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BACKGROUND: Although targeted biological treatments have transformed the outlook for patients with rheumatoid arthritis, 40% of patients show poor clinical response, which is mechanistically still unexplained. Because more than 50% of patients with rheumatoid arthritis have low or absent CD20 B cells-the target for rituximab-in the main disease tissue (joint synovium), we hypothesised that, in these patients, the IL-6 receptor inhibitor tocilizumab would be more effective. The aim of this trial was to compare the effect of tocilizumab with rituximab in patients with rheumatoid arthritis who had an inadequate response to anti-tumour necrosis factor (TNF) stratified for synovial B-cell status. METHODS: This study was a 48-week, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial (rituximab vs tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis; R4RA) done in 19 centres across five European countries (the UK, Belgium, Italy, Portugal, and Spain). Patients aged 18 years or older who fulfilled the 2010 American College of Rheumatology and European League Against Rheumatism classification criteria for rheumatoid arthritis and were eligible for treatment with rituximab therapy according to UK National Institute for Health and Care Excellence guidelines were eligible for inclusion in the trial. To inform balanced stratification, following a baseline synovial biopsy, patients were classified histologically as B-cell poor or rich. Patients were then randomly assigned (1:1) centrally in block sizes of six and four to receive two 1000 mg rituximab infusions at an interval of 2 weeks (rituximab group) or 8 mg/kg tocilizumab infusions at 4-week intervals (tocilizumab group). To enhance the accuracy of the stratification of B-cell poor and B-cell rich patients, baseline synovial biopsies from all participants were subjected to RNA sequencing and reclassified by B-cell molecular signature. The study was powered to test the superiority of tocilizumab over rituximab in the B-cell poor population at 16 weeks. The primary endpoint was defined as a 50% improvement in Clinical Disease Activity Index (CDAI50%) from baseline. The trial is registered on the ISRCTN database, ISRCTN97443826, and EudraCT, 2012-002535-28. FINDINGS: Between Feb 28, 2013, and Jan 17, 2019, 164 patients were classified histologically and were randomly assigned to the rituximab group (83 [51%]) or the tocilizumab group (81 [49%]). In patients histologically classified as B-cell poor, there was no statistically significant difference in CDAI50% between the rituximab group (17 [45%] of 38 patients) and the tocilizumab group (23 [56%] of 41 patients; difference 11% [95% CI -11 to 33], p=0·31). However, in the synovial biopsies classified as B-cell poor with RNA sequencing the tocilizumab group had a significantly higher response rate compared with the rituximab group for CDAI50% (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse events (rituximab group 76 [70%] of 108 patients vs tocilizumab group 94 [80%] of 117 patients; difference 10% [-1 to 21) and serious adverse events (rituximab group 8 [7%] of 108 vs tocilizumab group 12 [10%] of 117; difference 3% [-5 to 10]) were not significantly different between treatment groups. INTERPRETATION: The results suggest that RNA sequencing-based stratification of rheumatoid arthritis synovial tissue showed stronger associations with clinical responses compared with histopathological classification. Additionally, for patients with low or absent B-cell lineage expression signature in synovial tissue tocilizumab is more effective than rituximab. Replication of the results and validation of the RNA sequencing-based classification in independent cohorts is required before making treatment recommendations for clinical practice. FUNDING: Efficacy and Mechanism Evaluation programme from the UK National Institute for Health Research. ispartof: LANCET vol:397 issue:10271 pages:305-317 ispartof: location:England status: published

Familial hypercholesterolaemia is a common genetic disorder of lipid metabolism in which patients have a significantly elevated risk of early coronary heart disease, which can be substantially lowered by treatment with the statin class of drugs. In many countries in Europe, tracing of relatives using DNA information, once the family mutation has been identified, is being actively carried out. The present review examines the specificity and clinical utility of DNA testing in patients with familial hypercholesterolaemia.Technological progress has improved the detection rate in patients with the strongest clinical suspicion of familial hypercholesterolaemia to more than 70-80%. Patients carrying a mutation have, on average, higher low-density lipoprotein cholesterol levels and greater risk of early coronary heart disease, and studies have reported the utility of DNA information in the identification of affected relatives. More than 1000 different molecular causes of familial hypercholesterolaemia are documented in the University College London database, and although more than 90% of these clearly cause familial hypercholesterolaemia, the remainder require careful interpretation.DNA testing, as an adjunct to the measurement of plasma low-density lipoprotein cholesterol levels, has clinical utility in providing an unequivocal diagnosis in patients and in identifying affected relatives at an early age so that they can be offered lifestyle advice and appropriate lipid-lowering therapies. Researchers and DNA diagnostic laboratories need to interpret novel sequence changes with caution in order to avoid a false positive diagnosis.

Purpose of review Cascade testing is an important method for identifying individuals at risk of a genetic condition. Recent advances in its application to familial hypercholesterolaemia are reviewed to identify potential problems impeding its application and the extent to which current data address these concerns.Recent findings Different paradigms for cascade testing are being applied in national programmes. Current data demonstrates cost-effectiveness, and an increased uptake of preventive measures. The relationship between molecular and clinical diagnostic methods is discussed. Psychological impacts of a diagnosis of familial hypercholesterolaemia are in line with the risks associated with the disorder. The efficacy of statins in improving vascular function of children with familial hypercholesterolaemia has been demonstrated, but extensive safety data are lacking. Ethical arguments support that it is equally acceptable for relatives of familial hypercholesterolaemia patients to be contacted by healthcare workers as by family members, but the former is likely to be more efficient. Concerns about increased life insurance premiums are valid but insurance companies are assessing risk realistically, so this should not be a barrier to cascade testing.Summary Current data support the implementation of cascade testing for familial hypercholesterolaemia as being feasible and cost-effective, but national implementation is limited to a small number of countries. Funding and the infrastructure to support it may be the major stumbling blocks in implementing this technique in many countries. Concerns about the ethics of carrying out cascade testing, and the potential psychological damage of DNA testing, appear to have been largely addressed for familial hypercholesterolaemia.

In the current issue of Heart , Gray et al report the results of a pilot study to identify patients with familial hypercholesterolaemia (FH) in general practice ( see article on page 754 ).1 Why is this important and how did they do it? FH is a common disorder where subjects have markedly raised low-density lipoprotein-cholesterol (LDL-C), and consequently have premature coronary heart disease (CHD) and myocardial infarction. Studies carried out in the 1970s in the UK and the USA2 3 suggest that, if untreated, 50% of men with FH will have developed CHD by the age of 55 years and 50% of women by the age of 65 years (women show the same degree of elevation of LDL-C but are protected somewhat from the atherosclerosis until after the menopause). Thankfully, patients with FH are now well treated by statins and their overall standardised CHD mortality rate has fallen from 8.1 in 20–59-year-olds before statins to 3.7 after statins.4 This translates into roughly 9 life-years gained, and models have shown that treatment of patients with FH, even at a young age, is highly cost effective as measured by the cost for each life-year gained.5 Management of other CHD risk factors is also important in patients with FH, the dietary and lifestyle advice, particular smoking cessation, being a benefit, and with the new and more powerful statins now available, it is a realistic possibility for people with FH to have a normal life expectancy. How many patients with FH are there in the UK, and are they being well managed? The estimated prevalence of FH is 1 in 500, suggesting that there are probably more than 100 000 people with FH in the UK. A recent survey of the 130 lipid clinics currently active in the UK suggests that …

Wald et al suggest that screening children for high cholesterol at the time of immunisation, and then testing the parents of affected children, is an effective screening method for familial hypercholesterolaemia.1 However, their paper does not address acceptability or cost effectiveness. Earlier data from our group showed that universal screening was much less cost effective than cascade testing (family …