Peripheral quantitative computed tomography in the assessment of bone mineral density in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients

Introduction Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. Methods Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. Results We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p<0.017 after Bonferroni’s correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. Conclusions BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Anti-Inflammatory Effects of Endogenously Released Adenosine in Synovial Cells of Osteoarthritis and Rheumatoid Arthritis Patients

Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.

TNF drives AKI-to-CKD transition downstream of proximal tubule EGFR

Inflammation is a key driver of fibrosis and progression of human chronic kidney disease (CKD), often caused or worsened by acute kidney injury (AKI-to-CKD transition). Sustained epidermal-growth-factor-receptor (EGFR) activation in injured proximal-tubule-cells (PTC) is strongly pro-inflammatory and has emerged as a key paradigm in AKI-to-CKD transition and CKD progression. Whether the key Type 1 inflammatory cytokine tumor-necrosis-factor (TNF) has a role in CKD progression and how TNF relates to the PTC-EGFR pathway is unknown, but retrospective analysis of patients using TNF biologic inhibitors suggests that TNF inhibition reduces incident CKD and CKD progression in humans. Here, we compared mice treated with control, TNF inhibition (murine etanercept, soluble TNF-scavenger), EGFR inhibition (erlotinib, EGFR-kinase-inhibitor) or their combination in an AKI-to-CKD bilateral renal-ischemia-reperfusion model. TNF- or EGFR-inhibition did not affect initial kidney injury, but significantly overlapped in reducing kidney injury-upregulated cytokines and equally strongly reduced kidney fibrosis, while combination treatment had no additive effect, suggesting EGFR and TNF act in the same fibrosis pathway. TNF exerted its profibrotic effects downstream of PTC-EGFR, as TNF-inhibition did not affect tubular EGFR activation in vivo. Consistent with this, TNF PTC-KO did not reduce inflammation or fibrosis, suggesting that PTC-derived TNF does not contribute to profibrotic PTC-EGFR activation. Kidney single-cell RNAseq analysis identified macrophages, dendritic cells and T cells, but not PTC, as dominant TNF sources after AKI. Only EGFR inhibition, but not TNF inhibition significantly blocked injury-induced kidney ingress of chemokine-receptor-2 (CCR2) positive cells and accumulation of macrophages, however, macrophage numbers where equal one month after AKI independent of treatment. Thus EGFR inhibition reduces ingress and accumulation of TNF-producing proinflammatory and profibrotic immune cells whereas TNF inhibition mechanistically largely acts by neutralizing their proinflammatory and profibrotic activities. Our work provides mechanistic background to motivate examination of TNF pathway inhibition in human AKI or CKD.

OP0117 LONGITUDINAL CHANGE IN THE CENTRAL NERVOUS SYSTEM PAIN RESPONSE AFTER TREATMENT WITH CERTOLIZUMAB OR PLACEBO. A POST-HOC ANALYSIS FROM THE PRECEPRA TRIAL

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

Synoviocyte-targeted therapy synergizes with TNF inhibition in arthritis reversal

Fibroblast-like synoviocytes (FLS) are joint-lining cells that promote rheumatoid arthritis (RA) pathology. Current disease-modifying antirheumatic agents (DMARDs) operate through systemic immunosuppression. FLS-targeted approaches could potentially be combined with DMARDs to improve control of RA without increasing immunosuppression. Here, we assessed the potential of immunoglobulin-like domains 1 and 2 (Ig1&2), a decoy protein that activates the receptor tyrosine phosphatase sigma (PTPRS) on FLS, for RA therapy. We report that PTPRS expression is enriched in synovial lining RA FLS and that Ig1&2 reduces migration of RA but not osteoarthritis FLS. Administration of an Fc-fusion Ig1&2 attenuated arthritis in mice without affecting innate or adaptive immunity. Furthermore, PTPRS was down-regulated in FLS by tumor necrosis factor (TNF) via a phosphatidylinositol 3-kinase–mediated pathway, and TNF inhibition enhanced PTPRS expression in arthritic joints. Combination of ineffective doses of TNF inhibitor and Fc-Ig1&2 reversed arthritis in mice, providing an example of synergy between FLS-targeted and immunosuppressive DMARD therapies.

P257 Real-world evidence of TNF inhibition in axial spondyloarthritis: can we generalise the results from clinical trials?

Background The development and utility of management guidelines assumes that clinical trial findings are generalisable. Seldom is data available to test this. We aimed to determine, in the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS), the proportion of patients commencing TNF inhibition (TNFi) that would/would not have been eligible for clinical trials that led to TNFi treatment guidelines, and whether treatment response differed between the trials and this real-world population. Methods Biologic-naïve spondyloarthritis patients were recruited from across Great Britain. Data was obtained from clinical records, and participants completed postal questionnaires. Participant characteristics were extracted from the placebo-controlled randomised trials in the NICE Health Technology Assessment: TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis (TA383). Descriptive statistics were used to examine differences, including treatment response (ASAS-20), between BSRBR-AS participants who would/would not have been eligible for the clinical trials, and the trial participants. Results 816/2420 (34%) BSRBR-AS participants were commencing TNFi. They were younger (mean age 44 versus 50yrs) with shorter disease duration (15 versus 22yrs), more active disease (BASDAI 6.4 versus 4.0), and poorer function (BASFI 6.2 versus 3.8). Fourteen clinical trials were identified. Compared to trial populations, fewer BSRBR-AS participants were male (67% versus 71%; difference: -4.1% (95%CI: -7.8%, -0.4%)) and fewer were HLA-B27 positive (76% versus 82%; difference: -6.6% (-10.6%, -2.6%)). BSRBR-AS participants were 6yrs older than trial participants, with longer symptom duration. They reported similar disease activity (BASDAI: 6.4 versus 6.2; difference 0.2 (-0.3, 0.7)), although significantly poorer function (BASFI: 6.2 versus 5.1; difference 1.1 (0.5, 1.8)) and spinal mobility (BASMI: 4.2 versus 3.3; difference 1.0 (0.8, 1.1)). Only 333 (41%) of BSRBR-AS participants commencing TNFi would have been eligible for any of the relevant trials. Ten trials reported ASAS20 response criteria, and 864/1401 participants reported a positive treatment response (61.7%). Follow-up data was available for 318 (39%) BSRBR-AS participants, of whom 163 (51.3%) achieved an ASAS20 treatment response (difference: 10.4% (4.4%, 16.5%)). There was no difference in ASAS20 response between those who would/would not have been eligible for clinical trials (50% versus 52%; difference 2.0% (-9.4%, 13.4%)). Conclusion In this real-world population, although the likelihood of meeting response criteria was unrelated to factors determining trial eligibility, the proportion of patients responding to TNFi was lower than in the clinical trial literature. Could this be explained by selection bias? Although fewer BSRBR-AS participants provided follow-up data than in the clinical trials, to account for the observed difference participants lost to follow-up would have to be one-third more likely to achieve ASAS20 response than those who provided follow-up data. We believe this is unlikely. These findings have important implications for the generalisability of trial results, and also for the cost-effectiveness of TNFi agents. Disclosures G.T. Jones: Grants/research support; GTJ is/was a grant holder for research funded by Pfizer, AbbVie, UCB and Celgene., GTJ is/was involved in research that received financial support from Novartis. L.E. Dean: Grants/research support; LED is/was involved in research that received financial support from Pfizer, AbbVie, UCB and Novartis. E. Pathan: None. G.J. Macfarlane: Grants/research support; GJM is/was a grant holder for research funded by Pfizer, AbbVie, UCB and Celgene., GJM is/was involved in research that received financial support from Novartis.