Lieke Scheepers - Academia.edu (original) (raw)

Papers by Lieke Scheepers

ERJ Open Research, 2020

BackgroundCompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with ... more BackgroundCompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with asthma-worsening events, was recently developed. Further characterisation of CompEx Asthma is needed to illustrate the applicability of this end-point. The objective was to evaluate CompEx Asthma as a rate end-point to determine how seasonal and geographical factors impact this novel outcome.MethodsSeven 24–56-week randomised controlled trials of budesonide/formoterol (BUD/FORM) and benralizumab were analysed. Annualised event rates (AERs) and treatment effects (hazard ratio (HR)) were analysed with Poisson and Andersen–Gill models, respectively. Seasonality was analysed by month and five geographical regions were evaluated.ResultsThe studies included 10 815 patients (63% female, mean age 42–49 years). CompEx Asthma AER mirrored seasonal variations in SevEx AER. CompEx Asthma AERs were higherversusSevEx in BUD/FORM and benralizumab trials (range 2.7–4.5-fold and 1.3–2.0-fold increase, re...

Respiratory Medicine, 2020

BACKGROUND Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations i... more BACKGROUND Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients. METHODS In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations. FINDINGS At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size. INTERPRETATION COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.

D101. CLINICAL AND TRANSLATIONAL STUDIES IN ASTHMA AND COPD, 2019

Alzheimer's & Dementia, 2019

Introduction: Low serum urate (sU) has been suggested to increase the risk of dementia since a re... more Introduction: Low serum urate (sU) has been suggested to increase the risk of dementia since a reduction might impair antioxidant capacity. On the other hand, high sU is associated with increased cardiovascular risk which might increase the risk of dementia, especially for vascular dementia. Methods: In 1968-1969, a population-based sample of 1462 women aged 38 to 60 years was examined and were followed up over 44 years (mean 33.1 years). We examined whether sU (determined in 1968-1969 and 1992-1994) is associated with risk of late-life dementia. Results: During 44 years of follow-up, a higher sU (per standard deviation of 76.5 mmol/L) was associated with lower risk for dementia (n 5 320; hazard ratio [HR] 0.81; confidence interval [CI] 0.72-0.91), Alzheimer's disease (n 5 152; HR 0.78; CI 0.66-0.91), and vascular dementia (n 5 52; HR 0.66; CI 0.47-0.94). Discussion: Our findings support the hypothesis that sU has a protective role in the development of dementia, regardless of dementia subtype. This may have important implications in the treatment of dementia and treatment goals for hyperuricemia in patients with gout.

FRIDAY, 15 JUNE 2018, 2018

The study cohort included 192.037 patients with gout, 82.6% of those were males. There was a prog... more The study cohort included 192.037 patients with gout, 82.6% of those were males. There was a progressive increase in the number of hospitalised patients with gout from 12 851 patients in 2005 to 23 318 in 2015; this was associated with an increase in mortality, reaching its highest value in 2015 with a 4.9% of gout hospitalised patients. The average age at dead in 2015 was 79.2 years and 85.16 years in male and female respectively, an age slightly lower than in the general population. The average cost in these hospitalised patients was 4931 C ¼ , reaching a peak of 5384 C ¼ in the last year. The hospital stay reached its lowest numbers in 2015 with an average of 8.9 days per patient. These comorbidities had statistical association with an added mortality risk in cerebrovascular disease (odds ratio [OR] 1.57, 95% confidence interval [CI]1.46-1.49), liver disease (OR 2.61 95% CI 2.34-2.9), kidney disease (OR 1.34 95% CI 1.28-1.41), dementia (OR 2.13 95% CI 1.88-2.42). On the contrary, in type 2 diabetes (OR 0.92 95% CI 0.87-0.96), we found a statistically significant lower mortality risk. Furthermore, it was found a statistically reduced mortality risk in females (OR 0.85 95%

Rheumatology (Oxford, England), Jan 8, 2018

When urate lowering therapy is indicated in patients with gout, medication adherence is essential... more When urate lowering therapy is indicated in patients with gout, medication adherence is essential. This study assesses non-persistence and non-adherence in patients with newly diagnosed gout, and identifies factors associated with poor medication adherence. A retrospective data analysis was performed within the UK Clinical Practice Research Datalink (1987-2014) among incident gout patients, aged ⩾40 years and starting allopurinol (n = 48 280). The proportion of patients non-persistent (a first medication gap of ⩾90 days) after 1 and 5 years, and median time until a first 90-day gap was estimated using Kaplan-Meier statistics in those starting allopurinol and restarting after a first interruption. Non-adherence (proportion of days covered <80%) over the full observation period was calculated. Multivariable Cox- or logistic regressions assessed factors associated with non-persistence or non-adherence, respectively. Non-persistence increased from 38.5% (95% CI: 38.1, 38.9) to 56.9% ...

Seminars in arthritis and rheumatism, Jan 7, 2017

In the management of chronic gout, a large proportion of patients need long-term management with ... more In the management of chronic gout, a large proportion of patients need long-term management with urate lowering therapy (ULT). This study reviews medication adherence to ULT and summarizes factors associated with adherence. We performed a systematic literature search for studies on adherence to ULT among gout patients in PubMed, Embase, CINAHL, and PsycINFO. We conducted meta-analysis, with a random effect model, for the studies reporting the proportion of patients considered adherent to at least 80% of prescribed medication or time taken. We explored potential sources of heterogeneity, including geographic area and measure of adherence. Narrative summaries were made for data on adherence assessed/defined by Medication Event Monitoring System (MEMS)/pill-count or patient-reported, occurrence of a gap in therapy ≥30 days (non-persistence), and factors associated with adherence. Of the 24 studies, 16 assessed adherence using prescription/claims data, two by the MEMS or pill count, and...

Annals of the Rheumatic Diseases, 2016

up studies and prospective interventional studies are required to confirm this positive associati... more up studies and prospective interventional studies are required to confirm this positive association between SUA and lung function.

Annals of the Rheumatic Diseases, 2016

Characteristics of patients developing skin reactions with both allopurinol and febuxostat (5/24)... more Characteristics of patients developing skin reactions with both allopurinol and febuxostat (5/24) Gender Age Allopurinol start Febuxostat start Rash with Outcome with febuxostat benzbromarone Dosage GFR Dosage GFR (mg/d) (mL/min) (mg/d) (mL/min) Female 70 50 78 120 77.2 Nonspecific No rash Male 69 N/A 90 40 90.5 SJS No rash Female 68 100 52 80 80.3 Nonspecific No rash Male 45 50 90 80 90.9 Nonspecific No rash Female 41 300 40 5 40.9 Nonspecific No rash GFR: glomerular filtration rate; SSJ: Stevens-Johnson syndrome. developed skin reactions with febuxostat (see table): in four cases a nonspecific rash, but one suffered from a Stevens-Johnson syndrome. None of these patients presented skin reactions to benzbromarone. Conclusions: In our series, one out five patients with previous skin reaction to allopurinol also developed after febuxostat. Larger studies are needed to confirm these results, but this finding strengths caution when using febuxostat in this subgroup of patients. References: [1]

Annals of the Rheumatic Diseases, 2016

Background: One of the causes of insufficient response to biological drugs is the production of a... more Background: One of the causes of insufficient response to biological drugs is the production of anti-drug antibodies (ADA) (1). These antibodies can decrease the effectiveness of treatment by altering bioavailability or by neutralizing the drug. In addition, they may contribute to hypersensitivity reactions. Some ADA are directed against IgG allotypes, which are protein polymorphisms able to induce an immune response in incompatible subjects. Infliximab (INX) and adalimumab (ADM) have the G1m17,1 allotypes, while about 50% of the Europeans are homozygous for the incompatible G1m3,n allotypes. Therefore, the allotypes could contribute to ADA and, in this way, explain the recently described loss of efficiency of INX in allotype-incompatible RA patients (2). Objectives: We aimed to analyze the usefulness of IgG1 allotypes as biomarker of the development of ADA against INX and ADM. Methods: The presence of ADA was determined in 252 consecutive patients with inflammatory arthritis in the Hospital La Paz (116 with rheumatoid arthritis (RA), 74 with ankylosing spondylitis (AS), 26 with psoriatic arthritis, 17 with non-radiographic spondylitis, 11 with spondylitis and inflammatory bowel disease, 3 with uveitis and 5 with other arthropathies). Patients were assessed during INX treatment (151), or with ADM (82), or sequentially during treatment with INX and ADM (19). ADA were determined by two-site bridging ELISA as described (1). Allotypes of IgG1 were determined by genotyping 2 SNPs, rs1071803 (for allotype G1m17/G1m3) and rs11621259 (for allotype G1m1/null) with the SNaPshot Multiplex kit (Applied Biosystems) as reported (2). Results: Patients with compatible allotypes (carriers of G1m17,1) showed a larger frequency of ADA (33% vs. 20%, p=0.02) and a trend toward higher titers of these antibodies (18.0x10 3 vs. 8.3x10 3 AU, ns) than patients with incompatible allotypes (homozygous for G1m3,n). This association was clearer in patients treated with INX (41% vs. 25%, p=0.03) than in those treated with ADM (18% vs. 12%, ns). ADA were more frequent in patients treated with INX than in those treated with ADM, as already known. Multivariate analysis showed that the frequency of ADA was increased in patients with RA compared to other diseases (OR =7.6, p<0.0001), and decreased in older patients (OR =0.65 per 10 years, p<0.001). Other factors, such as sex, having AS against other diseases, and treatment with methotrexate or corticosteroids, were not associated with ADA. Conclusions: Patients with compatible allotypes showed more frequently ADA than patients with incompatible allotypes, showing for the first time this association in patients treated with INX and reinforcing the previously reported association for ADM (3). These results suggest a genetic factor in linkage with the allotype, but different from it, that will predispose to ADA.

Journal of hypertension, May 1, 2017

Elevated serum uric acid concentration has been associated with high blood pressure (BP) and hype... more Elevated serum uric acid concentration has been associated with high blood pressure (BP) and hypertension. A putative underlying mechanism is the accumulation of reactive oxygen species when uric acid is generated by an increased enzyme activity of xanthine oxidase (XO). The aims of the present study were to investigate the associations between plasma uric acid concentration, purine metabolite ratios, as proxies for increased XO activity, and SBP and DBP in school-age children. Cross-sectional analyses were performed in 246 children (46% boys; mean age 7.1 years) from the Dutch KOALA Birth Cohort Study. Purine metabolites were determined with ultra-performance liquid chromatography-tandem mass spectrometry. During a home visit, a nurse collected a blood sample and measured BP three times; in addition, parents measured their child's BP on three consecutive days, in the morning and evening. Generalized estimating equations were used for analyses while controlling for variables suc...

Journal of hypertension, Nov 6, 2016

The enzyme xanthine oxidoreductase (XOR) generates uric acid in the terminal steps of the purine ... more The enzyme xanthine oxidoreductase (XOR) generates uric acid in the terminal steps of the purine metabolism; meanwhile reactive oxygen species are formed. We hypothesized that uric acid production, as assessed indirectly from XOR variants, is associated with hypertension. Among 2769 participants (48.3% men; mean age 40.7 years) randomly recruited from European populations, we genotyped 25 tagging XOR SNPs and measured blood pressure (BP) at baseline and follow-up (median 8.8 years). The relation between variants of the XOR gene with changes in pulse pressure and mean arterial pressure over time; and incidence of hypertension, were analyzed. Compared with nonminor allele carriers, pulse pressure increased approximately 2 mmHg more in minor allele carriers of rs11904439 (P = 0.01), whereas mean arterial pressure and DBP increased approximately 1 mmHg less in minor allele carriers of rs2043013 (P = 0.01). In 2050, participants normotensive at baseline, hazard ratios contrasting risk of...

Clinical Rheumatology, 2016

The objective of the present study is to explore knowledge, illness perceptions and stated practi... more The objective of the present study is to explore knowledge, illness perceptions and stated practice behaviour in relation to gout in primary care. This is a mixed methods study among 32 general practitioners (GPs). The quantitative assessment included the Gout Knowledge Questionnaire (GKQ; range 0-10; better) and Brief Illness Perceptions Questionnaire (BIPQ; nine items, range 0-10; stronger). Structured individual interviews obtained further qualitative insight into knowledge and perceptions, in the context of daily practice. Among 32 GPs, 18 (56.3 %) were male, mean age 44.4 years (SD 9.6) and mean working experience 17.1 years (SD 9.7). Median score [interquartile ranges (IQR)] on the GKQ was 7.

International journal of obesity (2005), 2015

To investigate whether the intestinal microbiota composition in early infancy is associated with ... more To investigate whether the intestinal microbiota composition in early infancy is associated with subsequent weight development in children. Analyses were conducted within the KOALA Birth Cohort Study (n = 2834). This cohort originates from two recruitments groups: pregnant women with a conventional lifestyle (no selection based on lifestyle) and pregnant women recruited through alternative channels (organic shops, anthroposophic clinicians/midwives, Steiner schools and relevant magazines). From 909 one-month-old infants, fecal samples were collected and analyzed by quantitative PCR targeting bifidobacteria, Bacteroides fragilis group, Clostridium difficile, Escherichia coli, Lactobacilli and total bacteria counts. Between the ages of 1 and 10 years, parent-reported weight and height was collected at 7 time points. Age- and gender-standardized body mass index (BMI) z-scores were calculated. Data were analyzed using generalized estimating equation. Colonization with B. fragilis group ...

Glossary of terms related to genetics or medication adherence 7 Chapter 1 General introduction Pa... more Glossary of terms related to genetics or medication adherence 7 Chapter 1 General introduction Part I Uric acid and blood pressure: the role of uric acid production Chapter 2 Xanthine oxidase gene variants and their association with blood pressure and incident hypertension: a population study Chapter 3 Associations of plasma uric acid and purine metabolites with blood pressure in children: the KOALA birth cohort study Chapter 4 Uric acid and blood pressure: exploring the role of uric acid 73 production in The Maastricht Study Part II Gout management by the patient and general practitioner Chapter 5 Medication adherence among gout patients initiated allopurinol: a retrospective cohort study in the Clinical Practice Research Datalink Chapter 6 Medication adherence among patients with gout: a systematic review and meta-analysis Chapter 7 Knowledge, illness perceptions and stated clinical practice behaviour in management of gout: a mixed methods study in general practice Chapter 8 Summary and general discussion Addendum Valorisation Samenvatting 183 Acknowledgments 189 Curriculum vitae 195 List of publications  7 Glossary of terms related to genetics or medication adherence Genetic terms Allele A specific variation of a single-nucleotide polymorphism or gene. Enzyme Molecules that accelerate, or catalyse, chemical reactions. Gene Comprises a DNA sequence, including introns, exons, and regulatory regions, related to transcription of a given RNA. 18  Chapter 1 Adherence to medications Persistence Non-persistence Discontinuation Initiation Time End of prescibing Last dose First dose First prescription Adherence to medications Persistence Non-persistence Discontinuation Initiation Time End of prescibing Last dose First dose First prescription only the side-effects, or are more afraid for the side effects of the medication than for the disease. Across seven common chronic conditions including hypertension, osteoporosis, and diabetes, patients suffering from gout had the poorest medication adherence. 76 A systematic overview of available literature addressing the problem of poor medication adherence among gout patients is needed. Definition and measurement of medication adherence According to the World Health Organization adherence is defined as 'the extent to which a person's behaviour-taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a healthcare provider'. 77 There is no "gold standard" for measuring adherence. 78 Medication adherence can be measured either directly, for example by measuring drug metabolites or drug levels in blood, urine or tissues, or indirectly, by self-report, electronic monitoring, pharmacy records or healthcare provider assessment. Independently of the measurement technique used, the threshold for defining "good" and "poor" medication adherence is arbitrary. 78 To characterize medication adherence different concepts should be studied. According to the new taxonomy from 2012 it includes initiation, implementation, non-persistence, and overall adherence during observation time (Figure 3). 79 Poor medication adherence can thus occur in the following situations or combinations thereof: late or non-initiation of the prescribed treatment, sub-optimal implementation of the dosing regimen, or early discontinuation of the treatment. 79 General introduction  19 1 comorbidities like hypertension and diabetes, and the use of anti-hypertensive medication were associated with higher adherence rates, but these factors have not or poorly (e.g. age) been studied in relation to persistence. Gout management by the general practitioner General practitioners are the most relevant healthcare professional when it comes to the diagnosis and treatment of gout. Several societies published recommendations for the management of gout, including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). 81-83 Despite these recommendations, the management of gout is considered suboptimal. 84-86 A study conducted in the UK among primary care physicians showed that lifestyle advice was infrequently offered and allopurinol was only prescribed to a minority. 86 Appropriate initiation and dosing of uric acid lowering therapy are the main factors to achieve the therapeutic target level for serum uric acid. 87 Whenever this fails, patients are at increased risk for having more gout flares and for developing tophi and subsequent joint damage. Furthermore, a more severe and untreated disease will in the long run lead to increased gout-related healthcare costs. 88,89 Clinical practice behaviour is influenced by several aspects, including gout knowledge and illness perceptions. Up to now only a few small qualitative studies have been performed to elucidate barriers from the general practitioner side. They showed a moderate knowledge of the causes and consequences of gout. 6,90 Some general practitioners revealed that they still had a negative stereotype view and perceived stigma that the disease is self-inflicted and only a consequence of an unhealthy lifestyle. 6 In some cases gout was still considered as an acute disease rather than a chronic disease, and the long-term management could therefore be inadequate. 6,91 Although it is recommended to prescribe uric acid lowering therapy in patients with recurrent flares or tophi, this is only done for a small percentage of patients. The same applies to measurement of serum uric acid concentrations on a regular basis. 73,91 Taken together, knowledge, illness perceptions, and clinical behaviour of the general practitioner are important aspects to achieve optimal gout management. Because of the complex interactions between these aspects, studies addressing all these aspects at the same time are essential when aiming to improve gout management. However, this has not been done yet. Main aims The research presented in this thesis was conducted in several population-based cohort studies and made use of general practitioner interviews. The aim of this thesis was twofold: (i) to investigate the role of uric acid production in the association between uric acid and blood pressure; and 20  Chapter 1 (ii) to explore medication adherence among gout patients and gout management by the general practitioner. OUTLINE OF THIS THESIS This thesis is divided into two parts. In Part I we examined the association between uric acid and blood pressure, in particular the role of uric acid production. In Part II of this thesis we studied medication adherence among gout patients and gout management of general practitioners. Part I Uric acid and blood pressure: the role of uric acid production In chapter 2, we examined associations of genetic variation in the XOR gene, reflecting uric acid production, with secular trends in the steady and pulsatile blood pressure components and the risk of hypertension. The study was conducted in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) and the European Project on Genes in Hypertension (EPOGH). The FLEMENGHO study is a prospective populationbased cohort study. 92 From August 1985 to November 1990 participants were recruited in the geographically defined area in Northern Belgium. The EPOGH project recruited participants from 1999 to 2001 in four centres: Pilsen (Czech Republic), Mirano (Italy), Kraków (Poland), and Novosibirsk (Russian Federation). 93 In EPOGH, one follow-up 22  Chapter 1 III, randomized, double-blind, parallel-group trial.

ERJ Open Research, 2020

BackgroundCompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with ... more BackgroundCompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with asthma-worsening events, was recently developed. Further characterisation of CompEx Asthma is needed to illustrate the applicability of this end-point. The objective was to evaluate CompEx Asthma as a rate end-point to determine how seasonal and geographical factors impact this novel outcome.MethodsSeven 24–56-week randomised controlled trials of budesonide/formoterol (BUD/FORM) and benralizumab were analysed. Annualised event rates (AERs) and treatment effects (hazard ratio (HR)) were analysed with Poisson and Andersen–Gill models, respectively. Seasonality was analysed by month and five geographical regions were evaluated.ResultsThe studies included 10 815 patients (63% female, mean age 42–49 years). CompEx Asthma AER mirrored seasonal variations in SevEx AER. CompEx Asthma AERs were higherversusSevEx in BUD/FORM and benralizumab trials (range 2.7–4.5-fold and 1.3–2.0-fold increase, re...

Respiratory Medicine, 2020

BACKGROUND Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations i... more BACKGROUND Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients. METHODS In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx. Diary events were tested against predefined threshold values for peak expiratory flow, reliever medication use, and symptoms. A COPDCompEx event was defined as first occurrence of a diary event, a moderate or severe exacerbation, or a study dropout. Ratios of event frequency, treatment effect and future trial sample size were compared between COPDCompEx and moderate and severe exacerbations. FINDINGS At 3 months, the proportion of patients experiencing COPDCompEx events increased over 3-fold versus exacerbations alone. All components contributed to COPDCompEx event rate. Treatment effects at 3 months were closely matched between COPDCompEx and exacerbations, and the large net gain in power substantially reduced the required sample size. INTERPRETATION COPDCompEx may be used to predict treatment effect on moderate and severe exacerbations of chronic obstructive pulmonary disease. This may enable the design of shorter Phase 2 clinical trials requiring fewer patients when compared with current exacerbation studies, with exacerbations as a key Phase 3 endpoint. This would, therefore, allow more efficient decision-making with reduced burden and risk to study participants.

D101. CLINICAL AND TRANSLATIONAL STUDIES IN ASTHMA AND COPD, 2019

Alzheimer's & Dementia, 2019

Introduction: Low serum urate (sU) has been suggested to increase the risk of dementia since a re... more Introduction: Low serum urate (sU) has been suggested to increase the risk of dementia since a reduction might impair antioxidant capacity. On the other hand, high sU is associated with increased cardiovascular risk which might increase the risk of dementia, especially for vascular dementia. Methods: In 1968-1969, a population-based sample of 1462 women aged 38 to 60 years was examined and were followed up over 44 years (mean 33.1 years). We examined whether sU (determined in 1968-1969 and 1992-1994) is associated with risk of late-life dementia. Results: During 44 years of follow-up, a higher sU (per standard deviation of 76.5 mmol/L) was associated with lower risk for dementia (n 5 320; hazard ratio [HR] 0.81; confidence interval [CI] 0.72-0.91), Alzheimer's disease (n 5 152; HR 0.78; CI 0.66-0.91), and vascular dementia (n 5 52; HR 0.66; CI 0.47-0.94). Discussion: Our findings support the hypothesis that sU has a protective role in the development of dementia, regardless of dementia subtype. This may have important implications in the treatment of dementia and treatment goals for hyperuricemia in patients with gout.

FRIDAY, 15 JUNE 2018, 2018

The study cohort included 192.037 patients with gout, 82.6% of those were males. There was a prog... more The study cohort included 192.037 patients with gout, 82.6% of those were males. There was a progressive increase in the number of hospitalised patients with gout from 12 851 patients in 2005 to 23 318 in 2015; this was associated with an increase in mortality, reaching its highest value in 2015 with a 4.9% of gout hospitalised patients. The average age at dead in 2015 was 79.2 years and 85.16 years in male and female respectively, an age slightly lower than in the general population. The average cost in these hospitalised patients was 4931 C ¼ , reaching a peak of 5384 C ¼ in the last year. The hospital stay reached its lowest numbers in 2015 with an average of 8.9 days per patient. These comorbidities had statistical association with an added mortality risk in cerebrovascular disease (odds ratio [OR] 1.57, 95% confidence interval [CI]1.46-1.49), liver disease (OR 2.61 95% CI 2.34-2.9), kidney disease (OR 1.34 95% CI 1.28-1.41), dementia (OR 2.13 95% CI 1.88-2.42). On the contrary, in type 2 diabetes (OR 0.92 95% CI 0.87-0.96), we found a statistically significant lower mortality risk. Furthermore, it was found a statistically reduced mortality risk in females (OR 0.85 95%

Rheumatology (Oxford, England), Jan 8, 2018

When urate lowering therapy is indicated in patients with gout, medication adherence is essential... more When urate lowering therapy is indicated in patients with gout, medication adherence is essential. This study assesses non-persistence and non-adherence in patients with newly diagnosed gout, and identifies factors associated with poor medication adherence. A retrospective data analysis was performed within the UK Clinical Practice Research Datalink (1987-2014) among incident gout patients, aged ⩾40 years and starting allopurinol (n = 48 280). The proportion of patients non-persistent (a first medication gap of ⩾90 days) after 1 and 5 years, and median time until a first 90-day gap was estimated using Kaplan-Meier statistics in those starting allopurinol and restarting after a first interruption. Non-adherence (proportion of days covered <80%) over the full observation period was calculated. Multivariable Cox- or logistic regressions assessed factors associated with non-persistence or non-adherence, respectively. Non-persistence increased from 38.5% (95% CI: 38.1, 38.9) to 56.9% ...

Seminars in arthritis and rheumatism, Jan 7, 2017

In the management of chronic gout, a large proportion of patients need long-term management with ... more In the management of chronic gout, a large proportion of patients need long-term management with urate lowering therapy (ULT). This study reviews medication adherence to ULT and summarizes factors associated with adherence. We performed a systematic literature search for studies on adherence to ULT among gout patients in PubMed, Embase, CINAHL, and PsycINFO. We conducted meta-analysis, with a random effect model, for the studies reporting the proportion of patients considered adherent to at least 80% of prescribed medication or time taken. We explored potential sources of heterogeneity, including geographic area and measure of adherence. Narrative summaries were made for data on adherence assessed/defined by Medication Event Monitoring System (MEMS)/pill-count or patient-reported, occurrence of a gap in therapy ≥30 days (non-persistence), and factors associated with adherence. Of the 24 studies, 16 assessed adherence using prescription/claims data, two by the MEMS or pill count, and...

Annals of the Rheumatic Diseases, 2016

up studies and prospective interventional studies are required to confirm this positive associati... more up studies and prospective interventional studies are required to confirm this positive association between SUA and lung function.

Annals of the Rheumatic Diseases, 2016

Characteristics of patients developing skin reactions with both allopurinol and febuxostat (5/24)... more Characteristics of patients developing skin reactions with both allopurinol and febuxostat (5/24) Gender Age Allopurinol start Febuxostat start Rash with Outcome with febuxostat benzbromarone Dosage GFR Dosage GFR (mg/d) (mL/min) (mg/d) (mL/min) Female 70 50 78 120 77.2 Nonspecific No rash Male 69 N/A 90 40 90.5 SJS No rash Female 68 100 52 80 80.3 Nonspecific No rash Male 45 50 90 80 90.9 Nonspecific No rash Female 41 300 40 5 40.9 Nonspecific No rash GFR: glomerular filtration rate; SSJ: Stevens-Johnson syndrome. developed skin reactions with febuxostat (see table): in four cases a nonspecific rash, but one suffered from a Stevens-Johnson syndrome. None of these patients presented skin reactions to benzbromarone. Conclusions: In our series, one out five patients with previous skin reaction to allopurinol also developed after febuxostat. Larger studies are needed to confirm these results, but this finding strengths caution when using febuxostat in this subgroup of patients. References: [1]

Annals of the Rheumatic Diseases, 2016

Background: One of the causes of insufficient response to biological drugs is the production of a... more Background: One of the causes of insufficient response to biological drugs is the production of anti-drug antibodies (ADA) (1). These antibodies can decrease the effectiveness of treatment by altering bioavailability or by neutralizing the drug. In addition, they may contribute to hypersensitivity reactions. Some ADA are directed against IgG allotypes, which are protein polymorphisms able to induce an immune response in incompatible subjects. Infliximab (INX) and adalimumab (ADM) have the G1m17,1 allotypes, while about 50% of the Europeans are homozygous for the incompatible G1m3,n allotypes. Therefore, the allotypes could contribute to ADA and, in this way, explain the recently described loss of efficiency of INX in allotype-incompatible RA patients (2). Objectives: We aimed to analyze the usefulness of IgG1 allotypes as biomarker of the development of ADA against INX and ADM. Methods: The presence of ADA was determined in 252 consecutive patients with inflammatory arthritis in the Hospital La Paz (116 with rheumatoid arthritis (RA), 74 with ankylosing spondylitis (AS), 26 with psoriatic arthritis, 17 with non-radiographic spondylitis, 11 with spondylitis and inflammatory bowel disease, 3 with uveitis and 5 with other arthropathies). Patients were assessed during INX treatment (151), or with ADM (82), or sequentially during treatment with INX and ADM (19). ADA were determined by two-site bridging ELISA as described (1). Allotypes of IgG1 were determined by genotyping 2 SNPs, rs1071803 (for allotype G1m17/G1m3) and rs11621259 (for allotype G1m1/null) with the SNaPshot Multiplex kit (Applied Biosystems) as reported (2). Results: Patients with compatible allotypes (carriers of G1m17,1) showed a larger frequency of ADA (33% vs. 20%, p=0.02) and a trend toward higher titers of these antibodies (18.0x10 3 vs. 8.3x10 3 AU, ns) than patients with incompatible allotypes (homozygous for G1m3,n). This association was clearer in patients treated with INX (41% vs. 25%, p=0.03) than in those treated with ADM (18% vs. 12%, ns). ADA were more frequent in patients treated with INX than in those treated with ADM, as already known. Multivariate analysis showed that the frequency of ADA was increased in patients with RA compared to other diseases (OR =7.6, p<0.0001), and decreased in older patients (OR =0.65 per 10 years, p<0.001). Other factors, such as sex, having AS against other diseases, and treatment with methotrexate or corticosteroids, were not associated with ADA. Conclusions: Patients with compatible allotypes showed more frequently ADA than patients with incompatible allotypes, showing for the first time this association in patients treated with INX and reinforcing the previously reported association for ADM (3). These results suggest a genetic factor in linkage with the allotype, but different from it, that will predispose to ADA.

Journal of hypertension, May 1, 2017

Elevated serum uric acid concentration has been associated with high blood pressure (BP) and hype... more Elevated serum uric acid concentration has been associated with high blood pressure (BP) and hypertension. A putative underlying mechanism is the accumulation of reactive oxygen species when uric acid is generated by an increased enzyme activity of xanthine oxidase (XO). The aims of the present study were to investigate the associations between plasma uric acid concentration, purine metabolite ratios, as proxies for increased XO activity, and SBP and DBP in school-age children. Cross-sectional analyses were performed in 246 children (46% boys; mean age 7.1 years) from the Dutch KOALA Birth Cohort Study. Purine metabolites were determined with ultra-performance liquid chromatography-tandem mass spectrometry. During a home visit, a nurse collected a blood sample and measured BP three times; in addition, parents measured their child's BP on three consecutive days, in the morning and evening. Generalized estimating equations were used for analyses while controlling for variables suc...

Journal of hypertension, Nov 6, 2016

The enzyme xanthine oxidoreductase (XOR) generates uric acid in the terminal steps of the purine ... more The enzyme xanthine oxidoreductase (XOR) generates uric acid in the terminal steps of the purine metabolism; meanwhile reactive oxygen species are formed. We hypothesized that uric acid production, as assessed indirectly from XOR variants, is associated with hypertension. Among 2769 participants (48.3% men; mean age 40.7 years) randomly recruited from European populations, we genotyped 25 tagging XOR SNPs and measured blood pressure (BP) at baseline and follow-up (median 8.8 years). The relation between variants of the XOR gene with changes in pulse pressure and mean arterial pressure over time; and incidence of hypertension, were analyzed. Compared with nonminor allele carriers, pulse pressure increased approximately 2 mmHg more in minor allele carriers of rs11904439 (P = 0.01), whereas mean arterial pressure and DBP increased approximately 1 mmHg less in minor allele carriers of rs2043013 (P = 0.01). In 2050, participants normotensive at baseline, hazard ratios contrasting risk of...

Clinical Rheumatology, 2016

The objective of the present study is to explore knowledge, illness perceptions and stated practi... more The objective of the present study is to explore knowledge, illness perceptions and stated practice behaviour in relation to gout in primary care. This is a mixed methods study among 32 general practitioners (GPs). The quantitative assessment included the Gout Knowledge Questionnaire (GKQ; range 0-10; better) and Brief Illness Perceptions Questionnaire (BIPQ; nine items, range 0-10; stronger). Structured individual interviews obtained further qualitative insight into knowledge and perceptions, in the context of daily practice. Among 32 GPs, 18 (56.3 %) were male, mean age 44.4 years (SD 9.6) and mean working experience 17.1 years (SD 9.7). Median score [interquartile ranges (IQR)] on the GKQ was 7.

International journal of obesity (2005), 2015

To investigate whether the intestinal microbiota composition in early infancy is associated with ... more To investigate whether the intestinal microbiota composition in early infancy is associated with subsequent weight development in children. Analyses were conducted within the KOALA Birth Cohort Study (n = 2834). This cohort originates from two recruitments groups: pregnant women with a conventional lifestyle (no selection based on lifestyle) and pregnant women recruited through alternative channels (organic shops, anthroposophic clinicians/midwives, Steiner schools and relevant magazines). From 909 one-month-old infants, fecal samples were collected and analyzed by quantitative PCR targeting bifidobacteria, Bacteroides fragilis group, Clostridium difficile, Escherichia coli, Lactobacilli and total bacteria counts. Between the ages of 1 and 10 years, parent-reported weight and height was collected at 7 time points. Age- and gender-standardized body mass index (BMI) z-scores were calculated. Data were analyzed using generalized estimating equation. Colonization with B. fragilis group ...

Glossary of terms related to genetics or medication adherence 7 Chapter 1 General introduction Pa... more Glossary of terms related to genetics or medication adherence 7 Chapter 1 General introduction Part I Uric acid and blood pressure: the role of uric acid production Chapter 2 Xanthine oxidase gene variants and their association with blood pressure and incident hypertension: a population study Chapter 3 Associations of plasma uric acid and purine metabolites with blood pressure in children: the KOALA birth cohort study Chapter 4 Uric acid and blood pressure: exploring the role of uric acid 73 production in The Maastricht Study Part II Gout management by the patient and general practitioner Chapter 5 Medication adherence among gout patients initiated allopurinol: a retrospective cohort study in the Clinical Practice Research Datalink Chapter 6 Medication adherence among patients with gout: a systematic review and meta-analysis Chapter 7 Knowledge, illness perceptions and stated clinical practice behaviour in management of gout: a mixed methods study in general practice Chapter 8 Summary and general discussion Addendum Valorisation Samenvatting 183 Acknowledgments 189 Curriculum vitae 195 List of publications  7 Glossary of terms related to genetics or medication adherence Genetic terms Allele A specific variation of a single-nucleotide polymorphism or gene. Enzyme Molecules that accelerate, or catalyse, chemical reactions. Gene Comprises a DNA sequence, including introns, exons, and regulatory regions, related to transcription of a given RNA. 18  Chapter 1 Adherence to medications Persistence Non-persistence Discontinuation Initiation Time End of prescibing Last dose First dose First prescription Adherence to medications Persistence Non-persistence Discontinuation Initiation Time End of prescibing Last dose First dose First prescription only the side-effects, or are more afraid for the side effects of the medication than for the disease. Across seven common chronic conditions including hypertension, osteoporosis, and diabetes, patients suffering from gout had the poorest medication adherence. 76 A systematic overview of available literature addressing the problem of poor medication adherence among gout patients is needed. Definition and measurement of medication adherence According to the World Health Organization adherence is defined as 'the extent to which a person's behaviour-taking medication, following a diet, and/or executing lifestyle changes, corresponds with agreed recommendations from a healthcare provider'. 77 There is no "gold standard" for measuring adherence. 78 Medication adherence can be measured either directly, for example by measuring drug metabolites or drug levels in blood, urine or tissues, or indirectly, by self-report, electronic monitoring, pharmacy records or healthcare provider assessment. Independently of the measurement technique used, the threshold for defining "good" and "poor" medication adherence is arbitrary. 78 To characterize medication adherence different concepts should be studied. According to the new taxonomy from 2012 it includes initiation, implementation, non-persistence, and overall adherence during observation time (Figure 3). 79 Poor medication adherence can thus occur in the following situations or combinations thereof: late or non-initiation of the prescribed treatment, sub-optimal implementation of the dosing regimen, or early discontinuation of the treatment. 79 General introduction  19 1 comorbidities like hypertension and diabetes, and the use of anti-hypertensive medication were associated with higher adherence rates, but these factors have not or poorly (e.g. age) been studied in relation to persistence. Gout management by the general practitioner General practitioners are the most relevant healthcare professional when it comes to the diagnosis and treatment of gout. Several societies published recommendations for the management of gout, including the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). 81-83 Despite these recommendations, the management of gout is considered suboptimal. 84-86 A study conducted in the UK among primary care physicians showed that lifestyle advice was infrequently offered and allopurinol was only prescribed to a minority. 86 Appropriate initiation and dosing of uric acid lowering therapy are the main factors to achieve the therapeutic target level for serum uric acid. 87 Whenever this fails, patients are at increased risk for having more gout flares and for developing tophi and subsequent joint damage. Furthermore, a more severe and untreated disease will in the long run lead to increased gout-related healthcare costs. 88,89 Clinical practice behaviour is influenced by several aspects, including gout knowledge and illness perceptions. Up to now only a few small qualitative studies have been performed to elucidate barriers from the general practitioner side. They showed a moderate knowledge of the causes and consequences of gout. 6,90 Some general practitioners revealed that they still had a negative stereotype view and perceived stigma that the disease is self-inflicted and only a consequence of an unhealthy lifestyle. 6 In some cases gout was still considered as an acute disease rather than a chronic disease, and the long-term management could therefore be inadequate. 6,91 Although it is recommended to prescribe uric acid lowering therapy in patients with recurrent flares or tophi, this is only done for a small percentage of patients. The same applies to measurement of serum uric acid concentrations on a regular basis. 73,91 Taken together, knowledge, illness perceptions, and clinical behaviour of the general practitioner are important aspects to achieve optimal gout management. Because of the complex interactions between these aspects, studies addressing all these aspects at the same time are essential when aiming to improve gout management. However, this has not been done yet. Main aims The research presented in this thesis was conducted in several population-based cohort studies and made use of general practitioner interviews. The aim of this thesis was twofold: (i) to investigate the role of uric acid production in the association between uric acid and blood pressure; and 20  Chapter 1 (ii) to explore medication adherence among gout patients and gout management by the general practitioner. OUTLINE OF THIS THESIS This thesis is divided into two parts. In Part I we examined the association between uric acid and blood pressure, in particular the role of uric acid production. In Part II of this thesis we studied medication adherence among gout patients and gout management of general practitioners. Part I Uric acid and blood pressure: the role of uric acid production In chapter 2, we examined associations of genetic variation in the XOR gene, reflecting uric acid production, with secular trends in the steady and pulsatile blood pressure components and the risk of hypertension. The study was conducted in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) and the European Project on Genes in Hypertension (EPOGH). The FLEMENGHO study is a prospective populationbased cohort study. 92 From August 1985 to November 1990 participants were recruited in the geographically defined area in Northern Belgium. The EPOGH project recruited participants from 1999 to 2001 in four centres: Pilsen (Czech Republic), Mirano (Italy), Kraków (Poland), and Novosibirsk (Russian Federation). 93 In EPOGH, one follow-up 22  Chapter 1 III, randomized, double-blind, parallel-group trial.