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The practice of science communication is fundamentally changing. This requires science communication practitioners to continuously adapt their practice to an ever-changing ecosystem and highlights the importance of reflective practice for science communication. In this study, we supported 21 science communication practitioners in developing a reflective practice. Our study shows that reflective practice enabled practitioners in becoming aware of their own stance towards science or assumptions regarding audiences (single-loop learning), underlying and sometimes conflicting values or worldviews present in science communication situations (double-loop learning), and facilitated practitioners to adapt their practice accordingly. Triple-loop learning, allowing practitioners to fundamentally rethink and transform their mode of science communication, was less observed. We argue that reflective practice contributes to opening-up public conversations on science — including a conversation on underlying values, worldviews, and emotions, next to communicating scientific facts.

Science communication is at the heart of many of the challenges our societies face today. At the same time, on-going changes in the relationship between science and society and the digitalisation of society can make science communication itself into a complex challenge. How can science communication adapt to an ever-changing landscape and take on new roles? In this issue we explore the potential of ‘responsible science communication’ to support and develop meaningful, open and trustworthy relationships between science and society. We present a selection of papers that review three crucial dimensions of ‘responsible science communication: reflexivity, inclusivity and co-creation’. Integrating theory and practice, this issue advocates that researchers and practitioners should be mindful of these dimensions to create meaningful conversations about science and our future.

Background:Glucocorticoids (GC) are potent drugs used for treating many inflammatory diseases. While GCs are effective in many immune diseases, dose and duration of administration is limited due to significant side effects. Resting immune cells have very little TNF expression on the cell surface and it is only in an activated state that TNF expression is upregulated. Upon immune cell stimulation, TNF is upregulated and although a significant amount of TNF is cleaved from an activated cell, a portion remains on the cell surface. We have observed that anti-TNF antibodies bind to transmembrane TNF (tmTNF) and undergo endocytosis to the lysosome (1). We have developed a stable antibody drug conjugate (ADC), ABBV-3373, that has a proprietary, highly potent, glucocorticoid receptor modulator (GRM) payload linked to an anti-TNF monoclonal antibody (mAb) that is able to deliver the GC payload to activated immune cells.Objectives:We hypothesized that a TNF ADC with a GRM payload would be able to deliver increased efficacy through both TNF inhibition and targeted GRM payload delivery to activated immune cells while sparing systemic glucocorticoid side effects.Methods:A mouse surrogate TNF GRM ADC was characterized in an acute in vivo contact hypersensitivity model of inflammation (CHS) and in a mouse model of collagen induced arthritis (mCIA). Additionally, the human anti-TNF GRM ADC, ABBV-3373 has been characterized in healthy volunteers.Results:In the CHS model the anti-TNF GRM ADC significantly inhibited the inflammatory response with minimal effect on systemic GC biomarkers. In mCIA a single dose of an anti-TNF GRM ADC, administered at disease onset, was able to completely inhibit arthritis for greater than 30 days while an anti-TNF mAb only partially inhibited disease. ABBV-3373, a human anti-TNF GRM ADC with a GC payload, was evaluated in a Phase 1 study in healthy volunteers. ABBV-3373 demonstrated antibody-like PK profile and ABBV-3373 did not impact cortisol levels at predicted efficacious doses while control subjects that received a single oral dose of 10 mg prednisone demonstrated expected decreases in cortisol levels.Conclusion:These data suggest that an anti-TNF ADC delivering a GRM payload into activated immune cells may provide improved efficacy in immune mediated diseases, while minimizing systemic side effects associated with standard GC treatment.References:[1]Deora, A. et al. MABs. 2017;9(4):680-695.Disclosure of Interests:Bob Stoffel Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Michael McPherson Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Axel Hernandez Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Christian Goess Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Suzanne Mathieu Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Wendy Waegell Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Shaughn Bryant Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Adrian Hobson Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Melanie Ruzek Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Yinuo Pang Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Hartmut Kupper Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Ronilda D’Cunha Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Julie Parmentier Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie, Timothy Radstake Shareholder of: AbbVie, Grant/research support from: AbbVie, Employee of: AbbVie

Background:ABBV-3373 is a novel antibody drug conjugate composed of adalimumab (ADA) linked to a proprietary and highly potent glucocorticoid receptor modulator (the anti-inflammatory payload) currently evaluated for the treatment of rheumatoid arthritis (RA).Objectives:To assess the efficacy and safety of ABBV-3373 vs ADA in RA patients (pts).Methods:This was a 24-week (wk) randomized, double-blind, double-dummy, active-controlled Phase 2a study of intravenously (IV)-administered ABBV-3373 100 mg (for 12 wks followed by placebo [PBO] for 12 wks) vs subcutaneous injections of ADA 80 mg every other wk (for 24 wks) in pts on background methotrexate. The primary endpoint was the change from baseline (BL) in DAS28(CRP) at Wk 12. Pre-planned statistical methods incorporating pre-specified historical ADA data both alone (pre-specified success criterion, 2-sided P ≤0.1) and supplemented with in-trial ADA data (pre-specified success criterion, probability >95%) were used to achieve adequate statistical power with a reduced trial size. Assay sensitivity was evaluated through construction of a synthetic PBO arm by propensity score matching, using individual pt-level PBO data from 3 recent sponsor-run trials of similar populations and trial settings. Secondary endpoints at Wk 12 included 1) mean change from BL in CDAI, SDAI, DAS28(ESR), HAQ-DI; 2) proportion of pts achieving DAS28(CRP)≤3.2, ACR20/50/70 responses, HAQ-DI≤-0.22. Continuous and categorical efficacy variables were analyzed using mixed effect model repeated measurements and Cochran-Mantel-Haenszel test, respectively; non-responder imputation was applied to missing categorical data. Treatment-emergent adverse events were summarized through Wk 12.Results:A total of 48 pts were randomized and treated (ABBV-3373: 31; ADA: 17); 46 pts (96%) completed 12 wks of study treatment. BL demographics and disease characteristics were indicative of established RA and similar among the 2 treatment arms and the synthetic PBO arm. ABBV-3373 demonstrated significant improvement in mean DAS28(CRP) at Wk 12 vs the pre-specified historical ADA (-2.65 vs -2.13; P=0.022) and numerically greater improvement vs the combined in-trial and historical ADA arm (-2.65 vs -2.29; probability 90%; Figure). Comparable improvements in disease activity and targets were observed for ABBV-3373 and in-trial ADA. Assay sensitivity was supported by the fact that both ABBV-3373 and ADA arms were superior to synthetic PBO (PTable 1.Treatment Emergent Adverse Events up to Week 12Event, n (%)ADA(N = 17)ABBV-3373(N = 31)Adverse event (AE)12 (70.6)11 (35.5)AE with reasonable possibility of being drug related$3 (17.6)2 (6.5)Severe AE01 (3.2)Serious AE04 (12.9) #AE leading to Discontinuation of Study Drug1 (5.9)1 (3.2)Serious infections02 (6.5)Opportunistic infection excluding Tuberculosis00Allergic Reactions Including Hypersensitivity, Angioedema, and Anaphylaxis2 (11.8) &1 (3.2) ^Systemic glucocorticoid events00All deaths00$As assessed by investigator. #Serious AEs: 1 non-cardiac chest pain, 1 pneumonia, 1 upper respiratory tract disease and 1 anaphylactic shock. &1 Type I hypersensitivity, 1 Pruritus ^1 Anaphylactic shockConclusion:These data demonstrate the clinical efficacy of ABBV-3373 and its potential to provide improved outcomes for RA pts compared to ADA. The safety profile of ABBV-3373 was generally similar to ADA.Acknowledgements:AbbVie and the authors we thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Yang Yang of AbbVie Inc for supporting the statistical analysis and data reporting. Medical writing support was provided by Ramona Vladea, PhD of AbbVie, Inc.Disclosure of Interests:Frank Buttgereit Consultant of: AstraZeneca, AbbVie, Grünenthal, Horizon Pharma, Pfizer, and Roche, Grant/research support from: AbbVie, Horizon Pharma, Pfizer, and Roche, Jacob Aelion Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Eli Lilly, Galapagos/Gilead, Genentech, GlaxoSmithKline, Horizon, Janssen, Mallinckrodt, Nektar, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, Selecta, UCB, Bernadette Rojkovich: None declared, Anna Zubrzycka-Sienkiewicz Consultant of: Astellas and Roche, Grant/research support from: AbbVie, Astellas, Galapagos NV, Gilead Sciences, Janssen, Lilly, Mabion, Pfizer, Roche, and UCB SA, Timothy Radstake Shareholder of: AbbVie, Employee of: AbbVie, Su Chen Shareholder of: AbbVie, Employee of: AbbVie, Dilek Arikan Shareholder of: AbbVie, Employee of: AbbVie, Hartmut Kupper Shareholder of: AbbVie, Employee of: AbbVie, Howard Amital Consultant of: Abbvie, Janssen, Novartis, Roche, Perrigo, Pfizer, Neopharm, Elly Lilly, Gilead, Sanofi, Teva and Rafa, Grant/research support from: Yansen, Pfizer

Background JIA is the most common chronic inflammatory rheumatic disease of childhood. TNF inhibitors are used for long-term control of pJIA disease. Objectives To evaluate the 7 year (y) safety of Adalimumab treatment with or without methotrexate (ADA±MTX) when used in current clinical practice for treatment of patients (pts) with active pJIA. Methods This is a 7 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with pJIA with up to10 y safety follow-up. Included pts were treated with ADA±MTX or MTX alone as comparison arm according to routine clinical care in PRINTO/PRCSG centres in EU, USA and Australia. MedDRA observational adverse events (AEs) were recorded from 1st day in the registry through last contact, irrespective of duration of registry treatment. Results In January 2014, enrollment was complete. As of June 1, 2016 cut-off date, 838 pts (301- MTX arm and 537 - ADA±MTX arm) were treated in the registry. There were 39 pts who rolled over from MTX to ADA±MTX arm. At registry entry mean pJIA disease duration was 1.3 y and 3.7 y and mean AJC71 was 5.8 and 5.2 for MTX and ADA±MTX arms, respectively. CHAQ disability index was 0.6 for both arms. Mean duration of study drug exposure in registry was 2.0 y (range: 0.0 – 7.1) and 2.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Mean duration of observation in registry was 3.9 y (range: 0.0 – 7.2) and 3.5 y (range: 0.0 – 7.9) for MTX and ADA±MTX arms, respectively. Overall, 213 pts (70.8%) in MTX and 225 pts (41.9%) in ADA±MTX arms discontinued registry drug through 7 y. Main reasons (not exclusively) for registry drug discontinuation for MTX arm: pts required additional therapy (32.6%), other (13.3%), lack of efficacy (11.6%), AEs (9.3%), or pts achieved JIA remission (8.6%); for ADA±MTX arm: lack of efficacy (17.9%), other (7.3%), lost to follow-up (5.6%), AEs (5.4%), or pts achieved JIA remission (5.0%). Frequencies and rates of treatment-emergent AEs (from 1st dose date of registry drug in registry up to last dose + 70 days in registry, excluding AEs occurring during treatment interruption) were similar to those reported for observational AEs (from 1st day in registry up to last contact irrespective of drug treatment duration) (Table). Rate of serious infections was similar between MTX and ADA±MTX arms. One pt (0.2%) reported an event of opportunistic infection (fungal oesophagitis) in ADA±MTX arm. No reports of deaths, malignancies, active tuberculosis, oral candidiasis, demyelination, or congestive heart failure. Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. The retention rate for registry drug was higher in ADA±MTX arm compared to MTX arm. Acknowledgements AbbVie sponsored the study & contributed with PRINTO & PRCSG to analysis, review, approval of the abstract. X. Leahy & A. Deshmukh (AbbVie) contributed to research. Medical writing: G. Patki (AbbVie). Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Takeda, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, K. Nanda Consultant for: Medac Pharma, Inc., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, C. Rabinovich Grant/research support from: UCB Pharma, Janssen, D. Kingsbury: None declared, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, and Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, and Sanofi, K. Minden Grant/research support from: Pfizer, AbbVie and Roche/Chugai, Consultant for: Pfizer, Roche, and Pharma-Allergan, Speakers bureau: Pfizer, Roche, and Pharma-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, Novartis, and Roche, Speakers bureau: AbbVie, Novartis, Sobi, Pfizer, and Roche, R. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune, D. Lovell Consultant for: AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech, Amgen and Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Background Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti-TNFs) is likely to improve psoriasis in patients with prior anti-TNF treatment. Objective The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti-TNF treatment. Methods The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16-week, double-blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1–15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti-TNFs. Results Of 730 patients enrolled, 282 (38.6%) had prior anti-TNFs and 448 (61.4%) were anti-TNF-naive. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti-TNFs achieved PASI 75 at week 16, compared with 71.7% of anti-TNF-naive patients (P = 0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti-TNF agent had been used, the number of prior anti-TNFs tried, or reasons for discontinuation of prior anti-TNF therapy. Adverse event incidences were similar between patients with and without prior anti-TNF therapy. Conclusion Adalimumab was effective and well-tolerated in patients with psoriasis previously treated with anti-TNF therapy.

Objective:To evaluate the effect of adalimumab on the frequency of anterior uveitis (AU) flares in patients with active ankylosing spondylitis (AS).Methods:We determined the history of ophthalmologist-diagnosed AU in 1250 patients with active AS who were enrolled in a multinational, open-label, uncontrolled clinical study of treatment with adalimumab, 40 mg every other week for up to 20 weeks. All AU flares were documented throughout the adalimumab treatment period plus 70 days. We compared the rates of AU flares per 100 patient years (PYs) reported during the year before adalimumab treatment with rates during adalimumab treatment, in total and by patient subgroups.Results:The AU flare rates before adalimumab treatment were 15/100 PYs in all patients (n = 1250), 68.4/100 PYs in 274 patients with a history of AU flares, 176.9/100 PYs in 106 patients with a recent history of AU flares, 192.9/100 PYs in 28 patients with symptomatic AU at baseline and 129.1/100 PYs in 43 patients with a history of chronic uveitis. During adalimumab treatment, the rate of AU flares was reduced by 51% in all patients, by 58% in 274 patients with a history of AU, by 68% in 106 patients with a recent history of AU, by 50% in 28 patients with symptomatic AU at baseline and by 45% in 43 patients with chronic uveitis. AU flares during adalimumab treatment were predominantly mild. Two patients with periods of high AS disease activity had new-onset AU during the treatment period.Conclusions:Results of this prospective open-label study suggest that adalimumab had a substantial preventive effect on AU flares in patients with active AS, including patients with a recent history of AU flares.Clinical trials:ClinicalTrials.gov Identifier: NCT00478660.

Objective: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). Design: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). Results: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. Conclusion: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. Trial registration number: NCT00085644.

Objective. To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. Methods. ReAct (Research in Active Rheumatoid Arthritis) was a large, open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers. Patients selfadministered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase. Measures of adalimumab effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, Disease Activity Score 28 (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ DI). Results. Of 6610 patients, 899 had a history of etanercept and/or infliximab therapy; these patients experienced substantial clinical benefit from adalimumab treatment. At week 12, 60% of patients had an ACR20 and 33% had an ACR50 response; 76% had a moderate and 23% had a good EULAR response. In addition, 12% achieved a DAS28 < 2.6, indicating clinical remission, and 13% achieved a HAQ DI score < 0.5. The allergic adverse event rate, regardless of relationship to adalimumab, was 6.5/100-patient-years (PYs) in previously TNF antagonist-exposed patients and 4.3/100-PYs in TNF antagonist naive patients. A multiple regression analysis indicated no statistically significantly increased risk of serious infections in patients who received prior TNF antagonists compared with TNF antagonist naive patients. Conclusion. In typical clinical practice, adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and/or infliximab.

Objective To evaluate the safety and efficacy of adalimumab, a fully human recombinant IgG1 monoclonal antibody that specifically targets human tumor necrosis factor, in patients with active ankylosing spondylitis (AS). Methods This was a multicenter, randomized (2:1 ratio), double-blind, placebo-controlled study to evaluate a subcutaneous injection of adalimumab, 40 mg every other week, compared with placebo for 24 weeks. The primary efficacy end point was the percentage of patients with a 20% response according to the ASsessment in Ankylosing Spondylitis International Working Group criteria for improvement (ASAS20) at week 12. Secondary outcome measures included the ASAS20 at week 24 and multiple measures of disease activity, spinal mobility, and function, as well as ASAS partial remission. Results At week 12, 58.2% of adalimumab-treated patients (121 of 208) achieved an ASAS20 response, compared with 20.6% of placebo-treated patients (22 of 107) (P < 0.001). More patients in the adalimumab group (45.2% [94 of 208]) than in the placebo group (15.9% [17 of 107]) had at least a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index at week 12 (P < 0.001). Significant improvements in the ASAS40 response and the response according to the ASAS5/6 criteria at weeks 12 and 24 were also demonstrated (P < 0.001). Partial remission was achieved by more adalimumab-treated patients than placebo-treated patients (22.1% versus 5.6%; P < 0.001). Adalimumab-treated patients reported more adverse events (75.0% versus 59.8% of placebo-treated patients; P < 0.05), but there was no statistically significant difference in the incidence of infections. Most adverse events were mild or moderate in severity. Conclusion Adalimumab was well-tolerated during the 24-week study period and was associated with a significant and sustained reduction in the signs and symptoms of active AS.

Contains fulltext : 57885.pdf (Publisher’s version ) (Closed access) OBJECTIVE: This randomized, placebo-controlled, double-blind, Phase 1 study assessed the magnitude, onset, and duration of response with intravenous (i.v.) and subcutaneous (s.c.) adalimumab (Humira, Abbott Laboratories) combined with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite previous MTX therapy. METHODS: Fifty-four patients were randomized to two injections of i.v. or s.c. adalimumab (1 mg/kg) or placebo while continuing on MTX (mean dose, 15.7 mg/week). Dosing intervals were determined by the European League Against Rheumatism (EULAR) response criteria, and were allowed to range from 1 to 3 months. Efficacy was mainly assessed using the EULAR response criteria and the American College of Rheumatology (ACR) response criteria. RESULTS: Moderate EULAR response was achieved at least once within 29 days after the first injection in 83% and 61% of patients receiving i.v. and s.c. adalimumab respectively, compared with 44% for placebo [probability (p) < or = 0.05 for i.v. adalimumab versus placebo]. A 20% improvement in disease activity according to the ACR criteria (ACR20 response) was achieved by 72% and 67% of patients receiving i.v. and s.c. adalimumab respectively, compared with 28% for placebo (p < or = 0.01 and p < or = 0.05, respectively, versus placebo). By Day 15 after the first and second injections, statistically significant moderate EULAR and ACR20 response rates were achieved with either i.v. or s.c. adalimumab compared with placebo (p < or = 0.05). The mean times to second injection for i.v. adalimumab, s.c. adalimumab, and placebo were 42.2 days (range: 27-84 days), 38.3 days (range: 26-85 days), and 28.4 days (range: 26-32 days), respectively (minimum time allowed by the protocol between the first and second injections was 4 weeks). Adalimumab in combination with MTX was well tolerated, with no patients being withdrawn because of adverse events. CONCLUSION: Either i.v. or s.c. adalimumab added to MTX significantly improved the signs and symptoms of RA compared with MTX alone. Subcutaneously administered adalimumab appeared to provide a response that was as great, as rapid, and as enduring as that with i.v. adalimumab.

Objective: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. Methods: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was ≥20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). Results: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p⩽0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p⩽0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p⩽0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p⩽0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (−0.29, −0.39, −0.38, −0.49 v −0.07; p⩽0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p⩽0.05). Conclusion: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.

Contains fulltext : 142630.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To evaluate efficacy, dose response, safety, and tolerability of adalimumab (D2E7) in disease modifying antirheumatic drug (DMARD) refractory patients with longstanding, active rheumatoid arthritis (RA). METHODS: During a 12 week, double blind, placebo controlled study, 284 patients were randomly allocated to receive weekly subcutaneous injections of adalimumab 20 mg (n = 72), 40 mg (n = 70), or 80 mg (n = 72) or placebo (n = 70) without concomitant DMARDs. RESULTS: Adalimumab significantly improved the signs and symptoms of RA for all efficacy measures. ACR20 responses with adalimumab were significant at each assessment versus placebo (p

Monocyte phenotype, their phagocytic capacity as well as the cytokine production from 10 patients with sepsis with low interleukin-6 (IL-6) serum concentrations (1000 pg/mL) and 8 patients with sepsis with high IL-6 (or = 1000 pg/mL) plasma concentrations were investigated within 24 hours of fulfilling the criteria for sepsis. Monocytes from patients with high IL-6 levels had higher levels of human leukocyte antigen (HLA)-DR, HLA-ABC, CD64, and CD71, and the production of tumor necrosis factor-alpha (TNF-alpha) and IL-8, as well as the capacity of monocytes to phagocytose, was significantly elevated. Of 8 patients with high levels of plasma IL-6, 4 patients died. In contrast, all 10 patients with low plasma IL-6 concentrations survived until day 28. Patients who died had constant high IL-6 concentrations during the first 3 days, whereas IL-6 levels in patients who survived decreased by 88%. Our data indicate that IL-6 levels are a better prognostic parameter in the early phase of sepsis than the monocyte HLA-DR expression.

Agents capable of reversing P-glycoprotein-associated multidrug resistance have usually failed to enhance chemotherapy activity in patients with solid tumours. Based on its toxicity profile and experimental potency, dexverapamil, the R-enantiomer of verapamil, is considered to be promising for clinical use as a chemosensitizer. The purpose of this early phase II trial was to evaluate the effects of dexverapamil on epirubicin toxicity, activity and pharmacokinetics in patients with metastatic breast cancer. A two-stage design was applied. Patients first received epirubicin alone at 120 mg m(-2) i.v. over 15 min, repeated every 21 days. Patients with refractory disease continued to receive epirubicin at the same dose and schedule but supplemented with oral dexverapamil 300 mg every 6 h x 13 doses. The Gehan design was applied to the dexverapamil/epirubicin cohort of patients. Thirty-nine patients were entered on study, 25 proceeded to receive epirubicin plus dexverapamil. Dexverapamil did not increase epirubicin toxicity. The dose intensity of epirubicin was similar when used alone or with dexverapamil. In nine intrapatient comparisons, the area under the plasma concentration-time curve (AUC) of epirubicin was significantly reduced by dexverapamil (mean 2968 vs 1901 microg ml[-1] h[-1], P= 0.02). The mean trough plasma levels of dexverapamil and its major metabolite nor-dexverapamil were 1.2 and 1.5 microM respectively. The addition of dexverapamil to epirubicin induced partial responses in 4 of 23 patients evaluable for tumour response (17%, CI 5-39%, s.e.P 0.079). The remissions lasted 3, 8, 11 and 11+ months. These data suggest that the concept of enhancing chemotherapy activity by adding chemosensitizers may function not only in haematological malignancies but also in selected solid tumours. An increase in the AUC and toxicity of cytotoxic agents does not seem to be a prerequisite for chemosensitizers to enhance anti-tumour activity.

Background JIA is the most common chronic inflammatory rheumatic diseases of childhood. Due to their long-term safety and efficacy, biologic disease modifying antirheumatic drugs (DMARD) are commonly necessary for control of pJIA patients (pts). Objectives To evaluate 6-year (y) safety and 2 y effectiveness profile of Adalimumab with or without methotrexate (ADA±MTX) when used in current clinical practice for the treatment of moderately to severely active pJIA. Methods This is a 6 y interim analysis of an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA with up to10 y safety follow-up. Included pts are treated with either ADA±MTX or MTX alone as part of their routine clinical care enrolled in the US, EU, and Australia. MedDRA observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of the duration of registry treatment. Effectiveness was assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. Results As of January 2014, enrollment was complete. As of June 1, 2015 cut-off date, 846 pts (543 in ADA±MTX and 303 in MTX groups) were treated in the registry. There were 39 pts who rolled over from the MTX to the ADA±MTX arm. At registry entry mean pJIA disease duration was 1.4 y and 3.7 y for MTX and ADA±MTX arms, respectively. At baseline (BL), mean AJC71 was 5.8 and 5.3 for MTX and ADA±MTX arms, respectively, and Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI) was 0.6 for both arms. At data cutoff, the mean duration of study exposure was 1.81 y and 2.15 y for MTX and ADA±MTX arms, respectively. Overall, 206 pts (68%) in the MTX and 216 pts (39.8%) in the ADA±MTX arms discontinued registry drug through 6 y. The main reasons for registry drug discontinuation for the MTX arm: pts required additional therapy (32.3%), other (11.9%), lack of efficacy (10.9%), AEs (8.3%), or pts achieved JIA remission (7.6%), and for ADA±MTX arm: lack of efficacy (16%), lost to follow-up (7.2%), other (5.9%), and AEs (5.3%). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs (Table). There were no reports of deaths, malignancies, opportunistic infections, active TB, oral candidiasis, or CHF. Mean JADAS27 (CRP) improved from 12.2 at BL to 9.7, 5.2, 4.4, 3.5, 2.2 at months 1, 6, and 12, 18, 24 for pts in the MTX and from 11.8 at BL to 7.0, 4.-2, 4.2, 3.6, 3.9 in the ADA±MTX arms, respectively (observed data). Conclusions Overall, ADA±MTX was well-tolerated in these pts with pJIA with no new safety signals. Discontinuations from the registry drug were relatively high through 6 y, but greater in the MTX only arm. Acknowledgement AbbVie sponsored the study & contributed with PRINTO & PRCSG to the analysis, review, and approval of the abstract. Xiaolei Leahy & Ashish Deshmukh of AbbVie contributed to the research. Medical writing support was provided by Gaurav Patki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfgroupaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Phgroupaceuticals., Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, D. J. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, and Genentech, Speakers bureau: Wyeth Pharmaceuticals, and served on data and safety monitoring boards for Amgen and Forest Research, C. Wallace Grant/research support from: Pfizer and Amgen, Consultant for: Amgen and Novartis., M. Toth: None declared, I. Foeldvari Consultant for: AbbVie and Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech and Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., and AbbVie, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie., P. Quartier Grant/research support from: AbbVie, Novartis, Consultant for: AbbVie, Novartis, K. Minden Grant/research support from: Pfizer and Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac and Pharma-Allergan., E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche, Speakers bureau: AbbVie, Novartis, Pfizer, and Roche, R. M. Kuester Grant/research support from: AbbVie Inc. and Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac, Pfizer, Roche, and UCB, M. Heinrich Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, H. Kupper Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, J. Kalabic Shareholder of: AbbVie Inc, Employee of: AbbVie Inc, A. Martini Grant/research support from: AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, and MedImmune., H. I. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals.

Multidrug resistance (MDR) in a variety of human tumours such as renal cell carcinoma (RCC) is thought to be caused by expression of the MDR1 gene and may be reversed by applying modern chemosensitisers such as dexverapamil, which inhibit the MDR1 gene product P-glycoprotein. This preliminary report gives information on a clinical study complying with good clinical practice regulations in patients with advanced RCC. The final evaluation is pending. Vinblastine, if anything the most effective chemotherapeutic agent (5-day continuous regimen), was combined with oral dexverapamil (6 times per day) as a chemosensitiser and dexamethasone to increase dexverapamil tolerance. All patients had histologically proven RCC, which was metastatic and progressive at study entry. The statistical design featured a pre-study regimen of two cycles of vinblastine alone followed by evaluation. If no response was documented, with all patients thus serving as their own control, dexverapamil and dexamethasone were added for three cycles of combination therapy. Having obtained institutional permission from the ethical review committee, we enrolled patients of whom 25 qualified for the combined-treatment arm; 13 patients finished the study, 5 patients failed to complete all treatment cycles (1 because of treatment-related toxicity, 3 for personal reasons, not related to treatment, 1 for tumour-related reasons) and 7 patients were at too early a stage for evaluation. Altogether, 61% of all patients tolerated a dose of dexverapamil of at least 2400 mg/day with peak serum levels reaching, in some cases, approximately 8 microM (the sum of dexverapamil plus nordexverapamil levels). WHO grade 3 and 4 toxicities were mainly myelosuppression (5/18). The combination of 1.4 mg m-2 day-1 vinblastine plus dexverapamil was generally felt to be safe and well tolerated. One partial response and 7 stable diseases were noted in this heavily pretreated study population. Four-hourly administration of dexverapamil in combination with dexamethasone plus escalation to the individually tolerated doses have permitted increases in serum levels of dexverapamil.

Clinical resistance of malignant tumors against cytostatic agents is a major obstacle to effective chemotherapy. A cell surface molecule (P-170) which acts as a pump has been identified as the underly

P>Background Data are lacking on the use of topical therapies in combination with tumour necrosis factor blockers for the treatment of psoriasis. Objectives To assess the efficacy and safety of adalimumab (ADA) with topical calcipotriol/betamethasone (C/B) in patients with psoriasis resembling those treated in routine clinical practice. Methods A 16-week, randomized, vehicle-controlled trial was conducted in patients with moderate to severe psoriasis and previous failure, intolerance or contraindications to two or more systemic treatments. All patients received ADA (80 mg, week 0; 40 mg every other week, weeks 1-15) in addition to either topical C/B or drug-free vehicle applied once daily for 4 weeks, and as needed thereafter. The primary endpoint was 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 16. Results A total of 730 patients received either ADA + C/B (n = 366) or ADA + vehicle (n = 364). PASI 75 response was initially higher with the combination therapy [14 center dot 8% for ADA + C/B vs. 5 center dot 8% for ADA + vehicle at week 2 (P < 0 center dot 001); and 40 center dot 7% vs. 32 center dot 4%, respectively, at week 4 (P = 0 center dot 021)]. After week 4, the trend was towards a higher response with ADA monotherapy, with no statistical difference in the PASI 75 response at week 16 (64 center dot 8% for ADA + C/B vs. 70 center dot 9% for ADA monotherapy, P = 0 center dot 086). Safety findings were consistent with previous ADA trials. Conclusions ADA + C/B resulted in more rapid and higher efficacy within the first 4 weeks; thereafter, the trend was towards a higher response with ADA monotherapy. There was no statistical difference in the PASI 75 response at week 16. Both treatment regimens were well tolerated.

Objectives:To evaluate the effectiveness of adalimumab in patients with psoriatic arthritis (PsA) and identify predictors of good clinical response for joint and skin lesions.Methods:Patients received adalimumab 40 mg every other week in addition to standard therapy in this prospective, 12-week, open-label, uncontrolled study. Four definitions of good clinical response were used: ⩾50% improvement in American College of Rheumatology response criteria (ACR50), good response according to European League Against Rheumatism (EULAR) guidelines, a ⩾3-grade improvement in Physician Global Assessment of psoriasis (PGA) and a ⩾50% improvement in the Nail Psoriasis Severity Index (NAPSI). Response predictors were determined by logistic regression with backward elimination (selection level was 5%).Results:Of 442 patients, 94% completed 12 weeks of treatment. At week 12, 74%, 51% and 32% of the patients had achieved ACR20, 50 and 70, respectively; 87% and 61% experienced moderate and good responses according to EULAR criteria, respectively. The percentage of patients with PGA results of “clear/almost clear” increased from 34% (baseline) to 68%. The mean NAPSI score was reduced by 44%. No new safety signals were detected. A lower Health Assessment Questionnaire Disability Index (HAQ-DI) score, greater pain assessment, male sex and absence of systemic glucocorticoid therapy were strongly associated with achievement of ACR50 and good response according to EULAR criteria. In addition, greater C-reactive protein concentration and polyarthritis predicted ACR50, and non-involvement of large joints predicted a good response according to EULAR criteria.Conclusions:Adalimumab was effective in patients with PsA. Lower impairment of physical function, greater pain, male sex and no systemic treatment with glucocorticoids were factors that increased the chance of achieving a good clinical response.

Objectives. To evaluate the effectiveness and safety of adalimumab in treating patients with AS and advanced structural damage. Methods. Patients with active AS [Bath AS Disease Activity Index (BASDAI) 54] received 40 mg of adalimumab every other week plus their standard anti-rheumatic therapies in this 12-week, open-label study. Investigators documented the presence or absence of advanced ankylosis based on previous radiographs. Stages IV (from 50 to

Objectives. This study evaluated the patients' perspective of burden of disease among 505 patients with severe, long-standing rheumatoid arthritis receiving adalimumab. Methods. Health-related quality-of-life and resource use data were collected during a 144-week open-label study. Results. Adalimumab maintained pain control and reduced the duration of morning stiffness. Work impairment decreased and work productivity was maintained over the duration of the study. Costs were estimated atE2100 over the course of the study, and personal help and transportation costs comprised a large percentage of total costs. Conclusions. These results suggest that adalimumab could improve many aspects of a patient's burden of disease. Health care systems are moving towards increasing the respon- sibility of patients, particularly with regard to costs and copayments. The clinical and financial burden of chronic diseases such as RA can be overwhelming for patients. Because there is no cure for RA and clinical remission is infrequent, research efforts must then focus on ways to improve the burden of illness of these patients. However, the different facets of the burden of illness are quite heterogeneous for chronic diseases overall, even within the field of rheumatology. In 2003, the World Health Organization reported that musculoskeletal conditions, such as RA, critically impair the health-related quality of life (HRQOL) of the patient. In its view, this impact was affected not only by the clinical manifestations of the illness but also by socioeconomic, personal, environmental and other factors (1). Based on the World Health Organization assessment, the following domains would be considered of major concern for patients with RA: HRQOL (e.g. physical well-being, oppressive fatigue), psychosocial factors (e.g. social impact, impact on family life, loss in personal interaction), pain, burden on caregivers (e.g. time consumption, direct and indirect costs, mental implications), work-related issues (e.g. lost income, less productivity) and copayments or out-of- pocket expenditures (OOPEs). Although there are many published clinical studies describing the epidemiology and clinical aspects of RA and its treatment, few publications focus on the cost and additional burden of the disease. Even fewer publications address the burden of the disease and its different facets from the perspective of the patient (2). Understanding the view of the patient may be important for the interpretation of study results in this field of research. A patient's expectations toward an effective novel therapy may be different from a clinical expert's definition of an effective therapy. Similarly, a patient's satisfaction with a specific treatment may vary from a clinical assessor's point of view. Both expectations and satisfaction influence treatment preference decisions made by patients, who, as mentioned, are becoming increasingly responsible for their overall health care budget. Fortunately, patient-reported outcomes (PROs) are gaining importance among regulatory agencies such as the US Food and Drug Administration and the European Medicines Agency, who now consider the role of PROs in the evaluation of medicines not only for terminal diseases but also for chronic conditions such as RA (3, 4). This article describes the burden of illness from the point of view of patients with long-standing severe RA receiving the tumour necrosis factor antagonist adalimumab during a 3-year open-label observational study. Adalimumab is the first fully human anti- tumour necrosis factor monoclonal antibody available for the treatment of RA. In clinical trials in patients with RA, adalimumab significantly reduced the signs and symptoms of the disease, improved physical function, and inhibited radiographic progres- sion of joint damage (5-7). Effects were sustained during long-term treatment of up to 4 yrs (8, 9). Results from clinical trials and post- marketing surveillance studies have demonstrated the safety of adalimumab in patients with RA (10). In economic evaluations, adalimumab achieved favourable cost-effectiveness ratios as compared with traditional DMARDs (11, 12).

Adalimumab (Humira, Abbott Laboratories, Abbott Park, IL, USA) is the first fully human recombinant IgG1 monoclonal antibody that acts by inhibiting tumor necrosis factor-alpha (TNF-α or TNF) (Fig. 3.1) (Abbott Laboratories 2006). In contrast to infliximab, a chimeric antibody comprising both mouse and human domains that may elicit immune responses that potentially limit its long-term use in patients with chronic conditions such as rheumatoid arthritis, adalimumab is fully human, lowering the potential for immunogenicity (van de Putte et al. 2003).

Background Juvenile idiopathic arthritis (JIA) is one of the most common childhood rheumatic diseases. Adalimumab (ADA) is approved for moderate to severe polyarticular JIA (pJIA) in patients (pts) ≥4 yrs in Australia and Japan and for pts ≥2 yrs in the US and EU. Objectives To evaluate long-term safety and effectiveness of ADA in pts with moderately to severely active pJIA who are prescribed and treated with ADA in routine clinical practice. Methods This is an ongoing, multicenter, non-interventional, observational registry of pts with moderately to severely active pJIA who are treated with either ADA ± methotrexate (MTX) or MTX alone as part of their routine clinical care. 800 pts (500 ADA/300 MTX) were to be enrolled in the US, EU, and Australia. The follow-up observational period is 10 yrs from enrollment into one of the treatment arms. Observational adverse events (AEs) were recorded from the first day in the registry through last contact, irrespective of registry treatment duration. Clinical outcomes were assessed by 27-joint juvenile arthritis disease activity score (JADAS27), based on CRP. 5 yr interim data are presented. Results As of January 2014, enrollment is complete. 842 pts (540 ADA/302 MTX) were treated as of the March 28, 2014 cutoff. Mean pJIA disease duration at enrollment was 1.3 and 3.7 yrs and mean duration of study exposure was 643 and 653 days for MTX and ADA arms, respectively. Baseline mean AJC73 was 5.8 and 5.4 for MTX and ADA, respectively, and CHAQ-DI was 0.6 for both groups. Overall, 153 pts (50.7%) in the MTX arm and 132 pts (24.4%) in the ADA arm discontinued registry drug. Of those, 22 (7.3%) and 23 (4.3%) in the MTX and ADA arm, respectively, discontinued due to an AE, and 39 of the 153 pts in the MTX arm discontinued as they switched to the ADA arm. The observational AEs are summarized (Table). No deaths, malignancies, or opportunistic infections were reported. In the ADA arm, there were 13 (2.4%) pts with serious infectious AEs (abdominal abscess, acute tonsillitis, appendicitis, cellulitis, gastroenteritis, mononucleosis, viral meningitis, pneumonia, pyelonephritis, scarlet fever, subcutaneous abscess, tonsillitis, urinary tract infection, and varicella). Frequencies and rates of treatment-emergent AEs were similar to those reported for observational AEs. Mean JADAS27 improved from 12.1 at baseline to 9.4, 6.1, 5.1, 4.4 at months 1, 3, 6, and 12 for pts in the MTX arm and from 12.1 at baseline to 7.4, 5.5, 4.4, 4.5 in the ADA arm, respectively (observed data). Conclusions Overall, ADA is well-tolerated in these pts with active pJIA. No new safety signals were observed, and based on this interim analysis, the known safety profile of ADA remains unchanged. Acknowledgements AbbVie sponsored the study (NCT00783510), contributed with PRINTO and PRCSG to the design, and participated in data collection, analysis, and interpretation, and in the writing, review, and approval of the abstract. Medical writing support was provided by Jessica L. Suboticki, PhD, of AbbVie. Disclosure of Interest N. Ruperto Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, and Wyeth Pharmaceuticals. NR has served on speaker9s bureau for Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, and Wyeth/Pfizer, H. Brunner Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Boehringer-Ingelheim, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UCB, and Genentech, Speakers bureau: Genentech Pharmaceuticals, C. Wallace Grant/research support from: Pfizer, Amgen, Consultant for: Amgen, Novartis, M. Toth: None declared, I. Foeldvari Consultant for: AbbVie, Novartis, J. Bohnsack Consultant for: Novartis, D. Milojevic Consultant for: Genentech, Novartis, E. Rabinovich Grant/research support from: UCB Pharma, Janssen Research & Development, LLC, Hoffmann-La Roche Inc., AbbVie, P. Vavrincova: None declared, D. Kingsbury Grant/research support from: AbbVie, K. Marzan Grant/research support from: AbbVie, P. Quartier Grant/research support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum; Participates on a data management committee of a phase 3 trial by Sanofi, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, K. Minden Grant/research support from: Pfizer, Abbvie, Consultant for: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, Speakers bureau: Pfizer, Abbvie, Roche/Chugai, Novartis, Medac, Pharm-Allergan, E. Chalom Speakers bureau: AbbVie, G. Horneff Grant/research support from: AbbVie, Pfizer, and Roche and speaker9s fees from AbbVie, Novartis, Pfizer, Roche, R.-M. Kuester Grant/research support from: AbbVie, Wyeth/Pfizer, J. Dare Grant/research support from: AbbVie, AstraZeneca, Bristol-Myers Squibb, Horizon Pharma, Medac GmbH, UCB Biosciences, M. Bereswill Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Employee of: GASLINI Hospital, which has received contributions to support the research activities of the network of PRINTO from AbbVie Inc., AstraZeneca, Bristol-Myers Squibb, Janssen Biologics B.V., Eli Lilly and Co., “Francesco Angelini”, GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Speakers bureau: Astellas, AstraZeneca, Bristol-Myers Squibb, Italfarmaco, MedImmune, D. Lovell Consultant for: AbbVie Inc., AstraZeneca, Centocor, Bristol-Myers Squibb, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Xoma, Genentech; served on data and safety monitoring boards for Amgen, Forest Research, Speakers bureau: Wyeth Pharmaceuticals

Background Minimal disease activity (MDA) criteria for psoriatic arthritis (PsA) treatment encompass clinical aspects of PsA including arthritis, psoriasis, enthesitis, pain, patient assessment of disease activity, and physical function. Radiographic changes impact future functional status and as such, a measure of radiographic structural damage may be a meaningful addition to MDA as a composite treatment target. Objectives To evaluate a composite endpoint including MDA and low radiographic progression in patients (pts) with PsA treated with adalimumab (ADA) Methods In ADEPT (NCT00646386), pts with moderately to severely active PsA were randomized to receive ADA or placebo (PBO) for 24 weeks. Radiographs of hands and feet were obtained at baseline (BL) and wk 24. In this post hoc analysis, the proportion of pts achieving clinical endpoints of MDA 1 , DAS28 Results At wk 24, data were available for 121 pts (ADA 61, PBO 60). At wk 24, 39% of ADA-treated pts achieved MDA (Table 1) compared to 7% of PBO-treated pts, similar to frequencies observed in pts achieving DAS28 remission. DAS28 LDA was achieved by 44% of ADA-treated pts vs. 12% of PBO pts. ΔmTSS ≤0.5 was achieved at wk 24 by 84% of ADA-treated pts and 60% of PBO pts. 34.4% (21/61) of ADA-treated pts achieved both MDA + ΔmTSS ≤0.5 vs. 6.7% (4/60) of PBO pts. Pts achieving MDA had less radiographic progression (Table 2). Pts achieving MDA, with or without low radiographic progression, had lower baseline joint counts and HAQ scores than those who did not achieve MDA. Conclusions In this analysis, the addition of low radiographic progression to MDA, DAS28 remission, or DAS28 LDA appeared to increase the stringency of the endpoint achieved on anti-TNF therapy in PsA pts. Further analysis is needed to determine whether this novel composite endpoint translates into long-term pt benefits. References Mease P et al. J Rheumatol. First Release March 15 2013; doi:10.3899/jrheum.120970. Acknowledgements AbbVie funded the study (NCT00646386), contributed to its design and was involved in the collection, analysis, and interpretation of the data, and in the writing, review, and approval of the publication. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie. Disclosure of Interest P. Mease Grant/research support: AbbVie, Amgen, Biogen Idec, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Consultant for: AbbVie, Amgen, Biogen Idec, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, Speakers bureau: AbbVie, Amgen, Biogen Idec, Bristol Myers, Celgene, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, and Vertex, P. Karunaratne Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, M. Hojnik Shareholder of: AbbVie, Employee of: AbbVie, A. Dorr Shareholder of: AbbVie, Employee of: AbbVie, I. McInnes Grant/research support: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB, Consultant for: AbbVie, Amgen, Janssen, Novartis, Pfizer, and UCB DOI 10.1136/annrheumdis-2014-eular.1431

Background Genetic factors related to treatment response in rheumatoid arthritis (RA) have been described. International recommendations for the management of RA suggest initial therapy with synthetic DMARDs, with methotrexate (MTX) typically administered as first-line therapy. However, responses to MTX are variable, and more than 30% 1 of patients fail to respond. Despite many studies, few genetic factors specifically associated with MTX response have been identified. Objectives To identify genetic variants associated with response to MTX in patients with early RA. Methods OPTIMA was a 78-week, multicenter, randomized, double-period, double-blind study in which patients were randomized 1:1 to combination therapy with adalimumab plus MTX or MTX alone during the initial study period (26 weeks). Enrolled patients were invited to participate in a genetic sub-study and asked to provide written, informed consent. 384 variants in genes previously shown to be associated with RA or treatment response were assayed using the Illumina BeadXpress GoldenGate Assay. Changes in the 28-joint disease activity score (DAS28) and the total Sharp score (TSS) following 26 weeks of treatment were assessed for association with allele status using genotypic tests. Results A total of 448 patients randomized to MTX were included in the genetic sub-study. Two SNPs in MTHFR (rs1801133 and rs1801131) and one SNP in ATIC (rs2372536) 1 , previously shown to be associated with MTX response, were not associated with a change in DAS28 or TSS following MTX treatment. However, other SNPs within genes that have been associated with RA or treatment response, such as ABCB1, TNF-alpha, PTPRC, STAT4 and HLA-DRB1, did show association with MTX treatment (Table). For some genes, such as ABCB1, multiple SNPs were identified, suggesting that haplotype analysis could identify stronger associations. SNPs within ABCB1 and PTPRC were also associated with a change in TSS. In addition, a SNP within ADORA2a associated with a change in TSS. SNPs within this gene have previously been associated with MTX toxicity, however, analysis of the impact of this gene on efficacy have been more limited. Conclusions Genetic polymorphisms in genes such as ABCB1, TNF-alpha, PTPRC, STAT4 and HLA-DRB1 were shown to associate with MTX treatment in the OPTIMA study. These results may prove useful for the development of future diagnostic tests or personalized therapeutics for MTX treatment. References Malik et al. Pharmacogenomics (2013). 14(3), 305-314. Acknowledgements AbbVie sponsored the study (NCT00420927), contributed to its design, and 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 Laurel M. Farmer, PhD, of AbbVie Inc. Disclosure of Interest A. Skapenko: None declared, H. Schulze-Koops Consultant for: AbbVie Inc., V. Devanarayan Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., K. Idler Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., F. Hong Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., J. Smolen Grant/research support: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Janssen, Glaxo, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz, and UCB, Consultant for: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Janssen, Glaxo, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz, and UCB, A. Kavanaugh Grant/research support: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Consultant for: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, H. Kupper Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., J. Waring Shareholder of: AbbVie Inc., Employee of: AbbVie Inc. DOI 10.1136/annrheumdis-2014-eular.1318

Background Rheumatoid arthritis (RA) treat to target (tgt) recommendations advocate clinical remission (REM) as the tgt; targeting low disease activity (LDA) is an alternative for patients (pts) who cannot attain REM. Consequences of targeting LDA versus REM, or by using different definitions of REM, may vary based upon initial choice of therapy. Objectives To evaluate week (wk) 52 consequences of achieving different tgts at wk26 in early and established RA pts treated with methotrexate (MTX) alone or adalimumab (ADA)+MTX. Methods This post hoc analysis included pts treated with ADA+MTX or placebo (PBO)+MTX from 2 clinical trials in early RA (PREMIER1, OPTIMA2,3) and 1 in established RA (DE0194). Disease activity at wk26 was categorized as follows: LDA (2.6≤DAS28

Background In patients (pts) with Rheumatoid Arthritis (RA), adalimumab (ADA) plus methotrexate (MTX) treatment is associated with greater improvements in clinical, patient-reported, and work related outcomes compared to MTX monotherapy. Objectives To evaluate the effects of ADA+MTX versus PBO+MTX on work instability, and to assess the impact of disease activity and functional impairment on work instability. Methods A post-hoc analysis at week (wk) 26 and wk 24 from the OPTIMA 1 and PROWD 2 trials, respectively, was conducted for employed pts with baseline RA-WIS score ≥10. Work instability and work productivity were assessed using the RA-Work Instability Scale (RA-WIS) and the Work Productivity and Activity Impairment Questionnaire (WPAI), respectively. Correlation analyses between the change in RA-WIS scores and changes in HAQ-DI, DAS28 and CDAI, were performed to assess the impact of disease activity and functional impairment on work instability (job insecurity due to a mismatch of functional ability and job demands). Chi-square tests assessed treatment group differences in pts with improvements of ≥1 risk category in the WIS score (>17, ≥10 to ≤17, and Results At baseline, 320/1032 pts in OPTIMA and 124/148 in PROWD, were employed with RA-WIS score ≥10. In both studies, mean DAS28 of 6.1, mean HAQ-DI of 1.6 and mean RA-WIS score of 16.8 at baseline indicate high disease activity, substantial physical disability and medium to high risk for employment loss. In OPTIMA, pts receiving ADA+MTX vs. PBO+MTX had significantly (p Conclusions Among early RA pts with elevated risk of employment loss, compared with PBO+MTX, ADA+MTX therapy was associated with a significant and clinically meaningful reduction in work instability. Work instability was correlated to functional impairment and disease activity. References Kavanaugh A, et al. Ann Rheum Dis 2013; 72:64-71. Bejarano V, et al. Arthritis Rheum 2008;59(10):1467-74. Acknowledgements AbbVie sponsored the studies, participated in study design, data collection, analysis and interpretation; and in the writing, reviewing, and approval of the final version. Medical writing was provided by Jessica L. Suboticki, PhD, of AbbVie. Disclosure of Interest P. Emery Grant/research support: AbbVie Inc., Pfizer, Novartis, BMS, and Roche, Consultant for: AbbVie Inc., Pfizer, MSD, UCB, Roche, Novartis, and BMS, J. Smolen Grant/research support: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz, and UCB, Consultant for: AbbVie Inc., Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Glaxo, Lilly, Pfizer, MSD, Novo-Nordisk, Roche, Sandoz, and UCB, A. Ganguli Shareholder of: AbbVie, Employee of: AbbVie, S. Meerwein Shareholder of: AbbVie, Employee of: AbbVie, Y. Bao Shareholder of: AbbVie, Employee of: AbbVie, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie, N. Chen Shareholder of: AbbVie, Employee of: AbbVie, M. Karunaratne Shareholder of: AbbVie, Employee of: AbbVie, A. Kavanaugh Grant/research support: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Consultant for: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB DOI 10.1136/annrheumdis-2014-eular.1128

Background Objectives To evaluate the long-term efficacy and safety of the fully human anti-TNF antibody adalimumab (D2E7) given by the s.c. route to patients with active rheumatoid arthritis. Methods 24 patients with active rheumatoid arthritis who had previously failed a mean of 3.5 DMARDs were included in this 12-week randomised double blind, placebo-controlled study (DE004), and continued thereafter in an open label part of the study for up to two years on adalimumab. Initially, patients were assigned to either 0.5 mg/kg adalimumab s.c. weekly (18 patients) or placebo (6 patients). 22 patients entered the open-label part of the study: 15 patients who achieved EULAR response continued their previous adalimumab treatment schedule (0.5 mg/kg weekly), 2 patients who did not achieve a EULAR response at week 8 increased their adalimumab dose to 1 mg/kg weekly, and 5 patients previously on placebo received 1 mg/kg adalimumab s.c. weekly. Patient characteristics at baseline: 60 years mean age, 10 years mean RA duration, 5.35 mean Disease Activity Score (DAS). Results The overall efficacy results for the open label period of 24 months are summarised in the Table 1 below. Adverse events were well matched between the adalimumab treatment arm and placebo during the placebo-controlled period. After two years of treatment 14 patients were still receiving study drug. Reasons for drop out were lack of efficacy (4 pts), adverse events (3 pts), death (1 pt on placebo, 1 on adalimumab, both myocardial infarction), and protocol violation (1 pt). Conclusion Repeated weekly s.c. injections of a dose of 0.5 mg/kg or 1 mg/kg adalimumab (D2E7) given to patients with active rheumatoid arthritis over a period of two years were efficacious and well tolerated.

Background Objectives To evaluate the long-term efficacy and safety of a combination of methotrexate (MTX) with the fully human anti-TNF antibody adalimumab (D2E7) in patients with active rheumatoid arthritis (RA). Methods 54 patients, who were partial responders to standard doses of MTX (mean 16 mg/week), were included in this randomised double blind, placebo-controlled study (DE010). Initially, patients were randomised into three treatment arms of 18 patients each and then injected double blind (first and second injection) with either 1 mg/kg adalimumab i.v., 1 mg/kg adalimumab s.c., or placebo (double dummy). Thereafter, all patients received open-label s.c. injections of 1 mg/kg adalimumab. The frequency of administration (every other week up to every other month) depended on the individual response to treatment. Results The overall efficacy results for the open label period of 24 months are summarised in the Table 1 below. Adverse events were well matched between both adalimumab treatment arms and placebo during the initial double blind study period. A total of 44 patients (81%) were able to complete the 2-year study period. Reasons for drop out were adverse events (6 pts), lack of efficacy (2 pts), death (1 pt, myocardial infarction), and protocol violation (1 pt). Conclusion Repeated subcutaneous injections of 1 mg/kg adalimumab (D2E7) over a period of two years showed sustained efficacy and were well tolerated when given in combination with stable standard doses of MTX to patients with active RA.

Objective: This study investigated whether treatment with the anti-tumor necrosis factor-or monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/ml, Design: Multicenter, double-blind, randomized, placebo-controlled study. Setting: Eighty-four intensive care units in academic medical centers in Europe and Israel. Patients: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222), Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. Interventions: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. Measurements and Main Results:The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p

Background The PREMIER trial demonstrated the superiority of initial adalimumab (ADA)+MTX vs the individual monotherapies in MTX-naive patients (pts) with early, aggressive rheumatoid arthritis (RA) 1 . Objectives To assess long-term outcomes in pts treated with ADA, with or without MTX, for up to 10 years (yrs). Methods Pts completing the 2yr blinded study were eligible to receive open-label (OL) ADA for up to an additional 8 yrs; MTX could be added at the investigator’s discretion. This post hoc analysis evaluated data as observed (ie, no imputation for missing data); results are summarized overall and by initial treatment arm. DAS28(CRP) and HAQ-DI were used to assess clinical and functional outcomes, respectively. Radiographic progression (change from baseline in mTSS) was assessed in 10yr completers with radiographic data available at baseline and yr 10. Adverse events (E) of interest were summarized for pts receiving ≥1 ADA dose and presented as E/100-pt yrs (PY). Results Of the 799 pts randomized, 497 (62%) entered the OL extension; 250 (31%) maintained OL ADA±MTX through yr 10. MTX co-therapy was (re)initiated in 261 pts (53%) during the OL extension. Overall, pts completing 10 yrs of therapy continued to demonstrate effective disease control (mean DAS28=2.4; mean HAQ-DI=0.6; mean ΔmTSS=7.8). Although the addition of OL ADA±MTX to the initial MTX and ADA arms at yr 2 led to increases in the proportions achieving DAS28(CRP) Table ). Further, ΔmTSS remained significantly lower over time in the initial ADA+MTX arm compared with the 2 monotherapy arms (ΔmTSS =4.0, 11.0, and 8.8 at yr 10 for the initial ADA+MTX, MTX, and ADA arms, respectively; both P P >0.05). No new safety signals arose following 3708 PY of ADA exposure (N=697 pts): serious infections =2.6 E/100-PY; TB =0.2 E/100-PY; malignancy (other than NMSC) SIR (95% CI) =0.89 (0.62, 1.26). There were 23 deaths during this 10yr study, resulting in an SMR (95% CI) of 0.72 (0.49, 1.02). Conclusions ADA±MTX maintained effective disease control for up to 10 yrs in pts with early, aggressive RA. Of the pts who continued in the study, those who initiated ADA+MTX combination therapy retained better outcomes through 10 yrs than pts who began treatment with MTX or ADA monotherapy. References Breedveld et al. Arthritis & Rheum . 2006; 54(1):26-37. Acknowledgements AbbVie Inc. sponsored the study (NCT00195663), contributed to its design, and 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 Benjamin Wolfe, PhD, of AbbVie Inc. Disclosure of Interest E. Keystone Grant/research support from: AbbVie Inc., Amgen, AstraZeneca, BMS, Centocor, Genzyme, Merck, Novartis, Pfizer, Roche, UCB, Consultant for: AbbVie Inc., AstraZeneca, Biotest, BMS, Centocor, Genentech, Merck, Nycomed, Pfizer, Roche, UCB, Speakers bureau: AbbVie Inc., Amgen, BMS, Janssen, Merck, Pfizer, Roche, UCB, F. Breedveld Consultant for: Centocor, Schering-Plough, Amgen/Wyeth, AbbVie Inc, D. van der Heijde Consultant for: AbbVie Inc., Amgen, AstraZeneca, BMS, Centocor, Chugai, Eli-Lilly, GSK, Merck, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB, Wyeth, and is the director of Imaging Rheumatology bv, R. Landewe Consultant for: AbbVie Inc., Amgen, BMS, Centocor, GSK, Merck, Novartis, Pfizer, Roche, Schering-Plough, UCB, Wyeth, and is the owner of Rheumatology Consultancy bv, S. Florentinus Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., U. Arulmani Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., S. Liu Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., H. Kupper Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., A. Kavanaugh Grant/research support from: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB, Consultant for: AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCB

Background There has been increased interest in understanding whether biologics can be safely withdrawn from patients (pts) receiving combination therapy with MTX once a clinical target has been achieved. The ability of the biologic to maintain the target as monotherapy has received less consideration. Objectives To evaluate long-term clinical and radiographic outcomes in pts treated with open-label (OL) adalimumab (ADA) as monotherapy following attainment of low-disease activity (LDA). Methods PREMIER was a 2-year (yr), phase 3, randomized, controlled trial (RCT) in MTX-naive pts with early RA who were randomized to MTX, ADA (40 mg every other week), or ADA+MTX. 1 Pts completing the RCT were eligible to receive OL ADA for up to an additional 8 yrs (this trial is ongoing); MTX could be added at the investigator’s discretion. This post hoc analysis included data from pts who were in an LDA state [defined as DAS28(CRP) Results Of the 497 pts who enrolled in the OL extension, 313 were in an LDA state at the end of the RCT (ie, Yr 2). Among the LDA responders, 173 (55%) received ADA as monotherapy during the OL period. One-half (n/N=87/173, 50%) of the pts who entered the OL period with LDA maintained this disease activity state at Yr 8 with ADA monotherapy (Table). More than half (n/N=99/173, 57%) completed 6 yrs of OL ADA monotherapy and had DAS28(CRP) values at Yr 8, with 88% (n/N=87/99) maintaining LDA at the Yr 8 assessment. Further, OL ADA monotherapy was associated with clinically insignificant radiographic progression for pts completing Yr 8 (annual progression rate between Yrs 2 and 8, ΔmTSS =0.4 units/yr). Conclusions OL ADA effectively maintained pts in a state of LDA and with minimal radiographic progression following 6 yrs of treatment. These data suggest that ADA monotherapy can be effective in some pts whose disease activity does not necessitate supplemental MTX therapy. References Breedveld FC, et al. Arthritis Rheum 2006;54:26-37. Disclosure of Interest E. Keystone Grant/Research support from: Abbott, AstraZeneca, Biotest, BMS, Centocor, Genentech, Merck, Nycomed, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, AstraZeneca, BMS, Centocor, Genzyme, Merck, Novartis, Pfizer, UCB, F. Breedveld Consultant for: Centocor, Schering-Plough, Amgen/Wyeth, Abbott, H. Kupper Shareholder of: Abbott, Employee of: Abbott, S. Liu Shareholder of: Abbott, Employee of: Abbott, S. Florentinus Shareholder of: Abbott, Employee of: Abbott

Background Adalimumab is usually used in combination with 15-20 mg methotrexate (MTX) weekly in early rheumatoid arthritis (RA). Lower doses of MTX have not been evaluated in controlled clinical trials. Objectives To evaluate the MTX dose-response of MTX-related toxicities in patients (pts) with early RA receiving ADA in combination with MTX. Methods CONCERTO was a 26-week (wk), phase 3, double-blind, parallel-arm study in MTX-naive pts with active RA Results Of the 395 randomized pts, 358 (91%) completed 26 wks. The safety population included 98, 100, 99, and 98 pts in the 2.5, 5, 10, and 20 mg arms, respectively. 9 pts (2.3%) discontinued study drug due to an AE that was not necessarily MTX-related. The percentage of pts with any AE was 62%, 59%, 67%, and 69% in the 2.5, 5, 10, and 20 mg arms, respectively. The overall incidence of MTX-related AEs was low. MTX-related AEs are shown in the table. Two infections in the 5 mg arm were serious AEs, appendicitis and sepsis, but did not result in study discontinuation. Infection and abnormal hair loss appeared to have a MTX dose relationship. No differences in mean change from baseline in hematocrit, neutrophil count, platelet count, ALT, or AST values were observed at wk 26 among the 4 doses of MTX. The number (percentage) of pts with ALT values >upper limit of normal (ULN) at wk 26 were 3(3%), 1(1%), 6(6%) and 6(6%) in the 2.5, 5, 10, and 20 mg arms, respectively. Regarding AST, 4(4%), 0, 3(3%), and 3(3%) in the 2.5, 5, 10, and 20 mg arms, respectively, had AST values >ULN. Conclusions Overall, MTX-related AEs were infrequent. The frequency of some AEs appeared to increase with MTX dose, suggesting the lowest effective MTX dose in combination with ADA might be used. Acknowledgements AbbVie Inc funded the study (NCT01185301). AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Essex/Schering-Plough, Novartis, Roche, Wyeth, Consultant for: AbbVie, Essex/Schering-Plough, Novartis, Roche, Wyeth, Speakers bureau: AbbVie, Essex/Schering-Plough, Novartis, Roche, Wyeth, A. Kivitz Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Janssen, Pfizer, UCB, Consultant for: BMS, Genentech, UCB, Speakers bureau: BMS, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Human Genome Sciences, Merck, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, Human Genome Sciences, Merck, Pfizer, Roche, UCB, S. Florentinus Shareholder of: AbbVie, Employee of: AbbVie, P. Karunaratne Shareholder of: AbbVie, Employee of: AbbVie Inc, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie Deutschland GmbH & Co., M. Dougados Grant/research support from: AbbVie, BMS, Merck, Novartis, Pfizer, Sanofi-Aventis, UCB, Consultant for: AbbVie, BMS, Merck, Novartis, Pfizer, Sanofi-Aventis, UCB, R. Fleischmann Grant/research support from: AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, Astra-Zeneca, BMS, Janssen, Lilly, Novartis, Consultant for: AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, Astra-Zeneca, BMS, Janssen, Lilly, Novartis

Background DE020 was a long-term, open-label (OL) roll-over study for 4 studies in the early development program of adalimumab (ADA). All 4 studies enrolled patients (pts) with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) and/or other DMARD(s). Objectives To describe long-term efficacy and safety following up to 10 years (yrs) of ADA exposure in pts with long-standing RA and previous MTX failure. Methods Adult pts with active RA who completed 1 of 4 ADA early assessment studies were eligible for enrollment in this 10-yr OL roll-over study; pts could receive supplemental DMARD therapy at the investigator’s discretion. This post hoc analysis included observed data through 10 yrs of treatment. Baseline demographics and disease characteristics reflected start of the early assessment study. Clinical and functional responses were assessed as the percentage of pts achieving ACR20/50/70 responses, DAS28(CRP) low-disease activity (LDA, ≤3.2) and remission ( Results A total of 846 pts enrolled in this OL roll-over study. At baseline of the early assessment studies, pts on average were typical of a population with long-standing and active RA: 78% were female, mean age was 55 yrs, mean disease duration was 11.1 yrs, 73% were rheumatoid factor positive, 77% received concomitant MTX, mean DAS28(CRP) was 5.7, mean HAQ-DI was 1.4, and mean CRP was 18.0 mg/L. A total of 286 (33.8%) pts completed 10 yrs of ADA treatment; AEs were the primary reason for study discontinuation (22.9%). The improvements in clinical signs and symptoms initially observed with ADA in the early assessment studies continued through an additional 10 yrs of ADA exposure (Table), with more than one-third (37%) simultaneously achieving LDA and normal function at Yr 10. No new safety signals arose following 5223.9 pt-yrs of ADA exposure, and rates of AEs were consistent with the known safety profile of TNF inhibitors: serious AEs (18.2AE/100PY), serious infections (3.1AE/100PY), TB (0.1AE/100PY), malignancies other than lymphoma and NMSC (1.3AE/100PY), and lymphoma (0.2AE/100PY). Furthermore, there was no increase in the overall mortality rate [SMR (95% CI) =0.69 (0.47, 0.98)]. Conclusions Treatment with ADA provided disease relief and improved quality of life through 10 yrs in pts with established, severe RA despite DMARD therapy. Disclosure of Interest M. Weinblatt Grant/Research support from: Abbott, Consultant for: Abbott, D. Furst Grant/Research support from: Amgen, Janssen, Roche, UCB, Consultant for: Amgen, Janssen, Roche, UCB, A. Kavanaugh Consultant for: Abbott, F. Faccin Shareholder of: Abbott, Employee of: Abbott, H. Kupper Shareholder of: Abbott, Employee of: Abbott, K. Obermeyer Shareholder of: Abbott, Employee of: Abbott, C. Birbara: None Declared

Background It is unknown which pts may be able to achieve BFDC after initially responding to combination therapy with ADA plus MTX. Objectives To identify variables predictive of 1) stable DAS28(CRP) Methods MTX-naive pts ≥18 yrs with RA 3.2, and ESR≥28 mm/hr or CRP≥1.5 mg/dL], and either >1 erosion, RF+, or anti-CCP+ were randomized to ADA+MTX or placebo (PBO)+MTX for 26 wks. Pts who achieved stable DAS28 P Results At wks 22 & 26, 44% (207/466) ADA+MTX and 24% (112/460) MTX pts achieved stable DAS28 P P =.002). Significant predictors of successful BFDC in pts who withdrew ADA included MD GA at BL and CRP levels at wk 26 (table). Conclusions Lower disease activity levels early during treatment were predictive of achieving an initial stable DAS28 Disclosure of Interest J. Smolen Grant/Research support from: Abbott, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, Consultant for: Abbott, Amgen, Astra-Zeneca, BMS, Celgene Centocor-Janssen, Glaxo, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCB, P. Emery Consultant for: Pfizer Inc, Merck, Abbott, Roche, BMS, UCB, R. Fleischmann Consultant for: Abbott, R. van Vollenhoven Grant/Research support from: Abbott, Glaxo Smithkline, Merck, Pfizer, Roche, UCB Pharma, Consultant for: Abbott, Glaxo Smithkline, Merck, Pfizer, Roche, UCB Pharma, S. Florentinus Shareholder of: Abbott, Employee of: Abbott, S. Santra Shareholder of: Abbott, Employee of: Abbott, H. Kupper Shareholder of: Abbott, Employee of: Abbott, A. Kavanaugh Grant/Research support from: Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB, Consultant for: Abbott, Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB

Background Anti-TNF plus methotrexate (MTX) is more effective than either as monotherapy. Thus far, no controlled data are available on the benefit:risk of different doses of MTX in combination with anti-TNF. Objectives To determine the effect of MTX dose in combination with adalimumab (ADA) on efficacy, pharmacokinetics, and safety in patients (pts) with early rheumatoid arthritis (RA). Methods CONCERTO was a 26-week (wk), double-blind, parallel-arm trial in MTX and biologic-naive pts with active RA [DAS28(CRP) ≥3.2; CRP ≥1.5 mg/dL or ESR ≥28 mm/hr; ≥1 erosion or RF+ or ACPA+] of Results Of the 395 randomized pts, 358 (83, 93, 93, and 89 from the 2.5, 5, 10, and 20 mg arms, respectively) completed 26 wks. At wk 26, there was a statistically significant trend in the proportion of pts achieving LDA with increasing dose of MTX in combination with OL ADA ( Table ). Significant trends were noted as early as wk 12 and sustained through wk 26. Similar results were observed for ACR50/70/90 and DAS28(CRP)/SDAI/CDAI remission. Numerically increasing trends were also apparent in the proportions achieving radiographic nonprogression and ΔHAQ-DI ≤-0.22 at wk 26. Clinical and radiographic outcomes generally appeared comparable between the 10 and 20 mg arms. ADA serum concentrations were similar in the 10 and 20 mg MTX arms, with slightly lower mean ADA serum concentrations in the 2.5 and 5 mg arms. AEs were consistent with the known profile of anti-TNF and were generally consistent between arms, occurring most frequently in the 20 mg arm. Conclusions MTX and biologic-naive pts with early RA demonstrated robust and dose-dependent clinical responses with increasing doses of MTX in combination with OL ADA through 26 wks. Interestingly, clinical responses and ADA serum concentrations generally appeared similar between the 10 and 20 mg MTX arms. Acknowledgements AbbVie Inc. sponsored the study (NCT01185301), contributed to its design, and 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 Benjamin Wolfe, PhD, of AbbVie Inc. Disclosure of Interest G. Burmester Grant/research support from: AbbVie Inc., BMS, Merck, Roche, Pfizer, UCB, Consultant for: AbbVie Inc., BMS, Merck, Roche, Pfizer, UCB, Speakers bureau: AbbVie Inc., BMS, Merck, Roche, Pfizer, UCB, A. Kivitz Grant/research support from: AbbVie Inc., Pfizer, Genentech, UCB, Amgen, Celgene, BMS, Astra-Zeneca, Janssen, Consultant for: Genentech, UCB, BMS, Speakers bureau: BMS, H. Kupper Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., U. Arulmani Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., S. Florentinus Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., S. Goss Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., S. Rathmann Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., R. Fleischmann Grant/research support from: AbbVie Inc., Pfizer, Merck, Roche, UCB, Celgene, Amgen, Astra-Zeneca, BMS, Janssen, Lilly, Novartis, Consultant for: AbbVie Inc., Pfizer, Merck, Roche, UCB, Celgene, Amgen, Astra-Zeneca, BMS, Janssen, Lilly, Novartis