One Proposal to Reduce Thiopurine Combination Therapy

Posted on July 26, 2016 by gutsandgrowth

A recent review (X Roblin et al. Inflamm Bowel Dis 2016; 22: 1496-1501) provided a useful review of thiopurine/biologic combination therapy. The part of this review that I found intriguing was their Figure 3: “Proposed algorithm that may guide drug discontinuation or de-escalation in patients with IBD who achieved sustained deep remission while on combination therapy.”

In those (in sustained deep remission) with an infliximab trough level >5 mcg/mL, this algorithm recommends discontinuation of thiopurine.
In those with an infliximab trough level 3-5 mcg/mL and with 6-TGN >250, this algorithm recommends reduction of thiopurine to obtain 6-TGN level >125.
In those with an infliximab trough level <2 mcg/mL and with 6-TGN >250, this algorithm recommends discuss stopping infliximab.

The authors acknowledge that this algorithm has not been studied and “needs to be investigated in prospective trials specifically addressing this issue.”

My take: Until more studies emerge, the best way to balance control of IBD and minimize drug toxicity remains uncertain.

Unrelated references:

“Crohn’s disease of the ileoanal pouch” AL Lightner et al. Inflamm Bowel Dis 2016; 22: 1502-8.
SZ Koh et al. Inflamm Bowel Dis 2016; 22: 1397-1402. This reference describes clinical factors associated with development of Crohn’s disease in patients with IBDU who have undergone ileal pouch (e.g. younger age).

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Arthur Ravenel Jr Bridge

Disease extent and need for higher infliximab dosing

Posted on July 25, 2016 by gutsandgrowth

A recent study (JM Shapiro et al. JPGN 2016; 62: 867-72) reviewed 98 pediatric patients treated with infliximab (2012-2014) with inflammatory bowel disease (IBD).

The authors divided their patients into three groups, mainly based on extent of colonic involvement. In those with limited colonic involvement, they were labelled “limited” disease (n=53). In those with patchy inflammation involving the entire colon, they were considered to have “moderate” disease (n=27). In contrast, those with continuous pancolitis were ascribed to have “extensive” disease (n=18). Overall, Crohn’s disease accounted for 85 patients (87%), ulcerative colitis for 11 patients (11%), IBDU for 2 patients (2%). Interestingly, the majority (9 of 11) of those patients without Crohn’s disease were considered to have extensive disease.

Key findings:

“Patients with moderate and extensive disease, started taking 5 mg/kg per dose, showed statistically significant shorter times to escalation that those with limited disease.”
70% of those with extensive disease required dose escalation, compared with 58.3% of those with moderate disease and 26.4% of those with limited disease.
The authors note that patients (n=8) with extensive disease who started with 10 mg/kg dosing “exhibited longer treatment durability;” all 8 patients who started on 10 mg/kg dosing remained on this dose at the study’s conclusion. Among the 10 patients that started on 5 mg/kg dosing, only 7 were on IFX therapy at the study conclusion–3 remained on 5 mg/kg, 4 were escalated to 10 mg/kg; there were 3 patients who stopped IFX therapy (1 infusion reaction, 2 with nonresponse).

My take: This is a small study. Yet, the implication is that early optimal dosing of IFX is likely helpful, especially in the setting of extensive disease.

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Chattahoochee River

Better Hydration –Less Obesity?

Posted on July 24, 2016 by gutsandgrowth

Perhaps the Dos Equis’ guy’s slogan “Stay Thirsty My Friends” is not such great advice.

According to a study, summarized by NPR, inadequate hydration was associated with increased odds of obesity. While an association does not prove causation, it adds another potential reason to drink plenty of water.

NPR Story: Thirsty? New Study Links Good Hydration with Slimmer Waistlines

Here’s an excerpt:

A new study published in the Annals of Family Medicineadds to the evidence that hydration may play a role in weight management.

“What we found was that people who were inadequately hydrated had increased odds of being obese,” says study author Tammy Chang of the Department of Family Medicine at the University of Michigan.

The study was based on data collected by a federal health survey, in which researchers had documented weight and height of participants. They also conducted urine tests to establish an objective measure of participants’ level of hydration.

Chang and her colleagues found the odds of being obese were 1.59 times higher for people who were not well-hydrated. And overall, they found that a lack of proper hydration was associated with higher body mass index.

On a neighborhood walk

Dubin-Johnson Syndrome

Posted on July 23, 2016 by gutsandgrowth

From NEJM:

A 48-year-old woman scheduled to receive a laparoscopic cholecystectomy underwent a preoperative evaluation that disclosed conjugated hyperbilirubinemia…

A biopsy specimen revealed coarse, deep-brown, pigmented granules on periodic acid–Schiff staining (Panel B), primarily at the canalicular pole of the hepatocytes and especially in the pericentral zones, with otherwise well-preserved lobular architecture. Expression of the multidrug-resistance–associated protein 2 (MRP2) was absent on anti–MRP2 immunohistochemical analysis (Panel C; see also comparison with control specimen [inset]). A diagnosis of the Dubin–Johnson syndrome was confirmed. This syndrome is an autosomal recessive disorder that is caused by a mutation in MRP2 that results in deficient canalicular expression of MRP2 and impaired secretion of conjugated bilirubin into the bile. Such mutations cause an isolated increase in serum levels of conjugated bilirubin and the appearance of a black liver, without associated sequelae.

Bioactive Components of Breastmilk

Posted on July 22, 2016 by gutsandgrowth

An entire supplement (J Pediatr 2016; 173: S1-S65) provides an in-depth review of the bioactive components of breastmilk. The two components reviewed most extensively were lactoferrin and milk fat globule membrane (MFGM).

Lactoferrin: this glycoprotein is present in high concentrations in human milk, compared to formulas and cow’s milk. It is highest in concentration in early lactation. Its importance lies in its direct antibacterial effects. It is likely to reduce the risk of necrotizing enterocolitis and sepsis in preterm infants, which has been shown as well with bovine lactoferrin.

MFGM: this triglyceride is derived from a triple phospholipid membrane is absent from infant formulas. It has a role in both gastrointestinal and immune development. It appears to convey benefits in “terms of cognitive, metabolic, and health outcomes.”

My take: this supplement provides data that lactoferrin and MFGM “isolated from bovine milk retain bioactivity and are safe and efficacious additions to infant formula”

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All Bleeding Stops (part 2)

Posted on July 21, 2016 by gutsandgrowth

Several years ago, this blog provided a summary of the guidelines for stopping upper gastrointestinal bleeding (All bleeding stops | gutsandgrowth). Most of the recommendations are unchanged. A nice review of this topic (L Laine. NEJM 2016; 374: 2367-76), specifically focused on peptic ulcers, provides a few new pointers.

Two areas with more data:

Transfusion. “A randomized trial showed lower rates of death (the primary outcome), rebleeding, and adverse events with a transfusion threshold of 7 g per deciliter than with a transfusion threshold of 9 g per deciliter.”
Proton pump inhibitors. “A recent meta-analysis showed that intermittent oral or intravenous proton-pump inhibitor therapy results in outcomes that were non inferior to those after continuous infusion.” (JAMA Intern Med 2014; 174: 1755-62) For adults, the suggested dosing was 80 mg followed by 40 to 80 mg twice daily for 72 hours.

As before, the author recommends preoperative (30 min prior) erythromycin (250 mg) and states that a nasogastric tube in not needed. The author also recommends that in patients with idiopathic ulcers (not due to NSAIDs or H pylori) that ongoing (indefinite) use of once-daily maintenance therapy with a proton-pump inhibitor is recommended to prevent rebleeding.

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An Overlooked Finding in a Recent Acute Severe Ulcerative Colitis Study

Posted on July 20, 2016 by gutsandgrowth

A recent study (S Choshen et al. JPGN 2016; 63: 58-64) examined 283 children who were treated with IV steroids for acute severe ulcerative colitis. This study focused on steroid dosing. Their conclusion: “there does not seem to be a consistent superiority of high dose (>2 mg/kg/day) versus standard (1.25 mg/kg/day) or low-dose (1 mg/kg/day) methylprednisolone in pediatric acute severe colitis.”

Before looking into the details a little closer, one finding that was not even discussed in the abstract or discussion was the colectomy rate of 31%. Previous pediatric studies of patients with ulcerative colitis had found rates generally half that rate but notably included patients with milder presentations of ulcerative colitis. Thus, this rate of 31% (by 1 year after discharge) is useful information to reference when considering pediatric patients with acute severe colitis (ACS).

This study used datasets from the prospective Outcome of Steroid therapy in Colitis Individuals (OSCI) (n=128) and from the retrospective OSCI study (n=99).

Other results:

By day 5 of steroids, 45% had at most mild disease (ie PUCAI <35)
31% had failed IV steroids and required salvage therapy (biologic or calcineurin inhibitor)
20% had colectomy by discharge
When examining steroid dosage and outcomes, the authors could not discern any differences in need for salvage therapy, PUCAI <35 at day 5, or need for salvage therapy within 1 year. There was a mild difference in length of stay with 9 days in the low-dose group and 10-days in the high dose group.

My take: This large cohort provides some reassurance that current steroid dosing recommendations are probably right, in that there was no discernible improvement with higher doses. This is in agreement with previous studies in adults which have not shown advantages of methylprednisolone >60 mg/day. The high colectomy rate of 31% is worth keeping in mind in this population.

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Do You Know When Hepatitis C Virus Transmission Peaked?

Posted on July 19, 2016 by gutsandgrowth

According to a recent study (AC Spaulding, LS Miller. Lancet Infect Dis. 2016 Mar 30. doi: 10.1016/S1473-3099[16 …), peak transmission of hepatitis C virus (HCV) peaked about 1950, likely due to reuse of metal and glass syringes.

This study counters the idea that HCV transmission was “primarily due to injection drug use, unsafe tattooing, high-risk sex, and travel to high endemic areas during youth,” according to the researchers. Here’s the link: Apportioning blame in the North American Hepatitis C virus epidemic

My take: Will this take away some of the stigma of HCV infection? Probably not. But, hopefully as the costs for treatment reduce, more individuals can be infection-free and avoid complications related to infections.

Expanding VEO Variants

Posted on July 18, 2016 by gutsandgrowth

A recent study (Q Li, CH Lee, LA Peters, et al. Gastroenterol 2016; 150: 1196-1207) provides a description of a new genetic variant causing very early onset inflammatory bowel disease (VEOIBD), which designates cases of IBD which presents <6 years of age.

Using whole exome sequencing, the authors identified TRIM22 mutations in 3 infants with fistulizing perianal disease and granulomatous colitis. The authors further characterized the defect using functional studies that showed TRIM22 is important in the regulation of nucleotide binding oligomerization domain containing 2 (NOD2)–dependednt activation of interferon-beta signaling and nuclear factor (NF)-κB.

“NOD2 has long been recognized as a critical player in Crohn’s disease pathogenesis, where it is proposed to regulate innate immunity through NF-κB induced proinflammatory responses triggered by peptidoglycan…Simarlarly, mutations in XIAP..are associate with loss of NOD-2-dependent mediated NF-κB signaling” and has a similar phenotype.

My take: Identification of the numerous mutations that lead to VEOIBD is likely to help understand the pathogenesis and ultimately to better therapies.

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Addicts and Anti-Diarrhea Drugs

Posted on July 17, 2016 by gutsandgrowth

According to NY Times:

Addicts Who Can’t Find Painkillers Turn to Anti-Diarrhea Drugs

Here’s an excerpt:

The active ingredient, loperamide, offers a cheap high if it is consumed in extraordinary amounts. But in addition to being uncomfortably constipating, it can be toxic, even deadly, to the heart.

A report published online in Annals of Emergency Medicine recently described two deaths in New York after loperamide abuse. And overdoses have been linked to deaths or life-threatening irregular heartbeats in at least a dozen other cases in five states in the last 18 months.

Most physicians just recently realized loperamide could be abused, and few look for it. There is little if any national data on the problem, but many toxicologists and emergency department doctors suspect that it is more widespread than scattered reports suggest.

Meerkat, Atlanta Zoo 2016