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Background: Due to the heterogeneity of sarcoidosis, there is a need to define clinical phenotypes to allow for tailoring of clinical care and identification of more homogenous populations to facilitate research., Methods: We utilized data from a prospectively collected registry of sarcoidosis patients seen at a single quaternary referral center between January 2019 and February 2021. We used multiple correspondence analysis (MCA) and k-means clustering to investigate if the clusters previously identified in the GenPhenReSa study were reproducible in a US population. We also investigated if these clusters were stable when the population was stratified by race., Results: We replicated 3 of the 5 clusters seen in the GenPhenReSa study in our cohort. We likewise identified similar clusters between White and Black patients with sarcoidosis. Differences in organ manifestations associations between White and Black patients were seen primarily in relation to cardiac, neurologic, and ocular involvement., Conclusions: The organ clusters of liver-spleen, isolated pulmonary, and musculoskeletal-skin were reproducible in a US cohort, and in both Black and White patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: LJH, AT, SH, XW have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.JCS:Lecture honoraria - Kinevant, Boehringer IngelheimRB:Research Grants - Celgene, Actelion, aTyr, Genentech, Gilead, Bellerophon, Bayer, Mallinckrodt, Foundation for Sarcoidosis Research.Scientific Advisor - Astra Zeneca, Actelion, aTyr, Kinevant, Xentria, Mallinckrodt, Boehringer Ingelheim, Foresee Pharmaceuticals, Ann Theodore Foundation.Speaker's Bureau - Mallinckrodt, United Therapeutics, Boehringer IngelheimDAC:Steering Committee - Boehringer-IngelheimClinical Trials – Atyr, AI Therapeutics, MallinckrodtConsulting – Foresee Pharmaceuticals, Molecure, KinevantCommittee Honoraria – Pliant, FibroGen., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin 2, which is upregulated on immune cells in response to lung inflammation., Research Question: What is the tolerability, safety, and effect on outcomes of efzofitimod in pulmonary sarcoidosis?, Study Design and Methods: In this randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every 4 weeks for 24 weeks, randomized patients (2:1) underwent a steroid taper to 5 mg/d by week 8 or < 5 mg/d after week 16. The primary end point was the incidence of adverse events (AEs); secondary end points included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality-of-life scales., Results: Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected AEs and no dose-dependent AE incidence. Average daily steroid doses through end of study were 6.8 mg, 6.5 mg, and 5.6 mg for the 1 mg/kg, 3 mg/kg, and 5 mg/kg groups compared with 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9%, and 22%, respectively. Clinically meaningful improvements were achieved across several patient-reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but nonsignificant trend toward improved lung function also was observed for 3 and 5 mg/kg., Interpretation: Efzofitimod was safe and well tolerated and was associated with dose-dependent improvements of several clinically relevant end points compared with placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis., Trial Registry: ClinicalTrials.gov; No.: NCT03824392; URL: www., Clinicaltrials: gov., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction:   activity tracker device usage can help analyze the impact of disease state and therapy on patients in clinical practice.  factors such as age, race, and gender may contribute to difficulties with using such technology.  Objective: we evaluated the effect of age, race, and gender on the usability of the Fitbit OneTM activity tracking device in sarcoidosis patients and the impact of device on sarcoidosis patients' activity., Method: patients participated in a six-month prospective study where were asked to wear a Fitbit OneTM activity tracker daily. device usage education was provided at study enrollment.  weekly data download and submission reports to participating centers was required. patients were asked to complete a post-study questionnaire reviewing the motivation of the activity tracker on daily activity., Results: at three centers, 91 patients completed all study visits and the post study questionnaire with a mean age of 55 and 75% were female and 34% african american. accurate downloads occurred >75% of the time, regardless of age, race, or sex. results of the post-study questionnaire did not show a correlation between the likelihood of wearing the device and motivation to increase activity., Conclusion: using an activity tracking device to evaluate and/or correlated with quality of life (QOL) instruments may prove beneficial for gathering more data on patients.  age, race, and gender did not contribute to differences in usability among sarcoidosis patients.

Background: Prucalopride is a selective serotonin type 4 (5-HT 4 ) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT 4 receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride., Methods: In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of 14 C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02-640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated., Results: Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150-10,000 times lower than that for the 5-HT 4 receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo., Conclusion: This series of non-clinical and clinical studies suggest low abuse potential for prucalopride., Competing Interests: Disclosure and potential conflicts of interest: KD is an employee of Takeda Development Center Americas, Inc., and is a stockholder of Takeda Pharmaceutical Company Limited. HW was an employee of Takeda Development Center Americas, Inc. at the time of this analysis and is a present employee of Pfizer. ZL was an employee of Takeda Development Center Americas, Inc., at the time of this analysis and is a present employee of H3 Biomedicine. RB was an employee of Takeda Development Center Americas, Inc., at the time of this analysis and is now a self-employed consultant. Portions of this work have previously been presented in the following abstracts: Derakhchan K, Wang H, Papaioannou N, Lou Z, Baughman R, Carey G. Evaluation of prucalopride, a highly selective serotonin-4 (5-hydroxytryptamine)-4 receptor agonist, demonstrates a low potential for abuse liability. J Pharmacol Toxicol Methods. 2020;105:106699; Lou Z, Welty D. Investigating the Tissue Distribution of [14C]-Prucalopride Following a Single Oral Dose in Rats. Am J Gastroenterol. 2019;S274; and Welty D, Lou Z. P196 – Investigating the Tissue Distribution of [14C]-Prucalopride Following a Single Oral Dose in Rats, 12th International ISSX Meeting; 2019. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2023/01/dic.2022-6-1-COI.pdf, (Copyright © 2023 Derakhchan K, Lou Z, Wang H, Baughman R.)

Anti-arrhythmics can be useful for ventricular arrhythmias in cardiac sarcoidosis (CS) that are refractory to immunosuppression. However, there is conflicting evidence on the efficacy of immunosuppression for treating arrhythmias in CS patients and a lack of data to support using immunosuppression alone as an initial strategy. The objective of this study was to assess for differences in arrhythmia burden over time with currently used immunosuppression and anti-arrhythmic regimens. Patients with CS and implanted cardiac devices were identified from a single-center registry. Study participants were retrospectively classified based on the medication regimen as follows: control (no therapy), immunosuppression, anti-arrhythmics, or dual therapy. Device interrogations were reviewed for premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (NSVT), and device firings over time. Interrogations for 42 patients were reviewed over a mean period of 31 months. Regression analysis showed a significant decrease in the frequencies of PVCs (slope, -1.47; P = .04) and NSVT (slope, -0.05; P = .01) for patients on dual therapy compared to an increase or no change in the other groups. Across all patients, there was no difference between groups in the percentage of patients experiencing device firings. In a subset analysis of patients with implantable cardioverter-defibrillators for primary prevention, 6% on dual therapy required device firings compared to 43% and 40% on single or no therapy, respectively ( P = .049, χ 2 = 6.02). In conclusion, patients on both immunosuppression and anti-arrhythmics had a reduction in PVCs and NSVT over time. Overall, there were no differences between groups in terms of device firings, except in a subset analysis of patients with no history of ventricular tachycardia., Competing Interests: The authors report no conflicts of interest for the published content. No funding information was provided., (Copyright: © 2022 Innovations in Cardiac Rhythm Management.)

Background: This study was performed to satisfy a US Food and Drug Administration post-marketing requirement to compare the dose responses for Technosphere ® Insulin (TI; MannKind Corporation, Westlake Village, CA, USA) and subcutaneous insulin lispro (LIS) across a wide range of doses., Objectives: This single-center, open-label, randomized, cross-over study defined the pharmacokinetic/pharmacodynamic curves for inhaled TI vs subcutaneous LIS in persons with type 1 diabetes mellitus., Methods: Each volunteer received six treatments while undergoing euglycemic clamps: three doses of TI (10, 30 and 120 U) and LIS (8, 30, and 90 U). Primary endpoint was area under the glucose infusion rate vs time curve from start of treatment administration to end of clamp. Key secondary endpoints included readouts of insulin exposure and timing of pharmacokinetic/pharmacodynamic profiles., Results: Insulin exposure was more than dose proportional, increasing with dose 1.08 for LIS and dose 1.35 for TI. Time to reach 10% of the maximum glucose infusion rate was 7 to 15 min for TI vs 21 to 38 min for LIS. End of effect was dose dependent for both treatments, ranging from 2 to 6 h (TI) and 5 to 10 h (LIS). Glucose infusion rate exhibited saturation for both treatments. Technosphere Insulin produced a lesser total effect per unit insulin than LIS due to its faster absorption and correspondingly shorter duration of exposure. The difference was large enough to require significantly different doses to achieve the same total effect., Conclusions: Technosphere Insulin has a considerably faster onset and shorter duration of action than LIS. Consequently, the overall effect of TI is smaller than that of LIS and unit-for-unit dose conversion is not appropriate., Clinical Trial Registration: ClinicalTrials.gov, NCT02470637; 12 June, 2015., (© 2021. The Author(s).)