Improvement in Patient-Reported Outcomes in Patients with Psoriatic Arthritis Treated with Upadacitinib Versus Placebo or Adalimumab: Results from SELECT-PsA 1

Introduction: The aim of this work is to assess the effect of upadacitinib versus adalimumab and placebo on patient-reported outcomes (PROs) in psoriatic arthritis (PsA) patients with inadequate responses to ≥ 1 non-biologic disease-modifying anti-rheumatic drugs (non-bDMARD-IR) in SELECT PsA-1. Methods: In this placebo- and active comparator, phase 3 randomized, controlled trial, patients received daily upadacitinib 15 or 30 mg, placebo, or adalimumab 40 mg every other week through 56 weeks. At week 24, placebo-assigned patients were rerandomized to upadacitinib 15 or 30 mg. PROs included Patient Global Assessment of Disease Activity (PtGA), pain, Health Assessment Questionnaire Disability Index (HAQ-DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Short Form 36 Health Survey (SF-36), EQ-5D-5L index score, Bath Ankylosing Spondylitis Disease Activity Index, morning stiffness, Self-Assessment of Psoriasis Symptoms, and Work Productivity and Activity Impairment. Mean changes from baseline in PROs, improvements ≥ minimum clinically important differences (MCID), scores ≥ normative values, and sustained clinically meaningful responses were compared between treatment groups. Results: At weeks 12 and 24, upadacitinib treatment resulted in improvements from baseline versus placebo across all PROs as well as improvements versus adalimumab in HAQ-DI and SF-36 Physical Component Summary score (nominal p < 0.05). Improvements in PtGA, pain, and HAQ-DI were reported as early as week 2. At week 12, significantly (nominal p < 0.05) more upadacitinib- versus placebo-treated patients reported improvements ≥ MCID across all PROs including seven SF-36 domains. The proportions of upadacitinib-treated patients reporting clinically meaningful improvements at week 12 were similar to or greater than with adalimumab and sustained through week 56. Significantly (nominal p < 0.05) more upadacitinib-treated (both doses) patients reported scores ≥ normative values at week 12 versus placebo, and scores were generally similar to or greater than adalimumab. Conclusions: Upadacitinib treatment provides rapid, sustained, and clinically meaningful improvements in PROs in non-bDMARD-IR patients with PsA. SELECT-PsA 1 ClinicalTrials.gov number, NCT03104400

Rapid and sustained improvements in health-related quality of life, fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus methotrexate over 1 year: results from the RAPID 1 randomized controlled trial

Abstract Introduction The objective of this study was to assess the impact of certolizumab pegol (CZP) treatment on health-related quality of life (HRQoL), fatigue and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA). Methods Patients with active RA (N = 982) were randomized 2:2:1 to subcutaneous CZP (400 mg at weeks 0, 2 and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo (PBO) plus MTX. PRO assessments included HRQoL, fatigue, physical function, arthritis pain and disease activity. Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance (ANCOVA) applying last observation carried forward (LOCF) imputation. The proportion of patients achieving clinically meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal. The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation. Results Patients treated with CZP plus MTX reported significant (P < 0.001), clinically meaningful improvements in HRQoL at the first assessment (week 12); reductions in fatigue, disease activity and pain and improvements in physical function were reported at week 1. In particular, CZP-treated patients reported improvements in mental health. Mean changes from baseline in the SF-36 Mental Component Summary (MCS) at week 52 for CZP 200 mg and 400 mg plus MTX, and PBO plus MTX were 6.4, 6.4 and 2.1, respectively (P < 0.001). In addition, mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms. Improvements in all PROs were sustained. Similar benefits were reported with both CZP doses. Changes in SF-36 MCS scores had the lowest correlation with disease activity scores (DAS28) and American College of Rheumatology 20% improvement (ACR20) response rates, while improvements in pain showed the highest correlation. Conclusions Treatment with CZP plus MTX resulted in rapid and sustained improvements in all PROs, indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis. Trial Registration ClinicalTrials.gov NCT00152386

Development of a new radiolabel (lead-203) and new chelating agents for labeling monoclonal anntibodies for imaging

High liver uptake and slow body clearance presently limit the usefulness of /sup 111/In labeled antibodies for tumor imaging. We have investigated /sup 203/Pb as an alternate and better antibody label. The DTPA and cyclohexyl EDTA (CDTA) conjugates of an anticolon carcinoma antibody, 17-1A were labeled (bicyclic anhydride method) with /sup 203/Pb and /sup 111/In with 60 and 90% labeling yields, respectively. The biodistribution of /sup 203/Pb-17-1A conjugates was compared with the corresponding /sup 111/In-labeled preparations and with /sup 203/Pb-DTPA, /sup 203/Pb-nitrate and nonrelevant antibody controls in normal and human tumor (SW948) xenografted nude mice at 24, and 96 hr. Lead-203-labeled CDTA and DTPA antibody conjugates gave similar in vivo distributions. Even though the lead bound to these chelate-antibody conjugates was more labile in serum and in vivo, compared to indium, it cleared much faster from the liver and the whole body. A new series of chelating agents based on the incorporation of a trans-1,2- diaminocyclohexane moiety into the carbon backbone of polyaminocarboxylates is being synthesized. These are expected to provide stronger complexing ability for lead and produce greater in vivo stability. These ligands are also expected to be superior to EDTA and DTPA for labeling antibodies with other radiometals, including indium. 32 refs., 3 tabs

Achieving minimal disease activity in psoriatic arthritis predicts meaningful improvements in patients’ health-related quality of life and productivity

Background Although psoriatic arthritis is complex and involves multiple domains, recent advances in treatments have made remission or near-remission of most symptoms a potentially achievable goal for many patients. We sought to evaluate whether achieving minimal disease activity (MDA) criteria represented meaningful improvement from the patient perspective. Methods Data were combined from two randomized, multinational, 24 week clinical studies of ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, in biological drug-naïve or experienced adults. MDA required 5 of 7 of: tender joint count ≤1; swollen joint count ≤1; Psoriasis Area and Severity Index total score ≤ 1 or body surface area ≤ 3%; patient’s assessment of pain visual analogue scale (VAS) ≤15; patient’s global assessment of disease activity VAS ≤20; Health Assessment Questionnaire Disability Index ≤0.5; and tender entheseal points ≤ 1. MDA responders and non-responders were compared for mean change from baseline on the 36-Item Short Form Health Survey (SF-36), European Quality of Life 5 Dimension 5 Level Health Questionnaire (EQ-5D-5 L); EQ-5D-5 L VAS; and Work Productivity and Activity Impairment–Specific Health Problem (WPAI-SHP) questionnaire. Results MDA responders had significantly greater improvements versus non-responders in each SF-36 domain and in the SF-36 physical summary score; improvements were also greater in the EQ-5D-5 L and EQ-5D-5 L VAS, and in 3 of the 4 WPAI-SHP domains. MDA responders were more likely to achieve minimal clinically important differences than non-responders. Conclusion These findings support MDA response as being strongly associated with achieving improved disease status based on measures of patient reported health-related quality of life and productivity. Trial registration SPIRIT-P1, NCT01695239, First Posted: September 27, 2012; and SPIRIT-P2, NCT02349295, First Posted: January 28, 2015

A survey of cost-sensitive decision tree induction algorithms

The past decade has seen a significant interest on the problem of inducing decision trees that take account of costs of misclassification and costs of acquiring the features used for decision making. This survey identifies over 50 algorithms including approaches that are direct adaptations of accuracy based methods, use genetic algorithms, use anytime methods and utilize boosting and bagging. The survey brings together these different studies and novel approaches to cost-sensitive decision tree learning, provides a useful taxonomy, a historical timeline of how the field has developed and should provide a useful reference point for future research in this field

Explicit guidance of drag-modulated aeroassisted transfer between elliptical orbits

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/77072/1/AIAA-20103-582.pd

Adalimumab for long-term treatment of psoriatic arthritis: 2-year data from the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT)

Objective: To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA). Methods: Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n = 245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study. Results: After 24 weeks of double- blind treatment, the mean change in mTSS was -20.2 for the adalimumab group (N = 144) and 1.0 for the placebo group (N = 152; p20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment. Conclusions: The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk-benefit profile in patients with PsA

Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial

To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo controlled, 24-week trial