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Romy van der Groef,1 Pascal HP de Jong,1 Dirk Jan Hijnen,2 Christien J van der Woude,3 Jan AM van Laar,4 P Hugo M van der Kuy,5 Jan-Dietert Brugma,6 Annelieke Pasma1 1Department of Rheumatology, Erasmus University Medical Center, Rotterdam, the Netherlands; 2Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands; 3Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands; 4Department of Internal Medicine and Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; 5Department of Clinical Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands; 6Department of Outpatient Pharmacy, Erasmus University Medical Center, Rotterdam, the NetherlandsCorrespondence: Romy van der Groef, Erasmus University Medical Center, Department of Rheumatology, Room Na-523, PO Box 2040, 3000 CA, Rotterdam, the Netherlands, Tel +31 648284141, Email r.vandergroef@erasmusmc.nlPurpose: During the SARS-CoV-2 pandemic, national and international societies have recommended continuing biological agents in patients with immune-mediated inflammatory diseases (IMID) in the absence of SARS-CoV-2 symptoms. However, adherence to biological treatment might decrease, because these recommendations contradict patients’ beliefs. Especially an increased concern about side effects could have influenced the adherence to biological treatment during the first lockdown. The primary objective was to investigate the impact of the first SARS-CoV-2 lockdown on adherence to biological treatment in IMID patients.Patients and Methods: In this prospective cohort study, IMID patients who received a biological agent before and during the first SARS-CoV-2 lockdown (March 2020- June 2020) were included. Patients were excluded if they did not complete the medication adherence report scale-5 (MARS-5) questionnaire at ≥ 1 visit before the lockdown and ≥ 1 visit during the lockdown. Adherence to biological treatment was measured with the MARS-5 and Medication Possession Ratio (MPR).Results: We included 157 IMID patients. The percentage of adherent patients, defined as MARS-5 score > 21, was significantly lower during the lockdown compared to the period before the lockdown (88.5% vs 84.1%, p< 0.001). Additionally, the overall percentage of adherent patients during the lockdown based on the MPR ≥ 90% was significantly lower compared to adherence based upon the MARS-5 (65.1% vs 84.1%, p< 0.001).Conclusion: This study showed that the first SARS-CoV-2 lockdown negatively impacts adherence to biological treatment in IMID patients. Therefore, treating physicians should be aware of this problem to minimize the potential harmful effects of non-adherence.Keywords: adherence, biological, SARS-CoV-2, immune-mediated inflammatory diseases

Objectives: To investigate whether patients with rheumatoid arthritis (RA) can discontinue glucocorticoids (GC) after GC 'bridging' in the initial treatment step and to identify factors that may affect this., Methods: Data from 7 clinical trial arms (with 1653 patients) that included a GC bridging schedule, previously identified in a systematic literature search, were combined in an individual patient data meta-analysis. Outcomes were GC use (yes/no) at predefined time points (1/3/6/12/18 months after bridging had ended), cumulative GC dose and continuous (≥3 months) GC use after bridging had ended. Age, sex, ACPA status, initial GC dose, duration of bridging schedule, oral versus parenteral GC administration and initial co-treatment were univariably tested with each outcome., Results: The probability of using GC 1 month after bridging therapy had ended was 0.18, decreasing to 0.07 from 6 until 18 months after bridging had ended. The probability of continuous GC use after bridging had ended was 0.18 at 1 year and 0.30 at 2 years of follow-up. In oral GC bridging studies only, the probabilities of later and continuous GC use and the cumulative GC doses were higher compared to the combined analyses with also parenteral GC bridging studies included. A higher initial dose and a longer GC bridging schedule were associated with higher cumulative GC doses and more patients on GC at 18 months after bridging had ended., Conclusions: Based on these RA clinical trial arms with an initial GC bridging schedule, the probability of subsequent ongoing GC use following bridging is low., Competing Interests: Competing interests: LvO, MB, PHPdJ, RBML, JSS and TWJH declare no competing interests. PV: holds the Pfizer Chair Early Rheumatoid Arthritis Management at KU Leuven and received consultancy and/or speaker honoraria from AbbVie, Celltrion, Eli Lilly, Galapagos, Gilead, Nordic Pharma, Roularta and Sidekick Health within the last 24 months. SAB: received an ASPIRE grant from Pfizer. CFA: received study grants for BeSt and IMPROVED from Centocor (now Janssen) and AbbVie, respectively. PE: provided expert advice to AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Janssen, MSD, Lilly, Novartis, Pfizer, Roche, Samsung. And clinical trials: AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, Samsung. WL received study grants from Pfizer, and consultancy speaker fees from Eli Lilly, Pfizer, Amgen, Galapagos and UCB., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fertility is impaired in women with rheumatoid arthritis (RA), whereas less is known about male fertility problems. Pregnancy outcome in patients with RA is slightly less favorable compared with the general population, especially in patients with active disease. Disease activity usually improves during pregnancy, but less than previously thought. Although several antirheumatic drugs are contraindicated in pregnancy, more treatment options are available. There is evidence on the safety of TNF inhibitors in pregnancy. Given the impact of active disease on fertility and pregnancy outcome, a treat-to-target strategy is recommended for patients who are pregnant or have a wish to conceive., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate direct and indirect costs per quality adjusted life year (QALY) for different initial treatment strategies in very early RA., Methods: The 1-year data of the treatment in the Rotterdam Early Arthritis Cohort trial were used. Patients with a high probability (>70%) according to their likelihood of progressing to persistent arthritis, based on the prediction model of Visser, were randomized into one of following initial treatment strategies: (A) initial triple DMARD therapy (iTDT) with glucocorticoids (GCs) intramuscular (n = 91); (B) iTDT with an oral GC tapering scheme (n = 93); and (C) initial MTX monotherapy (iMM) with GCs similar to B (n = 97). Data on QALYs, measured with the Dutch EuroQol, and direct and indirect cost were used. Direct costs are costs of treatment and medical consumption, whereas indirect costs are costs due to loss of productivity., Results: Average QALYs (sd) for A, B and C were, respectively, 0.75 (0.12), 0.75 (0.10) and 0.73 (0.13) for Dutch EuroQol. Highest total costs per QALY (sd) were, respectively, €12748 (€18767), €10 380 (€15 608) and €17 408 (€21 828) for strategy A, B and C (P = 0.012, B vs C). Direct as well as indirect costs were higher with iMM (strategy C) compared with iTDT (strategy B). Higher direct costs were due to ∼40% more biologic usage over time. Higher indirect costs, on the other hand, were caused by more long-term sickness and reduction in contract hours. iTDT was >95% cost-effective across all willingness-to-pay thresholds compared with iMM., Conclusion: iTDT was more cost-effective and had better worker productivity compared with iMM., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: With early and intensive treatment many patients with early RA attain remission. Aims were to investigate (1) the frequency and time to sustained remission and subsequent tapering in patients initially treated with conventional synthetic disease modifying anti-rheumatic drug ((cs)DMARD) strategies and (2) the frequency and time to flare and regained remission in patients tapering csDMARDs and biological (b)DMARDs during 2 years of follow-up., Methods: Two-year follow-up data from the treatment in the Rotterdam Early Arthritis Cohort (tREACH) cohort were used. Patients were randomised to initial treatment with triple DMARD therapy (iTDT) with glucocorticoid (GC) bridging or methotrexate monotherapy (iMM) with GC bridging. Patients were evaluated every 3 months. In case Disease Activity Score (DAS) was >2.4 treatment was switched to a TNF-blocker. In case DAS<1.6 at 2 consecutive time points, tapering was initiated according to protocol. Outcomes were rates of sustained remission (DAS<1.6 at 2 consecutive time points), flare (medication increase after tapering) and remission after flare (DAS<1.6). Data were analysed using Kaplan-Meier analyses., Results: During 2 years of follow-up, sustained remission was achieved at least once by 159 (57%) of patients, of whom 118 and 23 patients initiated tapering of csDMARDs and bDMARDs, respectively. Thirty-four patients achieved drug-free remission. Flare rates were 41% and 37% and within 1 year, respectively. After flare, 65% of patients tapering csDMARDs re-achieved remission within 6 months after treatment intensification., Conclusions: Regardless of initial treatment strategy, 57% of patients achieved sustained remission during 2 years of follow-up. Flare rates were 41% and 37% within 12 months in patients tapering csDMARDs and bDMARDs, respectively., Trial Registration Number: ISRCTN26791028; Post-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Introduction: Patients with rheumatoid arthritis (RA) can be separated into two major subpopulations based on the absence or presence of serum anti-citrullinated protein antibodies (ACPAs). The more severe disease course in ACPA(+) RA and differences in treatment outcome between these subpopulations suggest that ACPA(+) and ACPA(-) RA are different disease subsets. The identification of T-helper (Th) cells specifically recognizing citrullinated peptides, combined with the strong association between HLA-DRB1 and ACPA positivity, point toward a pathogenic role of Th cells in ACPA(+) RA. In this context we recently identified a potential pathogenic role for CCR6(+) Th cells in RA. Therefore, we examined whether Th cell population distributions differ by ACPA status., Methods: We performed a nested matched case-control study including 27 ACPA(+) and 27 ACPA(-) treatment-naive early RA patients matched for disease activity score in 44 joints, presence of rheumatoid factor, sex, age, duration of complaints and presence of erosions. CD4(+)CD45RO(+) (memory) Th cell distribution profiles from these patients were generated based on differential chemokine receptor expression and related with disease duration., Results: ACPA status was not related to differences in total CD4(+) T cell or memory Th cell proportions. However, ACPA(+) patients had significantly higher proportions of Th cells expressing the chemokine receptors CCR6 and CXCR3. Similar proportions of CCR4(+) and CCR10(+) Th cells were found. Within the CCR6(+) cell population, four Th subpopulations were distinguished based on differential chemokine receptor expression: Th17 (CCR4(+)CCR10(-)), Th17.1 (CXCR3(+)), Th22 (CCR4(+)CCR10(+)) and CCR4/CXCR3 double-positive (DP) cells. In particular, higher proportions of Th22 (p = 0.02), Th17.1 (p = 0.03) and CCR4/CXCR3 DP (p = 0.01) cells were present in ACPA(+) patients. In contrast, ACPA status was not associated with differences in Th1 (CCR6(-)CXCR3(+); p = 0.90), Th2 (CCR6(-)CCR4(+); p = 0.27) and T-regulatory (CD25(hi)FOXP3(+); p = 0.06) cell proportions. Interestingly, CCR6(+) Th cells were inversely correlated with disease duration in ACPA(-) patients (R(2) = -0.35; p < 0.01) but not in ACPA(+) (R(2) < 0.01; p = 0.94) patients., Conclusions: These findings demonstrate that increased peripheral blood CCR6(+) Th cells proportions distinguish ACPA(+) RA from ACPA(-) RA. This suggests that CCR6(+) Th cells are involved in the differences in disease severity and treatment outcome between ACPA(+) and ACPA(-) RA.

Objective: To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events., Methods: We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1-5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication., Results: In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=-0.005), MTX-PG2 (ß=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (ß=-0.004) were associated (p<0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (ß=-0.015), MTX-PG3 (ß=-0.010), MTX-PG4 (ß=-0.008) and total MTX-PG (ß=-0.003) were associated with lower DAS28 over 9 months. None of the MTX-PGs was associated with adverse events., Conclusions: In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA1c ) levels in rheumatoid arthritis (RA) patients., Methods: The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease-modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu1-5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA1c were compared by paired t-test. Associations of MTXGlu concentrations with changes in the level of HbA1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort., Results: In the derivation cohort, the mean change in HbA1c level after 3 months of treatment was -1.9 mmoles/mole (-0.18%) (P = 0.001). Levels of HbA1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, -5.5 mmoles/mole (-0.50%) (P < 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, -3.7 mmoles/mole (-0.34%) (P < 0.001), for the MTX treatment arm, -0.8 mmoles/mole (-0.08%) (P = 0.018), and for the HCQ treatment arm, -2.0 mmoles/mole (-0.19%) (P = 0.175). Increased levels of MTXGlu2 (β = -0.20, P = 0.005), MTXGlu3 (β = -0.31, P < 0.001), MTXGlu4 (β = -0.33, P < 0.001) after treatment, MTXGlu5 (β = -0.39, P < 0.001), and total MTXGlu (β = -0.29, P < 0.001) were associated with decreased levels of HBA1c . In the validation cohort, levels of HbA1c were decreased by 2.6 mmoles/mole (0.23%) (P < 0.001) after treatment, and MTXGlu3 was associated with decreased levels of HbA1c (β = -0.26, P = 0.018)., Conclusion: MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA1c levels, and glucocorticoid treatment resulted in increased levels of HbA1c ., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: To compare 1-year clinical efficacy of (1) initial triple disease-modifying antirheumatic drug therapy (iTDT) with initial methotrexate (MTX) monotherapy (iMM) and (2) different glucocorticoid (GC) bridging therapies: oral versus a single intramuscular injection in early rheumatoid arthritis., Methods: In a single-blinded randomised clinical trial patients were randomised into three arms: (A) iTDT (methotrexate+sulfasalazine+hydroxychloroquine) with GCs intramuscularly; (B) iTDT with an oral GC tapering scheme and (C) MTX with oral GCs similar to B. Primary outcomes were (1) area under the curve (AUC) of Health Assessment Questionnaire (HAQ) and Disease Activity Score (DAS) and (2) the proportion of patients with radiographic progression., Results: 281 patients were randomly assigned to arms A (n=91), B (n=93) or C (n=97). The AUC DAS and HAQ were respectively -2.39 (95% CI -4.77 to -0.00) and -1.67 (95% CI -3.35 to 0.02) lower in patients receiving iTDT than in those receiving iMM. After 3 months, treatment failure occurred less often in the iTDT group, resulting in 40% fewer treatment intensifications. The difference in treatment intensifications between the arms required to maintain the predefined treatment goal remained over time. No differences were seen between the two GC bridging therapies. Respectively 21%, 24% and 23% of patients in arms A, B and C had radiographic progression after 1 year. Patients receiving iTDT had more adjustments of their medication owing to adverse events than those receiving iMM., Conclusions: Treatment goals are attained more quickly and maintained with fewer treatment intensifications with iTDT than with iMM. However, no difference in radiographic progression is seen. Both GC bridging therapies are equally effective and, therefore, both can be used., Trial Registration Number: ISRCTN26791028., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX)., Methods: A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype., Results: In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (β = -0.15, P = 0.037) and the validation cohort (β = -0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events., Conclusion: A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months., (Copyright © 2013 by the American College of Rheumatology.)

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.

Objective: To optimize use of the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA) by adding the "squeeze test" of forefeet., Methods: The squeeze test is used to examine bilateral compression pain (BCP) across the metatarsophalangeal (MTP) joints. For this study, data for patients participating in the Treatment in the Rotterdam Early Arthritis Cohort study, an ongoing clinical trial that evaluates different induction therapies in patients with early RA, were randomly divided into 2 subsets. In subset 1 (149 patients and 819 disease activity assessments), the mathematical function of the DAS28-squeeze was constructed using a linear regression model with the DAS as the dependent variable and the DAS28 and squeeze test as the independent variables. A DAS28-BCP disease state was also constructed, in which DAS28 disease state categorizations were upgraded one state if the result of the squeeze test was positive. In subset 2 (153 patients and 754 assessments), concordance in disease states between the DAS28, DAS28-squeeze, and DAS28-BCP disease states was compared, using both the DAS and Boolean-defined remission criteria as reference., Results: Agreement between the DAS and the DAS28-squeeze (82%) was significantly higher than agreement between the DAS and the DAS28 (76%). When we assessed the group of patients who had arthritis of the forefeet only (22 patients and 46 assessments), overall agreement between the DAS and the DAS28 was 40%, while agreement between the DAS and the DAS28-squeeze was 59% and that between the DAS and the DAS28-BCP disease state was 65%. Furthermore, the specificities of the DAS28-squeeze and the DAS28-BCP (80% and 81%, respectively) were higher than that of the DAS28 (76%), while the sensitivities of the DAS28, DAS28-squeeze, and DAS28-BCP to identify true remission according to the Boolean criteria were 88%, 87%, and 81%, respectively., Conclusion: Adding the squeeze test of forefeet to the DAS28 has value for dependably classifying the disease state in patients with early RA., (Copyright © 2012 by the American College of Rheumatology.)

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.

Objective: To evaluate the therapeutic and economic consequences of various disease activity indices (DAIs) in RA according to 1987 and 2010 criteria., Methods: Data on disease activity states from all sustained visits were assessed from all patients who participate in the treatment in the Rotterdam Early Arthritis Cohort (tREACH) study, a stratified randomized trial to evaluate different treatment strategies in patients with a symptom duration of <1 year. Frequencies of treatment adaptations, based upon exclusive thresholds of various DAIs, were visualized in reclassification tables. The Stuart-Maxwell test was applied to analyse any significant differences between treatment decisions according to the different DAIs. Simulated annual median medication costs were estimated using the tREACH medication protocol with standard national costs., Results: DAIs perform similar in RA according to 1987 and 2010 criteria. A total of 1104 DASs per DAI were available from 296 patients. DAIs differ significantly, compared with DASs, in classifying a patient's disease state. Consequently, treatment intensifications occur more frequently with SDAI, CDAI and DAS-28 usage, compared with DAS. Tapering treatment occurs less frequently with SDAI and CDAI and more frequently with DAS-28 usage. Simulated annual median medication costs are significantly higher if DAS-28, SDAI and CDAI are used compared with DAS usage., Conclusion: Usage of various DAIs in a single patient leads to inconsistent disease state categorizations. Consequently, these inconsistencies significantly influence therapeutic decisions and accompanying costs. As DAI usage is imperative to uphold current European League Against Rheumatology (EULAR) treatment recommendations, physicians should consider these therapeutic and economic consequences before choosing a particular DAI.

Recently we reported that reacetylation of N,N,N-trimethyl chitosan (TMC) reduced the adjuvant effect of TMC in mice after intranasal (i.n.) administration of whole inactivated influenza virus (WIV) vaccine. The aim of the present study was to elucidate the mechanism of this lack of adjuvanticity. Reacetylated TMC (TMC-RA, degree of acetylation 54%) was compared with TMC (degree of acetylation 17%) at six potentially critical steps in the induction of an immune response after i.n. administration in mice. TMC-RA was degraded in a nasal wash to a slightly larger extent than TMC. The local i.n. distribution and nasal clearance of WIV were similar for both TMC types. Fluorescently labeled WIV was taken up more efficiently by Calu-3 cells when formulated with TMC-RA compared to TMC and both TMCs significantly reduced transport of WIV over a Calu-3 monolayer. Murine bone-marrow derived dendritic cell activation was similar for plain WIV, and WIV formulated with TMC-RA or TMC. The inferior adjuvant effect in mice of TMC-RA over that of TMC might be caused by a slightly lower stability of TMC-RA-WIV in the nasal cavity, rather than by any of the other factors studied in this paper., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this study was to assess the influence of structural properties of N,N,N-trimethyl chitosan (TMC) on its adjuvanticity. Therefore, TMCs with varying degrees of quaternization (DQ, 22-86%), O-methylation (DOM, 0-76%) and acetylation (DAc 9-54%) were formulated with whole inactivated influenza virus (WIV). The formulations were characterized physicochemically and evaluated for their immunogenicity in an intranasal (i.n.) vaccination/challenge study in mice. Simple mixing of the TMCs with WIV at a 1:1 (w/w) ratio resulted in comparable positively charged nanoparticles, indicating coating of WIV with TMC. The amount of free TMC in solution was comparable for all TMC-WIV formulations. After i.n. immunization of mice with WIV and TMC-WIV on days 0 and 21, all TMC-WIV formulations induced stronger total IgG, IgG1 and IgG2a/c responses than WIV alone, except WIV formulated with reacetylated TMC with a DAc of 54% and a DQ of 44% (TMC-RA44). No significant differences in antibody titers were observed for TMCs that varied in DQ or DOM, indicating that these structural characteristics play a minor role in their adjuvant properties. TMC with a DQ of 56% (TMC56) formulated with WIV at a ratio of 5:1 (w/w) resulted in significantly lower IgG2a/c:IgG1 ratios compared to TMC56 mixed in ratios of 0.2:1 and 1:1, implying a shift towards a Th2 type immune response. Challenge of vaccinated mice with aerosolized virus demonstrated protection for all TMC-WIV formulations with the exception of TMC-RA44-WIV. In conclusion, formulating WIV with TMCs strongly enhances the immunogenicity and induces protection against viral challenge in mice after i.n. vaccination. The adjuvant properties of TMCs as i.n. adjuvant are strongly decreased by reacetylation of TMC, whereas the DQ and DOM hardly affect the adjuvanticity of TMC.

Severe hyponatraemia was observed in a 35-year-old man with progressive malaise; this was caused by hypopituitarism and secondary hypocortisolism as a result ofneurosarcoidosis. Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology which can develop in any of the body's organs or tissues. The central nervous system is affected in only 5-15% of patients with sarcoidosis. Neurosarcoidosis is a rare disorder with clinical heterogeneity. Extensive diagnostic procedures, including MRI of the cerebrum and histological investigation, and structural outpatient follow-up are mandatory in patients in whom neurosarcoidosis is suspected. Treatment consists mainly of high-dose corticosteroids, which usually have to be taken long-term. Clinical course and prognosis are variable, and depend on the accompanying symptoms.

Docetaxel (DCTX) and paclitaxel (PTX) are very potent anti-cancer drugs, but the currently marketed formulations, Taxotere and Taxol, respectively, are associated with vehicle-related toxicity. An attractive alternative to formulate these hydrophobic cytotoxic agents are polymeric micelles. In this study, the loading of taxanes into oligomeric micelles composed of mPEG750-b-oligo(epsilon-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group was investigated. Next, the release characteristics and cytotoxicity of the loaded micelles were studied. MPEG750-b-OCL5 -OH micelles loaded with taxanes formed unstable particles with rapid leakage of the drug. In contrast, the presence of an aromatic end group (Bz or Np) resulted in the formation of small (10nm), almost monodisperse micelles with stable encapsulation of 10% (w/w) of PTX or DCTX. This was ascribed to a better compatibility between the micellar core and the drug as compared to the oligomers with the hydroxyl end group. 1H NMR studies showed that the micellar core was liquid, and that PTX was molecularly dissolved in the core. The in vitro stability was studied in PBS at 37 degrees C, which showed that leakage of PTX from 10% and 5% (w/w) loaded mPEG750-b-OCL5-Bz micelles started after 8 and 24h, respectively. The presence of albumin did not affect the stability, suggesting that the micelles are not destabilised and the drug was not extracted from the micellar core by this protein. The in vitro cytotoxic effect of the taxane-loaded micelles on C26 carcinoma cells was comparable to that of the commercial formulations, but the empty micelles were far less toxic than the Cremophor EL vehicle. The results show that mPEG-b-oligo(epsilon-caprolactone) micelles hold good promise for the formulation of taxanes.

Objective: To determine the influence of NSAIDs on the international normalized ratio (INR) in patients with cytochrome P450 (CYP)-2C9 enzyme variants starting acenocoumarol (an oral coumarin) therapy during the first 7 days after total hip replacement surgery., Methods: In this prospective study, an age-dependent protocol was used for the initiation of the acenocoumarol dose. Low-molecular-weight heparin was given for 5 days. The study included 100 patients undergoing total hip replacement surgery. After the inclusion of the last patient, polymerase chain reaction CYP2C9 mutation testing was performed for all patients. Drug-use evaluation of NSAIDs and other potential coumarin-drug interactions was also performed., Results: Eleven patients had an INR on 1 or more days >4.9. There were 52 patients who were using NSAIDs. Patients with a CYP2C9 mutation had a mean INR curve similar to patients without the mutation when NSAIDs were not coadministered. Within the group of patients heterozygous for a CYP2C9 mutation (n=30) only concomitant use of a NSAID resulted in an INR >4.9 (0% vs 38.9%, p<0.05)., Conclusion: In the group of patients with a CYP2C9 variant (*2 or *3 alleles), only concomitant use of a NSAID resulted in INRs >4.9. The cost effectiveness of CYP2C9 screening before elective surgery has yet to be determined.

Objective: To describe the use of contraceptives among women aged 10-59, particularly in relation to the type of oral contraceptives (OCs) among starting users and women already using OCs., Design: Descriptive., Method: Data on the use of medication in the period 1994-2002 by women in the age range 10-59 years were selected from the Interaction Database of North and East Netherlands. The study population was 33,795 women in 1994 and 102,894 in 2002. Cross-sectional studies were performed of prevalent and incident OC users per year and the contribution of the various types of OC was measured., Results: The use of contraceptives among women aged 10-59 years has remained fairly constant since 1994, being about 33%. However, Dutch women started using OCs at an increasingly younger age: 47% of the 15-19-year-olds in 2002 compared with 35% in 1994. The use of third-generation OCs among young starting OC-users (10-19 years of age) in 2002 was very low (3.5% of all OCs). Among women who already used OCs, the switch from third- to second-generation OCs was less pronounced. In 2002, 23% of all OC-users used third-generation preparations compared with 46.5% in 1994. The proportion using cyproteron-ethinylestradiol increased slightly over the years., Conclusion: After 1994, mainly second-generation OCs have been prescribed. The switch from third- to second-generation OCs was especially marked among the young starting users. The use of cyproteron-ethinylestradiol increased slightly during the years.