Sexual dysfunction in male patients treated with methorexate for arthritis: Analysis of the IIEF5 questionnaire and hormonal status.

OBJECTIVE: The aim of this study is to evaluate the impact of methotrexate (MTX) on erectile function in male patients through the International Index of Erectile Function (IIEF5) questionnaire and hormonal dosage. METHODS: Male patients affected by inflammatory arthritis (rheumatoid arthritis [RA] or psoriatic arthritis [PsA]) with good disease control and treated with chronic MTX were enrolled. Age-matched patients affected by chronic arthritis not treated with MTX were enrolled as controls. Each patient had a complete sexual hormone evaluation. IIEF5 questionnaire was administered to each patient. RESULTS: One hundred and nine patients were included, 77 in the MTX group and 32 as controls. The median weekly MTX dose was 10mg (IQR 7.5) with a median MTX duration therapy of 8 years (IQR 17). The total IIEF5 score was lower in patients MTX exposed compared to the control group without a significant result. The total IIEF5 score of patients treated with MTX≥5 years was statistically significantly lower when compared to those non-MTX exposed patients (17 [IQR 15] versus 20 [IQR 7.7]; P=0.04) and compared to those treated for<5 years (17 [IQR 15] versus 20 [IQR 7]; P=0.01). A negative correlation was identified between the total IIEF5 score and MTX time exposure (r=-0.20 CI [-0.38 to -0.04]; P=0.039). MTX exposure was still associated with a lower IIEF5 score when adjusted for age (ß Estimate=-2.63; CI [-5.13 to -0.13]; P=0.039). Hormonal dosage was similar in both groups for all hormones evaluated. CONCLUSION: MTX exposure was associated with a lower IIEF5 score in male patients adjusted for age. The preliminary results need to be confirmed in larger prospective studies.

Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis.

Biologic and targeted synthetic DMARDs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Among these, polyarticular JIA (pJIA) and RA display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, the therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. The mechanisms and determinants of this heterogeneous response are diverse and complex, such that the development of true 'precision'-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in pJIA in comparison with what is known in RA. Although some biomarkers have been identified that stratify with respect to the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment-response mechanisms. Consequently, we propose a pragmatic, patient-centred and clinically based approach, i.e. personalized instead of biomarker-based precision medicine in JIA.

Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis.

OBJECTIVES: Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups. METHODS: RNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections. RESULTS: PCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers. CONCLUSION: In this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.

Should We Use bDMARDs as an Induction Therapy in Early and Severe Rheumatoid Arthritis? Results at 5 years from the ERA UCLouvain Brussels Cohort.

INTRODUCTION: This study sought to analyze the benefit of an early induction therapy with a biological disease-modifying anti-rheumatic drugs (bDMARD) during the first year of treatment with a 5-year follow-up in early rheumatoid arthritis (ERA). METHODS: We included ERA patients from the UCLouvain Brussels cohort who met the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 classification criteria and were naïve to DMARDs. ERA patients were divided into two groups according to whether they received an induction bDMARD therapy or a standard therapy with methotrexate (MTX). Clinical response after the induction treatment at 6 and 12 months followed by a MTX maintenance therapy at 36 and 60 months was evaluated. RESULTS: Data from 470 ERA patients were collected, 189 received a bDMARD and 281 initiated MTX alone. In the bDMARD group, disease activity and HAQ were higher at baseline. A total of 391 patients were followed up to 5 years. We then divided each group into two subgroups according to the last treatment they received at 5 years: bDMARD > MTX (n = 95), bDMARD > bDMARD (n = 59); MTX > MTX (n = 134), MTX > bDMARD (n = 103). During the induction, we observed a clinical response with a large number of patients achieving DAS28-CRP remission. According to a treat-to-target (T2T) approach, remission rate was stable on MTX monotherapy or rescued by the addition or prolongation of a bDMARD. Interestingly, bDMARD followed by a MTX maintenance therapy experienced a stable and sustained DAS28-CRP remission rate in 53% of the ERA patients at year 5. CONCLUSIONS: Long-term remission is an achievable goal in ERA. Our results suggest that a bDMARD induction therapy followed by MTX maintenance therapy could be an interesting option.

Long-Term Efficacy and Safety of Upadacitinib in Patients with Rheumatoid Arthritis: Final Results from the BALANCE-EXTEND Open-Label Extension Study.

INTRODUCTION: Upadacitinib (UPA) is an oral, selective Janus kinase inhibitor that has demonstrated favorable efficacy with an acceptable safety profile across a global, phase 3 program in rheumatoid arthritis (RA). This phase 2 open-label extension investigated the efficacy and safety of UPA through 6 years of treatment. METHODS: Patients from two phase 2b trials (BALANCE-1 and -2) enrolled in BALANCE-EXTEND (NCT02049138) and received open-label UPA 6 mg twice daily (BID). Dose increases to 12 mg BID were required for patients with < 20% improvement in swollen or tender joint counts at weeks 6 or 12 and permitted for those not achieving Clinical Disease Activity Index (CDAI) low disease activity (LDA; CDAI 2.8 to ≤ 10). Dose reduction to UPA 6 mg BID was permitted only for safety or tolerability reasons. After January 2017, the 6/12 mg BID doses were replaced by 15/30 mg once-daily extended-release equivalents. Efficacy and safety were monitored up to 6 years of UPA treatment; outcomes included rates of achievement of LDA or remission. Data were analyzed for patients who received the lower UPA dose throughout; titrated up to the higher UPA dose from weeks 6 or 12; or titrated to the higher UPA dose and back down. RESULTS: Overall, 493 patients entered BALANCE-EXTEND ('Never titrated', n = 306; 'Titrated up', n = 149; 'Titrated up and down', n = 38), and 223 patients (45%) completed the 6-year study. Total cumulative exposure was 1863 patient-years. Rates of LDA and remission were maintained through 6 years. Overall, 87%/70%/73% of patients in the 'Never titrated'/'Titrated up'/'Titrated up and down' groups achieved CDAI LDA at week 312, while the respective rates of Disease Activity Score 28 with C-reactive protein meeting LDA and remission criteria were 85%/69%/70% and 72%/46%/63%. Improvements in patient-reported outcomes were similar among the three groups. No new safety signals were identified. CONCLUSIONS: In this open-label extension of two phase 2 studies, UPA demonstrated sustained efficacy and an acceptable safety profile through 6 years of treatment in patients who completed the study. These data support a favorable long-term benefit-risk profile of UPA in patients with RA. TRIAL REGISTRATION: Trial registration number: NCT02049138.

Comparison between 2D FSE T2-weighted Dixon MRI and contrast-enhanced 2D FSE and 3D FSPGR T1-weighted Dixon MRI to quantify inflammation in hands of patients with early rheumatoid arthritis.

PURPOSE: The purpose of this study was to compare two-dimensional (2D) T2-weighted, contrast-enhanced 2D T1-weighted and contrast-enhanced three-dimensional (3D) T1-weighted Dixon MRI sequences to assess disease activity using the RAMRIS scoring system in hands of patients with early rheumatoid arthritis. MATERIALS AND METHODS: Twenty-five patients (19 women, 6 men; mean age 51.4 years ± 12.7 years [SD], age range: 28-70 years) with rheumatoid arthritis prospectively underwent MRI examination of both hands at 1.5 T using 2D fast spin-echo (FSE) T2-weighted, contrast-enhanced 2D FSE T1-weighted and contrast-enhanced 3D fast spoiled gradient echo (FSPGR) T1-weighted Dixon sequences. Three radiologists independently assessed disease activity according to RAMRIS using Dixon water-only and fat-only images. Intraclass correlation coefficients (ICC) were calculated to assess inter-technique and interobserver agreements. RESULTS: Agreement to assess total RAMRIS score was very good between the MRI protocols (mean ICC ranging from 0.81 to 0.93) and between readers (mean ICC ranging from 0.91 to 0.94). Mean total RAMRIS scores of the three readers were significantly greater with contrast-enhanced 3D FSPGR T1-weighted (42.73 ± 29.39) than with contrast-enhanced 2D FSE T1-weighted (35.81 ± 25.48) and 2D FSE T2-weighted (32.20 ± 25.06) Dixon sequences. CONCLUSION: 2D FSE T2-weighted, contrast-enhanced 2D FSE T1-weighted Dixon and contrast-enhanced 3D FSPGR T1-weighted Dixon protocols are reproducible alternatives for the RAMRIS scoring in hands of patients with early rheumatoid arthritis. Coupling contrast-enhanced 3D FSPGR T1-weighted and 2D FSE T2-weighted sequences might be the most efficient option to completely assess the rheumatoid arthritis -related synovial and bone changes with the Dixon method.

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study.

OBJECTIVE: This phase 2a randomised, double blind, placebo controlled, parallel group study evaluated the safety and efficacy of a first-in-class drug candidate ABX464 (obefazimod, 50 mg and 100 mg per day), which upregulates the biogenesis of the mRNA inhibitor micro-RNA (miR)-124, in combination with methotrexate (MTX) in 60 patients (1:1:1 ratio) with moderate-to-severe active rheumatoid arthritis (RA) who have inadequate response to MTX or/and to an anti-tumour necrosis factor alpha (TNFα) therapy. METHODS: The primary end point was the safety of ABX464; efficacy endpoints included the proportion of patients achieving American College of Rheumatology (ACR)20/50/70 responses, disease activity scores (DAS) 28, simplified disease activity score, clinical disease activity score), European League Against Rheumatism response, DAS28 low disease activity or remission. RESULTS: ABX464 50 mg was safe and well tolerated. Two serious adverse events were reported (one on placebo group and one on ABX464 100 mg). Eleven patients were withdrawn for AEs (9 patients on 100 mg, 1 on 50 mg and 1 on placebo). Drug discontinuation was mainly due to gastrointestinal disorders. No cases of opportunistic infection, no malignancies and no death were reported. Compared with placebo, ABX464 50 mg showed significantly higher proportions of patients achieving ACR20 and ACR50 responses at week 12. DAS28-C reactive protein (CRP) and DAS28-erythrocyte sedimentation rate decreased significantly and rates of categorical DAS28-CRP response or CDAI remission increased significantly on ABX464 at week 12. A significant upregulation of miR-124 was observed in blood for every patient dosed with ABX464. CONCLUSION: ABX464 50 mg was safe, well tolerated and showed a promising efficacy. Mild-to-moderate gastrointestinal AEs led to a high drop-out rate of patients on ABX464 100 mg, which may not be a relevant dose to use. These findings warrant exploration of ABX464 at 50 mg per day or less for treating patients with RA. TRIAL REGISTRATION NAME: Phase IIa randomised, double blind, placebo controlled, parallel group, multiple dose study on ABX464 in combination with MTX, in patients with moderate to severe active RA who have inadequate response to MTX or/and to an anti- TNFα therapy or intolerance to anti-TNFα therapy.EUDRACT number: 2018-004677-27 TRIAL REGISTRATION NUMBER: NCT03813199.

Identification of poor prognostic joint locations in an early rheumatoid arthritis cohort at risk of rapidly progressing disease: a post-hoc analysis of the Phase III AGREE study.

BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease with established poor prognostic factors such as seropositivity, joint damage, and high disease activity at an early, treatment-naïve stage of disease. However, few studies have examined if specific joint locations are correlated with these factors in such a population. This analysis explored the potential correlation of individual swollen and erosive joints with other disease characteristics at baseline and with remission rates in a post-hoc analysis of the Phase III randomized AGREE study. METHODS: Methotrexate (MTX)-naïve, erosive, RF- and/or ACPA-positive early RA patients (N = 509) were retrospectively evaluated. Baseline joint swelling was analyzed for large and small joints. Baseline erosions were analyzed for wrist, MCP1-5, IP1, PIP2-5 and MTP1-5. Remission rates were assessed after 6 months of treatment with abatacept (ABA) + MTX (N = 256) or MTX (N = 253). The following statistical tests were used: Chi-Square or Fisher's exact test (categorical variables); Student's t-test or Wilcoxon rank-sum test (continuous variables); continuity-corrected Chi-square test (efficacy remission endpoints). RESULTS: Baseline swelling was most frequent in wrist (91.9%) and MCP2 joint (89.1%), while baseline erosion was most frequent in MTP5 joint (43.5%). Swollen shoulder was significantly correlated (p < 0.0001) with swelling of almost all other large or medium joints. Baseline swelling in the knee, temporomandibular joint (TMJ), wrist and elbow was highly correlated (p < 0.001) with higher tender and swollen joint counts, higher DAS28(CRP) and higher SDAI and CDAI. Baseline swelling was not correlated with erosion per joint, except for MCP2. The largest difference in mean Boolean remission rates at 6 months was in patients with baseline swollen wrist favoring ABA + MTX (14.0% vs 4.4%; p < 0.001). CONCLUSIONS: Swelling in the large and medium joints (knee, TMJ, elbow and wrist) was highly correlated with severe disease activity while MCP2 swelling seemed to be correlated with joint damage. The correlation of joint locations at an early, treatment-naïve stage with poor prognostic factors, higher disease activity and joint damage, could establish a rapidly progressing anatomical pattern in early RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00122382, registered July 2005.

EULAR points to consider for minimal reporting requirements in synovial tissue research in rheumatology.

BACKGROUND: Synovial tissue research has become widely developed in several rheumatology centres, however, large discrepancies exist in the way synovial tissue is handled and, more specifically, how data pertaining to biopsy procedure, quality check and experimental results are reported in the literature. This heterogeneity hampers the progress of research in this rapidly expanding field. In that context, under the umbrella of European Alliance of Associations for Rheumatology, we aimed at proposing points to consider (PtC) for minimal reporting requirements in synovial tissue research. METHODS: Twenty-five members from 10 countries across Europe and USA met virtually to define the key areas needing evaluation and formulating the research questions to inform a systematic literature review (SLR). The results were presented during a second virtual meeting where PtC were formulated and agreed. RESULTS: Study design, biopsy procedures, tissue handling, tissue quality control and tissue outcomes (imaging, DNA/RNA analysis and disaggregation) were identified as important aspects for the quality of synovial tissue research. The SLR interrogated four databases, retrieved 7654 abstracts and included 26 manuscripts. Three OPs and nine PtC were formulated covering the following areas: description of biopsy procedure, overarching clinical design, patient characteristics, tissue handling and processing, quality control, histopathology, transcriptomic analyses and single-cell technologies. CONCLUSIONS: These PtC provide guidance on how research involving synovial tissue should be reported to ensure a better evaluation of results by readers, reviewers and the broader scientific community. We anticipate that these PtC will enable the field to progress in a robust and transparent manner over the coming years.

Anti-TNF Induced Sarcoidosis-Like Disease in Rheumatoid Arthritis Patients: Review Cases from the RA UCLouvain Brussels Cohort.

INTRODUCTION: Drug-induced sarcoidosis-like disease is a rare side effect of anti-tumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA) patients. The most commonly involved organs in such condition are the lungs, skin, and lymph nodes. The aim of this study is to report the number of cases and the clinical manifestations of sarcoidosis induced by anti-TNF in our RA UCLouvain Brussels cohort. METHODS: All case records of RA patients ever treated with a TNF inhibitor and presenting anti-TNF induced sarcoidosis in our rheumatology centers from 2000 to 2021 were retrospectively reviewed. RESULTS: Our RA UCLouvain Brussels cohort includes 2492 patients. Among them, 697 patients have been or are exposed to a TNF inhibitor. Only four patients with sarcoidosis induced by anti-TNF were identified and reviewed. Patient 1 was classified as incomplete Heerfordt syndrome. Patient 2 was a case of sarcoid-like granulomatosis manifesting as life-threatening hypercalcemia, acute kidney injury and atypical parenchymal pneumopathy. Patients 3 and 4 developed pulmonary sarcoidosis with hilar adenopathies. The TNF inhibitor was etanercept for the first three patients and infliximab for the last one. The time occurrence of sarcoidosis was highly variable after anti-TNF exposure. All patients recovered after glucocorticoid treatment and the discontinuation of the anti-TNF agent. CONCLUSIONS: This case highlights this rare paradoxical side effect and the variability of the clinical presentation. Further studies should analyze the immunopathology of such conditions.

Long-term safety and efficacy of upadacitinib or adalimumab in patients with rheumatoid arthritis: results through 3 years from the SELECT-COMPARE study.

OBJECTIVES: To assess the long-term safety and efficacy of the Janus kinase inhibitor upadacitinib versus adalimumab over 3 years in the ongoing long-term extension (LTE) of SELECT-COMPARE, a randomised controlled phase 3 trial of patients with active rheumatoid arthritis and inadequate response to methotrexate (MTX). METHODS: Patients on stable background MTX were randomised 2:2:1 to upadacitinib 15 mg, placebo or adalimumab 40 mg. Patients with an insufficient response were switched by week 26 from placebo to upadacitinib, upadacitinib to adalimumab or adalimumab to upadacitinib. Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years. Safety and efficacy results were analysed here through 3 years. Treatment-emergent adverse events (AEs) were summarised based on exposure to upadacitinib and adalimumab. Efficacy was analysed by original randomised groups (non-responder imputation), as well as separately by treatment sequence (as observed). RESULTS: Rates of several AEs were generally comparable between upadacitinib and adalimumab, including AEs leading to discontinuation, serious infections and serious AEs, malignancies, major adverse cardiac events, venous thromboembolism and deaths. Consistent with earlier results, herpes zoster, lymphopaenia, hepatic disorder and CPK elevation were reported at higher rates with upadacitinib versus adalimumab. In terms of efficacy, upadacitinib continued to show numerically better clinical responses than adalimumab over 3 years across all endpoints, including low disease activity and remission. CONCLUSION: The safety profile of UPA 15 mg was consistent with previous study-specific and integrated safety reports. Higher levels of clinical response continued to be observed with upadacitinib versus adalimumab through 3 years of treatment.

Safety of vaccination against SARS-CoV-2 in people with rheumatic and musculoskeletal diseases: results from the EULAR Coronavirus Vaccine (COVAX) physician-reported registry.

OBJECTIVES: To describe the safety of vaccines against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal disease (I-RMD). METHODS: Physician-reported registry of I-RMD and non-inflammatory RMD (NI-RMDs) patients vaccinated against SARS-CoV-2. From 5 February 2021 to 27 July 2021, we collected data on demographics, vaccination, RMD diagnosis, disease activity, immunomodulatory/immunosuppressive treatments, flares, adverse events (AEs) and SARS-CoV-2 breakthrough infections. Data were analysed descriptively. RESULTS: The study included 5121 participants from 30 countries, 90% with I-RMDs (n=4604, 68% female, mean age 60.5 years) and 10% with NI-RMDs (n=517, 77% female, mean age 71.4). Inflammatory joint diseases (58%), connective tissue diseases (18%) and vasculitis (12%) were the most frequent diagnostic groups; 54% received conventional synthetic disease-modifying antirheumatic drugs (DMARDs), 42% biological DMARDs and 35% immunosuppressants. Most patients received the Pfizer/BioNTech vaccine (70%), 17% AstraZeneca/Oxford and 8% Moderna. In fully vaccinated cases, breakthrough infections were reported in 0.7% of I-RMD patients and 1.1% of NI-RMD patients. I-RMD flares were reported in 4.4% of cases (0.6% severe), 1.5% resulting in medication changes. AEs were reported in 37% of cases (37% I-RMD, 40% NI-RMD), serious AEs in 0.5% (0.4% I-RMD, 1.9% NI-RMD). CONCLUSION: The safety profiles of SARS-CoV-2 vaccines in patients with I-RMD was reassuring and comparable with patients with NI-RMDs. The majority of patients tolerated their vaccination well with rare reports of I-RMD flare and very rare reports of serious AEs. These findings should provide reassurance to rheumatologists and vaccine recipients and promote confidence in SARS-CoV-2 vaccine safety in I-RMD patients.

MRI of Hands with Early Rheumatoid Arthritis: Usefulness of Three-Point Dixon Sequences to Quantitatively Assess Disease Activity.

The use of efficient treatment with a treat-to-target strategy combined with early detection of the disease completely changed the imaging presentation and outcome of newly diagnosed rheumatoid arthritis (RA) patients. Magnetic Resonance Imaging (MRI) has become the reference technique in clinical research to detect and quantify inflammatory involvement of the soft tissues (synovitis and tenosynovitis) and bone marrow (osteitis) along with structural damages of the bone (erosions) in hands of patients with RA. Three-point Dixon MRI may be a valuable alternative to the currently recommended sequences as it yields effective fat signal suppression, high imaging quality and reproducible assessment of disease activity.

Treatment innovation for patients: a collaborative network in the Benelux and an inside view of 20 years of Galapagos.

A better understanding of disease pathology, improvements in relevant disease outcomes, better treatment strategies and the development of novel therapies all contribute to improving healthcare and treatment options. However, the global drug development model today is under increasing pressure, with very high drug development costs. Collaborative research is critical for bringing together different capabilities and expertise to increase the success of drug development, and large-scale collaborations with multiple partners are becoming increasingly common. Research clusters supported by local governments play an important role in bringing together academic centres, hospitals, scientists, and pharmaceutical and biotechnology industries. The 'triple helix' model, with academia, industry and governments working together, has been an important factor in the successful development of novel therapies. During the past 20 years, Galapagos has worked closely with academic centres, hospitals, governments and pharmaceutical companies to conduct innovative research and to develop a novel therapy for rheumatoid arthritis. These collaborations have brought unique knowledge, expertise and skills together, as well as crucial funding at various stages. Local governments in the Benelux have operated in this triple helix model to provide the necessary environment and to stimulate companies to achieve innovation through collaboration. Although the triple helix has already proved successful, evolution to a quadruple helix that includes patients and patient representatives could be the next step to ensure innovation remains transformational.

Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database.

OBJECTIVE: To report long-term safety from the completed extension trial of baricitinib, an oral selective Janus kinase inhibitor, in patients with active rheumatoid arthritis (RA). METHODS: Treatment-emergent adverse events are summarised from an integrated database (9 phase III/II/Ib and 1 long-term extension) of patients who received any baricitinib dose (All-bari-RA). Standardised incidence ratio (SIR) for malignancy (excluding non-melanoma skin cancer (NMSC)) and standardised mortality ratio (SMR) were estimated. Additional analysis was done in a subset of patients who had ever taken 2 mg or 4 mg baricitinib. RESULTS: 3770 patients received baricitinib (14 744 patient-years of exposure (PYE)). All-bari-RA incidence rates (IRs) per 100 patient-years at risk were 2.6, 3.0 and 0.5 for serious infections, herpes zoster and major adverse cardiovascular events (MACE), respectively. In patients aged ≥50 with ≥1 cardiovascular risk factor, the IR for MACE was 0.77 (95% CI 0.56 to 1.04). The IR for malignancy (excluding NMSC) during the first 48 weeks was 0.6 and remained stable thereafter (IR 1.0). The SIR for malignancies excluding NMSC was 1.07 (95% CI 0.90 to 1.26) and the SMR was 0.74 (95% CI 0.59 to 0.92). All-bari-RA IRs for deep vein thrombosis (DVT)/pulmonary embolism (PE), DVT and PE were 0.5 (95% CI 0.38 to 0.61), 0.4 (95% CI 0.26 to 0.45) and 0.3 (95% CI 0.18 to 0.35), respectively. No clear dose differences were noted for exposure-adjusted IRs (per 100 PYE) for deaths, serious infections, DVT/PE and MACE. CONCLUSIONS: In this integrated analysis including long-term data of baricitinib from 3770 patients (median 4.6 years, up to 9.3 years) with active RA, baricitinib maintained a similar safety profile to earlier analyses. No new safety signals were identified. TRIAL REGISTRATION NUMBER: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT02265705, NCT01721044, NCT01721057, NCT01711359 and NCT01885078.

India ink artifact on Dixon out-of-phase images can be used as a landmark to measure joint space width at MRI.

PURPOSE: The purpose of this study was to test the feasibility of joint space width (JSW) measurement on Dixon MR images with the "India ink" artifact between cartilage and bone marrow as a landmark for the subchondral plate and to correlate it with radiographic JSW. MATERIALS AND METHODS: Both hands of six volunteers (three women, three men; mean age, 36.7 ± 10.4 [SD] years) and 24 patients with early rheumatoid arthritis (16 women, 8 men; mean age, 45.7 ± 14.5 [SD] years) were imaged with MRI Dixon sequences and radiographs. Two radiologists (R1, R2) separately measured JSW in 11 joints per hand on all Dixon images in volunteers, on contrast-enhanced T1-weighted out-of-phase images in patients and on radiographs in both groups. Inter-technique, intra-observer and inter-observer agreements were assessed using intraclass correlation coefficient (ICC) and Bland Altman analysis. RESULTS: In volunteers, agreement between JSW measurements on MRI and radiographs was the highest with T1-weighted Dixon out-of-phase images (mean ICC ranging from 0.69 to 0.76 for R1 and 0.65 to 0.74 for R2). In patients, median bias between JSW measurements at first and second readings was not statistically significantly different from 0 on T1-weighted Dixon out-of-phase images (mean bias of 0.00 and + 0.01 mm) and radiographs (mean bias of 0.00 and +0.01 mm). Median bias of the difference between measurements of R1 and R2 was statistically significantly different from 0 on T1-weighted Dixon out-of-phase images (mean bias of -0.11 and -0.09 mm; P < 0.039) and radiographs (mean bias of -0.24 and -0.20 mm; P < 0.035). CONCLUSION: Measurement of hand JSW on T1-weighted Dixon out-of-phase images using India ink artifact as a landmark for the subchondral plate is repeatable and reproducible.

An international audit of the management of dyslipidaemia and hypertension in patients with rheumatoid arthritis: results from 19 countries.

AIMS: To assess differences in estimated cardiovascular disease (CVD) risk among rheumatoid arthritis (RA) patients from different world regions and to evaluate the management and goal attainment of lipids and blood pressure (BP). METHODS AND RESULTS: The survey of CVD risk factors in patients with RA was conducted in 14 503 patients from 19 countries during 2014-19. The treatment goal for BP was <140/90 mmHg. CVD risk prediction and lipid goals were according to the 2016 European guidelines. Overall, 21% had a very high estimated risk of CVD, ranging from 5% in Mexico, 15% in Asia, 19% in Northern Europe, to 31% in Central and Eastern Europe and 30% in North America. Of the 52% with indication for lipid-lowering treatment (LLT), 44% were using LLT. The lipid goal attainment was 45% and 18% in the high and very high risk groups, respectively. Use of statins in monotherapy was 24%, while 1% used statins in combination with other LLT. Sixty-two per cent had hypertension and approximately half of these patients were at BP goal. The majority of the patients used antihypertensive treatment in monotherapy (24%), while 10% and 5% as a two- or three-drug combination. CONCLUSION: We revealed considerable geographical differences in estimated CVD risk and preventive treatment. Low goal attainment for LLT was observed, and only half the patients obtained BP goal. Despite a high focus on the increased CVD risk in RA patients over the last decade, there is still substantial potential for improvement in CVD preventive measures.