Rituximab versus tocilizumab and b-cell status in tnf-alpha inadequate-responder rheumatoid arthritis patients: the r4-ra rct

Background Although biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells). Design The R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor. Participants Synovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population. Main outcome measures The primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of < 10.1, defined for simplicity as CDAI major treatment response (CDAI-MTR). Secondary outcomes included the assessment of CDAI response in the B-cell-rich cohort, in which the non-inferiority of rituximab compared with tocilizumab was evaluated. Safety data up to week 48 are reported. Results In total, 164 patients were randomised: 83 patients received rituximab and 81 received tocilizumab. Eighty-one out of 83 rituximab patients and 73 out of 81 tocilizumab patients completed treatment up to week 16 (primary end point). Baseline characteristics were comparable between the treatment groups. In the histologically classified B-cell-poor population (n = 79), no significant difference was observed in the primary outcome, an improvement in CDAI score of ≥ 50% from baseline (risk ratio 1.25, 95% confidence interval 0.80 to 1.96). A supplementary analysis of the CDAI-MTR, however, did reach statistical significance (risk ratio 1.96, 95% confidence interval 1.01 to 3.78). In addition, when B-cell-poor classification was determined molecularly, both the primary end point and the CDAI-MTR were statistically significant (risk ratio 1.72, 95% confidence interval 1.02 to 2.91, and risk ratio 4.12, 95% confidence interval 1.55 to 11.01, respectively). Moreover, a larger number of secondary end points achieved significance when classified molecularly than when classified histologically. In the B-cell-rich population, there was no significant difference between treatments in the majority of both primary and secondary end points. There were more adverse events and serious adverse events, such as infections, in the tocilizumab group than in the rituximab group. Conclusion To our knowledge, this is the first biopsy-based, multicentre, randomised controlled trial of rheumatoid arthritis. We were unable to demonstrate that tocilizumab was more effective than rituximab in patients with a B-cell-poor pathotype in our primary analysis. However, superiority was shown in most of the supplementary and secondary analyses using a molecular classification. These analyses overcame possible unavoidable weaknesses in our original study plan, in which the histological method of determining B-cell status may have misclassified some participants and our chosen primary outcome was insufficiently sensitive. Given the significant results observed using the molecular classification, future research will focus on refining this stratification method and evaluating its clinical utility

Diving into the vertical dimension of elasmobranch movement ecology

Knowledge of the three-dimensional movement patterns of elasmobranchs is vital to understand their ecological roles and exposure to anthropogenic pressures. To date, comparative studies among species at global scales have mostly focused on horizontal movements. Our study addresses the knowledge gap of vertical movements by compiling the first global synthesis of vertical habitat use by elasmobranchs from data obtained by deployment of 989 biotelemetry tags on 38 elasmobranch species. Elasmobranchs displayed high intra- and interspecific variability in vertical movement patterns. Substantial vertical overlap was observed for many epipelagic elasmobranchs, indicating an increased likelihood to display spatial overlap, biologically interact, and share similar risk to anthropogenic threats that vary on a vertical gradient. We highlight the critical next steps toward incorporating vertical movement into global management and monitoring strategies for elasmobranchs, emphasizing the need to address geographic and taxonomic biases in deployments and to concurrently consider both horizontal and vertical movements

Planck 2018 results. IV. Diffuse component separation

We present full-sky maps of the cosmic microwave background (CMB) and polarized synchrotron and thermal dust emission, derived from the third set of Planck frequency maps. These products have significantly lower contamination from instrumental systematic effects than previous versions. The methodologies used to derive these maps follow closely those described in earlier papers, adopting four methods (Commander, NILC, SEVEM, and SMICA) to extract the CMB component, as well as three methods (Commander, GNILC, and SMICA) to extract astrophysical components. Our revised CMB temperature maps agree with corresponding products in the Planck 2015 delivery, whereas the polarization maps exhibit significantly lower large-scale power, reflecting the improved data processing described in companion papers; however, the noise properties of the resulting data products are complicated, and the best available end-to-end simulations exhibit relative biases with respect to the data at the few percent level. Using these maps, we are for the first time able to fit the spectral index of thermal dust independently over 3 degree regions. We derive a conservative estimate of the mean spectral index of polarized thermal dust emission of beta_d = 1.55 +/- 0.05, where the uncertainty marginalizes both over all known systematic uncertainties and different estimation techniques. For polarized synchrotron emission, we find a mean spectral index of beta_s = -3.1 +/- 0.1, consistent with previously reported measurements. We note that the current data processing does not allow for construction of unbiased single-bolometer maps, and this limits our ability to extract CO emission and correlated components. The foreground results for intensity derived in this paper therefore do not supersede corresponding Planck 2015 products. For polarization the new results supersede the corresponding 2015 products in all respects

Studies in the supercalendering of paper

SIGLEAvailable from British Library Document Supply Centre- DSC:D66053/86 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Some Evidence on the Interdependence of National Stock Markets and the Gains from Portfolio Diversification

Gains from international portfolio diversification may be limited if national stock markets are cointegrated. In addition, the implied Granger-causality would be consistent with inefficiency. This possibility is discussed and the relationships between stock market indices of the US, the UK, Japan, West Germany and the Netherlands are investigated using bivariate and multivariate techniques. Contrary to some earlier empirical results, with the exception of the UK and Japan, there is no convincing evidence that international stock markets were cointegrated in the period following the abolition of exchange controls in the UK