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Introduction Timely matching of patients to beneficial targeted therapy is an unmet need in rheumatoid arthritis (RA). A molecular signature response classifier (MSRC) that predicts which patients with RA are unlikely to respond to tumor necrosis factor-α inhibitor (TNFi) therapy would have wide clinical utility. Methods The protein–protein interaction map specific to the rheumatoid arthritis pathophysiology and gene expression data in blood patient samples was used to discover a molecular signature of non-response to TNFi therapy. Inadequate response predictions were validated in blood samples from the CERTAIN cohort and a multicenter blinded prospective observational clinical study (NETWORK-004) among 391 targeted therapy-naïve and 113 TNFi-exposed patient samples. The primary endpoint evaluated the ability of the MSRC to identify patients who inadequately responded to TNFi therapy at 6 months according to ACR50. Additional endpoints evaluated the prediction of inadequate response at 3 and 6 months by ACR70, DAS28-CRP, and CDAI. Results The 23-feature molecular signature considers pathways upstream and downstream of TNFα involvement in RA pathophysiology. Predictive performance was consistent between the CERTAIN cohort and NETWORK-004 study. The NETWORK-004 study met primary and secondary endpoints. A molecular signature of non-response was detected in 45% of targeted therapy-naïve patients. The MSRC had an area under the curve (AUC) of 0.64 and patients were unlikely to adequately respond to TNFi therapy according to ACR50 at 6 months with an odds ratio of 4.1 (95% confidence interval 2.0–8.3, p value 0.0001). Odds ratios (3.4–8.8) were significant (p value, Plain Language Summary A blood-based molecular signature response classifier (MSRC) integrating next-generation RNA sequencing data with clinical features predicts the likelihood that a patient with rheumatoid arthritis will have an inadequate response to TNFi therapy. Treatment selection guided by test results, with likely inadequate responders appropriately redirected to a different therapy, could improve response rates to TNFi therapies, generate healthcare cost savings, and increase rheumatologists’ confidence in prescribing decisions and altered treatment choices. The MSRC described in this study predicts the likelihood of inadequate response to TNFi therapies among targeted therapy-naïve and TNFi-exposed patients in a multicenter, 24-week blinded prospective clinical study: NETWORK-004. Patients with a molecular signature of non-response are less likely to have an adequate response to TNFi therapies than those patients lacking the signature according to ACR50, ACR70, CDAI, and DAS28-CRP with significant odds ratios of 3.4–8.8 for targeted therapy-naïve patients and 3.3–26.6 for TNFi-exposed patients. This MSRC provides a solution to the long-standing need for precision medicine tools to predict drug response in rheumatoid arthritis—a heterogeneous and progressive disease with an abundance of therapeutic options. These data validate the performance of the MSRC in a blinded prospective clinical study of targeted therapy-naïve and TNFi therapy-exposed patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00330-y.

Objectives Apremilast monotherapy was evaluated up to 5 years in PALACE 4 (fourth PsA Long-term Assessment of Clinical Efficacy study) DMARD-naïve patients with PsA. Methods Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg or apremilast 20 mg twice a day. Placebo patients were rerandomized to apremilast at week 16 or 24. Double-blind apremilast continued to week 52, with a 4-year open-label extension (≤260 weeks of exposure). Analyses through week 260 were based on observed data. Results A total of 527 patients were treated. Among patients randomized to apremilast 30 mg at baseline, 45.5% completed week 260. At study end, 24.8% reported conventional synthetic DMARD or steroid use for any reason. At week 260, 65.8%/39.0%/20.3% of apremilast 30 mg patients achieved ACR20/ACR50/ACR70 responses, respectively. PsA sign and symptom improvements were sustained up to week 260 with continued treatment, including reductions in swollen (84.8%) and tender (76.4%) joint counts. Among apremilast 30 mg patients with baseline enthesitis or dactylitis, 71.2% achieved a Maastricht Ankylosing Spondylitis Enthesitis Score of 0 and 95.1% achieved a dactylitis count of 0. Over 50% of patients achieved a HAQ Disability Index minimal clinically important difference (≥0.35). In patients with ≥3% baseline psoriasis-involved body surface area, 60.3% and 47.6% achieved ≥50% and ≥75% improvement in Psoriasis Area and Severity Index scores, respectively. Patients continuing apremilast 20 mg also demonstrated consistent, sustained improvements. The most common adverse events were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. No new safety concerns were observed long term. Conclusions Apremilast led to sustained PsA efficacy up to 260 weeks and was well tolerated. Trial registration ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423.

Introduction To evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD). Methods Data from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population. Results In RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports. Conclusions Long-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated. Trial registration ClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

Introduction This open-label study evaluated the immunogenicity, safety, and efficacy of sarilumab monotherapy in patients with active, moderate-to-severe rheumatoid arthritis (RA) and inadequate response or intolerance to prior conventional synthetic disease-modifying antirheumatic drugs. Methods Adults with RA (n = 132) were randomized to receive subcutaneous sarilumab (150 [n = 65] or 200 mg [n = 67]) every 2 weeks (q2w) for 24 weeks. Endpoints included incidence of antidrug antibodies (ADAs) at week 24, safety, and efficacy. Results Persistent ADAs occurred in eight patients (12.3%) receiving sarilumab 150 mg q2w, seven of whom (10.8%) had neutralizing antibodies (NAbs), and in four patients (6.1%) receiving sarilumab 200 mg q2w, two of whom (3.0%) had NAbs; all exhibited low antibody titers. Infections and neutropenia were the most common adverse events (AEs). There were three serious AEs, no reports of anaphylaxis, and few hypersensitivity reactions (e.g., rash) with no notable differences in hypersensitivity reactions in ADA-positive patients relative to ADA-negative patients. Changes in absolute neutrophil count, alanine aminotransferase level, and platelet count were consistent with interleukin-6 signaling blockade and in agreement with previous observations. At week 24, overall American College of Rheumatology 20%/50%/70% improvement criteria responses were 73.8%/53.8%/29.2%, respectively, with sarilumab 150 mg q2w and 71.6%/50.7%/29.9% with sarilumab 200 mg q2w. No patients with an ADA-positive response showed loss of efficacy. Conclusions ADA titers were low and persistent ADAs and NAbs occurred relatively infrequently in both sarilumab dose groups. ADA did not meaningfully impact the safety or efficacy of either dose of sarilumab over 24 weeks. Trial Registration ClinicalTrials.gov, identifier NCT02121210. Funding Sanofi Genzyme and Regeneron Pharmaceuticals, Inc. Plain Language Summary Plain language summary available for this article. Electronic Supplementary Material The online version of this article (10.1007/s40744-019-0157-3) contains supplementary material, which is available to authorized users.

Objective To evaluate the effect of upadacitinib (UPA) monotherapy vs MTX on patient-reported outcomes (PROs) in patients with RA who were MTX-naïve or who had an inadequate response to MTX (MTX-IR). Methods PROs from the SELECT-EARLY and SELECT-MONOTHERAPY randomized controlled trials were evaluated at Weeks 2 and 12/14. Patients were ≥18 years of age with RA symptoms for ≥6 weeks (SELECT-EARLY, MTX-naïve) or diagnosed RA for ≥3 months (SELECT-MONOTHERAPY, MTX-IR) and received UPA monotherapy (15 or 30 mg) or MTX. PROs included Patient Global Assessment of Disease Activity (PtGA), pain visual analogue scale, HAQ Disability Index (HAQ-DI), morning stiffness duration/severity, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (SELECT-EARLY), health-related quality of life (HRQOL) by the 36-iem Short Form Health Survey and Work Productivity and Activity Impairment (WPAI; SELECT-EARLY). Least square mean (LSM) changes and proportions of patients reporting improvements greater than or equal to the minimum clinically important differences and normative values were determined. Results In 945 MTX-naïve and 648 MTX-IR patients, UPA monotherapy (15 mg, 30 mg) vs MTX resulted in greater reported LSM changes from baseline at Weeks 12/14 in PtGA, pain, HAQ-DI, morning stiffness duration/severity, FACIT-F (SELECT-EARLY), HRQOL and WPAI (SELECT-EARLY). These changes were statistically significant with both doses of UPA vs MTX at Weeks 12/14 in both RCTs. Improvements were reported as early as week 2. Compared with MTX, more UPA-treated MTX-naïve and MTX-IR patients reported improvements greater than or equal to the minimum clinically important differences and scores greater than or equal to normative values. Conclusion Among MTX-naïve and MTX-IR patients with active RA, UPA monotherapy at 15 or 30 mg for 12/14 weeks resulted in statistically significant and clinically meaningful improvements in pain, physical function, morning stiffness, HRQOL and WPAI compared with MTX alone. Clinical trial registration number SELECT-EARLY (NCT02706873) and SELECT-MONOTHERAPY (NCT02706951) are registered with ClinicalTrials.gov.

Objectives The PALACE 4 trial evaluated apremilast monotherapy in patients with active PsA who were DMARD-naive. Methods Eligible patients were randomized (1:1:1) to placebo, apremilast 20 mg twice a day or apremilast 30 mg twice a day. At week 16 or 24, placebo patients were rerandomized to apremilast. Double-blind apremilast treatment continued to week 52, with extension up to 4 years. The primary endpoint was the proportion of patients achieving ⩾20% improvement in ACR response criteria (ACR20) at week 16; secondary endpoints included the mean change in the HAQ Disability Index (HAQ-DI) score at week 16. Results A total of 527 patients with mean disease duration of 3.4 years and high disease activity were randomized and received treatment. More apremilast patients achieved ACR20 response at week 16 [placebo, 15.9%; 20 mg, 28.0% (P = 0.0062); 30 mg, 30.7% (P = 0.0010)]. The mean HAQ-DI improvements were −0.17 (20 mg; P = 0.0008) and −0.21 (30 mg; P < 0.0001) vs 0.03 (placebo). Both apremilast doses showed significant ACR50 responses vs placebo at week 16 and improvements in secondary efficacy measures (swollen/tender joint counts) and psoriasis assessments, with sustained improvements through week 52. Common adverse events (AEs) over 52 weeks were diarrhoea, nausea, headache and upper respiratory tract infection; most events were mild or moderate. Serious AEs and AEs leading to discontinuation were comparable between groups. Laboratory abnormalities were infrequent and transient. Conclusions In DMARD-naive patients, apremilast monotherapy improved PsA signs/symptoms over 52 weeks and was generally well tolerated. Trial registration ClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423.

ObjectiveThis study assessed the mode of application (oral, intravenous or subcutaneous (SC)) currently employed in the treatment of rheumatoid arthritis (RA) in patients from Qatar in comparison with patients’ individual preferences for the mode of application of their treatment.MethodsThis study included 294 RA patients visiting three clinics at the main referral hospital in Qatar who were interviewed using a standard questionnaire to determine their preference of mode of application for their disease-modifying antirheumatic drug (DMARD) treatment in relation to their currently employed mode of application.ResultsThe majority of patients were female (76%), and 93% of male patients and 61% of female patients in the study clinics were of a nationality other than Qatari. The highest patient preference recorded was for an oral therapy (69%), compared with injection (23%) and intravenous (8%) therapy. In total, 85% of patients expressed a preference to remain on oral therapy compared with 63% and 58% of intravenous and SC injection patients indicating a preference to remain on their current method of administration.ConclusionsThis high preference for oral therapies highlights the considerable need for incorporation of new oral targeted synthetic DMARD therapies into clinical practice within the region.

Background Upadacitinib (UPA), a selective JAK1 inhibitor, has demonstrated efficacy and safety in patients with rheumatoid arthritis (RA) as monotherapy and in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) such as methotrexate (MTX).1,2 However, UPA monotherapy has not been compared directly with UPA combination therapy in the Phase 3 program. Objectives To compare the efficacy of UPA monotherapy and UPA in combination with MTX using data from two Phase 3 trials of RA patients with an inadequate response (IR) to prior MTX therapy. Methods In SELECT-MONOTHERAPY, 648 MTX-IR patients were randomized to receive UPA 15 mg or 30 mg monotherapy once daily (QD), or continue with MTX monotherapy (cMTX; given as a blinded study drug), for 14 weeks. In SELECT-NEXT, 661 csDMARD-IR patients were randomized to receive UPA 15 mg or 30 mg QD or placebo (PBO) for 12 weeks on a background of csDMARDs. Only patients receiving concomitant MTX (with or without additional csDMARDs) at baseline in SELECT-NEXT were included in this analysis. The primary endpoints of both studies were the proportion of patients achieving ACR20 and DAS28(CRP) ≤3.2. Additional endpoints included ACR50/70, DAS28(CRP) Results A total of 1114 patients were included in the analysis, of whom 648 received monotherapy in SELECT-MONOTHERAPY and 466 received combination therapy in SELECT-NEXT. Of the patients receiving combination therapy, 338 (72.5%) were receiving MTX background therapy only and 128 (27.5%) were receiving MTX plus other csDMARDs. Baseline characteristics were generally similar between the study cohorts; the majority of patients in both studies were female and of white ethnicity, with a mean age of approximately 55 years and a mean MTX dose of approximately 17 mg/week. Consistent with previously reported results from SELECT-MONOTHERAPY1 and SELECT-NEXT,2 both UPA monotherapy and UPA combination therapy led to significant improvements in efficacy outcomes versus cMTX/PBO+MTX (Table). No significant differences were observed between UPA monotherapy and UPA combination therapy across a range of clinical endpoints, including ACR20/50/70 responses and measures of LDA and remission. In addition, improvements in quality of life as measured by HAQ-DI were similar with UPA monotherapy and combination therapy. Efficacy was comparable between the two UPA doses in the combination therapy group, whereas in the monotherapy group numerically higher responses were observed with UPA 30 mg versus UPA 15 mg. Conclusion In MTX-IR patients with RA, the efficacy of UPA appears comparable when administered as monotherapy or when given in combination with MTX. References 1Smolen J, et al. Ann Rheum Dis 2018;77:67?8; 2Burmester GR, et al. Lancet 2018;391:2503-12 Acknowledgement AbbVie, Inc was the study sponsor, contributed to the study design, data collection, analysis & interpretation, and to writing, reviewing, and approval of the final version. Medical writing support was provided by John Ewbank, PhD, of 2 the Nth. Disclosure of Interests Maya Buch Grant/research support from: Pfizer LTD, UCB, Consultant for: AbbVie, Eli Lilly, EMD Serono, Pfizer Ltd., Sanofi, Alvin F. Wells Consultant for: AbbVie, Andrea Rubbert-Roth Consultant for: Abbvie, Speakers bureau: AbbVie, Manish Jain Consultant for: Abbvie, Novartis, Celgene, Medac, and Takeda., Speakers bureau: Abbvie, Novartis, Celgene, Medac, and Takeda., Casey Schlacher Shareholder of: AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: AbbVie, Employee of: AbbVie, Yihan Li Shareholder of: AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: AbbVie, Employee of: AbbVie, Peter Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB

Background:In PALACE 4, DMARD-naive patients (pts) with moderately active (ModDA) psoriatic arthritis (PsA) at baseline (BL) were more likely to achieve Clinical Disease Activity Index for PsA (cDAPSA) treatment targets (cDAPSA remission [REM] or low disease activity [LDA]) at Week 52 with continued apremilast 30 mg BID (APR) treatment than pts with high disease activity (HDA) at BL. Pts who achieved cDAPSA treatment targets also had no or mild articular and extra-articular disease activity by Week 52. Whether specific PsA manifestations other than arthritis impact the achievement of cDAPSA treatment targets in this population is unknown.Objectives:To assess the predictive value of BL clinical disease status on achieving cDAPSA treatment targets in DMARD-naive pts in PALACE 4 with PsA in ModDA or HDA who exhibited manifestations of skin involvement, enthesitis, and/or dactylitis at BL.Methods:This post hoc analysis included APR-treated pts in ModDA or HDA with available cDAPSA data at BL and Week 52 who exhibited any of the PsA manifestations at BL, including skin-involved body surface area (BSA) ≥3%, Maastricht Ankylosing Spondylitis Entheses Score (MASES) >0, or dactylitis count >0. Pts were divided into 4 subgroups based on number of manifestations: ≥1, only 1, any 2, or all 3. The proportions of pts who shifted across ModDA (>13 to ≤27) and HDA (>27) cDAPSA categories at BL to REM (≤4) and LDA (>4 to ≤13) treatment targets at Week 52 were calculated (data as observed).Results:In 176 PALACE 4 pts with PsA receiving APR, 165 had involvement in ≥1 PsA manifestation in addition to peripheral arthritis (ie, skin/enthesitis/dactylitis) at BL. This population had a mean age of 48.8 years, PsA duration of 3.6 years, Psoriasis Area and Severity Index (PASI) score of 6.6, MASES of 3.8, and dactylitis count of 3.5 (Table 1). Within this subgroup, 32.7% had only 1 of these non-arthritic PsA manifestations, 50.9% had any 2, and 16.4% had all 3. In pts with ≥1 manifestation, a greater proportion in ModDA achieved REM/LDA at Week 52 than those in HDA (66.7% vs 32.2%; risk difference: 0.34) (Figure 1). Similarly, greater rates of treatment target achievement were observed in subgroups of pts in ModDA vs HDA and only 1 (72.2% vs 39.1%; risk difference: 0.33), any 2 (57.1% vs 28.6%; risk difference: 0.29), or all 3 (75.0% vs 33.3%; risk difference: 0.42) PsA manifestations (Figure 1).Conclusion:In DMARD-naive pts exhibiting various non-arthritic manifestations of active PsA (ie, skin/enthesitis/dactylitis), those in ModDA at BL were more likely to achieve cDAPSA REM or LDA at Week 52 of APR treatment than pts in HDA. This observation was consistent whether pts had only 1 or multiple manifestations. These findings are consistent with the probability of achieving treatment targets demonstrated in the overall population in PALACE 4 (61.7% ModDA vs 28.2% HDA).Table 1.BL Demographics and Disease Characteristics in Pts With ≥1 Manifestations of PsA (Skin Involvement, Enthesitis, and/or Dactylitis) Treated With APR (N = 165)Age*, years48.8 (12.5)Women, n (%)87 (52.7)BMI*, kg/m229.9 (6.5)Duration of PsA*, years3.6 (5.0)Duration of psoriasis*, years15.5 (13.3)cDAPSA (0-154)*39.4 (19.7)Swollen joint count (0-66)*10.3 (7.7)Tender joint count (0-68)*18.5 (12.9)Pt’s Assessment of Pain (VAS 0-100 mm)*52.8 (21.5)Pt’s Global Assessment (VAS 0-100 mm)*53.8 (20.1)Physician’s Global Assessment (VAS 0-100 mm)*52.2 (17.6)PASI score (0-72)*,†6.6 (5.1)MASES (0-13)*,‡3.8 (3.0)Dactylitis count (0-20)*,§3.5 (3.3)Corticosteroid use, n (%)13 (7.9)NSAID use, n (%)126 (76.4)*Mean (SD).†In pts with BSA ≥3% at BL.‡In pts with enthesitis at BL.§In pts with dactylitis at BL.Acknowledgements:This study was funded by Celgene. Additional analyses were funded by Amgen Inc. Writing support was funded by Amgen Inc. and provided by Kristin Carlin, RPh, MBA, of Peloton Advantage, LLC, an OPEN Health company.Figure 1.Disclosure of Interests:Philip J Mease Speakers bureau: AbbVie, Amgen Inc., Eli Lilly, Janssen, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen Inc., Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Galapagos, GSK, Novartis, Pfizer, Sun, and UCB, Grant/research support from: AbbVie, Amgen Inc., Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Galapagos, GSK, Novartis, Pfizer, Sun, and UCB, Arthur Kavanaugh Grant/research support from: AbbVie, Amgen Inc., AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Alexis Ogdie Consultant of: AbbVie, Amgen Inc., BMS, Celgene, Corrona, Eli Lilly, Gilead, Novartis, Pfizer, and UCB, Grant/research support from: Novartis and Pfizer, Alvin F. Wells Speakers bureau: AbbVie, Alexion, Amgen Inc., BMS, Celgene, Horizon, Lilly, Novartis, and UCB, Consultant of: AbbVie, Alexion, Amgen Inc., BMS, Celgene, Horizon, Lilly, Novartis, and UCB, Grant/research support from: AbbVie, Celgene, and Lilly, Martin Bergman Shareholder of: Johnson & Johnson, Speakers bureau: AbbVie, Amgen Inc., Novartis, Pfizer, and Sanofi, Consultant of: AbbVie, BMS, Celgene, Genentech, Janssen, Merck, Novartis, Pfizer, and Sanofi, Dafna D Gladman Consultant of: AbbVie, Amgen, BMS, Celgene Corporation, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, BMS, Celgene Corporation, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Frank Behrens Speakers bureau: AbbVie, Biotest, Boehringer Ingelheim, Celgene, Chugai, Eli Lilly, Genzyme, Janssen, Novartis, Pfizer, Roche, and UCB, Grant/research support from: AbbVie, Chugai, Janssen, Roche, and Pfizer, Yuri Klyachkin Employee of: Amgen Inc., Sven Richter Employee of: Amgen Inc., Lichen Teng Employee of: Amgen Inc., Josef S. Smolen Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi, and UCB, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, MSD, Novartis, Pfizer, Roche, Samsung, Sanofi, and UCB, Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Medimmune, Pfizer, and Roche.

Objective To assess joint disease activity by ultrasound (US) in patients with rheumatoid arthritis (RA) initiating treatment with adalimumab (ADA) plus methotrexate (MTX). Methods Data for this post hoc analysis originated from the MUSICA trial (ClinicalTrials.gov identifier: NCT01185288), which evaluated the efficacy of initiating ADA (40 mg every other week) plus 7.5 or 20 mg/week MTX in 309 patients with RA with an inadequate response to MTX. Synovial vascularization over 24 weeks was assessed bilaterally at metacarpophalangeal joint 2 (MCP2), MCP3, MCP5, metatarsophalangeal joint 5, and the wrists by power Doppler US (PDUS). A semiquantitative 4-grade scale was used. Disease activity was assessed using the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and Simplified Disease Activity Index (SDAI). The correlation between continuous variables was assessed using Pearson's correlation coefficient. Results After 24 weeks of treatment with ADA plus MTX, rapid improvements in the mean synovial vascularity score were observed; the greatest improvements were in MCP2 (−0.5), MCP3 (−0.4), and the wrist (−0.4). At week 24, patients with the lowest DAS28-CRP ( 0.9). Synovial vascularity scores correlated poorly with DAS28, swollen joint count in 66 joints (SJC66), SJC28, tender joint count in 68 joints (TJC68), TJC28, Clinical Disease Activity Index (CDAI), SDAI, physician's global assessment, patient's global assessment of pain, and disease duration (ρ

Background:Apremilast (APR) is associated with comparable ACR response rates in DMARD-naive vs DMARD-experienced patients (pts) with psoriatic arthritis (PsA).1,2A question that remains is if DMARD-naive pts treated with APR have greater chances of achieving treatment targets than DMARD-experienced pts. cDAPSA is a commonly used treatment target.Objectives:To assess the predictive value of baseline (BL) clinical disease status on achieving long-term cDAPSA treatment targets at Wk 52 among DMARD-naive subjects in PALACE 4; to compare these findings vs those recently reported from the PALACE 1-3 studies in subjects with prior exposure to DMARDs; and to provide further evidence that at a group level, achievement of cDAPSA disease targets with APR is associated with no or mild articular and extra-articular disease activity by Wk 52.Methods:This post hoc analysis included subjects assigned to APR 30 mg twice daily at BL who had available cDAPSA data at BL. We calculated the probabilities of shifting across different cDAPSA categories (remission [REM]: ≤4; low disease activity [LDA]: >4 to ≤13; moderate disease activity [Mod]: >13 to ≤27; high disease activity [HDA]: >273) from BL to Wk 52. Mean values of articular and non-articular variables (e.g., PASI, SJC/TJC, MASES, dactylitis) from BL to Wk 52 were assessed by cDAPSA category achieved at Wk 52 to determine the association between achievement of targets and control of articular and non-articular manifestations. Results from the current analyses were compared with the previously reported results from PALACE 1-3.Results:A total of 175 subjects receiving APR were included; at BL, 66.3% were in HDA, 31.4% in Mod, and 2.3% were in LDA. Overall, subjects who achieved treatment targets (LDA or REM) by Wk 52 had lower levels of disease activity at BL, as shown by a lower number of swollen and tender joints and lower presence of enthesitis and dactylitis. Higher prevalence of psoriasis-involved body surface area ≥3% at BL was observed. Subjects in Mod at BL were estimated to be more than twice as likely to achieve REM or LDA at Wk 52 vs subjects in HDA at BL; for subjects in LDA at BL, the estimated probability of achieving cDAPSA treatment targets was 100% (Figure). PALACE 4 subjects with LDA and Mod at BL exhibited higher estimated probabilities of achieving treatment targets (100.0% and 61.7%, respectively) than those observed in the DMARD-experienced population of PALACE 1-3 (71.1% and 46.9%). Subjects in PALACE 4 who achieved REM or LDA by Wk 52 showed no or mild articular and extra-articular disease activity by Wk 52, similar to what was observed in the PALACE 1-3 population.4Conclusion:DMARD-naive subjects in PALACE 4 who had LDA or Mod at BL had the highest likelihood of achieving treatment targets (cDAPSA REM or LDA) by Wk 52 with continued APR treatment. Results from the current probability analyses revealed higher probability rates than those observed in the DMARD-experienced PALACE 1-3 population; control of articular and extra-articular manifestations was observed in the DMARD-naive and DMARD-experienced populations.References:[1]Wells AF, et al. Rheumatology. 2018;57:1253-63. 2. Kavanaugh A, et al. Arthritis Res Ther. 2019;21:118. 3. Machado PM. Ann Rheum Dis. 2016;75:787-90. 4. Mease PJ, et al. Arthritis Care Res. 2020 Jan 7.Disclosure of Interests:Philip J Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – grant/research support, Consultant of: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Sun Pharmaceutical, UCB – consultant, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Eli Lilly, Genentech, Janssen, Pfizer, UCB – speakers bureau, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Alexis Ogdie Grant/research support from: Novartis, Pfizer – grant/research support, Consultant of: AbbVie, BMS, Eli Lilly, Novartis, Pfizer, Takeda – consultant, Alvin F. Wells Grant/research support from: AbbVie, Celgene Corporation, Lilly – grant/research support, Consultant of: AbbVie, Alexion, Amgen, BMS, Celgene Corporation, Horizon, Lilly, Novartis, UCB – consultant, Speakers bureau: AbbVie, Alexion, Amgen, BMS, Celgene Corporation, Horizon, Lilly, Novartis, UCB – speakers bureau, Martin Bergman Shareholder of: Johnson & Johnson – stockholder, Consultant of: AbbVie, BMS, Celgene Corporation, Genentech, Janssen, Merck, Novartis, Pfizer, Sanofi – consultant, Speakers bureau: AbbVie, Celgene Corporation, Novartis, Pfizer, Sanofi – speakers bureau, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Frank Behrens Grant/research support from: AbbVie, Chugai, Janssen, Roche, Pfizer – grant/research support, Consultant of: AbbVie Biotest, Boehringer Ingelheim, Celgene Corporation, Chugai, Eli Lilly, Genzyme, Janssen, Novartis, Pfizer, Roche, UCB – consultant, Speakers bureau: AbbVie, Biotest, BMS, Celgene Corporation, Chugai, Eli Lilly, Genzyme, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sandoz, UCB - speaker, Sven Richter Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of study conduct, Michele Brunori Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of study conduct, Lichen Teng Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of study conduct, Benoit Guerette Employee of: Amgen Inc. – employment; Celgene Corporation – employment at the time of study conduct, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche – grant/research support, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – consultant, Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – speaker

Background Apremilast (APR) is an oral phosphodiesterase 4 inhibitor that helps regulate the immune responses that cause joint inflammation and other manifestations of psoriatic arthritis (PsA), including skin disease. Objectives To describe the long-term (5 year) efficacy and safety of APR monotherapy in DMARD-naive subjects with active PsA from the phase 3 PALACE 4 study. Methods Subjects were randomised (1:1:1) to receive placebo, APR 30 mg BID (APR30), or APR 20 mg BID (APR20). At Week 16, subjects were eligible for early escape; placebo subjects were re-randomised to APR treatment, and APR subjects remained on their assigned dose. At Week 24, all subjects remaining on placebo were re-randomised to APR. Double-blind treatment continued to Week 52, with open-label APR treatment for up to 4 additional years. Results A total of 527 subjects were randomised and received ≥1 dose of placebo (n=176), APR30 (n=176), or APR20 (n=175). Among subjects randomised to APR30 at baseline, 45.5% (80/176) completed the Week 260 visit. At Week 52, modified ACR20, ACR50, and ACR70 responses were achieved by 58.0%, 29.8%, and 15.5% of subjects receiving APR30, respectively, regardless of when APR was started (baseline, Week 16, or Week 24). Rates of improvement in PsA signs and symptoms and physical function were sustained up to Week 260 with continued APR30 treatment, including reduction rates in SJC of 84.8% and in TJC of 76.4% (table 1). At Week 260, 65.8%, 39.0%, and 20.3% of subjects achieved a modified ACR20, ACR50, and ACR70 response, respectively, and 71.2% of APR30 subjects with baseline enthesitis achieved a MASES of 0; 95.1% with baseline dactylitis achieved a dactylitis count of 0. At Week 260, 52.9% of subjects achieved a HAQ-DI MCID ≥0.35, 60.3% achieved a PASI-50 response, and 47.6% achieved a PASI-75 response (table 1). No new safety concerns were identified with APR up to 260 weeks. During Weeks>208 to≤260, the most common adverse event (AEs) among APR30-exposed subjects was nasopharyngitis (6.9%). Serious AEs occurred in 5 APR30 subjects; serious infections were reported in 2 APR30 subjects (pelvic abscess and bacterial urinary tract infection), and no opportunistic infections were reported during Weeks>208 to≤260. Conclusions APR monotherapy demonstrated sustained response or improvements in PsA signs and symptoms, including SJC and TJC, enthesitis, dactylitis, physical function, and psoriasis in the population of subjects continuing treatment over 260 weeks. APR continued to demonstrate a favourable safety profile and was generally well tolerated. Disclosure of Interest A. Wells Grant/research support from: Celgene Corporation, C. Edwards Grant/research support from: Celgene Corporation; Pfizer, Roche, Samsung, Consultant for: Celgene Corporation, Pfizer, Roche, Samsung, Speakers bureau: Abbott, GSK, Pfizer, Roche, A. Kivitz Consultant for: Celgene Corporation, Speakers bureau: Celgene Corporation, P. Bird Grant/research support from: Celgene Corporation, B. Guerette Employee of: Celgene Corporation, N. Delev Employee of: Celgene Corporation, M. Paris Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Aelion Grant/research support from: Celgene Corporation; AbbVie, Ardea Biosciences, AstraZeneca, BMS, Centocor, Eli Lilly, Galapagos, Genentech, GSK, Human Genome Sciences, Janssen, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, Takeda Pharmaceuticals, UCB, Vertex Pharmaceuticals

Introduction This article evaluates the efficacy and safety of baricitinib 4 mg versus placebo in United States including Puerto Rico (US) and rest of the world (ROW) subpopulations using data pooled from RA-BEAM and RA-BUILD, which enrolled patients with moderate-to-severe adult-onset rheumatoid arthritis (RA). Methods In RA-BEAM, patients with an inadequate response (IR) to methotrexate, at least one X-ray erosion, and high sensitivity C-reactive protein (hsCRP) ≥ 6 mg/L were randomized to placebo or orally administered baricitinib 4 mg daily or subcutaneously administered adalimumab 40 mg every other week. In RA-BUILD, patients with an IR to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) and with hsCRP ≥ 3.6 mg/L were randomized to placebo or baricitinib 2 or 4 mg daily. Patients in both trials were biologic naive. In this post hoc analysis, data from both studies were pooled (714 baricitinib 4 mg-treated, 716 placebo-treated patients). Results Overall, 188 US and 1242 ROW patients were included. Subgroups differed in baseline characteristics including race, weight, age, time since RA diagnosis, current corticosteroid use, and previous csDMARD use. At weeks 12 and 24, baricitinib-treated patients had larger responses compared to placebo-treated patients for multiple efficacy outcomes: American College of Rheumatology 20/50/70 response, low disease activity, remission, Disease Activity Score 28-C-reactive protein, and Health Assessment Questionnaire-Disability Index. Overall, similar efficacy was observed in US and ROW subgroups with no notable safety differences between subgroups at weeks 12 or 24. Conclusion Baricitinib 4 mg was efficacious compared to placebo in US and ROW subpopulations. Safety was similar between subgroups. Funding Eli Lilly & Company and Incyte Corporation. Trial Registration ClinicalTrials.gov identifiers, NCT01721057; NCT01710358.

Background Improving and preserving patient (pt) physical function is an important goal for psoriatic arthritis (PsA). Objectives To evaluate apremilast9s (APR) effects on physical function/functional status for up to 3 yrs in DMARD/biologic-experienced (PALACE 1–3 [PAL1–3] pooled data) and DMARD-naive (PALACE 4 [PAL4]) pts with active PsA. Methods Pts were randomized (1:1:1) to placebo (PBO), APR 30 mg BID (APR30), or 20 mg BID (APR20) at baseline (BL). The primary endpoint was at Wk16; a long-term extension is ongoing. A detailed study design has been previously presented. Assessed were mean change from BL HAQ-DI scores and proportions of pts reaching HAQ-DI MCID and reaching scores ≤1.0 (below clinically significant disability), ≤0.5 (minimal disability), and ≤0.25 (general population). Wk16 data were analyzed by LOCF. Wk156 data are as observed. Mean change and MCID outcomes are for all pts receiving APR30 at any time during the study; disability level data are for pts randomized to APR30 at BL. Results PAL1–3 (biologic/DMARD-experienced) and PAL4 (DMARD-naive) pts had similar BL SJC/TJC and DAS-28 (CRP), indicating active PsA. PAL1–3 pts had longer mean duration of PsA and psoriasis, higher PASI scores, and greater corticosteroid use at BL. Despite differences, BL physical disability was clinically significant in both populations (mean HAQ-DI, PAL1–3: 1.2; PAL4: 1.1). Marked disability at BL was seen in some pts randomized to APR30, with HAQ-DI scores up to 2.63–2.88. More PAL1–3 vs PAL4 APR30 pts had BL HAQ-DI >1.0 (60% vs 54%), >1.5 (marked difficulty/need for assistive devices, 31%vs 21%), and >1.75 (major disability, 19% vs 10%), highlighting need for early, effective treatment (tx). Few APR30 pts had BL scores ≤0.5 (18–22%) or ≤0.25 (10–14%). At Wk16, physical function significantly improved with APR30 vs PBO (mean HAQ-DI change, PAL1–3: −0.23 vs −0.08; PAL4: −0.21 vs 0.03; both P Conclusions With APR30 tx, physical disability improved early; functionality was maintained for up to 3 yrs. Most pts achieved HAQ-DI ≤1.0; many attained minimal/mild physical impairment. Over 40% of pts receiving APR30 earlier in the tx paradigm had functional ability similar to population norms after 3 yrs; shorter disease duration and no prior DMARD/biologics use in this population suggests that earlier APR tx may increase the likelihood of maximal functionality for some pts. Disclosure of Interest P. Mease Grant/research support from: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Biogen Idec, BMS, Celgene Corporation, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Roche, UCB, Speakers bureau: Abbott, Amgen, Biogen Idec, BMS, Genentech, Janssen, Eli Lilly, Pfizer, UCB, A. Wells Grant/research support from: Celgene Corporation, J. Wollenhaupt Grant/research support from: Abbott, BMS, MSD, Pfizer, UCB, Consultant for: Abbott, BMS, MSD, Pfizer, UCB, S. Hall Consultant for: Boehringer Ingelheim, MSD, Roche, Schering-Plough, Servier, Wyeth, Paid instructor for: Amgen, AstraZeneca, Boehringer Ingelheim, Centocor, GSK, MSD, Pfizer, Sanofi Aventis, Sanofi Pasteur, Schering-Plough, Serono, Wyeth, Speakers bureau: Boehringer Ingelheim, GSK, MSD, Pfizer, Roche, Sanofi Aventis, Schering-Plough, Wyeth, F. Van den Bosch Consultant for: AbbVie, Celgene Corporation, Merck, Pfizer, UCB, Janssen, E. Lespessailles Grant/research support from: Amgen, Eli Lilly, Novartis, Servier, Speakers bureau: Amgen, Eli Lilly, Novartis, Servier, M. McIlraith Employee of: Celgene Corporation, D. Nguyen Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, C. Edwards Grant/research support from: Celgene Corporation, Pfizer, Roche, Samsung, Consultant for: Celgene Corporation, Pfizer, Roche, Samsung, Speakers bureau: Abbott, GSK, Pfizer, Roche

Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors.In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295.Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4-45·2]; p0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1-39.8]; p0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported.Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab.Eli Lilly and Company.

Objectives: The patient referred to a rheumatology clinic for workup of suspected Systemic Lupus Erythematosus (SLE) often presents a difficult diagnostic problem; until recently, there have been no objective tests validated to rule in or rule out SLE and the diagnosis is based on a list of criteria that may be open to interpretation. Methods: To approach this problem, a serologic rule out test for SLE was developed based on antigen microarray profiling of multiplex antibody reactivities. This SLE-key® test was developed by ImmunArray and, using stored serum samples from recognized academic centers, was validated to rule out SLE with 94% sensitivity, 75% specificity and a negative predictive value (NPV) of 93%. In clinical practice, however, patients are referred one at a time from peripheral clinical units, often with incomplete documentation. Results: We report here the usefulness of the SLE-key® test in aiding the management of a cohort of suspected SLE patients in a large clinical rheumatology practice. We compared the diagnosis and disposition of 163 referrals in whom we used the SLE-key® Rule-Out test to our typical experience with referrals before the test was available. This paper shows that the SLE-key® test provided actionable clinical information and helped us with patient management in several ways; in some patients we were able to definitively rule out a diagnosis of SLE, saving time and evaluation costs; in other patients, we were able to accelerate the diagnosis of SLE and the initiation of therapy. Conclusions: The SLE-key® Rule-Out test increased efficiency in saving undue concern, time and resources both to the patient and to the healthcare system.

Advances in rheumatology occur at a rapid pace and staying abreast of important changes is a challenge for all. Both novel drug development and enhanced understanding of conventional or historic therapies have molded current day rheumatologic practice. Rheumatology has led the way in the use of outcome measures and imaging modalities in common disorders like rheumatoid arthritis, osteoarthritis, and gout. The expertise of the rheumatologist has widened such that knowledge of economics, legal issues, related disorders and extraarticular disease is essential. In February 2013, the 6th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2013 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c-s.com.

Objective.This article reports 1-year clinical outcomes in the subgroup of patients with rheumatoid arthritis in the Abatacept study to Gauge Remission and joint damage progression in methotrexate-naive patients with Early Erosive rheumatoid arthritis (AGREE) who achieved radiographic nonprogression at the end of the double-blind phase.Methods.Patients who achieved radiographic nonprogression (change from baseline in total Sharp score ≤ 0 at 12 months) with abatacept plus methotrexate (MTX) or MTX alone were eligible for this analysis. Clinical outcomes were remission, defined by 28-joint Disease Activity Score (DAS28) using C-reactive protein (CRP), low Disease Activity Score (LDAS), American College of Rheumatology (ACR) scores, physical function (Health Assessment Questionnaire), and tender and swollen joint counts. Safety was assessed at each visit.Results.Patients in the abatacept plus MTX and MTX monotherapy groups had similar baseline characteristics and were similar to the overall study population. The proportion of patients who achieved DAS28 (CRP) remission or LDAS was greater with abatacept plus MTX vs MTX alone [43.2% vs 22.7% (p < 0.001) and 57.4% vs 40.6% (p = 0.008), respectively]. More patients receiving abatacept plus MTX achieved key ACR responses, including major clinical response (27.3% vs 11.9%; p < 0.001). Safety profiles were similar in both treatment groups.Conclusion.More MTX-naive patients with early RA who achieved radiographic nonprogression taking abatacept plus MTX also achieved DAS28 (CRP)-defined remission and LDAS compared with patients who received MTX alone, supporting the use of abatacept as a first-line biologic in combination with disease-modifying antirheumatic drugs.

Ultrasonography is a sensitive imaging modality that provides valuable information regarding early inflammatory changes that are not detected by clinical examination or X-rays, such as subclinical synovitis and erosions. This information may improve the management of rheumatoid arthritis by providing a more timely and accurate diagnosis, identifying poor prognostic factors, more accurately monitoring response to therapeutic intervention, improving treatment decisions and more accurately assessing remission. Ultrasonography could play a critical role in minimizing disease activity through strict monitoring and aggressive therapeutic adjustment, which has emerged as an approach to improve long-term outcomes for patients with rheumatoid arthritis.

The evidence base for disease-modifying anti-rheumatic drugs used in psoriatic arthritis (PsA) is surprisingly weak, with most having little robust evidence to support their clinical use. Furthermore, there remain safety and tolerability concerns with both these and more recently available biological therapies. Apremilast , a novel, small molecule, represents the first oral therapy specifically developed for PsA.This review describes the pharmacokinetic properties of apremilast and available data demonstrating significant benefits to both clinical and histological features of inflammatory arthritis. The key findings from a large Phase III clinical program will also be discussed, including short- and long-term efficacy outcomes and, importantly, the safety profile. Indications other than PsA will also be briefly reviewed. Given the recent nature of much of the data, published literature as well as information available only in the abstract format are included in this review.Studies show that treatment with apremilast results in significant improvement in both skin psoriasis and PsA symptoms. Apremilast has been approved by both the United States FDA and European Medicines Agency for treatment of PsA. Use of this medication is recommended in active PsA patients, according to local licensing.

Biologic disease-modifying antirheumatic drugs have been developed that antagonise the actions of interleukin-1 (IL-1) and tumor necrosis factor α (TNFα). However, as many as 30% of patients with rheumatoid arthritis treated with the currently approved agents either do not respond or fail to maintain their clinical response over time. This necessitates the development of other anticytokine therapies to treat several inflammatory disorders. This article will briefly review data on agents under development that target IL-6, IL-12, IL-15 and IL-17.

Purpose The goal of this study was to compile all available evidence regarding the efficacy of tumor necrosis factor–α (TNF) inhibitors, non-TNF biologics, and tofacitinib for TNF-experienced patients who have rheumatoid arthritis (RA). Methods A systematic literature review of MEDLINE, EMBASE, and rheumatology conference abstracts was performed to identify observational studies and randomized controlled trials (RCTs) reporting American College of Rheumatology response rates (ACR 20/50/70) for adult patients with RA who switched from at least 1 TNF to another TNF or a non-TNF therapy. A direct random effects meta-analysis was performed to evaluate ACR 20/50/70 response rates for TNF and non-TNF therapies. Separate analyses were conducted among 3-, 6-, and 12-month observational studies and for 6-month RCTs. Findings A total of 18 observational studies and 6 RCTs were selected. Among 3-month observational studies, the percentages of ACR20/50/70 responders switching to another TNF were similar to those switching to a non-TNF biologic (ACR20, 54.5% vs 58.6%; ACR50, 33.3% vs 33.3%; and ACR70, 13.0% vs 14.6%, respectively). Among 6-month observational studies, the percentages of TNF ACR20/50/70 responders were higher than those of non-TNF responders (ACR20, 67.7% vs 50.4%; ACR50, 50.4% vs 26.6%; and ACR70, 24.9% vs 11.6%). Among 6-month RCTs, the percentages of non-TNF biologic ACR20/50/70 responders were similar to those in the 6-month non-TNF observational studies (ACR20, 50.7% vs 50.4%; ACR50, 27.5% vs 26.6%; and ACR70, 11.9% vs 11.6%). For 12-month observational studies, TNF biologic ACR20/50/70 percentages were higher than those of non-TNF therapies (ACR20, 72.2% vs 57.0%; ACR50, 42.1% vs 28.9%; and ACR70, 22.9% vs 10.0%). Implications For TNF-experienced patients with RA, subsequent TNF therapy and non-TNF biologic therapy have comparable efficacy.

Glucocorticosteroids (GCs) have been employed extensively for the treatment of rheumatoid arthritis (RA) and other autoimmune and systemic inflammatory disorders. Their use is supported by extensive literature and their utility is reflected in their incorporation into current treatment guidelines for RA and other conditions. Nevertheless, there is still some concern regarding the long-term use of GCs because of their potential for clinically important adverse events, particularly with an extended duration of treatment and the use of high doses. This article systematically reviews the efficacy for radiological and clinical outcomes for low-dose GCs (defined as ≤10 mg/day prednisone equivalent) in the treatment of RA. Results reviewed indicated that low-dose GCs, usually administered in combination with synthetic DMARDs, most often MTX, significantly improve structural outcomes and decrease symptom severity in patients with RA. Safety data indicate that GC-associated adverse events are dose related, but still occur in patients receiving low doses of these agents. Concerns about side effects associated with GCs have prompted the development of new strategies aimed at improving safety without compromising efficacy. These include altering the structure of existing GCs and the development of delayed-release GC formulations so that drug delivery is timed to match greatest symptom severity. Optimal use of low-dose GCs has the potential to improve long-term outcomes for patients with RA.

There are now more therapeutic options for the treatment of rheumatoid arthritis (RA) than ever before, involving a range of mechanisms of action and different routes of administration. The T-cell costimulation modulator abatacept is the first biologic therapy for RA to be available in both subcutaneous (SC) and intravenous (IV) formulations. This review evaluates the utility of SC abatacept, with a particular focus on patient-reported outcomes, including physical function, pain, fatigue, and quality of life. Practical questions relating to the clinical use of SC abatacept are also addressed, including the relevance of abatacept’s mechanism of action; whether IV and SC abatacept are comparable; if patients can easily switch from IV to SC abatacept; whether an IV loading dose is needed; and if temporary treatment interruptions or lack of concomitant methotrexate can affect efficacy or safety. Topics that are of particular concern to patients when using SC biologics, such as injection-site reactions, are also discussed. Observational data from registries and meta-analyses of clinical studies suggest comparable clinical efficacy between biologic disease-modifying antirheumatic drugs; however, such analyses rarely focus on key determinants of patient quality of life such as pain, fatigue, and physical function. The head-to-head AMPLE study is one of the first studies powered to directly compare two biologics in patients with RA. Patient-reported outcomes from year 1 of the ongoing study are evaluated, demonstrating comparable improvements in physical function, pain, fatigue, Short Form-36 Health Survey, and Routine Assessment of Patient Index Data 3 scores between SC abatacept and SC adalimumab when administered with concomitant methotrexate. In summary, the data presented herein show that the SC formulation of abatacept provides a valuable addition to the range of available therapy options for patients with RA, capable of significantly improving key patient considerations such as pain, disability, loss of function, fatigue, and quality of life.

Fibromyalgia (FM) is a widespread chronic pain condition that represents a significant economic burden for patients and health care systems. Effective treatment of FM requires a multidisciplinary management strategy that incorporates pharmacologic and nonpharmacologic therapy. Steps such as reducing the time to diagnosis and improving treatment decisions can result in significant cost savings and improved patient outcomes. An FM management framework, based on patient education and goal setting, has emphasized the need for ongoing care of patients with FM. In this article, we discuss how this framework could be further improved through the use of health information technology, including electronic health records. Health information technology/electronic health records can be incorporated at every stage of patient care, from initial presentation to diagnosis, through to making treatment decisions and maintaining ongoing patient management. This can lead to a number of potential benefits for patients with FM (by improving their level of care), primary care providers (by creating greater efficiencies), and the health care system (by reducing costs). Ultimately, the treatment and care of patients with FM need be no more burdensome to primary care providers than any other chronic illness. Through the greater efficiencies and optimized treatment approaches facilitated by health information technology/electronic health records, it should be possible to drive best-practice care for patients with FM and improve patient outcomes.

Background Apremilast (APR) is an oral phosphodiesterase 4 inhibitor that helps regulate the immune response that causes joint inflammation and other manifestations of psoriatic arthritis (PsA), including skin disease. Primary findings from the PALACE 4 study (NCT01307423) demonstrated greater efficacy with APR vs. placebo in DMARD-naive patients with active PsA. 1,2 Objectives Describe the long-term efficacy and safety of APR monotherapy in DMARD-naive patients in PALACE 4 for up to 156 weeks. Methods Patients were randomized (1:1:1) to placebo, APR 30 mg BID (APR30), or APR 20 mg BID (APR20). Patients whose swollen joint count (SJC) and tender joint counts (TJC) had not improved by ≥20% at Week 16 were considered non-responders and required to be re-randomized (1:1) to APR30 or APR20 if they were initially randomized to placebo, or continued on their initial APR dose. At Week 24, all patients remaining on placebo were re-randomized to APR30 or APR20. Double-blind treatment continued to Week 52 with open-label APR for up to 4 additional years. Results A total of 527 patients were randomized and received ≥1 dose of placebo (n=176), APR30 (n=176), and APR20 (n=175). Of the patients entering the third year of therapy, 88.0% (272/309) completed the Week 156 visit. At Week 52, 58.0% (119/205) of patients receiving APR30 and 55.4% (107/193) receiving APR20 achieved a 20% improvement in modified American College of Rheumatology (ACR20) response (Table). At Week 156, rates of improvement in PsA signs and symptoms and physical function were sustained, as shown by modified ACR20/ACR50/ACR70 responses, mean percent change in SJC/TJC, mean change in Health Assessment Questionnaire-Disability Index (HAQ-DI) score, proportion of patients with HAQ-DI exceeding the minimal clinically important differences (MCID) ≥0.30 threshold, achievement of Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) of 0 and dactylitis count of 0, and 75% and 50% reduction from baseline Psoriasis Area and Severity Index (PASI-75 and PASI-50) responses (Table). During Weeks >104 to ≤156, the most common adverse events (AEs) among APR-exposed patients were upper respiratory tract infection (3.2%) and nasopharyngitis (3.9%); serious AEs occurred in 5.2% of APR patients, and no opportunistic infections occurred. In general, no change in the types of AEs and no increase in the incidence and severity of AEs were seen with longer-term exposure. Conclusions Over 156 weeks, APR monotherapy demonstrated sustained response and improvements in PsA signs and symptoms, including SJC, TJC, enthesitis, dactylitis, physical function, and psoriasis. APR continued to demonstrate an acceptable safety profile and was generally well tolerated. References Edwards et al. Arthritis Rheum. 2014;66(11 Suppl)S694–5. Abstract 1572. Wells et al. Arthritis Rheum. 2014;66(11 Suppl)S264–5. Abstract 602. Disclosure of Interest A. Wells Grant/research support from: Celgene Corporation, C. Edwards Grant/research support from: Celgene Corporation, Pfizer Inc, Roche, Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc, Roche, A. Kivitz Grant/research support from: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc, UCB, Consultant for: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc, UCB, Speakers bureau: Pfizer Inc, P. Bird Grant/research support from: Celgene Corporation, D. Nguyen Employee of: Celgene Corporation, K. Shah Employee of: Celgene Corporation, L. Teng Employee of: Celgene Corporation, J. Aelion Grant/research support from: Ardea, Astra Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer Inc, Roche, UCB Biosciences, Sanofi-Aventis, Takeda, Vertex, Consultant for: Ardea, Astra Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer Inc, Roche, UCB Biosciences, Sanofi-Aventis, Takeda, Vertex, Speakers bureau: AbbVie, Amgen, UCB

Background African Americans are twice as likely as Caucasians to develop gout, but they are less likely to be treated with urate-lowering therapy (ULT). Furthermore, African Americans typically present with more comorbidities associated with gout, such as hypertension, obesity, and renal impairment. We determined the efficacy and safety of ULT with febuxostat or allopurinol in African American subjects with gout and associated comorbidities and in comparison to Caucasian gout subjects. Methods This is a secondary analysis of the 6-month Phase 3 CONFIRMS trial. Eligible gouty subjects with baseline serum urate (sUA) ≥ 8.0 mg/dL were randomized 1:1:1 to receive febuxostat 40 mg, febuxostat 80 mg, or allopurinol (300 mg or 200 mg depending on renal function) daily. All subjects received gout flare prophylaxis. Primary efficacy endpoint was the proportion of subjects in each treatment group with sUA < 6.0 mg/dL at the final visit. Additional endpoints included the proportion of subjects with mild or with moderate renal impairment who achieved a target sUA < 6.0 mg/dL at final visit. Adverse events (AEs) were recorded throughout the study. Results Of the 2,269 subjects enrolled, 10.0% were African American and 82.1% were Caucasian. African American subjects were mostly male (89.5%), obese (BMI ≥ 30 kg/m2; 67.1%), with mean baseline sUA of 9.8 mg/dL and mean duration of gout of 10.4 years. The proportions of African American subjects with a baseline history of diabetes, renal impairment, or cardiovascular disease were significantly higher compared to Caucasians (p < 0.001). ULT with febuxostat 80 mg was superior to both febuxostat 40 mg (p < 0.001) and allopurinol (p = 0.004). Febuxostat 40 mg was comparable in efficacy to allopurinol. Significantly more African American subjects with mild or moderate renal impairment achieved sUA < 6.0 mg/dL in the febuxostat 80 group than in either the febuxostat 40 mg or allopurinol group (p < 0.05). Efficacy rates in all treatment groups regardless of renal function were comparable between African American and Caucasian subjects, as were AE rates. Conclusions In African American subjects with significant comorbidities, febuxostat 80 mg is significantly more efficacious than either febuxostat 40 mg or allopurinol 200/300 mg. Febuxostat was well tolerated in this African American population. Please see related article: http://www.biomedcentral.com/1741-7015/10/15

Connective tissue disease-like illness has been associated with silicone breast implants. However, no data are currently available on the immunopathology of the capsule surrounding the breast implants. Sera from women with breast implants were collected and assayed for interleukin-6 (IL-6), IL-2, and hyaluronic acid. Capsular biopsies were stained with a probe for HYA or with monoclonal antibodies specific for human macrophages (CD68), T cells (CD4), IL-6, and IL-2. Control specimens consisted of breast biopsies from women undergoing reduction mammoplasty. Our results revealed an increased local amount of hyaluronic acid in the capsule of patients with breast implants compared with control breast tissue. The HYA was localized extracellularly in areas containing fibrosis and cellular infiltrates. The infiltrating cells were determined to be primarily macrophages and T cells. No IL-6 was localized in any of the tissue sections. In contrast, large amounts of IL-2 were found in regions of infiltrating lymphocytes. No significant increase in IL-6, IL-2, or hyaluronic acid was found in the sera. The role of hyaluronic acid and cytokines in the inflammatory response in the capsules of silicone breast implants is discussed.

Despite the prevalence of clinical data on human Lyme disease, little is known about the immunopathologic effects of the causative organism on the host. We studied the effect of Borrelia burgdorferi on hyaluronan (hyaluronic acid, HYA) production and the effect on interleukin-6 (IL-6) synthesis by cultured fibroblasts. The cell line employed in this study produced an average of 1406 ng of hyaluronan/ml within 48 h. Using both a morphological staining protocol and a quantitative radiometric assay, we noted that in the presence of a low dose of Borrelia (9.4 x 10(5) cells/ml) the hyaluronan production decreased to an average of 1008 ng/ml, a significant difference (p < 0.05) from the amount of hyaluronan produced by the cells alone. The reduction was even more significant (p < 0.01) when a higher dose of Borrelia (9.4 x 10(6) cells/ml) was used giving an average hyaluronan concentration of 682 ng/ml. In contrast, we found that Borrelia stimulated the cells to produce IL-6 from a baseline of 293 pg/ml to a maximal value of 842 pg/ml (p < 0.01). The spirochetes had no significant effect on cell viability, nor were we able to demonstrate invasion of the cells by the bacteria. Both a decrease in hyaluronan and an increase in IL-6 may correlate with the pathogenicity of Lyme disease in man.

Objective Because musculoskeletal ultrasound (MSUS) is highly user dependent, we aimed to establish whether non-mentored learning of MSUS is sufficient to achieve the same level of diagnostic accuracy and scanning reliability as has been achieved by rheumatologists recognized as international experts in MSUS. Methods A group of 8 rheumatologists with more experience in MSUS and 8 rheumatologists with less experience in MSUS participated in an MSUS exercise to assess patients with musculoskeletal abnormalities commonly seen in a rheumatology practice. Patients' established diagnoses were obtained from chart review (gout, osteoarthritis, rotator cuff syndrome, rheumatoid arthritis, and seronegative arthritis). Two examining groups were formed, each composed of 4 less experienced and 4 more experienced examiners. Each group scanned 1 predefined body region (hand, wrist, elbow, shoulder, knee, or ankle) in each of 8 patients, blinded to medical history and physical examination. Structural abnormalities were noted with dichotomous answers, and an open-ended answer was used for the final diagnosis. Results Less experienced and more experienced examiners achieved the same diagnostic accuracy (US-established diagnosis versus chart review diagnosis). The interrater reliability for tissue pathology was slightly higher for more experienced versus less experienced examiners (κ = 0.43 versus κ = 0.34; P = 0.001). Conclusion Non-mentored training in MSUS can lead to the achievement of diagnostic accuracy in MSUS comparable to that achieved by highly experienced international experts. Reliability may increase slightly with additional experience. Further study is needed to determine the minimal training requirement to achieve proficiency in MSUS.

We describe here the use of northern blotting, PCR and in situ hybridization for the analysis of cytokine gene expression. These techniques, each with their advantages and disadvantages, have been used to monitor cytokine gene expression in sites of immune reactivity and in the developing thymus. Whilst expression of a gene usually correlates well with protein production from that gene, this may not always be the case. The development of methods to analyze protein production in situ, for instance by immunohistochemistry, together with analysis of mRNA expression will allow us to begin to understand the role of cytokines within the immune system of the intact animal.

Background Apremilast (APR) is an oral phosphodiesterase 4 inhibitor that helps regulate the immune response that causes joint inflammation and other manifestations of psoriatic arthritis (PsA), including skin disease. Objectives Compare the efficacy and safety of APR monotherapy with placebo (PBO) in patients with active PsA who were DMARD-naive for up to 104 weeks. Methods Patients were randomized (1:1:1) to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30). Patients whose swollen/tender joint counts (SJC/TJC) had not improved by ≥20% at Week 16 were considered non-responders and were required to be re-randomized (1:1) to APR20 or APR30 if they were initially randomized to PBO, or continued on their initial APR dose. At Week 24, all remaining PBO patients were re-randomized to APR20 or APR30. Double-blind treatment continued to Week 52; patients could continue to receive APR for up to 4 additional years. Results 527 patients were included in the modified intent-to-treat population in which patients who were randomized in error and did not receive study medication were excluded (PBO: n=176; APR20: n=175; APR30: n=176). At Week 52, a modified ACR20 response was achieved by 58.0% (119/205 [APR30]) and 55.4% (107/193; [APR20]) of patients (Table); $≈ $84% of patients completing 1 year of APR treatment were maintained on therapy at the data cutoff during their second year of APR exposure. At Week 104, patients taking APR demonstrated sustained improvements, as shown by modified ACR20/ACR50/ACR70 response rates, SJC/TJC mean percent change, HAQ-DI mean change, proportion of patients with HAQ-DI exceeding the MCID ≥0.30 threshold, changes in MASES and dactylitis severity scores, and PASI-50/PASI-75 responses (Table). During Weeks >52 to ≤104, the most common adverse events (AEs) among APR-exposed patients were upper respiratory tract infection (4.8%) and nasopharyngitis (3.2%); serious AEs occurred in 5.3%. In general, no change in the types of AEs and no increase in the incidence/severity of AEs were seen with longer-term exposure. Diarrhea and nausea occurred at lower rates in Weeks >52 to ≤104 vs. Weeks 0 to ≤52. Conclusions Over 104 weeks, APR monotherapy demonstrated sustained response and improvements in PsA signs/symptoms, including enthesitis, dactylitis, physical function, and psoriasis. The ACR20 response was 61% for patients receiving APR30 therapy for 2 years. APR continued to demonstrate an acceptable safety profile and was generally well tolerated. Disclosure of Interest A. Wells Grant/research support from: Celgene Corporation, C. Edwards Grant/research support from: Celgene Corporation, Pfizer Inc, Roche, and Samsung, Consultant for: Celgene Corporation, Pfizer Inc, Roche, and Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc, and Roche, A. Adebajo: None declared, A. Kivitz Grant/research support from: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc, and UCB, Consultant for: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc, and UCB, Speakers bureau: Pfizer Inc, P. Bird Grant/research support from: Celgene Corporation, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, J. Aelion Grant/research support from: Ardea, Astra Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer Inc, Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Consultant for: Ardea, Astra Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer Inc, Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, and UCB

Background Patients (pts) with rheumatoid arthritis (RA), who achieve clinical disease remission by treatment with disease-modifying agents may have residual joint inflammation and vascularization, which can be detected by Power Doppler (PD) ultrasonography. The aim of this analysis was to evaluate the proportion of RA pts with PD activity, 24 weeks (wks) after the addition of adalimumab (ADA) to methotrexate (MTX). Methods MUSICA (NCT01185288), a 24 wk double-blind, randomized, controlled trial evaluated the efficacy of 2 different dosages of MTX (7.5 or 20 mg/wk) plus ADA (40 mg every other wk) in RA pts with inadequate response to MTX. For this analysis, the MTX dosage groups were combined. Synovial vascularization was assessed by PD US at 10 joints (bilateral dorsal and volar views of metacarpophalangeal joints 2, 3, 5; dorsal images alone of metatarsophalangeal joint 5 and wrists), at baseline (BL), wks 4, 8, 12, 16, 20 and 24. Images were scored by ultrasound-experienced rheumatologists using a semi-quantitative 4-grade scale. Joint swelling was assessed for the same 10 joints (SJC10). Disease activity was assessed by 28-joint count disease activity score using C-reactive protein (DAS28[CRP]) (remission 26). Pearson9s coefficient (ρ) was used to assess correlation between continuous variables. Results After 24 wks of treatment with ADA +MTX, 44/309 pts (14%) were in DAS28(CRP) remission (mean PD score, 3.3); 18/309 (5.8%) pts were in SDAI remission (mean PD score, 2.7). At wk 24, for the 10 joints selected, 30/44 (68%) of pts in DAS28(CRP) remission had positive PD scores, while only 15 pts (34%) had ≥1 swollen joint, and only 6 pts (13.6%) had ≥1 tender joint. Ten out of 18 (55%) pts in SDAI remission had a positive PD score, while none had swollen/tender joints. A poor correlation (ρ Conclusions In agreement with other studies, residual joint inflammation was detected by PD US in pts in clinical remission; therefore ultrasound can offer additional information to that obtained from clinical disease measures. Acknowledgements AbbVie sponsored the study (NCT01185288), contributed to its design, participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. Medical writing support was provided by Naina Barretto, Ph.D., of AbbVie. Disclosure of Interest G. Kaeley Consultant for: AbbVie, M. Nishio Speakers bureau: AbbVie, J. Goyal Consultant for: AbbVie, D. MacCarter Consultant for: AbbVie, Speakers bureau: AbbVie, A. Wells Consultant for: AbbVie, A. Cardoso Employee of: AbbVie, S. Liu Employee of: AbbVie, J. Kalabic Employee of: AbbVie, H. Kupper Employee of: AbbVie

The glycosaminoglycan hyaluronan is not only involved in cellular differentiation and migration but may also play a role in several inflammatory diseases. We have previously demonstrated an increased local production of hyaluronan in chronically rejected kidneys and the correspondingly affected renal vessels. In this report, we demonstrate the presence of hyaluronan in acutely rejecting kidneys. A total of 77 biopsies classified as either acute rejection or nonrejecting were analyzed using a biotin-labeled hyaluronan-binding protein in conjunction with an avidin-biotin peroxidase detection system and graded using an arbitrary scale from 0 to 3. Those biopsies classified as nonrejecting did not contain any peritubular hyaluronan in the cortex, with hyaluronan being localized only in the medulla. In contrast, those biopsies exhibiting acute rejection had an increase of hyaluronan both in the cortex and in the medulla. This increase was significantly different (P = 0.0001) and correlated with edema and interstitial inflammation. The detection of the local hyaluronan production may be a useful marker to measure acute rejection episodes.

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 4 compared the efficacy/safety of APR with placebo (PBO) in patients (pts) with active PsA who were DMARD-naive. Objectives Assess safety and tolerability of APR for up to 52 wks. Methods Pts were randomized 1:1:1 to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30). Pts with

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 4 compared APR efficacy/safety with placebo (PBO) in patients (pts) with active PsA who were DMARD-naive. Objectives Evaluate the impact of APR over 52 wks on physical function among PALACE 4 pts. Methods Pts were randomized 1:1:1 to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30). Pts with Results At Wk 16, a significantly greater proportion of pts treated with APR achieved a modified ACR20 response vs PBO (primary endpoint). Mean changes in HAQ-DI at Wk 16 (key secondary endpoint) were 0.03 (PBO), -0.17 (APR20; P=0.0008), and -0.21 (APR30; P Conclusions Over 52 wks, APR continued to demonstrate clinically meaningful improvements in physical function in active PsA pts who were DMARD-naive. APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks. References Kwok T. J Rheumatol. 2010;37:1024. Mease PJ. J Rheumatol. 2011;38:2461. Revicki DA. Health Qual Life Outcomes. 2008;6:75. Disclosure of Interest A. Wells Grant/research support: Celgene Corporation, C. Edwards Grant/research support: Celgene Corporation, Pfizer Inc, Roche, and Samsung, Consultant for: Celgene Corporation, Pfizer Inc, Roche, and Samsung, Speakers bureau: Abbott, Glaxo-SmithKline, Pfizer Inc, and Roche, A. Adebajo: None declared, A. Kivitz Grant/research support: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc, and UCB, Consultant for: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc, and UCB, Speakers bureau: Pfizer Inc, P. Bird Grant/research support: Celgene Corporation, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, R. Stevens Employee of: Celgene Corporation, J. Aelion Grant/research support: Ardea, Astra Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer Inc, Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Consultant for: Ardea, Astra Zeneca, Bristol-Myers Squibb, Celgene Corporation, Centocor, Galapagos, Genentech, GlaxoSmithKline, Human Genome Sciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, Novo Nordisk, Pfizer Inc, Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, and UCB DOI 10.1136/annrheumdis-2014-eular.1096

Background Control of disease activity in patients with rheumatoid arthritis (RA) has become achievable using synthetic and biologic disease modifying anti-rheumatic drugs, both as monotherapy or in combination. However, residual inflammatory disease can be revealed by sensitive imaging techniques such as ultrasonography in patients with remission of disease activity. Objectives To evaluate ultrasonographic vascularity changes in the joints of RA patients with previous methotrexate (MTX) inadequate-response upon initiation of adalimumab (ADA) combination therapy with two different doses of MTX. Methods MUSICA was a double-blind, randomized, controlled trial evaluating the efficacy of 2 different dosages of MTX (7.5 or 20 mg/wk) in combination with ADA (40 mg every other wk) for 24 wks in RA patients with previous inadequate response to MTX. Dorsal and volar Power Doppler (PD) images of bilateral metacarpophalangeal (MCP) joints 2, 3, 5, and dorsal images alone of metatarsophalangeal joint 5 (MTP5) and wrists were scored by 2 of 4 independent ultrasound-experienced rheumatologists using a semi-quantitative 4-grade scale. Patients with baseline and wk-24 ultrasonographic images were subgrouped based on 28-joint count disease activity score using C-reactive protein (DAS28[CRP] Results After 24-wk treatment of ADA with 7.5 or 20 mg/wk MTX, rapid decreases in mean synovial vascularity were observed regardless of achievement of disease control, with most improvement occurring within the first 4 wks. The wrist had the most baseline PD activity, 1.6 out of 6. Improvements in vascularity were greatest in MCP2 (-0.5), MCP3 (-0.4), and wrist (-0.4) after 24 wks of ADA + MTX treatment. Dorsal and volar PD vascularity incidence and activity were similar in MCP2, but differed in MCP3 and MCP5 where dorsal imaging encompassed most activity. After 24 wks of ADA + MTX, mean vascularity of the bilateral 5-joint composite score was lowest in patients that achieved DAS28 (CRP) Conclusions Upon initiating ADA in MTX inadequate-responders, rapid reduction in joint vascularity was observed in many patients, regardless of MTX dose. Low overall baseline ultrasonographic vascularity values may have partially reflected suppression of inflammation due to prior MTX treatment. Improvements in vascularity in patients were observed irrespective of achieving low disease activity or remission with a numeric trend for lower mean vascularity in patients achieving lower disease activity. Acknowledgements AbbVie sponsored the study (NCT01185288), contributed to its design, participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. Statistical support was provided by Shufang Liu, Ph.D., of AbbVie. Medical writing support was provided by Douglas E. Dylla, Ph.D., of AbbVie. Disclosure of Interest G. Kaeley Consultant for: AbbVie, M. Nishio Speakers bureau: AbbVie, J. Goyal Consultant for: AbbVie, D. MacCarter Consultant for: AbbVie, Speakers bureau: AbbVie, A. Wells Consultant for: AbbVie, A. Cardoso Shareholder of: AbbVie, Employee of: AbbVie, S. Chen Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie DOI 10.1136/annrheumdis-2014-eular.1389

Background Apremilast (APR), an oral phosphodiesterase 4 inhibitor, works intracellularly to regulate inflammatory mediators. PALACE 4 compared the efficacy/safety of APR with placebo (PBO) in patients (pts) with active PsA who were DMARD-naive. Objectives Evaluate the impact of APR treatment over 52 wks on enthesitis and dactylitis among PALACE 4 pts. Methods Pts were randomized 1:1:1 to PBO, APR 20 mg BID (APR20), or APR 30 mg BID (APR30). Pts with Results At Wk 16, a significantly greater proportion of pts receiving APR20 or APR30 achieved the modified ACR20 response vs PBO (primary endpoint). In pts initially randomized to APR and with enthesitis (n=228) and dactylitis (n=173) at BL, APR was associated with improvements in enthesitis and dactylitis over 52 wks, as evidenced by reductions in the MASES and dactylitis count. At Wk 16, median percent changes in MASES were 0.0% (PBO), -20.0% (APR20; P =0.2948), and -50.0% (APR30; P =0.0008). In pts initially randomized to APR and completing 52 wks, median percent changes in MASES were -66.7% (APR20) and -75% (APR30) (Table); 39.6% (APR20) and 45.9% (APR30) of pts achieved a score of 0, indicating no pain at any of the entheses assessed. Median percent changes in dactylitis count at Wk 16 were -50.0% (PBO), -70.8% (APR20; P =0.0691), and -69.2% (APR30; P =0.1494). In pts initially randomized to APR and completing 52 wks, both doses resulted in a median 100% decrease in the dactylitis count; a dactylitis count of 0 was achieved in 68.6% (APR20) and 68.8% (APR30) of pts. The most common AEs reported during the PBO-controlled period were nausea (12.6%), diarrhea (9.4%), and headache (6.0%). The safety profile of APR for up to 52 wks was similar to that observed with APR for up to 24 wks of treatment (PBO-controlled period). Conclusions Among pts continuously treated with APR through 52 wks, sustained improvements in both enthesitis and dactylitis were observed in pts with active PsA, who had enthesitis and dactylitis at BL. APR demonstrated an acceptable safety profile and was generally well tolerated for up to 52 wks. Disclosure of Interest C. Edwards Grant/research support: Celgene Corporation, Pfizer Inc., Roche and Samsung, Consultant for: Celgene Corporation, Pfizer Inc., Roche and Samsung, Speakers bureau: Abbott, Glaxo-Smith Kline, Pfizer Inc., and Roche, A. Wells Grant/research support: Celgene Corporation, A. Adebajo: None declared, A. Kivitz Grant/research support: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc., and UCB, Consultant for: Amgen, Janssen, Eli Lilly, Novartis, Pfizer Inc., and UCB, Speakers bureau: Pfizer Inc., P. Bird Grant/research support: Celgene Corporation, K. Shah Employee of: Celgene Corporation, C. Hu Employee of: Celgene Corporation, R. Stevens Employee of: Celgene Corporation, J. Aelion Grant/research support: Ardea, AstraZeneca, Bristol-MyersSquibb, CelgeneCorporation, CentocorGalapagos, Genetech, GlaxoSmithKline, HumanGenomeSciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, NovoNordisk, PfizerInc., Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Consultant for: Ardea, AstraZeneca, Bristol-MyersSquibb, CelgeneCorporation, CentocorGalapagos, Genetech, GlaxoSmithKline, HumanGenomeSciences, Janssen, Eli Lilly, Merck, Mesoblast, Novartis, NovoNordisk, PfizerInc., Roche, UCB Biosciences, Sanofi-Aventis, Takeda, and Vertex, Speakers bureau: AbbVie, Amgen, and UCB DOI 10.1136/annrheumdis-2014-eular.1574

The human thymus is required for establishment of a normal T cell repertoire in fetal development, as children born without a thymus (DiGeorge Syndrome) lack thymus-derived (T) and T cell immunity. While the function of the thymus in children for production of new T cells is clear, it has not been obvious that the adult thymus can produce significant numbers of new T cells. Until recently, no assays were available to directly evaluate postnatal thymic function. This paper reviews work on human thymic aging at Duke University School of Medicine and discusses the relevance of this work to devising new strategies for T cell immune reconstitution in man.

Hyaluronan (hyaluronic acid [HYA]) is one of the extracellular matrix components involved in normal cell physiology and is localized mainly in bodily fluids and connective tissues. Increased amounts of HYA in serum have been demonstrated in a number of neoplastic and inflammatory conditions, among them breast cancer. Tubular breast carcinoma (TC) and radial scar (RS) are two breast lesions that microscopically display characteristic stromal alterations and possess gross and microscopic similarities. Due to the importance of HYA as a component of the extracellular matrix, we investigated its presence in these lesions and in normal breast tissue. Using a biotinylated HYA-binding region for the in situ detection of HYA, we noted an increased amount of HYA in both TC and RS as compared with that in normal breast tissue specimens. A strong reactivity was observed predominantly around glandular structures and in the interlobular stroma of both TC and RS. Perivascular HYA staining also was distinctly observed in these lesions (TC and RS). Some HYA was observed in the connective tissue of the intralobular regions, around small blood vessels, and in the perivascular connective tissue of the normal breast. The distribution of HYA adjacent to the epithelium in the normal breast suggests a role for HYA in the interaction between epithelium and stroma of the normal breast. Its increase in the connective tissue of both TC and RS reflects the derangement of the stroma commonly observed in these conditions and supports the notion that these lesions may be associated.

Objective. To determine whether the increased levels of circulating hyaluronan seen in patients with arthritis also occur locally. Methods. Biopsy specimens of normal synovium and synovium from patients with various arthropathies were studied using histochemical and immunohistochemical staining procedures, to determine the tissue distribution of hyaluronan and infiltrating cells. Results. Hyaluronan was found in increased concentrations in inflamed tissues, and was co-localized in sites containing Ki-67 + cells. In vitro analyses showed that macrophage-released factors increased hyaluronan production by fibroblasts. Hydrocortisone inhibited this in vitro production of hyaluronan. Conclusion. Edema and swelling seen in inflamed joints may be due to the presence of large amounts of hyaluronan. One possible mechanism of action of corticosteroids in the alleviation of acute joint inflammation may occur via the inhibition of hyaluronan production.

Hyaluronic acid (HA) is an important stabilizing consistent of the loose connective tissue and regulates water homeostasis. Thus, excessive accumulation of HA in interstitial tissue immobilizes water and may thereby contribute to interstitial tissue edema. By the use of biotin labeled core protein and an avidin-enzyme system, we visualized HA in grafted rat kidney, rat heart, rat small bowel and also in human kidneys. By an extraction procedure the tissue amounts of HA were measured in the experimental grafts. Simple techniques for measuring water content were also employed. The extracellular amounts of HA increased between 100% and 350% in rejecting tissues as compared to syngeneic controls. The relative water content also increased and correlated well with the HA accumulation. The clinical value of these experimental observations was confirmed in human transplantation where rejecting kidney allograft demonstrated a highly significant increase in HA staining in the interstitium as compared to non-rejecting biopsy specimens. We therefore concluded that transplantation edema — a key features of graft rejection — is regulated by the accumulation of HA not only under experimental conditions but also in the clinical setting.

The histochemical distribution of hyaluronan (hyaluronic acid, HYA) was analysed in various types of muscles in the rat by use of a hyaluronan-binding protein (HABP) and the avidin-biotin/peroxidase complex staining procedure. Microwave-aided fixation was used to retain the extracellular location of the glycosaminoglycan. In skeletal muscles, HYA was detected in the connective tissue sheath surrounding the muscles (epimysium), in the septa subdividing the muscle fibre bundles (perimysium) and in the connective tissue surrounding each muscle fibre (endomysium). HYA was heterogeneously distributed in all striated muscles. In skeletal muscles with small fibre dimensions (e.g., the lateral rectus muscle of the eye and the middle ear muscles), HYA was predominantly accumulated around the individual muscle fibres. Perivascular and perineural connective tissue formations were distinctly HYA-positive. In cardiac muscles, HYA was randomly distributed around the branching and interconnecting muscle fibres. In comparison, smooth muscle tissue was devoid of HYA.

The perpetuation of inflammatory changes within joints elicited by persisting, poorly biodegradable group A streptococcal cell walls (peptidoglycan-polysaccharide complexes [PG-PS]) is well documented. Chronic changes in the bloodstream induced by PG-PS have not been described previously. We demonstrated that leukocytosis occurs within 3 days after intraperitoneal injection of PG-PS and remains elevated 20 weeks later. Chronic neutrophilia, monocytosis, and lymphocytosis were observed in all experiments. Chronic changes in platelet, erythrocyte, and reticulocyte counts were not seen. The newly documented leukocytosis, lasting for months after PG-PS administration, provided a circulating pool of leukocytes that may participate in chronic inflammatory events in the joint. Although the central role of the macrophage in PG-PS-mediated inflammation has been emphasized (F. G. Dalldorf, W. J. Cromartie, S. K. Anderle, R. L. Clark, and J. H. Schwab, Am. J. Pathol. 100:383-402, 1980), the polymorphonuclear cell may be involved in periods of exacerbation of streptococcal cell wall-mediated polyarthritis. This was supported by our observations that neutrophilia and monocytosis correlate well with the degree of chronic joint inflammation.

The systemic administration of an anesthetic dosage of a combination of xylazine and ketamine hydrochloride produced an acute exposure keratopathy which progressed into a syndrome resembling keratoconjunctivitis sicca. Within a few minutes corneal changes occurred that were characterized by viscous mucus, loss of corneal luster and dryness. Other acute but transient changes included development of cataracts, mydriasis and proptosis. Progressive changes were observed in the cornea within 4 days which lasted at least 8 weeks in some cases, and included punctate epithelial keratopathy progressing to devitalized or keratinized epithelial plaques. Polymorphonuclear cell infiltration of the corneal stroma associated with plaques occurred. Epithelial denudation and neovascularization of the cornea, dilation and engorgement of iridial blood vessels, as well as flare in the anterior chamber were also seen. The ocular lesions induced by xylazine/ketamine should be considered carefully when designing or interpreting research on the anterior segment. Ketamine hydrochloride with sodium pentobarbital produced excellent anesthesia without any significant ocular side-effects and may be preferred in many instances.

Hyaluronan (HYA) is a large glycosaminoglycan with a high capacity to immobilize water. Increased levels of HYA have previously been observed in plasma as well as in affected tissues in various inflammatory conditions. The morphological localization of HYA has, however, not been described in normal or rejected human kidneys. Using a recently developed method for localization of HYA in tissue sections by means of a biotin-labeled hyaluronan binding protein used as a probe, we have now investigated the distribution of HYA in normal and irreversibly rejected human kidneys. In the normal kidney HYA was essentially confined to the medulla. In the rejected kidneys increased amounts of HYA were observed primarily in the cortex and in sclerotic vessels. Incubating tissue sections with hyaluronidase abolished the staining for HYA, showing the specificity of the staining procedure. The increased amounts of HYA of the rejected kidney may play a role in local edema formation, and thereby alter graft function.