Understanding the psychosocial determinants of effective disease management in rheumatoid arthritis to prevent persistently active disease: a qualitative study.

BACKGROUND: According to epidemiological studies, psychosocial factors are known to be associated with disease activity, physical activity, pain, functioning, treatment help-seeking, treatment waiting times and mortality in people with rheumatoid arthritis (RA). Limited qualitative inquiry into the psychosocial factors that add to RA disease burden and potential synergistic interactions with biological parameters makes it difficult to understand patients' perspectives from the existing literature. AIM: This study aimed to gather in-depth patient perspectives on psychosocial determinants that drive persistently active disease in RA, to help guide optimal patient care. METHODS: Patient research partners collaborated on the research design and materials. Semistructured interviews and focus groups were conducted online (in 2021) with patients purposively sampled from diverse ethnicities, primary languages, employment status and occupations. Data were analysed using inductive thematic analysis. RESULTS: 45 patients participated across 28 semistructured interviews and three focus groups. Six main themes on psychosocial determinants that may impact RA management were identified: (1) healthcare systems experiences, (2) patient education and health literacy, (3) employment and working conditions, (4) social and familial support, (5) socioeconomic (dis)advantages, and (6) life experiences and well-being practices. CONCLUSION: This study emphasises the importance of clinicians working closely with patients and taking a holistic approach to care that incorporates psychosocial factors into assessments, treatment plans and resources. There is an unmet need to understand the relationships between interconnected biopsychosocial factors, and how these may impact on RA management.

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

BACKGROUND: Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept. METHODS: The APIPPRA study was a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial done in 28 hospital-based early arthritis clinics in the UK and three in the Netherlands. Participants (aged ≥18 years) at risk of rheumatoid arthritis positive for ACPA and rheumatoid factor with inflammatory joint pain were recruited. Exclusion criteria included previous episodes of clinical synovitis and previous use of corticosteroids or disease-modifying antirheumatic drugs. Participants were randomly assigned (1:1) using a computer-generated permuted block randomisation (block sizes of 2 and 4) stratified by sex, smoking, and country, to 125 mg abatacept subcutaneous injections weekly or placebo for 12 months, and then followed up for 12 months. Masking was achieved by providing four kits (identical in appearance and packaging) with pre-filled syringes with coded labels of abatacept or placebo every 3 months. The primary endpoint was the time to development of clinical synovitis in three or more joints or rheumatoid arthritis according to American College of Rheumatology and European Alliance of Associations for Rheumatology 2010 criteria, whichever was met first. Synovitis was confirmed by ultrasonography. Follow-up was completed on Jan 13, 2021. All participants meeting the intention-to-treat principle were included in the analysis. This trial was registered with EudraCT (2013-003413-18). FINDINGS: Between Dec 22, 2014, and Jan 14, 2019, 280 individuals were evaluated for eligibility and, of 213 participants, 110 were randomly assigned to abatacept and 103 to placebo. During the treatment period, seven (6%) of 110 participants in the abatacept group and 30 (29%) of 103 participants in the placebo group met the primary endpoint. At 24 months, 27 (25%) of 110 participants in the abatacept group had progressed to rheumatoid arthritis, compared with 38 (37%) of 103 in the placebo group. The estimated proportion of participants remaining arthritis-free at 12 months was 92·8% (SE 2·6) in the abatacept group and 69·2% (4·7) in the placebo group. Kaplan-Meier arthritis-free survival plots over 24 months favoured abatacept (log-rank test p=0·044). The difference in restricted mean survival time between groups was 53 days (95% CI 28-78; p<0·0001) at 12 months and 99 days (95% CI 38-161; p=0·0016) at 24 months in favour of abatacept. During treatment, abatacept was associated with improvements in pain scores, functional wellbeing, and quality-of-life measurements, as well as low scores of subclinical synovitis by ultrasonography, compared with placebo. However, the effects were not sustained at 24 months. Seven serious adverse events occurred in the abatacept group and 11 in the placebo group, including one death in each group deemed unrelated to treatment. INTERPRETATION: Therapeutic intervention during the at-risk phase of rheumatoid arthritis is feasible, with acceptable safety profiles. T-cell co-stimulation modulation with abatacept for 12 months reduces progression to rheumatoid arthritis, with evidence of sustained efficacy beyond the treatment period, and with no new safety signals. FUNDING: Bristol Myers Squibb.

No Waning of Pneumococcal Vaccine Responses over Time in People with Inflammatory Arthritis: Findings from a Single Centre Cohort.

BACKGROUND: Vaccination against pneumococcus reduces the risk of infective events, hospitalisation, and death in individual with inflammatory arthritis, particularly in those on immunomodulating therapy who are at risk of worse outcomes from pneumococcal disease. The objective of this study was to investigate the serological protection following vaccination against pneumococcal serovars over time. Methods: This was a single centre, retrospective cohort study of individuals with rheumatoid arthritis, psoriatic arthritis, or axial spondylarthritis who had previously received the PPSV23 polysaccharide pneumococcal vaccine (Pneumovax). Data were retrieved between January 2021 to August 2023. Dates of previous pneumococcal vaccination were identified using linked primary care records. Serum serotype levels were collected. The primary outcome was serological response defined as a titre ≥0.35 mcg/mL in at least five from a total of 12 evaluated pneumococcal serovars, examined using a Luminex platform. Multivariate logistic regression models adjusting for age, gender, ethnicity, co-morbidities, and the use of prednisolone, conventional synthetic and biological DMARDs were used to determine the odds of a sustained serological response according to time categorised into ≤5 years, 5-10 years, and ≥10 years since vaccination. Results: Serological response was measured in 296 individuals with inflammatory arthritis, with rheumatoid arthritis the most common diagnosis (74% of patients). The median time between pneumococcal vaccine administration and serological assessment was 6 years (interquartile range 2.4 to 9.9). A positive serological response to at least 5 serovars was present in 195/296 (66%) of patients. Time since vaccination did not significantly associate with serological protection compared with those vaccinated <5 years, the adjusted ORs of vaccine response was 1.15 (95% CI 0.64 to 2.07) in those 5-10 years and 1.26 (95% CI: 0.64 to 2.48) in those vaccinated over 10 years ago. No individual variable from the multivariate model reached statistical significance as an independent predictor of vaccine response, although steroid use at the time of vaccine had a consistent detrimental impact on serological immunity. Conclusions: We demonstrated that antibody titres following vaccination against pneumococcal serovars do not appear to wane over time. It appears more critical to focus on maximising the initial vaccine response, which is known to be diminished in this patient population.

Ongoing shielding behavior one year post COVID-19: results from a longitudinal study of patients with inflammatory arthritis.

Many patients with inflammatory arthritis (IA) were instructed to shield during the COVID-19 pandemic. Despite the ending of lockdowns and vaccination, large proportions of IA patients were continuing to shield when it is no longer needed. Given the detrimental effects of shielding on mental and physical health, understanding the rates and reasons for shielding is needed to help clinicians advise patients accordingly. This study was a 12-month prospective study following participants with IA during the COVID-19 pandemic. The proportions of IA patients shielding at each time point were calculated. Additionally, regressions and odds ratios for shielding were determined to assess medication type, mental health, and risk perception. While the extent of shielding fluctuated over the year of lockdowns, nearly all IA patients (93.5%) were still engaging in some shielding in 2021, with nearly half (43%) still shielding most or all of the time. Medications that were previously considered higher risk were not significantly associated with higher rates of shielding (OR = 1.60, p = 0.29), but greater symptoms of depression in June 2020 (OR = 1.07, p = 0.03) was both associated with increased the odds of shielding in June 2021. The high rates of IA patients continuing to shield in 2021 put more strain on patients and professionals as social isolation is linked with worsening mental and physical health, as well as greater difficulty with self-management. It is important for clinicians to be aware of this trend to ease the stress on patients.

Mental health, quality of life and self-management behaviours: online evaluation of inflammatory arthritis patients over 1 year of COVID-19 lockdowns.

Objective: Patients with inflammatory arthritis were especially vulnerable to the psychosocial and health impacts of coronavirus disease 2019 (COVID-19) and the lockdowns. This study investigated the impact of these changes on mental health, physical health and quality of life for inflammatory arthritis patients over 1 year following the initial lockdown in the UK. Methods: Three hundred and thirty-eight participants with inflammatory arthritis completed an ambidirectional study consisting of online questionnaires at four time points for 1 year. The questionnaires assessed demographic information, inflammatory arthritis condition, mental health, physical symptoms, self-management behaviours, COVID-19 status and impacts. Means, linear regressions and structural equation modelling for mediations were conducted over 12 months. Results: Physical health concerns peaked during June 2020, then declined, but did not return to baseline. Depression was associated with worse quality of life at baseline, as shown by the beta coefficient, (ß= 0.94, P < 0.01), September (ß = 0.92, P < 0.01), November (ß= 0.77, P < 0.01) and 1 year (ß = 0.77, P < 0.01). Likewise, anxiety was associated with worse quality of life at baseline (ß = 1.92, P < 0.01), September (ß = 2.06, P < 0.01), November (ß = 1.66, P = 0.03) and 1 year (ß = 1.51, P = 0.02). The association between depression and quality of life was mediated by physical activity (ß= 0.13, P < 0.01) at baseline. The association between anxiety and quality of life was also mediated by physical activity (ß = 0.25, P = 0.04) at baseline. Conclusion: Physical health continued to be worse 1 year later compared with before the COVID-19 lockdowns in patients with inflammatory arthritis. Mental health showed long-term effects on quality of life, with an impact for ≥12 months. Lastly, physical activity mediated between mental health and quality of life in the short term.

Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial.

BACKGROUND: From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. METHODS: TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). FINDINGS: Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62-1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88-2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. INTERPRETATION: Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation. FUNDING: UK Medical Research Council, UK National Institute for Health Research Cambridge Biomedical Research Centre, Eli Lilly and Company, Alexion Pharmaceuticals, and Addenbrooke's Charitable Trust.

A Systematic Review and Meta-Analysis of Anti-Rheumatic Drugs and Pneumococcal Vaccine Immunogenicity in Inflammatory Arthritis.

BACKGROUND: Pneumococcal pneumonia is an important cause of morbidity and mortality amongst patients with inflammatory arthritis. Vaccination is recommended by the National Institute for Health and Care Excellence (NICE) but it remains unclear how vaccine efficacy is impacted by different immunosuppressive agents. Our objective was to compare the chance of a seroconversion following vaccination against pneumococcus in patients with inflammatory arthritis to that in the general population, as well as to compare the chance of seroconversion across different targeted therapies. METHODS: We searched MEDLINE, Embase and the Cochrane Library databases from inception until 20 June 2023. We included randomized controlled trials and observational studies. Aggregate data were used to undertake a pairwise meta-analysis. Our primary outcome of interest was vaccine seroconversion. We accepted the definition of serological response reported by the authors of each study. RESULTS: Twenty studies were identified in the systematic review (2807 patients) with ten reporting sufficient data to be included in the meta-analysis (1443 patients). The chance of seroconversion in patients receiving targeted therapies, relative to the general population, was 0.61 (95% CI 0.35 to 1.08). The reduced odds of response were skewed strongly by the effects of abatacept and rituximab with no difference between patients on TNF inhibitors (TNFis) or IL-6 inhibition and healthy controls. Within different inflammatory arthritis populations the findings remained consistent, with rituximab having the strongest negative impact on vaccine response. TNF inhibition monotherapy was associated with a greater chance of vaccine response compared with methotrexate (2.25 (95% CI 1.28 to 3.96)). JAK inhibitor (JAKi) studies were few in number and did not present comparable vaccine response endpoints to include in the meta-analysis. The information available does not suggest any significant detrimental effects of JAKi on vaccine response. CONCLUSION: This updated meta-analysis confirms that, for most patients with inflammatory arthritis, pneumococcal vaccine can be administered with confidence and that it will achieve comparable seroconversion rates to the healthy population. Patients on rituximab were the group least likely to achieve a response and further research is needed to explore the value of multiple-course pneumococcal vaccination schedules in this population.

Implementing treat-to-target urate-lowering therapy during hospitalisations for gout flares.

OBJECTIVES: To evaluate a strategy designed to optimise care and increase uptake of urate-lowering therapy (ULT) during hospitalisations for gout flares. METHODS: We conducted a prospective cohort study to evaluate a strategy that combined optimal in-hospital gout management with a nurse-led, follow-up appointment, followed by handover to primary care. Outcomes, including ULT initiation, urate target attainment, and re-hospitalisation rates, were compared between patients hospitalised for flares in the 12 months post-implementation and a retrospective cohort of hospitalised patients from 12 months pre-implementation. RESULTS: 119 and 108 patients, respectively, were hospitalised for gout flares in the 12 months pre- and post-implementation. For patients with 6-month follow-up data available (n = 94 and n = 97, respectively), the proportion newly initiated on ULT increased from 49.2% pre-implementation to 92.3% post-implementation (age/sex-adjusted odds ratio (aOR) 11.5; 95% confidence interval (CI) 4.36-30.5; p < 0.001). After implementation, more patients achieved a serum urate ≤360 micromol/L within 6 months of discharge (10.6% pre-implementation vs. 26.8% post-implementation; aOR 3.04; 95% CI 1.36-6.78; p = 0.007). The proportion of patients re-hospitalised for flares was 14.9% pre-implementation vs. 9.3% post-implementation (aOR 0.53, 95% CI 0.22 to 1.32; p = 0.18). CONCLUSION: Over 90% of patients were initiated on ULT after implementing a strategy to optimise hospital gout care. Despite increased initiation of ULT during flares, recurrent hospitalisations were not more frequent following implementation. Significant relative improvements in urate target attainment were observed post-implementation; however, for the majority of hospitalised gout patients to achieve urate targets, closer primary-secondary care integration is still needed.

Extracellular matrix rigidity modulates physical properties of SCS macrophage-B cell immune synapses.

Subcapsular sinus (SCS) macrophages (SSMs) play a key role in immune defence by forming immunological barriers that control the transport of antigens from lymph into lymph node follicles. SSMs participate in antibody responses by presenting antigens directly to naive B cells and by supplying antigens to follicular dendritic cells to propagate germinal centre reactions. Despite the prominent roles that SSMs play during immune responses, little is known about their cell biology because they are technically challenging to isolate and study in vitro. Here, we used multi-colour fluorescence microscopy to identify lymph node-derived SSMs in culture. We focused on the role of SSMs as antigen-presenting cells, and found that their actin cytoskeleton regulates the spatial organisation and mobility of multivalent antigens (immune complexes, ICs) displayed on the cell surface. Moreover, we determined that SSMs are mechanosensitive cells that respond to changes in extracellular matrix (ECM) rigidity by altering the architecture of the actin cytoskeleton, leading to changes in cell morphology, membrane topography, and immune complex mobility. Changes to ECM rigidity also modulate actin remodelling by both SSMs and B cells when they form an immune synapse. This alters synapse duration but not IC internalisation nor NF-κB activation in the B cell. Taken together, our data reveal that the mechanical microenvironment may influence B cell responses by modulating physical characteristics of antigen presentation by SSMs.

Rheumatoid arthritis prevention in arthralgia: fantasy or reality?

The concept of a 'window of opportunity' in treating a disease assumes the existence of a time frame during which the trajectory of the disease can be effectively and permanently modified. In rheumatoid arthritis (RA), optimal timing of this period is presumed to be during the phase before arthritis is clinically apparent and disease is diagnosed. Several proof-of-concept trials of treatment during the 'arthralgia' phase of RA have been completed in the past 4 years, with the underlying notion that temporary treatment at this stage could prevent the development of RA or induce a sustained reduction in the burden of disease. This Review summarizes the results of these trials and reflects on the outcomes in relation to the patients' perspectives. Overall, the majority of symptomatic at-risk individuals could benefit from a fixed period treatment, even if RA does not develop. Various factors must be taken into consideration when translating these findings into clinical practice. More evidence is needed to target the individuals at highest risk, and additional tools are needed to monitor treatment and guide decisions about whether treatment can be discontinued. Without these tools, there is a paradoxical risk of seemingly increasing the incidence of the disease and prolonging disease duration, which is the opposite of what the concept of intervening in the window of opportunity entails.

JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications.

OBJECTIVES: To estimate the association of Janus kinase inhibitors (JAKi) with the incidence of malignancy, compared with placebo, tumour necrosis factor (TNF)-α inhibitors (TNFi) and methotrexate. METHODS: Systematic searches of databases were performed, to December 2022, to identify phase II/III/IV randomised clinical trials (RCTs) and long-term extension (LTE) studies of JAKi (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib) compared with placebo, TNFi or methotrexate, in adults with rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthritis, inflammatory bowel disease or atopic dermatitis. Network and pairwise meta-analyses were performed to estimate incidence rate ratios (IRRs) for malignancy between JAKi and comparators. Bias was assessed using the Cochrane Risk of Bias-2 tool. RESULTS: In 62 eligible RCTs and 16 LTE studies, there were 82 366 person-years of exposure to JAKi, 2924 to placebo, 7909 to TNFi and 1074 to methotrexate. The overall malignancy incidence rate was 1.15 per 100 person-years in RCTs, and 1.26 per 100 person-years across combined RCT and LTE data. In network meta-analyses, the incidence of all malignancies including non-melanomatous skin cancers (NMSCs) was not significantly different between JAKi and placebo (IRR 0.71; 95% CI 0.44 to 1.15) or between JAKi and methotrexate (IRR 0.77; 95% CI 0.35 to 1.68). Compared with TNFi, however, JAKi were associated with an increased incidence of malignancy (IRR 1.50; 95% CI 1.16 to 1.94). Findings were consistent when analysing NMSC only and when analysing combined RCT/LTE data. CONCLUSIONS: JAKi were associated with a higher incidence of malignancy compared with TNFi but not placebo or methotrexate. Cancers were rare events in all comparisons. PROSPERO REGISTRATION NUMBER: CRD42022362630.

Treat-to-target urate-lowering therapy and hospitalizations for gout: results from a nationwide cohort study in England.

OBJECTIVE: To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout. METHODS: Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalizations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalizations for gout. RESULTS: Of 292 270 people with incident gout, 7719 (2.64%) had one or more hospitalizations for gout, with an incidence rate of 4.64 hospitalizations per 1000 person-years (95% CI 4.54, 4.73). There was an associated increased risk of hospitalizations within the first 6 months after ULT initiation, when compared with people who did not initiate ULT [adjusted Hazard Ratio (aHR) 4.54; 95% CI 3.70, 5.58; P < 0.001]. Hospitalizations did not differ significantly between people prescribed vs not prescribed colchicine prophylaxis in fully adjusted models. From 12 months after initiation, ULT associated with a reduced risk of hospitalizations (aHR 0.77; 95% CI 0.71, 0.83; P < 0.001). In ULT initiators, attainment of a serum urate <360 micromol/l within 12 months of initiation associated with a reduced risk of hospitalizations (aHR 0.57; 95% CI 0.49, 0.67; P < 0.001) when compared with people initiating ULT but not attaining this target. CONCLUSION: ULT associates with an increased risk of hospitalizations within the first 6 months of initiation but reduces hospitalizations in the long term, particularly when serum urate targets are achieved.

Gout incidence and management during the COVID-19 pandemic in England, UK: a nationwide observational study using OpenSAFELY.

BACKGROUND: Gout is the most prevalent inflammatory arthritis, yet one of the worst managed. Our objective was to assess how the COVID-19 pandemic impacted incidence and quality of care for people with gout in England, UK. METHODS: With the approval of National Health Service England, we did a population-level cohort study using primary care and hospital electronic health record data for 17·9 million adults registered with general practices using TPP health record software, via the OpenSAFELY platform. The study period was from March 1, 2015, to Feb 28, 2023. Individuals aged 18-110 years were defined as having incident gout if they were assigned index diagnostic codes for gout, were registered with TPP practices in England for at least 12 months before diagnosis, did not receive prescriptions for urate-lowering therapy more than 30 days before diagnosis, and had not been admitted to hospital or attended an emergency department for gout flares more than 30 days before diagnosis. Outcomes assessed were incidence and prevalence of people with recorded gout diagnoses, incidence of gout hospitalisations, initiation of urate-lowering therapy, and attainment of serum urate targets (≤360 µmol/L). FINDINGS: From a reference population of 17 865 145 adults, 246 695 individuals were diagnosed with incident gout. The mean age of individuals with incident gout was 61·3 years (SD 16·2). 66 265 (26·9%) of 246 695 individuals were female, 180 430 (73·1%) were male, and 189 035 (90·9%) of 208 050 individuals with available ethnicity data were White. Incident gout diagnoses decreased by 30·9% in the year beginning March, 2020, compared with the preceding year (1·23 diagnoses vs 1·78 diagnoses per 1000 adults). Gout prevalence was 3·07% in 2015-16, and 3·21% in 2022-23. Gout hospitalisations decreased by 30·1% in the year commencing March, 2020, compared with the preceding year (9·6 admissions vs 13·7 admissions per 100 000 adults). Of 228 095 people with incident gout and available follow-up, 66 560 (29·2%) were prescribed urate-lowering therapy within 6 months. Of 65 305 individuals who initiated urate-lowering therapy with available follow-up, 16 790 (25·7%) attained a serum urate concentration of 360 µmol/L or less within 6 months of urate-lowering therapy initiation. In interrupted time-series analyses, urate-lowering therapy prescribing improved modestly during the pandemic, compared with pre-pandemic, whereas urate target attainment was similar. INTERPRETATION: Using gout as an exemplar disease, we showed the complexity of how health care was impacted during the COVID-19 pandemic. We observed a reduction in gout diagnoses but no effect on treatment metrics. We showed how country-wide, routinely collected data can be used to map disease epidemiology and monitor care quality. FUNDING: None.

Incidence and management of inflammatory arthritis in England before and during the COVID-19 pandemic: a population-level cohort study using OpenSAFELY.

Background: 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. Methods: 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. Findings: 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 (5·1 vs 6·4 diagnoses per 10 000 adults). The median time to first rheumatology assessment was shorter during the pandemic (18 days; IQR 8-35) than before (21 days; 9-41). The proportion of patients prescribed DMARDs in primary care was similar before and during the pandemic; however, during the pandemic, fewer people were prescribed methotrexate or leflunomide, and more were prescribed sulfasalazine or hydroxychloroquine. Interpretation: Inflammatory 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. Funding: None.

Infection profile of immune-modulatory drugs used in autoimmune diseases: analysis of summary of product characteristic data.

OBJECTIVE: Serious infection remains a concern when prescribing immune-modulatory drugs for immune-mediated inflammatory diseases. The 'summary of product characteristics' (SmPCs) provide information on adverse events for example, infections, from clinical trials and postmarketing pharmacovigilance.This review aimed to compare infection frequency, site and type across immune-modulatory drugs, reported in SmPCs. METHODS: The Electronic Medicines Compendium was searched for commonly prescribed immune-modulatory drugs used for: rheumatoid arthritis, spondyloarthritis, connective tissue disease, autoimmune vasculitis, autoinflammatory syndromes, inflammatory bowel disease, psoriasis, multiple sclerosis and/or other rarer conditions.Information was extracted on infection frequency, site and organisms. Frequency was recorded as per the SmPCs: very common (≥1/10); common (≥1/100 to<1/10); uncommon (≥1/1,000 to<1/100); rare (≥1/10,000 to<1/1,000); very rare (<1/10 000). RESULTS: 39 drugs were included, across 20 indications: 9 conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), 6 targeted synthetic DMARDs, 24 biologic (b)DMARDs.Twelve infection sites were recorded. Minimal/no site information was available for most csDMARDs, certolizumab pegol and rituximab. Upper respiratory tract was the most common site, especially with bDMARDs. Lower respiratory, ear/nose/throat and urinary tract infections were moderately common, with clustering within drug groups.Data for 27 pathogens were recorded, majority viruses, with herpes simplex and zoster and influenza most frequent. Variable/absent reporting was noted for opportunistic and certain high-prevalence infections for example, Epstein-Barr. CONCLUSION: Our findings show differences between drugs and can aid treatment decisions alongside real-world safety data. However, data are likely skewed by trial selection criteria and varying number of trials per drug and highlight the need for robust postmarketing pharmacovigilance.

Management of gout following 2016/2017 European (EULAR) and British (BSR) guidelines: An interrupted time-series analysis in the United Kingdom.

Background: Following studies reporting sub-optimal gout management, European (EULAR) and British (BSR) guidelines were updated to encourage the prescription of urate-lowering therapy (ULT) with a treat-to-target approach. We investigated whether ULT initiation and urate target attainment has improved following publication of these guidelines, and assessed predictors of these outcomes. Methods: We used the Clinical Practice Research Datalink to assess attainment of the following outcomes in people (n = 129,972) with index gout diagnoses in the UK from 2004-2020: i) initiation of ULT; ii) serum urate ≤360 µmol/L and ≤300 µmol/L; iii) treat-to-target urate monitoring. Interrupted time-series analyses were used to compare trends in outcomes before and after updated EULAR and BSR management guidelines, published in 2016 and 2017, respectively. Predictors of ULT initiation and urate target attainment were modelled using logistic regression and Cox proportional hazards. Findings: 37,529 (28.9%) of 129,972 people with newly-diagnosed gout had ULT initiated within 12 months. ULT initiation improved modestly over the study period, from 26.8% for those diagnosed in 2004 to 36.6% in 2019 and 34.7% in 2020. Of people diagnosed in 2020 with a serum urate performed within 12 months, 17.1% attained a urate ≤300 µmol/L, while 36.0% attained a urate ≤360 µmol/L. 18.9% received treat-to-target urate monitoring. No significant improvements in ULT initiation or urate target attainment were observed after updated BSR or EULAR management guidance, relative to before. Comorbidities, including chronic kidney disease (CKD), heart failure and obesity, and diuretic use associated with increased odds of ULT initiation but decreased odds of attaining urate targets within 12 months: CKD (adjusted OR 1.61 for ULT initiation, 95% CI 1.55 to 1.67; adjusted OR 0.51 for urate ≤300 µmol/L, 95% CI 0.48 to 0.55; both p < 0.001); heart failure (adjusted OR 1.56 for ULT initiation, 95% CI 1.48 to 1.64; adjusted OR 0.85 for urate ≤300 µmol/L, 95% CI 0.76 to 0.95; both p < 0.001); obesity (adjusted OR 1.32 for ULT initiation, 95% CI 1.29 to 1.36; adjusted OR 0.61 for urate ≤300 µmol/L, 95% CI 0.58 to 0.65; both p < 0.001); and diuretic use (adjusted OR 1.49 for ULT initiation, 95% CI 1.44 to 1.55; adjusted OR 0.61 for urate ≤300 µmol/L, 95% CI 0.57 to 0.66; both p < 0.001). Interpretation: Initiation of ULT and attainment of urate targets remain poor for people diagnosed with gout in the UK, despite updated management guidelines. If the evidence-practice gap in gout management is to be bridged, strategies to implement best practice care are needed. Funding: National Institute for Health Research.

Interferon-α-mediated therapeutic resistance in early rheumatoid arthritis implicates epigenetic reprogramming.

OBJECTIVES: An interferon (IFN) gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients where it has been shown to negatively impact initial response to treatment. We wished to validate this effect and explore potential mechanisms of action. METHODS: In a multicentre inception cohort of eRA patients (n=191), we examined the whole blood IGS (MxA, IFI44L, OAS1, IFI6, ISG15) with reference to circulating IFN proteins, clinical outcomes and epigenetic influences on circulating CD19+ B and CD4+ T lymphocytes. RESULTS: We reproduced our previous findings demonstrating a raised baseline IGS. We additionally showed, for the first time, that the IGS in eRA reflects circulating IFN-α protein. Paired longitudinal analysis demonstrated a significant reduction between baseline and 6-month IGS and IFN-α levels (p<0.0001 for both). Despite this fall, a raised baseline IGS predicted worse 6-month clinical outcomes such as increased disease activity score (DAS-28, p=0.025) and lower likelihood of a good EULAR clinical response (p=0.034), which was independent of other conventional predictors of disease activity and clinical response. Molecular analysis of CD4+ T cells and CD19+ B cells demonstrated differentially methylated CPG sites and dysregulated expression of disease relevant genes, including PARP9, STAT1, and EPSTI1, associated with baseline IGS/IFNα levels. Differentially methylated CPG sites implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α). CONCLUSIONS: Our data suggest that, in eRA, IFN-α can cause a sustained, epigenetically mediated, pathogenic increase in lymphocyte activation and proliferation, and that the IGS is, therefore, a robust prognostic biomarker. Its persistent harmful effects provide a rationale for the initial therapeutic targeting of IFN-α in selected patients with eRA.

Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade.

Checkpoint blockade with Pembrolizumab, has demonstrated durable clinical responses in advanced non-small cell lung cancer, however, treatment is offset by the development of high-grade immune related adverse events (irAEs) in some patients. Here, we show that in these patients a deficient Breg checkpoint fails to limit self-reactive T cell enhanced activity and auto-antibody formation enabled by PD-1/PD-L1 blockade, leading to severe auto-inflammatory sequelae. Principally a failure of IL-10 producing regulatory B cells as demonstrated through functional ex vivo assays and deep phenotyping mass cytometric analysis, is a major and significant finding in patients who develop high-grade irAEs when undergoing treatment with anti-PD1/PD-L1 checkpoint blockade. There is currently a lack of biomarkers to identify a priori those patients at greatest risk of developing severe auto-inflammatory syndrome. Pre-therapy B cell profiling could provide an important tool to identify lung cancer patients at high risk of developing severe irAEs on checkpoint blockade.