As noted yesterday, in my view, “bad” inflammatory bowel disease (IBD) occurs when treatments are not working; though, many would argue that any IBD is bad IBD. Over the next few days, reviewed articles will focus on the problem of IBD that is not responding well to treatment. This article reports on the use of tofacitinib to avoid colectomy in children with severe ulcerative colitis.
This small (n=11) retrospective single-center cohort study of consecutive hospitalized pediatric patients initiating tofacitinib for refractory ulcerative colitis from 2018 to 2021. All patients demonstrated nonresponse to both intravenous corticosteroids and anti-TNF therapy prior to tofacitinib initiation.
Eight of 11 patients remained colectomy-free at 90 days following hospital admission and 6 remained colectomy-free over median 182-day follow-up, including 4 of whom remained on tofacitinib
The authors note that three patients started with TID dosing and eight received BID dosing (10 mg per dose). The higher dosing was influenced by a case control study by Bernstein et al which showed a 15% 90-day colectomy rate among adults with acute severe ulcerative colitis (ASUC), particularly those dosed at TID (Open Access: Clin Gastroenterol Hepatol 2021; 19: 2112-2120. Tofacitinib for Biologic-Experienced Hospitalized Patients With Acute Severe Ulcerative Colitis: A Retrospective Case-Control Study)
“Remission rates peaked at 12-16 weeks and decreased at 6 months…tofacitinib may …bridge to slower-acting and possibly safer long-term therapies such as ustekinumab or vedolizumab”
The median time to corticosteroid discontinuation was 89 days
No serious tofacitinib-related adverse events were observed
My take: Given the small numbers, this is clearly an area where cooperation (& ImproveCareNow) could be helpful in determining the safety and effectiveness of tofacitinib for pediatric ASUC. Also, if tofacitinib is used as a ‘bridge’ this is likely to present insurance coverage issues.
Hoisnard L, Pina Vegas L, Dray-Spira R, et al. Annals of the Rheumatic Diseases Published Online First: 05 October 2022. doi: 10.1136/ard-2022-222824. Risk of major adverse cardiovascular and venous thromboembolism events in patients with rheumatoid arthritis exposed to JAK inhibitors versus adalimumab: a nationwide cohort study Methods: This was a nationwide population-based cohort study (n=15,835) of the French national health data system, the exposed group initiating a JAKi and non-exposed group initiating adalimumab Key findings: Risk of major adverse cardiovascular events (MACEs) for the exposed versus non-exposed group was not significant: HRw 1.0 (95% CI 0.7 to 1.5) (p=0.99), nor was risk of VTEs significant: HRw 1.1 (0.7 to 1.6) (p=0.63). This study provides reassuring data regarding the risks of MACEs and VTEs in patients initiating a JAKi versus adalimumab, including patients at high risk of cardiovascular diseases.
Background: “A major challenge that pharmacoepidemiologic studies often face is the susceptibility to protopathic bias. Protopathic bias occurs when a pharmaceutical agent is prescribed for an early manifestation of a disease and then appears to cause the disease when it is eventually diagnosed…Here, we used a modified lag-time approach to investigate the association between PPI use and all-cause and cause-specific mortality”
Methods: This was a prospective cohort study using data collected from the Nurses’ Health Study (2004–2018) and the Health Professionals Follow-up Study (2004–2018). Study participants: 50,156 women and 21,731 men followed for 831,407 person-years and a median of 13.8 years.
Upon applying lag times of up to 6 years, the mortality associations were attenuated and no longer statistically significant:
Longer duration of PPI use did not confer higher risks for all-cause and cause-specific mortality.
My take: This study provides convincing evidence that PPI use does not increase the risk of mortality. Protopathic bias can make PPI use appear to increase the risk of mortality (HR, 1.19 in this study) compared to PPI non-users. It is still a good idea to use these agents for appropriate indications and at appropriate doses.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. 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
Also, worldwide COVID-19 deaths are at a low point since the beginning of the pandemic (both reported and estimated excess deaths).
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.