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

A novel HPLC MS/MS assay for the biochemical detection of adherence to tofacitinib with evidence of sensitive measurement using real-world patient samples is reported.

Background Biologic and nonbiologic immunomodulators, used to treat immune-mediated inflammatory diseases (IMIDs), could impair the immune response to COVID-19 vaccines and thus vaccine effectiveness. Objectives Our objective was to investigate the association between biologic and nonbiologic immunomodulators and seroconversion following the first and second dose of COVID-19 vaccines in patients with IMIDs. Methods Serum samples were collected following the first or second dose of the BNT162b2 or AZD1222 vaccines from patients receiving biologic and/or nonbiologic immunomodulators for one or more of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease or systemic lupus erythematosus. Seroconversion was defined as a positive Roche Elecsys® Anti-SARS-CoV-2 S (spike protein subunit S1/receptor binding domain) immunoassay (≥ 0.8 U mL–1). Association between immunomodulator exposure and seroconversion was assessed using logistic regression, adjusting for age and sex. Results After excluding those with prior COVID-19, post-first vaccine dose samples from 193 participants and post-second dose samples from 312 participants were included in the analysis. Following the first vaccine dose, 17.6% (n = 34) of participants did not seroconvert. Seroconversion was reduced for those on nonbiologic [adjusted odds ratio (OR) 0.29, 95% confidence interval (CI) 0.12–0.69] or combined nonbiologic and biologic treatment (adjusted OR 0.14, 95% CI 0.045–0.45) compared with those on biologic monotherapy. Subgroup analysis demonstrated reduced odds of seroconversion in those on methotrexate (adjusted OR 0.097, 95% CI 0.19–0.49) or prednisolone treatment (adjusted OR 0.044, 95% CI 0.002–1.00) relative to tumour necrosis factor-α inhibitor monotherapy. No participants receiving rituximab (n < 5) seroconverted after the first vaccine dose. Following the second vaccine dose, 1.6% of all participants did not seroconvert. Non-seroconversion was associated with receiving rituximab (n = 3 of 4) compared with those receiving other therapies (n = 2 of 308, P < 0.001). Post hoc analyses demonstrated that non-seroconversion was associated with age [adjusted OR 0.18, 95% CI 0.037–0.93 for those aged 60 years and over (reference category age 18–39 years)], but not sex, ethnicity or vaccine type. Conclusions Treatment with nonbiologics, particularly methotrexate, is associated with impaired seroconversion following two BNT162b2 or AZD1222 vaccine doses, in patients with IMIDs. These findings are consistent with those of other published studies. While this could indicate reduced protection against COVID-19, the immunological parameters that correlate most closely with vaccine effectiveness need to be defined to reach this conclusion.

Objective: To determine the association between race/ethnicity and COVID-19 outcomes in individuals with systemic lupus erythematosus (SLE).Methods: Individuals with SLE from the United States with data entered into the COVID-19 Global Rheumatology Alliance (GRA) registry between 24 March 2020 and 27 August 2021 were included. Variables included age, sex, race and ethnicity (White, Black, Hispanic, other), comorbidities, disease activity, pandemic time period, glucocorticoid dose, antimalarials, and immunosuppressive drug use. The ordinal outcome categories were: not hospitalized, hospitalized with no oxygenation, hospitalized with any ventilation or oxygenation, and death. We constructed ordinal logistic regression models evaluating the relationship between race/ethnicity and COVID-19 severity, adjusting for possible confounders.Results: We included 523 patients; 486 (90.7%) were female and the mean age was 46.6 (SD: 14.0) years. Three hundred and fifty-eight (74.6%) patients were not hospitalized; 40 (8.3%) patients were hospitalized without oxygen, 64 (13.3%) patients were hospitalized with any oxygenation and 18 (3.8%) died. In a multivariable model, Black [OR=2.73 (1.36-5.53)] and Hispanic [OR=2.76 (1.34-5.69)] individuals had higher odds of more severe outcomes than White individuals. Conclusions: Black and Hispanic individuals with SLE experienced more severe COVID-19 outcomes, which is consistent with findings in the US general population. These results likely reflect socioeconomic and health disparities and suggest that more aggressive efforts are needed to prevent and treat infection in this population.

We aim to utilise real world data in evidence synthesis to optimise an evidence base for the effectiveness of biologic therapies in rheumatoid arthritis in order to allow for evidence on first-line therapies to inform second-line effectiveness estimates. We use data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) to supplement RCT evidence obtained from the literature, by emulating target trials of treatment sequences to estimate treatment effects in each line of therapy. Treatment effects estimates from the target trials inform a bivariate network meta-analysis (NMA) of first and second-line treatments. Summary data were obtained from 21 trials of biologic therapies including 2 for second-line treatment and results from six emulated target trials of both treatment lines. Bivariate NMA resulted in a decrease in uncertainty around the effectiveness estimates of the second-line therapies, when compared to the results of univariate NMA, and allowed for predictions of treatment effects not evaluated in second-line RCTs. Bivariate NMA provides effectiveness estimates for all treatments in first- and second-line, including predicted effects in second-line where these estimates did not exist in the data. This novel methodology may have further applications, for example for bridging networks of trials in children and adults. [Abstract copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.]

Objectives Clinicians concerned about long-term safety of biologics in JIA may consider tapering or stopping treatment once remission is achieved despite uncertainty in maintaining drug-free remission. This analysis aims to (i) calculate how many patients with JIA stop biologics for remission, (ii) calculate how many later re-start therapy and after how long, and (iii) identify factors associated with re-starting biologics. Methods Patients starting biologics between 1 January 2010 and 7 September 2021 in the UK JIA Biologics Register were included. Patients stopping biologics for physician-reported remission, those re-starting biologics and factors associated with re-starting, were identified. Multiple imputation accounted for missing data. Results Of 1451 patients with median follow-up of 2.7 years (IQR 1.4, 4.0), 269 (19%) stopped biologics for remission after a median of 2.2 years (IQR 1.7, 3.0). Of those with follow-up data (N = 220), 118 (54%) later re-started therapy after a median of 4.7 months, with 84% re-starting the same biologic. Patients on any-line tocilizumab (prior to stopping) were less likely to re-start biologics (vs etanercept; odds ratio [OR] 0.3; 95% CI: 0.2, 0.7), while those with a longer disease duration prior to biologics (OR 1.1 per year increase; 95% CI: 1.0, 1.2) or prior uveitis were more likely to re-start biologics (OR 2.5; 95% CI: 1.3, 4.9). Conclusions This analysis identified factors associated with successful cessation of biologics for remission in JIA as absence of uveitis, prior treatment with tocilizumab and starting biologics earlier in the disease course. Further research is needed to guide clinical recommendations.

Objective: To investigate how social support, financial status, and lifestyle influence the development of excess disability in rheumatoid arthritis (RA). Methods: Data were obtained from the Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort study of people with RA. A previous analysis identified groups with similar inflammation trajectories but markedly different disability over 10 years; those in the higher disability trajectory groups were defined as having “excess disability.” Self-reported data regarding contextual factors (social support, financial situation, lifestyle) were obtained from participants, and they completed patient-reported outcome measures (pain, fatigue, anxiety, depression) at baseline. The direct effect of the contextual factors on excess disability and the effect mediated by patient-reported outcome measures were assessed using structural equation models. Findings were validated in 2 independent data sets (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN]). Results: Of 538 included ESPOIR participants (mean age ± SD 48.3 ± 12.2 years; 79.2% women), 200 participants (37.2%) were in the excess disability group. Less social support (β = 0.17 [95% confidence interval (95% CI) 0.08, 0.26]), worse financial situation (β = 0.24 [95% CI 0.14, 0.34]), less exercise (β = 0.17 [95% CI 0.09–0.25]), and less education (β = 0.15 [95% CI 0.06, 0.23]) were associated with excess disability group membership; smoking, alcohol consumption, and body mass index were not. Fatigue and depression mediated a small proportion of these effects. Similar results were seen in NOAR and ERAN. Conclusion: Greater emphasis is needed on the economic and social contexts of individuals with RA at presentation; these factors might influence disability over the following decade.

Background/Aims MTX non-adherence is associated with reduced response, increased healthcare costs to the NHS and reduced quality of life for the patient. Often the prescriber is unable to determine if a patient is taking their medication as prescribed. There is a need to measure adherence directly to facilitate more precise and objective measurements of adherence to add to the clinicians tools and help to open up honest discussions and supportive interventions with patients. Our group has previously developed a sensitive biochemical assay for the detection of MTX adherence, MIRA is a feasibility trial designed to assess the feasibility of a randomised controlled trial of MTX biochemical adherence biofeedback. Methods MIRA is a prospective multi-centre randomised controlled trial to examine the feasibility of a fully powered randomised controlled trial to examine if a biochemical adherence guided intervention is superior to standard clinical care in RA patients prescribed MTX. RA patients prescribed oral MTX for ≥ two years were randomised 1:1 to receive biochemical adherence biofeedback or control. Clinico-demographics, biochemical MTX adherence and DAS-28 and were measured at baseline and three months. Participants in the intervention cohort were telephoned with their biochemical adherence results and adherence was explored. Ethical approval for MIRA was given by the North West - Haydock Research Ethics Committee (19/NW/0047) and all participants provided written informed consent. Results 57 participants were recruited, withdrawal rate was 14% and reasons given were intercurrent illness, lost contact, withdrawn consent and one patient died during follow-up leaving full outcome data available for 49 participants. Baseline clinico-demographics were similar in control and intervention cohorts (Table 1). Biochemical adherence worsened in the control cohort and improved in the intervention cohort (17 to 30%, 15 to 8% respectively). Change in DAS(CDP)-28 during the trial worsened in the control cohort but improved in the intervention cohort (-0.04 STD 1.26 and 0.38 STD 0.78 respectively). Conclusion The results of the MIRA trial have demonstrated that the use of a biochemical adherence blood test with biofeedback is feasible as part of a clinical trial. The intervention demonstrated early evidence for efficacy justifying the need for a full definitive trial. Disclosure J. Bluett: None. K.L. Hyrich: None. B. Keevil: None. P. Doran: None. A. Barton: None.

Background/Aims Hydroxychloroquine (HCQ) is an antimalarial drug commonly used in autoimmune conditions such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). In SLE, it has been shown to significantly improve survival and morbidity, but is known to be rarely associated with sight-threatening retinopathy. Data from the US suggested HCQ retinopathy was significantly more common than previously thought (up to 7%), causing the Royal College of Ophthalmology to recommend increased screening in 2018. Natural language processing (NLP) is a machine learning technique which purports to be able to identify patients with a specific diagnosis or taking specific mediations from unstructured data such as clinic letters. This study aimed to understand whether NLP could be used to (i) identify patients taking HCQ and (ii) determine rates of HCQ retinopathy from clinic letters in a UK tertiary Rheumatology centre. Methods The study was set across the Kellgren Centre for Rheumatology (regional tertiary lupus centre) and the Manchester Eye Hospital. Analysis was performed using CogStack/MedCat, an open source self-supervised NLP framework which extracts SNOMED coded items from unstructured electronic health data such as clinic letters. All clinical documents 2012-2022 were identified for patients attending clinics coded as HCQ retinopathy screening. These were processed through Cogstack/MedCat in two stages. Firstly, it identified all patients exposed to HCQ according to their clinic letters. Subsequently, MedCat searched all clinical documents for those patients for references to HCQ retinopathy, HCQ retinopathy screening or retinopathy. Diabetic retinopathy was used to sense-check for other forms of retinopathy. Finally, manual validation of the HCQ retinopathy positive cases was performed. Results From an original 202,704 documents, HCQ exposure was identified in 3904 unique patients. These patients had 74,377 associated clinical documents, from which the NLP process indicated 2815 referenced HCQ retinopathy or retinopathy alone (including screening). From clinic codes 1299 individual patients (33.3% of the HCQ exposed population) were confirmed to have undergone screening; 1094 (84.2%) were female, mean age 54.8 years at the time of screening. Of those screened, NLP highlighted 568 references to HCQ retinopathy from 507 patients, within which 10 (0.77%) were confirmed to have HCQ retinopathy by manual validation. Conclusion The study has demonstrated that NLP is a promising technique to quickly identify subsets of patients (e.g. those taking HCQ) from large numbers of outpatient clinic letters. Further training of the algorithm may improve its ability to identify rare but important clinical outcomes. In a tertiary SLE centre, roughly one third of patients on HCQ were screened for HCQ retinopathy and 0.77% confirmed HCQ retinopathy. This is much lower than data from the previous studies in the US, but is in keeping with more recent publications in UK data, reflected in recent amendments to screening guidelines. Disclosure Y. Mushtaq: None. G. Tilston: None. K.L. Hyrich: None. A. Barton: None. N. Peek: None. B. Parker: None. D. Griffiths: None. J.H. Humphreys: None.

Background/Aims Interleukin 6 inhibitors (IL-6i) can increase LDL cholesterol levels, which raises concerns about the risk of myocardial infarction (MI) in patients with rheumatoid arthritis (RA) receiving this therapy. This study aims to compare the risk of MI between people with RA in the UK clinical setting receiving IL-6i or tumour necrosis factor inhibitors (TNFi) overall or by line of therapy (LoT). Methods Patients with RA registered between 01/10/2001 and 27/05/2022 with BSRBR-RA starting IL-6i or TNFi treatments were included. Occurrence of MI was identified from clinical follow-up forms and through cause of death reported by the national UK death register. Only those MIs occurring whilst the patient was actively receiving drug were included. The risk of MI in patients receiving IL6i compared to TNFi was compared using Cox regression, adjusted for baseline co-variates using propensity scores (PS, see Table 1). Follow-up commenced at the start of the drug of interest and patients were censored at occurrence of MI, death, discontinuation of therapy or last follow-up visit, whichever came first. Multiple imputation was used for missing data. To account for known differences in LoT use of TNFi and IL6i (with IL6i more likely as a later line bDMARD), overall analyses adjusted for LoT in PS and secondary analyses by LoT were conducted. Direct switches between originator to biosimilars were considered the same treatment. Results A total of 29,596 IL6i or TNFi treatments in 20,725 patients were included (3,098 IL-6i; 26,498 TNFi), representing 153,913 person-years of exposure. Compared to patients receiving TNFi, patients starting IL-6i treatment were older, had longer disease duration, less likely to use methotrexate and steroids, and had more comorbidities. During follow-up, 372 MIs occurred, 27 on IL-6i and 345 on TNFi, with an overall lower crude rate of MI in patients receiving IL6i compared to TNFi. After PS adjustment, the risk of MI was not significantly different between the two treatment overall (HR 0.77, 95% CI 0.48-1.24) or when stratified by LoT (Table 1). Conclusion This study could not identify any difference in risk of MI between IL-6i and TNFi treatment after patient characteristics and LoT were considered. Disclosure Z. Tian: None. L. Kearsley-Fleet: None. K. Lauper: Honoraria; Celltrion, Pfizer, Viatris, Galapagos. S. Haughton: None. K. Watson: None. M. Lunt: None. J. Mclaughlin: None. A. Verma: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; Pfizer, BMS.

Background/Aims As recommended by the NICE guidelines, methotrexate (MTX) is typically prescribed as the first line therapy for patients with rheumatoid arthritis (RA). However, around 40% of patients do not respond to MTX at 6 months and around 80% experience adverse events (AEs). Our previous systematic review identified that clinical prediction models of MTX outcomes suffered from methodological limitations, including a lack of validation, suboptimal handling of missing data, and no consideration of competing risks, such as patients discontinuing due to adverse events (AEs). These shortcomings resulted in high risk of bias and should be addressed to aid the implementation of outcome prediction in clinical practice. Therefore, this study aimed to (i) develop a multinomial prediction model for estimating an individual’s risks of not achieving low disease activity (LDA) and discontinuing due to AEs at 6 months after starting MTX, using information observable at the starting point of treatment, (ii) update prognosis at 3 months, and (iii) internally validate these models to assess performance. Methods Data came from the national multi-centre (n = 38) Rheumatoid Arthritis Medication Study (RAMS), which recruited patients with a diagnosis of RA or undifferentiated polyarthritis starting MTX for the first time. We conducted a Patient and Public Involvement focus group with past and current MTX users, which informed our outcome choice of LDA (DAS28 ≤3.2). A multinomial logistic regression (MLR) was used to develop a prediction model that estimated the probabilities of three outcomes: 1) not in LDA, 2) achieved LDA, and 3) discontinued due to AEs. The updated model at 3 months was conditional on patients not having achieved LDA. Missing data was handled using multiple imputation and models were internally validated through bootstrapping. Calibration, discrimination, and variance explained was assessed to quantify model performance. Results A total of 1632 patients were included in the analysis. At 6 months, 756 (46%) patients achieved LDA, 730 (45%) were not in LDA, and 146 (9%) discontinued due to AEs. The updated model at 3 months included 1179 (72%) patients as they had not achieved LDA. For the LDA outcome pair, the c-statistic was 0.73 (0.70, 0.75), while it was 0.54 (0.49, 0.59) for the AEs outcome. The calibration slope was 0.99 (0.85, 1.12) and 0.74 (0.23, 1.23), respectively. Predictive performance at 3 months was similar to baseline. Conclusion Our MLR models handled outcomes of disease activity and AEs simultaneously. We were able to predict outcomes of LDA more accurately than AEs and performance was better in terms of calibration, which is crucial for the clinical utility of a prediction model. This modelling approach could provide more clinically useful and realistic predictions of MTX outcomes, as competing risks such as AEs have previously been ignored. Disclosure C.K. Gehringer: None. G.P. Martin: None. K.L. Hyrich: Honoraria; Abbvie. Grants/research support; BMS and Pfizer. S.M.M. Verstappen: None. J.C. Sergeant: None.

Background/Aims Inhibitors of the IL-13 pathway, such as dupilumab and tralokinumab, are licensed to treat atopic diseases such as eczema and asthma. Musculoskeletal adverse events that resemble enthesitis and psoriatic arthritis (PsA) after dupilumab initiation have been reported, but evidence is limited to case reports and spontaneous pharmacovigilance with uncertain causal inference. Naturally occurring genetic variation in drug targets can provide insight into their potential adverse effects. We used population-level data to investigate whether genetically proxied IL-13 inhibition (IL-13i) increases risk of PsA and other spondyloarthritis-related diseases. Methods Dupilumab is recognised to reduce eosinophil count in clinical studies; we therefore used it as the biomarker of IL-13i. We instrumented IL-13i using missense (protein coding) variants within the IL13 gene that are associated with circulating eosinophil count at genome-wide significance (p Results One missense variant, rs20541, was selected to proxy IL-13i. Genetically proxied IL-13i was associated with increased risk of PsA (OR 37.39; 95%CI 11.52, 121.34), psoriasis (OR 20.08; 4.38, 92.01), Crohn’s disease (OR 3.49; 1.38, 8.81), but not ulcerative colitis, ankylosing spondylitis or iritis. IL-13i was associated with reduced risk of positive control outcomes, but not with the negative control (Table 1). Conclusion Genetically proxied IL-13 inhibition is associated with increased risk of PsA, psoriasis and Crohn’s disease, which may be a class effect relevant to other IL-13i that are not yet reported to have Th17-type adverse events. These findings are compatible with the hypothesis that Th2 cytokines IL-4/-13 may act as a restraint toward Th17-type disease activation in some organs. Clinicians assessing adverse events after dupilumab initiation should be aware of incident PsA and related features. This study demonstrates the value of MR in evaluating rare adverse events in the study of drug safety. Disclosure S. Zhao: None. K.L. Hyrich: None. Z.Z.N. Yiu: None. A. Barton: None. J. Bowes: None.

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

ObjectiveTo investigate the relationship between age and symptom duration at initial presentation to pediatric rheumatology for juvenile idiopathic arthritis (JIA).MethodsIn children and young people (CYP) enrolled in the Childhood Arthritis Prospective Study prior to March 2018, an association between age at presentation (< 5, 5–11, and > 11 yrs) and symptom duration was tested by multivariable linear regression.ResultsIn 1577 CYP, 5- to 11-year-olds took 3.2 months longer and > 11-year-olds 6.9 months longer to reach pediatric rheumatology than < 5-year-olds.ConclusionAdolescents take longer to reach pediatric rheumatology, potentially affecting their longer-term outcomes given the window of opportunity for JIA treatment.

ObjectivesSome adults with rheumatic and musculoskeletal diseases (RMDs) are at increased risk of COVID-19-related death. Excluding post-COVID-19 multisystem inflammatory syndrome of children, children and young people (CYP) are overall less prone to severe COVID-19 and most experience a mild or asymptomatic course. However, it is unknown if CYP with RMDs are more likely to have more severe COVID-19. This analysis aims to describe outcomes among CYP with underlying RMDs with COVID-19.MethodsUsing the European Alliance of Associations for Rheumatology COVID-19 Registry, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry, and the CARRA-sponsored COVID-19 Global Paediatric Rheumatology Database, we obtained data on CYP with RMDs who reported SARS-CoV-2 infection (presumptive or confirmed). Patient characteristics and illness severity were described, and factors associated with COVID-19 hospitalisation were investigated.Results607 CYP with RMDs ConclusionsThis is the most significant investigation to date of COVID-19 in CYP with RMDs. It is important to note that the majority of CYP were not hospitalised, although those with severe systemic RMDs and obesity were more likely to be hospitalised.

ObjectivesTo investigate factors associated with severe COVID-19 in people with psoriasis (PsO), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).MethodsDemographic data, clinical characteristics and COVID-19 outcome severity of adults with PsO, PsA and axSpA were obtained from two international physician-reported registries. A three-point ordinal COVID-19 severity scale was defined: no hospitalisation, hospitalisation (and no death) and death. ORs were estimated using multivariable ordinal logistic regression.ResultsOf 5045 cases, 18.3% had PsO, 45.5% PsA and 36.3% axSpA. Most (83.6%) were not hospitalised, 14.6% were hospitalised and 1.8% died. Older age was non-linearly associated with COVID-19 severity. Male sex (OR 1.54, 95% CI 1.30 to 1.83), cardiovascular, respiratory, renal, metabolic and cancer comorbidities (ORs 1.25–2.89), moderate/high disease activity and/or glucocorticoid use (ORs 1.39–2.23, vs remission/low disease activity and no glucocorticoids) were associated with increased odds of severe COVID-19. Later pandemic time periods (ORs 0.42–0.52, vs until 15 June 2020), PsO (OR 0.49, 95% CI 0.37 to 0.65, vs PsA) and baseline exposure to TNFi, IL17i and IL-23i/IL-12+23i (OR 0.57, 95% CI 0.44 to 0.73; OR 0.62, 95% CI 0.45 to 0.87; OR 0.67, 95% CI 0.45 to 0.98; respectively; vs no disease-modifying antirheumatic drug) were associated with reduced odds of severe COVID-19.ConclusionOlder age, male sex, comorbidity burden, higher disease activity and glucocorticoid intake were associated with more severe COVID-19. Later pandemic time periods, PsO and exposure to TNFi, IL17i and IL-23i/IL-12+23i were associated with less severe COVID-19. These findings will enable risk stratification and inform management decisions for patients with PsO, PsA and axSpA during COVID-19 waves or similar future respiratory pandemics.

Introduction JAK-inhibitors have emerged as a new treatment option for rheumatoid arthritis, with five molecules currently available in different parts of the world: tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib. These molecules have been the subject of numerous trials looking at their efficacy (how well they perform in controlled conditions) but also some observational studies from the general population to assess their effectiveness (how well treatment perform under real conditions). With each their own weaknesses and strengths, they give different but complementary information. Areas covered We will review what we can learn from trials and real-world studies on how effective JAK-inhibitors are in the treatment of rheumatoid arthritis. Expert opinion Trials of JAK-inhibitors have shown that JAK-inhibitors are efficacious for the treatment of rheumatoid arthritis. However, their main outcomes are not clinically meaningful as their aim is mainly the regulatory authorisation of the product. Real-world studies are important as they evaluate the real-life effectiveness of the compounds, however, they are scarce at the moment, mainly evaluating tofacitinib and of variable quality. Future high-quality studies are needed to assess the real-world effectiveness of JAK-inhibitors in a more complete manner.

Objectives Burden of comorbidities are largely unknown in JIA. From 2000, national and international patient registries were established to monitor biologic treatment, disease activity and adverse events in patients with JIA. The aim of this analysis was to investigate in parallel, for the first time, three of the largest JIA registries in Europe/internationally—UK JIA Biologic Registers (BCRD/BSPAR-ETN), German biologic registers (BiKeR/JuMBO), multinational Pharmachild—to quantify the occurrence of selected comorbidities in patients with JIA. Methods Information on which data the registers collect were compared. Patient characteristics and levels of comorbidity were presented, focussing on four key conditions: uveitis, MAS, varicella, and history of tuberculosis. Incidence rates of these on MTX/biologic therapy were determined. Results 8066 patients were registered into the three JIA registers with similar history of the four comorbidities across the studies; however, varicella vaccination coverage was higher in Germany (56%) vs UK/Pharmachild (16%/13%). At final follow-up, prevalence of varicella infection was lower in Germany (15%) vs UK/Pharmachild (37%/50%). Prevalence of TB (0.1–1.8%) and uveitis (15–19%) was similar across all registers. The proportion of systemic-JIA patients who ever had MAS was lower in Germany (6%) vs UK (15%) and Pharmachild (17%). Conclusion This analysis is the first and largest to investigate the occurrence of four important comorbidities in three JIA registries in Europe and the role of anti-rheumatic drugs. Combined, these three registries represent one of the biggest collection of cases of JIA worldwide and offer a unique setting for future JIA outcome studies.

This systematic literature review (SLR) regarding the efficacy, duration of use and safety of glucocorticoids (GCs), was performed to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). Studies on GC efficacy were identified from a separate search on the efficacy of disease-modifying antirheumatic drugs (DMARDs). A combined search was performed for the duration of use and safety of GCs in RA patients. Dose-defined and time-defined GC treatment of any dose and duration (excluding intra-articular GCs) prescribed in combination with other DMARDs were considered. Results are presented descriptively. Two included studies confirmed the efficacy of GC bridging as initial therapy, with equal efficacy after 2 years of initial doses of 30 mg/day compared with 60 mg/day prednisone. Based on a recently performed SLR, in clinical trials most patients starting initial GC bridging are able to stop GCs within 12 (22% patients continued on GCs) to 24 months (10% patients continued on GCs). The safety search included 12 RCTs and 21 observational studies. Well-known safety risks of GC use were confirmed, including an increased risk of osteoporotic fractures, serious infections, diabetes and mortality. Data on cardiovascular outcomes were Inconsistent. Overall, safety risks increased with increasing dose and/or duration, but evidence on which dose is safe was conflicting. In conclusion, this SLR has confirmed the efficacy of GCs in the treatment of RA. In clinical trials, most patients have shown to be able to stop GCs within 12–24 months. Well-known safety risks of GC use have been confirmed, but with heterogeneity between studies.

ObjectivesTo develop EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in patients with autoimmune inflammatory rheumatic diseases (AIIRD).MethodsAn international Task Force (TF) (22 members/15 countries) formulated recommendations, supported by systematic literature review findings. Level of evidence and grade of recommendation were assigned for each recommendation. Level of agreement was provided anonymously by each TF member.ResultsFour overarching principles (OAP) and eight recommendations were developed. The OAPs highlight the need for infections to be discussed with patients and with other medical specialties, in accordance with national regulations. In addition to biologic/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for which screening for latent tuberculosis (TB) should be performed, screening could be considered also before conventional synthetic DMARDs, glucocorticoids and immunosuppressants. Interferon gamma release assay should be preferred over tuberculin skin test, where available. Hepatitis B (HBV) antiviral treatment should be guided by HBV status defined prior to starting antirheumatic drugs. All patients positive for hepatitis-C-RNA should be referred for antiviral treatment. Also, patients who are non-immune to varicella zoster virus should be informed about the availability of postexposure prophylaxis should they have contact with this pathogen. Prophylaxis againstPneumocystis jiroveciiseems to be beneficial in patients treated with daily doses >15–30 mg of prednisolone or equivalent for >2–4 weeks.ConclusionsThese recommendations provide guidance on the screening and prevention of chronic and opportunistic infections. Their adoption in clinical practice is recommended to standardise and optimise care to reduce the burden of opportunistic infections in people living with AIIRD.

BackgroundJAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers.MethodsIn this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk.ResultsWe included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA.ConclusionThe adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

Objective The incidence and prevalence of JIA was last estimated in the UK in 1994. Since then the disease has been reclassified, the specialty of paediatric rheumatology has evolved and there has been a significant shift in disease management with new advanced therapies. This study aimed to provide up-to-date national estimates of this disease. Methods Children and young people (CYP) with JIA were identified in the Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases, which source data from the two most commonly used primary care electronic health record systems in the UK. These databases were combined and the cohort was identified (2000–18) using predefined code lists. Validation was performed through linkage to the England Hospital Episode Statistics. Annual incidence and prevalence rates were calculated and stratified by gender, age group and nation of the UK. Direct standardization to the UK population was performed and 5 year incidence rates were calculated between 2003 and 2018. Results The age-standardized incidence rate was 5.61 per 100 000 population. The age-standardized prevalence rate in 2018 was 43.5 per 100 000. Rates were higher in Scotland compared with England: incidence rate ratio 1.27 (95% CI 1.11, 1.46). The 5 year incidence rates did not change significantly over time. Conclusions This study has provided the first contemporaneous estimates of occurrence of JIA in the UK in 25 years. These data provide important estimates to inform resource allocation and health service development for management of JIA.

Patients with inflammatory rheumatic and musculoskeletal diseases (iRMDs) are often treated with immunomodulatory or immunosuppressive medications; consequently, they have been excluded alongside other immunocompromised patients from late stages of SARS-CoV-2 vaccine trials. SARS-CoV-2 vaccine efficacy in this population is unclear, though initial data are reassuring overall. However, a slightly lower SARS-CoV-2 immunogenicity of vaccines has been documented in some patients with iRMD.1 2 Some common rheumatic and musculoskeletal disease (RMD) medications have been highlighted as possible influential factors on immunogenicity, particularly rituximab (RTX), mycophenolate mofetil (MMF), methotrexate (MTX), abatacept and glucocorticoids.3–7 The European Alliance of Associations for Rheumatology (EULAR) launched a COVID-19 registry in March 2020, capturing COVID-19 outcomes in the European RMD population. Questions on reinfection and vaccination were added in January 2021. A further EULAR registry (COVAX) was launched in February 2021 to collect data on COVID-19 vaccination and related adverse events among patients with RMD. Here we describe a series of patients who contracted SARS-CoV-2 infection after COVID-19 vaccination between 19 January 2021 and 27 July 2021. The series consists of 38 adults with iRMDs, 8 from the COVID-19 registry (

Objective As young people enter adulthood, the interchangeable use of child and adult outcome measures may inaccurately capture changes over time. This study aimed to use item response theory (IRT) to model a continuous score for functional ability that can be used no matter which questionnaire is completed. Methods Adolescents (ages 11-17 years) in the UK Childhood Arthritis Prospective Study (CAPS) self-completed an adolescent Childhood Health Assessment Questionnaire (CHAQ) and a Health Assessment Questionnaire (HAQ). Their parents answered the proxy-completed CHAQ. Those children with at least 2 simultaneously completed questionnaires at initial presentation or 1 year were included. Psychometric properties of item responses within each questionnaire were tested using Mokken analyses to assess the applicability of IRT modeling. A previously developed IRT model from the Pharmachild-NL registry from The Netherlands was validated in CAPS participants. Agreement and correlations between IRT-scaled functional ability scores were tested using intraclass correlations and Wilcoxon's signed rank tests. Results In 303 adolescents, the median age at diagnosis was 13 years, and 61% were female. CHAQ scores consistently exceeded HAQ scores. Mokken analyses demonstrated high scalability, monotonicity, and the fact that each questionnaire yielded reliable scores. There was little difference in item response characteristics between adolescents enrolled in CAPS and Pharmachild-NL (maximum item residual 0.08). Significant differences were no longer evident between IRT-scaled HAQ and CHAQ scores. Conclusion IRT modeling allows the direct comparison of function scores regardless of different questionnaires being completed by different people over time. IRT modeling facilitates the ongoing assessment of function as adolescents transfer from pediatric clinics to adult services.

Introduction/Background Biosimilar therapies are considered to have comparable efficacy to their originators and prescribing is encouraged in the UK for significant cost-savings to the NHS. However, real-world evidence comparing originators and biosimilars is limited, particularly in children and young people. The objective of this analysis was to compare the effectiveness of the anti-TNF adalimumab originator and a biosimilar in the treatment of JIA in children and young people, by comparing change in disease activity after six months. Description/Method This analysis included children and young people with JIA from the Biologics for Children with Rheumatic Diseases (BCRD) study. Data are collected at the point of starting biologic therapy, and after 6 months, including patient demographics, biologic therapy, and disease activity. Patients were included if they were starting adalimumab (originator or biosimilar) as their first biologic. Patients with follow-up data at 6 months were assessed for outcomes at 6 months. Change in Juvenile Arthritis Disease Activity Score (JADAS-71) from baseline to 6 months was calculated and compared between therapies using linear regression. Multivariable logistical regression was used to compare remission (JADAS-71 ≤1) at 6 months between therapies. Both regression models were adjusted for baseline characteristics at the start of biologic therapy: age, gender, disease duration, ILAR category, history of uveitis, number of comorbidities (0/1/2+), and JADAS-71. Multiple imputation was used to account for missing data. Discussion/Results A total of 457 patients were registered starting adalimumab as their first biologic: 413 on originator, 44 on biosimilar (Table). Of these, 63% were female, median age at start of therapy was 11 years old (IQR 6, 14), and median disease duration was 2 years (IQR 1, 5). The majority of patients had RF-negative polyarticular JIA (29%), persistent oligoarticular (20%) or extended oligoarticular JIA (18%). There were 47% of patients who had a history of uveitits when starting biologic therapy, and 68% reported at least one comorbidity. Baseline characters were similar between both therapies. There were 429 patients with follow-up data after six months of treatment: 393 on originator and 36 on biosimliar. The median JADAS-71 improved by -4.4 (IQR -9.9, -0.2) with no difference seen between the originator and the biosimilar patients (adjusted b-coefficient: -0.4; 95% CI -2.6, 1.8; p = 734). There were 36% of patients in remission, with no difference between the two therapies (odds ratio 1.2; 95% CI 0.5, 2.9; p = 0.543). Key learning points/Conclusion There was no significant difference in disease activity response between children and young people with JIA treated with adalimumab originator versus biosimilar. These results support that the adalimumab biosimilar is similar in effectiveness to the originator in treating JIA, although more research is needed regarding safety and tolerability.

ObjectivesTo update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA).MethodsThis systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022.ResultsOf 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission.ConclusionThe results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA.

ObjectivesThe expanded therapeutic arsenal in rheumatoid arthritis (RA) raises new clinical questions. The objective of this study is to compare the effectiveness of cycling Janus kinase inhibitors (JAKi) with switching to biologic disease-modifying antirheumatic drug (bDMARD) in patients with RA after failure to the first JAKi.MethodsThis is a nested cohort study within data pooled from an international collaboration of 17 national registries (JAK-pot collaboration). Data from patients with RA with JAKi treatment failure and who were subsequently treated with either a second JAKi or with a bDMARD were prospectively collected. Differences in drug retention rates after second treatment initiation were assessed by log-rank test and Cox regression analysis adjusting for potential confounders. Change in Clinical Disease Activity Index (CDAI) over time was estimated using a linear regression model, adjusting for confounders.Results365 cycling and 1635 switching patients were studied. Cyclers were older and received a higher number of previous bDMARDs. Both strategies showed similar observed retention rates after 2 years of follow-up. However, adjusted analysis revealed that cycling was associated with higher retention (p=0.04). Among cyclers, when the first JAKi was discontinued due to an adverse event (AE), it was more likely that the second JAKi would also be stopped due to an AE. Improvement in CDAI over time was similar in both strategies.ConclusionsAfter failing the first JAKi, cycling JAKi and switching to a bDMARD appear to have similar effectiveness. Caution is advised if an AE was the reason to stop the first JAKi.

Published by Elsevier Ltd., Background: Differences in the distribution of individual-level clinical risk factors across regions do not fully explain the observed global disparities in COVID-19 outcomes. We aimed to investigate the associations between environmental and societal factors and country-level variations in mortality attributed to COVID-19 among people with rheumatic disease globally. Methods: In this observational study, we derived individual-level data on adults (aged 18-99 years) with rheumatic disease and a confirmed status of their highest COVID-19 severity level from the COVID-19 Global Rheumatology Alliance (GRA) registry, collected between March 12, 2020, and Aug 27, 2021. Environmental and societal factors were obtained from publicly available sources. The primary endpoint was mortality attributed to COVID-19. We used a multivariable logistic regression to evaluate independent associations between environmental and societal factors and death, after controlling for individual-level risk factors. We used a series of nested mixed-effects models to establish whether environmental and societal factors sufficiently explained country-level variations in death. Findings: 14 044 patients from 23 countries were included in the analyses. 10 178 (72·5%) individuals were female and 3866 (27·5%) were male, with a mean age of 54·4 years (SD 15·6). Air pollution (odds ratio 1·10 per 10 μg/m3 [95% CI 1·01-1·17]; p=0·0105), proportion of the population aged 65 years or older (1·19 per 1% increase [1·10-1·30]; p, MAG is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K01 AR070585 and K24 AR074534 [JY]). KDW is supported by the Department of Veterans Affairs and the Rheumatology Research Foundation Scientist Development award. JAS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation (K Supplement Award and R Bridge Award), the Brigham Research Institute, and the R. Bruce and Joan M. Mickey Research Scholar Fund. NJP is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32-AR-007258). AD-G is supported by grants from the Centers for Disease Control and Prevention and the Rheumatology Research Foundation. RH was supported by the Justus-Liebig University Giessen Clinician Scientist Program in Biomedical Research to work on this registry. JY is supported by grants from the National Institutes of Health (K24 AR074534 and P30 AR070155).

Objectives This study aimed to measure (1) the proportion of children who continue to receive specialist care (rheumatology/ophthalmology) as adults, (2) the characteristics associated with continuing specialist care, and (3) the frequency of specialist care appointments in both paediatric and adult services. Methods A retrospective cohort of young people with JIA was identified from UK primary care electronic health records (Clinical Practice Research Datalink) between 1 April 2003 and 31 December 2018. To be included in the study, cases needed to have at least 1 year of registration at their general practice beyond age 18 and linkage to Hospital Episodes Statistics data for secondary care information. All specialist care outpatient visits were identified from Hospital Episodes Statistics outpatient data. Results There were 666 young people included in the study. Of these, 427 (64%) received specialist care beyond age 18, 90 (13%) had their last recorded contact at 16–17 years and 149 (22%) did not continue after 16 years. Older age at diagnosis, female gender, less deprivation and a childhood diagnosis of uveitis were associated with continuing specialist care beyond age 18. Of those continuing beyond 18, 35% (n = 153) were subsequently discharged by the study end date. Of all those discharged, 32% had a missed appointment recorded after the last attended visit, suggesting failure to attend. Conclusions Two-thirds of young people with JIA continue to receive specialist care beyond age 18. This is useful information for children and young people with JIA and their families planning for their future, and for clinicians planning health-care services.

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

Objective: Some patients with rheumatic diseases might be at higher risk for coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS). We aimed to develop a prediction model for COVID-19 ARDS in this population and to create a simple risk score calculator for use in clinical settings. Methods: Data were derived from the COVID-19 Global Rheumatology Alliance Registry from March 24, 2020, to May 12, 2021. Seven machine learning classifiers were trained on ARDS outcomes using 83 variables obtained at COVID-19 diagnosis. Predictive performance was assessed in a US test set and was validated in patients from four countries with independent registries using area under the curve (AUC), accuracy, sensitivity, and specificity. A simple risk score calculator was developed using a regression model incorporating the most influential predictors from the best performing classifier. Results: The study included 8633 patients from 74 countries, of whom 523 (6%) had ARDS. Gradient boosting had the highest mean AUC (0.78; 95% confidence interval [CI]: 0.67-0.88) and was considered the top performing classifier. Ten predictors were identified as key risk factors and were included in a regression model. The regression model that predicted ARDS with 71% (95% CI: 61%-83%) sensitivity in the test set, and with sensitivities ranging from 61% to 80% in countries with independent registries, was used to develop the risk score calculator. Conclusion: We were able to predict ARDS with good sensitivity using information readily available at COVID-19 diagnosis. The proposed risk score calculator has the potential to guide risk stratification for treatments, such as monoclonal antibodies, that have potential to reduce COVID-19 disease progression.

Objective To describe people with gout who were diagnosed with coronavirus disease 2019 (COVID-19) and hospitalized and to characterize their outcomes. Methods Data on patients with gout hospitalized for COVID-19 between March 12, 2020, and October 25, 2021, were extracted from the COVID-19 Global Rheumatology Alliance registry. Descriptive statistics were used to describe the demographics, comorbidities, medication exposures, and COVID-19 outcomes including oxygenation or ventilation support and death. Results One hundred sixty-three patients with gout who developed COVID-19 and were hospitalized were included. The mean age was 63 years, and 85% were male. The majority of the group lived in the Western Pacific Region (35%) and North America (18%). Nearly half (46%) had two or more comorbidities, with hypertension (56%), cardiovascular disease (28%), diabetes mellitus (26%), chronic kidney disease (25%), and obesity (23%) being the most common. Glucocorticoids and colchicine were used pre-COVID-19 in 11% and 12% of the cohort, respectively. Over two thirds (68%) of the cohort required supplemental oxygen or ventilatory support during hospitalization. COVID-19-related death was reported in 16% of the overall cohort, with 73% of deaths documented in people with two or more comorbidities. Conclusion This cohort of people with gout and COVID-19 who were hospitalized had high frequencies of ventilatory support and death. This suggests that patients with gout who were hospitalized for COVID-19 may be at risk of poor outcomes, perhaps related to known risk factors for poor outcomes, such as age and presence of comorbidity.

Objectives This systematic review aims to summarize rates of adverse events (AEs) in patients with RA or inflammatory arthritis starting MTX as monotherapy or in combination with other csDMARDs, and to identify reported predictors of AEs. Methods Three databases were searched for studies reporting AEs in MTX-naïve patients with RA. Randomized controlled trials (RCTs) and observational cohort studies were included. Prevalence rates of AEs were pooled using random effects meta-analysis, stratified by study design. Results Forty-six articles (34 RCTs and 12 observational studies) were identified. The pooled prevalence of total AEs was 80.1% in RCTs (95% CI: 73.5, 85.9), compared with 23.1% in observational studies (95% CI: 12.3, 36.0). The pooled prevalence of serious AEs was 9.5% in RCTs (95% CI: 7.4, 11.7), and 2.1% in observational studies (95% CI: 1.0, 3.4). MTX discontinuation due to AEs was higher in observational studies (15.5%, 95% CI: 9.6, 22.3) compared with RCTs (6.7%, 95% CI: 4.7, 8.9). Gastrointestinal events were the most commonly reported AEs (pooled prevalence: 32.7%, 95% CI: 18.5, 48.7). Five studies examined predictors of AEs. RF status, BMI and HAQ score were associated with MTX discontinuation due to AEs; ACPA negativity, smoking and elevated creatinine were associated with increased risk of elevated liver enzymes. Conclusion The review provides an up-to-date overview of the prevalence of AEs associated with MTX in patients with RA. The findings should be communicated to patients to help them make informed choices prior to commencing MTX.

Methotrexate (MTX) is a common first-line treatment for new-onset rheumatoid arthritis (RA). However, MTX is ineffective for 30–40% of patients and there is no way to know which patients might benefit. Here, we built statistical models based on serum lipid levels measured at two time-points (pre-treatment and following 4 weeks on-drug) to investigate if MTX response (by 6 months) could be predicted. Patients about to commence MTX treatment for the first time were selected from the Rheumatoid Arthritis Medication Study (RAMS). Patients were categorised as good or non-responders following 6 months on-drug using EULAR response criteria. Serum lipids were measured using ultra‐performance liquid chromatography–mass spectrometry and supervised machine learning methods (including regularized regression, support vector machine and random forest) were used to predict EULAR response. Models including lipid levels were compared to models including clinical covariates alone. The best performing classifier including lipid levels (assessed at 4 weeks) was constructed using regularized regression (ROC AUC 0.61 ± 0.02). However, the clinical covariate based model outperformed the classifier including lipid levels when either pre- or on-treatment time-points were investigated (ROC AUC 0.68 ± 0.02). Pre- or early-treatment serum lipid profiles are unlikely to inform classification of MTX response by 6 months with performance adequate for use in RA clinical management.

Objectives To describe how many people with RA reduce their baseline physical activity level over the first year of MTX treatment, and which factors predict this. Methods Data came from the Rheumatoid Arthritis Medication Study (RAMS), a prospective cohort of people with early RA starting MTX. Participants reported demographics and completed questionnaires at baseline, and 6 and 12 months, including reporting the number of days per week they performed ≥20 min of physical activity, coded as none, low (1–3 days) or high (4–7 days). The physical activity levels of participants over 12 months are described. Predictors of stopping physical activity were assessed using multivariable logistic regression. Results In total, 1468 participants were included [median (interquartile range) age 60 (50, 69) years; 957 (65.2%) women]. At baseline, the physical activity levels of the people with RA were: none = 408 (27.8%), low = 518 (35.3%) and high = 542 (36.9%). Eighty percent of participants maintained some physical activity or began physical activity between assessments (baseline to 6 months = 79.3%, 6 months to 12 months = 80.7%). In total, 24.1% of participants reduced physical activity and 11.3% of participants stopped performing physical activity between baseline and 6 months (6 months to 12 months: 22.6% and 10.2%, respectively). Baseline smoking, higher disability and greater socioeconomic deprivation were associated with stopping physical activity. Conclusion Many people with early RA were not performing physical activity when starting MTX, or stopped performing physical activity over the first year of treatment. These people may require interventions to stay active. These interventions need to be mindful of socioeconomic barriers to physical activity participation.

In the management of rheumatoid arthritis (RA), there is a clinical need to identify which patients are at high-risk of not responding to methotrexate (MTX), or experiencing adverse events (AEs), to enable earlier alternative treatments. Many clinical prediction models (CPMs) have previously been developed, but a summary of such models and their methodological quality is lacking. This systematic review aimed to (i) identify and summarize previously published CPMs of MTX outcomes in biologic-naïve RA patients, and (ii) critically appraise their methodological properties.Medline and Embase were searched to identify studies developing or validating CPMs of MTX outcomes in RA patients. The risk of bias (ROB) was assessed using PROBAST (prediction model risk of bias assessment tool). A fixed effects meta-analysis summarised discrimination for models with multiple external validations.The systematic review identified 20 CPMs across 13 studies, and 4 validation studies. Three outcome types were used: a state of disease activity (n = 14, 70%); EULAR response criteria (n = 4, 20%); or discontinuation due to AEs (n = 2, 10%). Only one model accounted for potential competing risks, and nine (45%) were internally validated. Eight (40%) models used multiple imputation for missing data, others were often limited to complete case analysis. There was overall high ROB. The meta-analysis summarised c-statistics for two models with multiple external validations was 0.77 (95% CI: 0.69, 0.84) and 0.68 (0.64, 0.71).This review highlights several methodological shortcomings that should be addressed in future model development to increase potential for implementation into practice.

Objectives Whether patients with RA benefit from repeated trials of biologic or targeted synthetic DMARDs (b/tsDMARDs) after three or more attempts is unknown. We aimed to describe treatment outcomes in each line of b/tsDMARD therapy. Methods Using data from the British Society for Rheumatology Biologics Register for RA from 2001 to 2020, change to a new b/tsDMARD (except biosimilar switches) was defined as a new line of therapy. Treatment outcomes were compared across lines of therapy, including DAS28 remission (≤2.6), low disease activity (LDA, ≤3.2) at 6 months and median time to drug discontinuation. Multiple imputation was used for missing data. Results A total of 22 934 individuals starting a first b/tsDMARD were included (mean age 56 years, 76% female), among whom 10 823 commenced a second-line drug, 5056 third, 2128 fourth, 767 fifth and 292 sixth. Most (71%) had sufficient data for DAS28-derived outcome analyses. TNF inhibitors were the most common first-line drug, but choice of subsequent-line drugs changed over time. Seventeen percent achieved DAS28 remission following first-line, 13% second and 8–13% with third through sixth. LDA was achieved in 29% of first-line, 23% second, 17–22% through to the sixth. Patients stayed on first-line therapy for a median of 2.6 years, ranging from 1.0–1.4 years for lines two to six. Conclusion Many patients will eventually benefit after repeated trials of b/tsDMARD. Further research to improve treatment selection are needed to prevent prolonged trial and error approaches in some patients.