Early microRNA and metabolite changes after anterior cruciate ligament reconstruction surgery.

OBJECTIVES: Anterior cruciate ligament (ACL) reconstruction after injury does not prevent post-traumatic osteoarthritis (PTOA). Circulating microRNA (miRNA) and metabolite changes emerging shortly after ACL injury and reconstruction remain insufficiently defined, potentially harbouring early cues contributing to PTOA evolution. Moreover, their differential expression between females and males also may influence PTOA's natural trajectory. This study aims to determine alterations in plasma miRNA and metabolite levels in the early stages following ACL reconstruction and between females and males. METHODS: A cohort of 43 ACL reconstruction patients was examined. Plasma was obtained at baseline, 2 weeks, and 6 weeks post-surgery (129 biospecimens in total). High-throughput miRNA sequencing and metabolomics were conducted. Differentially expressed miRNAs and metabolites were identified using negative binomial and linear regression models, respectively. Associations between miRNAs and metabolites were explored using time and sex as co-variants, (pre-surgery versus 2 and 6 weeks post-surgery). Using computational biology, miRNA-metabolite-gene interaction and pathway analyses were performed. RESULTS: Levels of 46 miRNAs were increased at 2 weeks post-surgery compared to pre-surgery (baseline) using miRNA sequencing. Levels of 13 metabolites were significantly increased while levels of 6 metabolites were significantly decreased at 2 weeks compared to baseline using metabolomics. Hsa-miR-145-5p levels were increased in female subjects at both 2 weeks (log2-fold-change 0.71, 95%CI 0.22,1.20) and 6 weeks (log2-fold-change 0.75, 95%CI 0.07,1.43) post-surgery compared to males. In addition, hsa-miR-497-5p showed increased levels in females at 2 weeks (log2-fold-change 0.77, 95%CI 0.06,1.48) and hsa-miR-143-5p at 6 weeks (log2-fold-change 0.83, 95%CI 0.07,1.59). Five metabolites were decreased at 2 weeks post-surgery in females compared to males: L-leucine (-1.44, 95%CI -1.75,-1.13), g-guanidinobutyrate (-1.27, 95%CI 1.54,-0.99), creatinine (-1.17, 95%CI -1.44,-0.90), 2-methylbutyrylcarnitine (-1.76, 95%CI -2.17,-1.35), and leu-pro (-1.13, 95%CI -1.44,-0.83). MiRNA-metabolite-gene interaction analysis revealed key signalling pathways based on post-surgical time-point and in females versus males. CONCLUSION: MiRNA and metabolite profiles were modified by time and by sex early after ACL reconstruction surgery, which could influence surgical response and ultimately risk of developing PTOA.

GRAPPA 2023 Collaborative Research Network Meeting.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Collaborative Research Network (CRN)/research committee met during the GRAPPA 2023 annual meeting. Updates were provided on GRAPPA research projects, including the Axial Involvement in Psoriatic Arthritis (AXIS), Axial Psoriatic Arthritis Molecular and Clinical Characterisation Study, Diagnostic Ultrasound Enthesitis Tool (DUET), and Sex- and Gender-Based Analysis of the Effectiveness of Advanced Therapies (SAGE) studies, as well as the Health Initiatives in Psoriasis and Psoriatic Arthritis Consortium European States (HIPPOCRATES) and Elucidating the Landscape of Immunoendotypes in Psoriatic Skin and Synovium (ELLIPSS) studies. The highlight of the meeting was a presentation and discussion on the use of digital tools to study psoriatic disease.

Biomarkers in Psoriasis and Psoriatic Arthritis: Where Are We Now?

At the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual conference and trainee symposium, the status of psoriatic disease (PsD) biomarkers was discussed in a workshop. The significant heterogeneity of PsD causes disease management to be very challenging, but biomarkers can prove helpful in disease diagnosis, stratification, and precision medicine. Although a few potential biomarkers have been discovered, none have been fully validated. Recent studies have used omic technologies that show promise but need further verification and validation. Many challenges remain, but the anticipated results of studies being conducted by recently established large consortia may lead to the identification of clinically actionable biomarkers.

Advances in Psoriatic Disease Research: Insights From GRAPPA Pilot Research Awardees.

Research progress from the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) pilot award program was presented and discussed at the GRAPPA 2023 annual meeting. Topics included identification of protein biomarkers associated with enthesitis in psoriatic arthritis (PsA), the role of HLA-B27 on gut microbial dysbiosis in PsA, single-cell profiling of synovial fluid vs psoriatic skin lesions in PsA, and the role of mechanotransduction in hyperactivation of transforming growth factor-ß via αVß6 integrin in psoriatic epidermis.

Duration of Postvaccination Neutralizing Antibodies to SARS-CoV-2 and Medication Effects: Results from the Safety and Immunogenicity of COVID-19 Vaccination in Systemic Immune-Mediated Inflammatory Diseases Cohort Study.

OBJECTIVE: In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications. METHODS: Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5. RESULTS: Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses. CONCLUSION: Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.

Caffeine Boosts Weight-Lifting Performance in Rats: A Pilot Study.

Caffeine is a well-described ergogenic aid used to enhance athletic performance. Using animal models can greatly increase our understanding of caffeine's mechanisms in performance. Here, we adapted an animal weight-lifting exercise model to demonstrate caffeine's ergogenic effect in rats. Male Wistar rats (315 ± 35 g) were randomly divided into two groups: one group received 5 mg·kg-1 of caffeine (0.5 mL; CEx; n = 5) and the other 0.9% NaCl (0.5 mL; PEx; n = 4) through an orogastric probe (gavage) one hour before exercise. Weight-lifting exercise sessions were performed over three subsequent days, and the number of complete squats performed was counted. Analyses of the area under the curve in all three experiments showed that the CEx group responded more to stimuli, performing more squats (1.7-, 2.0-, and 1.6-fold; p < 0.05) than the control group did. These three days' data were analyzed to better understand the cumulative effect of this exercise, and a hyperbolic curve was fitted to these data. Data fitting from the caffeine-supplemented group, CEx, also showed larger Smax and Kd (2.3-fold and 1.6-fold, respectively) than the PEx group did. Our study demonstrated an acute ergogenic effect of caffeine in an animal weight-lifting exercise model for the first time, suggesting potential avenues for future research.

Deciphering difficult-to-treat psoriatic arthritis (D2T-PsA): a GRAPPA perspective from an international survey of healthcare professionals.

Objectives: This study contributes to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)'s effort to define 'difficult-to-treat' PsA (D2T-PsA), leveraging insights of healthcare professionals who are GRAPPA members. The primary objective is to inform GRAPPA's D2T PsA project, ensuring the consensus definition reflects clinical experience and expertise. Methods: An online survey was conducted among GRAPPA's healthcare professionals managing PsA patients. The survey covered demographic details, structured questions, and open-ended queries to gather comprehensive insights into the experts' viewpoints. Results: About 223 physicians completed the survey, comprising 179 (80.2%) rheumatologists and 40 (17.9%) dermatologists. The majority, 184 (82.5%), favoured establishing distinct definitions for D2T-PsA and complex-to-manage PsA (C2M-PsA). Furthermore, 202 (90.5%) supported a definition that includes objective inflammation signs (clinical, laboratory, imaging, among others). However, opinions varied on the criteria for prior treatment failures, with most (93, 41.7%) favouring a definition that includes at least one conventional synthetic disease-modifying anti-rheumatic drug and two or more biological- or targeted-synthetic-DMARDs with different mechanisms of action. Conclusion: The survey reveals a majority opinion among GRAPPA experts favouring the differentiation between D2T-PsA and C2M-PsA, and the inclusion of objective inflammatory markers in these definitions. However, there is less than 50% agreement on the specific treatment failure criteria, particularly regarding the number of therapies needed to classify PsA as D2T. These findings suggest a need for continued discussion to reach a more unified approach in defining D2T-PsA, reflecting the complexity of the condition.

Total Hip Arthroplasty Versus Education and Exercise: A Propensity-Matched Analysis of 266 Patients Who Have Hip Osteoarthritis.

BACKGROUND: Total hip arthroplasty (THA) for osteoarthritis (OA) is a major health system cost. Education and exercise (Edu + Ex) programs may reduce the number of THAs needed, but supporting data are limited. This study aimed to estimate the treatment effect of THA versus Edu + Ex on pain, function, and quality of life outcomes 3 and 12 months after treatment initiation for hip OA. METHODS: Patients who had hip OA who underwent THA or an Edu + Ex program were included in this propensity-matched study. In 778 patients (Edu + Ex, n = 303; THA, n = 475), propensity scores were based on pretreatment characteristics, and patients were matched on a 1:1 ratio. Between-group treatment effects (pain, function, and quality of life) were estimated as the mean difference (MD) in change from pretreatment to 3-month and 12-month follow-up using linear mixed models. RESULTS: The matched sample consisted of 266 patients (Edu + Ex, n = 133; THA, n = 133) who were balanced on all pretreatment characteristics except opioid use. At 12-month follow-up, THA resulted in significantly greater improvements in pain (MD 35.4; 95% confidence interval [CI] 31.4 to 39.4), function (MD 30.5; 95% CI 26.3 to 34.7), and quality of life (MD 33.6; 95% CI 28.8 to 38.4). Between 17% and 30% of patients receiving Edu + Ex experienced a surgical threshold for clinically meaningful improvement in outcomes, compared to 84% and 90% of THA patients. CONCLUSIONS: A THA provides greater improvements in pain, function, and quality of life. A notable proportion of Edu + Ex patients had clinically meaningful improvements, suggesting Edu + Ex may result in THA deferral in some patients, but confirmatory trials are needed.

Investigating protease-mediated peptides of inflammation and tissue remodeling as biomarkers associated with flares in psoriatic arthritis.

BACKGROUND: Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. PsA disease involves flares, which are associated with increased joint inflammation and tissue remodeling. There is a need for identifying biomarkers related to PsA disease activity and flares to improve the management of PsA patients and decrease flares. The tissue turnover imbalance that occurs during the inflammatory and fibro-proliferative processes during flares leads to an increased degradation and/or reorganization of the extracellular matrix (ECM), where increased proteolysis plays a key role. Hence, protease-mediated fragments of inflammatory and tissue-remodeling components could be used as markers reflecting flares in PsA patients. METHODS: A broad panel of protease-mediated biomarkers reflecting inflammation and tissue remodeling was measured in serum and synovial fluid (SF) obtained from PsA patients experiencing flares (acutely swollen joint[s], PsA-flare). In serum, biomarker levels assessed in PsA-flare patients were compared to controls and in early-diagnosed PsA patients not experiencing flares (referred to as PsA without flare). Furthermore, the biomarker levels assessed in SF from PsA-flare patients were compared to the levels in SF of osteoarthritis (OA) patients. RESULTS: In serum, levels of the PRO-C3 and C3M, reflecting formation and degradation of the interstitial matrix, were found significantly elevated in PsA-flare compared to controls and PsA without flare. The remodeling marker of the basement membrane, PRO-C4, was significantly elevated in PsA-flare compared to PsA without flare. The inflammation and immune cell activity related markers, CRPM, VICM, and CPa9-HNE were significantly elevated in PsA-flare patients compared to controls and PsA without flare. In addition, VICM (AUC = 0.71), CPa9-HNE (AUC = 0.89), CRPM (AUC = 0.76), and PRO-C3 (AUC = 0.86) showed good discriminatory performance for separating PsA-flare from PsA without flare. In SF, the macrophage activity marker, VICM, was significantly elevated whereas the type II collagen formation marker, PRO-C2, was significantly reduced in the PsA-flare compared to OA. The combination of five serum markers reflecting type III and IV collagen degradation (C3M and C4M, respectively), type III and VI collagen formation (PRO-C3 and PRO-C6, respectively), and neutrophil activity (CPa9-HNE) showed an excellent discriminatory performance (AUC = 0.98) for separating PsA-flare from PsA without flares. CONCLUSIONS: The serum biomarker panel of C3M, C4M, PRO-C3, PRO-C6, and CPa9-HNE reflecting synovitis, enthesitis, and neutrophil activity may serve as novel tool for quantitatively monitoring flares in PsA patients.

When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Challenges in the Metabolomics-Based Biomarker Validation Pipeline.

As end-products of the intersection between the genome and environmental influences, metabolites represent a promising approach to the discovery of novel biomarkers for diseases. However, many potential biomarker candidates identified by metabolomics studies fail to progress beyond analytical validation for routine implementation in clinics. Awareness of the challenges present can facilitate the development and advancement of innovative strategies that allow improved and more efficient applications of metabolite-based markers in clinical settings. This minireview provides a comprehensive summary of the pre-analytical factors, required analytical validation studies, and kit development challenges that must be resolved before the successful translation of novel metabolite biomarkers originating from research. We discuss the necessity for strict protocols for sample collection, storage, and the regulatory requirements to be fulfilled for a bioanalytical method to be considered as analytically validated. We focus especially on the blood as a biological matrix and liquid chromatography coupled with tandem mass spectrometry as the analytical platform for biomarker validation. Furthermore, we examine the challenges of developing a commercially viable metabolomics kit for distribution. To bridge the gap between the research lab and clinical implementation and utility of relevant metabolites, the understanding of the translational challenges for a biomarker panel is crucial for more efficient development of metabolomics-based precision medicine.

Residual Disease Activity in Canadian Patients With Psoriatic Arthritis Treated With Advanced Therapies: Results From a Multiregistry Analysis (UNISON-PsA).

OBJECTIVE: Although patient outcomes in psoriatic arthritis (PsA) have improved with the advent of advanced therapies, there remains a high unmet need to treat residual disease activity. The objective of the current study was to quantify residual disease activity and burden of disease in Canadian patients with PsA. METHODS: This was a multiregion, observational, retrospective analysis of patient data extracted from the Rhumadata and the International Psoriasis and Arthritis Research Team (IPART) registries, analyzing deidentified data from patients who had initiated advanced therapy for the treatment of PsA between January 2010 and December 2019. The primary endpoint was the proportion of patients failing to achieve minimal disease activity (MDA) within 6 months; secondary endpoints included clinical and patient-reported burden of disease. Descriptive statistics included summaries by region, treatment class, and number of prior advanced therapies. RESULTS: One thousand five hundred ninety-six patients were included. The proportions of patients who failed to achieve MDA within 6 months of an advanced therapy were 64.8% in Ontario, 68.3% in Western Canada, 74.8% in Quebec, and 75% in the Atlantic/East region. Failure to achieve MDA was higher among patients receiving an IL-17i compared with a TNFi in all regions except the Atlantic/East. Between 73.2% and 78.6% of patients reported pain at 6 months, and continuing functional impairment varied from 24% in the West to 83.3% in the Atlantic/East. CONCLUSION: There is substantial burden and unmet need for improved therapies for Canadians with PsA. There is a wide regional variation in outcomes that requires further assessment.

Use of Apremilast to Achieve Psoriatic Arthritis Treatment Goals and Satisfaction at 1 Year in the Canadian Real-World APPRAISE Study.

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 < 0.001). Apremilast was well tolerated; the most frequent adverse events (AEs) leading to discontinuation were diarrhea (9/102 [8.8%]), nausea (4/102 [3.9%]), and migraine (4/102 [3.9%]). CONCLUSION: In this real-world study conducted in Canadian rheumatology clinics, apremilast demonstrated clinical effectiveness in patients with active PsA, along with patient satisfaction with treatment. Safety findings were consistent with previously reported clinical data. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03608657.

Total Knee Arthroplasty Versus Education and Exercise for Knee Osteoarthritis: A Propensity-Matched Analysis.

OBJECTIVE: We estimate the treatment effect of total knee arthroplasty (TKA) versus an education and exercise (Edu+Ex) program on pain, function, and quality of life outcomes 3 and 12 months after treatment initiation for knee osteoarthritis (OA). METHODS: Patients with knee OA who had undergone TKA were matched on a 1:1 ratio with participants in an Edu+Ex program based on a propensity score fitted to a range of pretreatment covariates. After matching, between-group differences in improvement (the treatment effect) in Knee Injury and Osteoarthritis Outcome Score 12-item version (0, worst to 100, best) pain, function, and quality of life from baseline to 3 and 12 months were estimated using linear mixed models, adjusting for unbalanced covariates, if any, after matching. RESULTS: The matched sample consisted of 522 patients (Edu+Ex, n = 261; TKA, n = 261) who were balanced on all pretreatment characteristics. At 12-month follow-up, TKA resulted in significantly greater improvements in pain (mean difference [MD] 22.8; 95% confidence interval [95% CI] 19.7-25.8), function (MD 21.2; 95% CI 17.7-24.4), and quality of life (MD 18.3; 15.0-21.6). Even so, at least one-third of patients receiving Edu+Ex had a clinically meaningful improvement in outcomes at 12 months compared with 75% of patients with TKA. CONCLUSION: TKA is associated with greater improvements in pain, function, and quality of life, but these findings also suggest that Edu+Ex may be a viable alternative to TKA in a meaningful proportion of patients, which may reduce overall TKA need. Confirmatory trials are needed.

Classifying patients with psoriatic arthritis according to their disease activity status using serum metabolites and machine learning.

INTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis, affecting approximately a quarter of patients with psoriasis. Accurate assessment of disease activity is difficult. There are currently no clinically validated biomarkers to stratify PsA patients based on their disease activity, which is important for improving clinical management. OBJECTIVES: To identify metabolites capable of classifying patients with PsA according to their disease activity. METHODS: An in-house solid-phase microextraction (SPME)-liquid chromatography-high resolution mass spectrometry (LC-HRMS) method for lipid analysis was used to analyze serum samples obtained from patients classified as having low (n = 134), moderate (n = 134) or high (n = 104) disease activity, based on psoriatic arthritis disease activity scores (PASDAS). Metabolite data were analyzed using eight machine learning methods to predict disease activity levels. Top performing methods were selected based on area under the curve (AUC) and significance. RESULTS: The best model for predicting high disease activity from low disease activity achieved AUC 0.818. The best model for predicting high disease activity from moderate disease activity achieved AUC 0.74. The best model for classifying low disease activity from moderate and high disease activity achieved AUC 0.765. Compounds confirmed by MS/MS validation included metabolites from diverse compound classes such as sphingolipids, phosphatidylcholines and carboxylic acids. CONCLUSION: Several lipids and other metabolites when combined in classifying models predict high disease activity from both low and moderate disease activity. Lipids of key interest included lysophosphatidylcholine and sphingomyelin. Quantitative MS assays based on selected reaction monitoring, are required to quantify the candidate biomarkers identified.

Derivation and Internal Validation of a Disease-Specific Cardiovascular Risk Prediction Model for Patients With Psoriatic Arthritis and Psoriasis.

OBJECTIVE: To address suboptimal cardiovascular risk prediction in patients with psoriatic disease (PsD), we developed and internally validated a five-year disease-specific cardiovascular risk prediction model. METHODS: We analyzed data from a prospective cohort of participants with PsD without a history of cardiovascular events. Traditional cardiovascular risk factors and PsD-related measures of disease activity were considered as potential predictors. The study outcome included nonfatal and fatal cardiovascular events. A base prediction model included 10 traditional cardiovascular risk factors. Eight PsD-related factors were assessed by adding them to the base model to create expanded models, which were controlled for PsD therapies. Variable selection was performed using Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression with 10-fold cross-validation. Model performance was assessed using measures of discrimination and calibration and measures of sensitivity and specificity. RESULTS: Between 1992 and 2020, 85 of 1,336 participants developed cardiovascular events. Discrimination of the base model (with traditional cardiovascular risk factors alone) was excellent, with an area under the receiver operator characteristic curve (AUC) of 85.5 (95% confidence interval [CI] 81.9-89.1). Optimal models did not select any of the tested disease-specific factors. In a sensitivity analysis, which excluded lipid lowering and antihypertensive treatments, the number of damaged joints was selected in the expanded model. However, this model did not improve risk discrimination compared to the base model (AUC 85.5, 95% CI 82.0-89.1). CONCLUSION: Traditional cardiovascular risk factors alone are effective in predicting cardiovascular risk in patients with PsD. A risk score based on these factors performed well, indicating excellent discrimination and calibration.

Pharmacodynamic effects of filgotinib treatment driving clinical improvement in patients with active psoriatic arthritis enrolled in the EQUATOR trial.

OBJECTIVES: The goal of this study was to identify protein and transcriptional biomarkers and pathways associated with baseline disease state, the effect of filgotinib (FIL) treatment on these biomarkers, and to investigate the mechanism of action of FIL on clinical improvement in patients with active psoriatic arthritis (PsA). METHODS: The phase II EQUATOR (NCT03101670) trial evaluated the efficacy of FIL, a Janus kinase 1-preferential inhibitor, in patients with PsA. Peripheral protein and gene expression levels in association with clinical state at baseline and post-treatment were assessed in 121 patients using linear mixed effects models for repeated measures analyses. Mediation analysis and structural equation modelling (SEM) were performed to investigate the mechanism of action of FIL at week 4 on downstream clinical improvement at week 16. RESULTS: Baseline analyses showed that markers of inflammation were significantly associated with multiple PsA clinical metrics, except for Psoriasis Area and Severity Index (PASI), which corresponded to Th17 markers. FIL treatment resulted in sustained transcriptional inhibition of immune genes and pathways, a sustained increase in B-cell fraction and mature B-cells in circulation, and a transient effect on other cell fractions. Mediation analysis revealed that changes in B cells, systemic inflammatory cytokines and neutrophils at week 4 were associated with changes in clinical metrics at week 16. SEM suggested that FIL improved PASI through reduction of IL-23 p19 and IL-12 p40 proteins. CONCLUSIONS: Our results revealed that FIL treatment rapidly downregulates inflammatory and immune pathways associated with PsA disease activity corresponding to clinical improvement in PsA. TRIAL REGISTRATION NUMBER: NCT03101670.

Identifying Serum Metabolomic Markers Associated with Skin Disease Activity in Patients with Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a chronic, systemic, immune-mediated inflammatory disease causing cutaneous and musculoskeletal inflammation that affects 25% of patients with psoriasis. Current methods for evaluating PsA disease activity are not accurate enough for precision medicine. A metabolomics-based approach can elucidate psoriatic disease pathogenesis, providing potential objective biomarkers. With the hypothesis that serum metabolites are associated with skin disease activity, we aimed to identify serum metabolites associated with skin activity in PsA patients. We obtained serum samples from patients with PsA (n = 150) who were classified into mild, moderate and high disease activity groups based on the Psoriasis Area Severity Index. We used solid-phase microextraction (SPME) for sample preparation, followed by data acquisition via an untargeted liquid chromatography-mass spectrometry (LC-MS) approach. Disease activity levels were predicted using identified metabolites and machine learning algorithms. Some metabolites tentatively identified include eicosanoids with anti- or pro-inflammatory properties, like 12-Hydroxyeicosatetraenoic acid, which was previously implicated in joint disease activity in PsA. Other metabolites of interest were associated with dysregulation of fatty acid metabolism and belonged to classes such as bile acids, oxidized phospholipids, and long-chain fatty acids. We have identified potential metabolites associated with skin disease activity in PsA patients.

Investigational monoclonal antibodies in early development for psoriatic arthritis: beyond the biosimilars.

INTRODUCTION: Psoriatic Arthritis (PsA) is an inflammatory arthritis that is present in approximately 25% of psoriasis patients. Currently, several targeted therapies are available to manage PsA; however, many patients fail these therapies. Several new therapeutic options, with differing mechanisms of action, are currently being evaluated. AREAS COVERED: This article reviews available results from phase I to phase III trials of several investigational monoclonal antibodies that the FDA has not yet approved for PsA. The proposed mechanisms of the new therapeutic agents and their relevance to the pathogenesis of PsA will be discussed. The investigational agents' efficacy and safety will be summarized, and their potential clinical applications for managing PsA will be contemplated. EXPERT OPINION: Due to recent advances in understanding psoriatic arthritis, therapeutic agents are increasingly focused on inhibiting interleukin-17 and interleukin-23 pathways. Various strategies have been used to inhibit these cytokines, demonstrating favorable efficacy and acceptable safety profile.

Autoantibodies in psoriatic disease.

Psoriasis is an inflammatory skin disease affecting over 8 million people in the US and Canada. Approximately, a quarter of psoriasis patients have an inflammatory arthritis termed psoriatic arthritis (PsA). Psoriatic disease encompassing both psoriasis and PsA is regarded as an immune-mediated inflammatory disease, exhibiting both autoimmune and autoinflammatory features. A review of the current literature on the presence and clinical significance of autoantibodies found in psoriatic disease are presented. The frequency of several autoantibodies in psoriasis and PsA patients as well as their clinical significance regarding disease diagnosis, disease activity and treatment response are reviewed. Additionally, the basic principles of antibody assays are presented, and the methods used for each study are analyzed. Despite historically described as a rheumatoid factor negative (seronegative) disease, an array of autoantibodies has been identified in patients with psoriatic disease. This points to an autoimmune component potentially playing a role in psoriatic disease; however, additional evidence is needed to determine the clinical utility of these autoantibodies.