CYpHER: Catalytic extracellular targeted protein degradation with high potency and durable effect.

Many disease-causing proteins have multiple pathogenic mechanisms, and conventional inhibitors struggle to reliably disrupt more than one. Targeted protein degradation (TPD) can eliminate the protein, and thus all its functions, by directing a cell's protein turnover machinery towards it. Two established strategies either engage catalytic E3 ligases or drive uptake towards the endolysosomal pathway. Here we describe CYpHER (CatalYtic pH-dependent Endolysosomal delivery with Recycling) technology with potency and durability from a novel catalytic mechanism that shares the specificity and straightforward modular design of endolysosomal uptake. By bestowing pH-dependent release on the target engager and using the rapid-cycling transferrin receptor as the uptake receptor, CYpHER induces endolysosomal target delivery while re-using drug, potentially yielding increased potency and reduced off-target tissue exposure risks. The TfR-based approach allows targeting to tumors that overexpress this receptor and offers the potential for transport to the CNS. CYpHER function was demonstrated in vitro with EGFR and PD-L1, and in vivo with EGFR in a model of EGFR-driven non-small cell lung cancer.

Effectiveness of Tofacitinib in Patients Initiating Therapy for Psoriatic Arthritis: Results from the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry.

INTRODUCTION: Randomized controlled trials have demonstrated tofacitinib efficacy for psoriatic arthritis (PsA); however, real-world effectiveness data are limited. This real-world analysis assessed baseline demographics/disease characteristics and tofacitinib effectiveness in patients with PsA in the CorEvitas PsA/Spondyloarthritis Registry. METHODS: This study (NCT05195814) included patients with PsA initiating tofacitinib from December 2017-December 2021, as monotherapy or with oral small molecules (methotrexate/leflunomide/sulfasalazine/apremilast), pre-existing use, or initiated concurrently. OUTCOMES: mean change from baseline in disease activity/patient-reported outcomes, proportion of patients achieving low disease activity (LDA)/remission at 6 ± 3 months, and discontinuation rates. RESULTS: Of 222 patients with PsA who initiated tofacitinib (60.8% as monotherapy), 123 patients had 6 ± 3 months of follow-up. At initiation, 59.7% were female, 92.3% were White, mean age was 56.3 years, PsA duration since diagnosis was 8.2 years, and 25.7% were biologic disease-modifying antirheumatic drug (bDMARD)-naïve. Improvements to 6 ± 3 months were observed with tofacitinib for Clinical Disease Activity Index for PsA (cDAPSA), DAPSA, PsA Disease Activity Score (PASDAS), Clinical Disease Activity Index, body surface area (BSA), tender/swollen joint count, patient fatigue, pain, Patient Global Skin Assessment, and Health Assessment Questionnaire-Disability Index. At 6 ± 3 months, 25.0%/7.8% of patients treated with tofacitinib achieved cDAPSA-defined LDA/remission, 18.2% achieved minimal disease activity, 30.8% had PASDAS ≤ 3.2, 42.9%/29.4% had resolved enthesitis/dactylitis, and 22.5% achieved BSA = 0%. Tofacitinib discontinuation occurred in 51.2% of patients (51.6% of monotherapy initiators) at/prior to 6 ± 3 months (27.6%/23.6%), 57.1% of whom switched to tumor necrosis factor/interleukin-17 inhibitors. Reasons for discontinuation were not reported in 85.3%/79.3% of patients who discontinued at/prior to 6 ± 3 months. CONCLUSIONS: This real-world US cohort analysis described patients with PsA newly initiating tofacitinib; most were bDMARD-experienced or receiving monotherapy treatment. In patients who remained on therapy (48.8%), tofacitinib was effective across multiple PsA domains at 6 ± 3 months. Limitations included small patient numbers at follow-up and potential selection bias. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05195814.

Efficacy of tofacitinib on enthesitis in patients with active psoriatic arthritis: analysis of pooled data from two phase 3 studies.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post hoc analysis assessed tofacitinib efficacy on enthesitis by baseline location and severity, and impact on disease activity and patient-reported outcomes (PROs), in patients with PsA. METHODS: Data were pooled from two phase 3 studies (NCT01877668/NCT01882439) in patients with PsA receiving tofacitinib 5 or 10 mg twice daily to month (M)6 or placebo to M3. Endpoints were: change from baseline in Leeds Enthesitis Index (LEI) or Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC); proportions of patients with enthesitis, relapsed enthesitis after resolution, de novo enthesitis, low disease activity (LDA) or remission (minimal disease activity/very low disease activity; Psoriatic Arthritis Disease Activity Score; Disease Activity Index for Psoriatic Arthritis, and Composite Psoriatic Disease Activity in Psoriatic Arthritis); and PROs (Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F] total and arthritis pain Visual Analog Scale scores). Descriptive statistics were generated by visit and treatment. Change from baseline in PROs was evaluated by multivariate linear regression. RESULTS: Seven hundred ten patients from two studies were included: 479 had LEI > 0; 545 had SPARCC > 0; and 136 had LEI = 0 and SPARCC = 0 at baseline. At baseline, among patients with LEI > 0 or SPARCC > 0, mean LEI and SPARCC across treatments and enthesitis locations/severities ranged from 1.0-4.4 and 1.3-9.4, respectively. Across several baseline enthesitis locations/severities, changes from baseline in LEI and SPARCC up to M3 were greater with tofacitinib (-2.0-0.4 and -3.5-0.2) vs placebo (-|0.9-|0.4 and -1.5-1.1). Enthesitis at M6 was more common in patients with greater baseline enthesitis severity. At M6, ≤ 40% of patients with baseline LEI > 0 or SPARCC > 0 whose enthesitis had resolved by M1/M3 experienced a relapse, and < 14% of patients with baseline LEI = 0 and SPARCC = 0 had de novo enthesitis. LDA/remission rates generally increased with tofacitinib over time. Baseline LEI location was significantly associated with change from baseline in arthritis pain score, while baseline SPARCC severity was significantly associated with change from baseline in FACIT-F total and arthritis pain scores. CONCLUSION: Tofacitinib treatment resulted in improvements in enthesitis in patients with PsA, regardless of baseline location or severity. TRIAL REGISTRATION: NCT01877668;NCT01882439.

NTSR1 glycosylation and MMP dependent cleavage generate three distinct forms of the protein.

NTSR1 abnormal expression by cancer cells makes it a strategic target for antitumoral therapies, such as compounds that use NTSR1 binding probes to deliver cytotoxic agents to tumor cells. Success of these therapies relies on NTSR1 protein availability and accessibility; therefore, understanding the protein's biology is crucial. We studied NTSR1 protein in exogenously and endogenously expressing non-tumoral and tumoral cells. We found NTSR1 to be expressed as three distinct protein forms: the NTSR1-high form, a glycosylated protein; the NTSR1-low form, a N-terminally cleaved and de-glycosylated protein; and the NTSR1-LP protein with the MW size predicted by its NTSR1 amino acid sequence. We show that the NTSR1-high form is cleaved by MMPs to generate the NTSR1-low form, a process that is promoted by the Neurotensin (NTS) ligand. In addition, NTS induced the internalization of plasma membrane localized NTSR1 and degradation of NTSR1-low form via the proteasome. Importantly, we found NTSR1-low form to be the most abundant form in the tumoral cells and in PDAC Patient Derived Xenograft, demonstrating its physiopathological relevance. Altogether, our work provides important technical and experimental tools as well as new crucial insights into NTSR1 protein biology that are required to develop clinically relevant NTSR1 targeting anti-tumoral therapies.

Effect of tofacitinib on dactylitis and patient-reported outcomes in patients with active psoriatic arthritis: post-hoc analysis of phase III studies.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). This post-hoc analysis of two phase III studies in patients with PsA treated with tofacitinib assessed dactylitis by location, and the impact on patient-reported outcomes (PROs). METHODS: Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo. Endpoints included change from baseline in Dactylitis Severity Score (DSS), proportions of patients with dactylitis, Psoriatic Arthritis Disease Activity Score (PASDAS), and PROs (Health Assessment Questionnaire-Disability Index [HAQ-DI]; Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-F]; Short Form-36 Health Survey [SF-36] Physical Component Summary [PCS], Mental Component Summary [MCS], and physical functioning [PF]; arthritis pain; and Work Limitations Questionnaire [WLQ]). Descriptive statistics were generated by visit and treatment. Change from baseline in PROs were evaluated by multivariate linear regression. RESULTS: The analysis included 373/337 patients with baseline DSS > 0/DSS = 0. Regardless of location, DSS improvements in patients with DSS > 0 were greater from month 1 with tofacitinib (10 mg BID) versus placebo. For patients with DSS > 0/DSS = 0, both doses of tofacitinib led to mean dactylitis presence ≤ 15%/< 2% for all digits at month 6, and PASDAS (by dactylitis location) was lower versus placebo at month 3. Dactylitis location was not significantly associated with change from baseline in PROs. CONCLUSION: Tofacitinib resulted in sustained improvements in dactylitis irrespective of location, with minimal emergence of new dactylitis. Trial registration NCT01877668; NCT01882439.

An Intensive Approach to Improving Diversity, Equity, and Inclusion in an Academic Emergency Department.

A healthcare workforce that demonstrates cultural competence and humility while reflecting the diversity of the surrounding community has the potential to significantly benefit the patient population it serves. In this context and given numerous societal influences and the events of 2020, the leadership of the Department of Emergency Medicine at Albany Medical Center recognized the need to promote diversity, equity, and inclusion (DEI) in multiple areas. These included premedical education, medical education, postgraduate medical education, faculty development, staff satisfaction, and patient care. The department formed a DEI taskforce that developed an ongoing, multipronged, interdisciplinary approach to address these important aspects of our work and clinical environment with the goals of improving staff wellbeing, reducing burnout, and promoting the health of our community. Our experience is shared here to illustrate how a small, dedicated team can implement a variety of DEI initiatives quickly and with relatively little cost at a large academic medical center.

Relationships of dermatologic symptoms and quality of life in patients with psoriatic arthritis: analysis of two tofacitinib phase III studies.

OBJECTIVES: Evaluate relationships between changes in dermatologic assessments and quality of life (QoL) measures; quantify dermatologic symptom severity impacts on QoL in patients with psoriatic arthritis (PsA) treated with tofacitinib. METHODS: Data were from two phase III studies; patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg every other week, or placebo advancing to tofacitinib 5 or 10 mg BID at Month 3. Repeated measures longitudinal models assessed relationships between dermatologic assessments (predictors) Itch Severity Item (ISI), Physician's Global Assessment of Psoriasis (PGA-PsO), and Patient's Global Joint and Skin Assessment-Visual Analog Scale-Psoriasis question (PGJS-VAS-PsO), and QoL measures (outcomes) Dermatology Life Quality Index (DLQI) and Short Form-36 Health Survey Version 2 (SF-36v2). Models included one predictor and one outcome. RESULTS: Direct, approximately linear relationships existed between predictors and outcomes. ISI/PGA-PsO/PGJS-VAS-PsO improvements from baseline of ≥3/≥2/≥40-mm VAS corresponded with clinically meaningful DLQI improvements; improvements from baseline of ≥4/≥3/≥40-mm VAS generally corresponded with clinically meaningful improvements across component scores and all SF-36v2 domains. CONCLUSIONS: Substantial links exist between dermatologic symptoms and QoL in patients with PsA, potentially informing patient-centered care and research. Rheumatologists should be aware of dermatologic manifestations and QoL impacts in patients with PsA. CLINICALTRIALS.GOV: NCT01877668; NCT01882439.

Early Real-World Experience of Tofacitinib for Psoriatic Arthritis: Data from a United States Healthcare Claims Database.

INTRODUCTION: This study characterized real-world demographic and baseline clinical characteristics, as well as treatment persistence and adherence, in patients with psoriatic arthritis (PsA) who had newly initiated tofacitinib treatment. METHODS: This retrospective cohort study included patients aged 18 years or older in the IBM MarketScan™ US database with at least one tofacitinib claim (first = index) between December 14, 2017 and April 30, 2019; PsA diagnoses on/within 12 months pre-index; and no diagnoses of rheumatoid arthritis any time pre-index. Patients were continuously enrolled for 12 months pre-index and 6 months post-index, with no pre-index claims for tofacitinib. Patient demographic and clinical characteristics on the day of index, and history of advanced treatments (including tofacitinib monotherapy or combination therapy), were recorded. Outcomes at 6 months post-index included tofacitinib persistence (less than 60-day gap without tofacitinib treatment) and adherence (proportion of days covered [PDC] and medication possession ratio 80% or higher). RESULTS: Of the 10,354 patients with tofacitinib claims within the study period, 318 patients with PsA met the inclusion criteria. More than 60% of patients received tofacitinib monotherapy post-index, with a mean duration of PsA of 760.5 days at index. For patients who received tofacitinib combination therapy post-index, methotrexate was the most common concomitant conventional synthetic disease-modifying antirheumatic drug. At 6 months post-index, persistence was similar in patients receiving tofacitinib monotherapy (69.8%) versus combination therapy (73.1%); adherence (as measured by PDC ≥ 0.8) was numerically lower in patients receiving tofacitinib monotherapy (56.8%) versus combination therapy (65.5%). CONCLUSIONS: This analysis of US-based claims data described patients who had newly initiated tofacitinib treatment an average of 2 years after PsA diagnosis, with approximately two-thirds of patients receiving tofacitinib monotherapy. Observed rates of tofacitinib persistence were similar across patients who received tofacitinib monotherapy and combination therapy 6 months after initiation; adherence rates were numerically lower in patients receiving monotherapy.

Tofacitinib is a drug approved to treat patients with psoriatic arthritis (PsA) that has been shown to improve PsA symptoms and quality of life in controlled clinical trials. However, there is not much information on everyday use of tofacitinib outside of clinical trials in the USA. This study is one of the first to describe the characteristics of patients with PsA in the USA who take tofacitinib, including their typical age, sex, where they live, how long they have had PsA, and how they use tofacitinib. Use of tofacitinib included how patients followed tofacitinib prescription timings and dose (adherence) and how long they took tofacitinib for after it was prescribed (persistence). We used data collected from a US health insurance claims database (IBM MarketScan™) for patients with PsA and at least one claim for tofacitinib. In total, 318 patients were included and over 60% of them received tofacitinib therapy only (monotherapy; no conventional synthetic disease-modifying antirheumatic drug [csDMARD] therapy). For patients treated with both tofacitinib and a csDMARD (combination therapy), methotrexate was the most common drug prescribed. Six months after their first prescription of tofacitinib, around 70% of patients were still taking tofacitinib (monotherapy or combination therapy). However, a slightly lower number of patients taking tofacitinib monotherapy were taking it as originally instructed (adherence 57%), compared with those taking tofacitinib combination therapy (adherence 66%). Our results provide valuable information on the use of tofacitinib in US real-life settings outside of clinical trials and could help to improve the quality of care for patients with PsA.

Multiplex analysis of mass imaging data: Application to the pathology of experimental myocardial infarction.

AIM: Imaging mass cytometry (IMC) affords simultaneous immune-labelling/imaging of multiple antigens in the same tissue. Methods utilizing multiplex data beyond co-registration are lacking. This study developed and applied an innovative spatial analysis workflow for multiplex imaging data to IMC data determined from cardiac tissues and revealed the mechanism(s) of neutrophil-mediated post-myocardial-infarction damage. METHODS: IMC produced multiplex images with various redox/inflammatory markers. The cardiac peri-infarct zone (PIZ) was determined to be up to 240 µm from the infarct border based on the presence of neutrophils. The tissue region beyond the infarct was defined as the remote area (RA). ImageJ was used to quantify the immunoreactivity. Functional assessments included infarct size, cell necro/apoptosis, total thiol assay and echocardiogram. RESULTS: Expression of damage markers decreased in order from the infarct area to PIZ and then RA, reflecting the neutrophil density in the regions. Concentrically spaced "shoreline contour analysis" around the cardiac infarct extending into the PIZ showed that immunoreactivity for damage markers decreased linearly with increasing distance from the infarct, concomitant with a decreasing neutrophil-myeloperoxidase (MPO) gradient from the infarct to the PIZ. Stratifying by concentric bands around individual MPO+ -signal identified that the immunoreactivity of haem-oxygenase-1 (HO-1) and phosphorylated-p38 mitogen-activated protein kinase (pP38) peaked near neutrophils. Furthermore, spatial dependence between neutrophils and markers of cardiac cellular damage was confirmed by nearest-neighbour distance analysis. Post-infarction tissue exhibited declined functional parameters that were associated with neutrophil migration from the infarct to PIZ. CONCLUSION: This image-based quantitative protocol revealed the spatial association and provided potential molecular pathways responsible for neutrophil-mediated damage post-infarction.

Knowledge of the Good Samaritan Drug Overdose Act and possession of a naloxone kit among people recently released from prison.

PURPOSE: This study aims to describe knowledge of Canada's Good Samaritan Drug Overdose Act (GSDOA) and take home naloxone (THN) training and kit possession among people being released from provincial correctional facilities in British Columbia. DESIGN/METHODOLOGY/APPROACH: The authors conducted surveys with clients of the Unlocking the Gates Peer Health Mentoring program on their release. The authors compared the characteristics of people who had and had not heard of the GSDOA and who were in possession of a THN kit. FINDINGS: In this study, 71% people had heard of the GSDOA, and 55.6% were in possession of a THN kit. This study found that 99% of people who had heard of the GSDOA indicated that they would call 911 if they saw an overdose. Among people who perceived themselves to be at risk of overdose, 28.3% did not have a THN kit. Only half (52%) of participants had a mobile phone, but 100% of those with a phone said they would call 911 if they witnessed an overdose. ORIGINALITY/VALUE: The authors found that people with knowledge of the GSDOA were likely to report that they would call 911 for help with an overdose. Education about the GSDOA should be a standard component of naloxone training in correctional facilities. More than one in four people at risk of overdose were released without a naloxone kit, highlighting opportunities for training and distribution. Access to a cellphone is important in enabling calls to 911 and should be included in discharge planning.

Itch as Major Mediator of Effect of Tofacitinib on Health-Related Quality of Life in Psoriatic Arthritis: A Mediation Analysis.

Patients with psoriatic arthritis (PsA) experience impaired health-related quality of life (HRQoL). Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA, which has been associated with improvements in dermatologic endpoints in patients with PsA. To assess the extent to which tofacitinib affects patient HRQoL via improvements in dermatologic symptoms, including itch, data were pooled from patients with PsA who received tofacitinib in phase III studies (NCT01866668 and NCT01882439). Mediation modeling assessed the indirect effects (via Itch Severity Item [ISI] and Physician's Global Assessment of Psoriasis [PGA-PsO]) and direct effects (via all other factors) of tofacitinib treatment on dermatology-specific HRQoL (measured by Dermatology Life Quality Index [DLQI]). In the initial model, the treatment effect on DLQI was largely mediated by itch (ISI; p < 0.0001) and PGA-PsO (p < 0.01). The model was re-specified to assess the indirect effects only of itch and PGA-PsO on DLQI. Here, 17.7% of the treatment effect on DLQI was attributable to PGA-PsO (p = 0.0006), and 82.3% to itch (p < 0.0001). Tofacitinib-dependent improvements in DLQI were primarily mediated by itch relief, in addition to improvements in PGA-PsO.

Exploring the Quality of Communication Between Patients with Psoriatic Arthritis and Physicians: Results of a Global Online Survey.

INTRODUCTION: Effective communication between patients with psoriatic arthritis (PsA) and their physicians is important for optimizing treatment outcomes. We assessed the quality of patient-physician communication in terms of awareness and impact of PsA symptoms, their levels of satisfaction, and their perceptions of communications. METHODS: A global online survey was conducted by The Harris Poll in adult patients with PsA and physicians managing patients with PsA in eight countries. Participating physicians were either rheumatologists or dermatologists seeing ≥ 10 and ≥ 5 patients with PsA per month, respectively. Patient and physician groups were unmatched. Patient-physician communication was assessed with 35-60 questions regarding discussion topics during consultations, levels of satisfaction with communication, and specific communication issues. RESULTS: A total of 1286 patients with PsA (983 and 303 whose primary treating physician was a rheumatologist or dermatologist, respectively) and 1553 physicians (795 rheumatologists and 758 dermatologists) completed the survey. Regardless of whether they were primarily treated by a rheumatologist or dermatologist, most patients reported a social (84% and 81%, respectively) or work (81% and 80%, respectively) impact of PsA, and a major/moderate negative impact on their physical activity levels (79% and 74%, respectively) or emotional/mental wellbeing (69% and 68%, respectively). Physician responses were generally consistent with this; however, physicians often appeared to under-recognize the extent to which PsA affects patients. Most (≥ 85%) patients and physicians were very/somewhat satisfied with their patient-physician communication, and most (≥ 86%) patients were comfortable raising their concerns/fears with their physician. However, > 40% of patients were identified as being at risk of suboptimal communication. These patients were significantly less likely to report their PsA symptoms even when asked, were less comfortable discussing the impacts of PsA with their physician, and were more likely to experience major/moderate impacts of PsA on their health-related quality of life (HRQoL). CONCLUSIONS: Physicians often underestimate the impacts of PsA, compared with patients, and some patients may be at risk of suboptimal communication with their attending physician, which may worsen the HRQoL impacts of PsA. These findings highlight a need for ways to improve communication between patients with PsA and their healthcare providers.

Psoriatic arthritis (PsA) is a disease that can cause swollen and painful joints, as well as skin psoriasis. To effectively treat PsA, it is important that doctors and patients communicate well. We used a survey to ask patients with PsA and doctors from around the world about their communications about PsA. We also asked how PsA affects patients' quality of life. In total, 1286 patients and 1553 doctors took the survey. Most patients said that PsA affected their social and work lives. Similarly, PsA had a negative impact on physical activity and on emotional and/or mental wellbeing in most patients who answered the survey. Doctors answered similarly, but they were generally less likely to recognize how severely PsA can impact patients, compared with patients themselves. Most patients and doctors were happy with their patient­doctor communication, and most patients felt comfortable talking about their worries and/or fears with their doctor. However, some patients (about four out of 10) felt that communication with their doctors was not good; these patients were less likely/comfortable to talk about their PsA symptoms and the impacts of PsA with their doctor. PsA was also more likely to negatively impact these patients' quality of life. This survey shows that it is important to find ways to improve communication between patients with PsA and their doctors.

Supporting people leaving prisons during COVID-19: perspectives from peer health mentors.

PURPOSE: Currently, people leaving prisons face concurrent risks from the COVID-19 pandemic and the overdose public health emergency. The closure or reduction of community services people rely on after release such as treatment centres and shelters has exacerbated the risks of poor health outcomes and harms. This paper aims to learn from peer health mentors (PHM) about changes to their work during overlapping health emergencies, as well as barriers and opportunities to support people leaving prison in this context. DESIGN/METHODOLOGY/APPROACH: The Unlocking the Gates (UTG) Peer Health Mentoring Program supports people leaving prison in British Columbia during the first three days after release. The authors conducted two focus groups with PHM over video conference in May 2020. Focus groups were recorded and transcribed, and themes were iteratively developed using narrative thematic analysis. FINDINGS: The findings highlighted the importance of peer health mentorship for people leaving prisons. PHM discussed increased opportunities for collaboration, ways the pandemic has changed how they are able to provide support, and how PHM are able to remain responsive and flexible to meet client needs. Additionally, PHM illuminated ways that COVID-19 has exacerbated existing barriers and identified specific actions needed to support client health, including increased housing and recovery beds, and tools for social and emotional well-being. ORIGINALITY/VALUE: This study contributes to our understanding of peer health mentorship during the COVID-19 pandemic from the perspective of mentors. PHM expertise can support release planning, improved health and well-being of people leaving prison and facilitate policy-supported pandemic responses.

Impact of baseline body mass index on the efficacy and safety of tofacitinib in patients with psoriatic arthritis.

OBJECTIVES: This post-hoc analysis explored the impact of body mass index (BMI) on tofacitinib efficacy/safety in patients with active psoriatic arthritis (PsA). METHODS: Data were pooled from two phase 3 studies (NCT01877668; NCT01882439). Analyses included patients randomised to tofacitinib 5/10 mg twio times a day or placebo, stratified by baseline BMI: <25 kg/m2, ≥25-<30 kg/m2, ≥30-<35 kg/m2 or ≥35 kg/m2. Endpoints (month 3): American College of Rheumatology (ACR20/50/70), Health Assessment Questionnaire-Disability Index (HAQ-DI) and Psoriasis Area and Severity Index (PASI) 75 response rates; dactylitis/enthesitis resolution rates; changes from baseline Short Form-36 Health Survey version 2 (SF-36v2) Physical/Mental Component Summary (PCS) scores and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score. Safety was also reported. RESULTS: Analysis included 710 patients; 43.8% were obese (BMI ≥30 kg/m2). Tofacitinib demonstrated higher efficacy response rates at month 3, compared with placebo, regardless of baseline BMI. Generally, ACR20/50/70 and HAQ-DI response rates, enthesitis resolution rates and changes from baseline in SF-36v2 PCS score and FACIT-F total score (month 3) were reduced in patients with baseline BMI ≥35 kg/m2 versus patients with lower BMIs. Elevated alanine aminotransferase/aspartate aminotransferase levels were reported in patients with baseline BMI ≥35 kg/m2 receiving tofacitinib 5 mg but not 10 mg two times a day. CONCLUSION: Tofacitinib demonstrated greater efficacy than placebo in patients with PsA, regardless of baseline BMI. For all treatment arms, reduced efficacy was observed in patients with baseline BMI ≥35 kg/m2. Safety was generally comparable across BMI categories, although the effect of tofacitinib on liver enzymes in patients with baseline BMI ≥35 kg/m2 was inconclusive.

Allyship in Residency: An Introductory Module on Medical Allyship for Graduate Medical Trainees.

INTRODUCTION: Lack of diversity impacts research, medical curricula, and medical trainees' ability to provide equitable patient care. The concept of allyship, defined as a supportive association between identities with power and privilege and marginalized identities, provides an optimal framework for enhancing education about health equity. Currently, there are no established curricula focused on allyship and limited mention within current medical training literature. We propose use of allyship to increase graduate medical trainee understanding of diversity and focus on health equity. METHODS: We developed a 1-hour workshop aimed at helping residents understand the definition of allyship, effective allyship to patients and colleagues, and allyship differences across communities. The workshop consisted of pre- and postassessment surveys, a didactic presentation module, and facilitated case study discussions. It was conducted locally on four occasions across pediatrics, family medicine, surgery, and emergency medicine residency programs. RESULTS: An analysis of the 101 preassessment and 58 postassessment survey responses revealed an increased level of knowledge regarding allyship (p < .001) and increased comprehension of allyship competencies (p < .001). All workshop learning objectives demonstrated positive change postmodule. DISCUSSION: With an increasing need for curricula to address health equity in medical trainees, this workshop serves as a unique and effective approach to expanding cultural responsiveness skills under the lens of allyship. Specifically, the workshop functions as a constructive introduction to allyship principles and practices and can serve as a foundation on which residents can build more robust skills as a part of their allyship journey.

Tofacitinib in Patients With Psoriatic Arthritis and Metabolic Syndrome: A Post hoc Analysis of Phase 3 Studies.

OBJECTIVE: Metabolic syndrome (MetS) is a cluster of concurrent risk factors for cardiovascular disease and type 2 diabetes. This post hoc analysis explored key efficacy and safety endpoints in patients with psoriatic arthritis (PsA) and MetS treated with tofacitinib. METHODS: Tofacitinib 5 and 10 mg twice daily and placebo data were pooled from two Phase 3 studies (OPAL Broaden [12 months; ClinicalTrials.gov identifier NCT01877668]; OPAL Beyond [6 months; ClinicalTrials.gov identifier NCT01882439]); patients received one background conventional synthetic disease-modifying antirheumatic drug. Patients were stratified by baseline presence/absence of MetS. Efficacy and safety were reported to month 3 (tofacitinib and placebo) and 6 (tofacitinib only). Efficacy outcomes included: American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI) response, Psoriasis Area Severity Index (PASI)75 response, and enthesitis/dactylitis resolution rates; and changes from baseline (Δ) in C-reactive protein, HAQ-DI, Patient's/Physician's Global Assessment of Arthritis, and patient-reported outcomes. Safety outcomes included treatment-emergent all-causality adverse events (AEs), Δ in lipid/hepatic values, and liver parameter increases. RESULTS: Of 710 patients, 41.4% (n = 294) had baseline MetS. All efficacy outcomes improved with both tofacitinib doses versus placebo, to month 3; tofacitinib efficacy was consistent to month 6, regardless of MetS status. MetS did not appear to affect the incidence of AEs or Δ in lipid/hepatic values with tofacitinib up to month 3 or 6. Arterial thromboembolism and myocardial infarction (adjudicated major adverse cardiovascular events) were each reported once in tofacitinib-treated patients with MetS. CONCLUSION: Regardless of baseline MetS status, tofacitinib showed greater efficacy versus placebo in patients with active PsA. The tofacitinib safety profile appeared similar in patients with versus without MetS.

Treatment Mode Preferences in Psoriatic Arthritis: A Qualitative Multi-Country Study.

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.

Costs and Health Outcomes Associated with Tofacitinib Treatment for Active Psoriatic Arthritis in the United States.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. DISCLOSURES: 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.

Supporting women leaving prison through peer health mentoring: a participatory health research study.

BACKGROUND: During the transition between prison and community, people are at greatly increased risk for adverse health outcomes. This study describes a peer health mentoring program that supports women in the first 3 days after their release from a provincial correctional facility in British Columbia. METHODS: We used a participatory health research framework to develop multimethod processes to describe the Unlocking the Gates Peer Health Mentoring Program. Mentors are women with incarceration experience. Between 2013 and 2018, women released from Alouette Correctional Centre for Women were invited to access the program. All program clients were invited to participate in the surveys and interviews. We analyzed survey and interview data using descriptive analysis for quantitative data and content analysis for qualitative data. RESULTS: There were 346 program contacts from 340 women over the study period. For every contact, a telephone interview was conducted. Among the 346 contacts, 173 women met their mentor, of whom 172 (99.4%) completed the intake and consent forms. A total of 105 women (61.0%) completed a program activity feedback survey at the end of the mentoring period. Women identified a range of needed supports during the transition from prison to community, including access to clothing, social assistance, housing and health care. Participants described a mix of emotions surrounding release, including excitement, anxiety, hope, and a wish for understanding and support. Within 3 days of release, 49 participants (46.7%) had accessed a family physician, and 89 (84.8%) had accessed at least 1 community resource. Ninety-eight participants (93.3%) reported that their mentor assisted them in accessing community resources. INTERPRETATION: Peer health mentoring provides valuable, multifaceted support in helping women to navigate health and social services and to meet their basic needs. Strengthening health supports during the transition from prison to community is critical to promoting the health and well-being of women leaving prison.