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Max Schlueter,1 Elaine Finn,1 Silvia Díaz,2 Tatiana Dilla,2 José Inciarte-Mundo,3 Walid Fakhouri41IQVIA, Real World Evidence, London N1 9JY, UK; 2Lilly Spain, Health Outcomes & RWE, Alcobendas 28108, Spain; 3Lilly Spain, Medical, Alcobendas 28108, Spain; 4Lilly, Global Patient Reported Outcomes and Real World Evidence (GPORWE) International, Windlesham, Surrey GU20 6PH, UKBackground: Baricitinib is an oral janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and is approved in Europe for use in adults with moderately-to-severely active RA and an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy. To date, no economic evaluations have assessed the cost-effectiveness of baricitinib in the Spanish setting.Objectives: To evaluate the cost-effectiveness of baricitinib versus adalimumab for the treatment of moderately-to-severely active RA in the Spanish setting.Methods: A discrete event simulation model was developed in Microsoft Excel. Costs and outcomes were estimated over a lifetime horizon using the Spanish national payer perspective. The model compared baricitinib 4 mg once daily in combination with methotrexate with adalimumab 40 mg every other week in combination with methotrexate. Effectiveness and physical function were captured using the American College of Rheumatology criteria and the Health Assessment Questionnaire–Disability Index, input values of which were derived from a phase 3, double-blind, placebo- and active-controlled trial (RA-BEAM; funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358). Costs are presented in Euros, 2018 values.Results: In the base case analysis, baricitinib was associated with a quality-adjusted life year gain of 0.09 years over a lifetime horizon, at an incremental cost of –€558 versus adalimumab. Results of various scenario analyses and probabilistic sensitivity analysis generally were consistent with the base case analysis.Conclusion: This analysis suggests that baricitinib is a cost-effective treatment option compared to adalimumab for Spanish patients with moderately-to-severely active RA and a previous inadequate response or intolerance to csDMARD therapy.Keywords: baricitinib, adalimumab, cost-effectiveness, JAK inhibitor, rheumatoid arthritis

Walid Fakhouri,1 Pedro Lopez-Romero,2 Silvia Antonelli,3 Serena Losi,4 Veronica Rogai,4 Stefano Buda,5 Diego Sangiorgi,5 Valentina Perrone,5 Luca Degli Esposti5 1Eli Lilly & Company, Erl Wood, UK; 2Eli Lilly & Company, Madrid, Spain; 3Eli Lilly Italy S.p.A., Roma, Italy; 4Eli Lilly Italy S.p.A., Sesto Fiorentino, Italy; 5CliCon S.r.l. Health, Economics & Outcomes Research, Ravenna, Italy Objectives: This study aimed to: 1) describe treatment patterns and drug utilization profile (in terms of therapeutic strategy used, switch, persistence and drug consumption variation) among adult patients affected by rheumatoid arthritis (RA), and 2) estimate the health care resource utilization and its associated direct cost for the management of RA patients. Methods: A retrospective cohort analysis, using administrative databases of six Local Health Units in Italy, was performed. All adult patients with a confirmed diagnosis of RA between January 1, 2010 and December 31, 2014 were enrolled. The date of the first RA diagnosis according to the study criteria during the study period represented the index date (ID) for each patient. Patients enrolled were observed from the ID for at least 12 months (follow-up period), and their clinical characteristics were investigated for 12 months prior to the ID.Results: A total of 10,401 patients with a confirmed RA diagnosis were included. Mean age was 63.0 years and 25% were male; 67% of patients were untreated at ID. During the follow-up period, 67.8% of patients treated with biologic agents were persistent with initial therapy, compared to 45.7% for patients on conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), while 11% of patients treated with biologic agents switched during the follow-up period, compared to 17.6% of csDMARDs-treated ones. At the end of the follow-up period, 14.7% of all patients in the analysis had an increase and 12.6% of them had a decrease in their initial drug consumption. The mean cost per RA patient was €3,743.Conclusion: Our study showed that there is still much that needs to be learned about the prescription of csDMARDs and biologics to RA patients in Italy and to identify areas for future research. The knowledge of RA management in a real-life clinical setting could offer an opportunity to improve the management of RA in Italy. Keywords: rheumatoid arthritis, treatment patterns, drug utilization, real-world data

Interferon regulatory factor 6 ( IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. Haploinsufficiency of IRF6 causes Van der Woude and popliteal pterygium syndrome, 2 syndromic forms of cleft lip and palate. Around 85% of patients with Van der Woude express pits on the lower lip that continuously or intermittently drain saliva, and patients with the common cleft lip and palate have a higher prevalence of dental caries and gingivitis. This study aims to identify the role of IRF6 in development of exocrine glands, specifically the major salivary glands. Our transgenic mouse model that expresses LacZ reporter under the control of the human IRF6 enhancer element showed high expression of IRF6 in major and minor salivary glands and ducts. Immunostaining data also confirmed the endogenous expression of IRF6 in the developing ductal, serous, and mucous acinar cells of salivary glands. As such, we hypothesized that Irf6 is important for proper development of salivary glands and potentially other exocrine glands. Loss of Irf6 in mice causes an increase in the proliferation level of salivary cells, disorganized branching morphogenesis, and a lack of differentiated mucous acinar cells in submandibular and sublingual glands. Expression and localization of the acinar differentiation marker MIST1 were altered in Irf6-null salivary gland and pancreas. The RNA-Seq analysis demonstrated that 168 genes are differentially expressed and confer functions associated with transmembrane transporter activity, spliceosome, and transcriptional regulation. Furthermore, expression of genes involved in the EGF pathway-that is, Ereg, Ltbp4, Matn1, Matn3, and Tpo-was decreased at embryonic day 14.5, while levels of apoptotic proteins were elevated at postnatal day 0. In conclusion, our data report a novel role of Irf6 in exocrine gland development and support a rationale for performing exocrine functional tests for patients with IRF6-damaging mutations. [ABSTRACT FROM AUTHOR]

Celine J Van De Laar,1 Martijn AH Oude Voshaar,1,2 Walid KH Fakhouri,3 Liliana Zaremba-Pechmann,3 Francesco De Leonardis,3 Inmaculada De La Torre,3 Mart AFJ Van De Laar1,2 1Transparency in Healthcare BV, Hengelo, the Netherlands; 2Department of Psychology and Communication of Health and Risk, Institute for Behavioural Research, University of Twente, Enschede, the Netherlands; 3Eli Lilly & Company, Indianapolis, IN, USACorrespondence: Celine J Van De Laar Tel +31 74-43032645Email c.vandelaar@tihealthcare.nlBackground: Baricitinib is a janus kinase (JAK1/JAK2) inhibitor developed for the treatment of patients suffering from rheumatoid arthritis (RA). Treating RA to the target of remission is current common practice. Cost-effectiveness of different treat-to-target (T2T) strategies, especially ones including new treatments is important for development and preference policy for treatment centers. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines are currently unclear about preference between a JAK1/JAK2 versus a biological disease-modifying antirheumatic drug (bDMARD).Objective: The main goal of this paper was to evaluate the cost-effectiveness of baricitinib versus first biological for methotrexate inadequate responders in a T2T strategy using a Markov model that incorporates hospital costs as well as societal costs. Costs and utilities over five years were compared between the two strategies.Methods: A Monte Carlo simulation model was developed to conduct cost–utility analysis from the societal perspective over 5 years. Health states were based on the DAS28-erythrocyte sedimentation rate (ESR) categories. Effectiveness of baricitinib was retrieved from randomized controlled trials. Effectiveness of all other treatments, health state utilities, medical costs, and productivity loss were retrieved from the Dutch RhEumatoid Arthritis Monitoring (DREAM) cohorts. Annual discount rates of 1.5% for utility and 4% for costs were used. Probabilistic sensitivity analysis was employed to incorporate uncertainty and assess robustness of the results.Results: Probabilistic sensitivity analysis results showed the baricitinib strategy yielded lower costs and higher utility over a 5-year period. Scenario analyses showed the baricitinib strategy to be cost-effective in both the moderate and severe RA populations.Conclusion: Results suggest that the use of a JAK1/JAK2 inhibitor instead of a bDMARD in a T2T approach is cost-effective in csDMARD refractory RA patients.Keywords: Markov model, rheumatoid arthritis, baricitinib, cost-effectiveness, health economic model, treat-to-target

Introduction: We aim to assess the association of patient-reported pain and remission or low disease activity (LDA) at 3 months (M) in patients receiving baricitinib or other treatments in RA-BE-REAL., Methods: RA-BE-REAL reports on patients with rheumatoid arthritis (RA) who were prescribed, for the first time, baricitinib (cohort A) or a tumour necrosis factor inhibitor (TNFi) (cohort B-TNFi) or any other mode of action (OMA) (cohort B-OMA). Pain was measured using the visual analogue scale (VAS) (0-100 mm) and clinically meaningful pain improvement thresholds of ≥ 30%, ≥ 50% and ≥ 70% from baseline to 3, 6, 12 and 24 M., Results: At 3 M, the mean change from baseline (CFB) pain VAS of patients in remission/LDA was - 32.6 mm (cohort A), - 27.3 mm (cohort B-TNFi) and - 28.0 mm (cohort B-OMA). Almost half the patients who were in remission/LDA receiving baricitinib achieved ≥ 70% pain relief. At 3 M, the proportion of patients in remission/LDA with pain VAS ≤ 20 mm was 62.1% (cohort A), 55.0% (cohort B-TNFi) and 55.6% (cohort B-OMA), while for those not in remission/LDA, it was 8.5% and 8.7% (cohort A and B-TNFi, respectively) and 5.3% (B-OMA). More patients on baricitinib achieved pain improvement in all analyzed thresholds than patients in cohort B-TNFi and B-OMA at 3 M. At 24 M, - 26.2 mm (cohort A), - 20.8 mm (cohort B-TNFi) and - 16.0 mm (cohort B-OMA) mean CFBs in pain measurement were observed. For baricitinib and the other treatments, residual pain decreased with achievement of remission/LDA and was sustained up to 24 M., Conclusions: Patients in remission/LDA receiving baricitinib are more likely to achieve pain control than patients receiving TNFi/OMA., Competing Interests: Declarations. Conflict of Interest: Walid Fakhouri, Samuel Ogwu, Ewa Haladyj and Inmaculada de la Torre are employees and minor shareholders of Eli Lilly and Company. Peter C. Taylor reports grants or contract from Galapagos (AlfaSigma) made to University of Oxford; received consulting fees from Abbvie, Biogen, Fresenius, Galapagos (AlfaSigma), Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, UCB, Acelyrin Inc.; received support for attending meetings/travel from Lilly and Galapagis (AlfaSigma); has participated on a Data Safety Monitoring Board/Advisory Board from Immunovant, Sanofi and Moonlake. Bruno Fautrel reports support for medical writing from Lilly; grants or contracts AbbVie, Lilly, MSD, Pfizer; received consulting fees from AbbVie, Amgen, Biogen, BMS, Celltrion, Fresenius Kabi, Galapagos, Gilead, Janssen, Lilly, Medac, MSD, NORDIC Pharma, Novartis, Pfizer, Roche, Sandoz, Sanofi-Genzyme, SOBI, UCB, Viatris; payment/honoraria from Lilly; support for attending meetings and/or travel from Lilly. Rieke Alten reports consulting fees from Abbvie, BMS, Lilly, Pfizer, Celltrion, UCB, Gilead, Galapagos; received payment or honoraria from Abbvie, BMS; Lilly; Pfizer, Celltrion, UCB, Gilead, Galapagos; received support for attending meetings/travel from Abbvie, BMS, Lilly, Pfizer, Celltrion, UCB, Gilead, Galapagos; has participated on a Data Safety Monitoring Board/Advisory Board from Abbvie, BMS, Lilly, Pfizer, Celltrion, UCB, Gilead, Galapagos. Peter Nash reports consulting fees from Abbvie, Lilly, Pfizer, Amgen, Janssen, Novartis, UCB; payment or honoraria from Abbvie, Lilly, Pfizer, Amgen, Janssen, Novartis, UCB; support for attending meeting/travel from Pfizer, Novartis and stocks/stock options from Pfizer Amgen Lilly GSK Merck. Eugen Feist reports support for medical writing and article processing from Lilly; received grant support to institution from Lilly, Pfizer, Alfasigma; consulting fees from Lilly, Novartis, Abbvie, Sobi, UCB; payment or honoraria from Lilly, Novartis, Abbvie, Sobi, UCB; support for attending meetings/travel from Novartis and Lilly; has participated on a Data Safety Monitoring Board/Advisory Board from Novartis, Abbvie. Ethical Approval: This study was conducted in accordance with Good Pharmacoepidemiology Practice, the principles of the Declaration of Helsinki, and local laws and regulations in the five European countries included in the study. The study protocol was approved by relevant ethics committees in each participating country. All patients provided written informed consent prior to entry to the study. Patients or the public were not involved in the design, conduct, reporting, or dissemination plans of our research., (© 2024. The Author(s).)

The effectiveness of incorporating an audience response system (ARS) in improving the learning environment and student performance was assessed in a didactic biomedical science course at a large US dental school. Instructors and students were surveyed for their experiences of using Top Hat-based ARS in a multi-disciplinary biomedical science course. Average exam scores and grade distribution for challenging sections on immunology and developmental biology were compared before and after incorporating ARS. Pearson's chi-squared test, likelihood ratio test, Student's t-test and Fisher's exact test using beta regression model were used to assess statistical significance (p < 0.05). Student survey results with 78% (82/105) response rate, indicated that incorporating ARS improved student engagement, reinforced lecture material, and prepared them better for exams (p < 0.0001). Sixty seven percent of student respondents recommended continued integration of ARS questions in lectures (p < 0.0001). Although faculty survey data (n = 5, 100% response rate) were not statistically significant, the majority of faculty agreed that real-time feedback through ARS allowed them to appropriately pace lecture delivery and restructure forthcoming material. The average exam scores and grade distribution for challenging sections showed modest improvement after incorporation of ARS (p < 0.05). There was no significant correlation between final course grades and ARS grades for participation or correctness. Incorporating the ARS in a multi-disciplinary biomedical science course is perceived by faculty and students as an effective instructional approach that improves the learning environment, teaching strategies, and student performance., (© 2024 International Union of Biochemistry and Molecular Biology.)

Obstructive sleep apnea (OSA) is highly prevalent and associated with oxidative stress, chronic inflammation, and adverse cardiovascular consequences. The comorbid condition of obesity remains epidemic. Both obesity and OSA are highly comorbid in patients with cardiovascular disease including atrial fibrillation, resistant hypertension, congestive heart failure, and coronary artery disease. Patients with these preexisting cardiovascular conditions should be screened for OSA with a low threshold to treat, even if OSA severity is mild. Nephroblastoma overexpressed (NOV/CCN3) protein has been identified in multiple chronic inflammatory states, most notably in obesity and more recently in OSA, even in the absence of obesity. As such, NOV may represent an important biomarker for oxidative stress in OSA and may lead to a deeper understanding of the relationship between OSA and its clinical sequelae., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: This study aims to assess the impact of hospital-specific guidelines on the optimal utilization of carbapenems and to examine their effects on patient outcomes., Design: Quasi-experimental study., Setting: Tertiary care hospital in Turkey where infectious diseases (IDs) consultation and antibiotic approval are mandatory for carbapenem use., Participants: All inpatients ≥18 years of age who received a carbapenem for at least 24 hours during the study periods were enrolled., Intervention: Hospital-specific treatment guidelines were introduced in April 2019. The control group was the year 2018, when there were no guidelines (pre-GP). The year 2020 was analyzed as the intervention period (post-GP)., Results: A total of 678 patients were analyzed, 326 in the pre-GP period and 352 in the post-GP period. Following guideline implementation, there was a significant increase in appropriate carbapenem use (49.1% in pre-GP vs 71.9% in post-GP, P < .001). The duration of carbapenem use decreased significantly ( P = .019). However, there was no significant change in the incidence of new infection episodes within the subsequent 30 days (27.6% in pre-GP vs 28.3% in post-GP), or in the length of hospitalization [median (25%-75%) = 28 (16-46) in pre-GP, 28 (15-47.5) in post-GP, P = .678]. Mortality rates were similar at day 7 post-GP (1.7%) compared to pre-GP (0.03%) ( P = .125)., Conclusions: The implementation of guidelines increased the appropriate utilization of carbapenems, without resulting in extended hospital stays or recurrent episodes. Despite an increased number of patients admitted to the ICU during the latter period, infection-related mortality rates remained comparable., Competing Interests: All authors report no conflicts of interest relevant to this article., (© The Author(s) 2024.)

Background: The psoriatic arthritis (PsA) Observational Study of Persistence of Treatment (PRO-SPIRIT) assesses effectiveness and persistence of real-world PsA treatments. Ixekizumab (IXE) is an interleukin (IL)-17A inhibitor (i) (IL-17Ai), approved for the treatment of adult PsA., Methods: The aim of this predefined interim analysis was to report baseline characteristics along with early (3-month) descriptive and comparative real-world effectiveness in patients with PsA prescribed with advanced treatment including IL-17Ai; IXE or secukinumab (SEC), IL-12/23i, IL-23i, tumour necrosis factor (TNFi) or Janus kinase (JAKi)., Results: 1192 patients across 6 countries were analysed. At baseline, patients receiving IXE had longer disease duration and higher previous biological/targeted-synthetic disease-modifying antirheumatic drugs experience than patients starting TNFi and SEC 150, and less concomitant conventional-synthetic DMARD use than TNFi and JAKi. Comparative analyses at 3 months showed that: (a) versus TNFi, IXE exhibited similar improvement in clinical Disease Activity in PsA (cDAPSA) but significantly greater improvement in body surface area affected by psoriasis (BSA) and global assessments (physician GA, patient GA (PatGA)); (b) versus IL-12/23i and IL-23i (pooled), IXE showed significantly greater improvement in cDAPSA and PatGA; (c) IXE was as fast as JAKi in improving joint disease activity. Ad hoc analysis indicated that more patients with active psoriasis (BSA ≥3%) achieved minimal disease activity with IXE than JAKi or IL-12/23i. The responses to SEC varied by dosage., Conclusions: This study confirms the rapid 3-month effectiveness of IXE on joint disease activity-as fast as TNFi and JAKi (cDAPSA), and exceeding IL-12/23i and IL-23i-along with clear benefits to skin., Competing Interests: Competing interests: LEK has received honoraria or fees for serving as a speaker or consultant from AbbVie, Amgen, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Gilead, GSK, Janssen, Merck, Novartis, Pfizer and UCB. He has received investigator-initiated study grants from AbbVie, Biogen, Eli Lilly and Company, Janssen, Novartis, Pfizer and UCB. KJN and MN are employees and minor shareholders of Eli Lilly and Company. JM has received grants, speaker honoraria or travel support, or participated on an advisory board for AbbVie, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Fresenius Kabi, Galapagos, Medac, Mylan, Novartis, Pfizer, Roche Chugaï, Sanofi and Viatris. EL has received speaker honoraria from AbbVie, Eli Lilly and Company, Janssen, Novartis and UCB. WT has received grants, consulting fees, speaker honoraria and/or travel support from AbbVie, Eli Lilly and Company, GSK, Janssen, Novartis, Ono-Pharma, Pfizer and UCB. RA has received consulting fees, speaker honoraria and/or travel support from AbbVie, Amgen, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Galapagos, Gilead, Janssen, Mylan, Novartis, Pfizer, Roche Chugaï, Viatris and UCB. VC has received grants, royalties or consulting fees, or had a leadership role in, AbbVie, Amgen, Bristol Myers Squibb, Canadian Psoriasis Network, Eli Lilly and Company, Fresenius Kabi, Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), Janssen, Novartis, UCB and University Health Network. AMF has received speaker honoraria, payment for expert testimony and/or travel support from AbbVie, Eli Lilly and Company, Janssen, Pfizer, Novartis and UCB. BZ, DK and TH are employees and minor shareholders of Eli Lilly and Company. NG has received grants, consulting fees, speaker honoraria, travel support or equipment/services, or participated on an advisory board for AbbVie, AstraZeneca, Eli Lilly and Company, Galapagos, Janssen, Novartis and UCB. AK, WF and IdlT are employees and minor shareholders of Eli Lilly and Company. DGMcG has received consulting fees, speaker honoraria, research grant support and/or travel support from AbbVie, Almiral, Bristol Myers Squibb, Eli Lilly and Company, Janssen, Novartis, Pfizer and UCB., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aim: This real-world study aimed to describe patient and clinical characteristics, treatment patterns and outcomes for patients with HR+/HER2- metastatic breast cancer receiving abemaciclib in France, Italy and Spain. Materials & methods: A multicenter chart review was conducted for adult females with HR+/HER2- advanced/metastatic breast cancer who received abemaciclib in routine care. Real-world progression-free survival (rwPFS) was estimated via Kaplan-Meier curves. Results: This study included 151, 173 and 175 patients from France, Italy and Spain, respectively. Abemaciclib was mostly prescribed as first-line therapy concomitantly with hormone therapy. Median rwPFS was >20 months and the 1-year rwPFS rate was >70%. Conclusion: Effectiveness was similar across the three countries and aligns with pivotal studies.

Introduction: RA-BE-REAL has the overall aim of defining a profile of patients with rheumatoid arthritis (RA) starting baricitinib or any other targeted synthetic (ts) or any biologic (b) disease-modifying antirheumatic drug (DMARD) for the first time, and the primary objective of estimating time until discontinuation from any cause (excluding sustained response) of the initial treatment., Methods: RA-BE-REAL is an ongoing, prospective, observational, 36-month study in patients with RA initiating treatment with baricitinib (cohort A) or any other tsDMARD or any bDMARD (cohort B) for the first time. The primary objective is to assess the time until treatment discontinuation from any cause (excluding sustained response) at 24 months, (i.e., the rate of discontinuation of initial baricitinib or ts/bDMARD). Patient profiles of each cohort are described and compared. Post-baseline data are descriptively analyzed. This manuscript presents baseline and interim (6-month) outcomes for European patients with RA participating in the global RA-BE-REAL study., Results: Data from 1074 patients (cohort A: 509; cohort B: 565) were analyzed. For cohorts A and B, respectively, the 6-month cumulative incidence (95% confidence interval) of treatment discontinuation was 16.5 (12.9-21.1) and 23.3 (19.1-28.2), and the proportions of patients achieving remission were 25.6% and 18.5%. At baseline, mean patient age was 59.1 and 57.0 years (p = 0.010) and mean disease duration was 10.0 and 8.9 years (p = 0.047), respectively. The proportions of patients exposed to ts/bDMARDs at any time before study entry were 51.9% and 39.1%, and the proportions of patients initiated on monotherapy were 50.9% and 31.2%, respectively., Conclusion: In real-world settings, patients with RA initiating treatment with baricitinib were older and had longer disease duration than those initiating treatment with any other tsDMARD or any bDMARD. Initial descriptive data regarding treatment discontinuation (including reasons for discontinuation), effectiveness, and treatment patterns will be enriched as the study progresses., (© 2022. The Author(s).)

Background: Identification of rheumatoid arthritis (RA) patients at high risk of adverse health outcomes remains a major challenge. We aimed to develop and validate prediction models for a variety of adverse health outcomes in RA patients initiating first-line methotrexate (MTX) monotherapy., Methods: Data from 15 claims and electronic health record databases across 9 countries were used. Models were developed and internally validated on Optum® De-identified Clinformatics® Data Mart Database using L1-regularized logistic regression to estimate the risk of adverse health outcomes within 3 months (leukopenia, pancytopenia, infection), 2 years (myocardial infarction (MI) and stroke), and 5 years (cancers [colorectal, breast, uterine] after treatment initiation. Candidate predictors included demographic variables and past medical history. Models were externally validated on all other databases. Performance was assessed using the area under the receiver operator characteristic curve (AUC) and calibration plots., Findings: Models were developed and internally validated on 21,547 RA patients and externally validated on 131,928 RA patients. Models for serious infection (AUC: internal 0.74, external ranging from 0.62 to 0.83), MI (AUC: internal 0.76, external ranging from 0.56 to 0.82), and stroke (AUC: internal 0.77, external ranging from 0.63 to 0.95), showed good discrimination and adequate calibration. Models for the other outcomes showed modest internal discrimination (AUC < 0.65) and were not externally validated., Interpretation: We developed and validated prediction models for a variety of adverse health outcomes in RA patients initiating first-line MTX monotherapy. Final models for serious infection, MI, and stroke demonstrated good performance across multiple databases and can be studied for clinical use., Funding: This activity under the European Health Data & Evidence Network (EHDEN) has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806968. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA., Competing Interests: Declaration of Competing Interest CY, RDW, JRA, EB, TDS, MJ, RK, JAK, LK, APU, SR, HMS, and COT report no competing interests related to this work. JNS, AGS, JW, and PR are employees of Janssen Research & Development, a pharmaceutical company of Johnson & Johnson, and shareholders of Johnson & Johnson. At the time the study was conducted, ESB was an employee of Janssen Research & Development, a pharmaceutical company of Johnson & Johnson, shareholder of Johnson & Johnson, and shareholder of Takeda Pharmaceuticals. LC reports her institute has been hired for methodological consultancy by AbbVie Spain, S.L.U., Astellas Pharma, SA, Bristol-Myers Squibb, S.A.U. (BMS), Daiichi-Sankyo España, S.A., Dentsply Sirona Iberia, S.A.U., Eisai Farmacéutica, SA, Fresenius Kabi España, S. A. U., Laboratorios Gebro Pharma, SA, Lilly, S.A., Merck Sharp & Dohme España, S.A., Novartis Farmaceutica, SA, Pfizer, S.L.U., Roche Farma, S.A, Sanofi Aventis, UCB Pharma, S.A., outside the submitted work. KC reports consultancy fees from Eli Lilly, AbbVie, and Pfizer, outside the submitted work. WF is an employee and shareholder of Eli Lilly. AHO is an employee of Lilly Deutschland GmbH. JL reports grants from Versus Arthritis, grants from Medical Research Council, outside the submitted work. AM is an employee of Bayer AG. At the time the study was conducted, KM was an employee of Servier. KV works for a research institute which receives/received unconditional research grants from Yamanouchi, Pfizer/Boehringer Ingelheim, Novartis, GSK, UCB, Amgen, Chiesi, none of these are related to the content of this paper. DV reports personal fees from Bayer, during the conduct of the study and outside the submitted work. DPA reports grants and other (DPA's department has received fees for speaker services and advisory board membership) from AMGEN, grants, non-financial support and other (DPA's department has received fees for consultancy services) from UCB Biopharma, grants from Les Laboratoires Servier, outside the submitted work; and Janssen, on behalf of IMI-funded EHDEN and EMIF consortiums, and Synapse Management Partners have supported training programmes organised by DPA's department and open for external participants. PRR works for a research institute who receives/received unconditional research grants from Yamanouchi, Pfizer-Boehringer Ingelheim, GSK, Amgen, UCB, Novartis, AstraZeneca, Chiesi, Janssen Research and Development, none of which relate to the content of this work., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

This expert opinion article explores the strategy of adopting a holistic approach to the management of rheumatoid arthritis (RA) by incorporating the wellness practices of exercise, optimised sleep, optimised nutrition, mindfulness, social connectedness and positive emotions into the management plan. The aim is to attain optimal health for each patient beyond that achievable by limiting disease management to pharmacological treatment to attain the lowest achievable composite scores of disease activity, as recommended with the current treat-to-target approach, and addressing the recent recognition of pain control as a key patient-reported outcome. Incorporating wellness practices into a busy clinical setting requires creativity and customisation based on the individual practice setting and the individual needs of each patient. Such practices can help people living with RA to achieve optimum wellness through the introduction of measures-according to individual need-designed to improve the aspects of life most impacted for that person, thereby complementing treat-to-target and pain control strategies with pharmacological agents. Clinicians must consider wellness practices in addition to treat-to-target pharmacological agents for the holistic management of people with RA., Competing Interests: Competing interests: PT: Research grants from Celgene and Galapagos and consultation fees from AbbVie, Biogen, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Pfizer, BMS, Roche, Sanofi, Nordic Pharma, Fresenius and UCB. SJ has served as a consultant, member of advisory boards and/or speaker bureaus for Eli Lilly, Otsuka, Pamlab and Sunovion. MVdL reports educational grants and speaker’s–advisory fees from Eli Lilly and Company not related to this work. AL has been member of speaker bureaus for Lilly, Novartis, Amgen, Exage, Myria and Pfizer and a consultant for Amgen. WF, AQ and IdlT are employees of Eli Lilly and Company., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to evaluate the treatment patterns and pharmacoutilization of patients with rheumatoid arthritis (RA) in real-world settings in Italy. This retrospective observational analysis was based on administrative databases of selected Italian entities. All adult patients with RA diagnosis confirmed by ≥1 discharge diagnosis of RA (ICD-9-CM code = 714.0) or an active exemption code (006.714.0) were enrolled in 2019. Two cohorts were created: one included patients prescribed baricitinib, the other those prescribed biological disease-modifying antirheumatic drugs (bDMARDs). Overall, 47,711 RA patients were identified, most of them without DMARD prescription. As a first-line prescription, 43.2% of patients were prescribed conventional synthetic DMARDs (csDMARDs), 5.2% bDMARDs and 0.3% baricitinib. In 2019, 82.6% of csDMARD users continued with the same DMARD category, 15.9% had a bDMARD, while 1.5% had baricitinib as second-line therapy. Overall, 445 patients used baricitinib during 2019. During follow-up, baricitinib was prescribed as monotherapy to 31% of patients, as cotreatment with csDMARDs and corticosteroids to 27% of patients, with corticosteroids to 28% of patients and with csDMARDs to 14% of patients. In line with previous findings, a trend of bDMARD undertreatment was observed. The treatment patterns of baricitinib patients could help to better characterize patients eligible for new therapeutic options that will be available in the future.

Objective: RA is a progressive, chronic autoimmune disease. We summarize the impact of disease activity as measured by the DAS in 28 joints (DAS28-CRP scores) and pain on productivity and ability to work using the Work Productivity and Activity Impairment questionnaire (WPAI) scores, in addition to the impact of disease duration on the ability to work., Methods: Data were drawn from the Burden of RA across Europe: a Socioeconomic Survey (BRASS), a European cross-sectional study in RA. Analyses explored associations between DAS28-CRP score and disease duration with stopping work because of RA, and regression analyses assessed impacts of pain and DAS28-CRP on early retirement and WPAI., Results: Four hundred and seventy-six RA specialist clinicians provided information on 4079 adults with RA, of whom 2087 completed the patient survey. Severe disease activity was associated with higher rates of stopping work or early retirement attributable to RA (21%) vs moderate/mild disease (7%) or remission (8%). Work impairment was higher in severe (67%) or moderate RA (45%) compared with low disease activity [LDA (37%)] or remission (28%). Moreover, patients with severe (60%) or moderate pain (48%) experienced increased work impairment [mild (34%) or no pain (19%)]. Moderate to severe pain is significant in patients with LDA (35%) or remission (22%). A statistically significant association was found between severity, duration and pain vs work impairment, and between disease duration vs early retirement., Conclusion: Results demonstrate the high burden of RA. Furthermore, subjective domains, such as pain, could be as important as objective measures of RA activity in affecting the ability to work., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Introduction: The objective of this study was to evaluate treatment patterns in patients with rheumatoid arthritis (RA), with a focus on the utilization of baricitinib, an oral highly selective Janus kinase 1 and 2 inhibitor, in an Italian real-world setting., Methods: This observational retrospective analysis was based on data collected in selected Italian administrative databases. Patients aged ≥ 18 years with a diagnosis of RA defined by hospitalization discharge diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 714.0) or by disease exemption code 006 for RA in 2018 were included. The index date (ID) was defined as the date of first prescription for a drug indicated for RA during the inclusion period. Patients without a prescription for biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) before the ID were considered to be b/tsDMARD naïve. A further analysis was performed on patients only receiving baricitinib., Results: A total of 41,290 RA patients were enrolled, of whom 55.6% were not treated with conventional synthetic DMARDs (csDMARDs) or b/tsDMARDs, 39.4% were receiving therapy with csDMARDs, and 5.0% were using b/tsDMARDs. In the latter group, 2.7% (n = 56) were receiving therapy with baricitinib. In 2018, 13.2% of csDMARD-treated patients switched to b/tsDMARDs, of whom 4.3% (n = 93) of these switched to baricitinib. In total, 149 patients (mean age ± standard deviation 57.6 ± 12.1; 12.8% male) had a baricitinib prescription, of whom 51% were b/tsDMARD naïve. At baseline, 61.7% of baricitinib users were receiving combination therapy with csDMARDs plus corticosteroids, 26.2% were receiving combination therapy with corticosteroids, and 8.1% were receiving combination therapy with csDMARDs; 4% were receiving baricitinib monotherapy. During follow-up, the proportion of patients receiving baricitinib monotherapy increased to 38.9%, while 26.9, 18.8, and 15.4% of baricitinib users received combination therapy with corticosteroids, csDMARDs plus corticosteroids, and csDMARDs, respectively., Conclusion: This study provides a current view of the treatment patterns in Italian patients with RA in a real-world setting of daily clinical practice, with a focus on baricitinib utilization.

Background/objectives: This article compares the effectiveness of baricitinib (BARI) 4 mg (oral, Janus kinase [JAK] 1/2 inhibitor) versus other targeted synthetic/biologic disease-modifying antirheumatic drugs, in combination with methotrexate (MTX), in moderate-to-severe rheumatoid arthritis patients with inadequate response (IR) to MTX., Methods: A systematic literature review was conducted to identify randomized controlled trials (RCTs) of the interventions of interest. Bayesian network meta-analyses (NMA) were used to compare American College of Rheumatology (ACR) responses at 24 weeks. A series of prespecified sensitivity analyses addressed the potential impact of, among others, baseline risk, treatment effect modifiers, and trial design on treatment response., Results: Nineteen RCTs were included in the NMA (primary analysis). For ACR20, BARI 4 mg + MTX was found to be more effective than adalimumab (ADA) 40 mg + MTX (Odds Ratio [OR] 1.33), abatacept (ABA) 10 mg + MTX (IV/4 weeks) (OR 1.45), infliximab (IFX) 3 mg + MTX (IV/8 wks) (OR 1.63), and rituximab (RTX) 1000 mg + MTX (OR 1.63). No differences were found on ACR50. For ACR70, BARI 4 mg + MTX was more effective than ADA 40 mg + MTX (OR 1.37), ABA 10 mg + MTX (OR 1.86), and RTX 1000 mg + MTX (OR 2.26). Sensitivity analysis including 10 additional RCTs with up to 20% of patients with prior biologic use showed BARI 4 mg + MTX to be more effective than tocilizumab (TCZ) 8 mg + MTX on ACR20 (OR 1.44). Results for all sensitivity analyses were consistent with the direction and magnitude of the primary results. Key limitations include the time span in which trials were conducted (1999-2017), during which patient characteristics and treatment approaches might have changed., Conclusion: This NMA suggests that BARI 4 mg + MTX is an efficacious treatment option in the MTX-IR population as evidenced by the robustness of results.

Objectives : The approval in more than 50 countries of baricitinib, an oral Janus Kinase inhibitor for the treatment of Rheumatoid Arthritis (RA), warrants a framework for corresponding economic evaluations. To develop a comprehensive economic model assessing the cost-effectiveness of baricitinib for the treatment of moderately-to-severely active RA patients in comparison to other relevant treatments, considering the natural history of the disease, real world treatment patterns, and clinical evidence from the baricitinib trials. Methods : A systematic literature review of previously developed models in RA was conducted to inform the model structure, key modeling assumptions and data inputs. Consultations with rheumatologists were undertaken to validate the modeling approach and underlying assumptions. Results : A discrete event simulation model was developed to international best practices with flexibility to assess the cost-effectiveness of baricitinib over a lifetime in a variety of markets. The model incorporates treatment sequencing to adequately reflect treatment pathways in clinical practice. Outcomes assessed include cost and quality-adjusted life years, allowing for a full incremental analysis of cost-effectiveness of competing treatments and treatment sequences. Conclusion : The economic model developed provides a robust framework for future analyses assessing the cost-effectiveness of baricitinib for the treatment of RA in specific country settings.

Background: The aim of this retrospective study was to examine the longitudinal association between disease activity and radiographic damage in a cohort of patients with early RA (symptom onset < 1 year) treated according to treat-to-target (T2T) therapy., Methods: Baseline to 3-year follow-up data were used from patients included in the DREAM remission induction cohort. Patients received protocolized T2T treatment, aimed at 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR) remission. Disease activity (DAS28-ESR and C-reactive protein, CRP) were assessed at least every 3 months; X-rays of the hand and feet at inclusion, 6 months, and 1, 2, and 3 years were scored using modified Sharp/van der Heijde scoring (SHS). Between and within-person associations between time-integrated disease activity and radiographic progression over time were examined., Results: A subset of 229 out of 534 included patients were available for analysis. At the between-patient level, time-integrated DAS28-ESR scores were not significantly correlated with progression at the 6 month and 2-year follow-up and only weakly at the 1-year (Pearson's correlation coefficient r = 0.17, P < 0.05) and 3-year follow-up (r = 0.21, P < 0.05). Individual slopes of the relationship between DAS28-ESR and progression scores in each time interval were significantly correlated over time and the slope of the first 6 months was moderately associated with this slope at later time points (r between 0.39 and 0.59; P values < 0.001). Between 15.9 to 22.7% and 16.7 to 38.5% of patients with low and moderate time-integrated disease activity, respectively, experienced relevant (ΔSHS ≥ 3) radiographic progression at the different time intervals. Analyses using CRP showed similar results., Conclusions: In early RA patients treated according to T2T, radiographic progression appears to be an individually determined disease process, driven by factors other than consistent high disease activity. For individual patients, the intra-patient relation between disease activity and cumulative radiographic damage during the first 6 months is a good indicator for this relation in later years., Trial Registration: Netherlands Trial Register NTR578, 12 January 2006.

Objective: To retrospectively compare the long-term clinical, functional, and cost outcomes for early RA patients (symptoms < 1 year) who did or did not achieve early remission in a treat-to-target strategy., Method: Five-year data of 471 patients included in the DREAM remission induction cohort were used. Patients were treated according to a pre-specified 28-joint Disease Activity Score (DAS28) remission driven step-up treatment strategy starting with methotrexate, addition of sulfasalazine, and exchange of sulfasalazine for biological medication in case of failure. Two- and 3-year healthcare costs were available for selected subsamples of patients only., Results: DAS28 remission was achieved in 27.7%, 38.2%, and 51.6% of patients at 2, 3, and 6 months, respectively. Achieving DAS28 remission at 2, 3, or 6 months was consistently associated with significantly lower DAS28 and Health Assessment Questionnaire-Disability scores at 1, 3, and 5 years of follow-up (all P values < 0.02). Patients in remission at 2, 3, or 6 months also had significantly lower medication costs per patient over the first 2 and 3 years of treatment, mainly due to lower biologic use, but differences in total healthcare resource costs (hospital admissions plus consultations) were less pronounced. Mean total medication and total healthcare resource costs at 3 years were €1131 and €1757 for patients in remission at 6 months vs. €7533 (P < 0.01) and €2202 (P = 0.09) for those not in remission., Conclusion: Achieving early remission was associated with beneficial clinical outcomes for early RA patients and lower costs in the long term. Key Points • Previous studies in rheumatoid arthritis patients have demonstrated that early good response is associated with sustained remission and better long-term clinical outcomes. • This study extents these findings by examining the long-term benefits of achieving early remission on clinical, patient-reported, and economic outcomes in a real-world cohort of patients with very early rheumatoid arthritis treated according to treat-to-target principles. • The findings of this study clearly demonstrate that aiming for early remission in rheumatoid arthritis patients is beneficial in the long-term in terms of better clinical and functional outcomes and lower healthcare costs.

Oral liquid formulations are compounded by pharmacists to meet the needs of patients when a suitable commercially available product is not available. To minimize the errors associated with measuring multiple excipients and to enhance the shelf-life of the medicines, commercially available suspending bases are commonly used. This review aims to compare the stability and shelf life of commercially available extemporaneous formulation to traditional formulation methods. Five (5) databases were searched (Pubmed, SCOPUS, Science direct, Embase, and EBSCOhost). Twelve articles, comprising of seven cardiovascular medications (amiodarone, captopril, carvedilol, furosemide, nifedipine, sotalol, and valsartan), met the study inclusion criteria and were reviewed. Chemical stability of the drugs was comparable between the two formulation methods except for furosemide, captopril, and valsartan. The traditional compounding method provided superior stability for furosemide (90 vs. 14 days) and captopril (50 vs. 14 days), while the commercial vehicles provided superior stability for valsartan (90 vs. 14 days). Physical stability tests indicated that sedimentation does occur with both formulation methods. Microbial studies within the data were lacking and further research can be undertaken in this area. This review highlights the importance of assessing the suitability of compounding ingredients prior to preparation of the formulation.