Support for Step-Up Therapy and Thiopurines

Posted on February 13, 2017 by gutsandgrowth

A retrospective study (H Bar-Yoseph et al. Clin Gastroenterol Hepatol 2017; 15: 69-75) indicated that thiopurine use before infliximab (IFX) was associated with the prevention of antidrug antibody formation in patients with Crohn’s disease.

The authors had 207 eligible patients which included 93 who received IFX monotherapy, 52 who received combination therapy after response to thiopurine, 34 who received IFX after lack of response to thiopurines (but continued with combination treatment), and 28 who received de novo combination therapy. The total number of patients followed in these centers is much higher, but they excluded those with episodic infusions and for other reasons that could affect their conclusions.

Key findings:

Prior thiopurine therapy was associated with lower antidrug antibodies (ADA). At 1 year, past thiopurine responders had 19.3% ADA, past thiopurine failures had 16.1% ADA; both were much lower that the monotherapy rate of 46.6% The de novo combination group had a rate of 21.9% which did not reach significance.
Interestingly, after the first 5 months, the de novo combination group did not develop further ADA but during the first 5 months the rate of ADA was quite similar to the monotherapy rate. This could be related to the notion that thiopurines may take 3-6 months to achieve full effect.
Combination therapy (compiled) was associated with higher rates of clinical remission (58.8% vs 40.9%) and lower rates of active disease (8.8% vs. 21.5%).

Overall, this study showed high rates of ADA compared to many studies but the conclusions are similar to other published studies. It could be that many of those with positive ADA were lower antibody levels and that many of these levels may not be clinically significant. The study has limitations mainly related to being a retrospective study.

My take: This study supports the following:

Combination therapy is more effective than monotherapy
Using an immunomodulator before starting infliximab may reduce ADA formation more effectively than starting combination therapy de novo.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing/usage of medications (along with potential adverse effects) should be confirmed by prescribing 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.

Nutrition in Immune Balance -New Website for Inflammatory Bowel Disease

Posted on February 12, 2017 by gutsandgrowth

Dr. David Suskind and colleagues have developed a website which provides a great deal of information regarding nutritional therapy, particularly the Specific Carbohydrate Diet (SCD), and inflammatory bowel disease. The website also facilitates contributions to Seattle Children’s Hospital and buying a book on the SCD.

Here’s a link to website: NIMBAL.org

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Near Shem Creek, SC

ACG Guideline for Helicobacter Pylori

Posted on February 11, 2017 by gutsandgrowth

Link: ACG Clinical Guideline: Treatment of Helicobacter pylori Infection

The American Journal of Gastroenterology , (10 January 2017) | doi:10.1038/ajg.2016.563

William D Chey, Grigorios I Leontiadis, Colin W Howden and Steven F Moss

Helicobacter pylori (H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer. H. pylori may also have a role in uninvestigated and functional dyspepsia, ulcer risk in patients taking low-dose aspirin or starting therapy with a non-steroidal anti-inflammatory medication, unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. While choosing a treatment regimen for H. pylori, patients should be asked about previous antibiotic exposure and this information should be incorporated into the decision-making process. For first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance amongst H. pylori isolates is known to be low. Most patients will be better served by first-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. When first-line therapy fails, a salvage regimen should avoid antibiotics that were previously used. If a patient received a first-line treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first-line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. Details regarding the drugs, doses and durations of the recommended and suggested first-line and salvage regimens can be found in the guideline.

My take: Recent draft guidelines from our pediatric group, NASPGHAN, suggested that triple therapy, in addition to quadruple therapy, would still be considered a first-line approach. When the NASPGHAN report is completed/published, it will be of interest to see whether this discrepancy persists.

Related blog posts:

Vedolizumab: summary of latest data

Posted on February 10, 2017 by gutsandgrowth

BG Feagan et al. Clin Gastroenterol Hepatol 2017; 15: 229-39.

From Clin Gastroenterol Hepatol, Feb 2017 Issue Highlights Link from AGA twitter feed:Vedolizumab in Anti-Tumor Necrosis Factor Naïve or Previously Exposed Ulcerative Colitis Patients

“Feagan et al present data comparing patients based on past exposure to anti-TNF agents. This post-hoc analysis compared 464 patients who received vedolizumab or placebo who were naïve to TNF antagonists to 367 patients who had been exposed but had an inadequate response, loss of response, or intolerance to TNF antagonists…

The investigators describe greater differences in efficacy for vedolizumab (versus placebo) in patients who were naïve to TNF inhibitors than for patients with prior exposure to anti-TNF agents.

Week 6 reponse rates to vedolizumab or placebo were 53% vs 26% amongst patients naïve to TNF antagonists (absolute difference 26%) compared to 39% vs 21% in patients with prior anti-TNF exposure (absolute difference 18%).

Week 52 remission rates with vedolizumab and placebo were 47% and 19%, respectively, for patients naïve to TNF antagonists (absolute difference 28%) compared with 36% and 5%, respectively, in patients with prior exposure to TNF biologics (absolute difference 29.5%).

Thus, while vedolizumab demonstrated significantly greater efficacy as induction and maintenance therapy for UC patients whether or not they had previously received therapy with anti-TNF agents, there were numerically greater treatment benefit at week 6 among patients who had never received prior biologic therapy.“

My take: Given the higher response in anti-TNF naive patients along with the favorable safety profile, vedolizumab could be considered as a first-line therapy.

Related Blog Posts:

Induction endpoints in TNF-failure patients by type of failure. Forest plots show difference from placebo and 95% CIs for percentages of patients with (A) clinical response, (B) clinical remission, and (C) mucosal healing at Week 6. Patients with more than one type of TNF antagonist failure were evaluated by each type of failure; thus the number of patients in the subgroups may total more than the number of enrolled patients.

Closer Look at Ustekinumab Data

Posted on February 9, 2017 by gutsandgrowth

At a recent dinner, we had the opportunity to hear a review of some of the recent data on ustekinumab. These notes may include some errors in transcription and errors of omission. Most of this data is derived from a recent publication that has been summarized in this blog: Landmark Publication for Ustekinumab (Stelara) | gutsandgrowth

Some key points:

In numerous studies of biologic agents, longer duration of disease is associated with a much lower response to therapy. For the UNITI-1/UNTI-2 studies, the patients enrolled had long duration of disease (~10 years in UNIT1-1, ~8 years in UNITI-2)
Recent data indicate that vedolizumab is effective for Crohn’s disease, but works slowly. It likely takes ~6 months to determine if it is working.
With ustekinumab, most patients respond within 3 weeks of the induction dose; however, among nonresponders, many responded after the first maintenance dose. Thus, probably need to give at least the induction dose and the first maintenance dose for determining whether ustekinumab is effective.
Overall safety profile looks very good for ustekinumab. More than 4000 patients in a psoriasis registry showed no serious safety signals (though psoriasis patients receive a lower dose).
Overall, the 6 mg/kg induction dose outperformed the 130 mg dose with regard to objective measures.
High placebo rate in the IM-UNITI study likely is due to some residual response to the initial induction dose.
Every 8 week dosing for ustekinumab was more effective than every 12 week dosing in these studies, though, there are likely patients who need more frequent and some who could benefit from less frequent dosing.
2.3% of patients in IBD studies had detectable antibody to ustekinumab but this did not preclude efficacy.
~20% of IBD patients do not develop increased CRP
Pediatric studies of ustekinumab are ongoing testing different dosing regimens.
One other anecdote in regards to magical thinking about which premedications are most effective: A man with a ridiculous hat was approached as he walked in an Atlanta.suburb. A lady asked him why he wore such an unusual hat. He replied that “the hat keeps elephants far away.” The lady said, “there are no elephants around here.” He said, “See it is working.”

Fasting Probably Not Needed Before Checking Lipids

Posted on February 8, 2017 by gutsandgrowth

A cross-sectional study (LN Anderson et al. J Pediatr 2017; 180: 47-52) of 2713 children extends prior observations that there is little evidence supporting the need for fasting prior to measurement of lipids.

Prior blog on this topic: Is Fasting Needed Before Checking Lipids

This study showed that fasting duration (0-5 hrs) was not significantly associated with total cholesterol, LDL, HDL, or triglycerides. This is most evident on the graphs on their Figure.

In the discussion, the authors note that the NHANES study 1999-2008 had similar results for the younger children. Overall, there were 12,744 children aged 3-17 years; 80% fasted at least 8 hrs. In this study, fasting did have a small effect on lipids, but among children 3-5 yrs, only LDL was statistically affected by fasting status.

My take: Based on this study and others, fasting seems to have only a small effect on lipid measurement and for routine screening, it is probably not needed.

Yosemite Natl Park

Bariatric Surgery and Reversal of NASH

Posted on February 7, 2017 by gutsandgrowth

A small prospective study (M Manco et al. J Pediatr 2017; 180: 31-7) provides evidence that bariatric surgery/sleeve gastrectomy is effective at reversing nonalcoholic steatohepatitis (NASH) and hepatic fibrosis in adolescents (n=20).

All patients in this study had BMI >35 and weere 13-17 yrs of age.

Key findings at one year following intervention:

Among the 20 patients who underwent sleeve gastrectomy, there was a 21.5% loss in baseline weight, which compared with weight loss of 3.4% among 20 patients who received intragastric balloon device and weight increase of 1.7% among 53 patients who received lifestyle intervention counseling.
Sleeve gastrectomy group had resolution of NASH in all 20 and disappearance of hepatic fibrosis in 18 (90%). In the intragastric balloon group, NASH reverted in 24% and fibrosis in 37% whereas there was no improvement in the lifestyle intervention group.

Full text link: Sleeve Gastrectomy for NASH

Limitations are discussed in the editorial by Inge and Xanthakos (pgs 6-7) and included small sample size, absence of patients with type 2 diabetes, and short followup period. Nevertheless, this is “the largest and most informative series…in select adolescents with severe obesity.”

My take: Given the lack of effective pharmaceutical therapy and the typically impotent effects of lifestyle intervention, this data supports bariatric surgery to facilitate weight loss/NASH reversal in select adolescents.

Related article: JCF Leung et al. Hepatology 2017; 65: 54-64. This study showed that the histologic severity and clinical outcomes are modestly better in nonobese patients (n=72) with NAFLD compared with obese patients (n=307). High triglycerides and higher creatinine were associated with more advanced liver disease in nonobese patients.

Briefly noted: D Houghton et al. Clin Gastroenterol Hepatol 2017; 15: 96-102. This study with 24 subjects with nonalcoholic steatohepatitis showed that exercise reduced hepatic triglyceride content, visceral fat, and plasma triglycerides. However, circulating markers of inflammation and fibrosis was not reduced. The implication is that exercise should be part of NASH treatment but that weight management/diet are needed as well.

Glacier Natl Park

. Related blog posts:

Guideline Links: Infant Cholestasis and Esophageal Atresia-Tracheoesophageal fistula

Posted on February 6, 2017 by gutsandgrowth

One way that I use this blog is to use the search function for previous posts with useful links. For example, I know if I search “foreign” that I will come across a post that has a summary as well as a link to the NASPGHAN recommendations on Foreign Bodies (Foreign Bodies in Children -Expert Guidance).

This post has two links :

NASPGHAN Guideline for the Evaluation and Management of Cholestasis in Infants (2017) One new suggestion in the evaluation: “a low threshold for gene panels or exome sequencing”

NASPGHAN-ESPGHAN Guideline for Esophageal Atresia -Tracheoesophageal Fistula (2016) This guideline has been summarized in a previous post: Guidelines for EA-TEF

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Picture of the Day

Posted on February 5, 2017 by gutsandgrowth

Thanks to Steven Liu for a chuckle & go Falcons!

Picture Quiz: Intestinal Cause of Edema

Posted on February 5, 2017 by gutsandgrowth

Link to full text from AGA twitter feed: A Rare Cause of Generalized Edema

Background: “A 19-year-old boy presented to our hospital because of a 6-month history of progressive dyspnea and generalized edema. He developed cough, abdominal fullness, diarrhea, and leg edema 5 years ago. Liver cirrhosis was suspected at that time…Chest radiography showed bilateral pleural effusions (Figure A). Abdominal computed tomography demonstrated large amount of ascites (Figure B). … Subsequently, antegrade double-balloon enteroscopy …demonstrated nodular mucosal lesions with a milk-like surface in the duodenum (Figure C). Moreover, snow flake appearance of mucosa was found in the jejunum and proximal ileum (Figure D). However, a normal appearance of mucosa was identified in the middle ileum (Figure E).”

The Answer:

“Histologic examination shows chronic inflammation of the ileum characterized by increased lymphoplasma cell infiltration of lamina propria without malignancy. Moreover, marked dilatation of lymphatic ducts that involved the mucosa was identified (Figure F)… a diagnosis of primary intestinal lymphangiectasia (PIL) was made.

gutsandgrowth

Pediatric Gastroenterology