Background Upadacitinib (UPA) is an oral reversible Janus kinase inhibitor. In patients (pts) with RA, UPA 15 mg once daily (QD) demonstrated better clinical responses at 12 weeks (wks) vs adalimumab (ADA) 40 mg every other week (EOW) in the phase 3 SELECT-COMPARE study; these were maintained through 3 years (yrs) in the ongoing long-term extension (LTE), along with an acceptable safety profile.[1,2] Objectives To assess the safety and efficacy of UPA vs ADA through 5 yrs in the SELECT-COMPARE LTE. Methods Pts receiving background methotrexate were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg EOW. Rescue (PBO to UPA, UPA to ADA, or ADA to UPA) was mandated for lack of response (<20% improvement in tender or swollen joint counts at wks 14, 18, or 22), or failure to achieve Clinical Disease Activity Index (CDAI) low disease activity (LDA) at wk 26. All remaining PBO pts switched to UPA at wk 26. Pts who completed the 48-wk double-blind period could continue to receive open-label UPA or ADA in the LTE for up to 10 yrs total. Rates of treatment-emergent adverse events (TEAEs) and AEs of special interest were calculated per 100 pt-yrs through 5 yrs for all pts receiving UPA or ADA. Efficacy assessments at 5 yrs were performed by original randomized group for CDAI LDA (≤10) and remission (≤2.8), and disease activity score for 28-joints C-reactive protein (DAS28[CRP]) ≤3.2 and <2.6. Radiographic progression (change from baseline in modified total Sharp score [mTSS]) and proportion of pts with no radiographic progression (change from baseline in mTSS ≤0) were assessed at 192 wks (latest available timepoint; data collected at wks 96/192/520 only) by treatment sequence. No formal statistical comparisons were performed. Results Through 5 yrs, 1417 pts were exposed to UPA (4497 pt-yrs) and 579 to ADA (1472 pt-yrs). UPA was generally well tolerated, with similar rates of TEAEs, serious TEAEs, TEAEs leading to discontinuation of study drug, and COVID-related TEAEs vs ADA (Figure 1). Rates of most AEs of special interest with UPA were similar vs ADA, except for numerically higher rates of herpes zoster, creatine phosphokinase elevation, lymphopenia, and hepatic disorder (mainly transaminase elevations) with UPA. In the 651 and 327 pts originally randomized to UPA and ADA, respectively, greater proportions of pts achieved CDAI LDA and remission, and DAS28(CRP) scores ≤3.2 and <2.6, with UPA vs ADA (Table 1). Through 192 wks, similar proportions of pts treated with UPA vs ADA had no radiographic progression; mean changes from baseline in mTSS were similar, except for a numerically smaller change with continuous UPA (Table 1). Conclusion The safety profile of UPA over 5 yrs was consistent with the 3-yr results and the integrated phase 3 safety analysis.[1,2] Consistent with the 3-yr analyses,[2] UPA continued to show numerically better clinical responses than ADA at 5 yrs. Radiographic progression remained similarly low through 192 wks with UPA and ADA. References [1]Cohen SB, et al. Ann Rheum Dis 2020. doi:10.1136/annrheumdis-2020-218510[2]Fleischmann R, et al. RMD Open 2022. doi:10.1136/rmdopen-2021-002012 Acknowledgements AbbVie funded this trial and participated in the trial design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Laura Chalmers, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie. Disclosure of Interests Roy M. Fleischmann Consultant of: AbbVie, Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galapagos, Galvani, Gilead, GSK, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Biosplice, Bristol-Myers Squibb, Flexion, Gilead, Horizon, Eli Lilly, Galvani, Janssen, Novartis, Pfizer, Sanofi-Aventis, Selecta, Teva, UCB, Viela, and Vorso, Jerzy Swierkot Speakers bureau: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Consultant of: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Grant/research support from: AbbVie, Accord, BMS, Janssen, MSD, Pfizer, Roche, Sandoz, and UCB, Sara Penn Employee of: AbbVie, and may hold stock or options, Patrick Durez Speakers bureau: AbbVie, Galapagos, Lilly, Nordimed, and Thermofischer, Louis Bessette Speakers bureau: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Consultant of: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, and UCB, Xianwei Bu Employee of: AbbVie, and may hold stock or options, Nasser Khan Employee of: AbbVie, and may hold stock or options, Yihan Li Employee of: AbbVie, and may hold stock or options, Charles Peterfy Shareholder of: Spire Sciences, Inc, Consultant of: Daiichi Sankyo, Eli Lilly, Five Prime, Genentech, Gilead, GlaxoSmithKline, Istesso, Labcorp, Paradigm, SetPoint, Sorrento, and UCB, Employee of: Spire Sciences, Inc, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, GSK, Janssen, Lilly, Mitsubishi Tanabe, MSD, Novartis, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, UCB, and YL Biologics, Grant/research support from: AbbVie, Asahi Kasei, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, GSK, Janssen, Lilly, Mitsubishi Tanabe, MSD, Novartis, Ono, Pfizer, Sanofi, Taisho Toyama, Takeda, UCB, and YL Biologics, Eduardo Mysler Speakers bureau: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi, Paid instructor for: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi, Grant/research support from: AbbVie, Amgen, AZ, BMS, Janssen, Lilly, Novartis, Pfizer, Roche, Sandoz, and Sanofi.Table 1Efficacy endpointsAt 5 yrs, by original randomized group (non-responder imputation)UPA N=651a,bADA N=327a,cCDAI ≤1036.4 (32.7, 40.1)26.9 (22.1, 31.7)CDAI ≤2.824.6 (21.3, 27.9)18.7 (14.4, 22.9)DAS28(CRP) ≤3.234.7 (31.1, 38.4)24.8 (20.1, 29.4)DAS28(CRP) <2.631.8 (28.2, 35.4)23.2 (18.7, 27.8)At 192 wks, by treatment sequence (as observed)PBO to UPA N=442UPA N=288UPA to ADA N=150ADA N=109ADA to UPA N=111Radiographic progression (change from baseline in mTSS, mean [95% CI])1.3 (0.8, 1.7)0.5 (0.2, 0.9)1.7 (0.7, 2.8)1.2 (0.5, 1.9)0.9 (0.2, 1.5)No radiographic progression (mTSS change from baseline ≤0)77.1(73.2, 81.1)80.9(76.4, 85.4)74.0(67.0, 81.0)78.0(70.2, 85.8)77.5(69.7, 85.2)Data are % of pts (95% confidence interval) unless otherwise stated.aPts rescued at or before wk 26 were considered non-responders. b252 rescued. c159 rescued.

Aim: Monitoring treatment of tenosynovial giant cell tumor (TGCT) is complicated by the irregular shape and asymmetrical growth of the tumor. We compared responses to pexidartinib by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with those by tumor volume score (TVS) and modified RECIST (m-RECIST). Materials & methods: MRIs acquired every two cycles were assessed centrally using RECIST 1.1, m-RECIST and TVS and tissue damage score (TDS). Results: Thirty-one evaluable TGCT patients were treated with pexidartinib. From baseline to last visit, 94% of patients (29/31) showed a decrease in tumor size (median change: -60% [RECIST], -66% [m-RECIST], -79% [TVS]). All methods showed 100% disease control rate. For TDS, improvements were seen in bone erosion (32%), bone marrow edema (58%) and knee effusion (46%). Conclusion: TVS and m-RECIST offer potentially superior alternatives to conventional RECIST for monitoring disease progression and treatment response in TGCT. TDS adds important information about joint damage associated with TGCT.

Objectives: To compare reliabilities of assessing synovitis in hand osteoarthritis (OA) using Magnetic Resonance Imaging (MRI) with/without gadolinium (Gd). Methods: Three readers scored synovitis on non-enhanced two-dimensional (2D) proton density (PD)weighted MRI and Gd-enhanced (3D) MRI of hand joints in 20 patients. Inter-reader reliabilities were examined. Results: Reliability was good for Gd-enhanced MRI, but poor for non-enhanced PD-weighted MRI (intraclass correlation coefficient 0.83 and 0.21, respectively). Agreement between the two sequences was poor (weighted kappa 0.18). Conclusion: Gd-enhanced MRI was more reliable than PD-weighted MRI for assessing synovitis. Gd-enhancement, but also resolution and tissue contrast, might have contributed to this. (c) 2021 Elsevier Inc. All rights reserved.

Background: In the SELECT-COMPARE study, the Janus kinase inhibitor, upadacitinib (UPA), demonstrated significant improvements in the signs and symptoms of rheumatoid arthritis (RA) when administered at 15 mg once daily (QD) on background methotrexate (MTX) compared with adalimumab (ADA) plus MTX at Week 12 that were maintained through 72 weeks in patients with prior inadequate response to MTX. 1 Objectives: To assess the long-term safety and efficacy of UPA vs ADA over 3 years in the ongoing long-term extension (LTE). Methods: Patients receiving background MTX were randomized 2:2:1 to UPA 15 mg QD, placebo (PBO), or ADA 40 mg every other week. Between Weeks 14-26, rescue was mandated for either lack of response (<20% improvement in tender or swollen joint counts: Weeks 14, 18, 22) or failure to achieve a targeted disease outcome (CDAI low disease activity: Week 26). Patients who completed the 48-week double-blind period could enter an LTE for up to 10 years total. This analysis describes patients through 3 years of treatment. Treatment-emergent adverse events (TEAEs) per 100 patient years (PY), including events of special interest (AESI), were summarized up to 3 years based on exposure to UPA and to ADA. Efficacy was analyzed by original randomized groups. Patients who were rescued or prematurely discontinued study drug were categorized as non-responders for visits after rescue or discontinuation. Descriptive analyses were performed without formal statistical comparisons. Results: In total, 651, 651, and 327 patients were randomized at baseline to receive UPA, PBO, and ADA, respectively. Between Weeks 14-26, 252 (39%) patients were rescued from UPA to ADA, 159 (49%) were rescued from ADA to UPA, and all PBO patients were switched to UPA by Week 26. 1 A higher proportion of patients randomized to UPA completed 3 years without rescue compared to those randomized to ADA (47% vs 36%, respectively). UPA was generally well-tolerated as assessed by the rates of TEAEs, including serious AEs, AEs leading to discontinuation of study drug, and AESIs, including serious and opportunistic infections, malignancies, adjudicated major adverse cardiac events or venous thromboembolism; Figure 1). Consistent with previous analyses, the event rates of AESIs were generally comparable between the UPA and ADA groups, while herpes zoster, lymphopenia, hepatic disorder, and CPK elevation were reported at higher rates with UPA. Consistent with earlier time points, greater proportions of patients randomized to UPA achieved low disease activity and remission at 3 years based on CDAI, as well as DAS28(CRP) ≤3.2 or <2.6, compared with patients randomized to ADA (Table 1). Conclusion: The safety profile of UPA was consistent with the results reported previously and with the integrated Phase 3 safety analysis. 1,2 Higher levels of clinical response continued to be observed with UPA vs ADA through 3 years of treatment. References: [1]Fleischmann R, et al. Ann Rheum Dis 2020;79:323. [2]Cohen SB, et al. Ann Rheum Dis 2020; doi: 10.1136/annrheumdis-2020-218510. Table 1. Efficacy Endpoints at 3 Years (NRI) Endpoints, % (95% CI ) UPA 15 mg QD N=651* ADA 40 mg EOW N=327* CDAI ≤10 39 (36, 43) 29 (24, 34) CDAI ≤2.8 24 (21, 28) 17 (12, 21) DAS28(CRP) ≤3.2 37 (33, 41) 26 (21, 31) DAS28(CRP) <2.6 32 (29, 36) 22 (17, 26) ADA, adalimumab; CI, confidence interval; DAS28(CRP), Disease Activity Score for 28-joints C-Reactive Protein; CDAI, clinical disease activity index; EOW, every other week; NRI, non-responder imputation; QD, once daily; UPA, upadacitinib. *Patients who were rescued prior to/at Week 26 were considered non-responders. 252/651 and 159/327 patients were rescued of those randomized to UPA and ADA, respectively. Acknowledgements: AbbVie and the authors thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Dr. Tim Shaw of AbbVie Inc. for his support with the interpretation of the data. Medical writing support was provided by Ramona Vladea, PhD, of AbbVie, Inc. Disclosure of Interests: Roy Fleischmann Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB, Grant/research support from: AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer Inc, Regeneron, Roche, Sanofi-Aventis and UCB, Eduardo Mysler Consultant of: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Grant/research support from: AbbVie, AstraZeneca, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Louis Bessette Consultant of: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis, Gilead, Charles Peterfy Shareholder of: Spire Sciences, Inc, Speakers bureau: Amgen, Bristol-Myers Squibb, Consultant of: Aclaris, Centrexion, Daiichi Sankyo, EMD, Serono, Five Prime, Flexion Therapeutics, Genentech, Gilead, GlaxoSmithKline, Istresso, Eli Lilly, Myriad Genetics, Novartis, Roche, SetPoint, Sorrento, UCB, Employee of: Spire Sciences, Inc, Patrick Durez Speakers bureau: BMS, Sanofi, Eli Lilly, Celltrion, Yoshiya Tanaka Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Consultant of: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Teijin, Grant/research support from: Asahi-kasei, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Ono, Jerzy Swierkot Speakers bureau: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Consultant of: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Grant/research support from: AbbVie, Sandoz, Pfizer, Roche, BMS, UCB, MSD, Accord, Janssen, Nasser Khan Shareholder of: AbbVie, Employee of: AbbVie, Xianwei Bu Shareholder of: AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie, Employee of: AbbVie.

Purpose: Intraarticular corticosteroid (IACS) injection is often used to manage moderate to severe knee osteoarthritis (OA) pain. Retrospective analyses have raised concerns of potential negative effects on joint structure and progression of OA, but these studies were limited by incomplete radiographic reporting and lack of data on prior IACS treatment. Additionally, patients seeking IACS for pain relief may represent a population with more severe OA and ongoing structural progression. There is a need for prospective clinical trials to assess the immediate and long-term effects of IACS in knee OA. Here we present the radiographic safety findings from 2 clinical trials that assessed the effects of single and repeated IACS injections in patients with knee OA. Methods: Study 1 (NCT02357459) was a Phase 3 randomized controlled trial in which patients had a single IA injection of an extended-release formulation of triamcinolone acetonide (TA-ER, 32 mg), a crystalline suspension of TA (TAcs, 40 mg) or saline placebo (PBO). Study 2 (NCT03046446) was a single-arm trial in which patients had IA injection of TA-ER 32 mg at baseline and a second IA injection of TA-ER at either Week 12, 16, 20, or 24, the timing of which was based on the response to the first injection. Both studies enrolled patients aged ≥40 years with symptomatic knee OA ≥6 months and Kellgren-Lawrence Grade (KLG) 2-3 (Study 1) or KLG 2-4 (Study 2). In Study 1, index-knee radiographs (weight-bearing, fixed-flexion technique with standardized knee positioning frame) were obtained at baseline and Week 24 and assessed for chondrolysis based on joint-space narrowing (JSN) using the OARSI method, as well as for development of osteonecrosis (ON) and subchondral insufficiency fracture (SIF). In Study 2, the same radiographic assessments were performed at baseline and Week 52 (or early termination). Chondrolysis was defined as >1 unit increase in JSN within 24 weeks or ≥2 units within 52 weeks. All radiographs were scored by 2 independent, expert radiologists blinded to visit order; the 2 radiologists’ scores for each patient were averaged. Disagreements between the 2 radiologists on ON or SIF were adjudicated by a third expert radiologist. Results: Study 1 enrolled 484 patients, 322 of whom were randomized to TA-ER or TAcs. Baseline characteristics were balanced between arms; 45% of index knees were KL2 (46% TA-ER/TAcs); 55% were KL3 (54% TA-ER/TAcs); 24.8% of patients had prior IACS in the index knee (24.5% TA-ER/TAcs). Study 2 enrolled 208 patients; 32%, 38%, and 30% of index knees were KL2, 3, and 4, respectively; 52% had prior IACS. Treatments were well tolerated in both studies. No patients developed ON in either study. 1 TAcs patient in Study 1 developed SIF noted at Week 24. Only 1 patient from either study showed JSN progression >1 (PBO arm of Study 1: JSN 0 to 2). Of patients in Study 1 with both baseline and week 24 radiographs (140 TA-ER, 145 TAcs, 148 PBO), mild progression of JSN (≤1 unit) was seen in 5.0% of the TA-ER arm, 3.5% of the TAcs arm, and 4.1% of the PBO arm (Table). In Study 2, mild progression of JSN (≤1) occurred in 18.8% of patients, of which 15.2% were only a ½ -point increase within a 52-week period, a follow-up period which was roughly twice as long as that in Study 1.TableRadiographic EvaluationsStudy 1, Baseline - Week 24Study 2, Baseline - Week 52TA-ER 32 mg, n=140, n (%)TAcs 40 mg, n=145, n (%)PBO, n=148, n (%)TA-ER 32 mg, n=165, n (%)JSN increase ≤17 (5.0)5 (3.5)5 (3.4)31 (18.8)JSN increase >1001 (0.7)0Other findings: ON, SIF, RPOA01 (0.7)*Insufficiency fracture noted in one patient at Week 24. JSN, joint space narrowing; ON, osteonecrosis; PBO, saline placebo; RPOA, rapidly progressive osteoarthritis; SIF, subchondral insufficiency fracture; TAcs, triamcinolone acetonide crystalline suspension; TA-ER, triamcinolone acetonide extended-release.00∗ Insufficiency fracture noted in one patient at Week 24. JSN, joint space narrowing; ON, osteonecrosis; PBO, saline placebo; RPOA, rapidly progressive osteoarthritis; SIF, subchondral insufficiency fracture; TAcs, triamcinolone acetonide crystalline suspension; TA-ER, triamcinolone acetonide extended-release. Open table in a new tab Conclusions: Of 450 patients with knee OA who were treated with single or repeated doses of IACS and with radiographic follow-up (84.7% of IACS-dosed patients), no signs of ON or chondrolysis were observed over 6-12 months, and only 1 patient (0.17%) showed evidence suggesting SIF. Of note, no subchondral bone change, osteonecrosis, or radiographically documented rapidly progressive osteoarthritis was identified in patients treated with TA-ER. Larger prospective studies with repeat dosing and longer follow-up, along with the use of additional methods, such as magnetic resonance imaging and biochemical markers, are recommended to define more fully the risks of IACS treatment of knee OA. Sponsor: This study was funded by Flexion Therapeutics (Burlington, MA, USA).

Background: For patients with rheumatoid arthritis (RA), long-term prevention of structural joint damage is a key treatment goal. 1 In the SELECT-EARLY and SELECT-COMPARE trials, upadacitinib (UPA), an oral JAK inhibitor, inhibited the progression of structural joint damage at 6 months and 1 year when used either as monotherapy or in combination with methotrexate (MTX) in patients (pts) with active RA. 2 Objectives: To describe the radiographic progression up to 2 years (96 wks) among pts with RA receiving UPA either as monotherapy or in combination with MTX. Methods: Both the SELECT-EARLY and SELECT-COMPARE phase 3, randomized controlled trials enrolled pts at high risk for progressive structural damage with baseline (BL) erosive joint damage and/or seropositivity. 3,4 In SELECT-EARLY, MTX-naïve pts (N=945) were randomized to UPA 15 mg or 30 mg once daily (QD) or MTX monotherapy. In SELECT-COMPARE, pts with an inadequate response to MTX (N=1629) were randomized to UPA 15 mg, placebo (PBO), or adalimumab (ADA) 40 mg every other wk, with all pts continuing background MTX; at wk 26, all pts receiving PBO were switched to UPA 15 mg, regardless of response. In both trials, mean changes from BL in modified Total Sharp Score (mTSS), joint space narrowing, and joint erosion as well as the proportion of pts with no radiographic progression (change in mTSS ≤0) were evaluated based on X-rays taken at wks 24/26, 48, and 96 for those patients in whom wk 96 X-rays were available. Data are reported as observed (AO). Results: BL demographics have been reported previously. 3,4 In the SELECT-EARLY study, at wk 96 UPA monotherapy (15 mg and 30 mg doses) significantly inhibited radiographic progression compared with MTX as measured by mean change in mTSS and by the proportion of patients with no radiographic progression (Figures 1 and 2). When patients who were rescued (MTX added to UPA or UPA added to MTX) were removed from the analysis, changes in mTSS from baseline remained similar. By the same measures, in SELECT-COMPARE, the degree of inhibition of structural progression observed was comparable between UPA and ADA. Following the switch of all PBO patients to UPA, the rate of progression slowed and was comparable to that observed in pts receiving UPA from BL. Among pts from both studies that had no radiographic progression at wk 24/26, >90% remained without radiographic progression at wk 48 and 96. Conclusion: UPA was effective in inhibiting the progression of structural joint damage through 2 years both in MTX-naïve patients receiving UPA monotherapy and MTX-inadequate responder patients receiving UPA in combination with MTX. References: [1]Smolen, et al. Ann Rheum Dis 2017;76(6):960-77. [2]Peterfy, et al. Ann Rheum Dis 2019;78(suppl 2):369-370. [3]Fleischmann, et al. Arthritis Rheumatol 2019;71(11):1788-1800. [4]Van Vollenhoven, et al. Arthritis Rheumatol 2018;70(suppl 10). Disclosure of Interests: : Charles Peterfy Consultant of: AbbVie, Acerta, Amgen, AstraZeneca, Bristol Myers Squibb, Centrexion, Daiichi Sankyo, Five Prime Therapeutics, Genentech, Gilead, Hoffman-La Roche, Janssen, Lilly USA, MedImmune, Merck, Myriad, Novartis, Plexxikon, Pfizer, Sanofi, Salix Santarus, Samsung, Samumed, Setpoint, Sorrento, UCB, Vorso, Employee of: founder and CEO of Spire Sciences, which provides imaging services to multiple pharmaceutical companies, Speakers bureau: Amgen, Vibeke Strand Consultant of: AbbVie, Amgen, Biogen, Celltrion, Consortium of Rheumatology Researchers of North America, Crescendo Bioscience, Eli Lilly, Genentech/Roche, GlaxoSmithKline, Hospira, Janssen, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, UCB, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme, Alan Friedman Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, Jose Jeffrey Enejosa Shareholder of: AbbVie, Employee of: AbbVie, Stephen Hall Grant/research support from: Abbvie, UCB, Janssen, Merck, Eduardo Mysler Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer., Speakers bureau: AbbVie, Amgen, Bristol Myers Squibb, Roche, Eli Lilly, Novartis, Janssen, Sanofi, and Pfizer, Patrick Durez Speakers bureau: AbbVie, Bristol-Myers Squibb, Celltrion, Eli Lilly, Pfizer, Sanofi, Xenofon Baraliakos Grant/research support from: Grant/research support from: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Consultant of: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Speakers bureau: AbbVie, BMS, Celgene, Chugai, Merck, Novartis, Pfizer, UCB and Werfen, Tim Shaw Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, In-Ho Song Shareholder of: AbbVie Inc., Employee of: AbbVie Inc.

Background Animal studies suggested that inhibiting IL-1α/β with lutikizumab (formerly, ABT-981) may reduce pain and slow structural progression in OA. Objectives This study (NCT02087904; ILLUSTRATE-K) assessed the safety and efficacy of lutikizumab in subjects with knee OA. Methods Subjects (n=350; 347 analysed) with Kellgren-Lawrence (KL) grade 2–3 knee OA, synovitis on MRI or US, and visual analogue scale knee pain score 4–8 (range, 0–10) were randomised to receive placebo (PBO) or lutikizumab 25, 100, or 200 mg subcutaneously (sc) every 2 wk (E2W) for 50 wk. The primary endpoints were change from baseline (BL) in WOMAC pain at wk 16 and change from BL in MRI synovitis at wk 26. Other endpoints included WOMAC function and OMERACT/OARSI response (wk 16, 26, and 52) MRI cartilage volume (wk 26 and 52), and x-ray joint space narrowing (JSN) (wk 52). Results BL demographics and disease characteristics were balanced (KL grade 3, 36.0%%–38.8%; mean WOMAC pain (scale 0–50), 26.2–28.4). The primary endpoint of WOMAC pain at wk 16 improved significantly, compared with PBO, with lutikizumab 100 mg (p=0.050;), but not 25 mg (p=0.834) or 200 mg (p=0.415). WOMAC pain reduction in all lutikizumab groups was sustained from wk 16 to 52, but differences between lutikizumab and PBO for WOMAC pain and other key signs and symptoms were not significant (table 1). Synovitis-related imaging, cartilage volume endpoints, and JSN were similar between lutikizumab and PBO groups at wk 26 and 52. lutikizumab was well tolerated; serious adverse events (SAEs), treatment-related SAEs, and infections and serious infections were similar with lutikizumab vs PBO. Injection site reactions, grade 2/3 neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab vs PBO. Lutikizumab exposures reached steady state after wk 6 and were stable through wk 52. Pharmacodynamic responses (neutrophil and high-sensitivity CRP levels) plateaued at the 100 mg dose and data were similar at 200 mg. The low immunogenicity to lutikizumab did not meaningfully affect outcomes. Conclusions Lutikizumab was generally well tolerated and met the primary endpoint of reduction in WOMAC pain at wk 16 compared with placebo at a dose of 100 mg, but not at 25 mg or 200 mg; cartilage thickness, synovitis, and other structural endpoints were similar between lutikizumab and PBO. Acknowledgements AbbVie funded the study (NCT02087904), contributed to its design and participated in data collection, analysis and interpretation of the data, and in writing, review, and approval of the publication. Medical writing (funded by AbbVie): Richard M. Edwards, PhD, and Michael J. Theisen, PhD of CPS. Disclosure of Interest R. Fleischmann Grant/research support from: AbbVie, Consultant for: AbbVie, H. Bliddal Consultant for: AbbVie Inc., Roche, Pfizer, Lilly, F. Blanco Consultant for: AbbVie Inc., Pfizer, UCB, Bristol, Roche, Bioiberica, Sanofi, Grünenthal, GlaxoSmithKline, Lilly, Janssen, Regeneron, TRB Chemedica (DISSCO), T. Schnitzer Grant/research support from: AbbVie, Consultant for: AbbVie, C. Peterfy Shareholder of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), Employee of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), S. Chen Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, P. Conaghan Consultant for: AbbVie Inc., Medivir, Merck Serono, Novartis, Pfizer, Speakers bureau: AbbVie, F. Berenbaum Consultant for: AbbVie, Pfizer, Regeneron, J.-P. Pelletier Consultant for: AbbVie, J. Martel-Pelletier Consultant for: AbbVie, O. Vaeterlein Employee of: Bioclinica, W. Liu Shareholder of: AbbVie, Employee of: AbbVie, G. Levy Shareholder of: AbbVie, Employee of: AbbVie, L. Zhang Shareholder of: AbbVie, Employee of: AbbVie, J. Medema Shareholder of: AbbVie, Employee of: AbbVie, M. Levesque Shareholder of: AbbVie, Employee of: AbbVie

Background Development of disease-modifying drugs for OA has been challenging, partly due to lack of predictive biomarkers. Objectives Our primary objective was to identify baseline (BL) biomarkers predicting greater treatment effects on WOMAC pain among knee OA subjects in the lutikizumab (formerly ABT-981) ILLUSTRATE-K trial (NCT02087904). Methods Subjects (n=347) with Kellgren-Lawrence (KL) grade 2–3 knee OA, synovitis on MRI or ultrasound, and knee pain score 4–8 (range, 0–10) were randomised to placebo (PBO) or lutikizumab 25, 100, or 200 mg subcutaneously every 2 wk for 50 wk. The primary endpoints were change from BL (CFB) in WOMAC pain at wk 16 and CFB in MRI synovitis at wk 26. Demographics, patient-reported outcomes (WOMAC, ICOAP, global assessment [PGA]), x-ray joint space width, and Whole Organ MRI Score (WORMS) were determined at BL. The Patient Rule Induction Method, Sequential Batting, and the Adaptive Index Model were used to identify BL predictive biomarkers and OA subsets with greater lutikizumab treatment effects. Continuous efficacy endpoints were assessed using ANCOVA with treatment, age group, and KL grade as main factors and BL measurements as covariates with LOCF imputation for WOMAC pain. Results WORMS Global Total Osteophyte Score (GTOS), which semi-quantitatively summates osteophyte severity from 14 regions of the knee, identified a subset of subjects with a greater lutikizumab treatment effect vs PBO; the optimal GTOS cutoff for discriminating treatment effects was 14 (figure 1). Among subjects with a GTOS ≥14, the PBO WOMAC pain response was markedly reduced and only marginally improved for ABT-981. At wk 16, among subjects with GTOS ≥14, the standardised mean difference (95% CI) of WOMAC pain for the lutikizumab 100 mg dose group vs PBO was −0.62 (−0.16 to −1.09) vs −0.30 (0 to −0.61) for all subjects. Compared with the total study population, the 41% of subjects with GTOS ≥14 not only had a greater ABT-981 treatment effect vs PBO on WOMAC pain, but also other measures of OA symptoms. BL systemic markers of synovitis (serum C1M and C3M) and potential markers of macrophage activation by IL-1 (serum alkaline phosphatase) were positively associated with greater lutikizumab treatment effects vs PBO but to a lesser extent than GTOS. Other data supported the robustness of the GTOS predictive marker because 1) a priori, KL grade was used to stratify subjects, 2) subject characteristics were balanced and 3) osteophyte formation is directly linked with synovial macrophage numbers in humans and OA synovial macrophages are the predominant source of IL-1, which is an important mediator of pain. Conclusions The GTOS biomarker predicted improvement of knee OA pain and other symptoms with lutikizumab treatment. We hypothesise that subjects with more severe osteophytes may have had more inflammation-dependent pain that was less responsive to PBO, suggesting that IL-1 inhibitors should be studied further as a treatment for knee OA symptoms in this subset of patients. Acknowledgements AbbVie: study sponsor, contributed to design, data collection, analysis, interpretation; and writing, reviewing, approval of final version. AbbVie Funded Medical writing: RM Edwards, MJ Theisen of CPS. Disclosure of Interest S. Feng Shareholder of: AbbVie, Employee of: AbbVie, S. Chen Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, C. Peterfy Shareholder of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), Employee of: Spire Sciences, Inc. (which provides imaging services for clinical trials to multiple pharmaceutical companies), V. Kraus Consultant for: AbbVie, R. Kamath Shareholder of: AbbVie, Employee of: AbbVie, L. Zhang Shareholder of: AbbVie, Employee of: AbbVie, Y. Luo: None declared, L. Cui Shareholder of: AbbVie, Employee of: AbbVie, J. Medema Shareholder of: AbbVie, Employee of: AbbVie, M. Levesque Shareholder of: AbbVie, Employee of: AbbVie

Background Magnetic resonance imaging (MRI) allows objective assessment of inflammation in peripheral joints and entheses. MRI scoring systems have until now focused on assessing specific parts of the musculoskeletal system in detail, e.g. the Rheumatoid Arthritis MRI Scoring System (RAMRIS), which is applied to wrist and metacarpophalangeal joints and adjacent tendon sheaths. The interest in a whole-body MRI approach is growing as modern MRI scanners now permit whole-body scanning within an acceptable time frame, and future improvements in MRI hardware and pulse sequences are expected to improve scan time and image resolution further. Objectives To develop a whole-body MRI scoring system for inflammation of peripheral joints and entheses and to investigate its feasibility and reliability. Methods Definitions of the key pathologies and locations for assessment have been agreed upon in the OMERACT MRI Working Group1. In a first round in June 2017, 9 readers (AJM/DG/FG/IE/MØ/PB/SJP/SK/WPM) scored MR images of 2 patients with spondyloarthritis using a draft web-based scoring system. Results were discussed and the scoring system was slightly modified. Hereafter, in a second round in October 2017, 14 MRI readers (3 musculoskeletal radiologist (IE/JLJ/RGL) and 11 rheumatologists with varying exposure to MRI (AJM/DG/FG/MS/MØ/PB/RP/SJP/SK/VF/WPM), scored 5 similar patients by the modified scoring system. Using a semiquantitative scale 0–3 (none/mild/moderate/severe), synovitis and osteitis were scored separately for 83 joints, and soft tissue inflammation and osteitis were scored separately for 33 entheses. Discrepancies between readers were discussed during an online meeting to obtain consensus, to train inexperienced readers, and to identify potential pitfalls when applying the scoring system. Results Inter-reader reliability was overall moderate for joint scores and poor for enthesis scores; however, among the 3 musculoskeletal radiologists, enthesis scores were as reliable as joint scores (Table). Reliability did not improve between the first and second round, possibly because patients with several very conspicuous inflammatory lesions were selected as cases in the first round.Abstract SAT0671 – Table 1 Inter-reader reliability of scoring inflammation of peripheral joints and enthuses (Cohen’s kappa with squared weights for individual scores, ICC(3,1), agreement, for sum scores). All values are median (IQR; range) of all reader pairs (36 reader pairs for 9 readers, 91 reader pairs for 14 readers, 3 reader pairs for 3 readers [values for 3 reader pairs provided]). Conclusions It is feasible to perform online multi-reader scoring exercises of whole-body MRI using a web-based scoring interface. MRI readers need to be further trained and calibrated in the semiquantitative scoring approach used to increase inter-reader reliability. Reference [1] Østergaard M, et al. J Rheumatol2017;44:1699–1705. Disclosure of Interest None declared

Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.

Purpose: Knee osteoarthritis (OA) is a significant cause of disability and is associated with an increased risk of comorbidities such as cardiovascular disease. Understanding the characteristics of subjects enrolled in knee OA clinical trials and the reasons that subjects are declared ineligible for these trials is important since it may not only reduce the screen failure rate in future trials but may also better delineate the epidemiology of knee OA phenotypes and provide insight into optimal use of knee OA therapies in clinical practice. Methods: The ILLUSTRATE-K study (NCT02087904) is an ongoing 1 year study in North America, Western Europe, and Australia, assessing the symptomatic and structural efficacy of ABT-981 (an anti-IL-1α/β dual variable domain [DVD] immunoglobulin) for treatment of Kellgren-Lawrence (KL) 2–3 knee OA subjects with evidence of synovitis on MRI or ultrasound, a BMI between 18 and 34 and moderate to severe knee pain ≥ 4 and ≤ 8 on a NRS-11 scale. At baseline screening, 350 subjects were enrolled and 1,221 subjects were deemed ineligible for the study. The demographic characteristics of subjects (age, sex, and race) enrolled in the study versus those deemed ineligible were compared with t tests for continuous variables and with chi-square tests for dichotomous variables. The frequencies of each inclusion and exclusion criteria for which subjects were deemed ineligible for the study were tabulated. Fisher's exact tests were conducted to identify demographic differences associated with not satisfying each of the individual inclusion and exclusion criteria. Results: Subjects enrolled in the ILLUSTRATE-K study were more likely to be female (64.9% vs. 55.1%; p = 0.001) and white (87.7 vs. 80.3; p = 0.002) compared to subjects deemed ineligible for the study, respectively (Table 1). The most frequent reasons for screen failure were absence of KL 2–3 knee OA (33.5%), evidence of severe knee mal-alignment (14.0%), absence of synovitis (10.5%), clinical chemistry and/or hematology laboratory abnormalities (9.8%), a recent history of drug or alcohol abuse (6.1%), pain or patient global assessment (PGA) of arthritis out of range (5.0%). Among the subjects excluded from the trial due to an absence of synovitis, there were equal proportions of subjects with similar demographic differences and disease characteristics compared to enrolled subjects. However, there were a disproportionate number of male subjects excluded from the trial due to an absence of KL 2–3 knee OA and/or the presence of severe knee mal-alignment on imaging and a disproportionate number of male, non-white subjects excluded from the trial due to clinical laboratory abnormalities, a recent history of drug or alcohol abuse and/or a pain or PGA of arthritis out of range (Table 2). Conclusions: A higher proportion of male subjects and non-white subjects were excluded from the ILLUSTRATE-K trial during the screening process. Imaging criteria were the most frequent reasons for study exclusion. Male subjects were not excluded disproportionately due to absence of synovitis but were primarily excluded due to an absence of KL 2–3 knee OA and due to severe knee mal-alignment on imaging. Other factors (clinical laboratory abnormalities, a recent history of drug or alcohol abuse and/or a pain or PGA of arthritis out of range) accounted for the disproportionate exclusion of non-white subjects.Tabled 1Table 1. Baseline CharacteristicsVariableEnrolled (n=350)Ineligible (n=1221)Total (N=1571)P valuen350482832Mean ± SD age, y60.2±8.860.0±8.260.1±8.50.827*n35012211571Sex, n (%)0.001†Female227 (64.9)673 (55.1)900 (57.3)Male123 (35.1)548 (44.9)671 (42.7)Race, n35082111710.002†White307 (87.7)659 (80.3)966 (82.5)Non-white43 (12.3)162 (19.7)205 (17.5)Missing0400400*T test. †Chi-square. Open table in a new tab Tabled 1Table 2. Disproportionate Enrollment by Sex and Race vs Reason for ExclusionReason for Exclusion from Trial EnrollmentFemale, n/N (%)Male, n/N (%)P ValueWhite, n/N (%)Non-white, n/N (%)P ValueNone (enrolled)227/350 (64.9)123/350 (35.1)–307/350 (87.7)43/350 (12.3)–KL grade out of range221/409 (54.0)188/409 (46.0)0.0030238/277 (85.9)39/277 (14.1)0.5516Severe knee mal-alignment65/171 (38.0)106/171 (62.0)<0.000180/92 (87.0)12/92 (13.0)0.8595Absence of synovitis84/128 (65.6)44/128 (34.4)0.914092/103 (89.3)11/103 (10.7)0.7320Clinical laboratory abnormalities63/120 (52.5)57/120 (47.5)0.022152/72 (72.2)20/72 (27.8)0.0017Recent history of drug or alcohol abuse29/75 (38.7)46/75 (61.3)<0.000122/43 (51.2)21/43 (48.8)<0.0001Pain or patient global assessment of arthritis out of range25/61 (41.0)36/61 (59.0)0.000618/26 (69.2)8/26 (30.8)0.0148 Open table in a new tab *T test. †Chi-square.

On page 699 the published text conflates the fixed flexion and MTP techniques so that neither are correct. The published text states: "The most commonly used techniques used at this time are the fixed-flexion PA view and the fluoroscopically aligned Lyon-Schuss PA view, with the use of a SynaFlexer positioning frame (BioClinica (formerly Synarc), San Francisco, CA). In the Lyon Schuss view, the patellae and thighs are in contact with the film cassette and coplanar with the tips of the great toes. In the (MTP) fixed flexion view the patellae are in contact with the cassette and aligned vertically with the first MTP joints with the feet externally rotated 5. This results in reproducible flexion of the knee at approximately 20. The X-ray beam is angulated 10 caudad and centered on a reproducibly identifiable point in the popliteal fossa of a single knee or midway between the two knees at the level of the popliteal fossa if both knees are imaged simultaneously, with the aim of aligning the beam tangential with the floor of the medial tibial plateau. The Lyon Schuss technique uses the same positioning and beam centering, but fluoroscopically aligns the anterior and posterior rims of the medial tibial plateau. The published text should read: "The most commonly used techniques used at this time are the fixed-flexion PA view and the fluoroscopically aligned Lyon-Schuss PA view, with the use of a SynaFlexer positioning frame (BioClinica (formerly Synarc), San Francisco, CA). In the fixed-flexion view, the patellae and thighs are in contact with the film cassette and coplanar with the tips of the great toes with the feet externally rotated 5 degrees. This results in reproducible flexion of the knee at approximately 20 degrees. The X-ray beam is angulated 10 degrees caudad and centered on a reproducibly identifiable point in the popliteal fossa of a single knee or midway between the two knees at the level of the popliteal fossa if both knees are imaged simultaneously, with the aim of aligning the beam tangential with the floor of the medial tibial plateau. The Lyon Schuss technique uses the same positioning and beam centering, but fluoroscopically aligns the anterior and posterior rims of the medial tibial plateau." The authors apologise for any inconvenience caused. OARSI Clinical Trials Recommendations: Knee imaging in clinical trials in osteoarthritisOsteoarthritis and CartilageVol. 23Issue 5PreviewSignificant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations. Full-Text PDF Open Archive

Charles Peterfy, MD, PhD, William D. Tap, MD, Julie DiCarlo, PhD, Zev A. Wainberg, MD, Chao Zhang, PhD, Arthur P. Staddon, MD, Allen Lee Cohn, MD, Geoffrey Shapiro, MD, PhD, Igor Puzanov, MD, Eunice L. Kwak, MD, PhD, Henry H. Hsu, MD, Paul S. Lin, MBA, MD, Sandra Tong, MD, John H. Healey, MD. Spire Sciences, Inc., Boca Raton, FL, USA, Memorial Sloan Kettering Cancer Center, New York, NY, USA, UCLA, Los Angeles,, CA, USA, Plexxikon Inc., Berkeley, CA, USA, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, Rocky Mountain Cancer Center/US Oncology, Denver, CO, USA, DanaFarber Cancer Institute, Boston, MA, USA, Vanderbilt University Medical Center, Nashville, TN, USA.

Twenty years ago, prior to the introduction of effective structure modifying treatments for RA, rheumatologists had little use for imaging in daily practice. Why gather detailed anatomical information if it wasn9t going to substantively affect patient management? The success of the biologics revolution and introduction of treat-to-target management has changed that, however, and rheumatologists today increasingly use advanced imaging techniques, beyond conventional radiography, to manage their patients. Radiography has been the mainstay of imaging evaluation of RA for decades, but it9s ability to probe structural damage is limited to only bone erosions and joint-space narrowing; it cannot not directly identify damage to tendons or ligaments nor visualize the upstream inflammatory drivers of tissue damage (synovitis, ostietis, ethesitis, tenosynovitis/tendointis). Radiography is also relatively insensitive to change; typically six to twelve months are necessary to demonstrate progression reliably. MRI is more sensitive for bone erosion and cartilage loss than radiography is, and therefore can identify patients with the erosive phenotype much earlier in the course of their disease and direct them to appropriate therapy sooner. MRI can detect progression of bone erosion and cartilage loss in as little as 3 months, and suppression of synovitis and osteitis in only 2 weeks. Ultrasound also can detect bone erosion more sensitively than radiography can, and it also can visualize synovitis and tenosynovitis/tendonitis directly. Composite clinical measures of disease activity, such as DAS28, SDAI and CDAI are responsive to treatment, but they often fail to identify patients who continue to progress structurally despite satisfying clinical criteria for remission. MRI and ultrasound can therefore serve as useful adjuncts to clinical measures in treat-to-target patient management. This presentation will review in detail the relative strengths and weaknesses of radiography, MRI and ultrasound in these roles, and provide recommendations for their use in clinical practice. Disclosure of Interest C. Peterfy Shareholder of: Spire Sciences, Inc., Consultant for: AbbVie, Amgen, Acerta, AstraZeneca, Bristol Myers Squibb, Celgene, Five Prime, Genentech, Lilly, Medimmune, Merck, Novartis, Pfizer, Roche, Salix-Santaris, Samsung, Employee of: Spire Sciences, Inc., Speakers bureau: Amgen

Background Joint space narrowing (JSN), reflecting cartilage damage, is an important aspect of joint damage in rheumatoid arthritis (RA). A scoring system of JSN on magnetic resonance imaging (MRI) has been developed as an OMERACT initiative. However, further validation is needed before the system can be implemented in clinical trials and clinical use. Computed tomography (CT) provides optimal depiction of bone surfaces and is well suited as standard reference for assessment of JSN by MRI and X-ray. Objectives To validate the OMERACT MRI JSN scoring system (1) for RA wrist and MCP joints by investigating its agreement with CT and X-ray, and its intrareader and interreader reliability. Methods MRI and CT images of wrist and MCP2-5 from 14 RA patients and 1 healthy control were assessed independently twice for JSN by three readers. X-rays were scored by a single reader by the Sharp-van der Heijde method. Reliability was assessed by intraclass correlation coefficients (ICC). Images came from a clinical trial and represented a broad range of JSN on X-ray. Results The median (range) JSN score of the assessed hand was on MRI: 13 (0-57), CT: 23 (0-58) and X-ray: 14 (0-29). MRI scores of JSN were very highly correlated with CT scores (MCP: 0.94; wrist: 0.92; MCP+wrist: 0.92). X-ray JSN scores correlated with MRI and CT (MCP2-5: 0.49 and 0.56; wrist: 0.55 and 0.43), see table. On MRI and CT, high intraobserver (ICCs≥0.91 and ≥0.75, respectively) and interobserver (ICCs≥0.82 and ≥0.66, respectively) reliability was observed. In general, lower agreement was found in MCP joints compared to the wrist. Conclusions The OMERACT-RAMRIS MRI JSN scoring system showed very high agreement with CT assessment, whereas X-ray scores were moderately correlated. Both MRI and CT scores showed a high intra- and interreader reliability. The MRI JSN score may, after further validation, become a useful tool in RA clinical trials. References Østergaard M, et al.: 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. J Rheumatol. 2011;38:2045-50. Disclosure of Interest None Declared

Background Sensitive imaging biomarkers are needed to complement clinical measures for development of drugs for rheumatoid arthritis (RA). Objectives In this double-blind randomized methodology study, Dynamic Contrast Enhanced (DCE)-MRI and RA MRI Score (RAMRIS) were compared with conventional clinical scoring [DAS28(CRP)] after short-term treatment with infliximab or placebo. Methods Sixty-one patients with active RA despite methotrexate treatment and with MRI-documented synovitis were randomized to infliximab 3 mg/kg IV or placebo at 4 clinical sites in Europe. MRI of the most severe hand and wrist was acquired at baseline and weeks 2, 4, and 14. Both the wrist and hand were scanned simultaneously in a single field of view using a knee coil. In addition to repeated clinical assessments with DAS28(CRP), the transfer rate of gadolinium contrast from plasma to synovium (Ktrans, primary endpoint) was measured. Two radiologists blinded to visit order also independently scored synovitis, osteitis and erosion using RAMRIS and cartilage loss using the 9-point MRI scale.1 Results Participants were 92% female with mean (±SD) age 50 (10) years and baseline DAS28(CRP) 6.2 (0.7). Infliximab showed greater decrease from baseline in DAS28(CRP) and DCE-MRI Ktrans in the wrist at all visits than placebo did. RAMRIS scores for synovitis and osteitis were also significantly better than placebo at each visit. RAMRIS scores for bone erosion and cartilage loss were significantly different from placebo at 14 weeks (Table). Treatment effect sizes of infliximab therapy were similar for DAS28(CRP) (1.08), wrist Ktrans (1.00), RAMRIS synovitis (0.85) and RAMRIS osteitis (0.99). Correlation between change in DAS28(CRP) and wrist Ktrans after 14 weeks of infliximab treatment was not significant (0.10). Change in RAMRIS synovitis, however, correlated significantly with DAS28(CRP) (0.37), as did baseline wrist Ktrans (0.39) and RAMRIS synovitis (0.55), osteitis (0.21) and erosion (0.46). Conclusions DCE-MRI and RAMRIS both showed suppression of synovitis in only 2 weeks in this multisite controlled trial with only 30 subjects per arm. RAMRIS further demonstrated suppression of osteitis in 2 weeks and suppression of erosion and cartilage loss in 14 weeks. References Peterfy, et al. Arthritis Res Ther. 2012;14(3):R131 Liang, et al. The Indian Journal of Statistics. 2000; 62: 134-148. Disclosure of Interest C. Beals Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., R. Baumgartner Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., C. Peterfy Shareholder of: Spire Sciences, LLC, Grant/research support from: Amgen, Centocor / Janssen, Pfizer / Wyeth, Abbott, Roche, Genentech, Bayer, Consultant for: Abbott, Articulinx, Merck/ Schering-Plough, Roche, UCB, Pfizer /Wyeth, AstraZeneca, Bristol Myers-Squibb, BioClinica, Celgene, Genentech, Icon Medical Imaging, Lilly, Medimmune, Moximed, Novartis, Perceptive Informatics, VirtualScopics, Jennsen, Genzyme/Sanofi, Biogen-Idec, Employee of: Spire Sciences, LLC, A. Balanescu: None Declared, G. Mirea: None Declared, A. Harabagiu: None Declared, S. Popa: None Declared, A. Cheng Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., D. Feng Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., R. Fox Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., M.-H. Vallee Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp., E. Ashton: None Declared, J. DiCarlo Consultant for: Abbott, Amgen, AstraZeneca, BioClinica, Biogen-Idec, Bristol-Myers Squibb, Celgene, Centocor, Core Lab Partners, Crescendo, Eli Lilly, Genentech, Genzyme, Icon Medical Imaging, Johnson & Johnson, Merck, Novartis, Perceptive Informatics, Pfizer, Rigel, Roche, Sanofi, Samsung, UCB, Virtual Scopics, Wyeth, Employee of: Spire Sciences, LLC, B. Dardzinski Shareholder of: Merck Sharp & Dohme Corp., Employee of: Merck Sharp & Dohme Corp.