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Human liver possesses a persistent and tightly regulated immune response. Maintaining this homeostatic state is the key to prevent pathological processes, as a failure in clearing dangerous stimuli, is associated with tissue damage. A dysregulation of the liver immune homeostasis is involved in many disease processes and the use of the immunosuppression aims to control the inflammatory response, where the physiologic mechanisms failed. The use of steroids which targets broadly the inflammatory cascade and the immune system activation have been extensively employed in both acute and chronic liver diseases. They currently are the backbone of the treatment of autoimmune diseases such as autoimmune hepatitis or IgG4 sclerosing cholangitis. The steroid use in acute liver injury, especially alcohol mediated and drug induced liver injury (DILI), have been debated, despite the biological rationale. The immunosuppression molecules currently employed in liver diseases target the immune system broadly, causing multiple side effects either intrinsic in the mechanisms of the drug or secondary to off-target toxicity. The future of immunosuppressant treatment is moving towards more selective strategies, targeting disease specific pathways. This review aims to explore the rationale of use of immunosuppression in non-transplant hepatology. A broad summary of the immune biology of liver immune mediated diseases will be provided to the readers in order to highlight the potential therapeutic targets. An extensive description of the molecules employed in liver diseases will follow and the clinical evidences in AIH, IgG4 related cholangitis, alcoholic hepatitis and DILI will be reviewed.Immunosuppression handling plays a key role in the early and long-term results of transplantation. The development of multiple immunosuppressive drugs led to numerous clincial trials searching to reach the ideal regimen. Due to heterogeneity of the studied patient cohorts and flaws in many, even randomized controlled, study designs, the answer still stands out. Nowadays triple-drug immunosuppression containing a calcineurin inhibitor (preferentially tacrolimus), an antimetabolite (using mycophenolate moffettil or Azathioprine) and short-term steroids with or without induction therapy (using anti-IL2 receptor blocker or anti-lymphocytic serum) is the preferred option in both liver and intestinal transplantation. This chapter aims, based on a critical review of the definitions of rejection, corticoresistant rejection and standard immunosuppression to give some reflections on how to reach an optimal immunosuppressive status and to conduct trials allowing to draw solid conclusions. Endpoints of future trials should not anymore focus on biopsy proven, acute and chronic, rejection but also on graft and patient survival. Correlation between early- and long-term biologic, immunologic and histopathologic findings will be fundamental to reach in much more patients the status of operational tolerance.The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. MK-8245 Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.After solid organ transplantation the cornerstone of immunosuppression is based on calcineurin inhibitors (CNIs), mostly tacrolimus. However, CNIs have a very narrow therapeutic window. The most important and serious side-effects of CNIs are nephrotoxicity, high blood pressure, post-transplant diabetes mellitus (PTMD), i.e., new-onset diabetes after transplantation (NODAT), dyslipidemia, and modification to the cardiovascular-risk profile. In this review, we will focus on tacrolimus-related toxicities in the setting of liver transplantation.Life-long immunosuppression has always been considered the key in managing liver graft protection from recipient rejection. However, it is associated with severe adverse effects that lead to increased morbidity and mortality, including infections, cardiovascular diseases, kidney failure, metabolic disorders and de novo malignancies. This explains the great interest that has developed in the concept of tolerance in recent years. The liver, thanks to its marked tolerogenicity, is to be considered a privileged organ up to 60% of selected patients undergoing liver transplantation could safely withdraw immunosuppression.Heritage small molecule immunosuppressants and the immune-acting biologics have a major place in the management of luminal gastrointestinal disease and especially so in inflammatory bowel disease. This narrative review considers their current use, concentrating on issues not already well addressed in the literature. An evidence-based approach is taken, supplemented by advice based on observations from clinical practice when data are missing. There is a general trend towards earlier use of the biologics for perceived greater safety and impact on disease modification, despite their substantially greater cost and systemic administration. Early semi-prophylactic treatment is now considered for patients with high-risk Crohn's disease. In other conditions the immune active agents remain a back-up for those failing to respond to simpler options. There are few and mostly unimportant differences between the different antibodies to TNFα, but it is beginning to be possible to identify patients who could be preferentially treated with an anti-integrin approach or by addressing other cytokines.In recent years, the clinician has a more diverse approach to immunosuppression. Now, for many conditions, such as solid organ transplantation or treatment of some autoimmune diseases, the consequences of immunosuppression becomes a greater risk than organ failure from immune-mediated disease. Some of the consequences of immunosuppression can be prevented by prophylaxis, immunisation, surveillance and pharmacological intervention. Infections and malignancy are major causes of morbidity and mortality in the immunosuppressed. Screening for evidence of latent infection and immunisation prior to introduction of immunosuppression (where possible and appropriate) will help reduce the risk of infection. Surveillance for those cancers that are increased in association with immunosuppression (especially skin cancers, melanoma, anal canal, Kaposi, post-transplant lymphoproliferative disease) will allow early detection and intervention and, where appropriate, alteration of agent.The innate and adaptive immune systems work as a complex interplay between different cell types, involving cytokines and chemokines mediating extracellular and paracrine effects. At the intracellular level, the inflammatory cascade is mediated by multifaceted processes that have been better described in the last 10 years. Immunosuppressive agents available in clinical practice act at different points of those cascades at the intracellular or extracellular level. Those drugs can mediate their effects on one or more cell types finally limiting inflammation and immune responses to antigens. Every immunosuppressive agent is characterized by intrinsic toxicity and side effects that may be due to the same therapeutic pathways or to off-target secondary effect of each molecule. We will here review the mechanisms of action of the most widely used immunosuppressive agents in the field of solid organ transplantation and autoimmune disorders, describing the mechanisms underlying both the therapeutic and secondary effects.Immunosuppressive drugs have been key to the success of liver transplantation and are essential components of the treatment of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). For many but not all immunosuppressants, therapeutic drug monitoring (TDM) is recommended to guide therapy. In this article, the rationale and evidence for TDM of tacrolimus, mycophenolic acid, the mammalian target of rapamycin inhibitors, and azathioprine in liver transplantation, IBD, and AIH is reviewed. New developments, including algorithm-based/computer-assisted immunosuppressant dosing, measurement of immunosuppressants in alternative matrices for whole blood, and pharmacodynamic monitoring of these agents is discussed. It is expected that these novel techniques will be incorporate into the standard TDM in the next few years.

Patients with ankylosing spondylitis (AS) have a heterogenic disease course and treatment response. Cluster-based phenotypes are useful for predicting AS disease course. Here, we compared drug retention and clinical efficacy of biologic disease-modifying anti-rheumatic drugs (bDMARDs) in AS patients with cluster A and cluster B phenotypes.

AS patients enrolled in the Korean College of Rheumatology BIOlogics registry were divided into cluster A (axial symptoms predominant) and cluster B (both axial and peripheral symptoms). Retention of bDMARDs was measured using Kaplan-Meier curve and Cox regression analyses. Clinical efficacy (BASDAI50, ASAS20, ASAS40, ASDAS inactive state, and clinically important improvement/major improvement of ASDAS) at 1-year follow-up was measured by logistic regression analysis. Also, propensity score (PS)-matched analyses were conducted.

1600 AS patients (1468 for cluster A, 132 for cluster B) were included. Kaplan-Meier curve analysis revealed that the drug retention rate was lower in cluster B patients (p=0.03). PS-matched analyses showed that the hazard ratio (HR) for drug discontinuation was signi cantly higher in cluster B patients (HR=1.568; 95% con dence interval =1.055-2.329). The odds ratio for BASDAI50 at 1-year was comparable between cluster A and cluster B patients in PS-matched and multivariate logistic regression analyses. A similar result was obtained in other clinical efficacy assessments.

The drug retention rate was lower in cluster B patients than in cluster A patients; clinical efficacy was comparable between the two groups at 1-year follow-up. These results may help predict drug retention and clinical efficacy in AS patients.

The drug retention rate was lower in cluster B patients than in cluster A patients; clinical efficacy was comparable between the two groups at 1-year follow-up. These results may help predict drug retention and clinical efficacy in AS patients.A healthy lifestyle is critical to maintaining safety and preventing rheumatic disease before reaching old age. Rheumatoid arthritis (RA) is a chronic autoimmune and systemic illness involving joint changes, including inflammation, joint pain, tiredness, elevated risk of developing coronary and heart disease, and rapid loss of muscle mass. The role of exercise in improving the inflammatory pattern has tended to focus on the latest research. However, some physical activities represent a non-pharmacological treatment strategy due to their many benefits, such as improved muscle mass, strength, and efficiency, especially in patients with RA. During exercise, skeletal muscle releases myokines, triggering a direct anti-inflammatory effect with each activity or enhancing comorbidity. The level of inflammatory biomarkers, such as tumour necrosis factor, C-reactive protein, and interleukin-6, is significantly lower for athletes and patients with RA who exercise regularly. However, understanding the precise roles of some environmental and genetic factors can help to prevent rheumatic disorders.