Association between inactivated influenza vaccine and primary care consultations for autoimmune rheumatic disease flares: a self-controlled case series study using data from the Clinical Practice Research Datalink.

Objectives: To examine the association between inactivated influenza vaccine (IIV) administration and primary care consultation for joint pain, rheumatoid arthritis (RA) flare, corticosteroid prescription, vasculitis and unexplained fever in people with autoimmune rheumatic diseases (AIRDs). METHODS: We undertook within-person comparisons using self-controlled case-series methodology. AIRD cases who received the IIV and had an outcome of interest in the same influenza cycle were ascertained in Clinical Practice Research Datalink. The influenza cycle was partitioned into exposure periods (1-14 days prevaccination and 0-14, 15-30, 31-60 and 61-90 days postvaccination), with the remaining time-period classified as non-exposed. Incidence rate ratios (IRR) and 95% CI for different outcomes were calculated. RESULTS: Data for 14 928 AIRD cases (69% women, 80% with RA) were included. There was no evidence for association between vaccination and primary care consultation for RA flare, corticosteroid prescription, fever or vasculitis. On the contrary, vaccination associated with reduced primary care consultation for joint pain in the subsequent 90 days (IRR 0.91 (95% CI 0.87 to 0.94)). CONCLUSION: This study found no evidence for a significant association between vaccination and primary care consultation for most surrogates of increased disease activity or vaccine adverse-effects in people with AIRDs. It adds to the accumulating evidence to support influenza vaccination in AIRDs

What is the incidence of methotrexate or leflunomide discontinuation related to cytopenia, liver enzyme elevation or kidney function decline?

OBJECTIVES: To examine incidence of treatment changes due to abnormal blood-test results and, to explore rates of treatment changes due to liver, kidney and haematological blood-test abnormalities in autoimmune rheumatic diseases (AIRD) treated with low-dose methotrexate or leflunomide. METHODS: Data for people with AIRDs prescribed methotrexate or leflunomide were extracted from the Clinical Practice Research Datalink. Participants were followed-up from first prescription of methotrexate or leflunomide in primary-care. Primary outcome of interest was drug discontinuation, defined as a prescription gap of ≥ 90 days following an abnormal (or severely abnormal) blood-test result. Dose reduction was examined between consecutive prescriptions. Incidence rates per 1,000 person-years were calculated. RESULTS: 15,670 and 2,689 participants contributing 46,571 and 4,558 person-years follow-up were included in methotrexate and leflunomide cohorts respectively. The incidence of methotrexate and leflunomide discontinuation with abnormal (severely abnormal) blood-test was 42.24(6.16) and 106.53(9.42)/1,000 person-years in year-1, and 22.44(2.84) and 31.69(4.40)/1,000 person-years respectively thereafter. The cumulative incidence of methotrexate and leflunomide discontinuation with abnormal (severely abnormal) blood-tests was 1 in 24(1 in 169), 1 in 9(1 in 106) at 1-year; and 1 in 45(1 in 352), 1 in 32(1 in 227) per-year respectively thereafter. Raised liver enzymes were the commonest abnormality associated with drug discontinuation. Methotrexate and leflunomide dose reduction incidence were comparable in year-1, however, thereafter methotrexate dose was reduced more often than leflunomide (16.60(95% CI; 13.05-21.13) vs. 8.10(95% CI; 4.97-13.20)/1,000 person-years). CONCLUSION: Methotrexate and leflunomide were discontinued for blood-test abnormalities after year-1 of treatment, however, discontinuations for severely abnormal results were uncommon

Do β-adrenoreceptor blocking drugs associate with reduced risk of symptomatic osteoarthritis and total joint replacement in the general population? A primary care-based, prospective cohort study using the Clinical Practice Research Datalink.

INTRODUCTION: To investigate if β-adrenoreceptor blocking drug (β-blocker) prescription reduces the risk of knee or hip osteoarthritis, total joint replacement and analgesic prescription. SETTING: Primary care. METHODS AND ANALYSIS: This is a cohort study using data from the Clinical Practice Research Datalink. Two separate analyses will be performed. Study 1 will be on the association between β-blocker prescription and incident knee/hip osteoarthritis. Inclusion criteria will be age ≥40 years. Exposed participants will be those with ≥2 continuous β-blocker prescriptions, and the index date will be the date of the first prescription of β-blocker. Unexposed participants will include up to four controls matched for age, sex, general practice surgery and propensity score for β-blocker prescription. Exclusion criteria will include contraindications to β-blockers, consultations for osteoarthritis or potent analgesic prescription before the index date. Outcomes will be knee osteoarthritis (primary outcome), hip osteoarthritis, knee pain and hip pain. Study 2 will be on the association between β-blocker prescription and total joint replacement and analgesic prescription in people with osteoarthritis. Inclusion criteria will be age ≥40 years, knee or hip osteoarthritis, and index date will be as in study 1. Unexposed participants will be as in study 1, additionally matched for consultation for knee or hip osteoarthritis prior to the index date. Exclusion criteria will include contraindications to β-blockers and osteoarthritis in other joints prior to the index date. Outcomes will be total knee replacement (primary outcome), total hip replacement and new analgesic prescription. STATISTICAL ANALYSIS: Kaplan-Meier curves will be plotted, and Cox proportional HRs and 95% CIs will be calculated. Stratified analysis will be performed by class of β-blocker, intrinsic sympathomimetic effect and indication(s) for prescription. ETHICS AND DISSEMINATION: This study was ethically approved by the Independent Scientific Advisory Committee of the Medicines and Healthcare Authority (Ref 18_227R). The results of this study will be published in peer-reviewed journals and presented at conferences. SUMMARY: This prospective cohort study will evaluate the analgesic potential of commonly used drugs for osteoarthritis pain

β-blocker prescription is associated with lower cumulative risk of knee osteoarthritis and knee pain consultations in primary care: a propensity score matched cohort study

OBJECTIVES: To examine the association between β-blocker prescription and first primary-care consultation for knee osteoarthritis (OA), hip OA, knee pain and hip pain. METHODS: Data source: Clinical Practice Research Datalink. Participants aged ≥40 years in receipt of new oral β-blocker prescriptions were propensity score (PS) matched to an unexposed control. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CI) were calculated, and adjusted for non-osteoporotic fractures, number of primary-care consultations for knee or hip injury, and, the number of primary-care consultations, out-patient referrals and hospitalizations in the 12-months preceding cohort entry. Analysis was stratified according to β-blocker class and for commonly prescribed drugs. p< 0.05 was statistically significant.  . RESULTS: 111 718 β-blocker exposed participants were 1:1 PS matched to unexposed controls. β-blocker prescription was associated with reduced cumulative risk of knee OA, knee pain, and hip pain consultations with aHR(95%CI) 0.90(0.83-0.98); 0.88(0.83-0.92), and 0.85(0.79-0.90), respectively. Propranolol and atenolol were associated with a lower incidence of knee OA and knee pain consultations with aHRs between 0.78-0.91. β-blockers were associated with reduced incidence of consultation for large-joint lower-limb OA/pain as a composite outcome, defined as earliest of knee OA, knee pain, hip OA or hip pain consultation (aHR(95%CI) 0.87(0.84-0.90)). CONCLUSION: Commonly used β-blockers have analgesic properties for musculoskeletal pain. Atenolol might be a therapeutic option for OA and cardiovascular co-morbidities in which β-blockers are indicated, while propranolol may be suitable for people with co-morbid anxiety. A confirmatory randomised controlled trial is needed before clinical practice is changed

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

Abstract Objective To examine the incidence and pattern of mycophenolate discontinuation associated with abnormal monitoring blood-tests. Methods Data from people prescribed mycophenolate for common inflammatory conditions in the Clinical Practice Research Datalink was used. Participants were followed from first mycophenolate prescription. Primary outcome was drug discontinuation with an associated abnormal blood-test result within 60 days. Secondary outcomes were drug discontinuation for any reason, and discontinuations associated with severely abnormal blood-test results within 60 days. Multivariable cox-regression was used to examine factors associated with primary outcome. Results The cohort included 992 participants (68.9% female, mean age 51.95 years, 47.1% with SLE) contributing 1,885 person-years of follow-up. The incidence of mycophenolate discontinuation associated with any (severely) abnormal blood-test results was 153.46 (21.07) per 1000 person-years in the first, and 32.39 (7.91) per 1000 person-years in later years of prescription, respectively. 11.5% (1.7%) patients prescribed mycophenolate discontinued treatment with any (severely) abnormal blood-test results in the first year of prescription. After this period mean 2.6% (0.7%) patients discontinued treatment with any (severely) abnormal blood-test results per year. Increased serum creatinine and cytopenia were more commonly associated with mycophenolate discontinuation than elevated liver enzymes. CKD-stage ≥3 was significantly associated with mycophenolate discontinuation with any blood-test abnormalities (aHR (95%CI) 2.22 (1.47–3.37)). Conclusion Mycophenolate is uncommonly discontinued for blood-test abnormalities, and, even less often discontinued for severe blood-test abnormalities after the first year of prescription. Consideration may be given for less frequent monitoring after one-year of treatment, especially in those without CKD-stage ≥3. </jats:sec

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

Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p &lt; 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival

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, and self-controlled case series adjusted for season and age were performed among 62574 patients with gout, and 1421 patients with gout flare and cardiovascular event, respectively. Exposures Gout flares were ascertained using hospitalization, primary-care outpatient consultation 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 (aOR) and adjusted incidence rate ratios (aIRR) with 95% confidence intervals (95%CI) in a nested case-control study and a self-controlled case series, respectively. Results Among patients with a new diagnosis of gout (mean age 76.5 years, 69.3% men), 10475 patients with subsequent cardiovascular events were matched to 52099 patients without cardiovascular events. Patients with cardiovascular events, compared to those without cardiovascular events, had significantly higher odds of gout flare within the prior 0-60 days (204/10475 (2.0%) vs 743/52099 (1.4%); aOR, 1.93 (95%CI, 1.57-2.38)) and 61-120 days (170/10475 (1.6%) vs 628/52099 (1.2%); aOR, 1.57 (95%CI, 1.26-1.96). There was no significant difference in the odds of gout flare within prior 121-180 days (148/10475 (1.4%) vs 662/52099 (1.3%); aOR, 1.06 (95%CI, 0.84-1.34)). In the self-controlled case series (N=1421), cardiovascular event rates (95%CI) were 2.49 (2.16-2.82); 2.16 (1.85-2.47); 1.70 (1.42-1.98)/1000 person-days during 0-60, 61-120, 121-180 days after gout flare compared to 1.32 (1.23-1.41)/1000 person-days during the 180 days before and 181-540 days after the gout flare. Compared with 180 days before and 181-540 days after a gout flare, incidence rate differences (95%CI) and aIRRs (95%CI) for cardiovascular events were 1.17 (0.83-1.52), 0.84 (0.52-1.17), 0.38 (0.09-0.67)/1000 person-days, and 1.89 (1.54-2.30); 1.64 (1.45-1.86); 1.29 (1.02-1.64) within 0-60, 61-120, and 121-180 days after a gout flare, respectively. 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