Arthritis Research Research Articles

Dosing Variation at Initiation of Adalimumab and Etanercept and Clinical Outcomes in Juvenile Idiopathic Arthritis: A Childhood Arthritis and Rheumatology Research Alliance Registry Study.

To determine the dose-response relationship of tumor necrosis factor (TNF) inhibition in the treatment of juvenile idiopathic arthritis (JIA). Participants of the Childhood Arthritis and Rheumatology Research Alliance Registry were eligible for inclusion in the analyses if they started TNF inhibition treatment for JIA. The primary treatment response was determined 3 to 7 months after the start of treatment, based on the JIA American College of Rheumatology Pediatric criteria for improvement, clinical Juvenile Arthritis Disease Activity Score, and persistence of treatment after 6 months. Subsequently, pooled logistic regression models were performed to include long-term follow-up data. The models were adjusted for risk factors associated with poor treatment response. Dosing was expressed by body weight, body surface area, ideal body weight, fat free mass, and lean body mass. Participants treated with adalimumab (n=328) and etanercept (n=437) were included in the analyses (median dose 0.82 mg/kg body weight [interquartile range (IQR) 0.66-1.04] and 0.83 mg/kg body weight [IQR 0.75-0.95], respectively). The majority of analyses did not show a relationship between dose and outcome. Where associations were found, results were conflicting. Alternative dosing characteristics based on ideal body weight, fat free mass, and lean body mass did not result in stronger or more consistent associations. This study was not able to confirm our hypothesis that increased dosing of TNF inhibitors results in improved treatment outcomes. Although adjustment was performed for risk factors of impaired treatment response, residual confounding by indication likely explains the negative associations found in this study.

Trends and frontiers in natural products for arthritis, 2000-2021: A bibliometric analysis.

Arthritis has become one of the trouble diseases that upsets people. A growing number of studies have shown that natural products have great potential for the treatment of arthritis. However, few bibliometrics have been systematically studied in this area. This paper analyzes the literature data of natural products on the arthritis research, and the research hot spots and future research directions of the treatment of arthritis by natural products were explored. Through CiteSpace, VOSviewer software and Bibliometricx under the R language environment, the article and review literatures on the treatment of arthritis with natural drugs in the Web of Science core collection database were analyzed by bibliometric analysis. On December 28, 2021, a total of 2102 records were retrieved, 81.69% publications were issued in 2012 to 2021, mainly in China-dominated Asian countries, with cooperation among countries. The analysis of the number of articles published by institutions shows that the number of articles published by China Academy of Chinese Medical Sciences is up to 82. Lu, Aiping and Smolen, JS are the authors with the highest citation frequency and co-citation frequency. Keywords analysis showed that the research of natural drugs mainly focused on gene expression, anti-inflammatory and other mechanisms and signaling pathways. With the progress of science and technology and the integration of multi-disciplines, the research on natural drugs for arthritis will be more in-depth and specific. In this study, literature metrology analysis was conducted on natural products in the treatment of arthritis, in order to grasp the background, trends and frontiers of the research, and predict possible research hotspots in the future. It is expected to provide some reference value and direction for future scholars in this field.

Implementation of Rheumatology Health Care Transition Processes and Adaptations to Systems Under Stress: A Mixed-Methods Study.

Despite poor health care transition outcomes among young adults with pediatric rheumatic diseases, adoption of transition best practices is low. We sought to understand how structured transition processes were operationalized within pediatric rheumatology practices and what factors were perceived to enable adaptations during a global pandemic. We conducted a mixed methods study of team leaders' experiences during an interim analysis of a pilot project to implement transition policy discussions at sites in the Childhood Arthritis and Rheumatology Research Alliance Transition Learning Collaborative. We combined quantitative assessments of organizational readiness for change (9 sites) and semistructured interviews of team leaders (8 sites) using determinants in the Exploration, Preparation, Implementation, Sustainment Framework. Engagement of nursing and institutional improvement efforts facilitated decisions to implement transition policies. Workflows incorporating educational processes by nonphysicians were perceived to be critical for success. When the pandemic disrupted contact with nonphysicians, capacity for automation using electronic medical record (EMR)-based tools was an important facilitator, but few sites could access these tools. Sites without EMR-based tools did not progress despite reporting high organizational readiness to implement change at the clinic level. Lastly, educational processes were often superseded by acute issues, such that youth with greater medical/psychosocial complexity may not receive the intervention. We generated several considerations to guide implementation of transition processes within pediatric rheumatology from the perspectives of team leaders. Careful assessment of institutional and nursing support is advisable before conducting complex transition interventions. Ideally, new strategies would ensure interventions reach youth with high complexity.

Modified Juvenile Spondyloarthritis Disease Activity Index in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.

To validate the Juvenile Spondyloarthritis Disease Activity Index (JSpADA), and modified versions thereof, in a North American cohort of patients with enthesitis-related arthritis (ERA). We utilized the Childhood Arthritis and Rheumatology Research Alliance Registry database ERA cohort to validate the JSpADA and its modifications (JSpADA6-no Schober, no C-reactive protein [CRP]/erythrocyte sedimentation rate [ESR]; JSpADA7-no Schober; and JSpADA7-no CRP/ESR) using the Outcome Measures in Rheumatology principles of face validity, discriminative validity, and responsiveness to change. There were 51 subjects (64 visits) with complete JSpADA data with a mean age of 13.7 years and disease duration of 30.9 months. Subjects were predominantly White (84.3%), and 56.9% were male and 50% were HLA-B27 positive. The JSpADA showed high correlation with the clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10; r = 0.81), moderate-to-high correlation with physician global assessment (PGA; r = 0.69), and low-to-fair correlation with Childhood Health Assessment Questionnaire (CHAQ; r = 0.22). The modifications of the JSpADA (JSpADA7-no Schober; JSpADA7-no CRP/ESR; and JSpADA6-no Schober, no CRP/ESR) performed similarly with high correlation with cJADAS10 (r = 0.81, 0.79, and 0.80, respectively), moderate-to-high correlation with PGA (r = 0.65, 0.67, 0.64, respectively), and low-to-fair correlation with CHAQ (r = 0.35, 0.34, 0.39, respectively). All modified versions of JSpADA had good responsiveness to change. All versions of JSpADA had excellent discriminative validity. We propose the term modified JSpADA for the modification of JSpADA with 6 elements (JSpADA6-no Schober, no CRP/ESR). This shorter disease activity index may improve implementation of JSpADA in both clinical practice and research trials.

Pharmacokinetics of hydroxychloroquine in paediatric lupus: data from a novel, direct-to-family clinical trial

ObjectiveDetermine the pharmacokinetics (PK) and exposure–response of hydroxychloroquine (HCQ) and desethylhydroxychloroquine (DHCQ) in paediatric SLE (pSLE).MethodsWe conducted an exploratory phase 2, direct-to-family trial. Children enrolled in the Childhood Arthritis and...

Acute kidney injury requiring kidney replacement therapy in childhood lupus nephritis: a cohort study of the Pediatric Nephrology Research Consortium and Childhood Arthritis and Rheumatology Research Alliance.

Acute kidney injury (AKI) is common in lupus nephritis (LN) and a risk factor for development of chronic kidney disease. In adults with LN, AKI severity correlates with the incidence of kidney failure and patient survival. Data on AKI outcomes in children with LN, particularly those requiring kidney replacement therapy (KRT), are limited. A multicenter, retrospective cohort study was performed in children diagnosed between 2010 and 2019 with LN and AKI stage 3 treated with dialysis (AKI stage 3D). Descriptive statistics were used to characterize demographics, clinical data, and kidney biopsy findings; treatment data for LN were not included. Logistic regression was used to examine the association of these variables with kidney failure. Fifty-nine patients (mean age 14.3years, 84.7% female) were identified. The most common KRT indications were fluid overload (86.4%) and elevated blood urea nitrogen/creatinine (74.6%). Mean follow-up duration was 3.9 ± 2.9years. AKI recovery without progression to kidney failure occurred in 37.3% of patients. AKI recovery with later progression to kidney failure occurred in 25.4% of patients, and there was no kidney recovery from AKI in 35.6% of patients. Older age, severe (> 50%) tubular atrophy and interstitial fibrosis, and National Institutes of Health (NIH) chronicity index score > 4 on kidney biopsy were associated with kidney failure. Children with LN and AKI stage 3D have a high long-term risk of kidney failure. Severe tubular atrophy and interstitial fibrosis at the time of AKI, but not AKI duration, are predictive of kidney disease progression. A higher resolution version of the Graphical abstract is available as Supplementary information.

Bibliometric and visualization analysis of macrophages associated with osteoarthritis from 1991 to 2021

BackgroundMacrophages significantly contributes to symptomology and structural progression of osteoarthritis (OA) and raise increasing attention in the relative research field. Recent studies have shown that tremendous progress has been made in the research of macrophages associated with osteoarthritis. However, a comprehensive bibliometric analysis is lacking in this research field. This study aimed to introduce the research status as well as hotspots and explore the field of macrophages research in OA from a bibliometric perspective.MethodsThis study collected 1481 records of macrophages associated with osteoarthritis from 1991 to 2021 in the web of science core collection (WoSCC) database. CiteSpace, VOSviewer, and R package “bibliometrix” software were used to analyze regions, institutions, journals, authors, and keywords to predict the latest trends in macrophages associated with osteoarthritis research.ResultsThe number of publications related to macrophages associated with osteoarthritis is increasing annually. China and the USA, contributing more than 44% of publications, were the main drivers for research in this field. League of European Research Universities was the most active institution and contributed the most publications. Arthritis and Rheumatism is the most popular journal in this field with the largest publications, while Osteoarthritis and Cartilage is the most co-cited journal. Koch AE was the most prolific writer, while Bondeson J was the most commonly co-cited author. “Rheumatology”, “Orthopedics”, and “Immunology” were the most widely well-represented research areas of OA associated macrophages. “Rheumatoid arthritis research”, “clinical symptoms”, “regeneration research”, “mechanism research”, “pathological features”, and “surgery research” are the primary keywords clusters in this field.ConclusionThis is the first bibliometric study comprehensively mapped out the knowledge structure and development trends in the research field of macrophages associated with osteoarthritis in recent 30 years. The results comprehensively summarize and identify the research frontiers which will provide a reference for scholars studying macrophages associated with osteoarthritis.

Reliability of the Pediatric Specific Musculoskeletal Ultrasound Scoring Systems for the Elbow, Wrist, and Finger Joints.

Musculoskeletal ultrasound (MSUS) is increasingly being used in the evaluation of pediatric musculoskeletal diseases. In order to provide objective assessments of arthritis, reliable MSUS scoring systems are needed. Recently, joint-specific scoring systems for arthritis of the pediatric elbow, wrist, and finger joints were proposed by the Childhood Arthritis and Rheumatology Research Alliance (CARRA) MSUS workgroup. This study aimed to assess the reliability of these scoring systems when used by sonographers with different levels of expertise. Members of the CARRA MSUS workgroup attended training sessions for scoring the elbow, wrist, and finger. Subsequently, scoring exercises of B mode and power Doppler (PD) mode still images for each joint were performed. Interreader reliability was determined using 2-way single-score intraclass correlation coefficients (ICCs) for synovitis and Cohen [Formula: see text] for tenosynovitis. Seventeen pediatric rheumatologists with different levels of MSUS expertise (1-15 yrs) completed a 2-hour training session and calibration exercise for each joint. Excellent reliability (ICC > 0.75) was found after the first scoring exercise for all the finger and elbow views evaluated on B mode and PD mode, and for all of the wrist views on B mode. After a second training session and a scoring exercise, the wrist PD mode views reached excellent reliability as well. The preliminary CARRA MSUS scoring systems for assessing arthritis of the pediatric elbow, wrist, and finger joints demonstrate excellent reliability among pediatric MSUS sonographers with different levels of expertise. With further validation, this reliable joint-specific scoring system could serve as a clinical tool and scientific outcome measure.

P01 Development of a toolkit enabling schools and colleges to confidently support children and young people with Juvenile Idiopathic Arthritis

Introduction/BackgroundChildren and Young People (CYP) spend a considerable amount of time at school, college or other educational settings. Whilst most CYP with Juvenile Idiopathic Arthritis (JIA) are able to access education, many require adaptations, awareness of their needs or specific support to enable them to fully engage in learning. Families of CYP with JIA have reported a lack of awareness and understanding and requested resources to enable schools to support their children in school. The aim of this work was to develop a School Toolkit to allow teachers and other school staff to confidently support CYP with JIA.Description/MethodUsing a network of parents of CYP with JIA, UK-based charity Juvenile Arthritis Research developed a series of resources aimed at schools, colleges, pre-schools and other educational settings. Given awareness of childhood arthritis is low, the Toolkit includes awareness-raising resources, aimed both at staff and all families connected to the school. Increased awareness can help improve diagnosis times and timely access to treatment in those not yet diagnosed. In addition, the Toolkit contains information about what JIA is, resources for schools to provide targeted interventions, and information on how schools can successfully support CYP with JIA. Finally, each Toolkit contains both a presentation for explaining arthritis to children in a classroom or group assembly setting, and a training presentation for delivery to staff, as well as digital copies of key materials and awareness-raising resources for distribution to parents and families.Discussion/ResultsIn the week after launching the new School Toolkit, over 20 kits were sent to schools in the UK, potentially providing information that arthritis affects children to over 20,000 families with a further 35 Toolkits in the subsequent month.Schools have advised they are using the resources in their settings, including giving lessons to children to explain what arthritis is, putting up posters highlighting the key signs and symptoms of JIA, and utilising the staff training resources. Feedback from schools was entirely positive, with one teacher reporting “Wow- it's fantastic, the student presentation is particularly impressive with how it translates all the key information in a child friendly manner.”Key learning points/ConclusionThe development and supply of a Toolkit specifically for use in schools and colleges has helped raise awareness that children get arthritis and provided resources to train and support school staff enabling them to confidently support CYP with JIA. Utilising the experience and skills of parents and teachers in the development of the Toolkit has ensured all resources are relevant and address the needs of both families and schools. Toolkits can be requested free of charge by schools in the UK from http://www.jarproject.org/toolkitAcknowledgementsThanks to the children, young people, families and schools involved in the development of this vital resource.

P02 ThinkJIA: A campaign to raise awareness that children and young people get arthritis, enabling families and frontline health professionals to recognise symptoms and refer to specialist services

Introduction/BackgroundAwareness that Children and Young People (CYP) may develop arthritis (Juvenile Idiopathic Arthritis, JIA) is low within the general population and amongst non-rheumatology frontline health professionals. This can lead to delays in diagnosis and reduced access to treatment, with consequential risk of joint damage and permanent eye complications through undiagnosed JIA-associated uveitis. The aim of this work was to develop a campaign to enable frontline health professionals and families to be aware that CYP can develop arthritis, to know the main signs and symptoms, and to pursue early referral to speciality services.Description/MethodAn awareness-raising campaign was developed by UK charity Juvenile Arthritis Research working with parents of CYP with JIA, adults with JIA, teachers, campaigners, paediatric rheumatologists, ophthalmologists, and other interested lay and professional individuals. The campaign, called #ThinkJIA, includes postcards with key messages and a supporting website, www.thinkjia.orgResources are aimed at both the general population, to help improve recognition of the signs and symptoms and encourage early attendance at primary care health services; and at non-rheumatology frontline health professionals to support recognition of JIA symptoms and the need for prompt referral. Whilst the key messaging is common to both audiences, the language used differs to reflect the lay and medical professional expectations.Once draft campaign resources were developed, they were shared with clinical professionals and tested by parents and school teachers.Discussion/ResultsOf the pilot group of parents and teachers receiving draft resources, 100% of parents and 68% of teachers agreed that they would feel confident in seeking medical attention if their child, or a child in their school, started showing signs of JIA. Following feedback from recipients in the pilot group resources have been updated with clearer imagery. These are also supported by posters for use in health clinics and general circulation.Key learning points/ConclusionThe development of the #ThinkJIA awareness-raising resources has helped ensure frontline health professionals and the general population can have access to information about JIA. This can help facilitate early referral and improved access to treatment. The broad rollout of awareness resources is essential to appropriately support CYP with JIA and ensure they receive the treatment they require promptly.AcknowledgementsThanks to Prof Helen Foster for her vital role in the initial development of these resources, and to all those involved in the development and pilot testing.

Patient-Reported Outcomes Among Transition-Age Young Adults With Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry.

To evaluate patient-reported care utilization and outcomes among young adults with juvenile idiopathic arthritis (JIA), including factors associated with complete transfer to adult rheumatology. We included young adults with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry from 2015 to 2019 with age ≥ 18 years at their last clinical site visit. We used data from the CARRA Registry Long-term Follow-up program, which follows inactive CARRA Registry patients and collects patient-reported information through phone surveys. We compared the characteristics of respondents with complete and incomplete transfer to adult rheumatology care at their first Long-term Follow-up phone survey. We identified 540 young adults with JIA; 187 (35%) responded to the Long-term Follow-up phone survey. The 54% of respondents with complete transfer to adult rheumatology were slightly older and reported more self-assessed disease activity, morning stiffness, and pain compared to those with incomplete transfer. Biologic use was high at both timepoints and did not differ by transfer status. Patients who completed the transfer were more likely to have private insurance and be actively pursuing postsecondary education compared to those with an incomplete transfer. Across the cohort, 65% reported problems with pain or discomfort and 45% with anxiety or depression. Young adult respondents with JIA in the CARRA Registry commonly report persistent medication use, but still report more problems with pain as compared to population norms. Additional work is needed to understand how best to address comorbid pain around the period of transition to adult care.

"You can't touch, you can't bond": Exploring COVID-19 pandemic impacts on rheumatoid arthritis patient goals and communication with clinicians.

"You can't touch, you can't bond": Exploring COVID-19 pandemic impacts on rheumatoid arthritis patient goals and communication with clinicians.

Pediatric rheumatologists’ perspectives on diagnosis, treatment, and outcomes of Sjögren disease in children and adolescents

BackgroundSjögren disease in children and adolescents (pedSD) presents differently than adult disease. Diagnosis and classification are controversial, optimal treatment is unknown and outcomes are poorly understood. Here, we describe the current perspectives of pediatric rheumatologists on diagnosis, treatment, and outcomes of pedSD.MethodsA voluntary, 17-question survey was distributed to providers in the Childhood Arthritis and Rheumatology Research Alliance and/or the American College of Rheumatology Childhood Sjögren’s Study Group at the 2020 Convergence Virtual Conference. Findings are reported using descriptive statistics and chi-square testing.ResultsOf 465 eligible providers, 157 (34%) responded with 135 (29%) completing the survey. The majority (85%) saw five or fewer patients with pedSD in the past year. Parotitis, dry eye and/or dry mouth, and constitutional symptoms were among the most specific and common clinical features. Most providers (77%) used clinical judgment guided by adult criteria for diagnosis. The vast majority (86–99%) of survey participants indicated routine use of serologic testing, while salivary gland ultrasound, minor salivary gland biopsy and other diagnostic tests were less often used. The most commonly prescribed systemic immunomodulators were hydroxychloroquine, corticosteroids, methotrexate, rituximab, and mycophenolate. Seven providers reported malignancy in a patient with pedSD, including one death.ConclusionsPediatric rheumatologists diagnose and treat pedSD; however, most only see a few patients per year and rely on clinical judgment and laboratory testing for diagnosis. Treatment frequently includes systemic immunomodulators and malignancies are reported. More studies are needed to better understand natural history, risk factors, and the impact of interventions on outcomes.

Association of Race and Ethnicity With Medication Use for Pediatric Lupus in the Childhood Arthritis and Rheumatology Research Alliance Registry.

Black and Hispanic children with pediatric lupus (pSLE) have higher morbidity and mortality than non-Hispanic White children. The extent to which differences in outcomes are due to treatment disparities, including medication use, is unknown. We aimed to determine whether medication use in pSLE is associated with race and ethnicity in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Patients with pSLE enrolled in the CARRA Registry from 2017 to 2020 were included. Multivariable mixed-effect logistic regression, adjusted for site of care, was used to compare use of antimalarials, high-dose oral glucocorticoids, and rituximab in Black and Hispanic children. We identified 639 children with pSLE, of whom 480 had at least 1 year of follow-up. At enrollment, 89% of patients were prescribed an antimalarial and 50% were on high-dose glucocorticoids. Of those with 1 year of follow-up, 12% received rituximab. Nephritis, shorter disease duration, and higher Systemic Lupus Erythematosus Disease Activity Index 2000 scores were associated with high-dose glucocorticoid use. Antimalarial use was higher among those with nephritis and lower in children with no insurance. Rituximab use was associated with Black race in the fixed-effects model but not when adjusted for site of care. We identified differences in medication use by race and insurance status. Site of care was associated with the racial differences observed in rituximab use. Further research is needed to optimize pSLE treatments particularly where use is highly variable, including glucocorticoid dosing and use of rituximab, and understand the impact of practice variation on disparities in pSLE outcomes.

Effectiveness and Safety of High-Dose Biologics in Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance.

To describe high-dose biologic use when treating juvenile idiopathic arthritis (JIA). Patients with JIA enrolled in the Childhood Arthritis and Rheumatology Research Alliance Registry and treated with a biologic after enrollment were eligible. We described the frequency of high-dose biologic use and characteristics of patients receiving high-dose biologics. We used regression modeling to compare 6-month outcomes (using disease activity measures) between those who increased their biologic from standard to high dose (high-dose group) to those who initiated and remained on standard dosing (no-change group), and to those who switched biologic agents (biologic-switch group). We also compared serious adverse events (SAEs) between groups. A total of 5,352 patients with JIA were treated with biologics following enrollment; 1,080 (20%) had ever received a high-dose biologic. There were no significant differences in outcomes between the high-dose group and the biologic-switch group; both improved disease activity measures, including the clinical Juvenile Arthritis Disease Activity Score 10 (-3.53 and -3.95, respectively; P=0.68). Although the SAE rates in the high-dose group and the biologic-switch group were numerically higher than the no-change group, the event rates were similar, and neither rate was significantly higher than in the no-change group (unadjusted incident rate ratio 2.5 [95% confidence interval (95% CI) 0.7-8.5] and 1.8 [95% CI 0.7-4.6], respectively). Dosing escalation appears to be a reasonable choice to improve disease control, but large, prospective, randomized studies evaluating specific biologic agents are needed.

Baseline characteristics of children with juvenile dermatomyositis enrolled in the first year of the new Childhood Arthritis and Rheumatology Research Alliance registry

BackgroundTo report baseline characteristics, patient reported outcomes and treatment of children with Juvenile Dermatomyositis (JDM) in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry.MethodsChildren newly diagnosed with JDM were enrolled in the CARRA Registry from 41 pediatric rheumatology centers. Baseline patient demographics, disease characteristics, assessments, patient reported outcome and treatments were recorded.ResultsIn the first year, 119 JDM participants were enrolled. Most were female (63.4%), and white (72.3%) with a median diagnosis age 8.0 years (IQR 4.0–11.5), and median age of disease onset 7.0 years (IQR 3.5–7.5). They had characteristic rashes (92.4%), elevated muscle enzymes (83.2%), physician global score 4.0 (IQR 2.5–5.0) and manual muscle testing score 63.5 (IQR 51.0–75.0). Calcinosis (3.4%) and interstitial lung disease (< 1%) were uncommon. Myositis specific antibodies were measured and reported in nearly half of participants enrolled where anti-MJ followed by Anti-p155/140 were most common (11/49 and 7/53 respectively).Childhood Health Assessment Questionnaire (CHAQ) results showed mild-moderate disability (median 0.750, IQR 0.030–1.875), as did patient/parent global assessments of disease activity (median 3, patient IQR: 1.75–5.25; parent IQR: 1–7). Patient Reported Outcomes Measurement Information System (PROMIS®) Pediatric Global Health 7 scores, Pain Interference, Physical Function scores for Mobility, and Upper Extremity Function were commonly worse than 95% of the general pediatric population.ConclusionsIn its inaugural year, 119 JDM patients were successfully enrolled in participapte in the New CARRA Registy. This registry will provide the necessary foundation to advance clinical research to improve outcomes using traditional measures and patient reported outcomes. With the CARRA biorepository, this infrastructure will enable future translational research. Together, these efforts may aid in future clinical trials, including comparative effectiveness trials.

Investigation of Inactive Disease States Among Patients With Juvenile Idiopathic Arthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry.

ObjectiveInactive disease is the treatment goal for juvenile idiopathic arthritis (JIA), but there are multiple measures for disease activity. The objective was to compare individuals with JIA who meet different definitions for inactive disease.MethodsDisease activity measures were determined at the 1‐year follow‐up visit for all patients with JIA enrolled in a North American multicenter registry from 2015 to 2019, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Patient and disease characteristics between those who met only one composite definition of inactive disease were compared by χ2 for categorical variables and Wilcoxon rank sum for continuous variables. The Spearman correlation coefficient was calculated for simple disease measures.ResultsAmong all 2904 patients with JIA enrolled in the CARRA Registry with 1‐year visit data, 1984 (68%) had no active joints, 1485 (51%) had a physician global score of 0, 1366 (47%) had a patient/parent global score of 0, 1293 (45%) met the American College of Rheumatology provisional criteria for clinical inactive disease (ACR CID), and 1325 (46%) had a clinical Juvenile Arthritis Disease Activity Score (cJADAS10) of 1 or less. Almost half (47%) did not meet either composite definition of inactive disease, and 38% met both ACR CID and cJADAS10 of 1 or less.ConclusionIn a multicenter cohort of patients with JIA in North America, a large proportion of patients had inactive disease by single or composite measures after 1 year of observation in the Registry. There was significant overlap between patients who met ACR CID criteria and those who had a cJADAS10 of 1 or less. Additional studies are needed to evaluate the reasons for discordance in inactive disease measures.

Mitochondrial Dysfunction Affects the Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis Differently.

There is growing evidence regarding the role of mitochondrial dysfunction in osteoarthritis (OA) and rheumatoid arthritis (RA). However, quantitative comparison of synovial mitochondrial derangements in these main arthritis forms is missing. A prospective clinical study was conducted on adult patients undergoing knee surgery. Patients were allocated into RA and OA groups based on disease-specific clinical scores, while patients without arthritis served as controls. Synovial samples were subjected to high-resolution respirometry to analyze mitochondrial functions. From the total of 814 patients, 109 cases were enrolled into the study (24 RA, 47 OA, and 38 control patients) between 1 September 2019 and 31 December 2021. The decrease in complex I-linked respiration and dyscoupling of mitochondria were characteristics of RA patients, while both arthritis groups displayed reduced OxPhos activity compared to the control group. However, no significant difference was found in complex II-related activity between the OA and RA groups. The cytochrome C release and H2O2 formation were increased in both arthritis groups. Mitochondrial dysfunction was present in both arthritis groups; however, to a different extent. Consequently, mitochondrial protective agents may have major benefits for arthritis patients. Based on our current study, we recommend focusing on respiratory complex I in rheumatoid arthritis research.

Osteoarthritis & stroke: a bidirectional mendelian randomization study

The epidemiological evidence on the link between osteoarthritis (OA) and stroke remains inconclusive. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) study to determine the causality relationship between OA and stroke. Summary-level data derived from the published genome-wide association studies (GWAS) were employed for analyses. The data for OA at any site (n=455,211), knee OA (n=403,124), and hip OA (n=393,873) were obtained from a meta-analysis of GWAS available in the UK Biobank and Arthritis Research UK Osteoarthritis Genetics resources. The MEGASTROKE consortium provided data for stroke (n=446,696), ischemic stroke (IS) (n=440,328) and its subtypes, and intracerebral hemorrhage (ICH) (n=3,026). The main MR analysis was conducted by the inverse variance weighted (IVW) method. MR-Egger regression, MR pleiotropy residual sum and outlier, weighted median, Cochran Q statistic, and leave-one-out analysis approach were leveraged as supplements. We detected that higher risk of hip OA was significantly associated with overall stroke [IVW odds ratio (OR): 1.12, 95% confidence interval (CI): 1.06-1.20, P= 0.0002], IS (OR: 1.13, 95%CI: 1.06-1.21, P= 0.0003), and small vessel IS (OR: 1.25, 95%CI: 1.10-1.42, P= 0.0006). However, we found no evidence that stroke and subtypes had casual effects on OA in the reverse MR analyses. The present study provides genetic support that hip OA is a potential risk factor for overall stroke, IS, and small vessel IS. Further studies are warranted to elucidate the underlying mechanisms of causal associations between site-specific OA and stroke subtypes.

N1-methylpseudouridine-incorporated mRNA enhances exogenous protein expression and suppresses immunogenicity in primary human fibroblast-like synoviocytes.

Studies conducted using murine arthritis models have indicated that the use of in vitro-transcribed messenger RNA (IVT mRNA) is an effective therapeutic approach for joint diseases. However, the use of IVT mRNA in human synovial cells has not been widely studied. Recently, the outbreak of the novel coronavirus disease has accelerated the development of innovative mRNA vaccines, such as those containing a modified nucleic acid, N1-methylpseudouridine-5′-triphosphate (m1ψ). IVT mRNA is an attractive tool for biological experiments and drug discovery. To verify the protein expression from IVT mRNA in vitro, primary cultured fibroblast-like synoviocytes (FLS) and MH7A human synovial fibroblast cells were transfected with enhanced green fluorescent protein (EGFP) mRNA with or without m1ψ incorporation. EGFP was detected using western blotting and fluorescence microscopy. A multiplex assay was performed to comprehensively understand IVT mRNA-induced immunogenicity. Gene expression levels were measured using reverse transcription polymerase chain reaction. In both MH7A cells and FLS, cells transfected with EGFP mRNA containing m1ψ generated higher levels of EGFP than those transfected with unmodified EGFP or control mRNAs. The multiplex assay of the FLS culture supernatant and reverse transcription polymerase chain reaction for FLS revealed that both concentration and expression of IL-6, TNF-α, and CXCL10 were upregulated by unmodified EGFP mRNA, whereas they were suppressed by EGFP mRNA with m1ψ. Overall, m1ψ incorporation enhanced protein expression and decreased the expression of cytokines. These findings may contribute to arthritis research.