Jelle Vehof

TFOS DEWS II Epidemiology Report

The subcommittee reviewed the prevalence, incidence, risk factors, natural history, morbidity and questionnaires reported in epidemiological studies of dry eye disease (DED). A meta-analysis of published prevalence data estimated the impact of age and sex. Global mapping of prevalence was undertaken. The prevalence of DED ranged from 5 to 50%. The prevalence of signs was higher and more variable than symptoms. There were limited prevalence studies in youth and in populations south of the equator. The meta-analysis confirmed that prevalence increases with age, however signs showed a greater increase per decade than symptoms. Women have a higher prevalence of DED than men, although differences become significant only with age. Risk factors were categorized as modifiable/non-modifiable, and as consistent, probable or inconclusive. Asian ethnicity was a mostly consistent risk factor. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable, particularly costs due to reduced work productivity. Questionnaires used to evaluate DED vary in their utility. Future research should establish the prevalence of disease of varying severity, the incidence in different populations and potential risk factors such as youth and digital device usage. Geospatial mapping might elucidate the impact of climate, environment and socioeconomic factors. Given the limited study of the natural history of treated and untreated DED, this remains an important area for future research.

Shared genetic factors underlie chronic pain syndromes

Summary Using a large population‐representative sample and multivariate twin modeling, the presence of shared genetic factors underlying chronic pain syndromes was found. ABSTRACT Chronic pain syndromes (CPS) are highly prevalent in the general population, and increasingly the evidence points to a common etiological pathway. Using a large cohort of twins (n = 8564) characterized for chronic widespread musculoskeletal pain (CWP), chronic pelvic pain (PP), migraine (MIG), dry eye disease, and irritable bowel syndrome (IBS), we explored the underlying genetic and environmental factors contributing to CPS and the correlation between them. The sample was predominantly female (87.3%), with a mean age of 54.7 (±14.7) years. Prevalence of the different CPS ranged from 7.4% (PP) to 15.7% (MIG). For all CPS the within‐twin correlation in monozygotic twin pairs was higher than in dizygotic pairs, suggesting a heritable component. Estimated heritability ranged from 19% (IBS) to 46% (PP). Except for MIG, we found significant pairwise phenotypic correlations between the CPS. The phenotypic correlation was highest between CWP and IBS (0.40; 95% confidence interval: 0.27 to 0.46). Excluding MIG from further analyses, cross‐twin cross‐trait correlations were higher in monozygotic compared with dizygotic twin pairs, suggestive of shared genetic factors between CWP, PP, IBS, and dry eye disease. Twin modeling analysis revealed the common pathway model as the model best explaining the observed pattern of correlation between the traits, with an estimated heritability of 66% of the underlying latent variable. These results are evidence of shared genetic factors in conditions manifesting chronic pain and justify the search for underlying genetic variants.

Prevalence and risk factors of dry eye disease in a British female cohort

Background/aims To estimate the prevalence and risk factors of dry eye disease (DED) in a female cohort in the UK. Methods Population-based cross-sectional association study of 3824 women from the TwinsUK cohort aged 20–87 years. A questionnaire was used to evaluate DED and several risk factors. Binary logistic regression, corrected for age, was used to examine the association between DED and risk factors. Results 9.6% of women had a DED diagnosis and concomitant use of artificial tears, and 20.8% experienced DED symptoms in the past 3 months. Risk factors that were significantly associated with DED were age, asthma, eczema, the presence of any allergy, cataract surgery, rheumatoid arthritis, osteoarthritis, migraine and stroke. The highest effect sizes were found with depression, pelvic pain, irritable bowel syndrome and chronic widespread pain syndrome (all p<0.0005). Subjects with DED symptoms scored significantly lower on self-perceived health, compared with controls (p=0.001). Conclusions DED is common and increases with age within this cohort of female twins. We confirmed established risk factors for the first time in a British population, and found important risk factors that might relate to an underlying aetiology involving chronic pain predisposition or somatisation.

Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics : a replication study

In two previous studies we found an association between HTR2C polymorphisms and the prevalence of the metabolic syndrome in patients using antipsychotics. In this study, we set out to replicate our findings in a third separate sample of patients. Data for this cross-sectional study came from the ongoing Pharmacotherapy Monitoring and Outcome survey study, investigating the association between schizophrenia and metabolic or cardiovascular risk factors. Primary end point was the prevalence of the metabolic syndrome. Primary determinants were two polymorphisms in the HTR2C gene: rs3813929 (−759 C/T) and rs1414334:C>G. Carriership of the variant rs1414334 C-allele was significantly associated with an increase prevalence of the metabolic syndrome (odds ratio (OR) 3.73; 95% confidence interval (CI) 1.29–10.79, P=0.015). No association was found between the HTR2C −759 C/T polymorphism and the metabolic syndrome. This study confirms previous findings that the variant C-allele of the rs1414334 polymorphism is associated with the metabolic syndrome.

Clinical response to antipsychotic drug treatment: Association study of polymorphisms in six candidate genes

Pharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response.

Chronic widespread pain : clinical comorbidities and psychological correlates

Abstract Recent studies have provided consistent evidence for a genetic influence on chronic widespread pain (CWP). The aim of this study was to investigate (1) the etiological structure underlying CWP by examining the covariation between CWP and psychological comorbidities and psychoaffective correlates and (2) the decomposition of the covariation into genetic and environmental components. A total of 3266 female twins (mean age 56.6 years) were subject to multivariate analyses. Using validated questionnaires to classify twins as having CWP, the prevalence of CWP was 20.8%. In the multivariate analysis, the most suitable model was the common pathway model. This model revealed 2 underlying latent variables, one common to anxiety, emotional intelligence, and emotional instability (f1) and the other common to depression and CWP (f2), the latter being highly heritable (86%). Both latent variables (f1 and f2) shared an additive genetic and a nonshared environmental factor. In addition, a second additive genetic factor loading only on f2 was found. This study reveals the structure of genetic and environmental influences of CWP and its psychoaffective correlates. The results show that the clustering of CWP and depression is due to a common, highly heritable, underlying latent trait. In addition, we found evidence that CWP, anxiety, emotional instability, and emotional intelligence are influenced by different underlying latent traits sharing the same genetic and nonshared environmental factors. This is the first study to reveal the structure and relative importance of genetic and environmental influences on complex etiological mechanisms of CWP and its correlates.

The heritability of dry eye disease in a female twin cohort.

PURPOSE We estimated the relative importance of genes and environment in dry eye disease (DED) using a classic twin study. METHODS A large sample of 3930 female monozygotic and dizygotic twins from the UK Adult Twin Registry (TwinsUK) was questioned about the presence of a DED diagnosis and about DED symptoms in the preceding 3 months. In addition, a subset of 606 twins was examined for several dry eye signs. Genetic and environmental effects were estimated using maximum likelihood structural equation modeling. RESULTS All DED outcome variables showed higher correlation in monozygotic twin pairs than in dizygotic twin pairs, suggesting genes have a contributory role in DED. The DED symptoms showed a heritability of 29% (95% confidence interval [CI], 18%-40%). A clinicians diagnosis of DED with concurrent use of artificial tears showed a heritability of 41% (95% CI, 26%-56%). Estimates of the heritability of DED signs were 25% (95% CI, 7%-42%) for interblink interval, 58% (95% CI, 43%-70%) for Schirmer value, 40% (95% CI, 25%-53%) for tear osmolarity, and 78% (95% CI, 59%-90%) for the presence of blepharitis. The unique environment explained the remainder of the variance. We found no significant heritability for tear breakup time. CONCLUSIONS Genetic factors contribute moderately to the diagnosis, symptoms, and the signs of DED. Compared to other ocular phenotypes, the lower heritability might reflect some of the difficulties in objective phenotyping of DED in a population-based sample. However, future genetic studies are now justified and may help in unraveling the pathophysiology of DED.

Association Between the 1291-C/G Polymorphism in the Adrenergic α-2a Receptor and the Metabolic Syndrome

The prevalence of the metabolic syndrome is increased in patients with schizophrenia compared with the general population. The strong interindividual differences in susceptibility to developing the metabolic syndrome suggests that the genetic makeup is a modulating factor. Part of the genetic puzzle can possibly be explained by variations in the gene coding for the adrenergic &agr;-2a receptor (ADRA2A) because this receptor plays an important role in lipolysis. Three studies have found an association between the &agr;-2a 1291-C/G polymorphism and antipsychotic induced weight gain, with conflicting results between whites and Asians. No studies have been published investigating the association between the 1291-C/G polymorphism and the metabolic syndrome. The primary objective of this cross-sectional study was to investigate the association between the ADRA2A 1291-C/G polymorphism and the metabolic syndrome in 470 patients using antipsychotic drugs. There was no significant association between carriership of the variant 1291-G allele and prevalence of the metabolic syndrome (odds ratio, 0.73; 95% confidence interval, 0.49-1.15). Exploratory analysis showed an association between carriership of the variant 1291-G allele and a reduced prevalence of the metabolic syndrome in patients not currently using antipsychotics (odds ratio, 0.05; 95% confidence interval, 0.003-0.97; P = 0.048). In conclusion, this study shows that the ADRA2A 1291-C/G polymorphism does not seem to be a strong predictor for long-term occurrence of the metabolic syndrome in antipsychotic using patients. Studies investigating this association using a prospective, or retrospective, design, as well as studies investigating this association in a nonpsychiatric population, are warranted.

Predictors for starting depot administration of risperidone in chronic users of antipsychotics.

Background: Risperidone long-acting injectable (RLAI), the first second-generation depot antipsychotic, has extensively been studied before introduction. Thereafter, questions about the type of patients actually treated with RLAI in daily practice remain to be answered for making valid antipsychotic treatment comparisons involving RLAI in observational studies. Objective: We aimed to determine in chronic antipsychotic users who switched treatment, predictors for the prescription of (1) depot versus oral antipsychotics and (2) RLAI versus first-generation antipsychotics (FGAs) depot. Methods: We used pharmacy dispensing data from 53 community pharmacies in the northeast of the Netherlands containing approximately 500,000 persons. Chronic antipsychotic users were defined and followed up for a switch in antipsychotic treatment within the first period that RLAI was on the market. Multivariable analysis was performed to relate patient, prescriber, and medication characteristics to prescription of a new antipsychotic drug. Results: Predictors for switching to depot versus oral antipsychotics were male sex, previous use of depot antipsychotics, recent anticholinergic drug use, and a gap in antipsychotic dispensation history. Predictors for switching to RLAI versus FGA depot were previous use of depot and consulting a specialist. Conclusions: The results suggest that, compared with oral antipsychotics, patients receiving a depot are less compliant users, with more extrapyramidal side effects. Compared with FGA depot, patients receiving RLAI tend to be more severely ill patients. We conclude that RLAI may be partly channeled to patients as a last resort, which may have important consequences for the interpretation of observational effectiveness comparisons between RLAI and other antipsychotics in daily practice.

Diffusion of a New Drug: A Comparative Analysis of Adoption, Treatment Complexity, and Persistence of Risperidone Long-Acting Injectable Therapy in the Netherlands

OBJECTIVE The studys objective was to analyze the adoption and persistence of risperidone long-acting injectable (RLAI) therapy after its introduction in the Netherlands in 2003 compared with the adoption and persistence of existing first-generation antipsychotic (FGA) depot drugs as an example of the diffusion of a new drug in the Netherlands. METHODS Data on antipsychotic use were obtained from the InterAction DataBase (IADB.nl), a database containing pharmacy dispensing records of patients in the northern Netherlands, from May 20, 2003, to December 31, 2006. Treatment complexity for patients prescribed RLAI was analyzed on the basis of psychotropic comedication at baseline and during treatment, as well as on the number of previous antipsychotic therapies. Differences in treatment complexity between patients using RLAI and those using FGA depot drugs were estimated using parametric regressions. To evaluate persistence, survival analysis techniques were applied to estimate the probability of patients continuing the use of RLAI or FGA depot drugs over time. RESULTS Data on 435 patients who were treated with depot antipsychotics were extracted from the IADB.nl. Patients had a mean (SD) age of 40.7 (13.8) years, and 65% of them were male. The results of this analysis indicated that persistence for patients prescribed RLAI was significantly lower compared with other depot antipsychotics (RLAI vs zuclopenthixol, P = 0.002; RLAI vs all other depot antipsychotics, P = 0.009). At the initiation of treatment, patients prescribed RLAI had more previous psychotropic comedication and had, on average, approximately 5 and approximately 1.5 times more prior depot drug therapies compared with zuclopenthixol and any other FGA depot drug, respectively. CONCLUSIONS The findings of this study suggest that RLAI has been prescribed more often for difficult-totreat patients than have other available depot antipsychotics. This may explain the low adoption and poor persistence observed in the first few years after the introduction of RLAI. Further research with more extensive data should be pursued to obtain better understanding of the current diffusion of RLAI in daily clinical practice.