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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.

Natural language processing (NLP) is a form of machine learning which enables the processing and analysis of free text. When used with medical notes, it can aid in the prediction of patient outcomes, augment hospital triage systems, and generate diagnostic models that detect early-stage chronic disease. These applications may be particularly useful in critical care where there is more patient data to analyse and prediction of patient mortality is routine. In addition to its natural language understanding (NLU) ability, NLP can also accomplish natural language generation (NLG), providing an interface for patients to ask questions and access relevant information in the form of chatbots. There are challenges to the use of NLP in medicine. Unbiased training data is an essential requirement if the conclusions reached by NLP algorithms are to be trusted. Clinicians will need training to understand how NLP can be safely used as part of routine practice. In the future, NLP applications are likely to be integrated into the clinical environment, working with clinicians to suggest problem lists, as patient facing applications to streamline triage systems, and as a tool to interrogate vast amounts of free text data, which could contribute to personalised, up to the minute evidence based medicine.

OBJECTIVE: To study the temperature and haemodynamic effects of room versus body temperature 20% albumin fluid bolus therapy (FBT). DESIGN: Single-centre, prospective, before–after trial. SETTING: A tertiary intensive care unit (ICU) in Australia. PARTICIPANTS: Sixty ventilated post-cardiac surgery patients. INTERVENTION: Room versus body temperature 100 mL 20% albumin FBT. MAIN OUTCOME MEASURES: We recorded haemodynamic data from FBT start to 30 minutes after FBT. The cardiac index (CI) response was defined by a CI increase > 15%, and the mean arterial pressure (MAP) response was defined by a MAP increase > 10%. OUTCOMES: Immediately after FBT, median blood temperature decreased by -0.1°C (interquartile range [IQR], -0.1 to 0.0°C) with room temperature albumin versus 0.0°C (IQR, -0.1 to 0.0°C) with body temperature albumin (P < 0.001). The CI or MAP responses were similar. There was, however, a time and study group interaction for blood temperature (P < 0.001) for absolute and relative changes. In addition, mean pulmonary arterial pressure (PAP) (P = 0.002) increased more with body temperature albumin and remained higher for most of the observation period. CONCLUSION: Compared with room temperature albumin FBT, body temperature 20% albumin FBT prevents FBT-associated blood temperature fall and increases mean PAP. However, CI and MAP changes were the similar between the two groups, implying that fluid temperature has limited haemodynamic effects in these patients.

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.

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 The treatment of rheumatoid arthritis (RA) has improved since the introduction of targeted biological disease-modifying antirheumatic drugs (bDMARDs), such as adalimumab. However, no treatment options for RA are universally effective. Psychological factors may have an important role in treatment response. Published data reported that pre-treatment psychological variables such as an increased treatment necessity belief correlated with better adherence to adalimumab in RA patients. This current study aimed to investigate whether psychological factors correlate with change in 4V-DAS28-CRP as well as subcomponents of the score in adalimumab-treated RA patients. Methods Psychological, clinical and demographic data and DAS28 scores were collected pre-treatment, and at 3,6, and 12-months post-treatment, as part of a prospective national study, BRAGGSS. Sixteen pre-treatment clinical and psychological variables were tested for association with treatment response at 3 and 12 months. Multiple linear regression models were analysed and a Bonferroni corrected p-value of < 0.003 was applied at each interval to assess significance. Results Data was available for 501 patients at 3 months follow up. Pre-treatment Beliefs about Medicine Questionnaire (BMQ) scores with regards to treatment necessity (P = 0.001), and two domains of the Illness Perception Questionnaire (IPQ), which were treatment belief and treatment control (P = 0.0001), correlated with the change in DAS28 by 3 months (Table 1). At 12 months, data were available for 362 patients. The treatment belief domain of the pre-treatment Illness Perception Questionnaire correlated with the change in tender joint count (P = 0.001) (Table 1). At 12 months no other sub-components correlated with the psychological variables. Conclusion Pre-treatment scores with regards to Illness Perception and Beliefs about Medicine correlated with 4V-DAS28-CRP response at 3 months. Of the subcomponents of DAS28, the psychological variables showed the highest correlation with tender joint count; as the tender joint count receives the highest weighting in the 4 variable DAS28 score, this may confound the assessment of treatment response. It will be necessary to undertake further analyses to assess the predictive value of these potentially modifiable psychological variables identified, but to also understand factors contributing to these psychological scores, such as the role of severe disease itself on psychological beliefs. Disclosure N. Raza: None. N. Nair: None. D. Plant: None. K. Hyrich: None. A.W. Morgan: None. J. Isaacs: None. A.G. Wilson: None. A. Barton: None.

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 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.

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.

BACKGROUND: Studies in critically ill patients suggest a relationship between mechanical power (an index of the energy delivered by the ventilator, which includes driving pressure, respiratory rate, tidal volume and inspiratory pressure) and complications. OBJECTIVE: We aimed to assess the association between intra-operative mechanical power and postoperative pulmonary complications (PPCs). DESIGN: Post hoc analysis of a large randomised clinical trial. SETTING: University-affiliated academic tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. PATIENTS: Adult patients undergoing major noncardiothoracic, nonintracranial surgery. INTERVENTION: Dynamic mechanical power was calculated using the power equation adjusted by the respiratory system compliance (CRS). Multivariable models were used to assess the independent association between mechanical power and outcomes. MAIN OUTCOME MEASURES: The primary outcome was the incidence of PPCs within the first seven postoperative days. The secondary outcome was the incidence of acute respiratory failure. RESULTS: We studied 1156 patients (median age [IQR]: 64 [55 to 72] years, 59.5% men). Median mechanical power adjusted by CRS was 0.32 [0.22 to 0.51] (J min-1)/(ml cmH2O-1). A higher mechanical power was also independently associated with increased risk of PPCs [odds ratio (OR 1.34, 95% CI, 1.17 to 1.52); P

ObjectiveIn these studies, we examined the association of single nucleotide polymorphisms (SNPs) of the IL1RN gene with radiographic severity of symptomatic knee osteoarthritis (SKOA) and the risk of incident OA. We also explored these genetic polymorphisms in patients with new onset rheumatoid arthritis (RA).MethodsOver 1000 subjects who met American College of Rheumatology criteria for tibiofemoral OA were selected from three independent, National Institute of Health (NIH)-funded cohorts. CTA and TTG haplotypes formed from three SNPs of the IL1RN gene (rs419598, rs315952, rs9005) were assessed for association with radiographic severity, and risk for incident radiographic OA (rOA) in a nested case–control cohort. These IL1RN haplotypes were also assessed for association with disease activity (DAS28) and plasma inflammatory markers in patients with RA.ResultsCarriage of the IL1RN TTG haplotype was associated with increased odds of more severe rOA compared with age-matched, sex-matched and body mass index-matched individuals. Examination of the osteoarthritis initiative Incidence Subcohort demonstrated that carriage of the TTG haplotype was associated with 4.1-fold (p=0.001) increased odds of incident rOA. Plasma IL-1Ra levels were lower in TTG carriers, while chondrocytes from TTG carriers exhibited decreased secretion of IL-1Ra. In patients with RA, the TTG haplotype was associated with increased DAS28, decreased plasma IL-1Ra and elevations of plasma inflammatory markers (hsCRP, interleukin 6 (IL-6)).ConclusionCarriage of the IL1RN TTG haplotype is associated with more severe rOA, increased risk for incident OA, and increased evidence of inflammation in RA. These data suggest that the IL1RN TTG risk haplotype, associated with decreased IL-1Ra plasma levels, impairs endogenous ‘anti-inflammatory’ mechanisms.

Genetic variants in C5orf30 have been associated with development of the autoimmune conditions primary biliary cirrhosis and rheumatoid arthritis. In rheumatoid arthritis, C5orf30 expression is cell-specific, with highest expression found in macrophages and synovial fibroblasts. C5orf30 is highly expressed in inflamed joints and is a negative regulator of tissue damage in a mouse model of inflammatory arthritis. Transcriptomic analysis from ultrasound-guided synovial biopsy of inflamed joints in a well characterized clinical cohort of newly diagnosed, disease-modifying antirheumatic drugs–naive rheumatoid arthritis patients was used to determine the clinical association of C5orf30 expression with disease activity. A combined molecular and computational biology approach was used to elucidate C5orf30 function in macrophages both in vitro and in vivo. Synovial expression of C5orf30 is inversely correlated with both clinical measures of rheumatoid arthritis disease activity and with synovial TNF mRNA expression. C5orf30 plays a role in regulating macrophage phenotype and is differentially turned over in inflammatory and anti-inflammatory macrophages. Inhibition of C5orf30 reduces wound healing/repair–associated functions of macrophages, reduces signaling required for resolution of inflammation, and decreases secretion of anti-inflammatory mediators. In an animal model of wound healing (zebrafish), C5orf30 inhibition increases the recruitment of macrophages to the wound site. Finally, we demonstrate that C5orf30 skews macrophage immunometabolism, demonstrating a mechanism for C5orf30-mediated immune regulation.

There is much discussion concerning ‘digital transformation’ in healthcare and the potential of artificial intelligence (AI) in healthcare systems. Yet it remains rare to find AI solutions deployed in routine healthcare settings. This is in part due to the numerous challenges inherent in delivering an AI project in a clinical environment. In this article, several UK healthcare professionals and academics reflect on the challenges they have faced in building AI solutions using routinely collected healthcare data.These personal reflections are summarised as 10 practical tips. In our experience, these are essential considerations for an AI healthcare project to succeed. They are organised into four phases: conceptualisation, data management, AI application and clinical deployment. There is a focus on conceptualisation, reflecting our view that initial set-up is vital to success. We hope that our personal experiences will provide useful insights to others looking to improve patient care through optimal data use.

Background:Upadacitinib (UPA) is an oral Janus kinase inhibitor approved for rheumatoid arthritis (RA). The safety and efficacy of UPA has been evaluated across a spectrum of patients (pts) with RA in the phase 3 SELECT clinical program.1,2Objectives:To describe long-term laboratory profiles (cutoff date: June 30, 2020) associated with exposure to UPA, adalimumab (ADA), and methotrexate (MTX) in pts with RA treated in the SELECT trials.Methods:Data were analyzed from 6 randomized controlled UPA RA trials.1,2 The proportions of pts experiencing potentially clinically significant laboratory changes at a single time point were summarized for the following groups: pooled UPA 15 mg once daily (QD; UPA15; 6 trials), pooled UPA 30 mg QD (UPA30; 4 trials), ADA 40 mg every other week (EOW; 1 trial), and MTX monotherapy (1 trial). Pts received UPA with/without background conventional synthetic disease-modifying antirheumatic drugs. Treatment-emergent adverse events are reported as exposure-adjusted event rates (events/100 pt-years [E/100 PY]). Toxicity was graded per OMERACT criteria, or NCI CTCAE for creatine phosphokinase (CPK) and creatinine.Results:4413 pts received ≥1 dose of UPA (UPA15, n=3209; UPA30, n=1204). Exposures were comparable between treatment groups (Table). Proportions of pts with Grade (Gr) 3 and 4 decreases in hemoglobin were highest with UPA30 and MTX (Table). Rates of anemia, as reported by the investigator, were comparable between UPA15, ADA, and MTX groups (Figure); the frequency of UPA-treated pts who discontinued due to anemia was low in all arms. Gr 3 and 4 decreases in neutrophils and lymphocytes with UPA were dose-dependent and higher vs ADA or MTX. Discontinuations due to neutropenia and lymphopenia were rare (Table 1.Pts with potentially clinically significant laboratory changesVariable, n (%)MTX monotherapy (n=314; 637.4 PY)ADA 40 mg EOW (n=579; 1051.8 PY)UPA 15 mg QD (n=3209; 7023.8 PY)UPA 30 mg QD (n=1204; 3091.6 PY)Mean (SD) exposure, weeks106 (67)95 (70)114 (64)134 (66)Median (range) exposure, weeks144 (1, 221)118 (2, 231)136 (0, 232)160 (0, 231)Hemoglobin, g/LGr 3 (70–28a (9.0)24b (4.2)254d (7.9)169f (14.2)Gr 4 (16a (5.1)16b (2.8)101d (3.2)78f (6.5)Neutrophils, 109/LGr 3 (0.5–3a (1.0)3b (0.5)40d (1.2)37g (3.1)Gr 4 (1a (0.3)1b (0.2)10d (0.3)5g (0.4)Lymphocytes, 109/LGr 3 (0.5–74a (23.7)53b (9.2)802d (25.1)423g (35.5)Gr 4 (5a (1.6)3b (0.5)75d (2.3)47g (3.9)ALT, U/LGr 3 (3.0–8.0 × ULN)26a (8.3)13c (2.3)152e (4.8)71h (5.9)Gr 4 (>8.0 × ULN)5a (1.6)4c (0.7)26e (0.8)10h (0.8)AST, U/LGr 3 (3.0–8.0 × ULN)15a (4.8)9c (1.6)101e (3.2)36h (3.0)Gr 4 (>8.0 × ULN)1a (0.3)5c (0.9)18e (0.6)8h (0.7)CPK, U/LGr 3 (>5.0–10.0 × ULN)2a (0.6)3c (0.5)65e (2.0)36i (3.0)Gr 4 (>10.0 × ULN)0a (0)3c (0.5)27e (0.8)15i (1.3)Creatinine, μmol/LGr 3 (>3.0–6.0 × ULN)0a (0)1c (0.2)3e (2j (0.2)Gr 4 (>6.0 × ULN)0a (0)4c (0.7)8e (0.3)1j (an=312. bn=576. cn=577. dn=3201. en=3199. fn=1193. gn=1192. hn=1195. in=1196. jn=1197ULN, upper limit of normalConclusion:This long-term analysis of UPA-treated pts with RA showed dose-dependent relationships for several laboratory abnormalities. Incidences of these with UPA15 were typically higher than with ADA but similar to MTX, except for increased CPK elevations. Treatment discontinuations due to laboratory abnormalities were infrequent and similar across all treatment groups.References:[1]Tanaka Y. Mod Rheumatol 2020;30:779–87; 2. Rubbert-Roth A, et al. N Engl J Med 2020;383:1511–21.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Russell Craddock, PhD, of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Christina Charles-Schoeman Consultant of: AbbVie, Gilead, Pfizer, and Sanofi/Regeneron, Grant/research support from: AbbVie, Bristol-Myers Squibb, and Pfizer, Jon T Giles Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Pfizer, and UCB, Grant/research support from: Pfizer, Nancy Lane Consultant of: Amgen, Mallinckrodt, Pfizer, and Roche, Ernest Choy Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Chugai, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, Regeneron, Roche, Sanofi, and UCB, Consultant of: AbbVie, Amgen, Biocon, Biogen, Chugai, Eli Lilly, Gilead, Janssen, Merck Serono, Novartis, Pfizer, Regeneron, Roche, R-Pharm, and Sanofi, Grant/research support from: Bio-Cancer, Biogen, Novartis, Pfizer, Roche, Sanofi, and UCB, Daniel Furst Speakers bureau: AbbVie, Continuing Medical Education, and Novartis, Consultant of: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, Novartis, and Pfizer, Grant/research support from: Actelion, Amgen, Bristol-Myers Squibb, Corbus, Galapagos, GSK, NIH, Novartis, Pfizer, Roche/Genentech, and Sanofi, Jiří Vencovský Speakers bureau: AbbVie, Biogen, MSD, Pfizer, Roche, Sanofi, and UCB, Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Gilead, and Octapharma, Anthony G Wilson: None declared, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Consultant of: AbbVie, Eli Lilly, Gilead, Janssen, MSD, Pfizer, Roche, and UCB, Tim Shaw Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Yanna Song Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Heidi Camp Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Nasser Khan Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Jillian Yee Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Samuel Anyanwu Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Iain McInnes Consultant of: AbbVie, Celgene, Janssen, Novartis, and UCB, Grant/research support from: Celgene, Janssen, Novartis, Pfizer, Roche, and UCB

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

Rheumatoid arthritis is a complex, inflammatory autoimmune disease, which is characterized by pain, swelling and joint damage driven by the altered behavior of a number of different cell types such as synovial fibroblasts macrophages and lymphocytes. The mechanism underlying pathogenesis is unclear but increasing evidence points to altered epigenetic regulation within these cell types which promotes the activated destructive behavior that underlies disease pathogenesis. This review summarizes the key epigenetic modifications in the most important cells types in rheumatoid arthritis, which are associated with disease activity. We also discuss emerging avenues of research focusing on readers of epigenetic markers which may serve to be potential therapeutic targets.

Background Chronic illnesses, such as Rheumatoid Arthritis (RA), are a growing burden on health care systems worldwide. Self-management emphasises the patient’s central role in managing their illness. This is pertinent given the majority of care is provided by the individual themselves; yet how individuals make sense of self-management in everyday life is largely unseen. Objective The purpose of this study was to capture the strengths and concerns of individuals with RA in self-managing their illness, raise awareness of their lived experience and spark a dialogue among stakeholders. Methods A community-based participatory approach, Photovoice, was adopted. A purposive sample of participants were tasked with taking photographs to represent the challenges and solutions to living with RA. Group workshops and semi-structured interviews were conducted to facilitate reflection, dialogue and analysis. Data analysis followed Braun and Clarke’s thematic analysis. Public exhibitions were held throughout the Autumn of 2019. Results Eight women and three men (n = 11) across suburban and urban regions of Ireland were recruited (mean age 57 years, disease duration 4–21 years). Participants identified four main themes which reflected the lived experience of self-managing RA: (i) I’m Here but I’m Not, (ii) Visible Illness, (iii) Medicine in All its Forms, (iv) Mind Yourself. These themes captured the challenge of reduced agency, limited contribution and participation, and a complex relationship between visible and invisible illness. Solutions focused on improving psychological and emotional resilience, particularly through personal reflection and increased agency. Conclusions Our findings suggest that RA is experienced as a fluid relationship between states of masking and surfacing of illness shaped by contextual and situational factors. Photovoice was a highly effective tool to capture and communicate this complexity. Supporting increased agency among individuals with RA to control the (in)visibility of illness and disability can inform the development of future self-management support.

Background 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. Methods 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. Results 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. Conclusions 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.

Artificial intelligence and the sub-field of machine learning offer the potential to deliver data-driven healthcare solutions that can improve patient care and increase efficiency in healthcare services. Despite this, the methods and models are new and complicated, to those who work in healthcare. This chapter explores the implementation of such solutions in healthcare settings, through five real-world case studies of experts applying this technology in a variety of clinical settings and at different stages of implementation. These cases highlight the challenges and opportunities posed by implementing artificial intelligence and data-driven solutions, and the lessons learnt from colleagues pioneering its adoption in the healthcare sector.

Introduction Amongst critically ill trauma patients admitted to ICU and still alive and in ICU after 24 hours, it is unclear which trauma scoring system offers the best performance in predicting in-hospital mortality. Methods The Australia and New Zealand Intensive Care Society Adult Patient Database and Victorian State Trauma Registry were linked using a unique patient identification number. Six scoring systems were evaluated: the Australian and New Zealand Risk of Death (ANZROD), Acute Physiology and Chronic Health Evaluation III (APACHE III) score and associated APACHE III Risk of Death (ROD), Trauma and Injury Severity Score (TRISS), Injury Severity Score (ISS), New Injury Severity Score (NISS) and the Revised Trauma Score (RTS). Patients who were admitted to ICU for longer than 24 hours were analysed. Performance of each scoring system was assessed primarily by examining the area under the receiver operating characteristic curve (AUROC) and in addition using standardised mortality ratios, Brier score and Hosmer-Lemeshow C statistics where appropriate. Subgroup assessments were made for patients aged 65 years and older, patients between 18 and 40 years of age, major trauma centre and head injury. Results Overall, 5,237 major trauma patients who were still alive and in ICU after 24 hours were studied from 25 ICUs in Victoria, Australia between July 2008 and January 2018. Hospital mortality was 10.7%. ANZROD (AUROC 0.91; 95% CI 0.90-0.92), APACHE III ROD (AUROC 0.88; 95% CI 0.87-0.90), and APACHE III (AUROC 0.88; 95% CI 0.87-0.89) were the best performing tools for predicting hospital mortality. TRISS had acceptable overall performance (AUROC 0.78; 95% CI 0.76-0.80) while ISS (AUROC 0.61; 95% CI 0.59-0.64), NISS (AUROC 0.68; 95% CI 0.65-0.70) and RTS (AUROC 0.69; 95% CI 0.67-0.72) performed poorly. The performance of each scoring system was highest in younger adults and poorest in older adults. Conclusion In ICU patients admitted with a trauma diagnosis and still alive and in ICU after 24 hours, ANZROD and APACHE III had a superior performance when compared with traditional trauma-specific scoring systems in predicting hospital mortality. This was observed both overall and in each of the subgroup analyses. The anatomical scoring systems all performed poorly in the ICU population of Victoria, Australia.

OBJECTIVE Monogenic Behcet's disease (BD)-like conditions are increasingly recognized and to date have been found to predominantly involve loss-of-function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD-like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls). METHODS Whole-exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v-rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA-/- mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF-κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild-type and truncated RELA in experimental systems and patient samples. RESULTS A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA-/- mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild-type RELA; however, there was no difference in RELA nuclear translocation. In RelA-/- MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98-fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild-type RELA (P = 0.036). CONCLUSION Our data indicate that RELA loss-of-function mutations cause BD-like autoinflammation and NMO via impaired NF-κB signaling and increased apoptosis.

Background As chronic illnesses, such as rheumatoid arthritis (RA), place an increased burden on health‐care systems, the ability of individuals to self‐manage these diseases is crucial. Objective To identify and synthesize the lived experience of self‐management described by adults living with RA. Design A systematic search of five electronic databases (MEDLINE, CINAHL, EMBASE, PsycINFO and ASSIA) was undertaken to identify relevant studies. Data were extracted and quality‐assessed using CASP guidelines. A meta‐synthesis was conducted based on Thomas and Harden's thematic synthesis approach. Results The search identified 8423 publications. After removing duplicates, 6527 records remained of which 32 studies met the inclusion criteria. Quality of studies was moderate to high, yet a considerable lack of reflection on researcher bias was evident. Our analysis identified 28 dimensions of self‐management RA across six domains: (a) cognitive‐emotional, (b) behavioural, (c) social, (d) environmental, (e) physical and (f) technological. Cognitive‐emotional experiences dominated the analysis. Renegotiating ‘the self’ (self‐concept, self‐esteem, self‐efficacy) was a key focus of self‐management among individuals with RA. Conclusion Our findings highlight the focus of ‘the self’ as a central concern in the self‐management of RA. Standardized self‐management programmes may primarily focus on disease management and daily functioning. However, we suggest that personal biographies and circumstances should move to the fore of self‐management support. Registration PROSPERO International Prospective Register of Systematic Reviews 2018: CRD42018100450. Patient or Public Contribution Patient and public involvement was not explicit in this review. However, three authors provided a patient perspective on the self‐management of arthritis and autoimmune disease.

Background: In view of the growth of published papers, there is an increasing need for studies that summarise scientific research. An increasingly common review is a 'Methodology scoping review', which provides a summary of existing analytical methods, techniques and software, proposed or applied in research articles, which address an analytical problem or further an analytical approach. However, guidelines for their design, implementation and reporting are limited. Methods: Drawing on the experiences of the authors, which were consolidated through a series of face-to-face workshops, we summarise the challenges inherent in conducting a methodology scoping review and offer suggestions of best practice to promote future guideline development. Results: We identified three challenges of conducting a methodology scoping review. First, identification of search terms; one cannot usually define the search terms a priori and the language used for a particular method can vary across the literature. Second, the scope of the review requires careful consideration since new methodology is often not described (in full) within abstracts. Third, many new methods are motivated by a specific clinical question, where the methodology may only be documented in supplementary materials. We formulated several recommendations that build upon existing review guidelines. These recommendations ranged from an iterative approach to defining search terms through to screening and data extraction processes. Conclusion: Although methodology scoping reviews are an important aspect of research, there is currently a lack of guidelines to standardise their design, implementation and reporting. We recommend a wider discussion on this topic., 22 pages, 2 tables

Introduction: Rheumatoid Arthritis (RA) varies from a mild to a severe, unremitting illness characterized by uncontrolled inflammation with consequent damage to cartilage and bone of joints. Individualized therapeutic approaches based on likely outcome would facilitate a personalized therapeutic approach.Areas covered: Genetics is known to contribute a significant component of the variability in RA outcome, estimated at 45–60%. A number of candidate gene studies have been associated with variability in radiologically assessed joint damage; however a more comprehensive genome wide analysis is required to more fully characterize the genetic basis of RA severity.Expert commentary: Genetic profiling of patient presenting with RA has the potential to aid stratification based on predicted prognosis, this would inform the clinical development of a personalized therapeutic approach. It will also result in the identification of novel mediators of tissue damage in RA.

OBJECTIVE: To determine whether using a reweighted disease activity score that better reflects joint synovitis, i.e., the 2-component Disease Activity Score in 28 joints (DAS28) (based on swollen joint count and C-reactive protein level), produces more clinically relevant treatment outcome trajectories compared to the standard 4-component DAS28.METHODS: Latent class mixed modeling of response to biologic treatment was applied to 2,991 rheumatoid arthritis (RA) patients in whom treatment with a biologic disease-modifying antirheumatic drug was being initiated within the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate cohort, using both 4-component and 2-component DAS28 scores as outcome measures. Patient groups with similar trajectories were compared in terms of pretreatment baseline characteristics (including disability and comorbidities) and follow-up characteristics (including antidrug antibody events, adherence to treatments, and blood drug levels). We compared the trajectories obtained using the 4- and 2-component scores to determine which characteristics were better captured by each.RESULTS: Using the 4-component DAS28, we identified 3 trajectory groups, which is consistent with previous findings. We showed that the 4-component DAS28 captures information relating to depression. Using the 2-component DAS28, 7 trajectory groups were identified; among them, distinct groups of nonresponders had a higher incidence of respiratory comorbidities and a higher proportion of antidrug antibody events. We also identified a group of patients for whom the 2-component DAS28 scores remained relatively low; this group included a high percentage of patients who were nonadherent to treatment. This highlights the utility of both the 4- and 2-component DAS28 for monitoring different components of disease activity.CONCLUSION: Here we show that the 2-component modified DAS28 defines important biologic and clinical phenotypes associated with treatment outcome in RA and characterizes important underlying response mechanisms to biologic drugs.

Expression of the macrophage immunometabolism regulator gene (MACIR) is associated with severity of autoimmune disease pathology and the regulation of macrophage biology through unknown mechanisms. The 206 amino acid protein lacks homology to any characterized protein sequence and is a disordered protein according to structure prediction algorithms. Here we identify specific interactions of MACIR using a fragment complementation-based affinity pull down of cellular proteins prepared with a membrane solubilization buffer. Quantitative mass spectrometry showed enrichment of nuclear and mitochondrial proteins and of 63 significant interacting proteins, binding to the nuclear transport receptor TNPO1 and trafficking proteins UNC119 homolog A and B were validated by immunoprecipitation. Analysis of mutations in two candidate recognition motifs in the MACIR amino acid sequence confirmed TNPO1 binds via a PY-NLS motif (aa98-117). Characterizing nuclear MACIR activity in macrophage and fibroblasts is a priority with respect to developing strategies for treatment of autoimmune disease.

ObjectivesIdentifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.MethodsDNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.ResultsIn the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.ConclusionThese data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.

rs26232, located in intron one of C5orf30, is associated with the susceptibility to and severity of rheumatoid arthritis (RA). Here, we investigate the relationship between this variant and the biological activities of rheumatoid arthritis synovial fibroblasts (RASFs). RASFs were isolated from the knee joints of 33 RA patients. The rs26232 genotype was determined and cellular migration, invasion, and apoptosis were compared using in vitro techniques. The production of adhesion molecules, chemokines, and proteases was measured by ELISA or flow cytometry. Cohort genotypes were CC n = 16, CT n = 14, TT n = 3. In comparison with the RASFs of the CT genotype, the CC genotype showed a 1.48-fold greater invasiveness in vitro (p = 0.02), 1.6-fold higher expression intracellular adhesion molecule (ICAM)-1 (p = 0.001), and 5-fold IFN-&gamma, inducible protein-10 (IP-10) (p = 0.01). There was no association of the rs26232 genotype with the expression levels of either total C5orf30 mRNA or any of the three transcript variants. The rs26232 C allele, which has previously been associated with both the risk and severity of RA, is associated with greater invasive activity of RASFs in vitro, and with higher expression of ICAM-1 and IP-10. In resting RASFs, rs26232 is not a quantitative trait locus for C5orf30 mRNA, indicating a more complex mechanism underlying the genotype‒phenotype relationship.

ObjectivesWe sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response.MethodsWe studied the relation of TNFi response, quantified by change in swollen joint counts ( Δ SJC) and erythrocyte sedimentation rate ( Δ ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation.ResultsWe detected a statistically significant association between Δ SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between Δ SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance.ConclusionsThe association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Expression of the macrophage immunometabolism regulator gene (MACIR) is associated with severity of autoimmune disease pathology and with the regulation of macrophage biology through unknown mechanisms. The encoded 206 amino acid protein lacks homology to any characterized protein sequence and is a disordered protein according to structure prediction algorithms. To identify interactions of MACIR with proteins from all subcellular compartments, a membrane solubilization buffer is employed, that together with a high affinity EF hand based pull down method, increases the resolution of quantitative mass spectrometry analysis with significant enrichment of interactions from membrane bound nuclear and mitochondrial compartments compared to samples prepared with radioimmunoprecipitation assay buffer. A total of 63 significant interacting proteins are identified and interaction with the nuclear transport receptor TNPO1 and the trafficking proteins UNC119 homolog A and B are validated by immunoprecipitation. Mutational analysis in two candidate nuclear localization signal motifs in the MACIR amino acid sequence shows the interaction with TNPO1 is likely via a non-classical proline/tyrosine-nuclear localization signal motif (aa98-117). It is shown that employing a highly specific and high affinity pull down method that performs efficiently in this glycerol and detergent rich buffer is a powerful approach for the analysis of uncharacterized protein interactomes.

Background: Rheumatoid arthritis (RA) is characterized by chronic, uncontrolled joint inflammation and tissue destruction. Macrophages are thought to be key mediators in both the initiation and perpetuation of this pathology.1,2 The RA synovium contains a complex inflammatory milieu that can stimulate macrophage-dependent production of proinflammatory cytokines through multiple signaling pathways.1,2 Existing evidence indicates that toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) along with their agonists, damage-associated molecular patterns (DAMPs) and IL-1β, are highly expressed in RA joints and are important mediators of synovial macrophage activation and proinflammatory cytokine production.1-9 IRAK4 (interleukin-1 receptor-associated kinase 4) is a serine/threonine kinase that facilitates TLR and IL-1R signaling in many cell types, including macrophages.10 IRAK4 inhibition represents an opportunity to reduce proinflammatory cytokine production in the joints of patients with RA. Objectives: To investigate the effect of a highly selective IRAK4 inhibitor on proinflammatory cytokine production from human macrophages stimulated with synovial fluid from patients with RA. Methods: Primary human monocytes from 2 independent donors were differentiated for 6 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) to generate human monocyte-derived macrophages (hMDMs). hMDMs were then pretreated with an IRAK4 inhibitor for 1 hour and subsequently stimulated for 24 hours with RA synovial fluid from 5 patients. Culture supernatants were then assessed for secretion of proinflammatory cytokines by MesoScale Discovery. Results: RA synovial fluid stimulation of hMDMs resulted in the production of several proinflammatory cytokines, including IL-6, IL-8, and TNFα. Pretreatment of hMDMs with an IRAK4 inhibitor resulted in the dose-dependent inhibition of IL-6, IL-8, and TNFα production, with an average EC50 ± SD of 27 ± 31, 26 ± 41, and 28 ± 22 nM, respectively. Maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 76 ± 8.8, 73 ± 15, and 77 ± 13, respectively. To evaluate the specific IRAK4-dependent signaling pathways mediating this response, hMDMs were pretreated with inhibitors of TLR4 (TAK242) and IL-1R (IL-1RA) prior to stimulation with RA synovial fluid. Both TAK242 and IL-1RA inhibited proinflammatory cytokine production. For TAK242, maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 39 ± 25, 48 ± 24, and 50 ± 21, respectively. For IL-1RA maximal percent suppression ± SD of IL-6, IL-8, and TNFα were 18 ± 18, 20 ± 23, and 16 ± 18, respectively. The broad range of inhibition across each stimulation highlights the complexity and variability in the signaling pathways mediating proinflammatory cytokine production from hMDMs stimulated with RA synovial fluid, but demonstrates that RA synovial fluid can stimulate proinflammatory cytokine production in hMDMs, at least partly, through IRAK4-dependent pathways. Conclusion: This work demonstrates that IRAK4 inhibition can suppress proinflammatory cytokine production from macrophages stimulated with synovial fluid from patients with RA and supports a potential pathophysiological role for IRAK4 in perpetuating chronic inflammation in RA. References: [1]Smolen JS, et al. Nat Rev Dis Primers. 2018;4:18001. [2]Udalova IA, et al. Nat Rev Rheumatol. 2016;12(8):472-485. [3]Joosten LAB, et al. Nat Rev Rheumatol. 2016;12(6):344-357. [4]Huang QQ, Pope RM. Curr Rheumatol Rep. 2009;11(5):357-364. [5]Roh JS, Sohn DH. Immune Netw. 2018;18(4):e27. [6]Sacre SM, et al. Am J Pathol. 2007;170(2):518-525. [7]Ultaigh SNA, et al. Arthritis Res Ther. 2011;13(1):R33. [8]Bottini N, Firestein GS. Nat Rev Rheumatol. 2013;9(1):24-33. [9]Firestein GS, McInnes IB. Immunity. 2017;46(2):183-196. [10]Janssens S, Beyaert R. Mol Cell. 2003;11(2):293-302. Disclosure of Interests: Adam Yadon Employee of: Gilead, Debbie Ruelas Employee of: Gilead, Gundula Min-Oo Employee of: Gilead, James Taylor Employee of: Gilead, Matthew R. Warr Employee of: Gilead

Background:Tocilizumab (TCZ) is a biological disease-modifying antirheumatic drug that blocks IL-6 signalling and is effective in ameliorating disease activity in rheumatoid arthritis (RA). However, approximately 50% of patients do not respond adequately to TCZ and some patients report adverse events. Considering there is growing evidence that DNA methylation is implicated in RA susceptibility and response to some biologics (1, 2), we investigated DNA methylation as a candidate biomarker for response to TCZ in RA.Objectives:To identify differential DNA methylation signatures in whole blood associated with TCZ response in patients with RA.Methods:Epigenome-wide DNA methylation patterns were measured using the Infinium EPIC BeadChip (Illumina) in whole blood-derived DNA samples from patients with RA. DNA was extracted from blood samples taken pre-treatment and following 3 months on therapy, and response was determined at 6 months using the Clinical Disease Activity Index (CDAI). Patients who had good response (n=10) or poor response (n=10) to TCZ by 6 months were selected. Samples from secondary poor responders (n=10) (patients who had an improvement of CDAI and were in remission at 3 months, followed by a worsening of CDAI at 6 months) were also analysed. Differentially methylated positions and regions (DMPs/DMRs) were identified using linear regression, adjusting for gender, age, cell composition, smoking status, and glucocorticoid use. Gene Set Enrichment Analysis (GSEA) was used to identify significant pathways associated with response and Functional Epigenetic Module analysis of interactome hotspots in regions of differential methylation.Results:20 DMPs were significantly associated with response status at 6 months in the pre-treatment samples. Another 21 DMPs were associated with response in the 3 month samples. Within good responders, 10 DMPs showed significant change in methylation level between pre-treatment and the 3 month samples (unadjusted P-value -6). One DMP, cg03121467, was significantly less methylated in good responders compared to poor responders in the pre-treatment samples. This DMP is close toEPB41L4Aand thought to have a role in β–catenin signalling. GSEA of DMRs in non- and secondary non- responders identified histone acetyltransferase pathways and included theKAT2Agene, which is a repressor of NF-κB. Additional analysis of interaction hotspots of differential methylation identified significant interactions withSTAMBPandPTPN12associated with response status.Conclusion:These preliminary results provide evidence that DNA methylation patterns may predict response to TCZ. Validation of these findings in other larger data sets is required.References:[1]Liu,Y., Aryee,M.J., Padyukov,L., Fallin,M.D., Hesselberg,E., Runarsson,A., Reinius,L., Acevedo,N., Taub,M., Ronninger,M.,et al.(2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis.Nat. Biotechnol.,31, 142–147.[2]Plant,D., Webster,A., Nair,N., Oliver,J., Smith,S.L., Eyre,S., Hyrich,K.L., Wilson,A.G., Morgan,A.W., Isaacs,J.D.,et al.(2016) Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis.Arthritis Rheumatol. (Hoboken, N.J.),68, 1353–60.Disclosure of Interests:Nisha Nair: None declared, Darren Plant: None declared, John Isaacs Consultant of: AbbVie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche, Ann Morgan Grant/research support from: I have received a grant from Roche Products Ltd to establish a registry for GCA patients treated with tocilizumab., Consultant of: I have undertaken consultancy work for Roche, Chugai, Regeneron, Sanofi and GSK in the area of GCA therapeutics., Speakers bureau: I have presented on tocilizumab therapy for GCA and glucocorticoid toxicity on behalf of Roche products ltd., Kimme Hyrich Grant/research support from: Pfizer, UCB, BMS, Speakers bureau: Abbvie, Anne Barton Consultant of: AbbVie, Anthony G Wilson: None declared

Background:Rheumatoid arthritis (RA) is a widespread chronic disease affecting about 1% of the population in the West. It is characterised by pain, fatigue and inflammation that can flare-up without warning. This makes the condition difficult to predict and manage. Bury (1982) introduced the concept of chronic illness as a disruptive experience to one’s self-identity. This is often an invisible part of managing the illness and taken for granted by others, such as family members, friends and health care professionals. Thus, there is a need to raise awareness of the patients’ lived experiences of self-managing this long-term chronic illness.Objectives:We aimed to collaborate with people with RA to (i) record and reflect the community’s strengths and concerns; (ii) raise awareness of the lived experience of self-managing RA (iii) spark a dialogue among key stakeholders around the self-management of RA.Methods:A purposeful sample of people with RA (n=12) was recruited. An innovative qualitative methodology, Photovoice, was used (Wang & Burris, 1997). A series of small group workshops took place. Participants were provided with cameras and appropriate training. They were asked to take photographs of the“challenges and solutions to living with RA” over approximately two weeks. Semi-structured interviews were conducted incorporating photo elicitation. As a group, the participants, a visual artist and researcher co-created a photo exhibition for the public.Results:Participants selected 32 photographs for the exhibition. They carried out a thematic analysis of the photos identifying four themes:•I’m Here but I’m Not– this theme reflected feelings of alienation and social isolation.•Medicine in all its forms –this theme captured attitudes towards medication and devices, as well as the creative ways people coped with RA.•Visible illness– this concerned the recognition of RA. It captures the experience of RA as a “contested illness” and the challenge of gaining medical and cultural legitimacy.•Mind yourself –this theme highlighted the value of self-care, often closely connected with the natural world and engagement with social activities.Exhibitions were held at a community arts centre and a large central hospital in Dublin city. A plain language report was also collaboratively produced.Conclusion:This study shows how participatory methods can be used to explore the hidden experience of living with an invisible illness. This research design enabled participants to use photographs to reflect on their experiences and the meaning they intended to convey, thereby increasing trustworthiness of the findings through individual and group member checking. This approach extends beyond traditional written and verbal responses to share the worldview of participants. It demonstrates how to work with patients to create opportunities to improve awareness and spark dialogue among those who play a role in supporting the self-management of chronic illness. The integration of creative arts and participatory methods can have a positive impact for those involved in research and can enhance public engagement with research.References:[1]Bury, Michael (1982) Chronic Illness as Biographical Disruption. Sociology of Health & Illness. 4. 167-82.[2]Wang, C., & Burris, M. A. (1997). Photovoice: Concept, Methodology, and Use for Participatory Needs Assessment.Health Education & Behavior,24(3), 369–387.Acknowledgments:Funding is awarded from the UCD Wellcome Trust Institutional Strategic Support Fund as part of a Medical Humanities and Social Science Collaboration Scheme (ref 204844/Z/16/Z).As part of a Patient and Public Involvement (PPI) strand, a Research Advisory Group composed of people living with RA was supported the design and execution of this project.Disclosure of Interests:None declared

Involving patients in research broadens a researcher’s field of influence and may generate novel ideas. Preclinical research is integral to the progression of innovative healthcare. These are not patient-facing disciplines and implementing meaningful public and patient involvement (PPI) can be a challenge. A discussion forum and thematic analysis identified key challenges of implementing public and patient involvement for preclinical researchers. In response we developed a “PPI Ready” planning canvas. For contemporaneous evaluation of public and patient involvement, a psychometric questionnaire and an open source tool for its evaluation were developed. The questionnaire measures information, procedural and quality assessment. Combined with the open source evaluation tool, researchers are notified if public and patient involvement is unsatisfactory in any of these areas. The tool is easy to use and adapts a psychometric test into a format familiar to preclinical scientists. Designed to be used iteratively across a research project, it provides a simple reporting grade to document satisfaction trend over the research lifecycle.

Involving patients in research broadens a researchers field of influence and may generate novel ideas. Basic and preclinical research is integral to the progression of innovative healthcare. These are not patient-facing disciplines and implementing meaningful patient and public involvement (PPI) can be a challenge. A discussion forum and thematic analysis identified key challenges of implementing PPI for preclinical researchers. In response we developed a strategic planning tool, called PPI Ready Researcher Planning Canvas. For contemporaneous evaluation of PPI, a psychometric questionnaire and an open source tool for its evaluation were developed. The questionnaire measures information, procedural and quality assessment. Combined with the open source evaluation tool, researchers are notified if PPI is unsatisfactory in any of these areas. The tool is easy to use and adapts a psychometric test into a format familiar to preclinical scientists. Designed to be used iteratively across a research project, it provides a simple reporting grade to document satisfaction trend over the research lifecycle.

Genetic variants in

Background Methotrexate (MTX) is recommended as the first-line disease modifying anti-rheumatic drug (csDMARD) for the treatment of rheumatoid arthritis (RA), but up to 40% patients do not respond adequately, or experience adverse effects1; therefore, identifying blood-based biomarkers that predict treatment response is a research priority. DNA methylation is an epigenetic marker that modifies but does not alter DNA sequence; MTX may act, at least in part, by inhibiting intracellular methyl donor transfer leading to DNA hypomethylation2 so DNA methylation may act as a biomarker of MTX response. Objectives To identify differential DNA methylation signatures in whole blood associated with response to MTX in patients with RA. Methods DNA methylation was measured using the HumanMethylation450 BeadChip in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study (RAMS). Demographic and clinical data were collected prior to starting MTX (baseline) and at 6 months after commencing MTX. DNA was extracted from whole blood samples collected at baseline and at 4 weeks from patients who, at 6 months, had a EULAR good response (n=36) or EULAR poor response (n=36) to MTX. Differentially methylated positions (DMPs) between baseline and 4 weeks, and between good and poor response groups were identified using a linear model, adjusting for gender, age, cell composition, baseline disease activity score (DAS28), and smoking status. Additional analyses were performed to assess the association between methylation and change in DAS28 score and the individual DAS28 components over 6 months. DMPs with significant differences were selected for replication by pyrosequencing in an independent group of 100 patients with both baseline and 4 week samples available for testing. Using genome-wide genotype data for the same patients, replicated DMPs were investigated for methylation QTLs (meQTLs). Results The initial analysis identified differential methylation between good and poor responders at 2 CpG sites (DMPs) in samples taken at 4 weeks, with response status determined at 6 months (p-value Conclusions These results suggest DNA methylation may provide a biomarker of MTX response but requires replication in other larger data sets. References [1] Verstappen SMM, et al. Int. J. Clin. Rheu2012;7(5):559–567. [2] Kim Y, et al. J. Lab. Clin. Med1996;128:165–172. Disclosure of Interest None declared

Background Public and Patient Involvement (PPI) encompasses a variety of ways researchers engage with people for whom their research holds relevance. Active and formal PPI can result in increased patient support for research and improved likelihood of patient involvement in the case of clinical research, including improved relevance to patient quality of life. As a research centre, we decided to develop our own PPI initiative. In order to develop a meaningful and productive partnership, we have developed this initiative from conception with our patient insight partners. Objectives The overall objective is to improve our research quality, relevance and outcomes. We aim to ensure that the real-life experiences of people living with arthritis are considered in the decision making processes around arthritis research. Methods A community approach to recruitment of patient insight partners was used. Social media, advocacy charities, and local community events were the predominant source of recruitment. Three initiatives were proposed: steering committee, patient insight panels, and a patient educator programme. A discussion forum between patients and researchers was used to determine the feasibility, interest and accessibility of proposed initiatives. An independent facilitator was commissioned to prepare an unbiased report of the discussion forum, upon which the PPI strategy was developed. Results Patient support for the PPI initiative was overwhelmingly positive. A number of potential barriers to participation were identified. 1) Steering committee: Risk of tokenism and the potential intimidation of a structure that was too formal. Mechanisms to overcome included multiple patient representatives, detailed terms of reference and a supportive environment with a rotating chair. Our patient insight partners proposed a three-tier structure: a patient focus group that nominates the steering committee members and a plenary meeting to be kept informed about research they are involved in. 2) Insight Panels: Access to technology was viewed as the major barrier to remote involvement. Mechanisms to overcome included multiple modes of communication: online, telephone, postal communication. Providing the opportunity for face-to-face or speaking directly with a researcher in an informal setting was seen as crucial in building interpersonal relationships and sustaining involvement. 3) Patient Educator: Extremely well received. Barriers to participation revolved largely around travel and physical accessibility. This can be overcome with in-house resources. Our research strategy is being revised with the PPI strategy as a central tenet. We are adopting the new steering committee under the three-tier format and yearly research meeting with plenary session. We have a PPI newsletter, the editorial board for which is made up of researchers and patient insight partners. A patient educator module is under review for incorporation into a new PhD programme. We have expanded our research into multidisciplinary areas, with new sociology researchers and psychology collaborators. Conclusions The development a true patient partnership in our group has fundamentally changed the scope and remit of our research, allowing us to expand our biomedical and clinical research into a more holistic model. Disclosure of Interest None declared

Background Behcet’s disease (BD) has a complex multifactorial pathogenesis and presents with phenotypic heterogeneity predominantly mucocutaneous ulcerations, ocular lesions and skin manifestations. More recently, there have been reported cases of monogenic spectrum defects presented with BD-like similarities or phenotype. Objectives We investigated an Irish Caucasian family of eleven that included two half-sisters with early-onset BD, and another sister with neuromyelitis optica, all who were born to asymptomatic non-consanguines parents. More recently, one of the sisters’ daughter developed recurrent oral aphthosis at the age of 10 years old. Methods Peripheral blood mononuclear cells were extracted from patients and non-affected donor blood using standard fractionation methods. Following quality assessment and quantification whole exome sequencing was performed on all participants. Results Whole exome sequencing data identified segregation of a novel pathogenic stop codon mutation in the nuclear factor NF-κB p65 subunit (RelA) resulting in a non-functional protein. The mutation involves cytosine deletion and results in a His487ThrfsTer7 frameshift (His487ThrfsTer7) RelA resulting in loss of transcription activation-1 (TA1) and a portion of TA2 from RelA. The mutation was seen within the three generations, including the three half-sisters, their father as well as one of the proband’s daughter, potentially describing a new syndrome. Conclusions Our study suggests that loss-of-function mutations in the NF-κB pathway, a pivotal mediator of inflammation and apoptosis, are linked with the development of familial early-onset BD-like syndromes. Better insights and further understanding of this ”orphan” immunogenetic syndrome carries high clinical impact to assist early disease recognition and potential discoveries of novel targeted therapies. Disclosure of Interest None declared

OBJECTIVES: To investigate the admission characteristics and hospital outcomes for Indigenous and non-Indigenous patients admitted to intensive units (ICUs) after major trauma. DESIGN, SETTING: Retrospective analysis of Australian and New Zealand Intensive Care Society (ANZICS) Adult Patient Database data from 92 Australian ICUs for the 6-year period, 2010-2015. PARTICIPANTS: Patients older than 17 years of age admitted to public hospital ICUs with a primary diagnosis of trauma. MAIN OUTCOME MEASURES: ICU and overall hospital lengths of stay, hospital discharge destination, and ICU and overall hospital mortality rates for Indigenous and non-Indigenous patients. RESULTS: 23 804 people were admitted to Australian public hospital ICUs after major trauma; 1754 (7.4%) were Indigenous Australians. The population-standardised incidence of admissions was consistently higher for Indigenous Australians than for non-Indigenous Australians (847 per million v 251 per million population; incidence ratio, 3.37; 95% CI, 3.19-3.57). Overall hospital mortality rates were similar for Indigenous and non-Indigenous patients (adjusted odds ratio [aOR], 1.04; 95% CI, 0.82-1.31). Indigenous patients were more likely than non-Indigenous patients to be discharged to another hospital (non-Indigenous v Indigenous: aOR, 0.84; 95% CI, 0.72-0.96) less likely to be discharged home (non-Indigenous v Indigenous: aOR, 1.17; 95% CI, 1.04-1.31). CONCLUSION: The population rate of trauma-related ICU admissions was substantially higher for Indigenous than non-Indigenous patients, but hospital mortality rates after ICU admission were similar. Indigenous patients were more likely to be discharged to a another hospital and less likely to be discharged home than non-Indigenous patients.

Public and patient involvement (PPI) is increasingly an expectation of funders and policy-makers. Not all areas of health research are obvious or accessible to patients. Involving the public in preclinical and laboratory-based research in a mutually beneficial way can be challenging. Fundamentally, there is confusion among preclinical researchers as to what PPI is and how it is applied.1 PPI is not about unleashing the public into your laboratory; rather it is about increasing research relevance and cooperating with people living with rheumatic disease to enable careful and deliberate study design. In practice, how can you involve patients meaningfully and in line with European League Against Rheumatism recommendations2 if you have not already established mutual respect, a supportive environment and a relationship built on equal status? Too often, the literature aimed at guiding researchers …

Objective Hallux valgus (HV) affects ∼36% of Caucasian adults. Although considered highly heritable, the underlying genetic determinants are unclear. We conducted the first genome-wide association study (GWAS) aimed to identify genetic variants associated with HV. Methods HV was assessed in three Caucasian cohorts (n=2263, n=915 and n=1231 participants, respectively). In each cohort, a GWAS was conducted using 2.5 M imputed SNPs. Mixed-effect regression with the additive genetic model adjusted for age, sex, weight and within-family correlations was used for both sex-specific and combined analyses. To combine GWAS results across cohorts, fixed-effect inverse-variance meta-analyses were used. Following meta-analyses, top-associated findings were also examined in an African American cohort (n=327). Results The proportion of HV variance explained by genome-wide genotyped SNPs was 50% in men and 48% in women. A higher proportion of genetic determinants of HV were sex specific. The most significantly associated SNP in men was rs9675316 located on chr17q23-a24 near the AXIN2 gene (p=0.000000546×10−7); the most significantly associated SNP in women was rs7996797 located on chr13q14.1-q14.2 near the ESD gene (p=0.000000721×10−7). Genome-wide significant SNP-by-sex interaction was found for SNP rs1563374 located on chr11p15.1 near the MRGPRX3 gene (interaction p value =0.0000000041×10−9). The association signals diminished when combining men and women. Conclusions The findings suggest that the potential pathophysiological mechanisms of HV are complex and strongly underlined by sex-specific interactions. The identified genetic variants imply contribution of biological pathways observed in osteoarthritis as well as new pathways, influencing skeletal development and inflammation.

At the population level, rheumatoid arthritis (RA) is generally viewed as autoimmune in nature with a small subgroup of cases having a palindromic form or systemic autoinflammatory disorder (SAID) phenotype. Herein, we describe resistant cases of classical autoantibody associated RA that had clinical, genetic and therapeutic responses indicative of coexistent autoinflammatory disease. Five patients with clinically overlapping features between RA and SAID including polysynovitis and autoantibody/shared epitope positivity, and who had abrupt severe self-limiting attacks including fevers and serositis, are described. Mutations or single nucleotide polymorphisms in recognised autoinflammatory pathways were evident. Generally, these cases responded poorly to conventional Disease-modifying anti-rheumatic drugs (DMARD) treatment with some excellent responses to colchicine or interleukin 1 pathway blockade. A subgroup of RA cases have a mixed autoimmune-autoinflammatory phenotype and genotype with therapeutic implications.