Don’t be Fooled About Withdrawing Immunomodulator Cotherapy -Look Past the Headline

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The coverage on a recent study (Clinical Gastroenterology and Hepatology 2015: 13(3): 514-521.e4) suggests that it should be fine to stop immunomodulator co-therapy.  I recommend reading the entire study (or at least this blog post)–you will probably come to a different conclusion.
Brief summary from AGA website: Withdrawal of Immuonomodulators after Co-therapy Does Not Reduce Trough Level of Infliximab in Crohn’s Patients

“The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to one year in patients with Crohn’s disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. David Drobne and colleagues studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). Reporting in Clinical Gastroenterology and Hepatology, they find that, in a retrospective analysis, withdrawal of immunomodulators after at least six months (median, 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn’s disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response.”

Clinical Gastroenterology and Hepatology 2015: 13(3): 514-521.e4

Some additional details:

This was a retrospective open-label cohort study with 223 patients and median followup of 34 months. At baseline, 65 received infliximab (IFX) monotherapy and 158  received co-therapy with an immunomodulator (46 methotrexate, 112 thiopurine).  Immunomodulators were withdrawn “only in patients with durable response (ongoing clinical benefit with lasting disease control with low C-reactive protein [CRP] [below 10 mg/L]).”  Among the 158 on co-therapy, 117 reached a durable response and had withdrawal of immunomodulator after >6 months of combination therapy (median time 13 months).

Key findings:

  • At baseline, co-therapy patients, compared to monotherapy patients, had higher IFX trough levels (adjusted mean increase of 1.44-fold) and lower likelihood of antibodies to infliximab (ATI): 35/158 (22%) compared with 25/65 (38%), P=.01.
  • When immunomodulator was withdrawn, IFX levels remained stable: before 3.2 mcg/mL compared with after 3.7 mcg/mL. However, 45 of 117 (38%) required increasing doses of IFX and 21 of 117 (18%) discontinued IFX.
  • Trough levels of IFX and CRP  were most strongly associated with response to IFX dosing on monotherapy.
  • “Only 9 of 74 patients (12%) with detectable IFX trough levels at the time of immunomodulator withdrawal developed undetectable IFX trough levels during the subsequent follow-up.”
  • None of the 27 patients with IFX trough level >5 mcg/mL at time of immunomodulator withdrawal lost response to IFX during median follow-up of 29 months.

Though the headlines covering this article have suggested that IFX levels will stay stable when immunomodulators are withdrawn after >6 months, the authors proposed algorithm only recommends withdrawal for those with IFX trough level >5 mcg/mL.  In addition, the data showed that a large number of patients required dose escalation and/or lost detectable IFX levels. Despite their proposed algorithm to withdraw in this small group, the authors further backtrack in their conclusion:  “a prospective parallel group trial during a period of 5-10 years in a large group of patients is required to ascertain the real long-term benefit to risk ratio of continuing combined infliximab and immunomodulator treatment.”

Bottomline: If a patient is doing well, withdrawing immunomodulator co-therapy still has risks. I worry that the misleading reporting of this article will result in detrimental outcomes.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing 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.

 

Fatty Liver at Birth

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A provocative study (Patel KR, White FV, Deutsh GH. JPGN 2015; 60: 152-58) shows that hepatic steatosis/fatty liver is prevalent at birth in at-risk stillborns.

The authors retrospectively examined autospy results from 33 stillborns (20-40 weeks) delivered to women with diabetes (pregestational or gestational) along with 48 age-matched controls.  The majority of women (54%) were African American women; 27% were white and 9% were hispanic.

Key findings:

  • Hepatic steatosis was common and severe in the stillborns of diabetic women.  Prevalence: 78.8% (26/33) compared with 16.6% (8/48) of controls.
  • No direct correlation was identified between steatosis and glycemic control.

Whether nonalcoholic fatty liver disease (NAFLD) begins at birth is not known and what happens to the fat in newborns with hepatic steatosis is not clear.  This study indicates that maternal diabetes may increase the risk of NAFLD.

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Methotrexate Dosing in Dual Therapy

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A recent retrospective study (DOI: http://dx.doi.org/10.1093/ecco-jcc/jjv027 first published online: 23 January 2015 -reference from KT Park’s twitter feed) has suggested that high-dose methotrexate (MTX) (15-25 mg/week) is more effective than low-dose MTX (≤12.5 mg/week) as part of dual therapy for inflammatory bowel disease.

Here’s the abstract: Optimal Doses of Methotrexate

Background and Aims: Methotrexate is sometimes used as part of combination therapy for the treatment of inflammatory bowel disease (IBD), however the optimal MTX dose for combination therapy has not been established. This study compared the efficacy of lower dose and higher dose methotrexate with anti-TNF therapy among IBD patients.

Methods: Retrospective chart review was performed of 88 IBD patients at our center between 2010-2013. Low-dose methotrexate was defined as ≤ 12.5mg/week and high-dose methotrexate as 15-25mg/week. Patients who met the criteria for clinical remission (Harvey-Bradshaw Index ≤ 4, Simple Clinical Colitis Activity Index ≤ 2) at baseline were followed for up to 42 months. Chart review occurred in six-month intervals. The primary outcome was consecutive months in remission prior to relapse. Secondary outcomes included other indicators of worsening disease (endoscopic inflammation, steroid use, therapy escalation/addition, or surgery) and adverse events. Regression analysis and Kaplan-Meier survival analysis were completed.

Results: We identified 73 (83%) dual-therapy patients, of which 32 low-dose and 14 high-dose individuals achieved remission. When compared with high-dose patients, low-dose patients were more likely to relapse (log-rank test, P<0.01). Secondary indicators of worsening disease occurred during 34.4% of low-dose review periods and 31.4% of High-dose review periods (P=0.67). 3/52 (6%) low-dose patients and 3/21 (14%) high-dose patients (P=0.34) discontinued methotrexate therapy due to adverse events.

Conclusions: When combined with anti-TNF therapy, methotrexate at doses of >12.5mg/week were more effective at maintaining clinical remission than lower doses. These findings will guide management of combination therapy in IBD patients.

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Do You Think Fruit Drinks Are Healthy?

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According to a recent report in USA Today, a large number of parents have been misled into thinking that sugary beverages and fruit drinks are healthy. Here’s an excerpt:

That’s the conclusion of a new study from the Rudd Center for Food Policy and Obesity at University of Connecticut, published today in Public Health Nutrition.

Many parents believe that drinks with high amounts of added sugar — particularly fruit drinks, sports drinks and flavored water — are “healthy” options for kids, according to the report, funded by the Robert Wood Johnson Foundation, which focuses on improving health and health care…

The vast majority of parents give kids sugary drinks regularly…Equally significant, nearly half of parents surveyed rated flavored waters as healthy, and more than one-quarter considered fruit drinks and sports drinks to be healthy…

Parents said they were particularly influenced by nutritional claims appearing on the packages — such as claims that the items are “real” or “natural” or contained vitamin C or antioxidants, or were low in sodium or calories.

Bottomline: This information reinforces the fact that many parents do not realize basic nutrition information.

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Cyclophilin Inhbitor for Chronic Hepatitis B

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From AGAblog: A New Approach to Hepatitis B?

Cyclophilins are involved in multiple steps of the hepatitis B virus (HBV) life cycle in hepatocytes—cyclophilin inhibitors reduce viral replication and HBV envelope protein production and secretion, researchers report in the February issue of Gastroenterology. The cyclophilin inhibitor alisporivir, combined with the HBV polymerase inhibitor, reduces markers of HBV infection and HBV replication in cells, revealing a possible new therapeutic approach for chronic hepatitis B.

What’s Going on with Hepatitis A and Hepatitis B?

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Despite the excitement regarding Hepatitis C, Hepatitis A and Hepatitis B remain important challenges. Here’s the latest:

1. Collier MG, et al. “Hepatitis A Hospitalizations in United States, 2002-2011” Hepatology 2015; 61: 481-85. The authors examined the changes in demographics and frequency of HAV hospitalization during the study period. Key findings:

  • Rates of hospitalization dropped from 0.72/100,000 to 0.29/100,000.
  • Average age of hospitalized patient increased from 37.6 years to 45.5 years and more comorbidities were noted.
  • No changes were noted in length-of-stay or in-hospital deaths

2. DiBisceglie AM et al. “Recent US Food and Drug Administration Warnings on Hepatitis B Reactivation with Immune-Suppressing and Anticancer Drugs: Just the Tip of the Iceberg?” Hepatology 2015; 61: 703-11. Key recommendation: “There is good evidence to support routine screening of all patients for hepatitis B prior to undergoing chemotherapy or immunosuppressive treatment; use of prompt antiviral treatment appears to diminish the risk of severe or fatal reactivation of hepatitis B. Different organizations suggest disparate screening recommendations (Table 4).  AASLD suggests HBsAg, and anti-HBc.  CDC suggests adding anti-HBs.

3. Reddy KR, et al. Gastroenterology 2015; 148: 215-19, technical review 221-44.  AGA Guideline on the Prevention and Treatment of HBV Reactivation During Immunosuppressive Therapy. Key Recommendations:

  • Screen patients with HBsAg and anti-HBc, followed by a sensitive HBV DNA test if positive
  • Treat at-risk patients with antivirals with high barrier to resistance for at least 6 months after discontinuation of immunosuppressive therapy (except in patients taking B cell depleting agents who it is recommended to treat for at least 12 months afterwards)

Reactivation risk: (For all of the specifics — Full text article link)

  • High risk of reactivation (>10%): B cell depleting agents (eg. rituximab, ofatumumab), anthracycline derivatives (eg. doxorubicin, epirubicin), and daily moderate to high dose steroids (>10 mg) for at least 4 weeks.
  • Moderate risk of reactivation (1-10%): anti-TNF therapy, integrin inhibitors (eg. ustekinimab, vedolizumab), tyrosine kinase inhibitors, low-dose steroids daily (<10 mg/day) for at least 4 weeks (if HBsAg-positive but not if only anti-HBc-positive)
  • Low risk of reactivation (<1%): azathiopurine, 6-mercaptopurine, methotrexate.  No antiviral prophylaxis required.

For those interested in a more detailed summary of the recommendations: AGA Website HBV Reactivation Recommendations

4. Corsa AC et al. “No Resistance to Tenofovir Disoproxil Fumarate Through 96 Weeks of Treatment in Patients with Lamivudine-Resistant Chronic Hepatitis B. Clin Gastroenterol Hepatol 2014; 12: 2106-12.  This study followed 280 patients–no resistance to tenofovir was observed.

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Bile Acid Therapy for BAAT

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In a previous post (From theory to bedside practice | gutsandgrowth), I reviewed an article which described the diagnosis of a rare inborn error of bile acid metabolism –bile acid CoA:amino acid N-acyl transferase (BAAT).  A new report (Hepatology 2015; 61: 268-74) describes treatment and outcome in five patients with BAAT (I am thankful for acronyms!).

Treatment with 15 mg/kg of glycocholic acid (GCA) improved duodenal bile acid concentrations (to 23.3 ± 19.1 mmol/L).  Patients also received oral vitamin D2 (1000 IU/kg) and tocopherol (100 IU/kg).  With the combination of GCA and fat soluble vitamin provision, there was improvement in growth (3/3 prepubertal patients) and in fat-soluble vitamin absorption.

Bottomline: In patients with neonatal cholestasis growth failure, or fat-soluble vitamin deficiencies, identification of BAAT with fast atom bombardment mass spectrometry allows for institution of GCA which is efficacious and safe.

Also noted: FDA approves Cholbam to treat rare bile acid synthesis disorders FDA announcement 3/17/15, an excerpt: the first FDA approved treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for patients with peroxisomal disorders (including Zellweger spectrum disorders). Patients with these rare, genetic, metabolic conditions exhibit manifestations of liver disease, steatorrhea (presence of fat in the stool) and complications from decreased fat-soluble vitamin absorption. Individuals with these rare disorders lack the enzymes needed to synthesize cholic acid, a primary bile acid normally produced in the liver from cholesterol. The absence of cholic acid in these patients leads to reduced bile flow, accumulation of potentially toxic bile acid intermediates in the liver (cholestasis), and malabsorption of fats and fat-soluble vitamins in the diet. If untreated, patients fail to grow and can develop life-threatening liver injury. Cholbam is approved as an oral treatment for children aged three weeks and older, and adults.

NPR: “Craptastic Voyage” and Fart Analysis

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Surely a story for every gastroenterologist: “Before The Gas is Passed, Researchers Aim to Measure it in The Gut.”

An excerpt:

Kalantar-Zadeh and his colleagues propose in a paper in Trends in Biotechnologyonline Thursday two new devices that could keep a vigilant eye, or a nose in this case, on what’s going on deep in the gut….

The jar is pretty straightforward. A spoonful of poop goes in and a technician squeezes on a lid containing a sensor that detects the molecules of gas fuming inside and at what concentration…but he’s most excited about their other invention.

It’s a robotic pill that sniffs its way along a craptastic voyage through the gut. As the pill tumbles through, a membrane on the pill lets gasses pass onto a small molecular sensor inside that serves as its nose. The membrane blocks the other stuff sloshing around in the gut.

The pill notes the gasses that gut microbes produce, including oxygen, methane, hydrogen and hydrogen sulfide, which smells like rotten eggs. The pill’s sensor figures out how much of each gas is present, and beams the information out of the patient’s body through a tiny antenna…

The researchers aim to detect changes in gas content. As people’s health waxes or wanes because of stress or disease their intestinal ecosystems change too. Certain microbes may thrive in the new conditions while others struggle. As the populations shift, so will the concentrations of their distinctive gassy waste products.

My Take: This story reminds me about the joke I heard from a mentor about how can you tell if a person is an optimist.  An optimist is a person who finds a pile of manure under the tree on Christmas morning and declares: ‘Oh boy, I’m getting a pony.’

This story shows us that some researchers are true optimists as well; they see a lot of opportunity in studying stool and intestinal gases. Will this research will be useful or wind up being a pile of stool?

Also on NPR: Why Is Insulin So Expensive in the U.S. -summarizes recent commentary (N Engl J Med 2015; 372:1171-1175). This article is important for anyone concerned about escalating medicine costs.

Related blog post: “There is No ‘Healthy’ Microbiome” | gutsandgrowth

Emigration -One Way to Acquire Inflammatory Bowel Disease

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A recent study (Shitrit AB, et al. Inflamm Bowel Ds 2015; 21: 631-35) highlights the phenomenon of acquiring inflammatory bowel disease (IBD) by moving from a non-developed country to a developed country; the implication is that the changes in environment and diet predispose towards the development of IBD.

This study examined Ethiopian Jews who migrated to Israel.  Using a case-control study, the authors compared 32 Ethiopian immigrants to 33 Ashkenazi patients with IBD.

Key findings:

  • No Ethiopian immigrants had a positive family history compared with 42% of Ashkenazi group.
  • Crohn’s disease was more prevalent in the Ethiopian immigrants: 94% versus 73%.
  • The Ethiopian immigrants lived in Israel for at least 8 years before developing IBD an da median duration of 13 years.

The study discusses the difficulty of diagnosing IBD in rural Africa but speculates that rather than an underdiagnosis of IBD, it is likely to have a true low prevalence of IBD.

Take-home message: It takes many years for the environment exposures to allow for the development of IBD.  Additional work is needed to establish the clinical, genetic, and microbial factors that influence the acquisition of IBD in immigrants to developing countries.  Understanding the susceptibility of immigrants would have widespread application.

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More on Breastfeeding and Intelligence

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A recent prospective study with 30 year followup indicates that breastfeeding is associated with improved IQ and income.

A summary of the study from NBC/Today Health.  An excerpt:

Babies who are breastfed for at least a year grow up to be significantly more intelligent as adults and they earn more money, too, a new study shows….

Many experts have questioned whether it’s breastfeeding that makes babies grow up healthier and smarter, or something else that their mothers do — maybe spending more time with them. In other studies done in the U.S. and Europe, mothers who breastfeed longer tend to be more educated and affluent — and that clearly has an effect on their kids.

This study was different.

“What is unique about this study is the fact that, in the population we studied, breastfeeding was not more common among highly educated, high-income women, but was evenly distributed by social class,” Horta said.

Coverage of story from NY Times with link to original study: an excerpt:

The study, in the April issue of Lancet Global Health, began in 1982 with 5,914 newborns. The duration of breast-feeding and the age when the babies began eating solid foods was recorded. Thirty years later, researchers were able to interview and test 3,493 of the original group….

Still, the authors acknowledge that this is an observational study, and that many other unmeasured factors could have influenced their results.

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