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Background: Guselkumab (human monoclonal antibody) selectively inhibits the interleukin (IL)-23p19 subunit. Objectives: Assess the longer-term pharmacodynamic effects of guselkumab and explore associations between such effects and clinical responses in patients with active psoriatic arthritis (PsA). Design: DISCOVER-2 randomized 739 biologic-naïve patients with active PsA (swollen/tender joint counts each ⩾5, C-reactive protein (CRP) ⩾0.6 mg/dL) to guselkumab (100 mg every 4 weeks (Q4W) or at Weeks 0, 4, and then Q8W) or placebo. Guselkumab-randomized participants with available serum biomarker data (randomly selected to reflect demographic and disease characteristics of the DISCOVER-2 population) comprised inflammatory ( N = 100) and collagen ( N = 178) biomarker cohorts. Methods: Pharmacodynamic effects of guselkumab through 2 years on inflammatory and collagen biomarker levels (general linear model) and associations between biomarkers and improvements in composite measures of joint, skin, and overall disease activity (Spearman linear regression) through 2 years were assessed. The relationship between the pharmacodynamic effects of guselkumab and achieving ⩾50% improvement in the American College of Rheumatology response criteria (ACR50) was assessed using a general linear model. Results: With guselkumab, pharmacodynamic effects on inflammatory (CRP, IL-6, serum amyloid A (SAA), IL-17A, IL-17F, IL-22, and beta-defensin 2 (BD-2)) and collagen (matrix metalloproteinase-degradation type I, III, IV, and VI collagen (C1M, C3M, C4M, and C6M)) biomarker levels were sustained or enhanced through Week 100. Throughout follow-up timepoints (Week 24/52/100), decreases in CRP, IL-6, C1M, and C6M levels correlated ( r = 0.26–0.30; p

Abstract Introduction The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS). Methods The COAST-V 52-week, double-blind, placebo-controlled, randomized phase III trial examined the efficacy of ixekizumab in patients with active AS; adalimumab was used as an active reference arm. Treatment effects on reduction in pain were assessed by objective measures of controlled and persisting inflammation (defined by magnetic resonance imaging [MRI], C-reactive protein [CRP], or MRI + CRP status). Pathway analysis was used to analyze treatment effect that was not attributable to reduction in inflammation biomarkers. Results In patients with AS, when inflammation was controlled as assessed by MRI, patients treated with ixekizumab experienced a reduction in spinal pain at night (SP-N, numeric rating scale, ixekizumab mean = − 3.9, p

Abstract Introduction The APPRAISE study was conducted to better understand the 12-month effectiveness, tolerability, and patient satisfaction with apremilast treatment for patients with psoriatic arthritis (PsA) in real-world settings. Methods APPRAISE (NCT03608657), a prospective, multicenter, observational study, enrolled adults with active PsA prescribed apremilast per routine care between July 2018 and March 2020. Patients were followed for 12 months with visits suggested every 4 months. The primary outcome measure was achievement of remission (REM) or low disease activity (LDA), defined as a Clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) score ≤ 13. Results Of the 102 patients who enrolled, 45 (44.1%) discontinued the study by 12 months. Most patients (75.5%) had moderate or high disease activity, and 24.5% were in REM/LDA at baseline based on cDAPSA score. Achievement of cDAPSA REM/LDA was 63.7%, 67.2%, and 53.8% at months 4, 8, and 12, respectively. In those continuing in the study, significant improvements were seen in swollen and tender joint counts, pain visual analog scale, psoriasis body surface area, and complete dactylitis resolution. Enthesitis reduction was also observed. Improvements in treatment satisfaction and patient-reported outcomes, including Health Assessment Questionnaire-Disability Index and the 36-item Short Form physical and mental component scores, were observed over 12 months. The proportion of patients achieving a Patient-Acceptable Symptom State (PASS) increased significantly from baseline at months 4, 8, and 12 (P

Abstract Introduction To evaluate the effect of guselkumab on work productivity and nonwork daily activity impairment and general health status through 2 years in patients who were biologic-naïve with active psoriatic arthritis (PsA) in the phase 3 DISCOVER-2 clinical trial. Methods Adult patients with PsA were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W); at weeks 0, 4, then every 8 weeks (Q8W); or placebo (through week 24 with crossover to guselkumab Q4W). Work productivity and nonwork daily activity impairment were assessed using the Work Productivity and Activity Impairment Questionnaire for PsA (WPAI-PsA) and patient-reported general health status using the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index and EQ-Visual Analog Scale (EQ-VAS). Least-squares (LS) mean changes from baseline in WPAI-PsA domains and EQ-5D-5L/EQ-VAS were assessed through week 100. Changes in employment status were utilized to estimate potential indirect savings from improved work productivity. Results Of 739 randomized patients, 738 had available baseline data for the analyses (Q4W 245; Q8W 248; placebo 245). At week 24, greater improvements in work productivity, nonwork daily activity, and EQ-5D-5L/EQ-VAS were observed in the Q4W and Q8W groups versus the placebo group. At week 100, LS mean reductions in work productivity impairment (− 23.8% to − 28.0%) and nonwork daily activity impairment (– 26.6% to − 29.2%) and improvements in EQ-5D-5L/EQ-VAS (0.14 to 0.15/21.2 to 25.0) were maintained in patients receiving guselkumab. Among patients employed at baseline, 12.1–16.4% were not employed at week 100, and 20.0–25.3% shifted from not employed at baseline to employed at week 100. Potential yearly indirect cost savings (USD) from improved work productivity at week 100 ranged from $16,529 to $19,409. Conclusion Patients with active PsA treated with guselkumab demonstrated reduced impairment in work productivity and nonwork daily activity, together with improvement in general health status and substantial potential cost savings, over a 2-year period. Trial Registration Clinicaltrials.gov identifier: NCT03158285.

Abstract Background We report long-term, end-of-study program safety outcomes from 25 randomized clinical trials (RCTs) in adult patients with psoriasis (PsO), psoriatic arthritis (PsA), or axial spondyloarthritis (axSpA) [including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)] who received ≥ 1 dose of Ixekizumab (IXE) over 5 years (PsO) or up to 3 years (PsA, axSpA). Methods This integrated safety analysis consists of data from patients who received any dose of IXE, across 25 RCTs (17 PsO, 4 PsA, 4 axSpA). Rates of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and selected adverse events (AEs) of interest were analyzed for all pooled studies by years of therapy and overall, through March 2022. Results were reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) overall and at successive year intervals. Results Six thousand eight hundred ninety two adult patients with PsO, 1401 with PsA, and 932 with axSpA (including AS and nr-axSpA), with a cumulative IXE exposure of 22,371.1 PY were included. The most commonly reported TEAE across indications was nasopharyngitis (IRs per 100 PY: 8.8 (PsO), 9.0 (PsA), 8.4 (axSpA)). SAEs were reported by 969 patients with PsO (IR 5.4), 134 patients with PsA (IR 6.0), and 101 patients with axSpA (IR 4.8). Forty-five deaths were reported (PsO, n = 36, IR 0.2; PsA, n = 6, IR 0.3; axSpA, n = 3, IR 0.1). TEAEs did not increase during IXE exposure: IRs per 100 PY, PsO: 88.9 to 63.2 (year 0–1 to 4–5), PsA: 87 to 67.3 (year 0–1 to 2–3), axSpA: 82.1 to 55.4 (year 0–1 to > = 2). IRs per 100 PY of discontinuation from IXE due to AE were 2.9 (PsO), 5.1 (PsA), and 3.1 (axSpA). IRs per 100 PY of injection site reactions were 5.9 (PsO), 11.6 (PsA) and 7.4 (axSpA); Candida: 1.9 (PsO), 2.0 (PsA), and 1.2 (axSpA); depression, major adverse cerebro-cardiovascular events and malignancies: ≤ 1.6 across all indications. Adjudicated IRs per 100 PY of inflammatory bowel disease were ≤ 0.8 across indications (0.1 [PsO]; 0.1 [PsA]; 0.8 [axSpA]). Conclusions In this integrated safety analysis, consisting of over 22,000 PY of exposure, the long-term safety profile of IXE was found to be consistent with previous, earlier reports, with no new safety signals identified. Trial registration NCT registration numbers for RCTs included in this integrated analysis can be found in Additional File 1.

Abstract Background To explore the trajectory of, and factors contributing to, achievement of individual criteria of minimal disease activity (MDA) in patients with active psoriatic arthritis (PsA) treated with guselkumab. Methods The Phase 3, randomized, placebo-controlled DISCOVER-2 study enrolled adults (N = 739) with active PsA despite standard therapies who were biologic/Janus kinase inhibitor-naive. Patients were randomized 1:1:1 to guselkumab 100 mg every 4 weeks; guselkumab 100 mg at week 0, week 4, then every 8 weeks; or placebo. In this post hoc analysis, patients randomized to guselkumab were included and pooled (N = 493). Longitudinal trajectories of achieving each MDA criterion through week 100 were derived using non-responder imputation. Time to achieve each criterion was estimated with Kaplan-Meier analysis. Multivariate regression for time to achieve each criterion (Cox regression) and achievement at week 100 (logistic regression) was used to identify contributing factors. Results Continuous improvement across all MDA domains was shown over time. ~70% of patients achieved near remission in swollen joint count (SJC), Psoriasis Area and Severity Index (PASI), and enthesitis through week 100. Median times to achieve individual criteria differed significantly (p

Abstract Background Genomic heterozygosity has been shown to confer a health advantage in humans and play a protective role in complex diseases. Given osteoarthritis (OA) is a highly polygenic disease, we set out to determine if an association exists between OA and genomic heterozygosity. Results End-stage knee and hip OA patients and healthy controls were recruited from the Newfoundland and Labrador (NL) population. The Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium database was utilized as a replication cohort. DNA was extracted from blood samples and genotyped. Individual rates of observed heterozygosity (HetRate) and heterozygosity excess (HetExcess) relative to the expected were mathematically derived, and standardized to a z-score. Logistic regression modeling was used to examine the association between OA and HetRate or HetExcess. A total of 559 knee and hip OA patients (mean age 66.5 years, body mass index (BMI) 33.7 kg/m2, and 55% females) and 118 healthy controls (mean age 56.4 years, BMI 29.5 kg/m2, and 59% female) were included in the NL cohort analysis. We found that OA had an inverse relationship with HetRate and HetExcess with odds ratios of 0.64 (95% CI: 0.45–0.91) and 0.65 (95% CI: 0.45–0.93) per standard deviation (SD), respectively. The arcOGEN data included 2,019 end-stage knee and hip OA patients and 2,029 healthy controls, validating our findings with HetRate and HetExcess odds ratios of 0.60 (95% CI: 0.56–0.64) and 0.44 (95% CI: 0.40–0.47) per SD, respectively. Conclusions Our results are the first to clearly show evidence, from two separate cohorts, that reduced genomic heterozygosity confers a risk for the future development of OA.

Abstract Background While genomic data sharing can facilitate important health research and discovery benefits, these must be balanced against potential privacy risks and harms to individuals. Understanding public attitudes and perspectives on data sharing is important given these potential risks and to inform genomic research and policy that aligns with public preferences and needs. Methods A cross sectional online survey measured attitudes towards genomic data sharing among members of the general public in an Eastern Canadian province. Results Results showed a moderate comfort level with sharing genomic data, usually into restricted scientific databases with controlled access. Much lower comfort levels were observed for sharing data into open or publicly accessible databases. While respondents largely approved of sharing genomic data for health research permitted by a research ethics board, many general public members were concerned with who would have access to their data, with higher rates of approval for access from clinical or academic actors, but much more limited approval of access from commercial entities or governments. Prior knowledge about sequencing and about research ethics boards were both related to data sharing attitudes. Conclusions With evolving regulations and guidelines for genomics research and data sharing, it is important to consider the perspectives of participants most impacted by these changes. Participant information materials and informed consent documents must be explicit about the safeguards in place to protect genomic data and the policies governing the sharing of data. Increased public awareness of the role of research ethics boards and of the need for genomic data sharing more broadly is also needed.

(1) Background: Osteoarthritis (OA) is a heterogeneous disorder, and subgroup classification of OA remains elusive. The aim of our study was to identify endotypes of hip OA and investigate the altered pathways in the different endotypes. (2) Methods: Metabolomic profiling and genome-wide genotyping were performed on fasting blood. Transcriptomic profiling was performed on RNA extracted from cartilage samples. Machine learning methods were used to identify endotypes of hip OA. Pathway analysis was used to identify the altered pathways between hip endotypes and controls. GWAS was performed on each of the identified metabolites. Transcriptomic data was used to examine the expression levels of identified genes in cartilage. (3) Results: 180 hip OA patients and 120 OA-free controls were classified into three clusters based on metabolomic data. The combination of arginine, ornithine, and the average value of 7 lysophosphatidylcholines had an area under the curve (AUC) of 0.97 (95% CI: 0.96–0.99) to discriminate hip OA from controls, and the combination of γ-aminobutyric acid, spermine, aconitic acid, and succinic acid had an AUC of 0.96 (95% CI: 0.94–0.99) to distinguish two hip OA endotypes. GWAS identified 236 SNPs to be associated with identified metabolites at GWAS significance level. Pro-inflammatory cytokine levels were significantly different between two endotypes (all p < 0.05). (4) Conclusions: Hip OA could be classified into two distinct molecular endotypes. The primary differences between the two endotypes involve changes in pro-inflammatory factors and energy metabolism.

Abstract Objectives To (i) determine whether sustained disease activity states, as measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS), impact function, and (ii) evaluate characteristics predicting sustained low functional impairment in a prospective axial spondyloarthritis (axSpA) cohort. Methods Biologic Treatment Registry Across Canada (BioTRAC) was a multi-center, prospective registry that collected real-world data on axSpA patients receiving infliximab or golimumab between 2006 and 2017. Generalized estimating equations (GEE) were used to test baseline characteristics, treatment, and duration (at 6 and 12 months vs. only at 6 or 12 months vs. neither) of low BASDAI (

Objective Previous analyses of pooled DISCOVER‐1 and DISCOVER‐2 data through Week 24 showed significantly higher rates of dactylitis resolution in patients treated with guselkumab compared with placebo. Here, we investigate associations between dactylitis resolution and other outcomes through 1 year. Methods Patients were randomized 1:1:1 to receive subcutaneous injections of guselkumab 100 mg at Week 0, Week 4, and then every 4 or 8 weeks, or placebo with crossover to guselkumab at Week 24. Independent assessors determined dactylitis severity score (DSS; 0‐3/digit; total = 0‐60). Dactylitis resolution (DSS = 0) (prespecified) and at least 20%, at least 50%, and at least 70% DSS improvement from baseline (post hoc) were determined through Week 52 (nonresponder imputation for treatment failure through Week 24 and for missing data through Week 52). ACR50, tender/swollen joints, low disease activity (LDA) as assessed by composite indices, and radiographic progression (DISCOVER‐2 only) were assessed in patients with dactylitis versus without dactylitis resolution at Week 24 and Week 52. Results Patients with dactylitis at baseline (473 of 1118) had more severe joint and skin disease than those without dactylitis (645 of 1118). At Week 52, approximately 75% of guselkumab‐randomized patients with dactylitis at baseline had complete resolution; approximately 80% had at least 70% DSS improvement. Through Week 52, new‐onset dactylitis (DSS ≥1) was uncommon among patients with a DSS of 0 at baseline. Guselkumab‐randomized patients with dactylitis resolution were more likely to achieve ACR50, at least 50% reduction in tender and swollen joints, and LDA at Week 24 and Week 52 than those without resolution. At Week 52, patients with dactylitis resolution had numerically less radiographic progression from baseline (DISCOVER‐2). Conclusion Through 1 year, approximately 75% of guselkumab‐randomized patients had complete resolution of dactylitis; patients exhibiting resolution were more likely to achieve other important clinical outcomes. Given the high burden of dactylitis, resolution may be associated with better long‐term patient outcomes.

Abstract Background Guselkumab, a fully human monoclonal antibody targeting the interleukin (IL)-23p19 subunit, is approved to treat adults with active psoriatic arthritis (PsA). In the Phase 3 DISCOVER-2 trial of 739 bilogico-naïve patients with active PsA, guselkumab 100 mg resulted in less radiographic progression, assessed via change from baseline in PsA-modified van der Heijde-Sharp (vdH-S) score, compared with placebo at week (W) 24 when given at W0, W4, and then every 4 weeks (Q4W) or Q8W. The least squares mean differences from placebo were -0.66 for guselkumab Q4W (p=0.011) and -0.43 for guselkumab Q8W (p=0.072). Reports suggest baseline C-reactive protein (CRP) and joint erosions are strongly prognostic of poor outcomes, especially radiographic progression, in PsA patients. We designed a trial (APEX) to further assess the effect of guselkumab on radiographic progression in patients with active PsA and risk factors for radiographic progression. Methods Patients are eligible for APEX if they have had PsA for ≥6 months and active disease (≥3 swollen and ≥3 tender joints, CRP ≥0.3 mg/dL) despite prior therapy with conventional synthetic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs, with ≥2 joints with erosions on baseline radiographs (hands and feet). The primary and major secondary endpoints are the proportion of patients achieving ≥20% improvement in American College of Rheumatology response criteria (ACR20) response at W24 and change from baseline at W24 in PsA-modified vdH-S score, respectively. Sample sizes of 350/250/350 for guselkumab Q8W/guselkumab Q4W/placebo are expected to provide >99% power to detect significant differences in W24 ACR20 response rates for each guselkumab group vs placebo, as well as ≥90% (Q4W vs placebo) and ≥80% (Q8W vs placebo) power to detect a significant difference in PsA-modified vdH-S score change at W24. A Cochran-Mantel-Haenszel test and analysis of covariance will compare treatment efficacy for the primary and major secondary endpoints, respectively. Discussion DISCOVER-2 findings informed the design of APEX, a Phase 3b study intended to further evaluate the impact of guselkumab in patients with active PsA and known risk factors for radiographic progression. Trial registration This trial was registered at ClinicalTrials.gov, NCT04882098 . Registered on 11 May 2021.

Abstract Background Skeletal muscles are essential components of the neuromuscular skeletal system that have an integral role in the structure and function of the synovial joints which are often affected by osteoarthritis (OA). The aim of this study was to identify the baseline metabolomic signatures for the longitudinal reduction of muscle strength over 10 years in the well-established community-based Tasmanian Older Adult Cohort (TASOAC). Methods Study participants were 50–79 year old individuals from the TASOAC. Hand grip, knee extension, and leg strength were measured at baseline, 2.6-, 5-, and 10-year follow-up points. Fasting serum samples were collected at 2.6-year follow-up point, and metabolomic profiling was performed using the TMIC Prime Metabolomics Profiling Assay. Generalized linear mixed effects model was used to identify metabolites that were associated with the reduction in muscle strength over 10 years after controlling for age, sex, and BMI. Significance level was defined at α=0.0004 after correction of multiple testing of 129 metabolites with Bonferroni method. Further, a genome-wide association study (GWAS) analysis was performed to explore if genetic factors account for the association between the identified metabolomic markers and the longitudinal reduction of muscle strength over 10 years. Results A total of 409 older adults (50% of them females) were included. The mean age was 60.93±6.50 years, and mean BMI was 27.12±4.18 kg/m2 at baseline. Muscle strength declined by 0.09 psi, 0.02 kg, and 2.57 kg per year for hand grip, knee extension, and leg strength, respectively. Among the 143 metabolites measured, 129 passed the quality checks and were included in the analysis. We found that the elevated blood level of asymmetric dimethylarginine (ADMA) was associated with the reduction in hand grip (p=0.0003) and knee extension strength (p=0.008) over 10 years. GWAS analysis found that a SNP rs1125718 adjacent to WISP1gene was associated with ADMA levels (p=4.39*10-8). Further, we found that the increased serum concentration of uric acid was significantly associated with the decline in leg strength over 10 years (p=0.0001). Conclusion Our results demonstrated that elevated serum ADMA and uric acid at baseline were associated with age-dependent muscle strength reduction. They might be novel targets to prevent muscle strength loss over time.

As COVID-19 vaccines become available, different model-based approaches have been developed to evaluate strategic priorities for vaccine allocation to reduce severe illness. One strategy is to directly prioritize groups that are likely to experience medical complications due to COVID-19, such as older adults. A second strategy is to limit community spread by reducing importations, for example by vaccinating members of the mobile labour force, such as rotational workers. This second strategy may be appropriate for regions with low disease prevalence, where importations are a substantial fraction of all cases and reducing the importation rate reduces the risk of community outbreaks, which can provide significant indirect protection for vulnerable individuals. Current studies have focused on comparing vaccination strategies in the absence of importations, and have not considered allocating vaccines to reduce the importation rate. Here, we provide an analytical criteria to compare the reduction in the risk of hospitalization and intensive care unit (ICU) admission over four months when either older adults or rotational workers are prioritized for vaccination. Vaccinating rotational workers (assumed to be 6,000 individuals and about 1% of the Newfoundland and Labrador (NL) population) could reduce the average risk of hospitalization and ICU admission by 42%, if no community spread is observed at the time of vaccination, because epidemic spread is reduced and vulnerable individuals are indirectly protected. In contrast, vaccinating all individuals aged 75 and older (about 43,300 individuals, or 8% of the NL population) would lead to a 24% reduction in the average risk of hospitalization, and to a 45% reduction in the average risk of ICU admission, because a large number of individuals at high risk from COVID-19 are now vaccinated. Therefore, reducing the risk of hospitalization and ICU admission of the susceptible population by reducing case importations would require a significantly lower number of vaccines. Benefits of vaccinating rotational workers decrease with increasing infection prevalence in the community. Prioritizing members of the mobile labour force should be considered as an efficient strategy to indirectly protect vulnerable groups from COVID-19 exposure in regions with low disease prevalence.

Objective Evaluate relationship between radiographic progression and clinical outcomes in post hoc analyses of patients with psoriatic arthritis (PsA) receiving up to 2 years of guselkumab therapy in the phase 3, placebo-controlled, randomised trial, DISCOVER-2.Methods Biologic-naïve adults with active PsA (≥5 swollen joints /≥5 tender joints ; C reactive protein ≥0.6 mg/dL) were randomised to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, then every 8 weeks (Q8W); or placebo→guselkumab 100 mg Q4W (week 24). Radiographs (hands/feet) at week 0, week 24, week 52 and week 100 were scored via PsA-modified van der Heijde-Sharp (vdH-S) methodology. In these post hoc analyses, mean changes in vdH-S scores were summarised according to achievement of American College of Rheumatology 20/50/70 response; low disease activity (LDA) defined by Disease Activity in Psoriatic Arthritis (DAPSA) ≤14 or Psoriatic ArthritiS Disease Activity Score (PASDAS) ≤3.2, or minimal/very low disease activity (MDA/VLDA); and normalised physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI) ≤0.5). Response rates for achieving MDA/VLDA and each component were determined among patients with and without radiographic progression (change in total vdH-S score >0.5). No formal hypothesis testing was performed.Results 664 of 739 treated patients in DISCOVER-2 continued study treatment at week 52 and were included in these analyses. Mean changes in vdH-S scores from weeks 0 to 100 among all patients in the Q4W and Q8W groups were 1.7 and 1.5, respectively. Among all guselkumab-randomised patients, those who achieved ACR20/50/70, DAPSA LDA, PASDAS LDA, MDA, VLDA and HAQ-DI ≤0.5 (normalised physical function) had smaller mean changes in vdH-S scores than did non-responders at week 52 (0.2–1.2 vs 1.7–4.1) and week 100 (0.3–1.2 vs 2.0–4.6). Relative to patients with radiographic progression, those without progression were more likely to achieve the MDA criteria related to swollen and tender joint counts, patient-reported pain and global assessment, and normalised physical function through week 100.Conclusion In these post hoc analyses, the achievement of low levels of disease activity, including MDA, was associated with diminished rates of radiographic progression observed in patients receiving up to 2 years of guselkumab. Radiographic non-progressors were more likely to achieve patient-reported MDA criteria of minimal pain and normalised physical function compared with radiographic non-responders.Trial registration number NCT03158285.

Introduction Psoriatic arthritis (PsA) is a complex, immune-mediated disease associated with skin psoriasis that, if left untreated, can lead to joint destruction. Up to 30% of patients with psoriasis progress to PsA. In most cases, psoriasis precedes synovio-entheseal inflammation by an average of 5–7 years, providing a unique opportunity for early and potentially preventive intervention in a susceptible and identifiable population. Guselkumab is an effective IL-23p19 inhibitor Food and Drug Administration (FDA)-approved for treatment of moderate-to-severe psoriasis and PsA. The Preventing Arthritis in a Multicentre Psoriasis At-Risk cohort (PAMPA) study aims to evaluate the efficacy of guselkumab in preventing PsA and decreasing musculoskeletal power Doppler ultrasound (PDUS) abnormalities in a population of patients with psoriasis who are at-increased risk for PsA progression.Methods and analysis The PAMPA study is a multicentre, randomised, double-blind, placebo-controlled, interventional, preventive trial comparing PDUS involvement and conversion to PsA in patients with psoriasis at-increased risk for progression treated with guselkumab compared with non-biological standard of care. The study includes a screening period, a double-blind treatment period (24 weeks) and an open-label follow-up period (72 weeks). At baseline, 200 subjects will be randomised (1:1) to receive either guselkumab 100 mg (arm 1) or placebo switching to guselkumab 100 mg starting at week 24 (arm 2). Arm 3 will follow 150 at-risk psoriasis patients who decline biological therapy and randomisation. Changes from baseline in the PDUS score at week 24 and the difference in proportion of patients transitioning to PsA at 96 weeks will be examined as the coprimary endpoints.Ethics and dissemination Ethics approval for this study was granted by the coordinating centre’s (NYU School of Medicine) Institutional Review Board (IRB). Each participating site received approval through their own IRBs. The findings will be shared in peer-reviewed articles and scientific conference presentations.Trial registration number NCT05004727.

Abstract Background This analysis assessed improvements in patients with radiographic axial spondyloarthritis (r-axSpA) treated with ixekizumab in the Assessment of Spondyloarthritis International Society (ASAS) treatment response domains and additional patient-reported outcomes at 1 year of treatment. Methods COAST-V and COAST-W were 52-week, phase 3, randomized controlled trials evaluating the efficacy and safety of ixekizumab in biologic disease-modifying antirheumatic drug (bDMARD)-naïve and tumor necrosis factor inhibitor (TNFi)-experienced patients with radiographic spondyloarthritis, respectively. Patients were treated with 80-mg ixekizumab either every 2 weeks or every 4 weeks. Patient-reported outcomes included Patient Global Disease Activity, Spinal Pain, stiffness as measured by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) Questions 5 and 6, function as measured by the Bath Ankylosing Spondylitis Functional Index, fatigue as measured by the Fatigue Numeric Rating Scale and BASDAI question 1, Spinal Pain at Night, and sleep quality as measured by the Jenkins Sleep Evaluation Questionnaire. Mixed-effects models for repeated measures were used to analyze changes from baseline in patient-reported outcomes from weeks 1 to 16, and descriptive statistics were reported from weeks 20 to 52. Analysis of covariance with Scheffé’s method was used for the ASAS response association analyses. Results This study assessed 341 bDMARD-naïve and 316 TNFi-experienced patients in the placebo-controlled blinded treatment dosing period (weeks 1–16) as well as 329 bDMARD-naïve and 281 TNFi-experienced patients in the dose double-blind extended treatment period (weeks 20–52). bDMARD-naïve or TNFi-experienced patients treated with ixekizumab every 2 weeks and every 4 weeks reported improvements in patient global disease activity, spinal pain, function, stiffness, fatigue, spinal pain at night, and sleep quality through week 52. Greater correlations with improvements in all response domains were seen when comparing ASAS40 responders to ASAS20 non-responders (p

Abstract Background The interleukin-23p19-subunit inhibitor guselkumab effectively treats signs and symptoms of psoriatic arthritis (PsA). We evaluated the effect of guselkumab on fatigue. Methods Across two phase 3 trials of guselkumab (DISCOVER-1, DISCOVER-2), patients with active PsA despite standard therapy were randomized to subcutaneous injections of guselkumab 100 mg every 4 weeks (Q4W, N = 373); guselkumab 100 mg at week 0, week 4, and then Q8W (N = 375); or placebo (N = 372) through week 24, after which patients in the placebo group crossed over to guselkumab Q4W. Fatigue was measured as a secondary endpoint using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue instrument (range 0–52, higher scores indicate less fatigue). Least-squares mean changes in FACIT-Fatigue scores were compared between treatments using a mixed-effect model for repeated measures. Mediation analysis was used to adjust for indirect effects on fatigue deriving from improvement in other outcomes, including ≥20% improvement in American College of Rheumatology criteria (ACR20; prespecified), minimal disease activity (MDA; post hoc), or C-reactive protein (CRP; post hoc). Results Baseline mean (SD) FACIT-Fatigue scores in DISCOVER-1 (N = 381) and DISCOVER-2 (N = 739), ranging from 29.1 (9.5) to 31.4 (10.1), indicated substantial levels of fatigue relative to the United States general population (43.6 [9.4]). Across studies, mean improvements, and proportions of patients with ≥4-point improvements, in FACIT-Fatigue scores at week 24 with guselkumab Q4W and Q8W (5.6–7.6 and 54–63%, respectively) were larger vs placebo (2.2–3.6 and 35–46%). Improvement in FACIT-Fatigue scores with guselkumab was sustained from week 24 to week 52, with moderate-to-large effect sizes (Cohen’s d = 0.52–0.81 at week 24; 0.66–0.91 at week 52). Mediation analyses demonstrated that substantial proportions of the effects of guselkumab vs placebo on fatigue were direct effect, after adjusting for achievement of ACR20 (Q4W 69–70%, Q8W 12–36% direct effect) or MDA (72–92% across dosing regimens) response or for change in serum CRP concentrations (82–88% across dosing regimens). Conclusions In patients with active PsA, guselkumab 100 mg Q4W or Q8W led to clinically meaningful and sustained improvements in fatigue through 1 year. A substantial portion of the improvement in FACIT-Fatigue scores induced by guselkumab was independent of effects on the achievement of other select outcomes. Trial registration Name of the registry: ClinicalTrials.gov Trial registrations: DISCOVER-1, NCT03162796; DISCOVER-2, NCT03158285 Date of registration: DISCOVER-1, May 22, 2017; DISCOVER-2, May 18, 2017 URLs of the trial registry record: DISCOVER-1, https://clinicaltrials.gov/ct2/show/NCT03162796?term=NCT03162796&draw=1&rank=1 DISCOVER-2, https://clinicaltrials.gov/ct2/show/NCT03158285?term=NCT03158285&draw=2&rank=1

The Janssen and Newfoundland and Labrador Health Innovation Partnership (JANL-HIP) was established to carry out Real-World Evidence (RWE) projects to generate evidence about disease pathways, healthcare delivery, the effects of clinical interventions. Doing so will support and influence clinical decision-making in Newfoundland and Labrador (NL). This case study describes the foundational elements necessary for a~real-world evidence~generation project in NL and may provide learning for the effective execution of real-world studies in other jurisdictions. It uses an ongoing project in psoriatic disease in NL to illustrate the partnership and the benefits of RWE studies. Ultimately, the JANL-HIP RWE project aims to inform decisions that will drive improvements in health outcomes, system delivery, and policy mutually beneficial to health ecosystem stakeholders.

Abstract Background Limitations in spinal mobility are a characteristic feature of Axial Spondyloarthritis. Current clinical measurements of spinal mobility have shown low criterion-concurrent validity. This study sought to evaluate criterion-concurrent validity for a clinically feasible measurement method of measuring spine mobility using tri-axial accelerometers. Methods Fifteen radiographic-Spondyloarthritis patients were recruited for this study. Two postural reference radiographs, followed by three trials in forward, left and right lateral bending were taken. For all trials, three measurements were collected: tape (Original Schober’s, Modified Schober’s, Modified-Modified Schober’s, Lateral Spinal Flexion Test and Domjan Test), followed immediately by synchronized radiograph and accelerometer measurements at end range of forward and bilateral lateral flexion. The criterion-concurrent validity of all measurement methods was compared to the radiographic measures using Pearson’s correlation coefficients. A Bland-Altman analysis was conducted to assess agreement. Results In forward bending, the accelerometer method (r = 0.590, p = 0.010) had a stronger correlation to the radiographic measures than all tape measures. In lateral bending, the Lateral Spinal Flexion tape measure (r = 0.743, p = 0.001) correlated stronger than the accelerometer method (r = 0.556, p = 0.016). The Domjan test of bilateral bending (r = 0.708, p = 0.002) had a stronger correlation to the radiographic measure than the accelerometer method. Conclusions Accelerometer measures demonstrated superior criterion-concurrent validity compared to current tape measures of spinal mobility in forward bending. While a moderate correlation exists between accelerometer and radiographs in lateral bending, the Lateral Spinal Flexion Test and Domjan Test were found to have the best criterion-concurrent validity of all tests examined in this study.

Abstract Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders.

Abstract Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40–50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4+ transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein–protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.

Abstract Background The objectives of this study were to describe the profile of ankylosing spondylitis (AS) patients treated with either infliximab (IFX) or subcutaneous golimumab (GLM) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety. Methods AS patients who were eligible for treatment with IFX or subcutaneous GLM as per their respective Canadian product monographs were enrolled into the BioTRAC registry from 2005 to 2017. The study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in clinical outcomes and acute phase reactants. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates. Results A total of 389 IFX- and 421 GLM-treated patients were enrolled. A significant decrease in disease duration at baseline was observed in the IFX cohort, from a median of 8.0 in 2005–2008 to 1.0 years in 2009–2015 (p

Abstract Background Long-term clinical registries are essential tools to evaluate new therapies in a patient population that differs from those in randomized clinical trials. The objectives are to describe the profile of rheumatoid arthritis (RA) patients treated with anti-TNF agents in Canadian routine care. Methods RA patients eligible for treatment with Infliximab (IFX), golimumab (GLM) or intravenous golimumab (GLM-IV) as per their respective Canadian product monographs were enrolled into the BioTRAC registry between 2002 and 2017. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in disease activity. Safety was evaluated by the incidence of adverse events (AEs) and drug survival. Results Of the 890 IFX-, 530 GLM- and 157 GLM-IV-treated patients, the proportion of females ranged from 77.0–86.6%, the mean ages from 55.8–57.7 and the mean disease duration from 6.5–8.6 years. A significant decrease in baseline disease duration and disease activity parameters (DAS, TJC, SJC, HAQ, AM stiffness, MDGA, PtGA, CRP, ESR) was observed over time. Treatment with IFX, GLM- and GLM-IV significantly improved all disease parameters over time. The incidence of AEs was 105, 113 and 82.6 /100 PYs and the incidence of SAEs was 11.7, 11.2 and 4.68 /100 PYs for IFX, GLM- and GLM-IV-treated patients, respectively. Conclusion Differences in baseline characteristics between patients treated with an anti-TNFs over time shows the evolution of treatment modalities over time. All treatments significantly reduced disease activity and improved functionality in a similar fashion. The incidence of adverse events was consistent with the safety profiles of IFX and GLM. Trial registration ClinicalTrials.gov Identifier: NCT00741793 (Retrospectively registered on August 26, 2008).

Abstract Introduction Patients with ankylosing spondylitis (AS) are burdened with symptoms impacting work productivity measured by presenteeism, absenteeism, overall work impairment, and activity impairment. Ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been demonstrated to improve disease signs and symptoms in two phase 3 trials of AS. This study investigated for 52 weeks the effect of ixekizumab treatment on work productivity in patients with active AS. Methods COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, controlled trials investigating the efficacy of ixekizumab 80 mg every 4 weeks (Q4W) and every 2 weeks (Q2W) in patients with AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) or who were inadequate responders or intolerant to tumor necrosis factor inhibitors (TNFi; COAST-W). Work productivity was measured with the Work Productivity and Activity Impairment Questionnaire for Spondyloarthritis at weeks 16 and 52. Absenteeism, presenteeism, and overall work impairment were assessed for patients reporting paid work. Activity impairment was assessed regardless of work status. Results At baseline, 66.2% (434/656) of patients reported paid work. At week 16, bDMARD-naïve patients treated with both ixekizumab dose regimens and TNFi-experienced patients treated with ixekizumab Q2W reported significant improvements in activity impairment (p

Abstract Background The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3). Methods Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥ 1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3 years for adverse events. Results Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6). Conclusions The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis. Trial registration SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

Summary: Understanding host cell heterogeneity is critical for unraveling disease mechanism. Utilizing large-scale single-cell transcriptomics, we analyzed multiple tissue specimens from patients with life-threatening COVID-19 pneumonia, compared with healthy controls. We identified a subtype of monocyte-derived alveolar macrophages (MoAMs) where genes associated with severe COVID-19 comorbidities are significantly upregulated in bronchoalveolar lavage fluid of critical cases. FCGR3B consistently demarcated MoAM subset in different samples from severe COVID-19 cohorts and in CCL3L1-upregulated cells from nasopharyngeal swabs. In silico findings were validated by upregulation of FCGR3B in nasopharyngeal swabs of severe ICU COVID-19 cases, particularly in older patients and those with comorbidities. Additional lines of evidence from transcriptomic data and in vivo of severe COVID-19 cases suggest that FCGR3B may identify a specific subtype of MoAM in patients with severe COVID-19 that may present a novel biomarker for screening and prognosis, as well as a potential therapeutic target.

Objective Secukinumab provided sustained efficacy, low radiographic progression and consistent safety over 52 weeks in patients with psoriatic arthritis (PsA) in the FUTURE 5 study. Here, we report 2-year (end-of-study) results from this study.Methods Adults with active PsA were randomised 2:2:2:3 to receive subcutaneous secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load or placebo at baseline; weeks 1, 2, 3 and 4; and every 4 weeks thereafter. Secukinumab could be escalated from 150 mg to 300 mg starting at week 52, if active signs of disease were observed based on physician’s assessment. Assessments at week 104 (2 years) included clinical end points and radiographic damage (mean change in van der Heijde-modified total Sharp score (vdH-mTSS)). Safety analysis included all patients who received ≥1 dose of study medication.Results Of the 996 patients randomised, 783 patients (78.6%) completed 2 years of treatment. Improvement in clinical end points was sustained through 2 years. The vdH-mTSS (mean change (SD)) was 0.10 (1.74; 300 mg), 0.52 (2.66; 150 mg) and 0.41 (2.20; 150 mg no load) at 2 years. The proportion of patients with no radiographic progression (change from baseline in vdH-mTSS ≤0.5) at 2 years was 89.5% (300 mg), 82.3% (150 mg) and 81.1% (150 mg no load).Conclusion Secukinumab with and without loading regimen provided sustained clinical efficacy and low radiographic progression through 2 years in patients with PsA. No new safety findings were reported.Trial registration number NCT02404350.

Abstract Background Identification of the optimal treatment for a given patient is of paramount importance. This is of particular relevance in osteoarthritis (OA) because of the high prevalence of the disease, extensive heterogeneity of the disease, and need for long-term treatment. The aim of the study was to examine whether serum lysophosphatidylcholines (lysoPCs) to phosphatidylcholines (PCs) ratio can predict clinical response to licofelone and naproxen treatments in symptomatic knee OA patients. Methods One hundred fifty-eight OA patients who completed the study according to protocol (ATP) of a previous 24-month clinical trial cohort comparing the effect of licofelone vs. naproxen in symptomatic knee OA patients were included. Symptomatic responses to either treatments were classified according to the OARSI-OMERACT criteria based on the WOMAC scores at 24 months. Total concentrations of PCs and lysoPCs were measured in the serum samples collected before the initiation of the treatments, and the lysoPCs to PCs ratio was calculated. Student’s t test was utilized to compare the difference in the ratio of lysoPCs to PCs between the symptomatic responders and non-responders. Logistic regression was utilized to adjust for the potential confounders. Receiver operating characteristic (ROC) analysis was performed to identify the optimal cutoff of the ratio for prediction. Results Data showed that 61.4% of the patients symptomatically responded to licofelone and naproxen and 38.6% were deemed as therapeutic failures (non-responders). There was no difference in responders between licofelone and naproxen (p = 0.87). Responders had a significantly higher lysoPCs to PCs ratio than non-responders (0.097 ± 0.003 vs. 0.085 ± 0.003; p = 0.006). Patients with a ratio greater than the optimal cutoff of 0.088 had 2.93 times more likely to respond to licofelone and naproxen (p = 0.002). Conclusions Serum lysoPCs to PCs ratio is a marker for response to licofelone and naproxen and may aid in the personalized treatment to knee OA.

In many jurisdictions, public health authorities have implemented travel restrictions to reduce coronavirus disease 2019 (COVID-19) spread. Policies that restrict travel within countries have been implemented, but the impact of these restrictions is not well known. On 4 May 2020, Newfoundland and Labrador (NL) implemented travel restrictions such that non-residents required exemptions to enter the province. We fit a stochastic epidemic model to data describing the number of active COVID-19 cases in NL from 14 March to 26 June. We predicted possible outbreaks over nine weeks, with and without the travel restrictions, and for contact rates 40–70% of pre-pandemic levels. Our results suggest that the travel restrictions reduced the mean number of clinical COVID-19 cases in NL by 92%. Furthermore, without the travel restrictions there is a substantial risk of very large outbreaks. Using epidemic modelling, we show how the NL COVID-19 outbreak could have unfolded had the travel restrictions not been implemented. Both physical distancing and travel restrictions affect the local dynamics of the epidemic. Our modelling shows that the travel restrictions are a plausible reason for the few reported COVID-19 cases in NL after 4 May.

Obesity is a global pandemic, but there is yet no effective measure to control it. Recent metabolomics studies have identified a signature of altered amino acid profiles to be associated with obesity, but it is unclear whether these findings have actionable clinical potential. The aims of this study were to reveal the metabolic alterations of obesity and to explore potential strategies to mitigate obesity. We performed targeted metabolomic profiling of the plasma/serum samples collected from six independent cohorts and conducted an individual data meta-analysis of metabolomics for body mass index (BMI) and obesity. Based on the findings, we hypothesized that restriction of branched-chain amino acids (BCAAs), phenylalanine, or tryptophan may prevent obesity and tested our hypothesis in a dietary restriction trial with eight groups of 4-week-old male C57BL/6J mice (n = 5/group) on eight different types of diets, respectively, for 16 weeks. A total of 3397 individuals were included in the meta-analysis. The mean BMI was 30.7 ± 6.1 kg/m2, and 49% of participants were obese. Fifty-eight metabolites were associated with BMI and obesity (all p ≤ 2.58 × 10−4), linked to alterations of the BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways. The restriction of BCAAs within a high-fat diet (HFD) maintained the mice’s weight, fat and lean volume, subcutaneous and visceral adipose tissue weight, and serum glucose and insulin at levels similar to those in the standard chow group, and prevented obesity, adipocyte hypertrophy, adipose inflammation, and insulin resistance induced by HFD. Our data suggest that four metabolic pathways, BCAA, phenylalanine, tryptophan, and phospholipid metabolic pathways, are altered in obesity and restriction of BCAAs within a HFD can prevent the development of obesity and insulin resistance in mice, providing a promising strategy to potentially mitigate diet-induced obesity.

Objectives The objectives of this study were to describe the demographic profile and baseline disease characteristics of patients with psoriatic arthritis (PsA) treated with either infliximab (IFX), subcutaneous golimumab (GLM) or ustekinumab (UST) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety.Methods Patients with PsA were enrolled into the Biologic Treatment Registry Across Canada registry (ClinicalTrials.gov Identifier: NCT00741793) from 2005 to 2017. The study visits occurred at study enrolment (baseline) and every 6 months thereafter. Effectiveness was assessed by changes in disease parameters (joint counts, Psoriasis Area Severity Index (PASI), Health Assessment Questionnaire, patient/physician global, minimal disease activity, enthesitis, dactylitis, erythrocyte sedimentation rate, C reactive protein). Improvements from baseline were explored with the paired t-test and the McNemar’s test. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates.Results A total of 111 IFX-treated, 281 GLM-treated and 70 UST-treated patients were enrolled. Most baseline disease parameters remained similar over time in all three cohorts. UST-treated patients had lower mean baseline Disease Activity Score in 28 joints CRP, swollen joint based on 28 joints and higher PASI compared with patients treated with GLM. Treatment with IFX, GLM and UST was associated with significant improvements in all disease parameters over time (p

Abstract Background There appears to be large regional variation for susceptibility, severity, and mortality for COVID‐19 infections. Numerous potential factors could explain the wide variability in the number of infections and death among the countries. We examined genetic differences in the human angiotensin‐converting enzyme 2 (hACE2) gene, as its receptor serves as a cellular entry for SARS‐CoV‐2. At present, there is a paucity of data regarding the differences for ACE2 polymorphisms and expression levels between ethnicities. Methods We compared the allele frequency of mutations between European and East Asians. Molecular dynamic simulation were performed to investigate the influences of significant mutant on protein structure. The binding free energies were calculated between S protein and hACE2. We also examined hACE2 gene expression in eight global populations from HapMap3. Results Four missense mutations showed significant minor allele frequency difference between Asians and Caucasians. Molecular dynamic demonstrated that two of these variants (K26R and I468V) may affect binding characteristics between S protein of the virus and hACE2 receptor. We also noted marginal differences in gene expression for some populations in HapMap3 as compared to the Chinese population. Conclusion Our studies reveal subtle changes in the genetics of hACE2 between human populations, but the magnitude of the difference was small and the significance is not clear in the absence of further in vitro and functional studies.

Approximately 30% of psoriasis patients develop psoriatic arthritis (PsA) and early diagnosis is crucial for the management of PsA. Here, Patrick et al. develop a computational pipeline involving statistical and machine-learning methods that can assess the risk of progression to PsA based on genetic markers.

Abstract Background The study aimed to assess 52-week efficacy and safety of secukinumab self-administration by autoinjector in patients with active psoriatic arthritis (PsA) in the FUTURE 3 study (ClinicalTrials.gov NCT01989468). Methods Patients (≥ 18 years of age; N = 414) with active PsA were randomized 1:1:1 to subcutaneous (s.c.) secukinumab 300 mg, 150 mg, or placebo at baseline, weeks 1, 2, 3, and 4, and every 4 weeks thereafter. Per clinical response, placebo-treated patients were re-randomized to s.c. secukinumab 300 or 150 mg at week 16 (nonresponders) or week 24 (responders) and stratified at randomization by prior anti-tumor necrosis factor (TNF) therapy (anti-TNF-naïve, 68.1%; intolerant/inadequate response (anti-TNF-IR), 31.9%). The primary endpoint was the proportion of patients achieving at least 20% improvement in American College of Rheumatology response criteria (ACR20) at week 24. Autoinjector usability was evaluated by Self-Injection Assessment Questionnaire (SIAQ). Results Overall, 92.1% (300 mg), 91.3% (150 mg), and 93.4% (placebo) of patients completed 24 weeks, and 84.9% (300 mg) and 79.7% (150 mg) completed 52 weeks. In the overall population (combined anti-TNF-naïve and anti-TNF-IR), ACR20 response rate at week 24 was significantly higher in secukinumab groups (300 mg, 48.2% (p < 0.0001); 150 mg, 42% (p < 0.0001); placebo, 16.1%) and was sustained through 52 weeks. SIAQ results showed that more than 93% of patients were satisfied/very satisfied with autoinjector usage. Secukinumab was well tolerated with no new or unexpected safety signals reported. Conclusions Secukinumab provided sustained improvements in signs and symptoms in active PsA patients through 52 weeks. High acceptability of autoinjector was observed. The safety profile was consistent with that reported previously. Trial registration ClinicalTrials.gov NCT01989468. Registered 21 November 2013. EudraCT 2013–004002-25. Registered 17 December 2013.

Psoriasis is an immune-mediated skin disease with a complex genetic architecture. Here, Elder and colleagues identify 16 novel psoriasis susceptibility loci using GWAS meta-analysis with a combined effective sample size of over 39,000 individuals.

We recently conducted a large association analysis to compare the genetic profiles between patients with psoriatic arthritis (PsA) and cutaneous-only psoriasis (PsC). Despite including over 7,000 genotyped patients, only the MHC achieved genome-wide significance. In this study, we hypothesized that appropriate epigenomic elements (H3K27ac marks for active enhancers) can guide us to reveal valuable information about the loci with suggestive evidence of association. Our aim is to investigate these loci and explore how they may lead to the development of PsA. We evaluated this potential by investigating the genes connected with these loci from the perspective of pharmacogenomics and gene expression. We illustrated that markers with suggestive evidence of association outside the MHC region are enriched in H3K27ac marks for osteoblast and chondrogenic differentiated cells; using pharmacogenomics resources, we showed that genes near these markers are targeted by existing drugs used to treat psoriatic arthritis. Significantly, six of the ten suggestive significant loci overlapping the regulatory elements encompass genes differentially expressed (FDR < 5%) in differentiated osteoblasts, including genes participating in the Wnt signaling such as RUNX1, FUT8, and CTNNAL1. Our approach shows that epigenomic information can be used as cost-effective approach to enhance the inferences for GWAS results, especially in situations when few genome-wide significant loci are available. Our results also point the way to more directed investigations comparing the genetics of PsA and PsC.

Objectives To describe the profile of patients with ankylosing spondylitis (AS) treated with infliximab in Canadian routine care and to assess the effectiveness and safety of infliximab in real world.Setting 46 primary care rheumatology practices across Canada.Participants 303 biological-naïve patients with AS or patients previously treated with a biological for

Rat bite fever is rare in Western countries. It can be very difficult to diagnose as blood cultures are typically negative and a history of rodent exposure is often missed. Unless a high index of suspicion is maintained, the associated polyarthritis can be mistaken for rheumatoid arthritis. We report a case of culture-positive rat bite fever in a 46-year-old female presenting with fever and polyarthritis. The clinical presentation mimicked rheumatoid arthritis. Infection was complicated by discitis, a rare manifestation. We discuss the diagnosis and management of this rare zoonotic infection. We also review nine reported cases of rat bite fever, all of which had an initial presumptive diagnosis of a rheumatological disorder. Rat bite fever is a potentially curable infection but can have a lethal course if left untreated.

Darren D O’Rielly, Proton RahmanFaculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland, CanadaAbstract: Rheumatoid arthritis (RA) is a chronic heterogeneous autoimmune disorder of unknown etiology resulting in inflammation in the synovium, cartilage, and bone. Genetic factors play an important role in susceptibility to RA as the heritability of RA is between 50% and 60%, with the human leukocyte antigen (HLA) locus accounting for at least 30% of overall genetic risk. Outside the major histocompatibility complex (MHC) region, six additional risk loci have been identified and validated including PTPN22, STAT4, PADI4, CTLA4, TNFAIP3-OLIG3, and TRAF1/C5. Genetic factors are also important in RA pharmacotherapy due to the gene-dependent activity of enzymes involved in the pharmacokinetics and/or pharmacodynamics of RA medications. Indeed, there is great variability in drug efficacy as well as adverse events associated with any anti-rheumatic therapy and genetics is thought to contribute significantly to this inter-individual variability in response. This review will summarize the genetic factors that have been implicated in the pathogenesis of RA, and how these determinants may factor into the potential pharmacogenetics of this disease. We will also review the therapeutic agents that are currently being utilized or presently being evaluated in the treatment of RA, along with potential pharmacogenetic markers that have been proposed for such medications.Keywords: rheumatoid arthritis, susceptibility genes, pharmacogenetics

A newly-described syndrome called Aneurysm-Osteoarthritis Syndrome (AOS) was recently reported. AOS presents with early onset osteoarthritis (OA) in multiple joints, together with aneurysms in major arteries, and is caused by rare mutations in SMAD3. Because of the similarity of AOS to idiopathic generalized OA (GOA), we hypothesized that SMAD3 is also associated with GOA and tested the hypothesis in a population-based cohort.Study participants were derived from the Chingford study. Kellgren-Lawrence (KL) grades and the individual features of osteophytes and joint space narrowing (JSN) were scored from radiographs of hands, knees, hips, and lumbar spines. The total KL score, osteophyte score, and JSN score were calculated and used as indicators of the total burden of radiographic OA. Forty-one common SNPs within SMAD3 were genotyped using the Illumina HumanHap610Q array. Linear regression modelling was used to test the association between the total KL score, osteophyte score, and JSN score and each of the 41 SNPs, with adjustment for patient age and BMI. Permutation testing was used to control the false positive rate.A total of 609 individuals were included in the analysis. All were Caucasian females with a mean age of 60.9±5.8. We found that rs3825977, with a minor allele (T) frequency of 20%, in the last intron of SMAD3, was significantly associated with total KL score (β = 0.14, Ppermutation = 0.002). This association was stronger for the total JSN score (β = 0.19, Ppermutation = 0.002) than for total osteophyte score (β = 0.11, Ppermutation = 0.02). The T allele is associated with a 1.47-fold increased odds for people with 5 or more joints to be affected by radiographic OA (Ppermutation = 0.046).We found that SMAD3 is significantly associated with the total burden of radiographic OA. Further studies are required to reveal the mechanism of the association.

Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS.A total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke' Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates.We identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74 × 10(-4)) and rs1235192 [OR 1.92, p = 1.17 × 10(-3)]) adjusted by covariates.This is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.

The primary objective of this study was to create a genome-wide high resolution map (i.e., >100 bp) of 'rearrangement hotspots' which can facilitate the identification of regions capable of mediating de novo deletions or duplications in humans. A hierarchical method was employed to fragment segmental duplications (SDs) into multiple smaller SD units. Combining an end space free pairwise alignment algorithm with a 'seed and extend' approach, we have exhaustively searched 409 million alignments to detect complex structural rearrangements within the reference-guided assembly of the NA18507 human genome (18× coverage), including the previously identified novel 4.8 Mb sequence from de novo assembly within this genome. We have identified 1,963 rearrangement hotspots within SDs which encompass 166 genes and display an enrichment of duplicated gene nucleotide variants (DNVs). These regions are correlated with increased non-allelic homologous recombination (NAHR) event frequency which presumably represents the origin of copy number variations (CNVs) and pathogenic duplications/deletions. Analysis revealed that 20% of the detected hotspots are clustered within the proximal and distal SD breakpoints flanked by the pathogenic deletions/duplications that have been mapped for 24 NAHR-mediated genomic disorders. FISH Validation of selected complex regions revealed 94% concordance with in silico localization of the highly homologous derivatives. Other results from this study indicate that intra-chromosomal recombination is enhanced in genic compared with agenic duplicated regions, and that gene desert regions comprising SDs may represent reservoirs for creation of novel genes. The generation of genome-wide signatures of 'rearrangement hotspots', which likely serve as templates for NAHR, may provide a powerful approach towards understanding the underlying mutational mechanism(s) for development of constitutional and acquired diseases.

Ankylosing spondylitis (AS) is a common inflammatory arthritic condition. Overt inflammatory bowel disease (IBD) occurs in about 10% of AS patients, and in addition 70% of AS cases may have subclinical terminal ileitis. Spondyloarthritis is also common in IBD patients. We therefore tested Crohn's disease susceptibility genes for association with AS, aiming to identify pleiotropic genetic associations with both diseases. Genotyping was carried out using Sequenom and Applied Biosystems TaqMan and OpenArray technologies on 53 markers selected from 30 Crohn's disease associated genomic regions. We tested genotypes in a population of unrelated individual cases (n = 2,773) and controls (n = 2,215) of white European ancestry for association with AS. Statistical analysis was carried out using a Cochran-Armitage test for trend in PLINK. Strong association was detected at chr1q32 near KIF21B (rs11584383, P = 1.6 × 10(-10), odds ratio (OR) = 0.74, 95% CI:0.68-0.82). Association with disease was also detected for 2 variants within STAT3 (rs6503695, P = 4.6 × 10(-4). OR = 0.86 (95% CI:0.79-0.93); rs744166, P = 2.6 × 10(-5), OR = 0.84 (95% CI:0.77-0.91)). Association was confirmed for IL23R (rs11465804, P = 1.2 × 10(-5), OR = 0.65 (95% CI:0.54-0.79)), and further associations were detected for IL12B (rs10045431, P = 5.2 × 10(-5), OR = 0.83 (95% CI:0.76-0.91)), CDKAL1 (rs6908425, P = 1.1 × 10(-4), OR = 0.82 (95% CI:0.74-0.91)), LRRK2/MUC19 (rs11175593, P = 9.9 × 10(-5), OR = 1.92 (95% CI: 1.38-2.67)), and chr13q14 (rs3764147, P = 5.9 × 10(-4), OR = 1.19 (95% CI: 1.08-1.31)). Excluding cases with clinical IBD did not significantly affect these findings. This study identifies chr1q32 and STAT3 as ankylosing spondylitis susceptibility loci. It also further confirms association for IL23R and detects suggestive association with another 4 loci. STAT3 is a key signaling molecule within the Th17 lymphocyte differentiation pathway and further enhances the case for a major role of this T-lymphocyte subset in ankylosing spondylitis. Finally these findings suggest common aetiopathogenic pathways for AS and Crohn's disease and further highlight the involvement of common risk variants across multiple diseases.