Optimizing thiopurine therapy in autoimmune hepatitis: A multi-center study on monitoring metabolite profiles and co-therapy with allopurinol.

BACKGROUND AIMS: In autoimmune hepatitis (AIH), achieving complete biochemical remission (CBR) with current weight-based thiopurine dosing is challenging. We investigated whether patients could be stratified regarding CBR according to a target range of thiopurine metabolites. Moreover, we explored the effects of azathioprine dosage increases and co-therapy of allopurinol with low-dose thiopurines on metabolite profiles and treatment response. APPROACH RESULTS: The relation between metabolites and treatment response was assessed in 337 individuals from four European centers. In a global, cross-sectional analysis, active metabolites 6-thioguanin nucleotides (6TGN) were similar in those with and without CBR. However, analyzing patients with sequential measurements over 4 years (N=146) revealed higher average 6TGN levels in those with stable CBR (260 pmol/0.2 ml) compared to those failing to maintain CBR (181 pmol/0.2 ml;p=0.0014) or never achieving CBR (153 pmol/0.2 ml;p<0.0001), with an optimal 6TGN-cutoff of ≥223 pmol/0.2 ml (sensitivity: 76%, specificity: 78%). Only 42% exhibited 6TGN ≥223 pmol/0.2 ml following weight-based dosing, as doses weakly correlated with 6TGN but with 6-methylmercaptopurine (6MMP), a metabolite associated with toxicity. Azathioprine dose increases led to preferential 6MMP formation (+127% vs. 6TGN +34%;p<0.0001). Conversely, adding allopurinol to thiopurines in difficult-to-treat patients (N=36) raised 6TGN (168→321 pmol/0.2 ml;p<0.0001) and lowered 6MMP (2125→184 pmol/0.2 ml;p<0.0001), resulting in improved transaminases in all patients and long-term CBR in 75%. CONCLUSIONS: Maintaining CBR in AIH was associated with 6TGN ≥223 pmol/0.2 ml. For patients who fail to achieve CBR and therapeutic 6TGN levels despite thiopurine dose increase due to preferential 6MMP formation, co-medication of allopurinol alongside low-dose thiopurines represents an efficient alternative.

[Autoimmune hepatitis : From autoantibodies to cirrhosis]. / Autoimmune Hepatitis : Von Autoantikörpern bis Zirrhose.

Autoimmune Hepatitis (AIH) is an immune-mediated liver disease of unknown origin. Its clinical presentation is heterogeneous and ranges from asymptomatic courses over several years to acute forms with acute liver failure. Accordingly, the diagnosis is only made at the stage of cirrhosis in about one third of affected individuals. Early diagnosis and a consistent, adequate, individualized, immunosuppressive therapy are crucial for the prognosis, which is excellent when treated properly. AIH is rare in the general population and can be easily overlooked due to its variable clinical picture and sometimes difficult diagnosis. AIH should be considered as a differential diagnosis in any unclear acute or chronic hepatopathy. The therapy initially consists of remission induction and subsequently maintenance therapy with (often lifelong) immunosuppressants.

Histological and serological features of acute liver injury after SARS-CoV-2 vaccination.

Background & Aims: Liver injury with autoimmune features after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is increasingly reported. We investigated a large international cohort of individuals with acute hepatitis arising after SARS-CoV-2 vaccination, focusing on histological and serological features. Methods: Individuals without known pre-existing liver diseases and transaminase levels ≥5x the upper limit of normal within 3 months after any anti-SARS-CoV-2 vaccine, and available liver biopsy were included. Fifty-nine patients were recruited; 35 females; median age 54 years. They were exposed to various combinations of mRNA, vectorial, inactivated and protein-based vaccines. Results: Liver histology showed predominantly lobular hepatitis in 45 (76%), predominantly portal hepatitis in 10 (17%), and other patterns in four (7%) cases; seven had fibrosis Ishak stage ≥3, associated with more severe interface hepatitis. Autoimmune serology, centrally tested in 31 cases, showed anti-antinuclear antibody in 23 (74%), anti-smooth muscle antibody in 19 (61%), anti-gastric parietal cells in eight (26%), anti-liver kidney microsomal antibody in four (13%), and anti-mitochondrial antibody in four (13%) cases. Ninety-one percent were treated with steroids ± azathioprine. Serum transaminase levels improved in all cases and were normal in 24/58 (41%) after 3 months, and in 30/46 (65%) after 6 months. One patient required liver transplantation. Of 15 patients re-exposed to SARS-CoV-2 vaccines, three relapsed. Conclusion: Acute liver injury arising after SARS-CoV-2 vaccination is frequently associated with lobular hepatitis and positive autoantibodies. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. A close follow-up is warranted to assess the long-term outcomes of this condition. Impact and implications: Cases of liver injury after vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) have been published. We investigated a large international cohort of individuals with acute hepatitis after SARS-CoV-2 vaccination, focusing on liver biopsy findings and autoantibodies: liver biopsy frequently shows inflammation of the lobule, which is typical of recent injury, and autoantibodies are frequently positive. Whether there is a causal relationship between liver damage and SARS-CoV-2 vaccines remains to be established. Close follow-up is warranted to assess the long-term outcome of this condition.

Analysis of the humoral and cellular response after the third COVID-19 vaccination in patients with autoimmune hepatitis.

BACKGROUND & AIMS: To explore the humoral and T-cell response to the third COVID-19 vaccination in autoimmune hepatitis (AIH). METHODS: Anti-SARS-CoV-2 antibody titers were prospectively determined in 81 AIH patients and 53 healthy age- and sex-matched controls >7 days (median 35) after the first COVID-19 booster vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of patients. RESULTS: Median antibody levels were significantly lower in AIH compared to controls (10 908 vs. 25 000 AU/ml, p < .001), especially in AIH patients treated with MMF (N = 14, 4542 AU/ml, p = .004) or steroids (N = 27, 7326 AU/ml, p = .020). Also, 48% of AIH patients had antibody titers below the 10% percentile of the healthy controls (9194 AU/ml, p < .001). AIH patients had a high risk of failing to develop a spike-specific T-cell response (15/34 (44%) vs. 2/16 (12%), p = .05) and showed overall lower frequencies of spike-specific CD4 + T cells (median: 0.074% vs 0.283; p = .01) after the booster vaccination compared to healthy individuals. In 34/81 patients, antibody titers before and after booster vaccination were available. In this subgroup, all patients but especially those without detectable/low antibodies titers (<100 AU/ml) after the second vaccination (N = 11/34) showed a strong, 148-fold increase. CONCLUSION: A third COVID-19 vaccination efficiently boosts antibody levels and T-cell responses in AIH patients and even seroconversion in patients with the absent immune response after two vaccinations, but to a lower level compared to controls. Therefore, we suggest routinely assessing antibody levels in AIH patients and offering additional booster vaccinations to those with suboptimal responses.

SARS-CoV-2 vaccination response in patients with autoimmune hepatitis and autoimmune cholestatic liver disease.

BACKGROUND/AIMS: In this observational study, we explored the humoral and cellular immune response to SARS-CoV-2 vaccination in patients with autoimmune hepatitis (AIH) and patients with cholestatic autoimmune liver disease (primary sclerosing cholangitis [PSC] and primary biliary cholangitis [PBC]). METHODS: Anti-SARS-CoV-2 antibody titers were determined using the DiaSorin LIAISON and Roche immunoassays in 103 AIH, 64 PSC, and 61 PBC patients and 95 healthy controls >14 days after the second COVID-19 vaccination. The spike-specific T-cell response was assessed using an activation-induced marker assay (AIM) in a subset of individuals. RESULTS: Previous SARS-CoV-2 infection was frequently detected in AIH but not in PBC/PSC (10/112 (9%), versus 4/144 (2.7%), p = 0.03). In the remaining patients, seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. However, in 13/94 AIH patients antibody levels were lower than in any healthy control, which contributed to lower antibody levels of the total AIH cohort when compared to PBC/PSC or controls (641 vs. 1020 vs. 1200 BAU/ml, respectively). Notably, antibody levels were comparably low in AIH patients with (n = 85) and without immunosuppression (n = 9). Also, antibody titers significantly declined within 7 months after the second vaccination. In the AIM assay of 20 AIH patients, a spike-specific T-cell response was undetectable in 45% despite a positive serology, while 87% (13/15) of the PBC/PSC demonstrated a spike-specific T-cell response. CONCLUSION: Patients with AIH show an increased SARS-CoV-2 infection rate as well as an impaired B- and T-cell response to SARS-CoV-2 vaccine compared to PBC and PSC patients, even in the absence of immunosuppression. Thus, antibody responses to vaccination in AIH patients need to be monitored and early booster immunizations considered in low responders.