Bayesian estimation of the prevalence of antimicrobial resistance: a mathematical modelling study.

BACKGROUND: Estimates of the prevalence of antimicrobial resistance (AMR) underpin effective antimicrobial stewardship, infection prevention and control, and optimal deployment of antimicrobial agents. Typically, the prevalence of AMR is determined from real-world antimicrobial susceptibility data that are time delimited, sparse, and often biased, potentially resulting in harmful and wasteful decision-making. Frequentist methods are resource intensive because they rely on large datasets. OBJECTIVES: To determine whether a Bayesian approach could present a more reliable and more resource-efficient way to estimate population prevalence of AMR than traditional frequentist methods. METHODS: Retrospectively collected, open-source, real-world pseudonymized healthcare data were used to develop a Bayesian approach for estimating the prevalence of AMR by combination with prior AMR information from a contextualized review of literature. Iterative random sampling and cross-validation were used to assess the predictive accuracy and potential resource efficiency of the Bayesian approach compared with a standard frequentist approach. RESULTS: Bayesian estimation of AMR prevalence made fewer extreme estimation errors than a frequentist estimation approach [n = 74 (6.4%) versus n = 136 (11.8%)] and required fewer observed antimicrobial susceptibility results per pathogen on average [mean = 28.8 (SD = 22.1) versus mean = 34.4 (SD = 30.1)] to avoid any extreme estimation errors in 50 iterations of the cross-validation. The Bayesian approach was maximally effective and efficient for drug-pathogen combinations where the actual prevalence of resistance was not close to 0% or 100%. CONCLUSIONS: Bayesian estimation of the prevalence of AMR could provide a simple, resource-efficient approach to better inform population infection management where uncertainty about AMR prevalence is high.

The use of parent-completed questionnaires to investigate developmental outcomes in large populations of children exposed to antiseizure medications in pregnancy.

OBJECTIVE: This study was undertaken to assess the utility of the Ages and Stages Questionnaire-3rd Edition (ASQ-3) and the Vineland Adaptive Behavior Scales-2nd Edition (VABS-II) as neurodevelopmental screening tools for infants exposed to antiseizure medications in utero, and to examine their suitability for use in large-population signal generation initiatives. METHODS: Participants were women with epilepsy who were recruited from 21 hospitals in England and Northern Ireland during pregnancy between 2014 and 2016. Offspring were assessed at 24 months old using the Bayley Scales of Infant Development-3rd Edition (BSID-III), the VABS-II, and the ASQ-3 (n = 223). The sensitivity and specificity of the ASQ-3 and VABS-II to identify developmental delay at 24 months were examined, using the BSID-III to define cases. RESULTS: The ASQ-3 identified 65 children (29.1%) as at risk of developmental delay at 24 months using standard referral criteria. Using a categorical approach and standard referral criteria to identify delay in the ASQ-3 and BSID-III at 24 months, the ASQ-3 showed excellent sensitivity (90.9%) and moderate specificity (74.1%). Utilizing different cut-points resulted in improved properties and may be preferred in certain contexts. The VABS-II exhibited the strongest psychometric properties when borderline impairment (>1 SD below the mean) was compared to BSID-III referral data (sensitivity = 100.0%, specificity = 96.6%). SIGNIFICANCE: Both the ASQ-3 and VABS-II have good psychometric properties in a sample of children exposed to antiseizure medications when the purpose is the identification of at-risk groups. These findings identify the ASQ-3 as a measure that could be used effectively as part of a tiered surveillance system for teratogenic exposure by identifying a subset of individuals for more detailed investigations. Although the VABS-II has excellent psychometric properties, it is more labor-intensive for both the research team and participants and is available in fewer languages than the ASQ-3.

Lower hepatocellular carcinoma surveillance in metabolic dysfunction-associated steatotic liver disease: Impact on treatment eligibility.

BACKGROUND AND AIM: This study aimed to compare the determinants and impact of hepatocellular carcinoma (HCC) surveillance rates for people with metabolic dysfunction-associated steatotic liver disease (MASLD) versus other chronic liver diseases. METHODS: A dataset of HCC patients from a UK hospital (2007-2022) was analyzed. The Mann-Whitney U-test compared continuous variables. The χ2 and two-tailed Fisher exact tests compared categorical data. Regression modeling analyzed the impact of MASLD on the size and number of HCC nodules and curative treatment. The Cox proportional hazards model assessed the influence of MASLD on overall survival. RESULTS: A total of 176 of 687 (25.6%) HCC patients had MASLD. Fewer people with MASLD HCC were enrolled in HCC surveillance compared to non-MASLD HCC (38 [21.6%] vs 215 [42.1%], P < 0.001). Patients with MASLD HCC were less likely to have been under secondary care (n = 57 [32.4%] vs 259 [50.7%], P < 0.001) and less likely to have cirrhosis (n = 113 [64.2%] vs 417 [81.6%], P < 0.001). MASLD was associated with a 12.3-mm (95% confidence interval [CI] 10.8-14.0 mm) greater tumor diameter compared to people without MASLD (P = 0.002). Patients with MASLD HCC had 0.62 reduced odds (95% CI 0.43-0.91) of receiving curative treatment compared to non-MASLD HCC (P = 0.014). Overall survival was similar for patients with MASLD HCC versus non-MASLD HCC (hazard ratio 1.03, 95% CI 0.85-1.25, P = 0.748). CONCLUSION: Patients with MASLD are less likely to have been enrolled in HCC surveillance due to undiagnosed cirrhosis or presenting with non-cirrhotic HCC. Patients with MASLD HCC present with larger tumors and are less likely to receive curative treatment.

Fast approximate inference for multivariate longitudinal data.

Collecting information on multiple longitudinal outcomes is increasingly common in many clinical settings. In many cases, it is desirable to model these outcomes jointly. However, in large data sets, with many outcomes, computational burden often prevents the simultaneous modeling of multiple outcomes within a single model. We develop a mean field variational Bayes algorithm, to jointly model multiple Gaussian, Poisson, or binary longitudinal markers within a multivariate generalized linear mixed model. Through simulation studies and clinical applications (in the fields of sight threatening diabetic retinopathy and primary biliary cirrhosis), we demonstrate substantial computational savings of our approximate approach when compared to a standard Markov Chain Monte Carlo, while maintaining good levels of accuracy of model parameters.

The predictive accuracy of cardiovascular risk prediction tools in inflammatory arthritis and psoriasis: an observational validation study using the Clinical Practice Research Datalink.

OBJECTIVES: Cardiovascular risk prediction tools developed for the general population often underperform for individuals with rheumatoid arthritis (RA), and their predictive accuracy are unclear for other inflammatory conditions that also have increased cardiovascular risk. We investigated performance of QRISK-3, Framingham Risk Score (FRS) and Reynolds Risk Score (RRS) in RA, psoriatic disease (psoriatic arthritis (PsA) and psoriasis) and ankylosing spondylitis (AS). We considered osteoarthritis as a non-inflammatory comparator. METHODS: We utilised primary care records from the Clinical Practice Research Datalink (CPRD) Aurum database to identify individuals with each condition and calculated 10-year cardiovascular risk using each prediction tool. Discrimination and calibration of each tool in each disease was assessed. RESULTS: Time-dependent AUC for QRISK3 was 0.752 for RA (95% CI 0.734-0.777), 0.794 for AS (95% CI 0.764-0.812), 0.764 for PsA (95% CI 0.741-0.791),0.815 for psoriasis (95% CI 0.789-0.835), and 0.698 for osteoarthritis (95% CI 0.670-0.717) indicating reasonably good predictive performance. AUC for FRS were similar, and slightly lower for RRS. FRS was reasonably well calibrated for each condition but underpredicted risk for patients with RA. RRS tended to underpredict CVD risk, whilst QRISK3 overpredicted CVD risk, especially for the most high-risk individuals. CONCLUSIONS: CVD risk for individuals with RA, AS and psoriatic disease were generally less accurately predicted using each of the 3 CVD risk prediction tools than reported accuracies in the original publications. Individuals with osteoarthritis also had less accurate predictions suggesting inflammation is not the sole reason for underperformance. Disease specific risk prediction tools may be required.

Neurodevelopment of babies born to mothers with epilepsy: A prospective observational cohort study.

OBJECTIVE: Despite widespread monotherapy use of lamotrigine or levetiracetam during pregnancy, prospectively collected, blinded child development data are still limited. The NaME (Neurodevelopment of Babies Born to Mothers With Epilepsy) Study prospectively recruited a new cohort of women with epilepsy and their offspring for longitudinal follow-up. METHODS: Pregnant women of <21 weeks gestation (n = 401) were recruited from 21 hospitals in the UK. Data collection occurred during pregnancy (recruitment, trimester 3) and at 12 and 24 months of age. The primary outcome was blinded assessment of infant cognitive, language, and motor development on the Bayley Scales of Infant and Toddler Development (3rd edition) at 24 months of age with supplementary parent reporting on the Vinelands Adaptive Behavior Scales (2nd edition). RESULTS: There were 394 live births, with 277 children (70%) completing the Bayley assessment at 24 months. There was no evidence of an association of prenatal exposure to monotherapy lamotrigine (-.74, SE = 2.9, 95% confidence interval [CI] = -6.5 to 5.0, p = .80) or levetiracetam (-1.57, SE = 3.1, 95% CI = -4.6 to 7.7, p = .62) with poorer infant cognition, following adjustment for other maternal and child factors in comparison to nonexposed children. Similar results were observed for language and motor scores. There was no evidence of an association between increasing doses of either lamotrigine or levetiracetam. Nor was there evidence that higher dose folic acid supplementation (≥5 mg/day) or convulsive seizure exposure was associated with child development scores. Continued infant exposure to antiseizure medications through breast milk was not associated with poorer outcomes, but the number of women breastfeeding beyond 3 months was low. SIGNIFICANCE: These data are reassuring for infant development following in utero exposure to monotherapy lamotrigine or levetiracetam, but child development is dynamic, and future follow-up is required to rule out later emerging effects.

Rapid antigen testing in COVID-19 management for school-aged children: an observational study in Cheshire and Merseyside, UK.

BACKGROUND: Twice weekly lateral flow tests (LFTs) for secondary school children was UK Government policy from 8 March 2021. We evaluate use of LFTs (both supervised at test centres, and home test kits) in school-aged children in Cheshire and Merseyside. METHODS: We report (i) number of LFT positives (ii) proportion of LFT positive with confirmatory reverse transcription polymerase chain reaction (PCR) test within 2 days, and (iii) agreement between LFT-positive and confirmatory PCR, and dependence of (i-iii) on COVID-19 prevalence. FINDINGS: 1 248 468 LFTs were taken by 211 255 12-18 years old, and 163 914 by 52 116 5-11 years old between 6 November 2020 and 31 July 2021. Five thousand three hundred and fourteen (2.5%) 12-18 years old and 1996 (3.8%) 5-11 years old returned LFT positives, with 3829 (72.1%) and 1535 (76.9%) confirmatory PCRs, and 3357 (87.7%) and 1383 (90.1%) confirmatory PCR-positives, respectively.Monthly proportions of LFT positive with PCR negative varied between 4.7% and 35.3% in 12-18 years old (corresponding proportion of all tests positive: 9.7% and 0.3%).Deprivation and non-White ethnicity were associated with reduced uptake of confirmatory PCR. INTERPRETATION: Substantial inequalities in confirmatory testing need more attention to avoid further disadvantage through education loss. When prevalence is low additional measures, including confirmatory testing, are needed. Local Directors of Public Health taking more control over schools testing may be needed. FUNDING: DHSC, MRC, NIHR, EPSRC.

Association of SARS-CoV-2 viral load distributions with individual demographics and suspected variant type: results from the Liverpool community testing pilot, England, 6 November 2020 to 8 September 2021.

BackgroundThe PCR quantification cycle (Cq) is a proxy measure of the viral load of a SARS-CoV-2-infected individual.AimTo investigate if Cq values vary according to different population characteristics, in particular demographic ones, and within the COVID-19 pandemic context, notably the SARS-CoV-2 type/variant individuals get infected with.MethodsWe considered all positive PCR results from Cheshire and Merseyside, England, between 6 November 2020 and 8 September 2021. Cq distributions were inspected with Kernel density estimates. Multivariable quantile regression models assessed associations between people's features and Cq.ResultsWe report Cq values for 188,821 SARS-CoV-2 positive individuals. Median Cqs increased with decreasing age for suspected wild-type virus and Alpha variant infections, but less so, if not, for Delta. For example, compared to 30-39-year-olds (median age group), 5-11-year-olds exhibited 1.8 (95% CI: 1.5 to 2.1), 2.2 (95% CI: 1.8 to 2.6) and 0.8 (95% CI: 0.6 to 0.9) higher median Cqs for suspected wild-type, Alpha and Delta positives, respectively, in multivariable analysis. 12-18-year-olds also had higher Cqs for wild-type and Alpha positives, however, not for Delta. Overall, in univariable analysis, suspected Delta positives reported 2.8 lower median Cqs than wild-type positives (95% CI: 2.7 to 2.8; p < 0.001). Suspected Alpha positives had 1.5 (95% CI: 1.4 to 1.5; p < 0.001) lower median Cqs than wild type.ConclusionsWild-type- or Alpha-infected school-aged children (5-11-year-olds) might transmit less than adults (> 18 years old), but have greater mixing exposures. Smaller differences in viral loads with age occurred in suspected Delta infections. Suspected-Alpha- or Delta-infections involved higher viral loads than wild type, suggesting increased transmission risk. COVID-19 control strategies should consider age and dominant variant.

GC-MS Techniques Investigating Potential Biomarkers of Dying in the Last Weeks with Lung Cancer.

Predicting when a patient with advanced cancer is dying is a challenge and currently no prognostic test is available. We hypothesised that a dying process from cancer is associated with metabolic changes and specifically with changes in volatile organic compounds (VOCs). We analysed urine from patients with lung cancer in the last weeks of life by headspace gas chromatography mass spectrometry. Urine was acidified or alkalinised before analysis. VOC changes in the last weeks of life were identified using univariate, multivariate and linear regression analysis; 12 VOCs increased (11 from the acid dataset, 2 from the alkali dataset) and 25 VOCs decreased (23 from the acid dataset and 3 from the alkali dataset). A Cox Lasso prediction model using 8 VOCs predicted dying with an AUC of 0.77, 0.78 and 0.85 at 30, 20 and 10 days and stratified patients into a low (median 10 days), medium (median 50 days) or high risk of survival. Our data supports the hypothesis there are specific metabolic changes associated with the dying. The VOCs identified are potential biomarkers of dying in lung cancer and could be used as a tool to provide additional prognostic information to inform expert clinician judgement and subsequent decision making.

Evaluation of the aMAP score for hepatocellular carcinoma surveillance: a realistic opportunity to risk stratify.

BACKGROUND AND AIMS: The aMAP score is a model that predicts risk of hepatocellular carcinoma (HCC) development in patients with chronic hepatitis. Its performance in a 'real world' surveillance setting has not yet been ascertained. PATIENTS AND METHODS: We had access to a cohort of 3473 individuals enrolled in a rigorously implemented and prospectively accrued surveillance programme (patients undergoing regular ultrasound and biomarker examination between 1998 and 2021). During this period 445 had HCC detected. Of these, 77.8% had early stage disease (within Milan criteria), permitting potentially curative therapy to be implemented in nearly 70% of cases. We applied the recently developed aMAP score to classify patients according to their initial aMAP score in to low, medium and high-risk groups as proposed in the original publication. The performance of the aMAP score was assessed according to the concordance-index and calibration (i.e. agreement between observed and predicted risk). Allowance was made for competing causes of death. RESULTS: The aMAP score achieved an overall C-index of 0.81 (95% CI: 0.79-0.82) consistent with the initial report and was unaffected by allowance for competing causes of death. Sub-group analysis showed that the results did not change significantly according to gender, or aetiology. However, aMAP discrimination was greater for younger individuals (versus older individuals), and also for individuals without cirrhosis. The HCC incidence rate was 0.98, 7.05 and 29.1 events per 1000 person-years in the low-, moderate- and high-risk aMAP groups, respectively. CONCLUSIONS: The results from this 'real-world' cohort demonstrate that risk stratification is a realistic prospect and that identification of a subgroup of chronic liver disease patients who have a very low risk of HCC is feasible.

Changing patterns of SARS-CoV-2 infection through Delta and Omicron waves by vaccination status, previous infection and neighbourhood deprivation: a cohort analysis of 2.7 M people.

BACKGROUND: Our study examines if SARS-CoV-2 infections varied by vaccination status, if an individual had previously tested positive and by neighbourhood socioeconomic deprivation across the Delta and Omicron epidemic waves of SARS-CoV-2. METHODS: Population cohort study using electronic health records for 2.7 M residents in Cheshire and Merseyside, England (3rd June 2021 to 1st March 2022). Our outcome variable was registered positive test for SARS-CoV-2. Explanatory variables were vaccination status, previous registered positive test and neighbourhood socioeconomic deprivation. Cox regression models were used to analyse associations. RESULTS: Originally higher SARS-CoV-2 rates in the most socioeconomically deprived neighbourhoods changed to being higher in the least deprived neighbourhoods from the 1st September 2021, and were inconsistent during the Omicron wave. Individuals who were fully vaccinated (two doses) were associated with fewer registered positive tests (e.g., individuals engaged in testing between 1st September and 27th November 2021-Hazards Ratio (HR) = 0.48, 95% Confidence Intervals (CIs) = 0.47-0.50. Individuals with a previous registered positive test were also less likely to have a registered positive test (e.g., individuals engaged in testing between 1st September and 27th November 2021-HR = 0.16, 95% CIs = 0.15-0.18. However, the Omicron period saw smaller effect sizes for both vaccination status and previous registered positive test. CONCLUSIONS: Changing patterns of SARS-CoV-2 infections during the Delta and Omicron waves reveals a dynamic pandemic that continues to affect diverse communities in sometimes unexpected ways.

Effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines for reducing susceptibility to infection with the Delta variant (B.1.617.2) of SARS-CoV-2.

BACKGROUND: From January to May 2021 the alpha variant (B.1.1.7) of SARS-CoV-2 was the most commonly detected variant in the UK. Following this, the Delta variant (B.1.617.2) then became the predominant variant. The UK COVID-19 vaccination programme started on 8th December 2020. Prior to the Delta variant, most vaccine effectiveness studies focused on the alpha variant. We therefore aimed to estimate the effectiveness of the BNT162b2 (Pfizer-BioNTech) and the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in preventing symptomatic and asymptomatic infection with respect to the Delta variant in a UK setting. METHODS: We used anonymised public health record data linked to infection data (PCR) using the Combined Intelligence for Population Health Action resource. We then constructed an SIR epidemic model to explain SARS-CoV-2 infection data across the Cheshire and Merseyside region of the UK. Vaccines were assumed to be effective after 21 days for 1 dose and 14 days for 2 doses. RESULTS: We determined that the effectiveness of the Oxford-AstraZeneca vaccine in reducing susceptibility to infection is 39% (95% credible interval [34, 43]) and 64% (95% credible interval [61, 67]) for a single dose and a double dose respectively. For the Pfizer-BioNTech vaccine, the effectiveness is 20% (95% credible interval [10, 28]) and 84% (95% credible interval [82, 86]) for a single-dose and a double dose respectively. CONCLUSION: Vaccine effectiveness for reducing susceptibility to SARS-CoV-2 infection shows noticeable improvement after receiving two doses of either vaccine. Findings also suggest that a full course of the Pfizer-BioNTech provides the optimal protection against infection with the Delta variant. This reinforces the need to complete the full course programme to maximise individual protection and reduce transmission.

Pharmacist responsiveness and readiness for oral antivirals for COVID-19: A rebuttal to the AMA statement regarding the Biden administration's test-to-treat plan.

On March 4, 2022, the American Medical Association (AMA) released a statement in response to the Biden administration's plan of a test-to-treat plan allowing pharmacists to serve as locations to test and provide prescriptions for oral antiviral therapies for the treatment of coronavirus disease 2019 (COVID-19) after a positive test result. The statement by AMA contradicts and underrepresents the impact pharmacists have on clinical practice. Pharmacists have been a crucial part of many efforts including mass vaccination efforts and furnishing of prescriptions for other complex disease states (e.g., pre-exposure prophylaxis and postexposure prophylaxis therapy). Furthermore, health systems have proven that novel approaches to mitigate operational and clinical barriers to COVID-19 therapies may offset the increased demand needed by communities. Herein, this commentary will discuss a viewpoint and counterpoint to the statement put out by AMA, with a focus on pharmacists.

Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma.

BACKGROUND & AIMS: Ultrasound (US)-based screening has been recommended for patients with an increased risk of hepatocellular carcinoma (HCC). US analysis, however, is limited in patients who are obese or have small tumors. The addition of serum level of α-fetoprotein (AFP) measurements to US analysis can increase detection of HCC. We analyzed data from patients with chronic liver disease, collected over 15 years in an HCC surveillance program, to develop a model to assess risk of HCC. METHODS: We collected data from 3450 patients with chronic liver disease undergoing US surveillance in Japan from March 1998 through April 2014, and followed them up for a median of 8.83 years. We performed longitudinal discriminant analysis of serial AFP measurements (median number of observations/patient, 56; approximately every 3 months) to develop a model to determine the risk of HCC. We validated the model using data from 2 cohorts of patients with chronic liver disease in Japan (404 and 2754 patients) and 1 cohort in Scotland (1596 patients). RESULTS: HCC was detected in 413 patients (median tumor diameter, 1.8 cm), during a median follow-up time of 6.60 years. In the development data set, the model identified patients who developed HCC with an area under the curve of 0.78; it correctly identified 74.3% of patients who did develop HCC, and 72.9% of patients who did not. Overall, 73.1% of patients were classified correctly. The model could be used to assign patients to a high-risk group (27.5 HCCs/1000 patient-years) vs a low-risk group (4.9 HCCs/1000 patient-years). A similar performance was observed when the model was used to assess patients with cirrhosis. Analysis of the validation cohorts produced similar results. CONCLUSIONS: We developed and validated a model to identify patients with chronic liver disease who are at risk for HCC based on change in serum AFP level over time. The model could be used to assign patients to high-risk vs low-risk groups, and might be used to select patients for surveillance.

Depression and anxiety symptoms at TNF inhibitor initiation are associated with impaired treatment response in axial spondyloarthritis.

OBJECTIVES: Depression and anxiety are associated with more severe disease in cross-sectional studies of axial spondyloarthritis (axSpA). We examined the association between baseline symptoms of depression or anxiety and response to TNF inhibitors (TNFi) in axSpA. METHODS: Biologic naïve participants from a national axSpA register completed the Hospital Anxiety and Depression Scale (HADS) before initiating TNFi. Symptoms of anxiety and depression were each categorized as moderate-severe (≥11), mild (8-10) and 'none' (≤7), and compared against change in disease indices [BASDAI and AS Disease Activity Score (ASDAS)] over time and time to treatment discontinuation using marginal structural models. Inverse-probability weights balanced baseline age, gender, BMI, deprivation, education and baseline values of respective disease indices. RESULTS: Of the 742 participants (67% male, mean age 45 years), 176 (24%) had moderate-severe and 26% mild depression; 295 (40%) had moderate-severe and 23% mild anxiety. Baseline disease activity was higher in higher HADS symptom categories for both depression and anxiety. Participants with moderate-severe depression had significantly poorer response compared with those with 'none' throughout follow-up. At 6 months, the difference was approximately 2.2 BASDAI and 0.8 ASDAS units after balancing their baseline values. Equivalent comparisons for anxiety were 1.7 BASDAI and 0.7 ASDAS units. Treatment discontinuation was 1.59-fold higher (hazard ratio 95% CI: 1.12, 2.26) in participants with moderate-severe anxiety compared with 'none'. CONCLUSIONS: Symptoms of depression and anxiety at TNFi initiation are associated with poorer treatment outcomes. Targeted interventions to optimize mental health have potential to substantially improve treatment response and persistence.

Diagnostic delay in axial spondyloarthritis: a systematic review and meta-analysis.

BACKGROUND: Delay to diagnosis in axial SpA (axSpA) is longer than in many other rheumatic diseases. Prolonged delay is associate with poorer outcomes, including functional impairment and quality of life. Our aims were to describe global variation in delay to diagnosis, factors associated with delay, and delay compared with PsA. METHODS: We searched MEDLINE, PubMed, Embase and Web of Science using a predefined protocol. Diagnostic delay was defined as years between the age at symptom onset and at diagnosis. We pooled the mean delay using random effects inverse variance meta-analysis. We examined variations in pooled estimates using prespecified subgroup analyses and sources of heterogeneity using meta-regression. RESULTS: A total of 64 studies reported the mean diagnostic delay in axSpA patients. The pooled mean delay was 6.7 years (95% CI 6.2, 7.2) with high levels of heterogeneity. Delay to diagnosis did not improve over time when stratifying results by year of publication. Studies from high-income countries (defined by the World Bank) reported longer delays than those from middle-income countries. Factors consistently reported to be associated with longer delays were lower education levels, younger age at symptom onset and absence of extra-articular manifestations (EAMs). The pooled estimate for diagnostic delay from 8 PsA studies was significantly shorter, at 2.6 years (95% CI 1.6, 3.6). CONCLUSION: For axSpA patients, delay to diagnosis remains unacceptably prolonged in many parts of the world. Patient factors (e.g. education) and disease presentation (onset age and EAMs) should inform campaigns to improve delay.

Association between comorbidities and disease activity in axial spondyloarthritis: results from the BSRBR-AS.

OBJECTIVE: Whether comorbidities influence disease activity assessment in axial SpA (axSpA) is unclear. Comorbidities inflate DAS28 in rheumatoid arthritis through the patient global score. We examined whether axSpA disease activity measures are differentially affected, and whether comorbidities inflate the AS disease activity score (ASDAS) through the patient global component. METHODS: We used baseline data from the British Society for Rheumatology Biologics Register for AS, including 14 physician diagnosed comorbidities. Linear models were used to compare disease activity (BASDAI, spinal pain, ASDAS) and ESR/CRP according to comorbidity count, adjusted for age, gender, BMI, smoking, socioeconomic status, and education. The same models were used to examine whether the patient global score was associated with comorbidities, additionally adjusting for other ASDAS components. RESULTS: The number of participants eligible for analysis was 2043 (67% male, mean age 49 years); 44% had at least one comorbidity. Each additional comorbidity was associated with higher BASDAI by 0.40 units (95% CI: 0.27, 0.52) and spinal pain by 0.53 (95% CI: 0.37, 0.68). Effect size for ASDAS (0.09 units; 95% CI: 0.03, 0.15) was not clinically significant. ESR and CRP were not associated with comorbidity count. Depression, heart failure and peptic ulcer were consistently associated with higher disease activity measures, but not CRP/ESR. Patient global was associated with comorbidity count, but not independently of other ASDAS components (P = 0.75). CONCLUSION: Comorbidities were associated with higher patient reported disease activity in axSpA. Clinicians should be mindful of the potential impact of comorbidities on patient reported outcome measures and consider additionally collecting ASDAS when comorbidities are present.

Comorbidity and response to TNF inhibitors in axial spondyloarthritis: longitudinal analysis of the BSRBR-AS.

OBJECTIVE: Comorbidities influence disease assessment in axial spondyloarthritis (axSpA), but their association with response to TNF inhibitors (TNFi) is unclear. We examined associations between comorbidity history at TNFi initiation and: (i) change in disease indices over time; (ii) binary response definitions; and (iii) time to treatment discontinuation. METHODS: We studied participants starting their first TNFi from a national axSpA register. Comorbidity categories were created from 14 physician-diagnosed conditions and compared against: change in disease indices over time using linear mixed effects models; BASDAI50/2 (50% or 2-unit reduction) and BASDAI < 4 at 6 months using logistic models; and time to treatment discontinuation using Cox models. Models were adjusted for age, gender, BMI, deprivation and education. RESULTS: In total, 994 were eligible for analysis (68% male, mean age 45 years); 21% had one comorbidity and 11% had ≥2. Baseline disease severity was higher in those with comorbidities across all indices, but absolute improvement over time was comparable for BASDAI and spinal pain. Participants with ≥2 comorbidities had smaller absolute improvement in BASFI and quality of life. This group also had numerically reduced odds of achieving BASDAI50/2 [odds ratio (OR) 0.81; 95% CI: 0.45, 1.45] and BASDAI < 4 (OR 0.57; 95% CI: 0.32, 1.04). Treatment discontinuation was increased in those with two comorbidities [hazard ratio (HR) 1.32; 95% CI: 0.88, 2.00] and ≥3 comorbidities (HR 2.18; 95% CI: 1.20, 3.93) compared with none. CONCLUSIONS: Participants with multiple comorbidities had poorer treatment outcomes, particularly increased treatment discontinuation and poorer improvements in function and quality of life. These results inform clinicians and educate patients about response to the first TNFi given comorbidity burden.

The incidence and prevalence of cardiovascular diseases in gout: a systematic review and meta-analysis.

The aims of this systematic review and meta-analysis were to describe prevalence of cardiovascular disease in gout, compare these results with non-gout controls and consider whether there were differences according to geography. PubMed, Scopus and Web of Science were systematically searched for studies reporting prevalence of any cardiovascular disease in a gout population. Studies with non-representative sampling, where a cohort had been used in another study, small sample size (< 100) and where gout could not be distinguished from other rheumatic conditions were excluded, as were reviews, editorials and comments. Where possible meta-analysis was performed using random-effect models. Twenty-six studies comprising 949,773 gout patients were included in the review. Pooled prevalence estimates were calculated for five cardiovascular diseases: myocardial infarction (2.8%; 95% confidence interval (CI)s 1.6, 5.0), heart failure (8.7%; 95% CI 2.9, 23.8), venous thromboembolism (2.1%; 95% CI 1.2, 3.4), cerebrovascular accident (4.3%; 95% CI 1.8, 9.7) and hypertension (63.9%; 95% CI 24.5, 90.6). Sixteen studies reported comparisons with non-gout controls, illustrating an increased risk in the gout group across all cardiovascular diseases. There were no identifiable reliable patterns when analysing the results by country. Cardiovascular diseases are more prevalent in patients with gout and should prompt vigilance from clinicians to the need to assess and stratify cardiovascular risk. Future research is needed to investigate the link between gout, hyperuricaemia and increased cardiovascular risk and also to establish a more thorough picture of prevalence for less common cardiovascular diseases.

Comorbidities in psoriatic arthritis: a systematic review and meta-analysis.

The aims of this systematic review and meta-analysis were to: (1) describe the prevalence of commonly reported comorbidities in psoriatic arthritis (PsA), (2) compare the incidence and/or prevalence of comorbidities between PsA and control populations; and (3) examine the impact of comorbidities on PsA outcomes. We systematically searched Medline, PubMed, Scopus, and Web of Science using a predefined protocol in accordance with PRISMA guidelines. Studies reporting only one comorbidity, or a few closely related diseases within one organ system, were excluded. Where possible, meta-analysis was performed using random-effects models. We included 39 studies amounting to over 152 thousand PsA patients. We performed meta-analysis for the prevalence of 21 commonly reported comorbidities. The most prevalent comorbidities were hypertension (pooled prevalence 34%), metabolic syndrome (29%), obesity (27%), hyperlipidaemia (24%) and any cardiovascular diseases (19%). Eleven studies consistently showed higher prevalence of comorbidities in PsA than controls. Five studies showed that comorbid patients had more severe disease, poorer quality of life, and increased discontinuation of treatment. Comorbidities, particularly cardiometabolic disorders, were highly prevalent in PsA and more common than in healthy controls. Comorbidities were associated with adverse disease features, but more research is needed on their impact on longitudinal outcomes such as treatment response, work productivity and mortality.