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Background: Much remains unknown surrounding the disease-modifying drugs (DMDs) used to treat multiple sclerosis and infection-related healthcare use in the 'real-world' setting. We examined if DMD exposure was associated with altered infection-related healthcare use., Methods: We assessed if DMD (versus no) exposure was associated with altered infection-related hospitalizations, physician claims, and prescriptions filled in British Columbia, Canada (1996-2017). Healthcare use was assessed using negative binomial and proportional means regression models, reported as sex-/age-/comorbidity-/calendar year-/socioeconomic-adjusted rate and hazard ratios [aRR, aHR], with 95% confidence intervals [CIs])., Findings: We identified 19,360 multiple sclerosis cases (13,940/19,360; 72.0% women; mean age at study start = 44.5 standard deviation, SD = 13.3; mean follow-up = 11.7 [SD = 7.3] years). Relative to unexposed periods, exposure to any DMD was associated with a lower infection-related rate of physician claims (aRR = 0.88; 95% CI:0.85-0.92) and hazard of hospitalization (aHR = 0.64; 95% CI:0.56-0.73), and a higher rate of infection-related prescriptions (aRR = 1.14; 95% CI:1.08-1.20). Exposure to any injectable or oral DMD was associated with a lower infection-related rate of physician claims (injectable aRR = 0.88; 95% CI:0.84-0.92, oral aRR = 0.83; 95% CI:0.77-0.90) and hazard of hospitalization (injectable aHR = 0.65; 95% CI:0.56-0.75, oral aHR = 0.54; 95% CI:0.38-0.77), whereas intravenous DMD exposure was not (aRR = 0.99; 95% CI:0.86-1.14, aHR = 0.73; 95% CI:0.49-1.09). Exposure to any injectable or intravenous DMD was associated with a higher rate of infection-related prescriptions (injectable aRR = 1.15; 95% CI:1.08-1.22, intravenous = 1.34; 95% CI:1.15-1.56), whereas oral DMDs were not (aRR = 0.98; 95% CI:0.91-1.05)., Interpretation: DMD exposure for the treatment of MS was associated with differences in infection-related healthcare use. While infection-related hospitalizations and physician visits were lower, prescription fills were higher. How these differences in infection-related healthcare use affect outcomes in persons with multiple sclerosis warrants consideration., Funding: Canadian Institutes of Health Research (CIHR); German Research Foundation (DFG)., Competing Interests: Jonas Graf has received in the last 3 years travel/meeting/accommodation reimbursements from Merck Serono, Sanofi-Genzyme, Grifols, and a Research Fellowship from the Deutsche Forschungsgemeinschaft (project number 438899010, GZ: GR 5665/1-1). Huah Shin Ng has received funding from the MS Society of Canada’s endMS Postdoctoral Fellowship, and the Michael Smith Foundation for Health Research Trainee Award. Feng Zhu, Yinshan Zhao, José M A Wijnands, and Charity Evans declare no conflicts. John Fisk receives research funding from CIHR, the MS Society of Canada, Crohn’s and Colitis Canada, Research Nova Scotia, the Nova Scotia Health Authority Research Fund, and licensing and distribution fees from MAPI Research Trust. Ruth Ann Marrie receives research funding from: CIHR, Research Manitoba, MS Canada, Multiple Sclerosis Scientific Foundation, Crohn’s and Colitis Canada, National Multiple Sclerosis Society, CMSC, the US Department of Defense, the Arthritis Society, Biogen Idec (no funds to her/her institution) and Roche (no funds to her/her institution), and is supported by the Waugh Family Chair in Multiple Sclerosis. Helen Tremlett has received research support in the last 3 years from the: Canada Research Chair program, National MS Society, Canadian Institutes of Health Research, Canada Foundation for Innovation, MS Society of Canada, and the MS Scientific Research Foundation., (© 2023 Published by Elsevier Ltd.)

We described emergency department (ED) visits (all visits and infection-related) by persons with multiple sclerosis (MS) in British Columbia, Canada (1 April 2012 to 31 December 2017). We identified 15,350 MS cases using health administrative data; 73.4% were women, averaging 51.4 years at study entry. Over 4.9 years of follow-up (mean), 56.0% of MS cases visited an ED (mean = 0.6 visits/person/year; total = 37,072 visits). A diagnosis was documented for 25,698 (69.3%) ED visits, and 18.4% (4725/25,698) were infection-related. Inpatient admissions were reported for 20.4% (5238/25,698) of all and 29.2% (1380/4725) of infection-related ED visits. Findings suggest that the ED plays a substantial role in MS healthcare and infection management.

Background: There is increasing evidence of prodromal multiple sclerosis (MS)., Objective: The aim of this study was to determine whether fatigue, sleep disorders, anaemia or pain form part of the MS prodrome., Methods: This population-based matched cohort study used linked administrative and clinical databases in British Columbia, Canada. The odds of fatigue, sleep disorders, anaemia and pain in the 5 years preceding the MS cases' first demyelinating claim or MS symptom onset were compared with general population controls. The frequencies of physician visits for these conditions were also compared. Modifying effects of age and sex were evaluated., Results: MS cases/controls were assessed before the first demyelinating event (6863/31,865) or MS symptom onset (966/4534). Fatigue (adj.OR: 3.37; 95% CI: 2.76-4.10), sleep disorders (adj.OR: 2.61; 95% CI: 2.34-2.91), anaemia (adj.OR: 1.53; 95% CI: 1.32-1.78) and pain (adj.OR: 2.15; 95% CI: 2.03-2.27) during the 5 years preceding the first demyelinating event were more frequent among cases, and physician visits increased for cases relative to controls. The association between MS and anaemia was greater for men; that between MS and pain increased with age. Pre-MS symptom onset, sleep disorders (adj.OR: 1.72; 95% CI: 1.12-2.56) and pain (adj.OR: 1.53; 95% CI: 1.32-1.76) were more prevalent among cases., Conclusion: Fatigue, sleep disorders, anaemia and pain were elevated before the recognition of MS. The relative anaemia burden was higher in men and pain more evident among older adults.

Background: The multiple sclerosis (MS) prodrome is poorly characterized., Objective: To phenotype the MS prodrome via health care encounters., Methods: Using data from a population-based cohort study linking administrative and clinical data in four Canadian provinces, we compared physician and hospital encounters and prescriptions filled (via International Classification of Diseases chapters, physician specialty or drug classes) for MS subjects in the 5 years before the first demyelinating claim in an administrative cohort or the clinical symptom onset in an MS clinic-derived cohort, to age-, sex- and geographically matched controls. Rate ratios (RRs), 95% confidence intervals (95% CIs) and proportions were estimated., Results: The administrative and clinical cohorts included 13,951/66,940 and 3202/16,006 people with and without MS (cases/controls). Compared to controls, in the 5 years before the first demyelinating claim or symptom onset, cases had more physician and hospital encounters for the nervous (RR (range) = 2.31; 95% CI: 1.05-5.10 to 4.75; 95% CI: 3.11-7.25), sensory (RR (range) = 1.40; 95% CI: 1.34-1.46 to 2.28; 95% CI: 1.72-3.02), musculoskeletal (RR (range) = 1.19; 95% CI: 1.07-1.33 to 1.70; 95% CI: 1.57-1.85) and genito-urinary systems (RR (range) = 1.17; 95% CI: 1.05-1.30 to 1.59; 95% CI: 1.48-1.70). Cases had more psychiatrist and urologist encounters (RR (range) = 1.48; 95% CI: 1.36-1.62 to 1.80; 95% CI: 1.61-2.01), and higher proportions of musculoskeletal, genito-urinary or hormonal-related prescriptions (1.1-1.5 times higher, all p  < 0.02). However, cases had fewer pregnancy-related encounters than controls (RR = 0.78; 95% CI: 0.71-0.86 to 0.88; 95% CI: 0.84-0.92)., Conclusion: Phenotyping the prodrome 5 years before clinical recognition of MS is feasible.

We examine the impact of nondifferential outcome misclassification on odds ratios estimated from pair-matched case-control studies and propose a Bayesian model to adjust these estimates for misclassification bias. The model relies on access to a validation subgroup with confirmed outcome status for all case-control pairs as well as prior knowledge about the positive and negative predictive value of the classification mechanism. We illustrate the model's performance on simulated data and apply it to a database study examining the presence of ten morbidities in the prodromal phase of multiple sclerosis., (Copyright © 2017 John Wiley & Sons, Ltd.)

Background: Little is known about infection risk in multiple sclerosis (MS)., Objective: We examined infection-related health care utilization in people with and without MS., Methods: Using population-based health administrative data from British Columbia, Canada, people with MS were followed from their first demyelinating claim (1996-2013) until death, emigration, or study end (2013). Infection-related hospital, physician, and prescription data of MS cases were compared with sex-, age-, and geographically matched controls using adjusted regression models. Sex and age differences (18-39, 40-49, 50-59, 60+ years) were explored., Results: Relative to 35,837 controls, 7179 MS cases were over twice as likely to be hospitalized for infection (adjusted odds ratio: 2.39; 95% confidence interval (CI): 2.16-2.65), had 41% more physician visits (adjusted rate ratio (aRR): 1.41; 95% CI: 1.36-1.47), and filled 57% more infection-related prescriptions (aRR: 1.57; 95% CI: 1.49-1.65). Utilization was disproportionately higher in MS men than women and was elevated across all ages. MS cases had nearly twice as many physician visits and two to three times more hospitalizations for pneumonia, urinary system infections, and skin infections (aRRs ranged from 1.6 to 3.3) and over twice as many hospitalizations for intestinal infections (aRR = 2.6) and sepsis (aRR = 2.2)., Conclusion: Infection-related health care utilization was increased in people with MS across all age groups, with a higher burden for men.

Objective: Gout has been associated with a large number of co-morbidities. As yet, no co-morbidity measure has been validated for use in clinical studies in gout. This study aims to evaluate the content and construct validity of the Rheumatic Diseases Comorbidity Index (RDCI) and a gout-specifically modified RDCI (mRDCI) in patients with gout., Methods: In a cross-sectional sample of 122 patients with gout, data on co-morbidities were obtained during an interview, chart review and clinical examination. The data were used to compute the RDCI/mRDCI, a simple co-morbidity count, the Charlson Comorbidity Index (CCI) and the Functional Comorbidity Index (FCI). Content and construct validity was explored by assessing Spearman correlations between the two RDCI versions and between RDCI/mRDCI and the other co-morbidity indices, as well as demographic and clinical outcomes. In addition, we assessed the independent association between the RDCI/mRDCI and physical functioning (HAQ disability index), physical health (36-Item Short Form Health Survey) and direct health care and non-health care costs using multivariable regression analyses., Results: The correlation between the RDCI and mRDCI was 0.86. Correlations between the RDCI/mRDCI and simple co-morbidity count, CCI or FCI varied between 0.72 and 0.88. Correlations with generic and gout-specific health outcomes were moderate and weak, respectively, with slightly better results for the mRDCI. Multivariable analyses showed that both the RDCI and mRDCI contributed to the variation in physical functioning, physical health and direct health care and non-health care costs., Conclusion: Both the RDCI and mRDCI have appropriate content and construct validity to evaluate the influence of co-morbidity on outcome in patients with gout., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To compare limitations in health between Dutch patients with gout and the general population and to determine factors influencing societal and patient values for health as assessed with different utility approaches., Methods: A cross-sectional study was done among 110 patients with gout under the care of a rheumatologist, with patients completing the EuroQol 5-domain instrument (EQ-5D), the EQ-5D visual analog scale (EQ-5D VAS), and the Short Form 6-dimensions health survey (SF-6D). Scores on EQ-5D domains were compared with age- and sex-matched general population data. Agreement between utility measures was assessed using the intraclass correlation coefficient (ICC). Mixture modeling was used to assess factors associated with the different approaches to assess utility., Results: Compared to the general population, gout patients reported more limitations in mobility (66% versus 12%), self-care (24% versus 8%), daily activities (49% versus 24%), and pain (76% versus 45%), but equal anxiety/depressive symptoms (18% versus 19%). For patients with gout, utilities were reduced: the mean, median, and interquartile range, respectively, were 0.74, 0.81, and 0.69-0.84 for EQ-5D, 0.69, 0.67, and 0.59-0.81 for SF-6D, and 66, 70, and 57-77 for EQ-5D VAS. ICC agreement between each pair of utilities was only moderate (0.52-0.59). Only minor differences were seen in the type of variables associated with each utility approach, with worse Health Assessment Questionnaire scores, cardiovascular disease (CVD), gout concern, and gout pain consistently associated with lower utility. The strength of contribution of these variables, however, differed among the 3 approaches., Conclusion: Patients with gout experience substantially impaired health compared to the general population. Although absolute values of utility varied between instruments and perspectives, functional disability, CVD, and higher gout impact contributed to utility independently of which instrument was used., (© 2015, American College of Rheumatology.)

Objective: Arterial stiffness may be a mechanism to explain the association between uric acid and cardiovascular disease. We aimed to analyse associations between serum uric acid and regional and local arterial stiffness, and assess potential differences related to sex and glucose metabolism status., Methods: A cross-sectional study was performed in 614 adults [52.6% men; mean age 58.7 ± 8.5 years; 23.2% type 2 diabetes mellitus (by design)] from The Maastricht Study. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV), distensibility, and compliance coefficient of the carotid and femoral artery, and carotid artery Young's elastic modulus., Results: Higher uric acid (per SD of 74 μmol/l) was associated with greater stiffness indicated by a significantly higher cfPWV [β = 0.216 (95% confidence interval 0.061, 0.372); P = 0.006] and lower carotid distensibility coefficient [β = -0.633 (95% confidence interval -1.099, -0.166); P = 0.008] after adjustment for sex, age, and glucose metabolism status. Associations lost significance after adjusting for mean arterial pressure, BMI, waist, smoking status, heart rate, total : high-density lipoprotein cholesterol ratio, triglycerides, estimated glomerular filtration rate, use of lipid-lowering, antihypertensive, and diabetes medication, and use of secondary uricosurics. No associations were found between uric acid and carotid compliance coefficient, carotid Young's elastic modulus, or stiffness of the femoral artery. A significant interaction (P < 0.10) with glucose metabolism status was found for cfPWV. However, none of the stratified associations were significant. There was no interaction with sex., Conclusion: Uric acid was not significantly associated with stiffness of the aorta, or the carotid or femoral artery among adults aged 40-75 years without and with type 2 diabetes mellitus.

Objective: Microvascular dysfunction has been suggested as a possible underlying mechanism for the association between uric acid and various diseases, such as hypertension, renal disease and cardiomyopathies. We therefore analysed the association between serum uric acid and skin microvascular function, a model of generalized microvascular function., Methods: A cross-sectional study was performed in 610 individuals [51.8% men; mean age 58.7 ± 8.6 years; 23.6% with type 2 diabetes (by design)] from The Maastricht Study. We assessed skin capillary density (capillaries/mm) by capillaroscopy at baseline, after 4 min of arterial occlusion, and after 2 min of venous congestion. Capillary recruitment after arterial occlusion and during venous congestion was expressed as the absolute change in capillary density after recruitment and as the percentage change in capillary density from baseline., Results: Crude linear regression analyses showed that serum uric acid [per +1 standard deviation (SD) of 74 μmol/l] was not associated with baseline capillary density [β = -0.21 (95% confidence interval, 95% CI -1.61 to 1.19) P = 0.765], while an inverse association was found between uric acid and absolute change in capillary density after arterial occlusion [β = -1.15 (95% CI -2.36 to 0.06) P = 0.062] and during venous congestion [β = -1.41 (95% CI -2.68 to -0.14) P = 0.029]. However, after adjustment for sex, age and glucose metabolism status, these associations were no longer statistically significant. In addition, we found no association between uric acid and percentage capillary recruitment after arterial occlusion [β = -1.66 (95% CI -3.97 to 0.65) P = 0.159] or during venous congestion [β = -2.02 (95% CI -4.46 to 0.42) P = 0.104] in unadjusted analyses; multivariable analyses gave similar results., Conclusion: These results do not support the hypothesis that generalized microvascular dysfunction (as estimated in skin microcirculation) is the underlying mechanism for the association between uric acid and cardiovascular and renal diseases. The possibility that uric acid is associated with microvascular dysfunction in specific end-organs, for example heart or kidney, needs further investigation.

Objective: To estimate costs of illness in a cross-sectional cohort of patients with gout attending an outpatient rheumatology clinic, and to evaluate which factors contribute to higher costs., Methods: Altogether, 126 patients with gout were clinically assessed. They completed a series of questionnaires. Health resource use was collected using a self-report questionnaire that was cross-checked with the electronic patient file. Productivity loss was assessed by the Work Productivity and Activity Impairment Questionnaire, addressing absenteeism and presenteeism. Resource use and productivity loss were valued by real costs, and annual costs per patient were calculated. Factors contributing to incurring costs above the median were explored using logistic univariable and multivariable regression analysis., Results: Mean (median) annual direct costs of gout were €5647 (€1148) per patient. Total costs increased to €6914 (€1279) or €10,894 (€1840) per patient per year when adding cost for absenteeism or both absenteeism and presenteeism, respectively. Factors independently associated with high direct and high indirect costs were a positive history of cardiovascular disease, functional limitations, and female sex. In addition, pain, gout concerns, and unmet gout treatment needs were associated with high direct costs., Conclusion: The direct and indirect costs-of-illness of gout are primarily associated with cardiovascular disease, functional limitations, and female sex.

Studies on the occurrence of gout show a large range in estimates. However, a clear insight into the factors responsible for this variation in estimates is lacking. Therefore, our aim was to review the literature on the prevalence and incidence of gout systematically and to obtain insight into the degree of and factors contributing to the heterogeneity. We searched MEDLINE, EMBASE, and Web of Science (January 1962 to July 2012) to identify primary studies on the prevalence and incidence of gout in the general population. Data were extracted by two persons on sources of clinical heterogeneity, methodological heterogeneity, and variation in outcome reporting. Meta-analysis and meta-regression analysis were performed for the prevalence of gout. Of 1,466 articles screened, 77 articles were included, of which 71 reported the prevalence and 12 the incidence of gout. The pooled prevalence (67 studies; N = 12,226,425) based on a random effects model was 0.6% (95% CI 0.4; 0.7), however there was a high level of heterogeneity (I(2) = 99.9%). Results from a mixed-effects meta-regression model indicated that age (p = 0.019), sex (p < 0.001), continent (p < 0.001), response rate (p = 0.016), consistency in data collection (p = 0.002), and case definition (p < 0.001) were significantly associated with gout prevalence and jointly accounted for 88.7% of the heterogeneity. The incidence in the total population ranged from 0.06 to 2.68 per 1,000 person-years. In conclusion, gout is a common disease and the large variation in the prevalence data on gout is explained by sex, continent on which the study was performed, and the case definition of gout.

Objectives: The aims of this study were to investigate (i) associations between uric acid and prevalent cardiovascular disease (CVD), ankle-arm blood pressure index (AAIx) and carotid intima-media thickness (CIMT) in the total population and in predefined subgroups according to glucose metabolism status and (ii) the extent to which these associations are explained by low-grade inflammation., Methods: Cross-sectional analyses were conducted among 530 individuals [60.6% men, mean age 58.9 years (s.d. 6.9), 52.6% normal glucose metabolism (NGM)] at increased risk of CVD from the Cohort of Diabetes and Atherosclerosis Maastricht study. A low-grade inflammation score was computed by averaging the z-scores of eight inflammation markers [CRP, TNF-α, IL-6, IL-8, serum amyloid A, intercellular adhesion molecule 1 (ICAM-1), ceruloplasmin and haptoglobin]., Results: After adjustment for traditional CVD risk factors, plasma uric acid (per s.d. of 81 μmol/l) was associated with CVD in individuals with NGM [odds ratio (OR) = 1.66, 95% CI 1.06, 2.58] but not with disturbed glucose metabolism (DGM) (OR = 0.81, 95% CI 0.55, 1.19, P interaction = 0.165). Uric acid was associated with CIMT in the total population (β = 0.024, 95% CI 0.007, 0.042) and slightly more strongly in individuals with NGM (β = 0.030, 95% CI 0.006, 0.054) than DGM (β = 0.018, 95% CI -0.009, 0.044, P interaction = 0.443). There was no association between uric acid and AAIx in any group (P interaction = 0.058). Uric acid was associated with low-grade inflammation in the total population (β = 0.074, 95% CI 0.013, 0.134, P interaction = 0.737). Adding low-grade inflammation to the models did not attenuate any of the associations., Conclusion: The associations for uric acid with CIMT, and with CVD in NGM only, were not explained by low-grade inflammation. A difference in the strength of the associations between individuals with NGM and DGM was suggested., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Large epidemiologic studies of gout can improve insight into the etiology, pathology, impact, and management of the disease. Identification of monosodium urate monohydrate crystals is considered the gold standard for diagnosis, but its application is often not possible in large studies. Therefore, under such circumstances, several proxy approaches are used to classify patients as having gout, including ICD coding in several types of databases or questionnaires that are usually based on the existing classification criteria. However, agreement among these methods is disappointing. Moreover, studies use the terms acute, recurrent, and chronic gout in different ways and without clear definitions. Better definitions of the different manifestations and stages of gout may provide better insight into the natural course and burden of disease and can be the basis for valid approaches to correctly classifying patients within large epidemiologic studies.