Title: Mycophenolate Mofetil Versus Azathioprine as a First-Line Treatment for Autoimmune
Hepatitis: A Comparative Systematic Review and Meta-Analysis
Version: 4 Date: 11 May 2025
Reviewer's report:
In this study, the authors made a systematic review and meta-analysis  to evaluate the efficacy
and safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) combined with steroids
as first-line treatment for the management of AIH patients.
Studies comparing MMF to AZA combined with steroids in treatment-naïve patients with
AIH were included. Overall, out of 344 search results, four studies comparing MMF to AZA
combined with steroids in treatment-naïve patients with AIH that met the inclusion criteria were
delected, encompassing a total of 512 patients.
They found that MMF combined with prednisolone significantly improved both short-term
complete biochemical remission (CBR) rates (OR, 2.56; 95% CI, 1.18–5.55) and long-term CBR
rates (OR, 5.51; 95% CI, 1.7–17.91) compared to AZA-prednisolone. MMF treatment displayed
a significantly lower occurrence of serious adverse events. Thus the authros concluded that
compared to AZA-based regimens, MMF-based first-line therapy for AIH appears to be a more
promising, effective, and safe treatment option, yielding higher CBR rates and lower serious
adverse event rate requiring treatment discontinuation.
The study addresses an important issue, however, there are several issues that should be
addressed to sustain the study conclusions.
-Of the selected studies to perform the meta-analysis, 3  (2 Dalekos,1 Zachou) come from the
same center. This include a significant bias.
-In a study comparing standard first-line treatment of AIH with another (steroid-MMF), a critical
aspect is the dose and treatment schedule of the steroid. The optimal treatment schedule after the
starting dose (1-2 mg/kg) should be modified (tapering) according to the biochemical response
to avoid that too early tapering of steroid may cause an arrest of the biochemical response
without achieving a satisfactory response that should aim at normalization of transaminases.
The guidelines offer a framework on how to combine the steroid with azathiorpine but suggest
guiding the duration and tapering of the steroid based on the steroid response. Therefore, rigidly
applying a steroid tapering schedule without taking into account the transaminase value could
explain a response rate to first-line therapy with steroid + azathioprine that does not reflect
clinical practice published in the literature.
-Safety profile. MMF is a well-known immunosuppressive agent with optimal results in patients
intolerant to AZA, however, this treatment must require fertility issues in young female, the
majority of AIH patients.
Title: Mycophenolate Mofetil Versus Azathioprine as a First-Line Treatment for Autoimmune
Hepatitis: A Comparative Systematic Review and Meta-Analysis
Version: 4 Date: 11 May 2025
Reviewer's report:
In this study, the authors made a systematic review and meta-analysis  to evaluate the efficacy
and safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) combined with steroids
as first-line treatment for the management of AIH patients.
Studies comparing MMF to AZA combined with steroids in treatment-naïve patients with
AIH were included. Overall, out of 344 search results, four studies comparing MMF to AZA
combined with steroids in treatment-naïve patients with AIH that met the inclusion criteria were
delected, encompassing a total of 512 patients.
They found that MMF combined with prednisolone significantly improved both short-term
complete biochemical remission (CBR) rates (OR, 2.56; 95% CI, 1.18–5.55) and long-term CBR
rates (OR, 5.51; 95% CI, 1.7–17.91) compared to AZA-prednisolone. MMF treatment displayed
a significantly lower occurrence of serious adverse events. Thus the authros concluded that
compared to AZA-based regimens, MMF-based first-line therapy for AIH appears to be a more
promising, effective, and safe treatment option, yielding higher CBR rates and lower serious
adverse event rate requiring treatment discontinuation.
The study addresses an important issue, however, there are several issues that should be
addressed to sustain the study conclusions.
-Of the selected studies to perform the meta-analysis, 3  (2 Dalekos,1 Zachou) come from the
same center. This include a significant bias.
-In a study comparing standard first-line treatment of AIH with another (steroid-MMF), a critical
aspect is the dose and treatment schedule of the steroid. The optimal treatment schedule after the
starting dose (1-2 mg/kg) should be modified (tapering) according to the biochemical response
to avoid that too early tapering of steroid may cause an arrest of the biochemical response
without achieving a satisfactory response that should aim at normalization of transaminases.
The guidelines offer a framework on how to combine the steroid with azathiorpine but suggest
guiding the duration and tapering of the steroid based on the steroid response. Therefore, rigidly
applying a steroid tapering schedule without taking into account the transaminase value could
explain a response rate to first-line therapy with steroid + azathioprine that does not reflect
clinical practice published in the literature.
-Safety profile. MMF is a well-known immunosuppressive agent with optimal results in patients
intolerant to AZA, however, this treatment must require fertility issues in young female, the
majority of AIH patients.
Please review this paper.
user
Title: Mycophenolate Mofetil Versus Azathioprine as a First-Line Treatment for Autoimmune
Hepatitis: A Comparative Systematic Review and Meta-Analysis
Version: 4 Date: 11 May 2025
Reviewer's report:
In this study, the authors made a systematic review and meta-analysis  to evaluate the efficacy
and safety of mycophenolate mofetil (MMF) versus azathioprine (AZA) combined with steroids
as first-line treatment for the management of AIH patients.
Studies comparing MMF to AZA combined with steroids in treatment-naïve patients with
AIH were included. Overall, out of 344 search results, four studies comparing MMF to AZA
combined with steroids in treatment-naïve patients with AIH that met the inclusion criteria were
delected, encompassing a total of 512 patients.
They found that MMF combined with prednisolone significantly improved both short-term
complete biochemical remission (CBR) rates (OR, 2.56; 95% CI, 1.18–5.55) and long-term CBR
rates (OR, 5.51; 95% CI, 1.7–17.91) compared to AZA-prednisolone. MMF treatment displayed
a significantly lower occurrence of serious adverse events. Thus the authros concluded that
compared to AZA-based regimens, MMF-based first-line therapy for AIH appears to be a more
promising, effective, and safe treatment option, yielding higher CBR rates and lower serious
adverse event rate requiring treatment discontinuation.
The study addresses an important issue, however, there are several issues that should be
addressed to sustain the study conclusions.
-Of the selected studies to perform the meta-analysis, 3  (2 Dalekos,1 Zachou) come from the
same center. This include a significant bias.
-In a study comparing standard first-line treatment of AIH with another (steroid-MMF), a critical
aspect is the dose and treatment schedule of the steroid. The optimal treatment schedule after the
starting dose (1-2 mg/kg) should be modified (tapering) according to the biochemical response
to avoid that too early tapering of steroid may cause an arrest of the biochemical response
without achieving a satisfactory response that should aim at normalization of transaminases.
The guidelines offer a framework on how to combine the steroid with azathiorpine but suggest
guiding the duration and tapering of the steroid based on the steroid response. Therefore, rigidly
applying a steroid tapering schedule without taking into account the transaminase value could
explain a response rate to first-line therapy with steroid + azathioprine that does not reflect
clinical practice published in the literature.
-Safety profile. MMF is a well-known immunosuppressive agent with optimal results in patients
intolerant to AZA, however, this treatment must require fertility issues in young female, the
majority of AIH patients.
assistant