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.

A novel fluorescence optical imaging scoring system for hand synovitis in rheumatoid arthritis-validity and agreement with ultrasound.

OBJECTIVES: To develop and validate a new semiquantitative fluorescence optical imaging (FOI) scoring system-the FOI Enhancement-Generated RA Score (FOIE-GRAS) for synovitis assessment in the hand. METHODS: The development of FOIE-GRAS was based on consensus of four experts in musculoskeletal imaging. Forty-six RA patients, eligible for treatment intensification and with ≥1 clinically swollen joints in the hands, and 11 healthy controls were included. FOI, ultrasound and clinical assessment of both hands were obtained at baseline and for RA patients after 3 and 6 months' follow-up. Twenty RA patients had an FOI rescan after 4 h. Synovitis was scored using FOIE-GRAS and the OMERACT ultrasound synovitis scoring system. All FOI images were scored by two readers. Inter-scan, inter- and intra-reader reliability were determined. Furthermore, FOIE-GRAS agreement with ultrasound and responsiveness was assessed. RESULTS: FOIE-GRAS synovitis was defined as early enhancement, and scores were based on the degree of coverage of the specific joint region after 3 s (0-3). Inter-scan, intra- and inter-reader intraclass correlations coefficients (ICC) were good to excellent for all baseline scores (0.76-0.98) and moderate to good for change (0.65-76).The FOIE-GRAS had moderate agreement with ultrasound (ICC 0.30-0.54) for total score, a good standardized response mean (>0.80), and moderate correlation with clinical joint assessment and DAS28-CRP. The median (interquartile range) reading time per FOI examination was 133 (109, 161) s. Scores were significantly lower in controls [1 (0, 4)] than RA patients [11 (6, 19)]. CONCLUSION: The FOIE-GRAS offers a feasible and reliable assessment of synovitis in RA, with a moderate correlation with ultrasound and DAS28-CRP, and good responsiveness.

Doppler ultrasound predicts successful discontinuation of biological DMARDs in rheumatoid arthritis patients in clinical remission.

OBJECTIVE: To assess the ability of ultrasound to predict successful tapering and successful discontinuation of biological DMARDs (bDMARDs) at the 2-year follow-up in RA patients in sustained remission. METHODS: Patients in sustained remission (DAS28-CRP ≤ 2.6) and with no radiographic progression the previous year tapered bDMARDs according to a standardized regime. A total of 119 of these patients were included in this ultrasound substudy. At baseline, clinical assessment, MRI, X-ray and ultrasound of 24 joints were performed. Ultrasound-detected synovitis was defined and scored 0-3 using the OMERACT scoring system at the joint level for both grey-scale and Doppler activity. Sum scores for each ultrasound modality were calculated for 24 joints at the patient level. The final state of treatment was assessed after 2 years. The predictive value of ultrasound measures for successful tapering and discontinuation at the 2-year follow-up was assessed via logistic regression analyses. RESULTS: Negative IgM-RF [odds ratio (OR) = 0.29, 95% CI: 0.10-0.85; P = 0.024] and lower Doppler sum score of 24 joints (OR = 0.44, 95% CI: 0.15, 0.87; P = 0.014) were independent predictors for successful discontinuation of bDMARDs at the 2-year follow-up. The predictive value of the Doppler sum score was independent of MRI findings. Previous numbers of bDMARDs were predictive of successful tapering (OR = 0.58, 95% CI: 0.35, 0.91; P = 0.018), whereas ultrasound was not. Clinical parameters were not predictive of successful tapering/discontinuation. CONCLUSION: Doppler sum score was an independent predictor for successful discontinuation of bDMARDs at the 2-year follow-up-the odds for achieving successful discontinuation decreased by 56% per one-unit increase in Doppler sum score. Ultrasound could not predict successful tapering.

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.

Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in routine care - 2-year outcomes and predictors.

Objectives: A cohort of routine care RA patients in sustained remission had biological DMARD (bDMARDs) tapered according to a treatment guideline. We studied: the proportion of patients whose bDMARD could be successfully tapered or discontinued; unwanted consequences of tapering/discontinuation; and potential baseline predictors of successful tapering and discontinuation. Methods: One-hundred-and-forty-three patients (91% receiving TNF inhibitor and 9% a non-TNF inhibitor) with sustained disease activity score (DAS28-CRP)⩽2.6 and no radiographic progression the previous year were included. bDMARD was reduced to two-thirds of standard dose at baseline, half after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP ⩾ 2.6 and ΔDAS28-CRP ⩾ 1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level. Results: One-hundred-and-forty-one patients completed 2-year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving two-thirds of standard dose, 39 (28%) half dose and 22 (16%) having discontinued; and 54 patients (38%) were receiving full dose. ΔDAS28-CRP0-2yrs was 0.1((-0.2)-0.4) (median (interquartile range)) and mean ΔTotal-Sharp-Score0-2yrs was 0.01(1.15)(mean(s.d.)). Radiographic progression was observed in nine patients (7%). Successful tapering was independently predicted by: ⩽1 previous bDMARD, male gender, low baseline MRI combined inflammation score or combined damage score. Negative IgM-RF predicted successful discontinuation. Conclusion: By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and combined damage scores were independent predictors for successful tapering.

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.

Intramuscular versus ultrasound-guided intratenosynovial glucocorticoid injection for tenosynovitis in patients with rheumatoid arthritis: a randomised, double-blind, controlled study.

OBJECTIVE: The aim of this study was to compare the efficacy of intramuscular versus ultrasound (US)-guided intratenosynovial glucocorticoid injection in providing disease control after 2, 4 and 12 weeks in patients with rheumatoid arthritis(RA) with tenosynovitis. METHODS: Fifty patients with RA and tenosynovitis were randomised into two double-blind groups: (A) 'intramuscular group', receiving intramuscular injection of betamethasone and US-guided intratenosynovial isotonic saline injection and (B) 'intratenosynovial group' receiving saline intramuscularly and US-guided intratenosynovial betamethasone injection. All patients were in stable disease-modifying anti-rheumatic drug treatment prior to and during the study. Patients were excluded, and considered non-responders, if any treatments were altered during the follow-up period. 'US tenosynovitis remission', defined as US tenosynovitis grey-scale score ≤1 and colour Doppler score=0, was assessed at week 4 (primary outcome), and weeks 2 and 12, using non-responder imputation for missing data. RESULTS: US tenosynovitis remission at week 4 was achieved in 25% (6/24) in the 'intramuscular group' versus 64% (16/25) in the 'intratenosynovial group', that is, a difference of -39 percentage point (pp) (CI -65pp to -13pp), Fisher exact test p=0.001. Corresponding values for the 'intramuscular group' versus the 'intratenosynovial group' at 2 and 12 weeks were 21% (5/24) versus 48% (13/25), that is, a difference of -27pp (CI -53pp to -2pp), p=0.072 and 8% (2/24) versus 44% (11/25), that is, difference of -36pp (-58pp to -13pp), p=0.003. Most US, clinical and patient-reported scores improved more in the 'intratenosynovial group' at all follow-up visits. CONCLUSIONS: In this randomised double-blind clinical trial, patients with RA and tenosynovitis responded significantly better to US-guided intratenosynovial glucocorticoid injection than to intramuscular glucocorticoid injection, both at 4 and 12 weeks follow-up. TRIAL REGISTRATION NUMBER: EudraCT nr: 2013-003486-34.

Magnetic resonance imaging assessed inflammation in the wrist is associated with patient-reported physical impairment, global assessment of disease activity and pain in early rheumatoid arthritis: longitudinal results from two randomised controlled trials.

OBJECTIVES: To examine whether MRI assessed inflammation and damage in the wrist of patients with early rheumatoid arthritis (RA) are associated with patient-reported outcomes (PROs). METHODS: Wrist and hand MRIs of 210 patients with early RA from two investigator-initiated, randomised controlled studies (CIMESTRA/OPERA) were assessed according to the Outcome Measures in Rheumatology RA MRI score (RAMRIS) for synovitis, tenosynovitis, osteitis, bone erosions and joint space narrowing (JSN) at baseline, 1 and 5 years follow-up. These features, and changes therein, were assessed for associations with health assessment questionnaires (HAQ), patient global visual analogue scales (VAS-PtGlobal) and VAS-pain using Spearman's correlations, generalised estimating equations and univariate/multivariable linear regression analyses. MRI features were further tested for trends against specific hand-related HAQ items using Jonckheere trend tests. RESULTS: MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS-pain for status and change scores, independently of C reactive protein and swollen joint count. MRI-assessed synovitis was most consistently associated with PROs, particularly VAS-PtGlobal and VAS-pain. MRI-assessed synovitis and tenosynovitis mean scores were positively associated with patient-reported difficulty to cut meat and open a milk carton (p<0.01), and similar patterns were seen for other hand-related HAQ items. Incorporating metacarpophalangeal joints in the analyses did not strengthen the associations between MRI pathology and PROs. CONCLUSIONS: MRI-assessed inflammation, but not damage, in early RA wrists is associated with patient-reported physical impairment, global assessment of disease activity and pain and influences the physical function in the hand. TRIAL REGISTRATION NUMBER: NCT00660647.

Tenosynovitis Evaluation Using Image Fusion and B-Flow - A Pilot Study on New Imaging Techniques in Rheumatoid Arthritis Patients.

Aim The aim of this study was to compare the assessment of tenosynovitis by ultrasound (US) and magnetic resonance imaging (MRI) using the image fusion technique and to investigate whether US B-flow imaging (BFI) is an alternative to Doppler US when assessing tenosynovitis. Materials and Methods 15 patients with rheumatoid arthritis (RA) had US-verified tenosynovitis in the wrist/hand. An MRI was performed of the wrist/hand with subsequent repeated US and image fusion. Images were compared in three steps: 1. Visual image comparison, 2. Quantitative measurement of transverse areas of the affected tendon and tendon sheath, using two tendon measures on MRI, area 1 and area 2, excluding and including partial volume artifacts, respectively, 3. Assessment using the OMERACT semi-quantitative scoring systems for US and MRI. Furthermore, BFI was assessed as: 0: No flow, 1: Focal flow, 2: Multifocal flow, 3: Diffuse flow, in the tendon sheath. Results The median areas on US and MRI (areas 1 and 2) were 0.16 cm2 (25;75 pctl: 0.10; 0.25), 0.9 cm2 (0.06; 0.18) and 0.13 cm2 (0.10; 0.25), respectively, for included tendons and 0.18 cm2 (0.13; 0.26), 0.27 cm2 (0.20; 0.45) and 0.23 cm2 (0.16; 0.40) for tendon sheaths. No statistically significant difference was found between US tendon area and MRI tendon area 2 (Wilcoxon's test; p = 0.47). Overall, the agreement between grayscale and color Doppler (CD) US and MRI tenosynovitis visualization and scoring was good, but not between CD and BFI. Conclusion US and MRI have high agreement using image fusion for the assessment of tenosynovitis when partial volume artifacts are taken into account. BFI is not an alternative to CD for the measurement of slow flow in tenosynovitis.

Correlation of Professional Antigen-Presenting Tbet+CD11c+ B Cells With Bone Destruction in Untreated Rheumatoid Arthritis.

OBJECTIVE: Subsets of CD21-/low memory B cells (MBCs), including double-negative (DN, CD27-IgD-) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21-/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21-/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA). METHODS: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity. RESULTS: CD21-/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor-related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction. CONCLUSION: This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization.

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.

Radiographic airway abnormalities in untreated early rheumatoid arthritis are associated with peripheral neutrophil activation.

BACKGROUND: The role of the lung for the initiation and progression of rheumatoid arthritis (RA) is still unclear. Up to 10% of RA patients develop interstitial lung disease which remains a clinical challenge. Understanding early disease mechanisms is of great importance. The objective of this study was to determine whether there is an association between peripheral neutrophil phenotypes and presence of pulmonary abnormalities (PA) on chest high-resolution computed tomography (HRCT) in untreated early RA (ueRA). METHODS: Clinical data and blood were collected, and HRCT performed at diagnosis on 30 consecutive anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) positive ueRA patients. HRCTs were evaluated for the presence of RA-associated parenchymal, airway and/or pleural abnormalities. Expression of phenotype markers on neutrophils were determined by flow cytometry. Levels of calprotectin, ACPA and RF were measured using immunoassays. RESULTS: The frequency of having any PA was 60%. Airway abnormalities were present in 50%, parenchymal nodules in 43% and interstitial lung abnormalities (ILA) in 10%. Unsupervised multivariate data analysis showed clustering of any PA with neutrophil activation, parameters of inflammation and RF titres. In univariate analysis, the patients with PA displayed significantly increased CD11b and decreased CD62L expression on neutrophils (1.2-fold, p = 0.014; 0.8-fold, p = 0.012) indicating activation and significantly increased RF IgM titre and CRP (5.7-fold, p = 0.0025; 2.3-fold, p = 0.0035) as compared to no PA. Titres of RF, but not ACPA, correlated with expression of the neutrophil activation marker CD11b. A stratified analysis demonstrated that airway involvement was the PA subtype with the strongest association with neutrophil activation. CONCLUSION: We report a strong association between radiographic airway findings and activation of circulating neutrophils in early RA supporting a role of innate immunity and the lung at disease onset. Our results also indicate different contributions of RF and ACPA in the RA pathogenesis.

Flare during tapering of biological DMARDs in patients with rheumatoid arthritis in routine care: characteristics and predictors.

OBJECTIVE: To identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs). METHODS: Sustained clinical remission was defined as Disease Activity Score for 28 joints (DAS28)-C reactive protein (CRP) ≤2.6 without radiographic progression for >1 year. bDMARDs were tapered according to a mandatory clinical guideline to two-thirds of standard dose at baseline, half of dose at week 16 and discontinuation at week 32. Prospective assessments for 2 years included clinical evaluation, conventional radiography, ultrasound and MRI for signs of inflammation and bone changes. Flare was defined as DAS28-CRP ≥2.6 with ∆DAS28-CRP ≥1.2 from baseline. Baseline predictors of flare were assessed by logistic regression analyses. RESULTS: Of 142 included patients, 121 (85%) flared during follow-up of which 86% regained remission within 24 weeks after flare. Patients that flared were more often rheumatoid factor positive, had tried more bDMARDs and had higher baseline ultrasound synovitis sum scores than those not flaring. For patients on standard dose, predictors of flare within 16 weeks after reduction to two-thirds of standard dose were baseline MRI-osteitis (OR 1.16; 95% CI 1.03 to 1.33; p=0.014), gender (female) (OR 6.71; 95% CI 1.68 to 46.12; p=0.005) and disease duration (OR 1.06; 95% CI 1.01 to 1.11; p=0.020). Baseline predictors for flare within 2 years were ultrasound grey scale synovitis sum score (OR 1.19; 95% CI 1.02 to 1.44; p=0.020) and number of previous bDMARDs (OR 4.07; 95% CI 1.35 to 24.72; p=0.007). CONCLUSION: The majority of real-world patients with RA tapering bDMARDs flared during tapering, with the majority regaining remission after stepwise dose increase. Demographic and imaging parameters (MR-osteitis/ultrasound greyscale synovitis) were independent predictors of immediate flare and flare overall and may be of importance for clinical decision-making in patients eligible for tapering.

Whole-body Magnetic Resonance Imaging in Psoriatic Arthritis, Rheumatoid Arthritis, and Healthy Controls: Interscan, Intrareader, and Interreader Agreement and Distribution of Lesions.

OBJECTIVE: Whole-body MRI (WBMRI) is a promising technique for monitoring patients' global disease activity in inflammatory joint diseases. The validation of WBMRI is limited; no studies have evaluated the test-retest agreement (interscan agreement) and only a few have assessed the intra- and interreader agreement. Therefore, we first examined the interscan agreement of WBMRI in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), and healthy controls (HC); and second, we evaluated the intra- and interreader agreement and agreement with conventional hand MRI and determined the distribution of lesions. METHODS: WBMRI was performed twice at a 1-week interval in 14 patients with PsA, 10 with RA, and 16 HC. Images were anonymized and read in pairs with unknown chronological order by experienced readers according to the Outcome Measures in Rheumatology (OMERACT) WBMRI, Canada-Denmark MRI, and the RA MRI scoring system (RAMRIS) and the PsA MRI scoring system (PsAMRIS). Ten image sets were reanonymized for assessment of intra- and interreader agreement. Agreement was calculated on lesion level by percentage exact agreement (PEA) and Cohen κ, and for sum scores by absolute agreement, single-measure intraclass correlation coefficient (ICC). RESULTS: WBMRI of the spine and peripheral joints and entheses generally showed moderate to almost perfect interscan agreement with PEA ranging from 95% to 100%, κ 0.71-1.00, and ICC 0.95 to 1.00. Intra- and interreader data generally showed moderate to almost perfect agreement. Agreement with conventional MRI varied. More lesions were found in patients than in HC. CONCLUSION: WBMRI showed good interscan agreement, implying that repositioning of the patient between examinations does not markedly affect scoring of lesions. Intra- and interreader agreement were moderate to almost perfect.

Serial magnetic resonance imaging and ultrasound examinations demonstrate differential inflammatory lesion patterns in soft tissue and bone upon patient-reported flares in rheumatoid arthritis.

BACKGROUND: Magnetic resonance imaging (MRI) and ultrasonography (US) are more sensitive than clinical evaluation in assessing inflammation in rheumatoid arthritis (RA). Data is scarce regarding potential link between patient-reported flares and inflammation on imaging. The aim of the study was to explore the pattern and longitudinal associations of inflammatory lesions detected by serial MRI and US in relation to patient-reported flares in patients with RA. METHODS: Eighty RA patients with baseline DAS28CRP < 3.2 and no swollen joints were examined at baseline and followed for 1 year. Patients were requested to contact the hospital in case of patient-reported hand flare accompanied by ≥ 1 tender and swollen joint. The 29 patients who reported hand flare had four extra visits within 4 months from flare onset comprising clinical examination, patient-reported outcomes, MRI, and US of wrists and hands. MRI synovitis/tenosynovitis/bone marrow edema (BME) and US synovitis/tenosynovitis were scored. MRI and US scores at and after the flare were compared to baseline before the flare, and associations were explored by linear mixed models for repeated measurements. RESULTS: Synovitis and tenosynovitis by MRI/US increased significantly at flare onset. Synovitis waned quickly, as did US tenosynovitis. BME showed delayed increase yet persisted, once the patient-reported flare had resolved, as did MRI tenosynovitis. In univariate models, patient-reported flares were associated with all MRI and US inflammatory markers, except for BME, which was only associated with SJC28 and long-lasting flares > 14 days. Independent associations were observed between patient-reported flares and tenosynovitis by MRI and US (p < 0.05). CONCLUSIONS: Patient-reported flares were linked to inflammation detected by serial MRI and US. Differential patterns of inflammatory lesion evolution were observed by serial imaging with early synovial and tenosynovial inflammation, followed by delayed-onset BME.

Atlas of the OMERACT Heel Enthesitis MRI Scoring System (HEMRIS).

OBJECTIVE: Assessment of enthesitis, a key feature in spondyloarthritis (SpA) and psoriatic arthritis (PsA), using objective and sensitive methods is pivotal in clinical trials. MRI allows detection of both soft tissue and intra-osseous changes of enthesitis. This article presents an atlas for the Outcome Measures in Rheumatology (OMERACT) Heel Enthesitis Magnetic Resonance ImagingMRI Scoring System (HEMRIS). METHODS: Following a preliminary selection of potential examples of each grade, as per HEMRIS definitions, the images along with detailed definitions and reader rules were discussed at web-based, interactive meetings between the members of the OMERACT MRI in Arthritis Working Group. RESULTS: Reference images of each grade of the MRI features to be assessed using HEMRIS, along with reader rules and recommended MRI sequences are depicted. CONCLUSION: The presented reference images can be used to guide scoring Achilles tendon and plantar fascia (plantar aponeurosis) enthesitis according to the OMERACT HEMRIS in clinical trials and cohorts in which MRI enthesitis is used as an outcome.

Association between MRI findings and patient-reported outcomes in patients with rheumatoid arthritis in clinical remission and at relapse.

OBJECTIVE: To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse. METHODS: Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n = 70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests. RESULTS: Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P < .01), independent of clinical and radiographic measures, and was also associated with most of the hand-related HAQ items (P < .03). In multivariate models including MRI, SvH scores were not associated with PROs. MRI-assessed inflammation was not associated with PROs at remission or relapse. CONCLUSION: Magnetic resonance imaging-assessed wrist/hand damage, but not inflammation, in patients with established RA is associated with patient-reported physical impairment at remission and relapse. The amount of damage in the wrist/hand is associated with reduced hand function.

Validity and Responsiveness of Combined Inflammation and Combined Joint Damage Scores Based on the OMERACT Rheumatoid Arthritis MRI Scoring System (RAMRIS).

OBJECTIVE: The RAMRIS [Outcome Measures in Rheumatology rheumatoid arthritis (RA) magnetic resonance imaging (MRI) Scoring system] is used in clinical RA trials. We have investigated methods to combine the RAMRIS features into valid and responsive scores for inflammation and joint damage. METHODS: We used data from 3 large randomized early RA trials to assess 5 methods to develop a combined score for inflammation based on RAMRIS bone marrow edema, synovitis, and tenosynovitis scores, and a combined joint damage score based on erosions and joint space narrowing. Methods included unweighted summation, normalized summation, and 3 different variants of weighted summation of the RAMRIS features. We used a derivation cohort to calculate summation weights to maximize the responsiveness of the combined score. Construct validity of the combined scores was examined by assessing correlations to imaging, clinical, and biochemical measures. Responsiveness was tested by calculating the standardized response mean (SRM) and the relative efficiency of each score in a validation cohort. RESULTS: Patient characteristics, as well as baseline and followup RAMRIS scores, were comparable between cohorts. All combined scores were significantly correlated to other imaging, clinical, and biochemical measures. Inflammation scores combined by normalized and weighted summation had significantly higher responsiveness in comparison to unweighted summation, with SRM (95% CI) for unweighted summation 0.62 (0.51-0.73), normalized summation 0.73 (0.63-0.83), and weighted summation 0.74 (0.64-0.84). For the damage score, there was a trend toward higher responsiveness for weighted summation. CONCLUSION: Combined MRI scores calculated by normalized or weighted summation of individual MRI pathologies were valid and responsive.

Development and Validation of an OMERACT MRI Whole-Body Score for Inflammation in Peripheral Joints and Entheses in Inflammatory Arthritis (MRI-WIPE).

OBJECTIVE: To develop a whole-body magnetic resonance imaging (MRI) scoring system for peripheral arthritis and enthesitis. METHODS: After consensus on definitions/locations of MRI pathologies, 4 multireader exercises were performed. Eighty-three joints were scored 0-3 separately for synovitis and osteitis, and 33 entheses 0-3 separately for soft tissue inflammation and osteitis. RESULTS: In the last exercise, reliability was moderate-good for musculoskeletal radiologists and rheumatologists with previously demonstrated good scoring proficiency. Median pairwise single-measure/average-measure ICC were 0.67/0.80 for status scores and 0.69/0.82 for change scores; κ ranged 0.35-0.77. CONCLUSION: Whole-body MRI scoring of peripheral arthritis and enthesitis is reliable, which encourages further testing and refinement in clinical trials.

The OMERACT MRI in Enthesitis Initiative: Definitions of Key Pathologies, Suggested MRI Sequences, and a Novel Heel Enthesitis Scoring System.

OBJECTIVE: To develop and validate an enthesitis magnetic resonance imaging (MRI) scoring system for spondyloarthritis/psoriatic arthritis, using the heel as model. METHODS: Consensus definitions of key pathologies and 3 heel enthesitis multireader scoring exercises were done, separated by discussion, training, and calibration. RESULTS: Definitions for bone and soft tissue pathologies were agreed. In the final exercise, median pairwise single-measures intraclass correlation coefficients (ICC; patient-level) for entheseal inflammation status/change scores were 0.83/0.82 for all readers. For radiologists and selected rheumatologists, ICC were 0.91/0.84 and quadratic-weighted κ (lesion-level) 0.57-0.91/0.45-0.81. CONCLUSION: The proposed definitions and Heel Enthesitis Scoring System (HEMRIS) are reliable among trained readers and promising for clinical trials.