Biologic treatments (other than anti-TNF therapy) licensed for use in rheumatoid arthritis

Despite the huge progress made by the use of tumour necrosis factor (TNF) inhibitors in the treatment of rheumatoid arthritis (RA), there was still an unmet need for discovering and implementing new biologic therapies for RA patients who lost response or had side-effects to TNF inhibitors. The advances in molecular biology and understanding of the complex pathogenesis of RA enabled the identification of other pivotal molecules, whose blockage was associated with clinical benefits in RA. This chapter reviews the clinical efficacy, safety profile and cost-effectiveness of several biologic agents licensed for use in RA patients, which target different interleukins (IL), such as IL1 (anakinra) and IL6 (tocilizumab), or are associated with B cell depletion (rituximab), T cell co-stimulatory blockage (abatacept) and small molecule inhibition (tofacitinib). In addition, we discuss the national and international guidelines for use of these biologic agents in relation to the use of TNF inhibitors in patients with moderatesevere RA, providing examples of switching between various biologic therapies

New biologic agents and biosimilars developed for rheumatoid arthritis

The pathogenesis of rheumatoid arthritis (RA) is characterised by interactions between several types of immune cells, which are associated with the release of multiple inflammatory cytokines. Recently, numerous biologic treatments targeting classes of immune cells, cytokines or intra-cellular pathways of pro-inflammatory signals have been developed. Some of them are currently under research as potential therapeutic options for RA patients. This chapter reviews the available evidence regarding the safety and efficacy of new biologic agents targeting B cells, proinflammatory interleukins (IL), T helper 17 (Th17) pathway and intracellular enzymes. This chapter reviews the most relevant randomised controlled trials (RCTs) which have proven the efficacy of different biologic agents and small molecule inhibitors in controlling the inflammation associated with RA. The management of RA remains a dynamic and evolving field. The development of less expensive ‘biosimilar’ drugs, analogous to existing licensed biologic therapies, is an emerging area of research that deserves particular attention

Tumour necrosis factor inhibitors used in the treatment of rheumatoid arthritis: Evidence of safety, efficacy and health implication

Rheumatoid arthritis (RA) is a systemic autoimmune condition characterised by inflammation and destruction of synovial joints. The pathogenesis of inflammation is underpinned by interaction and activation of immune cells, which release inflammatory cytokines such as tumour necrosis factor (TNF) and interleukins. These mechanisms of disease pathogenesis were targeted by specific drugs in the form of monoclonal antibodies (mAb) or soluble receptors. The advent of biological disease modifying therapies (bDMARDs) has revolutionised the management of RA. These agents dramatically reduce synovial inflammation, halt the progression of radiographic joint damage, and improve functional ability and health related quality of life outcomes. This has a positive impact on the socioeconomic burden of RA. This chapter reviews the pathogenesis of RA and evidence behind the use of TNF inhibitors licensed for RA treatment. We focus on clinical efficacy, safety profile and cost-effectiveness of infliximab, etanercept, adalimumab, certolizumab, golimumab. Additionally, we discuss national and international recommendations for the clinical use of TNF inhibitors, with further consideration of the financial implications. Examples of clinical randomised controlled trials (RCTs), which have proven the efficacy of different TNF inhibitors in RA are also included in this chapter. The use of TNF inhibitor biosimilars will be discussed in chapter 11

Non-linear operations in quantum information theory

Quantum information theory is used to analize various non-linear operations on quantum states. The universal disentanglement machine is shown to be impossible, and partial (negative) results are obtained in the state-dependent case. The efficiency of the transformation of non-orthogonal states into orthogonal ones is discussed.Comment: 11 pages, LaTeX, 3 figures on separate page

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

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

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA): Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease-Opportunities for Therapy.

Two of the key functions of arteries in the brain are (1) the well-recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri-arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment

OpenSAFELY: The impact of COVID‐19 on azathioprine, leflunomide and methotrexate monitoring, and factors associated with change in monitoring rate

Aims The COVID-19 pandemic created unprecedented pressure on healthcare services. This study investigates whether disease-modifying antirheumatic drug (DMARD) safety monitoring was affected during the COVID-19 pandemic. Methods A population-based cohort study was conducted using the OpenSAFELY platform to access electronic health record data from 24.2 million patients registered at general practices using TPP's SystmOne software. Patients were included for further analysis if prescribed azathioprine, leflunomide or methotrexate between November 2019 and July 2022. Outcomes were assessed as monthly trends and variation between various sociodemographic and clinical groups for adherence with standard safety monitoring recommendations. Results An acute increase in the rate of missed monitoring occurred across the study population (+12.4 percentage points) when lockdown measures were implemented in March 2020. This increase was more pronounced for some patient groups (70–79 year-olds: +13.7 percentage points; females: +12.8 percentage points), regions (North West: +17.0 percentage points), medications (leflunomide: +20.7 percentage points) and monitoring tests (blood pressure: +24.5 percentage points). Missed monitoring rates decreased substantially for all groups by July 2022. Consistent differences were observed in overall missed monitoring rates between several groups throughout the study. Conclusion DMARD monitoring rates temporarily deteriorated during the COVID-19 pandemic. Deterioration coincided with the onset of lockdown measures, with monitoring rates recovering rapidly as lockdown measures were eased. Differences observed in monitoring rates between medications, tests, regions and patient groups highlight opportunities to tackle potential inequalities in the provision or uptake of monitoring services. Further research should evaluate the causes of the differences identified between groups