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Background Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. Objectives We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. Methods PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm 3 ; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. Conclusion We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

The results suggest that high vs. low caloric food stimulation in healthy individuals can induce significant changes in resting state networks. These changes can be detected using graph theory measures in conjunction with support vector machine. Additionally, we found that the BMI affects the response of the nucleus accumbens when high caloric food is consumed.

Background:We have previously observed in RA patients that central nervous system (CNS) response to compression of a painful joint, measured using functional MRI (fMRI) of the brain as the number of blood oxygen level dependent (BOLD) signal positive voxels, is rapidly ameliorated, much earlier than any clinical response with anti-TNF treatment and a high baseline CNS pain response could predict better response to certolizumab pegol (CZP) treatment. Pre-CePRA was designed and conducted to test this effect in a randomized, placebo controlled trial of CZP and showed an incremental linear trend of DAS28 low disease activity (LDA) across study groups treated with placebo, and two CZP arms stratified as low or high pre-treatment CNS pain response.Objectives:To explore and describe pre-treatment CNS pain response associations with post treatment course of RA disease activity components and patient-physician discrepancy in global disease assessment.Methods:Patients fulfilling the 2010 ACR/EULAR classification criteria with moderate-severe disease activity (DAS-28>3.2) under stable DMARD treatment were recruited. Patients underwent an fMRI scan, stratified by a whole-brain BOLD positive voxel count threshold of 700 units and randomized to treatment with CZP or placebo in a 2:1 ratio. We descriptively assessed components of RA disease activity (Table 1 + 2). We summarized the mean results and 95% confidence intervals of these measurements at study timepoints and compared the 3 study groups at week 12 using one-way ANOVA and post-hoc Tukey tests.Results:156 eligible patients were screened and 139 (99 females, 71%) patients with moderate-high disease activity were randomized. ANOVA and pairwise comparisons showed that PGA-VAS improvement was larger in the CZP-H group whereas more similar to that in placebo in the CZP-L group. PhysGA-VAS however was similarly reduced in both CZP groups. Patients in the CZP-L group constantly rated their pain numerically higher than physicians whereas in the CZP-H group an initially higher discrepancy numerically reduced over time.Conclusion:These results suggest that improved patient global disease activity assessment could be the main driver of improved DAS-28 LDA rates with CZP treatment in patients with a high CNS pain response. Our findings indicate a potential role of fMRI imaging of the brain to further understand disease activity perception in RA patients.Figure 1.Course of disease activity components through trial timepoints. *indicates log-transformed y axis. *#x002A; Discrepancy equals Patient global minus physician global assessment.Disclosure of Interests:Hannah Schenker: None declared, Jürgen Rech Consultant of: BMS, Celgene, Novartis, Roche, Chugai, Speakers bureau: AbbVie, Biogen, BMS, Celgene, MSD, Novartis, Roche, Chugai, Pfizer, Lilly, Koray Tascilar: None declared, Melanie Hagen: None declared, Verena Schönau: None declared, Marina Sergeeva: None declared, Mageshwar Selvakumar: None declared, Laura Konerth: None declared, Jutta Prade: None declared, Sandra Strobelt: None declared, Larissa Valor: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, EIT Health, EU-IMI, DFG, Universität Erlangen (EFI), Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis,Abbvie, Speakers bureau: Novartis, Lilly, Frank Behrens Grant/research support from: Abbvie, Pfizer, Roche, Chugai, Janssen, Consultant of: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Speakers bureau: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Christoph Baerwald Consultant of: CGB received speaker or consulting fees from AbbVie, Paid instructor for: CGB received speaker or consulting fees from AbbVie, Speakers bureau: CGB received speaker or consulting fees from AbbVie, Stephanie Finzel: None declared, Reinhard Voll: None declared, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Arnd Doerfler: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Andreas Hess: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB

BackgroundTumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as one third of patients do not respond adequately to TNFi.ObjectivesWe investigated whether brain activity associated to arthritis measured by functional magnetic resonance imaging (fMRI) can function as a predictor of response to TNFiin RA patients.MethodsThis is an interim analysis of the first 50 patients of the PreCePRA trial, a multi-center, double-blind, placebo-controlled fMRI trial on patients with RA. [1] [2] Active RA patients failing csDMARDs with a DAS28-ESR >3.2 and at least three tender and/or swollen joints received a baseline brain BOLD fMRI scan upon joint compression at screening. Patients werethen randomized into a 12-week double-blinded treatment phase with placebo (arm 1) or 200mg certolizumab-pegol eow (arm 2; fMRI Bold signal>2000 voxel i.e. 2cm3, arm 3; fMRI Bold signal <2000 voxel). LDA 3mo. Primary end point was DAS28-ESR low disease activity at 12 weeks. A 12 weeks follow-up phase in which patients were switched from the placebo to the treatment arm folowed the blinded phase. fMRIwas carried out at baseline as well as after 12 and 24 weeks of or placebo.ResultsIn 31 patients (responders) baseline signal volume i.e. sum of significantly coupled voxels after the FDR thresholding was significatly higher compared to 19 patients (non-responders) (p<0.001) allowing discrimination between the two groups prior to treatment. In responders we detected an persitent decrease of the BOLD volume from baseline to week 12 and week 24 (r2=0.561) whereas the BOLD volume in non-responders persitently increased (r2=0.589).ConclusionsBased on this interim analysis we conclude that high BOLD volumes in fMRI, indicating high-level brain representation of pain in arthritis. These data represent the first encouring signal of the PreCePRA brain fMRI study supporting the concept that increased RA-related brain activity is related to response to TNFi.References Rech, J., et al., Association of brain functional magnetic resonance activity with response to tumor necrosis factor inhibition in rheumatoid arthritis. Arthritis Rheum, 2013.65(2): p. 325–33.Hess, A., et al., Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A, 2011.108(9): p. 3731–6. Disclosure of InterestNone declared

Functional magnetic resonance imaging (fMRI) visualizes brain structures at increasingly higher resolution and better signal-to-noise ratio (SNR) as field strength increases. Yet, mapping the BOLD response to distinct neuronal processes continues to be challenging. Here, we performed 3T and 7T-fMRI analysis of motor-task activation and resting-state connectivity with adjusted SNR. We then applied graph theory to analyze resting-state neuronal networks detected by fMRI after a simple motor task. Despite adjusted SNR, 7T achieved a higher functional specificity of the BOLD response than 3T-fMRI. Following the motor task, 7T-fMRI therefore enabled the detection of an ‘offline replay’ that was directly linked to brain regions associated with memory consolidation. These findings reveal how memory processing is initiated even after simple motor tasks and begins earlier than previously shown. Thus, the superior capability of 7T-fMRI to detect subtle functional dynamics promises to improve diagnostics and therapeutic assessment of neurological diseases.

Background:Tumor necrosis factor inhibitors have revolutionized the treatment of rheumatoid arthritis (RA). However, only about 50% of the patients respond well to TNF inhibitors. Therefore, markers that predict response to TNF inhibitors are valuable. Previously we demonstrated that central nervous system (CNS) response to nociceptive stimuli, measured by fMRI of the brain as blood oxygen level dependent (BOLD) signals, decreases already after 24 hours of anti-TNF administration a higher pre-treatment BOLD signal volume seems to predict clinical response to treatment with certolizumabpegol (CZP)1,2. We therefore hypothesized that the baseline volume of BOLD signal in the CNS could predict anti-TNF treatment response.Objectives:To perform a randomized placebo controlled trial in active RA patients to test the effect of TNF inhibition on arthritis induced pain activity in the brain and to test whether patients with high-level RA-related brain activation react differently to TNF-inhibitors than patients with low-level brain activation.Methods:Adult RA patients fulfilling the 2010 ACR/EULAR classification criteria with a DAS28>3.2 receiving stable DMARD treatment for at least 3 months were eligible. Patients underwent the first fMRI at screening measuring BOLD signal upon MCP joint compression and were stratified into low (< 700 units) and high (>700 units) voxel counts. Then patients were randomized to CZP or placebo with a 2:1 ratio. The second and third fMRI were performed after 12 and 24 weeks, respectively. Control stimulation was done by measuring brain activation after non-painful finger tapping.Results:156 RA patients with moderate-to-high disease activity participated in the study. In the finger tapping control, fMRI showed no significant changes in BOLD signal in the CZP-L and CZP-H arms, but a slight but significant decrease (p=0.043) was observed. After joint compression, the CZP-L group showed significant increase in the BOLD signal volume (p=0.043) in fMRI-2 as compared to fMRI-1 with no further significant changes. In contrast, in the CZP-H group, the BOLD signal volume significantly decreased (p=0.037) in fMRI-2 and continued to decrease further, p=0.007. No significant changes were observed in the placebo arm over time.Conclusion:TNF inhibition improves arthritis-related brain activity in the subgroup of RA patients with high baseline BOLD activity in the fMRI.References:[1]Hess, A.et al.PNAS (2011).[2]Rech, J. et al. Arthritis & Rheumatism (2013).Fig 1.BOLD fMRI responses to painful stimulationAcknowledgments:The study was supported by an unrestricted grant of UCB Biopharma SPRL Brussels, BelgiumDisclosure of Interests:Jürgen Rech Consultant of: BMS, Celgene, Novartis, Roche, Chugai, Speakers bureau: AbbVie, Biogen, BMS, Celgene, MSD, Novartis, Roche, Chugai, Pfizer, Lilly, Koray Tascilar: None declared, Hannah Schenker: None declared, Melanie Hagen: None declared, Marina Sergeeva: None declared, Mageshwar Selvakumar: None declared, Laura Konerth: None declared, Jutta Prade: None declared, Sandra Strobelt: None declared, Verena Schönau: None declared, Larissa Valor: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, EIT Health, EU-IMI, DFG, Universität Erlangen (EFI), Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis, Abbvie, Speakers bureau: Novartis, Lilly, Frank Behrens Grant/research support from: Abbvie, Pfizer, Roche, Chugai, Janssen, Consultant of: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Speakers bureau: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Christoph Baerwald Consultant of: CGB received speaker or consulting fees from AbbVie, Paid instructor for: CGB received speaker or consulting fees from AbbVie, Speakers bureau: CGB received speaker or consulting fees from AbbVie, Stephanie Finzel: None declared, Reinhard Voll: None declared, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Arnd Doerfler: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Andreas Hess: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB

Background:Personalization of RA treatment is not optimal due to lack of predictors. We previously demonstrated in RA patients that central nervous system (CNS) pain response to tender joint compression, measured by using functional MRI (fMRI) of the brain rapidly wanes after 24 hours of anti-TNF administration and that a higher pre-treatment BOLD signal volume seems to predict clinical response to treatment with certolizumab-pegol (CZP)1,2. We therefore hypothesized that the CNS pain response upon compression of a painful joint could predict subsequent anti-TNF treatment response.Objectives:To compare disease activity after 12-weeks of CZP treatment to that of placebo in DMARD-refractory RA patients based on pre-treatment baseline CNS pain response measured using BOLD fMRI.Methods:Adult RA patients fulfilling the 2010 ACR/EULAR classification criteria with a DAS28>3.2 under stable DMARD treatment for at least 3 months were eligible. Patients underwent fMRI scanning of the brain at screening for stratification by CNS pain response. Whole brain BOLD-signal-voxel-count of 700 units classifying between low and high, and were randomized to CZP or placebo (2:1) The primary outcome was low disease activity (LDA, DAS28 ≤3.2) after 12 weeks of treatment.Results:156 RA patients, inadequate responders to csDMARD, signed the informed consent. 139 patients (46/47, 46/49 and 42/43) (99 females, 71%) with moderate-high disease activity (mean (SD) DAS-28: 4.83 (1.03)) could be included respectively and completed the 12-week study treatment. Geometric mean (SD) numbers of baseline BOLD signal positive voxels were 559 (10), 81 (12) and 2498 (3) in the 3 arms respectively. The mean DAS28 (SD) scores after 12 weeks of study treatment were Placebo: 3.89 (1.29), CZP-L: 3.42 (1.06) and CZP-H: 3.06 (1.04). LDA was achieved in 12/47 patients (25.5 %) in placebo, 22/49 (44.9%) in the CZP-L, and 25/43, (58.1%) in the CZP-H arm. The linear effect term for the ordinal study group variable supported a linear trend of increasing CZP treatment effect with increasing baseline CNS pain response. RR (95% CI) for achieving LDA with each unit increase in treatment category over placebo was 1.79 (1.24 to 2.74, p=0.003).Conclusion:A higher pre-treatment brain activity in response to pain measured with fMRI predicts the chance of achieving low disease activity with CZP treatment.References:[1] Hess, A.et al.PNAS (2011)[2] Rech, J.et al. Arthritis & Rheumatism(2013).Acknowledgments :The study was supported by an unrestricted grant from UCB Biopharma SPRL, Brussels, BelgiumDisclosure of Interests:Jürgen Rech Consultant of: BMS, Celgene, Novartis, Roche, Chugai, Speakers bureau: AbbVie, Biogen, BMS, Celgene, MSD, Novartis, Roche, Chugai, Pfizer, Lilly, Koray Tascilar: None declared, Hannah Schenker: None declared, Marina Sergeeva: None declared, Mageshwar Selvakumar: None declared, Laura Konerth: None declared, Jutta Prade: None declared, Sandra Strobelt: None declared, Melanie Hagen: None declared, Verena Schönau: None declared, Larissa Valor: None declared, Axel Hueber Grant/research support from: Novartis, Lilly, Pfizer, EIT Health, EU-IMI, DFG, Universität Erlangen (EFI), Consultant of: Abbvie, BMS, Celgene, Gilead, GSK, Lilly, Novartis, Speakers bureau: GSK, Lilly, Novartis, David Simon Grant/research support from: Else Kröner-Memorial Scholarship, Novartis, Consultant of: Novartis, Lilly, Arnd Kleyer Consultant of: Lilly, Gilead, Novartis,Abbvie, Speakers bureau: Novartis, Lilly, Frank Behrens Grant/research support from: Abbvie, Pfizer, Roche, Chugai, Janssen, Consultant of: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, Speakers bureau: Abbvie, Pfizer, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly; Boehringer; Sandoz, José Antonio P. da Silva Grant/research support from: Pfizer, Abbvie, Consultant of: Pfizer, AbbVie, Roche, Lilly, Novartis, Christoph Baerwald Consultant of: CGB received speaker or consulting fees from AbbVie, Paid instructor for: CGB received speaker or consulting fees from AbbVie, Speakers bureau: CGB received speaker or consulting fees from AbbVie, Stephanie Finzel: None declared, Reinhard Voll: None declared, Eugen Feist Consultant of: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Speakers bureau: Novartis, Roche, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Sanofi, Arnd Doerfler: None declared, Nemanja Damjanov Grant/research support from: from AbbVie, Pfizer, and Roche, Consultant of: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Speakers bureau: AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche, Andreas Hess: None declared, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche and UCB