We have shown previously that mycophenolate mofetil (MMF) might be used as first-line treatment instead of azathioprine (AZA) in individuals with autoimmune hepatitis (AIH). Herein, we present our long-term prospective data on response and outcome after first-line therapy with MMF in treatment-naïve individuals with AIH, as similar data are missing. During the 21 years of the study, 292 individuals with AIH were included (females: 213; median age: 59 [17-85] years). Patients received either prednisolone 0.5-1 mg/kg/day alone (n = 19) or in combination with AZA 1-2 mg/kg/day (n = 64) or MMF (n = 183). The tapering schedule of prednisolone was identical between groups. We assessed the rates of complete biochemical response (CBR) at 6 months, 12 months, and the end of follow-up; non-response (4 weeks of treatment); CBR off prednisolone; adverse effects; CBR off treatment; histological remission; and overall and liver-related mortality between the AZA and MMF groups. The MMF group had lower non-response (p = 0.02) and higher CBR rates at 12 months (86 vs. 71.8%; p <0.05) and the end of follow-up (96 vs. 87.2%; p = 0.03) than the AZA group. Treatment change was more frequent in the AZA group (43.7 vs. 11%; p <0.001), mostly because of intolerance, whereas MMF was proven safe (serious complications 3.8 vs. 18.8%; p = 0.0003). MMF-treated patients were more frequently eligible to stop immunosuppression according to the guidelines (p 60 years, and longer disease duration were independent predictors of liver-related mortality. MMF seems an efficient alternative first-line treatment option for AIH, bearing lower non-response at 4 weeks and higher CBR rates at 12 months and the end of follow-up than AZA. In addition, MMF was proven to be safe, leading more frequently to the eligibility for stopping immunosuppression according to the guidelines. For more than 40 years, azathioprine (AZA) has been considered the standard treatment for induction and maintenance of response in autoimmune hepatitis (AIH). However, treatment usually needs to be maintained for life, as relapses are common after AZA cessation. Therefore, alternative treatment options are needed. Herein, we showed that the use of mycophenolate mofetil (MMF) as an alternative first-line immunosuppressant was much more efficient in the long-term than AZA as attested by the lower non-response rates at 4 weeks and higher response rates at 12 months and the end of follow-up. Moreover, AZA-treated patients were more prone to change treatment because of intolerance, whereas MMF-treated patients were more often eligible to achieve treatment withdrawal.

Background: We conducted a study in order to determine the usefulness and diagnostic value of International Autoimmune Hepatitis Group (IAHG) score in non-autoimmune hepatitis (AIH) hepatic disorders as well as in AIH/overlap syndromes and in cases with coexistence of AIH and other liver diseases. Methods: We applied the IAHG score in 423 patients with liver diseases excluding patients with AIH, AIH/overlap syndromes and AIH with concurrent other liver disease namely, patients with chronic hepatitis B (n = 109), chronic hepatitis C (n = 95), chronic hepatitis D (n = 4), alchoholic liver disease (n = 28), non-alcoholic fatty liver disease (n = 55), autoimmune cholestatic liver diseases (n = 77), liver disorders of undefined origin (n = 32) and with miscellaneous hepatic disorders (n = 23). 24 patients with AIH associated with any kind of liver disorder including 10 patients with AIH/overlap syndromes and 14 AIH with concurrent other liver disease were also investigated. 43 patients with AIH consisted the control group. Results: The specificity of the score was 98.1% while the sensitivity in unmasking AIH in patients with either AIH/overlap syndromes or AIH with concurrent other liver diseases was only 50% and 78.6%. In the binary logistic regression model, the presence of other autoimmune diseases (p < 0.001), the total histological score (p < 0.001) and positivity for autoantibodies (p < 0.05) were identified as independent predictors for the presnce of AIH/ovea syndromes o AI with concurren other liver diseass. Conclusion: The IAHG scoring system has very good specificity for excluding AIH in patients with chronic liver diseases but not that sensitivity in order to unmask AIH/overlap syndromes or AIH with concurrent other liver diseases. The presence of other autoimmune diseases or autoantibody markers in the absence of hepatitis viral markers should alarm physicians for the possible presence of AIH either as "pure" AIH or in association with other liver disorders (AIH/overlap syndromes or AIH with concurrent other liver diseases). Under these conditions, liver histology seems essential and it must always be included in the work up of hepatic patients.

The cartilage oligomeric matrix protein (COMP) and Golgi-protein-73 (GP73) have been proposed as markers of liver fibrosis and hepatocellular carcinoma (HCC). Our aim was to assess the performance of the combination of these markers in diagnosing cirrhosis and predicting HCC development. Sera from 288 consecutive patients with chronic liver diseases were investigated by using COMP and GP73-ELISAs. Dual positivity for COMP (>15 U/L) and GP73 (>20 units) was observed in 24 (8.3%) patients, while 30 (10.4%) were GP73(+)/COMP(−), 37/288 (12.8%) GP73(−)/COMP(+), and 197 (68.5%) GP73(−)/COMP(−). Positivity for both markers was associated with cirrhosis [23/24 (95.8%) for GP73(+)/COMP(+) vs. 22/30 (73.3%) for GP73(+)/COMP(−) vs. 25/37 (67.6%) for GP73(−)/COMP(+) vs. 46/197 (23.4%) for GP73(−)/COMP(−); P < 0.001]. The combination of GP73, COMP, the aspartate aminotransferase/platelets ratio index, and the Fibrosis-4 score had even higher diagnostic accuracy to detect the presence of cirrhosis [AUC (95% CI): 0.916 (0.878–0.946)] or significant liver fibrosis (METAVIR ≥ F2) [AUC (95% CI): 0.832 (0.768–0.883)] than each marker alone. Kaplan-Meier analysis showed that positivity for both GP73 and COMP was associated with higher rates of HCC development (P < 0.001) and liver-related deaths (P < 0.001) during follow-up. In conclusion, the combination of GP73 and COMP seems efficient to detect cirrhosis and predict worse outcomes and the development of HCC in patients with chronic liver diseases.

Risk stratification of coronavirus disease-19 (COVID-19) patients by simple markers is critical to guide treatment. We studied the predictive value of soluble interleukin-2 receptor (sIL-2R) for the early identification of patients at risk of developing severe clinical outcomes. sIL-2R levels were measured in 197 patients (60.9% males; median age 61 years; moderate disease, n = 65; severe, n = 132, intubated and/or died, n = 42). All patients received combined immunotherapies (anakinra ± corticosteroids ± intravenous immunoglobulin ± tocilizumab) according to our local treatment algorithm. The endpoint was the composite event of intubation due to severe respiratory failure (SRF) or mortality. Median (interquartile range) sIL-2R levels were significantly higher in patients with severe disease, compared with those with moderate disease (6 (6.2) vs. 5.2 (3.4) ng/mL, p = 0.017). sIL-2R was the strongest laboratory predictive factor for intubation/death (hazard ratio 1.749, 95%CI 1.041–2.939, p = 0.035) after adjustment for other known risk factors. Youden’s index revealed optimal sIL-2R cut-off for predicting intubation/death at 9 ng/mL (sensitivity: 67%; specificity: 86%; positive and negative predictive value: 57% and 91%, respectively). Delta sIL-2R between the day of event or discharge minus admission date was higher in patients that intubated/died than in those who did not experience an event (2.91 (10.42) vs. 0.44 (2.88) ng/mL; p = 0.08)). sIL-2R on admission and its dynamic changes during follow-up may reflect disease severity and predict the development of SRF and mortality.

Autoimmune hepatitis (AIH) is a relatively rare autoimmune disease with a strong genetic background. The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148 M (rs738409 C/G) variant has been associated with hepatic inflammation and fibrosis in chronic hepatic diseases beyond metabolic dysfunction-associated steatotic liver disease (MASLD). Our aim was to investigate the significance of PNPLA3 I148 M variant in AIH. Two hundred AIH patients, followed in our centre, were evaluated while 100 healthy subjects served as controls. Genotyping was performed with allelic discrimination end-point polymerase chain reaction (PCR). The I148 M variant was present in 95/200 (47.5 %) AIH patients compared to 47/100 (47 %) healthy controls (p = 1.000). Patients with GG/CG genotypes were more likely to present with decompensated cirrhosis at diagnosis (GG/CG 6.3 % vs. CC 1 %, p = 0.039). Comorbidity with cardiometabolic risk factors and concurrence of MASLD was similar across genotypes. Simple steatosis was present in 37/186 (19.9 %) and steatohepatitis in 14/186 (7.5 %) patients with available liver biopsy without correlation with PNPLA3 genotype. Fibrosis stage and grade of inflammation were not correlated with any genotype. Response to treatment was also independent of the presence of the I148 M variant, even though a longer time was needed to achieve complete biochemical response in those carrying the GG/CG genotypes (p = 0.07). On Kaplan Meier analysis homozygosity for the G allele corelated with reduced survival free of decompensation (p = 0.006), cirrhotic events (decompensation, liver transplantation, hepatocellular carcinoma; p = 0.001) and liver-related death or liver transplantation (p = 0.011) in treated patients. The PNPLA3 I148 M variant in AIH patients is associated with increased risk of advanced disease at diagnosis and reduced survival free of cirrhotic events and liver-related death or liver transplantation, regardless of the presence of MASLD. This signifies a potential role for the PNPLA3 I148 M variant as a new AIH biomarker allowing to identify patients at increased risk of disease progression.