that enrolled participants from 2007 to 2011. All 607 children who were randomized to receive antibiotic (n = 302) or placebo (n = 305) were included. Children with urinary tract anomalies, premature birth, or major comorbidities were excluded from participation.

Interventions Trimethoprim-sulfamethoxazole or placebo taken orally, once daily, for 2 years.

Results Participants had a median age of 12 months (range, 2-71 months) and 558 of 607 (91.9%) were female. Anthropometric data were complete at the 24-month visit for 428 children (214 in the trimethoprim-sulfamethoxazole group and 214 in the placebo group). Weight gain in the trimethoprim-sulfamethoxazole group and the placebo group was similar (mean [SD] change in weight-for-age z score: +0.14 [0.83] and +0.18 [0.85], respectively; difference, −0.04 [95% CI, −0.19 to 0.12]; P = .65). There was no significant difference in weight gain at 6, 12, or 18 months or in the prevalence of overweight or obesity at 24 months (24.8% vs 25.7%; P = .82). Subgroup analyses showed no significant interaction between weight gain effect and age, sex, history of breastfeeding, prior antibiotic use, adherence to study medication, or development of urinary tract infection during the study.

My take: Whether antibiotics could contribute to obesity is not entirely clear –even the possibility could encourage better stewardship of antimicrobials.

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Triglyceride Levels and Pancreatitis

Posted on March 15, 2017 by gutsandgrowth

A recent study (JAMA Intern Med 2016; 176: 1834-42) suggests that even mild to moderate hypertriglyceridemia may increase risk of pancreatitis.

Among two large cohorts that were followed prospectively for a median of 6.7 years, 434 out of 116,550 patients developed acute pancreatitis.

Key finding (which persisted after adjustment of multiple potential confounding factors):

More complete summary at GI & Hepatology News: “Mild, moderate hypertriglceridemia tied to pancreatitis”

What’s Happening on the Edge of Viability

Posted on March 14, 2017 by gutsandgrowth

A study (N Younge et al. NEJM 2017; 376: 617-28) provides some data on the slowly changing survival and neurodevelopmental outcomes among periviable infants (22-24 weeks gestation).

From epoch 1 (2000-2003), to epoch 3 (2008-2011), there has been some improvements. Overall survival increased from 30% to 36% and the percentage without neurodevelopmental impairment increased from 16% to 20%.

Mortality and Neurodevelopmental Outcomes at ~18 months of age (combined data and 11 centers)

The insightful commentary (pgs 694-6) notes that there has not been improvement in survival in infants born at 22 weeks. Furthermore, in reviewing multiple studies on outcomes, neurodevelopmental impairment was >94% in patients born at 22 weeks and between 80-90% for infants born at 23 weeks. At 24 weeks, neurodevelopmental impairment was present between 51-72%

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