Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort.

OBJECTIVES: To estimate the effect of SLE disease activity, observed over a 12-month period, on the risk of irreversible organ damage and mortality, adjusted for potential confounding factors. METHODS: Patients were enrolled into a prospective cohort study and followed up from 1991. This study retrospectively analyses the data captured in the prospective cohort study. The study population consisted of 350 patients with SLE (meeting four or more of the revised ACR criteria) enrolled at University College Hospital, London lupus clinic. Disease activity was assessed during the observation year using the classic BILAG system and a mean total BILAG score was calculated for that time period. Organ damage outcomes, assessed over a subsequent follow-up period, were based on SLICC/ACR damage index scores and included new damage overall and by specific organ systems (renal, CNS or cardiovascular/musculoskeletal/pulmonary systems) or reaching a serious level of damage (SDI ≥ 3). Adjusted hazard ratios (HRs) for the association between disease activity and subsequent organ damage or mortality were calculated using Cox proportional hazards regression. RESULTS: Disease activity as measured by mean total BILAG score was associated with mortality (HR = 1.15, P = 0.008), new organ damage (HR = 1.08, P = 0.009) and CV/pulmonary or musculoskeletal damage (HR = 1.11, P = 0.007) after adjustment for age, sex, ethnicity, SLE duration, steroid exposure level, NSAID, anti-malarial or immunosuppressant use, renal activity and complement C3 or anti-dsDNA levels. Of these adjustment factors, age, renal activity, immunosuppressant use and pre-existing organ damage were additional independent predictors. CONCLUSIONS: Disease activity as measured by global BILAG score during a 12-month observation period predicts the risk of subsequent organ damage and mortality after adjustment for key covariates.

An exploration of cognitive subgroups in Alzheimer's disease.

Heterogeneity is observed in the patterns of cognition in Alzheimer's disease (AD). Such heterogeneity might suggest the involvement of different etiological pathways or different host responses to pathology. A total of 627 subjects with mild/moderate AD underwent cognitive assessment with the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale-2 (DRS-2). Latent class analysis (LCA) was performed on cognition subscale data to identify and characterize cognitive subgroups. Clinical, demographic, and genetic factors were explored for association with class membership. LCA suggested the existence of four subgroups; one group with mild and another with severe global impairment across the cognitive domains, one group with primary impairments in attention and construction, and another group with primary deficits in memory and orientation. Education, disease duration, age, Apolipoprotein E-epsilon4 (APOE epsilon4) status, gender, presence of grasp reflex, white matter changes, and early or prominent visuospatial impairment were all associated with class membership. Our results support the existence of heterogeneity in patterns of cognitive impairment in AD. Our observation of classes characterized by predominant deficits in attention/construction and memory respectively deserves further exploration as does the association between membership in the attention/construction class and APOE epsilon4 negative status.

Prevalence, correlates and course of behavioural and psychological symptoms of dementia in the population.

BACKGROUND: Behavioural and psychological symptoms of dementia (BPSD) are major contributors to the burden of dementia. AIMS: To describe the prevalence, correlates and course of BPSD in the population of England and Wales. METHOD: The prevalence of 12 symptoms was estimated in 587 participants with dementia and 2050 participants without dementia as part of a population-based longitudinal study of ageing. The effect of risk factors and the factor structure were estimated using 1782 interviews provided by participants with dementia throughout the study. RESULTS: Each symptom apart from sleeping problems was more common in the population with dementia. The co-occurrence of the symptoms was explained by a four-factor solution, corresponding to psychosis/apathy, depression/anxiety, irritability/persecution and wandering/sleep problems. Psychosis occurred more frequently with declining cognition. Anxiety and depression were more common in younger individuals and in those with poor self-reported health. Persistence varied between symptoms. CONCLUSIONS: Behavioural and psychological symptoms of dementia affect nearly all people with dementia. Symptoms co-occur, and the symptoms that affected individuals experience are related to their socio-demographic and clinical characteristics.

Risk stratification integrating genetic data for factor VIII inhibitor development in patients with severe hemophilia A.

Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were "high risk" F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.

Quantifying the burden of steroid-related damage in SLE in the Hopkins Lupus Cohort.

OBJECTIVE: Corticosteroids are a mainstay of SLE treatment; however, cumulative steroid exposure may lead to organ damage. This study aimed to quantify the risk of new diabetes, hypertension, cataracts, osteoporosis and avascular necrosis that is attributable to cumulative corticosteroid exposure in SLE. METHODS: Using data from the Hopkins Lupus Cohort, a longitudinal study of lupus activity, organ damage and quality of life in patients with SLE, five matched case-control analyses nested within a prospectively enrolled SLE cohort were performed. Two randomly selected controls were matched to each case using incidence-density sampling from defined risk sets. Attributable risk was calculated for steroid exposure (dose and duration, separately). Cumulative steroid dose was modelled as a four-level categorical variable using clinically relevant thresholds: 0 g (no exposure); >0 and <3.65 g (<10 mg/day for a year); ≥3.65 g and <18.25 g (1-5 years at 10 mg/day); and ≥18.25 g (>5 years at 10 mg/day). RESULTS: Eligible cases were identified for diabetes (n=42), hypertension (n=79), cataract (n=132), osteoporosis (n=118) and avascular necrosis (n=38). The unadjusted OR for a one-category increase in cumulative steroid exposure ranged from 1.157 (cataract (0.889 to 1.506); p=0.2779) to 2.183 (avascular necrosis (1.162 to 4.103); p=0.0153). After adjusting for confounding variables, a one-category increase in the cumulative steroid dose was significantly associated with risk of cataract (OR (95% CI) 1.855 (1.190 to 2.892); p=0.0064) and osteoporosis (OR (95% CI) 1.604 (1.067 to 2.412); p=0.0232). ORs for avascular necrosis, diabetes and hypertension suggested a moderately increased risk (not significant). Duration of steroid exposure was not associated with any of the outcomes. The proportion of risk attributable to steroid exposure after adjustment for covariates was 0.711 for cataract and 0.540 for osteoporosis. CONCLUSIONS: Cumulative steroid exposure was associated with an increased risk of cataract and osteoporosis in patients with SLE. TRIAL REGISTRATION NUMBER: NCT01616472.

Renal Remission Status and Longterm Renal Survival in Patients with Lupus Nephritis: A Retrospective Cohort Analysis.

OBJECTIVE: This observational study was a retrospective analysis of prospectively collected Hopkins Lupus Cohort data to compare longterm renal survival in patients with lupus nephritis (LN) who achieved complete (CR), partial (PR), or no remission following standard-of-care LN induction therapy. METHODS: Eligible patients with biopsy-proven LN (revised American College of Rheumatology or Systemic Lupus Collaborating Clinics criteria) were identified and categorized into ordinal (CR, PR, or no remission) or binary (response or no response) renal remission categories at 24 months post-diagnosis [modified Aspreva Lupus Management Study (mALMS) and modified Belimumab International Lupus Nephritis Study (mBLISS-LN) criteria]. The primary endpoint was longterm renal survival [without endstage renal disease (ESRD) or death]. RESULTS: In total, 176 patients met the inclusion criteria. At Month 24 postbiopsy, more patients met mALMS remission criteria (CR = 59.1%, PR = 30.1%) than mBLISS-LN criteria (CR = 40.9%, PR = 16.5%). During subsequent followup, 18 patients developed ESRD or died. Kaplan-Meier plots suggested patients with no remission at Month 24 were more likely than those with PR or CR to develop the outcome using either mALMS (p = 0.0038) and mBLISS-LN (p = 0.0097) criteria for remission. Based on Cox regression models adjusted for key confounders, those in CR according to the mBLISS-LN (HR 0.254, 95% CI 0.082-0.787; p = 0.0176) and mALMS criteria (HR 0.228, 95% CI 0.063-0.828; p = 0.0246) were significantly less likely to experience ESRD/mortality than those not in remission. CONCLUSION: Renal remission status at 24 months following LN diagnosis is a significant predictor of longterm renal survival, and a clinically relevant endpoint.

Presentation of SLE in UK primary care using the Clinical Practice Research Datalink.

OBJECTIVES: To describe the presenting symptoms of SLE in primary care using the Clinical Practice Research Database (CPRD) and to calculate the time from symptom presentation to SLE diagnosis. METHODS: Incident cases of SLE were identified from the CPRD between 2000 and 2012. Presenting symptoms were identified from the medical records of cases in the 5 years before diagnosis and grouped using the British Isles Lupus Activity Group (BILAG) symptom domains. The time from the accumulation of one, two and three BILAG domains to SLE diagnosis was investigated, stratified by age at diagnosis (<30, 30-49 and ≥50 years). RESULTS: We identified 1426 incident cases (170 males and 1256 females) of SLE. The most frequently recorded symptoms and signs prior to diagnosis were musculoskeletal, mucocutaneous and neurological. The median time from first musculoskeletal symptom to SLE diagnosis was 26.4 months (IQR 9.3-43.6). There was a significant difference in the time to diagnosis (log rank p<0.01) when stratified by age and disease severity at baseline, with younger patients <30 years and those with severe disease having the shortest times and patients aged ≥50 years and those with mild disease having the longest (6.4 years (IQR 5.8-6.8)). CONCLUSIONS: The time from symptom onset to SLE diagnosis is long, especially in older patients. SLE should be considered in patients presenting with flaring or chronic musculoskeletal, mucocutaneous and neurological symptoms.

Using Social Listening Data to Monitor Misuse and Nonmedical Use of Bupropion: A Content Analysis.

BACKGROUND: The nonmedical use of pharmaceutical products has become a significant public health concern. Traditionally, the evaluation of nonmedical use has focused on controlled substances with addiction risk. Currently, there is no effective means of evaluating the nonmedical use of noncontrolled antidepressants. OBJECTIVE: Social listening, in the context of public health sometimes called infodemiology or infoveillance, is the process of identifying and assessing what is being said about a company, product, brand, or individual, within forms of electronic interactive media. The objectives of this study were (1) to determine whether content analysis of social listening data could be utilized to identify posts discussing potential misuse or nonmedical use of bupropion and two comparators, amitriptyline and venlafaxine, and (2) to describe and characterize these posts. METHODS: Social listening was performed on all publicly available posts cumulative through July 29, 2015, from two harm-reduction Web forums, Bluelight and Opiophile, which mentioned the study drugs. The acquired data were stripped of personally identifiable identification (PII). A set of generic, brand, and vernacular product names was used to identify product references in posts. Posts were obtained using natural language processing tools to identify vernacular references to drug misuse-related Preferred Terms from the English Medical Dictionary for Regulatory Activities (MedDRA) version 18 terminology. Posts were reviewed manually by coders, who extracted relevant details. RESULTS: A total of 7756 references to at least one of the study antidepressants were identified within posts gathered for this study. Of these posts, 668 (8.61%, 668/7756) referenced misuse or nonmedical use of the drug, with bupropion accounting for 438 (65.6%, 438/668). Of the 668 posts, nonmedical use was discouraged by 40.6% (178/438), 22% (22/100), and 18.5% (24/130) and encouraged by 12.3% (54/438), 10% (10/100), and 10.8% (14/130) for bupropion, amitriptyline, and venlafaxine, respectively. The most commonly reported desired effects were similar to stimulants with bupropion, sedatives with amitriptyline, and dissociatives with venlafaxine. The nasal route of administration was most frequently reported for bupropion, whereas the oral route was most frequently reported for amitriptyline and venlafaxine. Bupropion and venlafaxine were most commonly procured from health care providers, whereas amitriptyline was most commonly obtained or stolen from a third party. The Fleiss kappa for interrater agreement among 20 items with 7 categorical response options evaluated by all 11 raters was 0.448 (95% CI 0.421-0.457). CONCLUSIONS: Social listening, conducted in collaboration with harm-reduction Web forums, offers a valuable new data source that can be used for monitoring nonmedical use of antidepressants. Additional work on the capabilities of social listening will help further delineate the benefits and limitations of this rapidly evolving data source.

Risk of Cardiovascular Disease Associated with a Restless Legs Syndrome Diagnosis in a Retrospective Cohort Study from Kaiser Permanente Northern California.

INTRODUCTION: Recent cross-sectional studies suggest that restless legs syndrome (RLS) may be associated with an increased prevalence of cardiovascular disease (CVD) comorbidity or risk factors. We evaluated whether primary or secondary RLS was associated with an increased risk of incident cardiovascular disease in a retrospective cohort study within Kaiser Permanente Northern California (KPNC). METHODS: We identified members of KPNC with primary RLS and secondary RLS between 1999 and 2008 by an algorithm that incorporated longitudinal clinical records related to the diagnosis and treatment of RLS and comorbidities. We then matched each RLS case with up to 50 individuals with no clinical records of RLS by age, sex, race/ethnicity, zip code, and membership duration. For the analyses we excluded any individual with coronary artery disease (CAD: angina, acute myocardial infarction, coronary revascularization procedure, CAD death), CVD (CAD plus stroke), and hypertension at baseline. New cardiovascular events were determined from clinical records. Follow-up ended at an outcome event, disenrollment from KPNC, or death, whichever occurred earliest. There were over 473,358 person-y of follow-up in this cohort analysis with a mean follow-up time of 3.91 y and range from 6 mo to 12 y. Survival analysis techniques, including survival curves and proportional hazard regression models, were used to assess the association between RLS status and CVD. RESULTS: There were 7,621 primary RLS and 4,507 secondary RLS cases identified and included in the study. In general, primary RLS cases were younger and had less comorbidity than secondary RLS cases. During the follow-up period, CVD was diagnosed in 478 primary RLS cohort members, CAD was diagnosed in 310, and hypertension events were identified in 1,466. Diagnosis in secondary RLS cohort members was made during the follow-up period with 451, 338, and 598 CVD, CAD, and hypertension events, respectively. Subjects with primary RLS had a similar risk of incident CVD (hazard ratio (HR) = 0.95; 95% confidence interval (CI) = 0.86-1.04) and CAD (HR = 0.99; 95% CI = 0.89-1.13) to the comparison cohort, with a slight elevation in the risk of hypertension events (HR = 1.19; 95% CI = 1.12-1.25), after multivariable adjustment. Individuals classified as secondary RLS had a significant increased risk of CVD (HR = 1.33; 95% CI = 1.21-1.46), CAD (HR = 1.40; 95% CI = 1.25-1.56), and hypertension (HR = 1.28; 95% CI = 1.18-1.40). CONCLUSION: Primary restless legs syndrome (RLS) was not associated with new-onset cardiovascular disease (CVD) or coronary artery disease (CAD) but was associated with a slight increased risk of hypertension. In contrast, secondary RLS was associated with an increased risk of CVD, CAD, and hypertension.

The systemic lupus international collaborating clinics (SLICC) damage index: a systematic literature review.

OBJECTIVES: We performed a systematic literature review to determine factors that influence damage and damage progression in SLE patients and how damage relates to mortality in this population. METHODS: A search of Medline, Embase and Web of Science was performed, with papers included if they met the requirements of containing keywords relating to SLE and damage assessment using the SDI, published between 1990 and October 2012. RESULTS: A total of 358 articles were identified, with 50 included in this review. From 17 studies reporting damage at more than 2 time points, damage progressed over time, but the rate of damage accrual reported was variable across studies. Demographic factors that influence the accrual of damage in several reports include male gender, older age, longer disease duration, Afro-Caribbean and Indo-Asian ethnicity. Patients with higher disease activity at a single time point or over time accrue greater damage. Certain organ system involvement also predicts damage accrual, in particular renal and neuropsychiatric involvement. Corticosteroids, cyclophosphamide and azathioprine all show an association with damage accrual, while hydroxychloroquine appears to have a "protective" effect. Four studies, which examined prognosis, all demonstrated that damage is a predictor of future mortality. CONCLUSIONS: Damage in SLE patients increases over time and predicts future mortality. Patients at risk of damage can be identified from demographics factors and the pattern of clinical involvement. Disease activity, corticosteroids and immunosuppressive therapy are also associated with future damage but further studies are needed to separate the mechanisms of these associations from the problem of residual confounding.

Plasma lipoprotein-associated phospholipase A2 activity in Alzheimer's disease, amnestic mild cognitive impairment, and cognitively healthy elderly subjects: a cross-sectional study.

INTRODUCTION: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulating enzyme with pro-inflammatory and oxidative activities associated with cardiovascular disease and ischemic stroke. While high plasma Lp-PLA2 activity was reported as a risk factor for dementia in the Rotterdam study, no association between Lp-PLA2 mass and dementia or Alzheimer's disease (AD) was detected in the Framingham study. The objectives of the current study were to explore the relationship of plasma Lp-PLA2 activity with cognitive diagnoses (AD, amnestic mild cognitive impairment (aMCI), and cognitively healthy subjects), cardiovascular markers, cerebrospinal fluid (CSF) markers of AD, and apolipoprotein E (APOE) genotype. METHODS: Subjects with mild AD (n = 78) and aMCI (n = 59) were recruited from the Memory Clinic, University Hospital, Basel, Switzerland; cognitively healthy subjects (n = 66) were recruited from the community. Subjects underwent standardised medical, neurological, neuropsychological, imaging, genetic, blood and CSF evaluation. Differences in Lp-PLA2 activity between the cognitive diagnosis groups were tested with ANOVA and in multiple linear regression models with adjustment for covariates. Associations between Lp-PLA2 and markers of cardiovascular disease and AD were explored with Spearman's correlation coefficients. RESULTS: There was no significant difference in plasma Lp-PLA2 activity between AD (197.1 (standard deviation, SD 38.4) nmol/min/ml) and controls (195.4 (SD 41.9)). Gender, statin use and low-density lipoprotein cholesterol (LDL) were independently associated with Lp-PLA2 activity in multiple regression models. Lp-PLA2 activity was correlated with LDL and inversely correlated with high-density lipoprotein (HDL). AD subjects with APOE-ε4 had higher Lp-PLA2 activity (207.9 (SD 41.2)) than AD subjects lacking APOE-ε4 (181.6 (SD 26.0), P = 0.003) although this was attenuated by adjustment for LDL (P = 0.09). No strong correlations were detected for Lp-PLA2 activity and CSF markers of AD. CONCLUSION: Plasma Lp-PLA2 was not associated with a diagnosis of AD or aMCI in this cross-sectional study. The main clinical correlates of Lp-PLA2 activity in AD, aMCI and cognitively healthy subjects were variables associated with lipid metabolism.

Restless legs syndrome: prevalence and impact in children and adolescents--the Peds REST study.

OBJECTIVES: Restless legs syndrome, a common neurologic sleep disorder, occurs in 5% to 10% of adults in the United States and Western Europe. Although approximately 25% of adults with restless legs syndrome report onset of symptoms between the ages of 10 and 20 years, there is very little literature looking directly at the prevalence in children and adolescents. In this first population-based study to use specific pediatric diagnostic criteria, we examined the prevalence and impact of restless legs syndrome in 2 age groups: 8 to 11 and 12 to 17 years. METHODS: Initially blinded to survey topic, families were recruited from a large, volunteer research panel in the United Kingdom and United States. Administration was via the Internet, and results were stratified by age and gender. National Institutes of Health pediatric restless legs syndrome diagnostic criteria (2003) were used, and questions were specifically constructed to exclude positional discomfort, leg cramps, arthralgias, and sore muscles being counted as restless legs syndrome. RESULTS: Data were collected from 10,523 families. Criteria for definite restless legs syndrome were met by 1.9% of 8- to 11-year-olds and 2.0% of 12- to 17-year-olds. Moderately or severely distressing restless legs syndrome symptoms were reported to occur > or = 2 times per week in 0.5% and 1.0% of children, respectively. Convincing descriptions of restless legs syndrome symptoms were provided. No significant gender differences were found. At least 1 biological parent reported having restless legs syndrome symptoms in > 70% of the families, with both parents affected in 16% of the families. Sleep disturbance was significantly more common in children and adolescents with restless legs syndrome than in controls (69.4% vs 39.6%), as was a history of "growing pains" (80.6% vs 63.2%). Various consequences were attributed to restless legs syndrome, including 49.5% endorsing a "negative effect on mood." Data were also collected on comorbid conditions and restless legs diagnosis rates. CONCLUSIONS: These population-based data suggest that restless legs syndrome is prevalent and troublesome in children and adolescents, occurring more commonly than epilepsy or diabetes.