Subcutaneous administration, higher age and lower renal function are associated with erythrocyte methotrexate accumulation in Crohn's disease: a cross-sectional study

Background: Methotrexate is an immunomodulatory drug for patients with Crohn’s disease. Erythrocyte MTX-polyglutamates (MTX-PG1-5) may be used for therapeutic drug monitoring (TDM) as MTX-PG is thought to mediate MTX’s efficacy. Information on determinants of the concentration of MTX-PG in patients with Crohn’s disease is lacking. We aim to identify clinical and biochemical determinants of the erythrocyte MTX-PG1-5 and MTX-PGtotal concentration in patients with Crohn’s disease. Methods: Adults with Crohn’s disease on methotrexate treatment who visited the outpatient clinic of Amsterdam UMC were included. Erythrocyte MTX-PGs were measured by tandem mass spectrometry. Results: Nineteen patients were included, with a median duration of MTX use of 77 months (range 7–202). Twelve patients received MTX monotherapy, whereas 7 patients were on concomitant TNF-α inhibitors. The mean dose of MTX was 15.5 mg (SD ± 2.8) and 12 (63%) patients used subcutaneous MTX. MTX-PG1-5 were successfully measured in 18 patients, showing substantial variability in concentrations of MTX-PGtotal and individual species. The median MTX-PGtotal was 117.1 nmol/L (range 46.4–258.7) with preferential accumulation of MTX-PG3 (43.1 nmol/L, range 15.3–96.1). Patients on subcutaneous compared to oral MTX had higher median MTX-PG(4,5) levels (55 versus 9 nmol/L, p = 0.01). Higher age (β = 0.71) and lower estimated glomerular filtration rate (β = − 0.52) were associated with a significantly higher MTX-PGtotal concentration (R2 = 0.60, p = 0.001). Conclusion: MTX-PG concentrations display a considerable inter-individual variability. Higher MTX-PG accumulation is associated with subcutaneous administration, higher age, and lower renal function in Crohn’s disease patients

Cumulative exposure to immunomodulators increases risk of cervical neoplasia in women with inflammatory bowel disease

BACKGROUND: Women with inflammatory bowel disease (IBD) are at increased risk of high-grade cervical intraepithelial neoplasia and cervical cancer (CIN2+). AIM: To assess the association between cumulative exposure to immunomodulators (IM) and biologic agents (BIO) for IBD and CIN2+ METHODS: Adult women diagnosed with IBD before December 31st 2016 in the Dutch IBD biobank with available cervical records in the nationwide cytopathology database were identified. CIN2+ incidence rates in IM- (i.e., thiopurines, methotrexate, tacrolimus and cyclosporine) and BIO- (anti-tumour necrosis factor, vedolizumab and ustekinumab) exposed patients were compared to unexposed patients and risk factors were assessed. Cumulative exposure to immunosuppressive drugs was evaluated in extended time-dependent Cox-regression models. RESULTS: The study cohort comprised 1981 women with IBD: 99 (5%) developed CIN2+ during median follow-up of 17.2 years [IQR 14.6]. In total, 1305 (66%) women were exposed to immunosuppressive drugs (IM 58%, BIO 40%, IM and BIO 33%). CIN2+ risk increased per year of exposure to IM (HR 1.16, 95% CI 1.08-1.25). No association was observed between cumulative exposure to BIO or both BIO and IM and CIN2+. In multivariate analysis, smoking (HR 2.73, 95%CI 1.77-4.37) and 5-yearly screening frequency (HR 1.74, 95% CI 1.33-2.27) were also risk factors for CIN2+ detection. CONCLUSION: Cumulative exposure to IM is associated with increased risk of CIN2+ in women with IBD. In addition to active counselling of women with IBD to participate in cervical screening programs, further assessment of the benefit of intensified screening of women with IBD on long-term IM exposure is warranted

A Prediction Model for Successful Increase of Adalimumab Dose Intervals in Patients with Crohn's Disease: Secondary Analysis of the Pragmatic Open-Label Randomised Controlled Non-inferiority LADI Trial

BACKGROUND: In the pragmatic open-label randomised controlled non-inferiority LADI trial we showed that increasing adalimumab (ADA) dose intervals was non-inferior to conventional dosing for persistent flares in patients with Crohn's disease (CD) in clinical and biochemical remission. AIMS: To develop a prediction model to identify patients who can successfully increase their ADA dose interval based on secondary analysis of trial data. METHODS: Patients in the intervention group of the LADI trial increased ADA intervals to 3 and then to 4 weeks. The dose interval increase was defined as successful when patients had no persistent flare (> 8 weeks), no intervention-related severe adverse events, no rescue medication use during the study, and were on an increased dose interval while in clinical and biochemical remission at week 48. Prediction models were based on logistic regression with relaxed LASSO. Models were internally validated using bootstrap optimism correction. RESULTS: We included 109 patients, of which 60.6% successfully increased their dose interval. Patients that were active smokers (odds ratio [OR] 0.90), had previous CD-related intra-abdominal surgeries (OR 0.85), proximal small bowel disease (OR 0.92), an increased Harvey-Bradshaw Index (OR 0.99) or increased faecal calprotectin (OR 0.997) were less likely to successfully increase their dose interval. The model had fair discriminative ability (AUC = 0.63) and net benefit analysis showed that the model could be used to select patients who could increase their dose interval. CONCLUSION: The final prediction model seems promising to select patients who could successfully increase their ADA dose interval. The model should be validated externally before it may be applied in clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377

Cost-effectiveness analysis of increased adalimumab dose intervals in Crohn's disease patients in stable remission: The Randomized Controlled LADI Trial

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377

Complete Endoscopic Healing Is Associated With Lower Relapse Risk After Anti-TNF Withdrawal in Inflammatory Bowel Disease

BACKGROUND & AIMS: Discontinuation of anti-tumor necrosis factor-α treatment (anti-TNF) (infliximab and adalimumab) in patients with inflammatory bowel disease (IBD) is associated with a high relapse risk that may be influenced by endoscopic activity at the time of stopping. We assessed the relapse rate after anti-TNF withdrawal in patients with endoscopic healing and studied predictors of relapse including the depth of endoscopic healing. METHODS: This was a multicenter, prospective study in adult patients with Crohn's disease (CD), ulcerative colitis (UC), or IBD-unclassified (IBDU), with ≥6 months of corticosteroid-free clinical remission (confirmed at baseline) and endoscopic healing (Mayo <2/SES-CD <5 without large ulcers), who discontinued anti-TNF between 2018 and 2020 in the Netherlands. We performed Kaplan-Meier and Cox regression analyses to assess the relapse rate and evaluate potential predictors: partial (Mayo 1/SES-CD 3-4) versus complete (Mayo 0/SES-CD 0-2) endoscopic healing, anti-TNF trough levels, and immunomodulator and/or mesalamine use. RESULTS: Among 81 patients (CD: n = 41, 51%) with a median follow-up of 2.0 years (interquartile range, 1.6-2.1), 40 patients (49%) relapsed. Relapse rates in CD and UC/IBDU patients were comparable. At 12 months, 70% versus 35% of patients with partial versus complete endoscopic healing relapsed, respectively (adjusted hazard rate [aHR], 3.28; 95% confidence interval [CI], 1.43-7.50). Mesalamine use was associated with fewer relapses in UC/IBDU patients (aHR, 0.08; 95% CI, 0.01-0.67). Thirty patients restarted anti-TNF, and clinical remission was regained in 73% at 3 months. CONCLUSIONS: The relapse risk was high after anti-TNF withdrawal in IBD patients with endoscopic healing, but remission was regained in most cases after anti-TNF reintroduction. Complete endoscopic healing and mesalamine treatment in UC/IBDU patients decreased the risk of relapse

Effect of amylose:amylopectin ratio and rice bran addition on starchfilms properties

The influence of the amylose:amylopectin ratio on the properties of pea, potato and cassava starch films and the effect of the incorporation of rice bran of two different particle sizes were studied. The structural, mechanical, optical and barrier properties of the films were analyzed after 1 and 5 weeks. The high content of amylose gave rise to stiffer, more resistant to fracture, but less stretchable films, with lower oxygen permeability and greater water binding capacity. Although no changes in the water vapour permeability values of the films were observed during storage, their oxygen permeability decreased. Throughout storage, films became stiffer, more resistant to break, but less stretchable. Rice bran with the smallest particles improved the elastic modulus of the films, especially in high amylose content films, but reduced the film stretchability and its barrier properties, due to the enhancement of the water binding capacity and the introduction of discontinuities.The authors acknowledge the financial support from the Spanish Ministerio de Economia y Competitividad throughout the project AGL2010-20694, co-financed with FEDER founds. Amalia Cano also thanks Spanish Ministerio de Educacion, Cultura y Deporte for the FPU grant.Cano Embuena, AI.; Jiménez Marco, A.; Cháfer Nácher, MT.; González Martínez, MC.; Chiralt Boix, MA. (2014). Effect of amylose:amylopectin ratio and rice bran addition on starchfilms properties. Carbohydrate Polymers. 111:543-555. https://doi.org/10.1016/j.carbpol.2014.04.075S54355511

Non-consensual sterilization of women living with HIV

Women living with HIV are stigmatized and discriminated against. They often wish to have children, but they are subjected to the practice of forced (involuntary) sterilization in at least 27 countries under the guise of protecting maternal health and preventing the birth of infected infants. Some women are not asked to give consent, or a third party consents on their behalf. Others are given insufficient information or fed misinformation. The circumstances under which such women have been asked to sign consent forms for sterilization include fear, coercion, intimidation and undue influence. Courts have been clear that such practice is a breach of human rights. But, so far, it has not been formally declared in courts that such practice constitutes discrimination. More needs to be done in terms of education, sanctions against those who carry out this practice and help for victims

Fish consumption and its motives in households with versus without self-reported medical history of CVD: A consumer survey from five European countries

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to explore the cross-cultural differences in the frequency of fish intake and in motivations for fish consumption between people from households with (CVD+) or without (CVD-) medical history of cardiovascular disease, using data obtained in five European countries.</p> <p>Methods</p> <p>A cross-sectional consumer survey was carried out in November-December 2004 with representative household samples from Belgium, the Netherlands, Denmark, Poland and Spain. The sample consisted of 4,786 respondents, aged 18–84 and who were responsible for food purchasing and cooking in the household.</p> <p>Results</p> <p>Individuals from households in the CVD+ group consumed fish more frequently in Belgium and in Denmark as compared to those in the CVD- group. The consumption of fatty fish, which is the main sources of omega-3 PUFA associated with prevention of cardiovascular diseases, was on the same level for the two CVD groups in the majority of the countries, except in Belgium where CVD+ subjects reported to eat fatty fish significantly more frequently than CVD- subjects. All respondents perceived fish as a very healthy and nutritious food product. Only Danish consumers reported a higher subjective and objective knowledge related to nutrition issues about fish. In the other countries, objective knowledge about fish was on a low level, similar for CVD+ as for CVD- subjects, despite a higher claimed use of medical information sources about fish among CVD+ subjects.</p> <p>Conclusion</p> <p>Although a number of differences between CVD- and CVD+ subjects with respect to their frequency of fish intake are uncovered, the findings suggest that fish consumption traditions and habits – rather than a medical history of CVD – account for large differences between the countries, particularly in fatty fish consumption. This study exemplifies the need for nutrition education and more effective communication about fish, not only to the people facing chronic diseases, but also to the broader public. European consumers are convinced that eating fish is healthy, but particular emphasis should be made on communicating benefits especially from fatty fish consumption.</p