Immunosuppressive drugs affect interferon (IFN)-γ and programmed cell death 1 (PD-1) kinetics in patients with newly diagnosed autoimmune hepatitis.

Autoimmune hepatitis (AIH) is characterized by overwhelming effector immune responses associated with defective regulatory T cells (Tregs ). Several lines of evidence indicate CD4 as the main effectors involved in autoimmune liver damage. Herein we investigate the in-vitro effects of prednisolone, 6-mercaptopurine, cyclosporin, tacrolimus, mycophenolic acid (MPA) and rapamycin, immunosuppressive drugs (ISDs) used in AIH treatment, on the expression of proinflammatory cytokines, co-inhibitory molecules and ability to proliferate of CD4+ CD25- cells, isolated from the peripheral blood of treatment-naive patients with AIH. We note that in healthy subjects (HS) following polyclonal stimulation and in the absence of ISDs, the expression of interferon (IFN)-γ, interleukin (IL)-17 and tumour necrosis factor (TNF)-α by CD4 effectors peaks at 48 h and decreases at 96 h to reach baseline levels. In contrast, in AIH the expression of all these proinflammatory cytokines continue rising between 48 and 96 h. Levels of programmed cell death-1 (PD-1), T cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) and cytotoxic T lymphocyte antigen-4 (CTLA-4) increase over 96-h culture both in HS and AIH, although with faster kinetics in the latter. Exposure to ISDs contains IFN-γ and PD-1 expression in AIH, where control over CD4+ CD25- cell proliferation is also noted upon exposure to MPA. Treatment with tacrolimus and cyclosporin render CD4+ CD25- cells more susceptible to Treg control. Collectively, our data indicate that in treatment-naive patients with AIH, all ISDs restrain T helper type 1 (Th1) cells and modulate PD-1 expression. Furthermore, they suggest that tacrolimus and cyclosporin may ameliorate effector cell responsiveness to Tregs .

Risk factors and clinical outcomes of acute esophageal necrosis: retrospective case series of a rare disease with "black" prognosis.

Acute esophageal necrosis is a rare syndrome classically characterized by black distal esophagus with a complex pathophysiology that usually involves a combination of esophageal ischemia, gastroesophageal reflux and impaired mucosal reparative mechanisms. We retrospectively analyzed the main risk factors, clinical characteristics and outcome in all patients diagnosed with acute esophageal necrosis between January 2015 and December 2020 at our center. Ten patients were identified in a total of 26854 upper digestive endoscopies (0.04%). Most patients were male (8/10) and the mean age of presentation was 71.1 years. The most common presenting symptoms were melena and hematemesis and half the patients required red blood cell transfusion. The most common risk factors were hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease, peripheral artery disease, coronary artery disease, cerebrovascular disease, heart failure and malignancy. Compromised hemodynamic state was the most common precipitating event in four patients. Other recognized precipitating events included surgical interventions, decompensated heart failure, gastrointestinal bleeding from gastric malignancy and methotrexate. Endoscopic findings revealed diffuse and circumferential black distal esophagus with abrupt transition at gastroesophageal junction and variable proximal extension at presentation. The 1-month mortality rate was 30%, mostly from severe underlying illness. In conclusion, acute esophageal necrosis is a rare cause of upper gastrointestinal bleeding that should be suspected in older patients with multiple comorbidities. Although associated with a high mortality rate, appropriate treatment may result in favorable outcome in most patients.

Real-world management of juvenile autoimmune liver disease.

BACKGROUND AND AIMS: Juvenile autoimmune liver disease (JAILD) includes paediatric forms of autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). Since evidence is scarce, there are currently no evidence-based management guidelines for juvenile AIH. This survey was carried out amongst the paediatric members of the International AIH Group (IAIHG) to describe their practices in the management of JAILD. METHODS: An online survey questionnaire was distributed to members of the IAIHG with active practice (https://www.surveymonkey.de/r/Juvenile_AILD). The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Fifty-eight surveys were sent to the IAIHG members, out of which 43 (74%, 22 countries, four continents) were returned. None reported budesonide as a first-line induction agent for the acute presentation of AIH. Sixteen (37%) routinely perform liver biopsy at three years of biochemical remission. Thirty-five respondents (81%) perform magnetic resonance cholangiography (MRC) at presentation. Ciclosporin is the most widely used second-line agent (number of patients treated = ∼360, 21 centres). Mycophenolate mofetil (n = ∼225, 31 centres), tacrolimus (n = ∼130, 21 centres) and sirolimus (n = ∼5, 3 centres) are less often reported. Rescue therapy with infliximab and rituximab has been tried in eight centres (n = ∼19) and nine centres (n = ∼16), respectively. CONCLUSIONS: Prednisolone remains the preferred first-line induction agent in JAILD. MRC at presentation is performed by the large majority of participants. Participants reported a wide variation in performing liver biopsy for therapy evaluation during follow-up. Within the paediatric members of the IAIHG there is considerable experience with second-line therapeutic agents.

Intracerebral Hodgkin's lymphoma in a patient with human immunodeficiency virus.

Central nervous system (CNS) involvement by Hodgkin Lymphoma (HL) is rarely reported. Retrospective and prospective cohort studies suggest an incidence of 0.2-0.5%, mostly in relapsed disease. In spite of a 3 to 18-fold increased risk of HL in patients with human immunodeficiency virus (HIV), only two cases have been reported so far. In this paper, we now report a third case of HIV patient with HL who progressed with isolated CNS infiltration after a standard chemotherapy induced clinical remission. In 1991, when the first case of intracerebral involvement in HIV+ HL was reported an increase of this type of cases would have been expected, but only one more case has been reported since then.

Expert clinical management of autoimmune hepatitis in the real world.

BACKGROUND: High-quality data on the management of autoimmune hepatitis (AIH) are scarce. Despite published guidelines, management of AIH is still expert based rather than evidence based. AIM: To survey expert hepatologists, asking each to describe their practices in the management of patients with AIH. METHODS: A survey questionnaire was distributed to members of the International AIH Group. The questionnaire consisted of four clinical scenarios on different presentations of AIH. RESULTS: Sixty surveys were sent, out of which 37 were returned. None reported budesonide as a first line induction agent for the acute presentation of AIH. Five (14%) participants reported using thiopurine S-methyltransferase measurements before commencement of thiopurine maintenance therapy. Thirteen (35%) routinely perform liver biopsy at 2 years of biochemical remission. If histological inflammatory activity is absent, four (11%) participants reduced azathioprine, whereas 10 (27%) attempted withdrawal altogether. Regarding the management of difficult-to-treat patients, mycophenolate mofetil is the most widely used second-line agent (n = ~450 in 28 centres), whereas tacrolimus (n = ~115 in 21 centres) and ciclosporin (n = ~112 in 18 centres) are less often reported. One centre reported considerable experience with infliximab, while rescue therapy with rituximab has been tried in seven centres. CONCLUSIONS: There is a wide variation in the management of patients with autoimmune hepatitis even among the most expert in the field. Although good quality evidence is lacking, there is considerable experience with second-line therapies. Future prospective studies should address these issues, so that we move from an expert- to an evidence- and personalised-based care in autoimmune hepatitis.

Autoimmune hepatitis: From mechanisms to therapy.

Autoimmune hepatitis (AIH) is a progressive inflammatory hepatopathy and an important cause of end-stage liver disease. Its aetiology remains unknown, though both genetic and environmental factors are involved in its development. The major mechanism of autoimmune liver damage involves immune reactions against host liver antigens. Numerical and functional defects of regulatory T-cells play a permissive role enabling autoimmune liver injury to occur and persist. The most typical features of AIH are female preponderance, hypergammaglobulinaemia, seropositivity for circulating autoantibodies and a picture of interface hepatitis on histology. Two types of AIH are distinguished according to serological profile: AIH type 1 patients are positive for anti-nuclear and/or anti-smooth muscle antibodies, whereas AIH type 2 patients are defined by the positivity for anti-liver kidney microsomal type 1 antibody and/or for anti-liver cytosol type 1 antibody. Clinical manifestations are variable, and AIH onset is often ill-defined, frequently mimicking acute hepatitis; its course may be fluctuating. AIH responds to immunosuppressive treatment in the majority of cases. Steroids with or without azathioprine should be instituted promptly upon diagnosis. Remission is achieved in some 80% of patients. For the remaining 20% of patients, alternative immunosuppressive agents such as mycophenolate mofetil and calcineurin inhibitors are an option. Liver transplantation should be considered for those patients who progress to cirrhosis and develop complications of end-stage liver disease, as well as for those presenting with acute liver failure; outcomes are excellent, although the disease may recur in the allograft.