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ObjectivesThe inflammatory protein calprotectin (MRP8/14) has been identified as a promising biomarker of treatment response in rheumatoid arthritis (RA). Our aim was to test MRP8/14 as a biomarker of response to tumour necrosis factor (TNF)-inhibitors in the largest RA cohort to date and to compare with C-reactive protein (CRP).MethodsSerum MRP8/14 was measured in 470 patients with RA about to commence treatment with adalimumab (n=196) or etanercept (n=274). Additionally, MRP8/14 was measured in the 3-month sera of 179 adalimumab-treated patients. Response was determined using European League against Rheumatism (EULAR) response criteria calculated using the traditional 4-component (4C) DAS28-CRP and alternate validated versions using 3-component (3C) and 2-component (2C), clinical disease activity index (CDAI) improvement criteria and change in individual outcome measures. Logistic/linear regression models were fitted for response outcome.ResultsIn the 3C and 2C models, patients with RA were 1.92 (CI: 1.04 to 3.54) and 2.03 (CI: 1.09 to 3.78) times more likely to be classified as EULAR responders if they had high (75th quartile) pre-treatment levels of MRP8/14 compared with low (25th quartile). No significant associations were observed for the 4C model. When only using CRP as a predictor, in the 3C and 2C analyses, patients above the 75th quartile were 3.79 (CI: 1.81 to 7.93) and 3.58 (CI: 1.74 to 7.35) times more likely to be EULAR responders and addition of MRP8/14 did not significantly improve model fit (p values=0.62 and 0.80, respectively). No significant associations were observed in the 4C analysis. Exclusion of CRP from the outcome measure (CDAI) did not result in any significant associations with MRP8/14 (OR 1.00 (CI: 0.99 to 1.01), suggesting that the associations were due to the correlation with CRP and that there is no additional utility of MRP8/14 beyond use of CRP in patients with RA starting TNFi therapy.ConclusionBeyond correlation with CRP, we found no evidence to suggest that MRP8/14 explains additional variability in response to TNFi in patients with RA over and above CRP alone.

Background/Aims Tumour necrosis factor inhibitors (TNFi) are commonly prescribed to treat rheumatoid arthritis (RA), but response to TNFi is not universal and there are no validated pre-treatment biomarkers of treatment response at present. Proteins have many features that make them ideal potential biomarkers, as they carry out diverse biological processes, interact with drugs and can reflect post-translational modifications. This study aimed to identify protein biomarkers associated with response to TNFi in patients with RA. Methods Participants were recruited from a UK-based prospective multi-centre study of patients fulfilling either the 1987 ACR or 2010 ACR/EULAR classification for RA starting biologic treatment for the first time. Quantitative proteomics was performed using Sequential Window Acquisition of all THeoretical fragment ion spectra mass spectrometry (SWATH-MS) in sera from study participants before and after three months of treatment with the TNFi etanercept. Linear regression models were used to study the association between protein levels and the composite 28-joint count Disease Activity Score (DAS28) and its sub-components, adjusting for baseline covariates including age, biological sex disease duration and baseline DAS28. Sub-network analysis was carried out using the DIAMOnD algorithm, followed by functional enrichment analysis. Results Of the total 180 participants recruited, 134 (74.44%) were female, with a median age of 56.90 years and median pre-treatment DAS28 of 5.9. Eight individual proteins were found to be significantly associated with RA clinical outcome measures (see Table). Sub-network analysis identified the ontological theme with the strongest association as being positive regulation of response to endoplasmic reticulum (ER) stress (-log10(P) ∼ 7). Conclusion This longitudinal study of 180 patients with RA commencing etanercept has identified several putative protein biomarkers of treatment response and identified ER stress as an underlying pathway. The ER stress pathway has been previously reported to contribute to RA pathogenesis via synoviocyte proliferation and stimulation of pro-inflammatory cytokine production. Disclosure S.F. Ling: None. C. Yap: None. N. Nair: None. J. Bluett: None. A.W. Morgan: None. J.D. Isaacs: None. A.G. Wilson: None. K.L. Hyrich: None. A. Barton: None. D. Plant: None.

ObjectiveTo develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs).MethodsThe points-to-consider were developed in accordance with EULAR standardised operation procedures by a multidisciplinary task force from eight European countries, based on a systematic literature review and expert consensus. Level of evidence and strength of the points-to-consider were determined, and mean levels of agreement among the task force were calculated using a 10-point rating scale.ResultsSix overarching principles and 13 points-to-consider were formulated. The level of agreement among the task force for the overarching principles and points-to-consider ranged from 8.4 to 9.9.The overarching principles define TDM and its subtypes, and reinforce the underlying pharmacokinetic/pharmacodynamic principles, which are relevant to all biopharmaceutical classes. The points-to-consider highlight the clinical utility of the measurement and interpretation of biopharmaceutical blood concentrations and antidrug antibodies in specific clinical scenarios, including factors that influence these parameters. In general, proactive use of TDM is not recommended but reactive TDM could be considered in certain clinical situations. An important factor limiting wider adoption of TDM is the lack of both high quality trials addressing effectiveness and safety of TDM and robust economic evaluation in patients with RMDs. Future research should focus on providing this evidence, as well as on further understanding of pharmacokinetic and pharmacodynamic characteristics of biopharmaceuticals.ConclusionThese points-to-consider are evidence-based and consensus-based statements for the use of TDM of biopharmaceuticals in inflammatory RMDs, addressing the clinical utility of TDM.

BackgroundGranulocyte–macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19.MethodsIn this randomised, sequential, multicentre, placebo-controlled, double-blind study, adults aged 18–79 years (Part 1) or ≥70 years (Part 2) with severe COVID-19, respiratory failure and systemic inflammation (elevated C-reactive protein/ferritin) received a single intravenous infusion of otilimab 90 mg (human anti-GM-CSF monoclonal antibody) plus standard care (NCT04376684). The primary outcome was the proportion of patients alive and free of respiratory failure at Day 28.ResultsIn Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28versus67% who received placebo; the model-adjusted difference of 5.3% was not statistically significant (95% CI −0.8–11.4%, p=0.09). A nominally significant model-adjusted difference of 19.1% (95% CI 5.2–33.1%, p=0.009) was observed in the predefined 70–79 years subgroup, but this was not confirmed in Part 2 (n=350 randomised) where the model-adjusted difference was 0.9% (95% CI −9.3–11.2%, p=0.86). Compared with placebo, otilimab resulted in lower serum concentrations of key inflammatory markers, including the putative pharmacodynamic biomarker CC chemokine ligand 17, indicative of GM-CSF pathway blockade. Adverse events were comparable between groups and consistent with severe COVID-19.ConclusionsThere was no significant difference in the proportion of patients alive and free of respiratory failure at Day 28. However, despite the lack of clinical benefit, a reduction in inflammatory markers was observed with otilimab, in addition to an acceptable safety profile.

To detail the unmet clinical and scientific needs in the field of rheumatology. After a 2-year hiatus due to the SARS-CoV-2 pandemic, the 22nd annual international Advances in Targeted Therapies meeting brought together more than 100 leading basic scientists and clinical researchers in rheumatology, immunology, epidemiology, molecular biology and other specialties. Breakout sessions were convened with experts in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematosus and connective tissue diseases (CTDs). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research, as well as highlight recent progress in meeting formerly identified unmet needs. Clinical trial design innovation was emphasised across all disease states. Within RA, developing therapies and trials for refractory disease patients remained among the most important identified unmet needs and within lupus and spondyloarthritis the need to account for disease endotypes was highlighted. The RA group also identified the need to better understand the natural history of RA, pre-RA states and the need ultimately for precision medicine. In CTD generally, experts focused on the need to better identify molecular, cellular and clinical signals of early and undifferentiated disease in order to identify novel drug targets. There remains a strong need to develop therapies and therapeutic strategies for those with treatment-refractory disease. Increasingly it is clear that we need to better understand the natural history of these diseases, including their ‘predisease’ states, and identify molecular signatures, including at a tissue level, which can facilitate disease diagnosis and treatment. As these unmet needs in the field of rheumatic diseases have been identified based on consensus of expert clinicians and scientists in the field, this document may serve individual researchers, institutions and industry to help prioritise their scientific activities.

Summary The interferon gene signature (IGS) is derived from the expression of interferon-regulated genes and is classically increased in response to type I interferon exposure. A raised whole blood IGS has increasingly been reported in rheumatic diseases as sequencing technology has advanced. Although its role remains unclear, we explore how a raised IGS can function as a clinically relevant biomarker, independent of whether it is a bystander effect or a key pathological process. For example, a raised IGS can act as a diagnostic biomarker when predicting rheumatoid arthritis in patients with arthralgia and anti-citrullinated protein antibodies, or predicting systemic lupus erythematous (SLE) in those with antinuclear antibodies; a theragnostic biomarker when predicting response for patients receiving disease modifying therapy, such as rituximab in rheumatoid arthritis; a biomarker of disease activity (early rheumatoid arthritis, dermatomyositis, systemic sclerosis, SLE); or finally a predictor of clinical characteristics, such as lupus nephritis in SLE or disease burden in primary Sjogren's syndrome. A high IGS does not uniformly predict worse clinical phenotypes across all diseases, as demonstrated by a reduced disease burden in primary Sjogren's syndrome, nor does it predict a universally poorer response to all therapies, as shown in rheumatoid arthritis. This dichotomy highlights both the complexity of type I interferon signalling in vivo and the current lack of standardisation when calculating the IGS. The IGS as a biomarker warrants further exploration, with beneficial clinical applications anticipated in multiple rheumatic diseases.

Objective As well as being an established oncoprotein and therapeutic target in cancer, proviral integration site for Moloney murine leukemia virus 1 (Pim-1) is implicated in human autoimmunity. This study was undertaken to investigate Pim-1 and its family members as potential therapeutic targets in early rheumatoid arthritis (RA). Methods A flow cytometry assay for PIM1 transcript measurement in peripheral blood mononuclear cells from patients with early arthritis was validated and applied as a biomarker of Pim-1 activity at the cellular level. Synovial protein expression was similarly determined by multiplex immunofluorescence in tissue samples from untreated RA patients and non-RA disease controls. Functional consequences of Pim kinase family manipulation in freshly isolated CD4+ T cells from these individuals were ascertained, along with the impact of Pim inhibition on mice with collagen-induced arthritis (CIA). Results The percentage of circulating CD4+ T cells positive for PIM1 transcript by flow cytometry proved a faithful surrogate for gene expression and was significantly higher in patients with early RA than in those with other diseases. Pim-1 protein levels were similarly up-regulated in synovial CD4+ T cells from patients with early RA. Ex vivo, exposure of T cell receptor-stimulated early RA CD4+ T cells to Pim kinase inhibitors restrained their activation and proliferative capacity. Diminished production of proinflammatory cytokines (interferon-γ and interleukin-17) and an expanded CD25high FoxP3+ Treg cell fraction were also observed in exposed versus unexposed cells. Finally, administration of Pim inhibitors robustly limited arthritis progression and cartilage destruction in CIA. Conclusion Our findings indicate that Pim kinases are plausible therapeutic targets in a readily identifiable subgroup of patients with early RA. Repurposing of Pim inhibitors for this disease should be considered.

BackgroundTargeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.MethodsA systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.ResultsThe consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still’s disease, Castleman’s disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.ConclusionsThe document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

Summary Background Current rheumatoid arthritis therapies target immune inflammation and are subject to ceiling effects. Seliciclib is an orally available cyclin-dependent kinase inhibitor that suppresses proliferation of synovial fibroblasts—cells not yet targeted in rheumatoid arthritis. Part 1 of this phase 1b/2a trial aimed to establish the maximum tolerated dose of seliciclib in patients with active rheumatoid arthritis despite ongoing treatment with TNF inhibitors, and to evaluate safety and pharmacokinetics. Methods Phase 1b of the TRAFIC study was a non-randomised, open-label, dose-finding trial done in rheumatology departments in five UK National Health Service hospitals. Eligible patients (aged ≥18 years) fulfilled the 1987 American College of Rheumatology (ACR) or the 2010 ACR–European League Against Rheumatism classification criteria for rheumatoid arthritis and had moderate to severe disease activity (a Disease Activity Score for 28 joints [DAS28] of ≥3·2) despite stable treatment with anti-TNF therapy for at least 3 months before enrolment. Participants were recruited sequentially to a maximum of seven cohorts of three participants each, designated to receive seliciclib 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg administered in 200 mg oral capsules. Sequential cohorts received doses determined by a restricted, one-stage Bayesian continual reassessment model, which determined the maximum tolerated dose (the primary outcome) based on a target dose-limiting toxicity rate of 35%. Seliciclib maximum concentration (Cmax) and area under the plasma concentration time curve 0–6 h (AUC0–6) were measured. This study is registered with ISRCTN, ISRCTN36667085. Findings Between Oct 8, 2015, and Aug 15, 2017, 37 patients were screened and 15 were enrolled to five cohorts and received seliciclib, after which the trial steering committee and the data monitoring committee determined that the maximum tolerated dose could be defined. In addition to a TNF inhibitor, ten (67%) enrolled patients were taking conventional synthetic disease modifying antirheumatic drugs. The maximum tolerated dose of seliciclib was 400 mg, with an estimated dose-limiting toxicity probability of 0·35 (90% posterior probability interval 0·18–0·52). Two serious adverse events occurred (one acute kidney injury in a patient receiving the 600 mg dose and one drug-induced liver injury in a patient receiving the 400 mg dose), both considered to be related to seliciclib and consistent with its known safety profile. 65 non-serious adverse events occurred during the trial, 50 of which were considered to be treatment related. Most treatment-related adverse events were mild; 20 of the treatment-related non-serious adverse events contributed to dose-limiting toxicities. There were no deaths. Average Cmax and AUC0–6 were two-times higher in participants developing dose-limiting toxicities. Interpretation The maximum tolerated dose of seliciclib has been defined for rheumatoid arthritis refractory to TNF blockade. No unexpected safety concerns were identified to preclude ongoing clinical evaluation in a formal efficacy trial. Funding UK Medical Research Council, Cyclacel, Research into Inflammatory Arthritis Centre (Versus Arthritis), and the National Institute of Health Research Newcastle and Birmingham Biomedical Research Centres and Clinical Research Facilities.

The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM.

Age-associated B cells (ABCs) are an immune cell subset linked to autoimmunity, infection and ageing, and whose pathophysiological importance was recently highlighted using single cell synovial tissue profiling. To elucidate their pathophysiological relevance, peripheral blood (PB) ABCs from early rheumatoid arthritis (eRA) patients naïve to disease-modifying anti-rheumatic drugs (DMARDs) were compared with their synovial fluid (SF) counterparts, and to PB ABCs from psoriatic arthritis patients and healthy controls. PB and SF B-cell subsets were phenotyped by multi-parameter flow cytometry, sorted and subjected to gene expression profiling (NanoString nCounter® Immunology V2 Panel) and functional characterization (stimulated cytokine measurements by immunoassay). PB ABCs of eRA patients, which are transcriptionally distinct from those of control cohorts, express chemokine receptors and adhesion molecules, such as CXCR3, that favour homing to inflammatory sites over lymphoid tissue. These cells are an activated, class-switched B-cell subset expressing high levels of HLA-DR, co-stimulatory molecules and T-bet. Their secretion profile includes IL-12p70 and IL-23 but low levels of IL-10. High surface expression of FcRL family members, including FcRL3, furthermore suggests a role for these cells in autoimmunity. Finally, and unlike in the periphery where they are rare, ABCs are the predominant B-cell subsets in SF. These observations indicate the predilection of ABCs for inflammatory tissue in RA, where their propensity for antigen presentation and pro-inflammatory phenotype may support autoimmune pathology. Their potential as a therapeutic target therefore warrants further study.

Objectives Interventions aimed at increasing TNF-α inhibitor serum drug levels (SDLs) may improve treatment response; however, previous studies suggesting SDL cut-offs have not accounted for treatment adherence. The aim of this study was to establish the relationship between adalimumab/certolizumab SDLs and EULAR good vs non-/moderate response and to define SDL cut-offs associated with good response in fully adherent patients. Methods In a prospective observational study, 475 patients with RA were treated with certolizumab (n = 192) or adalimumab (n = 283). At baseline and 3, 6 and 12 months, patients had 28-joint DAS, self-reported treatment adherence and SDLs measured. Fully adherent patients were analysed as a subgroup. Follow-up data at 3, 6 and 12 months were analysed separately. Median SDLs were compared in good vs non-/moderate response patients and receiver operating characteristics (ROC) curves were used to establish cut-off SDLs. Results Fully adherent good responders had significantly higher median adalimumab/certolizumab SDLs compared with non-/moderate responders (P = 0.04 and P = 0.0005, respectively). ROC analysis reported 3 month non-trough adalimumab SDLs discriminated good vs non-/moderate response with an area under the curve (AUC) of 0.63 (95% CI 0.52, 0.75), with a cut-off of 7.5 mg/l being 39.1% specific and 80.9% sensitive. Similarly, 3 month non-trough certolizumab SDLs discriminated good vs non-/moderate response with an AUC of 0.65 (95% CI 0.51, 0.78), with a cut-off of 26.0 mg/l being 43.9% specific and 77.8% sensitive. Conclusion In fully adherent patients, higher SDLs are detected in good responders, suggesting that interventions to improve SDLs, such as encouraging adherence, could improve treatment response. The 3 month non-trough SDL cut-offs of 7.5 mg/l for adalimumab and 26.0 mg/l for certolizumab may be useful in clinical practice.

Background/Aims Rheumatoid arthritis (RA) is an inflammatory joint disease that can lead to disability if inflammation is not controlled. Biologic disease modifying anti-rheumatic drugs (bDMARDs), including tumour necrosis factor inhibitors (TNFi), are an effective line of therapy for moderate to severe RA. However, treatment response to TNFi is not universal and cannot be predicted from clinical factors. In this study, a protein quantitative trait loci (pQTL) study and genetic risk score (GRS) analysis were combined to identify protein-based biomarkers that are predictive of TNFi treatment response. Methods Protein expression data were generated using Sequential Window Acquisition of All Theoretical Mass Spectra (SWATH-MS) in serum samples taken from 80 RA patients about to commence therapy with etanercept. Protein expression was log2 transformed and the k-nearest neighbour model was used to impute missing values. A pQTL study was performed in patients with available imputed genome-wide genetic variation data to detect cis-acting genetic markers (p < 1E-05). GRS for pQTLs were subsequently tested in 1,430 RA patients with available genome-wide genetic and TNFi treatment response data (improvement in DAS28 between pre-treatment and 3/6 months on drug). The GRS analysis was adjusted for baseline disease activity, sex, conventional synthetic DMARD co-therapy and the first 10 principal components, calculated from the genetic datasets. Results Following imputation, expression levels for 271 proteins were analysed in 69 RA patients with available genotype data. 514 cis-pQTLs were found for 16 proteins. GRS for the proteins Apolipoprotein(a) (UniProt ID P08519, p = 0.017) and Carboxypeptidase N subunit 2 (P22792, p = 0.027) were found to be modestly associated with treatment response; however, scores for both proteins explained less than 1% of the variance in DAS28 difference between time-points. Conclusion This study identified two protein-based genetic biomarkers of treatment response to TNFi. However, genetic scores based on these proteins are unlikely to be useful predictors, explaining little variance in on-treatment disease activity. Disclosure Z. Li: None. S.F. Ling: None. N. Nair: None. J.D. Isaacs: None. K.L. Hyrich: Honoraria; Abbvie. A.W. Morgan: None. A.G. Wilson: None. A. Barton: None. D. Plant: None.

Background/Aims Rituximab is widely used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) but clinical response varies. Efficacy is determined by the efficiency of depletion, which may depend on a variety of Fc gamma receptor (FcγR)-dependent mechanisms. Previous research was limited by complexity of the FCGR locus, not integrating copy number variation with functional SNP, and small sample size. Here, we aimed to assess the effect of the full range of FcγRs variants on depletion, clinical response and functional effect on NK-cell-mediated killing in two rheumatic diseases with a view to personalised B-cell depleting therapies. Methods A prospective longitudinal study was conducted in 873 patients (RA = 611; SLE=262) from four cohorts (BSRBR-RA, BILAG-BR, Leeds RA and Leeds SLE Biologics). For RA, the outcome measures were 3C-DAS28CRP and 2C-DAS28CRP at 6 (+/-3) months post-rituximab (adjusted for baseline DAS28). For SLE, major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using a commercial multiplex ligation-dependent probe amplification. Median NK cell FcγRIIIa expression (CD3-CD56+CD16+) and NK-cell degranulation (CD107a) in the presence of rituximab-coated Daudi/Raji B-cell lines were assessed using flow cytometry. Results In RA, for FCGR3A, carriage of V allele (coefficient -0.25 [SE 0.11]; p = 0.02) and increased copies of V allele (-0.20 [0.09]; p = 0.02) were associated with better 2C-DAS28 response. Irrespective of FCGR3A genotype, increased gene copies were associated with a better response. In SLE, 177/262 (67.6%) achieved BILAG response (MCR=34.4%; Partial=33.2%). MCR was associated with increased copies of FCGR3A-158V allele, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). Of patients with B-cells data in the combined cohort, 236/413 (57%) achieved complete depletion post-rituximab. Only homozygosity for V allele and higher copies of FCGR3A V allele were associated with increased odds of depletion. Patients with complete depletion had higher NK cell FcγRIIIa expression at rituximab initiation than those with incomplete depletion (p = 0.04) and this higher expression was associated with improved EULAR response in RA. Moreover, for FCGR3A, degranulation activity was increased in V allele carriers vs FF genotype in the combined cohort; p = 0.02. Conclusion FcγRIIIa is the major low affinity FcγR and increased copies of the FCGR3A-158V allele, encoding the allotype with a higher affinity for IgG1, was associated with clinical and biological responses to rituximab in two autoimmune diseases. This was supported by functional data on NK cell-mediated cytotoxicity. In SLE, increased copies of the FCGR2C-ORF allele was also associated with improved response. Our findings indicate that enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping could stratify patients for optimal treatment protocols. Disclosure M. Md Yusof: None. J. Robinson: None. V. Davies: None. D. Wild: None. M. Morgan: None. J. Taylor: None. Y. El-Sherbiny: None. D. Morris: None. L. Liu: None. A. Rawstron: None. M. Buch: None. D. Plant: None. H. Cordell: None. J. Isaacs: None. I. Bruce: None. P. Emery: Grants/research support; PE has received consultancy fees and funding for research from Roche within the last 3 years. A. Barton: None. T. Vyse: None. J. Barrett: None. E. Vital: Grants/research support; EMV has received consultancy fees and funding for research from Roche within the last 3 years. A. Morgan: None.

Background No reliable biomarkers to predict response to TNF inhibitors (TNFi) in RA patients currently exist. The aims of this study were to replicate changes in gene co-expression modules that were previously reported in response to TNFi therapy in RA; to test if changes in module expression are specific to TNFi therapy; and to determine whether module expression transitions towards a disease-free state in responding patients. Method Published transcriptomic data from the whole blood of disease-free controls (n = 10) and RA patients, treated with the TNFi adalimumab (n = 70) or methotrexate (n = 85), were studied. Treatment response was assessed using the EULAR response criteria following 3 or 6 months of treatment. Change in transcript expression between pre- and post-treatment was recorded for previously defined modules. Linear mixed models tested whether modular expression after treatment transitioned towards a disease-free state. Results For 25 of the 27 modules, change in expression between pre- and post-treatment in the adalimumab cohort replicated published findings. Of these 25 modules, six transitioned towards a disease-free state by 3 months (P Conclusion This study provides independent validation of changes in module expression in response to therapy in RA. However, these effects are not specific to TNFi. Further studies are required to determine whether specific modules could assist molecular classification of therapeutic response.

BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research. ispartof: LANCET vol:397 issue:10271 pages:305-317 ispartof: location:England status: published

Cure is the aspirational aim for the treatment of all diseases, including chronic inflammatory conditions such as rheumatoid arthritis (RA); however, it has only been during the twenty-first century that remission, let alone cure, has been a regularly achievable target in RA. Little research has been carried out on how to cure RA, and the term 'cure' still requires definition for this disease. Even now, achieving a cure seems to be a rare occurrence among individuals with RA. Therefore, this Review is aimed at addressing the obstacles to the achievement of cure in RA. The differences between remission and cure in RA are first defined, followed by a discussion of the underlying factors (referred to as drivers) that prevent the achievement of cure in RA by triggering sustained immune activation and effector cytokine production. Such drivers include adaptive immune system activation, mesenchymal tissue priming and so-called 'remote' (non-immune and non-articular) factors. Strategies to target these drivers are also presented, with an emphasis on the development of strategies that could complement currently used cytokine inhibition and thereby improve the likelihood of curing RA.

Aim: TNF inhibitor drugs are a treatment option for rheumatoid arthritis, but response is not universal. Response is typically measured using the composite 4-component (4C) disease activity score 28 (DAS28) which contains more subjective measures. This study used a validated 2-component (2C) DAS28 score to determine whether SNPs associated with response were replicated in the UK population. Materials & methods: A literature review identified TNF inhibitor response SNPs. Linear regression was conducted to replicate associations with 4C or 2C-DAS28 response. Results: Eighteen independent SNPs were analyzed in 1828 patients. One and four associations with 4C and 2C-DAS28 response respectively were identified (p ≤ 0.05). Conclusion: Further genetic associations were replicated using the 2C-DAS28 which may reflect the objective nature of 2C-AS28.

Tolerogenic dendritic cell (tolDC) therapies aim to restore self-tolerance in patients suffering from autoimmune diseases. Phase 1 clinical trials with tolDC have shown the feasibility and safety of this approach, but have also highlighted a lack of understanding of their distribution in vivo. Fluorine-19 magnetic resonance imaging (19F-MRI) promises an attractive cell tracking method because it allows for detection of 19F-labelled cells in a non-invasive and longitudinal manner. Here, we tested the suitability of nanoparticles containing 19F (19F-NP) for labelling of therapeutic human tolDC for detection by 19F-MRI. We found that tolDC readily endocytosed 19F-NP with acceptable effects on cell viability and yield. The MRI signal-to-noise ratios obtained are more than sufficient for detection of the administered tolDC dose (10 million cells) at the injection site in vivo, depending on the tissue depth and the rate of cell dispersal. Importantly, 19F-NP labelling did not revert tolDC into immunogenic DC, as confirmed by their low expression of typical mature DC surface markers (CD83, CD86), low secretion of pro-inflammatory IL-12p70, and low capacity to induce IFN-γ in allogeneic CD4+ T cells. In addition, the capacity of tolDC to secrete anti-inflammatory IL-10 was not diminished by 19F-NP labelling. We conclude that 19F-NP is a suitable imaging agent for tolDC. With currently available technologies, this imaging approach does not yet approach the sensitivity required to detect small numbers of migrating cells, but could have important utility for determining the accuracy of injecting tolDC into the desired target tissue and their efflux rate.

Summary Autoimmunity is currently managed with generalised immunosuppression, which is associated with serious side-effects such as infection and cancer. An ideal treatment strategy would be to induce immune tolerance—ie, to reprogramme the immune system to stop recognising the host itself as a threat. Drug-free remission should follow such an intervention, representing a change in the approach to the treatment of autoimmune disease. Tolerance induction is achievable in animal models of autoimmunity but translation to the clinic has been slow. Nonetheless, progress has been made—eg, restoration of therapeutic responsiveness and drug-free remission have been achieved with stem cell transplantation in refractory autoimmunity, and significant delays in onset of type 1 diabetes in individuals at high risk have been achieved following a brief treatment with anti-CD3 monoclonal antibody. In the future, antigen-specific interventions should provide highly targeted, personalised approaches, avoiding generalised immunosuppression entirely. Such trials have already started, using both direct autoantigenic peptide administration, cellular therapies, and other modalities. In this Series paper, we discuss the history of immune tolerance induction with a focus on rheumatological disease while also highlighting essential data from other specialties. We propose key unanswered questions, which will be covered in other papers in this Series.

Background Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated. Methods Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization. Results Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1–134.1) versus 19.2 U/L (8.5–29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1–63.7), 90.3 (51.9–128.7), and 115.6 U/L (91.6–139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies. Conclusions In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases. Trial Registration NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364. Electronic supplementary material The online version of this article (10.1007/s10620-020-06560-4) contains supplementary material, which is available to authorized users.

Over recent decades, treatment options for inflammatory diseases such as rheumatoid arthritis (RA) have increased dramatically. These range from orally available steroids and conventional synthetic disease modifying drugs (csDMARDs) to parenteral biological therapies (bDMARDs). Most recently, with advances in our understanding of cell signalling pathways, we can target small molecules associated with intracellular signal transduction.1 These orally available drugs form a new category of treatment known as targeted synthetic DMARDs (tsDMARDs).2 The first drug class within this category to gain marketing authorisations are the Janus Kinase inhibitors (JAK inhibitors or jakinibs).3 By inhibiting Janus Kinases, these drugs inhibit signalling through a variety of cytokine and haematopoietic growth factor receptors.4 There are four members of the JAK family, and all are receptor-associated tyrosine kinases (JAK1, JAK2, JAK3 and TYK2).4 Tyrosine kinases are phosphotransferase enzymes which transphosphorylate tyrosine residues on other proteins. This process can trigger (usually) or hinder (less commonly) the activity of the target protein, often as part of an enzymatic cascade.5,6 All JAKs work in a similar manner, usually in association with type I and II cytokine receptors, which are intrinsic elements of immune responses.7,8 Consequently, inhibiting these enzymes has great potential for controlling unwanted or overactive immune pathways.9 It is important to understand both the role of cytokines in regulating immune function and the JAK-STAT (signal transducer and activators of transcription) pathways in order to fully appreciate the true value of JAK inhibition, especially in relation to its role in diseases such as RA.5,8 Cytokines form a large family of (mostly) soluble mediators, which are responsible for controlling a wide range of bodily processes, from growth to haematopoiesis. They play an important role in both innate and adaptive arms of the immune response.9,10 Unsurprisingly, an imbalance of their activity is associated with a number of different autoimmune diseases and malignancies.11,12 Anti-inflammatory agents such as glucocorticoids, as well as csDMARDs, can impair cytokine secretion and downstream activities, but long-term use and off-target effects result in unwanted side effects, such as osteopenia and liver toxicity.13,14 Some bDMARDs (TNF inhibitors, IL-6 receptor blockers) target pro-inflammatory cytokines themselves, with significant benefit. These bDMARDs have contributed to the revolution in the management of autoimmunity but they are expensive, require parenteral administration, as well as co-prescription with methotrexate (MTX) to achieve optimal outcomes.15–17 Many patients with RA prefer oral drug therapy, triggering an unmet need for potent oral medications.17 Using synthetic, orally available drugs to target intracellular signalling pathways has the potential to meet this need, potentially matching biological efficacy within a pill.2–6 The JAK-STAT pathways provided rational targets due to their involvement in cytokine signalling, including cytokines thought to be active in RA, such as interleukins, interferons and growth factors.5,8

The goal of this narrative review was to summarize immunogenicity data of biosimilars or biosimilar candidates for rheumatic diseases, plaque psoriasis, or inflammatory bowel disease (IBD), available in peer-reviewed publications or regulatory documents. PubMed records and regulatory documents were searched for immunogenicity data of TNFα or CD20 inhibitor biosimilars or biosimilar candidates. Data collected included the proportion of patients positive for anti-drug antibodies (ADAbs), proportion with neutralizing antibodies (nAbs) among ADAb-positive patients, ADAb/nAb assay characteristics, cross-reactivity, and the effects of ADAbs on pharmacokinetics, pharmacodynamics, efficacy, and safety. We identified eight biosimilars or biosimilar candidates for adalimumab (BI 695501, SB5, ABP 501, GP2017, PF-06410293, MSB-11022, FKB-327, ZRC-3197) four for etanercept (SB4, GP2015, CHS-0214, LBEC0101), and three each for infliximab (SB2, CT-P13, GP1111) and rituximab (CT-P10, GP2013, PF-05280586) with immunogenicity data. Randomized, head-to-head trials with reference products varied in design and methodology of ADAb/nAb detection. The lowest proportions of ADAb-positive (0–13%) and nAb-positive patients (0–3%) were observed in the trials of etanercept and its biosimilars, and the highest with adalimumab, infliximab, and their biosimilars (ADAbs: ≤ 64%; nAbs: ≤ 100%). The most common method of ADAb detection was electrochemiluminescence, and ADAb positivity was associated with nominally inferior efficacy and safety. Overall, there were no significant immunogenicity differences between biosimilars and reference products. However, there are many discrepancies in assessing and reporting clinical immunogenicity. In conclusion, immunogenicity data of biosimilars or biosimilar candidates for TNFα or CD20 inhibitors were collected in trials that varied in design and procedures for ADAb/nAb detection. In general, immunogenicity parameters of biosimilars are similar to those of their reference products. Electronic supplementary material The online version of this article (10.1007/s40259-019-00394-x) contains supplementary material, which is available to authorized users.

The first EULAR provisional recommendations on the management of rheumatic and musculoskeletal diseases (RMDs) in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), largely based on expert opinion, were published in June 2020. Since then, an unprecedented number of clinical studies have accrued in the literature. Several SARS-CoV-2 vaccines have been approved for population-wide vaccination programmes in EULAR-affiliated countries. Studies regarding vaccination of patients with (inflammatory) RMDs have released their first results or are underway.EULAR found it opportune to carefully review to what extent the initially consensus expert recommendations stood the test of time, by challenging them with the recently accumulated body of scientific evidence, and by incorporating evidence-based advice on SARS-CoV-2 vaccination. EULAR started a formal (first) update in January 2021, performed a systematic literature review according to EULAR’s standard operating procedures and completed a set of updated overarching principles and recommendations in July 2021. Two points to consider were added in November 2021, because of recent developments pertaining to additional vaccination doses.

Despite the success of TNF-inhibitor therapy in rheumatoid arthritis treatment, up to 40% of patients fail to respond adequately. This study aimed to identify transcriptome-based biomarkers of adalimumab response in rheumatoid arthritis (RA) to aid timely switching in non-responder patients and provide a better mechanistic understanding of the pathways involved in response/non-response.The Affymetrix Human Transcriptome Array 2.0 (HTA) was used to measure the transcriptome in whole blood at pre-treatment and at 3 months in EULAR good- and non-responders to adalimumab therapy. Differential expression of transcripts was analysed at the transcript level using multiple linear regression. Differentially expressed genes were validated in independent samples using OpenArray™ RT-qPCR.In total, 813 transcripts were differentially expressed between pre-treatment and 3 months in adalimumab good-responders. No significant differential expression was observed between good- and non-responders at either time-point and no significant changes were observed in non-responders between time-points. OpenArray™ RT-qPCR was performed for 104 differentially expressed transcripts in good-responders, selected based on magnitude of effect or p value or based on prior association with RA or the immune system, validating differential expression for 17 transcripts.An early transcriptome signature of DAS28 response to adalimumab has been identified and replicated in independent datasets. Whilst treat-to-target approaches encourage early switching in non-responsive patients, registry evidence suggests that this does not always occur. The results herein could guide the development of a blood test to distinguish responders from non-responders at 3 months and support clinical decisions to switch non-responsive patients to an alternative therapy.

ObjectivesTo update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19.MethodsAccording to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting.ResultsWe updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapyConclusionsGrowing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

B cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays.We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A-158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics.One Sentence SummaryThe high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease

Background:Tumour necrosis factor inhibitors (TNFi) although effective in the treatment of rheumatoid arthritis (RA), show a variable response rate. Therefore, there is a need to identify treatment response predictors to inform therapy selection in order to practise precision medicine. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs that can alter gene expression by regulating messenger RNA translation. There is evidence for miRNA involvement in RA pathogenesis and they may serve as a useful biomarker of treatment response.Objectives:To identify miRNAs associated with response to TNFi in RA.Methods:Biologic naïve patients were selected from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), a prospective multi-center UK study investigating treatment response biomarkers to TNFi with a primary outcome measure of change in DAS28 scores. Patients were stratified into European League Against Rheumatism (EULAR) good or non-responders based on their 3 or 6-month DAS28-CRP score.Pre-treatment and 3-month post-treatment serum samples were substrates for miRNA profiling, which was conducted by FIRALIS using the HTG EdgeSeq miRNA whole transcriptome V2 targeted sequencing assay. Linear modelling using R package limma compared miRNA expression at (i) pre-treatment and at three-months, in EULAR good-responders and non-responders (ii) longitudinal change in expression from pre-treatment to three-months in EULAR good and non-responders.A literature search was conducted to identify miRNAs associated with RA as a diagnostic and/or treatment response predictor. Data on these miRNAs were extracted from the miRNAs identified in the serum samples. A correction for multiple testing was applied to statistical tests.Results:A total of 54 patients were analysed; of these, 35 (65%) were female, median disease duration [inter-quartile range] was 6 years [2 – 14] (n=51), and 44/51 (86%) patients were on a concomitant disease modifying anti-rheumatic drug. Of the 54 patients, 39 (72%) were classified as EULAR good-responders and 15 (28%) as non-responders. 1880 miRNAs were detected in the serum samples. 64 miRNAs were identified to be associated with RA from the literature, of which, 26 were identified in the serum samples tested.No difference in pre-treatment or three-month miRNA levels was seen comparing EULAR good-responders and non-responders (FDR p). There was a significant differential expression of four miRNAs at 3-months in good-responders compared with pre-treatment levels; miR-125a-3p (downregulated, p-value 0.002), miR-149-3p (upregulated, p-value 0.004), miR-766-3p (downregulated, p-value 0.008), miR-146b-5p (upregulated, p-value 0.006). No significant differences were observed between 3-months and baseline in non-responders.Conclusion:Although no pre-treatment miRNAs were associated with TNFi response, changes in the levels of four miRNAs were detected at 3-months compared to baseline in EULAR good-responders. Future work involves validation of these samples in a larger patient cohort and analysing miRNA levels at 6 and 12 months. Replication and validation of these results in larger studies are required to analyse the role of miRNAs in stratifying EULAR good-responders from non-responders at three-months, and as treatment response predictors to TNFi in RA.Acknowledgements:Joint last-author: Dr. Darren PlantDisclosure of Interests:Trixy David: None declared, Nisha Nair: None declared, James Oliver: None declared, Eric Schordan: None declared, Hüseyin Firat: None declared, Kimme Hyrich Consultant of: consultancy/honoraria from AbbVie, Grant/research support from: Pfizer, UCB, BMS, Ann Morgan: None declared, Anthony G Wilson: None declared, John D Isaacs Speakers bureau: consultancy/speaker fees from AbbVie, Gilead, Roche, UCB, Consultant of: consultancy/speaker fees from AbbVie, Gilead, Roche, UCB, Grant/research support from: Pfizer, Darren Plant: None declared, Anne Barton: None declared

Objectives Evidence suggests that factors beyond disease activity associate with functional disability in RA. The primary study objective was to explore associations between comorbidities, sociodemographic factors and functional outcomes at five and 10 years. Methods RA patients from two UK prospective cohorts were grouped into low ( Results In total, 2701 RA patients were recruited (mean age 56.1 years, 66.9% female). A total of 1718 (63.4%) had five-year and 820 (30.4%) 10-year follow-up data. In multivariable analysis, no association was found between RDCI and HAQ ≥ 1.5 at five or 10 years. Sociodemographic factors (increased age at disease onset, female gender, minority ethnicity) were associated with higher odds of HAQ ≥ 1.5 at five and 10 years, with worse deprivation additionally associated with HAQ ≥ 1.5 at 10 years (OR 0.79, 95% CI: 0.69, 0.90). Conclusion Comorbidities at baseline have not been found to be associated with worse RA functional outcome in the long-term. On the other hand, sociodemographic factors, independently of disease measures, are associated with worse functional outcome in RA at five and 10 years, in models adjusting for comorbidity burden. Tailoring management interventions according to not only clinical disease parameters but also patient sociodemographic factors may improve long-term outcomes including functional disability.