Rationale In the PREDMETH trial we investigated the efficacy of methotrexate (MTX) compared to prednisone as first line treatment of pulmonary sarcoidosis. We recently reported, (European Respiratory Society Conference), that MTX is as effective as prednisone as assessed by forced vital capacity (FVC) after 6 months of treatment. At present, there are no biomarkers that can predict MTX treatment response within the first 6 months. MTX works as a folate antagonist and upon administration is actively transported into cells where it is metabolized to its active forms by adding up to 6 glutamate residues forming MTX-polyglutamate(n) (MTX-PG(n)) resulting in enhanced cellular retention and anti-inflammatory activity. Intracellular MTX-PG(n) concentrations take about 3 to 4 months to reach a steady state where there is a balance between the process of adding and removing glutamate groups to the MTX molecules. In this study, we therefore address the question whether different MTX-PG(n) metabolite concentrations in red blood cells (RBC) measured after 16 weeks of MTX therapy correlate with response to treatment after 6 months of MTX therapy. Methods For this study, pelleted red blood cells (RBC) from sarcoidosis patients under MTX therapy were used, (mean dosage 21mg/week, SD±4,7). Effectiveness of therapy was assessed by change in forced vital capacity (FVC) between baseline and after 24 weeks of treatment. MTX-PG(n) concentrations after 16 weeks were measured from whole blood RBC by LC-MS/MS. Spearman's rho correlation coefficients were calculated to evaluate the relationship between changes in the FVC and MTXPG(n) metabolite concentrations. Linear regression analysis was used to estimate the linear relationship between efficacy of therapy and the MTX-PG metabolite concentrations. Results Pelleted RBC at 16 weeks after initiation of therapy were available from 36 patients. MTXP-G1 and MTXP-G2 metabolite concentrations in RBC after 16 weeks of therapy showed a significant negative correlation with effectiveness of therapy, defined as change in FVC between baseline and after 24 weeks of therapy (r= -0.551, p = <0.001 and r= -0.511, p = 0.001 respectively). MTX-PG(3-5) did not correlate with effectiveness of therapy. Conclusion Our results suggest a relation between MTX-PG1 and MTX-PG2 metabolite concentrations in RBC after 4 months of MTX therapy and change in FVC after 6 months in patients with sarcoidosis. This could partly explain the variability of response to MTX and be a first step in therapeutic drug monitoring when using MTX in patient with pulmonary sarcoidosis.
Rationale Prednisone is first-line treatment for pulmonary sarcoidosis; however, side effects can significantly diminish quality of life. Methotrexate appears to have fewer side effects but has not been studied as first-line treatment. In the PREDMETH trial we investigated the efficacy of methotrexate compared to prednisone. We recently reported, (European Respiratory Society Conference), that methotrexate is as effective as prednisone as assessed by forced vital capacity (FVC). Here, we report the frequency of adverse events (AEs) and patient reported outcomes (PROs). Methods The PREDMETH trial was a randomized, non-inferiority trial conducted at 17 hospitals in the Netherlands (NCT04314193). The study was designed by clinicians, researchers, and patients. Treatment-naïve patients with pulmonary sarcoidosis received prednisone or methotrexate (randomization 1:1) according to a predefined schedule. The primary endpoint was change in FVC% predicted at 24 weeks (protocol:PMID33076885). Safety assessment included all physician reported (serious)AEs. PROs on symptoms and quality of life were collected at all visits. Results We randomized 138 patients; 70 patients to prednisone (1 exclusion due to an alternative diagnosis) and 68 to methotrexate. Most patients were male (73.7%) and mean age was 46.6 years (SD11.86). Baseline FVC% predicted was 79.8% (SD15.44) for prednisone and 74.8%(SD12.68) for methotrexate. At 24 weeks, there was no significant difference in between group change in %predicted FVC; -1.8% (90%CI -4.40; 0.76). A total of 83% of the prednisone group and 81% of the methotrexate group received medication as per protocol. The total number of AEs did not differ between both groups(table1). At 24 weeks fewer AEs were ongoing in the methotrexate group compared to prednisone (104 versus 171). Most frequently reported AEs in the prednisone group were increased weight, insomnia, increased appetite, and cushingoid appearance. In the methotrexate group, nausea, fatigue, abnormal liver function values, abdominal pain, and respiratory tract infection were more commonly reported. Conclusion The PREDMETH study shows that methotrexate is as effective as prednisone for pulmonary sarcoidosis as assessed by FVC after 24 weeks of treatment. The total number of side effects was comparable; however, in the methotrexate group fewer side effects were ongoing at 24 weeks. Side effect profiles were clearly different. This study shows for the first time that methotrexate may be a good alternative for prednisone as first-line treatment. Difference in AE profiles provide important grounds for shared therapeutic decision making of patients and doctors. The results on PROs will be available at the time of the ATS conference.
Perfusion-cardiovascular MR (CMR) imaging has been shown to reliably identify patients with suspected or known coronary artery disease (CAD), who are at risk for future cardiac events and thus, allows for guiding therapy including revascularizations. Accordingly, it is an ideal test to exclude prognostically relevant coronary artery disease. Several guidelines, such as the ESC guidelines, currently recommend CMR as non-invasive testing in patients with stable chest pain. CMR has as an advantage over the more conventional pathways as it lacks radiation and it potentially reduces costs.
ABSTRACTObjectiveHypertensive disorders affect 3–10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy.MethodsCENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre‐eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA‐IPD guideline was followed and a two‐stage meta‐analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention.ResultsMain outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15–0.73); I2 = 0%; NNT, 51 (95% CI, 31.1–139.3)) as well as in the pre‐eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15–0.98); I2 = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05–3.6); I2 = 24%; NNH, 58 (95% CI, 31.1–363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0–29.6); I2 = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4–30.3); I2 not applicable).ConclusionIn women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a‐priori higher risk of progression to HELLP, such as those already presenting with pre‐eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.
Background Diagnosing pneumonia can be challenging in general practice but is essential to distinguish from other respiratory tract infections because of treatment choice and outcome prediction. We determined predictive signs, symptoms and biomarkers for the presence of pneumonia in patients with acute respiratory tract infection in primary care. Methods From March 2012 until May 2016 we did a prospective observational cohort study in three radiology departments in the Leiden-The Hague area, The Netherlands. From adult patients we collected clinical characteristics and biomarkers, chest X ray results and outcome. To assess the predictive value of C-reactive protein (CRP), procalcitonin and midregional pro-adrenomedullin for pneumonia, univariate and multivariate binary logistic regression were used to determine risk factors and to develop a prediction model. Results Two hundred forty-nine patients were included of whom 30 (12%) displayed a consolidation on chest X ray. Absence of runny nose and whether or not a patient felt ill were independent predictors for pneumonia. CRP predicts pneumonia better than the other biomarkers but adding CRP to the clinical model did not improve classification (− 4%); however, CRP helped guidance of the decision which patients should be given antibiotics. Conclusions Adding CRP measurements to a clinical model in selected patients with an acute respiratory infection does not improve prediction of pneumonia, but does help in giving guidance on which patients to treat with antibiotics. Our findings put the use of biomarkers and chest X ray in diagnosing pneumonia and for treatment decisions into some perspective for general practitioners.
