Patient research partner involvement in rheumatology research: a systematic literature review informing the 2023 updated EULAR recommendations for the involvement of patient research partners.

BACKGROUND: Patient research partners (PRPs) are people with a disease who collaborate in a research team as partners. The aim of this systematic literature review (SLR) was to assess barriers and facilitators to PRP involvement in rheumatology research. METHODS: The SLR was conducted in PubMed/Medline for articles on PRP involvement in rheumatology research, published between 2017 and 2023; websites were also searched in rheumatology and other specialties. Data were extracted regarding the definition of PRPs, their role and added value, as well as barriers and facilitators to PRP involvement. The quality of the articles was assessed. Quantitative data were analysed descriptively, and principles of thematic content analysis was applied to qualitative data. RESULTS: Of 1016 publications, 53 articles were included; the majority of these studies were qualitative studies (26%), opinion articles (21%), meeting reports (17%) and mixed-methods studies (11%). Roles of PRPs ranged from research partners to patient advocates, advisors and patient reviewers. PRPs were reported/advised to be involved early in the project (32% of articles) and in all research phases (30%), from the conception stage to the implementation of research findings. The main barriers were challenges in communication and support for both PRPs and researchers. Facilitators of PRP involvement included more than one PRP per project, training of PRPs and researchers, a supportive environment for PRPs (including adequate communication, acknowledgement and compensation of PRPs) and the presence of a PRP coordinator. CONCLUSION: This SLR identified barriers and facilitators to PRP involvement, and was key to updating the European Alliance of Associations for Rheumatology recommendations for PRP-researcher collaboration based on scientific evidence.

EULAR recommendations for the involvement of patient research partners in rheumatology research: 2023 update.

BACKGROUND: Since the publication of the 2011 European Alliance of Associations for Rheumatology (EULAR) recommendations for patient research partner (PRP) involvement in rheumatology research, the role of PRPs has evolved considerably. Therefore, an update of the 2011 recommendations was deemed necessary. METHODS: In accordance with the EULAR Standardised Operational Procedures, a task force comprising 13 researchers, 2 health professionals and 10 PRPs was convened. The process included an online task force meeting, a systematic literature review and an in-person second task force meeting to formulate overarching principles (OAPs) and recommendations. The level of agreement of task force members was assessed anonymously (0-10 scale). RESULTS: The task force developed five new OAPs, updated seven existing recommendations and formulated three new recommendations. The OAPs address the definition of a PRP, the contribution of PRPs, the role of informal caregivers, the added value of PRPs and the importance of trust and communication in collaborative research efforts. The recommendations address the research type and phases of PRP involvement, the recommended number of PRPs per project, the support necessary for PRPs, training of PRPs and acknowledgement of PRP contributions. New recommendations concern the benefits of support and guidance for researchers, the need for regular evaluation of the patient-researcher collaboration and the role of a designated coordinator to facilitate collaboration. Agreements within the task force were high and ranged between 9.16 and 9.96. CONCLUSION: The updated EULAR recommendations for PRP involvement are more substantially based on evidence. Together with added OAPs, they should serve as a guide for researchers and PRPs and will ultimately strengthen the involvement of PRPs in rheumatology research.

American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision.

OBJECTIVE: In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean-based and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the two sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. METHODS: We used data from four randomised trials comparing biological disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared with the original threshold of 1 cm (Boolean1.0). We analysed agreement between the Boolean-based and index-based criteria (Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire (HAQ) score≤0.5) and radiographic non-progression. RESULTS: Data from 2048 trial participants, 1101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared with Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes. CONCLUSION: Using the Boolean 2.0 criteria classifies, more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardising predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

Tenderness and radiographic progression in rheumatoid arthritis and psoriatic arthritis.

OBJECTIVE: The aim of this study was to assess the predictive value of tenderness in the absence of swelling with consideration of other potential risk factors for subsequent radiographic progression in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: Clinical and sonographic (grey scale and power Doppler (PD)) examination of 22 joints of the hand were performed in patients with RA and PsA. The impact of tenderness on progression after 2 years was analysed in non-swollen joints for RA and PsA separately with multilevel mixed logistic regression analysis. RESULTS: We included 1207 joints in 55 patients with RA and 352 joints in 18 patients with PsA. In RA, tenderness was associated with radiographic progression after 2 years (model 2: OR 1.85 (95% CI 1.01 to 3.27), p=0.047), although the association of PD (OR 2.92 (95% CI 1.71 to 5.00), p<0.001) and erosions (OR 4.74 (95% CI 2.44 to 9.23), p<0.001) with subsequent structural damage was stronger. In PsA, we found a positive but not significant association between tenderness and radiographic progression (OR 1.72 (95% CI 0.71 to 4.17), p=0.23). In contrast, similarly to RA, erosions (OR 4.62 (95% CI 1.29 to 16.54), p=0.019) and PD (OR 3.30 (95% CI 1.13 to 9.53), p=0.029) had a marked effect on subsequent structural damage. CONCLUSION: Our findings imply that tenderness in non-swollen joints in RA is associated with subsequent damage. In both diseases, additional risk factors, such as sonographic signs for synovitis and baseline radiographic damage are associated with radiographic progression.

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis.

BACKGROUND: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. OBJECTIVE: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. METHODS: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. RESULTS: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. CONCLUSION: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.

Torque Teno Virus quantification for monitoring of immunomodulation with biologic compounds in the treatment of rheumatoid arthritis.

OBJECTIVES: RA patients who fail to respond to MTX can receive biologic dMARDs (bDMARDs). The Torque Teno Virus (TTV) is a potential novel candidate for monitoring of immunosuppression. We explore TTV in these patients and its association with clinical response to bDMARDs. METHODS: The BioBio Study is a multicentre randomized open-label trial, including RA patients with insufficient response to MTX. Patients were randomized to either TNFi (infliximab, INF), anti-IL-6 (tocilizumab, TCZ), CTLA4-Ig (abatacept, ABA) or anti-CD20 (rituximab, RTX) in addition to MTX. PCR was used to quantify TTV in the peripheral blood. RESULTS: TTV was measured in 95 patients (INF, n = 23; TCZ, n = 22; ABA, n = 27; RTX; n = 23). TTV increased by a median of 4.5 × 104 copies/ml [c/ml; interquartile range (IQR) 0-7.5 × 105] after 3 months. TTV levels at month 3 were associated with the Simplified Disease Activity Index (SDAI) (P = 0.03) and the Clinical Disease Activity Index (CDAI) response (P = 0.026) at month 6. A TTV cut-off level of 1.2 × 106 c/ml at month 3 had a positive likelihood ratio of 2.7 for prediction of an 85% reduction in SDAI at month 6. CONCLUSION: Our data suggest that TTV levels increase upon TNF, CD20 and costimulation blockade and are associated with the clinical response to bDMARDs in RA patients. TRIAL REGISTRATION: ClinicalTrials.gov; https://clinicaltrials.gov; NCT01638715.

Role of joint damage, malalignment and inflammation in articular tenderness in rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

OBJECTIVES: To determine whether clinical tenderness can be considered a sign of inflammatory joint activity in patients with rheumatoid arthritis (RA), osteoarthritis (OA) or psoriatic arthritis (PsA) and to assess other possible factors associated with tenderness. METHODS: Patients diagnosed with RA, PsA and OA underwent clinical and ultrasound examination of wrists and finger joints. Radiographs of the hands were scored for erosions, joint space narrowing (JSN), osteophytes and malalignment. A binary damage score (positive if ≥1 erosion, JSN and/or presence of malalignment) was calculated. Differences in grey scale signs of synovitis and power Doppler (PD) between tender non-swollen (TNS) versus non-tender non-swollen (NTNS) joints were calculated. Disease duration was assessed,<2 years was regarded as early and >5 years as long-standing arthritis. RESULTS: In total, 34 patients (9 early and 14 long-standing) from patients with RA, 31 patients (7 early and 15 long-standing) with PsA and 30 with OA were included. We found equal frequencies of PD signal between TNS and NTNS joints in RA (p=0.18), PsA (p=0.59) or OA (p=0.96). However, PD had a significant association with tenderness in early arthritis both in RA (p=0.02) and in PsA (p=0.02). The radiographic damage score showed significant association with tenderness in RA (p<0.01), PsA (p<0.01) and OA (p=0.04). CONCLUSION: Tenderness might not always be a sign of active inflammation in RA, PsA and OA. While tenderness in early arthritis may be more related to inflammation, established disease is better explained by joint damage and malalignment.

2019 EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older.

OBJECTIVE: To establish European League Against Rheumatism (EULAR) points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older. METHODS: Points to consider were developed in accordance with EULAR standard operating procedures for EULAR-endorsed recommendations, led by an international multidisciplinary task force, including patient research partners and different health professionals from 10 European countries. Level of evidence and strength of recommendation were determined for each point to consider, and the mean level of agreement among the task force members was calculated. RESULTS: Two overarching principles and seven points to consider were formulated based on scientific evidence and the expert opinion of the task force. The two overarching principles focus on shared decisions between patients and non-physician health professionals and involvement of different non-physician health professionals in prevention and management of fragility fractures. Four points to consider relate to prevention: identification of patients at risk of fracture, fall risk evaluation, multicomponent interventions to prevent primary fracture and discouragement of smoking and overuse of alcohol. The remaining three focus on management of fragility fractures: exercise and nutritional interventions, the organisation and coordination of multidisciplinary services for post-fracture models of care and adherence to anti-osteoporosis medicines. The mean level of agreement among the task force for the overarching principles and the points to consider ranged between 8.4 and 9.6. CONCLUSION: These first EULAR points to consider for non-physician health professionals to prevent and manage fragility fractures in adults 50 years or older serve to guide healthcare practice and education.

Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal?

OBJECTIVES: This study aimed to evaluate different patient global assessment (PGA) cut-offs required in the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean remission definition for their utility in rheumatoid arthritis (RA). METHODS: We used data from six randomised controlled trials in early and established RA. We increased the threshold for the 0-10 score for PGA gradually from 1 to 3 in steps of 0.5 (Boolean1.5 to Boolean3.0) and omitted PGA completely (BooleanX) at 6 and 12 months. Agreement with the index-based (Simplified Disease Activity Index (SDAI)) remission definition was analysed using kappa, recursive partitioning (classification and regression tree (CART)) and receiver operating characteristics. The impact of achieving each definition on functional and radiographic outcomes after 1 year was explored. RESULTS: Data from 1680 patients with early RA and 920 patients with established RA were included. The proportion of patients achieving Boolean remission increased with higher thresholds for PGA from 12.4% to 19.7% in early and 5.9% to 12.3% in established RA at 6 months. Best agreement with SDAI remission occurred at PGA cut-offs of 1.5 and 2.0, while agreement decreased with higher PGA (CART: optimal agreement at PGA≤1.6 cm; sensitivity of PGA≤1.5 95%). Changing PGA thresholds at 6 months did not affect radiographic progression at 12 months (mean ꙙsmTSS for Boolean, 1.5, 2.0, 2.5, 3.0, BooleanX: 0.35±5.4, 0.38±5.14, 0.41±5.1, 0.37±4.9, 0.34±4.9, 0.27±4.7). However, the proportion attaining HAQ≤0.5 was 90.2%, 87.9%, 85.2%, 81.1%, 80.7% and 73.1% for the respective Boolean definitions. CONCLUSION: Increasing the PGA cut-off to 1.5 cm would provide high consistency between Boolean with the index-based remission; the integer cut-off of 2.0 cm performed similarly.

EULAR/eumusc.net standards of care for rheumatoid arthritis: cross-sectional analyses of importance, level of implementation and care gaps experienced by patients and rheumatologists across 35 European countries.

OBJECTIVE: As part of European League against Rheumatism (EULAR)/European Musculoskeletal Conditions Surveillance and Information Network, 20 user-focused standards of care (SoCs) for rheumatoid arthritis (RA) addressing 16 domains of care were developed. This study aimed to explore gaps in implementation of these SoCs across Europe. METHODS: Two cross-sectional surveys on the importance, level of and barriers (patients only) to implementation of each SoC (0-10, 10 highest) were designed to be conducted among patients and rheumatologists in 50 European countries. Care gaps were calculated as the difference between the actual and maximum possible score for implementation (ie, 10) multiplied by the care importance score, resulting in care gaps (0-100, maximal gap). Factors associated with the problematic care gaps (ie, gap≥30 and importance≥6 and implementation<6) and strong barriers (≥6) were further analysed in multilevel logistic regression models. RESULTS: Overall, 26 and 31 countries provided data from 1873 patients and 1131 rheumatologists, respectively. 19 out of 20 SoCs were problematic from the perspectives of more than 20% of patients, while this was true for only 10 SoCs for rheumatologists. Rheumatologists in countries with lower gross domestic product and non-European Union countries were more likely to report problematic gaps in 15 of 20 SoCs, while virtually no differences were observed among patients. Lack of relevance of some SoCs (71%) and limited time of professionals (66%) were the most frequent implementation barriers identified by patients. CONCLUSIONS: Many problematic gaps were reported across several essential aspects of RA care. More efforts need to be devoted to implementation of EULAR SoCs.

Development of semiquantitative ultrasound scoring system to assess cartilage in rheumatoid arthritis.

OBJECTIVES: To develop and test the reliability of a new semiquantitative scoring system for the assessment of cartilage changes by ultrasound in a web-based exercise as well as a patient exercise of patients with RA. METHODS: A taskforce of the Outcome Measures in Rheumatology Ultrasound Working Group performed a systematic literature review on the US assessment of cartilage in RA, followed by a Delphi survey on cartilage changes and a new semiquantitative US scoring system, and finally a web-based exercise as well as a patient exercise. For the web-based exercise, taskforce members scored a dataset of anonymized static images of MCP joints in RA patients and healthy controls, which also contained duplicate images. Subsequently, 12 taskforce members used the same US to score cartilage in MCP and proximal interphalangeal joints of six patients with RA in in a patient reliability exercise. Percentage agreement and prevalence of lesions were calculated, as intrareader reliability was assessed by weighted kappa and interreader reliability by Light's kappa. RESULTS: The three-grade semiquantitative scoring system demonstrated excellent intrareader reliability (kappa: 0.87 and 0.83) in the web-based exercise and the patient exercise, respectively. Interreader reliability was good in the web-based exercise (kappa: 0.64) and moderate (kappa: 0.48) in the patient exercise. CONCLUSION: Our study demonstrates that ultrasound is a reliable tool for evaluating cartilage changes in the MCP joints of patients with RA and supports further development of a new reliable semiquantitative ultrasound scoring system for evaluating cartilage involvement in RA.

Targeted inhibition of Janus kinases abates interfon gamma-induced invasive behaviour of fibroblast-like synoviocytes.

Objectives: The aim was to explore the function of the T-cell cytokine IFNγ for mesenchymal tissue remodelling in RA and to determine whether IFNγ signalling controls the invasive potential of fibroblast-like synoviocytes (FLS). Methods: To assess architectural responses, FLS were cultured in three-dimensional micromasses. FLS motility was analysed in migration and invasion assays. Signalling events relevant to cellular motility were defined by western blots. Baricitinib and small interfering RNA pools were used to suppress Janus kinase (JAK) functions. Results: Histological analyses of micromasses revealed unique effects of IFNγ on FLS shape and tissue organization. This was consistent with accelerated migration upon IFNγ stimulation. Given that cell shape and cell motility are under the control of the focal adhesion kinase (FAK), we next analysed its activity. Indeed, IFNγ stimulation induced the phosphorylation of FAK-Y925, a phosphosite implicated in FAK-mediated cell migration. Small interfering RNA knockdown of JAK2, but not JAK1, substantially abrogated FAK activation by IFNγ. Correspondingly, IFNγ-induced FAK activation and invasion of FLS was abrogated by the JAK inhibitor, baricitinib. Conclusion: Our study contributes insight into the synovial response to IFNγ and reveals JAK2 as a potential therapeutic target for FLS-mediated joint destruction in arthritis, especially in RA.

Social media use among young rheumatologists and basic scientists: results of an international survey by the Emerging EULAR Network (EMEUNET).

OBJECTIVES: To explore perceptions, barriers and patterns of social media (SM) use among rheumatology fellows and basic scientists. METHODS: An online survey was disseminated via Twitter, Facebook and by email to members of the Emerging European League Against Rheumatism Network. Questions focused on general demographics, frequency and types of SM use, reasons and barriers to SM use. RESULTS: Of 233 respondents (47 countries), 72% were aged 30-39 years, 66% female. 83% were active users of at least one SM platform and 71% were using SM professionally. The majority used SM for communicating with friends/colleagues (79%), news updates (76%), entertainment (69%), clinical (50%) and research (48%) updates. Facebook was the dominant platform used (91%). SM was reported to be used for information (81%); for expanding professional networks (76%); new resources (59%); learning new skills (47%) and establishing a professional online presence (46%). 30% of non-SM users justified not using SM due to lack of knowledge. CONCLUSIONS: There was a substantial use of SM by rheumatologists and basic scientists for social and professional reasons. The survey highlights a need for providing learning resources and increasing awareness of the use of SM. This could enhance communication, participation and collaborative work, enabling its more widespread use in a professional manner.

Reliability of patient-reported outcomes in rheumatoid arthritis patients: an observational prospective study.

OBJECTIVE: Patient-reported outcomes (PROs) such as pain, patient global assessment (PGA) and fatigue are regularly assessed in RA patients. In the present study, we aimed to explore the reliability and smallest detectable differences (SDDs) of these PROs, and whether the time between assessments has an impact on reliability. METHODS: Forty RA patients on stable treatment reported the three PROs daily over two subsequent months. We assessed the reliability of these measures by calculating intraclass correlation coefficients (ICCs) and the SDDs for 1-, 7-, 14- and 28-day test-retest intervals. RESULTS: Overall, SDD and ICC were 25 mm and 0.67 for pain, 25 mm and 0.71 for PGA and 30 mm and 0.66 for fatigue, respectively. SDD was higher with longer time period between assessments, ranging from 19 mm (1-day intervals) to 30 mm (28-day intervals) for pain, 19 to 33 mm for PGA, and 26 to 34 mm for fatigue; correspondingly, ICC was smaller with longer intervals, and ranged between the 1- and the 28-day interval from 0.80 to 0.50 for pain, 0.83 to 0.57 for PGA and 0.76 to 0.58 for fatigue. The baseline simplified disease activity index did not have any influence on reliability. Lower baseline PRO scores led to smaller SDDs. CONCLUSION: Reliability of pain, PGA and fatigue measurements is dependent on the tested time interval and the baseline levels. The relatively high SDDs, even for patients in the lowest tertiles of their PROs, indicate potential issues for assessment of the presence of remission.

Classification of rheumatoid arthritis: is it time to revise the criteria?

Classification criteria have been developed for rheumatoid arthritis (RA) and other rheumatic diseases in order to gather a homogeneous patient population for clinical studies and facilitate the timely implementation of therapeutic measures. Although classification criteria are not intended to be used for diagnosis, they are frequently used to support the diagnostic process in clinical practice, including clinical decision-making. The 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria for RA are capable of identifying the majority of symptomatic patients with RA already in the earliest stages of the disease who are not yet showing radiographic changes. These patients will also profit from the early implementation of therapy with disease-modifying antirheumatic drugs (DMARDs). However, the risk of misclassification is higher as compared with the former 1987 ACR criteria, which were considerably less sensitive to the recognition of patients with early RA. Of note, the presence of rheumatoid factors (RFs) and anticitrullinated protein antibodies (ACPAs) has been attributed equal weight in the 2010 ACR/EULAR criteria and may contribute up to 50% of the score needed for being classified as RA. However, while ACPAs have been proven to be the most specific serological markers of RA, the specificity of RF is moderate, especially at lower titres. This may lead to the misclassification of RF-positive patients and, consequently, the unjustified implementation of DMARD therapy. Therefore, issues arise on how comprehensive the criteria should be and whether they should be updated and adapted to findings from the past two decades that might increase both their specificity and sensitivity.