Long-term safety and efficacy of upadacitinib versus adalimumab in patients with rheumatoid arthritis: 5-year data from the phase 3, randomised SELECT-COMPARE study.

OBJECTIVES: To assess the safety and efficacy of upadacitinib versus adalimumab from SELECT-COMPARE over 5 years. METHODS: Patients with rheumatoid arthritis and inadequate response to methotrexate were randomised to receive upadacitinib 15 mg once daily, placebo or adalimumab 40 mg every other week, all with concomitant methotrexate. By week 26, patients with insufficient response to randomised treatment were rescued; patients remaining on placebo switched to upadacitinib. Patients completing the 48-week double-blind period could enter a long-term extension. Safety and efficacy were assessed through week 264, with radiographic progression analysed through week 192. Safety was assessed by treatment-emergent adverse events (TEAEs). Efficacy was analysed by randomised group (non-responder imputation (NRI)) or treatment sequence (as observed). RESULTS: Rates of TEAEs were generally similar with upadacitinib versus adalimumab, although numerically higher rates of herpes zoster, lymphopenia, creatine phosphokinase elevation, hepatic disorder and non-melanoma skin cancer were reported with upadacitinib. Numerically greater proportions of patients randomised to upadacitinib versus adalimumab achieved clinical responses (NRI); Clinical Disease Activity Index remission (≤2.8) and Disease Activity Score based on C reactive protein <2.6 were achieved by 24.6% vs 18.7% (nominal p=0.042) and 31.8% vs 23.2% (nominal p=0.006), respectively. Radiographic progression was numerically lower with continuous upadacitinib versus adalimumab at week 192. CONCLUSION: The safety profile of upadacitinib through 5 years was consistent with the known safety profile of upadacitinib, with no new safety risks. Clinical responses were numerically higher with upadacitinib versus adalimumab at 5 years. Upadacitinib demonstrates a favourable benefit-risk profile for long-term rheumatoid arthritis treatment. TRIAL REGISTRATION NUMBER: NCT02629159.

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.

Inhibition of structural joint damage progression with upadacitinib in rheumatoid arthritis: 1-year outcomes from the SELECT phase 3 program.

OBJECTIVES: To evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active RA receiving upadacitinib as monotherapy or in combination with MTX. METHODS: Radiographic progression was assessed in two phase 3 randomized controlled trials. MTX-naïve patients were randomized to upadacitinib 15 or 30 mg once daily or MTX monotherapy (SELECT-EARLY, n = 945), while MTX inadequate responders (IRs) were randomized to upadacitinib 15 mg once daily or adalimumab 40 mg every other week or placebo added to background MTX (SELECT-COMPARE, n = 1629). The mean changes from baseline in modified total Sharp score (mTSS), joint space narrowing and erosion scores were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as observed. RESULTS: In patients naïve or with limited exposure to MTX (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg and 1.00 for MTX based on linear extrapolation (P < 0.001 for both upadacitinib doses vs MTX). Among patients with an inadequate response to MTX (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus MTX group vs placebo plus MTX (0.28 vs 1.73; P < 0.001). The mean change from baseline in the adalimumab plus MTX group was 0.39. CONCLUSION: Upadacitinib monotherapy or in combination with background MTX was effective in inhibiting the progression of structural joint damage through week 48 in MTX-naïve and MTX-IR patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02706873 and NCT02629159.

Long-term outcomes of pexidartinib in tenosynovial giant cell tumors.

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

Longitudinal Reliability of the OMERACT Thumb Base Osteoarthritis Magnetic Resonance Imaging Scoring System (TOMS).

OBJECTIVE: To assess the longitudinal reliability of the Outcome Measures in Rheumatology (OMERACT) Thumb base Osteoarthritis Magnetic resonance imaging (MRI) Scoring system (TOMS). METHODS: Paired MRI of patients with hand osteoarthritis were scored in 2 exercises (6-mo and 2-yr followup) for synovitis, subchondral bone defects (SBD), osteophytes, cartilage assessment, bone marrow lesions (BML), and subluxation. Interreader reliability of delta scores was assessed. RESULTS: Little change occurred. Average-measure intraclass correlation coefficients were good-excellent (≥ 0.71), except synovitis (0.55-0.83) and carpometacarpal-1 osteophytes/cartilage assessment (0.47/0.39). Percentage exact/close agreement was 52-92%/68-100%, except BML in 2 years (28%/64-76%). Smallest detectable change was below the scoring increment, except in SBD and BML. CONCLUSION: TOMS longitudinal reliability was moderate-good. Limited change hampered assessment.

Atlas for the OMERACT thumb base osteoarthritis MRI scoring system (TOMS).

This paper presents an atlas for the Outcome Measures in Rheumatology Clinical Trials (OMERACT) thumb base osteoarthritis MRI scoring system (TOMS). The atlas includes reference images of each grade of each feature that is assessed in TOMS (synovitis grade 0-3, subchondral bone defects grade 0-3, osteophytes grade 0-3, cartilage assessment grade 0-3, subluxation and bone marrow lesions grade 0-3) in the first carpometacarpal and scapho-trapezio-trapezoid joint. The presented reference images can be used to guide scoring of thumb base MRIs in patients with hand osteoarthritis according to the OMERACT TOMS.

The OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging (MRI) Scoring System: Updated Recommendations by the OMERACT MRI in Arthritis Working Group.

OBJECTIVE: The Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis (RA) Magnetic Resonance Imaging (MRI) scoring system (RAMRIS), evaluating bone erosion, bone marrow edema/osteitis, and synovitis, was introduced in 2002, and is now the standard method of objectively quantifying inflammation and damage by MRI in RA trials. The objective of this paper was to identify subsequent advances and based on them, to provide updated recommendations for the RAMRIS. METHODS: MRI studies relevant for RAMRIS and technical and scientific advances were analyzed by the OMERACT MRI in Arthritis Working Group, which used these data to provide updated considerations on image acquisition, RAMRIS definitions, and scoring systems for the original and new RA pathologies. Further, a research agenda was outlined. RESULTS: Since 2002, longitudinal studies and clinical trials have documented RAMRIS variables to have face, construct, and criterion validity; high reliability and sensitivity to change; and the ability to discriminate between therapies. This has enabled RAMRIS to demonstrate inhibition of structural damage progression with fewer patients and shorter followup times than has been possible with conventional radiography. Technical improvements, including higher field strengths and improved pulse sequences, allow higher image resolution and contrast-to-noise ratio. These have facilitated development and validation of scoring methods of new pathologies: joint space narrowing and tenosynovitis. These have high reproducibility and moderate sensitivity to change, and can be added to RAMRIS. Combined scores of inflammation or joint damage may increase sensitivity to change and discriminative power. However, this requires further research. CONCLUSION: Updated 2016 RAMRIS recommendations and a research agenda were developed.

Whole-body Magnetic Resonance Imaging in Inflammatory Arthritis: Systematic Literature Review and First Steps Toward Standardization and an OMERACT Scoring System.

OBJECTIVE: Whole-body magnetic resonance imaging (WB-MRI) is a relatively new technique that can enable assessment of the overall inflammatory status of people with arthritis, but standards for image acquisition, definitions of key pathologies, and a quantification system are required. Our aim was to perform a systematic literature review (SLR) and to develop consensus definitions of key pathologies, anatomical locations for assessment, a set of MRI sequences and imaging planes for the different body regions, and a preliminary scoring system for WB-MRI in inflammatory arthritis. METHODS: An SLR was initially performed, searching for WB-MRI studies in arthritis, osteoarthritis, spondyloarthritis, or enthesitis. These results were presented to a meeting of the MRI in Arthritis Working Group together with an MR image review. Following this, preliminary standards for WB-MRI in inflammatory arthritides were developed with further iteration at the Working Group meetings at the Outcome Measures in Rheumatology (OMERACT) 2016. RESULTS: The SLR identified 10 relevant original articles (7 cross-sectional and 3 longitudinal, mostly focusing on synovitis and/or enthesitis in spondyloarthritis, 4 with reproducibility data). The Working Group decided on inflammation in peripheral joints and entheses as primary focus areas, and then developed consensus MRI definitions for these pathologies, selected anatomical locations for assessment, agreed on a core set of MRI sequences and imaging planes for the different regions, and proposed a preliminary scoring system. It was decided to test and further develop the system by iterative multireader exercises. CONCLUSION: These first steps in developing an OMERACT WB-MRI scoring system for use in inflammatory arthritides offer a framework for further testing and refinement.

Development and Validation of the OMERACT Rheumatoid Arthritis Magnetic Resonance Tenosynovitis Scoring System in a Multireader Exercise.

OBJECTIVE: To develop and validate a magnetic resonance imaging (MRI) tenosynovitis (TS) score for tendons at the wrist and metacarpophalangeal (MCP) joint levels in patients with rheumatoid arthritis (RA). METHODS: Axial T1-weighted precontrast and postcontrast fat-saturated MR image sets of the hands of 43 patients with RA initiating rituximab therapy were obtained at baseline and after 14, 26, 38, or 52 weeks. The MR images were scored twice by 4 readers. Nine tendon compartments of the wrist and 4 flexor tendon compartments at the MCP joints were assessed. Tenosynovitis was scored as follows: 0: No; 1: < 1.5 mm; 2: ≥ 1.5 mm but < 3 mm; 3: ≥ 3 mm peritendinous effusion and/or postcontrast enhancement. Intrareader and interreader intraclass correlation coefficients (ICC), smallest detectable change (SDC), percentage of exact and close agreement (PEA/PCA), and standardized response mean (SRM) were calculated. RESULTS: Intrareader and interreader ICC for status and change scores were very good (≥ 0.80) for total scores for all readers. Intrareader SDC was ≤ 3.0 and interreader SDC was < 2.0. The overall PEA/PCA intrareader and interreader agreements for change scores in all tendons were 73.8%/97.6% and 47.9%/85.0%, respectively. Average SRM was moderate for total scores and 60.5% of the patients had a tenosynovitis change score ≥ SDC. CONCLUSION: The TS score showed high intrareader and interreader agreement for wrist and finger tendons, with moderate responsiveness, and the majority of the patients showed a change above the SDC. This scoring system may be included as a component of the RAMRIS.

Validation of the OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) for the Hand and Foot in a Randomized Placebo-controlled Trial.

OBJECTIVE: To assess changes following treatment and the reliability and responsiveness to change of the Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) in a randomized controlled trial. METHODS: Forty patients with PsA randomized to either placebo or abatacept (ABA) had MRI of either 1 hand (n = 20) or 1 foot (n = 20) at baseline and after 6 months. Images were scored blindly twice by 3 independent readers according to the PsAMRIS (for synovitis, tenosynovitis, periarticular inflammation, bone edema, bone erosion, and bone proliferation). RESULTS: Inflammatory features improved numerically but statistically nonsignificantly in the ABA group but not the placebo group. Baseline intrareader intraclass correlation coefficients (ICC) were good (≥ 0.50) to very good (≥ 0.80) for all features in both hand and foot. Baseline interreader ICC were good (ICC 0.72-0.96) for all features, except periarticular inflammation and bone proliferation in the hand and tenosynovitis in the foot (ICC 0.25-0.44). Intrareader and interreader ICC for change scores varied. Guyatt's responsiveness index (GRI) was high for inflammatory features in the hand and metatarsophalangeal joints (GRI -0.67 to -3.13; bone edema not calculable). Minimal change and low prevalence resulted in low ICC and GRI for bone damage. CONCLUSION: PsAMRIS showed overall good intrareader agreement in the hand and foot, and inflammatory feature scores were responsive to change, suggesting that PsAMRIS may be a valid tool for MRI assessment of hands and feet in PsA clinical trials.

The Longitudinal Reliability and Responsiveness of the OMERACT Hand Osteoarthritis Magnetic Resonance Imaging Scoring System (HOAMRIS).

OBJECTIVE: To evaluate the interreader reliability of change scores and the responsiveness of the OMERACT Hand Osteoarthritis (OA) Magnetic Resonance Image (MRI) Scoring System (HOAMRIS). METHODS: Paired MRI (baseline and 5-yr followup) from 20 patients with hand OA were scored with known time sequence by 3 readers according to the HOAMRIS: Synovitis, erosive damage, cysts, osteophytes, cartilage space loss, malalignment, and bone marrow lesions (BML; 0-3 scales with 0.5 increments for synovitis, erosive damage, and BML). Interreader reliability for status and change scores were assessed by intraclass correlation coefficients (ICC), percentage exact agreement and percentage close agreement (PEA/PCA), and smallest detectable change (SDC). Responsiveness was assessed by standardized response means (SRM). RESULTS: Cross-sectional interreader ICC were good to very good (≥ 0.74) for all features except synovitis, cysts, and malalignment (ICC 0.50-0.58). The range of change values was small, leading to low ICC for change scores. The SDC values for sum scores (total range 0-24) varied between 1.97-3.05 (except 1.08 for malalignment). For status scores, PEA/PCA on scores in individual joints across the readers were 8.1-50.0 and 43.8-78.1, respectively. Similarly, PEA/PCA for change scores were 20.6-63.8 and 66.3-93.1, respectively. All features except cysts and BML demonstrated good responsiveness with higher SRM for sum scores (range 0.46-1.62) than for scores in individual joints (range 0.24-0.73). CONCLUSION: Good to very good interreader ICC values were found for cross-sectional readings, whereas the longitudinal reliability was lower because of a smaller range of change scores. All features, except cysts and BML, showed good responsiveness.

The OMERACT-RAMRIS rheumatoid arthritis magnetic resonance imaging joint space narrowing score: intrareader and interreader reliability and agreement with computed tomography and conventional radiography.

OBJECTIVE: To test the intrareader and interreader reliability of assessment of joint space narrowing (JSN) in rheumatoid arthritis (RA) wrist and metacarpophalangeal (MCP) joints on magnetic resonance imaging (MRI) and computed tomography (CT) using the newly proposed OMERACT-RAMRIS JSN scoring method, and to compare JSN assessment on MRI, CT, and radiography. METHODS: After calibration of readers, MRI and CT images of the wrist and second to fifth MCP joints from 14 patients with RA and 1 healthy control were assessed twice for JSN by 3 readers, blinded to clinical and imaging data. Radiographs were scored by the Sharp/van der Heijde method. Intraclass correlation coefficients (ICC) and smallest detectable differences (SDD) were calculated, and the performance of various simplified scores was investigated. RESULTS: Both MRI and CT showed high intrareader (ICC ≥ 0.95) and interreader (ICC ≥ 0.94) reliability for total (wrist + MCP) assessment of JSN. Agreement was generally lower for MCP joints than for wrist joints, particularly for CT. Intrareader SDD for MCP/wrist/MCP + wrist were 1.2/6.1/6.4 JSN units for MRI, while 2.7/8.3/9.9 JSN units for CT. JSN on MRI and CT correlated moderately well with corresponding radiographic JSN scores (MCP 2-5: 0.49 and 0.56; wrist areas assessed by Sharp/van der Heijde: 0.80 and 0.95), and high ICC between scores on MRI and CT were demonstrated (MCP: 0.94; wrist: 0.92; MCP + wrist: 0.92). CONCLUSION: The OMERACT-RAMRIS MRI JSN scoring system showed high intrareader and interreader reliability, and high correlation with CT scores of JSN. The suggested JSN score may, after further validation in longitudinal studies, become a useful tool in RA clinical trials.

Monitoring cartilage loss in the hands and wrists in rheumatoid arthritis with magnetic resonance imaging in a multi-center clinical trial: IMPRESS (NCT00425932).

INTRODUCTION: Magnetic resonance imaging (MRI) is increasingly being used in clinical trials of rheumatoid arthritis (RA) because of its superiority over x-ray radiography (XR) in detecting and monitoring change in bone erosion, osteitis and synovitis. However, in contrast to XR, the MRI scoring method that was used in most clinical trials did not include cartilage loss. This limitation has been an obstacle to accepting MRI as a potential alternative to XR in clinical trials. Cross-sectional studies have shown MRI to be sensitive for cartilage loss in the hands and wrist; although, longitudinal sensitivity to change has not yet been confirmed. In this study we examined the ability of MRI to monitor change in cartilage loss in patients with RA in a multi-site clinical trial setting. METHODS: Thirty-one active RA patients from a clinical trial (IMPRESS) who were randomized equally into treatment with either rituximab + methotrexate or placebo + methotrexate had MRI of the dominant hand/wrist at baseline, 12 weeks and 24 weeks at 3 clinical sites in the US. Twenty-seven of these patients also had XR of both hands/wrists and both feet at baseline and 24 weeks. One radiologist scored all XR images using the van der Heijde-modified Sharp method blinded to visit order. The same radiologist scored MR images for cartilage loss using a previously validated 9-point scale, and bone erosion using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI Score (RAMRIS) blinded to visit order and XR scores. Data from the two treatment arms were pooled for this analysis. RESULTS: Mean MRI cartilage score increased at 12 and 24 weeks, and reached statistical significance at 24 weeks. XR total Sharp score, XR erosion score and XR joint-space narrowing (JSN) score all increased at 24 weeks, but only XR total Sharp score increased significantly. CONCLUSIONS: To our knowledge, this is the first publication of a study demonstrating MRI's ability to monitor cartilage loss in a multi-site clinical trial. Combined with MRI's established performance in monitoring bone erosions in RA, these findings suggest that MRI may offer a superior alternative to XR in multi-site clinical trials of RA.

Evaluating joint-space narrowing and cartilage loss in rheumatoid arthritis by using MRI.

INTRODUCTION: Magnetic resonance imaging (MRI) has been shown to be superior to radiography (XR) for assessing synovitis, osteitis, and bone erosion in rheumatoid arthritis (RA), particularly in clinical trials. However, relatively little has been reported on the ability of MRI to evaluate articular cartilage loss, or joint-space narrowing (JSN), in the hands and wrists. In a previous study, we adapted the nine-point Genant-modified Sharp XR-JSN score for use with MRI (MRI-JSN). In this study, we compare MRI-JSN with XR-JSN by using images from two multicenter clinical trials. METHODS: Baseline XR and 1.5-Tesla MR images of one hand and wrist from each of 47 subjects with RA enrolled in one of two multicenter clinical trials were evaluated by using the XR-JSN and MRI-JSN methods by a single radiologist experienced in the two methods. Radiographs and MR images were read independently on different occasions. RESULTS: In total, 575 of 611 joints were compared (one metacarpophalangeal joint of the thumb and 35 proximal interphalangeal joints were outside the MRI field of view and could not be assessed). The 22 (47%) subjects showed JSN with both XR and MRI, and 25 (53%) subjects showed no JSN with either method. No subject showed JSN with only one or the other method. MRI showed high agreement with XR (intraclass correlation coefficient = 0.83). Sensitivity of MRI for JSN, by using XR as the gold standard, was 0.94; specificity was 0.91; accuracy was 0.91; positive predictive value was 0.64; and negative predictive value was 0.99. CONCLUSIONS: This validation exercise suggests that MRI JSN scoring may offer a viable alternative to XR JSN scoring in multicenter clinical trials of RA. However, the relative longitudinal sensitivity of MRI to change and the ability to discriminate therapeutic effect on JSN were not evaluated in this study.

Magnetic resonance imaging in rheumatoid arthritis clinical trials: emerging patterns based on recent experience.

OBJECTIVE: The current validated magnetic resonance imaging (MRI) scoring method for rheumatoid arthritis (RA) in clinical trials, RA MRI Score (RAMRIS), incorporates all metacarpophalangeal (MCP) and wrist joints except MCP-1. The experience with radiographic scoring, however, was that excluding certain bones in the wrist improved the discriminative power for changes over time. In this study, we pool MRI data from randomized controlled clinical trails (RCT) to determine which combination of MCP and wrist joints are most sensitive and discriminative for structural changes over time. METHODS: MR images from 4 multicenter RCT, including 522 RA patients, were read by 2 radiologists, using the RAMRIS scoring system for erosion, osteitis, and synovitis. In one RCT, joint-space narrowing (JSN) was assessed cross-sectionally by one radiologist using a previously validated method. Baseline frequencies of erosion, JSN, osteitis, and synovitis of different bones and joints in the hand and wrist were compared. Intraclass correlation coefficients between readers were determined for each location. Finally, 7 different combinations of bone/joint locations were compared for their ability to discriminate subjects showing increases or decreases from baseline greater than or equal to smallest detectable changes (SDC) at Weeks 12 or 24. RESULTS: Frequency of involvement and reliability for assessing change varied by location. As in earlier analyses, excluding certain wrist bones increased the percentage of subjects showing changes greater than or equal to SDC. CONCLUSION: These findings suggest that excluding wrist bones that do not frequently or reliably demonstrate structural changes improves the discriminative power of the RAMRIS scoring system.

The OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) is reliable and sensitive to change: results from an OMERACT workshop.

OBJECTIVE: The aim of this multireader exercise was to assess the reliability and sensitivity to change of the psoriatic arthritis magnetic resonance imaging score (PsAMRIS) in PsA patients followed for 1 year. METHODS: MRI was acquired from 12 patients with PsA before initiation of treatment and after 12 months. MR images were scored according to PsAMRIS (for synovitis, tenosynovitis, periarticular inflammation, bone marrow edema, bone erosion, and bone proliferation) under standardized conditions, in unknown chronological order. Intraobserver/interobserver reliability was examined by intraclass correlation coefficients (ICC) and sensitivity to change by standardized response means (SRM). RESULTS: The interobserver reliability of PsAMRIS was high for synovitis, tenosynovitis, periarticular inflammation, and bone edema status and change scores (interobserver ICC 0.87-0.97). The intraobserver reliability was moderate to high (ICC 0.60-0.98) for status and change scores, except for change in periarticular inflammation (ICC 0.33). PsAMRIS sensitivity to change was moderate for synovitis, tenosynovitis, and periarticular inflammation (SRM 0.5-0.8), while poor (SRM 0.1-0.3) for bone marrow edema, erosion, and bone proliferation. Rare occurrence and minimal change contributed to poor SRM and change-score ICC for bone parameters. CONCLUSION: This multireader exercise, performed under standardized conditions, confirmed PsAMRIS to have high interobserver and intraobserver reliability for hand PsA. Measures of inflammation were sensitive to change, implying that PsAMRIS may be a valuable tool for monitoring change in inflammation during PsA clinical trials.

Update on research and future directions of the OMERACT MRI inflammatory arthritis group.

The OMERACT Magnetic Resonance Imaging (MRI) Task Force has developed and evolved the psoriatic arthritis MRI score (PsAMRIS) over the last few years, and at OMERACT 10, presented longitudinal evaluation by multiple readers, using PsA datasets obtained from extremity MRI magnets. Further evaluation of this score will require more PsA imaging datasets. As well, due to improved image resolution since the development of the original rheumatoid arthritis MRI scoring system (RAMRIS), the Task Force has worked on semiquantitative assessment of joint space narrowing, and developed a reliable method as a potential RAMRIS addendum, although responsiveness will need to be evaluated. One of the strengths of MRI is the ability to detect subclinical synovitis, so the group worked on obtaining low disease activity/clinical remission datasets from a number of international centers and presented cross-sectional findings. Subsequent longitudinal evaluation of this unique resource will be a major continuing focus for the group.

Development and preliminary validation of a magnetic resonance imaging joint space narrowing score for use in rheumatoid arthritis: potential adjunct to the OMERACT RA MRI scoring system.

OBJECTIVE: To develop and validate a magnetic resonance imaging (MRI) method of assessment of joint space narrowing (JSN) in rheumatoid arthritis (RA). METHODS: Phase A: JSN was scored 0-4 on MR images of 5 RA patients and 3 controls at 15 wrist sites and 2nd-5th metacarpophalangeal (MCP) joints by 8 readers (7 once, one twice), using a preliminary scoring system. Phase B: Image review, discussion, and consensus on JSN definition, and revised scoring system. Phase C: MR images of 15 RA patients and 4 controls were scored using revised system by 5 readers (4 once, one twice), and results compared with radiographs [Sharp-van der Heijde (SvdH) method]. RESULTS: Phase A: Intraobserver agreement: intraclass correlation coefficient (ICC) = 0.99; smallest detectable difference (SDD, for mean of readings) = 2.8 JSN units (4.9% of observed maximal score). Interobserver agreement: ICC = 0.93; SDD = 6.4 JSN units (9.9%). Phase B: Agreement was reached on JSN definition (reduced joint space width compared to normal, as assessed in a slice perpendicular to the joint surface), and revised scoring system (0-4 at 17 wrist sites and 2nd-5th MCP; 0: none; 1: 1-33%; 2: 34-66%; 3: 67-99%; 4: ankylosis). Phase C: Intraobserver agreement: ICC = 0.90; SDD = 6.8 JSN units (11.0%). Interobserver agreement: ICC = 0.92 and SDD = 6.2 JSN units (8.7%). The correlation (ICC) with the SvdH radiographic JSN score of the wrist/hand was 0.77. Simplified approaches evaluating fewer joint spaces demonstrated similar reliability and correlation with radiographic scores. CONCLUSION: An MRI scoring system of JSN in RA wrist and MCP joints was developed and showed construct validity and good intra- and interreader agreements. The system may, after further validation in longitudinal data sets, be useful as an outcome measure in RA.

Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial.

OBJECTIVE: RANKL is essential for osteoclast development, activation, and survival. Denosumab is a fully human monoclonal IgG2 antibody that binds RANKL, inhibiting its activity. The aim of this multicenter, randomized, double-blind, placebo-controlled, phase II study was to evaluate the effects of denosumab on structural damage in patients with rheumatoid arthritis (RA) receiving methotrexate treatment. METHODS: RA patients received subcutaneous placebo (n = 75), denosumab 60 mg (n = 71), or denosumab 180 mg (n = 72) injections every 6 months for 12 months. The primary end point was the change from baseline in the magnetic resonance imaging (MRI) erosion score at 6 months. RESULTS: At 6 months, the increase in the MRI erosion score from baseline was lower in the 60-mg denosumab group (mean change 0.13; P = 0.118) and significantly lower in the 180-mg denosumab group (mean change 0.06; P = 0.007) than in the placebo group (mean change 1.75). A significant difference in the modified Sharp erosion score was observed as early as 6 months in the 180-mg denosumab group (P = 0.019) as compared with placebo, and at 12 months, both the 60-mg (P = 0.012) and the 180-mg (P = 0.007) denosumab groups were significantly different from the placebo group. Denosumab caused sustained suppression of markers of bone turnover. There was no evidence of an effect of denosumab on joint space narrowing or on measures of RA disease activity. Rates of adverse events were comparable between the denosumab and placebo groups. CONCLUSION: Addition of twice-yearly injections of denosumab to ongoing methotrexate treatment inhibited structural damage in patients with RA for up to 12 months, with no increase in the rates of adverse events as compared with placebo.