Prognostic factors for colchicine prophylaxis-related adverse events when initiating allopurinol for gout: retrospective cohort study.

OBJECTIVES: Colchicine is commonly used to prevent flares when starting urate-lowering therapy for gout. Patients with gout are frequently concurrently prescribed other medications (such as statins) that may interact with colchicine, increasing the risk of adverse events. The aim of this study was to describe potential prognostic factors for adverse events in patients prescribed colchicine when initiating allopurinol. METHODS: We conducted a retrospective cohort study in linked UK Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Adults initiating allopurinol for gout with colchicine (01/04/1997-30/11/2016) were included. Potential prognostic factors were defined, and the likelihood of adverse events, including diarrhoea, nausea or vomiting, myocardial infarction (MI), neuropathy, myalgia, myopathy, rhabdomyolysis, and bone marrow suppression, were estimated. RESULTS: From 01/04/1997-30/11/2016, 13 945 people with gout initiated allopurinol with colchicine prophylaxis (mean age 63.9 (SD 14.7) years, 78.2% male). One quarter (26%, 95% CI 25% to 27%) were prescribed ≥1 potentially interacting medicines, most commonly statins (21%, 95% CI 20% to 22%). Statins were not associated with increased adverse events, although other drugs were associated with some adverse outcomes. Diarrhoea and MI were associated with more comorbidities and more severe CKD. CONCLUSION: People were given colchicine prophylaxis despite commonly having preexisting prescriptions for medications with potential to interact with colchicine. Adverse events were more common in people who had more comorbidities and certain potentially interacting medications. Our findings will provide much-needed information about prognostic factors for colchicine-related adverse events that can inform treatment decisions about prophylaxis when initiating allopurinol.

The relationship between pain and depression and anxiety in patients with inflammatory arthritis: a systematic review protocol.

Pain is a major challenge for patients with inflammatory arthritis (IA). Depression and anxiety are common comorbidities in IA, associating with worse outcomes. How they relate to pain is uncertain, with existing systematic reviews (a) mainly considering cross-sectional studies, (b) focusing on the relationship between pain and mental health in the context of disease activity/quality of life, and (c) not specifically considering the impact of treating depression/anxiety on pain. This PROSPERO-registered (CRD42023411823) systematic review will address this knowledge-gap by synthesizing evidence to summarise the associations (and potential mediators) between pain and depression/anxiety and evaluate the impact of treating co-morbid depression/anxiety on pain in IA. Relevant databases will be searched, articles screened and their quality appraised (using Joanna Briggs Institute critical appraisal tools) by two reviewers. Eligible studies will include adults with rheumatoid arthritis or spondyloarthritis, be a clinical trial or observational study, and either (a) report the relationship between pain and depression/anxiety (observational studies/baseline trials), or (b) randomise participants to a pharmacological or psychological treatment to manage depression/anxiety with a pain outcome as an endpoint (trials). To synthesise data on the association between pain and depression/anxiety, where available adjusted coefficients from regression models will be pooled in a random-effects meta-analysis. A synthesis without meta-analysis will summarise mediators. To evaluate the impact of treating depression/anxiety on pain, endpoint mean differences between treatment arms will be combined in a random-effects meta-analysis. Through understanding how depression/anxiety contribute to pain in IA, our review has the potential to help optimise approaches to IA pain.

The Long-Term Use of Diagnostic Subdural Electroencephalogram Electrodes and Subdural Hematoma: A Prospective Cohort Study.

OBJECTIVES: Seizures and status epilepticus (SE) are frequent complications of acute subdural hematoma (aSDH) associated with increased morbidity and mortality. Therefore, we aimed to evaluate whether invasive subdural electroencephalogram recording leads to earlier seizure detection and treatment initiation in patients with aSDH. DESIGN: Prospective, single-center, cohort trial. SETTING: Neurologic and neurosurgical ICUs of one academic hospital in Germany. PATIENTS: Patients with aSDH undergoing surgical treatment. In total, 76 patients were enrolled in this study, 31 patients (40.8%) were assigned to the invasive electroencephalogram (iEEG) monitoring group and 45 patients (59.2%) to control group. INTERVENTIONS: The electrode group was implanted with a subdural strip electrode providing up to 7 days of real-time electroencephalogram recording in the neurointensive care unit, whereas the control group received regular normal surface electroencephalograms during the 7-day period. The primary outcomes were the prevalence and time to seizures and SE occurrence. Secondary outcomes included neurologic outcomes assessed using the Glasgow Outcome Scale (GOS) at discharge and 6-month follow-up and the prevalence of focal structural epilepsy within 2 years after discharge. MEASUREMENTS AND MAIN RESULTS: The trial was stopped after a study committee meeting when the prespecified criteria were met. The iEEG and control groups were well-matched for clinical characteristics at admission. Frequencies of seizures and SE detection were significantly higher in the iEEG group than in the control group (61% vs 15.6%; p < 0.001 and 38.7% vs 11.1%; p = 0.005). Time to seizure and SE detection was significantly earlier (median 29.2 vs 83.8 hr; p = 0.018 and 17.2 vs 83.8 hr; p = 0.033) in the iEEG group than in the control group. Favorable outcomes (GOS 4-5) were more frequently achieved in the iEEG group than in the control group (58% vs 31%; p = 0.065). No significant differences were detected in long-term mortality or post-traumatic epilepsy. CONCLUSIONS: Invasive subdural electroencephalogram monitoring is valuable and safe for early seizure/SE detection and treatment and might improve outcomes in the neurocritical care of patients with aSDH.

Safety of colchicine and NSAID prophylaxis when initiating urate-lowering therapy for gout: propensity score-matched cohort studies in the UK Clinical Practice Research Datalink.

OBJECTIVES: To determine the risk of adverse events associated with colchicine or non-steroidal anti-inflammatory drug (NSAID) prophylaxis when initiating allopurinol for gout. METHODS: We conducted two matched retrospective cohort studies in linked UK Clinical Practice Research Datalink and Hospital Episode Statistics datasets. Adults initiating allopurinol for gout with (1) colchicine or (2) NSAID prophylaxis were compared with those initiating without prophylaxis, individually matched by age, sex and propensity to receive the relevant prophylaxis. Weighted Cox proportional hazards models investigated associations between colchicine/NSAID and specified adverse events. RESULTS: 13 945 individuals prescribed colchicine were matched to 13 945 with no prophylaxis and 25 980 prescribed NSAID to 25 980 with no prophylaxis. Adverse event incidence rates were <200/10 000 patient-years except diarrhoea (784.4; 95% CI 694.0 to 886.5) and nausea (208.1; 95% CI 165.4 to 261.7) for colchicine and angina for NSAID (466.6; 95% CI 417.2 to 521.8). Diarrhoea (HR 2.22; 95% CI 1.83 to 2.69), myocardial infarction (MI) (1.55; 95% CI 1.10, 2.17), neuropathy (4.75; 95% CI 1.20 to 18.76), myalgia (2.64; 95% CI 1.45 to 4.81), bone marrow suppression (3.29; 95% CI 1.43 to 7.58) and any adverse event (1.91, 95% CI 1.65 to 2.20) were more common with colchicine than no prophylaxis, but not nausea/vomiting (1.34; 95% CI 0.97 to 1.85). Angina (1.60; 95% CI 1.37 to 1.86), acute kidney injury (1.56; 95% CI 1.20 to 2.03), MI (1.89; 95% CI 1.44 to 2.48), peptic ulcer disease (1.67; 95% CI 1.14 to 2.44) and any adverse event (1.63; 95% CI 1.44 to 1.85) were more common with NSAID than without. CONCLUSIONS: Adverse events were more common when allopurinol was initiated with prophylaxis, particularly diarrhoea with colchicine. Other events were uncommon, providing reassurance for patients and clinicians to enable shared decision-making.

Development and psychometric evaluation of the PMR-Impact Scale: a new patient reported outcome measure for polymyalgia rheumatica.

OBJECTIVES: PMR causes pain, stiffness and disability in older adults. Measuring the impact of the condition from the patient's perspective is vital to high-quality research and patient-centred care, yet there are no validated patient-reported outcome measures (PROMs) for PMR. We set out to develop and psychometrically evaluate a PMR-specific PROM. METHODS: Two cross-sectional postal surveys of people with a confirmed diagnosis of PMR were used to provide data for field testing and psychometric evaluation. A total of 256 participants completed the draft PROM. Distribution of item responses was examined, and exploratory factor analysis and Rasch analysis were used to inform item reduction, formation of dimension structure and scoring system development. Some 179 participants completed the PROM at two time points, along with comparator questionnaires and anchor questions. Test-retest reliability, construct validity and responsiveness were evaluated. RESULTS: Results from the field-testing study led to the formation of the PMR-Impact Scale (PMR-IS), comprising four domains (symptoms, function, psychological and emotional well-being, and steroid side effects). Construct validity and test-retest reliability met accepted quality criteria for each domain. There was insufficient evidence from this study to determine its ability to detect flares/deterioration, but the PMR-IS was responsive to improvements in the condition. CONCLUSION: The PMR-IS offers researchers a new way to assess patient-reported outcomes in clinical studies of PMR. It has been developed robustly, with patient input at every stage. It has good construct validity and test-retest reliability. Further work is needed to fully establish its responsiveness and interpretability parameters, and to assess its real-world clinical utility.

Analgesic prescribing in patients with inflammatory arthritis in England: observational studies in the Clinical Practice Research Datalink.

OBJECTIVES: Despite little evidence that analgesics are effective in inflammatory arthritis (IA), studies report substantial opioid prescribing. The extent this applies to other analgesics is uncertain. We undertook a comprehensive evaluation of analgesic prescribing in patients with IA in the Clinical Practice Research Datalink Aurum to evaluate this. METHODS: From 2004 to 2020, cross-sectional analyses evaluated analgesic prescription annual prevalence in RA, PsA and axial spondyloarthritis (axSpA), stratified by age, sex, ethnicity, deprivation and geography. Joinpoint regression evaluated temporal prescribing trends. Cohort studies determined prognostic factors at diagnosis for chronic analgesic prescriptions using Cox proportional hazards models. RESULTS: Analgesic prescribing declined over time but remained common: 2004 and 2020 IA prescription prevalence was 84.2/100 person-years (PY) (95% CI 83.9, 84.5) and 64.5/100 PY (64.2, 64.8), respectively. In 2004, NSAIDs were most prescribed (56.1/100 PY; 55.8, 56.5), falling over time. Opioids were most prescribed in 2020 (39.0/100 PY; 38.7, 39.2). Gabapentinoid prescribing increased: 2004 prevalence 1.1/100 PY (1.0, 1.2); 2020 prevalence 9.9/100 PY (9.7, 10.0). Most opioid prescriptions were chronic (2020 prevalence 23.4/100 PY [23.2, 23.6]). Non-NSAID analgesic prescribing was commoner in RA, older people, females and deprived areas/northern England. Conversely, NSAID prescribing was commoner in axSpA/males, varying little by deprivation/geography. Peri-diagnosis was high-risk for starting chronic opioid/NSAID prescriptions. Prognostic factors for chronic opioid/gabapentinoid and NSAID prescriptions differed, with NSAIDs having no consistently significant association with deprivation (unlike opioids/gabapentinoids). CONCLUSION: IA analgesic prescribing of all classes is widespread. This is neither evidence-based nor in line with guidelines. Peri-diagnosis is an opportune moment to reduce chronic analgesic prescribing.

Factors associated with change in health-related quality of life in people with gout: a 3-year prospective cohort study in primary care.

OBJECTIVE: To describe factors associated with change in health-related quality of life (HRQOL) in people living with gout in primary care. METHODS: In a UK prospective cohort study, adults with a diagnosis of gout registered with 20 general practices completed the Gout Impact Scale (GIS; scale 0-100), 36-item Short Form Physical Function subscale (PF-10; 0-100) and HAQ Disability Index (HAQ-DI; 0-3) via postal questionnaires at baseline and 6, 12, 24 and 36 months. Linear mixed modelling was used to investigate factors associated with changes in HRQOL over 3 years. RESULTS: A total of 1184 participants responded at baseline (adjusted response 65.6%); 990 (83.6%) were male, with a mean age of 65.6 years (s.d. 12.5). A total of 818, 721, 696 and 605 responded at 6, 12, 24 and 36 months, respectively. Factors associated with worse disease-specific and generic HRQOL over 3 years were flare frequency (five or more flares; GIS subscales, PF-10), oligo/polyarticular flares (GIS subscales, PF-10, HAQ-DI), worse pain (GIS subscales, PF-10, HAQ-DI), body pain (GIS subscales, PF-10, HAQ-DI) and more severe depression (GIS subscales, PF-10, HAQ-DI) (P ≤ 0.05). More severe anxiety was associated with worse disease-specific HRQOL only (GIS subscales). Older age (PF-10), being female (PF-10, HAQ-DI) and BMI (HAQ-DI) were associated with worse generic HRQOL (P ≤ 0.05). CONCLUSION: Gout-specific, comorbid and sociodemographic factors were associated with change in HRQOL over a 3-year period, highlighting people at risk of worse outcomes who could be targeted for interventions.

Analgesic prescribing in patients with inflammatory arthritis in England: an observational study using electronic healthcare record data.

OBJECTIVES: International data suggest inflammatory arthritis (IA) pain management frequently involves opioid prescribing, despite little evidence of efficacy, and potential harms. We evaluated analgesic prescribing in English National Health Service-managed patients with IA. METHODS: Repeated cross-sectional analyses in the Consultations in Primary Care Archive (primary care consultation and prescription data in nine general practices from 2000 to 2015) evaluated the annual prevalence of analgesic prescriptions in: (i) IA cases (RA, PsA or axial spondyloarthritis [SpA]), and (ii) up to five age-, sex- and practice-matched controls. Analgesic prescriptions were classified into basic, opioids, gabapentinoids and oral NSAIDs, and sub-classified into chronic and intermittent (≥3 and 1-2 prescriptions per calendar year, respectively). RESULTS: In 2000, there were 594 cases and 2652 controls, rising to 1080 cases and 4703 controls in 2015. In all years, most (65.3-78.5%) cases received analgesics, compared with fewer (37.5-41.1%) controls. Opioid prescribing in cases fell between 2000 and 2015 but remained common with 45.4% (95% CI: 42.4%, 48.4%) and 32.9% (95% CI: 29.8%, 36.0%) receiving at least 1 and ≥3 opioid prescriptions, respectively, in 2015. Gabapentinoid prescription prevalence in cases increased from 0% in 2000 to 9.5% (95% CI: 7.9%, 11.4%) in 2015, and oral NSAID prescription prevalence fell from 53.7% (95% CI: 49.6%, 57.8%) in 2000 to 25.0% (95% CI: 22.4%, 27.7%) in 2015. Across years, analgesic prescribing was commoner in RA than PsA/axial SpA, and 1.7-2.0 times higher in cases than controls. CONCLUSIONS: Analgesic prescribing in IA is common. This is at variance with existing evidence of analgesic efficacy and risks, and guidelines. Interventions are needed to improve analgesic prescribing in this population.

What non-pharmacological treatments do people with polymyalgia rheumatica try: results from the PMR Cohort Study.

Polymyalgia rheumatica (PMR) is common. The mainstay of treatment, glucocorticoids, are associated with significant adverse effects and many patients remain on high doses for a number of years. Little is known about the use of other, non-pharmacological therapies as adjuncts in PMR. The PMR Cohort Study is an inception cohort study of patients diagnosed with PMR in primary care. This analysis presents data on the use and perceived impact of non-pharmacological therapies from a long-term follow-up survey. Non-pharmacological treatments were classified as either diet, exercise, or complementary therapies. Results are presented as adjusted means, medians, and raw counts where appropriate. One hundred and ninety-seven participants completed the long-term follow-up questionnaire, of these 81 (41.1%) reported using non-pharmacological therapy. Fifty-seven people reported using a form of complementary therapy, 35 used exercise and 20 reported changing their diet. No individual non-pharmacological therapy appeared to be associated with long-term outcomes. The use of non-pharmacological therapies is common amongst PMR patients, despite the paucity of evidence supporting their use. This suggests that people perceive a need for treatment options in addition to standard glucocorticoid regimens. Further research is needed to understand patients' aims when seeking additional treatments and to strengthen the evidence base for their use so that patients can be guided towards effective options.

Onset of comorbidities and flare patterns within pre-existing morbidity clusters in people with gout: 5-year primary care cohort study.

OBJECTIVE: To investigate the onset of comorbidities and pattern of flares over 5 years according to baseline comorbidity clusters in people with gout. METHODS: In a prospective primary care-based cohort study, adults aged ≥18 years with gout were identified from primary care medical records in 20 general practices across the West Midlands, UK and followed up over 5 years. Four clusters of participants have been defined previously according to baseline comorbidity status. The associations of (i) incident comorbidities and (ii) gout flares with baseline cluster membership were estimated using age and sex-adjusted Poisson regression and mixed effects ordinal logistic regression, respectively. RESULTS: The comorbidity with the highest incidence was coronary artery disease (39.2%), followed by hypertension (36.7%), chronic kidney disease stage ≥3 (18.1%), obesity (16.0%), hyperlipidaemia (11.7%), diabetes (8.8%) and cancer (8.4%). There were statistically significant associations observed between cluster membership and incidence of coronary artery disease, hyperlipidaemia, heart failure and hypertension. In each cluster, nearly one-third of participants reported two or more gout flares at each time-point. History of oligo/polyarticular flares (odds ratio [OR]= 2.16, 95% confidence interval [CI]: 1.73, 2.70) and obesity (1.66, 95% CI: 1.21, 2.25) were associated with increasing flares whereas current use of allopurinol was associated with lower risk (0.42, 95% CI: 0.34-0.53). Cluster membership was not associated with flares. CONCLUSION: Substantial numbers of people in each cluster developed new comorbidities that varies by cluster membership. People also experienced multiple flares over time, but these did not differ between clusters. Clinicians should be vigilant for the development of new comorbidities in people with gout.

Vertebral fracture as a risk factor for self-harm: a retrospective cohort study.

BACKGROUND: The prevention of self-harm is an international public health priority. It is vital to identify at-risk populations, particularly as self-harm is a risk factor for suicide. This study aims to examine the risk of self-harm in people with vertebral fractures. METHODS: Retrospective cohort study. Patients with vertebral fracture were identified within the Clinical Practice Research Datalink and matched to patients without fracture by sex and age. Incident self-harm was defined by primary care record codes following vertebral fracture. Overall incidence rates (per 10,000 person-years (PY)) were reported. Cox regression analysis determined risk (hazard ratios (HR), 95 % confidence interval (CI)) of self-harm compared to the matched unexposed cohort. Initial crude analysis was subsequently adjusted and stratified by median age and sex. RESULTS: The number of cases of vertebral fracture was 16,293, with a matched unexposed cohort of the same size. Patients were predominantly female (70.1 %), median age was 76.3 years. Overall incidence of self-harm in the cohort with vertebral fracture was 12.2 (10.1, 14.8) /10,000 PY. There was an initial crude association between vertebral fracture and self-harm, which remained after adjustment (HR 2.4 (95 %CI 1.5, 3.6). Greatest risk of self-harm was found in those with vertebral fractures who were aged below 76.3 years (3.2(1.8, 5.7)) and male (3.9(1.8, 8.5)). CONCLUSIONS: Primary care patients with vertebral fracture are at increased risk of self-harm compared to people without these fractures. Male patients aged below 76 years of age appear to be at greatest risk of self-harm. Clinicians need to be aware of the potential for self-harm in this patient group.

Arsenic trioxide in pediatric cancer - a case series and review of literature.

Arsenic trioxide (ATO) has become an established component of treatment protocols for acute promyelocytic leukemia (APL) with excellent efficacy and no relevant sustained toxicity. Part of its action has been attributed to the inhibition of Hedgehog signaling (Hh) which enables a possible therapeutic approach as many pediatric tumor entities have been associated with increased Hh activity. We retrospectively analyzed 31 patients with refractory and relapsed pediatric cancer who were treated with ATO at the University Children's Hospital of Tuebingen. Additionally a literature review on the clinical and preclinical use of ATO in pediatric cancer treatment was performed.ATO alone as well as combinations with other drugs have proven effective in vitro and in mouse models of various pediatric malignancies. However, only few data on the clinical use of ATO in pediatric patients besides APL exist. In our patient sample, ATO was overall well tolerated in the treatment of various pediatric cancers, even in combination with other cytostatic drugs. Due to distinct tumor entities, differently progressed disease stages and varying co-medication, no clear statement can be made regarding the efficacy of ATO treatment. However, patients with proven Hh activation in molecular tumor profiling surpassed all other patients, who received ATO in an experimental treatment setting, in terms of survival. As molecular profiling of tumors increases and enhanced Hh activity can be detected at an early stage, ATO might expand its clinical use to other pediatric malignancies beyond APL depending on further clinical studies.

Longitudinal clusters of pain and stiffness in polymyalgia rheumatica: 2-year results from the PMR Cohort Study.

OBJECTIVES: To investigate potential subgroups of primary care-diagnosed patients with PMR based on self-reported pain and stiffness severity over time. METHODS: A total of 652 people with an incident PMR diagnosis were recruited from English general practices and completed a baseline postal questionnaire. They were followed up with a further six questionnaires over a 2 year period. A total of 446 people completed the 2 year follow-up. Pain and stiffness were reported on a 0-10 numerical rating scale. Latent class growth analysis was used to estimate the joint trajectories of pain and stiffness over time. A combination of statistical and clinical considerations was used to choose the number of clusters. Characteristics of the classes were described. RESULTS: Five clusters were identified. One cluster represented the profile of 'classical' PMR symptoms and one represented sustained symptoms that may not be PMR. The other three clusters displayed a partial recovery, a recovery followed by worsening and a slow, but sustained recovery. Those displaying classical PMR symptoms were in better overall health at diagnosis than the other groups. CONCLUSION: PMR is a heterogeneous condition, with a number of phenotypes. The spectrum of presentation, as well as varying responses to treatment, may be related to underlying health status at diagnosis. Future research should seek to stratify patients at diagnosis to identify those likely to have a poor recovery and in need of an alternative treatment pathway. Clinicians should be aware of the different experiences of patients and monitor symptoms closely, even where there is initial improvement.

Antibiotic use and the risk of rheumatoid arthritis: a population-based case-control study.

BACKGROUND: Antibiotic-induced disturbances of the human microbiota have been implicated in the development of chronic autoimmune conditions. This study aimed to assess whether antibiotic use is associated with the onset of rheumatoid arthritis (RA). METHODS: A nested case-control study was conducted utilising data from the primary care Clinical Practice Research Datalink (CPRD). Patients with an incident diagnosis of RA were identified (1995-2017). Each case was matched on age, gender, and general practice to ≥ 5 controls without RA. Conditional logistic regression was used to examine previous antibiotic prescriptions and RA onset after controlling for confounding factors. RESULTS: We identified 22,677 cases of RA, matched to 90,013 controls, with a median follow-up of 10 years before RA diagnosis. The odds of developing RA were 60% higher in those exposed to antibiotics than in those not exposed (OR 1.60; 95% CI 1.51-1.68). A dose- or frequency-dependent association was observed between the number of previous antibiotic prescriptions and RA. All classes of antibiotics were associated with higher odds of RA, with bactericidal antibiotics carrying higher risk than bacteriostatic (45% vs. 31%). Those with antibiotic-treated upper respiratory tract (URT) infections were more likely to be RA cases. However, this was not observed for URT infections not treated with antibiotics. Antifungal (OR = 1.27; 95% CI 1.20-1.35) and antiviral (OR = 1.19; 95% CI 1.14-1.24) prescriptions were also associated with increased odds of RA. CONCLUSION: Antibiotic prescriptions are associated with a higher risk of RA. This may be due to microbiota disturbances or underlying infections driving risk. Further research is needed to explore these mechanisms.

Symptoms associated with inflammatory arthritis are common in the primary care population: results from the joint symptoms survey.

OBJECTIVES: To describe the prevalence of self-reported inflammatory joint symptoms, such as joint pain, stiffness and swelling, in UK primary care patients consulting for both musculoskeletal (MSK) and non-musculoskeletal (non-MSK) complaints. METHODS: A joint symptoms questionnaire survey was sent to 10 161 individuals, of whom 5050 had consulted for MSK problems. These were matched by age, gender and general practice to non-MSK consulters. Participants provided data on relevant symptoms such as joint pain, stiffness and swelling. The prevalence of these symptoms, their severity and impact were compared between MSK and non-MSK consulters. RESULTS: A total of 4549 adults responded to the survey (adjusted response 45.8%) of whom 52.3% consulted for a MSK problem. The mean (s.d.) age was 61.6 (14.8) years and 58.9% were female. Persistent (on at least half of the days in the last month) inflammatory symptoms were common even in non-MSK consulters, with 42% reporting joint pain, 36% reporting joint stiffness and 18% reporting joint swelling. This is in comparison with 62% reporting joint pain, 50% stiffness and 24% swelling among MSK consulters. CONCLUSIONS: Although symptoms such as persistent joint pain, swelling and stiffness are predictive of inflammatory arthritis, large numbers of people consulting primary care for non-MSK reasons report these symptoms when asked by questionnaire. This compounds the challenges of diagnosing inflammatory arthritis in a non-specialist setting where new approaches are needed to ensure accurate, early diagnosis, facilitating a treat-to-target approach.

Venous thromboembolism in patients with gout and the impact of hospital admission, disease duration and urate-lowering therapy.

BACKGROUND: Systemic inflammatory diseases have been associated with increased risk of venous thromboembolism. We aimed to quantify the risk of venous thromboembolism in patients with gout, the most common inflammatory arthritis, and to assess how disease duration, hospital admission and urate-lowering therapy affect this risk. METHODS: We used data from the population-representative, England-based Clinical Practice Research Datalink linked to Hospital Episode Statistics, to identify incident gout cases between 1998 and 2017. We matched cases individually to 1 control without gout on age, gender, general practice and follow-up time. We calculated absolute and relative risks of venous thromboembolism, stratified by age, gender and hospital admission. Among those with gout, we assessed the risk of venous thromboembolism by exposure to urate-lowering therapy. RESULTS: We identified 62 234 patients with incident gout matched to 62 234 controls. Gout was associated with higher risk of venous thromboembolism compared with controls (absolute rate 37.3 [95% confidence interval (CI) 35.5-39.3] v. 27.0 [95% CI 25.5-28.9] per 10 000 person-years, adjusted hazard ratio [HR] 1.25, 95% CI 1.15-1.35). The excess risk in patients with gout, which was sustained up to a decade after diagnosis, was present during the time outside hospital stay (adjusted HR 1.30, 95% CI 1.18-1.42), but not during it (adjusted HR 1.01, 95% CI 0.83-1.24). The risk of venous thromboembolism was similar among patients prescribed versus not prescribed urate-lowering therapy (incidence rate ratio 1.04, 95% CI 0.89-1.23). INTERPRETATION: Gout was associated with higher risk of venous thromboembolism, particularly when the patient was not in hospital and regardless of exposure to urate-lowering therapy. Although the observed excess risk may not be sufficient to warrant preventive intervention, clinical vigilance may be required when caring for these patients.

The redox-sensitive module of cyclophilin 20-3, 2-cysteine peroxiredoxin and cysteine synthase integrates sulfur metabolism and oxylipin signaling in the high light acclimation response.

The integration of redox- and reactive oxygen species-dependent signaling and metabolic activities is fundamental to plant acclimation to biotic and abiotic stresses. Previous data suggest the existence of a dynamically interacting module in the chloroplast stroma consisting of cyclophilin 20-3 (Cyp20-3), O-acetylserine(thiol)lyase B (OASTL-B), 2-cysteine peroxiredoxins A/B (2-CysPrx) and serine acetyltransferase 2;1 (SERAT2;1). The functionality of this COPS module is influenced by redox stimuli and oxophytodienoic acid (OPDA), which is the precursor for jasmonic acid. The concept of an integrating function of these proteins in stress signaling was challenged by combining transcriptome and biochemical analyses in Arabidopsis mutants devoid of oastlB, serat2;1, cyp20-3 and 2-cysprxA/B, and wild-type (WT). Leaf transcriptomes were analyzed 6 h after transfer to light intensity 10-fold in excess of growth light or under growth light. The survey of KEGG-based gene ontology groups showed common upregulation of translation- and protein homeostasis-associated transcripts under control conditions in all mutants compared with WT. The results revealed that the interference of the module was accompanied with disturbance of carbohydrate, sulfur and nitrogen metabolism, and also citric acid cycle intermediates. Apart from common regulation, specific responses at the transcriptome and metabolite level linked Cyp20-3 to cell wall-bound carbohydrates and oxylipin signaling, and 2-CysPrx to photosynthesis, sugar and amino acid metabolism. Deletion of either OASTL-B or SERAT2;1 frequently induced antagonistic changes in biochemical or molecular features. Enhanced sensitivity of mutant seedlings to OPDA and leaf discs to NaHS-administration confirmed the presumed functional interference of the COPS module in redox and oxylipin signaling.

Risk of fracture among patients with polymyalgia rheumatica and giant cell arteritis: a population-based study.

BACKGROUND: Glucocorticoids are associated with increased fracture risk and are the mainstay of treatment in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). However, fracture risk in these conditions has not been previously quantified. The aim of this study was to quantify the risk of fracture among patients with PMR and GCA. METHODS: A retrospective cohort study was conducted using primary care records from the UK-based Clinical Practice Research Datalink. Individuals aged 40 years and over, with incident diagnoses of PMR or GCA were separately identified from 1990-2004 and followed up until 2015. For each exposed individual, four age-, sex- and practice-matched controls were randomly selected. Incidence rates of fracture per 10,000 person-years were calculated for each disease group and hazard rates were compared to the unexposed using Cox regression models. RESULTS: Overall, 12,136 and 2673 cases of PMR and GCA, respectively, were identified. The incidence rate of fracture was 148.05 (95% CI 141.16-155.28) in PMR and 147.15 (132.91-162.91) in GCA per 10,000 person-years. Risk of fracture was increased by 63% in PMR (adjusted hazard ratio 1.63, 95% CI 1.54-1.73) and 67% in GCA (1.67, 1.49-1.88) compared to the control populations. Fewer than 13% of glucocorticoid-treated cases were prescribed bisphosphonates. CONCLUSIONS: This study reports, for the first time, a similar increase in fracture risk for patients with PMR and GCA. More needs to be done to improve adherence to guidelines to co-prescribe bisphosphonates. Further research needs to identify whether lower glucocorticoid starting doses and/or aggressive dose reduction reduces fracture risk.

Incidence, prevalence and treatment burden of polymyalgia rheumatica in the UK over two decades: a population-based study.

OBJECTIVE: Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease in older people. Contemporary estimates of the incidence and prevalence are lacking, and no previous study has assessed treatment patterns at a population level. This study aims to address this. METHODS: We extracted anonymised electronic medical records of patients over the age of 40 years from the Clinical Practice Research Datalink in the period 1990-2016. The absolute rate of PMR per 100 000 person-years was calculated and stratified by age, gender and calendar year. Incidence rate ratios were calculated using a Poisson regression model. Among persons with PMR, continuous and total duration of treatment with glucocorticoids (GC) were assessed. RESULTS: 5 364 005 patients were included who contributed 44 million person-years of follow-up. 42 125 people had an incident diagnosis of PMR during the period. The overall incidence rate of PMR was 95.9 per 100 000 (95% CI 94.9 to 96.8). The incidence of PMR was highest in women, older age groups and those living in the South of England. Incidence appears stable over time. The prevalence of PMR in 2015 was 0.85 %. The median (IQR) continuous GC treatment duration was 15.8 (7.9-31.2) months. However, around 25% of patients received more than 4 years in total of GC therapy. CONCLUSIONS: The incidence rates of PMR have stabilised. This is the first population-based study to confirm that a significant number of patients with PMR receive prolonged treatment with GC, which can carry significant risks. The early identification of these patients should be a priority in future research.

Risk of fragility fracture among patients with gout and the effect of urate-lowering therapy.

BACKGROUND: Previous studies that quantified the risk of fracture among patients with gout and assessed the potential effect of urate-lowering therapy have provided conflicting results. Our study aims to provide better estimates of risk by minimizing the effect of selection bias and confounding on the observed association. METHODS: We used data from the Clinical Practice Research Datalink, which records primary care consultations of patients from across the United Kingdom. We identified patients with incident gout from 1990 to 2004 and followed them up until 2015. Each patient with gout was individually matched to 4 controls on age, sex and general practice. We calculated absolute rate of fracture and hazard ratios (HRs) using Cox regression models. Among patients with gout, we assessed the impact of urate-lowering therapy on fracture, and used landmark analysis and propensity score matching to account for immortal time bias and confounding by indication. RESULTS: We identified 31 781 patients with incident gout matched to 122 961 controls. The absolute rate of fracture was similar in both cases and controls (absolute rate = 53 and 55 per 10 000 person-years, respectively) corresponding to an HR of 0.97 (95% confidence interval 0.92-1.02). Our finding remained unchanged when we stratified our analysis by age and sex. We did not observe statistically significant differences in the risk of fracture among those prescribed urate-lowering therapy within 1 and 3 years after gout diagnosis. INTERPRETATION: Overall, gout was not associated with an increased risk of fracture. Urate-lowering drugs prescribed early during the course of disease had neither adverse nor beneficial effect on the long-term risk of fracture.