Reply to: “Mycophenolate mofetil in autoimmune hepatitis: Are we ready for primetime?”
Authors: Charlotte D. Slooter, Anna E.C. Stoelinga, Romée J.A.L.M. Snijders
Journal: Journal of Hepatology (2024)

An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitisJournal of HepatologyVol. 80Issue 4PreviewPatients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH. Full-Text PDF Open AccessMycophenolate Mofetil in Autoimmune Hepatitis: Are We Ready for Primetime?Journal of HepatologyPreviewWe read with interest the clinical trial by Snijders et al1 comparing azathioprine (Aza) or mycophenolate mofetil (MMF) in addition to prednisolone for inducing complete biochemical remission (CBR) in treatment-naive patients with autoimmune hepatitis (AIH). The trial provides important clinical evidence, suggesting that MMF is better tolerated and more effective than Aza when used in addition to prednisolone to achieve CBR. However, there are some areas of concern in this trial which need to be addressed. Full-Text PDF We extend our gratitude to Shalimar et al. for their interest in our recent randomized clinical trial comparing azathioprine (Aza) and mycophenolate mofetil (MMF), both combined with prednisolone, for inducing biochemical remission (BR) in treatment-naive patients with autoimmune hepatitis (AIH) (1Snijders R. Stoelinga A.E.C. Gevers T.J.G. et al.An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.J Hepatol. 2024; 80: 576-585Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar). We value the concerns raised in their letter (2Biswas S. Shalimar. Mycophenolate Mofetil in Autoimmune Hepatitis: Are We Ready for Primetime?.J Hepatol. 2024; Abstract Full Text Full Text PDF Google Scholar) and would like to address each point comprehensively. Firstly, we acknowledge the concern regarding the unequal distribution of patients between the Aza (n=31) and MMF (n=39) groups. Achieving balanced allocation across treatment arms was a critical consideration for us and we employed various strategies to achieve this. The protocol delineated randomization at a 1:1 ratio, employing blocks of variable sizes (4, 6, 8) – a particularly advantageous approach for small to moderate-sized RCTs – stratified per participating center and for presence of cirrhosis. However, factors such as enrollment discrepancies among sites, absence of inclusions during the COVID-19 pandemic, and consequently, the need to add multiple centers to participate, with some centers only able to include one or two patients per center, contributed to a skewed distribution. Comparing the original sample size calculation, which determined that 32 patients per arm were needed to detect a difference of 35% with 80% power, to the final group sizes and observed effects – the Aza group with 39 patients and 56.4% achieving BR, and the MMF group with 31 patients and 29% achieving BR – suggests that our study maintains sufficient statistical power. The authors suggest that Aza should have been withheld in patients with a serum bilirubin > 100 μmol/L, as recommended by the EASL practice guidelines on AIH (3European Association for the Study of the LEASL Clinical Practice Guidelines: Autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar). In the study, the baseline bilirubin levels corresponded to the initiation of prednisone, with Aza introduced four weeks later; at this point, only three patients had levels exceeding this threshold. Hepatotoxicity is relatively uncommon in patients receiving Aza, and it is unclear whether high bilirubin levels increase this risk. A RCT should be able to move the goal posts to beyond what is currently known or believed and our data help to inform clinicians making treatment decisions. The authors also suggest to explore the effect of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) on disease severity and prognosis in patients with AIH. The prevalence of MASLD in AIH is similar to the general population (4Zachou K. Azariadis K. Lytvyak E. et al.Treatment responses and outcomes in patients with autoimmune hepatitis and concomitant features of non-alcoholic fatty liver disease.JHEP Rep. 2023; 5100778PubMed Google Scholar) and in our study, histological evidence of steatosis was present in 23% (Aza) and 21% (MMF) of our patients. The presence of steatosis did not affect the primary outcome as BR within 24 weeks was similar (steatosis 8/15 vs. non steatosis 22/52, p = 0.559). The authors are concerned about the use of a fixed dose regimen of Aza, as this may result in potential undertreatment. Currently, there is no RCT-proven evidence demonstrating superior outcomes with higher doses of Aza. Moreover, had we adopted a weight-based dosing approach, it could have introduced another level of complexity and potential variability in treatment response. In our study, four patients that continued Aza treatment received less than the 1-2 mg/kg/day recommended range specified in the EASL guideline (3European Association for the Study of the LEASL Clinical Practice Guidelines: Autoimmune hepatitis.J Hepatol. 2015; 63: 971-1004Abstract Full Text Full Text PDF PubMed Scopus (873) Google Scholar). However, this did not affect the BR and mean daily Aza dose was similar (BR 1.27 SD 0.20 vs. no BR 1.21 SD 0.24, p = 0.259). Also, the mean daily dose was not associated with achieving BR (OR 3.85 95% CI 0.08-192.14, p = 0.499). Finally, we concur with Shalimar et al. regarding the importance of evaluating baseline variables—such as the presence of cirrhosis and baseline bilirubin and IgG levels— which may predict tolerance to and response with Aza. In our limited data, we do not observe any significant association between achieving BR and the presence of cirrhosis (OR 1.01 95% CI 0.16 - 7.06, p = 0.947), baseline bilirubin (OR 1.00 95% CI 0.99-1.01, p = 0.768), and IgG levels (OR 0.96 95% CI 0.87 – 1.06, p = 0.396). We defer the exploration of these issues, as well as the association of TPMT/NUDT-15 mutation analyses, to the realm of precision medicine. In conclusion, our clinical trial provides a robust answer to a single question, but also raises many other questions as Shalimar rightfully states. The next step is to collect 52-week data to judge whether the remission induced by MMF is sustained. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. CS: manuscript drafting; AS, RS: critical expert review and revision of the manuscript. No financial support was received for this letter. None