Systemic lupus erythematosus and associated healthcare resource consumption in selected cities from the Russian Federation, Republic of Kazakhstan and Ukraine: the ESSENCE study.

OBJECTIVES: To evaluate healthcare resource (HR) consumption associated with Systemic Lupus Erythematosus (SLE) management in adult patients with active autoantibody positive disease in the Russian Federation, Republic of Kazakhstan, and Ukraine. METHODS: The ESSENCE was a retrospective, observational study, and included data on patients' clinical characteristics and SLE-related HR use (laboratory, biopsy, imaging tests, medications, visits to specialists, outpatient visits, hospitalizations) during 2010 from the 12 specialized rheumatologic centers. RESULTS: A total of 436 SLE patients were included in the analyses, with 232 patients being enrolled in Russia, 110 in Kazakhstan, and 94 in Ukraine. The mean age was 36-42 years and median SLE duration was 3-6.8 years across the countries. Extrapolation to total country population showed that, in 2010, visits to specialists (who assign treatment for organs involved/damaged by SLE) were the most frequently used HR (from 13,439 visits in Kazakhstan to 23,510 in Russia), followed by hospitalizations (from 2,950 in Kazakhstan to 6,267 in Russia) and outpatient visits (from 1,654 visits in Russia to 8,064 in Kazakhstan). Compared to chronic active patients (SLE persistent during last year), patients with relapsing-remitting SLE (at least one flare alternated by one remission per year) had a higher rate of visits to specialists (100% vs 60.8%, p < .001) and hospitalizations (98.9% vs 60.8%, p < .001). Compared to patients without flares, patients experiencing flares had a higher rate of unplanned visits to specialists (86.2% vs 6.3%, p < .001), were more often hospitalized (both ICU and non-ICU) (100.0% vs 50.0%, p < .001), and had a longer duration of ICU hospitalization (25.9 days vs 17.5 days, p < .001). CONCLUSIONS: Specialist visits are the most frequently consumed SLE-related healthcare recourse in the Commonwealth of Independent States (CIS) countries. A relapsing-remitting SLE profile and the occurrence of flares significantly raise healthcare resource consumption.

Standard medical care of patients with systemic lupus erythematosus (SLE) in large specialised centres: data from the Russian Federation, Ukraine and Republic of Kazakhstan (ESSENCE).

OBJECTIVES: To describe disease characteristics and treatment regimens for adult patients with systemic lupus erythematosus (SLE) with autoantibody positive disease in three countries (the Russian Federation, Ukraine and Republic of Kazakhstan). METHODS: The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q wave Coronary Events (ESSENCE) study was a 1-year, retrospective, multicentre, observational study. Data included patients' characteristics, disease activity and severity, and healthcare resource use in 2010. RESULTS: Twelve centres enrolled 436 eligible patients: 232 in Russia, 110 in Kazakhstan and 94 in Ukraine. Mean age ranged from 36 to 42 years and median SLE duration from 3 to 6.8 years. According to study definitions, 69.2% of patients in Russia, 72.7% in Kazakhstan and 55.4% in Ukraine had severe disease at diagnosis. SLE activity (Nasonova classification, 1972) decreased from diagnosis to the last visit in 2010 in all countries. At the last visit, mean (SD) Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index score was 13.8 (10.5) in Russia, 19.4 (16.9) in Kazakhstan and 7.2 (6.8) in Ukraine, and Systemic Lupus International Collaborative Clinics/American College of Rheumatology damage index was 2.0 (2.2), 3.3 (3.2) and 2.2 (2.0), respectively. Treatment regimens included predominantly glucocorticoids (96.7-99.1%), immunosuppressants or cytotoxic drugs, for example, azathioprine and cyclophosphamide (20.7-53.2%), and antimalarial drugs (18.3-40.8%). CONCLUSIONS: The study provides reliable insight into the SLE clinical profiles in the referenced countries. Patients were 4-10 years younger in the study and had 3-7 years shorter SLE duration than in Western European countries and both SLE activity and severity were higher with higher rate of hospitalisations, but decreased during treatment. Local and international scales demonstrated correlation in SLE activity and organ damage evaluation. There were differences in clinical characteristics and healthcare features across the countries.

The prevalence and incidence of systemic lupus erythematosus (SLE) in selected cities from three Commonwealth of Independent States countries (the Russian Federation, Ukraine and Kazakhstan).

We assessed the prevalence and incidence of Systemic Lupus Erythematosus (SLE) in 2010 in adults from four cities in Russia, Kazakhstan and Ukraine. Individuals with SLE were identified retrospectively from the medical records of specialized centers. Prevalent SLE patients were nondeceased city residents, diagnosed prior to December 31, 2010; incident patients were residents newly diagnosed between January 1 and December 31, 2010. Population size was obtained from official census data. The observed prevalence rates (per 100,000, 95% CI) were 9.0 (7.1-11.2) in Kursk and Yaroslavl, Russian Federation; 20.6 (15.4-27.0) in Semey, Kazakhstan; and 14.9 (10.9-19.9) in Vinnitsa, Ukraine. The cumulative incidence rates (per 100,000, 95% CI) were 1.4 (0.7-2.4); 1.6 (0.4-4.1) and 0.3 (0.0-1.8), correspondingly. All rates were higher among females compared to males, and incidence peaked in the population aged 25-44. These rates appear slightly lower than those reported from Western Europe and the USA. This could be because of study design (case-ascertainment), local health care practices or true differences in disease risk. Case age and sex distribution was similar to the known epidemiology of SLE. The rates were highest in Kazakhstan, likely because of a predominantly ethnic Asian population.

Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit

OBJECTIVE: To revise the "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult" published in Critical Care Medicine in 2002. METHODS: The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (-) an intervention. A strong recommendation (either for or against) indicated that the intervention's desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase "We recommend …" is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase "We suggest …" is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. CONCLUSION: These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Autoantibodies to a 140-kd protein in juvenile dermatomyositis are associated with calcinosis.

OBJECTIVE: The identification of novel autoantibodies in juvenile dermatomyositis (DM) may have etiologic and clinical implications. The aim of this study was to describe autoantibodies to a 140-kd protein in children recruited to the Juvenile DM National Registry and Repository for UK and Ireland. METHODS: Clinical data and sera were collected from children with juvenile myositis. Sera that recognized a 140-kd protein by immunoprecipitation were identified. The identity of the p140 autoantigen was investigated by immunoprecipitation/immunodepletion, using commercial monoclonal antibodies to NXP-2, reference anti-p140, and anti-p155/140, the other autoantibody recently described in juvenile DM. DNA samples from 100 Caucasian children with myositis were genotyped for HLA class II haplotype associations and compared with those from 864 randomly selected UK Caucasian control subjects. RESULTS: Sera from 37 (23%) of 162 patients with juvenile myositis were positive for anti-p140 autoantibodies, which were detected exclusively in patients with juvenile DM and not in patients with juvenile DM-overlap syndrome or control subjects. No anti-p140 antibody-positive patients were positive for other recognized autoantibodies. Immunodepletion suggested that the identity of p140 was consistent with NXP-2 (the previously identified MJ autoantigen). In children with anti-p140 antibodies, the association with calcinosis was significant compared with the rest of the cohort (corrected P < 0.005, odds ratio 7.0, 95% confidence interval 3.0-16.1). The clinical features of patients with anti-p140 autoantibodies were different from those of children with anti-p155/140 autoantibodies. The presence of HLA-DRB1*08 was a possible risk factor for anti-p140 autoantibody positivity. CONCLUSION: This study has established that anti-p140 autoantibodies represent a major autoantibody subset in juvenile DM. This specificity may identify a further immunogenetic and clinical phenotype within the juvenile myositis spectrum that includes an association with calcinosis.

Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis.

OBJECTIVES: Myositis-specific autoantibodies (MSAs) may define homogeneous clinical subsets of adult patients with dermatomyositis (DM). Recently, there have been descriptions of novel autoantibodies in DM. This study was conducted to establish the clinical significance of anti-p155/140 autoantibodies in juvenile DM (JDM). METHODS: The first 116 children recruited to the JDM National Registry and Repository (UK and Ireland) were studied. Comprehensive clinical features were recorded and sera screened for anti-p155/140 autoantibodies using radio-immunoprecipitation. Sera from adults with DM (n = 20), PM (n = 25), SSc (n = 150), SLE (n = 40) and healthy subjects (n = 50) were used for comparison. Immunodepletion experiments were used to establish whether the p155/140 kDa targets recognized by JDM sera were the same as adult DM sera. RESULTS: Twenty-seven out of 116 (23%) JDM cases were positive for anti-p155/140 in comparison with 6/20 (30%) adults with DM. Immunodepletion confirmed that the 155/140 kDa proteins recognized by JDM and adult DM sera were the same targets. All other adult control sera were negative for anti-p155/140 autoantibodies. There was a higher frequency of males in the anti-p155/140-positive JDM group (P = 0.02). JDM patients with anti-p155/140 autoantibodies had significantly more cutaneous involvement including Gottron's papules (P = 0.003), ulceration (P = 0.005) and oedema (P = 0.013). The distribution of skin lesions was more extensive particularly periorbitally (P = 0.014) and over the small (P < 0.001) and large joints (P = 0.003). CONCLUSIONS: Anti-p155/140 autoantibodies are clinically significant in JDM and may define a clinical subset in terms of disease severity and outcome. The same autoantigen target is detected in adult DM patients.

Peripheral T-cell lymphoma in a five year old.

We report a case presenting with persistent pyrexia that led to the diagnosis of peripheral T-cell lymphoma, a rare malignancy in childhood. The case illustrates diagnostic conundrums in a patient who is not responding as expected to treatment.

HLA class II haplotype and autoantibody associations in children with juvenile dermatomyositis and juvenile dermatomyositis-scleroderma overlap.

OBJECTIVES: To investigate a large cohort of children with juvenile dermatomyositis (JDM), and those with JDM-scleroderma (JDM-SSc) overlap, using detailed serological analysis, HLA class II genotyping and clinical characterization. METHODS: Children (114) with JDM were recruited, and clinical data collected, through the JDM National Registry and Repository (UK and Ireland). Sera were assayed for ANA using standard immunofluorescence techniques and specific antibodies characterized using ELISA, immunodiffusion and radioimmunoprecipitation. Patients and controls (n = 537) were genotyped at the HLA-DRB1 and DQB1 loci, and then the DQA1 locus data was derived. RESULTS: Over 70% of the patients were ANA-positive. Clear differences in serological and genetic data were demonstrated between JDM and JDM-SSc overlap groups. Strong associations were seen for HLA-DRB1*03 (all cases vs controls, P(corr) = 0.02; JDM-SSc vs controls, P(corr) = 0.001) and HLA-DQA1*05 (all cases vs controls, P(corr) = 0.01; JDM-SSc vs controls, P(corr) = 0.005). The frequency of the HLA-DRB1*03-DQA1*05-DQB1*02 haplotype was significantly increased in the JDM-SSc (P = 0.003) and anti-PM-Scl antibody (P = 0.002) positive groups. All anti-U1-RNP antibody-positive patients had at least one copy of HLA-DRB1*04-DQA1*03-DQB1*03 haplotype. Associations were observed between serology and specific clinical features. CONCLUSIONS: We present clinical data, HLA genotyping and serological profiling on a large cohort of JDM patients and a carefully characterized subset of patients with JDM-SSc overlap. The results confirm known HLA associations and extend the knowledge by stratification of data in serological and clinical subgroups. In the future, a combination of serological and genetic typing may allow for better prediction of clinical course and disease subtype in JDM.

Characteristics and antecedents of progressive multifocal leukoencephalopathy in an insured population.

Based on health insurance claims from a large U.S. health insurer, the authors identified 44 progressive multifocal leukoencephalopathy (PML) cases from 2002 through 2004 and described their characteristics, including antecedent diagnoses and treatments as well as survival. Immunosuppressive conditions such as HIV/AIDS, rather than potentially immunosuppressive treatments, were the main antecedents of PML. A lower mortality was observed among PML patients whose antecedent diagnosis was HIV/AIDS, the majority of whom received highly active antiretroviral therapy.

Molecular dynamics simulations to aid the rational design of organic friction modifiers.

Molecular dynamics simulations were performed under conditions of constant volume and temperature and of constant pressure and temperature to elucidate the structure activity relationships of a series of non-ionic surfactant molecules derived from vegetable fat and employed as friction modifiers in commercial engine oils. The simulations show the extent to which intermolecular hydrogen bonding is important in determining the stability of the monolayer formed by the surfactant molecules and show that mono-alkanoyl glyceride molecules are able to pack more efficiently, forming significantly more intermolecular hydrogen bonds and occupying approximately half the volume needed by di-alkanoyl glyceride molecules. Density profiles are presented which show significant mixing of the hydrophobic tail groups and a non-polar solvent. The distribution of torsion angles in the tail groups shows that the conformation is consistent with a liquid at finite temperature rather than a crystal structure. The measured friction coefficients of equimolar solutions of the glycerides show that the efficacy as friction modifiers varies in the order mono-, di- and the tri-oleyl glyceride, which is consistent with the efficacy of film formation predicted by the molecular dynamics calculations.

The Juvenile Dermatomyositis National Registry and Repository (UK and Ireland)--clinical characteristics of children recruited within the first 5 yr.

OBJECTIVES: To identify epidemiological, clinical and laboratory characteristics of juvenile dermatomyositis (JDM) in a national multi-centre cohort of patients, and to review recent changes in the understanding of management and prognosis in the light of these data. METHODS: All children with idiopathic inflammatory myositis recruited to the Juvenile Dermatomyositis National Registry and Repository (UK and Ireland) were included. Features at presentation, and later in disease, were assessed and evaluated. A total of 63 out of 175 children with a new diagnosis of myositis were recruited at the time of diagnosis and followed prospectively. Out of the 175 children, 122 diagnosed prior to 2000 were recruited retrospectively, with subsequent data collected prospectively. RESULTS: One patient died (0.7%), which is equivalent to one death per 465 patient years. Data were available at the time of analysis on 151 registered patients. The most common presenting features were characteristic rash, weakness, tiredness, Gottron's patches and myalgia. Muscle biopsy, magnetic resonance imaging and muscle enzymes were frequently, but not always, abnormal. Muscle enzymes and erythrocyte sedimentation rate were not useful markers of disease activity. CONCLUSIONS: The JDM National Registry and Repository captures data on a significant cohort of children with inflammatory myositis. The current study reports the largest European cohort of children with dermatomyositis to date. This powerful resource will help improve our understanding of this rare disease. Prospective data collection will allow a fuller analysis of poor prognostic features, impact of therapy, and variable outcome of childhood myositis.

An international consensus survey of the diagnostic criteria for juvenile dermatomyositis (JDM).

OBJECTIVE: To develop revised criteria for the diagnosis of juvenile dermatomyositis (JDM) using an international consensus process. METHODS: An initial survey was circulated to members of the Network for JDM and the Paediatric Rheumatology International Trials Organisation (PRINTO). Each individual was asked to identify those criteria that were felt to be most helpful in the diagnosis of classical JDM. A second survey was derived from these results and used to rank these proposed criteria in order of their importance and usefulness in clinical practice. RESULTS: The first survey had a response rate of 49.8% (118 individuals) from 92 centres in 32 countries. All responders routinely used proximal muscle weakness and characteristic skin rash in the diagnosis of JDM, while 86.8% used elevated muscle enzymes. Muscle biopsy, magnetic resonance imaging (MRI) and changes on the electromyogram (EMG) were deemed important diagnostic criteria. Other criteria, including myositis-specific or -related antibodies, nailfold capillaroscopy, factor VIII-related antigen, muscle ultrasound, calcinosis and neopterin, were used by 35.3% of respondents. Seventy-eight respondents to the first survey (66%) responded to the second survey. Typical MRI and muscle biopsy changes were rated by all to be the most useful clinically relevant diagnostic criteria after proximal muscle weakness, characteristic skin rash and elevated muscle enzymes. These were followed by myopathic changes on EMG, calcinosis, dysphonia and nailfold capillaroscopy, which were ranked equally. CONCLUSION: This process identified nine criteria that clinicians felt to be helpful or important in the diagnosis of JDM. A further process of refinement and validation is necessary to agree an internationally acceptable, clinically usable set of diagnostic criteria.

Identification of 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT2C receptor agonists.

Synthesis and evaluation of the activity of new 4-methyl-1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles as 5-HT(2C) receptor agonists are described. Appropriately substituted, several analogs displayed selectivity against the other 5-HT(2) receptor subtypes of 1 order of magnitude or more. Selectivity was improved for several compounds versus the lead 1, increasing the therapeutic interest in this series of 5-HT(2C) receptor agonists.

Cardio-pulmonary involvement in juvenile systemic lupus erythematosus.

Cardio-pulmonary manifestations of systemic lupus erythematosus (SLE) are well recognized in adults. We report the occurrence of clinically significant cardio-pulmonary disease in a cohort of predominantly Caucasian children with SLE. All children with SLE attending the Royal Liverpool Children's NHS Trust between 1995 and 2003 were reviewed. Of 29 children with SLE, 27 (93%) were Caucasian. Nine (31%) had cardio-respiratory complications: cardiac only (n = 1); respiratory only (n = 4); both cardiac and respiratory manifestations (n = 4). Median (range) duration of follow-up of affected children: four years (six months to 11 years). Six out of eight (75%) presented with respiratory complications before SLE was diagnosed. Three children had pericardial effusions, one requiring pericardiocentesis for tamponade. One had cardiac conduction defects and another significant pulmonary hypertension. Respiratory complications comprised: interstitial lung disease (n = 4), with two showing evidence of pulmonary fibrosis; pleural effusions (n = 2), pulmonary haemorrhage (n = 1) and lupus pneumonitis (n = 1). Disease course was complicated by CMV infection in one child. Lung biopsy was performed in five cases. Seven were treated with cyclophosphamide with significant improvement in symptoms/lung function. Of this predominantly Caucasian paediatric cohort with SLE, 31% had significant cardio-pulmonary involvement. All children with SLE should have regular monitoring of their cardio-respiratory status.

Nutritional impairment in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the relationship between nutritional impairment, measured by body mass index (BMI), expressed as an age- and sex-standardized standard deviation score (BMI SDS), and disease and patient characteristics in a UK cohort of children with juvenile idiopathic arthritis (JIA). A subgroup with available dietary information were analysed separately. METHODS: Important disease and patient characteristics (age, gender, disease subtype, swollen joint count, painful joint count, restricted joint count, treatment and dietary assessment) were assessed as potential explanatory measures of BMI SDS in a multiple linear regression. RESULTS: Data were collected on 123 consecutive patients. Twenty were nutritionally impaired. In multiple regression analysis excluding the dietary data, disease subtype [persistent oligoarthritis and polyarthritis (rheumatoid factor-negative)], five or more joints with reduced range of movement and being younger were associated with lower BMI SDS (P<0.001). When energy and protein intake were included in the analysis for a subgroup of children, the resulting model retained only disease subtype as a predictor of a low BMI SDS (P = 0.013). CONCLUSIONS: In this unselected population of children with JIA, 16% had evidence of undernutrition. The most commonly affected subtype was oligoarthritis, a previously unreported finding. There is no evidence from this study that this nutritional impairment results from inadequate food intake and it is likely that it is multifactorial in aetiology, disease subtype being the most important factor.

Pamidronate in the treatment of childhood SAPHO syndrome.

BACKGROUND: SAPHO syndrome is increasingly recognized within the paediatric population. Conventional therapeutic approaches have often not been effective. Pamidronate is a second-generation bisphosphonate that affects bone turnover and demonstrates anti-inflammatory properties. In small case series it has given symptomatic relief to adults with this condition. OBJECTIVES: To report the clinical experience with pamidronate in childhood SAPHO syndrome. METHODS: A retrospective observational study of all children with SAPHO syndrome treated with pamidronate between 1996 and 2003 at a tertiary rheumatology centre. The standard dosing regime for pamidronate was 1 mg/kg to a maximum of 30 mg, administered daily for three consecutive days, repeated 3-monthly as required. Response to treatment was determined by clinical observation, patient subjective response and reduction in other treatments RESULTS: Seven girls were treated, with a median (range) age at diagnosis of 11 yr (9-15 yr). All patients demonstrated a beneficial clinical response, with relief of pain, increased activity and improved well-being. Subsequent courses of pamidronate were used in all patients. Other medications including corticosteroids and methotrexate could subsequently be stopped. Transient symptoms were associated with the initial course of pamidronate in some patients. No serious adverse events were reported. CONCLUSIONS: Pamidronate was associated with a marked improvement in function and well-being, and a reduction of pain and use of other medications in all patients, with no significant adverse effects. This study represents preliminary clinical data. A prospective multicentre study is necessary to assess the role and long-term safety of pamidronate in the management of childhood SAPHO syndrome

Indoline derivatives as 5-HT(2C) receptor agonists.

A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.