Treatments for “Bad” Inflammatory Bowel Disease (Part 2) & Reassuring Data on Tofacitinib

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.

BD Constant et al. JPGN 2022; 75: 724-730. Tofacitinib Salvage Therapy for Children Hospitalized for Corticosteroid- and Biologic-Refractory 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.

Key findings:

  • 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.

Related article:

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.

Related blog posts:

From Crohn’s and Colitis Foundation, Georgia Chapter, December Newsletter: Donate to Cohen-Saripkin Fund

Understanding Protopathic Bias and Safety of Proton Pump Inhibitors & COVID-19 Worldwide Nadir

C-H Lo et al. Gastroenterol 2022; 163: 852-861. Open Access! Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality

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.

Key findings:

Upon applying lag times of up to 6 years, the mortality associations were attenuated and no longer statistically significant:

  • All-cause mortality: HR, 1.04; 95% CI, 0.97–1.11
  • Cancer: HR, 1.07; 95% CI, 0.89–1.28
  • Cardiovascular diseases: HR, 0.94; 95% CI, 0.81–1.10
  • Respiratory diseases: HR, 1.20; 95% CI, 0.95–1.50
  • Digestive diseases: HR, 1.38; 95% CI, 0.88–2.18

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.

Related blog posts:

Beached Fishing Boats Jules Achille Noel. The Art Institute of Chicago.

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).

Encouraging Safety Data for Ustekinumab & ESPGHAN Obesity Position Paper

WJ Sandborn et al. Inflamm Bowel Dis 2021; 27: 994-1007. Full text: Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies

Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year; this included 2574 patients (1733 patient-years of follow-up)

Key Safety findings –Events per 100 patient years -placebo vs ustekinumab respectively:

  • Adverse events: 165.99 [95% CI, 155.81–176.67] vs 118.32 [95% CI, 113.25–123.55])
  • Serious AEs: 27.50 [95% CI, 23.45–32.04] vs 21.23 [95% CI, 19.12–23.51])
  • Infections 80.31 [95% CI, 73.28–87.84] vs 64.32 [95% CI, 60.60–68.21])
  • Serious infections: 5.53 [95% CI, 3.81–7.77] vs 5.02 [95% CI, 4.02–6.19])
  • Malignancies excluding nonmelanoma skin cancer: 0.17 [95% CI, 0.00–0.93] vs 0.40 [95% CI, 0.16–0.83])
  • Major cardiovascular events were rare with 2 in placebo group 0.34 and 2 in the ustekinumab group 0.12

More key findings:

  • 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.

Related blog posts:

Unrelated article: E Verduci et al. JPGN 2021; 72: 769-783: Full text: Role of Dietary Factors, Food Habits, and Lifestyle in Childhood Obesity Development: A Position Paper From the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition

Data on Mask Efficacy and COVID-19 Safety –How U.S. Compares

According to this ranking, U.S. is 58th in the world:

From Health Affairs, Full Text: Community Use Of Face Masks And COVID-19: Evidence From A Natural Experiment Of State Mandates In The US

Related blog posts:

Deconstructing PPI-Associated Risks with Nearly 8 Billion Data Points and More on COVID-19 GI Symptoms (Video)

Link: 22 minute video —COVID-19 and the GI Tract -What We Know Right Now

———————

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.

Key findings:

  • 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.

Discussion:

  • 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:


Also, IOIBD recommendations for IBD patients and COVID-19 have been published.

Here is link as well:

IOIBD (International Organization for the Study of Inflammatory Bowel Disease) Recommendations (#76) for IBD Patients with Regard to COVID-19:

Full link: IOIBD Update on COVID19 for Patients with Crohn’s Disease and Ulcerative Colitis (3/26/20)

 

“Tofacitinib: A Jak of All Trades”

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: W Sandborn 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.

Findings:

  • 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.”

Related blog posts -Tofacitinib:

Related blog posts -ASUC:

Ciutedella Park, Barcelona

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.

FDA Warning on Tofacitinib

From FDA: 7-26-19 FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR)

An excerpt:

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

Related blog posts:

University of Virginia

Reassuring Study on Colonoscopy Safety in Adults

Full Abstract: Low Rates of Gastrointestinal and Non-Gastrointestinal Complicaitons for Screening or Surveillance Colonoscopies in a Population-Based Study

(L Wang, et al. Gastroenterol 2018; 154: 540-555https://doi.org/10.1053/j.gastro.2017.10.006)

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.

Availlable online: graphical abstract

Key findings:

  • GI complications including perforation and GI bleeding were low but more common with colonoscopy than comparator procedures
  • Rates of serious non-GI complications including myocardial infarction, stroke, and serious pulmonary events were no higher than other low-risk comparator procedures.
  • Complication rates were higher with advancing age, particularly in those >70 years. see Figure 2 below

 

Image available online: Figure 2

 

Expert 2017 Opinion: Miralax is (Still) First Choice Laxative for Children

IJN Koppen et al. Journal of Pediatric Gastroenterology & Nutrition: October 2017 – Volume 65 – Issue 4 – p 361–363

Abstract:

 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).

Key Points:

  • 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)

Safety:

  • 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.”

Combatting Myths: 

  • 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.”

Related blog posts:

 

“Not Up For Debate: The Science Behind Vaccination”

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.