Efficacy and safety of mycophenolate mofetil and tacrolimus as second-line therapy for patients with autoimmune hepatitis

Background: Predniso(lo)ne, alone or in combination with azathioprine, is the standard of care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. Patients and methods: We performed a retrospective study of data (from 19 centres in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6–190 months). Patients were categorized according to their response to SOC. Patients in group 1 (n=108) had a complete response to the SOC, but were switched to second line therapy due to side effects of predniso(lo)ne or azathioprine, whereas patients in group 2 (n=93) had not responded to SOC. Results: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P=.639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P=.682). Significantly more group 2 patients given tacrolimus compared to MMF had a complete response (56.5 % vs. 34%, P=.029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P=.472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. Conclusions: Long-term therapy with MMF or tacrolimus was generally well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous non-responder patients compared to MMF

On leukocyte recruitment in endotoxemic liver injury

Leukocyte recruitment is a key feature of liver injury associated with endotoxemia and systemic inflammation. The aim of this thesis was to define the adhesive mechanisms underlying leukocyte endothelial cell interactions, and the therapeutic potential of interference with specific adhesion molecules in endotoxemic liver damage. Moreover, the causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand was investigated. For these purposes, intravital fluorescence microscopy of the liver microcirculation was adopted. It was found that TNF-alpha- and LPS-induced leukocyte rolling in hepatic postsinusoidal venules is primarily mediated by P-selectin, and not by E- nor L-selectin. This initial P-selectin-dependent leukocyte rolling was found to be a prerequisite for subsequent firm adhesion in postsinusoidal venules of the liver. Firm adhesion of leukocytes was found to be dependent on CD18/CD11a (LFA-1). Notably, inhibition of P-selectin and LFA-1 function protected against septic liver injury. For example, leukocyte recruitment, perfusion failure, hepatocellular injury and apoptosis were nearly abolished. In contrast, sinusoidal sequestration of leukocytes was not found to be a major determinant in endotoxemic liver injury. Moreover, the immunomodulator Linomide exerted potent protection against liver damage associated with endotoxemia. Taken together, this thesis indentifies fundamental adhesive mechanisms of leukocyte recruitment in septic liver injury, and defines a causal relationship between leukocyte recruitment in postsinusoidal venules and hepatic injury and apoptosis in endotoxemia. The beneficial effect of Linomide in endotoxemic liver injury demonstrated herein warrants further studies in clinical settings. Finally, it is suggested that P-selectin and LFA-1 constitute potential pharmacological targets against pathological inflammation in the liver

Protective effect of Linomide on TNF-alpha-induced hepatic injury.

Background/Aims: Linomide is an immunomodulator that ameliorates several autoimmune and inflammatory diseases. We assessed the effect of Linomide on microvascular perfusion failure, leukocyte recruitment and hepatocellular injury induced by tumor necrosis factor alpha (TNF-alpha) and D-Galactosamine (Gal).Methods: After 3 days of Linomide pretreatment (1, 10 and 100mg/kg/day), rats were challenged with TNF-alpha/Gal for 24h. Microvascular perfusion, leukocyte--endothelium interactions in hepatic postsinusoidal venules and leukocyte sequestration in sinusoids were evaluated using intravital microscopy. Liver enzymes were measured spectrophotometrically.Results: Challenge with TNF-alpha/Gal significantly reduced sinusoidal perfusion, and increased leukocyte rolling, adhesion and liver enzymes. Interestingly, pretreatment with Linomide (10 and 100mg/kg/day) significantly reduced TNF-alpha/Gal-induced leukocyte rolling by 65 and 63%, and leukocyte adhesion by 87 and 84%, respectively. Moreover, Linomide (10 and 100mg/kg/day) decreased sinusoidal sequestration of leukocytes by 71 and 51%, and markedly improved sinusoidal perfusion. Moreover, Linomide reduced aspartate aminotransferase by 87--97%, and alanine aminotransferase by 79--96%. However, Linomide had no protective effect when administered concomitantly with TNF-alpha/Gal.Conclusions: These data demonstrate a dose-dependent inhibitory effect of Linomide on perfusion failure, leukocyte recruitment and hepatocellular injury provoked by TNF-alpha. Indeed, these findings suggest that Linomide may be an effective substance for protection of the liver in sepsis