Autoimmune Hepatitis Regimens Carry Distinct Adverse Event Signals

Core immunosuppressive regimens used to treat autoimmune hepatitis (AIH) have distinct patterns of reported adverse drug events (ADEs), ranging from opportunistic infections with glucocorticoids to gastrointestinal intolerance with azathioprine, highlighting the potential value of regimen-specific safety monitoring, according to a pharmacovigilance analysis recently published in Frontiers in Pharmacology.¹

Long-Term AIH Treatment Options and Safety Concerns

AIH, a chronic inflammatory liver disease that can progress to cirrhosis and end-stage liver failure without timely treatment, disproportionately affects women, and its incidence and prevalence appear to be rising worldwide. Relapse is common after treatment is withdrawn, so most patients need long-term or lifelong immunosuppression.

The established first-line approach to inducing and maintaining remission is a glucocorticoid such as prednisolone combined with azathioprine. However, prolonged glucocorticoid exposure is linked to hypertension, hyperglycemia, and osteoporosis. In addition, azathioprine can cause bone marrow suppression and gastrointestinal effects that force some patients to stop treatment.

Although mycophenolate mofetil (MMF) has long been used as second-line therapy, it is increasingly being considered as a first-line alternative. In the randomized CAMARO trial (NCT02900443), 72.2% of treatment-naive patients reached biochemical remission at 24 weeks with MMF plus prednisolone, compared with 32.3% with azathioprine plus prednisolone.² Despite these shifts, investigators noted that comparative safety data for these agents in patients with AIH remain limited.¹

To address that gap, they analyzed reports to the FDA Adverse Event Reporting System (FAERS) that listed AIH as the indication for dexamethasone, methylprednisolone, prednisolone, azathioprine, or MMF. The reports spanned the first quarter of 2004 through the fourth quarter of 2024. The researchers identified signals using reporting ORs, proportional reporting ratios, and a Bayesian confidence propagation neural network, with the full FAERS database serving as the comparator.

ADE Signals Differed by Regimen

The final analysis included 720 ADE reports. Consistent with the female predominance of AIH, women accounted for a significantly higher proportion of ADE reports than men (62.9% vs 24.6%). Across all therapies, neoplasms had the strongest organ-system signal (77 cases; ROR, 1.86; 95% CI, 1.37-2.53), followed by infections and infestations (337 cases; ROR, 1.52; 95% CI, 1.31-1.76) and gastrointestinal disorders (227 cases; ROR, 1.24; 95% CI, 1.04-1.47).

For glucocorticoid monotherapy, at the system organ class (SOC) level, the strongest ADE signal was for infections and infestations (176 cases; ROR, 2.90; 95% CI, 2.40-3.50), followed by metabolism and nutrition disorders (30 cases; ROR, 1.91; 95% CI, 1.28-2.86), as well as endocrine disorders (16 cases; ROR, 2.76; 95% CI, 1.57-4.85).

At the preferred term (PT) level, the researchers identified robust signals for opportunistic infections, including both Candida infection (13 cases; ROR, 12.14; 95% CI, 5.30-27.79) and Aspergillus infection (10 cases; ROR, 8.45; 95% CI, 3.58-19.97), as well as Pneumocystis jirovecii pneumonia (9 cases; ROR, 5.97; 95% CI, 2.57-13.83). Because glucocorticoid monotherapy is not guideline-recommended for long-term use, they noted that these signals likely reflect off-protocol clinical scenarios.

With azathioprine monotherapy, at the SOC level, neoplasms demonstrated the strongest organ-system association (43 cases; ROR, 3.50; 95% CI, 2.45-4.99), with gastrointestinal and skin and subcutaneous tissue disorders also having statistically significant signals. At the PT level, drug intolerance had the strongest individual event signal (24 cases; ROR, 26.79; 95% CI, 12.40-57.87), with nausea, vomiting, and pancytopenia also disproportionately reported. When azathioprine was combined with glucocorticoids, drug intolerance became even more pronounced (20 cases; ROR, 42.9; 95% CI, 21.1-87.24), and infection and gastrointestinal signals persisted.

MMF monotherapy showed a different profile, centered on medication management rather than organ toxicity. Its ADE signals at the PT level included off-label use (95 cases; ROR, 2.80; 95% CI, 2.19-3.58) and drug ineffectiveness (45 cases; ROR, 3.34; 95% CI, 2.33-4.79). The authors linked these findings in part to MMF's substantial pharmacokinetic variability, as well as its relatively limited evidence base in AIH, given that the drug was originally developed to prevent transplant rejection.

The combination of glucocorticoids and MMF was associated with severe infectious and respiratory events, including acute respiratory distress syndrome (ROR, 49.42; 95% CI, 12.24-199.59), Escherichia sepsis (ROR, 33.40; 95% CI, 11.73-95.10), and acute respiratory failure (ROR, 13.07; 95% CI, 4.81-35.50). However, each signal was based on 6 or fewer cases.

Limitations Highlight Need for Cautious Interpretation

Based on these profiles, the researchers recommended that clinicians tailor monitoring to each regimen. At the same time, they acknowledged their study’s limitations, including that FAERS, as a spontaneous reporting system, is subject to underreporting, missing data, and reporting bias, which limits causal inference and reliable estimation of ADE incidence. In addition, several signals with limited case numbers lacked multiple comparison correction, raising the potential for false-positive findings and making the results preliminary.

“…because FAERS is a spontaneous reporting system, the observed associations should be interpreted cautiously and validated in large prospective studies,” the authors concluded.

References

1. Ma L, Fan Y, Gu R, et al. Detection of adverse event signals associated with key immunosuppressants for autoimmune hepatitis: insights from the Food and Drug Administration adverse event reporting system database. Front Pharmacol. 2026;17:1889345. doi:10.3389/fphar.2026.1889345
2. Snijders RJALM, Stoelinga AEC, Gevers TJG, 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(4):576-585. doi:10.1016/j.jhep.2023.11.032