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Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. This study evaluated the efficacy and safety of tofacitinib 5 mg twice daily monotherapy after methotrexate withdrawal. Methods: OPAL Balance was an open-label, long-term extension study of tofacitinib in patients with psoriatic arthritis who participated in the OPAL Broaden and OPAL Beyond phase 3 studies. This 12-month, randomised, double-blind, placebo-controlled, methotrexate withdrawal substudy (50 centres, 14 countries) included patients from OPAL Balance who completed tofacitinib treatment for 24 months or more (≥3 months' stable tofacitinib 5 mg twice daily) and were receiving methotrexate (7·5–20 mg/week). Patients were blindly randomised (1:1) using interactive response technology and received open-label tofacitinib 5 mg twice daily with either placebo (tofacitinib 5 mg twice daily plus placebo group) or continued methotrexate (tofacitinib 5 mg twice daily plus methotrexate group). Patients were masked to placebo or methotrexate, with identical capsules used. Coprimary endpoints were changes from substudy baseline in psoriatic arthritis disease activity score (PASDAS) and health assessment questionnaire-disability index (HAQ-DI) at month 6 in all randomised patients with one or more substudy drug dose. Safety was assessed throughout. No specific statistical hypothesis (either superiority or non-inferiority) was tested. The study (OPAL Balance) is registered with ClinicalTrials.gov ( NCT01976364) and is complete. Findings: Between Oct 30, 2017, and May 20, 2019, 180 patients from OPAL Balance who were eligible for the substudy were randomly assigned to treatment (90 patients received tofacitinib 5 mg twice daily plus placebo and 89 patients assigned to tofacitinib plus methotrexate; one patient was not treated because of randomisation error). At month 6, least squares mean (LSM) changes in PASDAS were 0·23 (SE 0·08) for tofacitinib 5 mg twice daily plus placebo and 0·14 (0·08) for tofacitinib 5 mg twice daily plus methotrexate (treatment difference LSM 0·09 [95% CI –0·13 to 0·31]), and changes in HAQ-DI were 0·04 (0·03) and 0·02 (0·03), respectively (treatment difference 0·03 [–0·05 to 0·10]). Rates of adverse events, discontinuations because of adverse events, adverse events of special interest, and laboratory changes were generally similar between treatment groups, although liver enzyme elevations were more common with tofacitinib 5 mg twice daily plus methotrexate than tofacitinib 5 mg twice daily plus placebo. Flares of worsening symptoms was reported in one (1%) of 90 patients in the tofacitinib 5 mg twice daily plus placebo group (recorded as psoriatic arthropathy). Interpretation: Some patients with psoriatic arthritis who are stable on tofacitinib 5 mg twice daily with background methotrexate might be able to discontinue methotrexate without clinically meaningful changes in disease activity and safety.

Background: There is evidence that patients and physicians are frequently misaligned in their perspectives on psoriatic arthritis (PsA) treatment priorities, which may be associated with increased disease activity, greater disability, and poorer health-related quality of life of PsA patients. Objective: To identify factors associated with patient–physician misalignment in satisfaction with PsA disease control. Methods: In a cross-sectional survey of physicians and their patients with PsA from the United States and Europe, satisfaction with disease control was examined and classified as satisfied, neutral, or dissatisfied. Bivariate and multivariate regression analyses explored alignment in satisfaction between physicians and patients. Results: There were 656 PsA patient–physician pairs included in the analysis. Misalignment occurred in 20.6% of cases. Greater disease impact, worse physician-reported disease severity, and lower patient-reported involvement in treatment decisions were associated with misalignment. Conclusion: Greater patient–physician engagement may improve satisfaction, alignment, and outcomes in PsA disease control.

Psoriatic arthritis (PsA) is a chronic progressive inflammatory condition associated with significant direct and indirect costs. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Economic evaluations, alongside clinical data, help inform papers and formulary decisions in the United States.To evaluate outcomes and costs of including tofacitinib in treatment strategies for PsA from a third-party U.S. payer perspective, using a health economic model.A decision tree model was developed to evaluate treatment sequences (up to 4 lines of advanced PsA therapy) with or without tofacitinib. Patients included in the model had active PsA and a previous inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drug (csDMARD) or tumor necrosis factor inhibitor (TNFi) therapy. The analysis time horizon was 2 years; decision points for continuing/switching treatments occurred quarterly, based on clinical response (assessed using the primary rheumatoid measure of efficacy, American College of Rheumatology [ACR]20 response only) and adverse drug reactions (ADRs). Costs included those related to ADRs and drug acquisition, monitoring, and administration. Other endpoints of PsA, such as assessment of enthesitis and dactylitis, were not integrated into the model.Treatment strategies including tofacitinib were associated with cost savings versus strategies without tofacitinib across all modeled scenarios, with an estimated 2-year cost saving of up to $8,454,858, based on 1 million insurants. Similarly, costs per member per month and per ACR20 responder were lower for sequences including tofacitinib versus sequences without. These savings arose because of lower ADR and drug acquisition/administration costs for sequences including tofacitinib. Deterministic sensitivity analyses showed these results to be robust.This analysis suggests that including tofacitinib in the treatment of active PsA in csDMARD-IR or TNFi-IR patients is a cost-saving alternative to sequences without tofacitinib, potentially reducing costs for PsA advanced therapies by up to $8.4 million over 2 years for payers insuring 1 million individuals.This work was sponsored by Pfizer Inc. Bungey is an employee of Decision Resources Group, which received financial support from Pfizer Inc to develop the treatment-cost model used in the development of this manuscript. Chang-Douglass was an employee of Decision Resources Group at the time of the analysis. During development of this publication, Chang-Douglass started a role at the National Institute for Health and Care Excellence (NICE). The publication only reflects her views and does not reflect the views of NICE. Hsu, Cappelleri, Young, and Woolcott are employees of Pfizer Inc and own stock or stock options in Pfizer Inc. The data reported in this manuscript have been previously presented at the American College of Rheumatology Annual Scientific Meeting; October 19-24, 2018; Chicago, IL, and the AMCP Annual Meeting and Expo; March 25-28, 2019; San Diego, CA.

Objective Qualitative research exploring patient preferences regarding the mode of treatment administration for psoriatic arthritis (PsA) is limited. We report patient preferences and their reasons across PsA treatment modes. Methods In this global, cross-sectional, qualitative study, interviews were conducted with adult patients with PsA in Brazil, France, Germany, Italy, Spain, the UK, and the US. Patients were currently taking a disease-modifying antirheumatic drug (DMARD). Patients indicated the order and strength of preference (0-100; 100 = strongest) across four modes of treatment administration: oral (once daily), self-injection (weekly), clinic injection (weekly), and infusion (monthly); reasons for preferences were qualitatively assessed. Descriptive statistics were reported. Fisher's exact tests and t-tests were conducted for treatment mode outcomes. Results Overall, 85 patients were interviewed (female, 60.0%; mean age, 49.8 years). First-choice ranking (%) and mean [standard deviation] preference points were: oral (49.4%; 43.9 [31.9]); self-injection (34.1%; 32.4 [24.8]); infusion (15.3%; 14.5 [20.0]); clinic injection (1.2%; 9.2 [10.0]). Of 48 (56.5%) patients with a strong first-choice preference (ie point allocation ≥60), 66.7% chose oral administration. Self-injection was most often selected as second choice (51.8%), clinic injection as third (49.4%), and infusion as fourth (47.1%). Oral administration was the first-choice preference in the US (88.0% vs 38.0% in Europe). The most commonly reported reason for oral administration as the first choice was speed and ease of administration (76.2%); for self-injection, this was convenience (75.9%). The most commonly reported reason for avoiding oral administration was concern about possible drug interactions (63.6%); for self-injection, this was a dislike of needles or the injection process (66.7%). Conclusion Patients with PsA preferred oral treatment administration, followed by self-injection; convenience factors were common reasons for these preferences. Overall, 43.5% of patients did not feel strongly about their first-choice preference and may benefit from discussions with healthcare professionals about PsA treatment administration options.

Introduction Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). We report the interim safety, tolerability, and efficacy of tofacitinib in PsA patients in OPAL Balance, a 3-year, open-label, long-term extension study (data cut-off: August 2017; database not locked, data may change). Methods Eligible patients from two phase (P) 3 (P3) tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered OPAL Balance ≤ 3 months after completing the P3 study or discontinuing for reasons other than study-drug-related adverse events (AEs). Patients received open-label tofacitinib 5 mg twice daily (BID), with adjustments to 10 mg BID permitted post-month (M) 1. Certain concomitant conventional synthetic disease-modifying antirheumatic drugs were allowed. Primary endpoints were incidence/severity of AEs and laboratory abnormalities, and changes from baseline in laboratory parameters (reported up to M36 and M30, respectively). Efficacy (clinical/patient-reported outcomes) was reported through M30. Results A total of 686 patients were treated; at data cut-off, 68.2% remained in the study. Mean (range) treatment duration was 641 (1–1032) days; total treatment duration was 1153.2 patient-years. By M36, 79.6, 13.8, and 8.6% of patients reported AEs, serious AEs, and discontinuations due to AEs, respectively. Five deaths occurred; one within the risk period (incidence rate [IR; patients with events/100 patient-years] 0.1). IRs for AEs of special interest were: all (non-serious and serious) herpes zoster, 1.7; serious infections, 0.9; opportunistic infections, 0.3 (all disseminated/multi-dermatomal herpes zoster); malignancies excluding non-melanoma skin cancer (NMSC), 0.8; NMSC, 1.0; major adverse cardiovascular events, 0.3; pulmonary embolisms, 0.1; and arterial thromboembolisms, 0.4. No patients had deep vein thrombosis. Alanine aminotransferase and aspartate aminotransferase levels were elevated ≥ 3-fold the upper limit of normal in 4.0 and 2.2% of patients, respectively. Changes in laboratory parameters were generally stable over time, although lymphocyte counts decreased slightly. Efficacy was maintained through M30. Conclusions In this interim analysis of OPAL Balance, tofacitinib safety and efficacy in patients with PsA appeared to be consistent with those of the P3 studies. Efficacy was maintained over time. Trial Registration ClinicalTrials.gov identifier: NCT01976364. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00209-4) contains supplementary material, which is available to authorized users., Plain Language Summary In many countries, tofacitinib is an approved medicine that can be used to treat psoriatic arthritis (PsA). In the study reported here (OPAL Balance), adult patients with PsA took tofacitinib for up to 3 years. We report a planned interim analysis, i.e., an analysis of information collected before the study finished. This early information suggests that the safety of tofacitinib, and how well it improved symptoms and quality of life (efficacy), was similar in this long study as in shorter studies. Information from the finished study will be reported later. OPAL Balance started on 17 February 2014. This interim analysis includes information collected by 31 August 2017. Before joining, patients had finished a 6-month or 12-month tofacitinib study (OPAL Broaden or OPAL Beyond). Patients in OPAL Balance took a 5 mg tofacitinib pill twice a day, but if PsA symptoms did not improve after 1 month, they could take a 10 mg pill twice a day. They could also take other medicines (including methotrexate or corticosteroids). Of the 686 patients who took tofacitinib, 546 (80%) experienced side effects over 3 years. These were considered serious for 95 patients (14%) and caused 59 patients (9%) to leave the study. Five patients died from causes not related to tofacitinib. Known tofacitinib side effects, including shingles (herpes zoster), serious infections (needing hospitalization), infections in patients with weakened immune systems, cancer, heart (cardiovascular) problems, and vein blockages (embolisms), were each reported by fewer than 20 patients. Most blood test results and tofacitinib efficacy were stable over 2.5 years. Electronic Supplementary Material The online version of this article (10.1007/s40744-020-00209-4) contains supplementary material, which is available to authorized users.

Summary Background Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma. Methods We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment. Findings Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status. Interpretation While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options. Funding None.

Background In psoriatic arthritis (PsA), further understanding of the relationships between clinical measures and patient-reported outcomes (PROs) is needed. This post hoc analysis evaluated associations between minimal disease activity (MDA) as a continuous outcome (termed ScoreMDA) or Psoriatic Arthritis Disease Activity Score (PASDAS) with selected PROs not included in the composite measures. Methods Data from two phase 3 studies of tofacitinib in PsA (OPAL Broaden [NCT01877668; N = 422]; OPAL Beyond [NCT01882439; N = 394]) were included. MDA (binary outcome) was defined as meeting ≥5/7 criteria. For ScoreMDA, each criterion was assigned a value (1 = true; 0 = false; score range, 0–7; scores ≥5 indicated MDA). For PASDAS (score range, 0–10), higher scores indicated worse disease activity. PROs analyzed included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Patient’s Assessment of Arthritis Pain visual analog scale (Pain VAS), and EuroQoL-Five Dimensions-Three Level Health Questionnaire visual analog scale (EQ-5D-3L VAS) and utility index. Relationships were evaluated using repeated measures regression models. Results Similar, approximately linear relationships were confirmed between PASDAS or ScoreMDA and PROs in both studies. In OPAL Broaden and OPAL Beyond, a one-point difference in PASDAS was associated with clinically relevant differences in PROs, including EQ-5D-3L VAS (− 6.7 mm, − 6.9 mm), Pain VAS (9.9 mm, 10.7 mm), and FACIT-F (− 2.8, − 3.3). A one-point difference in ScoreMDA was associated with clinically relevant differences in PROs, including EQ-5D-3L VAS (5.0 mm, 5.5 mm) and FACIT-F (1.9, 2.7) in OPAL Broaden and OPAL Beyond, respectively. Conclusions Linear associations between PASDAS or ScoreMDA and PROs provide interpretable and quantifiable metrics between composite clinical measures and PROs, highlighting the importance of these measures in understanding the relevance of treat-to-target goals in PsA. Trial registration ClinicalTrials.gov, NCT01877668. Registered on June 12, 2013. ClinicalTrials.gov, NCT01882439. Registered on June 18, 2013

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis. Here we report the final analysis of Oral Psoriatic Arthritis Trial (OPAL) Balance, a 36-month long-term extension study, with a 12-month methotrexate withdrawal substudy, that assessed tofacitinib safety, tolerability, and efficacy in patients with active psoriatic arthritis. Methods For this open-label, long-term extension study, which was run at 124 centres in 16 countries, eligible patients had participated in the OPAL Broaden or OPAL Beyond phase 3 studies. Patients could enter OPAL Balance up to 3 months after completing one of the qualifying studies or discontinuing for reasons other than an adverse event related to study drug. In OPAL Balance, patients received open-label tofacitinib 5 mg twice daily, with increases to 10 mg twice daily for inadequate symptom control allowed from month 1, and reductions to 5 mg twice daily allowed thereafter for safety. Specific conventional synthetic disease-modifying antirheumatic drugs could be continued concomitantly. The primary endpoints were incidence and severity of adverse events, the incidence of laboratory abnormalities, and changes from baseline in laboratory parameters. Participants who were eligible could enter the randomised, double-blind, methotrexate withdrawal substudy (open-label tofacitinib 5 mg twice daily plus either masked placebo or masked methotrexate); safety data from which are included here (up to month 48). Efficacy was reported up to month 36 (substudy data excluded). The risk period for safety outcomes was the time from treatment exposure to the last dose plus 28 days or date of last observation. OPAL Balance is registered with ClinicalTrials.gov (NCT01976364) and is now complete. Findings Between Feb 17, 2014, and March 28, 2016, 686 patients were enrolled and given tofacitinib 5 mg or 10 mg twice daily (179 patients were treated in the substudy and 453 [66%] of 686 completed the long-term extension study or substudy; mean treatment duration 794·6 days [SD 329·2] in long-term extension study, 879·0 days [396·6] in long-term extension study plus substudy). The mean age of participants in the all tofacitinib group was 48·8 years (SD 11·8) and 370 (54%) of 686 participants were female. Up to month 48, 574 (84%) of 686 participants reported all-cause adverse events, 115 (17%) reported serious adverse events, and 78 (11%) discontinued due to an adverse event. Six patients died, one within the risk period (incidence of 0·1 patients with events [95% CI 0·0–0·3] per 100 person-years). The incidences of adverse events of special interest, reported as number of patients with events per 100 person-years, included: 1·7 (1·2–2·5) for herpes zoster (non-serious and serious); 1·0 (0·6–1·6) for serious infections; 0·4 (0·1–0·8) for opportunistic infections; 0·7 (0·4–1·2) for malignancies (excluding non-melanoma skin cancer [NMSC]); 0·9 (0·5–1·5) for NMSC; 0·2 (0·1–0·6) for major adverse cardiovascular events; 0·1 (0·0–0·3) for pulmonary embolism; and 0·4 (0·1–0·8) for arterial thromboembolism. No deep vein thromboses occurred. Laboratory parameter changes were as expected with treatment. Efficacy was sustained up to month 36. Interpretation This analysis supports the long-term safety (up to 48 months) and efficacy (up to 36 months) of tofacitinib in patients with psoriatic arthritis, which were consistent with previous phase 3 studies.

Additional file 1 : Table S1. PROs included in the analysis. Table listing PROs and their descriptions included in the analysis of ScoreMDA and PASDAS.

Introduction Most patient-reported outcome (PRO) instruments that measure atopic dermatitis (AD) symptoms do not have sufficient documented evidence of content validity to satisfy regulatory agency guidance for inclusion in product-labelling claims in the USA or Europe. The objective of this study was to develop a PRO instrument in accordance with regulatory agency guidance to assess daily AD symptoms during the course of therapy and to establish its content validity and psychometric properties. Methods The Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD) daily diary was developed based on qualitative interviews with US adolescents and adults with mild-to-severe AD. Content validity, test–retest reliability, internal consistency reliability, clinically important difference, clinically important responder, convergent validity, and known-group validity were evaluated using correlational and regression methods from phase 2b data from US adults with moderate-to-severe AD who were treated with abrocitinib. Results Patient interviews conducted with US adolescents and adults with mild-to-severe AD identified 11 relevant symptoms (itch, dryness, redness, flaking, discolouration, pain, bleeding, cracking, bumps, swelling, and weeping/oozing) for inclusion in the PSAAD instrument. All PSAAD psychometric parameters were acceptable based on phase 2b data from US adults with moderate-to-severe AD. Convergent validity and known-group validity were confirmed by significant correlations between PSAAD and six other PRO measures (r = 0.24–0.91, all p ≤ 0.01) and Dermatology Life Quality Index category (p ≤ 0.0001), respectively. Conclusions Evidence supports the PSAAD instrument validity, reliability, responsiveness and definitions of clinically important changes/differences for adults with moderate-to-severe AD. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-020-00474-9.

ObjectiveTo describe the efficacy of tofacitinib in reducing pain in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) in a post-hoc analysis of randomised controlled trials.MethodsData were collected from patients in seven tofacitinib studies: six phase III (four RA, two PsA) and one phase II study (AS), and grouped into five analysis populations based on rheumatic disease diagnosis and category of prior inadequate response (IR) to treatment: conventional synthetic disease-modifying antirheumatic drugs-IR (RA and PsA), tumour necrosis factor inhibitors-IR (RA and PsA), or non-steroidal anti-inflammatory drugs-IR (AS). Only patients who received tofacitinib 5 or 10 mg twice daily or placebo were included. Pain assessments included: Patient’s Assessment of Arthritis Pain, Short-Form Health Survey 36v2 Question (Q)7 and Bodily Pain domain, Ankylosing Spondylitis Quality of Life Q9 and Q14, EuroQol Five Dimensions Pain/Discomfort dimension and Bath Ankylosing Spondylitis Disease Activity Index Q2 and Q3. Data were reported to month 6 (placebo to month 3) in the RA and PsA populations, and week 12 (tofacitinib and placebo) in the AS population.ResultsOverall, 3330 patients were included in this analysis. In the RA and PsA populations, pain improvements in tofacitinib-treated patients compared with placebo were observed at the earliest time point assessed and at month 3 (maintained to month 6). In the AS population, pain improvements compared with placebo were observed at week 12.ConclusionTofacitinib was associated with rapid and sustained improvements across multiple pain measures in patients with inflammatory rheumatic musculoskeletal diseases.

// Ming Yin 1, 6 , Petros Grivas 2, 7 , Hamid Emamekhoo 3 , Prateek Mendiratta 2 , Siraj Ali 4 , JoAnn Hsu 5 , Monali Vasekar 1 , Joseph J. Drabick 1 , Sumanta Pal 5 and Monika Joshi 1 1 Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA 2 Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 3 Department of Medicine, Division of Hematology-Oncology, University of Wisconsin Carbone Cancer Center, WI, USA 4 Foundation Medicine, Cambridge, MA, USA 5 Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA 6 Department of Medicine, Division of Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 7 Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA Correspondence to: Monika Joshi, email: mjoshi@pennstatehealth.psu.edu Keywords: biomarkers; prognosis; bladder cancer; genomic alterations; next generation sequencing Received: November 30, 2017 Accepted: March 02, 2018 Published: March 30, 2018 ABSTRACT Background: Mutations of DNA repair genes, e.g. ATM/RB1 , are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs. Results: In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126). Materials and Methods: Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS). Conclusions: ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.

Background Psoriasis impairs health-related quality of life (HRQoL). Objective To improve understanding of flare burden in patients with moderate to severe psoriasis. Methods A retrospective, cross-sectional study comparing data in U.S. patients with and without psoriasis flares. Physicians identified flaring patients as those not in remission, or in remission < 12 weeks, with worsening/unstable disease progression. Results Overall health status (EQ-5D-3L) was reduced in flaring versus matched non-flaring patients ( P = .001); this difference was clinically meaningful (> 0.074 difference in absolute value). Reduced HRQoL and activity impairment, measured by Dermatology Life Quality Index ( P = .0178) and Work Productivity and Activity Impairment Questionnaire ( P = .0002), respectively, were observed in flaring versus non-flaring patients. Anxiety was associated with flaring ( P = .0139). Flaring patients were less satisfied with treatment effectiveness than non-flaring patients ( P < .0001). The flaring group experienced a median of two flares over 12 months. Conclusion Flares are associated with reduced health status and HRQoL and lower treatment satisfaction.

Background IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1 h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD). Methods In this open-label study, patients underwent 6 weeks of conversion to IPX066 from their prior controlled-release (CR) ± immediate-release (IR) CD-LD therapy and 6 months of maintenance (with an additional 6 months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance. Results Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5 times/day compared with 2.6 times/day for CR plus 4.6 times/day for IR previously (and 4.7 times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ≥ 43.8% of patients were much or very much improved from their previous treatment, and ≥ 68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies. Conclusions These results suggest that advanced PD patients using CR CD-LD ± IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit. Trial registration: Clinicaltrials.gov NCT01411137 .

Background:Treatment effect on pain is a priority for patients (pts) with psoriatic arthritis (PsA) and physicians. As pain is multidimensional, there is growing interest to understand the mechanisms of pain relief during treatment. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Previous analyses showed that the effect of tofacitinib on pain in pts with PsA was partially mediated through improvement of inflammation as assessed by C-reactive protein (CRP) and Swollen Joint Count (SJC). Additional potential inflammation-associated mediators that might contribute to tofacitinib’s effect on pain include enthesitis and skin disease.Objectives:To describe the interrelationship between pain, tofacitinib treatment and potential inflammatory-associated outcomes, using mediation modelling.Methods:Data from two Phase 3 studies (OPAL Broaden [NCT01877668]; OPAL Beyond [NCT01882439]) of pts with active PsA treated with tofacitinib 5 mg twice daily (BID) or placebo were used; pts were tumour necrosis factor inhibitor (TNFi)-naïve or had previous inadequate response to ≥1 TNFi. All pts were treated continuously with a single conventional synthetic DMARD. Analyses were completed using pooled and individual study data at Months 1 and 3 (using mean scores across visits). Mediation modelling seeks to explain mechanisms underlying observed relationships between independent and dependent variables via other variables (mediators). This initial model included: treatment as the independent (explanatory) binary variable (tofacitinib 5 mg BID vs placebo); pain, measured by Patient’s Assessment of Arthritis Pain (VAS, 0–100 mm), as the dependent (outcome) variable; mediators were: pt-reported Itch Severity Index (ISI); CRP; SJC; Psoriasis Area and Severity Index (PASI); and enthesitis, measured by Leeds Enthesitis Index (LEI) or Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). The final model was revised based on results of the initial model.Results:The initial model (N=329; pooled data) showed that tofacitinib treatment affects pain mainly indirectly via ISI, CRP, SJC, PASI and enthesitis (LEI), with 16.0% (p=0.53) attributable to the direct effect. The indirect effect via SJC (Conclusion:The majority of tofacitinib treatment effect on pain in pts with PsA is collectively mediated by itch, enthesitis and CRP, with itch being the main mediator of treatment effect (~37%), using mediation modelling analyses.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Eric Comeau of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Kurt de Vlam Grant/research support from: Celgene, Eli Lilly, Pfizer Inc, Consultant of: AbbVie, Eli Lilly, Galapagos, Johnson & Johnson, Novartis, Pfizer Inc, UCB, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph F. Merola Consultant of: Merck, AbbVie, Dermavant, Eli Lilly, Novartis, Janssen, UCB Pharma, Celgene, Sanofi, Regeneron, Arena, Sun Pharma, Biogen, Pfizer, EMD Sorono, Avotres and LEO Pharma, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau

Background:Depression/anxiety are common in RA pts. SF-36 MCS ≤38 can identify probable major depressive disorder and/or probable generalised anxiety disorder (pMDD/pGAD) in RA pts. Tofacitinib is an oral JAK inhibitor for the treatment of RA.Objectives:To assess pMDD/pGAD prevalence in the tofacitinib RA program and efficacy by baseline (BL) pMDD/pGAD status.Methods:Data from pts receiving tofacitinib, ADA, or PBO were pooled from 5 Phase (P)3 and 1 P3b/4 trials. Demographics/BL characteristics were reported by BL pMDD/pGAD (SF-36 MCS ≤38, presence; >38, absence). Month (M)3/6/9/12 SF-36 MCS change from BL (Δ) was estimated, and % with pMDD/pGAD reported. M3/6/12 efficacy outcomes compared tofacitinib-treated pts by BL pMDD/pGAD.Results:BL pMDD/pGAD was seen in 44.5% (tofacitinib 5 mg BID), 39.8% (tofacitinib 10 mg BID), 45.4% (ADA 40 mg Q2W) and 39.1% (PBO) of pts. pMDD/pGAD pts had higher BL CRP and worse disability, fatigue, pain and sleep vs pts without. SF-36 MCS increases were greater for tofacitinib vs PBO/ADA (Fig 1a). The % of pts with BL pMDD/pGAD who continued to have pMDD/pGAD reduced over time, and was generally lower for tofacitinib vs PBO/ADA (Fig 1b). Regardless of BL pMDD/pGAD, efficacy was generally similar for tofacitinib 5 mg BID (Table) and 10 mg BID.Conclusion:~40% of RA pts had BL pMDD/pGAD. SF-36 MCS improvements were greater for tofacitinib vs PBO/ADA. With tofacitinib, % of pts with SF-36 MCS ≤38 reduced by ~60% at M12. Tofacitinib efficacy was similar in pts with/without BL pMDD/pGAD. Limitations include using SF-36 MCS to identify probable rather than confirmed MDD or GAD. Future research using gold standard psychiatric interviews to validate use of SF-36 MCS ≤38 is needed.Table.M3/6/12 efficacy with tofacitinib 5 mg BID, by BL pMDD/pGADaSF-36 MCS ≤38SF-36 MCS >38OR (95% CI)P valueACR20 (%)b,cM355.157.90.89 (0.74, 1.08)0.2330M661.762.80.96 (0.79, 1.16)0.6511M1258.458.60.99 (0.80, 1.22)0.9279ACR50 (%)b,cM325.929.20.85 (0.70, 1.03)0.1022M636.038.00.92 (0.76, 1.11)0.3724M1233.834.30.98 (0.80, 1.20)0.8366ACR70 (%)b,cM310.111.00.91 (0.69, 1.18)0.4704M616.516.51.00 (0.79, 1.26)0.9901M1218.317.51.06 (0.83, 1.34)0.6560DAS28-4(ESR))b,cM35.47.40.72 (0.49, 1.05)0.0872M65.98.50.68 (0.49, 0.94)0.0199*M128.011.90.64 (0.47, 0.89)0.0073**ΔHAQ-DI, LS meanc,dSF-36 MCS ≤38SF-36 MCS >38Difference (95% CI)P valueM3-0.41-0.430.01 (-0.04, 0.06)0.6008M6-0.49-0.48-0.01 (-0.06, 0.04)0.6617M12-0.52-0.52-0.01 (-0.06, 0.05)0.8475*paBL pMDD/pGAD = SF-36 MCS ≤38;bLogistic regression fit;cFor PBO pts advancing to tofacitinib post-M3, only PBO data were included;dMixed-effects linear model fitΔ, change from baseline; ACR, American College of Rheumatology; BID, twice daily; BL, baseline; CI, confidence interval; DAS28-4(ESR), Disease Activity Score in 28 joints, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; M, month; MCS, Mental Component Summary score; OR, odds ratio; P, Phase; pGAD, probable generalised anxiety disorder; PBO, placebo; pMDD, probable major depressive disorder; pt, patient; RA, rheumatoid arthritis; SF-36, Short Form-36 health surveyAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Gustavo Citera Grant/research support from: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Consultant of: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Rakesh Jain Grant/research support from: Allergan, Eli Lilly, Lundbeck, Otsuka, Pfizer Inc, Shire and Takeda, Consultant of: Acadia, Alfasigma, Allergan, Eisai, Eli Lilly, Evidera, Impel, Janssen, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Osmotica, Otsuka, Pamlab, Pfizer Inc, Shire, Sunovion, Supernus, Takeda and Teva, Speakers bureau: Alkermes, Allergan, Eli Lilly, Janssen, Lundbeck, Merck, Neos Therapeutics, Neurocrine, Otsuka, Pamlab, Pfizer Inc, Shire, Sunovion, Takeda, Teva and Tris Pharmaceuticals, Fedra Irazoque-Palazuelos Consultant of: Bristol-Myers Squibb, Janssen, Pfizer Inc, Roche and UCB, Renato Guzman: None declared, Hugo Madariaga: None declared, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Karina Santana Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Abbas Ebrahim Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Dario Ponce de Leon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Psoriatic arthritis (PsA) is a chronic, systemic inflammatory disease; the onset of dermatologic symptoms often precedes rheumatic manifestations.1 Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. It has been shown that tofacitinib can improve dermatologic symptoms in patients (pts) with PsA.2,3 Objectives To investigate the efficacy of tofacitinib in improving additional dermatologic endpoints in adult pts with active PsA. Methods This analysis included data from 2 placebo (PBO)-controlled, double–blind, Phase 3 studies in pts with active PsA and an inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) who were tumour necrosis factor inhibitor (TNFi)-naive (OPAL Broaden [12 months; NCT01877668]; N=422)2 or had an IR to ≥1 TNFi (OPAL Beyond [6 months; NCT01882439]; N=394).3 Pts must have had active plaque psoriasis at screening only and were required to receive a stable dose of 1 csDMARD. Pts were randomised to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or PBO (advanced to tofacitinib 5 or 10 mg BID at Month [M]3). Percentage (%) change from baseline (BL) (Δ) in Psoriasis Area and Severity Index (PASI) total score,% of pts achieving ≥75% PASI improvement from BL (PASI75) stratified by BL PASI severity (>0 to ≤10, or >10), and ΔPatient’s Global Joint and Skin Assessment-Visual Analogue Scale Psoriasis question (PGJS–VAS Psoriasis) were measured at M1, 3, 6, and at M9 and 12 (OPAL Broaden only).% ΔPASI total score and PASI75 were measured only in pts with BL affected body surface area (BSA) ≥3% and PASI >0. Safety endpoints were also analysed. Results BL demographics were similar between treatment groups and studies. BL median PASI scores (pts with BL BSA ≥3% and PASI >0) ranged from 5.6 to 7.8 (OPAL Broaden) and 7.1 to 8.8 (OPAL Beyond). BL mean PGJS–VAS Psoriasis ranged from 51.0 to 54.8 (OPAL Broaden) and 53.5 to 58.9 (OPAL Beyond). At M1 and 3,% ΔPASI total score, PASI75 response rates in pts with mild or moderate/severe dermatologic symptoms at BL, and ΔPGJS–VAS Psoriasis were improved vs PBO in tofacitinib-treated pts; these improvements were maintained to M12 in OPAL Broaden and M6 in OPAL Beyond (Table). Similar effects were observed in adalimumab-treated pts vs PBO in OPAL Broaden across these endpoints. Serious adverse events (AEs) and discontinuations due to AEs were similar across treatment groups up to M6 in OPAL Beyond and M12 in OPAL Broaden. Conclusion In pts with PsA (TNFi-naive or TNFi-IR), tofacitinib improved dermatologic endpoints, and responses were maintained to the end of each study. Tofacitinib may provide a treatment option for pts with active PsA, including the dermatologic symptoms of PsA. References [1] Gladman DD, et al. Ann Rheum Dis2005;64:ii14-7. [2] Mease P, et al. N Engl J Med2017;377:1537-50. [3] Gladman D, et al. N Engl J Med2017;377:1525-36. Acknowledgement This study was sponsored by Pfizer Inc. Medical writing support was provided by Mark Bennett, PhD, of CMC Connect, a division of McCann Health Medical Communications Ltd, Manchester, UK, and was funded by Pfizer Inc. Disclosure of Interests Joseph F. Merola Consultant for: Biogen IDEC, Abbvie, Amgen, Eli Lilly and Company, Novartis, Pfizer, Janssen, UCB, Samumed, Celgene, Sanofi Regeneron, Merck, and GSK, Kim Papp Grant/research support from: AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, Astellas, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Can-Fite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Galderma, Genentech, Gilead, GlaxoSmithKline, InflaRx GmbH, Janssen, Kyowa Hakko Kirin, Leo, MedImmune, Merck (MSD), Merck Serono, Moberg Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant/Bausch Health, Consultant for: AbbVie, Akros, Amgen, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Can-Fite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Janssen, Kyowa Hakko Kirin, Leo, Meiji Seika Pharma, Merck (MSD), Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant/Bausch Health; honoraria: AbbVie, Akros, Amgen, Baxter, Boehringer Ingelheim, Celgene, Coherus, Eli Lilly, Forward Pharma, Galderma, Janssen, Kyowa Hakko Kirin, Merck (MSD), Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, PRCL Research, Sanofi-Aventis/Genzyme, Takeda, UCB, Valeant/Bausch Health; steering committee: AbbVie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen, Kyowa Hakko Kirin, Merck (MSD), Merck Serono, Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, Valeant/Bausch Health; advisory boards: AbbVie, Amgen, Astellas, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dow Pharma, Eli Lilly, Galderma, Janssen, Merck (MSD) Novartis, Pfizer, Regeneron, Sanofi-Aventis/Genzyme, UCB, Valeant/Bausch Health, Speakers bureau: AbbVie, Amgen, Astellas, Celgene, Eli Lilly, Galderma, Janssen, Kyowa Hakko Kirin, Leo, Merck (MSD), Novartis, Pfizer, Sanofi-Aventis/Genzyme, Valeant/Bausch Health; scientific officer: Akros, Anacor, Kyowa Hakko Kirin, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Jordi Gratacos-Masmitja Grant/research support from: Pfizer Inc, Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, Wolf-Henning Boehncke Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, Diamant Thaci Grant/research support from: AbbVie, Almirall, Amgen, Bio Skin, Biogen-Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chugai, Dermira, Dignity, Eli Lilly, Forward Pharma, GlaxoSmithKline, Janssen Cilag, Leo Pharma, Novartis, Pfizer, Regeneron, Roche, Sandoz-Hexal, Sanofi, and UCB, Consultant for: AbbVie, Almirall, Bristol-Myers Squibb, Celgene, Dignity, Galapagos, Leo Pharma, Lilly, Novartis, Pfizer, and UCB; honoraria: AbbVie, Almirall, Amgen, Bio Skin, Celgene, Dignity, Janssen, Leo Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Roche-Posay, Sandoz-Hexal, Sanofi, and USB; advisory board: AbbVie, Bio Skin, Bristol-Myers Squibb, Celgene, Dignity, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen Cilag, Leo Pharma, Morphosis, Novartis, Pfizer, Sandoz, Sanofi, and UCB, Daniela Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Pamela Young Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background To evaluate the measurement properties (e.g., content validity, reliability, and ability to detect change) of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale in patients with active psoriatic arthritis (PsA). Methods One-on-one semi-structured qualitative interviews with adult patients with active PsA evaluated the content validity of FACIT-Fatigue. Quantitative measurement properties were evaluated using data from phase III tofacitinib randomized controlled trials (RCTs) in PsA: OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439). Results Of 12 patients included in the qualitative study, 2 (17%) had mild, 8 (67%) had moderate, and 2 (17%) had severe PsA disease activity; 7 (58%) attributed fatigue to PsA, and 7 (58%) rated fatigue as important or extremely important. Most patients considered the FACIT-Fatigue items relevant to their PsA experience, and understood item content and response options as intended. In the psychometric analysis of RCT data, a second-order confirmatory factor model fit the data well (Bentler’s Comparative Fit Index ≥0.92). FACIT-Fatigue demonstrated good internal consistency (Cronbach’s coefficient α ≥ 0.90), test-retest reliability (Intraclass Correlation Coefficient ≥ 0.80) and a strong correlation with SF-36 Vitality (r > 0.80). A robust relationship between disease activity (based on Patient’s Global Assessment of Psoriasis and Arthritis) and FACIT-Fatigue was observed (effect sizes > 1.4), with clinically important difference for the FACIT-Fatigue total score estimated as 3.1 points, and the responder definition estimated as a 4-point improvement for FACIT-Fatigue total score. Conclusion Fatigue was confirmed to be an important symptom to patients with PsA, and FACIT-Fatigue was found to be a reliable and valid measure in this population. Electronic supplementary material The online version of this article (10.1186/s41687-019-0115-4) contains supplementary material, which is available to authorized users.

Excessive red cell dehydration contributes to the pathophysiology of sickle cell disease (SCD). The densest fraction of sickle red cells (with the highest corpuscular hemoglobin concentration) undergoes the most rapid polymerization of deoxy-hemoglobin S, leading to accelerated cell sickling and increased susceptibility to endothelial activation, red cell adhesion, and vaso-occlusion. Increasing red cell volume in order to decrease red cell density can thus serve as an adjunct therapeutic goal in SCD. Regulation of circulating mouse red cell volume and density is mediated largely by the Gardos channel, KCNN4, and the K-Cl cotransporters, KCC3 and KCC1. Whereas inhibition of the Gardos channel in subjects with sickle cell disease increased red cell volume, decreased red cell density, and improved other hematological indices in subjects with SCD, specific KCC inhibitors have not been available for testing. We therefore investigated the effect of genetic inactivation of KCC3 and KCC1 in the SAD mouse model of sickle red cell dehydration, finding decreased red cell density and improved hematological indices. We describe here generation of mice genetically deficient in the three major red cell volume regulatory gene products, KCNN4, KCC3, and KCC1 in C57BL6 non-sickle and SAD sickle backgrounds. We show that combined loss-of-function of all three gene products in SAD mice leads to incrementally increased MCV, decreased CHCM and % hyperchromic cells, decreased red cell density (phthalate method), increased resistance to hypo-osmotic lysis, and increased cell K content. The data show that combined genetic deletion of the Gardos channel and K-Cl cotransporters in a mouse SCD model decreases red cell density and improves several hematological parameters, supporting the strategy of combined pharmacological inhibition of these ion transport pathways in the adjunct treatment of human SCD.

Background Despite the advent of checkpoint inhibitors (CPIs) for advanced genitourinary (GU) cancers, existing studies suggest that durable complete responses are observed in fewer than 10% of patients. This study sought to evaluate the association between expectations of cure reported by patients with advanced GU cancers initiating immunotherapy and quality of life (QOL), anxiety and depression. Patient and methods A single-institution, cross-sectional survey study was conducted with patients preparing to receive CPIs for treatment of metastatic renal cell carcinoma (RCC), urothelial cancer (UC) and prostate cancer (PC). Patients were assessed prior to initiation of immunotherapy for expectations of cure (divided into four quartiles), quality of life (QOL; Functional Assessment of Chronic Illness Therapy-General [FACT-G]), and symptoms of anxiety and depression (PROMIS). Results Sixty patients were enrolled, with metastatic RCC, UC and PC comprising 63, 28 and 8% of the study population, respectively. Median age of the cohort was 65 (range, 31–91), and 68% were male; 33% received CPI in the first-line setting. Despite extensive counseling from oncologists regarding potential clinical outcomes with immunotherapy, a substantial proportion of patients (23%) harbored inaccurate expectations regarding the potential benefit of immunotherapy. Importantly, patients with accurate expectations of cure reported lower anxiety scores using the PROMIS-Anxiety inventory. No significant differences were found between expectations of cure and quality of life or depression, using the FACT-G and PROMIS-Depression inventories, respectively. Conclusion The current study found that a considerable proportion of patients with advanced GU cancers harbor inaccurate expectations concerning the potential benefit of immunotherapy. These results suggest that more effective counselling may mitigate patient anxiety, and potentially promote treatment satisfaction and adherence.

Background To evaluate the measurement properties (e.g. content validity, reliability and ability to detect change) of the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale in patients with active psoriatic arthritis (PsA). Methods One-on-one semi-structured qualitative interviews with adult patients with active PsA evaluated the content validity of FACIT-Fatigue. Quantitative measurement properties were evaluated using data from phase III tofacitinib randomized controlled trials (RCTs) in PsA: OPAL Broaden (NCT01877668) and OPAL Beyond (NCT01882439). Results Of 12 patients included in the qualitative study, 2 (17%) had mild, 8 (67%) had moderate, and 2 (17%) had severe PsA disease activity; 7 (58%) attributed fatigue to PsA, and 7 (58%) rated fatigue as important or extremely important. Most patients considered the FACIT-Fatigue items relevant to their PsA experience and understood item content and response options as intended. In the psychometric analysis of RCT data, a second-order confirmatory factor model fit the data well (Bentler’s Comparative Fit Index ≥0.92). FACIT-Fatigue demonstrated good internal consistency (Cronbach’s coefficient α ≥ 0.90), test-retest reliability (Intraclass Correlation Coefficient ≥ 0.80) and a strong correlation with SF-36 Vitality (r > 0.80). A robust relationship between disease activity (based on Patient’s Global Assessment of Psoriasis and Arthritis) and FACIT-Fatigue was observed (effect sizes > 1.4), with clinically important difference for the FACIT-Fatigue total score estimated as 3.1 points, and the responder definition estimated as a 4-point improvement for FACIT-Fatigue total score. Conclusion Fatigue was confirmed to be an important symptom to patients with PsA, and FACIT-Fatigue was found to be a reliable and valid measure in this population.

Appendix 3: Test/retest reliability of FACIT-Fatigue in patients with PsA. (DOCX 12.4 kb)

Appendix 2: Patients and methods [19, 21]. (DOCX 870 kb)

ObjectivesTofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). We evaluated patient-reported outcomes (PROs) in patients with PsA refractory to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR) and tumour necrosis factor inhibitor-naïve in a 12-month, phase III randomised controlled trial (OPAL Broaden [NCT01877668]).MethodsPatients (N=422) received tofacitinib 5 mg or 10 mg twice daily, adalimumab 40 mg subcutaneously every 2 weeks or placebo advancing to tofacitinib 5 mg or 10 mg twice daily at month 3. Least squares mean changes from baseline and percentages of patients reporting improvements ≥minimum clinically important differences (MCID); and scores ≥normative values in: Patient Global Assessment of disease activity (PtGA), Pain, Patient Global Joint and Skin Assessment (PGJS), Short Form-36 Health Survey version 2 (SF-36v2), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), EuroQol 5-Dimensions-3-level questionnaire (EQ-5D-3L) and Ankylosing Spondylitis Quality of Life (ASQoL) were determined. Nominal p values were cited without multiple comparison adjustments.ResultsAt month 3, PtGA, Pain, PGJS, FACIT-Fatigue, EQ-5D-3L, ASQoL and SF-36v2 Physical Component Summary (PCS), physical functioning (PF), bodily pain (BP) and vitality domain scores exceeded placebo with both tofacitinib doses (p≤0.05); SF-36v2 social functioning with 5 mg twice daily (p≤0.05). Percentages reporting improvements ≥MCID in PtGA, Pain, PGJS, FACIT-Fatigue, ASQoL and SF-36v2 PCS, PF, BP and general health scores exceeded placebo with both tofacitinib doses (p≤0.05) and were similar with adalimumab.ConclusioncsDMARD-IR patients with active PsA reported statistically and clinically meaningful improvements in PROs with tofacitinib compared with placebo at Month 3.

Appendix 1: The FACIT-Fatigue scale. (DOCX 255 kb)

Levodopa (LD) combined with a peripheral inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa (CD), continues to be the most effective treatment of Parkinson disease and is well tolerated at all stages of the disease.1–3 Immediate-release formulations of LD require frequent dosing because of the short half-life of LD and result in marked fluctuations in the LD plasma concentrations. The pulsatile LD profile results in fluctuations in the clinical response such as on-off and wearing off and may play an important role in LD-induced dyskinesia.4,5 Intravenous and intraduodenal infusion of LD provide more stable plasma concentrations and can result in a smoother clinical response in patients with motor fluctuations.6–8 However, intravenous infusion is not practical for long-term therapy, and duodenal infusion requires surgery and may only be appropriate for the most severe patients. An oral product that provides more consistent LD absorption and more stable plasma concentrations would address a major unmet clinical need to enhance efficacy and reduce or prevent motor oscillations and drug-induced dyskinesias.9 However, current sustained-release formulations of CD-LD and the addition of a cathechol-O-methyltransferase inhibitor (eg, entacapone) to immediate-release CD-LD have been of limited value.10,11 Controlled-release formulations have been associated with erratic absorption, variable plasma concentrations, and a delayed onset of effect.12,13 Carbidopa-LD products containing entacapone have been associated with a shorter time to onset of dyskinesia and increased frequency of dyskinesia compared with CD-LD products.14 IPX066 (RYTARY [CD and LD]; Impax Laboratories, Inc, Hayward, Calif) is an extended-release multiparticulate capsule formulation of CD-LD that has demonstrated efficacy in patients with early and advanced Parkinson disease.15,16 IPX066 capsules are available in a 1:4 ratio of CD:LD in 4 CD-LD dose strengths: 23.75–95, 36.25–145, 48.75–195, and 61.25–245 mg of CD-LD. Food has been reported to affect the absorption of various drugs and, in particular, affect the performance of LD formulations.17–19 Absorption of LD occurs mainly in the proximal third of the small intestine. Delayed gastrointestinal transit may affect CD-LD absorption. Gastric emptying is affected by the composition and physicochemical properties of a meal. In addition, LD and its derivative dopamine have also been reported to affect gastric emptying.20,21 The objectives for this investigation were to characterize the dose proportionality of the 4 dose strengths of IPX066 capsules and to compare the pharmacokinetics of 1 and 2 capsules of the highest strength (61.25-245 mg of CD-LD). In addition, the effect of a high-fat, high-calorie breakfast and the effect of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 were assessed.

Background Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. Objective To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. Methods Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. Results Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. Conclusions Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

Background:Tofacitinib is an oral JAK inhibitor for the treatment of psoriatic arthritis (PsA).Objectives:To assess tofacitinib 5 mg BID as monotherapy after methotrexate (MTX) withdrawal vs with continued background MTX in patients (pts) with PsA.Methods:OPAL Balance (NCT01976364) was an open-label (OL) long-term extension (LTE) study of tofacitinib in pts with PsA who participated in Phase (P)3 studies (OPAL Broaden,NCT01877668; OPAL Beyond,NCT01882439). Pts who completed ≥24 months’ tofacitinib treatment in the LTE (stable 5 mg BID for ≥3 months) and were receiving oral MTX (7.5–20 mg/week; stable for ≥4 weeks) entered the multicentre, 12-month, double-blind, MTX withdrawal substudy. Pts remained on OL tofacitinib 5 mg BID and were randomised 1:1 to receive placebo (tofacitinib monotherapy, ie, blinded MTX withdrawal) or MTX (tofacitinib + MTX; same stable doses). Primary endpoints were changes from substudy baseline (Δ) in PASDAS and HAQ-DI at Month (M)6. Secondary efficacy endpoints were assessed at all time points. Safety was assessed throughout the substudy.Results:Of 180 pts randomised, 179 were treated (tofacitinib monotherapy n=90; tofacitinib + MTX n=89). Pt characteristics were similar between treatment arms. At M6, least squares mean (LSM) (standard error [SE]) ΔPASDAS was 0.229 (0.079) for tofacitinib monotherapy and 0.138 (0.081) for tofacitinib + MTX, and LSM (SE) ΔHAQ-DI was 0.043 (0.027) and 0.017 (0.028), respectively (Figure 1); no clinically meaningful differences were observed. Efficacy and pt-reported outcomes were generally similar between treatment arms at M6 and M12 (data not shown). Rates of pts achieving minimal disease activity, and maintaining an absence of enthesitis and dactylitis, were sustained to M12 in both treatment arms (Figure 2). Adverse event rates (Table) and laboratory parameters were comparable between treatment arms, but liver enzyme elevations were more common with tofacitinib + MTX.Conclusion:No clinically meaningful differences in efficacy and safety were observed in PsA pts who received OL tofacitinib 5 mg BID as monotherapy after MTX withdrawal vs with continued MTX. Safety was consistent with previous P3 studies. The substudy was an estimation study and not powered for hypothesis testing.Table.Safety outcomes to Month 12Pts with events, n (%) AEs of special interestTofacitinib monotherapy N=90Tofacitinib + MTXN=89AE43 (47.8)41 (46.1)Serious AE4 (4.4)3 (3.4)Discontinuations due to AE3 (3.3)4 (4.5)Death00 Herpes zoster (serious/non-serious)1 (1.1)2 (2.2) Serious infection02 (2.2) Opportunistic infectiona01 (1.1) Malignancy (excl. NMSC)a1 (1.1)1 (1.1) NMSCa00 Major adverse cardiovascular eventa00 Venous thromboembolismc00 Arterial thromboembolismc1 (1.1)0 Gastrointestinal perforationa00 Interstitial lung diseaseb00Laboratory parametersdALT ≥3×ULN05 (5.6) ALT (IU/L), mean (SE)-2.7 (1.6)2.5 (1.3)AST ≥3×ULN03 (3.4) AST (IU/L), mean (SE)-1.5 (1.2)1.7 (0.8)Reviewed by independentaexternal/binternal adjudication committeecPer Standardised MedDRA Query termsdWithout regard to baseline abnormalityALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normalAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Christina Viegelmann of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Laura C Coates: None declared, Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Alan Kivitz Shareholder of: AbbVie, Amgen, Gilead, GSK, Pfizer Inc, Sanofi, Consultant of: AbbVie, Boehringer Ingelheim,,Flexion, Genzyme, Gilead, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi, SUN Pharma Advanced Research, UCB, Paid instructor for: Celgene, Genzyme, Horizon, Merck, Novartis, Pfizer, Regeneron, Sanofi, Speakers bureau: AbbVie, Celgene, Flexion, Genzyme, Horizon, Merck, Novartis, Pfizer Inc, Regeneron, Sanofi, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Frank Behrens Grant/research support from: Pfizer, Janssen, Chugai, Celgene, Lilly and Roche, Consultant of: Pfizer, AbbVie, Sanofi, Lilly, Novartis, Genzyme, Boehringer, Janssen, MSD, Celgene, Roche and Chugai, James Cheng-Chung Wei Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, Eisai, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB Pharma, Dona Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cunshan Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ana Belen Romero Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Keith Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background:Tofacitinib is an oral JAK inhibitor that is being investigated for JIA.Objectives:To assess tofacitinib efficacy and safety in JIA patients (pts).Methods:This was a Phase 3, randomised, double-blind (DB), placebo (PBO)-controlled withdrawal study in pts aged 2−NCT02592434). In the 18-week open-label Part 1, pts received weight-based tofacitinib doses (5 mg BID or lower). Pts with ≥JIA ACR30 response at Week (W)18 were randomised 1:1 in the DB Part 2 (W18−44) to continue tofacitinib or switch to PBO. Primary endpoint: disease flare rate by W44. Key secondary endpoints: JIA ACR50/30/70 response rates; change from Part 2 baseline (Δ) in CHAQ-DI at W44. Other efficacy endpoints: time to disease flare in Part 2; JADAS27-CRP in Parts 1 and 2. PsA/ERA pts were excluded from these efficacy analyses. Safety was evaluated in all pts up to W44.Results:225 enrolled pts with pcJIA (n=184), PsA (n=20) or ERA (n=21) received tofacitinib in Part 1. At W18, 173/225 (76.9%) pts entered Part 2 (pcJIA n=142, PsA n=15, ERA n=16). In pcJIA pts, disease flare rate in Part 2 was significantly lower with tofacitinib vs PBO by W44 (p=0.0031; Fig 1a). JIA ACR50/30/70 response rates (Fig 1b) and ΔCHAQ-DI (Fig 1c) at W44, and time to disease flare in Part 2 (Fig 2a), were improved with tofacitinib vs PBO. Tofacitinib reduced JADAS27-CRP in Part 1; this effect was sustained in Part 2 (Fig 2b). Overall, safety was similar with tofacitinib or PBO (Table): 77.3% and 74.1% had adverse events (AEs); 1.1% and 2.4% had serious AEs. In Part 1, 2 pts had herpes zoster (non-serious) and 3 pts had serious infections (SIs). In Part 2, SIs occurred in 1 tofacitinib pt and 1 PBO pt. No pts died.Conclusion:In pcJIA pts, tofacitinib vs PBO resulted in significantly fewer disease flares, and improved time to flare, disease activity and physical functioning. Tofacitinib safety was consistent with that in RA pts.Table.Safety in all ptsPart 1Part 2TofacitinibaN=225TofacitinibaN=88PBO N=85Pts with events, n (%)AEs153 (68.0)68 (77.3)63 (74.1)SAEs7 (3.1)1 (1.1)2 (2.4)Permanent discontinuations due to AEs26 (11.6)16 (18.2)29 (34.1)AEs of special interest Death000 Gastrointestinal perforationb000 Hepatic eventb3 (1.3)00 Herpes zoster (non-serious and serious)2 (0.9)c00 Interstitial lung diseaseb000 Major adverse cardiovascular eventsb000 Malignancy (including non-melanoma skin cancer)b000 Macrophage activation syndromeb000 Opportunistic infectionb000 SI3 (1.3)1 (1.1)d1 (1.2) Thrombotic event (deep vein thrombosis, pulmonary embolismbor arterial thromboembolism)000 Tuberculosisb000a5 mg BID or equivalent weight-based lower dose in pts bAdjudicated eventscBoth non-seriousdOne SAE of pilonidal cyst repair was coded to surgical procedures instead of infections, and was inadvertently not identified as an SI. Following adjudication, the SAE did not meet opportunistic infection criteria; it is also included in the table as an SIAE, adverse event; BID, twice daily; PBO, placebo; pts, patients; SAE, serious AE; SI, serious infectionAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Nicolino Ruperto Grant/research support from: Bristol-Myers Squibb, Eli Lily, F Hoffmann-La Roche, GlaxoSmithKline, Janssen, Novartis, Pfizer, Sobi (paid to institution), Consultant of: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Speakers bureau: Ablynx, AbbVie, AstraZeneca-Medimmune, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lily, EMD Serono, GlaxoSmithKline, Hoffmann-La Roche, Janssen, Merck, Novartis, Pfizer, R-Pharma, Sanofi, Servier, Sinergie, Sobi, Takeda, Olga Synoverska Speakers bureau: Sanofi, Tracy Ting: None declared, Carlos Abud-Mendoza Speakers bureau: Eli Lilly, Pfizer Inc, Alberto Spindler Speakers bureau: Eli Lilly, Yulia Vyzhga Grant/research support from: Pfizer Inc, Katherine Marzan Grant/research support from: Novartis, Vladimir Keltsev: None declared, Irit Tirosh: None declared, Lisa Imundo: None declared, Rita Jerath: None declared, Daniel Kingsbury: None declared, Betül Sözeri: None declared, Sheetal Vora: None declared, Sampath Prahalad Grant/research support from: Novartis, Elena Zholobova Grant/research support from: Novartis and Pfizer Inc, Speakers bureau: AbbVie, Novartis, Pfizer Inc and Roche, Yonatan Butbul Aviel: None declared, Vyacheslav Chasnyk: None declared, Melissa Lerman Grant/research support from: Amgen, Kabita Nanda Grant/research support from: Abbott, AbbVie, Amgen and Roche, Heinrike Schmeling Grant/research support from: Janssen, Pfizer Inc, Roche and USB Bioscience, Heather Tory: None declared, Yosef Uziel Speakers bureau: Pfizer Inc, Diego O Viola Grant/research support from: Bristol-Myers Squibb, GSK, Janssen and Pfizer Inc, Speakers bureau: AbbVie and Bristol-Myers Squibb, Holly Posner Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Keith Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ann Wouters Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Cheng Chang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Richard Zhang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Irina Lazariciu Consultant of: Pfizer Inc, Employee of: IQVIA, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ricardo Suehiro Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Alberto Martini Consultant of: AbbVie, Eli Lily, EMD Serono, Janssen, Novartis, Pfizer, UCB, Daniel J Lovell Consultant of: Abbott (consulting and PI), AbbVie (PI), Amgen (consultant and DSMC Chairperson), AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb (PI), Celgene, Forest Research (DSMB Chairman), GlaxoSmithKline, Hoffman-La Roche, Janssen (co-PI), Novartis (consultant and PI), Pfizer (consultant and PI), Roche (PI), Takeda, UBC (consultant and PI), Wyeth, Employee of: Cincinnati Children’s Hospital Medical Center, Speakers bureau: Wyeth, Hermine Brunner Consultant of: Hoffman-La Roche, Novartis, Pfizer, Sanofi Aventis, Merck Serono, AbbVie, Amgen, Alter, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer, Bristol-Myers Squibb, Celgene, EMD Serono, Janssen, MedImmune, Novartis, Pfizer, and UCB Biosciences, Speakers bureau: GSK, Roche, and Novartis

Background:With multiple disease domains affected in PsA, clinical and patient-reported outcome (PRO) measures are important to assess disease improvement following treatment. Rapid, meaningful improvements in disease activity are a priority for physicians and patients (pts). Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Higher proportions of pts achieved responses in PROs and clinical measures when treated with tofacitinib for 3 months vs placebo (PBO).1-5Proportions of responders were also similar between tofacitinib and adalimumab (ADA) after 3, 6 and 12 months.2,3,5Objectives:To determine the time to initial response using responder definitions for selected PROs and clinical endpoints in pts with active PsA treated with tofacitinib, ADA or PBO switching to tofacitinib.Methods:In this post hoc analysis, data were collected from two Phase 3 studies (OPAL Broaden [12 months;NCT01877668]; OPAL Beyond [6 months;NCT01882439]).3,4Pts receiving tofacitinib 5 or 10 mg twice daily (BID), subcutaneous ADA 40 mg once every two weeks (Q2W; OPAL Broaden only), or PBO switching to tofacitinib 5 or 10 mg BID at Month (M)3, were included. Responder definitions included: HAQ-DI ≥0.35-point improvement from baseline (BL), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score ≥4-point improvement from BL, minimal disease activity (MDA) yes/no composite response (meeting at least 5 of 7 criteria) and PsA Disease Activity Score (PASDAS) post-BL score of ≤3.2 and >1.6-point improvement from BL. First post-BL data were collected at Week 2 (eg for HAQ-DI) or M1. Time-to-event analyses were performed using the Kaplan-Meier (KM) method, with pts censored at the last observed visit. Log-rank tests compared time to initial response across treatment groups.Results:KM analyses show days to initial response (Figure 1, Figure 2). Time to initial HAQ-DI response was significantly different between treatment groups in OPAL Broaden (pConclusion:Times to initial response in functional ability and disease activity were similar in pts treated with either tofacitinib or ADA. Time to initial response prior to first post-BL observation (Week 2 or M1) was not estimable in this analysis. These results may help physicians better understand the time frame for a meaningful response in pts receiving tofacitinib.References:[1]Strand et al. RMD Open 2019;5:e000808.[2]Strand et al. RMD Open 2019;5:e000806.[3]Mease et al. NEJM 2017;377:1537-50.[4]Gladman et al. NEJM 2017;377:1525-36.[5]Helliwell et al. Arthritis Res Ther 2018;20:242.Acknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Eric Comeau of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Laura C Coates: None declared, Joseph Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lara Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Andrew G Bushmakin Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Elizabeth Bacci Employee of: Evidera, Joseph C Cappelleri Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Philip Helliwell: None declared

β-thalassemia (β-Thal) is caused by defective β-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulating red blood cells. The hypochromic thalassemic red cells exhibit increased cell dehydration in association with elevated K+ leak and increased K-Cl cotransport activity, each of which has been linked to globin chain imbalance and related oxidative stress. We therefore tested the effect of genetic inactivation of K-Cl cotransporters KCC1 and KCC3 in a mouse model of β-thalassemia intermedia. In the absence of these transporters, the anemia of β-Thal mice was ameliorated, in association with increased MCV and reductions in CHCM and hyperdense cells, as well as in spleen size. The resting K+ content of β-Thal red cells was greatly increased, and Thal-associated splenomegaly slightly decreased. Lack of KCC1 and KCC3 activity in Thal red cells reduced red cell density and improved β-Thal-associated osmotic fragility. We conclude that genetic inactivation of K-Cl cotransport can reverse red cell dehydration and partially attenuate the hematologic phenotype in a mouse model of β-thalassemia.

Background Tofacitinib and other new treatments approved for use in psoriatic arthritis have only recently been included in psoriatic arthritis treatment guidelines, and studies evaluating the relative efficacy of available therapies are important to inform treatment decisions by healthcare professionals. Objective To perform a network meta-analysis to evaluate the efficacy and safety profiles of tofacitinib, biologic disease-modifying antirheumatic drugs (bDMARDs), and apremilast in patients with psoriatic arthritis naive to tumor necrosis factor inhibitor therapy (TNFi-naive) or with an inadequate response (TNFi-IR). Methods A systematic literature review used searches of MEDLINE, Embase, and The Cochrane Library on October 9, 2017. Randomized controlled trials including adult patients with psoriatic arthritis receiving treatment administered as monotherapy or with conventional synthetic DMARDs were selected. Efficacy outcomes included American College of Rheumatology 20 response, change from baseline in Health Assessment Questionnaire-Disability Index, ≥75% improvement in Psoriasis Area and Severity Index, and change from baseline in Dactylitis Severity Score and Leeds Enthesitis Index. Treatment effects were evaluated during placebo-controlled phases, using a binomial logit model for binary outcomes and a normal identify link model for other outcomes. Discontinuations due to adverse events and serious infection events were assessed as safety outcomes. Results The network meta-analysis included 24 published randomized controlled trials, of which 13 enrolled TNFi-naive patients only, 3 enrolled TNFi-IR patients only, and 8 enrolled both TNFi-naive and TNFi-IR patients. Placebo-controlled treatment durations ranged from 12 to 24 weeks. Indirect comparisons showed tofacitinib 5 and 10 mg BID to have similar efficacy compared with most bDMARDs and apremilast in improving joint symptoms (based on American College of Rheumatology 20 response), and with some bDMARDs in improving skin symptoms (based on Psoriasis Area and Severity Index) (tofacitinib 10 mg BID only in TNFi-IR) in patients with psoriatic arthritis who were TNFi-naive or TNFi-IR. Results also showed that, compared with placebo, the improvement in physical functioning (based on Health Assessment Questionnaire-Disability Index) with tofacitinib 5 and 10 mg BID was similar to that observed with most bDMARDs and apremilast in TNFi-naive patients, and similar to that observed with all bDMARDs with available data in the TNFi-IR population. Improvements in Dactylitis Severity Score and Leeds Enthesitis Index scores were comparable between treatments. Tofacitinib 5 and 10 mg BID were median-ranked 8 and 15, respectively, for discontinuation due to any adverse events, and 5 and 16, respectively, for a serious infection event out of a total of 20 treatments in the network (lower numbers are more favorable). Conclusions Tofacitinib provides an additional treatment option for patients with psoriatic arthritis, both in patients naive to TNFi and in those with TNFi-IR. (Curr Ther Res Clin Exp. 2020; 81:XXX–XXX)