What Comes after Ursodeoxycholic Acid in Primary Biliary Cholangitis?

2017 ◽  
Vol 35 (4) ◽  
pp. 359-366 ◽  
Author(s):  
Lin Lee Wong ◽  
Vinod S. Hegade ◽  
David E.J. Jones
Keyword(s):  
Ursodeoxycholic Acid ◽  
Disease Progression ◽  
Farnesoid X Receptor ◽  
European Medicines Agency ◽  
Primary Biliary Cholangitis ◽  
Inadequate Response ◽  
Primary Therapy ◽  
Chronic Cholestasis ◽  
Increased Risk ◽  
Risk Of Disease

Primary biliary cholangitis (PBC) is a rare autoimmune liver disease characterized by chronic cholestasis. Treatment with the accepted primary therapy ursodeoxycholic acid (UDCA) has been shown to be associated with delayed disease progression probably through reduced impact of cholestatic injury on the target biliary epithelial cells. Patients with inadequate response to UDCA (which can be identified through validated biochemical criteria) are at increased risk of disease progression, need for liver transplantation, and death. Obeticholic acid (OCA) is a farnesoid X receptor (FXR) agonist which has been evaluated as a second-line therapy in PBC and has been recently licensed by the Food and Drug Administration and European Medicines Agency for use in patients showing an inadequate response to UDCA or who are unable to tolerate it. Although evidence for biochemical improvement by OCA is compelling, there is, as yet, no evidence that OCA improves hard clinical outcomes or quality of life. In addition, OCA may not be suitable for PBC patients with pruritus as it can worsen the symptom. Other novel agents currently in clinical development may have better side-effect profile. Fibrates have the potential but currently lack high quality evidence to support their routine clinical use in PBC. Symptom management of PBC is challenging and ASBT inhibitors and rituximab are being evaluated for pruritus and fatigue, respectively.

scholarly journals The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1144
Author(s):  
Chiara Chiereghin ◽  
Erica Travaglino ◽  
Matteo Zampini ◽  
Elena Saba ◽  
Claudia Saitta ◽  
...  
Keyword(s):  
Disease Progression ◽  
Myelodysplastic Syndromes ◽  
Clinical Relevance ◽  
Driver Mutations ◽  
Significant Information ◽  
Hematopoietic Stem ◽  
Probability Of Survival ◽  
Mutational Status ◽  
Increased Risk ◽  
Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

scholarly journals Obeticholic acid—a new therapy in PBC and NASH

2020 ◽  
Vol 133 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Roger W Chapman ◽  
Kate D Lynch
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Ursodeoxycholic Acid ◽  
Farnesoid X Receptor ◽  
Primary Biliary Cholangitis ◽  
Second Line ◽  
Obeticholic Acid ◽  
Second Line Therapy ◽  
Line Therapy

Abstract Introduction Obeticholic acid (OCA) is a semi-synthetic hydrophobic bile acid (BA) analogue that is highly selective agonist of farnesoid X receptor (FXR), a key nuclear BA receptor, which induces expression of gut-derived hormones, in particular fibroblast growth factor 19. The resulting beneficial effects of OCA on glucose and lipid metabolism and particularly hepatic inflammation make it a candidate for the treatment of a variety of conditions including primary biliary cholangitis (PBC) and nonalcoholic steatohepatitis (NASH). Sources of data In PBC patients who have not initially responded to ursodeoxycholic acid, OCA has been shown in double-blind controlled clinical trials to significantly reduce serum alkaline phosphatase. To date, OCA is the only therapy licensed by the FDA, EMA and endorsed by NICE as second line therapy for PBC. No medications are currently approved in Europe or the USA for the treatment of NASH. In recent clinical trials, OCA has been shown encouraging results by improving liver blood tests and reducing liver fibrosis with no worsening of NASH. Areas of agreement OCA is the established second line therapy for PBC in those patients who fail to adequately respond to ursodeoxycholic acid. Areas of controversy The main side effects of OCA treatment in both PBC and NASH is that of dose-dependent pruritis which can lead to treatment discontinuation in ~1–10% of patients. In addition, OCA-treated patients may also exhibit (reversible) alterations in serum lipid levels; most notably a small decrease in high density lipoprotein cholesterol. It is not yet known whether these changes carry a long-term cardiovascular risk in NASH. In addition, the relatively high cost of OCA may limit its use in cash-limited health systems. Growing Points Additional clinical trials are in progress to ascertain the long-term effects of OCA on survival in PBC and NASH. Areas timely for developing research New FXR agonists with a lower rate of side effects are being developed and trialed. Combination therapy with other agents may offer increased efficacy.

Clostridium Difficile and Increased Risk of Surgery in Crohn’s Disease. Can Early Microbial Signatures Forecast Risk of Disease Progression?

2019 ◽  
Vol 26 (8) ◽  
pp. 1222-1224
Author(s):  
Alka Goyal
Keyword(s):  
Ulcerative Colitis ◽  
Crohn’S Disease ◽  
Clostridium Difficile ◽  
Crohn's Disease ◽  
Disease Progression ◽  
Clostridium Difficile Infection ◽  
Increased Risk ◽  
Risk Of Disease ◽  
Methionine Synthesis

Clostridium difficile infection (CDI) is associated with dysbiosis and a higher risk of complications in patients with ulcerative colitis. This study reveals a possible association between CDI, dysbiosis, suppression of methionine synthesis, and increased risk of surgery in Crohn’s disease.

Predictors of clinical metastases and survival among nonmetastatic prostate cancer (PC) patients (pts) treated with androgen-deprivation therapy (ADT) in Sweden.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e16066-e16066
Author(s):  
Rohini Khorana Hernandez ◽  
Johan Mesterton ◽  
Jonas Banefelt ◽  
Jan Stålhammar ◽  
Patrik Sobocki ◽  
...  
Keyword(s):  
Disease Progression ◽  
Specific Antigen ◽  
Significant Risk ◽  
Standard Of Care ◽  
Primary Therapy ◽  
Time Varying ◽  
Real World Data ◽  
Hazard Ratios ◽  
Increased Risk

e16066 Background: ADT is the standard of care in Sweden for PC pts with signs of recurrence after primary therapy (tx). Studies of predictors of metastasis (mets) and survival have largely focused on pt characteristics at cancer diagnosis. Time-varying factors, such as prostate-specific antigen (PSA) levels, may have greater impact on a pt’s risk of disease progression. This study examines predictors of mets and survival among men with PC treated with ADT. Methods: Using electronic medical records from Swedish urology clinics linked to national registries (Cancer Registry, National Pt Registry, Cause of Death Registry), we identified men with PC and no evidence of mets treated with ≥6 months (mos) ADT (gonadotropin-releasing hormone agonists/antagonists or bilateral orchiectomy) between 2000-2010 with ≥2 PSA values. Men were followed from ADT index date to mets, death, or end of follow-up (12/31/2010). Multivariate competing risks regression analysis was used to estimate hazard ratios (HR) and 95% CIs; predictors and covariates of interest included PC diagnosis year (yr), age, comorbidities, anti-androgen tx, region, and time-varying characteristics (PSA absolute value, PSA doubling time [DT]). Results: Cohort was 446 men with mean follow-up of 3.3 yrs. Most mets were to the bone (7-yr cumulative incidence 25% for bone, 30% for any mets). Median survival was 6 yrs (5.9 mos after bone mets, 6.1 mos after any mets). Higher PSA and shorter PSA DT were strong predictors of all outcomes. In particular, PSA DT ≤ 6 mos was associated with increased risk of bone mets (13.9 [8.0 – 24.1]), any mets (7.9 [4.9 – 12.8]), mortality (5.7 [3.9 – 8.5]), and bone mets-free survival (6.9 [4.7–10.1]) when compared to PSA DT > 6 mos. HRs were adjusted for age, Charlson comorbidity index, anti-androgen tx, and region. Conclusions: PC pts treated with ADT are at significant risk of bone mets, any mets, and death. This study based on real-world data demonstrates the importance of PSA measured after ADT initiation in defining high risk of these outcomes, particularly PSA DT ≤6 mos. PC pts may benefit from new tx to prevent disease progression since survival is short after bone or other mets.

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