Tag Archives: TPMT

Current Practices and Wide Variation in Autoimmune Hepatitis Treatment Across Europe

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M Cananzi et al. J Pediatr Gastroenterol Nutr. 2025;80:260–270. Current practice in the management of paediatric autoimmune liver disease in Europe

Methods: Thirty-six centers from 22 European countries responded to the survey that was sent to European Reference Network for Rare Liver Disorders (ERN RARE-LIVER) and members of the Hepatology Interest Group (HIG) of the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)

Key findings:

  • All centers use predniso(lo)ne as first-line therapy, alone (15/36) or with azathioprine (21/36)
  • Azathioprine and mycophenolate are the preferred second-line options in centres using first-line steroid monotherapy (11/15) or combined steroid-azathioprine (19/21)
  • Tacrolimus is used as third-line agent in 15/36 centers
  • Proactive measurement of drug metabolites and target levels vary widely among centers. About 27/36 centers have thiopurine methyltransferase (TPMT) genotyping available, of which 21 (58%) routinely perform this test before prescribing AZA. Among the 12 centres that reported target metabolite levels, 10 aim for levels between 200 and 300 pmol/8 × 108 red blood cells (RBC).
  • About 24/36 centers routinely incorporate PPIs into steroid treatment protocols, seven prescribe PPIs solely when there are risk factors for peptic ulcer disease, and the remainder refrain from using PPIs unless gastrointestinal symptoms occur.

My take: There is a great deal of variation in the management of autoimmune hepatitis indicating the need for more collaborative efforts to advance evidence-based therapeutic strategies.

Related blog posts:

White Temple, Chiang Rai, Thailand

Thiopurine Metabolite Testing -NASPGHAN Consensus Recommendations

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The inflammatory bowel disease committee of NASPGHAN has published a review and recommendations for the use of thiopurine metabolite testing (JPGN 2013; 56: 333-40).

The effectiveness of thiopurines is reviewed with a few key points:

  • Cochrane reviews have shown that azathioprine and 6-mercaptopurine are effective in inducing remission in Crohn’s disease.  For active disease the overall response rate has been reported as 54% compared with 33% for placebo.
  • For ulcerative colitis, a Cochrane analysis deemed the methodologic quality of 4 of the 6 studies as unsatisfactory and that all studies were small.  “The reviewers concluded that azathioprine may be effective treatment for patients with ulcerative colitis.”

The review covers the potential adverse effects of the thiopurines: myelosuppression, pancreatitis, elevated transaminases, susceptibility to infection, and malignancy.  The review suggests that the risk of non-Hodgkin lymphoma is probably increased up to 4-fold. Though, it is difficult to determine how much of the risk is truly due to the usage of thiopurines or other confounding factors.  The studies about the risk of non-melenoma skin cancer are not discussed.

Other covered topics: advantages of thiopurine metabolite testing (6-thioguanine [6-TGN] and 6-methylmercaptopurine[ 6-MMP]), potential disadvantages of metabolite testing (e.g.. cost), use of genotype versus phenotype (phenotypic testing is generally preferred), thiopurine metabolism, devising target levels, use of allopurinol, and misinterpretation of metabolite testing.

Specific Consensus Recommendations:

  • Obtain thiopurine methyltransferase (TPMT) testing prior to initiation of thiopurines.
  • Avoid use of thiopurines in individuals with extremely low TPMT activity or who are homozygous recessive for TPMT activity
  • TPMT testing does not predict all cases of leukopenia.  All individuals receiving thiopurines should have routine monitoring with CBCs.  “Most adverse effects from thiopurines are not directly related to 6-TGN or 6-MMP levels.”
  • Metabolite testing can help determine adherence to therapy
  • Metabolite testing may be helpful in guiding dose adjustment and/or adding allopurinol treatment
  • Routine and repetitive testing of metabolites is not recommended in patients who are doing well on an acceptable thiopurine dosage.

Related blog posts:

Improve Care Now

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Several years ago, “ImproveCareNow” Network was established with a goal of improving the quality of care children with inflammatory bowel disease. https://improvecarenow.org/ (http://www.youtube.com/watch?v=beG2eMROWqg)

Documentation of some outcomes of this effort have now been published (Pediatrics 2012; 129: e1030-e1041).  In this study from six U.S. centers, data from 843 children with Crohn’s disease and Ulcerative Colitis were available.  Centers were eligible to participate if they did not have extensive quality improvement (QI) experience and if they were able to enroll >75% of their IBD patients.  During the course of the study (2007-2010), there were increases in the proportion of patients with measurement of thiopurine methyltransferase (TPMT) before initiation of thiopurines, increased percentage of individuals receiving an appropriate thiopurine dosage, and an increased percentage of patients with inactive disease.  In Crohn’s disease, the number with inactive disease changed from 55% to 68%; in ulcerative colitis, the number increased from 61% to 72%.  

This study shows significant progress in these patients and the potential benefit of a more-structured approach.  However, some of the improvements in these outcomes may not be to process improvements. 

Study limitations:

  • The study does not document the rate of inactive disease in non-participating centers; thus there is not an adequate control population.  Given more widespread use of biologic therapies, this may account for much of the improvement in outcomes.   In fact, the study does not describe the percentage of patients receiving thiopurines or biologic agents.
  • The use of the physician global assessment (PGA) as indicative of disease activity.  The authors acknowledge that “PGA ….is a relatively subjective measure.”  A more reliable measure of disease activity like a stool calprotectin, endoscopy, or imaging study improvement would have been helpful.  
  • Better documentation or better outcomes? It is not clear whether some of the improvement reflects better documentation or improved care delivery.

Despite the limitations of this study, it is a good starting point.  The goal of improving the care of patients is shared by almost all physicians.  One way to start making a difference is measuring specific outcomes and targeting specific goals/checklists. Going forward with QI there are many QI hurdles: 

  • Defining optimal care is nearly impossible, there are few trials comparing efficacy & difficult to judge risk/benefit ratio of many therapies.
  • Difficulty selecting appropriate outcome measures -indications for hospitalization and surgery are not clear-cut in many cases.  Surgery may be an appropriate treatment rather than a negative outcome. 
  • Risk adjustment is an imperfect science.

Goals with Quality Improvement:

  • Plan-Do-Study-Act cycles.
  • Learning from high-performing centers -benchmarking

Warranted vs unwarranted variations:
Unwarranted: selecting inadequate dosing of medications, failure to check for TB before remicade/biologics, failure to consider drug interactions, failure to discuss options with families
Warranted: variation due to differences in disease (eg budesonide for ileitis but not pancolitis), variation driven by patient preferences (eg. using NG instead of corticosteroids)

“When you can measure what you are speaking about and express it in numbers, you know something about it; but when you cannot express it in numbers, your knowledge is of a meagre and unsatisfactory kind” –Lord Kelvin 1883

“Not everything that counts can be counted, and not everything that can be counted counts.” –Albert Einstein

Additional references on quality improvement:

  • Free Self Management Handbook endorsed by ImproveCareNow:

https://improvecarenow.org/patients/self-management-handbook

  • -JPGN 2009; 49: 272.  Review of quality measures/history.
  • -Kohn LT, et al. To Err is Human: Building Safer Health System.  Nat’l Academy Press; 2000
  • -Crossing the quality chasm.  Wash DC: Nat’l Academy Press; 2001.
  • -Clin Gastro & Hep 2010; 8: 709.  Quality indicator sets in cirrhosis.
  • -J Pediatr 2005; 146: 744-50.  Bucuvalas JC et al.  Adjusting calcinerin inhibitor dosing
  • -IBD guidelines: www.cincinnatichildrens.org/svc/alpha/health-policy/ev-based/ibd.htm
  • -JPGN 2009; 49: 297.  Variation in care in pediatric Crohn disease. (Our center participated in this study)
  • -J Pediatr 2009; 154: 582.  Ventilator assoc pneumonia reduced w bundle of hand hygiene, elevated HOB, not changing ventilator circuits except when soiled & mouth care
  • -“The Learning Curve”(Atul Gawande) in The Best American Essays 2003 -some CF ctrs outperform, extending life expectancy ~14yrs.
  • -” A Surgeons Notes on Performance-Atul Gawande
    -NEJM 2007; 357: 2652.  Nice editorial.
  • www.icsi.org
  • www.qualityforum.org
  • www.ambulatoryqualityalliance.org
  • www.ncqa.org
  • www.cms.hhs.gov/hospitalqualityinit

Comments from lead author forwarded to blog:

Thanks for including our recent paper in your blog.  I agree with the study limitations as you mentioned, but wanted to put a couple of things in context.  We actually thought very hard about the issue of a control group, and specifically how to determine what the remission rate would be without the intervention.  We could not come up with a reasonable comparator (very few people/groups outside of ICN even know what the remission rate of their population is).  One very rough measure (which we did not feel was legitimate to include) is the rate of remission for new sites as they are joining the collaborative.  Established sites with complete participation have better outcomes than newer sites or sites that participate less fully, suggesting that at least a significant portion of the effect is due to the QI intervention rather than secular trend.  As far as the objective measures for outcomes, I know you realize that we are not able to mandate specific objective evaluations for a QI/observational research study, so we may never be able to use mucosal healing (for example) as our measure of remission.  However you probably noticed in the paper that we did demonstrate improvements in objective measures including sPCDAI, PUCAI and use of corticosteroids.  Certainly improvements in process measures may have been due in part to better documentation, but it is unlikely that objective outcome measures improved due to documentation. Thanks again for sharing our work with your audience.