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Introduction Multiple myeloma (MM) patients with renal impairment (RI), especially dialysis-dependent (DD) RI, have poorer outcomes than MM patients with normal renal function. Autologous stem cell transplantation (ASCT) is a treatment option, but there is concern at a perceived higher risk of complications which may be limiting consideration of the use of ASCT in this population. The evidence is inconsistent among studies and interpretation is complicated by heterogeneous datasets, some dating to before the availability of novel agents. Finally, the reversibility of RI following ASCT is an important prognostic factor for both survival and quality of life. Aim To evaluate the safety and efficacy of ASCT in MM patients with DD RI transplanted in EBMT centres between 1997 and 2017. Methods Baseline characteristics at diagnosis, patient treatment regimens and clinical outcomes were collected using standardised report forms. OS was defined as the period between the date of ASCT and the date of death or the date of last observation. PFS was defined as the period between the date of ASCT and date of progression/relapse or death of any causes or the date of the last observation. Cox proportional hazard regression analysis was applied to assess risk factors for progression and death. Survival curves were plotted by the Kaplan-Meier method and compared using log-rank test. P Results A total of 109,959 adult MM patients are registered in the EBMT database as having undergone ASCT between 1997 and 2017. We further analysed 118 DD MM patients who had a first ASCT during this period. The median (range) age was 57 (27-71) years. Seventy (59%) patients were males. Forty nine patients (49/94 patients, 52%) had Karnofsky score ≥90. One hundred and ten patients were treated with hemodialysis and eight with peritoneal dialysis. A total of 68 (58%) patients had Light Chain MM, 43 kappa and 25 Lambda. In first-line induction therapy, 47/76 (62%) patients received bortezomib-based regimens. Forty-four (37%) patients achieved at least VGPR pre-ASCT. The median time from diagnosis to ASCT was 0.7 years (0.3-4.9). Melphalan doses were as follows: 140 mg/m2 (n=55, 67%), 70-100 mg/m2 (n=15, 18%), and >140 mg/m2 (n=12, 15%). The times to Neutrophil (>0.5) and Platelet (>20) engraftment were 12 (10-37) and 14 (4-128) days, respectively. The 30-day and 100-day transplant-related mortality (TRM) rates were 0.0% and 0.9%, respectively. ASCT was associated with a significant deepening of response (at least VGPR pre- vs post-ASCT: 36/93 (39%) vs 48/93 (52%), p < 0.001). The median PFS was 37 months (95% CI: 24-43) and 5-year PFS was 31% (95% CI: 20-41). The median OS was 102 months (95% CI: 67-129). Five-year OS post-ASCT was 62% (52-72) and 10-year OS 36% (17-55). Thirty-one (26%) DD MM patients achieved dialysis independence. There were no differences in PFS or OS when comparing the 1997-2007 and 2008-2017 cohorts: 5-year PFS - 28% (6-49) vs 31% (19-43) (p=0.7) and 5-year OS - 61% (38-84) vs 63% (51-74) (p=0.9), respectively. On univariate analysis of factors affecting PFS, achievement of an Overall Response Rate (ORR) (CR+VGPR+PR vs. Other) pre-ASCT was associated with a lower risk (HR 0.467, p=0.032) and older age (>55 years) with a higher risk (HR 1.786, p=0.035) of post-ASCT progression. Age higher than 55 (HR 2.033, 95%CI: 0.992 - 4.166, p=0.053) increased and achievement of at least VGPR pre-transplant (HR 0.494, 95%CI: 0.224 - 1.091, p=0.081, on the verge of statistical significance) decreased the risk of death. Conclusion To the best of our knowledge, the DIADEM study is the largest analysis of ASCT in DD MM pts to date. This cohort of 118 unselected patients had an OS comparable to patients without RI. This may reflect patient selection based on younger age, Karnofsky scores and pre-ASCT response. The low TRM and excellent outcomes support consideration of the use of ASCT in pts with DD RI. Notably, more than a quarter of patients became dialysis independent, an outcome likely to confer an improved Quality-of-Life.. These results can also inform the debate around the role of renal transplantation in younger DD MM patients who do not achieve dialysis independence. Disclosures Snowden: IDMC: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Mallinckrodt: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Basak:Teva: Honoraria; Celgene: Honoraria. Gyan:Pfizer: Honoraria. Hayden:Alnylam: Honoraria; Amgen: Honoraria. Beksac:Amgen: Consultancy; Celgene: Consultancy; Janssen&Janssen: Consultancy; Takeda: Consultancy. Schönland:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Sun Life Financial, uniQure, and United Healthcare. Whittington, Rind, and Pearson are employed by ICER. Through their affiliated institutions, Synnott and Lin received funding from ICER for the work described in this summary. In addition, Synnott reports support from Biogen for the Tufts Medical Center Cost-Effectiveness Analysis Registry, which is maintained by the Center for the Evaluation of Value and Risk in Health.

BACKGROUND: Direct-acting antiviral (DAA) regimens for hepatitis C virus (HCV) have varying potentials for drug-drug interactions (DDIs). OBJECTIVES: To (1) identify prevalence of potential DDI with glecaprevir-pibrentasvir (GLE-PIB) and sofosbuvir-velpatasvir (SOF-VEL) and (2) describe health care provider actions in response to pharmacist recommendations based on potential interactions with GLE-PIB or SOF-VEL, using 2 complementary data sources. METHODS: Possible interacting drugs were identified among adult patients in a United States electronic medical record database covering 21 health care organizations and 26 million patients in 2018. DDIs were categorized as potential weak interaction (Level 1), potential interaction (Level 2), or contraindicated (Level 3). Real-world recommendations and resultant actions regarding DDIs with GLE-PIB and SOF-VEL were obtained from a specialty pharmacy database. Categorical variable comparisons were done via chi-square analysis with subsequent z-tests of column proportions. RESULTS: DDI prevalence was higher for patients prescribed GLE-PIB (317/769 [41%]) compared with those prescribed SOF-VEL (170/633 [27%]), and the prevalence of a Level 3 (contraindicated) interaction was higher with GLE-PIB than SOF-VEL (61/769 [8%] vs 2/633 [< 1%]). Across all DDI levels, analgesics (139/317 [44%]), proton-pump inhibitors (129/317 [41%]), and lipid-lowering agents (59/317 [19%]) were the top drug classes for the GLE-PIB group with potential for DDI. For SOF-VEL prescribed patients, the top drug classes were proton-pump inhibitors (83/170 [49%]), histamine-2 blockers (42/170[25%]), and lipid-lowering agents (42/170 [25%]). In real-world care management, the overall prevalence of pharmacist recommendations regarding DDIs was significantly lower for SOF-VEL (28/419 [7%]) relative to GLE-PIB (151/1,216 [12%]). Recommended guidance from pharmacists was not followed for 39% (69/179) of patients, 36% (54/151) for GLE-PIB, and 54% (15/28) for SOF-VEL. CONCLUSIONS: The potential for DDIs with pangenotypic HCV DAAs is frequent and may be more frequent with GLE-PIB than SOF-VEL. Physician responses to pharmacist alerts regarding potential interaction can be highly variable, even in cases of contraindication. DISCLOSURES: Funding for this study was provided by Gilead Sciences, Inc. Trio Health Analytics received funding from Gilead Sciences, Inc., to conduct research for this study. Tsai consults for and has received grants and honoraria from Gilead, AbbVie, Merck, and Bristol Myers Squibb; he has also received lecture fees from Gilead and AbbVie. Curry consults for Trio Health Analytics and Gilead and has also consulted for and received grants from Mallinckrodt. Flamm consults for and has received lecture fees from Gilead and AbbVie; he has also received grants from Gilead and AbbVie. Milligan and Wick are employed by Trio Health Analytics and have received research support from Gilead, Merck, and AbbVie. Younossi has received grants from Gilead, Intercept, Bristol Myers Squibb, GlaxoSmithKline, and Novo Nordisk. Afdhal is a paid consultant/advisory board member for Gilead, Echosens, Ligand, Shionogi, and Trio Health; owns stock in Spring-Bank and Allurion and has stock options in SpringBank; receives royalty income from UpToDate; and is on the board of directors for the nonprofit Liver Institute for Education and Research. Data from this study were presented at the American Association for the Study of Liver Disease (AASLD) Liver Meeting 2019; November 8-12, 2019; Boston, MA, and the European Association for Study of the Liver (EASL) International Liver Congress 2020; August 27-29, 2020; virtual.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, Fluetsch, and Pearson are employed by ICER. Ollendorf received funding from ICER for work on this summary and reports consulting and other personal fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Executive Insight, Sunovion, University of Colorado, World Health Organization, and Eli Lilly, unrelated to this work. Lee and McQueen received funding from ICER for work on this summary.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Agboola, McKenna, and Pearson are employed by ICER. Lin and Kazi received funding from ICER for work on this report.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, McKenna, Rind, and Pearson are employed by ICER. Touchette received funding from ICER for work on this report and has also received fees from Monument Analytics and AstraZeneca, unrelated to this work. The University of Illinois at Chicago (UIC) and Touchette hold a patent for the model described in this report. The model is included in ICER's Interactive Modeler, for which a fee is paid to UIC and Touchette. Atlas also received funding from ICER for work on this report.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Agboola, Rind, Herron-Smith, and Pearson are employed by ICER. Walton and Quach, through the University of Illinois at Chicago, received funding from ICER for development of the economic model described in this report.

BACKGROUND: Oral semaglutide is the first oral formulation of a glucagon-like peptide 1 (GLP-1) receptor agonist to be approved in the United States for glycemic control in people with type 2 diabetes mellitus (T2DM). While oral semaglutide is not indicated for reduction of cardiovascular event risk, its label does include evidence of no increase in cardiovascular risk in people who received oral semaglutide. OBJECTIVE: To estimate the incremental value of oral semaglutide added to existing antihyperglycemic treatment for people with T2DM with additional risk for cardiovascular disease. METHODS: We estimated the lifetime cost-effectiveness of oral semaglutide added to current antihyperglycemic treatment for T2DM using a microsimulation model based primarily on the UK Prospective Diabetes Study (UKPDS) Outcomes Model 2 (OM2) equations. Oral semaglutide added to current antihyperglycemic treatment was separately compared with (a) ongoing background antihyperglycemic treatment, (b) sitagliptin, (c) empagliflozin, and (d) liraglutide. Comparators sitagliptin, empagliflozin, and liraglutide were added to ongoing antihyperglycemic treatment. We applied hazard ratios derived from a network meta-analysis for cardiovascular and renal outcomes to the UKPDS OM2 estimated baseline rates. Health state utilities and costs were derived from the published literature. We estimated total costs, life-years (LYs), quality-adjusted life-years (QALYs), clinical events, and cost per major adverse cardiovascular event (MACE) avoided, over a lifetime time horizon using discount rates of 3% for costs and outcomes. RESULTS: The lifetime total cost for people treated with oral semaglutide was $311,300, with costs for the other comparators ranging from $262,800 (background treatment alone) to $287,800 (liraglutide). Oral semaglutide resulted in the fewest MACE, including the fewest cardiovascular deaths. Among the 5 modeled treatment strategies, oral semaglutide had the highest LYs gained (8.43 vs. 7.76 [background treatment alone] to 8.29 [empagliflozin and liraglutide]) and the highest QALYs gained (4.11 vs. 3.70 [background treatment alone] to 4.03 [empagliflozin]). Oral semaglutide would likely be considered cost-effective compared with liraglutide (incremental cost-effectiveness ratio [ICER] = $40,100), and moderately cost-effective versus background treatment alone ([ICER] = $117,500/QALY) and sitagliptin (ICER = $145,200/QALY). The ICER for oral semaglutide compared with empagliflozin was approximately $458,400 per QALY. CONCLUSIONS: As modeled, oral semaglutide as an add-on therapy to background antihyperglycemic treatment produced incremental benefits in MACE avoided, along with greater QALYs compared with background antihyperglycemic treatment alone. Oral semaglutide use resulted in better outcomes than background treatment alone or sitagliptin, and similar outcomes to liraglutide or empagliflozin with overlapping 95% confidence ranges for QALYs. Oral semaglutide was estimated to be cost-effective compared with liraglutide and to have incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY versus sitagliptin and background therapy alone, but it did not meet these thresholds compared with empagliflozin. DISCLOSURES: Funding for this study was provided by the Institute for Clinical and Economic Review, an independent organization that evaluates the evidence on the value of health care interventions. ICER reports grants from Laura and John Arnold Foundation, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Rind, Fazioli, Chapman, and Pearson are employed by ICER. Guzauskas and Hansen have nothing to disclose. Study results were presented at the New England Comparative Effectiveness Public Advisory Council (New England CEPAC), November 14, 2019, at Brown University, Providence, RI.

Views on what is important in training for psychologists are evolving, reflecting a broadening understanding of the role psychologists can and should play in societal change. Since the development of the scientist-practitioner model after World War II, arguments around training have focused on the appropriate balance between training in the practice of psychology versus training in research related to psychology. Recent calls reflect more radical change to include an advocacy emphasis within the formal coursework of psychology doctoral programs, well articulated by Mallinckrodt, Miles, and Levy (2014) as the tripartite model of Scientist-Practitioner-Advocate. In this paper, we present the argument for expanding a model that incorporates advocacy training into clinical psychology internships and postdoctoral programs and describe why we believe voices for advocacy have been largely silent in public-sector clinical psychology training and practices. We outline how this may be accomplished in public sector training settings, and we articulate a call to action for public servants to speak out so their voice can ignite a passion for advocacy within public sector psychology service and training. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

BACKGROUND: Ulcerative colitis is a chronic immune-mediated inflammatory condition of the large intestine and rectum. Several targeted immune modulators (TIMs) have demonstrated effectiveness for the treatment of moderate to severe ulcerative colitis and are approved by the FDA. Patients may try multiple TIMs, and currently there are no biomarkers or prognostic factors to guide choice of treatment sequence. In 2020, the Institute for Clinical and Economic Review (ICER) conducted a review of TIMs for the treatment of ulcerative colitis as individual agents relative to conventional treatment but did not address the relative ranking of various treatment sequences to each other. OBJECTIVE: To extend the ICER framework to identify the optimal treatment sequence as informed by metrics such as maximizing incremental net health benefit (NHB), minimizing incremental total cost, or maximizing incremental quality-adjusted life-years (QALYs). METHODS: The model was developed as a Markov model with 8-week cycles over a lifetime time horizon from a US payer perspective, including only direct health care costs. Health states consisted of active moderate to severe ulcerative colitis, clinical response without achieving remission, clinical remission, and death. Efficacy of TIMs were informed by the ICER-conducted network meta-analysis. Up to 3 treatments were modeled in a sequence that consisted of 2 different TIMs followed by conventional treatment. Sequences were ranked according to each objective. NHB was calculated using a threshold of $150,000 per QALY gained. Probabilistic sensitivity analysis (PSA) was undertaken to estimate the probability of each sequence having the highest NHB rank under each objective. RESULTS: 21 possible sequences were evaluated in the base case. Two attempts at conventional treatment represented the lowest cost option and, while yielding the fewest QALYs, resulted in the highest NHB. None of the sequences had an incremental cost per QALY below $150,000 relative to 2 attempts with conventional treatment, so the resulting NHB was negative for all sequences. The sequence with the highest NHB was infliximab-dyyb followed by tofacitinib (-0.116). This regimen also had the lowest incremental costs ($37,266). For orally and subcutaneously administered TIMs, the sequence of golimumab-tofacitinib had the highest NHB (-0.344). Ustekinumab-vedolizumab was the top-ranked sequence as measured by QALY maximization (0.172 incremental QALYs) but also had the highest total incremental cost ($166,094). Results of the PSA were consistent with deterministic rankings for the top-ranking sequences but also showed that the top 2 or 3 regimens were often close together. CONCLUSIONS: Based on the results of this analysis, the optimal sequence of TIMs as measured by NHB and cost minimization was infliximab or biosimilars as first-line treatment, then moving to tofacitinib, adalimumab, or vedolizumab. Sequences that generated the most QALYs began with ustekinumab, followed by vedolizumab, tofacitinib, and adalimumab. DISCLOSURES: This study was based on an evidence synthesis and economic evaluation sponsored by the Institute for Clinical and Economic Review (ICER). Pandey and Fazioli are employees of ICER. Bloudek reports grants from ICER during the conduct of the study and personal fees from Astellas, Akcea, Dermira, GlaxoSmithKline, Sunovion, Seattle Genetics, and TerSera Therapeutics, outside the submitted work. Pandey reports grants from California Healthcare Foundation, Harvard Pilgrim Healthcare, Kaiser Foundation Health Plan Inc., and the Donoghue Foundation, during the conduct of the study, and other support from Aetna, America's Health Insurance Plans, Anthem, AbbVie, Alnylam, AstraZeneca, Biogen, Genentech/Roche, GlaxoSmithSline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, United Healthcare, HealthFirst, Pfizer, Boehringer-Ingelheim, uniQure, Evolve Pharmacy Solutions, and Humana, outside the submitted work. Fazioli reports grants from Arnold Ventures, California Healthcare Foundation, Harvard Pilgrim Healthcare, Kaiser Foundation Health Plan Inc., and The Donaghue Foundation, during the conduct of the study, and other support from Aetna, America's Health Insurance Plans, Anthem, AbbVie, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, United Healthcare, HealthFirst, Pfizer, Boehringer-lngelheim, uniQure, Evolve Phamacy Solutions, and Humana, outside the submitted work. Ollendorf reports grants from ICER, during the conduct of the study, along with other support from CEA Registry sponsors and personal fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Sunovion, University of Colorado, Center for Global Development, and Neurocrine, outside the submitted work. Carlson reports grants from ICER, during the conduct of the study, and personal fees from Allergan, outside the submitted work. The inputs and model framework that were leveraged for this analysis were presented as part of the ICER assessment of TIMs for the treatment of moderate to severe ulcerative colitis.

PurposeWe sought to exploit the heterogeneity afforded by patient-derived tumor xenografts (PDX) to optimize robust radiomic features associated with response to therapy in the context of a co-clinical trial and implement PDX-optimized image features in the corresponding clinical study to predict and assess response to therapy using machine-learning (ML) algorithms.MethodsTNBC patients and subtype-matched PDX were recruited into a co-clinical FDG-PET imaging study to predict response to therapy. One hundred thirty-one imaging features were extracted from PDX and human segmented tumors. Robust image features were identified based on reproducibility, cross-correlation, and volume independence. A rank importance of predictors using ReliefF was used to identify predictive radiomic features in the preclinical PDX trial in conjunction with ML algorithms: classification and regression tree (CART), Naïve Bayes (NB), and support vector machines (SVM). The top four PDX-optimized image features, defined as radiomic signatures (RadSig), from each task were then used to predict or assess response to therapy. Performance of RadSig in predicting/assessing response was compared to SUVmean, SUVmax, and lean body mass normalized SULpeak measures.ResultsSixty-four out of 131 preclinical imaging features were identified as robust. NB-RadSig performed highest in predicting and assessing response to therapy in the preclinical PDX trial. In the clinical study, the performance of SVM-RadSig and NB-RadSig to predict and assess response was practically identical and superior to SUVmean, SUVmax, and SULpeak, measures.ConclusionsWe optimized robust FDG-PET radiomic signatures (RadSig) to predict and assess response to therapy in a context of a co-clinical imaging trial.DECLARATIONSFundingThis work was supported by NCI grants U24CA209837, U24CA253531, and U54CA224083; U2CCA233303, and K12CA167540; Siteman Cancer Center (SCC) Support Grant P30CA091842; and Internal funds provided by Mallinckrodt Institute of Radiology.Conflicts of interest/Competing interests.None.Availability of data and materialAll the co-clinical data will be available for download through the Washington University School of Medicine Co-Clinical Imaging Research Resource web portal at https://c2ir2.wustl.edu/, co-clinical database (CCDB).Code availabilityNot applicable.Authors’ contributionsConceptualization: SR, FOA, KIS; Methodology: SR, TDW, SL, KIS; Formal analysis and investigation: SR, KIS; Writing - original draft preparation: SR; Writing - review and editing: RLW, FD, KIS; Funding acquisition: RWL, FOA, SL, KIS; Resources: SL; Supervision: FD, KIS. All authors read and approved the final manuscript.Ethics approvalAll studies were performed with approval from the Washington University Humans subjects research committee and animal studies committee.Consent to participateInformed consent to participate in the study was obtained from all participants.Consent for publicationNot applicable.

Background:Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for rheumatoid arthritis (RA). The safety and efficacy of UPA has been evaluated across a spectrum of patients (pts) with RA in the phase 3 SELECT clinical program.1,2Objectives:To describe long-term laboratory profiles (cutoff date: June 30, 2020) associated with exposure to UPA, adalimumab (ADA), and methotrexate (MTX) in pts with RA treated in the SELECT trials.Methods:Data were analyzed from 6 randomized controlled UPA RA trials.1,2 The proportions of pts experiencing potentially clinically significant laboratory changes at a single time point were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15; 6 trials), pooled UPA 30 mg QD (UPA30; 4 trials), ADA 40 mg every other week (EOW; 1 trial), and MTX monotherapy (1 trial). Pts received UPA with/without background conventional synthetic disease-modifying antirheumatic drugs. Treatment-emergent adverse events are reported as exposure-adjusted event rates (events/100 pt-years [E/100 PY]). Toxicity was graded per OMERACT criteria, or NCI CTCAE for creatine phosphokinase (CPK) and creatinine.Results:4413 pts received ≥1 dose of UPA (UPA15, n=3209; UPA30, n=1204). Exposures were comparable between treatment groups (Table). Proportions of pts with Grade (Gr) 3 and 4 decreases in hemoglobin were highest with UPA30 and MTX (Table). Rates of anemia, as reported by the investigator, were comparable between UPA15, ADA, and MTX groups (Figure); the frequency of UPA-treated pts who discontinued due to anemia was low in all arms. Gr 3 and 4 decreases in neutrophils and lymphocytes with UPA were dose-dependent and higher vs ADA or MTX. Discontinuations due to neutropenia and lymphopenia were rare (Table 1.Pts with potentially clinically significant laboratory changesVariable, n (%)MTX monotherapy (n=314; 637.4 PY)ADA 40 mg EOW (n=579; 1051.8 PY)UPA 15 mg QD (n=3209; 7023.8 PY)UPA 30 mg QD (n=1204; 3091.6 PY)Mean (SD) exposure, weeks106 (67)95 (70)114 (64)134 (66)Median (range) exposure, weeks144 (1, 221)118 (2, 231)136 (0, 232)160 (0, 231)Hemoglobin, g/LGr 3 (70–28a (9.0)24b (4.2)254d (7.9)169f (14.2)Gr 4 (16a (5.1)16b (2.8)101d (3.2)78f (6.5)Neutrophils, 109/LGr 3 (0.5–3a (1.0)3b (0.5)40d (1.2)37g (3.1)Gr 4 (1a (0.3)1b (0.2)10d (0.3)5g (0.4)Lymphocytes, 109/LGr 3 (0.5–74a (23.7)53b (9.2)802d (25.1)423g (35.5)Gr 4 (5a (1.6)3b (0.5)75d (2.3)47g (3.9)ALT, U/LGr 3 (3.0–8.0 × ULN)26a (8.3)13c (2.3)152e (4.8)71h (5.9)Gr 4 (>8.0 × ULN)5a (1.6)4c (0.7)26e (0.8)10h (0.8)AST, U/LGr 3 (3.0–8.0 × ULN)15a (4.8)9c (1.6)101e (3.2)36h (3.0)Gr 4 (>8.0 × ULN)1a (0.3)5c (0.9)18e (0.6)8h (0.7)CPK, U/LGr 3 (>5.0–10.0 × ULN)2a (0.6)3c (0.5)65e (2.0)36i (3.0)Gr 4 (>10.0 × ULN)0a (0)3c (0.5)27e (0.8)15i (1.3)Creatinine, μmol/LGr 3 (>3.0–6.0 × ULN)0a (0)1c (0.2)3e (2j (0.2)Gr 4 (>6.0 × ULN)0a (0)4c (0.7)8e (0.3)1j (an=312. bn=576. cn=577. dn=3201. en=3199. fn=1193. gn=1192. hn=1195. in=1196. jn=1197ULN, upper limit of normalConclusion:This long-term analysis of UPA-treated pts with RA showed dose-dependent relationships for several laboratory abnormalities. Incidences of these with UPA15 were typically higher than with ADA but similar to MTX, except for increased CPK elevations. Treatment discontinuations due to laboratory abnormalities were infrequent and similar across all treatment groups.References:[1]Tanaka Y. Mod Rheumatol 2020;30:779–87; 2. Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Sanofi/Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, and UCB, Grant/research support from: Pfizer, Nancy Lane Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm, and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi, and UCB, Daniel Furst Speakers bureau: AbbVie, Continuing Medical Education, and Novartis, Consultant of: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, Novartis, and Pfizer, Grant/research support from: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and Sanofi, Jiří Vencovský Speakers bureau: AbbVie, Biogen, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, and Octapharma, Anthony G Wilson: None declared, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Tim Shaw Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jillian Yee Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer, Roche, and UCB

Both sarcoidosis and chronic beryllium disease (CBD) are granulomatous diseases with overlapping clinical features, however, their clinical courses differ. CBD may have slow clinical progression and rarely resolves while sarcoidosis has variable progression and may resolve depending on the stage of the disease [1]. These commonalities and differences imply differences in antigen(s), and potentially clearance and persistence. Alveolar macrophages play an important role in this process driving innate [2] and adaptive immune responses [3]. Furthermore, subpopulations of macrophages may promote granulomatous inflammation and resolution of lung injury [4], key aspects of sarcoidosis and CBD. Using single-cell RNA sequencing (scRNA-seq), we explored the common and unique pathways between progressive (SarcP) and remitting (SarcR) sarcoidosis as well as CBD and sarcoidosis, focusing on macrophages and macrophages subpopulations (recruited versus resident). Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Lindner has nothing to disclose. Conflict of Interest: Dr. Liao has nothing to disclose. Conflict of Interest: Dr. Atif has nothing to disclose. Conflict of Interest: Dr. Mould has nothing to disclose. Conflict of Interest: Dr. Konigsberg has nothing to disclose. Conflict of Interest: Dr. Fu has nothing to disclose. Conflict of Interest: Dr. Davidson has nothing to disclose. Conflict of Interest: Dr. Li has nothing to disclose. Conflict of Interest: Dr. Fontenot reports grants from National Institutes of Health (NIH), during the conduct of the study. Conflict of Interest: Dr. Maier reports grants from National Institutes of Health, during the conduct of the study; grants from National Institutes of Health, grants from University of Cincinnati under a Mallinckrodt Foundation, grants from MNK14344100, grants from ATYR1923-C-002, outside the submitted work; and Dr. Maier is a member of the FSR Scientific Advisory Board. She does not receive any compensation for this activity. Conflict of Interest: Dr. Yang reports grants from NIH, during the conduct of the study and personal fees from Eleven P15, outside the submitted work. In addition, Dr. Yang has a patent Circulating Biomarkers of Preclinical Pulmonary Fibrosis pending.

Background:Upadacitinib (UPA) is an oral Janus kinase (JAK) inhibitor engineered to have greater selectivity for JAK1 vs JAK2, JAK3, and tyrosine kinase 2, and is approved for the treatment of RA. Across 2 double-blind, placebo (PBO)-controlled Phase 3 studies of UPA in patients with RA, after an initial increase through Week 8, lipid levels remained stable up to Week 24.1,2 Previous studies of JAK or IL-6 receptor inhibitors have reported a negative correlation between changes in lipid levels and RA disease activity.3,4Objectives:To determine the relationship between changes in lipid levels and disease activity outcomes in patients with RA treated with UPA.Methods:Patients with RA and an inadequate response to conventional synthetic/biologic DMARDs (cs/bDMARD-IR) from SELECT-NEXT/SELECT-BEYOND, respectively, were randomized to receive UPA 15 mg once daily (QD), UPA 30 mg QD, or PBO for 12 weeks followed by an extension of up to 5 years; patients randomized to PBO switched to UPA 15 or 30 mg after 12 weeks. Spearman correlations of maximum changes from baseline (BL) through Week 12 in fasting-state lipid levels (low- and high-density lipoprotein cholesterol [LDL-C; HDL-C], and total cholesterol [TC]) with clinical disease activity outcomes measured by change from BL in Clinical Disease Activity Index (CDAI), DAS of 28 joints using CRP (DAS28[CRP]), tender/swollen joint count in 28 joints (TJC28/SJC28), and pain by visual analog scale (VAS) at Weeks 12 and 24, were determined. Spearman correlations of maximum changes from BL in lipid levels and CRP through Week 12 were also determined.Results:Available fasting samples from 1,160 pooled patients (UPA 15 mg, n=386; UPA 30 mg, n=384; PBO, n=390) were included. Modest, but statistically significant, negative correlations were observed between maximum changes from BL in TC through Week 12 and change from BL in CDAI, DAS28(CRP), SJC28, and pain (VAS) at Week 12 with UPA 15 or 30 mg (Figure 1); similar trends were observed at Week 24. Significant correlations between changes in LDL-C and HDL-C and disease activity outcomes were also observed, but were not consistent across UPA doses and time points. No significant correlations were noted between changes in lipid levels and disease activity outcomes in the PBO group. Statistically significant weak negative relationships were observed between maximum changes from BL in lipid levels and CRP levels through Week 12 with UPA 15 mg (HDL-C and TC) or UPA 30 mg (LDL-C and TC) (Table 1).Conclusion:In this large pooled data set of patients receiving UPA, increases in lipid levels showed modest, but statistically significant, correlations with improvement in clinical disease activity outcomes in patients with cs/bDMARD-IR RA. These results add to evidence suggesting a relationship between systemic inflammation and lipid metabolism in patients with RA, which is modifiable with effective interventions, and reinforce the importance of monitoring for hyperlipidemia in these patients.References:[1]Burmester GR, et al. Lancet 2018;391:2503–12.[2]Genovese MC, et al. Lancet 2018;391:2513–24.[3]Kremer JM, et al. Arthritis Rheumatol 2017;69:943–52.[4]Cacciapaglia F, et al. Mediators Inflamm 2018;2018:2453265.Table 1.Spearman correlation of maximum changes from BL in lipid levels through Week 12 with maximum change from BL in CRP through Week 12UPA 15 mg QDUPA 30 mg QDPBOLDL-C-0.099 (n=303)-0.174** (n=302)-0.053 (n=303)HDL-C-0.184** (n=305)-0.087 (n=304)-0.024 (n=303)TC-0.189*** (n=305)-0.236*** (n=304)-0.056 (n=303)**pHDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoproteincholesterol; PBO, placebo; QD, once daily; TC, total cholesterol; UPA, upadacitinibAcknowledgements:AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing assistance was provided by Frances Smith, PhD, of 2 the Nth, which was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Regeneron-Sanofi., Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, and Gilead, Grant/research support from: Pfizer, Nancy Lane Speakers bureau: Amgen and Mallinckrodt, Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, AstraZeneca, Bio-Cancer, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospira, Janssen, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Synovate, Tonix, and UCB, Grant/research support from: AbbVie, Amgen, AstraZeneca, Bio-Cancer, Biogen, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Chugai Pharma, Eli Lilly, Ferring Pharmaceuticals, GlaxoSmithKline, Hospira, Janssen, Merck Sharp & Dohme, Napp, Novimmune, Novartis, ObsEva, Pfizer, Regeneron, Roche, R-Pharm, Sanofi, SynAct Pharma, Synovate, Tonix, and UCB, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer Inc., Roche, and UCB

Introduction IgA nephropathy (IgAN) is the most common glomerulonephritis with high risk of progression to end-stage renal disease in patients with proteinuria >1 g/24 hours. There are no known effective treatments in patients with IgAN. Methods We conducted a prospective open-label pilot study in patients with IgAN using adrenocorticotrophic hormone (ACTH) (Acthar Gel, Mallinckrodt Pharmaceuticals, Bedminster, NJ) at a dosage of 80 units subcutaneously twice weekly for a total of 6 months and followed patients for a total of 12 months. Patients had to have urinary protein >1 g/24 hours despite adequate renin-angiotensin-aldosterone system (RAAS) blockade and estimated glomerular filtration rate (eGFR) >30 ml/min at enrollment. Results A total of 19 patients were recruited and followed for 1 year. At baseline, the mean age was 34.9 ± 10.5 years with 11 men and 8 women, and 14 Caucasian and 5 Asian individuals. At 12 months, there was a statistically significant decline in 24-hour urinary protein from 2.6 to 1.3 g (P = 0.007) and significant increase in serum albumin (3.79 to 3.93, P = 0.02). There was no significant change in eGFR (65.5 to 61.1 ml/min, P = 0.1). There were 0 complete remissions and 8 partial remissions (42%). There were a total of 6 infections: 2 were viral and 4 required antibiotic therapy (2 sinusitis, 1 pneumonia, 1 otitis media). The most common adverse events included acne, hot flashes, soreness, and anxiety. Conclusion In summary, patients with IgAN with >1 g/24-hour urinary protein and eGFR >30 ml/min had a significant reduction in 24-hour urinary protein with stable eGFR at 12-month follow-up after being treated with 6 months of ACTH., Graphical abstract

Introduction Timely and effective resolution of multiple sclerosis (MS) relapse is critical to minimizing residual deficits, which can result in neurologic disability. Oral corticosteroids (OCS) and intravenous corticosteroids [intravenous methylprednisolone (IVMP)] are earlier line treatments; alternatives include repository corticotropin injection (RCI; H.P. Acthar® Gel), plasmapheresis (PMP), and intravenous immunoglobulin (IVIG). Contemporary insight into the use of relapse treatments and their effectiveness is needed. Objective To evaluate relapse rates, frequency of treatments used, and treatment effectiveness (i.e., relapse resolution). Methods A retrospective analysis of patients ages 18–89 years experiencing MS relapse from 1 January 2008 to 30 June 2015 was conducted using administrative claims data. MS relapse was defined based on established claims-based methodology. The first claim for relapse treatment (i.e., prescription or administration) was used to designate the treatment group and relapse date, respectively. Relapses occurring ≤ 30 days were considered an episode. The first relapse episode was identified for every patient. Treatment was deemed effective in resolving the relapse if no additional relapses followed within the episode; otherwise, the relapse was considered unresolved. A 5-day OCS taper following IVMP administration, designated IVMP ± OCS, was allowed. Relapse frequency, treatment use, and relapse resolution were quantified. Relapse resolution was likewise evaluated in patients continuously enrolled for 12 months before and after first treatment with RCI or PMP/IVIG, with PMP/IVIG administrations within 7 days of each other being considered a single course of therapy. Results During the study period, 9574 patients experienced ≥ 1 relapse; 26.0% of patients had ≥ 2 relapses/year. The mean number of relapse episodes was 2.6 over a mean follow-up of 2.7 years for an annualized relapse rate of 1.0. Corticosteroids were the first treatment used in 90.4% of relapses (OCS = 51.8%, IVMP = 38.6%), followed by IVIG (6.0%), RCI (2.2%) and PMP (1.5%). The proportion of patients achieving relapse resolution with their first treatment was 90.5% with OCS (n = 5710), 47.8% with IVMP ± OCS (n = 3425), 96.9% with RCI (n = 195), 50.7% with PMP (n = 73), and 43.9% with IVIG (n = 171). Among continuously enrolled patients (n = 373), relapse resolution was 95.7% with RCI (n = 232) and 66.0% with PMP/IVIG (n = 141); significant cohort differences were observed. Conclusions As demonstrated in other studies, OCS were generally effective. However, real-world effectiveness varied with other treatments. Relapse resolution of the first treatment with OCS was higher than with IVMP ± OCS; similarly, relapse resolution was higher with RCI as the first treatment than with PMP/IVIG. Results demonstrate RCI’s effectiveness in appropriate patients. Limitations pertaining to claims-based research apply. Funding Mallinckrodt Pharmaceuticals (Bedminster, NJ).

Intravenous administration of acetaminophen is an alternative to the oral and rectal routes, which may be contraindicated in particular clinical settings. This randomized, placebo‐controlled study of intravenous acetaminophen (Ofirmev, Mallinckrodt Pharmaceuticals, Bedminster, New Jersey) in neonate and infant patients with acute postoperative pain assessed pharmacokinetics (PK) and safety, in addition to efficacy and pharmacodynamics of repeated doses administered over 24 hours. Neonate and infant patients (

Despite little evidence supporting its superiority to glucocorticoid therapy, use and expenditures for repository corticotropin (rACTH) injection (H.P. Acthar Gel; Mallinckrodt) have increased dramatically in the last 5 years, particularly among a small number of nephrologists, rheumatologists, and neurologists. Recently, the manufacturer justified the extremely high and rapidly increasing cost of rACTH by citing the ongoing need to generate clinical data to support its use. We test this assertion by investigating the quality and provenance of the evidence likely to emerge in the foreseeable future. We identified all completed, in-progress, and proposed studies of rACTH registered at ClinicalTrials.gov. 75 studies representing 2,953 participants met inclusion criteria. Studies addressed primarily nephrologic (n = 23), rheumatologic (n = 28), and neurologic (n =22) indications. Of the 23 studies proposed for renal indications (enrollment, 33 ± 49 [mean ± SD]), 11 were not randomized, 8 compared only different rACTH treatment regimens, and 4 compared rACTH to placebo. No studies of rACTH proposed for renal indications included an rACTH-free arm receiving active treatment (ie, another form of immunosuppression). We conclude that evidence emerging in the foreseeable future is unlikely to broadly support rACTH use over lower-cost glucocorticoid-based alternatives for renal indications.

Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar [KD025-213], N=132). Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment. Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib [n=46] or ruxolitinib [n=38]) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced. With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs. The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score. FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively. Belumosudil was well tolerated, with >95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after last dose). There were no reports of cytomegalovirus reactivation or infection. Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020. Download : Download high-res image (508KB) Download : Download full-size image Disclosures Cutler: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee: Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta: Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal: Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar: BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia: Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.

RC is a consultant for Kyowa Kirin and served on an advisory board for Helsinn. JJS is a consultant for Kyowa Kirin, Takeda, Recordat, 4SC, Innate Pharma and Helsinn. She received a 1-year educational grant from Kyowa Kirin for work on quality of life in CTCL. She also has membership on an entity’s Board of Directors or advisory committees for Kyowa Kirin, Takeda, 4SC, Innate Pharma, Miragen and Helsinn. PLZ has received honoraria from MSD, Celltrion, Gilead, Janssen-Cilag, BMS and TG Therapeutics. He is also a consultant for MSD, EUSA Pharma, Sanofi and Verastem. He also has membership on an entity’s Board of Directors or advisory committees for MSD, Eusa Pharma, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, Immune Design, Celgene, Portola, Roche, Kyowa Kirin, TG Therapeutics, and Verastem. He has also been on a Speakers Bureau for MSD, EUSA Pharma, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Immune Design, Celgene, Portola, Roche, Kyowa Kirin and Verastem. JPN has received honoraria from Pharmaceutical Industries, TEVA, Novartis AG, Biogen GmbH, Almirall Hermal AG, Actelion Pharmaceuticals, UCB Pharma, LaRoche Posay, Takeda Pharmaceuticals and Kyowa Kirin. He is also a consultant for Novartis AG, Biogen GmbH, Almirall Hermal AG, Actelion Pharmaceuticals, Innate Pharma, Kyowa Kirin and Takeda Pharmaceuticals. He has also received grants and personal fees from Pharmaceutical Industries outside of the submitted work. LS is a consultant for Dren Bio and served on an advisory board for Kyowa Kirin, Kymera Therapeutics and EUSA Pharma. LP-B has been an advisory board for Epizyme, Morphosys, Helsinn, Verastem and Actelion. She is also a consultant for Acrotech. PQ has received honoraria from Actelion, Innate Pharma, Takeda, Kyowa Kirin, Helsinn and Therakos. He also been on an advisory board for Actelion, Innate Pharma, Takeda, Kyowa Kirin, Helsinn and Therakos. LI has served as a consultant and/or paid speaker for and/or participated in clinical trials sponsored by AbbVie, Almirall, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Centocor, Eli Lilly, Janssen-Cilag, Kyowa Kirin, LEO Pharma, MSD, Novartis, Pfizer, Sun Pharma and UCB. RD is a consultant for Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym and Second Genome. AM is an investigator for Menlo, Soligenix, Pfizer, Elorac and miRagen. She has also received honoraria from Kyowa Kirin. She also has a membership on an entity’s Board of Directors or advisory committees for Helsinn. FF has received honoraria from Seagen, Mallinckrodt and Kyowa Kirin. She is also a consultant for Miragen. She had also served on a Data Safety Monitoring Board for Celgene. She was also the President of the US Cutaneous Lymphoma Consortium. TI is an employee of Kyowa Kirin, Inc. J-PR is an employee of Kyowa Kirin, Inc. MCM is an employee of Kyowa Kirin, Inc.

Background: Sick neonates may require transport high frequency ventilation (HFV) with inhaled nitric oxide (iNO). Hospital based HFV-iNO systems are not transport capable. The neonatal transport HFPFV (Percussionaire, Sandpoint, ID) and the AeroNOx iNO system (International Biomedical, Austin, TX) are transport capable. The iNOmaxDSIR iNO system (Mallinckrodt Pharmaceuticals, Bedminster, NJ) is not approved with HFPFV. In-line iNOMaxDSIR alters the HFPFV clinical performance. One iNO delivery system for intra- and inter-hospital use has advantages: (1) lower costs and (2) single system maintenance. Primary Hypothesis: Effective iNO delivery can be achieved using side-stream iNOmaxDSIR injection into HFPFV. Secondary Hypothesis: The side-stream delivery will not clinically alter …

Gastroenteropancreatic neuroendocrine tumors (NETs) are slow-growing malignancies, expressing somatostatin receptors on their cell membranes. These receptors can be targets for therapy with 111In-labeled somatostatin analogues. In 1996 Eric Krenning injected for the first time intravenously 111In-Octreotide (OctreoScan®, Mallinckrodt, Petten, the Netherlands) as a new treatment approach to confrontate particularly unresectable neuroendocrine tumors. In our Institution, we started treating this rare category of neoplasms exclusively injecting intra-arterially 111In-Octreotide, in high activities, focused our interest on liver metastases after catheterization of the hepatic artery (“Aretaieion Protocol”). The radiopeptide was infused in repeated doses ranging from 4.070 GBq (110 mCi) to 5.920 GBq (160 mCi) with a time interval between the sessions of 6–8 weeks. It was aimed to achieve a tumor-absorbed dose according to the dosimetry followed, over 70 Gy and tumoricidal results due to the effect of the Auger and Internal Conversion 111Indium’s Electron Emission. Follow-up at bi-monthly intervals was performed by means of ultrasonography (U/S) and every 6 months by contrast material-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI). This therapeutic procedure is described in detail in this chapter, based on the follow-up experience in more than 80 patients exceeding in total 800 intra-arterial catheterizations, in a time period of more than a decade. Advantages and limitations as a first-line treatment scheme for the management of this rare category of tumors are analyzed. In parallel with other authors tightly working in the field using 90Y- and/or 117Lu-labeled peptides, we predicted the dynamic of PRRT with 111In-Octreotide plus best supportive care (30 mg Octreotide LAR) as first-line therapy in progressive neuroendocrine tumors, 20 years before its final establishment as such in 2017, after Netter-1 study publication.

BACKGROUND: Flare activity or worsening symptoms are not well defined for myositis. OBJECTIVES: To (a) characterize dermatomyositis (DM) and polymyositis (PM) flares from the patient perspective and (b) report the corresponding disability and rate of unplanned medical encounters. METHODS: Online survey data were collected from volunteer patients from The Myositis Association and Johns Hopkins Myositis Center. Flare frequency; Health Assessment Questionnaire Disability Index (HAQ-DI), HAQ-Pain Index, Work Productivity and Activity Impairment (WPAI) scales; emergency department/urgent care (ED/UC) visits; and hospital admissions during the past year were examined. RESULTS: 564 individuals with selfreported diagnoses of DM/PM were surveyed between December 2017 and May 2018. Recall of symptom flares was reported by 524 respondents (78.1% were female, mean age of 55 years). Among the respondents, 378 (72.1%) reported ≥ 1 flare in the past year. The pattern of flare frequency was similar for DM and PM respondents. The most common symptoms were muscle weakness (83%), extreme fatigue (78%), and muscle pain/discomfort (64%). Increasing flare frequency was associated with significantly (P < 0.01) greater mean HAQ-DI and HAQ-Pain scores, myositis-related ED/UC visits, hospital admissions, WPAI work productivity loss (among those employed), and WPAI nonwork activity impairment. CONCLUSIONS: DM/PM-related flares are common with exacerbations of muscle weakness and fatigue being the most common flare symptoms. Flare frequency was associated with greater disability, pain, work productivity loss, nonwork activity impairment, and increased ED/UC utilization. Higher frequency of patient-reported flares may serve as a marker of worsening physical functioning and intensifying health care needs and, therefore, suggests their importance in the clinical assessment of patients with DM/PM. DISCLOSURES: This study was supported by Mallinckrodt Pharmaceuticals (Bedminster, NJ) via grants to Vedanta Research and The Myositis Association. Christopher-Stine has received compensation from previous Mallinckrodt Advisory Board meetings, unrelated to this subject matter. Wan is an employee of Mallinckrodt Pharmaceuticals and is a stockholder of the company. Reed and Bostic received grant support from Mallinckrodt Pharmaceuticals for data collection and analysis. McGowan is an employee of The Myositis Foundation, which received grant funding to support study data collection. Kelly has no conflicts to disclose. This study was presented, in part or full, at the 2019 Annual American College of Rheumatology and Association of Rheumatology Professional Meeting (November 8-13, 2018; Atlanta, GA) and at the Third Global Conference on Myositis (March 27, 2019; Berlin, Germany).

Nonalcoholic fatty liver disease (NAFLD), including its severe form known as steatohepatitis or NASH, are increasingly common in patients with type 2 diabetes mellitus (T2DM) and can progress to cirrhosis. However, there is limited information on their comorbid medical conditions in “real world” practice. Thus, the disease characteristics of patients with NASH or NASH-cirrhosis (cirrhosis), with or without T2DM, was evaluated in TARGET-NASH, an ongoing longitudinal observational study of patients with NAFLD, who are managed according to local standards at 60 community and academic hepatology and endocrinology practices in the United States. Among 3085 patients enrolled with NASH or cirrhosis, 1645 had NASH (47% T2DM) and 1440 had cirrhosis (72% T2DM). Patients with T2DM were older (median 61 vs. 56 years) and had a higher median BMI (34.0 vs. 32.0 kg/m2, p In conclusion, patients with type 2 diabetes and NASH or cirrhosis had more advanced liver disease compared to those without type 2 diabetes. Patients with type 2 diabetes had more than twice the risk of cirrhosis compared to those without type 2 diabetes. These results support a strong link of type 2 diabetes and metabolic risk factors with advanced NASH. Disclosure K. Cusi: Consultant; Self; Allergan plc., AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., Gilead Sciences, Inc., Merck & Co., Inc. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Poxel SA, Zydus Pharmaceuticals, Inc. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. A.S. Barritt: Consultant; Self; GENFIT, Intercept Pharmaceuticals, Inc., TARGET PharmaSolutions. R.J. Firpi: None. V. Clark: Research Support; Self; GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk Inc. S. Klein: Advisory Panel; Self; Danone Nutricia, Merck & Co., Inc. Research Support; Self; Johnson & Johnson, Pfizer Inc. Stock/Shareholder; Self; Aspire Bariatrics. A. Lok: None. P. Newsome: Research Support; Self; Novo Nordisk A/S. K. Corbin: None. M.B. Vos: Advisory Panel; Self; TARGET PharmaSolutions. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Immuron, Intercept Pharmaceuticals, Inc., Mallinckrodt Pharmaceuticals, Novo Nordisk A/S. Research Support; Self; Bristol Myers Squibb. R. Reddy: Advisory Panel; Self; Ambys, Epigenomics AG, Mallinckrodt Pharmaceuticals, Merck & Co., Inc. Research Support; Self; Conatus Pharmaceuticals, Exact Sciences, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Mallinckrodt Pharmaceuticals, Merck & Co., Inc. C. Schoen: None. A.R. Mospan: Employee; Self; TARGET PharmaSolutions. J.L. Taunk: None. K. Wyne: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Sanofi. B. Neuschwander-Tetri: Advisory Panel; Self; 89Bio, Allysta, ARTham, Blade, Bristol-Myers Squibb, Gelesis, GENFIT, Histoindex, Madrigal Pharmaceuticals, Inc., Medpace, Merck & Co., Inc., Sagimet, Siemens Corporation. Consultant; Self; Arrowhead Pharmaceuticals, Inc., Axcella, DURECT Corporation, Enanta Pharmaceuticals, Inc., Fortress, Indalo, Innovo, Lipocine, Mundipharma International, pH-Pharma, TARGET PharmaSolutions. A. Sanyal: Consultant; Self; Intercept Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; DURECT Corporation, GENFIT, HemoShear, Sanyal Bio, Tiziana Life Sciences plc. Funding TARGET-NASH

Wolfram Syndrome (WFS) is a rare, genetic, neurodegenerative disorder with associated features of diabetes mellitus (DM), diabetes insipidus, deafness, and optic atrophy. In order to design intervention studies, concrete markers of disease progression are required. DM in WFS is believed to be due to endoplasmic reticulum stress-induced failure of insulin secretion. Therefore, progressive loss of insulin production may be a viable marker of disease progression. The purpose of this study was to examine progression of DM, measured by beta-cell function, in WFS patients over time. N=44 (25F/19M) participants with genetically confirmed WFS attended the Washington University Wolfram Research Clinic from 2010-2019. A mixed meal tolerance test was administered to assess beta cell function (i.e., C-peptide). A hierarchical random coefficients model was used to relate C-peptide as a function of DM duration. Most patients (91%) had DM at time of study enrollment (N=39) or developed DM during the study (N=1). There was a significant association between C-peptide and DM duration, such that C-peptide decreased over time (F= 39.44, p= Disclosure M. Ray: None. T. Hershey: None. L. Chen: None. N.H. White: None. B.A. Marshall: None. Funding Washington University (HD070855, U54HD087011); Clinical and Translational Science Award (UL1RR024992); National Institute on Drug Abuse (5T32DA007261-27); Diabetes Research Center (DK020579); Snow Foundation, George Decker and Julio V. Santiago Pediatric Diabetes Research Fund; Mallinckrodt Institute of Radiology; McDonnell Center for Systems Neuroscience

Background: Six million adults in the U.S. are living with painful diabetic neuropathy (PDN) and current treatments are ineffective for many. Preliminary data suggest 10 kHz spinal cord stimulation (SCS) relieves pain and may improve sensation in refractory patients. Methods: Prospective, multicenter, randomized controlled trial (SENZA-PDN) with 216 subjects assigned 1:1 to 10 kHz SCS (Nevro Corp.) combined with conventional medical management (CMM) or CMM alone. Patients with PDN symptoms ≥12 months, lower limb pain intensity ≥5cm (0-10cm visual analog scale [VAS]), hemoglobin A1c ≤10%, and upper limb pain intensity Results: Randomization of 113 subjects to 10 kHz SCS+CMM and 103 to CMM resulted in groups well-matched at baseline. There were 2 procedure-related infections in the 10 kHz SCS+CMM group (1.8%). At 3-month follow-up, there were clear differences in lower limb pain scores (Fig 1A) and Diabetes Quality of Life (Fig 1B). Patients in the 10 kHz SCS+CMM group demonstrated improvements in sensation on physical examination (Fig 1C) and by patient report of numbness (Fig 1D). In addition, differences between treatment groups were observed in 6-minute walk test distance (Fig 1E) and sleep (Fig 1F). Conclusion: SENZA-PDN is the largest RCT to-date of SCS management of PDN and will inform the treatment continuum. Disclosure E. Petersen: Consultant; Self; Abbott, Medtronic, Neuros Medical, Nevro. Research Support; Self; Medtronic, Neuros Medical, Nevro, ReNeuron. T. Stauss: None. J.L. White: Research Support; Self; Allergan plc., Astellas Pharma Inc., Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Eli Lilly and Company, Fitbit, Inc., Nevro, NovMetaPharma Co. Ltd., Theracos, Inc. S.M. Sills: None. K. Amirdelfan: Consultant; Self; Biotronik, Medtronic, Nevro Corporation, Saluda. M. Guirguis: Consultant; Self; Boston Scientific, nevro incop, spr. J. Xu: None. C. Yu: None. A. Nairizi: None. D.G. Patterson: Research Support; Self; Nevro Corporation. V. Galan: None. N. Mehta: Advisory Panel; Self; Nevro. Research Support; Self; Nevro. S.P. Lad: None. D. DiBenedetto: None. P.W. Wu: None. C.E. Nasr: Other Relationship; Self; Exilxis, Neurogastrx, Nevro Corp. R. Taylor: Consultant; Self; Nevro. E.S. Brooks: Employee; Self; Nevro. J. Subbaroyan: Employee; Self; Nevro Corp. B. Gliner: Employee; Self; Nevro Corp. D.L. Caraway: Employee; Self; Nevro. N. Mekhail: Consultant; Self; Boston Scientific, Nevro, Nuvectra, Relievant, Saluda, Sollis Therapeutics, Vertos Medical. Research Support; Self; Halyard, Mallinckrodt Pharmaceuticals, Mesoblast, Neuros Medical. Funding Nevro Corp.

Dr Sola has disclosed that he is the Vice President of Medical Affairs with Masimo Corporation. Drs Farina and Mir have disclosed no financial relationships relevant to the article. Dr Golombek has disclosed that he is on the speakers’ bureau with Mallinckrodt and a consultant with Prolacta. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. El Dr Sola es VP de Medical Affairs de Masimo Corporation. Los Dres. Farina y Mir declaran ausencia de conflicto de interes. El Dr Golombek pertenece al Speakers’ Bureau de Mallinckrodt, y es Consultor de Prolacta. Este articulo no contiene una discusion sobre el uso no aprobado / investigativo de un producto / dispositivo comercial. En este Consenso participaron 48 profesionales de 12 paises de Latinoamerica y Espana. La coordinacion y revision estuvo a cargo de los investigadores principales Dres. Farina, Mir y Sola quienes han condensado todo el material trabajado. Los participantes del Consenso por orden alfabetico fueron: Amparo del Socorro Acosta Polo, Aldana Avila, Hernando Baquero, Elizabeth Cespedes, Judith Dachesky, Carmen Davila, Patricia Fernandez, Rosana Fonseca, Maria del Carmen Fontal, Ines Garcia Fiorini, Flora Josefina Garcia, Larisa Genes, Gustavo Goldsmit, Zandra Grosso, Cecilia Juarez, Jose Lacarrubba, Gabriel Lara, Lourdes Lemus, Victoria Lima, Irama Lopez, Luciano Macias, Elvira Mendieta, Marcela Montano, Monica Morgues, Teresa Murguia, Diego Natta, Francisco Navarro, Sandra Navarrete, Ada Nidia Oviedo Barrantes, Anabel Pereira, Jorge Pleitez, Veronica Puga, Noemi Ruiz Lavado, Alejandro Rossi, Cristina Segovia, Lorena Velandia, Maria Elena Venegas, Federico Villafane, Dan Waisman, Alejandro Young. In 2003, a group of physicians in Latin America noted the painful and regrettable discrepancy between neonatal delivery of care and outcomes in the Latin American region. They formed SIBEN, the Ibero-American Society of Neonatology, a not-for-profit public charitable organization (501\[c\]\[3\]) committed to advancing positive change for improving …

Currently, there is a concern at the national level of the overuse of both prescription and nonprescription opioid use. The purpose of this study was to identify whether the use of the intravenous (IV) formulation of acetaminophen (Ofirmev; Mallinckrodt Pharmaceuticals, Staines-upon-Thames, United Kingdom) is an effective tool in the reduction of postoperative pain, with a secondary goal of reduction of postoperative narcotic use.A total of 72 patients with previously diagnosed either partial bony or complete bony impacted third molars were selected with care to avoid long-acting local anesthetics or dissociative anesthetic agents. The patients' postoperative pain scores at 4 and 24 hours were collected via a verbal rating scale by the primary investigator. The exclusion criteria included administration of bupivacaine or ketamine, hepatic or renal impairment, pregnancy, or allergy to any of the normally administered sedation medications.At all postoperative increments (immediately, 4 hours, and 24 hours), there was no significant difference at P .05 between scores for either the IV acetaminophen or placebo group. Although there was a recorded difference in reduction of pain at both 4 and 24 hours postoperatively, these were not statistically significant variables.The use of IV acetaminophen showed no statistically significant decrease in patient pain at either 4 or 24 hours postoperatively. Although there are not representative data suggesting the routine use of IV acetaminophen, on the basis of the abundance of literature on the treatment of pain for other procedures, this medication should not be discarded as ineffective.

Mallinckrodt Chemical Works was the earliest uranium processing facility in the Manhattan Project, beginning in 1942. Even then, concern existed about possible health effects resulting from exposure to radiation and pitchblende dust. This concern was well founded as the facility processed Belgian Congo pitchblende ore that was up to 60% pure uranium with high U content and up to 100 mg of radium per ton. Workers were exposed to external gamma radiation plus internal radiation from inhalation and ingestion of pitchblende dust (uranium, radium, and silica). Multiple sources of exposure were available for organ dose reconstruction to a degree unique for an epidemiologic study. Personal film badge measures available from 1945 captured external exposures. Additional external exposure included 15,518 occupational medical x-rays and 210 radiation exposure records from other facilities outside of Mallinckrodt employment. Organ dose calculations considered organ-specific coefficients that account for photon energy and job-specific orientation of workers to the radiation source during processing. Intakes of uranium and radium were based on 39,451 uranium urine bioassays and 2,341 breath radon measurements, and International Commission on Radiological Protection (ICRP) Publication 68 biokinetic models were used to estimate organ-specific radiation absorbed dose. Estimates of exposure to airborne radon and its short-lived progeny were based on radon measurements in work areas where radium-containing materials were handled or stored, together with estimated exposure times in these areas based on job titles. Dose estimates for radon and its short-lived progeny were based on models and methods recently recommended in ICRP Publication 137. This comprehensive dosimetric approach follows methods outlined by the National Council on Radiation Protection Scientific Committee 6-9 for the Million Worker Study. Annual doses were calculated for six organs: lung, brain, heart, kidney, colon and red bone marrow. Evaluation and adjustment for individual cumulative measures of pitchblende dust inhalation were made for lung and kidney diseases.

Objectives: To determine the characteristics of laser-protected endotracheal tubes (LPETs) valued by otolaryngologists performing transoral laser surgery in the head and neck and to measure LPET stiffness. Methods: An online questionnaire was completed by American Broncho-Esophagological Association (ABEA) and American Head and Neck Society (AHNS) members. LPET distal end compliance was measured in a biomechanics laboratory. Results: A total of 228 out of 2109 combined ABEA and AHNS members completed the survey. The following LPET characteristics, which were properties of the Medtronic Laser-Shield II tube (MLST), were highly valued: softness and flexibility, surface smoothness, and a tight-to-shaft balloon (all P < .01). Prior to industry-driven discontinuation of the MLST, 52% of surgeons (78% of fellowship-trained laryngologists [FTLs]) reported using it; afterward, 58% reported using the stainless steel, Mallinckrodt Laser-Flex tube (MLFT). Forty-six percent of all respondents (69% of FTLs) did not consider cost being a factor in LPET choice. Biomechanical testing revealed the distal end of the MLST to be 3.45 times more compliant than the MLFT ( P < .01). Conclusion: Members of the ABEA and AHNS, particularly FTLs, highly value distinguishing properties of the now discontinued MLST. Manufacturers should consider this in the design of new LPETs.

To compare the incidence of fiberoptic bronchoscope (FOB) use (1) during verification of initial placement and (2) for reconfirmation of correct placement following repositioning, when either a double-lumen tube (DLT) or video double-lumen tube (VDLT) was used for lung isolation during thoracic surgery.A randomized controlled study.Single-center university teaching hospital.The study comprised 80 patients who were 18 years or older requiring lung isolation for surgery.After institutional review board approval, patients were randomized prior to surgery to either DLT or VDLT usage. Attending anesthesiologists placed the Mallinckrodt DLT or Vivasight (ET View Ltd, Misgav, Israel) VDLT with conventional laryngoscopy or video laryngoscopy then verified correct tube position through the view provided with either VDLT external monitor or FOB.Data collected included: sex, body mass index, successful intubation and endobronchial placement, intubation time, confirmation time of tube position, FOB use, quality of view, dislodgement of tube, and ability to forewarn dislodgement of endobronchial cuff and complications. FOB use for verification of final position of the tube (VDLT 13.2% [5/38] v DLT 100% [42/42], p0.0001), need for FOB to correct the dislodgement (VDLT 7.7% [1/13] v DLT 100% [14/14], p0.0001), dislodgement during positioning (VDLT 61.5% [8/13] v DLT 64.3% [9/14], p = ns), dislodgement during surgery (VDLT 38.5% [5/13] v DLT 21.4% [3/14], p = ns), and ability to forewarn dislodgement of endobronchial cuff (VDLT 18.4% [7/38] v DLT 4.8% [2/42], p = 0.078).This study demonstrated a reduction of 86.8% in FOB use, which was a similar reduction found in other published studies.

// Perry Grigsby 1, 2, 3 , Adnan Elhammali 4 , Fiona Ruiz 1 , Stephanie Markovina 1, 2 , Michael D. McLellan 5 , Christopher A. Miller 5 , Anupama Chundury 1 , Ngoc-Anh L. Ta 6 , Ramachandran Rashmi 1 , John D. Pfeifer 7, 8 , Robert S. Fulton 5 , Todd DeWees 1 and Julie K. Schwarz 1, 2, 9 1 Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA 2 Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA 3 Division of Nuclear Medicine, Mallinckrodt Institute, Washington University School of Medicine, St. Louis, MO, USA 4 Department of Radiation Oncology, MD Anderson Cancer Center, University of Texas Health Science Center, Houston, TX, USA 5 McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA 6 Saint Louis University School of Medicine, St. Louis, MO, USA 7 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 8 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA 9 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA Correspondence to: Julie K. Schwarz, email: jschwarz@wustl.edu Keywords: obesity; cervical cancer; PI3K; PTEN; mutation Received: September 07, 2017 Accepted: December 13, 2017 Published: December 23, 2017 ABSTRACT The purpose of this study was to evaluate the effect of obesity and obesity-associated factors on the outcomes of patients with cervical cancer. Outcomes were evaluated in 591 patients with FIGO Ib to IV cervical cancer treated uniformly with definitive radiation. Patients were stratified into 3 groups based upon pretreatment Body Mass Index (BMI): A ≤ 18.5; B 18.6 – 34.9; and C ≥ 35. The 5-year freedom from failure rates were 58, 59, and 73% for BMI groups A, B, and C (p = 0.01). Overall survival rates were 50, 59, and 68%, respectively (p = 0.02). High expression of phosphorylated AKT (pAKT) was associated with poor outcomes only in non-obese patients. Obese patients with PI3K pathway mutant tumors had a trend toward favorable outcomes, while a similar effect was not observed in non-obese patients. Compared to similar tumors from non-obese hosts, PIK3CA and PTEN mutant tumors from obese patients failed to express high levels of phosphorylated AKT and its downstream targets. These results show that patients with obesity at the time of diagnosis of cervical cancer exhibit improved outcomes after radiation. PI3K/AKT pathway mutations are common in obese patients, but are not associated with activation of AKT signaling.

Background:Upadacitinib (UPA), an oral Janus kinase inhibitor, demonstrated significant improvements in signs, symptoms, and structural inhibition as monotherapy (mono) vs methotrexate (MTX) in MTX-naïve patients (pts) with rheumatoid arthritis (RA) through 48 weeks (wks).1Objectives:To report the efficacy and safety of UPA vs MTX mono up to 156 wks in pts with RA from the ongoing long-term extension (LTE) of the SELECT-EARLY trial.Methods:During the 48-wk double-blind study period, pts were randomized to UPA 15 or 30 mg once daily (QD) or MTX (titrated to 20 mg/wk by Wk 8). At Wk 26, pts who did not achieve Clinical Disease Activity Index (CDAI) remission (≤2.8) and had Results:Of 945 pts randomized and treated, 775 entered the LTE on study drug (including 57 rescued pts; MTX, 33; UPA 15 mg, 17; UPA 30 mg, 7). Overall, 161 (21%) pts discontinued during the LTE. At Wk 156, higher proportions of pts randomized to UPA achieved a 20/50/70% improvement in ACR response (ACR20/50/70), LDA, and remission vs MTX (Figure 1). Change from baseline in mTSS at Wk 96 favored UPA vs MTX (data not shown). Most AEs were numerically more frequent with UPA 30 mg. The overall rate of serious infection was numerically higher with UPA vs MTX (Table 1). Herpes zoster (HZ), neutropenia, non-melanoma skin cancer (NMSC), and creatine phosphokinase (CPK) elevation were more frequent with UPA vs MTX. Two active tuberculosis (TB) events were reported in each UPA arm; 3 adjudicated gastrointestinal (GI) perforation events were observed in the UPA 30 mg arm. Adjudicated major adverse cardiovascular events (MACEs) or venous thromboembolic events (VTEs) were comparable across treatment arms.Conclusion:UPA monotherapy showed sustained clinically meaningful responses including remission vs MTX through Wk 156 but higher rates of several AEs, including HZ, neutropenia, and CPK elevations; no new safety risks were observed compared with previous results.1,2References:[1]van Vollenhoven R, et al. Ann Rheum Dis 2019;78:376–7; 2. Cohen SB, et al. Ann Rheum Dis 2020;annrheumdis-2020-218510.Table 1.Safety overviewE/100 PY (95% CI)MTX mono(n=314; PY=601.9)UPA 15 mg QD mono(n=317; PY=703.4)UPA 30 mg QD mono(n=314; PY=687.6)Any AE240.2(228.0, 252.9)268.0(256.0, 280.4)292.5(279.8, 305.5)Any serious AE10.8 (8.3, 13.8)12.2 (9.8, 15.1)16.3 (13.4, 19.6)Any AE leading to discontinuation of study drug6.5 (4.6, 8.9)7.3 (5.4, 9.5)7.7 (5.8, 10.1)Any deatha0.7 (0.2, 1.7)0.9 (0.3, 1.9)1.0 (0.4, 2.1)Serious infection2.5 (1.4, 4.1)3.3 (2.1, 4.9)4.4 (2.9, 6.2)Opportunistic infection excluding TB and HZ0.2 (0.0, 0.9)0.1 (0.0, 0.8)0.3 (0.0, 1.1)HZ0.8 (0.3, 1.9)4.5 (3.1, 6.4)4.7 (3.2, 6.6)Active TB00.3 (0.0, 1.0)0.3 (0.0, 1.1)NMSC00.4 (0.1, 1.2)1.0 (0.4, 2.1)Malignancy other than NMSC1.0 (0.4, 2.2)0.6 (0.2, 1.5)1.2 (0.5, 2.3)Hepatic disorder14.1 (11.3, 17.5)12.5 (10.0, 15.4)15.0 (12.2, 18.2)GI perforationb000.4 (0.1, 1.3)Neutropenia2.2 (1.2, 3.7)4.5 (3.1, 6.4)5.7 (4.0, 7.8)CPK elevation1.8 (0.9, 3.3)7.7 (5.8, 10.0)15.4 (12.6, 18.6)MACEb0.3 (0.0, 1.2)0.4 (0.1, 1.2)0.6 (0.2, 1.5)VTEb0.3 (0.0, 1.2)0.4 (0.1, 1.2)0.6 (0.2, 1.5)Data were censored at the time of MTX or UPA addition for rescued ptsaIncludes treatment-emergent (≤30 days after the last dose of study drug) and non-treatment-emergent deaths. bAdjudicatedAcknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Ronald van Vollenhoven Speakers bureau: AbbVie, AstraZeneca, Biotest, Bristol-Myers Squibb, Galapagos, Gilead, GSK, Janssen, Pfizer, Sanofi, Servier, UCB, and Viela Bio, Consultant of: AbbVie, AstraZeneca, Biogen, Biotest, Bristol-Myers Squibb, Galapagos, Gilead, GSK, Janssen, Pfizer, Sanofi, Servier, UCB, and Viela Bio, Grant/research support from: Bristol-Myers Squibb, GSK, Eli Lilly, Pfizer, Roche, and UCB, Tsutomu Takeuchi Speakers bureau: AbbVie, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Gilead, Mitsubishi Tanabe, Novartis, Pfizer, and Sanofi, Consultant of: Astellas, Chugai, and Eli Lilly, Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Shionogi, Takeda, and UCB, Jacob Aelion Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos/Gilead, Genentech, GSK, Horizon, Janssen, Mallinckrodt, Nektar, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi, Selecta, and UCB, Nilmo Chávez Speakers bureau: AbbVie, Janssen, and Pfizer, Consultant of: AbbVie, Janssen, and Pfizer, Grant/research support from: AbbVie, Galapagos, Gilead, Pfizer, and Sanofi, Pablo Mannucci Walter Consultant of: AbbVie, Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Genentech/Roche, GSK, Janssen, and UCB, Atul Singhal Consultant of: AbbVie, Aclaris, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gilead, Idorsia, Novartis, Oscotec, Pfizer, Regeneron, Roche/Genentech, Sanofi, Selecta, Takeda, UCB, and Viela Bio, Grant/research support from: AbbVie, Aclaris, Amgen, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gilead, Idorsia, Novartis, Oscotec, Pfizer, Regeneron, Roche/Genentech, Sanofi, Selecta, Takeda, UCB, and Viela Bio, Jerzy Swierkot Speakers bureau: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Consultant of: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Grant/research support from: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Alan Friedman Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stocks or options in AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: May own stocks or options in AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: May own stocks or options in AbbVie, Employee of: AbbVie, Justin Klaff Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Vibeke Strand Consultant of: AbbVie, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Genentech/Roche, Gilead, GSK, Ichnos, Inmedix, Janssen, Kiniksa, MSD, Myriad Genetics, Novartis, Pfizer, Regeneron, Sandoz, Sanofi, Setpoint, and UCB

Background:Risankizumab (RZB) is a humanized immunoglobin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding its p19 subunit. RZB is being investigated as a treatment for adults with psoriatic arthritis (PsA).Objectives:To compare the efficacy and safety of RZB vs placebo (PBO) for the treatment of active PsA in patients who have had inadequate response or intolerance to 1 or 2 biologic therapies (Bio-IR) or to ≥ 1 conventional synthetic disease modifying antirheumatic drug (csDMARD-IR).Methods:KEEPsAKE 2 (NCT03671148) enrolled adults with active PsA (≥ 5 swollen joints [SJC] and ≥ 5 tender joints [TJC]) who were Bio-IR or csDMARD-IR. Patients were randomized to receive blinded subcutaneous RZB 150 mg or PBO at weeks 0, 4, and 16. The primary endpoint was the proportion of patients achieving ≥ 20% improvement in American College of Rheumatology score (ACR20) at week 24. Ranked secondary endpoints and other secondary endpoints are shown in the Table. Safety was assessed throughout the study. Results reported here are from the 24-week double-blind period; the open-label period with all patients receiving RZB is ongoing.Results:A total of 443 patients (RZB, N = 224; PBO, N = 219) were included in the analysis. Demographics and baseline disease characteristics were similar across treatment arms (mean SJC: 13.3; mean TJC: 22.6; mean duration of PsA: 8.2 years; mean body surface area involved with psoriasis [BSA] in patients with BSA ≥ 3%: 12.1%); 206 patients (46.5%) were Bio-IR. Significantly greater proportions of RZB-treated patients vs PBO-treated patients achieved the primary endpoint (51.3% vs 26.5%, respectively; P < .001) and all ranked secondary endpoints (P < .001 for all except for Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue; P < .009]; Table). Other secondary outcomes also showed improvement for RZB- vs PBO-treated patients (Table). Serious adverse events were reported for 4.0% and 5.5% of RZB- and PBO-treated patients, respectively; serious infections were reported for 0.9% and 2.3%.Conclusion:RZB resulted in significantly greater improvements in signs and symptoms of PsA compared with PBO and was well tolerated in patients who were Bio-IR or csDMARD-IR.Disclosure of Interests:Andrew Ostor Speakers bureau: AÖ has received speaker or consulting fees and/or research grants from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB., Consultant of: AÖ has received speaker or consulting fees and/or research grants from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB., Grant/research support from: AÖ has received speaker or consulting fees and/or research grants from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, and UCB., Filip van den Bosch Speakers bureau: FVdB has received speaker and/or consulting fees from Abbvie, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB., Consultant of: FVdB has received speaker and/or consulting fees from Abbvie, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, and UCB., Kim Papp Speakers bureau: KP has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as principal investigator from AbbVie, Amgen, Astellas, Bausch Health (Valeant), Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, EMD Serono, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Stiefel, Sun Pharma, Takeda, and UCB., Consultant of: KP has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as principal investigator from AbbVie, Amgen, Astellas, Bausch Health (Valeant), Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, EMD Serono, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Stiefel, Sun Pharma, Takeda, and UCB., Grant/research support from: KP has received honoraria or fees for serving on advisory boards, as a speaker, and as a consultant, as well as grants as principal investigator from AbbVie, Amgen, Astellas, Bausch Health (Valeant), Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Coherus, Dermira, EMD Serono, Forward Pharma, Galderma, Genentech, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, MedImmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Stiefel, Sun Pharma, Takeda, and UCB., CECILIA ASNAL Speakers bureau: CA has received honoraria or fees for serving on advisory boards or as a speaker, as well as research support from AbbVie, Genentech, Janssen, Lilly, Pfizer, and Roche., Grant/research support from: CA has received honoraria or fees for serving on advisory boards or as a speaker, as well as research support from AbbVie, Genentech, Janssen, Lilly, Pfizer, and Roche., Ricardo Blanco Speakers bureau: RB has received grants or research support from AbbVie, Merck, and Roche; and has received consultation fees or honoraria for serving as a speaker for AbbVie, Bristol-Myers Squibb, Janssen, Lilly, Merck, Pfizer, and Roche., Consultant of: RB has received grants or research support from AbbVie, Merck, and Roche; and has received consultation fees or honoraria for serving as a speaker for AbbVie, Bristol-Myers Squibb, Janssen, Lilly, Merck, Pfizer, and Roche., Grant/research support from: RB has received grants or research support from AbbVie, Merck, and Roche; and has received consultation fees or honoraria for serving as a speaker for AbbVie, Bristol-Myers Squibb, Janssen, Lilly, Merck, Pfizer, and Roche., Jacob Aelion Grant/research support from: JA has received grants or research support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Galapagos/Gilead, Genentech, GlaxoSmithKline, Lilly, Mallinckrodt, Nektar Therapeutics, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi, Selecta Biosciences, and UCB., Gabriela Alperovich Shareholder of: GA is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Employee of: GA is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Ying Zhang Shareholder of: YZ is a former AbbVie employee, and may hold AbbVie stock or stock options., Employee of: YZ is a former AbbVie employee, and may hold AbbVie stock or stock options., Zailong Wang Shareholder of: ZW is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Employee of: ZW is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Ahmed M. Soliman Shareholder of: AS is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Employee of: AS is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Ann Eldred Shareholder of: AE is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Employee of: AE is a full-time employee of AbbVie, and may hold AbbVie stock or stock options., Alan Kivitz Shareholder of: AK is a shareholder of or has received honoraria or fees as a consultant, speaker, or expert witness for AbbVie, Boehringer Ingelheim, Celgene, Flexion, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB., Speakers bureau: AK is a shareholder of or has received honoraria or fees as a consultant, speaker, or expert witness for AbbVie, Boehringer Ingelheim, Celgene, Flexion, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB., Consultant of: AK is a shareholder of or has received honoraria or fees as a consultant, speaker, or expert witness for AbbVie, Boehringer Ingelheim, Celgene, Flexion, Gilead, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Sun Pharma, and UCB.

Background:Remission, LDA and LDAS have been proposed as treatment goals for SLE. However, the independent impact of these states on damage accrual has not been fully evaluated.Objectives:To determine the independent impact of remission (both off & on treatment), LDA, and LLDAS on damage accrual.Methods:We studied a long-term longitudinal multinational SLE cohort, including patients completing at least two annual assessments. Remission off-treatment was defined as a SLEDAI (excluding serology) =0, without prednisone and immunosuppressive (IS) drugs. Remission on-treatment was defined as a SLEDAI (excluding serology) =0, prednisone daily doseResults:There were 1,652 patients, 1464 (88.6%) were female, mean age at diagnosis was 34.6 (SD 13.4) years and mean baseline disease duration was 5.5 (SD 4.1) months. Patients had a mean follow-up of 6.5 (SD 4.3) years, 11686 visits were included. 763 patients (46.2%) had an increase in SDI score ≥1 during follow-up. 2483 (21.2%) of the visits were classified as remission off-treatment, 2276 (19.5%) as remission on-treatment, 544 (4.7%) as LDA, 657 (5.6%) as LLDAS and 5726 (49.0%) as not-optimally controlled. Being in remission off-treatment, remission on-treatment, LDA and LLDAS were predictive of a lower probability of damage accrual [remission off-treatment IRR=0.403, 95% CI 0.301-0.541); remission on-treatment IRR=0.313 (95% CI 0.218-0.451) LDA: IRR=0.469 (CI 95% CI 0.272-0.809); LLDAS IRR=0.440 (95% CI 0.241-0.803)]. The multivariable model is summarized in Table 1.Table 1.Multivariable GEE model of the impact of disease activity states on damage accrual.Incidence Rate Ratio95% CIDisease activity stateRemission off treatment0.4030.301-0.541Remission on treatment0.3130.218-0.451LDA0.4690.272-0.809LLDAS0.4400.241-0.803Gender, male1.2741.086-1.495Age at diagnosis1.0241.020-1.029EthnicityCaucasian USRef.Caucasian other1.0170.849-1.217African1.4671.211-1.776Asian0.8630.693-1.075Hispanic1.2661.034-1.550Other1.1210.759-1.656Educational level, years0.9770.957-0.996Disease duration at baseline0.9600.801-1.150Follow-up time0.9420.923-0.960Antimalarial use0.7860.681-0.908Highest prednisone dose before baseline1.0021.001-1.007SDI before1.1001.050-1.1152LLDAS: Low lupus disease activity state LDA: Low disease activity SDI: SLICC/ACR Damage IndexConclusion:Remission on- and off-treatment, LDA and LLDAS were associated with less damage accrual, even adjusting for possible confounders and effect modifiers. This highlights the importance of treating to target in SLE.Disclosure of Interests:Manuel F. Ugarte-Gil Grant/research support from: Pfizer, Janssen, John Hanly: None declared, Murray B Urowitz: None declared, Caroline Gordon Speakers bureau: UCB, Consultant of: Center for Disease Control, Astra-Zeneca, MFP, Sanofi, UCB, Sang-Cheol Bae: None declared, Juanita Romero-Diaz: None declared, Jorge Sanchez-Guerrero: None declared, Sasha Bernatsky: None declared, Ann E Clarke Consultant of: AstraZeneca, BristolMyersSquibb, GlaxoSmithKline, and Exagen Diagnostics, Daniel J Wallace Grant/research support from: Exagen, David Isenberg: None declared, Anisur Rahman: None declared, Joan T Merrill: None declared, Paul Fortin: None declared, Dafna D Gladman Consultant of: Abbvie, Janssen, Pfizer, Novartis, Amgen, Grant/research support from: Abbvie, Janssen, Pfizer, Novartis, Amgen, Ian N. Bruce: None declared, Michelle A Petri: None declared, Ellen M Ginzler Grant/research support from: Aurinia pharmaceutical, M.A. Dooley: None declared, Rosalind Ramsey-Goldman: None declared, Susan Manzi: None declared, Andreas Jonsen: None declared, Ronald van Vollenhoven Speakers bureau: AbbVie, Galapagos, GSK, Janssen, Pfizer, UCB, Consultant of: Abbvie, AstraZeneca, Biogen, Biotest, Celgen, Galapagos, Gilead, Janssen, Pfizer, Sanofie, Servier, UCB, Vielabo, Grant/research support from: BMS, GSK, Lilly, UCB, Cynthia Aranow: None declared, Meggan Mackay: None declared, Guillermo Ruiz-Irastorza: None declared, S. Sam Lim: None declared, Murat Inanc: None declared, Kenneth C Kalunian Consultant of: Roche, Biogen, Janssen, AstraZeneca, Eli Lilly, Genetech, Gilead, ILTOO, Nektar, Viela, Equillium, Bristol-Meyers Squibb, Soren Jacobsen Grant/research support from: BMS, Christine Peschken: None declared, Diane L Kamen: None declared, Anca Askanase Consultant of: Abbvie, Grant/research support from: Glaxo Smith Kline, Astra Zeneca, Janssen, Eli Lilly and Company, Mallinckrodt, Pfizer, Bernardo Pons-Estel Consultant of: GSK, Janssen, Graciela S Alarcon: None declared.

Repository corticotropin injection (RCI) has anti-inflammatory and immune-modulatory effects and is approved for multiple indications, including several rheumatologic conditions. The aims of this nationally representative, retrospective, observational study were to describe patient characteristics, RCI treatment patterns, and barriers to RCI use in patients with rheumatologic disease, and to compare medical resource use (MRU) before and after RCI therapy. A random sample of US physicians was recruited to abstract the medical records of deidentified patients with a diagnosis of rheumatoid arthritis (RA), psoriatic arthritis (PsA), dermatomyositis/polymyositis (DM/PM), or systemic lupus erythematosus (SLE) who had been treated with RCI in the previous 24 months. Patient characteristics and patterns of RCI use were identified. Mean MRU in the 3 months before and after RCI therapy was compared using paired-samples t tests. A total of 449 physicians abstracted the medical records of 217 RA, 190 PsA, 254 DM/PM, and 95 SLE patients. In all groups combined, patients had received a mean of 3.3 treatment medications before initiating RCI. Most patients (75%–94%) were receiving RCI for the first time, indicating that repeated courses of RCI were uncommon. RCI was used as bridge therapy in 18% of patients. Approximately 24% of patients encountered an obstacle in accessing RCI, primarily insurance-related. After RCI therapy, the number of hospitalizations and hospital days were significantly reduced for all cohorts (all P

Introduction Repository corticotropin injection (RCI; H.P. Acthar® Gel; Mallinckrodt Pharmaceuticals Inc., Hampton, NJ) is a highly purified, prolonged-release porcine preparation of adrenocorticotropic hormone (ACTH) analogue that is FDA-approved for treatment of 19 autoimmune and inflammatory disorders. The diverse physiological actions of RCI at the melanocortin receptors (MCRs) affect processes involved in inflammation, pigmentation, steroidogenesis, and immunomodulation. Although RCI has been approved to treat inflammatory and autoimmune diseases for more than 60 years, recent progress in understanding both MCRs and the effects of RCI in modulating immune responses has led to increased interest in RCI as a therapeutic choice. The objective of this narrative literature review is to summarize key clinical and economic data on RCI treatment of seven disorders: infantile spasms (IS), multiple sclerosis (MS) relapses, proteinuria in nephrotic syndrome, rheumatoid arthritis (RA), dermatomyositis/polymyositis (DM/PM), systemic lupus erythematosus (SLE), and symptomatic sarcoidosis based on published literature and product information. An extended report is available as the Academy of Managed Care Pharmacy (AMCP) Formulary dossier for H.P. Acthar® Gel. Methods Key studies of clinical efficacy and healthcare utilization and cost from 1956 to 2016 are summarized. Results The evidence supports the efficacy of RCI across the seven indications. RCI is effective as a first-line therapy for IS. For the other six conditions, RCI may improve clinical outcomes during exacerbations or when the condition is resistant to conventional treatments. Use of RCI is associated with reduced use of biologics, corticosteroids, and disease-modifying antirheumatic drugs. Initiation of RCI therapy in patients with IS, MS, RA, SLE, or DM/PM has been associated with lower post-therapy healthcare utilization and medical costs, including decreases in hospitalizations, hospital length of stay, outpatient visits, and emergency department visits. Conclusion The evidence suggests that RCI may improve inflammatory and autoimmune disease control and patient quality of life, particularly in complex patients, and yield healthcare cost savings that demonstrate the medicine’s value. Funding Mallinckrodt Pharmaceuticals Inc. Electronic supplementary material The online version of this article (doi:10.1007/s12325-017-0569-9) contains supplementary material, which is available to authorized users.

IntroductionHigher educational institutions (HEI) have changed a lot during the past decades, mainly but not exquisitely owing to the Bologna process (Kryk, 2016). Universities used to create and foster strong communities, where teachers knew their students, developed their talents and have prepared them for life. Students used to form bonds for life and lasting friendships had been forged through/due to the demanding, but rewarding years of higher education (Baker, 2013; Androniceanu, Ohanyan, 2016; Jovovic et al., 2016; Berechet, 2016).However, the once elite education, which was available only for the selected few, has turned into something very different; showing the signs and bearing the disadvantages of mass education. The phenomenon is affecting not only the teacher-student, but the student-student relations. Students are not connected to each other the way they used to be; and the HEIs as means to create social embeddedness do not serve their purpose any more (Kezar, 2014). HEI have lost their power to retain their students (Gerdes, Mallinckrodt, 1994). Students do not identify themselves with their local university community; tend to make less and less friendships during their studies (Androniceanu, 2015; Popescu, Mourao, 2016). This lack of sufficient integration however, is affecting their commitment not only toward the HEI itself, but higher education in general (Tinto, 1987) and hence generates a vicious cycle. Online and blended learning, which is becoming a substantial component of the higher education system, is also an issue that cannot be neglected, when exploring the social embeddedness of students in HEI (Picciano, 2015; Shea, Bidjerano, 2010).Does this detachment mean that the students are lonely and lack the necessary social support because of the present way of how higher education is organised; or are the students different from those in the past favouring different kinds of contacts and connections, finding substitutes for HEIs as providers of social connections easy? Are the students of the 21st century well off regarding social support? Do they trust their peers more than their family members?The research presented in this paper aims to find answers to these questions. With the help of a quantitative research on 249 young adolescents in their bachelor studies I intend to identify the role of family and peers at the university in the social support of the respondents. Within this paper, I also tackle the importance of interpersonal trust and its effect on the social support of those in the sample.I am well aware that the research presented in the paper is not suitable to validate relations of the variables investigated, however, the data presented are indicative, and thought inducing; and it can also form a basis for further research with a more targeted sampling.1.Social supportHumans are social beings. Not only because in this modern age only very few of us would be capable of sustaining his/her life without the help of others, but because humans like to belong. Having (significant) others around provides motivation and reward, can be source of reassurance and punishment, offers resources and support in informational, tangible as well as emotional sense. Thompson (1995) defined social embeddedness as frequency of contacts with others, which has a potential to integrate individuals into a supportive community. Frequency of contact however is not the only feature to be taken into consideration when exploring social embeddedness. The social network, and its strength to provide resources and support for the individual is also dependent on the size, diversity, functionality and variability of the social network the individual possesses and the centrality of the very person within this network.According to Bourdieu (1997) social support is a form of capital - namely that of social capital, which is strongly connected to the individual and hence can provide increasing return to its owner when utilised as a resource. …

Purpose To perform an in-air air-kerma strength (Sĸ) calibration of the Bebig model Ir2.A85-2 192Ir high-dose rate (HDR) brachytherapy source manufactured by Mallinckrodt Medical (Wester-duinweg, Germany) with the NIST-traceable seven-distance technique established by the University of Wisconsin [1‒3]. A comparison was made between the reference air-kerma rate (RAKR) reported on a certificate from the Physikalisch-Technische Bundesanstalt (Berlin, Germany) (PTB) primary laboratory and the Sĸ determined at the University of Wisconsin Madison Radiation Research Center (UWMRRC). A theoretical sensitivity study was performed to investigate the impact that variations in the experimental setup have on the computed Sĸ from the seven-distance algorithm in order to determine if the uncertainty budget for the seven-distance method should be expanded. Methods The manufacturer-reported Sĸ for the source was compared to the Sĸ determined from the University of Wisconsin Accredited Dosimetry Calibration Laboratory (UWADCL) transfer standard well chambers and the seven-distance technique. Monte Carlo techniques (MCNP6) were employed to compare the theoretical Sĸ calibration coefficients of a Standard Imaging (Middleton,WI) HDR1000 Plus well chamber using Standard Imaging model 70010 and model 70110 source holders to determine if a holder dependence was present. Radiochromic film (EBT3, Ashland) exposures were performed to assess the dose distribution of the source in phantom. The seven-distance algorithm was coded in MATLAB®(R2013b) and benchmarked with MCNP6 with the capacity to model distance offset behaviors among nominal positions. This offset model was used in a Monte Carlo simulation coded in MATLAB to determine the average uncertainty in the Sĸ calculations from the seven-distance algorithm. Results The measured Sĸ using the seven-distance technique at the UWMRRC agreed with the RAKR reported on the PTB source certificate and the Sĸ on the Mallinckrodt source certificate to within 0.28% and ‒0.79%, respectively. It was found that the difference between the Sĸ measured from the transfer standard well chambers at the UWADCL and the seven-distance method was between 0.13% and 0.30% at the 95% confidence level. Monte Carlo results showed negligible differences between the simulated Sĸ calibration coefficient for an HDR1000 Plus well chamber using the model 70010 or model 70110 source holder. The autoradiographs from the source in Virtual Water™ showed that the dose distribution is symmetric. Additionally, the sensitivity study performed in MATLAB showed that the Sĸ calculated with the seven-distance algorithm could deviate by 0.24% from randomly generated distance offsets within 1mm in magnitude. Conclusion The differences between the Sĸ measurements determined from the seven-distance technique and the accredited UWADCL measurement results were within the k=2 uncertainty reported for an accredited calibration. Excellent agreement was found between the measured Sĸ and RAKR methods used at the UWMRRC and PTB, respectively. Additionally, the sensitivity study has shown that the seven-distance algorithm accurately determines the Sĸ of a source while having a variable chamber offset among nominal positions; the uncertainty budget for the seven-distance method does not need to be expanded at this time. It has been determined that the current standard used by the UWADCL for well chamber calibrations is valid for the Bebig model Ir2.A85-2 192Ir brachytherapy source. This article is protected by copyright. All rights reserved.

Introduction Use of the two commercially available anti CD19 chimeric antigen receptor T-cell (CAR T-cell) therapies in patients with relapsed and refractory (R/R) large B-cell lymphoma (LBCL) is associated with significant inpatient and outpatient resource utilization, which has not been systematically compared. We characterized institutional resources used around Tisagenlecleucel (tisa-cel) and Axicabtagene ciloleucel (axi-cel) infusion and identified factors that led to longer hospitalization during the first 100 days of therapy. Methods We reviewed medical records of consecutive adult patients with R/R LBCL treated with tisa-cel or axi-cel at our center from May 2018 to May 2020. Resource utilization data included inpatient hospital days, outpatient clinic visits, radiological studies, cardiac/neurologic studies, invasive procedures and pharmaceutical resources. "Days alive and out-of-hospital at Day 100" (DAOH100), were defined as the number of living days that a patient spent out-of-hospital, which served as a surrogate for institutional resource utilization, as it accounted for duration of index hospitalization, re-admissions and days lost due to premature death, within first 100 days of therapy. Data were collected from the day of leukapheresis through Day 100 post CAR T-cell infusion (day 0), and compared between tisa-cel and axi-cel recipients. Results Of 46 patients with R/R LBCL, axi-cel was used in 35 (76%) and tisa-cel in 11 (24%) patients. 30 (65%) patients were male, 44 (96%) were Caucasian, with median age of 61 (range, 25-77) years and 3 (range, 2-6) prior lines of therapy. Forty- one (89%) patients had stage III/IV disease, 24 (52%) had IPI 0-2, 36 (78%) had ECOG PS 0 or 1 and 29 (63%) had HCT-CI Median duration of hospitalization was 14 (range, 7-53) days, with 13 (28%) patients requiring ICU admission for a median of 3 days (range, 1-19). The median number of outpatient clinic visits, radiology studies, cardiac/neurologic evaluations and invasive diagnostic procedures through Day 100 were 5 (range, 0-11), 6 (range, 1- 31), 1 (range, 0-33) and 0 (range, 0-5), respectively. Patients required a median of 1 (range, 0-4) dose(s) of tocilizumab, 0 (range, 0-14) days of IV steroids, 7 (range, 0- 54) days of IV antibiotics and 7 (range, 0-60) blood product transfusions. When compared to patients receiving axi-cel, the tisa-cel group had significantly shorter hospital stay (P= 0.02), shorter IV steroid days (P= 0.006), fewer tocilizumab doses (P=0.04) and fewer blood product transfusions (P=0.0004) (Table 2). Cytokine release syndrome (CRS) and immune effector cell mediated neurotoxicity syndrome (ICANS) were seen in 35 (76%) and 23 (50%) patients, respectively. In comparison to axi-cel, significantly fewer patients with tisa-cel had moderate to severe (≥ Grade 2) CRS (18.18 % vs. 60%; P= 0.04), and moderate to severe (≥ Grade 2) ICANS (0% vs. 37.14%; P= 0.02) (Table 2). By Day 100, 15 (32.6%) patients had died and 4 (10.8%) had disease progression. The median DAOH100 were 86 (range, 0-93) days. Patients receiving tisa-cel experienced longer median DAOH100 compared to those receiving axi-cel (89 vs. 86; P= 0.01) (Table 2). DAOH100 were higher for patients with favorable ECOG PS (0 or 1) vs. unfavorable (≥ 2) (median of 87 vs 73 days, P=0.01). Patients with no/mild CRS, and those with no/mild ICANS, had longer DAOH100 vs. those with ≥ Grade 2 CRS and ≥ Grade 2 ICANS (median of 87 vs. 84 days; P= 0.047 & median of 87 vs. 70 days; P= 0.01), respectively. DAOH100 did not differ with respect to age, gender, stage, HCT-CI, IPI or number of prior therapies (Table 3). Conclusion Through the first 100 days of CAR T-cell therapy, R/R LBCL patients receiving tisa-cel had shorter hospital length of stay, more days alive and out-of-hospital, received fewer tocilizumab doses, steroid days and blood product transfusions, compared to those treated with axi-cel. Patients receiving tisa-cel also experienced lesser incidence of moderate/severe CRS and ICANS. Favorable ECOG PS and absence of moderate/severe CRS or ICANS significantly increased DAOH100. In light of these differences in toxicity and resource utilization, a future study is needed to compare efficacy of axi-cel vs. tisa-cel in larger patient cohorts. Disclosures Hill: Genentech: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Khouri:Sanofi Genzyme: Other: Advisory Board. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Regeneron: Research Funding; MEI Pharma: Research Funding. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Gerds:CTI Biopharma: Consultancy, Research Funding; Roche/Genentech: Research Funding; Incyte Corporation: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Pfizer: Research Funding. Majhail:Mallinckrodt: Honoraria; Anthem, Inc.: Consultancy; Nkarta Therapeutics: Honoraria; Incyte: Honoraria.

Introduction Early non-infectious pulmonary toxicity (NIPT) is a significant HCT complication and comprises diffuse alveolar hemorrhage (DAH), idiopathic pneumonia syndrome (IPS), and cryptogenic organizing pneumonia (COP) with an overall incidence ranging 1-10%. Treatment options are primarily immunosuppressive therapy and supportive care with limited efficacy. Mortality in IPS, for example, approaches 60-80% (PMID: 21531955). Therefore, to better identify potentially high-risk patients (pts) we performed a registry-based analysis of the incidence, risk factors, and outcomes of early NIPT after HCT. Methods This retrospective study included adult pts undergoing allogenic HCT for hematologic malignancies and non-malignant disorders as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008-2017). Data analyses were divided into four common disease categories (AML/ALL, CML/MDS/MPN, NHL/CLL/PCD, and non-malignant diseases) to minimize statistical interactions in the multivariate model. The primary outcome was the incidence of and risk factors for individual NIPT and a composite of the three NIPT (IPS, DAH, COP); the secondary outcome was overall survival (OS). Multivariable Cox proportional hazards regression models were developed to identify the risk factors for NIPT and OS. In addition to baseline pre-transplant covariates, post-transplant neutrophil recovery (>500/mcL x 3 consecutive days), platelet recovery (>20k/mcL x 3 consecutive days, without transfusion in 7 previous days) and grade 2-4 acute GVHD were included as time-dependent covariates in the multivariable models. Results Characteristics of 21,587 adult pts are shown in Table 1. Median age at HCT was 54 years, 59% were male, and 39% had KPS Table 2 shows the cumulative incidence of early NIPT amongst pts in the four disease categories. Multivariable analysis in the AML/ALL group identified TBI-based conditioning, grade 2-4 acute GVHD, HCT-CI score of 1-3, and prior autologous HCT were associated with increased risk of NIPT, while platelet recovery decreased the risk of NIPT. In the CML/MDS/MPN group, smoking history, grade 2-4 acute GVHD and HCT-CI scores of 2-5+ were associated with increased risk of NIPT, while non-TBI and non-myeloablative TBI conditioning and platelet recovery were associated with a lower risk. In the NHL/HD/CLL/PCD group, a higher risk of NIPT was seen with severe pulmonary comorbidity pre-HCT and chronic GVHD, while platelet recovery and non-TBI regimens were associated with a lower risk. In the non-malignant disease group, both neutrophil and platelet recovery were associated with a lower risk of NIPT. Furthermore, the multivariable analysis for OS (Table 2) showed across all disease groups, NIPT increased the risk of mortality (vs. no NIPT; HR of 4.3 in AML/ALL, 4.1 in CML/MDS/MPN, 3.5 in NHL/CLL/PCD, 6.8 in non-malignant diseases; p Conclusions This large registry-based analysis of allogeneic HCT pts highlights several risk factors for the development of early NIPT including smoking history, severe pulmonary comorbidity, myeloablative TBI conditioning, and acute and/or chronic GVHD. Identification of these risk factors can enhance appropriate selection of pts prior to HCT. We also found that post-transplant, platelet and neutrophil recovery was associated with a reduced risk of NIPT. Furthermore, early NIPT is associated with a several-fold higher mortality risk in the current era despite significant advances in supportive care. Future studies are needed to optimize risk factors such as conditioning regimen and graft source selection to reduce the risk of early NIPT. Disclosures Ustun: Kadmon: Honoraria. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Majhail:Anthem, Inc.: Consultancy; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Mallinckrodt: Honoraria. Sorror:Jazz Pharmaceutical: Other: Honorarium for Advisory role. . Stadtmauer:Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Novartis, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy. Pasquini:Bristol Myers Squibb: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Other; Novartis: Research Funding; Kite: Research Funding.

Background: Chronic graft versus host disease (cGVHD) is a major cause of morbidity and late non-relapse mortality after allogeneic hematopoietic cell transplantation and is commonly associated with prolonged immune suppression. Patients (pts) with inadequate response to steroids have few effective therapeutic options and represent an unmet medical need. Available therapies are associated with significant toxicity, immunosuppression, and increased risk of infections. Preclinical studies demonstrate that CSF-1/CSF-1R is a key regulatory pathway involved in the expansion and infiltration of donor-derived macrophages that mediate cGVHD. Axatilimab (SNDX-6352, axa) is a humanized, full-length IgG4 antibody with high affinity to CSF-1R. Axa affects the migration, proliferation, differentiation, and survival of monocytes and macrophages by binding to CSF-1R and blocking its activation by its two known ligands, CSF-1 and IL-34. It offers a novel therapeutic option for treatment of these pts Methods: SNDX-6352-0503 is a Phase 1/2 dose-escalation and dose-expansion study evaluating safety, tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and efficacy of axa in pts >6 years of age with active symptomatic cGVHD despite ≥2 prior lines of therapy. The Phase 1 endpoints were safety, tolerability, PK and PD with the primary objective of defining optimal biologic dose; the primary endpoint of the Phase 2 study is overall response rate (CR+PR) by 6 months. Pts were dosed in 28-day cycles. The data cutoff was 22 July 2020. Results: Twelve pts have been enrolled in the Phase 1 study. Median age at enrollment was 58y (range, 29-73y), 8 pts were male. Pts had failed a median of 5 prior lines of treatment (range 4-9). Doses included 0.15 mg/kg (n=1), 0.5mg/kg (n=1), 1mg/kg (n=3), 3 mg/kg (n=6) every 2 weeks (q2w), and 3mg/kg q4w (n=1). Of these, 5 pts (42%) are still receiving axa. The median number of cycles for all pts is 5 (range 1-12). Of the 3 pts whose starting dose was 3 mg/kg q2w and remain on study, 2 dose reduced; one to 2 mg/kg q4w and one to 1 mg/kg q2w. Seven pts (58%) discontinued due to: adverse events (3 mg/kg q2w, n=2); death due to traumatic fall (1 mg/kg q2w, n=1); investigator decision (0.5 mg/kg q2w, n=1); progressive cGVHD (1 and 0.15 mg/kg q2w, n=1 each); and non-compliance (3 mg/kg q2w, n=1). Two of 6 pts (17%) at a dose of 3 mg/kg q2w reported a treatment emergent adverse event that was considered a dose limiting toxicity (DLT): 1 with CTCAE Grade 4 creatine kinase increase with symptoms of myositis after dose 1, and the 2nd with an elevation in amylase/lipase that delayed the 3rd dose for >2 weeks. The latter pt restarted therapy at 1 mg/kg q2w and remains on treatment after 5 cycles. Four pts (1 at 0.15 mg/kg and 3 at 3 mg/kg q2w, 33%) had a related treatment emergent adverse event that was ≥Grade 3: increase in aspartate aminotransferase (n=2); increase in creatine phosphokinase (n=2); and increase in gamma-glutamyl transferase (n=2). Such biochemical elevations may be a consequence of CSF-1R blockade on Kupffer cells leading to an inhibition in the clearance of these enzymes, consistent with the mechanism of action of axa and when asymptomatic have not been associated with clinical manifestations of hepatitis, pancreatitis, or rhabdomyolysis. Periorbital edema was observed in 2 pts (≤Grade 2); no additional CSF-1Ri class-effect associated TEAEs were observed Clinical responses as defined by the 2014 NIH cGVHD Consensus Criteria have been observed in 7 pts (58%) across all dose levels; median time to response was 12 weeks. Organ-specific responses have been observed in esophagus (n=1/1), eyes (n=3/10), joints/fascia (n=5/9), mouth (n=1/7), and skin (n=3/8). Prior therapies received by the responders included ibrutinib (6 pts), ruxolitinib (5 pts), and KD025 (3 pts); 3 of the responding pts had received all of these. Six pts (50%) reported at least a 7-point improvement in the Lee Symptom Score. Preliminary PK profiles and pharmacodynamic endpoints, including circulating CD14+CD16+ nonclassical and CD14++CD16+ intermediate monocyte kinetics, are consistent with those observed in healthy volunteers and pts with solid tumors see figure below. Conclusions: These data demonstrate that axatilimab is clinically active with acceptable safety profile and responses observed in heavily pretreated pts with active cGVHD. Enrollment continues in the Phase 1 study at 3 mg/kg q4w and Phase 2 study at a dose of 1 mg/kg q2w. Figure Disclosures Arora: Syndax: Research Funding; Fate Therapeutics: Consultancy; Pharmacyclics: Research Funding; Kadmon: Research Funding. Jagasia:Janssen: Research Funding; Mallinckrodt: Research Funding; Ocugen: Other. Meyers:Syndax Pharmaceuticals, Inc: Current Employment. Quaranto:Syndax Pharmaceuticals, Inc: Current Employment. Schmitt:Syndax Pharmaceuticals, Inc: Current Employment. Sankoh:Syndax Pharmaceuticals, Inc: Current Employment. Abu Zaid:Syndax: Research Funding. Hill:Roche: Research Funding; Generon: Consultancy; CSL: Research Funding; Implicit Bioscience: Research Funding; Pharmacyclics: Research Funding; Compass Pharmaceuticals: Research Funding. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy. Blazar:BlueRock Therapeuetic: Consultancy; Magenta Therapeutics: Consultancy; BlueRock Therapeutics: Research Funding; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder; Fate Therapeutics Inc.: Research Funding. Ordentlich:Syndax Pharmaceuticals, Inc: Current Employment. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Novartis: Research Funding; Kadmon: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding. OffLabel Disclosure: The drug (Axatilimab) is a humanized antibody against CSF-1R. The study is a phase I trial testing this drug in patients with chronic graft versus host disease

BACKGROUND Autologous hematopoietic cell transplantation (AHCT) continues to be one of the most effective treatment modalities for AL amyloidosis (AL). There is a limited number of studies looking at the effect of different hematopoietic progenitor cell (HPC) mobilization regimens on HPC collection and AHCT outcomes in AL. We assessed key HPC mobilization, collection and AHCT outcomes in a cohort of AL patients. METHODS We conducted a retrospective cohort study of 50 AL patients (pts) who received AHCT and were mobilized with G-CSF alone (G) or G and Plerixafor (G+P) from March 2009 to April 2018. Per mobilization protocol, all pts received G four days prior to collection and P as rescue if peripheral blood (PB) CD34+ cell count was ≤20 on day 1. All patients received conditioning with high dose melphalan (140-200 mg/m2). The primary aim of the analysis was to evaluate the association of patient and disease variables (Revised Mayo stage, cardiac involvement, albumin, proteinuria, NT pro-BNP, thrombocytopenia) with HPC mobilization and AHCT outcomes (total CD34+ yield, day 1 CD34+ yield, PB CD34+, neutrophil and platelet engraftment, hospital length of stay, overall (OS) and progression-free survival (PFS)) using the two mobilization regimens. Variables were assessed relative to outcomes with Spearman correlation, Kruskal-Wallis test or Wilcoxon rank sum test. All variables were assessed relative to PFS and OS with Cox regression. RESULTS Fifty-four percent of pts were female, and median age was 60 years (range, 35-72). The majority of pts (64%) had single organ involvement (renal in 86%, cardiac in 18%). Median NT-pro BNP was 331 pg/ml (504); troponin was normal in all pts. A median of 1 line of therapy was given prior to HCT (range 0-5); 72% received cyclophosphamide, bortezomib and dexamethasone (CyBorD) (82% in G+P vs 66.7% in G cohort, p=0.33) with a median of 4 cycles prior to HCT (range 2-14). Lenalidomide-based therapy was used in 16% (29% in G+P vs 9% in G cohort, p=0.10). Thirty-three pts were mobilized with G and 17 with G+P. Relative to pts mobilized with G, those mobilized with G+P had a higher median bone marrow monotypic plasma cell % (BMPC) at diagnosis (15% in G+P vs 10% in G, p=0.029) and were older at the time of HPC collection. While the majority of pts in both groups had revised Mayo stage I AL at diagnosis, most pts with stage IV required rescue P (23% vs 3%). As shown in Table 1, there was no significant difference between the two mobilization groups with regard to the analyzed mobilization outcomes, AHCT outcomes or survival. Target collection goal of 5x10^6/kg CD34+ cells was reached in all patients within a median of 1 day (range, 1-5). Median total CD34+ yield was 6.04 (5.15-8.30)x10^6/kg with G and 6.84 (5.76-8.0) x10^6/kg with G+P. Pts who required P had a lower median collected total nucleated cell (TNC) dose (13.76 vs 9.36 x10^8/kg, p=0.045) and took 2 days longer to achieve platelet engraftment (13 vs 11, p=0.019). Pts with cardiac involvement had a lower median PB CD34+ on day 1 of collection (81 vs 48, p=0.048) but did not have a lower day 1 or total CD34+ yield. Adverse events at mobilization included weight gain, increased diuretic use, hypotension, or hospitalization and did not differ between groups. The mortality rate was 12% (6 deaths). No deaths occurred during mobilization. A higher 24-hour urine protein at diagnosis was associated with a higher mortality risk post HCT (HR 1.23, p=0.014). A higher serum albumin at diagnosis was associated with faster neutrophil engraftment (r=-0.315, p=0.026) and a signal towards a lower mortality risk however this did not reach statistical significance (HR 0.29, p=0.06). PFS and OS were similar in both groups. CONCLUSION In our relatively small cohort, salvage P effectively mobilized patients with low initial PB CD34 count. We found that AL patients who required rescue P (day 1 PB CD34+ cell count ≤20) had a lower TNC yield and took longer to achieve platelet engraftment speaking to suboptimal marrow reserve and possible slower engraftment kinetics. Proteinuria and potentially a low serum albumin at diagnosis may increase mortality risk post AHCT. Our study is limited by its small sample size and retrospective design. Larger cohort analyses are needed to evaluate factors associated with HPC mobilization and AHCT outcomes in AL. Disclosures Majhail: Mallinckrodt: Honoraria; Incyte: Honoraria; Nkarta Therapeutics: Honoraria; Anthem, Inc.: Consultancy. Hamilton:Syndax Pharmaceuticals: Consultancy, Honoraria. Hill:Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Jagadeesh:Regeneron: Research Funding; Debiopharm Group: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding. Anwer:Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau. Chaulagain:Sanofi Genzyme: Honoraria. Khouri:Sanofi Genzyme: Other: Advisory Board.

Background: Tumor-associated macrophages (TAMs) play a key role in cutaneous T cell lymphoma (CTCL) growth and neoplastic T cells escape immune surveillance via PD1-PD-L1 axis (Querfeld, C., et al., Blood 2019; Khodadoust, M.S., et al., J Clin Oncol, 2020). There remains a lack of knowledge about how cytokines regulate the mechanisms controlling tumor-growth and polarize the tumor microenvironment (TME). Methods and Results: To investigate PD-L1 and PD1 expression on TAMs and T cells in mycosis fungoides (MF) and the leukemic variant Sézary syndrome (SS) patients, we performed multiplex immunofluorescence (IF) staining of lesional skin samples of MF patients that demonstrated co-localization of PD-L1 on CD163+ M2 macrophages and PD1 expression on CD4+ and CD8+ T cells. In addition, significant enrichment of CD14+ and CD16+/CD14dim CD163+ M2-like monocytes/macrophages with upregulated PD-L1 expression in SS patients compared to healthy donors (HDs) was found via FACS analysis. We also performed 30-plex Luminex cytokine assay on plasma samples, which showed significantly increased IL-6, IL-10, IFNγ and TNFα levels in plasma of MF/SS compared to HDs. To investigate whether polarization towards an M2-like macrophage phenotype with increased PD-L1 expression correlated with the cytokine expression from CTCL-TME, we cultured total PBMCs from HDs with conditioned media (CM) from well established CTCL cell lines MyLa and HuT78 and analyzed PD-L1 mRNA, total PD-L1 protein and PD-L1 surface expression on M2-like macrophages. Significantly increased expression of PD-L1 protein in total PBMCs, especially on CD14+ and CD16+/CD14dim M2-like macrophages was seen. To understand whether distinct cytokines are associated with PD-L1 upregulation on CD163+ M2-like populations, total PBMCs from HDs were stimulated with human recombinant IL-6, IL-10, IFNγ or TNFα. Antibody blocking studies were conducted by adding anti human IL-6, IL-10, IFNγ or TNFα to the cultures with CM. TNFα stimulation significantly increased the CD14+ M2-like subset, but did not affect CD16+/CD14dim M2-like subset. We observed increased PD-L1 expression on both M2-like populations with TNFα compared to other cytokines. In contrast, blockade of TNFα significantly decreased the CD14+ M2-like subset with reduced PD-L1 expression and increased CD16+/CD14dim M2-like cells with upregulated PD-L1 expression. To explore whether the STAT pathway regulates PD-L1 expression through cytokines from CTCL TME, we incubated total PBMCs from HDs in CM of MyLa and HuT78 cells with/without a pan-STAT inhibitor, and in media alone. Inhibition of STAT signaling decreased CD14+ M2-like macrophage population, but did not alter the CD16+/CD14dim M2-like population. In addition, pan-STAT inhibition significantly reduced surface expression of PD-L1 on both CD14+ and CD16+/CD14dim M2-like macrophages. The effects of cytokines on STAT signaling components in regulating PD-L1 expression were also investigated by FACS and immunoblots. TNFα blockade significantly downregulated PD-L1, but also pSTAT1, pSTAT3 and pNF-κB levels, illustrating the role of TNFα on STAT1, STAT3 and NF-κB pathways in conjunction with PD-L1 expression. Stimulation with TNFα increased pSTAT3 level in CD14+ M2-like macrophages, while it did not significantly change pSTAT3 in CD16+/CD14dim M2-like macrophages. Anti-TNFα reduced pSTAT3 levels in CD14+ M2-like macrophages, but profoundly increased PD-L1 in CD16+/CD14dim M2-like macrophages, which aligns with our data of increased PD-L1 expression on CD16+/CD14dim M2-like macrophages following TNFα blockade. Conclusion: We profiled immune alterations of monocyte/macrophages populations and PD-L1 expression in CTCL regulated by selected cytokines. Our results support the dominant role of TNFα in the CTCL microenvironment. Here we show that TNFα potentiates the immunosuppressive TME through macrophage polarization and STAT-mediated PD-L1 regulation. Our results identify potential targets for combination immunotherapy. Disclosures Zain: Seattle Genetics: Research Funding; Mundai Pharma: Research Funding; Kyowa Kirlin: Research Funding. Abdulla:Johnson Johnson: Research Funding; Mallinckrodt: Consultancy, Speakers Bureau. Rosen:Seattle Genetics: Consultancy; NeoGenomics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; Pebromene: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; paradigm Medical Communications: Speakers Bureau. Querfeld:Trillium: Consultancy; Stemline: Consultancy; Bioniz: Consultancy; Helsinn: Consultancy; Celgene: Research Funding; Kyowa Kirin: Consultancy; MiRagen: Consultancy.

BACKGROUND: In a previous study we have shown that CD19-directed chimeric antigen receptor (CAR)-T cells do not appear to be inferior to alloHCT when used as standard cellular immunotherapy (CI) for patients with multiply r/r LBCL (EBMT 2020). The purpose of the present follow-up analysis was to further compare the risk profile of the 2 cohorts by applying the EASIX score (lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (109 cells per L)), and to assess if EASIX could be used as outcome predictor in patients with r/r LBCL undergoing CAR-T and alloHCT, respectively. METHODS: Eligible were all patients referred to our institution with relapsed/refractory (R/R) DLBCL and a tumor board decision recommending treatment with CAR-T cells between 07/2018 and 02/2020 and those recommending allogeneic donor search between 2004 and 2019. Patients with DLBCL transformed from CLL were excluded. EASIX was evaluated retrospectively using uni- and multivariable analyses (with regards to age, gender and number of failed therapy lines) and mortality using Cox regression analyses. RESULTS: 41 patients intended for CAR-T cells and 60 patients intended for alloHCT were included. In both cohorts nearly all patients had active disease at indication. Cohorts were comparable for sex, time from diagnosis, ZUMA1 eligibility, and PS, but CAR-T patients tended to be older (median 56 vs 51 years, p=0.093), and had more often primary refractory and bulky disease (p=0.004 and p=0.04, respectively). Median EASIX score across both cohorts was 1.50 (0.27-70.5), with significantly higher scores in the CART group both at indication (EASIX-ind; median 1.79 and 1.22 for CAR-T and alloHCT, respectively, p=0.031) and at conditioning for CI (EASIX-pre, median 2.24 vs 1.26, p=0.005). Median OS from indication was 475d for the CAR-T cohort vs 285d for the alloHCT cohort (p=0.88). On multivariate analysis, EASIX-ind was significantly associated with adverse OS if alloHCT was intended (HR per 2fold increase 1.43, 95%CI 1.08-1.90, p=0.013), but not if CAR-T was intended (HR per 2fold increase 1.16, 95%CI 0.88-1.53, p=0.3). After CI, 12-month estimates for NRM, relapse incidence, PFS, and OS for CAR-T vs alloHCT were 3% vs 21% (p=0.04), 59% vs 44% (p=0.12), 39% vs 33% (p=0.97), and 68% vs 54% (p=0.32). EASIX-pre predicted overall survival (OS) in both CAR-T (HR per 2fold increase 2.11, 95%CI 1.21-3.7, p=0.009) and alloHCT (HR per 2fold increase 3.69, 95%CI 1.54-8.31, p=0.003) cohorts. In the alloHCT group, the EASIX effect was largely driven by higher NRM risk with increasing EASIX-pre, while in the CAR-T group poorer OS with increasing EASIX-pre was largely relapse-related. CONCLUSIONS: In patients undergoing CI for r/r LBCL, EASIX measured prior to conditioning can predict mortality after both CAR-T and alloHCT. If applied already at indication for CI, the predictive capacity of EASIX is weaker and no longer significant if CAR-T is intended. Further studies for validation of this data appear to be warrantable. Disclosures Schmitt: MSD: Membership on an entity's Board of Directors or advisory committees, Other: PI of clinical trials on letermovir; TolerogenixX Ltd: Other: Co-Founder and shareholder; Hexal: Other: Travel grants , Research Funding; Apogenix: Research Funding; Kite: Other: Travel grants, educational activities and conferences; Novartis: Other: educational activities and conferences, Research Funding. Dietrich:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees. Schmitt:Hexal: Other: Travel grants ; TolerogenixX LtD: Other: Co-founder, Part-time employee ; Therakos/Mallinckrodt: Research Funding; Jazz Pharmaceuticals: Other: Travel grants . Dreger:Neovii: Research Funding; Roche: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy; Gilead: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; AbbVie: Consultancy, Speakers Bureau.

Background:Structural damage was identified as an important outcome domain in the Psoriatic Arthritis (PsA) Core Domain Set and should be assessed at least once in the development of a new therapeutic.Objectives:To conduct a systematic literature review (SLR) to identify studies addressing the measurement properties (MPs) for ROIs and appraise the evidence through the OMERACT Filter 2.1 Framework Instrument Selection Algorithm (OFISA). [1]Methods:An SLR was conducted in EMBASE and MEDLINE to identify full-text English studies developing or assessing MPs of ROIs in PsA. Determination of eligibility, data extraction and methodology asssessment were performed by 2 reviewers. MPs were rated according to the ‘Provisional Standards’ and assigned a Red/Amber/White/Green (RAWG) rating (Figure 1). [1, 2]Results:3621 references were screened, 531 full-text articles reviewed, and 12 were included (Figure 2). Nine instruments assessing peripheral radiographs and six assessing axial radiographs were identified (Table 1). Three of the nine peripheral radiographic instruments had adequate evidence for reliability and some evidence for construct validity: the modified Steinbrocker, Ratingen, and modified Sharp van der Heijde scores. There was scant evidence for reliability, construct validity and responsiveness for the axial ROIs, compounded by the lack of a standardized definition of axial PsA.Conclusion:This SLR summarizes the MPs of ROIs and identifies relevant knowledge gaps that need to be addressed prior to endorsement of an instrument for the PsA Core Domain Set.References:[1]Richards P and De Wit M, editors. The OMERACT Handbook (March 2019)[2]Mokkink LB and D’Agostino MA. Protocol for performing a systematic review on imaging techniques (unpublished)Figure 1.Criteria for the RAWG RatingFigure 2.PRISMA DiagramTable 1.Summary of Measurement PropertiesROIDomain MatchFeasibilityConstruct ValidityDiscriminationReliabilityResponsivenessInter-raterIntra-raterMeasurement ErrorLongitudinal Construct ValidityClinical Trial DiscriminationThresholds of MeaningOriginal Steinbrocker ScoreA[1]A[1]R[1]Modified Steinbrocker Score#G[2]G[2]A[1]A[2]Modified Larsen ScoreA[1]A[1]A[1]*Ratingen Score#A[1]G[3]G[3]A[3]A[1]mTSS-AA[1]A[1]A[1]mTSS-B#A[1]A[1]A[1]A[1]*mSvdHs#A[2]G[2]G[2]A[1]A[1]*ReXPsAR[0]SPARS#A[1]A[1]A[1]Axial PsA Definition 1MSASSS#A[2]R[0]BASRI - Total#A[2]R[0]PASRI#A[2]R[0]Axial PsA Definition 2MSASSS#A[1]R[1]A[1]A[1]BASRI - Spine#R[1]A[1]A[1]PASRI#A[1]A[1]A[1]Modified NYC#R[1]A[1]RASSS#R[1]A[1]A[1]A = Amber, R = Red, G = Green[Total available studies for synthesis following excluding studies with poor methodology]* RCT data available but no published effect sizes# Feasibility data availableDisclosure of Interests:Anna Antony: None declared, Richard Holland: None declared, Wieneke Mokkink: None declared, Maria-Antonietta d’Agostino: None declared, Walter P Maksymowych Grant/research support from: Received research and/or educational grants from Abbvie, Novartis, Pfizer, UCB, Consultant of: WPM is Chief Medical Officer of CARE Arthritis Limited, has received consultant/participated in advisory boards for Abbvie, Boehringer, Celgene, Eli-Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Received speaker fees from Abbvie, Janssen, Novartis, Pfizer, UCB., Heidi Bertheussen: None declared, Lori Schick: None declared, Niti Goel Shareholder of: UCB and Galapagos, Consultant of: VielaBio, Mallinckrodt, and IMMVention, Alexis Ogdie Grant/research support from: Pfizer, Novartis, Consultant of: Abbvie, Amgen, BMS, Celgene, Corrona, Janssen, Lilly, Pfizer, Novartis, Ana-Maria Orbai Grant/research support from: Abbvie, Eli Lilly and Company, Celgene, Novartis, Janssen, Horizon, Consultant of: Eli Lilly; Janssen; Novartis; Pfizer; UCB. Ana-Maria Orbai was a private consultant or advisor for Sun Pharmaceutical Industries, Inc, not in her capacity as a Johns Hopkins faculty member and was not compensated for this service., Pil Hoejgaard: None declared, Laura C Coates: None declared, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Robin Christensen: None declared, Ying Ying Leung Speakers bureau: Novartis, Janssen, Eli Lilly, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, William Tillett Grant/research support from: AbbVie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, MSD, Pfizer Inc, UCB, Speakers bureau: AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, Pfizer Inc, UCB

Background:Infections are the most common cause of morbidity and mortality in idiopathic inflammatory myositis (IIM). India is endemic for Tuberculosis (TB) with a prevalence of 2.3 cases per thousand population.Objectives:Thus, we studied the prevalence of TB in our cohort of IIM patients and compared with that in systemic lupus erythematosus (SLE).Methods:Medical records from paper charts and electronic medical records were reviewed for adults and juvenile patients with SLE (ACR criteria 1997) and IIM (Bohan and Peter criteria 1975) first presented at a tertiary care hospital in India from 1989 to 2016. Clinical variables including disease characteristics variables, the frequency, site, duration and complication of active TB as well as dose of corticosteroids and other immunosuppressive drugs were extracted retrospectively from the medical records. Descriptive statistics were used to describe the cohort and TB characteristics. Chi-square and t-test were used to evaluate association of TB with clinical diagnosis as well as medication data.Results:There were 167 (132 adults and 35 juvenile) IIM and 280 (131 adults and 149 juvenile) SLE in our cohort. Active TB occurred in 24 (14.4%) of all IIM cases (18, 13.6% adults; 6, 17.1% juvenile) as compared to 18 (6.4%) of all SLE cases (8, 6.1% adults; 10, 6.7% juvenile, p value < 0.01). Of all the TB in myositis, most often it was seen in Dermatomyositis (n=11, 45.8%) followed by Polymyositis (5, 20.8%), and occasionally in Overlap myositis (3, 12.5) and juvenile dermatomyositis (1,4.1%).Considering an annual TB rate of 211 per 100,000 of the general population, the risk of developing active TB was 62-fold higher in patients with IIM and 27-fold higher in those with lupus. Patients with IIM had higher odds of developing TB as compared with Lupus [odds ratio 2.86 (CI 1.5-5.47), p=0.007).Amongst 24 IIM patients with TB, 10 had pulmonary TB and 14 had extra-pulmonary TB. The median glucocorticoid dose at the diagnosis of TB was 0.25 (0-1.5) mg/kg/day. Half the cases of active TB occurred during inactive myositis. Seventeen patients with active TB were followed up over 27 months (8-184), with remission of TB in all cases but required prolonged courses of Anti-Tuberculous Therapy (ATT) in 25% cases with 10 ATT related adverse events in 8 patients and 5 patients with relapse of myositis due to lowering of immunosuppression.Conclusion:Patients with IIM have higher prevalence of active TB as compared with SLE patients. The risk is highest in patients with Dermatomyositis possibly related to high doses of steroids. Extra-pulmonary forms of TB are more common, and patients commonly require prolonged course of ATT and may suffer relapses of myositis during ATT. Screening for latent TB may be useful in IIM patients before prescribing steroids and other immunosuppressive drugs.References:[1]TB Statistics India | National, treatment outcome & state statistics [Internet]. TB Facts | TB, tests, drugs, statistics. [cited 2019 Jun 13]. Available from:https://www.tbfacts.org/tb-statistics-india/[2]Muhammed H, Gupta L, Zanwar A, Misra DP, Lawrence A, Agarwal V, Aggarwal A, Misra R;OPC0243: Infections are leading cause of in-hospital mortality in patients with inflammatory myositis; Indian J Rheumatol 2018;13, Suppl S2:93-241[3]Gaitonde S, Pathan E, Sule A, Mittal G, Joshi VR. Efficacy of isoniazid prophylaxis in patients with systemic lupus erythematosus receiving long term steroid treatment. Ann Rheum Dis. 2002 Mar;61(3):251–3.[18]He D, Bai F, Zhang S, Jiang T, Shen J, Zhu Q, et al. High incidence of tuberculosis infection in rheumatic diseases and impact for chemoprophylactic prevention of tuberculosis activation during biologics therapy. Clin Vaccine Immunol CVI. 2013 Jun;20(6):842–7.Figure 1.(A) Prevalence and (B) sites of tuberculosisTable 1.Table 2.Clinical profile of patients with TuberculosisDisclosure of Interests:Latika Gupta: None declared, Abhishek Zanwar: None declared, Rohit Aggarwal Grant/research support from: Pfizer, Genentech, BMS, Mallinckrodt, Consultant of: Pfizer, Genentech, BMS, Mallinckrodt, Bristol Myers-Squibb, octapharma, CSL Behring, AstraZeneca, Corbus, Kezar, Abbvie, Able Lawrence: None declared, Durga Misra: None declared, Vikas Agarwal: None declared, Ramnath Misra: None declared, Amita Aggarwal: None declared

Background:Osteoarthritis (OA) commonly affects joints in the hand. The natural history of hand OA is not well understood, and the local determinants of symptoms and structural changes over time remain unclear.Objectives:To investigate, in both cross-sectional and prospective studies, the association between imaging (ultrasound [US] and magnetic resonance imaging [MRI]) features and symptoms of hand OA, and to examine in prospective studies whether imaging-detected features at baseline predict subsequent clinical and radiographic outcomes.Methods:A systematic literature search was conducted in five databases including Medline, Web of Science, EMBASE, CINAHL and AMED in April 2018. The search was designed to capture published observational studies on the use of US and MRI in hand OA with no language restrictions. Odds ratios (OR), risk ratios (RR), and 95% confidence interval (CI) between [1] imaging features and hand OA symptoms at baseline, and [2] baseline-imaging features and follow-up outcomes were extracted and pooled using random effects model. Outcomes were defined as either incidence or progression of pre-existing features. Risk of bias assessment was performed using the Newcastle-Ottawa Scales. Heterogeneity and publication bias were assessed.Results:The search identified 2818 citations, which reduced to 2216 after duplicate removal. Screening of titles and abstracts found 140 articles which met the inclusion criteria. After full text screening, 25 were included for analysis, including 452 participants (87% women) for US and 298 participants (86% women) for MRI with mean ages 60.3 and 62.5, respectively. Imaging-detected structural OA features were preferentially found in distal interphalangeal joints (DIPJs) followed by carpometacarpal (CMCJ) and proximal interphalangeal (PIPJ) joints. Metacarpophalangeal joints were least affected. However, the distribution pattern was different for inflammatory features for which the CMCJ was the most affected, and with no clear difference between DIPJs and PIPJs (Figure 1).Figure 1.Hand map of grey-scale synovitis derived from pooled estimates of prevalence across studies (%[95% CI])Of 10 US and 5 MRI studies examining association at baseline, joint tenderness was associated with US osteophytes (pooled ORs 2.30, 95% CI 1.90-2.79), grey-scale synovitis (3.00, 2.33-3.84), synovial effusion (2.92, 2.29-3.72), and power Doppler (PD) (2.30, 1.68-3.15). Similar relationships were observed with MRI features (Figure 2). Six studies did not find any association between imaging features and self-reported outcomes. However, association was observed with US- and MRI-detected synovitis in one study each, and MRI-detected structural features in two. Statistical pooling was not possible for these outcomes due to heterogeneous data.Figure 2.Forest plot showing pooled odds ratio between baseline magnetic resonance imaging features of hand osteoarthritis and joint tenderness.Of the 9 US and 5 MRI studies for prediction, a dose-dependent relationship was observed between baseline PD and radiographic change at follow-up (Figure 3). Similar results were observed for MRI features and Kellgren-Lawrence change. The pooled ORs (95% CI) was 2.66 (1.88, 3.78) for bone marrow lesions, and 2.18 (1.53, 3.10) and 4.7 (3.08, 7.18) for grades 1 and 2 synovitis, respectively. Data to predict change in clinical outcomes however, were lacking.Figure 3.Forest plot showing pooled odds ratio between baseline power Doppler and radiographic change over timeConclusion:Imaging-detected inflammatory features and osteophytes associate with joint tenderness. In addition, imaging-detected inflammatory changes at baseline predict future development and progression of structural OA changes, indicating that inflammation may precede radiographically-detectable structural changes.Disclosure of Interests:Abasiama Obotiba: None declared, Subhashisa Swain: None declared, Jaspreet Kaur: None declared, Khalid Yaseen: None declared, Michael Doherty Grant/research support from: AstraZeneca funded the Nottingham Sons of Gout study, Consultant of: Advisory borads on gout for Grunenthal and Mallinckrodt, Weiya Zhang Consultant of: Grunenthal for advice on gout management, Speakers bureau: Bioiberica as an invited speaker for EULAR 2016 satellite symposium, Abhishek Abhishek Grant/research support from: AstraZeneca and OxfordImmunotech, Speakers bureau: Menarini pharmaceuticals

Background:Secukinumab was the first anti-interleukin 17A monoclonal antibody treatment approved by the FDA for ankylosing spondylitis (AS). There is scarce information on the characteristics of secukinumab vs other biologic initiators with AS.Objectives:To describe real-world physician and patient characteristics, and treatment patterns of secukinumab and tumor necrosis factor inhibitor (TNFi) initiators.Methods:Electronic health records (EHR) data from adult patients with AS who initiated a biologic therapy between January 2018 and March 2019 (index date) were included from the Columbus Repository, a network capturing EHR data from 120 US rheumatology providers. Physician and patient characteristics, and treatment patterns were reported for patients who were prescribed secukinumab and TNFis (adalimumab, etanercept, certolizumab pegol, infliximab, infliximab-abda, and golimumab). Categorical variables were summarized using frequency counts and percentages and continuous variables were presented using means and standard deviations. Standardized mean differences andPvalues were used to compare treatment groups.Results:As of March 2019, AS treatment data were available for 82 secukinumab initiators and 160 TNFi initiators. Regarding overall practice size, 33% of practices had a single physician, and 65% of physicians were located in the South US region. Secukinumab initiators were younger than TNFi initiators (47.4 vs 49.8 years) and had a similar prevalence of HLA-B27 positivity (≈ 55%; Table 1). Comorbid psoriatic arthritis (PsA) was more commonly reported among secukinumab initiators vs TNFi initiators (17% vs 9%), while hypertension (5% vs 11%), obesity (2% vs 11%), and uveitis (2% vs 9%) were less common (Figure 1). Secukinumab initiators were more likely to have prior opioid use vs TNFi initiators but were less likely to have prior methotrexate use (Figure 2A); 67% of secukinumab initiators and 49% of TNFi initiators were biologic experienced, of whom 73% and 76%, respectively, used 1 prior biologic, 25% and 20% used 2 prior biologics, and 2% and 4% used ≥ 3 prior biologics (Figure 2B). The most common reasons for discontinuation of prior biologics among secukinumab and TNFi initiators were because the biologic was no longer required (47% vs 41%) and lack of efficacy (20% vs 24%) (Figure 2C).Table 1.Baseline Demographics and Disease Characteristics Among Patients With AS at the Index Date..CharacteristicSecukinumab(N = 82)TNFi(N = 160)SMD*PValueAge, mean (SD), years47.4 (12.8)49.8 (14.6)0.170.21Female, n (%)43 (52)90 (56)0.080.57Race/ethnicity, n (%)N = 65N = 1290.200.66White52 (80)106 (82)Hispanic8 (12)13 (10)Black3 (5)8 (6)Asian1 (2)2 (2)Other1 (2)0Geographic distribution, n (%)0.370.05South49 (60)113 (71)Midwest27 (33)28 (18)West5 (6)16 (10)Northeast1 (1)3 (2)Health insurance, n (%)N = 79N = 1560.410.39Commercial57 (72)94 (60)Medicare8 (10)33 (21)Medicaid2 (3)4 (3)Other12 (15)25 (16)HLA-B27 positivity, n (%) [N]14 (54) [N = 26]31 (56) [N = 55]0.051.00Body mass index, mean (SD), kg/m230.6 (6.1)30.9 (7.7)0.030.82SMD, standardized mean difference.* Comparisons with SMD > 0.1 were suggestive of clinically relevant differences.Conclusion:Secukinumab initiators with AS were younger and more opioid and biologic experienced, were more likely to have a PsA diagnosis, and were more likely to discontinue their previous biologic because the biologic was no longer required compared to patients who initiated TNFis.Acknowledgments:This study was funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ. Support for third-party writing assistance for this abstract, furnished by Kheng Bekdache, PhD, of Health Interactions, Inc, was provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ.Disclosure of Interests:Howard Busch Speakers bureau: AbbVie, Amgen, Crescendo, Exagen, Genentech, Mallinckrodt, Novartis, Primus, Sanofi/Regeneron, and UCB, Jeffrey Curtis Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, UCB, Peter Hur Employee of: Novartis Pharmaceuticals Corporation, Esther Yi Employee of: Novartis Pharmaceuticals Corporation