Short-term risk of cardiovascular events in people newly diagnosed with gout.

OBJECTIVES: To investigate the temporal association between first diagnosis of gout and cardiovascular events in the short-term. METHODS: We performed a self-controlled case series analysis and a cohort study using data from linked primary care, hospitalisation, and mortality records from the UK's Clinical Practice Research Database (GOLD). We included individuals with a new diagnosis of gout either in the primary care or secondary care between 01/01/1997 and 31/12/2020. The first consultation at which gout was diagnosed was the exposure of interest. The main outcome consisted of cardiovascular events (i.e., a composite of fatal and non-fatal myocardial infarction, ischaemic or haemorrhagic stroke, and transient ischaemic attack). RESULTS: 4,398 patients (66.9% male, mean age 74.6 years) had a cardiovascular event within ±2 years of their first recorded diagnosis of gout. The incidence of cardiovascular events was significantly higher in the 30 days after the first diagnosis of gout compared to baseline (adjusted incidence rate ratio: 1.55 ((95% confidence interval) 95%CI: 1.33-1.83)). Among 76,440 patients (72.9% male, mean age 63.2 years) included in the cohort study, the incidence of cardiovascular events in the 30 days after the first gout diagnosis (31.2 events/1,000 person-years, 95%CI: 27.1-35.9) was significantly higher than in days 31-730 after gout diagnosis (21.6 events/1,000 person-years, 95%CI:20.8-22.4) with a rate difference of -9.6 events/1,000 person-years, 95%CI: -14.0 to -5.1). CONCLUSION: Individuals had a short-term increased risk of cardiovascular events in the 30 days following the first consultation at which gout was diagnosed.

Effectiveness of pneumococcal vaccination in adults with common immune-mediated inflammatory diseases in the UK: a case-control study.

BACKGROUND: People with immune-mediated inflammatory disease are at increased risk of pneumococcal pneumonia. The effectiveness of pneumococcal vaccination in people with immune-mediated inflammatory diseases has not been evaluated. We investigated the effectiveness of pneumococcal vaccination in preventing morbidity and mortality associated with pneumonia in patients with immune-mediated inflammatory diseases. METHODS: In this matched case-control study, we used primary-care electronic health record data from the Clinical Practice Research Datalink Gold database in the UK, with linked hospitalisation and mortality data. Adults with incident common immune-mediated inflammatory diseases diagnosed between April 1, 1997, and Dec 31, 2019, were followed up from the first diagnosis date to the occurrence of an outcome or date of last follow-up. Cases (ie, those with an outcome of interest) were age-matched and sex-matched to up to ten contemporaneous controls by use of incidence density sampling. Outcomes were hospitalisation due to pneumonia, death due to pneumonia, or primary-care consultation for lower respiratory tract infection requiring antibiotics. We defined hospital admission for pneumonia using hospital discharge diagnoses, death due to pneumonia using death certification data, and lower respiratory tract infection as present when primary-care consultation and antibiotic prescription occurred on the same date. We used multivariable, unconditional, logistical regression and constructed three models to examine the association between pneumococcal vaccination as an exposure and each of the three outcomes. FINDINGS: The first nested case-control analysis included 12 360 patients (7326 [59·3%] women and 5034 [40·7%] men): 1884 (15·2%) who were hospitalised due to pneumonia and 10 476 (84·8%) who were not admitted to hospital due to pneumonia. The second analysis included 5321 patients (3112 [58·5%] women and 2209 [41·5%] men): 781 (14·7%) who died due to pneumonia and 4540 (85·3%) who were alive on the index date. The third analysis included 54 530 patients (33 605 [61·6%] women and 20 925 [38·4%] men): 10 549 (19·3%) with lower respiratory tract infection treated with antibiotics and 43 981 (80·7%) without infection. In the multivariable analysis, pneumococcal vaccination was negatively associated with hospitalisation due to pneumonia (adjusted odds ratio 0·70 [95% CI 0·60-0·81]), death due to pneumonia (0·60 [0·48-0·76]), and lower respiratory tract infection treated with antibiotics (0·76 [0·72-0·80]). INTERPRETATION: Pneumococcal vaccination is associated with protection against hospitalisation and death due to pneumonia in patients with immune-mediated inflammatory diseases, without apparent residual confounding. However, residual unmeasured confounding cannot be fully excluded in observational research, which includes nested case-control studies. These findings should also be corroborated with data from other countries, given that this study used UK-based data. FUNDING: National Institute for Health and Care Research.

Uptake, safety and effectiveness of inactivated influenza vaccine in inflammatory bowel disease: a UK-wide study.

OBJECTIVE: To investigate (1) the UK-wide inactivated influenza vaccine (IIV) uptake in adults with inflammatory bowel disease (IBD), (2) the association between vaccination against influenza and IBD flare and (3) the effectiveness of IIV in preventing morbidity and mortality. DESIGN: Data for adults with IBD diagnosed before the 1 September 2018 were extracted from the Clinical Practice Research Datalink Gold. We calculated the proportion of people vaccinated against seasonal influenza in the 2018-2019 influenza cycle. To investigate vaccine effectiveness, we calculated the propensity score (PS) for vaccination and conducted Cox proportional hazard regression with inverse-probability treatment weighting on PS. We employed self-controlled case series analysis to investigate the association between vaccination and IBD flare. RESULTS: Data for 13 631 people with IBD (50.4% male, mean age 52.9 years) were included. Fifty percent were vaccinated during the influenza cycle, while 32.1% were vaccinated on time, that is, before the seasonal influenza virus circulated in the community. IIV was associated with reduced all-cause mortality (aHR (95% CI): 0.73 (0.55,0.97) but not hospitalisation for pneumonia (aHR (95% CI) 0.52 (0.20-1.37), including in the influenza active period (aHR (95% CI) 0.48 (0.18-1.27)). Administration of the IIV was not associated with IBD flare. CONCLUSION: The uptake of influenza vaccine was low in people with IBD, and the majority were not vaccinated before influenza virus circulated in the community. Vaccination with the IIV was not associated with IBD flare. These findings add to the evidence to promote vaccination against influenza in people with IBD.

Risk-stratified monitoring for sulfasalazine toxicity: prognostic model development and validation.

BACKGROUND: Sulfasalazine-induced cytopenia, nephrotoxicity and hepatotoxicity is uncommon during long-term treatment. Some guidelines recommend 3 monthly monitoring blood tests indefinitely during long-term treatment while others recommend stopping monitoring after 1 year. To rationalise monitoring, we developed and validated a prognostic model for clinically significant blood, liver or kidney toxicity during established sulfasalazine treatment. DESIGN: Retrospective cohort study. SETTING: UK primary care. Data from Clinical Practice Research Datalink Gold and Aurum formed independent development and validation cohorts. PARTICIPANTS: Age ≥18 years, new diagnosis of an inflammatory condition and sulfasalazine prescription. STUDY PERIOD: 1 January 2007 to 31 December 2019. OUTCOME: Sulfasalazine discontinuation with abnormal monitoring blood-test result. ANALYSIS: Patients were followed up from 6 months after first primary care prescription to the earliest of outcome, drug discontinuation, death, 5 years or 31 December 2019. Penalised Cox regression was performed to develop the risk equation. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. RESULTS: 8936 participants were included in the development cohort (473 events, 23 299 person-years) and 5203 participants were included in the validation cohort (280 events, 12 867 person-years). Nine candidate predictors were included. The optimism adjusted R2 D and Royston D statistic in the development data were 0.13 and 0.79, respectively. The calibration slope (95% CI) and Royston D statistic (95% CI) in validation cohort was 1.19 (0.96 to 1.43) and 0.87 (0.67 to 1.07), respectively. CONCLUSION: This prognostic model for sulfasalazine toxicity uses readily available data and should be used to risk-stratify blood-test monitoring during established sulfasalazine treatment.

Uptake and safety of pneumococcal vaccination in adults with immune mediated inflammatory diseases: a UK wide observational study.

OBJECTIVE: The uptake and safety of pneumococcal vaccination in people with immune mediated inflammatory diseases (IMIDs) is poorly understood. We investigated the UK wide pneumococcal vaccine uptake in adults with IMIDs and explored the association between vaccination and IMID flare. METHODS: Adults with IMIDs diagnosed on or before 01/09/2018, prescribed steroid-sparing drugs within the last 12 months and contributing data to the Clinical Practice Research Datalink Gold were included. Vaccine uptake was assessed using a cross-sectional study design. Self-controlled case series (SCCS) analysis investigated the association between pneumococcal vaccination and IMID flare. The SCCS observation period was up-to six-month before and after pneumococcal vaccination. This was partitioned into a 14-day pre-vaccination induction, 90-days post-vaccination exposed, and the remaining unexposed periods. RESULTS: We included 32 277 patients, 14 151 with RA, 13 631 with IBD, 3,804 with axial spondyloarthritis and 691 with SLE. Overall, 57% were vaccinated against pneumococcus. Vaccine uptake was lower in those younger than 45 years (32%), with IBD (42%), and without additional indication(s) for vaccination (46%). In the vaccine-safety study, data for 1,067, 935, and 451vaccinated patients with primary-care consultations for joint pain, AIRD flare and IBD flare respectively were included. Vaccination against pneumococcal pneumonia was not associated with primary-care consultations for joint pain, AIRD flare and IBD flare in the exposed period with incidence rate ratios (95% Confidence Interval) 0.95 (0.83-1.09), 1.05 (0.92-1.19), and 0.83 (0.65-1.06) respectively. CONCLUSION: Uptake of pneumococcal vaccination in UK patients with IMIDs was suboptimal. Vaccination against pneumococcal disease was not associated with IMID flare.

Discontinuation of anti-tumour necrosis factor alpha treatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

BACKGROUND: There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. OBJECTIVES: To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. METHODS: A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. RESULTS: The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. CONCLUSIONS: Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

Risk-stratified monitoring for thiopurine toxicity in immune-mediated inflammatory diseases: prognostic model development, validation, and, health economic evaluation.

Background: Patients established on thiopurines (e.g., azathioprine) are recommended to undergo three-monthly blood tests for the early detection of blood, liver, or kidney toxicity. These side-effects are uncommon during long-term treatment. We developed a prognostic model that could be used to inform risk-stratified decisions on frequency of monitoring blood-tests during long-term thiopurine treatment, and, performed health-economic evaluation of alternate monitoring intervals. Methods: This was a retrospective cohort study set in the UK primary-care. Data from the Clinical Practice Research Datalink Aurum and Gold formed development and validation cohorts, respectively. People age ≥18 years, diagnosed with an immune mediated inflammatory disease, prescribed thiopurine by their general practitioner for at-least six-months between January 1, 2007 and December 31, 2019 were eligible. The outcome was thiopurine discontinuation with abnormal blood-test results. Patients were followed up from six-months after first primary-care thiopurine prescription to up to five-years. Penalised Cox regression developed the risk equation. Multiple imputation handled missing predictor data. Calibration and discrimination assessed model performance. A mathematical model evaluated costs and quality-adjusted life years associated with lengthening the interval between blood-tests. Findings: Data from 5982 (405 events over 16,117 person-years) and 3573 (269 events over 9075 person-years) participants were included in the development and validation cohorts, respectively. Fourteen candidate predictors (21 parameters) were included. The optimism adjusted R2 and Royston D statistic in development data were 0.11 and 0.76, respectively. The calibration slope and Royston D statistic (95% Confidence Interval) in the validation data were 1.10 (0.84-1.36) and 0.72 (0.52-0.92), respectively. A 2-year period between monitoring blood-test was most cost-effective in all deciles of predicted risk but the gain between monitoring annually or biennially reduced in higher risk deciles. Interpretation: This prognostic model requires information that is readily available during routine clinical care and may be used to risk-stratify blood-test monitoring for thiopurine toxicity. These findings should be considered by specialist societies when recommending blood monitoring during thiopurine prescription to bring about sustainable and equitable change in clinical practice. Funding: National Institute for Health and Care Research.

Risk stratified monitoring for methotrexate toxicity in immune mediated inflammatory diseases: prognostic model development and validation using primary care data from the UK.

OBJECTIVE: To develop and validate a prognostic model to inform risk stratified decisions on frequency of monitoring blood tests during long term methotrexate treatment. DESIGN: Retrospective cohort study. SETTING: Electronic health records within the UK's Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum. PARTICIPANTS: Adults (≥18 years) with a diagnosis of an immune mediated inflammatory disease who were prescribed methotrexate by their general practitioner for six months or more during 2007-19. MAIN OUTCOME MEASURE: Discontinuation of methotrexate owing to abnormal monitoring blood test result. Patients were followed-up from six months after their first prescription for methotrexate in primary care to the earliest of outcome, drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or 31 December 2019. Cox regression was performed to develop the risk equation, with bootstrapping used to shrink predictor effects for optimism. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination. RESULTS: Data from 13 110 (854 events) and 23 999 (1486 events) participants were included in the development and validation cohorts, respectively. 11 candidate predictors (17 parameters) were included. In the development dataset, the optimism adjusted R2 was 0.13 and the optimism adjusted Royston D statistic was 0.79. The calibration slope and Royston D statistic in the validation dataset for the entire follow-up period was 0.94 (95% confidence interval 0.85 to 1.02) and 0.75 (95% confidence interval 0.67 to 0.83), respectively. The prognostic model performed well in predicting outcomes in clinically relevant subgroups defined by age group, type of immune mediated inflammatory disease, and methotrexate dose. CONCLUSION: A prognostic model was developed and validated that uses information collected during routine clinical care and may be used to risk stratify the frequency of monitoring blood test during long term methotrexate treatment.

Is Vaccination Against COVID-19 Associated With Inflammatory Bowel Disease Flare? Self-Controlled Case Series Analysis Using the UK CPRD.

INTRODUCTION: To investigate the association between vaccination against coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) flare. METHODS: Patients with IBD vaccinated against COVID-19 who consulted for disease flare between December 1, 2020, and December 31, 2021, were ascertained from the Clinical Practice Research Datalink. IBD flares were identified using consultation and corticosteroid prescription records. Vaccinations were identified using product codes and vaccination dates. The study period was partitioned into vaccine-exposed (vaccination date and 21 days immediately after), prevaccination (7 days immediately before vaccination), and the remaining vaccine-unexposed periods. Participants contributed data with multiple vaccinations and IBD flares. Season-adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) were calculated using self-controlled case series analysis. RESULTS: Data for 1911 cases with IBD were included; 52% of them were female, and their mean age was 49 years. Approximately 63% of participants had ulcerative colitis (UC). COVID-19 vaccination was not associated with increased IBD flares in the vaccine-exposed period when all vaccinations were considered (aIRR [95% CI] 0.89 [0.77-1.02], 0.79 [0.66-0.95], and 1.00 [0.79-1.27] in IBD overall, UC, and Crohn's disease, respectively). Analyses stratified to include only first, second, or third COVID-19 vaccinations found no significant association between vaccination and IBD flares in the vaccine-exposed period (aIRR [95% CI] 0.87 [0.71-1.06], 0.93 [0.75-1.15], and 0.86 [0.63-1.17], respectively). Similarly, stratification by COVID-19 before vaccination and by vaccination with vectored DNA or messenger RNA vaccine did not reveal an increased risk of flare in any of these subgroups. DISCUSSION: Vaccination against COVID-19 was not associated with IBD flares regardless of prior COVID-19 infection and whether messenger RNA or DNA vaccines were used.

Risk of Venous Thromboembolism With Gout Flares.

OBJECTIVE: Previous studies demonstrated that the risk of venous thromboembolism (VTE) is increased in patients with gout, but not whether there was a temporal association between gout flare and VTE. This study was undertaken to evaluate potential temporal associations between gout flare and VTE. METHODS: Data were obtained from electronic primary-care records from the UK's Clinical Practice Research Datalink, which links data from hospitalization and mortality registers. Using self-controlled case series analysis adjusted for season and age, we evaluated the temporal association between gout flare and VTE. The 90 days after primary-care consultation or hospitalization for gout flare was designated the exposed period. This was divided into three 30-day intervals. The baseline period was up to 2 years before the start of and up to 2 years after the end of the exposed period. The association between gout flare and VTE was measured using adjusted incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). RESULTS: In total, 314 patients met the inclusion criteria (age ≥18 years, incident gout, no presence of VTE or use of a primary-care anticoagulant prescription before the start of the pre-exposure period). Among the 314 patients, VTE incidence was significantly higher in the exposed period than in the baseline period (adjusted IRR 1.83, 95% CI 1.30-2.59). The adjusted IRR of VTE during the first 30 days after gout flare was 2.31 (95% CI 1.39-3.82) relative to the baseline period. No increase in the adjusted IRRs was observed in days 31-60 (adjusted IRR 1.49, 95% CI 0.79-2.81) and days 61-90 (adjusted IRR 1.67, 95% CI 0.91-3.06) relative to baseline. Results were consistent across sensitivity analyses. CONCLUSION: Among patients with gout, there was a transient increase in the rate of VTE within 30 days after primary-care consultation or hospitalization for gout flare.

Is vaccination against COVID-19 associated with autoimmune rheumatic disease flare? A self-controlled case series analysis.

OBJECTIVES: To investigate the association between vaccination against coronavirus disease 2019 (COVID-19) and autoimmune rheumatic disease (AIRD) flare. MATERIAL AND METHODS: Patients with AIRDs vaccinated against COVID-19 who consulted for disease flare between 1 December 2020 and 31 December 2021 were ascertained in Clinical Practice Research Datalink (Aurum). AIRD flare was defined as consultation for AIRD with CS prescription on the same day or the next day. Vaccination was defined using date of vaccination and product code. The observation period was partitioned into vaccine-exposed (21 days after vaccination), pre-vaccination (7 days before vaccination) and remaining vaccine-unexposed periods. Participants contributed data with multiple vaccinations and outcomes. Season adjusted incidence rate ratios (aIRR) and 95% CI were calculated using self-controlled case series analysis. RESULTS: Data for 3554 AIRD cases, 72% female, mean age 65 years and 68.3% with RA, were included. COVID-19 vaccination was associated with significantly fewer AIRD flares in the 21-day vaccine-exposed period when all vaccinations were considered [aIRR (95% CI) 0.89 (0.80, 0.98)]. Using dose-stratified analyses there was a statistically significant negative association in the 21 days after first COVID-19 vaccination but no association after the second or third COVID-19 vaccinations [aIRR (95% CI) 0.76 (0.66, 0.89), 0.94 (0.79, 1.11) and 1.01 (0.85, 1.20), respectively]. On AIRD-type stratified analyses, vaccination was not associated with disease flares. Vaccination without or after severe acute respiratory syndrome coronavirus 2 infection, and with vectored DNA or mRNA vaccines, associated with comparable reduced risk of AIRD flares in the vaccine-exposed period after first COVID-19 vaccination. CONCLUSIONS: Vaccination against COVID-19 was not associated with increased AIRD flares regardless of prior COVID-19, AIRD type, and whether mRNA or DNA vaccination technology were used.

The impact of repeated vaccination on relative influenza vaccine effectiveness among vaccinated adults in the United Kingdom.

Annual seasonal influenza vaccination is recommended for individuals at high risk of developing post-infection complications in many locations. However, reduced vaccine immunogenicity and effectiveness have been observed among repeat vaccinees in some influenza seasons. We investigated the impact of repeated influenza vaccination on relative vaccine effectiveness (VE) among individuals who were recommended for influenza vaccination in the United Kingdom with a retrospective cohort study using primary healthcare data from the Clinical Practice Research Datalink, a primary care database in the United Kingdom. Relative VE was estimated against general practitioner-diagnosed influenza-like illnesses (GP-ILI) and medically attended acute respiratory illnesses (MAARI) among participants who have been repeatedly vaccinated compared with first-time vaccinees using proportional hazards models. Relative VE against MAARI may be reduced for individuals above 65 years old who were vaccinated in the current and previous influenza seasons for some influenza seasons. However, these findings were not conclusive as we could not exclude the possibility of residual confounding in our dataset. The use of routinely collected data from electronic health records to examine the effects of repeated vaccination needs to be complemented with sufficient efforts to include negative control outcomes to rule out residual confounding.

Feasibility of conducting a randomized, placebo-controlled study assessing whether omega-3 fatty acids prevent gout flares when starting urate-lowering treatment.

Objective: The aim was to test the feasibility of a randomized controlled trial exploring whether omega-3 fatty acid supplementation limits gout flares during treat-to-target urate-lowering treatment (T2T-ULT). Methods: Adults with at least one gout flare in the past 12 months and serum urate (SU) ≥360 µmol/l were recruited from general practices (primary method) and randomly assigned 1:1 to receive omega-3 fatty acid supplementation (4 g/day) or placebo for 28 weeks. At week 5, participants began T2T-ULT. The primary outcome was drop-out rate. Secondary outcomes were recruitment rate, outcome data completeness, the number, severity and duration of gout flares between weeks 5 and 28, and study drug compliance. Results: Ninety-five per cent of randomized participants (n = 60) completed all study visits. The primary method recruitment rate was 2.2%. Fifty and 42 participants achieved SU < 360 and 300 µmol/l (6 and 5 mg/dl), respectively. The number of gout flares [median (interquartile range): active 1 (0-2) and placebo 1 (0-2)], flare duration [mean (s.d.): active 7.00 (4.52) days and placebo 7.06 (8.14) days] and time to first flare [hazard ratio (95% CI) 0.97 (0.50, 1.86)] were comparable between both arms. Study drug compliance was high and comparable in both arms [median (interquartile range) returned capsule count: active 57 (26-100) and placebo 58 (27-154)]; red blood cell omega-3 fatty acid index increased twofold in the active arm and remained unchanged in the control arm. Conclusion: The study demonstrated feasibility and provided useful metrics for conducting a community-based gout flare prophylaxis trial. Study registration: ISRCTN; https://www.isrctn.com/; ISRCTN79392964.

Association Between Gout Flare and Subsequent Cardiovascular Events Among Patients With Gout.

Importance: Gout is associated with cardiovascular diseases. The temporal association between gout flares and cardiovascular events has not been investigated. Objective: To investigate whether there is a transient increase in risk of cardiovascular events after a recent gout flare. Design, Setting, and Participants: A retrospective observational study was conducted using electronic health records from the Clinical Practice Research Datalink in England between January 1, 1997, and December 31, 2020. A multivariable nested case-control study was performed among 62 574 patients with gout, and a self-controlled case series, adjusted for season and age, was performed among 1421 patients with gout flare and cardiovascular event. Exposures: Gout flares were ascertained using hospitalization, primary care outpatient, and prescription records. Main Outcomes and Measures: The primary outcome was a cardiovascular event, defined as an acute myocardial infarction or stroke. Association with recent prior gout flares was measured using adjusted odds ratios (ORs) with 95% CIs in a nested case-control study and adjusted incidence rate ratios (IRRs) with 95% CIs in a self-controlled case series. Results: Among patients with a new diagnosis of gout (mean age, 76.5 years; 69.3% men, 30.7% women), 10 475 patients with subsequent cardiovascular events were matched with 52 099 patients without cardiovascular events. Patients with cardiovascular events, compared with those who did not have cardiovascular events, had significantly higher odds of gout flare within the prior 0 to 60 days (204/10 475 [2.0%] vs 743/52 099 [1.4%]; adjusted OR, 1.93 [95% CI, 1.57-2.38]) and within the prior 61 to 120 days (170/10 475 [1.6%] vs 628/52 099 [1.2%]; adjusted OR, 1.57 [95% CI, 1.26-1.96]). There was no significant difference in the odds of gout flare within the prior 121 to 180 days (148/10 475 [1.4%] vs 662/52 099 [1.3%]; adjusted OR, 1.06 [95% CI, 0.84-1.34]). In the self-controlled case series (N = 1421), cardiovascular event rates per 1000 person-days were 2.49 (95% CI, 2.16-2.82) within days 0 to 60; 2.16 (95% CI, 1.85-2.47) within days 61 to 120; and 1.70 (95% CI, 1.42-1.98) within days 121 to 180 after a gout flare, compared with cardiovascular event rates of 1.32 (95% CI, 1.23-1.41) per 1000 person-days within the 150 days before or the 181 to 540 days after the gout flare. Compared with 150 days before or the 181 to 540 days after a gout flare, incidence rate differences for cardiovascular events were 1.17 (95% CI, 0.83-1.52) per 1000 person-days, and adjusted IRRs were 1.89 (95% CI, 1.54-2.30) within days 0 to 60; 0.84 (95% CI, 0.52-1.17) per 1000 person-days and 1.64 (95% CI, 1.45-1.86) within days 61 to 120; and 0.38 (95% CI, 0.09-0.67) per 1000 person-days and 1.29 (95% CI, 1.02-1.64) within days 121 to 180 after a gout flare. Conclusions and Relevance: Among individuals with gout, those who experienced a cardiovascular event, compared with those who did not experience such an event, had significantly higher odds of a recent gout flare in the preceding days. These findings suggest gout flares are associated with a transient increase in cardiovascular events following the flare.

Incidence and pattern of mycophenolate discontinuation associated with abnormal monitoring blood-test results: cohort study using data from the Clinical Practice Research Datalink Aurum.

Objective: The aim was to examine the incidence and pattern of MMF discontinuation associated with abnormal monitoring blood-test results. Methods: Data from people prescribed MMF for common inflammatory conditions in the Clinical Practice Research Datalink were used. Participants were followed from the first MMF prescription. The primary outcome was drug discontinuation with an associated abnormal blood-test result within 60 days. Secondary outcomes were drug discontinuation for any reason and discontinuation associated with severely abnormal blood-test results within 60 days. Multivariable Cox regression was used to examine factors associated with the primary outcome. Results: The cohort included 992 participants (68.9% female, mean age 51.95 years, 47.1% with SLE) contributing 1885 person-years of follow-up. The incidence of MMF discontinuation associated with any (severely) abnormal blood-test results was 153.46 (21.07) per 1000 person-years in the first year of prescription and 32.39 (7.91) per 1000 person-years in later years. Of those patients prescribed MMF, 11.5% (1.7%) discontinued treatment with any (severely) abnormal blood-test results in the first year of prescription. After this period, a mean of 2.6% (0.7%) of patients discontinued treatment with any (severely) abnormal blood-test results per year. Increased serum creatinine and cytopenia were more commonly associated with MMF discontinuation than elevated liver enzymes. Chronic kidney disease stage 3 or higher was significantly associated with MMF discontinuation with any blood-test abnormalities [adjusted hazard ratio (95% CI) 2.22 (1.47, 3.37)]. Conclusion: MMF is uncommonly discontinued for blood-test abnormalities and even less often discontinued for severe blood-test abnormalities after the first year of prescription. Consideration can be given to less frequent monitoring after 1 year of treatment, especially in those without chronic kidney disease stage 3 or higher.

Development and validation of a prognostic model for leflunomide discontinuation with abnormal blood tests during long-term treatment: cohort study using data from the Clinical Practice Research Datalink Gold and Aurum.

OBJECTIVE: To develop and validate a prognostic model for LEF discontinuation with abnormal blood test results. METHODS: Data from the Clinical Practice Research Datalink Gold and Aurum were used for model development and external validation, respectively. Participants prescribed LEF between 1 January 2007 and 31 December 2019 were followed up from 6 months after the first general practitioner prescription to the earliest of date of outcome, death, 5 year follow-up or 31 December 2019. Candidate prognostic factors were ascertained using theory and data-driven approaches. Penalized Cox regression was performed to develop the risk equation, followed by internal validation using 500 bootstraps to correct for optimism. Multiple imputation was applied to handle missing data. Model performance was assessed in terms of calibration and discrimination. RESULTS: Data for 1487 and 2329 participants contributing 3140 and 5246 person-years follow-up were included in the development and validation cohorts, respectively. Thirteen candidate predictors were included in the model. Epilepsy and either cytopenia or elevated liver enzymes during the first 6 months of shared-care LEF prescription were strong predictors of drug discontinuation with a hazard ratio of 4.39 (95% CI 1.74, 11.06) and 3.06 (2.15, 4.35), respectively. The unadjusted and optimism-adjusted calibration slope in development data was 1.00 (95% CI 0.75, 1.25) and 0.72 (95% CI 0.47, 0.97), respectively. The calibration slope in validation data was 0.91 (95% CI 0.74, 1.07). The model showed prognostic separation with an optimism-adjusted Royston D statistic of 0.73 (95% CI 0.44, 1.02). CONCLUSION: We have developed and externally validated an easy-to-use prognostic model that may be used to risk stratify monitoring for LEF toxicity and to make informed choices about risks when choosing treatments.