Efficacy of Combination Therapies for Autoimmune Hepatitis: A Systematic Review and Meta-Analysis

Autoimmune hepatitis (AIH) is a hepatocellular disorder thought to be caused by an immune system that cannot tolerate autoantigens specific to hepatocytes. This study aims to evaluate the efficacy of using corticosteroids (prednisolone and azathioprine) as a combination therapy in treating AIH. This study aims to synthesize and analyze existing evidence to inform clinical practices concerning the overall clinical efficacy of this treatment approach in managing AIH. A comprehensive search was conducted across multiple online databases and search engines, including PubMed, Google Scholar, ScienceDirect, Medline, and Embase. RevMan 5.4 software was used for meta-analysis, with forest plots created for each outcome. Thirteen studies were included in this systematic review and meta-analysis. The results indicate that the combination of prednisolone and azathioprine for treating AIH leads to less recurrence and better disease control.


Introduction And Background
The hepatocellular disorder known as autoimmune hepatitis (AIH) is thought to be caused by an immune system that is unable to tolerate autoantigens that are unique to hepatocytes [1].Like other autoimmune diseases, AIH is a common illness that affects people of many racial and ethnic backgrounds, both in children and adults [2,3].AIH progresses at different rates in untreated individuals.Individuals who use immunosuppressive medications to induce remission have an extremely good prognosis.On the other hand, lifesaving orthotopic liver transplantation (OLT) is required for patients who present with acute liver failure (ALF) and those who exhibit or experience severe complications related to cirrhosis or hepatocellular carcinoma [4].Jan Waldenström described the typical clinical features of patients with AIH in September 1950 [5].The patient was a young woman who had elevated gamma globulin levels and hepatic dysfunction.Since then, AIH diagnostic standards have been developed and improved [6,7].AIH can be diagnosed in people of all ages and genders, and the condition is increasingly recognized as a global health issue [8,9].In Alaska Natives, the prevalence is very high at 42.9 cases per 100,000 people [10].According to early reports, the age distribution of AIH was bimodal, with two peaks: one between the ages of 40 and 50, and the other between the ages of 10 and 30 [11].However, biases in reporting from tertiary referral centers might have affected this finding.Furthermore, the disorder is now more widely recognized, with cases found in people of all ages, from newborns to those in their eighties [12][13][14].Regional and ethnic differences significantly impact the clinical presentation, course, and prognosis of AIH.Northern European descent shows a prevalence of 38%, while the African-American population shows a 56% to 85% prevalence [15,16].In the United States, people have early onset disease and respond to powerful immunosuppressive agents, while it is quite the opposite for the Japanese population [17,18].
The clinical side of AIH is challenging.There is a need to evaluate the efficacy of different treatment options.This study aims to study the effect of corticosteroids (prednisolone and azathioprine) in the treatment of AIH.

Search Strategy
Throughout the study, ethical considerations such as user privacy and confidentiality were carefully addressed (Table 1).

Population (P)
Patients with autoimmune hepatitis

Inclusion Criteria
Inclusion criteria for the study encompassed patients diagnosed with AIH, consideration of combination therapies targeting AIH, publications in peer-reviewed journals, and research studies with full-text articles.

Exclusion Criteria
Exclusion criteria consisted of studies that did not primarily focus on AIH, non-peer-reviewed publications, including conference abstracts and posters, research with insufficient or incomplete data, and studies focusing exclusively on pediatric populations or data derived solely from pediatric sources (Table 2).

Inclusion criteria Exclusion criteria
Patients

Information Sources
Several digital databases containing relevant literature such as PubMed, Google Scholar, ScienceDirect, and others were utilized.In addition, independent journals and other independent sources were included.

Search Strategy
The strategy is refined by including synonyms and variations of these terms in the search using Boolean operators (AND, OR).Search filters are used to limit the results to human-subject studies published in peerreviewed journals.Furthermore, reference lists of relevant articles and grey literature are manually searched to identify potential studies that would have been missed by electronic searches.The search strategy followed was ("autoimmune hepatitis" OR "AIH" OR "autoimmune liver disease") AND ("combination therapy" OR "combined treatment" OR "multimodal therapy") AND ("efficacy" OR "effectiveness" OR "outcome").The search strategy consists of a systematic and comprehensive search strategy that aims to be inclusive and comprehensive, capturing a diverse range of studies while remaining relevant to the research question.

Selection Process
The articles were double-screened.This review yielded a list of possible papers.Any disagreements were settled through discussion and the senior author's decision.Because the outcome measures in the metaanalysis studies were similar, they were chosen.The meta-analysis excluded studies that lacked sufficient comparable data or had poor methodological quality.

Data Collection
We searched peer-reviewed journals and publications for literature that met the inclusion criteria.To reduce the risk of publication bias, peer-reviewed journals were investigated after a thorough review of the literature.We worked to include or exclude eligible studies.Studies that failed to meet the screening criteria were labeled exclusion or dispute.Before eliminating a study from the literature, exclusion reasons were presented.It was sometimes caused by an interaction of exclusionary factors.

Quality Assessment
The quality assessment included three broad categories of questions: (1) Were the findings of the study validated?(2) What were the results?(3) Are the findings of the study applicable locally?Eleven questions for quality assessment were answered after careful consideration of study designs and findings.The questions were answered with Yes, No, and Can't tell.If you answered Yes to the first question, you should answer the remaining questions.There is some overlap in the questions.The explanations for the answers, as well as comments from researchers, have been included in the Results section.

Data Items
All articles evaluating endoscopic surveillance for dysplasia detection were found by searching PubMed, Science Direct, and Google Scholar.RevMan 5.4 was used for statistical analysis.Following further revision, a total of 13 articles were included in this systematic review after final screening.This screening includes the removal of review articles as well as articles that are unrelated to the study (Figure 1).

Data Characteristics
The detailed summary of all the included studies is given in Table 3.The combination therapy showed fewer relapsing events.

CASP Assessment
To evaluate the methodological quality of the studies included in the meta-analysis, a quality assessment table, designated as Table 4, was created using the Critical Appraisal Skills Program (CASP) tool.The evaluation was based on a modified version of the CASP criteria, which were first developed in 1993 by Guyatt et al. [32] (Table 4).

Meta-Analysis
Meta-analysis was done for the continuous variables using mean, standard deviation (SD), and sample size When these specific data were unavailable, the means and SDs of the intervention and control groups' outcome measurements were used as a substitute.Every study with relevant outcome data was included, and primary analyses were performed for each score.RevMan 5.4 from the Cochrane database was used.
ALT: To collect continuous data, a forest plot was created for each of the six different studies.The overall effect size was calculated using Cohen's d, with d = -46.87,95% confidence interval (CI) = -163.42 to 69.67.

Discussion
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were all evaluated in the meta-analysis.For each variable, forest plots were created separately.In terms of the specified biochemical markers, the results consistently favored the experimental group, indicating that the intervention had a positive impact on ALT, AST, and ALP levels.
The comprehensive analysis of the 13 included studies consistently highlights the strong therapeutic effectiveness of prednisolone and azathioprine combination therapy.This treatment strategy works well not only in the treatment of AIH in isolation but also when AIH coexists with primary biliary cholangitis (PBC).The synthesis of evidence from these studies emphasizes the importance of prednisolone and azathioprine's synergistic action, implying a valuable treatment avenue for clinicians managing patients with AIH, particularly in cases of PBC.
While prednisolone or prednisolone plus azathioprine is effective for 80% of patients, the remaining 20% face challenges such as refractory disease, poor compliance, or drug intolerance, according to a review.According to experts, non-responders and those with intolerance should take high-dose prednisolone with azathioprine.However, new evidence suggests that there may be alternatives, with budesonide promising due to its liver-specific metabolism and lower steroid-related side effects.Mycophenolate mofetil (MMF) is thought to be a promising remission maintenance treatment option, particularly in patients with azathioprine intolerance or refractory AIH [33].Another review emphasizes the importance of considering alternative strategies, particularly when standard therapy fails to achieve remission or when patients suffer from drug toxicity.These novel approaches are thought to improve treatment outcomes for people with AIH [34].
Another study suggests that patients with pre-symptomatic or symptomatic PBC and AIH should be treated as soon as possible.Ursodeoxycholic acid (UDCA) and corticosteroids are used in the proposed method [35].
While the reviews and studies discussed are useful, there are a few limitations to be aware of.To begin, the studies differ in terms of patient groups, treatments, and study designs.This may introduce bias and make it difficult to generalize the findings.Furthermore, some studies relied on self-reported data, while others examined historical data, which may not be the most reliable method of data collection.The ever-changing landscape of how we treat AIH and PBC may have also gone unnoticed in the studies we looked at.Finally, some studies may not have followed patients for a long enough period of time to determine how well the treatments worked.

Conclusions
The systematic review and meta-analysis presented a comprehensive evaluation of combination therapies, such as prednisolone and azathioprine, for treating autoimmune hepatitis.The inclusion criteria were meticulous, focusing on studies with specific interventions and measurable outcomes, which were methodically analyzed using RevMan 5.4.Despite the high prevalence and complex clinical profile of AIH, particularly in demographic groups like Alaska Natives, the findings suggest that combination therapies provide significant benefits in managing the disease, reducing recurrence rates, and improving overall patient outcomes.This review underscores the importance of targeted treatment approaches and highlights the need for ongoing research to refine and optimize therapeutic strategies for AIH, addressing both efficacy and safety.

FIGURE 1 :
FIGURE 1: PRISMA flowchart of included studies.PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses were very effective when used in combination.2024 Rashad et al.Cureus 16(5): e60049.DOI 10.7759/cureus.60049Chazouillères et al. found that in patients with PBC:(1) overlap syndrome with AIH was not uncommon (9%);(2) AIH flares can occur spontaneously or as a result of medication under UDCA therapy; and (3) most patients required a combination of UDCA and corticosteroids to achieve a complete clinical and biochemical response.prognoses improved significantly as a result of the treatment, allowing for biochemical remission of the disease.However, significant treatment side effects pointed to the need for further research into effective and safe therapy, particularly in the with AIH-PBC overlap syndrome responded less well to UDCA and steroid combination therapy and progressed more quickly to cirrhosis than patients with and investigated the activity of pamiparib plus tislelizumab in disease-specific cohorts.
taken account of the potential confounding factors in the design and/or in