To the Editor:
The focus point of our systematic review was to define endpoint criteria to allow interstudy comparisons. We performed a systematic review using a Delphi method process to provide a straightforward framework to define treatment response and endpoints in autoimmune hepatitis (AIH).
[1]
Endpoints can be used as reference points and as a standard that helps systematically report study results. This allows for a better comparison of outcomes across studies and facilitates data aggregation into systematic reviews to more accurately assess treatment efficacy.The International Autoimmune Hepatitis Group (IAIHG) agreed that non-response in AIH should be defined as ‘<50% reduction of serum transaminases within 4 weeks after initiation of treatment’.
[1]
Medas et al.[2]
aimed to validate the IAIHG definition of non-response and the ‘rapid response’ definition from Pape et al.,[3]
defined as a decrease of ≥80% in the level of aspartate aminotransferase (AST) after 8 weeks. They did so using a cohort of 60 patients with AIH and demonstrated that rapid response at 8 weeks predicts a higher probability of complete biochemical response than the IAIHG definition for (non-)response within 4 weeks.[1]
The authors did not include relevant clinical outcomes such as liver-related death or liver transplantation. Although the endpoint of ‘rapid response’ was not formally assessed in the Delphi survey and differs from the endpoint ‘non-response’, we agree with the authors that it is interesting to examine whether ‘rapid response’ after 8 weeks better discriminates between disease courses than non-response within 4 weeks.Ma et al.
[4]
validated the IAIHG response criteria, non-response, complete biochemical response, and insufficient response, in their large cohort of 650 Chinese patients with AIH. In contrast to the Portuguese study,[2]
4-week responders had a higher probability of achieving a complete biochemical response compared to non-responders (79.0% vs. 55.1%; p <0.001). In addition, they provided evidence on the prognostic value of non-response, and they reported that histological remission was more likely to occur in 4-week responders compared to non-responders (70.0% vs. 43.8%; p = 0.028).In order to validate ‘rapid response’ at 8 weeks, we performed a retrospective analysis using our adult AIH cohort which includes patients possessing a simplified IAIHG score ≥6. Patients with variant syndromes or competing liver diseases were excluded. We included 289 patients who were eligible for the study (75% females). At diagnosis, the median age was 51 years (IQR 38–66), and 59 patients had evidence of cirrhosis at diagnosis. The median follow-up time was 7 years (IQR 3.8–10.0). Most patients (n = 177; 61.2%) were considered rapid responders at 8 weeks after initiation of treatment. Patients with a rapid response, i.e., an ≥80% decrease in the level of AST after 8 weeks, had a similar risk of liver-related death and liver transplantation as patients with a disease course based on our IAIHG non-response definition (hazard ratio [HR] 0.143; 95% CI 0.031–0.656; p = 0.012 for rapid response at week 8 vs. HR 0.139; 95% CI 0.045–0.426; p <0.001 for the IAIHG non-response definition).
The clinical consequence of these observations is that all endpoints may serve as predictors of the long-term disease course. As clinicians, we are continuously searching for parameters that predict the future of a disease with the hope that our management may change the clinical behaviour of that disease. However, this thinking confounds the debate on endpoints. We defined a set of endpoints needed for standard reporting of study results in AIH. To bolster credibility, we tested these definitions against (future) clinical outcomes and showed discriminatory predictive value. Our effort was not to design a tool to predict disease behaviour, as this requires the combination of many more (bio)markers to optimize the predictive value.
[5]
While a complete biochemical response is clinically a highly relevant endpoint, both clinicians and patients may want other (early) predictors in management algorithms for patients with AIH. We chose the 4-week period based on the best-published data at the time and after consensus within the IAIHG group, and we simplified the concept of non-responsiveness. Indeed, we could not distinguish between populations with a non-response or rapid response at 8 weeks with respect to the risk of liver-related outcomes, supporting the clinical relevance of the 4-week response.The caveat is that our definitions help to compare AIH disease behaviour at a population level by implementing them in clinical studies. However, we think it is too early to use these definitions to guide individual management. It is important to consider that non-response does not necessarily imply that treatment should be changed, but it should alert the clinician since it is likely to have prognostic value, as we demonstrated above. It increases the transparency of the therapeutic pathway from the beginning of the AIH patient journey and can contribute to future clinical studies.
Financial support
No financial support was received for this letter.
Authors’ contributions
RS: data analysis and manuscript drafting; TG, MH and JD: critical expert review and revision of the manuscript.
Conflict of interest
The authors declare no conflicts of interest that pertain to this work.
Please refer to the accompanying ICMJE disclosure forms for further details.
Acknowledgments
There are no additional acknowledgments.
Supplementary data
The following are the supplementary data to this article:
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References
- Systematic review of response criteria and endpoints in autoimmune hepatitis by the International Autoimmune Hepatitis Group.J Hepatol. 2022; 76: 841-849
- 2022 International Autoimmune Hepatitis Group non-response criteria in autoimmune hepatitis: a too early endpoint?.J Hepatol. 2022; 77: 1461-1462
- Rapid response to treatment of autoimmune hepatitis associated with remission at 6 and 12 months.Clin Gastroenterol Hepatol. 2020; 18: 1609-1617 e1604
- Rapid response predicts complete biochemical response and histological remission in autoimmune hepatitis.J Hepatol. 2022; 77: 1463-1464
- Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1.United Eur Gastroenterol J. 2021; 9: 662-671
Article info
Publication history
Published online: August 16, 2022
Accepted:
July 28,
2022
Received:
July 26,
2022
Footnotes
Author names in bold designate shared co-first authorship
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Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
