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Introduction: Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls., Expert Opinion: Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ana Lleo reports a relationship with Gilead Sciences Inc that includes: speaking and lecture fees. Ana Lleo reports a relationship with Intercept Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees. Ana Lleo reports a relationship with Alfasigma SpA that includes: consulting or advisory and speaking and lecture fees. Ana Lleo reports a relationship with Albireo Pharma Inc that includes: consulting or advisory. Ana Lleo reports a relationship with GSK that includes: speaking and lecture fees. Ana Lleo reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory. Ana Lleo reports a relationship with Incyte Corporation that includes: speaking and lecture fees. Ana Lleo reports a relationship with Takeda Pharmaceutical Co Ltd that includes: consulting or advisory. Ana Lleo reports a relationship with Kowa Pharmaceutical Europe Co Ltd that includes: consulting or advisory. Ana Lleo reports a relationship with Merck Sharp & Dohme UK Ltd that includes: speaking and lecture fees. Ana Lleo reports a relationship with AbbVie Inc that includes: speaking and lecture fees. Francesca Colapietro reports a relationship with Intercept Pharmaceuticals Inc that includes: speaking and lecture fees. Research Grants: EU Project D-LIVER, EU COST Action EURO-Cholangio-Net, Italian Ministry of Health, Italian Association for Cancer Research (AIRC) Support for sponsored studies (via Humanitas Research Hospital): Falk, Intercept Pharma., (© 2023 The Authors.)

The serological hallmark of primary biliary cirrhosis (PBC) is the presence of antimitochondrial antibodies. However, antinuclear antibodies (ANA) are also detectable in approximately 50% of subjects with PBC. Most clinical laboratories use indirect immunofluorescence microscopy to detect ANA and two labeling patterns that predominate in PBC are ‘punctate nuclear rim’ and ‘multiple nuclear dots.’ Work over the past several years has shown that antibodies giving these patterns most often recognize nuclear pore membrane protein gp210 and nuclear body protein sp100, respectively. These ANA are highly specific for PBC and detected in approximately 25% of patients. Less frequently, ANA apparently unique to PBC recognize other proteins of the nuclear envelope and nuclear bodies. While antibodies against gp210, sp100 and some other nuclear proteins are very specific to PBC and may therefore be useful diagnostic markers, their connection to pathogenesis remains to be elucidated. [Copyright &y& Elsevier]

Aims: Patients with primary biliary cirrhosis (PBC) occasionally suffer complications from other autoimmune diseases. When PBC was associated with calcinosis, Raynaud''s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasias (CREST) symptoms, it has been proposed that it is a distinct clinical entity. This study aimed to investigate whether PBC associated with CREST symptoms is a distinct disease complex. Method: Clinicolaboratory data, HLA type of leukocytes and disease prognosis were compared between 31 patients with PBC associated with CREST symptoms and 68 patients with PBC alone. Results: The characteristic findings and significant differences observed in patients with PBC associated with CREST symptoms compared with PBC alone are as follows: all women with older age with milder clinical features of both PBC (asymptomatic PBC in 84%) and CREST syndrome (incomplete CREST in 81%), more frequent occurrence of esophageal varices (28.6 vs. 9.3%), better prognosis (87.5 vs. 45.5% in 10 years survival), lower serum levels of AST (39.8 vs. 63.6 IU/l) and IgM (460 vs. 676 mg/dl), higher prevalence of discrete speckled pattern of antinuclear antibodies (93.5 vs. 12.3%), higher median titers of anti-CENP-B antibodies (1.22 vs. 0.31), lower median titers of antimitochondrial antibody (1:80 vs. 1:160), and a higher prevalence of HLA-DR9 (54.5 vs. 24.3%). Conclusion: These findings support the presence of a subgroup in PBC as PBC associated with CREST symptoms. [Copyright &y& Elsevier]

Background & Aims: Obeticholic acid (OCA) is the second-line treatment approved for patients with primary biliary cholangitis (PBC) and an inadequate response or intolerance to ursodeoxycholic acid. We aimed to evaluate the effectiveness and safety of OCA under real-world conditions., Methods: Patients were recruited into the Italian PBC Registry, a multicentre, observational cohort study that monitors patients with PBC at national level. The primary endpoint was the biochemical response according to Poise criteria ; the secondary endpoint was the biochemical response according to normal range criteria , defined as normal levels of bilirubin, alkaline phosphatase (ALP), and alanine aminotransferase (ALT) at 12 months. Safety and tolerability were also assessed., Results: We analysed 191 patients until at least 12 months of follow-up. Median age was 57 years, 94% female, 61 (32%) had cirrhosis, 28 (15%) had histologically proven overlap with autoimmune hepatitis (PBC-AIH). At 12 months, significant median reductions of ALP (-32.3%), ALT (-31.4%), and bilirubin (-11.2%) were observed. Response rates were 42.9% according to Poise criteria , and 11% by normal range criteria . Patients with cirrhosis had lower response than patients without cirrhosis (29.5% vs. 49.2%, p  = 0.01), owing to a higher rate of OCA discontinuation (30% vs. 12%, p  = 0.004), although with similar ALP reduction (29.4% vs. 34%, p  = 0.53). Overlap PBC-AIH had a similar response to pure PBC (46.4% vs. 42.3%, p  = 0.68), with higher ALT reduction at 6 months (-38% vs. -29%, p  = 0.04). Thirty-three patients (17%) prematurely discontinued OCA because of adverse events, of whom 11 experienced serious adverse events. Treatment-induced pruritus was the leading cause of OCA discontinuation (67%)., Conclusions: Effectiveness and safety of OCA under real-world conditions mirror those in the Poise trial. Patients with cirrhosis had lower tolerability. Overlap PBC-AIH showed higher ALT reduction at 6 months compared with patients with pure PBC., Lay Summary: Obeticholic acid (OCA) was shown to be effective in more than one-third of patients not responding to ursodeoxycholic acid in a real-world context in Italy. Patients with cirrhosis had more side effects with OCA, and this led to suspension of the drug in one-third of patients. OCA was also effective in patients who had overlap between autoimmune hepatitis and primary biliary cholangitis., Competing Interests: The authors have no conflicts of interest to declare related to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Author(s).)