Citations

Abstract Background: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, autosomal dominant disorder driven by mutations in ACVR1 that render it responsive to Activin A. FOP is characterized by progressive heterotopic ossification (HO) and distressing inflammatory events called “flare-ups.” Flare-ups can precede new HO; however, limited prospective data exists on this phenomenon. Garetosmab (GAR), an investigational human monoclonal antibody against Activin A, blocks formation of new HO in FOP. Methods: This is a post-hoc analysis of LUMINA-1 (NCT03188666) a phase 2, randomized, double-blind, placebo-controlled study, which evaluated the safety and efficacy of GAR (10 mg/kg/week IV) versus placebo (PBO) in adult patients with FOP over 28 weeks. Patient-reported flare-ups were collected via a patient diary and severity level was reported as mild, moderate or severe. Clinician-reported flare-ups were collected as adverse events in the trial. HO lesions were imaged by 18F-NaF positron emission tomography (PET) and whole-body low-dose X-ray computed tomography (CT). Results: There was a two-fold higher proportion of patients who reported one or more flare-ups on PBO 17/24 (71%) compared with GAR 7/20 (35%). Clinicians reported a four-fold higher proportion of patients experiencing one or more flare-ups on PBO 10/24 (42%) compared with GAR 2/20 (10%). Overall rates of flare-up events were two-fold higher on PBO vs. GAR (1.4 vs. 0.65 events/patient/28 weeks) for patient-reported events and eight-fold higher on PBO vs. GAR by clinician report (0.83 vs. 0.10 events/patient/28 weeks). Most flare-ups occurred on the extremities and back; pain was the most commonly reported symptom. Patient-reported flare-ups on PBO were more frequently reported as severe (29.4%) compared with GAR (7.7%). Among subjects with at least 12 weeks of follow-up from start of patient-reported flare-up, development of new HO near the site was 5/27 (18.5%) on PBO and (0%) on GAR. Of all new HO lesions, 41% on PBO and 0% on GAR occurred with spatial and temporal relation to flare-up. Conclusions: Approximately two-thirds of patients on PBO reported flare-ups over 28 weeks. GAR was associated with reductions in frequency and severity of flare-ups. Fewer than 20% of patient-reported flare-ups were associated with new HO, indicating frequent discordance of these phenomena, and compatible with previous reports. GAR’s ability to reduce patient- and clinician-reported flare-ups, as well as new HO lesions may provide an important therapeutic option.

Abstract Objective The objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the pharmacological management of osteoporosis in postmenopausal women using romosozumab. Conclusions We reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.

Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC‐associated BTC (PSC‐BTC). Approach and Results We analyzed formalin‐fixed, paraffin‐embedded tumor tissue from 186 patients with PSC‐BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC‐BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC‐BTC include a significant number of putative actionable therapeutic targets. Notably, PSC‐BTC shows a distinct extrahepatic morpho‐molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC‐associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome‐based personalized treatment strategies in PSC‐BTC.

Abstract Objective The objective is to formulate clinical practice guidelines for the pharmacological management of osteoporosis in postmenopausal women. Conclusions Evidence from clinical trials and insights from clinical experience with pharmacologic therapies for osteoporosis were critically evaluated in formulating this guideline for the management of postmenopausal osteoporosis. Patient preferences, data on adherence and persistence, and risks and benefits from the patient and provider perspectives were also considered in writing committee deliberations. A consensus by the Writing Committee members was achieved for four management principles: (i) The risk of future fractures in postmenopausal women should be determined using country-specific assessment tools to guide decision-making. (ii) Patient preferences should be incorporated into treatment planning. (iii) Nutritional and lifestyle interventions and fall prevention should accompany all pharmacologic regimens to reduce fracture risk. (iv) Multiple pharmacologic therapies are capable of reducing fracture rates in postmenopausal women at risk with acceptable risk-benefit and safety profiles.

Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.

The United Kingdom‐Primary Biliary Cholangitis (UK‐PBC) risk scores are a set of prognostic models that estimate the risk of end‐stage liver disease in patients with PBC at 5‐, 10‐ and 15‐year intervals. They have not been externally validated outside the United Kingdom. In this retrospective, external validation study, data were abstracted from outpatient charts and discrimination and calibration of the UK‐PBC risk scores were assessed. A total of 464 patients with PBC treated with ursodeoxycholic acid were included. The median diagnosis age was 52.4 years, and 88% were female patients. The cumulative incidence of events was 6%, 9%, and 15% at 5, 10, and 15 years, respectively. Concordance (c‐statistic) was 0.88, 0.85, and 0.84 using the 5‐, 10‐ and 15‐year risk scores, respectively, which was slightly lower than values observed in the United Kingdom validation cohort. Using the 5‐year risk score, more events were observed than predicted (25 versus 16.8; P = 0.046); using the 10‐year risk score, there was no difference between the observed and predicted number of events (35 versus 44.9; P = 0.14); conversely, using the 15‐year risk score, fewer events were observed than predicted (46 versus 67.5; P = 0.009). Limiting evaluation by the 15‐year UK‐PBC risk score to those with >10 years of follow‐up demonstrated no difference between observed and predicted events. Using the 5‐year risk score, patients within the highest quartile had statistically significant worse event‐free survival compared to the rest of the cohort: 82% versus 98% at 5 years, 73% versus 97% at 10 years, and 58% versus 93% at 15 years. Conclusion: In patients assessed at a North American tertiary medical center, the UK‐PBC risk score had excellent discrimination and was reasonably calibrated both in the short and long term. (Hepatology Communications 2018;2:676‐682)

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients—obtained using the Illumina immunochip—with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10–9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

AbstractEpigenomics, the study of modifications to genetic material that do not alter the underlying DNA sequence, is generating increasing interest as a means to help clarify disease pathogenesis and outcomes. Although genome-wide association studies have identified several potential candidate genes that may be implicated in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), it is estimated that these genes explain less than 20% of the heritability of these diseases. Thus, to date, the origins of “missing heritability” for PBC and PSC remain elusive. The epigenome may provide a potentially elegant solution to this phenomenon, as it can be modified by both internal and external exposures (coined the “exposome”). This may explain differences in disease presentation, treatment response, and rates of progression between individuals. Epigenetic changes may also provide a framework for discovering potential biomarkers for diagnosis and screening of PBC and PSC. Importantly, because the epigenome is modifiable, it may also highlight novel pathways for therapeutic discovery and interventions of these diseases.

Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10 –9 ), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.