The Impact of Systemic Lupus Erythematosus Flares on Clinical and Economic Outcomes: The CHAMOMILE Claims Database Study in Germany.

INTRODUCTION: CHAMOMILE (CHaracteristics and impact of flares on clinicAl and econoMic OutcoMes In patients with systemic Lupus Erythematosus [SLE]) examined how flares in the year of SLE diagnosis impact future disease activity and damage, productivity, healthcare resource utilization (HCRU), and costs in patients with SLE in Germany. METHODS: CHAMOMILE was a retrospective cohort study of adults with an SLE diagnosis in the German Sickness Fund Database from 1 July 2010 to 31 December 2013. Patients were classified according to their greatest flare severity during the baseline year (none, mild, or moderate/severe). The number and severity of flares were assessed annually over 5-8.5 follow-up years, along with SLE organ/system damage, treatments, work disability, and HCRU metrics. RESULTS: Of 2088 patients (84.6% female; mean age [standard deviation] 51.4 [16.1] years; mean follow-up 6.8 [2.1] years), 34.3% (n = 716) were flare-free, 29.8% (n = 622) had mild flares, and 35.9% (n = 750) had moderate/severe flares at baseline. Baseline flare severity was related to future flares: rates during follow-up were higher in patients with moderate/severe baseline flares compared with those with mild or no baseline flares (89.6 vs 78.5 and 44.2 flares/100 patient years, respectively). Overall, 80.2% (n = 1675) of patients received glucocorticoids at least once during baseline and follow-up. Patients' HCRU was generally greatest in their baseline year. Costs were highest in patients with moderate/severe baseline flares. CONCLUSION: Baseline flare severity provided insight into a patient's disease course and the clinical and economic burden of SLE over time, highlighting the ramifications of uncontrolled disease for patients with SLE.

Burden of systemic lupus erythematosus in clinical practice: baseline data from the SLE Prospective Observational Cohort Study (SPOCS) by interferon gene signature.

OBJECTIVE: The longitudinal Systemic Lupus Erythematosus Prospective Observational Cohort Study (SPOCS) aims to assess SLE disease course overall and according to type I interferon 4 gene signature (IFNGS). Here, we describe SPOCS patient characteristics by IFNGS and baseline disease activity. METHODS: SPOCS (NCT03189875) is an international study of patients with SLE according to Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) criteria. Enrolled patients from 135 centres in 8 countries were followed biannually for ≤3 years from June 2017 to November 2022. Baseline demographics, disease characteristics, organ system involvement/damage and flares were analysed descriptively according to SLE Disease Activity Index-2000 score (SLEDAI-2K <10/≥10) and IFNGS status (high/low). RESULTS: The study population (n=823) was 93.2% female, with mean (SD) age 45.3 (13.9) years and 11.1 (9.2) years since diagnosis; 52.4% had baseline SLICC/ACR Damage Index score ≥1. Patients with SLEDAI-2K scores ≥10 (241 of 584, 41.3%) vs <10 were younger (mean 42.8 (13.7) vs 46.6 (14.2) years; nominal p=0.001), had shorter SLE duration (10.4 (8.6) vs 12.4 (9.6) years; nominal p=0.012) and more severe flares (12.9% vs 5.3%; nominal p=0.001). IFNGS-high patients (522 of 739, 70.6%) were younger than IFNGS-low patients at first SLE manifestation (30.0 (12.7) vs 36.8 (14.6) years; nominal p<0.001). Proportions of IFNGS-high patients differed according to race (nominal p<0.001), with higher proportions among Asian (83.3%) and black (86.5%) versus white patients (63.5%). Greater proportions of IFNGS-high versus IFNGS-low patients had haematological (12.6% vs 4.1%), immunological (74.4% vs 45.6%) or dermal (69.7% vs 62.2%) involvement. CONCLUSIONS: We identified key characteristics of patients with high disease activity and/or elevated type I IFN signalling, populations with SLE with high unmet needs. Baseline SLEDAI-2K ≥10 was associated with shorter disease duration and more severe flares. IFNGS-high patients were younger at diagnosis and had distinct patterns of organ involvement, compared with IFNGS-low patients.

Association Between Elevated Blood Eosinophils and Chronic Kidney Disease Progression: Analyses of a Large United States Electronic Health Records Database.

Background: Blood eosinophils can increase in response to infection, inflammation, and hypersensitivity reactions, yet their involvement in the progression of chronic kidney disease (CKD) is poorly understood. This study explores the relationship between blood eosinophils and CKD progression among patients in a real-world setting. Methods: This retrospective study analyzed data obtained from the Optum® de-identified electronic health records dataset in the United States. Patients diagnosed with CKD stage 3 or 4 (International Classification of Diseases diagnosis code or estimated glomerular filtration rate [eGFR] <60 mL/min) between January 2011 and March 2018 were included and followed until progression to the next CKD stage, death, or dropout. The primary objective of this study was to assess the relationship between blood eosinophil counts (bEOS) and CKD progression, adjusting for clinical and demographic features as well as known risk factors for CKD stages 3-4. The primary outcomes were CKD progression and all-cause mortality. Results: We found that high eosinophilic levels (bEOS ≥300 cells/µL) were associated with CKD progression from stage 3 to stages 4 or 5 (hazard ratio [HR] ranging from 1.30 to 1.50) and from stages 4 to 5 (HR ranging from 1.28 to 1.50). Among patients with CKD progression, those with blood eosinophils ≥300 cells/µL appeared to have a relatively lower eGFR, higher all-cause mortality, and reduced time to CKD progression and death than those with <300 cells/µL. Factors including sex, race, hypertension, anemia, and treatments for cardiovascular and hematopoietic drugs were associated with CKD progression. Conclusion: Elevated eosinophils may increase the risk for CKD progression. Larger studies are needed to assess whether the risk of mortality is increased among patients with elevated eosinophils.

Impact of SARS-CoV-2 infection on patients with systemic lupus erythematosus in England prior to vaccination: a retrospective observational cohort study.

OBJECTIVES: Determine the prevaccination healthcare impact of COVID-19 in patients with systemic lupus erythematosus (SLE) in England. DESIGN: Retrospective cohort study of adult patients with SLE from 1 May to 31 October 2020. SETTING: Clinical Practice Research Datalink (CPRD) Aurum and Hospital Episode Statistics (HES) databases from general practitioners across England combining primary care and other health-related data. PARTICIPANTS: Overall, 6145 adults with confirmed SLE diagnosis ≥1 year prior to 1 May 2020 were included. Most patients were women (91.0%), white (67.1%), and diagnosed with SLE at age <50 (70.8%). Patients were excluded if they had a COVID-19 diagnosis before 1 May 2020. PRIMARY AND SECONDARY OUTCOME MEASURES: Demographics and clinical characteristics were compared. COVID-19 severity was determined by patient care required and procedure/diagnosis codes. COVID-19 cumulative incidence, hospitalisation rates, lengths of stay and mortality rates were determined and stratified by SLE and COVID-19 severity. RESULTS: Of 6145 patients, 3927 had mild, 1288 moderate and 930 severe SLE at baseline. The majority of patients with moderate to severe SLE were on oral corticosteroids and antimalarial treatments. Overall, 54/6145 (0.88%) patients with SLE acquired and were diagnosed with COVID-19, with 45 classified as mild, 6 moderate and 3 severe COVID-19. Cumulative incidence was higher in patients with severe SLE (1.4%) compared with patients classified as mild (0.8%) or moderate (0.8%). Ten COVID-19-specific hospital admissions occurred (n=6 moderate; n=4 severe). Regardless of COVID-19 status, hospital admission rates and length of stay increased with SLE severity. Of 54 patients with SLE diagnosed with COVID-19, 1 (1.9%) COVID-19-related death was recorded in a patient with both severe SLE and severe COVID-19. CONCLUSIONS: SLE severity did not appear to impact COVID-19 outcomes in this study. The COVID-19 pandemic is evolving and follow-up studies are needed to understand the relationship between COVID-19 and SLE.

Real-World Investigation of Eosinophilic-Associated Disease Overlap (REVEAL): Analysis of a US Claims Database.

PURPOSE: The epidemiology of eosinophil-associated diseases (EADs) is not yet fully understood. While some studies have been conducted on stand-alone eosinophilic diseases, there is scarce evidence on the degree of overlap among rarer conditions. METHODS: The retrospective Real-world inVestigation of Eosinophilic-Associated disease overLap (REVEAL) study used data from the Optum® Clinformatics® insurance claims database to describe and characterize disease overlap among 11 EADs: allergic bronchopulmonary aspergillosis, atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic gastritis/gastroenteritis, eosinophilic granulomatosis with polyangiitis, eosinophilic esophagitis, bullous pemphigoid, chronic obstructive pulmonary disorder, chronic spontaneous urticaria, and non-cystic fibrosis bronchiectasis. Patient records with EADs of interest were identified between January 1, 2015, and June 30, 2018. RESULTS: Overall, 1,326,645 patients were included; 74.4% had 1 EAD, 20.5% had ≥ 2 EADs, and 5.1% had ≥ 3 EADs. Higher rates of disease overlap were associated with older age. Higher blood eosinophil counts were also observed in patients with a greater number of overlapping conditions, suggesting a common role for eosinophilic inflammation in the pathogenesis of multiple diseases. Furthermore, greater disease overlap was associated with higher disease severity in most cohorts. CONCLUSIONS: Results from this study have implications for quantifying unmet needs and can be used to inform treatment guidelines and raise the awareness of eosinophilic inflammation and EAD overlap among healthcare professionals from a range of disease specialties.

Characteristics, treatment patterns, health care resource utilization and costs in patients with bullous pemphigoid: A retrospective analysis of US health insurance claims data.

Background: Real-world data describing the impact of incident bullous pemphigoid (BP) on patients and health care resource utilization (HCRU) are limited. Objective: To examine characteristics, treatment patterns, HCRU, and costs for incident BP. Methods: Retrospective analysis of 2015 to 2019 US health insurance claims for patients ≥18 years with an incident BP diagnosis. Patients with BP were matched to those without on demographic and clinical characteristics. Statistics were descriptive. Results: The mean Charlson Comorbidity Index score was higher for patients with BP (n = 1108) than without (n = 4621) at baseline (mean [SD]: 3.3 [2.7] vs 2.8 [2.4]) and during follow-up (5.0 [4.9] vs 3.7 [3.0]). Hypertension, diabetes, skin ulcers, chronic pulmonary disease, dyslipidemia, sleep disorders, and congestive heart failure were higher with BP. Most patients with BP received antibiotics (>80%) and/or corticosteroids (>90%). Hospitalizations were more common (44.0% vs 17.1%) and monthly all-cause health care costs more than double ($3214 vs $1353) in patients with BP than without. Limitations: Diagnoses were based on billing codes. HCRU claims data may not reflect the true number of encounters. Conclusion: Incident BP is associated with considerable morbidity, HCRU, and costs. More effective, targeted treatments are needed to improve quality of life, while minimizing exposure to systemic corticosteroids.

Adverse Outcomes, Healthcare Resource Utilization, and Costs Associated with Systemic Corticosteroid use Among Adults with Systemic Lupus Erythematosus in the UK.

INTRODUCTION: This analysis was conducted to assess the incidence of adverse clinical outcomes, healthcare resource use (HCRU), and the costs associated with systemic corticosteroid (SCS) use in adults with systemic lupus erythematosus (SLE) in the UK. METHODS: We identified incident SLE cases using the Clinical Practice Research Datalink GOLD, Hospital Episode Statistics-linked healthcare, and Office for National Statistics mortality databases from January 1, 2005, to June 30, 2019. Adverse clinical outcomes, HCRU, and costs were captured for patients with and without prescribed SCS. RESULTS: Of 715 patients, 301 (42%) had initiated SCS use (mean [standard deviation (SD)] 3.2 [6.0] mg/day) and 414 (58%) had no recorded SCS use post-SLE diagnosis. Cumulative incidence of any adverse clinical outcome over 10-year follow-up was 50% (SCS group) and 22% (non-SCS group), with osteoporosis diagnosis/fracture most frequently reported. SCS exposure in the past 90 days was associated with an adjusted hazard ratio of 2.41 (95% confidence interval 1.77-3.26) for any adverse clinical outcome, with increased hazard for osteoporosis diagnosis/fracture (5.26, 3.61-7.65) and myocardial infarction (4.52, 1.16-17.71). Compared to low-dose SCS (< 7.5 mg/day), patients on high-dose SCS (≥ 7.5 mg/day) had increased hazard for myocardial infarction (14.93, 2.71-82.31), heart failure (9.32, 2.45-35.43), osteoporosis diagnosis/fracture (5.14, 2.82-9.37), and type 2 diabetes (4.02 1.13-14.27). Each additional year of SCS use was associated with increased hazard for any adverse clinical outcome (1.15, 1.05-1.27). HCRU and costs were greater for SCS users than non-SCS users. CONCLUSIONS: Among patients with SLE, there is a higher burden of adverse clinical outcomes and greater HCRU in SCS versus non-SCS users.

Healthcare Resource Use and Costs Associated with Organ Damage in Newly Diagnosed Adults with Systemic Lupus Erythematosus in the UK.

INTRODUCTION: This analysis compared healthcare resource use (HCRU) and costs associated with incident organ damage in a cohort of adult patients with systemic lupus erythematosus (SLE). METHODS: Incident SLE cases were identified (Clinical Practice Research Datalink [CPRD] and Hospital Episode Statistics-linked healthcare databases; January 1, 2005-June 30, 2019). Annual incidence of 13 organ damage domains was calculated from SLE diagnosis through follow-up. Annualized HCRU and costs were compared between organ damage and non-organ damage patient groups using generalized estimating equations. RESULTS: A total of 936 patients met the inclusion criteria for SLE. Mean age was 48.0 (standard deviation [SD] 15.7) years and 88% were female. Over a median follow-up period of 4.3 (interquartile range [IQR] 1.9-7.0) years, 59% (315/533) had evidence of post-SLE diagnosis incident organ damage (≥ 1 type), which was greatest for musculoskeletal (146/819 [18%]), cardiovascular (149/842 [18%]), and skin (148/856 [17%]) domains. Patients with organ damage had greater resource use for all organ systems, excluding gonadal, versus those without it. Overall, mean (SD) annualized all-cause HCRU was greater in patients with organ damage versus those without it (inpatient, 1.0 versus 0.2; outpatient, 7.3 versus 3.5; accident and emergency, 0.5 versus 0.2 days; primary care contacts, 28.7 versus 16.5; prescription medications, 62.3 versus 22.9). Adjusted mean annualized all-cause costs were significantly greater in both post- and pre-organ damage index periods for patients with organ damage versus those without it (all P < 0.05, excluding gonadal). Overall organ damage was associated with significantly increased adjusted mean annualized per-patient cost (£4442 greater [P < 0.0001]) ranging between £2709 and £7150 greater depending on the organ damage type. CONCLUSION: Organ damage was associated with higher HCRU and healthcare costs, before and after SLE diagnosis. More effective SLE management may slow disease progression, prevent organ damage onset, improve clinical outcomes, and reduce healthcare costs.

Meta-analysis of pazopanib and trabectedin effectiveness in previously treated metastatic synovial sarcoma (second-line setting and beyond).

Background: This study examined the efficacy/effectiveness of pazopanib and trabectedin in previously treated metastatic synovial sarcoma (mSS). Materials & methods: A literature search identified studies (2002-2019) reporting outcomes of pazopanib and trabectedin in previously treated mSS, including median overall survival (mOS) and overall response rate (ORR). A meta-analysis was conducted and sensitivity analyses examined outcomes by agent (pazopanib/trabectedin), study type (clinical trial [CT] or real-world [RW]) and sample size. Results: Sixteen studies were included (pazopanib: n = 7; trabectedin: n = 9). Pooled mOS was 10.4 months and was consistent across agents and in RW and CT (pazopanib: 10.3; trabectedin: 10.4; CT: 10.8; RW: 9.9). ORR results were more variable (pooled ORR: 14.7%). ORR was consistently higher for RW (17.7%) than for CT (9.5%) and for pazopanib (18.9%) compared with trabectedin (12.3%). Conclusion: Poor outcomes across agents and settings highlight a need for novel treatments with improved efficacy. This study serves as a benchmark for efficacy estimates in this rare disease.

Synovial sarcoma (SS) is a rare and aggressive type of soft tissue sarcoma. SS frequently spreads to other locations, referred to as metastatic SS (mSS) and is associated with a high death rate. Patients treated with first-line chemotherapy (1L setting), may need further lines of treatment (≥2L setting), which commonly involve the drugs pazopanib and trabectedin. This study assessed how well pazopanib and trabectedin work in people with ≥2L mSS, by examining both clinical trial (CT) and real-world (RW) studies. Overall, findings across 16 studies showed that mSS patients lived approximately 10 months after treatment with pazopanib or trabectedin in the ≥2L setting, and this was similar across both agents (10.3 months for pazopanib; 10.4 months for trabectedin) and between the CT (10.8 months) and the RW (9.9 months) settings. In terms of response to treatment, a higher percentage of people appeared to respond in RW settings (17.7%) than in CTs (9.5%), and to pazopanib (18.9%) compared with trabectedin (12.3%). These results show there is a need for better treatments for patients with previously treated mSS. These findings are useful benchmarks for the development of future treatment approaches for this rare disease.

Prevalence of chronic kidney disease in Asia: a systematic review and analysis.

INTRODUCTION: The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the variations in national prevalence within Asia. We aimed to consolidate available data and quantify estimates of the CKD burden in this region. METHODS: We systematically searched MEDLINE, Embase and Google Scholar for observational studies and contacted national experts to estimate CKD prevalence in countries of Asia (Eastern, Southern and South Eastern Asia). CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or the presence of proteinuria. For countries without reported data, we estimated CKD prevalence using agglomerative average-linkage hierarchical clustering, based on country-level risk factors and random effects meta-analysis within clusters. Published CKD prevalence data were obtained for 16 countries (of the 26 countries in the region) and estimates were made for 10 countries. RESULTS: There was substantial variation in overall and advanced (eGFR <30 mL/min/1.73 m2) CKD prevalence (range: 7.0%-34.3% and 0.1%-17.0%, respectively). Up to an estimated 434.3 million (95% CI 350.2 to 519.7) adults have CKD in Asia, including up to 65.6 million (95% CI 42.2 to 94.9) who have advanced CKD. The greatest number of adults living with CKD were in China (up to 159.8 million, 95% CI 146.6 to 174.1) and India (up to 140.2 million, 95% CI 110.7 to 169.7), collectively having 69.1% of the total number of adults with CKD in the region. CONCLUSION: The large number of people with CKD, and the substantial number with advanced CKD, show the need for urgent collaborative action in Asia to prevent and manage CKD and its complications.

Comparative effects of sulphonylureas, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors added to metformin monotherapy: a propensity-score matched cohort study in UK primary care.

AIM: To assess the comparative effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors, sulphonylureas (SUs) and dipeptidyl peptidase-4 (DPP-4) inhibitors on cardiometabolic risk factors in routine care. MATERIALS AND METHODS: Using primary care data on 10 631 new users of SUs, SGLT2 inhibitors or DPP-4 inhibitors added to metformin, obtained from the UK Clinical Practice Research Datalink, we created propensity-score matched cohorts and used linear mixed models to describe changes in glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), systolic blood pressure (BP) and body mass index (BMI) over 96 weeks. RESULTS: HbA1c levels fell substantially after treatment intensification for all drugs: mean change at week 12: SGLT2 inhibitors: -15.2 mmol/mol (95% confidence interval [CI] -16.9, -13.5); SUs: -14.3 mmol/mol (95% CI -15.5, -13.2); and DPP-4 inhibitors: -11.9 mmol/mol (95% CI -13.1, -10.6). Systolic BP fell for SGLT2 inhibitor users throughout follow-up, but not for DPP-4 inhibitor or SU users: mean change at week 12: SGLT2 inhibitors: -2.3 mmHg (95% CI -3.8, -0.8); SUs: -0.8 mmHg (95% CI -1.9, +0.4); and DPP-4 inhibitors: -0.9 mmHg (95% CI -2.1,+0.2). BMI decreased for SGLT2 inhibitor and DPP-4 inhibitor users, but not SU users: mean change at week 12: SGLT2 inhibitors: -0.7 kg/m2 (95% CI -0.9, -0.5); SUs: 0.0 kg/m2 (95% CI -0.3, +0.2); and DPP-4 inhibitors: -0.3 kg/m2 (95% CI -0.5, -0.1). eGFR fell at 12 weeks for SGLT2 inhibitor and DPP-4 inhibitor users. At 60 weeks, the fall in eGFR from baseline was similar for each drug class. CONCLUSIONS: In routine care, SGLT2 inhibitors had greater effects on cardiometabolic risk factors than SUs. Routine care data closely replicated the effects of diabetes drugs on physiological variables measured in clinical trials.

Cardiovascular Event Rates Among Hemodialysis Patients Across Geographical Regions-A Snapshot From The Dialysis Outcomes and Practice Patterns Study (DOPPS).

INTRODUCTION: Cardiovascular (CV) morbidity and mortality are excessively high among hemodialysis (HD) patients. Anemia is a common complication of chronic kidney disease (CKD) and a known risk factor for CV events. To understand the impact of the recent regulatory and guideline changes in anemia management, we examined regional CV event rates in high-risk and erythropoiesis-stimulating agent (ESA)-hyporesponsive HD patients. METHODS: A prospective cohort study including 16,560 HD patients, 8660 CV high-risk, and 884 hyporesponsive to ESAs, from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 4 (2009-2011) and phase 5 (2012-2015) was conducted to quantify all-cause mortality, major adverse cardiovascular events (MACE), and MACE plus heart failure and thromboembolic events (MACE+). RESULTS: The MACE+ rates (per 100 patient-years) were highest in North America (NA) (19.4; 95% CI = 18.2-20.7), followed by Europe (EU) (17.4; 95% CI = 16.6-18.1) and lowest in Japan (7.5; 95% CI = 6.9-8.1). When restricted to the high CV risk population, rates increased by 36% in NA, 45% in EU, and 72% in Japan. Mortality accounted for >74% of MACE+ events. MACE+ rates in ESA-hyporesponsive patients and high CV risk patients were similar in NA and EU cohorts. There were minimal differences in outcomes between the DOPPS phases 4 and 5. CONCLUSION: Cardiovascular event rates are high in the HD population, vary by geographic region, and are substantially higher in high CV risk patients and ESA-hyporesponsive patients; however, the rates appear not to be affected by anemia guideline changes. The findings from this study will be essential to contextualize the design of future CV anemia-related outcome studies and clinical trials.

Factors associated with choice of intensification treatment for type 2 diabetes after metformin monotherapy: a cohort study in UK primary care.

PURPOSE: To understand the patient characteristics associated with treatment choice at the first treatment intensification for type 2 diabetes. PATIENTS AND METHODS: This is a noninterventional study, using UK electronic primary care records from the Clinical Practice Research Datalink. We included adults treated with metformin monotherapy between January 2000 and July 2017. The outcome of interest was the drug prescribed at first intensification between 2014 and 2017. We used multinomial logistic regression to calculate the ORs for associations between the drugs and patient characteristics. RESULTS: In total, 14,146 people started treatment with an intensification drug. Younger people were substantially more likely to be prescribed sodium-glucose co-transporter-2 inhibitors (SGLT2is), than sulfonylureas (SUs): OR for SGLT2i prescription for those aged <30 years was 2.47 (95% CI 1.39-4.39) compared with those aged 60-70 years. Both overweight and obesity were associated with greater odds of being prescribed dipeptidyl peptidase-4 inhibitor (DPP4i) or SGLT2i. People of non-white ethnicity were less likely to be prescribed SGLT2i or DPP4i: compared with white patients, the OR of being prescribed SGLT2i among South Asians is 0.60 (95% CI 0.42-0.85), and for black people, the OR is 0.54 (95% CI 0.30-0.97). Lower socioeconomic status was also independently associated with reduced odds of being prescribed SGLT2is. CONCLUSION: Both clinical and demographic factors are associated with prescribing at the first stage of treatment intensification, with older and non-white people less likely to receive new antidiabetic treatments. Our results suggest that the selection of treatment options used at the first stage of treatment intensification for type 2 diabetes is not driven by clinical need alone.

A systematic review comparing the evidence for kidney function outcomes between oral antidiabetic drugs for type 2 diabetes.

Background: The development of kidney disease is a serious complication among people with type 2 diabetes mellitus, associated with substantially increased morbidity and mortality.  We aimed to summarise the current evidence for the relationship between treatments for type 2 diabetes and long-term kidney outcomes, by conducting a systematic search and review of relevant studies. Methods: We searched Medline, Embase and Web of Science, between 1st January 1980 and 15th May 2018 for published clinical trials and observational studies comparing two or more classes of oral therapy for type 2 diabetes. We included people receiving oral antidiabetic drugs. Studies were eligible that; (i) compared two or more classes of oral therapy for type 2 diabetes; (ii) reported kidney outcomes as primary or secondary outcomes; (iii) included more than 100 participants; and (iv) followed up participants for 48 weeks or more. Kidney-related outcome measures included were Incidence of chronic kidney disease, reduced eGFR, increased creatinine, 'micro' and 'macro' albuminuria. Results: We identified 15 eligible studies, seven of which were randomised controlled trials and eight were observational studies. Reporting of specific renal outcomes varied widely. Due to variability of comparisons and outcomes meta-analysis was not possible. The majority of comparisons between treatment with metformin or sulfonylurea indicated that metformin was associated with better renal outcomes. Little evidence was available for recently introduced treatments or commonly prescribed combination therapies. Conclusions: Comparative evidence for the effect of treatments for type 2 diabetes on renal outcomes, either as monotherapy or in combination is sparse.

Changing use of antidiabetic drugs in the UK: trends in prescribing 2000-2017.

OBJECTIVES: Guidelines for the use of drugs for type 2 diabetes mellitus (T2DM) have changed since 2000, and new classes of drug have been introduced. Our aim was to describe how drug choice at initiation and first stage of intensification have changed over this period, and to what extent prescribing was in accord with clinical guidelines, including adherence to recommendations regarding kidney function. DESIGN: Repeated cross-sectional study. SETTING: UK electronic primary care health records from the Clinical Practice Research Datalink. PARTICIPANTS: Adults initiating treatment with a drug for T2DM between January 2000 and July 2017. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were the proportion of each class of T2DM drug prescribed for initiation and first-stage intensification in each year. We also examined drug prescribing by kidney function and country within the UK. RESULTS: Of 280 241 people initiating treatment with T2DM drugs from 2000 to 2017, 73% (204 238/280 241) initiated metformin, 15% (42 288/280 241) a sulfonylurea, 5% (12 956/280 241) with metformin and sulfonylurea dual therapy and 7% (20 759/280 241) started other options. Clinicians have increasingly prescribed metformin at initiation: by 2017 this was 89% (2475/2778) of drug initiations. Among people with an estimated glomerular filtration rate of ≤30 mL/min/1.73 m2, the most common drug at initiation was a sulfonylurea, 58% (659/1135). In 2000, sulfonylureas were the predominant drug at the first stage of drug intensification (87%, 534/615) but by 2017 this fell to 30% (355/1183) as the use of newer drug classes increased. In 2017, new prescriptions for dipeptidyl peptidase-4 inhibitors (DPP4i) and sodium/glucose cotransporter-2 inhibitors (SGLT2i) accounted for 42% (502/1183) and 22% (256/1183) of intensification drugs, respectively. Uptake of new classes differs by country with DPP4is and SGLT2is prescribed more in Northern Ireland and Wales than England or Scotland. CONCLUSIONS: Our findings show markedly changing prescribing patterns for T2DM between 2000 and 2017, largely consistent with clinical guidelines.

Anemia and mortality in patients with nondialysis-dependent chronic kidney disease.

BACKGROUND: A combination of safety concerns and labeling changes impacted use of erythropoiesis-stimulating agents (ESAs) in renal anemia. Data regarding contemporary utilization in pre-dialysis chronic kidney disease (CKD) are lacking. METHODS: Electronic healthcare records and medical claims data of pre-dialysis CKD patients were aggregated from a large US managed care provider (2011-13). ESA use patterns, characteristics, and outcomes of ESA-treated/untreated patients were quantified. RESULTS: At baseline, 109/32,308 patients (0.3%) were ESA users. Treated patients were older, had more advanced CKD (58.8% vs 5.4% with stage 4/5 vs 3) and greater prevalence of comorbid diabetes, hypertension, heart failure, and peripheral vascular disease. An additional 266 patients initiated ESA: hemoglobin at initiation was 8-10 g/dL in 193 of these and >10 g/dL in the remainder; 61.7% had stage 4/5 CKD; prevalence of cardiovascular disease was high (50.8% heart failure; 25.2% prior myocardial infarction; 24.1% prior stroke). During follow-up, rates of death and cardiovascular events were higher in baseline ESA users and ESA naives versus non-users. CONCLUSIONS: ESA use in pre-dialysis CKD patients was exceedingly rare and directed disproportionately to older, sicker patients; these patients had high rates of death and cardiovascular events. These data provide context for contemporary use of ESA in pre-dialysis CKD.

Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID.

BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis. RESULTS: An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient's local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient's local healthcare provider. CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development.

Chronic kidney disease in Asia: Protocol for a collaborative overview.

AIM: The burden of chronic kidney disease (CKD) is growing rapidly around the world. However, there is limited information on the overall regional prevalence of CKD, as well as the prognostic implications and treatment patterns in Asian region. We have established the Asian Renal Collaboration (ARC) with the goal of consolidating region-wide data regarding CKD. METHODS: This collaborative project will synthesize data and perform meta-analyses of observational studies conducted in Asia. Studies will be identified through a systematic literature search including abstracts, proceedings of meetings, electronic databases such as MEDLINE and EMBASE. Personal enquiry among collaborators and experts in the region will identify additional studies, or other data sources such as registries. Both cross-sectional and longitudinal studies that describe the prevalence of CKD and its complications will be included, as will longitudinal studies that describe important clinical outcomes for people with CKD. Individual participant data will be sought, where possible, from each of the studies included in the collaboration for baseline parameters and subsequent outcomes, in order to maximize flexibility and consistency of data analyses. CONCLUSIONS: This study is an initiative offering a unique opportunity to obtain information about the prevalence and manifestations of CKD in Asia, as well as its risk factors. The ARC will also provide insights into important outcomes including progression of CKD, CKD complications, cardiovascular disease and death. These findings will improve our understanding of kidney disease in Asia, and thus help inform service provision, preventive care and further research across the region.

Children's liver chemistries vary with age and gender and require customized pediatric reference ranges.

Used to detect liver disease and injury, baseline liver chemistry distributions were evaluated by age and gender in children without known liver disease. Baseline liver chemistries [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL)] were analyzed from 24 randomized controlled pediatric clinical trials. Using quantile regression, liver chemistry distributions were examined by age and gender; upper limit normal (ULN) ranges were compared to the 97.5th percentiles of the distributions for the specified ages and genders. 5410 subjects without known liver disease (0-18 years; 60% male) were studied. The median ALT varied little with age. In males age 5-18, the ALT 97.5th percentile increased from 34 to 63 IU/L. In both genders, the median and 97.5th percentile AST decreased with age. After age 9, ALP decreased. TBIL increased with age. Despite most liver chemistry 97.5th percentiles changing substantively with age and gender, the reference lab ULN generally changed minimally and did not correlate with the 97.5th percentile. Gender and age specific 97.5th percentile data should therefore be considered for the reference laboratory ULN in children to more accurately detect liver injury and disease.

Age-related differences in reporting of drug-associated liver injury: data-mining of WHO Safety Report Database.

BACKGROUND/AIMS: Age-differences in the frequency and manifestations of drug-induced liver injury are not fully characterized. Data-mining analyses were performed to assess the impact of age on liver event reporting frequency with different phenotypes and agents. METHODS: 236 drugs associated with hepatotoxicity were evaluated using the Empirical Bayes Geometric Mean (EBGM) of the relative reporting ratio with 90% confidence interval (EB05 and EB95) calculated for the age groups: 0-17, 18-64, and⩾65years (or elderly), for overall, serious (acute liver failure), hepatocellular, and cholestatic liver injury, using the WHO Safety Report Database. RESULTS: Overall, cases of age 0-17, 18-64, and 65years or older comprised 6%, 62%, and 32% of liver event reports. Acute liver failure and hepatocellular injury were more frequently reported among children compared to adults and the elderly while reports with cholestatic injury were more frequent among the elderly (p<0.00001). A potential to cause mitochondrial dysfunction was more prevalent among the drugs with increased pediatric reporting frequency while high lipophilicity and biliary excretion were more common among the drugs associated with higher reporting frequency in the elderly. CONCLUSION: Age-specific phenotypes and potential drug properties associated with age-specific hepatotoxicity were identified in reported liver events; further analyses are warranted.