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Simple Summary: Abemaciclib is an important addition to the care of women with hormone receptor-positive breast cancer. To qualify for abemaciclib treatment, some women are advised to undergo axillary node clearance surgery as finding more than three axillary nodes with metastatic cancer allows access to abemaciclib. This paper explores the balance between the benefits of axillary node clearance in permitting access to abemaciclib and the harms of surgery. We examine how many women need to undergo axillary node clearance before one woman clinically benefits from the procedure. We show that for every 10 women undergoing axillary node clearance surgery, only one eventually qualifies for abemaciclib. The remaining nine would have axillary surgery but still not qualify for abemaciclib as less than four metastatic axillary nodes are found despite full axillary clearance. However, these women could still suffer the complications of axillary node clearance surgery. The monarchE study added the CDK4/6 inhibitor abemaciclib to the care of women with oestrogen-positive (ER+) breast cancers. Eligibility required meeting monarchE criteria—either >3 positive axillary nodes, or 1–3 positive sentinel nodes (SNB+) with tumour size >50 mm or grade 3 cancers. Women were advised to proceed to completion axillary node clearance (cANC) if size/grade criteria were not fulfilled for >3 positive nodes to be identified. However, cANC is associated with significant morbidity, conflicting with the potential benefits of abemaciclib. We analysed data of 229 consecutive women (2016-2022) with ER+ breast cancer and SNB+ who proceeded to cANC, keeping with contemporary treatment guidelines. We used this cohort to assess numbers that, under national guidance in place currently, would be advised to undergo cANC solely to check eligibility for abemaciclib treatment. Using monarchE criteria, 90 women (39%) would have accessed abemaciclib based on SNB+ and size/grade, without cANC. In total, 139 women would have been advised to proceed to cANC to check eligibility, with only 15/139 (11%) having >3 positive nodes after sentinel node biopsy and cANC. The remaining 124 (89%) would have undergone cANC but remained ineligible for abemaciclib. Size, age, grade, and Ki67 did not predict >3 nodes at cANC. Following cANC, a large majority of women with ER+, <50 mm, and grade 1–2 tumours remain ineligible for abemaciclib yet are subject to significant morbidity including lifelong lymphoedema risk. The monarchE authors state that 15 women need abemaciclib therapy for 1 to clinically benefit. Thus, in our cohort, 139 women undergoing cANC would lead to one woman benefitting. [ABSTRACT FROM AUTHOR]

Environmental context: Ammonia emissions from inorganic nitrogen fertilisers used in agriculture can impact air quality, human health and ecology. This study quantifies such emissions and their controlling factors from UK and Ireland agricultural soils. Emissions are variable and, from non-urea fertilisers, substantially exceed maximum emission factors used by the UK Department for Environment, Food and Rural Affairs. This suggests that UK emission factors need to be refined further, with consideration of inter alia land-use, fertiliser type, soil pH and chemical inhibitors. Rationale: Ammonia (NH3) emissions from inorganic nitrogen (N) fertilisers applied to agricultural soils have negative implications for environmental quality and human health. Despite this, efforts to reduce NH3 emissions in the UK have achieved limited success. This study aims to provide an overview of NH3 emissions from UK and Ireland agricultural soils receiving N fertilisers, their regulating factors and the potential role of inhibitors in reducing current NH3 losses. Methodology: A systematic literature search was performed to identify relevant experimental data and studies, and the extracted data (total of 298 field fertilisation events) were categorised and analysed systematically. Results: NH3 emissions ranged from −4.00 to 77.00% of applied fertiliser-N lost as NH3. In addition to fertiliser type, NH3 losses were also significantly affected by land-use type and soil pH. Urease and combined urease and nitrification inhibitors significantly reduced emissions by 74.50 and 70.00% compared to uninhibited-urea respectively. Discussion: In addition to fertiliser types, land-use and soil pH were found as factors for consideration as modifiers to the maximum NH3 emission factor (EFmax) values currently used in the UK, in order to improve estimations of NH3 emissions, particularly from non-urea fertilisers. This is imperative as NH3 losses exceeded current EFmax limits, particularly in the case of non-urea fertilisers, by ~34%, implying that NH3 emissions estimated from UK synthetic fertiliser require further refinements. NH3 losses are not completely inhibited, inhibitors cannot be solely relied upon for tackling NH3 emissions from UK and Ireland fertiliser usage and further research is needed into alternative mitigation methods to further reduce NH3 losses. Environmental context. Ammonia emissions from inorganic nitrogen fertilisers used in agriculture can impact air quality, human health and ecology. This study quantifies such emissions and their controlling factors from UK and Ireland agricultural soils. Emissions are variable and, from non-urea fertilisers, substantially exceed maximum emission factors used by the UK Department for Environment, Food and Rural Affairs. This suggests that UK emission factors need to be refined further, with consideration of inter alia land-use, fertiliser type, soil pH and chemical inhibitors. This article belongs to the collection Dedication to Prof. Edward Tipping. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to assess the possibility of HBV reactivation (HBVr) in patients with RA under anti-IL-6 treatment. Methods Using PubMed, Scopus and EMBASE, we performed a systematic literature search for articles related to HBVr in RA patients under anti-IL-6 treatment. The search was performed with no date limits and was last updated 28 January 2023. The results from all the databases were combined and duplicates were excluded, as were non-English articles, case reports, position articles, comments, and paediatric studies. Results Our initial search led to 427 articles; 28 were duplicates, 46 non-English, 169 reviews, 31 books/letters, 25 case reports, and 88 irrelevant to the meta-analysis aim; 21 were excluded due to inadequate information, leaving 19 articles, with a sum of 372 RA patients with chronic HBV (CHB) or resolved HBV infection, for further analysis. The overall risk for HBVr in RA patients with CHB was 6.7%, increasing to 37% when only RA patients with CHB and no antiviral prophylaxis were included. On the contrary, HBVr was close to 0% in RA patients with resolved HBV infection, irrespective of antiviral prophylaxis. All RA patients experiencing HBVr in these studies were successfully managed with antiviral treatment and/or drug withdrawal. Conclusion Overall, anti-IL-6 treatment comes with a significant risk of HBVr in RA patients with CHB; risk is diminished when antiviral prophylaxis is used. In contrast, in RA patients with resolved HBV infection, the risk of HBVr seems to be extremely low. Large, well-designed studies (either controlled trials or multicentre/international observational studies) are warranted to further validate these results. [ABSTRACT FROM AUTHOR]

Axon degeneration accounts for the poor clinical outcome in Guillain‐Barré syndrome (GBS), yet no treatments target this key pathogenic stage. Animal models demonstrate anti‐ganglioside antibodies (AGAb) induce axolemmal complement pore formation through which calcium flux activates the intra‐axonal calcium‐dependent proteases, calpains. We previously showed protection of axonal components using soluble calpain inhibitors in ex vivo GBS mouse models, and herein, we assess the potential of axonally‐restricted calpain inhibition as a neuroprotective therapy operating in vivo. Using transgenic mice that over‐express the endogenous human calpain inhibitor calpastatin (hCAST) neuronally, we assessed distal motor nerve integrity in our established GBS models. We induced immune‐mediated injury with monoclonal AGAb plus a source of human complement. The calpain substrates neurofilament and AnkyrinG, nerve structural proteins, were assessed by immunolabelling and in the case of neurofilament, by single‐molecule arrays (Simoa). As the distal intramuscular portion of the phrenic nerve is prominently targeted in our in vivo model, respiratory function was assessed by whole‐body plethysmography as the functional output in the acute and extended models. hCAST expression protects distal nerve structural integrity both ex and in vivo, as shown by attenuation of neurofilament breakdown by immunolabelling and Simoa. In an extended in vivo model, while mice still initially undergo respiratory distress owing to acute conduction failure, the recovery phase was accelerated by hCAST expression. Axonal calpain inhibition can protect the axonal integrity of the nerve in an in vivo GBS paradigm and hasten recovery. These studies reinforce the strong justification for developing further animal and human clinical studies using exogenous calpain inhibitors. [ABSTRACT FROM AUTHOR]

Odevixibat (Bylvay™; Bylvay®) has been approved for progressive familial intrahepatic cholestasis (PFIC) in patients aged ≥ 3 months in the USA and those aged ≥ 6 months in the EU and UK. In the pivotal double-blind placebo-controlled phase 3 PEDFIC 1 study, odevixibat 40 or 120 μg/kg once daily significantly reduced serum bile acids and pruritus. Odevixibat also improved growth, sleep and quality of life parameters compared with placebo in patients with PFIC. The clinical benefits of odevixibat were maintained with continued treatment for up to 72 weeks, according to an interim analysis of the ongoing open-label phase 3 PEDFIC 2 study. Odevixibat is generally well tolerated, with most adverse events being mild or moderate in severity. Longer-term safety data (up to 72 weeks of treatment) revealed no new safety concerns. Plain Language Summary: Progressive familial intrahepatic cholestasis (PFIC) is a rare inherited cholestatic liver disease that is characterized by disturbed bile homeostasis, pruritus, accumulation of biliary components and potentially fatal liver disease. Recently, ileal bile acid transporter (IBAT) inhibitors have emerged as a novel non-surgical approach for the treatment of PFIC. Odevixibat (Bylvay™; Bylvay®), a potent IBAT inhibitor, is approved in the USA for the treatment of pruritus in PFIC for patients aged ≥ 3 months and in the EU and UK for patients aged ≥ 6 months with PFIC. In patients with PFIC, odevixibat significantly decreased serum bile acids and improved pruritus symptoms compared with placebo. Furthermore, improvements in growth and sleep parameters, as well as measures of quality of life were also seen with odevixibat versus placebo. Odevixibat is generally well tolerated, with most adverse events being mild to moderate in severity. Thus, odevixibat is a valuable, effective and generally well-tolerated treatment option for patients with PFIC. [ABSTRACT FROM AUTHOR]

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87).Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. [ABSTRACT FROM AUTHOR]

Background: Patients with inflammatory bowel disease are currently managed with the assumption that trial data are applicable to all ethnic groups. Previous studies demonstrate differences in disease severity and phenotype of Asian patients with Crohn's disease (CD), including Bangladeshi Asians within the UK. No study has evaluated the impact of ethnicity on response to anti-TNFs.Aim: Our primary endpoint was a comparison of failure-free survival on first prescribed anti-TNF (anti-tumor necrosis factor) therapy in UK Bangladeshi and Caucasian patients with CD. Our secondary aims were to evaluate disease phenotype, indication for anti-TNF prescription, and duration from diagnosis until first anti-TNF prescribed between groups.Methods: The records of consecutive outpatient appointments over a 12-month period were used to identify Caucasian and Bangladeshi patients prescribed an anti-TNF for CD. Information on patient demographics, ethnicity, disease phenotype, immunomodulator use, outcome from first biologic, duration of therapy, and reason for cessation was recorded.Results: In total, 224 Caucasian and Bangladeshi patients were prescribed an anti-TNF for CD. Bangladeshi patients started an anti-TNF 4.3 years earlier after diagnosis than Caucasian patients (3.9 years vs. 8.2 years: p < 0.01). Bangladeshi patients experienced shorter failure-free survival than Caucasian patients (1.8 vs. 4.8 years p < 0.01). By 2 years, significantly more Bangladeshi patients had stopped anti-TNF due to loss of response (OR 6.35, p < 0.01).Conclusions: This is the first study to suggest that Bangladeshi patients resident in the UK with CD respond less well to treatment with TNF antagonists than Caucasian patients. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE) is a serious, preventable disease occurring frequently in the UK and globally. The costs to NHS related to VTE are likely to be underestimated but the risk of developing VTE is significant in surgical patients. The overall incidence of VTE in orthopaedic patients is up to 40–60%. Patients following orthopaedic surgery have multiple risk factors making them vulnerable to developing VTE. VTE prophylaxis can be divided into general, mechanical and pharmacological methods. General methods, including early mobilization and optimizing hydration, are simple approaches widely. Mechanical methods include anti-embolism stockings, intermittent pneumatic compression devices and foot pumps. These are commonly used in combination with pharmacological agents. The latter include antiplatelet and anticoagulant drugs such as aspirin, unfractionated heparin, low-molecular-weight heparin (LMWH), vitamin K antagonists, factor Xa inhibitors and direct thrombin inhibitors. Chemical thromboprophylaxis and antithrombotic drugs continue to be an area of debate and controversy within orthopaedics. There is no single universal answer to thromboprophylaxis but, in the UK, The National Institute for Health and Care Excellence (NICE) has produced guidelines and every surgeon and hospital should have an evidence-based protocol to adhere to. [ABSTRACT FROM AUTHOR]

Acute pericarditis accounts for -5% of presentations with acute chest pain. Tuberculosis is an important cause in the developing world, however, in the UK and other developed settings, most cases are idiopathic/viral in origin. Non- steroidal anti-inflammatory drugs (NSAIDs) remain the cornerstone of treatment. At least one in four patients are at risk of recurrence. The addition of 3 months of colchicine can more than halve the risk of this (number needed to treat = four). Low-dose steroids can be helpful second-line agents for managing recurrences as adjuncts to NSAIDs and colchicine but should not be used as first-line agents. For patients failing this approach and/or dependent on corticosteroids, the interleukin-1β antagonist anakinra is a promising option, and for the few patients who are refractory to medical therapy, surgical pericardiectomy can be considered. The long-term prognosis is good with <0.5% risk of constriction for patients with idiopathic acute pericarditis. [ABSTRACT FROM AUTHOR]

This review discusses the reasons behind the ever‐growing number of drug‐related deaths (DRDs) due to misuse in the UK, the principal types of drug involved, and practical ways in which prescribers can support patients to help reduce the risks. [ABSTRACT FROM AUTHOR]

The article discusses research which investigated how tumor necrosis factor inhibitor (TNFi) therapy influenced need for total hip and total knee replacement procedures in patients with rheumatoid arthritis (RA). Topics explored include the clinical characteristics, progression, and risk factors for RA, comparison of outcomes from TNFi and conventional synthetic disease-modifying antirheumatic drugs (DMARD) administration, and the reduction in total hip replacement in older patients.

Background Many countries have acquired antiviral stockpiles for pandemic influenza mitigation and a significant part of the stockpile may be focussed towards community-based treatment. Methods We developed a spreadsheet-based, decision tree model to assess outcomes averted and cost-effectiveness of antiviral treatment for outpatient use from the perspective of the healthcare payer in the UK. We defined five pandemic scenarios—one based on the 2009 A(H1N1) pandemic and four hypothetical scenarios varying in measures of transmissibility and severity. Results Community-based antiviral treatment was estimated to avert 14–23% of hospitalizations in an overall population of 62.28 million. Higher proportions of averted outcomes were seen in patients with high-risk conditions, when compared to non-high-risk patients. We found that antiviral treatment was cost-saving across pandemic scenarios for high-risk population groups, and cost-saving for the overall population in higher severity influenza pandemics. Antiviral effectiveness had the greatest influence on both the number of hospitalizations averted and on cost-effectiveness. Conclusions This analysis shows that across pandemic scenarios, antiviral treatment can be cost-saving for population groups at high risk of influenza-related complications. [ABSTRACT FROM AUTHOR]

Phantom limb pain (PLP) is a widespread and challenging neuropathic pain problem, occurring after both surgical and traumatic amputation of a limb. It may occur immediately after surgery or some months later, however, most cases it presents within the first 7 postoperative days. Patients report a range of pain characteristics in the absent limb, including burning, cramping, tingling and electric shock sensation. The incidence of PLP has been reported to be between 50% and 85% following amputation. Its management is notoriously difficult, with no clear consensus on optimal treatment. It is often resistant to classic balanced analgesia and typical neuropathic pain medications. Taking into account these issues, the authors aimed to improve the management of patients undergoing amputation at their institution, by ensuring accurate and holistic assessment, the selection of suitable interventions through critical analysis and synthesis of available evidence, and the appropriate evaluation and adaptation of treatment plans, to ensure patients achieved their individualised goals. [ABSTRACT FROM AUTHOR]

There is a lack of information on the health care of familial hypercholesterolemia (FH). The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere. A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark. The estimated percentage of patients diagnosed with the condition was low (overall <3%) in all countries, compared with ∼15% in the UK. Underdetection of FH was associated with government expenditure on health care (ϰ = 0.667, P <.05). Opportunistic and systematic screening methods, and the Dutch Lipid Clinic Network criteria were most commonly used to detect FH; genetic testing was infrequently used. Noninvasive imaging of coronary calcium and/or carotid plaques was underutilized in risk assessment. Patients with FH were generally not adequately treated, with <30% of patients achieving guideline recommended low-density lipoprotein cholesterol targets on conventional therapies. Treatment gaps included suboptimal availability and use of lipoprotein apheresis and proprotein convertase subtilsin-kexin type 9 inhibitors. A deficit of FH registries, training programs, and publications were identified in less economically developed countries. The demonstration of cost-effectiveness for cascade screening, genetic testing, and specialized treatments were significantly associated with the availability of subsidies from the health care system (ϰ = 0.571–0.800, P <.05). We identified important gaps across the continuum of care for FH, particularly in less economically developed countries. Wider implementation of primary and pediatric care, telehealth services, patient support groups, education/training programs, research activities, and health technology assessments are needed to improve the care of patients with FH in these countries. • We identified important gaps across the continuum of care for familial hypercholesterolemia (FH) in 12 countries. • Estimated percentage of patients diagnosed with FH was low (overall <3%). • Diagnosis of FH was associated with government expenditure on health care. • Use of lipoprotein apheresis and PCSK9 inhibitors were limited in most countries. • Availability of subsidy from the health care system is important for the care of FH. [ABSTRACT FROM AUTHOR]

Objectives Rituximab (RTX) may be a treatment option for children and young people with JIA, although it is not licensed for this indication. The aim of this study was to describe RTX use and outcomes among children with JIA. Methods This analysis included all JIA patients within the UK Biologics for Children with Rheumatic Diseases study starting RTX. Disease activity was assessed at RTX start and at follow-up. The total number of courses each patient received was assessed. Serious infections and infusion reactions occurring following RTX were reported. Results Forty-one JIA patients starting RTX were included, the majority with polyarthritis: polyarthritis RF negative [ n = 14 (35%)], polyarthritis RF positive [ n = 13 (33%)] and extended oligoarthritis [ n = 9 (23%)]. Most were female (80%) with a median age of 15 years [interquartile range (IQR) 12–16] and a median disease duration of 9 years (IQR 5–11). The median improvement in the clinical Juvenile Arthritis Disease Activity Score (cJADAS; three-variable 71-joint JADAS) from RTX start was 9 units (n = 7; IQR −14–2). More than half reported more than one course of RTX. The median time between each course was 219 days (IQR 198–315). During follow-up, 17 (41%) patients reported switching to another biologic, including tocilizumab (n = 8), abatacept (n = 6) and TNF inhibitor (n = 3). Three patients (7%) reported a serious infection on RTX (rate of first serious infection 6.2/100 person-years). Four patients (10%) reported an infusion reaction. Conclusions This real-world cohort of children with JIA, the majority with polyarticular or extended oligoarticular JIA, showed RTX may be an effective treatment option for children who do not respond to TNF inhibitor, with a low rate of serious infections on treatment. [ABSTRACT FROM AUTHOR]

The article presents the executive summary of the biologic disease-modifying antirheumatic drug safety guidelines in inflammatory arthritis by the British Society for Rheumatology. Biologics covered by the guideline are mentioned, including certolizumab pegol. The target audience is secondary care health professionals directly involved in the management of patients with inflammatory arthritis. The GRADE method was used to evaluate the quality of evidence and the strength of recommendation.

Objective To quantify the extent to which co-morbid FM is associated with higher disease activity, worse quality of life (QoL) and poorer response to TNF inhibitors (TNFis) in patients with axial SpA. Methods A prospective study recruiting across 83 centres in the UK. Clinical information and patient-reported measures were available, including 2011 criteria for FM. Multivariable linear regression was used to model the effect of meeting the FM criteria on disease activity, QoL and response to TNFis. Results A total of 1757 participants were eligible for analyses, of whom 22.1% met criteria for FM. Those with co-morbid FM criteria had higher disease activity [BASDAI average difference FM+ − FM− 1.04 (95% CI 0.75, 1.33)] and worse QoL [Ankylosing Spondylitis Quality of Life score difference 1.42 (95% CI 0.88, 1.96)] after adjusting for demographic, clinical and lifestyle factors. Among 291 participants who commenced biologic therapy, BASDAI scores in those with co-morbid FM were 2.0 higher at baseline but decreased to 1.1 higher at 12 months. There was no significant difference in the likelihood of meeting Assessment of SpondyloArthritis international Society 20 criteria at 12 months. Less improvement in disease activity and QoL over 3 months of TNFi therapy was most strongly related to high scores on the FM criteria symptom severity scale component. Conclusion Fulfilling criteria for FM has a modest impact on the assessment of axial SpA disease activity and QoL and does not significantly influence response to biologic therapy. Those with a high symptom severity scale on FM assessment may benefit from additional specific management for FM. [ABSTRACT FROM AUTHOR]

Background: Newer endothelin receptor antagonists (ERAs) used to treat patients with pulmonary arterial hypertension (PAH) are associated with fewer drug–drug interactions than bosentan and require less monitoring. This, combined with a pharmacokinetic basis for improved efficacy, means there may be a clinical rationale for changing therapies. However, this can be challenging and few data on its safety in patients with PAH are available. Aims: At the Royal Free Hospital in London, UK, home-based medication transitioning has been standard practice since 2009 to avoid unnecessary hospital visits for patients, unless there is a clinical imperative. In this audit of standard practice we evaluated the consequences of adopting such a strategy when transitioning PAH patients between ERA therapies. Methods and results: Using a Clinical Nurse Specialist-led, home-based transitioning strategy, 92 patients with PAH were transitioned from bosentan to macitentan or ambrisentan. Observational data were analysed retrospectively. The majority of patients were female with PAH associated with connective tissue disease and their ERA was changed in the hope of improving efficacy. The process was well tolerated with no adverse events associated with the process. Seventeen patients died during the study (macitentan, n = 5; ambrisentan, n = 12). None of the deaths was considered related to ERA treatment. The majority of patients remained clinically stable, based on WHO functional class and exercise capacity. Conclusion: An established home-based transitioning strategy can be adopted safely for patients with PAH changing ERA therapies. Most patients remained stable and the therapy change was well tolerated. [ABSTRACT FROM AUTHOR]

The spondyloarthropathies are an heterogenous group of inflammatory conditions with a diverse phenotype and multiple clinical manifestations involving joints, entheses, spine, skin and other tissues. Diagnosis is often delayed after symptom onset leading to significant disability and reduced quality of life in affected individuals. Emphasis therefore is given to informing and educating patients about their disease, treatment options and how to manage disease flares. These are some of the points collected in the National Institute of Health and Care Excellence (NICE) guidelines published in February of 2017 to alert Health professionals about these group of diseases. The guidelines highlight why it is important to be able to refer to a rheumatologist, as well as describing when a referral should be made. It also includes information on diagnosis, treatment, education, and an agenda for research. Since a significant number of people affected with these conditions, in particular those suffering from psoriatic arthritis are likely to be seen in the context of the dermatology clinic, the dermatology nurse may play an active part of this process. [ABSTRACT FROM AUTHOR]

Objectives. To analyse long-term survival and efficacy of TNFi, reasons for switching or discontinuing, baseline predictors of response and remission in axial spondyloarthritis (axSpA) patients in a UK cohort. Methods. All patients with a physician-verified diagnosis of axSpA attending two specialist centres who fulfilled the eligibility criteria for TNFi were included. Routinely recorded patient data were reviewed retrospectively. Initial TNFi was recorded as the index drug. Results. Six hundred and fifty-one patients (94% AS) were included; adalimumab (n = 332), etanercept (n = 205), infliximab (n = 51), golimumab (n = 40) and certolizumab pegol (n = 23) were index TNFi. The mean (S.D.) duration from symptom onset to time of diagnosis was 8.6 (8.7) years and mean (S.D.) duration from diagnosis to TNFi initiation was 12.6 (11.5) years. A total of 224 (34.4%) stopped index TNFi, and 105/224 switched to a second TNFi. Median drug survival for index and second TNFi were 10.2 years (95% CI: 8.8, 11.6 years) and 5.5 years (95% CI: 2.7, 8.3 years), respectively (P < 0.05). Survival rates were not influenced by choice of TNFi. HLA-B27 predicted BASDAI50 and/or two or more point reduction within 6 months and long-term drug survival (P < 0.05). Low disease activity was predicted by non-smoking and low baseline BASDAI (P < 0.05). Conclusion. We have observed good TNFi survival rates in axSpA patients treated in a real-life setting. This is best for first TNFi and not influenced by drug choice. [ABSTRACT FROM AUTHOR]

Objective. To determine the effect of medical treatment on work disability in patients with active PsA in a real-world setting. Methods. Four hundred patients with active PsA commencing or switching to anti-TNF or conventional synthetic DMARD (csDMARD) were recruited to a multicentre UK prospective observational cohort study. Work disability was measured using the work productivity and activity-specific health problem instrument and peripheral joint activity was measured with the disease activity in PsA composite measure. Results. Four hundred patients were recruited, of whom 229 (57.25%) were working (of any age). Sixty- two patients of working age (24%) were unemployed. At 6 months there was a 10% improvement in presenteeism (P = 0.007) and a 15% improvement in work productivity (P = 0.001) among working patients commenced on csDMARDs (n = 164) vs a larger and more rapid 30% improvement in presenteeism (P < 0.001) and 40% improvement in work productivity (P < 0.001) among those commenced on anti- TNF therapy (n = 65). Clinical response was poor among patients commenced on a csDMARD (n = 272), with an 8.4 point improvement in disease activity in PsA (P< 0.001) vs those commenced on anti-TNF therapy (n = 121), who had a 36.8 point improvement (P < 0.001). Conclusion. We report significant and clinically meaningful improvements in both work disability and clinical outcomes after commencement of anti-TNF therapy in a real-world setting. Improvements in all outcomes among those commencing csDMARDs were slower and of a smaller magnitude. [ABSTRACT FROM AUTHOR]

Introduction: Palbociclib, a CDK4/6 selective inhibitor first approved in 2016, is potentially the most efficacious, adjuvant treatment for hormone receptor-positive (HR+) and human epidemic growth factor 2 (HER2−) in advanced BC (breast cancer). Data are limited regarding its long-term efficacy in overweight or obese patients. These individuals are already at higher risk of cancer due to elevated oestrogen levels, hyperactivation of adipokines and poor oxidative stress regulation. There is also evidence for a higher risk of BC recurrence and obesity-related mortality during palbociclib treatment, thus variations in patient weight during treatment warrant investigation. Aims: To retrospectively review BC patients’ weight variation during palbociclib treatment and explore addressing any clinically significant outcomes. Objectives: Review trends in body mass index (BMI) during treatment and suggest future pharmacological/ lifestyle interventions for patients and increase the chances of progression-free survival (PFS). Perform statistical analysis via Minitab 17 Statistical Software, displaying descriptive/regression statistics per BMI category for 33 cycles (long-term data). Methods: NHS Foundation Trust X provided raw data (N = 89) to audit weight variation in postmenopausal women receiving palbociclib as part of their first-line adjuvant treatment for advanced HR+ and HER2- BC who had completed 33 cycles (January 2018 – October 2021). Microsoft Excel processed/illustrated the findings (N = 72 were deemed eligible for inclusion) and Minitab was used for statistical analyses between the baseline and final BMI reading. Statistical analysis was conducted using the 2-sample t-test to determine the p-value to review if palbociclib-associated weight variation was statistically significant. Results: Pre-treatment 22% of patients (N = 16) had a BMI’s classed as healthy, 46% (N = 33) overweight and 32% (N = 23) obese. Post-treatment clinically significant weight variation was evident with 7% (N = 5) of patients previously deemed healthy, 49% (N = 35) overweight p: 0.001 and 44% (N = 32) obese. Many palbociclib-treated patients are overweight/obese posttreatment, thus at higher risk of HR+/HER2− BC recurrence and mortality. Pooled long-term data illustrates the weight progression in 2–3 years of treatment and represents clinically significant weight variation in healthy and overweight BC patients. Discussion/conclusions: The findings suggest, fewer patients are a healthy weight following palbociclib treatment. This poses greater challenges in patient care and disease management with regard to obesity in advanced BC patients. Centred on these challenges, further investigations are warranted to assess the effective treatment and prophylaxis mechanisms needed to successfully target weight gain during BC treatment in overweight/obese patients with palbociclib. These could include providing support with smoking cessation, maintaining a healthy diet, promoting weight loss and reducing alcohol intake and ensuring this is within recommended limits. [ABSTRACT FROM AUTHOR]

Objectives. To identify and quantify resource required and associated costs for implementing TNF-α inhibitor (TNFi) drug level and anti-drug antibody (ADAb) tests in UK rheumatology practice. Methods. A microcosting study, assuming the UK National Health Service perspective, identified the direct medical costs associated with providing TNFi drug level and ADAb testing in clinical practice. Resource use and costs per patient were identified via four stages: identification of a patient pathway with resource implications; estimation of the resources required; identification of the cost per unit of resource (2015 prices); and calculation of the total costs per patient. Univariate and multiway sensitivity analyses were performed using the variation in resource use and unit costs. Results. Total costs for TNFi drug level and concurrent ADAb testing, assessed using ELISAs on trough serum levels, were £152.52/patient (range: £147.68-159.24) if 40 patient samples were tested simultaneously. For the base-case analysis, the pre-testing phase incurred the highest costs, which included booking an additional appointment to acquire trough blood samples. The additional appointment was the key driver of costs per patient (67% of the total cost), and labour accounted for 10% and consumables 23% of the total costs. Performing ELISAs once per patient (rather than in duplicate) reduced the total costs to £133.78/patient. Conclusion. This microcosting study is the first assessing the cost of TNFi drug level and ADAb testing. The results could be used in subsequent cost-effectiveness analyses of TNFi pharmacological tests to target treatments and inform future policy recommendations. [ABSTRACT FROM AUTHOR]

The authors offer views on a study published within the issue which investigated how tumor necrosis factor inhibitor (TNFi) therapy influenced need for total hip and total knee replacement procedures in patients with rheumatoid arthritis (RA). Topics discussed include the recorded decline in orthopedic surgery rates for RA patients, the outcomes presented by RA patients that received TNFi, and the possible contribution of RA treatment expansion to reduced joint replacement rates.

Objective. To explore the influence of TNF inhibitor (TNFi) therapy and rituximab (RTX) upon the incidence of cancer in patients with RA and prior malignancy. Methods. The study population comprised RA subjects with a prior malignancy reported to the UK national cancer registers, recruited to the British Society for Rheumatology Biologics Register from 2001 to 2013. We compared rates of first incident malignancy in a TNFi cohort, RTX cohort and synthetic DMARDs (sDMARD) cohort. Results. We identified 425 patients with a prior malignancy from 18 000 RA patients in the study. Of these, 101 patients developed a new malignancy. The rates of incident malignancy were 33.3 events/1000 person-years (py) in the TNFi cohort, 24.7 events/1000 py in the RTX cohort and 53.8 events/1000 py in the sDMARD cohort. The age- and gender-adjusted hazard ratio was 0.55 (95% CI: 0.35, 0.86) for the TNFi cohort and 0.43 (95% CI: 0.10, 1.80) for the RTX cohort in comparison with the sDMARDs cohort. The 17.0% of patients in the sDMARDs cohort had a recurrence of the same cancer in comparison with the 12.8% and the 4.3% in the TNFi and RTX cohorts, respectively. Conclusions. Although numbers are still low, it seems that patients with RA and prior malignancy selected to receive either a TNFi or RTX in the UK do not have an increased risk of future incident malignancy. [ABSTRACT FROM AUTHOR]

Objective. To determine feasibility of TNF inhibitor (TNFi) dose reduction for severe AS and PsA patients. Methods. A retrospective study in a real-world setting. Criteria for dose reduction of TNFi included BASDAI <4 for ≥6 months in AS; or DAS28-ESR ≤ 3.2 for ≥6 months in PsA. TNFi dose was reduced by one-third. Patients who flared (BASDAI > 4 in AS or DAS28-ESR > 3.2 in PsA) were re-escalated to standard treatment dose. Results. Twenty-six per cent (33/125) of AS and 18% (15/83) of PsA patients fulfilled criteria and underwent TNFi dose reduction. Fifty-eight per cent (19/33) of AS and 60% (9/15) of PsA patients maintained TNFi dose reduction for mean (S.D.) of 1.0 (0.8) years. Reinstating standard dose of TNFi recaptured low disease activity in all patients who failed dose reduction within 24 weeks, with no statistically significant difference in mean BASDAI compared with those maintaining TNFi dose reduction in AS at 24 weeks [mean (S.D.) BASDAI 2.4 (1.1) vs 1.9 (1.5), respectively (P = 0.229)]; however in PsA, those who failed dose reduction had higher disease activity compared with patients maintained on TNFi dose reduction at 24 weeks [mean (S.D.) DAS28-ESR 2.7 (0.6) vs 1.3 (0.5), respectively (P ≤ 0.001)]. In PsA, a lower DAS28-ESR prior to dose reduction of TNFi was associated with more successful dose reduction. Conclusions. In a real-world setting, 60% of individuals with severe AS and PsA who achieve low disease activity can successfully reduce the dose of TNFi therapy by a third for a mean of 1 year. [ABSTRACT FROM AUTHOR]

Background. Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management. Materials and Methods. Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables. Results. A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age <65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p < .0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort. Conclusion. Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation. [ABSTRACT FROM AUTHOR]

Objective Patients with rheumatoid arthritis (RA) are at an increased risk of ischemic stroke. Tumor necrosis factor inhibitors (TNFi) may influence risk and mortality after ischemic stroke by reducing inflammation. This study was undertaken to examine the association of TNFi with the risk of incident ischemic stroke and with 30-day and 1-year mortality after ischemic stroke. Methods Patients with RA starting therapy with TNFi and a biologics-naive comparator group treated with synthetic disease-modifying antirheumatic drugs (DMARDs) only were recruited to the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis from 2001 to 2009. Patients were followed up via clinical and patient questionnaires as well as the national death register. Incident strokes were classified as ischemic if brain imaging reports suggested ischemia or if ischemic stroke was reported as the underlying cause of death on a death certificate. Patients with a previous stroke were excluded. Risk of ischemic stroke was compared between patients receiving synthetic DMARDs only and those ever-exposed to TNFi using a Cox proportional hazards regression model adjusted for potential confounders. Mortality after ischemic stroke was compared between synthetic DMARD-treated patients and TNFi-treated patients using logistic regression, adjusted for age and sex. Results To April 2010, 127 verified incident ischemic strokes (21 in 3,271 synthetic DMARD-treated patients and 106 in 11,642 TNFi-treated patients) occurred during 11,973 and 61,226 person-years of observation, respectively (incidence rate 175 versus 173 per 100,000 person-years). After adjustment for confounders, there was no association between ever-exposure to TNFi and ischemic stroke (hazard ratio 0.99 [95% confidence interval (95% CI) 0.54-1.81]). Mortality 30 days or 1 year after ischemic stroke was not associated with concurrent TNFi exposure (odds ratio 0.18 [95% CI 0.03-1.21] and 0.60 [95% CI 0.16-2.28], respectively). Conclusion Exposure to TNFi does not appear to influence the occurrence of ischemic stroke in the medium term in patients with RA. The impact on mortality after ischemic stroke remains inconclusive. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis has many risk factors; however, the effect of anti-tumour necrosis factor therapy has not been investigated in depth. Our experience points to a detrimental clinical effect in overall prevalence of chronic rhinosinusitis, despite its benefit in certain subtypes. Method: A telephone survey was performed to parallel the findings of the Global Allergy and Asthma European Network chronic rhinosinusitis screening survey. This was itself based on the widely recognised European Position Paper on Rhinosinusitis and Nasal Polyps criteria. Results: A total of 120 patients responded to the survey. The prevalence of chronic rhinosinusitis in the anti-tumour necrosis factor therapy population was 20 per cent (95 per cent confidence interval = 12.84-27.16). When compared using a chi-square test, for a two-by-two contingency table, this finding was significant against the prevalence recorded in the normal population. Conclusion: This is the first observational study indicating increased prevalence of chronic rhinosinusitis in patients treated with anti-tumour necrosis factor therapy. These clinical findings require investigation in greater depth to clarify the nature of pathologies currently diagnosed and treated as chronic rhinosinusitis. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinum-based chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings. [ABSTRACT FROM AUTHOR]

Objectives. Pro-inflammatory cytokines such as TNF-a are important in the pathogenesis of fatigue in conditions such as RA. This study aimed to determine whether fatigue improved in a cohort of RA patients with clinically relevant fatigue commencing anti-TNF-a therapy and, if so, to identify predictors of improvement. Methods. Participants recruited to a long-term observational cohort study (the British Society for Rheumatology Biologics Register for RA) provided information on fatigue using the 36-item Short Form Health Survey (SF-36) vitality subscale. The prevalence of severe baseline fatigue (SF-36 vitality 412.5) was calculated and improvements, considered as (i) absolute values and (ii) improvement from severe to non-severe fatigue (SF-36 vitality >12.5), were examined 6 months subsequently. A comprehensive set of putative predictors of fatigue improvement were evaluated using multivariable logistic regression. Results. In 6835 participants the prevalence of severe baseline fatigue was 38.8%. Of those with severe fatigue, 70% reported clinically relevant improvement and 66% moved to the non-severe fatigue category (i.e. improvers). The mean change for improvers was three times the minimum clinically important difference for improvement (33.0 U). Independent baseline predictors of improvement were female sex [odds ratio (OR) 1.3 (95% CI 1.1, 1.7)], not being unemployed due to ill health [OR 1.5 (95% CI 1.2, 1.7)], low disability [OR 1.2 (95% CI 1.001, 1.5)], seropositivity [OR 1.2 (95% CI 0.98, 1.4)], not using steroids [OR 1.2 (95% CI 1.03, 1.5)], no history of hypertension [OR 1.4 (95% CI 1.1, 1.6)] or depression [OR 1.3 (95% CI 1.1, 1.5)] and good mental health [SF-36 mental health subscale >35; OR 1.4 (95% CI 1.2, 1.7)]. Conclusion. Fatigued RA patients reported substantial improvement in their fatigue after commencing anti-TNF-a therapy. Further, a number of clinical and psychosocial baseline factors identified those most likely to improve, supporting future stratified approaches to RA fatigue management. [ABSTRACT FROM AUTHOR]

The article presents abstracts of studies on epidemiology of rheumatology which include the correlation of comorbidity and functional disability in early rheumatoid arthritis (RA), the risk of pneumonia in patients with RA and the impact of small spinal curves in adolescents.

The article presents abstracts of studies on the comorbidities in rheumatoid arthritis (RA) which include the treatment intensity in RA, the management of cardiac risk profiles of RA patients and the effectiveness of rituximab in the treatment of RA.

Objective. Non-adherence to DMARDs is common, but little is known about adherence to biologic therapies and its relationship to treatment response. The purpose of this study was to investigate the association between self-reported non-adherence to s.c. anti-TNF therapy and response in individuals with RA.Methods. Participants about to start s.c. anti-TNF therapy were recruited to a large UK multicentre prospective observational cohort study. Demographic information and disease characteristics were assessed at baseline. Self-reported non-adherence, defined as whether the previous due dose of biologic therapy was reported as not taken on the day agreed with the health care professional, was recorded at 3 and 6 months following the start of therapy. The 28-joint DAS (DAS28) was recorded at baseline and following 3 and 6 months of therapy. Multivariate linear regression was used to examine these relationships.Results. Three hundred and ninety-two patients with a median disease duration of 7 years [interquartile range (IQR) 3–15] were recruited. Adherence data were available in 286 patients. Of these, 27% reported non-adherence to biologic therapy according to the defined criteria at least once within the first 6-month period. In multivariate linear regression analysis, older age, lower baseline DAS28 and ever non-adherence at either 3 or 6 months from baseline were significantly associated with a poorer DAS28 response at 6 months to anti-TNF therapy.Conclusion. Patients with RA who reported not taking their biologic on the day agreed with their health care professional showed poorer clinical outcomes than their counterparts, emphasizing the need to investigate causes of non-adherence to biologics. [ABSTRACT FROM PUBLISHER]

Objectives. Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level.Methods. Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4+ T cells.Results. Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4+ T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4+ T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4+ T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4+ T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17.Conclusion. Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4+ T cell responses. [ABSTRACT FROM PUBLISHER]

Objective. The aim of this study was to use whole transcriptome sequencing (RNA-Seq) of RA neutrophils to identify pre-therapy gene expression signatures that correlate with disease activity or response to TNF inhibitor (TNFi) therapy.Methods. Neutrophils were isolated from the venous blood of RA patients (n = 20) pre-TNFi therapy and from healthy controls (n = 6). RNA was poly(A) selected and sequenced on the Illumina HiSeq 2000 platform. Reads were mapped to the human genome (hg19) using TopHat and differential expression analysis was carried out using edgeR (5% false discovery rate). Signalling pathway analysis was carried out using Ingenuity Pathway Analysis (IPA) software. IFN signalling was confirmed by western blotting for phosphorylated signal transducer and activator of transcription (STAT) proteins. Response to TNFi was measured at 12 weeks using change in the 28-item DAS (DAS28).Results. Pathway analysis with IPA predicted activation of IFN signalling in RA neutrophils, identifying 178 IFN-response genes regulated by IFN-α, IFN-β or IFN-γ (P < 0.01). IPA also predicted activation of STAT1, STAT2 and STAT3 transcription factors in RA neutrophils (P < 0.01), which was confirmed by western blotting. Expression of IFN-response genes was heterogeneous and patients could be categorized as IFN-high or IFN-low. Patients in the IFN-high group achieved a better response to TNFi therapy [ΔDAS28, P = 0.05, odds ratio (OR) 1.4 (95% CI 1.005, 1.950)] than patients in the IFN-low group. The level of expression of IFN-response genes (IFN score) predicted a good response [European League Against Rheumatism (EULAR) criteria] to TNFi using receiver operating characteristic curve analysis (area under the curve 0.76).Conclusion. IFN-response genes are significantly up-regulated in RA neutrophils compared with healthy controls. Higher IFN-response gene expression in RA neutrophils correlates with a good response to TNFi therapy. [ABSTRACT FROM PUBLISHER]

Objective Tumor necrosis factor (TNF) signals via 2 receptors, TNFR type I (TNFRI) and TNFRII, with distinct cellular distribution and signaling functions. In rheumatoid arthritis (RA), the net effect of TNFR signaling favors inflammatory responses while inhibiting the activity of regulatory T cells. TNFRII signaling has been shown to promote Treg cell function. To assess the relative contributions of TNFRI and TNFRII signaling to inflammatory and regulatory responses in vivo, we compared the effect of TNF blockade, hence TNFRI/II, versus TNFRI alone in collagen-induced arthritis (CIA) as a model of RA. Methods Mice with established arthritis were treated for 10 days with anti-mouse TNFRI domain antibody (dAb; DMS5540), an isotype control dAb (DMS5538), or murine TNFRII genetically fused with mouse IgG1 Fc domain (mTNFRII-Fc) beginning on the day of arthritis onset, and disease progression was monitored. Systemic cytokine concentrations and numbers of T cell subsets in lymph nodes and spleens were measured, and intrinsic Treg cell function was determined by ex vivo suppression assays. Results Progression of CIA was suppressed similarly by TNFRI (DMS5540) and TNFRI/II (mTNFRII-Fc) blockade. However, blockade of TNFRI/II led to increased effector T cell activity, which was not observed after selective TNFRI blockade, suggesting an immunoregulatory role of TNFRII. In support of this, TNFRI blockade, but not TNFRI/II blockade, expanded and activated Treg cells. Furthermore, a dramatic increase in expression of the Treg cell signature genes FoxP3 and TNFRII was observed in joints undergoing remission, which supports the notion that these molecules have a physiologic role in the resolution of inflammation. Conclusion We propose that a therapeutic strategy that targets TNFRI while sparing TNFRII has the potential to both inhibit inflammation and promote Treg cell activity, which might be superior to TNF blockade. [ABSTRACT FROM AUTHOR]

Objective To assess the role of glycogen synthase kinase 3 (GSK-3) as a regulator of cartilage destruction in human tissue and a murine model of osteoarthritis (OA). Methods Surgical destabilization of the medial meniscus (DMM) was performed to induce experimental murine OA, and joint damage was assessed histologically. Bovine nasal and human OA cartilage samples were incubated with interleukin-1 (IL-1) plus oncostatin M (OSM) and GSK-3 inhibitor. Collagen and proteoglycan release was assessed by hydroxyproline measurement and dye binding assay, collagenase activity was assessed by bioassay, and gene expression was analyzed by real-time polymerase chain reaction. Human articular chondrocytes were isolated by enzymatic digestion and cultured prior to gene silencing and immunoblotting of cell lysates and nuclear fractions. Results Mice treated with GSK-3 inhibitor exhibited significantly greater cartilage damage compared with sham-operated control mice. GSK-3 inhibition in bovine cartilage dramatically accelerated IL-1 plus OSM-stimulated degradation, concomitant with a profound increase in collagenase activity. GSK-3 inhibitor induced collagen release from human OA cartilage in the presence of IL-1 plus OSM and increased proteoglycan loss. Gene expression profiling of resorbing OA cartilage revealed a marked procatabolic switch in gene expression upon GSK-3 inhibition. This was mirrored in human articular chondrocytes following GSK3 silencing, particularly with the GSK-3β isoform. GSK-3 inhibition or silencing led to enhanced IL-1 plus OSM-stimulated abundance and activity of Jun, and silencing of c- jun ameliorated GSK-3 inhibitor-mediated procatabolic gene expression. Conclusion GSK-3 is an important regulator of matrix metalloproteinase (MMP)-mediated joint destruction, the inhibition of which by proinflammatory stimuli de-represses catabolic gene expression. Therapeutic strategies that maintain cartilage GSK-3 activity may therefore help curtail aberrant MMP activity during pathologic joint destruction. [ABSTRACT FROM AUTHOR]

Objective. The aim of this study was to determine the short- and long-term efficacy and safety of 8-weekly canakinumab therapy in children with cryopyrin-associated periodic syndromes (CAPS) in routine clinical practice.Methods. A single-centre observational study was performed. Patients were assessed every 8 weeks at a dedicated clinic. Standardized assessments were the 10-domains DAS for CAPS, acute phase reactants (APRs), physician’s global assessment of disease activity, Child Health Assessment Questionnaire (CHAQ) and Child Health Questionnaire Parent Form 28 (CHQPF-28). The primary endpoint was clinical improvement, defined as a reduction of DAS score 8 weeks after commencing therapy. Secondary endpoints included sustained clinical improvement in APRs, relapses, CHAQ score and CHQPF-28 score.Results. Ten children with CAPS [eight Muckle-Wells syndrome (MWS), two chronic infantile cutaneous neurological articular (CINCA); median age 6.3 years] received 8-weekly canakinumab treatments at 2–8.7 mg/kg for a median of 21 months (range 12–31 months). Nine of 10 patients improved after the first dose: baseline median DAS of 7.5/20 decreased to 3.5/20 at 8 weeks (P = 0.04). This clinical improvement was sustained at a median follow-up of 21 months (range 12–31 months). Children with CINCA required higher doses of canakinumab than those with MWS. CHAQ and CHQ scores indicated improvement in functioning and health-related quality of life (HRQoL). Treatment was well tolerated, with no injection site reactions and no serious infections.Conclusion. Canakinumab, although costly, is a safe and effective treatment for CAPS in children, leading to sustained improvement in disease activity, serological markers, functional ability and HRQoL. [ABSTRACT FROM PUBLISHER]

Objective. To describe the use of and response to biologic therapies commenced in adults with JIA.Methods. Patients with arthritis onset <16 years were identified from the British Society for Rheumatology Biologics Register for rheumatoid arthritis (BSRBR-RA) and stratified into ILAR JIA subtypes. Patterns of biologic use and treatment persistence were explored, with disability levels (HAQ) and remission rates [28-Joint Disease Activity Score (DAS28)] evaluated at 6 and 12 months.Results. Arthritis with an onset of <16 years was confirmed in 225 patients and the ILAR subtype was determined in 154 (68%). Only 58 (26%) patients had a diagnosis of JIA recorded in the BSRBR-RA. The median age at biologic commencement was 31 years [interquartile range (IQR) 23–39] and 76% were female. The biologic therapies were etanercept (49%), infliximab (28%), adalimumab (22%) and anakinra (1%). Fifty per cent of patients received more than one biologic during follow-up (2 agents, n = 64; &geq;3 agents, n = 49). Treatment persistence at 1 year was 78% (95% CI 71%, 82%), falling to 42% (95% CI 34%, 49%) at 5 years. Both the HAQ and DAS28 improved significantly at 6 months, with 21% and 28% of patients in remission (DAS28 < 2.6) at 6 and 12 months, respectively.Conclusion. This study describes patterns and identifies outcomes of biologic use in a national cohort of adults with JIA. With no national guidance currently available in this area, the choice of first biologic was inconsistent, although treatment outcomes were good. These data confirm that biologic therapies are an important treatment option in adults with active JIA in adulthood. [ABSTRACT FROM AUTHOR]

Objective Anti-tumor necrosis factor (anti-TNF) therapies are highly effective in rheumatoid arthritis (RA) and psoriatic arthritis (PsA), but a significant number of patients exhibit only a partial or no therapeutic response. Inflammation alters local and systemic metabolism, and TNF plays a role in this. We undertook this study to determine if the patient's metabolic fingerprint prior to therapy could predict responses to anti-TNF agents. Methods Urine was collected from 16 RA patients and 20 PsA patients before and during therapy with infliximab or etanercept. Urine metabolic profiles were assessed using nuclear magnetic resonance spectroscopy. Discriminating metabolites were identified, and the relationship between metabolic profiles and clinical outcomes was assessed. Results Baseline urine metabolic profiles discriminated between RA patients who did or did not have a good response to anti-TNF therapy according to European League Against Rheumatism criteria, with a sensitivity of 88.9% and a specificity of 85.7%, with several metabolites contributing (in particular histamine, glutamine, xanthurenic acid, and ethanolamine). There was a correlation between baseline metabolic profiles and the magnitude of change in the Disease Activity Score in 28 joints from baseline to 12 months in RA patients ( P = 0.04). In both RA and PsA, urinary metabolic profiles changed between baseline and 12 weeks of anti-TNF therapy. Within the responders, urinary metabolite changes distinguished between etanercept and infliximab treatment. Conclusion The clear relationship between urine metabolic profiles of RA patients at baseline and their response to anti-TNF therapy may allow development of novel approaches to the optimization of therapy. Differences in metabolic profiles during treatment with infliximab and etanercept in RA and PsA may reflect distinct mechanisms of action. [ABSTRACT FROM AUTHOR]

Objective The importance of interleukin-17 (IL-17) is underscored both by its resistance to control by Treg cells and the propensity of Treg cells to produce this highly inflammatory cytokine. This study sought to address whether Th17 cells are inhibited by Treg cells in rheumatoid arthritis (RA) patients responding to anti-tumor necrosis factor (anti-TNF) therapy, and if so defining the underlying mechanisms of suppression. Methods Inhibition of Th17 cell responses was determined by Treg cell suppression assays. The Treg cell phenotype was analyzed using flow cytometry and enzyme-linked immunosorbent assay. Mechanisms of suppression were tested by cytokine addition or antibody blockade. Results Th17 responses were inhibited by Treg cells from RA patients responding to the anti-TNF antibody adalimumab (Tregada), but not by Treg cells from healthy individuals or patients with active RA. Furthermore, Tregada cells secreted less IL-17, even when exposed to proinflammatory monocytes from patients with active RA. Tregada cells suppressed Th17 cells through the inhibition of monocyte-derived IL-6, but this effect was independent of IL-10 and transforming growth factor β, which mediated the suppression of Th1 responses. Adalimumab therapy led to a reduction in retinoic acid receptor-related orphan nuclear receptor C-positive Th17 cells and an increase in FoxP3+ Treg cells lacking expression of the transcription factor Helios. However, this acquisition of IL-17-suppressor function was not observed in RA patients responding to treatment with etanercept, a modified TNF receptor-Fc fusion protein. Indeed, there was no alteration in Treg cell number, function, or phenotype in etanercept-treated patients, and Th17 responses remained unchecked. Conclusion Th1 and Th17 responses are controlled through distinct mechanisms by Treg cells from patients responding to anti-TNF antibody therapy. Adalimumab therapy, but not etanercept therapy, induces a potent and stable Treg cell population with the potential to restrain the progression of IL-17-associated inflammation in RA via regulation of monocyte-derived IL-6. [ABSTRACT FROM AUTHOR]

Objectives In the UK, there is a wide variation in the quality of care that people with ankylosing spondylitis (AS) receive. People with AS require early diagnosis and referral to a specialist team to commence treatment and optimize outcome. Methods At East Kent Hospitals University Foundation Trust, a specialist clinic led by an extended scope practitioner (ESP) physiotherapist has been set up for the assessment and monitoring of patients with AS. This report describes the service provided by the AS clinic. Results Over eight years, the number of patients seen has risen from 62 to 352, and annual consultations from 186 to 986, with an average of 2.8 visits per patient per year. Ninety-seven patients have started treatment with a Tumour Necrosis Factor (TNF) blocker. The service has expanded by the addition of a support worker and biologic clinics. Conclusion For the Trust, the specialist service provides an improved quality of care and cost-effective use of staff resources. Evaluation has demonstrated that patients welcome the new service. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Semagacestat, a γ-secretase inhibitor, reduces formation of amyloid beta peptide. Two single-dose (140 mg), open-label, randomized, 3-period, crossover studies evaluated the effect of formulation, food, and time of dosing on the pharmacokinetics and pharmacodynamics of semagacestat in healthy participants. The first study (n = 14) compared tablet to capsules. For all formulations, the median time to maximum plasma concentration (tmax) was generally 1.0 hour. Plasma elimination was rapid, with a half-life of approximately 2.5 hours. Tablet form II bioavailability (F) relative to capsule was approximately 100% (F = 1.03 [90% confidence interval (CI), 0.96-1.10]). In the second study, participants (n = 27) received semagacestat either fed or fasting in the morning or fasting in the evening. No significant change in exposure (AUC0-∞ [area under the concentration-time curve from 0 to infinity] ratio = 1.02, [90% CI, 0.990-1.05]) occurred with food, whereas maximum plasma concentration (Cmax) declined approximately 15%, and median tmax was delayed to 1.5 hours. Time of dosing made no significant difference in AUC0-∞, Cmax, or tmax (AUC0-∞ ratio 1.01, [90% CI, 0.975-1.04]). No clinically significant safety concerns occurred in either study. Accordingly, semagacestat may be dosed without regard to formulation, food, or time of administration. [ABSTRACT FROM PUBLISHER]

Objective Several rheumatoid arthritis (RA) susceptibility variants map close to genes involved in the tumor necrosis factor (TNF) signaling pathway, prompting the investigation of RA susceptibility variants in studies of predictors of response to TNF blockade. Based on a previously reported association of RA with the PTPRC genetic locus, the present study was undertaken to test established RA susceptibility variants, including PTPRC, in the prediction of response to TNF blockade in a large cohort of patients from the UK. Methods DNA was extracted from the blood of 1,115 UK patients with RA who were receiving anti-TNF biologic therapy. Samples were analyzed for 29 single-nucleotide polymorphisms (SNPs) previously established as RA susceptibility variants. In the primary analysis, the effect of each SNP on treatment response was assessed by linear regression, using an additive model, in which absolute change in the Disease Activity Score in 28 joints at 6 months of followup was the outcome measure. In a secondary analysis, logistic regression models were used to compare patients with a good treatment response (n = 274) to those with a poor response (n = 195), as defined using the European League Against Rheumatism response criteria. Results were combined with those from previous studies to confirm the findings by meta-analysis. Results The PTPRC rs10919563 SNP was associated with improved treatment response in both the primary analysis (regression coefficient 0.19, 95% confidence interval [95% CI] 0.09, 0.37; P = 0.04) and secondary analysis (odds ratio 0.62, 95% CI 0.40, 0.95; P = 0.03). A meta-analysis combining these data with the results from a previous study strengthened the evidence for association with the PTPRC SNP ( P = 5.13 × 10−5) . No convincing association of the treatment response with other candidate loci was detected. Conclusion Presence of the rs10919563 RA susceptibility variant at the PTPRC gene locus predicts improved response to anti-TNF biologic therapy. Fine-mapping studies are required to determine whether this SNP or another variant at the locus provides the greatest predictive accuracy for treatment response. [ABSTRACT FROM AUTHOR]