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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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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., Competing Interests: Competing interests: KLW has received research grants and/or consulting honoraria from Janssen Pfizer, AbbVie, Union Chimique Belge (UCB), Eli Lilly & Company, Galapagos, GlaxoSmithKline (GSK), Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis; JDI has received grants and/or consulting honoraria from Janssen, Pfizer, AbbVie, BMS, Gilead, Roche, UCB, Eli Lilly; PJM has received grants and/or consulting honoraria from AbbVie, Acelyrin, Aclaris, Amgen, Boehringer Ingelheim, BMS, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Inmagene, Janssen, Moonlake, Novartis, Pfizer, Sun Pharma, UCB; DTB has received grants/or consulting honoraria from AstraZeneca, Abbvie, Pfiser, GSK and Lilly; XB has received grants and/or consulting honoraria from AbbVie, BMS, MSD, Celgene, Chugai, Merck, Novartis, Pfizer, Sandoz, and UCB; J-EG has received grants and/or consulting honoraria from Abbvie, BMS, Gilead, Galapagos, Lilly, MSD, Novartis, Pfizer, Roche Chugai, Sanofi; SS has received grants and/or consulting honoraria from Amgen, AbbVie, Biogen, Eli Lilly, GSK, Janssen, UCB, Pfizer, Boehringer Ingelheim and Novartis; MM has received grants and/or consulting honoraria from Lilly, GSK, Astra Zeneca, UCB, Janssen, Abbvie and Pfizer; NB has received grants and/or consulting honoraria from Roche, MSD, Pfizer, GSK, Galapagos, Vifor and Lilly; RL has received grants and/or consulting honoraria from Abbvie, Boehringer-Ingelheim, Celgene, Eli-Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Sandoz, Kabi-Fresenius, Biosplice (formerly Samumed) and UCB; DA has received grants and/or consulting honoraria from Abbvie, Amgen, Galapagos, Lilly, Janssen, Merck, Novartis, Pfizer, Sandoz and Sanofi; IBM has received grants and/or consulting honoraria from AbbVie, Amgen, BMS, Causeway Therapeutics, Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi, UCB, Evelo, Compugen, AstraZeneca, Moonlake and serves as a NHS GGC board member, Evelo Board of Directors, Versus Arthritis Trustee Status; REV has received grants and/or consulting honoraria from AbbVie, Amgen, Boehringer Ingelheim, BMS, Janssen-Cilag, GSK, Hexal, Neutrolis, Novartis and Pfizer; EMG: serves as an associate editor at the New England Journal of Medicine; JSS has received research grants and/or consulting honoraria from AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Chugai, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, R-Pharma, Roche, Samsung and UCB serves as the editor of Annals of Rheumatic Diseases but was not involved in the handling or review of this manuscript., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The 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)., Methods: Serum 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., Results: In 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., Conclusion: Beyond 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., Competing Interests: Competing interests: KLH reports grants from BMS and Pfizer, and honoraria from AbbVie for speaking at an educational meeting, outside the submitted work. AB is an NIHR Senior Investigator and has received grants from BMS, Pfizer, Galapagos and Scipher Medicine as well as honoraria from Roche-Chugai for speaking at educational meetings. SV and DP have received grants from BMS outside the submitted work. AWM is an NIHR Senior Investigator and has received grants or honoraria on behalf of the University of Leeds from Roche-Chugai, Kiniska Pharmaceuticals, Regeneron, Sanofi, Vifor, Abbvie and GlaxoSmithKline for work unrelated to this manuscript. JDI has received research funding from GSK, Janssen and Pfizer, and speaker/consultancy fees from AbbVie, BMS, Gilead, Roche and UCB outside of this submitted work. KLH is an Associate Editor at the Annals of Rheumatic Diseases but had no role in the peer review of this work. All other authors declare no other competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

We previously hypothesized that functional cognitive disorder is characterized by heightened subjective mental effort, exhausted attentional reserve and metacognitive failure. To test this hypothesis, we administered a Stroop colour-word task in which attentional demand was varied by task difficulty (congruent versus incongruent cues) and the presence of a secondary auditory stimulus (passive or active listening to an oddball-type paradigm). We measured subjective mental effort, objective performance (reaction times and accuracy), metacognition and EEG-based biomarkers of mental workload. We tested 19 functional cognitive disorder patients and 23 healthy controls. Patients reported higher levels of depression, anxiety, fatigue, pain, sleep disruption, dissociation and obsessiveness. They rated their memory as significantly poorer than healthy controls; however, accuracy did not differ between groups in any condition. In contrast to healthy controls, patients rated their performance as poorer on the congruent Stroop task with background noise compared to silent conditions. Functional cognitive disorder was consistently associated with slower reaction times but this was not exacerbated by increased attentional demand. Patients but not healthy controls reported greater mental workload in noisy conditions but EEG biomarkers were similar between groups, regardless of task difficulty. Functional cognitive disorder has significant syndromic overlap with mood disorders and chronic fatigue and pain. It is associated with global metacognitive failure whereas local (task-specific) metacognition is only selectively impaired. Patients were slower than healthy controls, which might contribute to the 'brain fog' reported in this condition. Although subjective mental effort was increased in noisy conditions, we found no evidence of attentional exhaustion in functional cognitive disorder. Our results indicate that functional cognitive disorder is a multisystem condition affecting reaction time, subjective mental effort and global metacognition., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)

Sarcopenia, a disorder that involves the generalized loss of skeletal muscle strength and mass, was formally recognized as a disease by its inclusion in the International Classification of Diseases in 2016. Sarcopenia typically affects older people, but younger individuals with chronic disease are also at risk. The risk of sarcopenia is high (with a prevalence of ≥25%) in individuals with rheumatoid arthritis (RA), and this rheumatoid sarcopenia is associated with increased likelihood of falls, fractures and physical disability, in addition to the burden of joint inflammation and damage. Chronic inflammation mediated by cytokines such as TNF, IL-6 and IFNγ contributes to aberrant muscle homeostasis (for instance, by exacerbating muscle protein breakdown), and results from transcriptomic studies have identified dysfunction of muscle stem cells and metabolism in RA. Progressive resistance exercise is an effective therapy for rheumatoid sarcopenia but it can be challenging or unsuitable for some individuals. The unmet need for anti-sarcopenia pharmacotherapies is great, both for people with RA and for otherwise healthy older adults., (© 2023. Springer Nature Limited.)

People with rheumatoid arthritis (RA) are disproportionately affected by sarcopenia, the generalised loss of muscle strength and mass, consequently facing an increased risk of falls, functional decline and death. Currently, there are no approved pharmacological treatments for sarcopenia. RA patients who start tofacitinib (a Janus kinase inhibitor) develop small increases in serum creatinine that are not explained by renal function changes and could reflect sarcopenia improvement. The RAMUS Study is a proof of concept, single-arm observational study in which patients with RA who commence tofacitinib according to routine care will be offered participation according to eligibility criteria. Participants will undergo lower limb quantitative magnetic resonance imaging, whole-body dual energy x-ray absorptiometry, joint examination, muscle function testing and blood tests at three time points: prior to starting tofacitinib and 1 and 6 months afterwards. Muscle biopsy will be performed before and 6 months after starting tofacitinib. The primary outcome will be lower limb muscle volume changes following treatment initiation. The RAMUS Study will investigate whether muscle health improves following tofacitinib treatment for RA. Identifying a potential pharmacological treatment for sarcopenia could have important implications for individuals with RA and for older people in general. ISRCTN registry ID: 13364395., (Copyright: © 2023 Hylonome Publications.)

Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) and dysregulated myeloid cell responses are implicated in the pathophysiology and severity of COVID-19., Methods: In 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., Results: In Part 1 (n=806 randomised 1:1 otilimab:placebo), 71% of otilimab-treated patients were alive and free of respiratory failure at Day 28 versus 67% 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., Conclusions: There 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., Competing Interests: Conflict of interest: J. Patel, D. Bass, A. Cahn, K. Davy, S. Fernandes, A. Gupta, K. Hanrott, D. Inman, E. Jarvis, D. Lakshminarayanan, S. Mukherjee, C. O'Shea, L. Schifano, J.E. Smith, R. Williamson and M. Layton are shareholders and/or employees of GSK. A. Beishuizen, X. Bocca Ruiz, H. Boughanmi, H. Colombo, G.J. Criner, J. de-Miguel-Díez, P.A. Doreski, B. François, T. Hatlen, J.D. Isaacs, N. Kostina, T. Kropotina, J-C. Lacherade, P. Martinez-Ayala, C. McEvoy, F. Meziani, M. Monchi, R. Muñoz-Bermúdez, G. Plantefeve, L.E. Schwab, Z. Shahid, M. Shirano, E. Sprinz, C. Summers, N. Terzi and Y. Trefilova were investigators in the OSCAR trial, which was funded by GSK. X. Bocca Ruiz has served as a clinical trial investigator for AstraZeneca and Zambon. B. François reports consultancy fees with GSK, Enlivex, Inotrem, Takeda, Aridis, Transgene, AM-Pharma, Asahi-Kasai and Biomérieux within the past 36 months. R. Muñoz-Bermúdez has participated on an advisory board for GSK. J.D. Isaacs has received research funding from GSK, Janssen and Pfizer, and personal fees from AbbVie, BMS, Gilead, Roche and UCB, all outside the submitted work, as well as support for event attendance from Eli Lilly and Gilead. A. Beishuizen has received consultancy fees from GSK. C. McEvoy has received research funding from the National Institutes of Health, US Department of Defense, Patient-Centered Outcomes Research Institute, GSK and AstraZeneca. C. Summers’ institution has received research funding from GSK, AstraZeneca, the Wellcome Trust, The Medical Research Council and National Institute for Health Research to support her work outside the area of the submitted manuscript. C. Summers has received personal fees from AbbVie, Roche and GSK. G.J. Criner has received research grants from ALung Technologies Inc., American College of Radiology, American Lung Associations, AstraZeneca, BioScale Inc., Boehringer Ingelheim, BREATH Therapeutics Inc., COPD Foundation, Coridea/ZIDAN, Corvus, Dr Karen Burns of St Michael's Hospital, Fisher & Paykel Healthcare Ltd, Galapagos NV, GSK, Kinevent, Lungpacer Medical Inc., National Heart Lung and Blood Institute, Nurvaira Inc., Patient-Centered Outcomes Research Institute, Pulmonary Fibrosis Foundation, PulmonX, Respironics Inc., Respivant Sciences, Spiration Inc., Steward St Elizabeth's Medical Center of Boston Inc. and Veracyte Inc.; and received personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Broncus Medical, CSA Medical, EOLO Medical, Gala Therapeutics, GSK, Helios Medical, Ion, Merck, Medtronic, Mereo BioPharma, NGM Biopharmaceuticals, Novartis, Olympus, PulmonX, Respironics Inc., Respivant Sciences, The Implementation Group and Verona Pharma. J. Neisen is an employee and shareholder of AstraZeneca, and a shareholder and former employee of GSK. L.E. Schwab reports holding shares in Johnson & Johnson and BMS, and participated on the Holy Cross Health Institutional Review Board. Z. Shahid has received research funding from Karyopharm. M. Shirano is an investigator in separate trials funded by Roche and AstraZeneca, and has received payment for lectures from Gilead Sciences. E. Sprinz participates on a data safety monitoring board/advisory board for, and has received consulting fees and honoraria from, GSK, Janssen and Gilead. M.A. Tidswell received a fee for serving on the independent data monitoring committee for this study, as well as for serving on a data safety monitoring board/advisory board for Spectral Diagnostics Inc., ReAlta Life Sciences Inc., Celltrion Inc., AstraZeneca and Molecular Partners AG. Additionally, M.A. Tidswell has held a research contract with Edesa Biotech Research Inc., RevImmune SAS, Spectral Diagnostics, Beyond Air Inc., National Institutes of Health and National Heart, Lung, and Blood Institute. D. Wyncoll received a fee for serving on the independent data monitoring committee for this study, has served as a study adjudicator for AstraZeneca, and reports consulting fees and/or honoraria from Gilead and Shionogi. J. de-Miguel-Díez, H. Boughanmi, J-C. Lacherade, P. Martinez-Ayala, T. Hatlen, G. Plantefeve, N. Terzi, M. Shirano, N. Kostina, T. Kropotina, Y. Trefilova and M. Monchi have no other conflicts of interest to declare., (Copyright ©The authors 2023.)

Objective: To develop EULAR points-to-consider for therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases (RMDs)., Methods: The 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., Results: Six 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., Conclusion: These 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., Competing Interests: Competing interests: AvT: has received unrestricted research grants from Pfizer, Abbvie, Novartis, UCB and Biogen and consultancy fees from Novartis; AB: has received Grant/research support, fees for consultancies or as a speaker from Abbvie, Amgen, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, UCB, Roche; GLG: has acted as a consultant or received speakers fees from AbbVie, Boehringer-Mannheim, Eli Lilly, Novartis, Orion Pharma, Pfizer, Roche and UCB; MJ: has received travel expenses from Abbvie and speakers fees from Grifols in the last 5 years; PDWK: consultancy/speaker fees/sponsorship from Abbvie, Gilead, Lilly, Novartis, Sanofi, Sobi; DM: has acted as a consultant and given lectures on behalf of his institution for Pfizer, Novartis, Grifols; he has been invited to attend an international congress by Janssen-Cilag. His institution received grants for research from the non-governmental organisation Lions Club Tours Val de France; VN-C: has received research grants/honoraria from AbbVie, Janssen, Lilly, Novartis, Pfizer, and UCB; MP: speaker or consultancy from Abbvie, Celltrion, Gilead, Lilly, Biogen Janssen- Cilag. Unrestricted educational grants Abbvie, Celgene, Lilly, Roche, Grifols, Biogen; SRS: has received consulting/speaker’s fees from 67 Health, Ampersand Health, Envision Pharma Group, Janssen, and On The Pulse Consultancy, and is an employee of Envision Pharma Group, unrelated to the work presented in this manuscript; JDI: grant income from Pfizer, GSK, Janssen and consultancy/speaker fees/sponsorship from Abbvie, BMS, Gilead, Roche, UCB., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims and Method: This paper analyses how practice varied between patients aged <65 and ≥65 years in the 2019 UK national memory service audit., Results: Data on 3959 patients were analysed. Those aged <65 (7% of the sample) were less likely than those aged ≥65 to be diagnosed with dementia (23 v. 67%) and more likely to receive a functional, psychiatric or no diagnosis. Younger patients were more likely to have magnetic resonance imaging; use of dementia biomarkers was low in both groups. Frontotemporal dementia and functional cognitive disorder were diagnosed infrequently. Use of dementia navigators/advisors and carer psychoeducation was similar between groups; younger patients were less likely to be offered but more likely to accept cognitive stimulation therapy., Clinical Implications: Memory services seeing younger people need expertise in functional cognitive disorder, alongside clinical skills and technologies to diagnose rarer forms of dementia. Further work is needed to understand why cognitive stimulation therapy is less frequently offered to younger people.

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., Competing Interests: Competing interests: RBML received honoraria for lecturing and consultation from AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, UCB, is chair of EULAR’s committee for the quality of care and is owner and director of Rheumatology Consultancy BV. RBML is chair of EULAR’s committee of quality of care. AN received honoraria for lectures and consulting form BMS, UCB, Chigai and Roche. JWJB received honoraria for lectures and consulting from Fresnius, Galapagos, Syneos. GRB received honoraria for lectures and consulting from AbbVie, Amgen, BMS, Gilead, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis, Roche, UCB. RC received honoraria for lectures from AbbVie, Janssen, Roche, Sanofi. BC received honoraria for lecturing and consultation from AbbVie, BMS, Celltrion, Galapagos, Gilead, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Roche-Chugai. RC received honoraria for lectures and consulting or travel support from AbbVie, Janssen, Nordic Pharma, Roche and Sanofi. JRC received research grants and consulting from Amgen, AbbVie, BMS, GSK, Janssen, Lilly, Novartis, Pfizer, and chairs the ACR COVID Vaccine Guidance Task Force. OE received honoraria for lecturing and consultation from AbbVie, BMS, Celgene, Gilead, Janssen, Eli Lilly, Novartis, Pfizer and B.I. MWH Consultation and speaker’s fees from ALK and Roche. LH received a speaker’s fee from Grünenthal, honoraria for writing articles from MedMedia, and travel support from AbbVie, Biogen, BMS, MSD, Novartis and Roche. AI received consultancies, honoraria, speaker-fees from AbbVie, MSD, Alfasigma, Celltrion, BMS, Celgene, Eli Lilly, Sanofi, Genzyme, Pfizer, Galapagos, Gilead, Novartis, SOBI and research grants from MSD, Alfasigma, AbbVie. AI is acting president of EULAR. JDI received research grants from Pfizer, Janssen and GSK and honoraria for lectures, conference support from Eli Lilly and Gilead, and speaker/consulting fees from AbbVie, Gilead, Roche and UCB. XM received consulting fees from BMS, Gilead, Janssen, Pfizer, Samsung, UCB. BC received honoraria from AbbVie, BMS, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Roche-Chugai, Sanofi and UCB; and research grants from Novartis, Pfizer, and Roche. IBM received research grants from Lilly, Pfizer, BMS, Celgene, Janssen; and consulting fees from AbbVie, BMS, Celgene, Gilead, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis and UCB. IBM is past president of EULAR. HS-K received honoraria for lectures and consulting from AbbVie, Amgen, BMS, Gilead, Janssen, Lilly, Novartis, Pfizer, Sanofi-Aventis, Roche and UCB. JSS received grants to his institution from AbbVie, AstraZeneca, Janssen, Lilly, MSD, Pfizer and Roche and provided expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO Pharma, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB. JSS is editor of the Annals of Rheumatic Diseases. KW received honoraria and consultancy fees from AbbVie, Lilly, Roche, GSK, Novartis, BMS, Pfizer, UCB, Janssen, Regeneron and Sanofi. VN-C received research grants/honoraria from AbbVie, Janssen, Lilly, Novartis, Pfizer, and UCB. PMM received consulting/speaker’s fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

For many oncological conditions, the application of timely and patient-tailored targeted therapies, or precision medicine, is a major therapeutic development that has provided considerable clinical benefit. However, despite the application of increasingly sophisticated technologies, alongside advanced bioinformatic and machine-learning algorithms, this success is yet to be replicated for the rheumatic diseases. In rheumatoid arthritis, for example, despite an array of targeted biologic and conventional therapeutics, treatment choice remains largely based on trial and error. The concept of the 'precision gap' for rheumatic disease can help us to identify factors that underpin the slow progress towards the discovery and adoption of precision-medicine approaches for rheumatic disease. In a rheumatic disease such as rheumatoid arthritis, it is possible to identify four themes that have slowed progress, solutions to which should help to close the precision gap. These themes relate to our fundamental understanding of disease pathogenesis, how we determine treatment response, confounders of treatment outcomes and trial design., (© 2022. Springer Nature Limited.)

Background: Rituximab is widely used to treat autoimmunity but clinical response varies. Efficacy is determined by the efficiency of B-cell depletion, which may depend on various Fc gamma receptor (FcγR)-dependent mechanisms. Study of FcγR is challenging due to the complexity of the FCGR genetic locus. We sought to assess the effect of FCGR variants on clinical response, B-cell depletion and NK-cell-mediated killing in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)., Methods: A longitudinal cohort study was conducted in 835 patients [RA = 573; SLE = 262]. Clinical outcome measures were two-component disease activity score in 28-joints (2C-DAS28CRP) for RA and British Isles Lupus Assessment Group (BILAG)-2004 major clinical response (MCR) for SLE at 6 months. B-cells were evaluated by highly-sensitive flow cytometry. Single nucleotide polymorphism and copy number variation for genes encoding five FcγRs were measured using multiplex ligation-dependent probe amplification. Ex vivo studies assessed NK-cell antibody-dependent cellular cytotoxicity (ADCC) and FcγR expression., Findings: In RA, carriage of FCGR3A-158V and increased FCGR3A-158V copies were associated with greater 2C-DAS28CRP response (adjusted for baseline 2C-DAS28CRP). In SLE, MCR was associated with increased FCGR3A-158V, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF OR 1.93 (95% CI 1.09-3.40) copies. 236/413 (57%) patients with B-cell data achieved complete depletion. Homozygosity for FCGR3A-158V and increased FCGR3A-158V copies were associated with complete depletion in combined analyses. FCGR3A genotype was associated with rituximab-induced ADCC, and increased NK-cell FcγRIIIa expression was associated with improved clinical response and depletion in vivo. Furthermore, disease status and concomitant therapies impacted both NK-cell FcγRIIIa expression and ADCC., Interpretation: FcγRIIIa is the major low affinity FcγR associated with rituximab response. Increased copies of the FCGR3A-158V allele (higher affinity for IgG1), influences clinical and biological responses to rituximab in autoimmunity. Enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping may stratify patients for optimal treatment protocols., Funding: Medical Research Council, National Institute for Health and Care Research, Versus Arthritis., Competing Interests: Declaration of interests Prof Bruce has received research grants from GSK, consulting fees from GSK, UCB, Eli Lilly & Co, BMS, Aurinia, IL-TOO and AstraZeneca and speaker fees from AstraZeneca, GSK and UCB within the last 3 years. Dr Vital has received honoraria and consulting fees from Roche within the last 3 years. All other authors declare no competing interest related to the work described in this manuscript., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: There are few randomized clinical trials in vascular cognitive impairment (VCI). This trial tested the hypothesis that the PDE5 inhibitor tadalafil, a widely used vasodilator, increases cerebral blood flow (CBF) in older people with symptomatic small vessel disease, the main cause of VCI., Methods: In a double-blind, placebo-controlled, cross-over trial, participants received tadalafil (20 mg) and placebo on two visits ≥7 days apart (randomized to order of treatment). The primary endpoint, change in subcortical CBF, was measured by arterial spin labelling., Results: Tadalafil increased CBF non-significantly in all subcortical areas (N = 55, age: 66.8 (8.6) years) with greatest treatment effect within white matter hyperintensities (+9.8%, P = .0960). There were incidental treatment effects on systolic and diastolic blood pressure (-7.8, -4.9 mmHg; P < .001). No serious adverse events were observed., Discussion: This trial did not identify a significant treatment effect of single-administration tadalafil on subcortical CBF. To detect treatment effects may require different dosing regimens., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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 < 0.05), irrespective of clinical response. One module (M3.2), related to inflammation and TNF biology, significantly correlated with response to adalimumab. Similar patterns of modular expression, with reduced magnitude, were observed in the methotrexate cohort., 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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Control of disease activity in RA is a crucial part of its management to prevent long-term joint damage and disability. This study aimed to identify early predictors of poor disease activity at 5 and 10 years, focusing on comorbidities and clinical/sociodemographic factors at first presentation., Methods: Patients from two UK-based RA cohorts were classified into two groups; low (&lt;3.2) and moderate/high (≥3.2) DAS using 28 joint counts (DAS28) at 5/10 years. Clinical variables (e.g. rheumatoid nodules, erosions), sociodemographic factors (e.g. ethnicity, deprivation) and comorbidities were recorded at baseline and yearly thereafter. The Rheumatic Diseases Comorbidity Index quantified patient comorbidity burden. Binary logistic regression models (outcome low vs moderate/high DAS28) were fitted using multiple imputation., Results: A total of 2701 patients living with RA were recruited (mean age 56.1 years, 66.9% female); 5-year data were available for 1718 (63.4%) patients and 10-year data for 820 (30.4%). Baseline Rheumatic Diseases Comorbidity Index was not associated with DAS28 at 5 [odds ratio (OR) 1.05, 95% CI 0.91, 1.22] or 10 years (OR 0.99, 95% CI 0.75, 1.31) in multivariable analyses. Sociodemographic factors (female gender, worse deprivation) and poorer baseline HAQ-Disability Index were associated with DAS28 ≥3.2 at both timepoints. Being seropositive was associated with 5-year DAS28 ≥3.2., Conclusion: This study demonstrates an association between sociodemographic and clinical factors and long-term RA disease activity, in models adjusting for comorbidity burden. The findings call for more holistic and targeted patient management in patients with RA and provide insights for more individualized management plans even on first presentation to rheumatology., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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 ( 19 F-MRI) promises an attractive cell tracking method because it allows for detection of 19 F-labelled cells in a non-invasive and longitudinal manner. Here, we tested the suitability of nanoparticles containing 19 F ( 19 F-NP) for labelling of therapeutic human tolDC for detection by 19 F-MRI. We found that tolDC readily endocytosed 19 F-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, 19 F-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 19 F-NP labelling. We conclude that 19 F-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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer PR declared participation with the authors in the INSTRuCT Consortium to the handling editor., (Copyright © 2022 Cooke, Neal, Wood, de Vries, Anderson, Diboll, Pratt, Stanway, Nicorescu, Moyse, Hiles, Caulfield, Dickinson, Blamire, Thelwall, Isaacs and Hilkens.)

Objectives: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action., Methods: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS ( MxA, IFI44L, OAS1, IFI6, ISG15 ) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes., Results: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1 , associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α)., Conclusions: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA., Competing Interests: Competing interests: JDI discloses research grants from Pfizer, Janssen and GSK; conference support from Eli Lilly and Gilead; speaker/consulting fees from AbbVie, BMS, Gilead, Roche and UCB. FAHC discloses speaker fees from AstraZeneca.The remaining authors have no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Cerebral small vessel disease (SVD) is common in older people and is associated with lacunar stroke, white matter hyperintensities (WMH) and vascular cognitive impairment. Cerebral blood flow (CBF) is reduced in SVD, particularly within white matter.Here we quantified test-retest reliability in CBF measurements using pseudo-continuous arterial spin labelling (pCASL) in older adults with clinical and radiological evidence of SVD (N=54, mean (SD): 66.9 (8.7) years, 15 females/39 males). We generated whole-brain CBF maps on two visits at least 7 days apart (mean (SD): 20 (19), range 7-117 days).Test-retest reliability for CBF was high in all tissue types, with intra-class correlation coefficient [95%CI]: 0.758 [0.616, 0.852] for whole brain, 0.842 [0.743, 0.905] for total grey matter, 0.771 [0.636, 0.861] for deep grey matter (caudate-putamen and thalamus), 0.872 [0.790, 0.923] for normal-appearing white matter (NAWM) and 0.780 [0.650, 0.866] for WMH (all p<0.001). ANCOVA models indicated significant decline in CBF in total grey matter, deep grey matter and NAWM with increasing age and diastolic blood pressure (all p<0.001). CBF was lower in males relative to females (p=0.013 for total grey matter, p=0.004 for NAWM).We conclude that pCASL has high test-retest reliability as a quantitative measure of CBF in older adults with SVD. These findings support the use of pCASL in routine clinical imaging and as a clinical trial endpoint.All data come from the PASTIS trial, prospectively registered at: https://eudract.ema.europa.eu (2015-001235-20, registered 13/05/2015), http://www.clinicaltrials.gov (NCT02450253, registered 21/05/2015)., (© 2021. The Author(s).)

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 (<1.5) and high (≥1.5) five- and 10-year health assessment questionnaire (HAQ) score. Clinical variables (e.g. disease activity, rheumatoid nodules, erosions) and sociodemographic factors (e.g. ethnicity, deprivation) were recorded at baseline and yearly thereafter. Comorbidity was measured using the Rheumatic Diseases Comorbidity Index (RDCI). Binary logistic regression models were fitted using multiple imputation., 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Cerebral small vessel disease (SVD) causes lacunar stroke and vascular cognitive impairment in older people. The pathogenic pathways from vessel pathology to parenchymal damage in SVD are unknown. Neurofilaments are axonal structural proteins. Neurofilament-light (NfL) is an emerging biomarker for neurological disease. Here, we examined the high molecular weight form neurofilament-heavy (NfH) and quantified a characteristic pattern of peri-arterial (vasculocentric) NfH labeling. Subcortical frontal and parietal white matter from young adult controls, aged controls, and older people with SVD or severe Alzheimer disease (n = 52) was immunohistochemically labeled for hyperphosphorylated NfH (pNfH). The extent of pNfH immunolabeling and the degree of vasculocentric axonal pNfH were quantified. Axonal pNfH immunolabeling was sparse in young adults but a common finding in older persons (controls, SVD, or AD). Axonal pNfH was often markedly concentrated around small penetrating arteries. This vasculocentric feature was more common in older people with SVD than in those with severe AD (p = 0.004). We conclude that axonal pNfH is a feature of subcortical white matter in aged brains. Vasculocentric axonal pNfH is a novel parenchymal lesion that is co-located with SVD arteriopathy and could be a consequence of vessel pathology., (© 2022 American Association of Neuropathologists, Inc. All rights reserved.)

Objectives: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19., Methods: According 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., Results: We 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 therapy CONCLUSIONS: Growing 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., Competing Interests: Competing interests: AA, AN, HB, FC, GDM, RG, CM-C and JRC have nothing to declare. PMM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. G-RRB has received consulting and/or speaker’s fees from Abbvie, Gilead, Lilly, Roche, Sanofi, Pfizer all unrelated to this manuscript. IK-P has received consulting and/or speaker’s fees from Novartis, SOBI, Amgen, CHUGAI, Pfizer, LFB, Novimmune, Abbvie and PAtent for AIDAI score AVR has received speaker fees/Honoraria from Abbvie, Lilly, Roche, UCB, SOBI and Novartis all unrelated to this manuscript. DGM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. XM has received consulting and/or speaker’s fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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 Sjögren's syndrome. A high IGS does not uniformly predict worse clinical phenotypes across all diseases, as demonstrated by a reduced disease burden in primary Sjögren'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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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 CD25 high 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., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: It is not enough to optimize proteomics assays. It is critical those assays are robust to operating conditions. Without robust assays, proteomic biomarkers are unlikely to translate readily into the clinic. This study outlines a structured approach to the identification of a robust operating window for proteomics assays and applies that method to Sequential Window Acquisition of all Theoretical Spectra Mass Spectroscopy (SWATH-MS)., Methods: We used a sequential quality by design approach exploiting a fractional screening design to first identify critical SWATH-MS parameters, then using response surface methods to identify a robust operating window with good reproducibility, before validating those settings in a separate validation study., Results: The screening experiment identified two critical SWATH-MS parameters. We modelled the number of proteins and reproducibility as a function of those parameters identifying an operating window permitting robust maximization of the number of proteins quantified in human serum. In a separate validation study, these settings were shown to give good proteome-wide coverage and high quantification reproducibility., Conclusions: Using design of experiments permits identification of a robust operating window for SWATH-MS. The method gives a good understanding of proteomics assays and greater data-driven confidence in SWATH-MS performance., (© 2021. The Author(s).)

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., (© 2020. The Author(s).)

Background: Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism., Methods: The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data., Discussion: This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need., Trial Registration: The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 ., (© 2021. The Author(s).)

Background: Adaptive model-based dose-finding designs have demonstrated advantages over traditional rule-based designs but have increased statistical complexity but uptake has been slow especially outside of cancer trials. TRAFIC is a multi-centre, early phase trial in rheumatoid arthritis incorporating a model-based design., Methods: A Bayesian adaptive dose-finding phase I trial rolling into a single-arm, single-stage phase II trial. Model parameters for phase I were chosen via Monte Carlo simulation evaluating objective performance measures under clinically relevant scenarios and incorporated stopping rules for early termination. Potential designs were further calibrated utilising dose transition pathways., Discussion: TRAFIC is an MRC-funded trial of a re-purposed treatment demonstrating that it is possible to design, fund and implement a model-based phase I trial in a non-cancer population within conventional research funding tracks and regulatory constraints. The phase I design allows borrowing of information from previous trials, all accumulated data to be utilised in decision-making, verification of operating characteristics through simulation, improved understanding for management and oversight teams through dose transition pathways. The rolling phase II design brings efficiencies in trial conduct including site and monitoring activities and cost. TRAFIC is the first funded model-based dose-finding trial in inflammatory disease demonstrating that small phase I/II trials can have an underlying statistical basis for decision-making and interpretation., Trial Registration: Trials Registration: ISRCTN, ISRCTN36667085 . Registered on September 26, 2014.

Objectives: Severe systemic inflammation associated with some stages of COVID-19 and in fatal cases led therapeutic agents developed or used frequently in Rheumatology being at the vanguard of experimental therapeutics strategies. The aim of this project was to elaborate EULAR Points to consider (PtCs) on COVID-19 pathophysiology and immunomodulatory therapies., Methods: PtCs were developed in accordance with EULAR standard operating procedures for endorsed recommendations, led by an international multidisciplinary Task Force, including rheumatologists, translational immunologists, haematologists, paediatricians, patients and health professionals, based on a systemic literature review up to 15 December 2020. Overarching principles (OPs) and PtCs were formulated and consolidated by formal voting., Results: Two OPs and fourteen PtCs were developed. OPs highlight the heterogeneous clinical spectrum of SARS-CoV-2 infection and the need of a multifaceted approach to target the different pathophysiological mechanisms. PtCs 1-6 encompass the pathophysiology of SARS-CoV-2 including immune response, endothelial dysfunction and biomarkers. PtCs 7-14 focus on the management of SARS-CoV-2 infection with immunomodulators. There was evidence supporting the use of glucocorticoids, especially dexamethasone, in COVID-19 cases requiring oxygen therapy. No other immunomodulator demonstrated efficacy on mortality to date, with however inconsistent results for tocilizumab. Immunomodulatory therapy was not associated with higher infection rates., Conclusions: Multifactorial pathophysiological mechanisms, including immune abnormalities, play a key role in COVID-19. The efficacy of glucocorticoids in cases requiring oxygen therapy suggests that immunomodulatory treatment might be effective in COVID-19 subsets. Involvement of rheumatologists, as systemic inflammatory diseases experts, should continue in ongoing clinical trials delineating optimal immunomodulatory therapy utilisation in COVID-19., Competing Interests: Competing interests: AA, AN, HB, FC, GDM, RG, CM-C and JRC have nothing to declare. PMM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. GRB has received consulting and/or speaker’s fees from Abbvie, Gilead, Lilly, Roche, Sanofi, Pfizer all unrelated to this manuscript. IK-P has received consulting and/or speaker’s fees from Novartis, SOBI, Amgen, CHUGAI, Pfizer, LFB, Novimmune, Abbvie and PAtent for AIDAI score AVR has received speaker fees/Honoraria from Abbvie, Lilly, Roche, UCB, SOBI and Novartis all unrelated to this manuscript. DGM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. XM has received consulting and/or speaker’s fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Modern therapeutic agents and treatment regimens have made sustained remission an attainable target for many patients across a spectrum of immune-mediated inflammatory diseases, albeit at the risk of adverse events and the expense of drug prescription and safety monitoring. Clinicians and patients are thus increasingly faced with a novel treatment dilemma: whether and how best to stop immunomodulatory treatment in patients who achieve remission. In this final paper in a Series on therapeutic tolerance induction, we summarise our current knowledge of biomarkers of immune homeostasis in immune-mediated inflammatory diseases and their application to the prediction and attainment of sustained drug-free remission. We summarise evidence from prospective studies of immunomodulatory drug cessation across a range of immune-mediated inflammatory diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, and inflammatory bowel disease. We also consider current evidence for clinical, serological, proteomic, metabolomic, cellular, and microbiomic biomarkers of immune homeostasis. Finally, we discuss the steps necessary for clinical translation of these biomarkers, as well as the potential transformative effect of these biomarkers on management of patients with immune-mediated inflammatory diseases if clinical translation is successfully achieved., Competing Interests: Declaration of interests KFB reports grants to study drug-free remission in rheumatoid arthritis from the British Society for Rheumatology, Academy of Medical Sciences, JGW Patterson Foundation, and Wellcome Trust. KFB and JDI are named inventors on a patent application by Newcastle University (“Prediction of drug-free remission in rheumatoid arthritis”; International Patent Application Number PCT/GB2019/050902), and have an ongoing collaboration with Genentech to measure cytokines and chemokines in rheumatoid arthritis. JPXS declares no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 (C max ) and area under the plasma concentration time curve 0-6 h (AUC 0-6 ) 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 C max and AUC 0-6 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., (© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.)

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.

Biologic agents have become a core component of therapeutic strategies for many inflammatory rheumatic diseases. However, perhaps reflecting the specificity and generally high affinity of biologic agents, these therapeutics have been used by rheumatologists with less consideration of their pharmacokinetics than that of conventional synthetic DMARDs. Immunogenicity was recognized as a potential limitation to the use of biologic agents at an early stage in their development, although regulatory guidance was relatively limited and assays to measure immunogenicity were less sophisticated than today. The advent of biosimilars has sparked a renewed interest in immunogenicity that has resulted in the development of increasingly sensitive assays, an enhanced appreciation of the pharmacokinetic consequences of immunogenicity and the development of comprehensive and specific guidance from regulatory authorities. As a result, rheumatologists have a greatly improved understanding of the field in general, including the factors responsible for immunogenicity, its potential clinical consequences and the implications for everyday treatment. In some specialties, immunogenicity testing is becoming a part of routine clinical management, but definitive evidence of its cost-effectiveness in rheumatology is awaited.

Given considerable variation in diagnostic and therapeutic practice, there is a need for national guidance on the use of neuroimaging, fluid biomarkers, cognitive testing, follow-up and diagnostic terminology in mild cognitive impairment (MCI). MCI is a heterogenous clinical syndrome reflecting a change in cognitive function and deficits on neuropsychological testing but relatively intact activities of daily living. MCI is a risk state for further cognitive and functional decline with 5-15% of people developing dementia per year. However, ~50% remain stable at 5 years and in a minority, symptoms resolve over time. There is considerable debate about whether MCI is a useful clinical diagnosis, or whether the use of the term prevents proper inquiry (by history, examination and investigations) into underlying causes of cognitive symptoms, which can include prodromal neurodegenerative disease, other physical or psychiatric illness, or combinations thereof. Cognitive testing, neuroimaging and fluid biomarkers can improve the sensitivity and specificity of aetiological diagnosis, with growing evidence that these may also help guide prognosis. Diagnostic criteria allow for a diagnosis of Alzheimer's disease to be made where MCI is accompanied by appropriate biomarker changes, but in practice, such biomarkers are not available in routine clinical practice in the UK. This would change if disease-modifying therapies became available and required a definitive diagnosis but would present major challenges to the National Health Service and similar health systems. Significantly increased investment would be required in training, infrastructure and provision of fluid biomarkers and neuroimaging. Statistical techniques combining markers may provide greater sensitivity and specificity than any single disease marker but their practical usefulness will depend on large-scale studies to ensure ecological validity and that multiple measures, e.g. both cognitive tests and biomarkers, are widely available for clinical use. To perform such large studies, we must increase research participation amongst those with MCI., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Objectives: Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety., Methods: Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration., Results: The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale., Conclusion: The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management., Competing Interests: Competing interests: DA has received grants from AbbVie, Novartis and Roche, consulting and lecture fees from Abbvie, Amgen, Celgene, Lilly, Medac, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sandoz and Sanofi/Genzyme. W-HB has received a research grant from Pfizer and honoraria for advice from Abbvie, Alimirall, BMS, Celgene, Janssen, Leo, Lilly, Novartis and UCB. TD received study support and/or consulting fees by AbbVie, Celgene, Eli-Lilly, EMD/Merck, Janssen, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Biogen, Sandoz. PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly. XB, KG received consultancy and lecture fees from Novartis, Pfizer and Roche and investigational grants from Roche. EBL reports grants from Green pharma, Seoul, grants from Handoc, Seoul, and personal fees from Pfizer. PTN has received research grants and funding for clinical trials and honoraria for advice and lectures on behalf of Abbvie, BMS, Boehringer Ingelheim, Celgene, Eli-Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. JEP has consulted for Amgen, AbbVie, BMS, Celltrion, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Samsung, Sandoz, Sanofi, Teva, UCB. RMF has received research grants and funding for clinical trials and honoraria for adbice from Abbvie, Amgen, Astra-Zeneca, BMS, Celltrion, Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi, Tahio and UCB. DvdH received consulting fees AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv. JDI has received research funding or honoraria from Abbvie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche. AK has received lecture fees from Bristol-Myers Squibb, Celgene, Merck Sharp and Dohme and Pfizer. JK received grant support for clinical research from Abbvie, BMS, Lilly, Novartis, Pfizer and consulted with Abbvie, BMS, Lilly, Novartis, Pfizer and Regeneron/Sanofi. IBM has received research funding or honoraria from Abbvie, Astra Zeneca, Celgene, GSK, Lilly, Boehringer, Pfizer, Janssen, Novartis, UCB, BMS, Sanofi. WPM has served as a consultant, and/or received honoraria and/or has received research/educational grants from AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma, and is Chief Medical Officer of CARE Arthritis Limited. MV: no conflict of interest. JSS has received research Grants for his institution from AbbVie, BMS, Lilly, MSD, Pfizer, Roche and honoraria for consultancies and/or speaking engagements: Abbvie, Amgen, Astra-Zeneca, Astro-Celltrion, BMS, Celgene, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. MS-M has no conflicts of interest. LST received grant support from Janssen, GSK and Pfizer and honoraria for consultations and/or speaking engagements from Janssen, Pfizer, Sanofi, Abbvie and Lilly. TT received grants from Astellas, AbbVie GK, Eisai; speaking fee from: AbbVie GK, Eli Lilly Japan, Astellas, Eisai, Gilead, Pfizer Japan; and consultancy fees from: Astellas, AbbVie GK, Gilead. YT has received speaking fees and/or honoraria from Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen and has received research grants from Mitsubishi-Tanabe, Chugai, Abbvie, Takeda, UCB, Daiichi-Sankyo, Eisai. MT: Speaker for BMS, Falk Foundation, Gilead and MSD; advisory boards for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and Regulus. He further received unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. He is also co-inventor of patents on the medical use of norUDCA (filed by the medical University of Graz as previous employer). FvdB received consultancy and/or speaker fees from Abbvie, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer and UCB. MdW has received honoraria for consultancies and speaking through Stichting Tools from AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche. RW: honoraria for speaking engagements and advice from Galapagos, Gilead and Celltrion. KLW received grant support from BMS and Pfizer and honoraria for consultations and /or speaking engagements from Pfizer, BMS, Abbvie, Gilead, Galapagos, Lilly, GSK, UCB. RX received consultancy and/or speaker fees from Abbvie, Lilly, Pfizer, UCB, Janssen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Psoriatic arthritis (PsA) is a debilitating immune-mediated inflammatory arthritis of unknown pathogenesis commonly affecting patients with skin psoriasis. Here we use complementary single-cell approaches to study leukocytes from PsA joints. Mass cytometry demonstrates a 3-fold expansion of memory CD8 T cells in the joints of PsA patients compared to peripheral blood. Meanwhile, droplet-based and plate-based single-cell RNA sequencing of paired T cell receptor alpha and beta chain sequences show pronounced CD8 T cell clonal expansions within the joints. Transcriptome analyses find these expanded synovial CD8 T cells to express cycling, activation, tissue-homing and tissue residency markers. T cell receptor sequence comparison between patients identifies clonal convergence. Finally, chemokine receptor CXCR3 is upregulated in the expanded synovial CD8 T cells, while two CXCR3 ligands, CXCL9 and CXCL10, are elevated in PsA synovial fluid. Our data thus provide a quantitative molecular insight into the cellular immune landscape of psoriatic arthritis.

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dynactin-1 (DCTN1)-related Parkinson-plus disorder (Perry syndrome) is an autosomal dominant neurodegenerative disorder characterised by levodopa-resistant parkinsonism, weight loss, mood change and central hypoventilation. Ventilatory insufficiency is the predominant cause of death. It has been previously described in 87 people from 20 families with a worldwide distribution. It is now recognised as a distinct TDP-43 proteinopathy caused by a pathological mutation in DCTN1. Its rarity and clinical overlap with other neurodegenerative diseases increase the risk of delayed or incorrect diagnosis. Ventilatory support can improve life expectancy but this depends upon its recognition; overall its prognosis remains poor. We report a patient with DCTN1-related Parkinson-plus disorder, in whom genetic confirmation came only after death., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm., (Copyright © 2020 Elsevier Ltd. All rights reserved.)