Background Psoriasis, a chronic, inflammatory skin disease, requires long-term therapy. Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits interleukin 23 by binding to its p19 subunit. Objective The authors assessed the efficacy and safety of risankizumab compared with methotrexate in adults with moderate-to-severe plaque psoriasis. Methods IMMbrace was a phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study. Patients received subcutaneous risankizumab 150 mg at weeks 0, 4, and 16 plus oral placebo weekly, or oral methotrexate 5 mg weekly (with dose escalation up to 25 mg based on response and tolerability) plus subcutaneous placebo at weeks 0, 4, and 16. Primary efficacy endpoints were the proportions of patients who achieved ≥ 90% improvement in Psoriasis Area and Severity Index (PASI90) and static Physician’s Global Assessment of clear/almost clear (sPGA 0/1) at week 28. Safety was also assessed. Results Among 98 patients randomized (risankizumab, n = 50; methotrexate, n = 48), 95 completed the double-blind period. At week 28, significantly higher proportions of patients treated with risankizumab versus methotrexate achieved PASI90 (84.0% vs. 35.4%; p < 0.001); sPGA 0/1 was achieved by 90.0% and 64.6% of patients in the risankizumab and methotrexate groups (p ≤ 0.001). Risankizumab efficacy was maintained throughout week 112. Adverse event rates were similar in the two groups. Study limitations The sample size was small due to the difficulty of recruiting patients without methotrexate use. Conclusions Risankizumab demonstrated superior efficacy over methotrexate at week 28; efficacy was maintained, and no new safety findings were observed through week 112.

Background: Huntington's disease (HD) is still often defined by the onset of motor symptoms, inversely associated with the size of the CAG repeat expansion in the huntingtin gene. Although the cause of HD is known, much remains unknown about mechanisms underlying clinical symptom development, disease progression, and specific clinical subtypes/endophenotypes. Objective: In the iMarkHD study, we aim to investigate four discrete molecular positron emission tomography (PET) tracers and magnetic resonance imaging (MRI) markers as biomarkers for disease and symptom progression. Methods: Following MRI optimization in five healthy volunteers (cohort 1), we aim to recruit 108 participants of whom 72 are people with HD (PwHD) and 36 healthy volunteers (cohort 2). Pending interim analysis, these numbers could increase to 96 PwHD and 48 healthy controls. Participants will complete a total of 10 study visits, consisting of a screening visit followed by a clinical and MRI visit and PET visits at baseline, year 1, and year 2. PET targets include the cannabinoid 1, histamine 3, and serotonin 2A receptors, and phosphodiesterase 10A, whereas MRI will be multimodal, including, but not limited to, the assessment of cerebral blood flow, functional connectivity, and brain iron. Results: Recruitment is currently active and started in September 2022. Conclusions: By combining PET and multi-modal MRI assessments we expect to provide a comprehensive examination of the molecular, functional, and structural framework of HD progression. As such, the iMarkHD study will provide a solid base for the identification of treatment targets and novel outcome measures for future clinical trials.

BackgroundMinority ethnic groups have often been underrepresented in research, posing a problem in relation to external validity and extrapolation of findings. Here, we aimed to assess recruitment and retainment strategies in a large observational study assessing neurological complications following SARS-CoV-2 infection.MethodsParticipants were recruited following confirmed infection with SARS-CoV-2 and hospitalisation. Self-reported ethnicity was recorded alongside other demographic data to identify potential barriers to recruitment.Results807 participants were recruited to COVID-CNS, and ethnicity data were available for 93.2%. We identified a proportionate representation of self-reported ethnicity categories, and distribution of broad ethnicity categories mirrored individual centres’ catchment areas. White ethnicity within individual centres ranged between 44.5% and 89.1%, with highest percentage of participants with non-white ethnicity in London-based centres. Examples are provided how to reach potentially underrepresented minority ethnic groups.ConclusionsRecruitment barriers in relation to potentially underrepresented ethnic groups may be overcome with strategies identified here.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national longitudinal study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers and reduced anterior cingulate cortex volume one year after admission. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Treatment with corticosteroids during the acute phase appeared protective against cognitive deficits. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies. A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.

Journal Article Corrected proof Scientific Business Abstracts Get access Keith Siew, Keith Siew University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Vaksha Patel, Vaksha Patel University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jasminka Zimmermann, Jasminka Zimmermann University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Vaughan, Michael Vaughan University of Cork, Eire Search for other works by this author on: Oxford Academic PubMed Google Scholar Christopher Cheshire, Christopher Cheshire Crick Institute, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Angela Kubik, Angela Kubik NASA Ames Research Centre, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Rebecca Finch, Rebecca Finch University of Staffordshire, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Zhongwang Li, Zhongwang Li University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Selin Altinok, Selin Altinok University North Carolina, Chapel Hill, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Willian De Silvera, Willian De Silvera University of Staffordshire, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar ... 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Google Scholar S M Paddick, S M Paddick Faculty of Medical Science, University of Newcastle, Newcastle, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar C Leek C Leek Institute of Population Health, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar QJM: An International Journal of Medicine, hcad072, https://doi.org/10.1093/qjmed/hcad072 Published: 07 July 2023

Introduction Magnetic resonance imaging (MRI) of the brain could be a key diagnostic and research tool for understanding the neuropsychiatric complications of COVID-19. For maximum impact, multi-modal MRI protocols will be needed to measure the effects of SARS-CoV-2 infection on the brain by diverse potentially pathogenic mechanisms, and with high reliability across multiple sites and scanner manufacturers. Here we describe the development of such a protocol, based upon the UK Biobank, and its validation with a travelling heads study. A multi-modal brain MRI protocol comprising sequences for T1-weighted MRI, T2-FLAIR, diffusion MRI (dMRI), resting-state functional MRI (fMRI), susceptibility-weighted imaging (swMRI), and arterial spin labelling (ASL), was defined in close approximation to prior UK Biobank (UKB) and C-MORE protocols for Siemens 3T systems. We iteratively defined a comparable set of sequences for General Electric (GE) 3T systems. To assess multi-site feasibility and between-site variability of this protocol, N = 8 healthy participants were each scanned at 4 UK sites: 3 using Siemens PRISMA scanners (Cambridge, Liverpool, Oxford) and 1 using a GE scanner (King’s College London). Over 2,000 Imaging Derived Phenotypes (IDPs), measuring both data quality and regional image properties of interest, were automatically estimated by customised UKB image processing pipelines (S2 File). Components of variance and intra-class correlations (ICCs) were estimated for each IDP by linear mixed effects models and benchmarked by comparison to repeated measurements of the same IDPs from UKB participants. Intra-class correlations for many IDPs indicated good-to-excellent between-site reliability. Considering only data from the Siemens sites, between-site reliability generally matched the high levels of test-retest reliability of the same IDPs estimated in repeated, within-site, within-subject scans from UK Biobank. Inclusion of the GE site resulted in good-to-excellent reliability for many IDPs, although there were significant between-site differences in mean and scaling, and reduced ICCs, for some classes of IDP, especially T1 contrast and some dMRI-derived measures. We also identified high reliability of quantitative susceptibility mapping (QSM) IDPs derived from swMRI images, multi-network ICA-based IDPs from resting-state fMRI, and olfactory bulb structure IDPs from T1, T2-FLAIR and dMRI data. Conclusion These results give confidence that large, multi-site MRI datasets can be collected reliably at different sites across the diverse range of MRI modalities and IDPs that could be mechanistically informative in COVID brain research. We discuss limitations of the study and strategies for further harmonisation of data collected from sites using scanners supplied by different manufacturers. These acquisition and analysis protocols are now in use for MRI assessments of post-COVID patients (N = 700) as part of the ongoing COVID-CNS study.

Introduction: Pivotal phase 3 induction (ADVANCE and MOTIVATE) and maintenance (FORTIFY) studies established that treatment with risankizumab (RZB), a humanized monoclonal antibody with high specificity for the p19 subunit of interleukin-23, was superior to placebo for achieving clinical remission and endoscopic response in patients with moderate to severe Crohn's disease (CD). This exploratory analysis aimed to determine predictors of response to risankizumab induction and maintenance therapy. Methods: Pooled data from patients in the RZB 600 mg intravenous (IV) dosing groups in ADVANCE + MOTIVATE induction studies (n=527) and data from the RZB 360 mg subcutaneous (SC) dosing group in FORTIFY (n=141) were evaluated. Multivariate logistic regression models were used to determine predictors of clinical and endoscopic outcomes at Weeks 12 and 52. For FORTIFY, separate logistic regression models were used to access end-of-induction characteristics for the achievement of outcomes at Week 52. Results: Baseline characteristics found to be predictive of clinical and/or endoscopic outcomes at Week 12 and Week 52 are highlighted in the Table. Age and duration of disease were evaluated but were not predictive. Compared to patients with ileal disease, patients with colonic disease were more likely to achieve endoscopic endpoints at Week 12, while patients with ileal-colonic disease were more likely to achieve endoscopic response at Week 12; patients with either colonic or ileal-colonic disease were more likely to achieve endoscopic response at Week 52. Conversely, patients with prior bio-failure at BL were less likely to achieve endoscopic response at Week 12, and clinical and endoscopic responses at Week 52. Patients using corticosteroids at BL were less likely to achieve clinical endpoints at Weeks 12 and 52. Patients achieving clinical or endoscopic endpoints at Week 12 were more likely to achieve these endpoints at Week 52. Conclusion: For patients treated with risankizumab, baseline disease location predicted achievement of endoscopic responses, corticosteroid use predicted achievement of clinical endpoints, and prior bio-failure status predicted achievement of both clinical and endoscopic endpoints at Week 52. Notably, achievement of clinical or endoscopic outcomes after induction with risankizumab were associated with a higher likelihood of achieving long-term clinical and endoscopic outcomes. Table 1. - Induction Baseline Characteristics and FORTIFY Week 0 Clinical Outcomes as Predictors of Week 12 Response to Risankizumab Induction and Week 52 Response to Risankizumab Maintenance Dosing Week 12 SF/APS Clinical Remission RZB 600 mg IV Week 12 CDAI Clinical Remission RZB 600 mg IV Week 12 CDAI Clinical Response RZB 600 mg IV Week 12Endoscopic Response RZB 600 mg IV Week 12Endoscopic Remission RZB 600 mg IV Week 12Ulcer-free Endoscopy RZB 600 mg IV Week 52 SF/APS Clinical Remission RZB 360 mg SC Week 52 CDAI Clinical Remission RZB 360 mg SC Week 52 CDAI Clinical Response RZB 360 mg SC Week 52Endoscopic Response RZB 360 mg SC Week 52Endoscopic Remission RZB 360 mg SC Week 52Ulcer-free Endoscopy RZB 360 mg SC Induction Baseline Characteristics as Predictors of ResponseOdds Ratio [95% CI]P-value Colonic Disease Only 1.436 [0.766, 2.693]P=0.260 1.653 [0.883, 3.094]P=0.116 1.448 [0.774, 2.709]P=0.247 5.178 [2.411, 11.123] P< 0.001 3.077 [1.425, 6.644] P=0.004 3.393 [1.510, 7.624] P=0.003 0.654 [0.265, 1.614]P=0.357 0.886 [0.357, 2.203]P=0.795 0.938 [0.378, 2.328]P=0.890 4.909 [1.468, 16.410] P=0.010 2.135 [0.722, 6.317]P=0.170 2.428 [0.731, 8.060]P=0.147 Ileal-colonic Disease Only 0.751 [0.411, 1.370] P=0.350 0.821 [0.451, 1.492] P=0.517 0.906 [0.506, 1.622] P=0.739 2.880 [1.379, 6.017] P=0.005 1.262 [0.590, 2.702] P=0.548 0.767 [0.331, 1.775] P=0.535 0.634 [0.263, 1.529] P=0.311 1.032 [0.426, 2.503] P=0.944 0.806 [0.333, 1.952] P=0.632 4.351 [1.318, 14.366] P=0.016 1.826 [0.627, 5.321] P=0.270 2.018 [0.617, 6.602] P=0.246 Bio-Failure Status 0.675 [0.423, 1.076] P=0.098 0.789 [0.495, 1.258] P=0.320 0.867 [0.540, 1.393] P=0.556 0.438 [0.271, 0.709] P< 0.001 0.597 [0.352, 1.013] P=0.056 0.570 [0.317, 1.026] P=0.061 0.425 [0.229, 0.787] P=0.006 0.373 [0.200, 0.698] P=0.002 0.426 [0.225, 0.805] P=0.009 0.443 [0.233, 0.844] P=0.013 0.444 [0.228, 0.863] P=0.017 0.295 [0.144, 0.606] P< 0.001 Corticosteroid Use 0.506 [0.321, 0.799] P=0.003 0.491 [0.313, 0.769] P=0.002 0.440 [0.283, 0.683] P< 0.001 0.742 [0.466, 1.181] P=0.208 0.786 [0.463, 1.334] P=0.372 0.891 [0.493, 1.609] P=0.701 0.443 [0.243, 0.805] P=0.008 0.331 [0.178, 0.613] P< 0.001 0.374 [0.210, 0.668] P< 0.001 0.796 [0.430, 1.474] P=0.468 0.787 [0.403, 1.539] P=0.485 0.939 [0.450, 1.959] P=0.866 Induction Week 12 Clinical Outcomes as Predictors of Response at Maintenance Week 52Odds Ratio [95% CI]P-value SF/APS Clinical Response 1.538 [0.969, 2.442] P=0.068 1.418 [0.894, 2.249] P=0.137 1.596 [1.005, 2.535] P=0.048 2.880 [1.737, 4.774] P< 0.001 4.417 [2.466, 7.909] P< 0.001 3.517 [1.884, 6.565] P< 0.001 SF/APS Clinical Remission 2.084 [1.095, 3.967] P=0.025 1.429 [0.760, 2.684] P=0.268 1.704 [0.889, 3.267] P=0.109 3.696 [1.904, 7.172] P< 0.001 5.368 [2.542, 11.337] P< 0.001 5.091 [2.264, 11.448] P< 0.001 Endoscopic Response 1.066 [0.527, 2.156] P=0.860 0.886 [0.438, 1.793] P=0.736 1.279 [0.613, 2.666] P=0.512 3.592 [1.712, 7.540] P< 0.001 5.765 [2.663, 12.479] P< 0.001 6.314 [2.824, 14.120] P< 0.001 Endoscopic Remission 1.186 [0.503, 2.796] P=0.696 0.810 [0.344, 1.907] P=0.629 1.067 [0.433, 2.625] P=0.888 4.342 [1.732, 10.887] P=0.002 9.227 [3.436, 24.776] P< 0.001 8.036 [2.934, 22.006] P< 0.001

Background In previous clinical trials, patients with active rheumatoid arthritis (RA) treated with upadacitinib (UPA) have improved patient-reported outcomes (PROs). This post hoc analysis of SELECT-CHOICE, a phase 3 clinical trial, evaluated the impact of UPA vs abatacept (ABA) with background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on PROs in patients with RA with inadequate response or intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR). Methods Patients in SELECT-CHOICE received UPA (oral 15 mg/day) or ABA (intravenous). PROs evaluated included Patient Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), patient’s assessment of pain by VAS, Health Assessment Questionnaire Disability Index (HAQ-DI), morning stiffness duration and severity, 36-Item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Impairment (WPAI), and EQ-5D 5-Level (EQ-5D-5L) index score. Least squares mean (LSM) changes from baseline to weeks 12 and 24 were based on an analysis of covariance model. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCID) were compared using chi-square tests. Results Data from 612 patients were analyzed (UPA, n =303; ABA, n =309). Mean age was 56 years and mean disease duration was 12 years. One-third received ≥2 prior bDMARDs and 72% received concomitant methotrexate at baseline. At week 12, UPA- vs ABA-treated patients had significantly greater improvements in PtGA, pain, HAQ-DI, morning stiffness severity, EQ-5D-5L, 2/4 WPAI domains, and 3/8 SF-36 domains and Physical Component Summary (PCS) scores ( P <0.05); significant differences persisted at week 24 for HAQ-DI, morning stiffness severity, SF-36 PCS and bodily pain domain, and WPAI activity impairment domain. At week 12, significantly more UPA- vs ABA-treated patients reported improvements ≥MCID in HAQ-DI (74% vs 64%) and SF-36 PCS (79% vs 66%) and 4/8 domain scores ( P <0.05). Conclusions At week 12, UPA vs ABA treatment elicited greater improvements in key domains of physical functioning, pain, and general health and earlier improvements in HAQ-DI. Overall, more UPA- vs ABA-treated patients achieved ≥MCID in most PROs at all timepoints; however, not all differences were statistically significant. These data, however, highlight the faster response to UPA treatment. Trial registration NCT03086343 , March 22, 2017.

Background: In the phase 3 double-blind SELECT-CHOICE study of patients (pts) with prior inadequate response (IR) or intolerance to biologic disease-modifying antirheumatic drugs (bDMARDs), upadacitinib (UPA) showed superiority to abatacept (ABA) in change from baseline in 28-joint Disease Activity Score using C-reactive protein (DAS28[CRP]) and in the proportion of pts achieving DAS28(CRP) <2.6 at Week 12. Objectives: To describe clinical responses in pts receiving UPA or ABA by number and mechanism of action of prior bDMARDs. Methods: 612 pts were randomized to once-daily UPA 15 mg or monthly intravenous ABA (<60 kg, 500 mg; 60–100 kg, 750 mg; >100 kg, 1000 mg). All pts continued background therapy with stable conventional synthetic DMARDs. From Week 12, pts who did not achieve ≥20% improvement in both tender and swollen joint counts vs baseline at 2 consecutive visits had background medication(s) adjusted or added. In this post hoc analysis, pts were grouped by the number and/or type of bDMARD received prior to enrollment: 1) lack of efficacy (LoE) to ≥1 tumor necrosis factor (TNF) inhibitor; 2) LoE to ≥1 interleukin-6 (IL-6) inhibitor; 3) intolerance to prior bDMARDs; 4) number of prior bDMARDs (1, 2, or ≥3). Mean change from baseline in DAS28(CRP) and DAS28(CRP) <2.6 and other clinical endpoints were evaluated at Weeks 12/24. Results: Most pts had LoE to ≥1 TNF inhibitor (536, 87.6%); 96 (15.7%) had LoE to an IL-6 inhibitor; 79 (12.9%) had intolerance to prior bDMARDs; 408 (66.7%), 134 (21.9%), and 64 (10.5%) had received 1, 2, or ≥3 prior bDMARDs, respectively. Mean change from baseline in DAS28(CRP) was generally greater with UPA vs ABA across the different pt subgroups at Weeks 12/24 (Figure 1). Across endpoints, regardless of prior bDMARD therapy (except in those who failed ≥3 prior bDMARDs), UPA and ABA demonstrated similar responses at Week 12 compared with those observed for the overall treatment groups, even with more stringent criteria such as ACR70 and Clinical Disease Activity Index (CDAI) ≤2.8 (Table 1. below) Responses at Week 24 followed a similar trend to those at Week 12 for DAS28(CRP) <2.6 and other endpoints (Table 1). The safety profile across subgroups was consistent with each respective treatment in the overall study population (data not shown). Table 1. Efficacy endpoints by prior bDMARD subgroup (Week 12 [top] and Week 24 [bottom]) a ACR20 ACR50 ACR70 DAS28(CRP ) ≤3.2 DAS28(CRP) <2.6 CDAI ≤10 CDAI ≤2.8 HAQ-DI MCID b LoE to ≥1 TNF inhibitor UPA 15 mg n=263 75.3 77.9 44.9 59.7 22.8 38.8 49.0 61.2 30.4 46.8 40.7 58.6 9.1 22.8 75.5 74.3 ABA n=273 64.5 72.9 33.7 48.4 13.2 24.9 27.5 46.5 12.5 29.7 33.7 49.8 2.2 12.5 65.2 66.3 LoE to ≥1 IL-6 inhibitor UPA 15 mg n=48 70.8 85.4 37.5 66.7 20.8 29.2 45.8 66.7 25.0 41.7 41.7 58.3 6.3 16.7 78.3 78.3 ABA n=48 77.1 79.2 41.7 56.3 22.9 27.1 25.0 43.8 14.6 29.2 27.1 52.1 2.1 10.4 75.0 75.0 Intolerance to prior bDMARDs UPA 15 mg n=47 83.0 76.6 53.2 57.4 17.0 27.7 53.2 57.4 31.9 29.8 44.7 44.7 8.5 14.9 80.0 73.3 ABA n=32 62.5 71.9 28.1 50.0 0.0 31.3 21.9 56.3 6.3 31.3 21.9 56.3 3.1 9.4 61.3 67.7 1 prior bDMARD UPA 15 mg n=206 77.2 81.1 51.9 63.1 21.8 38.8 52.4 66.0 32.5 47.6 41.7 61.2 9.2 20.9 79.6 76.6 ABA n=202 67.3 77.7 35.1 53.5 15.8 33.7 29.2 51.5 12.4 35.6 36.1 55.9 3.0 16.3 66.7 71.7 2 prior bDMARDs UPA 15 mg n=64 78.1 76.6 34.4 56.3 23.4 39.1 51.6 62.5 26.6 50.0 45.3 54.7 4.7 23.4 73.8 70.5 ABA n=70 64.3 64.3 28.6 42.9 4.3 11.4 27.1 41.4 11.4 24.3 28.6 44.3 1.4 8.6 55.7 55.7 ≥3 prior bDMARDs UPA 15 mg n=29 55.2 65.5 24.1 44.8 17.2 24.1 27.6 41.4 20.7 27.6 27.6 48.3 10.3 17.2 58.6 72.4 ABA n=35 65.7 71.4 40.0 40.0 20.0 17.1 28.6 37.1 20.0 20.0 37.1 40.0 2.9 8.6 77.1 74.3 a Missing information was imputed using NRI. b HAQ-DI MCID=reduction from baseline of ≥0.22 ACR20/50/70, 20/50/70% improvement in ACR criteria; HAQ-DI, Health Assessment Questionnaire-Disability Index Conclusion: Although sample sizes were small for some subgroups, treatment with UPA led to greater clinical responses vs ABA at Week 12, including in pts with LoE to TNF or IL-6 inhibitors, and those with IR or intolerance to 1, 2, or ≥3 prior bDMARDs. 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 Grant Kirkpatrick, MSc of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests: Andrea Rubbert-Roth Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Gilead, Janssen, Novartis, Roche, and Sanofi, Ricardo Xavier Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Boulos Haraoui Consultant of: AbbVie, Amgen, Eli Lilly, Gilead, MSD, Pfizer, Sandoz, and UCB, Herbert S.B. Baraf Consultant of: Gilead, Janssen, and UCB, Grant/research support from: AbbVie, Eli Lilly, Genentech, Gilead, and Janssen, Maureen Rischmueller Consultant of: AbbVie, Bristol-Myers Squibb, CSL Behring, Eli Lilly, Gilead, Janssen, Pfizer, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, and UCB, Naomi Martin 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, Jessica Suboticki Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, John Cush Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, and Novartis.

Background: Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management. Objectives: To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials. Design: Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis. Setting: Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions). Participants: Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs. Interventions: Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care. Main outcome measures: Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments. Results: Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p < 0.001]. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management n = 15 vs. standard care n = 11) and other adverse events (intensive management n = 114 vs. standard care n = 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial. Limitations: The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’. Conclusion: The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission. Future work: Further research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management. Trial registration: Current Controlled Trials ISRCTN70160382. Funding: This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.

Background: Upadacitinib (UPA), an oral Janus kinase inhibitor, in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), showed significant improvements in clinical and functional measures compared with placebo (PBO) up to 12 weeks (wks), in patients (pts) from China, Brazil, and South Korea with rheumatoid arthritis (RA) and prior inadequate response to csDMARDs (csDMARD-IR). 1 Objectives: To assess the efficacy and safety of UPA up to 64 wks (long-term extension; LTE) in csDMARD-IR pts with RA from China, Brazil, and South Korea. Methods: Pts were randomized to 12 wks of blinded treatment with UPA 15 mg once daily (QD) or PBO, in combination with csDMARDs. From Wk 12 onward, pts could continue to receive open-label UPA 15 mg QD. Efficacy endpoints were analyzed by original randomized treatment group sequences over 64 wks and included American College of Rheumatology (ACR) responses, and key remission and low disease activity measures. Non-responder imputation was used to handle missing data for binary endpoints. Treatment-emergent adverse events (TEAEs) per 100 patient-years (PY) were summarized for pts receiving ≥1 dose of UPA from baseline through to Wk 64. Results: Of 338 randomized pts who received ≥1 dose of study drug, 310 (91.7%) entered the LTE and 275 (81.4%) completed 64 wks of treatment. Among those initially randomized to UPA, the proportion of pts achieving 20%/50%/70% improvement in ACR criteria, and key remission and low disease activity measures increased over 64 wks of treatment (Figure 1). Improvements from baseline in the Health Assessment Questionnaire-Disability Index and pts’ assessment of pain were observed over 64 wks of UPA treatment (data not shown). By Wk 64, efficacy results for pts who switched from PBO to UPA at Wk 12 followed a similar trajectory to those originally randomized to UPA. The observed rate of serious infections was 8.1 events/100 PY. Herpes zoster events were mostly non-serious, involving only 1 or 2 dermatomes. Most cases of hepatic disorders were Grade 1 or 2 hepatic transaminase elevations. There was 1 case of venous thromboembolic event (VTE; concurrent pulmonary embolism and deep vein thrombosis [DVT] in a patient with a history of DVT) and 3 cases of malignancy. Adjudicated major adverse cardiovascular events (Table 1) occurred in 2 pts (1 with non-fatal myocardial infarction and 1 with non-fatal stroke) who had underlying risk factors for cardiovascular disease. There were no deaths, active tuberculosis, or renal dysfunction. Conclusion: UPA 15 mg was effective in treating the signs and symptoms of RA and in improving physical function over 64 wks with no new safety signals 1 in csDMARD-IR pts with RA from China, Brazil, and South Korea. References: [1]Zeng A, et al. Ann Rheum Dis 2020;79(Suppl 1):1016 [abstract SAT0160] Table 1. TEAEs at Wk 64 Event (E/100 PY ) UPA 15 mg (n=322; PY=334.5 ) Any AE 421.5 (399.8–444.1) Serious AE 19.1 (14.7–24.4) AE leading to discontinuation of study drug 9.0 (6.1–12.8) Deaths a 0 AEs of special interest Serious infection 8.1 (5.3–11.7) Opportunistic infection 0.9 (0.2–2.6) Herpes zoster 9.0 (6.1–12.8) Hepatic disorder 42.2 (35.5–49.7) Gastrointestinal perforation (adjudicated) 0.3 (0.0–1.7) Any malignancy (excluding NMSC) 0.6 (0.1–2.2) NMSC 0.3 (0.0–1.7) MACE (adjudicated) b 0.6 (0.1–2.2) VTE (adjudicated) c 0.3 (0.0–1.7) Anemia 11.1 (7.8–15.2) Neutropenia 11.7 (8.3–15.9) Lymphopenia 7.8 (5.1–11.4) CPK elevation 11.1 (7.8–15.2) a Including non-treatment-emergent deaths. b Defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. c Including DVT and pulmonary embolism. AE, adverse event; CPK, creatine phosphokinase; E, events; MACE, major adverse cardiovascular event; NMSC, non-melanoma skin cancer Acknowledgements: 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. Yanna Song, PhD, of AbbVie provided statistical support. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests: Xiaofeng Zeng: None declared, Dongbao Zhao: None declared, Sebastiao Radominski: None declared, MAURO KEISERMAN: None declared, Chang-Keun Lee: None declared, Naomi Martin Employee of: AbbVie employee and may own stock or options, Sebastian Meerwein Employee of: AbbVie employee and may own stock or options, Yunxia Sui Employee of: AbbVie employee and may own stock or options, Won Park: None declared