Major cardiovascular events were rare with 2 in placebo group 0.34 and 2 in the ustekinumab group 0.12
No cases of progressive multifocal leukoencephalopathy or reversible posterior leukoencephalopathy
Antibodies to ustekinumab were identified in 3.6% of patients
My take: This study showed similar safety between ustekinumab and placebo, but is limited by short followup. The authors note that 5-year data from ustekinumab’s use with psoriasis has found no safety signals for malignancy.
A recent study (C Ma et al. Gastroenterol 2020; 158: 780-82) used cross-sectional data from the National Ambulatory Medical Care Survey (NAMCS) (2006-2015) with a total 7,872,115,883 weighted observations. They used this data to evaluate medication exposures and outcomes.
There was no association between PPI use and dementia, pneumonia, or intestinal infections. There was a trend towards intestinal infections (AOR 1.48, CI 0.80-2.71) but this did not reach statistical significance. “Sensitivity analysis showed an association between PPI use and C difficile.”
There was an association with chronic kidney disease (CKD) (AOR 1.26); however, this was seen with a multitude of drug classes including statins, calcium channel blockers, and beta-blockers.
This study notes that a recent large randomized controlled trial found no statistically significant differences between those receiving PPIs and those receiving placebo except for intestinal infections.
With regard to CKD, “it is extremely unlikely that all of these medications increase the risk of CKD, and therefore, it is likely that these findings are due to residual confounding.”
My take: With the exception of C difficile/intestinal infections, this study provides further evidence of the safety of PPIs and a lack of association between these medications and purported PPI-related adverse events. That said, it is still a good idea to limit use for appropriate indications.
Related blog posts:
PPIs: Good News on Safety Large randomized double-blind study of pantoprazole: “we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections.”
The clever title is derived from an editorial (KE Burke, AN Ananthakrishan. Clin Gastroenterol Hepatol 2019; 17: 1438-40) regarding three recent publications regarding Tofacitinib, a non-selective inhibitor of janus kinase (JAK) enzymes 1,2 and 3 which was FDA-approved in May 2018 for moderate to severe ulcerative colitis. This report was published prior to recent FDA warning regarding blood clots: FDA Warning on Tofacitinib
Two of the reports have been summarized previously on this blog:
The third study examines the safety of tofacitinib: WSandborn et al. Clin Gastroenterol Hepatol 2019; 17: 1541-50
Methods: This study analyzed data from phase 2 and phase 3 trials with 1157 patients who had a median treatment of 1.4 years (1613 person-years). More than three-fourths were receiving 10 mg BID.
Serious infections were infrequent but there was a dose response relationship associated with herpes zoster infections. At 10 mg BID, the frequency was 5% whereas the rate was 1.5% in those receiving 5 mg BID and 0.5% in placebo-treated patients. This is likely related to interference of interferon production related to JAK inhibitor disruption.
Sandborn et al conclude that the “safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher incidence rate of herpes zoster infection.”
The editorial recommends NOT using tofacitinib for acute severe ulcerative colitis (ASUC); it “should be encouraged only in selected patients and preferably in the context of a research study.” “Infliximab and cyclosporine [should be used] for steroid refractory UC;” however, they suggest that “one can consider initiating tofacitinib PRIOR to patients becoming steroid refractory. “It could be used upfront on day 1.”
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.
The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis…
Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed
19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers
Using California’s Ambulatory Services Databases, the authors identified 1.58 million surveillance/screening colonoscopies (2005-2011) and compared complications to patients who underwent other ambulatory procedures like joint aspiration, arthroscopy and cataract surgery.
According to international guidelines, polyethylene glycol (PEG) is the laxative of first choice in the treatment of functional constipation in children, both for disimpaction and for maintenance treatment. PEG acts as an osmotic laxative and its efficacy is dose dependent. PEG is highly effective, has a good safety profile, and is well tolerated by children. Only minor adverse events have been reported. Overall the use of PEG in children has been reported to be safe, although in patients predisposed to water and electrolyte imbalances monitoring of serum electrolytes should be considered.
Because this topic is of great importance to the families that are seen by pediatric gastroenterologists (and pediatricians), I wanted to review this brief article which describes the efficacy and safety of polyethylene glycol (aka miralax).
Polyethylene glycol (PEG) is the most widely used laxative in children and adults
It works by interacting “with water molecules by forming hydrogen bonds, in a ratio of 100 water molecules per 1 PEG molecule, which leads to an additional increase in colonic water content.” It is minimally absorbed.
Studies have demonstrated that PEG is better or noninferior to all of the following: lactulose, milk of magnesia, mineral oil, and flixweed (a medicinal herb)
Only minor adverse events have been reported in studies. In randomized, placebo-controlled trials, adverse events “did not occur more frequently in patients receiving PEG compared to patients receiving placebo.”
The main safety issue has been when it has been administered via nasogastric administration; improper placement can lead to severe pulmonary complications. In addition, PEG should be used “cautiously in children with swallowing problems…because of risk of aspiration.”
The authors assert that there has never been reports of physical or psychological dependence. Weaning from PEG is to prevent relapse of constipation.
There is no evidence to support loss of efficacy.
The phenomenon of “lazy bowel syndrome” in which there is worsened colonic function has not been described due to PEG; though, patients with underlying motility problems have had these problems misattributed to PEG use.
Despite anecdotal reports of tremors, tics, and obsessive-compulsive behavior in children taking PEG, there has been no evidence of a causal relationship. “These events …are still under investigation, but the FDA has decided that no action is necessary.” The authors note that the co-occurrence of neuro-behavioral problems and constipation is well-recognized in children with and without laxative use.
Clinical Pearl: Stimulant Laxatives After Repaired Anorectal Malformations:
“In children with constipation after repaired anorectal malformations, …stimulant laxatives (eg. senna) should be the laxative of choice.” (J Pediatr Surg 2017; 52: 84-8)
My take (borrowed from the authors): “PEG has rapidly become the treatment of first choice for children with functional constipation.”
Wednesday’s well publicized debate unfortunately discussed vaccination. Perhaps it is not surprising that a businessman/entertainer, Donald Trump, reiterated misinformation. Yet, the two former physicians (Ben Carson and Rand Paul) on the stage also provided misleading information. A good write-up of this issue from the NY Times: Not Up for Debate: The Science Behind Vaccination
Here’s an excerpt:
Here are the facts:
Vaccines aren’t linked to autism.
The number of vaccines children receive is not more concerning than it used to be.
Delaying their administration provides no benefit, while leaving children at risk.
All the childhood vaccines are important.
There is no evidence that links vaccines to autism. Many, many, many studies have confirmed this. The most recent Cochrane systematic review of research on the MMR vaccine included six self-controlled case series studies, two ecological studies, one case crossover trial, five time series trials, 17 case-control studies, 27 cohort studies and five randomized controlled trials. More than 15 million children took part in this research. No one could find evidence that vaccines are associated with autism….
It’s also not correct to call autism an “epidemic,” as Mr. Trump often seems to do. Autism is more prevalent as a diagnosis than it used to be. But much of that in recent years is because we’ve changed the definition of what it means to have “autism spectrum disorder.” For instance, 10 years ago, two-thirds of children diagnosed with autism had below-average intelligence. But today only about a third of those diagnosed with A.S.D. do. The fastest-growing group of children with autism have average or above average intelligence. We’re being more inclusive in the diagnosis…
Mr. Carson, though observing there was no evidence linking vaccines to autism, also said that many pediatricians were recognizing that “we are probably giving way too many in too short a period of time.” I know of no data that supports this assertion. Pediatricians, as a group, overwhelmingly support vaccines and the current vaccine schedule…
Spacing out vaccines provides no benefit, and leaves children susceptible to illnesses for a longer time…
Today, the number of antigens contained in all the vaccines given to a child by age 2 is less than 315. In contrast, it’s thought a child most likely fights off 2,000 to 6,000 antigens every day from the environment.
A recent review (Ann Intern Med 2013; 158: 365-8) notes that “over the past 12 years, since the publication of the Institute of Medicine’s report, ‘To Err is Human: Building a Safer Health System, ‘ improving patient safety has been the focus of considerable public and professional interest.” The following is a summary of this report (Epocrates docalert summary):
Patient-safety experts in North America and the U.K. systematically reviewed the growing evidence base for 158 patient-safety topics, including 41 strategies designated as most important to practitioners and patients. All reviews are published in the Agency for Healthcare Research and Quality (AHRQ) evidence report entitled “Making Health Care Safer II: An Updated Critical Analysis of the Evidence for Patient Safety Practices” to update the original 2001 publication. After carefully analyzing each patient-safety problem and its related safety strategy, the authors strongly recommend immediate adoption of the following 10 strategies:
Preoperative and anesthesia checklists to prevent operative and postoperative events
Bundles (with checklists) to prevent central line–associated bloodstream infections
Interventions to reduce urinary catheter use
Bundles to prevent ventilator-associated pneumonia
Do-not-use list for hazardous abbreviations
Multicomponent interventions to prevent pressure ulcers
Barrier precautions to prevent healthcare-associated infections
Real-time ultrasonography for central line placement
Interventions to improve prophylaxis for venous thromboembolism
The authors also provide a list of 12 “encouraged” (rather than “strongly encouraged”) patient-safety practices, these are listed in Table 2 of the paper.