BackgroundTofacitinib is the first oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA). We compared the effectiveness and safety of tofacitinib, disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor inhibitors (TNFi), and non-TNF biologics in patients with RA previously treated with methotrexate.MethodsWe used MarketScan® databases (2011–2014) to study methotrexate-exposed patients with RA who were newly prescribed tofacitinib, DMARDs other than methotrexate, and biologics. The date of first prescription was defined as the cohort entry. The therapy was considered effective if all of the following criteria from a claims-based algorithm were achieved at the first year of follow-up: high adherence, no biologic or tofacitinib switch or addition, no DMARD switch or addition, no increase in dose or frequency of index drug, no more than one glucocorticoid joint injection, and no new/increased oral glucocorticoid dose. The safety outcome was serious infections requiring hospitalization. Non-TNF biologics comprised the reference group.ResultsWe included 21,832 patients with RA, including 0.8% treated with tofacitinib, 24.7% treated with other DMARDs, 61.2% who had started therapy with TNFi, and 13.3% treated with non-TNF biologics. The rates of therapy effectiveness were 15.4% for tofacitinib, 11.1% for DMARDs, 18.6% for TNFi, and 19.8% for non-TNF biologics. In adjusted analyses, tofacitinib and non-TNF biologics appeared to have similar effectiveness rates, whereas DMARD initiators were less effective than non-TNF biologics. We could not clearly establish if tofacitinib was associated with a higher rate of serious infections.ConclusionsIn patients with RA previously treated with methotrexate, our comparisons of tofacitinib with non-TNF biologics, though not definitive, did not demonstrate differences with respect to hospitalized infections or effectiveness.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1539-6) contains supplementary material, which is available to authorized users.

Background Liver transplantation is associated with major bleeding and red blood cell (RBC) transfusions. No well-designed causal analysis on interventions used to reduce transfusions, such as an intraoperative phlebotomy, has been conducted in this population. MethodsWe conducted a historical cohort study among liver transplantations performed from July 2008 to January 2021 in a Canadian centre. The exposure was intraoperative phlebotomy. The outcomes were blood loss, perioperative RBC transfusions (intraoperative and up to 48 hr after surgery), intraoperative RBC transfusions, and one-year survival. We estimated marginal multiplicative factors (MFs), risk differences (RDs), and hazard ratios by inverse probability of treatment weighting both among treated patients and the whole population. Estimates are reported with 95% confidence intervals (CIs).

Original Clinical Science-Liver Background. Liver transplantation is a high-risk surgery associated with important perioperative bleeding and transfusion needs. Uncertainties remain on the association between preoperative fibrinogen level and bleeding in this population. Methods. We conducted a cohort study that included all consecutive adult patients undergoing a liver transplantation for end-stage liver disease in 1 center. We analyzed the association between the preoperative fibrinogen level and bleeding-related outcomes. Our primary outcome was intraoperative blood loss, and our secondary outcomes were estimated perioperative blood loss, intraoperative and perioperative red blood cell transfusions, reinterventions for bleeding and 1-y graft and patient survival. We estimated linear regression models and marginal risk models adjusted for all important potential confounders. We used restricted cubic splines to explore potential nonlinear associations and reported dose-response curves. Results. We included 613 patients. We observed that a lower fibrinogen level was associated with a higher intraoperative blood loss, a higher estimated perioperative blood loss and a higher risk of intraoperative and perioperative red blood cell transfusions (nonlinear effects). Based on an exploratory analysis of the dose-response curves, these effects were observed below a threshold value of 3 g/L for these outcomes. We did not observe any association between preoperative fibrinogen level and reinterventions, 1-y graft survival or 1-y patient survival. Conclusions. This study suggests that a lower fibrinogen level is associated with bleeding in liver transplantation. The present results may help improving the selection of patients for further studies on preoperative fibrinogen administration in liver transplant recipients with end-stage liver disease.

Background Switching antiretroviral regimens when HIV viremia is controlled for a new regimen is challenging when there is the potential for prior nucleoside reverse transcriptase inhibitor (NRTI) resistance. The objective was to study virologic outcomes after switching to dolutegravir compared to remaining on a boosted protease inhibitor (PI/r) regimen in people with HIV (PWH) with prior documented virologic failure and/or exposure to mono/dual NRTIs Methods We used the Quebec HIV Cohort including 10,219 PWH whose data were collected at four sites in Montreal, Canada. We included all PWH with documented virologic failure or exposure to mono/dual NRTI therapy who were virologically suppressed on PI/r-based regimen for at least 6 months on or after Jan 1st, 2014 (n=532). A marginal structural Cox model analysis was used to estimate the effect of the switch to dolutegravir on virologic outcome compared to remaining on PI/r. The outcome was defined as two consecutive viral loads (VL) >50 copies/mL or one VL>50 copies/mL if it occurred at the last VL available Results Among 532 eligible participants, 216 (40·6%) had their regimen switched to dolutegravir with two NRTIs whereas 316 (59·4%) remained on the PI/r with two NRTIs. The weighted hazard ratio (HR) for the effect of dolutegravir switch on virologic failure compared to patients whose regimen remained on PI/r was 0·57 (95% CI: 0·21-1·52) Conclusion We did not find evidence of an increased risk for virologic failure after switching to dolutegravir from PI/r among patients with previous virologic failure or prior exposure to mono/dual NRTI

In longitudinal settings, causal inference methods usually rely on a discretization of the patient timeline that may not reflect the underlying data generation process. This article investigates the estimation of causal parameters under discretized data. It presents the implicit assumptions practitioners make but do not acknowledge when discretizing data to assess longitudinal causal parameters. We illustrate that differences in point estimates under different discretizations are due to the data coarsening resulting in both a modified definition of the parameter of interest and loss of information about time‐dependent confounders. We further investigate several tools to advise analysts in selecting a timeline discretization for use with pooled longitudinal targeted maximum likelihood estimation for the estimation of the parameters of a marginal structural model. We use a simulation study to empirically evaluate bias at different discretizations and assess the use of the cross‐validated variance as a measure of data support to select a discretization under a chosen data coarsening mechanism. We then apply our approach to a study on the relative effect of alternative asthma treatments during pregnancy on pregnancy duration. The results of the simulation study illustrate how coarsening changes the target parameter of interest as well as how it may create bias due to a lack of appropriate control for time‐dependent confounders. We also observe evidence that the cross‐validated variance acts well as a measure of support in the data, by being minimized at finer discretizations as the sample size increases.