Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

Challenges and Opportunities in the Supply of Living Kidney Donation in the UK National Health Service: An Economic Perspective.

End-stage kidney disease is a significant burden on the healthcare systems of many countries, and this is likely to continue because of an increasingly aging and comorbid population. Multiple studies have demonstrated a significant clinical benefit in transplantation when compared with dialysis, however, there continues to be a shortage of donor kidneys available. This article provides an economic perspective on issues pertinent to living kidney donation and transplantation. Although ethics, equity, and cultural considerations often seem at odds with economic concepts around resource allocation, this article explains the situation around supply and demand for living kidneys and illustrates how this has been addressed in the economic literature. The article discusses different policy recommendations for resolving the imbalance between supply and demand in kidney donation, through policies under 3 main approaches: increasing supply, decreasing demand, and improving the allocation of kidney supply.

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.

COVID-19 admissions and mortality in patients with early inflammatory arthritis: Results from a UK national cohort.

OBJECTIVE: To describe the risks and predictors of COVID-19 hospitalisation and mortality amongst patients with early inflammatory arthritis (EIA), recruited to the National Early Inflammatory Arthritis Audit (NEIAA). METHODS: NEIAA is an observational cohort. We included adults with EIA from Feb 2020-May 2021. Outcomes of interest were hospitalisation and death due to COVID-19, using NHS Digital linkage. Cox proportional hazards were used to calculate hazard ratios for outcomes according to initial treatment strategy, with adjustment for confounders. RESULTS: From 14 127 patients with EIA, there were 143 hospitalisations and 47 deaths due to COVID-19: incidence rates per 100 person-years of 0.93 (95% CI 0.79-1.10) for hospitalisation and 0.30 (95% CI 0.23-0.40) for death. Increasing age, male gender, comorbidities and ex-smoking were associated with increased risk of worse COVID-19 outcomes. Higher baseline DAS28 was not associated with COVID admissions (confounder adjusted hazard ratio (aHR) 1.10; 95% CI 0.97-1.24) or mortality (aHR 1.11; 95% CI 0.90-1.37). Seropositivity was not associated with either outcome. Higher symptom burden on patient-reported measures predicted worse COVID-19 outcomes. In unadjusted models, corticosteroids associated with COVID-19 death (HR 2.29; 95% CI 1.02-5.13), and sulfasalazine monotherapy associated with COVID-19 admission (HR 1.92; 95% CI 1.04-3.56). In adjusted models, associations for corticosteroids and sulfasalazine were not statistically significant. CONCLUSION: Patient characteristics have stronger associations with COVID-19 than the initial treatment strategy in patients with EIA. An important limitation is that we have not looked at treatment changes over time.

High numbers of COVID-19 patients transit through non-COVID wards, and associated healthcare workers have high infection rates: An observational cross-sectional study.

Infection risk is high in healthcare workers working with COVID-19 patients but the risk in non-COVID clinical environments is less clear. We measured infection rates early in the pandemic by SARS-CoV-2 antibody and/or a positive PCR test in 1118 HCWs within various hospital environments with particular focus on non-COVID clinical areas. Infection risk on non-COVID wards was estimated through the surrogate metric of numbers of patients transferred from a non-COVID to a COVID ward. Staff infection rates increased with likelihood of COVID exposure and suggested high risk in non-COVID clinical areas (non patient-facing 23.2% versus patient-facing in either non-COVID environments 31.5% or COVID wards 44%). High numbers of patients admitted to COVID wards had initially been admitted to designated non-COVID wards (22-48% at peak). Infection risk was high during a pandemic in all clinical environments and non-COVID designation may provide false reassurance. Our findings support the need for common personal protective equipment standards in all clinical areas, irrespective of COVID/non-COVID designation.

The impact of consecutive COVID-19 lockdowns in England on mental wellbeing in people with inflammatory arthritis.

BACKGROUND: During the first UK COVID-19 lockdown, studies identified over half of inflammatory arthritis (IA) patients in the UK reported a worsening of emotional distress. Given the prolonged nature of the pandemic, and the strict 'shielding' restrictions imposed on 'extremely clinically vulnerable' populations, it is likely that the implementation of the second lockdown period in England, during November 2020, may also have had a negative impact on the mental health of IA patients. The aim of this study was to qualitatively explore the impact of consecutive lockdown periods on mental wellbeing in people with IA. METHODS: Nine IA patients took part in semi-structured telephone interviews at both baseline (June/July 2020) and follow-up (November 2020). The interview schedule, which was developed and piloted with a Patient Research Partner, explored patient experiences and mental health impacts of the COVID-19 lockdown periods. Interviews were analysed using inductive thematic analysis. RESULTS: Five males and four females, with rheumatoid arthritis, psoriatic arthritis, or spondylarthritis, aged between 24-79 years (mean = 49.9, SD = 20.9) were included in the sample. Four main themes impacting on mental wellbeing were identified from the data: (1) Pandemic fatigue versus pandemic acclimatisation, (2) Social interaction and isolation, (3) Clarity of information, (4) Seasonal changes. CONCLUSION: The first two COVID-19 lockdown periods in England had an ongoing impact on the mental health of patients with IA. Healthcare professionals, in conjunction with government support, should ensure that adequate information and mental health resources are available to support IA patients during periods of ongoing restrictions, whilst also continuing to encourage behaviours which promote good mental health and wellbeing.

Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune-modifying therapies: a nationwide cohort study in the OpenSAFELY platform.

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/IL­23 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.

A comprehensive high cost drugs dataset from the NHS in England - An OpenSAFELY-TPP Short Data Report.

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.

Mental health outcomes in patients with a long-term condition: analysis of an Improving Access to Psychological Therapies service.

BACKGROUND: Having a long-term condition (LTC) significantly affects mental health. UK policy requires effective mental health provisions for patients with an LTC, generally provided by Improving Access to Psychological Therapies (IAPT) services. National IAPT data suggest that patients with an LTC typically demonstrate poorer outcomes compared with patients without an LTC. However, exploration of confounding factors and different outcome variables is limited. AIMS: To establish the association of LTC status with demographic and clinical factors, and clinical mental health outcomes. METHOD: Anonymised patient-level data from a London IAPT service during January 2019 to October 2020 were used in this cohort study, to compare differences between LTC and non-LTC groups on sociodemographic and clinical variables. Binary logistic and multiple linear regression models were constructed for binary outcome variables (recovery and reliable improvement) and continuous outcomes (distress and functioning), respectively. RESULTS: Patients with an LTC were more likely to be female; older; from a Black, mixed or other ethnic background; and have greater social deprivation. Across the four clinical outcomes (recovery, reliable improvement, final psychological distress and final functioning), having an LTC significantly predicted poorer outcomes even after controlling for sociodemographic and clinical baseline variables. For three outcome variables, greater social deprivation and being discharged during the COVID-19 pandemic also predicted poorer clinical outcomes. CONCLUSIONS: LTC status has a negative effect on mental health outcomes in IAPT services, independent of associated variables such as severity of baseline mental health symptoms, ethnicity and social deprivation. Effective psychological treatment for patients with an LTC remains an unresolved priority.

The impact of COVID-19 on clinical care, self-management and mental health of patients with inflammatory arthritis.

OBJECTIVES: The coronavirus disease 2019 (COVID-19) lockdown and ongoing restrictions in the UK affected access to clinical care, self-management and mental health for many patients with inflammatory arthritis. The aim of this study was to determine the impact of lockdown on inflammatory arthritis clinical care, self-management, disease outcomes and mental health. METHODS: In total, 338 people with inflammatory arthritis participated in a prospective study, completing a series of online questionnaires. The questionnaires assessed demographics, inflammatory arthritis condition and management, clinical care, quality of life and mental health. Visual analogue scales (VASs) were completed at each assessment. Linear regression, controlling for confounders, was conducted to determine factors associated with physical and mental health outcomes. RESULTS: More than half of participants reported worsening VAS by >10 points for patient global assessment (PGA), pain, fatigue and emotional distress during the initial lockdown. Changes in clinical care were associated with worse PGA (b = 8.95, P = 0.01), pain (b = 7.13, P = 0.05), fatigue (b = 17.01, P < 0.01) and emotional distress (b = 12.78, P < 0.01). Emotional distress and depression were also associated with worse outcomes in PGA, pain and fatigue, whereas loneliness was not. In contrast, physical activity seemed to mitigate these effects. Loneliness did not show any associations with outcomes. Over time, these effects decreased or disappeared. CONCLUSION: Changes to clinical care owing to lockdown were associated with worse disease outcomes in patients with inflammatory arthritis. There has also been a clear impact on mental health, with possibly complex relationships between mental health and psychosocial factors. Physical activity emerged as a key influence on disease outcomes and mental health.

The impact of COVID-19 on self-management behaviours and healthcare access for people with inflammatory arthritis.

BACKGROUND: Inflammatory arthritis (IA) patients have been identified as at greater risk of severe illness from COVID-19. It is likely that lockdown restrictions (enforced by the UK government in response to the COVID-19 pandemic) and subsequent changes made to healthcare provision could impact patients' abilities to effectively manage their condition. The aim of this study was to qualitatively explore the impact of COVID-19 on self-management behaviours and healthcare access for people with IA. METHODS: Semi-structured interviews were conducted with 21 IA patients in June-July 2020, with nine follow-up interviews in November 2020. Interview schedules were developed with a Patient Research Partner and explored participants' experiences of the COVID-19 pandemic. Interviews were conducted via telephone and analysed using inductive thematic analysis. RESULTS: Participants were aged between 24 and 79 years (mean = 50.1, SD = 15.8), largely female (71%) and White British (86%). Four initial themes were identified: (1) Impact of COVID-19 on medication adherence, (2) Impact of COVID-19 on physical activity, (3) Impact of COVID-19 on diet, and (4) Impact of COVID-19 on healthcare access and delivery. Subthemes focused on positive and negative changes made to these areas, as well as behaviours which remained consistent. Follow-up interviews highlighted differences in participants' experiences during the two lockdown periods. CONCLUSION: COVID-19 has affected patients' abilities to manage their IA. Healthcare professionals need to recognise the ongoing impact of COVID-19 on patient self-management and healthcare access to ensure that adequate understanding and support is available to patients who may have inadequate disease control as a result.

A Knowledge Distillation Ensemble Framework for Predicting Short- and Long-Term Hospitalization Outcomes From Electronic Health Records Data.

The ability to perform accurate prognosis is crucial for proactive clinical decision making, informed resource management and personalised care. Existing outcome prediction models suffer from a low recall of infrequent positive outcomes. We present a highly-scalable and robust machine learning framework to automatically predict adversity represented by mortality and ICU admission and readmission from time-series of vital signs and laboratory results obtained within the first 24 hours of hospital admission. The stacked ensemble platform comprises two components: a) an unsupervised LSTM Autoencoder that learns an optimal representation of the time-series, using it to differentiate the less frequent patterns which conclude with an adverse event from the majority patterns that do not, and b) a gradient boosting model, which relies on the constructed representation to refine prediction by incorporating static features. The model is used to assess a patient's risk of adversity and provides visual justifications of its prediction. Results of three case studies show that the model outperforms existing platforms in ICU and general ward settings, achieving average Precision-Recall Areas Under the Curve (PR-AUCs) of 0.891 (95% CI: 0.878-0.939) for mortality and 0.908 (95% CI: 0.870-0.935) in predicting ICU admission and readmission.

Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.

BACKGROUND: 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 for those admitted with severe Covid 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 March 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. RESULTS: There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 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 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. CONCLUSION: There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.

The impact of COVID-19 on clinical care, self-management, and mental health of patients with inflammatory arthritis

Objectives The COVID-19 lockdown and ongoing restrictions in the UK affected access to clinical care, self-management, and mental health for many patients with Inflammatory Arthritis (IA). This study aimed to determine the impact of lockdown on IA clinical care, self-management, disease outcomes, and mental health. Methods In total, 338 people with IA participated in a prospective study completing a series of online questionnaires. The questionnaires assessed demographics, IA condition and management, clinical care, quality of life, and mental health. Visual analogue scales (VAS) were completed at each assessment. Linear regression, controlling for confounders, was conducted to determine factors associated with physical and mental health outcomes. Results Over half of participants reported worsening VAS by more than 10 points for Patient Global Assessment (PGA), pain, fatigue, and emotional distress during the initial lockdown. Changes in clinical care were associated with worse PGA (b = 8.95, p = 0.01), pain (b = 7.13, p = 0.05), fatigue (b = 17.01, p < 0.01) and emotional distress (b = 12.78, p < 0.01). Emotional distress and depression were also associated with worse outcomes in PGA, pain, and fatigue, while loneliness was not. In contrast, physical activity seemed to mitigate these effects. Loneliness did not show any associations with outcomes. Over time, these effects decreased or disappeared. Conclusions Changes to clinical care due to lockdown were associated with worse disease outcomes in patients with IA. There has been a clear impact on mental health as well, with possibly complex relationships between mental health and psychosocial factors. Physical activity emerged as a key influence on disease outcomes and mental health.

Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study.

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.

COVID-19-related acute kidney injury; incidence, risk factors and outcomes in a large UK cohort.

BACKGROUND: Acute kidney injury (AKI) is common among patients hospitalised with COVID-19 and associated with worse prognosis. The aim of this study was to investigate the epidemiology, risk factors and outcomes of AKI in patients with COVID-19 in a large UK tertiary centre. METHODS: We analysed data of consecutive adults admitted with a laboratory-confirmed diagnosis of COVID-19 across two sites of a hospital in London, UK, from 1st January to 13th May 2020. RESULTS: Of the 1248 inpatients included, 487 (39%) experienced AKI (51% stage 1, 13% stage 2, and 36% stage 3). The weekly AKI incidence rate gradually increased to peak at week 5 (3.12 cases/100 patient-days), before reducing to its nadir (0.83 cases/100 patient-days) at the end the study period (week 10). Among AKI survivors, 84.0% had recovered renal function to pre-admission levels before discharge and none required on-going renal replacement therapy (RRT). Pre-existing renal impairment [odds ratio (OR) 3.05, 95%CI 2.24-4,18; p <  0.0001], and inpatient diuretic use (OR 1.79, 95%CI 1.27-2.53; p <  0.005) were independently associated with a higher risk for AKI. AKI was a strong predictor of 30-day mortality with an increasing risk across AKI stages [adjusted hazard ratio (HR) 1.59 (95%CI 1.19-2.13) for stage 1; p < 0.005, 2.71(95%CI 1.82-4.05); p < 0.001for stage 2 and 2.99 (95%CI 2.17-4.11); p < 0.001for stage 3]. One third of AKI3 survivors (30.7%), had newly established renal impairment at 3 to 6 months. CONCLUSIONS: This large UK cohort demonstrated a high AKI incidence and was associated with increased mortality even at stage 1. Inpatient diuretic use was linked to a higher AKI risk. One third of survivors with AKI3 exhibited newly established renal impairment already at 3-6 months.

Clinical efficacy of COMPASS, a digital cognitive-behavioural therapy programme for treating anxiety and depression in patients with long-term physical health conditions: a protocol for randomised controlled trial.

INTRODUCTION: Approximately 30% of people with long-term physical health conditions (LTCs) experience mental health problems, with negative consequences and costs for individuals and healthcare services. Access to psychological treatment is scarce and, when available, often focuses on treating primary mental health problems rather than illness-related anxiety/depression. The aim of this study is to evaluate the clinical efficacy of a newly developed, therapist-supported, digital cognitive-behavioural treatment (COMPASS) for reducing LTC-related psychological distress (anxiety/depression), compared with standard charity support (SCS). METHODS AND ANALYSIS: A two-arm, parallel-group randomised controlled trial (1:1 ratio) with nested qualitative study will be conducted. Two-hundred adults with LTC-related anxiety and depression will be recruited through national LTC charities. They will be randomly allocated to receive COMPASS or SCS only. An independent administrator will use Qualtrics randomiser for treatment allocation, to ensure allocation concealment. Participants will access treatment from home over 10 weeks. The COMPASS group will have access to the digital programme and six therapist contacts: one welcome message and five fortnightly phone calls. Data will be collected online at baseline, 6 weeks and 12 weeks post-randomisation for primary outcome (Patient Health Questionnaire Anxiety and Depression Scale) and secondary outcomes (anxiety, depression, daily functioning, COVID-19-related distress, illness-related distress, quality of life, knowledge and confidence for illness self-management, symptom severity and improvement). Analyses will be conducted following the intention-to-treat principle by a data analyst blinded to treatment allocation. A purposively sampled group of COMPASS participants and therapists will be interviewed. Interviews will be thematically analysed. ETHICS AND DISSEMINATION: The study is approved by King's College London's Psychiatry, Nursing and Midwifery Research Ethics Subcommittee (reference: LRS-19/20-20347). All participants will provide informed consent to take part if eligible. Findings will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER: NCT04535778.

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study.

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.