Long-term efficacy of a 2-year MRI treat-to-target strategy on disease activity and radiographic progression in patients with rheumatoid arthritis in clinical remission: 5-year follow-up of the IMAGINE-RA randomised trial.

OBJECTIVE: To investigate whether a 2-year MRI treat-to-target strategy targeting the absence of osteitis combined with clinical remission, compared with a conventional treat-to-target strategy targeting clinical remission only (IMAGINE-rheumatoid arthritis (RA) trial) improves clinical and radiographic outcomes over 5 years in patients with RA in clinical remission. METHODS: IMAGINE-more was an observational extension study of the original 2-year IMAGINE-RA randomised trial (NCT01656278). Clinical examinations and radiographs (hands and feet) were obtained yearly. Prespecified coprimary outcomes at year 5 were Disease Activity Score in 28 joints C reactive protein (DAS28-CRP) remission rate (DAS28-CRP<2.6) and no radiographic progression (van der Heijde-modified Sharp score (vdHSS) ≤0) from baseline. Secondary outcomes included 5-year changes in radiographic, MRI and clinical measures of disease activity and physical function. RESULTS: In total 131 patients, 86 women (67%), mean age 61.2, disease duration 9.5 years, median baseline DAS28-CRP 1.9 (IQR 1.6-2.2) and vdHSS 16.0 (IQR 7.0-36.0) were included in the study; 59 (59%) patients from the original MRI treat-to-target group and 72 (72%) from the conventional group. At year 5, 47 patients (80%) in the MRI treat-to-target group vs 54 patients (75%) in the conventional treat-to-target group were in DAS28-CRP remission (OR 2.00 (95% CI 0.76 to 5.28); p=0.16) while 14 patients (24%) vs 19 patients (26%) had no radiographic progression (OR 0.70, (95% CI 0.28 to 1.71); p=0.43). CONCLUSION: A 2-year combined MRI and clinical treat-to-target strategy, compared with a conventional clinical treat-to-target strategy alone, had no effect on the long-term probability of achieving DAS28-CRP remission and of avoiding radiographic progression.

The impact of an ultrasound atlas for scoring salivary glands in primary Sjögren's syndrome: a pilot study.

The objective of this pilot study was to assess the impact of a salivary gland ultrasound (SGUS) atlas for scoring parenchymal changes in Sjögren's syndrome by assessing the reliability of the scoring system (0-3), without and with the use of the SGUS atlas. Ten participants with varying experience in SGUS contributed to the reliability exercise. Thirty SGUS images of the submandibular and parotid gland with abnormalities ranging from 0 to 3 were scored using the written definitions of the OMERACT SGUS scoring system and using the SGUS atlas based on the OMERACT scoring system. For intra-reader reliability, two rounds were performed without and with the atlas-in the 2nd round the 30 images were rearranged in random order by a physician not included in the scoring. Inter-reader reliability was also determined in both rounds. Without using the atlas, the SGUS OMERACT scoring system showed fair inter-reader reliability in round 1 (mean kappa 0.36; range 0.06-0.69) and moderate intra-reader reliability (mean kappa 0.55; range 0.28-0.81). With the atlas, inter-reader reliability improved in round 1 to moderate (mean kappa 0.52; range 0.31-0.77) and intra-reader reliability to good (mean kappa 0.69; range 0.46-0.86). Higher intra-reader reliability was noted in participants with previous SGUS experience. The SGUS atlas increased both intra- and inter-reader reliability for scoring gland pathology in participants with varying SGUS experience suggesting a possible future role in clinical practice and trials. Key Points • Ultrasonography can detect parenchymal changes in salivary glands in patients with Sjögren's disease. • An ultrasound atlas may improve reliability of scoring parenchymal changes in salivary glands.

Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial.

BACKGROUND: The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. METHODS: Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate-severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni's and Dunnet's procedures adjusted for multiple testing (significance level: 0.025). RESULTS: Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences.The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. CONCLUSIONS: Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments. TRIAL REGISTRATION NUMBER: NCT01491815.

The multidisciplinary approach to eosinophilia.

Eosinophilic granulocytes are normally present in low numbers in the bloodstream. Patients with an increased number of eosinophilic granulocytes in the differential count (eosinophilia) are common and can pose a clinical challenge because conditions with eosinophilia occur in all medical specialties. The diagnostic approach must be guided by a thorough medical history, supported by specific tests to guide individualized treatment. Neoplastic (primary) eosinophilia is identified by one of several unique acquired genetic causes. In contrast, reactive (secondary) eosinophilia is associated with a cytokine stimulus in a specific disease, while idiopathic eosinophilia is a diagnosis by exclusion. Rational treatment is disease-directed in secondary cases and has paved the way for targeted treatment against the driver in primary eosinophilia, whereas idiopathic cases are treated as needed by principles in eosinophilia originating from clonal drivers. The vast majority of patients are diagnosed with secondary eosinophilia and are managed by the relevant specialty-e.g., rheumatology, allergy, dermatology, gastroenterology, pulmonary medicine, hematology, or infectious disease. The overlap in symptoms and the risk of irreversible organ involvement in eosinophilia, irrespective of the cause, warrants that patients without a diagnostic clarification or who do not respond to adequate treatment should be referred to a multidisciplinary function anchored in a hematology department for evaluation. This review presents the pathophysiology, manifestations, differential diagnosis, diagnostic workup, and management of (adult) patients with eosinophilia. The purpose is to place eosinophilia in a clinical context, and therefore justify and inspire the establishment of a multidisciplinary team of experts from diagnostic and clinical specialties at the regional level to support the second opinion. The target patient population requires highly specialized laboratory analysis and therapy and occasionally has severe eosinophil-induced organ dysfunction. An added value of a centralized, clinical function is to serve as a platform for education and research to further improve the management of patients with eosinophilia. Primary and idiopathic eosinophilia are key topics in the review, which also address current research and discusses outstanding issues in the field.

Salivary gland ultrasound is associated with the presence of autoantibodies in patients with Sjögren's syndrome: A Danish single-centre study.

OBJECTIVES: To investigate whether ultrasound findings of major salivary glands are correlated with serological markers, autoantibodies, patient- or doctor-reported disease activity in a Danish cohort of patients with primary Sjögren's Syndrome (pSS). METHODS: In all, 49 patients at Odense University Hospital with pSS diagnosed according to the 2002 American-European Consensus Group (AECG) classification criteria were included. Patients were characterized using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI, score of systemic complications) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), serologic markers, Schirmer's test and salivary test. Salivary gland ultrasound (SGUS) was performed of the submandibular and parotid glands and scored according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) semi-quantitative scoring system. RESULTS: More patients with abnormal SGUS had antinuclear antibodies (ANA) (p = 0.002), anti-Ro52 (p = 0.001), anti-Ro60 (p<0.001), anti-La (p<0.001) and IgM-RF (p<0.001). Titers for ANA (p = 0.02) and anti-Ro52 (p = 0.03) were higher in patients with abnormal SGUS. Twenty-three of the pSS patients had no pathological findings on SGUS. There was no correlation between SGUS severity and ESSDAI- or ESSPRI-scores. CONCLUSIONS: Abnormal SGUS findings are associated with autoantibodies of high specificity for pSS but not with ESSDAI, ESSPRI or inflammatory markers.

Ultrasound joint examination by an automated system versus by a rheumatologist: from a patient perspective.

BACKGROUND: The Arthritis Ultrasound Robot (ARTHUR) is an automated system for ultrasound scanning of the joints of both hands and wrists, with subsequent disease activity scoring using artificial intelligence. The objective was to describe the patient's perspective of being examined by ARTHUR, compared to an ultrasound examination by a rheumatologist. Further, to register any safety issues with the use of ARTHUR. METHODS: Twenty-five patients with rheumatoid arthritis (RA) had both hands and wrists examined by ultrasound, first by a rheumatologist and subsequently by ARTHUR. Patient-reported outcomes (PROs) were obtained after the examination by the rheumatologist and by ARTHUR. PROs regarding pain, discomfort and overall experience were collected, including willingness to be examined again by ARTHUR as part of future clinical follow-up. All ARTHUR examinations were observed for safety issues. RESULTS: There was no difference in pain or discomfort between the examination by a rheumatologist and by ARTHUR (p = 0.29 and p = 0.20, respectively). The overall experience of ARTHUR was described as very good or good by 92% (n = 23), with no difference compared to the examination by the rheumatologist (p = 0.50). All (n = 25) patients were willing to be examined by ARTHUR again, and 92% (n = 23) would accept ARTHUR as a regular part of their RA clinical follow up. No safety issues were registered. CONCLUSIONS: Joint ultrasound examination by ARTHUR was safe and well-received, with no difference in PRO components compared to ultrasound examination by a rheumatologist. Fully automated systems for RA disease activity assessment could be important in future strategies for managing RA patients. TRIAL REGISTRATION: The study was evaluated by the regional ethics committee (ID: S-20200145), which ruled it was not a clinical trial necessary for their approval. It was a quality assessment project, as there was no intervention to the patient. The study was hereafter submitted and registered to Odense University Hospital, Region of Southern Denmark as a quality assessment project and approved (ID: 20/55294).

A retrospective cohort study of patients with eosinophilia referred to a tertiary centre.

INTRODUCTION: Patients with eosinophilia (an increased number of eosinophilic granulocytes > 0.5 × 108/l in the blood) are encountered in all medical specialties and frequently need thorough workup to identify the eliciting causes and decide whether treatment is indicated. In Denmark, highly specialised centres for eosinophilic diseases or conditions have been established to provide a foundation for the management of complicated cases. Here, we present experiences from such a multidisciplinary centre. METHODS: This was a retrospective study of all patients seen in our tertiary centre for eosinophilia in the 2016-2019 period. RESULTS: Referrals mainly derived from specialised secondary care and to a lesser degree from primary care physicians. Patients were either asymptomatic or exhibited symptoms from up to three organ systems and presented a median eosinophil count of 1.7 × 108/l. Up to eight new clonality analyses or imaging studies per patient were performed after referral. One of these, T-cell receptor analysis, was performed frequently but provided limited information, whereas, e.g., flow cytometry proved more clinically applicable owing to its broader diagnostic range. In total, 51 patients were evaluated and classified as secondary (59%), myeloid neoplasm with PDGFRA rearrangement (2%), idiopathic hypereosinophilic syndrome (31%) and idiopathic hypereosinophilia (8%). CONCLUSION: The value of a multidisciplinary and versatile approach in a highly specialised centre has a positive impact on diagnostic processes as well as on the evaluation of treatment need. FUNDING: none. TRIAL REGISTRATION: not relevant.

Ultrasound joint examination by an automated system versus by a rheumatologist: from a patient perspective

Abstract Background: The Arthritis Ultrasound Robot (ARTHUR) is an automated system for ultrasound scanning of the joints of both hands and wrists, with subsequent disease activity scoring using artificial intelligence. The objective was to describe the patient's perspective of being examined by ARTHUR, compared to an ultrasound examination by a rheumatologist. Further, to register any safety issues with the use of ARTHUR. Methods: Twenty-five patients with rheumatoid arthritis (RA) had both hands and wrists examined by ultrasound, first by a rheumatologist and subsequently by ARTHUR. Patient-reported outcomes (PROs) were obtained after the examination by the rheumatologist and by ARTHUR. PROs regarding pain, discomfort and overall experience were collected, including willingness to be examined again by ARTHUR as part of future clinical follow-up. All ARTHUR examinations were observed for safety issues. Results: There was no difference in pain or discomfort between the examination by a rheumatologist and by ARTHUR ( p =0.29 and p =0.20, respectively). The overall experience of ARTHUR was described as very good or good by 92% (n =23), with no difference compared to the examination by the rheumatologist ( p =0.50). All (n =25) patients were willing to be examined by ARTHUR again, and 92% (n =23) would accept ARTHUR as a regular part of their RA clinical follow up. No safety issues were registered. Conclusion: Joint ultrasound examination by ARTHUR was safe and well-received, with no difference in PRO components compared to ultrasound examination by a rheumatologist. Fully automated systems for RA disease activity assessment could be important in future strategies for managing RA patients. Trial registration: The study was evaluated by the regional ethics committee (ID: S-20200145), which ruled it was not a clinical trial necessary for their approval. It was a quality assessment project, as there was no intervention to the patient. The study was hereafter submitted and registered to Odense University Hospital, Region of Southern Denmark as a quality assessment project and approved (ID: 20/55294).

In vitro effect of biological and conventional disease-modifying antirheumatic drugs on fibrocyte differentiation in patients with rheumatoid arthritis and healthy controls.

OBJECTIVE: Fibrocytes are circulating bone-marrow-derived cells that migrate to organs with ongoing repair or inflammation. In the target organ, the cells differentiate, become long and spindle-shaped, and are able to produce extracellular matrix components. In fibrotic diseases, the levels of fibrocytes are increased, both in circulation and the diseased tissue. In rheumatoid arthritis (RA), fibrocytes have been proposed to be involved in the spread of the disease and possibly in RA fibrotic manifestations, as can be seen in RA interstitial lung disease (RA-ILD). Therefore, we aimed to investigate a range of current RA treatment modalities (corticosteroids and conventional and biological disease-modifying antirheumatic drugs (DMARDs)) regarding their effect on in vitro fibrocyte differentiation. METHODS: A total of 10 participants were included (5 patients with RA and 5 healthy controls). Peripheral blood mononuclear cells (PBMCs) were isolated and cultured for 5 days with prednisolone, conventional DMARDs (methotrexate, sulfasalazine, and hydroxychloroquine), and biological DMARDs (etanercept, tocilizumab, adalimumab, abatacept, and rituximab). The numbers of fibrocytes were counted. Dose-response data for abatacept and tocilizumab were collected. RESULTS: Abatacept and prednisolone significantly suppressed differentiation of PBMC into fibrocytes compared with control (p=0.02 and p<0.01, respectively) (n=10). In overall analysis (n=10), abatacept reduced fibrocyte levels with an average of 44% overall and 71% in the RA group compared with the control wells. Tocilizumab reduced the fibrocyte count by 63% overall and 45% in the RA group, although it was not significant (p=0.07 and p=0.06, respectively). Both tocilizumab and abatacept display a dose-response relationship. CONCLUSION: Abatacept and prednisolone suppress the differentiation of mononuclear cells to mature fibrocytes in vitro in patients with RA, and data indicate a similar effect of tocilizumab; this was further supported by the observed dose-response relationship. Clinical trials are needed to compare the effect of these drugs on fibrotic RA manifestations, for example, RA-ILD.

Fibrocytes in early and long-standing rheumatoid arthritis: a 6-month trial with repeated synovial biopsy, imaging and lung function test.

OBJECTIVES: To correlate the level of fibrocytes in peripheral blood, synovial tissue and in vitro culture in rheumatoid arthritis (RA) with changes in disease activity, imaging and pulmonary function. METHODS: Twenty patients with early RA (ERA) and 20 patients with long-standing RA (LRA) were enrolled in a 6-month prospective study. Sixteen patients undergoing wrist arthroscopy were healthy controls. Patients with RA underwent pulmonary function tests, ultrasound and synovial ultrasound-guided needle biopsy of the same wrist at baseline and 6 months. Wrist MRI was performed at baseline (all) and 6 months (ERA). Circulating fibrocytes were measured by flow cytometry, in vitro by the number of monocytes that were differentiated to fibrocytes and in synovial biopsies by counting in histological sections. RESULTS: Fibrocytes were primarily located around vessels and in the subintimal area in the synovium. Fibrocyte levels did not decline during the trial despite effective RA treatment. In the ERA group, increased synovitis assessed by ultrasound was moderate and strongly correlated with an increase in circulating and synovial fibrocyte levels, respectively. Increased synovitis assessed by MRI during the trial in the ERA group was moderately correlated with both increased numbers of circulating and cultured fibrocytes. Absolute diffusion capacity level was overall weakly negatively correlated with the level of circulating and synovial fibrocytes. The decline in diffusion capacity during the trial was moderately correlated with increased levels of synovial fibrocytes. CONCLUSION: Our findings suggest that fibrocytes are involved in RA pathogenesis, both in the synovium and the reduction in lung function seen in a part of patients with RA. TRIAL REGISTRATION NUMBER: NCT02652299.

Predictors of joint damage progression and stringent remission in patients with established rheumatoid arthritis in clinical remission.

OBJECTIVES: To study if clinical, radiographic and MRI markers can predict MRI and radiographic damage progression and achievement of stringent remission in patients with established RA in clinical remission followed by a targeted treatment strategy. METHODS: RA patients (DAS28-CRP <3.2, no swollen joints) receiving conventional synthetic DMARDs were randomized to conventional or MRI-targeted treat-to-target strategies with predefined algorithmic treatment escalations. Potentially predictive baseline variables were tested in multivariate logistic regression analyses. RESULTS: In the 171 patients included, baseline MRI osteitis independently predicted progression in MRI erosion [odds ratio (OR) 1.13 (95% CI 1.06, 1.22)], joint space narrowing [OR 1.15 (95% CI 1.07, 1.24)] and combined damage [OR 1.23 (95% CI 1.13, 1.37)], while tenosynovitis independently predicted MRI erosion progression [OR 1.13 (95% CI 1.03, 1.25)]. A predictor of radiographic erosion progression was age, while gender predicted progression in joint space narrowing. Following an MRI treat-to-target strategy predicted stringent remission across all remission definitions: Clinical Disease Activity Index remission OR 2.94 (95% CI 1.25, 7.52), Simplified Disease Activity Index remission OR 2.50 (95% CI 1.01, 6.66), ACR/EULAR Boolean remission OR 5.47 (95% CI 2.33, 14.13). Similarly, low tender joint count and low patient visual analogue scale pain and global independently predicted achievement of more stringent remission. CONCLUSION: Baseline MRI osteitis and tenosynovitis were independent predictors of 2 year MRI damage progression in RA patients in clinical remission, while independent predictors of radiographic damage progression were age and gender. Following an MRI treat-to-target strategy, low scores of patient-reported outcomes and low tender joint count predicted achievement of stringent remission. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT01656278.

Complement activation in human autoimmune diseases and mouse models; employing a sandwich immunoassay specific for C3dg.

In human autoimmune diseases, low plasma levels of complement factors C3 and C4 are commonly used as a proxy for complement activation. The measurements of C3 and C4 concentrations (the result of synthesis and consumption) however, show low sensitivity in patient follow-up. We find that the estimation of the C3dg fragment released during complement activation is a better parameter for complement activation. Available techniques for measuring the activation fragment C3dg, e.g. immune-electrophoresis or involving PEG-precipitation, are time-consuming and difficult to standardize. Here we examine the specificity and use of an antibody with mono-specificity for a neoepitope at the N-terminus of C3dg, which is only exposed after cleavage of C3. We present a stable, reproducible, and easy-to-use, time-resolved immunoassay with specificity for C3dg that can be used to directly evaluate ongoing complement activation. We demonstrate that the assay can be applied to clinical samples with a high specificity (95%) and a positive likelihood ratio of 10. It can also differentiate the complement related disease Systemic Lupus Erythematosus from controls and other immune-mediatedimmune mediated diseases like Rheumatoid Arthritis (86% specificity) and Spondyloarthritis (91% specificity). Further, we establish how the assay may also be used for experimental research in in vivo mouse models.

Use and utility of serologic tests for rheumatoid arthritis in primary care.

INTRODUCTION: In this retrospective, register-based population study, we evaluated if anti-citrullinated protein antibodies (ACPA) is a better choice than immunoglobulin M rheumatoid factor (IgM RF) in primary care when rheumatoid arthritis (RA) is suspected, as it determines predictive values in real-life settings. Furthermore, the study described ordering patterns to investigate the benefit of repeated testing. METHODS: Test result, requisitioning unit, test date and the patient's social security number were collected from the Department of Clinical Immunology at Odense University Hospital in 2007-2016 and merged with patient diagnoses from the Danish National Patient Registry. RESULTS: Overall, 5% were diagnosed with RA. IgM RF remained the preferred test during the entire period. Test sensitivity was 61% for IgM RF and 54% for ACPA. The test specificity was 88% for IgM RF and 96% for ACPA. Positive predictive value (PPV) was higher for ACPA than for IgM RF (30% versus 12%) and negative predictive value (NPV) was equal (99%) in primary care. Few individuals seroconverted from negative to positive (ACPA 2% and IgM RF 5%) and positive to negative (ACPA 3% and IgM RF 6%). CONCLUSIONS: ACPA has a higher PPV for RA than IgM RF, whereas their NPV is identical. ACPA is the better choice when testing for RA in primary care. Seroconversion is rare, and it is only rarely relevant to retest. FUNDING: The Department of Clinical immunology at Odense University Hospital funded the study. TRIAL REGISTRATION: not relevant.

Increased serum levels of microfibrillar-associated protein 4 (MFAP4) are not associated with clinical synovitis in rheumatoid arthritis but may reflect underlying cardiovascular comorbidity.

OBJECTIVES: To study circulating MFAP4 in rheumatoid arthritis (RA) and its associations with clinical phenotype. METHODS: Early RA (ERA): 47 patients with newly diagnosed, treatment naïve RA were included. Serum MFAP4, clinical and laboratory disease variables were recorded serially during 12 months of intensive synovitis suppressive treatment. Long-standing RA (LRA): 317 patients participated, all receiving DMARD treatment. Disease activity, autoantibody status, extra-articular manifestations and cardiovascular morbidity were recorded. Paired serum and synovial fluid samples were obtained from 13 untreated ERA patients. Healthy blood donors served as reference points. MFAP4 was quantified by AlphaLISA immunoassay. Univariate, multivariate and mixed effects regression models were applied in the statistical analysis. RESULTS: ERA: MFAP4 increased from baseline and was significantly elevated at the 12-month follow-up, 17.8 U/l [12.6;24.1] vs. healthy controls, 12.7 U/l [9.5;15.6], p<0.001. MFAP4 did not correlate with joint counts or C-reactive protein. LRA: MFAP4 was increased, 25.9 U/l [20.4;33.7] vs. healthy controls, 17.6 U/l [13.7;21.2], p<0.0001, but did not correlate with disease activity measures or presence of extra-articular manifestations. Notably, MFAP4 correlated inversely with smoking (p<0.0001) and presence of antibodies against cyclic citrullinated peptides (anti-CCP), p=0.005. There was a positive association with systolic blood pressure, p=0.001 and co-occurrence of three cardiovascular events and/or risk factors, p<0.0001. The serum:synovial fluid MFAP4 ratio was 2:1. CONCLUSIONS: MFAP4 increases from diagnostic baseline despite intensive treatment but does not associate with synovitis at early or late stages of RA. Correlation patterns indicate that increased MFAP4 may reflect enhanced RA-related vascular remodelling.

Six-month prospective trial in early and long-standing rheumatoid arthritis: evaluating disease activity in the wrist through sequential synovial histopathological analysis, RAMRIS magnetic resonance score and EULAR-OMERACT ultrasound score.

Introduction: Standardised scoring systems for rheumatoid arthritis (RA) joint disease activity include Larsen score for radiographs, rheumatoid arthritis magnetic resonance imaging score (RAMRIS) for MRI and using the European League Against Rheumatisms-Outcome Measures in Rheumatology (EULAR-OMERACT) score for ultrasound (US) images. The aim of this prospective study was to investigate the relationship between histological synovitis and radiological synovitis, assessed by conventional X-ray, US and MRI of the wrist radiocarpal joint. Methods: 20 patients with treatment naive early RA (ERA) and 20 with long-standing RA (LRA) were enrolled in a 6-month prospective study. Patients with RA underwent US-guided synovial biopsy, X-ray and US of the wrist at enrolment and 6 months. MRI at baseline and also at 6 months for the ERA group, and scored with the RAMRIS system. X-ray was scored by Larsen score and US by the EULAR-OMERACT system. Synovial biopsy inflammation was determined by the Krenn score. Results: In the ERA group at baseline, Krenn score was correlated strongly with both US combined score (r = 0.77 p < 0.001) and MRI synovitis score (r = 0.85 p < 0.001), while uncorrelated at 6 months. In the LRA group at baseline, these scores correlated strongly (r = 0.83, p < 0.001) to moderately (r = 0.61, p = 0.002), and persisted at 6 months for US score (r = 0.81 p < 0.001). For all patients with RA, change in Krenn score between baseline and 6 months was correlated with both change in US combined score (r = 0.65, p < 0.001) and change in MRI synovitis score (r = 0.50, p = 0.03). Conclusion: The MRI RAMRIS synovitis score and EULAR-OMERACT US scoring system are sensitive measures of histological synovitis in LRA and ERA. After 6 months, this correlation persists in the established RA group, but not in the ERA group. Overall, decreases in MRI/US synovitis are associated with reductions in histological synovitis. The study validates the use of MRI RAMRIS and EULAR-OMERACT US scores as surrogate markers of histological synovitis in established RA and early untreated RA.

Effect of Magnetic Resonance Imaging vs Conventional Treat-to-Target Strategies on Disease Activity Remission and Radiographic Progression in Rheumatoid Arthritis: The IMAGINE-RA Randomized Clinical Trial.

Importance: Whether using magnetic resonance imaging (MRI) to guide treatment in patients with rheumatoid arthritis (RA) improves disease activity and slows joint damage progression is unknown. Objective: To determine whether an MRI-guided treat-to-target strategy vs a conventional clinical treat-to-target strategy improves outcomes in patients with RA in clinical remission. Design, Setting, and Participants: Two-year, randomized, multicenter trial conducted at 9 hospitals in Denmark. Two hundred patients with RA in clinical remission (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] <3.2 and no swollen joints) were enrolled between April 2012 and June 2015. The final follow-up visit was April 2017. Interventions: Patients were randomly allocated (1:1) to an MRI-guided vs a conventional treat-to-target strategy. In the MRI-guided group, the treatment goal was absence of MRI bone marrow edema combined with clinical remission, defined as DAS28-CRP of 3.2 or less and no swollen joints. In the conventional group, the treatment goal was clinical remission. Main Outcomes and Measures: Co-primary outcomes were proportions of patients achieving DAS28-CRP remission (DAS28-CRP <2.6) and with no radiographic progression (no increase in total van der Heijde-modified Sharp score) at 24 months. Significance testing for the primary outcome was based on 1-sided testing. Secondary outcomes were clinical and MRI measures of disease activity, physical function, and quality of life. Results: Of 200 patients randomized (133 women [67%]; mean [SD] age, 61.6 [10.5] years; median baseline DAS28-CRP, 1.9 [interquartile range, 1.7-2.2]; van der Heijde-modified Sharp score, 18.0 [interquartile range, 7.0-42.5]), 76 patients (76%) in the MRI-guided group and 95 (95%) in the conventional group completed the study. Of these, 64 (85%) vs 83 (88%), respectively, reached the primary clinical end point (risk difference, -4.8% [1-sided 95% CI, -13.6% to + ∞; 1-sided P = .19]) and 49 (66%) vs 58 (62%), respectively, reached the primary radiographic end point (risk difference, 4.7% [1-sided 95% CI, -7.0% to + ∞; 1-sided P = .25). Of 10 key secondary end points, 8 were null and 2 showed statistically significant benefit for the MRI treat-to-target group. Seventeen patients (17%) in the MRI-guided treat-to-target group and 6 patients (6%) in the conventional treat-to-target group experienced serious adverse events. Conclusions and Relevance: Among patients with RA in clinical remission, an MRI-guided treat-to-target strategy compared with a conventional treat-to-target strategy did not result in improved disease activity remission rates or reduce radiographic progression. These findings do not support the use of an MRI-guided strategy for treating patients with RA. Trial Registration: ClinicalTrials.gov Identifier: NCT01656278.