Immune Mediated Disorders Associated with TNF Inhibitors Can Involve the Liver Too

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Yesterday’s post highlighted immune-mediated disorders likely caused by anti-TNF therapy; this includes rheumatoid arthritis, psoriasis, hidradenitis suppurativa, and chronic recurrent multifocal osteomyelitis. Anti-TNF inhibitors can be the reason for drug-induced liver disease (DILI) including autoimmune hepatitis (AIH) as well. 

  • In one study, 8% of children receiving anti-TNF therapy developed a new elevation in ALT.
  • Most often liver enzyme elevation is mild and transient
  • Differential diagnosis for persistent elevation can be due to DILI, autoimmune liver disease (eg. PSC, AIH), or rarely due to a combination (autoimmune drug-induced liver disease). The latter can improve with drug cessation and with corticosteroid treatment.

Some slides on this topic (courtesy of William. Balistreri):

My take: Serious liver injury related to anti-TNF therapy is rare. When liver enzymes are persistently elevated, consider DILI including anti-TNF agents.

Related blog posts:

Paradoxical Immune Mediated Disorders Associated with TNF Inhibitors

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Previously, it has been noted that several immune mediated problems paradoxically can be triggered by the use of TNF inhibitors (eg. infliximab, adalimumab) even though these medications are often used to treat these problems (see posts below).

Using 2 nationwide cohorts (Danish & French), Ward et al (Clin Gastroenterol Hepatol 2024; 22: 135-143. Open Access! Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases) report on the associated risk of developing a number of additional immune mediated inflammatory diseases (IMIDs) after treatment with anti-TNF agents for inflammatory bowel disease (IBD). The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD. Key findings:

  • Anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66) and the French cohort (HR, 1.78), with a pooled HR of 1.76
  • The absolute risk of IMIDs in the Danish cohort was 5.3/1000 person years compared to 3.8/1000 PY those who had not received anti-TNFs; in the French cohort, the rate in anti-TNF exposed was 5.4/1000 PY compared to 3.0/1000 PY in the unexposed group.
  • Anti-TNF therapy was also associated with an increased risk of the IMIDs when compared with azathioprine (pooled HR, 2.94).

The results suggest that anti-TNFs paradoxically increase the risk of IMIDs; however, individuals receiving anti-TNFs are likely at higher risk for these disorders and this could be difficult to control for in a retrospective study.

My take: While anti-TNF agents have been a tremendous advance in the treatment of IBD, in a small number of individuals, these agents appear to trigger a paradoxical reaction.

Related blog posts:

Chattahoochee River at Island Ford. Sandy Springs

“Efficacy” of Probiotics in Irritable Bowel Syndrome

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VC Goodoory, M Khasawneh et al. Gastroenterol 2023; 165: 1206-1218. Open Access! Efficacy of Probiotics in Irritable Bowel Syndrome: Systematic Review and Meta-analysis

After performing a systematic literature review, the authors identified randomized controlled trials (RCTs) recruiting adults with IBS, comparing probiotics with placebo were eligible; this included 82 eligible trials, containing 10,332 patients. However, only 24 RCTs were at low risk of bias across all domains.

Key findings:

  • There was some evidence to support the use of some probiotics for global IBS symptoms, abdominal pain, and abdominal bloating or distension (highly detailed analysis of the studies in article –Figures 1-3 and Tables 1-3)
  • There was moderate certainty in the evidence for a benefit of Escherichia strains, low certainty for Lactobacillus strains and L. plantarum 299V, and very low certainty for combination probiotics, LacClean Gold S, Duolac 7s, and Bacillus strains
  • For abdominal pain, there was low certainty in the evidence for a benefit of S. cerevisiae I-3856 and Bifidobacterium strains, and very low certainty for combination probiotics, Lactobacillus, Saccharomyces, and Bacillus strains
  • For abdominal bloating or distension, there was very low certainty in the evidence for a benefit of combination probiotics and Bacillus strains
  • The relative risk of experiencing any adverse event, in 55 trials, including more than 7000 patients, was not significantly higher with probiotics

My take: This study shows that it is difficult to confidently recommend specific probiotics for IBS as the certainty in the evidence for efficacy by GRADE criteria was low to very low. In addition, the quality control of production of most probiotics is uncertain.

Related blog posts:

Riverside Park, Sandy Springs

Year-in-Review for Pediatric Hepatology

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Recently, Dr. William Balistreri presented a review of some of the biggest advances in pediatric hepatology this past year on the Bowel Sounds Podcast (with the award-winning hosts).

He discussed the following:

  • IBAT inhibitors which are a game-changer for pruritic cholestatic disorders like Alagille syndrome. By reducing itching, it may help many avoid liver transplantation
  • HCV medications which usually result in a cure with typical therapy courses running 8-12 weeks
  • Emergence of a new treatment, Fazirsiran, for alpha-one antitrypsin deficiency (see blog post below)
  • More data showing the good liver safety of methotrexate in individuals without preexisting liver disease. Dr. Balistreri and colleagues showed pediatric patients with JRA did not develop liver fibrosis/clinical liver disease in 1997.
  • How Gilbert’s may be beneficial –>hopeful news for the mildly jaundiced children that we see. Science (M Leslie, 6/8/23): Can ‘toxic’ bilirubin treat a variety of illnesses

He kindly agreed to send me a few slides on the later two subjects at my request:

Related blog posts:

IBAT Inhibitors:

Hepatitis C

Alpha-One Antitrypsin

Dr. Balistreri

Life, Even in the ICU, is Better with Music

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S Mounier et al. J Pediatr 2024: 264: 113736. Music Therapy During Basic Daily Care in Critically Ill Children: A Randomized Crossover Clinical Trial

In this cross-over randomized controlled study with 50 children (median age 3.5 yrs), the authors assessed whether music therapy (MT) is effective to reduce pain during daily personal hygiene care (DPHC). The primary outcome was variation of the Face Legs Activity Cry Consolability (FLACC) score (range, 0-10). Key findings:

  • FLACC score was 0.0 (0.0-3.0) at baseline and 3.0 (1.0-5.5) during DPHC. With MT, these values were, respectively, 0.0 (0.0-1.0) and 2.0 (0.5-4.0).
  • Rates of FLACC scores of >4 during DPHC, which indicates severe pain, were 42% in standard conditions and 17% with MT (P = .013).

In their background, the authors note that MT “provides feelings of well-being and relaxation and acts as a distractor, leading to the inhibition of pain perception.”

My take: This study reinforces the importance of distraction to reduce pain. Life is better and less painful with music.

Of course, the scene from “Airplane!” shows that not all music therapy is beneficial: Clumsy Stewardess and Near Death Experience

LA Times: Dr. Lapado, Florida Surgeon General, is a “Dangerous Quack”

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LA Times, Michael Hiltzik (1/9/24): Column: Meet the most dangerous quack in America

An excerpt:

It used to be fairly easy to dismiss Florida’s surgeon general, Dr. Joseph A. Ladapo, as a clownish anti-vaccine quack posing a danger mostly to residents of his home state…Ladapo has moved from promoting useless treatments for COVID-19, such as the drugs hydroxychloroquine and ivermectin, to waging an ever-expanding fact-free campaign against the leading COVID vaccines…

Last January, a faculty committee at the University of Florida medical school found that Ladapo engaged in “careless, irregular and contentious” research practices that may have violated university rules…

That brings us to Ladapo’s latest adventure in medical quackery, his claim that no one should take the mRNA vaccines….Ladapo’s advice is based on what he says is research that the Pfizer and Moderna mRNA COVID vaccines contain fragments of DNA that are injected into human cells, which they can contaminate and turn into cancer cells…

The human cell has a panoply of mechanisms to destroy foreign DNA. Even if the fragments managed to penetrate the cell nucleus, which can’t happen, they would have to cut up the existing DNA, which would require a mechanism the fragments don’t have.

“So the chance that DNA could affect your DNA is zero,” Offit said..

Ladapo’s words and actions have surely contributed to his state’s pathetic performance in getting its citizens vaccinated against COVID. With 11.6% of its population fully vaccinated with a booster as of last May, Florida had a rate among the lowest in the nation. (California’s rate was 20.6%.) Among those 65 and older — purportedly the population that Florida strives to protect — only 31.2% were fully vaccinated. (California: 48.3%.)

Florida’s death rate from COVID of 375 per 100,000 people is among the worst in the country. (California: 283.) You can ignore the defense that the difference is due to Florida’s relatively older population; states with even older median ages have done much better: Vermont (170), New Hampshire (245) and Maine (252). The difference is the indifference of Ladapo and DeSantis to their own residents’ health.

Related blog posts:

As reported on 1/19/24

Is PPI Use Detrimental Before or After a Diagnosis of Inflammatory Bowel Disease?

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N Singh et al. Inflamm Bowel Dis 2023; 29: 1871-1878. Proton Pump Inhibitor Use Before and After a Diagnosis of Inflammatory Bowel Disease

The authors retrospectively utilized the University of Manitoba IBD Epidemiology Database includes all Manitobans diagnosed with IBD between 1984 and 2018 (n=5920). Key findings:

  • Rates of PPI use in control subjects increased gradually from 1.5% to 6.5% over 15 years
  • Persons with IBD had a higher rate of PPI use, peaking up to 17% within 1 year of IBD diagnosis with a rate ratio (RR) of 3.1

The authors noted an abrupt increase in PPI use within 6 months of an IBD diagnosis which could indicate that IBD-related symptoms are being mistakenly treated with a PPI or that IBD may increase reflux-related symptoms. Given the higher rate of PPI use in pre-IBD diagnosis patients, compared to controls, the authors note that “it is possible that their [PPI] use enhances the likelihood of an IBD diagnosis by their role in altering the gut microbiota.” In addition, they note that “a case-control study found that PPIs were associated with an increased risk of pediatric IBD” (NR Schwartz et al. J Pediatr Pharmacol Ther 2019; 24: 489-496).

My take: PPIs are being used more frequently. Whether PPIs are detrimental before or after a diagnosis with IBD is not clear.

Chattahoochee River at Island Ford

IBD Updates

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  1. Allopurinol makes thiopurines more effective. A Vasudevan et al. AP&T 2023; https://doi.org/10.1111/apt.17831 Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study)

This was  a multicenter, randomized, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD in 102 patients. Allopurinol was dosed at 100 mg. Key findings:

  • A higher proportion achieved the primary outcome (improved clinical score and fecal calprotectin <150) in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02

Related blog posts:

2. Newer treatments and lower colectomy rates in pediatric UC. D Ley et al. AJG 2023; 118:1997-2004 New Therapeutic Strategies Are Associated With a Significant Decrease in Colectomy Rate in Pediatric Ulcerative Colitis. Thanks to Ben Gold for this reference.

Medication exposure and disease outcomes were compared between 3 diagnostic periods: 1988 to 1993 (period [P] 1; pre-IS era), 1994 to 2000 (P2; pre-anti-TNF era), and 2001 to 2011 (P3; anti-TNF era).

  • Key finding: The risk of colectomy at 5 years decreased significantly over time (P1, 17%; P2, 19%; and P3, 9%; P = 0.045, P-trend = 0.027) and between the pre-anti-TNF era (P1 + P2, 18%) and the anti-TNF era (P3, 9%) (P = 0.013). 

Related blog posts:

3. More data indicating that anti-TNF therapy does not increase post-operative complications. D Bajzat et al. Inflamm Bowel Dis 2023; 29: 1971-1980. Safety Analysis of Preoperative Anti-TNF-α Therapy in Pediatric IBD After Intestinal Resection: A Systematic Review and Meta-analysis

In this systematic review, the authors identified 8 eligible articles with 526 pediatric patients with IBD. Key finding: “There is no significant association between preoperative anti-TNF-α therapy and postoperative complications in children with IBD after intestinal resection.”

Related blog posts:

Pics from Island Ford/Chattahoochee River

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.

Long-Term Outcomes off Immunosuppression in Children After Liver Transplant

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S Kortbeek et al. J Pediatr 2024; 264: 113744 .Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry

This was a retrospective case-control study with 33 patients who were off immunosuppression for at least 1 year. The median age at LT was 0.7 years. The median IS withdrawal time was 9 years after LT. 

Key findings:

  • No differences in allograft rejection rates, IS complications, or c-IO [composite ideal outcome] prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS.

This is a highly-selected group representing ~0.5% of pediatric liver transplants (1996-2015).

My take: In this small sample size, patients off IS had similar outcomes as patients who continued on IS. Understanding this group better could help extend this approach to more patients.

Related blog post: Liver Shorts: Stopping immunosuppression after transplant, toxicity of acetaminophen at therapeutic dosing, best imaging of PSC

Chattahoochee River at Island Ford

Why It is Hard to Do Histology EGD Studies -Case in Point: Endoscopy in Autism

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SA Ballal et al. J Pediatr 2024; 264: 113737. Comparing Gastrointestinal Endoscopy Findings in Children with Autism, Developmental Delay, or Typical Development

This retrospective study compared the findings of children with probable autism (ASD) to age- and gender-matched controls with developmental delay (DD) or with typical development (TD), (n= 526 ASD, 526 DD, 1052 TD). Key findings:

  • Children with ASD had higher rates of abnormal esophageal histology (ASD 38.4%; DD 33.4%; TD 30.4%, P = .008)
  • Stomach findings did not differ significantly among the groups: histologic inflammation was identified in ASD 13.3%, DD 18.5%, and TD 22.4% (P=.10).
  • In the duodenum, histologic abnormalities were observed with lower frequency in ASD (ASD 17.0%; DD 20.1%; TD 24.2%, P = .005).

The authors emphasize the importance of the esophageal findings (increased rates of esophagitis). However, there are some important caveats that are not discussed in the paper:

  • At baseline (prior to study), it was known that the ASD and DD groups had higher rates of eosinophilic esophagitis: ASD 9.1%, DD 9.5%, and TD 7.4% (Table 1). In addition, both of these groups had higher rates of gastroesophageal reflux at baseline: ASD 7.6%, DD 8.0%, and TD 6.5%. This selection bias is likely to negate much of the esophageal differences observed in their study. Also, the ASD group had much higher numbers receiving H2 blockers at time of procedure: ASD 11.4%, DD 10.3%, and TD 6.4%.
  • In addition, the TD group had a much higher rate of abdominal pain as the indication for endoscopy (TD 26.6%, ASD 17.5%, and DD 20.2%). It is well-recognized that isolated abdominal pain has a low yield on endoscopy.
  • The authors do not discuss the elephant in the room. What is the significance of microscopic esophagitis (or microscopic gastritis or microscopic duodenitis)? Previous authors have noted that “15% of healthy individuals may have microscopic esophagitis” (Gastroenterology 2018 (volume 154; pages 263-451 -see page 291). When we were looking at the variation of diagnostic yield for endoscopy, we decided to focus on colonoscopy because of the high rates of microscopic inflammation in the upper GI tract (related blog post: Our Study: Provider Level Variability in Colonoscopy Yield)

My take: In their discussion, the authors state that this study represents “significant progress in the understanding of gastrointestinal pathophysiology in children with ASD…suggest a unique fingerprint of findings in children with ASD.” In my view, the authors showed similar yield of EGD histologic abnormalities in all three groups and these microscopic findings are of uncertain significance. 

Related blog posts:

Chattahoochee River at Island Ford