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In this cross sectional study from a large UK centre, screening for mental illness in individuals with psoriasis has demonstrated a high burden of depression and anxiety. 85% of the cohort report that their psoriasis had affected their quality of life. Quality of life scores correlate with depression scores, emphasing the importance of managing individual's mental health alongside their psoriasis to improve overall quality of life.

Objective.To identify predictors of admission following emergency department (ED) attendances for gout flares and to describe barriers to optimal inpatient gout care.Methods.ED attendances and hospital admissions with primary diagnoses of gout were analyzed at 2 UK-based hospitals between January 1, 2017, and December 31, 2020. Demographic and clinical predictors of ED disposition (admission or discharge) and reattendance for gout flares were identified using logistic regression and survival models, respectively. Case note reviews (n = 59), stakeholder meetings, and process mapping were performed to capture detailed information on gout management and to identify strategies to optimize care.Results.Of 1220 emergency attendances for gout flares, 23.5% required hospitalization (median length of stay: 3.6 days). Recurrent attendances for flares occurred in 10.4% of patients during the study period. In multivariate logistic regression models, significant predictors of admission from ED were older age, overnight ED arrival time, higher serum urate (SU), higher C-reactive protein, and higher total white cell count at presentation. Detailed case note reviews showed that only 22.6% of patients with preexisting gout were receiving urate-lowering therapy (ULT) at presentation. Initial diagnostic uncertainty was common, yet rheumatology input and synovial aspirates were rarely obtained. By 6 months postdischarge, 43.6% were receiving ULT; however, few patients had treat-to-target dose optimization, and only 9.1% achieved SU levels ≤ 360 μmol/L.Conclusion.We identified multiple predictors of hospitalization for acute gout. Treat-to-target optimization of ULT following hospitalization remains inadequate and must be improved if admissions are to be prevented.

Background/Aims The impact of the pandemic on the incidence and management of inflammatory arthritis (IA) is not understood. Routinely-captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how IA was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for IA in England, and replicate key metrics from the National Early Inflammatory Arthritis Audit. Methods With the approval of NHS England, we used primary care and hospital data for 17 million adults registered with general practices using TPP health record software, to explore the following outcomes between 1 April 2019 and 31 March 2022: 1) incidence of IA diagnoses (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, undifferentiated IA) recorded in primary care; 2) time to first rheumatology assessment; 3) time to first prescription of a conventional synthetic DMARD (csDMARD) in primary care, and choice of first csDMARD. Results From 17,683,500 adults (representing 40% of the English population), there were 31,280 incident IA diagnoses recorded between April 2019 and March 2022. New IA diagnoses decreased by 39.7% in the early months of the pandemic. Overall, a 20.3% decrease in IA diagnoses was seen in the year commencing April 2020, relative to the preceding year (5.1 vs. 6.4 diagnoses per 10,000 adults, respectively). Further decreases coincided with rising COVID-19 numbers, before returning to pre-pandemic levels by the end of the study period. No rebound increase in IA incidence was observed as of April 2022. The median time from referral to first rheumatology assessment was shorter during the pandemic (18 days; IQR 8-35 days) than before (21 days; 9-41 days). The proportion of patients prescribed csDMARDs in primary care was comparable to before the pandemic; however, fewer people were prescribed methotrexate or leflunomide, and more were prescribed sulfasalazine or hydroxychloroquine. Conclusion IA diagnoses decreased markedly during the early phase of the pandemic; however, the impact on rheumatology assessment times and DMARD prescribing was less marked than might have been anticipated. This study demonstrates the feasibility of using routinely-captured, near real-time data in the secure OpenSAFELY platform to benchmark care quality on a national scale, without the need for manual data collection. Disclosure M.D. Russell: Honoraria; Lilly, Menarini, Biogen. Other; Lilly, Pfizer, Janssen, UCB. J.B. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB. C.D. Andrews: None. B. MacKenna: None. B. Goldacre: Grants/research support; Laura and John Arnold Foundation, NIHR, Mohn-Westlake Foundation, Wellcome Trust, Good Thinking Foundation, Health Data Research UK, Health Foundation, World Health Organisation, UKRI, Asthma UK, British Lung Foundation, and National Core Studies programme. A. Mehrkar: Other; Former employee and interim CMO of NHS Digital, and RCGP representative on GP Data Professional Advisory Group to NHS Digital. H.J. Curtis: None. B. Butler-Cole: None. T. O'Dwyer: None. S. Qureshi: Grants/research support; BMS. J.M. Ledingham: Other; Clinical director for NEIAA, Secretary for The Federation of Joint Royal Colleges of Physicians SCE Board, and trustee of the BSR. A. Mahto: Honoraria; Abbvie, Galapagos. Other; Lilly. A.I. Rutherford: Other; Lilly. M.A. Adas: None. E. Alveyn: None. S. Norton: None. A.P. Cope: Consultancies; BMS, Abbvie, GSK/Galvini. Member of speakers’ bureau; BMS, Abbvie. Grants/research support; BMS. Other; Executive committee of the EULAR research centre. K. Bechman: Grants/research support; Versus Arthritis and Pfizer Global Medical Grants.

The impact of the COVID-19 pandemic on the incidence and management of inflammatory arthritis is not understood. Routinely captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how care for patients with inflammatory arthritis was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for inflammatory arthritis in England and to replicate key metrics from the National Early Inflammatory Arthritis Audit.In this population-level cohort study, we used primary care and hospital data for 17·7 million adults registered with general practices using TPP health record software, to explore the following outcomes between April 1, 2019, and March 31, 2022: (1) incidence of inflammatory arthritis diagnoses (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and undifferentiated inflammatory arthritis) recorded in primary care; (2) time to first rheumatology assessment; (3) time to first prescription of a disease-modifying antirheumatic drug (DMARD) in primary care; and (4) choice of first DMARD.Among 17 683 500 adults, there were 31 280 incident inflammatory arthritis diagnoses recorded between April 1, 2019, and March 31, 2022. The mean age of diagnosed patients was 55·4 years (SD 16·6), 18 615 (59·5%) were female, 12 665 (40·5%) were male, and 22 925 (88·3%) of 25 960 with available ethnicity data were White. New inflammatory arthritis diagnoses decreased by 20·3% in the year commencing April, 2020, relative to the preceding year (5·1Inflammatory arthritis diagnoses decreased markedly during the early phase of the pandemic. The impact on rheumatology assessment times and DMARD prescribing in primary care was less marked than might have been anticipated. This study demonstrates the feasibility of using routinely captured, near real-time data in the secure OpenSAFELY platform to benchmark care quality on a national scale, without the need for manual data collection.None.

Objectives To evaluate the safety of treatment strategies in patients with early RA. Methods Systematic searches of MEDLINE, EMBASE and PubMed were conducted up to September 2020. Double-blind randomized controlled trials (RCTs) of licensed treatments conducted on completely naïve or MTX-naïve RA patients were included. Long-term extension studies, post-hoc and pooled analyses and RCTs with no comparator arm were excluded. Serious adverse events, serious infections and non-serious adverse events were extracted from all RCTs, and event rates in intervention and comparator arms were compared using meta-analysis and network meta-analysis (NMA). Results From an initial search of 3423 studies, 20 were included, involving 9202 patients. From the meta-analysis, the pooled incidence rates per 1000 patient-years for serious adverse events were 69.8 (95% CI: 64.9, 74.8), serious infections 18.9 (95% CI: 16.2, 21.6) and non-serious adverse events 1048.2 (95% CI: 1027.5, 1068.9). NMA showed that serious adverse event rates were higher with biologic monotherapy than with MTX monotherapy, rate ratio 1.39 (95% CI: 1.12, 1.73). Biologic monotherapy rates were higher than those for MTX and steroid therapy, rate ratio 3.22 (95% CI: 1.47, 7.07). Biologic monotherapy had a higher adverse event rate than biologic combination therapy, rate ratio 1.26 (95% CI: 1.02, 1.54). NMA showed no significant difference between strategies with respect to serious infections and non-serious adverse events rates. Conclusion The study revealed the different risk profiles for various early RA treatment strategies. Observed differences were overall small, and in contrast to the findings of established RA studies, steroid-based regimens did not emerge as more harmful.

ObjectiveOnline Patient reported outcome measures (PROMs) enable remote collection of perceptions of health status, function and wellbeing. We aimed to explore patterns of PROM completion in patients with early inflammatory arthritis (EIA) recruited to the national early inflammatory arthritis audit (NEIAA).MethodsNEIAA is an observational cohort study design, we included adults with a new diagnosis of EIA from May 2018-March 2020. Primary outcome was PROM completion, at baseline, three and 12 months. Mixed effects logistic regression and spatial regression models were used to identify associations between demographics (age, gender, ethnicity, deprivation, smoking and comorbidity), clinical commissioning groups, and PROM completion.Results11,986 EIA patients were included, of which 5,331 (44.5%) completed at least one PROM. Patients from ethnic minority backgrounds were less likely to return a PROM (Odds ratio 0.57, 95% CI 0.48 to 0.66). Greater deprivation (0.73, 95% CI 0.64 to 0.83), male gender (0.86, 95% CI 0.78 to 0.94), higher comorbidity burden (0.95, 95% CI 0.91 to 0.99) and current smoker status (0.73, 95% CI 0.64 to 0.82) also reduced odds of PROM completion. Spatial analysis identified two regions with high (North of England) and low (South-East of England) PROM completion.ConclusionWe define key patient characteristics (including ethnicity) that influence PROM engagement using a national clinical audit. We observed an association between locality and PROM completion with varying response rates across England regions. Completion rates could benefit from targeted education for these groups.

Background: The risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases and on immune-modifying drugs might not be fully mediated by comorbidities and might vary by factors such as ethnicity. We aimed to assess the risk of severe COVID-19 in adults with immune-mediated inflammatory diseases and in those on immune-modifying therapies. Methods: We did a cohort study, using OpenSAFELY (an analytics platform for electronic health records) and TPP (a software provider for general practitioners), analysing routinely collected primary care data linked to hospital admission, death, and previously unavailable hospital prescription data. We included people aged 18 years or older on March 1, 2020, who were registered with TPP practices with at least 12 months of primary care records before March, 2020. We used Cox regression (adjusting for confounders and mediators) to estimate hazard ratios (HRs) comparing the risk of COVID-19-related death, critical care admission or death, and hospital admission (from March 1 to Sept 30, 2020) in people with immune-mediated inflammatory diseases compared with the general population, and in people with immune-mediated inflammatory diseases on targeted immune-modifying drugs (eg, biologics) compared with those on standard systemic treatment (eg, methotrexate). Findings: We identified 17 672 065 adults; 1 163 438 adults (640 164 [55·0%] women and 523 274 [45·0%] men, and 827 457 [71·1%] of White ethnicity) had immune-mediated inflammatory diseases, and 16 508 627 people (8 215 020 [49·8%] women and 8 293 607 [50·2%] men, and 10 614 096 [64·3%] of White ethnicity) were included as the general population. Of 1 163 438 adults with immune-mediated inflammatory diseases, 19 119 (1·6%) received targeted immune-modifying therapy and 181 694 (15·6%) received standard systemic therapy. Compared with the general population, adults with immune-mediated inflammatory diseases had an increased risk of COVID-19-related death after adjusting for confounders (age, sex, deprivation, and smoking status; HR 1·23, 95% CI 1·20-1·27) and further adjusting for mediators (body-mass index [BMI], cardiovascular disease, diabetes, and current glucocorticoid use; 1·15, 1·11-1·18). Adults with immune-mediated inflammatory diseases also had an increased risk of COVID-19-related critical care admission or death (confounder-adjusted HR 1·24, 95% CI 1·21-1·28; mediator-adjusted 1·16, 1·12-1·19) and hospital admission (confounder-adjusted 1·32, 1·29-1·35; mediator-adjusted 1·20, 1·17-1·23). In post-hoc analyses, the risk of severe COVID-19 outcomes in people with immune-mediated inflammatory diseases was higher in non-White ethnic groups than in White ethnic groups (as it was in the general population). We saw no evidence of increased COVID-19-related death in adults on targeted, compared with those on standard systemic, therapy after adjusting for confounders (age, sex, deprivation, BMI, immune-mediated inflammatory diseases [bowel, joint, and skin], cardiovascular disease, cancer [excluding non-melanoma skin cancer], stroke, and diabetes (HR 1·03, 95% CI 0·80-1·33), and after additionally adjusting for current glucocorticoid use (1·01, 0·78-1·30). There was no evidence of increased COVID-19-related death in adults prescribed tumour necrosis factor inhibitors, interleukin (IL)-12/IL‑23 inhibitors, IL-17 inhibitors, IL-6 inhibitors, or Janus kinase inhibitors compared with those on standard systemic therapy. Rituximab was associated with increased COVID-19-related death (HR 1·68, 95% CI 1·11-2·56), with some attenuation after excluding people with haematological malignancies or organ transplants (1·54, 0·95-2·49). Interpretation: COVID-19 deaths and hospital admissions were higher in people with immune-mediated inflammatory diseases. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune-modifying drugs for immune-mediated inflammatory diseases compared with those on standard systemic therapy. Funding: UK Medical Research Council, NIHR Biomedical Research Centre at King's College London and Guy's and St Thomas' NHS Foundation Trust, and Wellcome Trust.

Background/Aims Sarcoidosis is a multi-system inflammatory disorder, characterised by the formation of non-caseating granulomas. In the UK, a decision was made to include sarcoid patients in the clinically extremely vulnerable group, and they were advised to shield during the COVID-19 pandemic. We investigated the incidence of covid-19 infection and uptake of COVID-19 vaccine within this patient group. Methods Consecutive patients attending the King’s College Hospital sarcoidosis clinic over 18 months between 1st January 2018 and 31st August 2020, and were still alive on 31st January 2020, were included in this report. Electronic primary care records and hospital records were reviewed for each patient to evaluate the incidence of RT-PCT confirmed covid-19 infection, hospitalisation, and vaccination status, defined as at least one vaccination. Hospitalisation data was available from four South-East London trusts. Results The King’s College Hospital database identified 416 patients with biopsy confirmed sarcoidosis. Of the complete cohort, the median age was 55.7 years, 193 patients (46%) were male, and 178 patients (43%) were of black ethnicity. A proportion of patients were taking prednisolone (n = 116, 28%) and DMARDs (n = 73, 18%). The incidence of RT-PCR confirmed covid-19 infection was 48/416 patients (12%). Of these infections, 16/48 (33%) were prior to vaccine availability, including one patient who required an intensive care admission. Post vaccine availability, 9/32 infections were in vaccinated individuals, 8/32 in unvaccinated and 15/32 were of unknown timing; there were 2 recorded hospital admissions but no intensive care admissions, neither patient was immunosuppressed and one was unvaccinated. Uptake of at least one covid-19 vaccine was 287/416 patients (69%). Of the cohort who opted not to have a vaccine (n = 129), the median age was 53.7 years, 60 patients (47%) were male, 58 (45%) were black ethnicity and 22 (17%) were white ethnicity. The only demographic variable to predict covid-19 vaccine uptake was ethnicity; patients of black ethnicity were less likely to have the vaccine than those of white ethnicity (OR = 0.56, p = 0.041). In vaccinated individuals, there were 9/287 cases (3%) of RT-PCT confirmed covid-19 infection, of which one patient required hospitalisation but not intensive care. Conclusion The incidence of covid-19 infection in our cohort is comparable to that of London (12%), despite an extremely clinically vulnerable population. Vaccine uptake was lower in sarcoid patients (69%) than the national comparator in adults (90%) and was especially low in the black ethnic population. Disclosure D. Nagra: None. S.A. Gunawardana: None. K. Bechman: None. S. Birring: None. A. Patel: None. J. Galloway: None.

Background/Aims The impact of dealing with COVID-19 for rheumatology higher specialist trainees has been profound. Sacrifices were made to their training to support the UK's pandemic response. Virtual Reality (VR) has long been used as a solution for specific surgical skills; providing a hands-on experience to enable specific delivery of outcomes. We utilised existing technology alongside a specialist VR and haptics team to review ways at delivering a valid and reliable training tool to administer joint injections, beginning with the review of this procedure specific to the knee. We aimed to describe this process. Methods A qualitative study using focus groups was undertaken, one medical student, four higher specialty trainees and two consultants were convened in a focus group to review existing mannequin-based training with the purpose of identifying a skill to develop in virtual reality. A story board was developed through collaboration with a graphic designer. The scenario was imbedded into a virtual reality environment in collaboration with a virtual reality partner. Results The focus group identified intra-articular knee injection as the most appropriate rheumatology skill to develop. Storyboarding built a series of scenarios around clinical situations which would require injection or aspiration. Working with the engineering team we successfully mapped knee joint anatomy and rendered an authentic clinical environment for the storyboards to run inside. Conclusion Virtual reality training scenarios are complex to develop but have enormous potential to create immersive training and assessment experiences which are not boundaried by the challenges of social distancing and COVID-19 risks. Disclosure B.D. Clarke: Honoraria; Abbvie. Grants/research support; Innovate UK. S. Balachandran: None. D. Nagra: None. M.D. Russell: Honoraria; Lilly, Pfizer, Janssen, UCB, Menarini. K. Bechman: None. M. Adas: None. A. Hope-Smith: None. M. Yates: Honoraria; Abbvie, UCB. A. Barrow: Grants/research support; Innovate UK. T. Smith: Grants/research support; Innovate UK. J. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi and UCB.

Background/Aims Online patient-reported outcome measures (PROMs) enable remote collection of perceptions of health status, function and wellbeing. Single-centre studies report that PROM completion is dependent on patient demographics. Here we use a large national prospective dataset to explore patterns of PROM completion. Methods Patients with a new diagnosis of early inflammatory arthritis (EIA) were recruited to the National Early Inflammatory Arthritis Audit (NEIAA) between May 2018 and March 2020 and followed up for one year. PROMs capturing the impact of disease using the MSK-HQ, disability using HAQ, mental health using PHQ4ADS, and work using the WPAI were requested at baseline, 3 and 12 months. Multivariable logistic regression was constructed to examine patient level associations with PROM completion. Mean PROM completion by clinical commissioning groups (CCG) were mapped across England and spatial regression models used to identify regional patterns. Results A total of 34,856 patients with suspected EIA were recruited to NEIAA. Of these, 11,986 were diagnosed with EIA across England, recruited from 205 CCGs. The cohort was evenly distributed across the indices of multiple deprivation (IMD) deciles. Thirteen percent were Black, Asian, or minority ethnic (BAME). At least one PROM was completed by 5,331 (44.5%) patients. Of these, 3,846 (72.1%) had completed half of all the available PROMs whilst 412 (7.7%) had completed all available PROMs. BAME participants were less likely to return a PROM in adjusted regression modelling (adj OR 0.57, 95% CI 0.48-0.66). Deprivation quintile (adj OR 0.73, 95% CI 0.64-0.83), male gender (adj OR 0.86, 95% CI 0.78-0.94), comorbidity burden (adj OR 0.95, 95% CI 0.91-0.99) and current smoker status (adj OR 0.73, 95% CI 0.64-0.82) also reduced the odds of PROM completion. The proportion with PROM completion varied across CCGs. Spatial analysis identified two autocorrelated regions in England with a hotspot of high PROM completion in the North and a cold spot in the South East. Conclusion This study defines key participant characteristics that influence PROM engagement in a national clinical audit and identifies a novel association between locality and PROM completion. Integral to the utility of PROMs in NEIAA is that they are representative of the population with EIA. Our results suggest there are under-represented groups with the potential to bias in favour of those likely to experience better outcome. Disclosure K. Bechman: None. M. Yates: None. H. Wright: None. M. Russell: None. D. Nagra: None. B.D. Clarke: None. J. Ledingham: None. S. Norton: None. J. Galloway: Consultancies; Abbvie, Sanofi, Novartis, Pfizer, UCB, Janssen. Grants/research support; Eli Lilly.

Background/Aims Sarcoidosis is a chronic inflammatory disorder, for which steroids are a common treatment. A side effect of long-term steroid therapy is an increased risk of osteoporosis, and calcium and/or vitamin D supplementation may be indicated. In sarcoidosis patients, increased expression of 1α-hydroxylase triggers the conversion of 25(OH)D3 to 1,25(OH)2D3 (calcitriol). Therefore, monitoring of calcium and vitamin D levels are recommended for patients taking supplementation, as they are at increased risk of hypercalcemia. Methods We conducted a retrospective analysis on community measurements of serum calcium and vitamin D levels, in sarcoidosis patients, who were prescribed calcium and/or vitamin D supplementation. Patients with biopsy confirmed sarcoidosis were identified using the King’s College Hospital sarcoidosis database and electronic primary care records were reviewed for each patient. Results The database identified 431 patients with biopsy confirmed sarcoidosis, of whom 102 patients (24%) had been prescribed calcium and/or vitamin D supplementation and were further evaluated. Of these 102 patients, 63 (62%) were taking calcium and vitamin D supplementation simultaneously; and 39 (38%) were taking vitamin D supplementation alone. In the last 12 months, 46 patients (45%) had measurements of serum calcium and vitamin D levels taken in the community. One patient taking vitamin D supplementation was identified as having hypercalcemia. Conclusion This audit has found infrequent monitoring of serum calcium and vitamin D levels over the last 12 months, in sarcoidosis patients, who were prescribed calcium and/or vitamin D supplementation. A Clinical Commissioning Group wide prescribing alert has been implemented to alert primary care physicians to the importance of monitoring these levels, to reduce the risk of hypercalcemia. Disclosure S. Gunawardana: None. D. Nagra: None. K. Bechman: None. S. Birring: None. J. Galloway: None. A. Patel: None.

Background/Aims To continue working, work in the same occupation or work the same number of hours is one of the most important outcomes for individuals with inflammatory arthritis but is often diminished during the very early phases of disease. Our objectives were to describe occupation and work status in individuals with early inflammatory arthritis (EIA) from the National Early Inflammatory Arthritis Audit (NEIAA) and assess the impact of occupation and treatment response on work disability. Methods NEIAA is an observational cohort of adults with newly diagnosed EIA seen in rheumatology services in England and Wales between May 2018 and March 2020. Self-reported occupation was coded using the UK Standard Occupational Classification and classified using the National Statistics Socio-Economic Classification (NS-SEC). Work disability was assessed at diagnosis, 3 months, and 12 months, using the work productivity and activity impairment (WPAI) score, with absenteeism data dichotomized between those who reported any sick-leave and those who did not. Multilevel mixed-effects linear regression models were used to examine associations between occupation and WPAI score at baseline and over 12 months. Variables for adjustment were decided a priori and included only age and sex. Results There were 12,663 individuals with EIA, with 5999 (48%) in paid work defined as greater than 20 hours per week. Occupation data were available for 3720 individuals, with the highest proportion of patients in lower managerial, administrative, professional (n = 773) and semi-routine (n = 761) roles. At diagnosis, 171 patients (4.7%) had stopped work and 336 (9.2%) had changed jobs because of their EIA. Absenteeism was reported by 685 patients (29.5%). Compared to the higher managerial, administration and professional occupation group, the other occupational types demonstrated a greater level of productivity loss due to presenteeism and overall work impairment. Individuals in semi routine and routine occupations were more likely to stop work due to EIA. In the 12 months after diagnosis, absenteeism, presenteeism and overall impairment improved across all occupations. Achieving a good EULAR response at 3 months, but not occupational type, was associated with improvement in work outcomes over time (p value Conclusion Work disability is prevalent in individuals with EIA at diagnosis, with variation across occupation types. In the first 12 months after diagnosis improvements in all work outcomes are seen, with the greatest change in those who achieve a good EULAR response. Disclosure K. Bechman: None. E. Cook: None. A. Houssien: None. P. Amlani-Hatcher: None. J. Ledingham: None. J. Galloway: Consultancies; Sanofi, Novartis, Pfizer, Janssen, UCB. Grants/research support; Eli Lilly. K. Walker-Bone: None.

Background: At the outset of the COVID-19 pandemic, there was no routine comprehensive hospital medicines data from the UK available to researchers. These records can be important for many analyses including the effect of certain medicines on the risk of severe COVID-19 outcomes. With the approval of NHS England, we set out to obtain data on one specific group of medicines, “high-cost drugs” (HCD) which are typically specialist medicines for the management of long-term conditions, prescribed by hospitals to patients. Additionally, we aimed to make these data available to all approved researchers in OpenSAFELY-TPP. This report is intended to support all studies carried out in OpenSAFELY-TPP, and those elsewhere, working with this dataset or similar data. Methods: Working with the North East Commissioning Support Unit and NHS Digital, we arranged for collation of a single national HCD dataset to help inform responses to the COVID-19 pandemic. The dataset was developed from payment submissions from hospitals to commissioners. Results: In the financial year (FY) 2018/19 there were 2.8 million submissions for 1.1 million unique patient IDs recorded in the HCD. The average number of submissions per patient over the year was 2.6. In FY 2019/20 there were 4.0 million submissions for 1.3 million unique patient IDs. The average number of submissions per patient over the year was 3.1. Of the 21 variables in the dataset, three are now available for analysis in OpenSafely-TPP: Financial year and month of drug being dispensed; drug name; and a description of the drug dispensed. Conclusions: We have described the process for sourcing a national HCD dataset, making these data available for COVID-19-related analysis through OpenSAFELY-TPP and provided information on the variables included in the dataset, data coverage and an initial descriptive analysis.

INTRODUCTION Janus Kinase inhibitors (JAKi) have shown to be highly effective in the treatment of immune-mediated inflammatory diseases, and several drugs in this class have been approved in recent years. As with all immunomodulatory therapies, careful assessment of any treatment-associated infection risk is essential to inform clinical decision-making. AREAS COVERED We summarise the current literature on infection rates among the licensed JAKi using published phase II/III trial results as well as post-licensing and registry data. EXPERT OPINION Data currently available for the licensed JAKi show an increased risk of infection across the class compared to placebo, most commonly affecting the respiratory and urinary tracts, nasopharynx and skin. This risk is dose-dependent, but similar at the licensed JAKi doses to that seen with biologic therapies. The risk is compounded by other risk factors for infection such as age and steroid co-prescription. Herpes zoster reactivation is more common with JAKi compared to other targeted immune modulation, making screening for varicella exposure and judicious vaccination in appropriate cohorts an advisable strategy. Crucially, these small risk increases must be balanced against the known harms (including infection) of uncontrolled autoimmune disease. JAKi are a safe and potentially transformative treatment when used for appropriately selected patients.

Background: COVID-19 vaccines have robust immunogenicity in the general population. However, data for individuals with immune-mediated inflammatory diseases who are taking immunosuppressants remains scarce. Our previously published cohort study showed that methotrexate, but not targeted biologics, impaired functional humoral immunity to a single dose of COVID-19 vaccine BNT162b2 (Pfizer-BioNTech), whereas cellular responses were similar. Here, we aimed to assess immune responses following the second dose.Methods: In this longitudinal cohort study, we recruited individuals with psoriasis who were receiving methotrexate or targeted biological monotherapy (ie, tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South-East England. The healthy control cohort were volunteers without psoriasis, not receiving immunosuppression. Immunogenicity was evaluated immediately before, on day 28 after the first BNT162b2 vaccination and on day 14 after the second dose (administered according to an extended interval regimen). Here, we report immune responses following the second dose. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as titres of total spike-specific IgG and of neutralising antibody to wild-type, alpha (B.1.1.7), and delta (B.1.617.2) SARS-CoV-2 variants, and cellular immunity defined as spike-specific T-cell responses (including numbers of cells producing interferon-γ, IL-2, IL-21).Findings: Between Jan 14 and April 4, 2021, 121 individuals were recruited, and data were available for 82 participants after the second vaccination. The study population included patients with psoriasis receiving methotrexate (n=14), TNF inhibitors (n=19), IL-17 inhibitors (n=14), IL-23 inhibitors (n=20), and 15 healthy controls, who had received both vaccine doses. The median age of the study population was 44 years (IQR 33-52), with 43 (52%) males and 71 (87%) participants of White ethnicity. All participants had detectable spike-specific antibodies following the second dose, and all groups (methotrexate, targeted biologics, and healthy controls) demonstrated similar neutralising antibody titres against wild-type, alpha, and delta variants. By contrast, a lower proportion of participants on methotrexate (eight [62%] of 13, 95% CI 32-86) and targeted biologics (37 [74%] of 50, 60-85; p=0·38) had detectable T-cell responses following the second vaccine dose, compared with controls (14 [100%] of 14, 77-100; p=0·022). There was no difference in the magnitude of T-cell responses between patients receiving methotrexate (median cytokine-secreting cells per 106 cells 160 [IQR 10-625]), targeted biologics (169 [25-503], p=0·56), and controls (185 [133-328], p=0·41).Interpretation: Functional humoral immunity (ie, neutralising antibody responses) at 14 days following a second dose of BNT162b2 was not impaired by methotrexate or targeted biologics. A proportion of patients on immunosuppression did not have detectable T-cell responses following the second dose. The longevity of vaccine-elicited antibody responses is unknown in this population.Funding: NIHR Biomedical Research Centre at Guy's and St Thomas' NHS Foundation Trust and King's College London; The Psoriasis Association.

Objective: To describe the frequency and predictors of nonserious infections (NSI) and compare incidence across biologic agents within the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA).Methods: The BSRBR-RA is a prospective observational cohort study. An NSI was defined as an infection that did not require hospitalization or intravenous therapy. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered “at risk” from the date of initiation of biologic treatment for up to 3 years. Drug exposure was defined by agent: tumor necrosis factor inhibitor (TNFi), interleukin-6 (IL-6) inhibitor, B cell depletion (rituximab), or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone. A multiple-failure Cox model was used with multivariable adjustment. Missing data were addressed using multiple imputation.Results: There were 17,304 NSI in 8,145 patients, with an event rate of 27.0 per person per year (95% confidence interval [95% CI] 26.6–27.4). Increasing age, female sex, comorbidity burden, glucocorticoid therapy, higher Disease Activity Score in 28 joints, and higher Health Assessment Questionnaire disability index were associated with an increased risk of NSI. There was a significant reduction in NSI risk with csDMARDs compared to biologic treatments. Compared to TNFi, IL-6 inhibition and rituximab were associated with a higher NSI risk (adjusted hazard ratio 1.45 [95% CI 1.29–1.63] and adjusted hazard ratio 1.28 [95% CI 1.14–1.45], respectively), while the csDMARD cohort had a lower risk (adjusted hazard ratio 0.64 [95% CI 0.59–0.70]). Within the TNFi class, adalimumab was associated with a higher NSI risk than etanercept (adjusted hazard ratio 1.11 [95% CI 1.05–1.17]).Conclusion: NSI occur frequently in RA, and predictors mirror those reported with serious infections. All biologics are associated with a greater risk of NSI, with differences observed between agents. While unmeasured confounding must be considered, the magnitude of effect is large, and a relationship between NSI and targeted immunomodulatory therapy likely exists.

BackgroundIt is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes.MethodsWith the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysingroutinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population; and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate).FindingsWe identified 17,672,065 adults; of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in individuals with IMIDs overall compared to individuals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56); however, this finding may relate to confounding.InterpretationCOVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics.RESEARCH IN CONTEXTEvidence before this studyWe searched PubMed on May 19th, 2021, using the terms “COVID-19”, “SARS-CoV-2” and “rheumatoid arthritis”, “psoriatic arthritis” “ankylosing spondylitis”, “Crohn’s disease” “ulcerative colitis” “hidradenitis suppurativa” and “psoriasis”, to identify primary research articles examining severe COVID-19 outcome risk in individuals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small sample sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease-specific registries are subject to selection bias and lack denominator populations.Added value of the studyIn our large population-based study of 17 million individuals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35).Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small.This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medicationsImplications of all of the available evidenceOur study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for individuals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.

Objective To evaluate drug survival with monotherapy compared with combination therapy with MTX in RA older adults. Methods Patients from the British Society for Rheumatology Biologics Register, a prospective observational cohort, who were biologic naïve and commencing their first TNF inhibitors (TNFi) were included. The cohort was stratified according to age: Results The analysis included 15 700 patients. Ninety-five percent were Conclusion TNFi monotherapy is associated with increased treatment failure. In older adults, the disadvantage of TNFi monotherapy on drug survival is no longer seen. Patients ≥75 have fewer discontinuations due to inefficacy than adverse events compared with younger patients. This likely reflects greater disposition to toxicity but perhaps also a decline in immunogenicity associated with immunosenescence.

Purpose of ReviewThis review discusses fungal infections associated with licenced small-molecule protein kinase inhibitors. For each major drug class, the mechanism of action and targeted pathways and the impact on host defence against fungi are described.Recent FindingsProtein kinase inhibitors are successfully used in the treatment of malignancies and immune-mediated diseases, targeting signalling pathways for a broad spectrum of cytokines and growth-stimuli. These agents predispose to fungal infections by the suppression of integral components of the adaptive and innate immune response.SummaryThe greatest risk of fungal infections is seen with bruton tyrosine kinase inhibitors, e.g. ibrutinib. Infections are also reported with agents that target mTOR, Janus kinase and break point cluster (Bcr) gene–Abelson (Abl) tyrosine kinase (BCR-ABL). The type of fungal infection fits mechanistically with the specific pathway targeted. Infections are often disseminated and present soon after the initiation of therapy. The pharmacokinetic profile, possibility of off-target kinase inhibition, and underlying disease pathology contribute to infection risk.

Objectives To investigate the relationship between occurrence of serious infection (SI) and lymphocyte counts in patients with RA using data from a single centre. Methods We used routinely captured data from a single tertiary rheumatology centre to explore the relationship between lymphopenia and SI risk. Adult RA patients were included over a 5-year follow-up period. Admissions due to confirmed SI were considered. SI rate with 95% confidence intervals was calculated. The association between SI with baseline lymphocyte counts, time-averaged lymphocyte counts throughout all follow-up, and a nadir lymphocyte count was assessed using Cox proportional hazards regression. The relationship between lymphopenia over time and SI was analysed using a mixed-effect model of lymphocyte counts prior to SI. Results This analysis included 1095 patients with 205 SIs during 2016 person-years of follow-up. The SI rate was 4.61/100 patient-years (95% CI: 3.76, 5.65). Compared with patients with nadir lymphocyte counts >1.5 × 109 cells/l, nadir lymphopenia Conclusion Lymphocyte counts below

Objectives Observational cohort studies in early RA are a key source of evidence, despite inconsistencies in methodological approaches. This narrative review assesses the spectrum of methodologies used in addressing centre-level effect and case-mix adjustment in early RA observational cohort studies. Methods An electronic search was undertaken to identify observational prospective cohorts of >100 patients recruited from two or more centres, within 2 years of an RA or early inflammatory arthritis diagnosis. References and author publication lists of all studies from eligible cohorts were assessed for additional cohorts. Results Thirty-four unique cohorts were identified from 204 studies. Seven percent of studies considered centre in their analyses, most commonly as a fixed effect in regression modelling. Reporting of case-mix variables in analyses varied widely. The number of variables considered in case-mix adjustment was higher following publication of the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement in 2007. Conclusion Centre effect is unreported or inadequately accounted for in the majority of RA observational cohorts, potentially leading to spurious inferences and obstructing comparisons between studies. Inadequate case-mix adjustment precludes meaningful comparisons between centres. Appropriate methodology to account for centre and case-mix adjustment should be considered at the outset of analyses.

Objective To evaluate whether polypharmacy is associated with treatment response and serious adverse events (SAEs) in patients with RA using data from the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study of biologic therapy starters and a DMARD comparator arm. A logistic regression model was used to calculate the odds of a EULAR ‘good response’ after 12 months of biologic therapy by medication count. Cox proportional hazards models were used to identify risk of SAEs. The utility of the models were compared with the Rheumatic Disease Comorbidity Index using Receiver Operator Characteristic and Harrell’s C statistic. Results The analysis included 22 005 patients, of which 83% were initiated on biologics. Each additional medication reduced the odds of a EULAR good response by 8% [odds ratios 0.92 (95% CI 0.91, 0.93) P < 0.001] and 3% in the adjusted model [adjusted odds ratios 0.97 (95% CI 0.95, 0.98) P < 0.001]. The Receiver Operator Characteristic demonstrated significantly greater areas under the curve with the polypharmacy model than the Rheumatic Disease Comorbidity Index. There were 12 547 SAEs reported in 7286 patients. Each additional medication equated to a 13% increased risk of an SAE [hazard ratio 1.13 (95% CI 1.12, 1.13) P < 0.001] and 6% in the adjusted model [adjusted hazard ratio 1.06 (95% CI 1.05, 1.07) P < 0.001]. Predictive values for SAEs were comparable between the polypharmacy and Rheumatic Disease Comorbidity Index model. Conclusion Polypharmacy is a simple but valuable predictor of clinical outcomes in patients with RA. This study supports medication count as a valid measure for use in epidemiologic analyses.

Summary Background Patients on therapeutic immunosuppressants for immune-mediated inflammatory diseases were excluded from COVID-19 vaccine trials. We therefore aimed to evaluate humoral and cellular immune responses to COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) in patients taking methotrexate and commonly used targeted biological therapies, compared with healthy controls. Given the roll-out of extended interval vaccination programmes to maximise population coverage, we present findings after the first dose. Methods In this cohort study, we recruited consecutive patients with a dermatologist-confirmed diagnosis of psoriasis who were receiving methotrexate or targeted biological monotherapy (tumour necrosis factor [TNF] inhibitors, interleukin [IL]-17 inhibitors, or IL-23 inhibitors) from a specialist psoriasis centre serving London and South East England. Consecutive volunteers without psoriasis and not receiving systemic immunosuppression who presented for vaccination at Guy's and St Thomas' NHS Foundation Trust (London, UK) were included as the healthy control cohort. All participants had to be eligible to receive the BNT162b2 vaccine. Immunogenicity was evaluated immediately before and on day 28 (±2 days) after vaccination. The primary outcomes were humoral immunity to the SARS-CoV-2 spike glycoprotein, defined as neutralising antibody responses to wild-type SARS-CoV-2, and spike-specific T-cell responses (including interferon-γ, IL-2, and IL-21) 28 days after vaccination. Findings Between Jan 14 and April 4, 2021, 84 patients with psoriasis (17 on methotrexate, 27 on TNF inhibitors, 15 on IL-17 inhibitors, and 25 on IL-23 inhibitors) and 17 healthy controls were included. The study population had a median age of 43 years (IQR 31–52), with 56 (55%) males, 45 (45%) females, and 85 (84%) participants of White ethnicity. Seroconversion rates were lower in patients receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in controls (17 [100%; 80–100] of 17), with the lowest rate in those receiving methotrexate (seven [47%; 21–73] of 15). Neutralising activity against wild-type SARS-CoV-2 was significantly lower in patients receiving methotrexate (median 50% inhibitory dilution 129 [IQR 40–236]) than in controls (317 [213–487], p=0·0032), but was preserved in those receiving targeted biologics (269 [141–418]). Neutralising titres against the B.1.1.7 variant were similarly low in all participants. Cellular immune responses were induced in all groups, and were not attenuated in patients receiving methotrexate or targeted biologics compared with controls. Interpretation Functional humoral immunity to a single dose of BNT162b2 is impaired by methotrexate but not by targeted biologics, whereas cellular responses are preserved. Seroconversion alone might not adequately reflect vaccine immunogenicity in individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression. Real-world pharmacovigilance studies will determine how these findings reflect clinical effectiveness. Funding UK National Institute for Health Research.

In January 2020, a new strain of coronavirus was described. Less than 3 months later, a pandemic was declared. Within 9 months, the first vaccine received emergency authorization.

Summary Objectives Multiple RCTs of interleukin-6 (IL-6) inhibitors in COVID-19 have been published, with conflicting conclusions. We performed a meta-analysis to assess the impact of IL-6 inhibition on mortality from COVID-19, utilising meta-regression to explore differences in study results. Methods Systematic database searches were performed to identify RCTs comparing IL-6 inhibitors (tocilizumab and sarilumab) to placebo or standard of care in adults with COVID-19. Meta-analysis was used to estimate the relative risk of mortality at 28 days between arms, expressed as a risk ratio. Within-study mortality rates were compared, and meta-regression was used to investigate treatment effect modification. Results Data from nine RCTs were included. The combined mortality rate across studies was 19% (95% CI: 18, 20%), ranging from 2% to 31%. The overall risk ratio for 28-day mortality was 0.90 (95% CI: 0.81, 0.99), in favour of benefit for IL-6 inhibition over placebo or standard of care, with low treatment effect heterogeneity: I2 0% (95% CI: 0, 53%). Meta-regression showed no evidence of treatment effect modification by patient characteristics. Trial-specific mortality rates were explained by known patient-level predictors of COVID-19 outcome (male sex, CRP, hypertension), and country-level COVID-19 incidence. Conclusions IL-6 inhibition is associated with clinically meaningful improvements in outcomes for patients admitted with COVID-19. Long-term benefits of IL-6 inhibition, its effectiveness across healthcare systems, and implications for differing standards of care are currently unknown.

Objectives Updated guidelines for patients with axial SpA (axSpA) have sought to reduce diagnostic delay by raising awareness among clinicians. We used the National Early Inflammatory Arthritis Audit (NEIAA) to describe baseline characteristics and time to diagnosis for newly referred patients with axSpA in England and Wales. Methods Analyses were performed on sociodemographic and clinical metrics, including time to referral and assessment, for axSpA patients (n = 784) recruited to the NEIAA between May 2018 and March 2020. Comparators were patients recruited to the NEIAA with RA (n = 9270) or mechanical back pain (MBP; n = 370) in the same period. Results Symptom duration prior to initial rheumatology assessment was longer in axSpA than RA patients (P 6 months, compared with 33.7% of RA patients and 76.0% of MBP patients. Following referral, the median time to initial rheumatology assessment was longer for axSpA than RA patients (36 vs 24 days; P Conclusion Diagnostic delay in axSpA remains a major challenge despite improved disease understanding and updated referral guidelines. Disease education is provided to fewer axSpA than RA patients, highlighting the need for specialist clinics and support programmes for axSpA patients.

Introduction: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes were different in the first and second waves. Methods: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and January 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. Findings: There were 3,457 COVID-19 admissions, 2,494 hospital discharges and 619 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (25.7% versus 13.2%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.41(0.30, 0.56)p

Objective JAK inhibitor therapies are effective treatment options for immune-mediated inflammatory diseases (IMIDs), but their use has been limited by venous thromboembolism (VTE) risk warnings from licensing authorities. We undertook this study to evaluate the VTE risk of JAK inhibitors in patients with IMIDs. Methods Systematic searches of Medline and Embase databases from inception to September 30, 2020 were conducted. Phase II and phase III double-blind, randomized controlled trials (RCTs) of JAK inhibitors at licensed doses were included in our analyses. RCTs with no placebo arm, long-term extension studies, post hoc analyses, and pooled analyses were excluded. Three researchers independently extracted data on exposure to JAK inhibitors or placebo and VTE events (e.g., pulmonary embolism [PE] and deep vein thrombosis [DVT]) and assessed study quality. Results A total of 42 studies were included, from an initial search that yielded 619. There were 6,542 JAK inhibitor patient exposure years (PEYs) compared to 1,578 placebo PEYs. There were 15 VTE events in the JAK inhibitor group and 4 in the placebo group. The pooled incidence rate ratios (IRRs) of VTE, PE, and DVT in patients receiving JAK inhibitors were 0.68 (95% confidence interval [95% CI] 0.36-1.29), 0.44 (95% CI 0.28-0.70), and 0.59 (95% CI 0.31-1.15), respectively. Conclusion This meta-analysis of RCT data defines the VTE risk with JAK inhibitors as a class in IMID patients. The pooled IRRs do not provide evidence that support the current warnings of VTE risk for JAK inhibitors. These findings will aid continued development of clinical guidelines for the use of JAK inhibitors in IMIDs.

As efficacy and safety data emerge, differences between JAK inhibitor subclasses are appearing. JAK1 selective drugs, upadacitinib and filgotinib, have broadly come with the same overarching safety recommendations as other immunosuppressive drugs for RA: caution is needed regarding infection risk; monitoring for laboratory abnormalities, including lipids and muscle enzymes, is indicated. A distinguishing feature of JAK inhibitors is a risk for zoster reactivation. Numerically, overall rates of serious infection are similar among JAK inhibitor classes. There are currently no signals for diverticular perforation. VTE incidence rates were similar across comparator groups for the JAK1 selective agents. These observations are not yet conclusive evidence for different safety profiles between JAK1 selective agents and other JAK inhibitors. Differences in study population, design, and concomitant steroid use are examples of potential confounders. It is too early to draw conclusions on long-term outcomes such as malignancy and cardiovascular risk. Post-marketing pharmacovigilance studies will be essential.

Low molecular weight, orally available, ‘small molecules’ which target and inhibit components of the Janus family tyrosine kinase (JAK) enzyme inflammatory signalling cascade have been lately considered as an important alternative to biologic therapies for rheumatoid arthritis (RA). JAK signalling is used by a number of pro-inflammatory cytokines known to be involved in RA pathogenesis, notably IL-6. Therefore, several JAK inhibitors with variable degrees of selectivity and specificity for the JAK enzymes have been investigated in treatment of RA. To date, two JAK inhibitors, tofacitinib and baricitinib, have been approved for treatment of RA in certain regions. This chapter discusses the safety, efficacy, trials, and future directions of these two JAK inhibitors.

Background Patients with rheumatoid arthritis (RA) are at an increased risk of infection. Most attention has been given to serious infections, but these are the tip of the iceberg. Non-serious infections (NSI) are far more frequent, and although not life-threatening, have potential to impact treatment outcomes (drug survival) and quality of life. Our objective was to describe frequency of NSI and compare incidence of NSI by biologic drug within the British Society for Rheumatology Biologics Register (BSRBR-RA). Methods The BSRBR-RA is a prospective observational cohort study. NSI was identified as not requiring hospitalisation, intravenous therapy or leading to disability or death. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered ‘at risk’ from the date of commencing biologic treatment for 3 years. Drug exposure was defined by agent; TNF inhibitor, IL-6 inhibitor, anti-CD20 or csDMARD only. To account for a high frequency of events, a multiple-failure Cox model was used. Multivariable adjustment included age, gender, DAS28-ESR, HAQ-DI, disease duration, smoking, steroid usage, year recruited to BSRBR-RA, line of biologic therapy and cumulative infection number. Results There were 17,304 NSI in 10,099 patients, with an event rate of 27.0 per year (95% CI 26.6 to 27.4). Increasing age, female gender, comorbidity burden, corticosteroid therapy, DAS28 and HAQ-DI were associated with an increased risk of NSI. The rate of NSI was numerically lowest with csDMARDs. Compared to TNFi, IL-6 inhibitor had a higher risk of NSI, whilst the csDMARD cohort had a lower risk. Between the TNFi agents, adalimumab had a higher risk than etanercept (Table 1). Conclusion These results confirm that NSI is a frequent occurrence for patients, which historically has received little attention in research literature. The data suggest biologics increase the risk of NSI, especially IL-6 inhibition. Whilst unmeasured confounding must be considered, the magnitude of effects are large and it seems likely that a causal link between targeted immunosuppression and NSI risk exists. Further research is needed to understand the impact of NSI on clinical outcomes including drug survival and quality of life. Disclosures K. Bechman: None. K. Halai: None. S. Norton: None. A.P. Cope: None. K.L. Hyrich: Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway: Honoraria; for speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

Background There is an established increase risk of infection in rheumatoid arthritis (RA). Most published data examine serious events, which affect 3-5% of patients annually. Approximately half of the patients experience non-serious infection, which does not require parental antibiotics or hospitalisation. Sinusitis events affecting patients on biologics (particularly TNF inhibition) have been observed but not well described, with a prevalence of 2-17%. Sinusitis is associated with treatment discontinuation and surgical interventions. We aim to describe the rates of sinusitis with different RA treatment strategies and provide estimates of risk difference. Methods The population was adults with RA, enrolled in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis registry (BSRBR-RA) during the first 3 years of study on biologic treatment. The predictor was treatment strategy at the time of event (csDMARD only, TNF inhibitors, IL-6 inhibitors and anti-CD20). The primary outcome was sinusitis according to MeddraPT codes reported by patients (via patient diary) or clinician (on an adverse event form). A multi-failure Cox survival model was used to compare risk across treatment groups. A multivariate model adjusted for confounders (age, gender, entry year in BSRBR-RA, disease duration, baseline disease activity by DAS-28, HAQ, comorbidities, smoking status and steroid use. Results 23,584 patients were included, contributing to a total of 64,035 patient-years of follow up. There were 797 infective events in 580 patients. This corresponded to a rate of 0.95 per year (95% CI 0.87 to 0.1.02). The sinusitis rate was numerically highest with anti-CD20 (Rituximab) and lowest with csDMARDs (Table 1). In the adjusted Cox proportional hazard model, all 3 biologics strategies had a significantly higher rate of sinusitis compared to csDMARD cohort; (TNFi 2.76 (95%CI 1.85 to 4.12); IL-6R 2.51 (1.00 to 6.29); anti-CD20 3.14 (1.46 to 6.72). Conclusion Sinusitis is more common in patients prescribed biologics compared to the csDMARD. The highest rate was seen with rituximab. This would fit biologically, as the primary immunodeficiency phenotype of recurrent sinusitis aligns with antibody defects e.g. common variable immunodeficiency. However, it is interesting to observe that sinusitis is more common across the treatment classes. Disclosures K. Halai None. K. Bechman None. S. Norton None. A.P. Cope None. K.L. Hyrich Honoraria; AbbVie paid to the institution and grant income from Pfizer and Bristol-Myers Squibb for activities outside of this work. J.B. Galloway Honoraria; or speaking or attending conferences from AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Pfizer and Union Chimique Belge.

Background Trial data indicate an increased risk of VTE with JAK inhibition. The EMA and FDA have given regulatory advice for their use as a result. To understand the context of any association, we need to understand VTE risk in the background population. Our objective was to describe the changing epidemiology of VTE risk including a breakdown of DVT and PE in the general population in England, over a 20-year period. Methods We utilised hospital episodes statistics data to study all patients presenting for hospital care in England between 1 January 1998 and 31 December 2017. We identified VTE events using ICD10 codes I26.0, I26.9, I80.1, I80.2 and I80.3. To estimate annualised event rates, we used the number of finished consultant episodes for admitted care where the primary diagnosis was VTE for the numerator; the denominator was the whole population estimate, from the office for National Statistics, for the relevant year for England. Rates were calculated per 100,000 population, and the Cochrane Armitage test was used to evaluate statistical significance of trends over time. Linear regression allowed modelling of estimates over time, with model assumptions tested using residual versus fitted plots. To explore non-linearity, we used a cubic spline model. Results The average VTE rate across the 20 years was 127/100,000. VTE rates have increased over time, climbing from 108/100,000 in 1998, to 151/100,000 in 2017. The relative frequency of DVTs and PEs has changed over this time: in 1998 DVT was more frequent than PE (rates 68/100,000 and 40/100,000 respectively). By 2018 this ratio had reversed (DVT 52/100,000: PE 98/100,000). This change was statistically significant (p < 0.0001). DVT rates declined in a linear manner over time. PE rates increased with a non-linear pattern, with a sharp rise apparent between 2008 and 2010. Conclusion The inversion in the frequency of DVTs and PEs is consistent with previous findings using European data. One possible explanation is changing diagnostics (CTPA replacing V/Q), capturing previously subclinical PE events. Limitations include our ecologic design as well as lack of linkage to mortality records. The presumed VTE risk associated with JAK inhibition is small. It is plausible that future shifts in population wide patterns of VTE could obscure or amplify any effect attributable to JAK inhibitors. As longer-term observational data become available, it is crucial they are interpreted in the context of background population trends. Disclosures S. Baroncini: None. M. Yates: None. K. Bechman: None. S. Patel: None. A. Rutherford: None. A. Kleymann: None. J. Galloway: None.

Objective.To investigate predictors of flare in rheumatoid arthritis (RA) patients with low disease activity (LDA) and to evaluate the effect of flare on 12-month clinical outcomes.Methods.Patients with RA who were taking disease-modifying antirheumatic drugs and had a stable 28-joint count Disease Activity Score (DAS28) < 3.2 were eligible for inclusion. At baseline and every 3 months, clinical (DAS28), functional [Health Assessment Questionnaire–Disability Index (HAQ-DI), EQ-5D, Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F), Medical Outcomes Study Short Form-36 (SF-36)], serum biomarkers [multibiomarker disease activity (MBDA) score, calprotectin, CXCL10], and imaging data were collected. Flare was defined as an increase in DAS28 compared with baseline of > 1.2, or > 0.6 if concurrent DAS28 ≥ 3.2. Cox regression analyses were used to identify baseline predictors of flare. Biomarkers were cross-sectionally correlated at time of flare. Linear regressions were performed to compare clinical outcomes after 1 year.Results.Of 152 patients, 46 (30%) experienced a flare. Functional disability at baseline was associated with flare: HAQ-DI had an unadjusted HR 1.82 (95% CI 1.20–2.72) and EQ-5D had HR 0.20 (95% CI 0.07–0.57). In multivariate analyses, only HAQ-DI remained a significant independent predictor of flare (HR 1.76, 95% CI 1.05–2.93). At time of flare, DAS28 and its components significantly correlated with MBDA and calprotectin, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers. Patients who flared had significantly worse outcomes at 12 months (HAQ-DI, EQ-5D, FACIT-F, SF-36, and radiographic progression).Conclusion.Flares occur frequently in RA patients with LDA and are associated with worse disease activity, quality of life, and radiographic progression. Higher baseline HAQ-DI was modestly predictive of flare, while biomarker correlation at the time of flare suggests a noninflammatory component in a majority of events.

Objective.Vaccination is a key strategy to reduce infection risk in patients with rheumatoid arthritis (RA) and is advocated in internationally recognized rheumatology society guidelines. The aim was to evaluate to the effect of antirheumatic drugs on influenza and pneumococcal vaccine immunogenicity.Methods.We conducted a systematic literature review and metaanalysis comparing the humoral response to influenza (pandemic and seasonal trivalent subunit vaccines) and pneumococcal (23-valent pneumococcal polysaccharide vaccine, 7- and 13-valent pneumococcal conjugated vaccines) vaccination in adult patients with RA treated with antirheumatic drugs. Vaccine immunogenicity was assessed by seroprotection rates measured 3 to 6 weeks postimmunization. Risk ratios (RR) and 95% CI were pooled.Results.Nine studies were included in the metaanalysis (7 studies investigating antirheumatic drug exposures and influenza humoral response, 2 studies investigating pneumococcal vaccine response). Influenza vaccine responses to all subunit strains (H1N1, H3N2, B strain) were preserved with methotrexate (MTX) and tumor necrosis factor inhibitor (TNFi) drug exposure. MTX but not TNFi drug exposure was associated with reduced 6B and 23F serotype pneumococcal vaccine response (RR 0.42, 95% CI 0.28–0.63 vs RR 0.98, 95% CI 0.58–1.67); however, limited data were available to draw any firm conclusions. Combination of MTX with tocilizumab or tofacitinib was associated with reduced pneumococcal and influenza vaccine responses.Conclusion.Antirheumatic drugs may limit humoral responses to vaccination as evidenced by pneumococcal responses with MTX exposure; however, they are safe and should not preclude immunization against vaccine-preventable disease. Vaccination should be considered in all patients with RA and encouraged as part of routine care. (Systematic review registration number: PROSPERO 2016: CRD42016048093.)

Background Sarcoidosis is a chronic inflammatory disease with a myriad of clinical manifestations. Treatment involves immunosuppression with corticosteroids or steroid-sparing agents. A proportion of patients does not respond to or are intolerant to therapy. Targeted immunotherapy with biologic agents has emerged as a novel approach with plausible mechanistic reasons to warrant study. Aims The aim of this review was to evaluate the evidence for the efficacy of biological therapy in sarcoidosis. Methods We conducted a systematic literature review and meta-analysis of all published randomised-controlled trials (RCT) evaluating biological therapy in sarcoidosis, using MEDLINE and Embase databases, through to September 2017. The search terms included sarcoidosis, infliximab, adalimumab, etanercept, golimumab, certolizumab, rituximab, abatacept, tocilizumab, anakinra, ustekinumab, secukinumab. Only articles reporting RCTs were selected. Improvements in respiratory disease were assessed by changes in forced vital capacity (FVC) by weighted mean difference (WMD). There were insufficient data on outcome measures in other organ systems to comparatively assess efficacy. Results The search identified 2,324 studies of which only 5 provided relevant and original data. This comprised a total of 364 patients, evaluating pulmonary, cutaneous and ocular sarcoidosis. One study in pulmonary disease and one study in cutaneous disease demonstrated improvements in the primary outcome. In pulmonary disease, meta-analysis of the treatment effect of anti-TNF therapy versus placebo on FVC revealed a WMD of 1.69 per cent (95 per cent confidence interval, 1.44–1.94). Conclusion There are insufficient data to suggest the long-term efficacy of anti-TNFα inhibitors in the treatment of sarcoidosis. This may be due to heterogeneity, small sample sizes and the lack of consistent reporting of outcome measures.