High-Dose Intravenous Iron with Either Ferric Carboxymaltose or Ferric Derisomaltose: A Benefit-Risk Assessment.

The intravenous iron formulations ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) offer the possibility of administering a large amount of iron in one infusion. This results in faster correction of anemia and the formulations being better tolerated than oral iron formulations. This triad of logistic advantages, improved patient convenience, and fast correction of anemia explains the fact that intravenous iron formulations nowadays are frequently prescribed worldwide in the treatment of iron deficiency anemia. However, these formulations may result in hypophosphatemia by inducing a strong increase in active fibroblast growth factor-23 (FGF-23), a hormone that stimulates renal phosphate excretion. This effect is much more pronounced with FCM than with FDI, and therefore the risk of developing hypophosphatemia is remarkably higher with FCM than with FDI. Repeated use of FCM may result in severe osteomalacia, which is characterized by bone pain, Looser zones (pseudofractures), and low-trauma fractures. Intravenous iron preparations are also associated with other adverse effects, of which hypersensitivity reactions are the most important and are usually the result of a non-allergic complement activation on nanoparticles of free labile iron-Complement Activation-Related Pseudo-Allergy (CARPA). The risk on these hypersensitivity reactions can be reduced by choosing a slow infusion rate. Severe hypersensitivity reactions were reported in < 1% of prospective trials and the incidence seems comparable between the two formulations. A practical guideline has been developed based on baseline serum phosphate concentrations and predisposing risk factors, derived from published cases and risk factor analyses from trials, in order to establish the safe use of these formulations.

The effect of a medication reconciliation program in two intensive care units in the Netherlands: a prospective intervention study with a before and after design.

BACKGROUND: Medication errors occur frequently in the intensive care unit (ICU) and during care transitions. Chronic medication is often temporarily stopped at the ICU. Unfortunately, when the patient improves, the restart of this medication is easily forgotten. Moreover, temporal ICU medication is often unintentionally continued after ICU discharge. Medication reconciliation could be useful to prevent such errors. Therefore, the aim of this study was to determine the effect of medication reconciliation at the ICU. METHODS: This prospective 8-month study with a pre- and post-design was carried out in two ICU settings in the Netherlands. Patients were included when they used ≥ 1 chronic medicine and when the ICU stay exceeded 24 h. The intervention consisted of medication reconciliation by pharmacists at the moment of ICU admission and prior to ICU discharge. Medication transfer errors (MTEs) were collected and the severity of potential harm of these MTEs was measured, based on a potential adverse drug event score (pADE = 0; 0.01; 0.1; 0.4; 0.6). Primary outcome measures were the proportions of patients with ≥ 1 MTE at ICU admission and after discharge. Secondary outcome measures were the proportions of patients with a pADE score ≥ 0.01 due to these MTEs, the severity of the pADEs and the associated costs. Odds ratio and 95% confidence intervals were calculated, by using a multivariate logistic regression analysis. RESULTS: In the pre-intervention phase, 266 patients were included and 212 in the post-intervention phase. The proportion of patients with ≥ 1 MTE at ICU admission was reduced from 45.1 to 14.6% (ORadj 0.18 [95% CI 0.11-0.30]) and after discharge from 73.9 to 41.2% (ORadj 0.24 [95% CI 0.15-0.37]). The proportion of patients with a pADE ≥ 0.01 at ICU admission was reduced from 34.8 to 8.0% (ORadj 0.13 [95% CI 0.07-0.24]) and after discharge from 69.5 to 36.2% (ORadj 0.26 [95% CI 0.17-0.40]). The pADE reduction resulted in a potential net cost-benefit of € 103 per patient. CONCLUSIONS: Medication reconciliation by pharmacists at ICU transfers is an effective safety intervention, leading to a significant decrease in the number of MTE and a cost-effective reduction in potential harm. Trial registration Dutch trial register: NTR4159, 5 September 2013, retrospectively registered.

Glucocorticoid sensitivity in health and disease.

Glucocorticoids regulate many physiological processes and have an essential role in the systemic response to stress. For example, gene transcription is modulated by the glucocorticoid-glucocorticoid receptor complex via several mechanisms. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors. Differences in sensitivity to glucocorticoids in healthy individuals are partly genetically determined by functional polymorphisms of the gene that encodes the glucocorticoid receptor. Hereditary syndromes have also been identified that are associated with increased and decreased sensitivity to glucocorticoids. As a result of their anti-inflammatory properties, glucocorticoids are widely used in the treatment of allergic, inflammatory and haematological disorders. The variety in clinical responses to treatment with glucocorticoids reflects the considerable variation in glucocorticoid sensitivity between individuals. In immune-mediated disorders, proinflammatory cytokines can induce localized resistance to glucocorticoids via several mechanisms. Individual differences in how tissues respond to glucocorticoids might also be involved in the predisposition for and pathogenesis of the metabolic syndrome and mood disorders. In this Review, we summarize the mechanisms that influence glucocorticoid sensitivity in health and disease and discuss possible strategies to modulate glucocorticoid responsiveness.

Response to glucocorticoids at 2 weeks predicts the effectiveness of DMARD induction therapy at 3 months: post hoc analyses from the tREACH study.

OBJECTIVE: To investigate if a glucocorticoid (GC) response at 2 weeks, defined by EULAR response criteria, can predict active disease (Disease Activity Score (DAS)>2.4) at 3 months. METHODS: For this study, data of the Treatment in the Rotterdam Early Arthritis Cohort study (tREACH), an ongoing clinical trial that evaluates different induction therapies in early rheumatoid arthritis, were used. We selected patients who had a high probability of progressing to persistent arthritis (>70% based on the prediction model of Visser). All patients within the high-probability stratum, who had a baseline DAS>2.2 and a DAS assessment at 2 weeks after randomisation, were included (n=120). Besides GC response at 2 weeks, we investigated which other factors were associated with active disease (DAS>2.4) after 3 months of disease-modifying antirheumatic drug (DMARD) treatment. All variables with a p≤0.25 were assessed in our logistic regression model with backward selection. Variables were eliminated until all remaining variables had a significant association (p<0.05). RESULTS: Patients who did not respond to GC bridging therapy at 2 weeks had an overall OR of having active disease at 3 months of 10.29 (95% CI 3.34 to 31.64; p<0.001) in comparison with responders. The corrected OR was 14.00 (95% CI 3.31 to 59.21; p<0.001). Our final model predicting response at 3 months included the following variables: gender, GC response, induction therapy arms and baseline DAS, which had an explained variance of 39%. CONCLUSIONS: GC response at 2 weeks is a useful tool for recognising those patients who will probably have active disease (DAS>2.4) after 3 months of DMARD treatment.

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis.

INTRODUCTION: The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9ß and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum. METHODS: We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9ß, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9ß or 9ß + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use. RESULTS: GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease. CONCLUSIONS: Differences in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.

In vitro glucocorticoid sensitivity is associated with clinical glucocorticoid therapy outcome in rheumatoid arthritis.

INTRODUCTION: Genetic and disease-related factors give rise to a wide spectrum of glucocorticoid (GC) sensitivity in rheumatoid arthritis (RA). In clinical practice, GC treatment is not adapted to these differences in GC sensitivity. In vitro assessment of GC sensitivity before the start of therapy could allow more individualized GC therapy. The aim of the study was to investigate the association between in vitro and in vivo GC sensitivity in RA. METHODS: Thirty-eight early and 37 established RA patients were prospectively studied. In vitro GC sensitivity was assessed with dexamethasone-induced effects on interleukin-2 (IL-2) and glucocorticoid-induced leucine zipper (GILZ) messenger RNA expression in peripheral blood mononuclear cells (PBMCs). A whole-cell dexamethasone-binding assay was used to measure number and affinity (1/KD) of glucocorticoid receptors (GRs). RESULTS: GR number was positively correlated with improvement in DAS. IL-2-EC50 and GILZ-EC50 values both had weak near-significant correlations with clinical improvement in DAS in intramuscularly treated patients only. HAQ responders had lower GILZ-EC50 values and higher GR number and KD. CONCLUSIONS: Baseline cellular in vitro glucocorticoid sensitivity is modestly associated with in vivo improvement in DAS and HAQ-DI score after GC bridging therapy in RA. Further studies are needed to evaluate whether in vitro GC sensitivity may support the development of tailor-made GC therapy in RA.