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OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

OBJECTIVE: Classification criteria for calcium pyrophosphate deposition (CPPD) disease will facilitate clinical research on this common crystalline arthritis. Our objective was to report on the first 2 phases of a 4-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member steering committee. Item generation (phase I) included a scoping literature review of 5 literature databases and contributions from a 35-member combined expert committee and 2 patient research partners. Item reduction and refinement (phase II) involved a combined expert committee meeting, discussions among clinical, imaging, and laboratory advisory groups, and an item-rating exercise to assess the influence of individual items toward classification. The steering committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The advisory groups eliminated items that they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item-rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the steering committee recommended focusing on imaging of the knee and wrist and 1 additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

ObjectiveThere is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout.MethodsA content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions.ResultsThe content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: 'asymptomatic hyperuricaemia', 'asymptomatic monosodium urate crystal deposition', 'asymptomatic hyperuricaemia with monosodium urate crystal deposition', 'gout', 'tophaceous gout', 'erosive gout', 'first gout flare' and 'recurrent gout flares'. There was consensus agreement that the label 'gout' should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus).ConclusionConsensus agreement has been established for the labels and definitions of eight gout disease states, including 'gout' itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

BackgroundGiven the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.MethodsUsing a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.ResultsAnalysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.ConclusionsWe found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Objectives Psoriatic arthritis (PsA) phenotypes are typically defined by their clinical components, which may not reflect patients’ overlapping symptoms. This post hoc analysis aimed to identify hypothesis-free PsA phenotype clusters using machine learning to analyse data from the phase III DISCOVER-1/DISCOVER-2 clinical trials.Methods Pooled data from bio-naïve patients with active PsA receiving guselkumab 100 mg every 8/4 weeks were retrospectively analysed. Non-negative matrix factorisation was applied as an unsupervised machine learning technique to identify PsA phenotype clusters; baseline patient characteristics and clinical observations were input features. Minimal disease activity (MDA), disease activity index for psoriatic arthritis (DAPSA) low disease activity (LDA) and DAPSA remission at weeks 24 and 52 were evaluated.Results Eight clusters (n=661) were identified: cluster 1 (feet dominant), cluster 2 (male, overweight, psoriasis dominant), cluster 3 (hand dominant), cluster 4 (dactylitis dominant), cluster 5 (enthesitis, large joints), cluster 6 (enthesitis, small joints), cluster 7 (axial dominant) and cluster 8 (female, obese, large joints). At week 24, MDA response was highest in cluster 2 and lowest in clusters 3, 5 and 6; at week 52, it was highest in cluster 2 and lowest in cluster 5. At weeks 24 and 52, DAPSA LDA and remission were highest in cluster 2 and lowest in clusters 4 and 6, respectively. All clusters improved with guselkumab treatment over 52 weeks.Conclusions Unsupervised machine learning identified eight PsA phenotype clusters with significant differences in demographics, clinical features and treatment responses. In the future, such data could help support individualised treatment decisions.

Baricitinib, an oral selective Janus kinase (JAK)1/JAK2 inhibitor, is approved as monotherapy or in combination with methotrexate for treating adults with moderate-to-severe active rheumatoid arthritis (RA) and provides improvements in clinical signs, symptoms and patient-reported outcomes. Currently, baricitinib is approved for treating RA in more than 75 countries. In several pivotal Phase II and III RA trials (RA-BALANCE, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BEYOND), up to seven years of baricitinib treatment was well tolerated and provided rapid and sustained efficacy, which was confirmed in real-world settings. Safety signals for another JAK inhibitor, tofacitinib, have emerged, as observed in the post-marketing Phase IIIb/IV trial Oral Rheumatoid Arthritis Trial (ORAL) Surveillance; safety signals were subsequently highlighted in a retrospective study of baricitinib and consequently new recommendations and warnings and precautions for all JAK inhibitors have been issued. Ongoing studies to further characterise and clarify the benefit:risk of JAK inhibitors include registries and controlled trials. This capstone review summarises clinical and real-world data outlining the benefit:risk profile of baricitinib, confirming that the improved disease activity and physical function of patients with RA treated with this JAK inhibitor observed in clinical trials is translated into effectiveness in clinical practice, with a low rate of discontinuations.

Abstract Objective The aim of this study was to investigate risk factors for cutaneous adverse reactions (CARs) in Kinh Vietnamese. Methods All patients were prospectively recruited in Ho Chi Minh City. Presence of the HLA-B*58:01 allele was determined by real-time PCR-sequence-specific amplification by using the PG5801 Detection Kit (Pharmigene, Taipei). Patients with severe (SCARs) and mild (MCARs) CARs and controls were compared for differences in features prospectively collected, and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Results On comparing 32 patients with SCARs and 395 tolerant controls, we identified eight strong risk factors: increased age (OR 15.1 [95% CI 5.8–40.1], P 150 mg (OR 316 [101–122], P

Abstract Background Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory musculoskeletal disease, manifesting as peripheral arthritis, enthesitis, dactylitis, spondylitis, and skin and nail psoriasis. A core set of domains for measuring the impact of PsA has been developed, including pain, patient global assessment, physical function, health-related quality of life (HRQoL), and fatigue. To understand the impact of PsA on health domains from a patient’s perspective, a global survey was developed and results reported in the context of the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) questionnaire. Methods An online patient-based global survey was conducted by The Harris Poll in Australia, Brazil, Canada, France, Spain, Taiwan, the UK, and the US between November 2, 2017 and March 12, 2018. Eligible patients were ≥ 18 years old with a diagnosis of PsA for > 1 year, had visited a rheumatologist/dermatologist in the past 12 months and reported using ≥ 1 synthetic/biologic disease-modifying antirheumatic drug for PsA. Patients reported on PsA severity and symptoms, and the impact of PsA on HRQoL. After survey completion, responses were aligned with PsAID health domains. Descriptive statistics and chi-square tests were conducted. Results This analysis included 1286 patients from eight countries. Most patients (97%) reported musculoskeletal symptoms relating to PsA in the past year. Common moderate/major impacts of PsA were on physical activity (78%), ability to perform certain activities (76%), work productivity (62%), and career path (57%). Skin/nail symptoms occurred in 80% of patients. Overall, 69% of patients reported that PsA had a moderate/major impact on emotional/mental wellbeing, 56% on romantic relationships/intimacy, and 44% on relationships with family and friends. Social impacts included emotional distress (58%), social shame or disapproval (32%), and ceased participation in social activities (45%). Over half of all patients experienced unusual fatigue over the past 12 months (52%). The health domains that patients reported as being impacted by PsA aligned with life impact domains of the patient-derived PsAID health domains. Conclusion These results highlight the impact of PsA on multiple health domains from a patient perspective that should be considered during shared decision-making processes between healthcare providers and patients.

Objectives To investigate the occurrence of sick leave (SL) and the impact of clinical and socioeconomic factors on SL in early axial spondyloarthritis (axSpA).Methods Patients with a clinical diagnosis of axSpA from the DEvenir des Spondyloarthrites Indifférenciées Récentes (DESIR) cohort with work-related data and up to 5-year follow-up were studied. Incidence, time to first SL and potential role of baseline and time-varying clinical and socioeconomic factors (age, gender, ethnicity, education, job type, marital and parental status) were analysed. Univariable analyses, followed by collinearity and interaction tests, guided subsequent multivariable time-varying Cox survival model building.Results In total, 704 axSpA patients were included (mean (SD) age 33.8 (8.6); 46% men). At baseline, 80% of patients were employed; of these, 5.7% reported being on SL. The incidence of SL among those at risk during the study period (n=620, 88%) was 0.05 (95% CI 0.03 to 0.06) per 1000 days of follow-up. Mean (SD) time to first SL was 806 (595) days (range: 175–2021 days). In multivariable models, male gender (HR 0.41 (95% CI 0.20 to 0.86)) and higher education (HR 0.48 (95% CI 0.24 to 0.95)) were associated with lower hazard of SL, while higher disease activity (HR 1.49 (95% CI 1.04 to 2.13)), older age, smoking and use of tumour necrosis factor inhibitors were associated with higher hazard of SL.Conclusions In this early axSpA cohort of young, working-age individuals, male gender and higher education were independently associated with a lower hazard of SL, whereas older age and higher disease activity were associated with higher hazard of SL. The findings suggest a role of socioeconomic factors in adverse work outcomes, alongside active disease.

Background: In a context of therapeutic inertia, the French Society of Rheumatology (SFR) published its first recommendations on gout in 2020, which were deliberately simple and concise. The objectives of the study were to determine the profile of patients referred to French gout-expert centres, and to examine the results of their management and the factors leading to those results. Methods: Three hundred patients attending a first visit for gout management in three French referral centres were retrospectively and randomly included in this multicentre observational study. Visits were performed at baseline (M0) and scheduled for month 6 (M6), month 12 (M12), and month 24 (M24). Results: Patients were 81% male and had a mean age 62.2 ± 15.2 years. Management followed French recommendations after the baseline visit in 94.9% of cases. SU levels were below 6.0 mg/dL in 59.4% of patients at M6, 67.9% at M12, and 78.6% at M24, with increasing clinical improvement (i.e., flare decrease) over 2 years of follow-up. At M24, 50% of patients were treated with allopurinol (313 ± 105 mg/d), which exceeded renal restrictions of doses in 61.5% of them, and 48.2% received febuxostat (84 ± 36 mg/d). The need for a sufficient dosage of ULT was the only predictive factor found for successful achievement of SU levels < 6.0 mg/dL at a given visit. Conclusions: Simple application of gout-management guidelines is feasible in clinical practice and is efficient, with a majority of patients achieving SU targets and clinical improvement.

Intra-articular (IA) hyaluronic acid (HA) and platelet-rich plasma (PRP) injections are increasingly being prescribed for knee osteoarthritis (KOA). However, failure of the medical treatment may result in total knee arthroplasty (TKA). We wondered if IA HA or PRP injections (intervention) may delay the time to TKA (outcome) among KOA patients (population), compared to KOA patients not receiving these injections (comparator). For this systematic literature review (SLR) and meta-analysis, we selected observational studies with at least one group of patients receiving IA HA or PRP and with TKA data available. The main outcome was time from the diagnosis of KOA to TKA. We included 25 articles in the SLR (2,824,401 patients) and four in the meta-analysis. The mean strengthening the reporting of observational studies in epidemiology (STROBE) score was 63%. For patients receiving versus not receiving HA injections, the delay between a declared diagnosis of KOA to TKA was increased by 9.8 months (95% CI (8.2–11.4)). As compared with standard of care, the effect size of HA injections for this outcome was 0.57 (95% CI (0.36–0.76)). Only one study described a median time from PRP injections to TKA of 4.1 years (range 0.3–14.7). IA HA injections were associated with increased time to TKA. Causality cannot be concluded because of missing confounder factors as comorbidities. Data were insufficient to conclude any effect of PRP injections on TKA delay.

Viscosupplementation (VS) is a symptomatic treatment for knee and other joint osteoarthritis (OA). Despite a long history of use, conflicting opinions remain on the best clinical indications and the most appropriate patients to be treated with intra-articular hyaluronic acid (IA-HA), the optimal dosing regimen and the modalities of retreatment. A multidisciplinary committee of European experts on OA (EUROVISCO) was constituted to formulate recommendations, aimed at helping physicians in the decision-making and the optimal achievement of VS. Before each session members were tasked to collate an exhaustive literature review. Level of evidence and strength of recommendation were based on the level of agreement for each item according to the Delphi method. In 2015, a consensus position was proposed for 24 statements. Among those that obtained a consensual agreement, the working group stressed that VS is effective in mild/moderate knee OA but is not an alternative to surgery in advanced OA, and that dosing regimen must be supported by controlled trials. In 2018, two decision algorithms for the retreatment with IA-HA in knee OA were published. Among the key recommendations, the experts recommended to re-treat every year patients with high risk of OA progression, even if not symptomatic. In 2020, EUROVISCO published two sets of recommendations for the design of clinical trials on the disease-modifying effect of VS and for optimizing the results of VS. The working group underlined that an accurate analysis of radiological features and symptoms and a careful clinical examination may improve the chances of success of VS, as well as good technique of injection and the use of imaging guidance. Based on the exhaustive analysis of the literature and their own clinical experience, the EUROVISCO experts offer a wide range of recommendations intended to help practitioners, particularly in certain cases where the specific characteristics of the patients make the therapeutic decision difficult.

Tropheryma whipplei infection can manifest as inflammatory joint symptoms, which can lead to misdiagnosis of inflammatory rheumatic disease and the use of disease-modifying antirheumatic drugs. We investigated the impact of diagnosis and treatment of Tropheryma whipplei infection in patients with inflammatory rheumatic disease. We initiated a registry including patients with disease-modifying antirheumatic drugs-treated inflammatory rheumatic disease who were subsequently diagnosed with Tropheryma whipplei infection. We collected clinical, biological, treatment data of the inflammatory rheumatic disease, of Tropheryma whipplei infection, and impact of antibiotics on the evolution of inflammatory rheumatic disease. Among 73 inflammatory rheumatic disease patients, disease-modifying antirheumatic drugs initiation triggered extra-articular manifestations in 27% and resulted in stabilisation (51%), worsening (34%), or improvement (15%) of inflammatory rheumatic disease. At the diagnosis of Tropheryma whipplei infection, all patients had rheumatological symptoms (mean age 58 years, median inflammatory rheumatic disease duration 79 months), 84% had extra-rheumatological manifestations, 93% had elevated C-reactive protein, and 86% had hypoalbuminemia. Treatment of Tropheryma whipplei infection consisted mainly of doxycycline plus hydroxychloroquine, leading to remission of Tropheryma whipplei infection in 79% of cases. Antibiotic treatment of Tropheryma whipplei infection was associated with remission of inflammatory rheumatic disease in 93% of cases and enabled disease-modifying antirheumatic drugs and glucocorticoid discontinuation in most cases. Tropheryma whipplei infection should be considered in inflammatory rheumatic disease patients with extra-articular manifestations, elevated C-reactive protein, and/or hypoalbuminemia before disease-modifying antirheumatic drugs initiation or in inflammatory rheumatic disease patients with an inadequate response to one or more disease-modifying antirheumatic drugs. Positive results of screening and diagnostic tests for Tropheryma whipplei infection involve antibiotic treatment, which is associated with complete recovery of Tropheryma whipplei infection and rapid remission of inflammatory rheumatic disease, allowing disease-modifying antirheumatic drugs and glucocorticoid discontinuation. • Tropheryma whipplei infections often present with inflammatory joint symptoms. • These symptoms may lead to misdiagnosis of inflammatory rheumatic diseases. • T. whipplei infection should be considered in patients with extra-articular manifestations, elevated CRP or hypoalbuminemia. • T. whipplei infection should be considered in patients with an inadequate response to disease-modifying antirheumatic drugs. • Antibiotic treatment of T. whipplei is associated with rapid remission of misdiagnosed inflammatory rheumatic diseases. [ABSTRACT FROM AUTHOR]

Abstract Background The objective of this pilot study was to identify biological, clinical or structural biomarkers of an intra-articular hyaluronic acid injection efficacy (HYMOVIS®) for the design of a larger placebo-controlled clinical trial studying the disease-modifying activity of this treatment. Methods Forty six patients with symptomatic knee Osteoarthritis (OA) were enrolled in this open-label, prospective, multicenter, pilot study. Patients received two treatment cycles of intra-articular injections (3 mL) of HYMOVIS® (8 mg/mL of hyaluronic acid hexadecylamide) at 6 months interval. Each treatment cycle involved two intra-articular injections 1 week apart. All patients had Magnetic Resonance Imaging (MRI) of the target knee at baseline and 1 year, and blood samples to assess joint biomarkers. The primary outcome was the change in type II collagen-specific biomarkers (Coll2–1, Coll2–1NO2 and CTX-II) after HYMOVIS® treatment versus baseline. Secondary endpoints included levels changes in aggrecan chondroitin sulfate 846 epitope (CS-846), Cartilage Oligomeric Matrix Protein (COMP), procollagen type II N-terminal propeptide (PIIANP), Matrix Metalloprotease (MMP)-3, Myeloperoxidase (MPO) and Interleukin (IL)-6 serum biomarkers, the ratio Coll2–1/PIIANP, CTX-II/PIIANP, variation of MRI cartilage volume, and Knee injury and Osteoarthritis Outcome Score (KOOS) index. Results Coll2–1 serum levels significantly increased overtime while Coll2–1NO2 levels were only increased at D360. Serum PIIANP levels also progressively and significantly enhanced with time. In contrast, other serum biomarker levels including CTX-II, CS-846, COMP, MMP-3, MPO or IL-6 did not change significantly overtime. Interestingly, the ratios Coll2–1/PIIANP and CTX-II/PIIANP decreased, indicating a decrease of cartilage catabolism. Compared to baseline value, MRI cartilage volume and thickness increased in lateral femoral and lateral trochlea compartments and not in medial compartment. These results, in addition to an improvement of T2 mapping score suggest a positive structural effect of the product. Interestingly, WORMS effusion score, an indicator of synovitis, significantly decreased. Finally, global KOOS score and subscales significantly increased overtime while pain at rest, walking pain and patients or investigators global assessment of disease activity decreased. The safety profile was favorable with a low incidence of injection-site pain. Conclusion HYMOVIS®, a well-tolerated intra-articular treatment, significantly enhanced type II collagen turnover as suggested by the increase in Coll2–1 and PIIANP levels and cartilage volume observed by MRI in lateral knee compartment. Importantly, this study provides critical information for the design of a larger phase III clinical trial investigating Disease Modifying effect of HYMOVIS®. Trial registration http://www.isrctn.com/ISRCTN12227846 11/02/2015.

The aim of this review is to present current evidence about the efficacy and safety of lesinurad in combination with xanthine oxidase inhibitors (XOIs) in the treatment of hyperuricemia in patients with gout. Gout is the most common inflammatory form of arthritis. It is caused by an elevated concentration of serum uric acid (UA) that leads to the formation of monosodium urate crystals in joints and different tissues. The goal of therapy is to maintain serum UA levels at

Abstract Introduction The rate of adverse renal events has been shown to be higher in patients treated with lesinurad plus a xanthine-oxidase inhibitor (XOI) than in patients treated only with a XOI. We reassessed the risks for various adverse renal events from a different perspective and devised a hypothesis to explain the results. Methods We used data from phase 3 trials that were publicly available from the full prescribing information document and estimated the relative risk and the number needed to treat for increased serum creatinine (sCri), renal failure, and renal lithiasis. We examined these risks for each treatment group and the risks stratified by estimated glomerular filtration rate (eGFR). Results Overall, the relative risk for sCri was > 1.0 with the 400 mg/day dose of lesinurad and higher with the 200 mg/day dose, but it was

Objectives To assess the distribution of bone erosions and two erosion scores in the feet of patients with gout and analyze the association between erosion scores and monosodium urate (MSU) crystal deposition using dual-energy computed tomography (DECT). Materials and methods We included all patients who underwent DECT of both feet between 2016 and 2019 in our radiology department, with positive detection of MSU deposits. Data on sex, age, treatment, serum urate, and DECT urate volumes were obtained. CT images were analyzed to score bone erosions in 31 sites per foot by using the semi-quantitative method based on the Rheumatoid Arthritis MRI Scoring (RAMRIS) system and the Dalbeth-simplified score. Reproducibility for the two scores was calculated with intraclass correlation coefficients (ICCs). Correlations between clinical features, erosion scores and urate crystal volume were analyzed by the Spearman correlation coefficient (r). Results We studied 61 patients (mean age 62.0 years); 3,751 bones were scored. The first metatarsophalangeal joint and the midfoot were the most involved in terms of frequency and severity of bone erosions. The distribution of bone erosions was not asymmetrical. The intra- and inter-observer reproducibility was similar for the RAMRIS and Dalbeth-simplified scores (ICC 0.93 vs 0.94 and 0.96 vs 0.90). DECT urate volume was significantly correlated with each of the two erosion scores (r = 0.58–0.63, p < 0.001). There was a high correlation between the two scores (r = 0.96, p < 0.001). Conclusions DECT demonstrates that foot erosions are not asymmetric in distribution and predominate at the first ray and midfoot. The two erosion scores are significantly correlated with DECT urate volume. An almost perfect correlation between the RAMRIS and Dalbeth-simplified scores is observed.

Abstract Cartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the development of OA. In primary chondrocytes, furin reduced the expression of MMP-13, which was reversed by treatment with the furin inhibitor α1-PDX. Furin also promoted the activation of Smad3 signaling, whereas activin receptor-like kinase 5 (ALK5) knockdown mitigated the effects of furin on MMP-13 expression. Mice underwent destabilization of the medial meniscus (DMM) to induce OA, then received furin (1 U/mice), α1-PDX (14 µg/mice) or vehicle. In mice with DMM, the OA score was lower with furin than vehicle treatment (6.42 ± 0.75 vs 9.16 ± 0.6, p

Abstract Background The uric acid (UA) level in patients with gout is a key factor in disease management and is typically measured in the laboratory using plasma samples obtained after venous puncture. This study aimed to assess the reliability of immediate UA measurement with capillary blood samples obtained by fingertip puncture with the HumaSensplus point-of-care meter. Methods UA levels were measured using both the HumaSensplus meter in the clinic and the routine plasma UA method in the biochemistry laboratory of 238 consenting diabetic patients. HumaSensplus capillary and routine plasma UA measurements were compared by linear regression, Bland-Altman plots, intraclass correlation coefficient (ICC), and Lin’s concordance coefficient. Values outside the dynamic range of the meter, low (LO) or high (HI), were analyzed separately. The best capillary UA thresholds for detecting hyperuricemia were determined by receiver operating characteristic (ROC) curves. The impact of potential confounding factors (demographic and biological parameters/treatments) was assessed. Capillary and routine plasma UA levels were compared to reference plasma UA measurements by liquid chromatography-mass spectrometry (LC-MS) for a subgroup of 67 patients. Results In total, 205 patients had capillary and routine plasma UA measurements available. ICC was 0.90 (95% confidence interval (CI) 0.87–0.92), Lin’s coefficient was 0.91 (0.88–0.93), and the Bland-Altman plot showed good agreement over all tested values. Overall, 17 patients showed values outside the dynamic range. LO values were concordant with plasma values, but HI values were considered uninterpretable. Capillary UA thresholds of 299 and 340 μmol/l gave the best results for detecting hyperuricemia (corresponding to routine plasma UA thresholds of 300 and 360 μmol/l, respectively). No significant confounding factor was found among those tested, except for hematocrit; however, this had a negligible influence on the assay reliability. When capillary and routine plasma results were discordant, comparison with LC-MS measurements showed that plasma measurements had better concordance: capillary UA, ICC 0.84 (95% CI 0.75–0.90), Lin’s coefficient 0.84 (0.77–0.91); plasma UA, ICC 0.96 (0.94–0.98), Lin’s coefficient 0.96 (0.94–0.98). Conclusions UA measurements with the HumaSensplus meter were reasonably comparable with those of the laboratory assay. The meter is easy to use and may be useful in the clinic and in epidemiologic studies.

Abstract Background Anti-tumor necrosis factor (anti-TNF) agents are an effective, but costly, treatment for spondyloarthritis (SpA). Worldwide, multiple sets of access criteria aim to restrict anti-TNF therapy to patients with specific clinical characteristics, yet the influence of access criteria on anti-TNF cost-effectiveness is unknown. Our objective was to use data from the DESIR cohort, a prospective study of early SpA patients in France, to determine whether the French anti-TNF access criteria are the most cost-effective in that setting relative to other potential restrictions. Methods We used data from the DESIR cohort to create five study populations of patients meeting anti-TNF access criteria from Canada, France, Germany, United Kingdom, and Hong Kong, respectively. For each study population, we calculated the costs and quality-adjusted life years (QALYs) over 1 year of patients treated and not treated with anti-TNF therapy. To control for differences between anti-TNF users and non-users, we used linear regression models to derive adjusted mean costs and QALYs. We calculated incremental cost-effectiveness ratios (ICERs) representing the incremental cost per additional QALY gained by treating with an anti-TNF within each of the five study populations, using bootstrapping to explore the range of uncertainty in costs and QALYs. A series of sensitivity analyses was conducted, including one to simulate the effect of a 24-week stopping rule for anti-TNF non-responders. Results Anti-TNF access criteria from France were satisfied by the largest proportion of DESIR patients (27.8%), followed by Germany (25.1%), Canada (23.8%), the UK (12.1%) and Hong Kong (8.6%). Confidence intervals around incremental costs and QALYs in the basecase analysis were overlapping, indicating that anti-TNF cost-effectiveness estimates derived from each subset were similar. In the sensitivity analysis that examined the effect of excluding costs accumulated past 24 weeks by anti-TNF non-responders, the incremental cost per QALY was reduced by approximately 25% relative to the basecase analysis (France: €857,992 vs. €1,105,859; Canada: € 626,459 vs. €818,186; Germany: € 422,568 vs. €545,808); UK €578,899 vs. €766,217; Hong Kong €335,418 vs. €456,850). Conclusions Anti-TNF cost-effectiveness is strongly affected by treatment continuation among non-responders. Access criteria could improve anti-TNF cost-effectiveness by defining patients likely to respond.

Abstract Gout, the most prevalent inflammatory arthritis worldwide, is associated with cardiovascular and renal diseases, and is an independent predictor of premature death. The frequencies of obesity, chronic kidney disease (CKD), hypertension, type 2 diabetes, dyslipidaemias, cardiac diseases (including coronary heart disease, heart failure and atrial fibrillation), stroke and peripheral arterial disease have been repeatedly shown to be increased in gout. Therefore, the screening and care of these comorbidities as well as of cardiovascular risk factors are of outmost importance in patients with gout. Comorbidities, especially CKD, and drugs prescribed for their treatment, also impact gout management. Numerous epidemiological studies have shown the association of asymptomatic hyperuricaemia with the above-mentioned diseases and cardiovascular risk factors. Animal studies have also produced a mechanistic approach to the vascular toxicity of soluble urate. However, causality remains uncertain because confounders, reverse causality or common etiological factors might explain the epidemiological results. Additionally, these uncertainties remain unsolved despite recent studies using Mendelian randomisation or therapeutic approaches. Thus, large randomised placebo-controlled trials are still needed to assess the benefits of treating asymptomatic hyperuricaemia.

Abstract Background Viscosupplementation is a symptomatic treatment of the knee osteoarthritis based on the intra-articular injection of hyaluronic acid (IAHA). Although many studies have investigated its effect on symptoms, few clinical studies have focused on its effects on biologicals markers of cartilage metabolism. In this study, we assessed the effect of an intra-articular injection of a reticulated hyaluronic acid compound on the level of a specific biomarker of type II collagen degradation. Methods Eighty one patients with symptomatic knee osteoarthritis were included in this randomized placebo controlled trial testing a reticulated hyaluronic acid (HA) with mannitol (KARTILAGE® CROSS, 16 mg/ml, one single injection of 2.2 mL; IAHA) versus saline solution. Primary outcome was the percentage of patients with a reduction of at least 10 nmol/l of serum Coll2-1 between baseline and day 90 (D90, 3 months after injection). Secondary outcomes concerned clinical evaluation and tolerance to the study product. Results A significant effect of IAHA was revealed by the sensitivity analysis of the decrease in cartilage marker. In the intention-to-treat population, the percentage of patients showing a decrease in the levels of serum Coll2-1 between inclusion and D90 showed was higher in HA (56.8%) than in placebo group (28.6%; P = 0.01). The same significant difference was observed between groups in the per protocol population (57.1% vs 29.0%; P = 0.02) corresponding to all patients having received the intra-articular injection (IA), being evaluated for the primary outcome on D-10 and D90, and with no major defined deviation. No significant differences between groups were observed on the changes in function (Lequesne index) or pain and on the number of adverse events. Conclusions This is the first randomized double-blind placebo controlled trial showing that IA injection of reticulated HA with mannitol in knee osteoarthritis patients can reduce the serum levels of Coll2-1, a marker specific of type II collagen degradation. This finding suggests that IAHA may have a beneficial effect on cartilage degradation and that Coll2-1 could be used for the assessment of a single intra-articular treatment in clinical trials. Trial registration NCT02951585 ; clinicaltrial.gov. Retrospectively registered on October 28, 2016.

(1) Background: To determine which factors are associated with the volume of monosodium urate (MSU) crystal deposition quantified by dual-energy computed tomography (DECT) in urate-lowering therapy (ULT)-naive gout patients. (2) Methods: In this multicenter cross-sectional study, DECT scans of knees and feet/ankles were prospectively obtained from ULT-naive gout patients. Demographic, clinical (including gout history and comorbidities), and biological data were collected, and their association with DECT MSU crystal volume was analyzed using bivariate and multivariate analyses. A second bivariate analysis was performed by splitting the dataset depending on an arbitrary threshold of DECT MSU volume (1 cm3). (3) Results: A total of 91 patients were included. In the bivariate analysis, age (p = 0.03), gout duration (p = 0.003), subcutaneous tophi (p = 0.004), hypertension (p = 0.02), diabetes mellitus (p = 0.05), and chronic heart failure (p = 0.03) were associated with the total DECT volume of MSU crystal deposition. In the multivariate analysis, factors associated with DECT MSU volumes ≥1 cm3 were gout duration (odds ratio (OR) for each 10-year increase 3.15 (1.60; 7.63)), diabetes mellitus (OR 4.75 (1.58; 15.63)), and chronic heart failure (OR 7.82 (2.29; 31.38)). (4) Conclusion: Specific comorbidities, particularly chronic heart failure and diabetes mellitus, are more strongly associated with increased MSU crystal deposition in knees and feet/ankles than gout duration, regardless of serum urate level.