Comorbidities in childhood atopic dermatitis: A population-based study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with allergic comorbidities. However, studies examining comorbidities in childhood AD are incomplete, which may contribute to suboptimal care. OBJECTIVE: The objective was to compare the risk of developing different allergic and non-allergic comorbidities among children with AD to that of a matched non-AD reference cohort in Sweden. METHODS: This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. Patients with AD were identified by confirmed diagnosis in primary or specialist care. The non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients. The risk of developing the following conditions was evaluated: hypersensitivity and allergic disorders, neurological disorders, psychiatric disorders, infections, immunological and inflammatory disorders, Type 1 diabetes (T1D), endocrine and metabolic disorders, skeletal disorders, ocular disorders and malignancies. RESULTS: This study included 165,145 patients with AD (mild-to-moderate [n = 126,681] and severe [n = 38,464]) and an equally sized reference cohort. Patients with AD displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D and skeletal disorders, compared with the reference cohort. The highest risk compared with the reference cohort was observed for hypersensitivity and allergic disorders (hazard ratio [HR]: 3.87), followed by malignancies (HR: 2.53) and immunological and inflammatory disorders (HR: 2.36). Patients with AD also had higher risk of developing multiple comorbidities (≥2). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission. CONCLUSIONS: The clinical burden of AD is substantial for children with AD and patients are at an increased risk of developing several comorbid conditions extending beyond the atopic march. Our results also showed a positive association between worsening severity of AD and an increased risk of comorbidity onset.

Tofacitinib real-world experience in ulcerative colitis in Finland (FinTofUC): a retrospective non-interventional multicenter patient chart data study.

OBJECTIVES: The aim was to define the effectiveness of tofacitinib and to characterize the patient population receiving tofacitinib in a real-world cohort clinical setting for ulcerative colitis (UC) in Finland. METHODS: This is a retrospective non-interventional multicenter patient chart data study conducted in 23 Finnish Inflammatory Bowel Disease (IBD) centers. Baseline demographic and clinical data, clinical remission, steroid-free remission rate and time to tofacitinib discontinuation, colectomy or UC-related hospitalization were studied. RESULTS: The study included 252 UC patients of which 69% were male. Most patients had extensive disease (71%) and were bio-experienced (81%). Tofacitinib demonstrated positive treatment outcomes with clinical response, clinical remission, and steroid-free clinical remission at one year in 33%, 34% and 31% of patients, respectively. Moreover, 64% of patients in pMayo remission at week 16 from the start of tofacitinib were still in remission at one year. Only no or mild disease activity compared to moderate activity at baseline was associated with a higher probability of achieving remission according to pMayo at six months, p = .008. Hospitalizations and/or colectomies during the study period (before treatment discontinuation/end of follow-up) were low (n = 24), with less than 5 colectomies. CONCLUSIONS: In this real-world cohort, including a majority of bio-experienced UC patients, tofacitinib was effective in achieving steroid-free clinical remission in a third of the population at one year. A majority of patients in remission at week 16 were also in remission at one year. Results are in line with earlier published real-world studies. Registration: ClinicalTrials.gov NCT05082428.

Influenza Adverse Events in Patients with Rheumatoid Arthritis, Ulcerative Colitis, or Psoriatic Arthritis in the Tofacitinib Clinical Development Programs.

INTRODUCTION: This post hoc analysis evaluated influenza adverse events (AEs) across rheumatoid arthritis (RA), ulcerative colitis (UC), and psoriatic arthritis (PsA) tofacitinib clinical programs. METHODS: Available data from phase 1, randomized phase 2/3/3b/4 clinical trials (completed by 2018), and long-term extension (LTE) studies (up to May 2019) in patients with RA, UC, and PsA were included [randomized or Overall (phase 1-3b/4 and LTE studies) tofacitinib cohorts]. Incidence rates (IRs; events per 100 patient-years) of combined influenza AEs (seasons 2004/2005 to 2018/2019) were analyzed, including by tofacitinib dose [5 or 10 mg twice daily (BID)] and age (< 65 versus ≥ 65 years). Logistic regression models evaluated risk factors for influenza AEs in the RA Overall tofacitinib cohort. RESULTS: In randomized cohorts, combined influenza AE IRs were generally similar across tofacitinib, adalimumab, methotrexate, and placebo groups, across indications. Among Overall tofacitinib cohorts, combined influenza AE IRs with tofacitinib 5/10 mg BID, respectively, were higher in the UC (3.66/5.09) versus RA (2.38/2.19) and PsA (1.74/1.29) cohorts. IRs were generally similar across tofacitinib dose and age groups. Most influenza AEs were nonserious and did not require changes to tofacitinib treatment. Significant risk factors for influenza AEs in patients with RA were geographic region, baseline oral corticosteroid and methotrexate use, and tofacitinib dose. CONCLUSIONS: In the RA, UC, and PsA clinical programs, combined influenza AE IRs were highest in UC, while in each indication they were generally similar across tofacitinib, placebo, and comparator groups. Influenza AEs were predominantly nonserious and not associated with changes to tofacitinib treatment. TRIAL REGISTRATION NUMBERS: NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661, NCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612, NCT01877668, NCT01882439, NCT01976364.

Peripheral Vascular Ageing in Pulmonary Arterial Hypertension as Assessed by Common Carotid Artery Intima Thickness and Intima/Media Thickness Ratio: An Investigation Using Non-Invasive High-Resolution Ultrasound.

BACKGROUND: Pulmonary arterial hypertension (PAH; World Heath Organization [WHO] Group 1) is associated with increased pulmonary arterial pressure and resistance, with pulmonary vascular remodelling. The vascular anatomy of the systemic arteries has been less well studied. METHOD: Nineteen (19) patients with PAH, confirmed by right heart catheterisation (RHC), 14 patients with left ventricular heart failure with reduced ejection fraction (LVrEF), and 30 healthy subjects were enrolled. Common carotid artery (CCA) intima thickness, intima/media (I/M) thickness ratio, and intima-media thickness (IMT) were assessed using non-invasive ultrasound (22 MHz centre frequency). RESULTS: The CCA intima thickness was correlated with several RHC variables (all p<0.05). The intima was 56% thicker (+0.05 mm; 95% CI 0.03, 0.06; p<0.0001) and the I/M thickness ratio was 128% greater (+0.21; 95% CI 0.13, 0.28; p<0.0001) in patients with PAH than healthy subjects. These values were also significantly higher than in patients with LVrEF. In ROC curve analysis, the c-values for CCA intima thickness (0.92) and I/M ratio (0.87), but not for IMT, correctly indicated which individuals belonged to the PAH or healthy control groups. The CCA IMT showed no corresponding significant group differences or associations and was of no use according to receiver operating curve analysis. CONCLUSIONS: Patients with PAH displayed signs of peripheral vascular remodelling, challenging the common opinion that vascular changes in PAH are restricted to the lung vasculature. Correlations with cardiopulmonary variables from RHC support peripheral vascular coupling and the association with vascular ageing. Results from this pilot study warrant further confirmation.

Validation of Patient Identification Algorithms for Atopic Dermatitis Using Healthcare Databases.

INTRODUCTION: The use of real-world data offers a possibility to perform large-scale epidemiological studies in actual clinical settings. Despite their many advantages, administrative databases were not designed to be used in research, and the validation of diagnoses and treatments in administrative databases is needed. The primary objective of this study was to validate an existing algorithm based on dispensed prescriptions and diagnoses of skin conditions to identify pediatric patients with atopic dermatitis (AD), using a diagnosis of AD in primary care as a gold standard. METHODS: Retrospective observational data were collected from nation-wide secondary care and pharmacy-dispensed medication databases and two regional primary care databases in Sweden. An existing algorithm and a Modified algorithm, using skin-specific diagnoses from secondary care and/or pharmacy-dispensed prescriptions to identify patients with AD, were assessed. To verify the presence of AD, diagnoses from primary care were used in the base case and complemented with diagnoses from secondary care in a sensitivity analysis. RESULTS: The sensitivity (30.0%) and positive predictive value (PPV) (40.7%) of the existing algorithm were low in the pediatric patient population when using primary care data only but increased when secondary care visits were also included in the Modified algorithm (sensitivity, 62.1%; PPV, 66.3%). The specificity of the two algorithms was high in both the base case and sensitivity analysis (95.1% and 94.1%). In the adult population, sensitivity and PPV were 20.4% and 8.7%, respectively, and increased to 48.3% and 16.9% when secondary care visits were also included in the Modified algorithm. CONCLUSION: The Modified algorithm can be used to identify pediatric AD populations using primary and secondary administrative data with acceptable sensitivity and specificity, but further modifications are needed to accurately identify adult patients with AD.

Clinical and Economic Burden of Pediatric Mild-to-Moderate Atopic Dermatitis: A Population-Based Nested Case-Control Study in Sweden.

INTRODUCTION: Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin condition characterized by pruritic, eczematous lesions. Recent evidence suggests that AD may be a systemic disorder, implying that management of this disease extends beyond merely controlling symptoms associated with AD. Even though this disease is highly prevalent in children and patients typically present with mild-to-moderate symptoms, the disease burden is not well established. METHODS: A large, retrospective cohort study of Swedish population data was conducted to compare the clinical burden in terms of healthcare resource use and direct medical costs for pediatric mild-to-moderate (pM2M) AD patients (≤ 14 years of age, N = 87,721) with matched controls. The burden of a severe AD cohort was also evaluated. Severity of AD was defined by treatment usage and systemic treatment was used as a proxy for severe AD. A robust approach was used by including any type of secondary care visits known to be more common in AD patients than in the general population; however, data for primary care visits were not available. RESULTS: For healthcare resource use, the incidence rate ratio (pM2M AD versus reference cohort) of secondary care visits ranged from 1.56 to 2.35 during each of 5 years after AD onset (all p < 0.001), with largest differences seen in years 1-2. The average direct medical cost (SD) was €1111 (3416) and €524 (2446) in the pM2M AD and reference cohorts, respectively. The corresponding estimate in the severe AD cohort was €1906 (7067). Including all secondary care visits and pharmacy-dispensed medications, the pM2M AD cohort was shown to have an additional €118.9 million in direct medical costs over 5 years compared with the reference cohort. CONCLUSIONS: This study shows significant clinical and economic burden of pM2M AD with important secondary care resource utilization, suggesting a need for further research to increase treatment options and improve the management of these patients.

Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation-a prospective, observational study.

OBJECTIVE: Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs. METHODS: This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5 g twice daily since at least 3 months. The 12-h drug exposure of the active MMF metabolite mycophenolic acid (MPA) was estimated by repeated analysis of plasma MPA over a 6-h period. This 12-h drug exposure was dose normalised to a daily intake of 3 g MMF (MPA_AUC3g) in order to compare subjects using MMF at different doses. Drug exposure was analysed in reference to the clinical characteristics including body weight, renal function, autoantibodies, intestinal dysbiosis, intestinal inflammation assessed by faecal (F)-calprotectin, intestinal symptoms assessed by the University of California Los Angeles Scleroderma Trial Consortium Gastrointestinal Tract Instrument 2.0 and concomitant drug usage including proton-pump inhibitors (PPI). RESULTS: Thirty-four out of 35 study participants completed the study. The mean daily MMF dose was 2.1 g. Drug exposure expressed as MPA_AUC3g varied up to 8-fold between patients (median 115, range 27-226 mg h/L). MPA_AUC3g was inversely related to body weight (rs = - 0.58, p < 0.001) and renal function (rs = - 0.34, p = 0.054). Anti-topoisomerase-1 antibodies and male sex were associated with lower MPA_AUC3g (87 vs 123 and 71 vs 141; p = 0.008 and p = 0.015, respectively). MPA_AUC3g was inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (rs = - 0.54, p = 0.004; rs = - 0.36, p = 0.034), but not to gastrointestinal symptoms. MPA_AUC3g was inversely related to PPI usage (rs = - 0.45, p = 0.007). We found no association between MPA_AUC3g and disease subtype, disease duration or disease activity. CONCLUSION: MMF-treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc.

Effects of inorganic nitrate in a rat model of monocrotaline-induced pulmonary arterial hypertension.

The nitrate-nitrite-nitric oxide (NO) pathway represents an alternative source of NO generation, which is independent of NO synthase and potentiated by hypoxia. Augmentation of this pathway by dietary nitrate has proven favourable effects in several cardiovascular disease models. However, less is known regarding its potential value in pulmonary arterial hypertension (PAH). The aim of this study was to assess the effects of oral inorganic nitrate administration in monocrotaline (MCT)-induced PAH. Male 12-week-old Wistar rats were injected subcutaneously with monocrotaline (MCT, 60 mg/kg). Nitrate treatment (0.3 or 1 mmol/kg/d; drinking water) commenced on day 12 following the MCT injection and continued for 16 days. Nitrate administration did not attenuate right ventricular (RV) hypertrophy, increased lung weight and up-regulated mRNA expression of brain natriuretic peptide. Plasma nitrate and nitrite levels were significantly increased as well as lung nitrate level, whereas nitrite lung level was decreased following nitrate treatment (1 mmol/kg/d). MCT-induced PAH resulted in an increased MnSOD protein level, which was not observed following nitrate treatment. MCT-associated up-regulation of nNOS in the lung appeared to be dose-dependently prevented by nitrate treatment. Western blot analysis did not reveal any differences in eNOS, iNOS, XO or gp91phox expression in the lungs among the groups. In conclusion, nitrate treatment did not significantly attenuate pathological RV and lung remodelling in the rat MCT model of PAH. The suppression of MnSOD and nNOS expression by nitrate could be interpreted as reduced demand of endogenous antioxidant defence in this model.

Effects of Oral Supplementation With Nitrate-Rich Beetroot Juice in Patients With Pulmonary Arterial Hypertension-Results From BEET-PAH, an Exploratory Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

BACKGROUND: The nitrate-nitrite-nitric oxide (NO) pathway may represent a potential therapeutic target in patients with pulmonary arterial hypertension (PAH). We explored the effects of dietary nitrate supplementation, with the use of nitrate-rich beetroot juice (BRJ), in patients with PAH. METHODS AND RESULTS: We prospectively studied 15 patients with PAH in an exploratory randomized, double-blind, placebo-controlled, crossover trial. The patients received nitrate-rich beetroot juice (∼16 mmol nitrate per day) and placebo in 2 treatment periods of 7 days each. The assessments included; exhaled NO and NO flow-independent parameters (alveolar NO and bronchial NO flux), plasma and salivary nitrate and nitrite, biomarkers and metabolites of the NO-system, N-terminal pro-B-type natriuretic peptide, echocardiography, ergospirometry, diffusing capacity of the lung for carbon monoxide, and the 6-minute walk test. Compared with placebo ingestion of BRJ resulted in increases in; fractional exhaled NO at all flow-rates, alveolar NO concentrations and bronchial NO flux, and plasma and salivary levels of nitrate and nitrite. Plasma ornithine levels decreased and indices of relative arginine availability increased after BRJ compared to placebo. A decrease in breathing frequency was observed during ergospirometry after BRJ. A tendency for an improvement in right ventricular function was observed after ingestion of BRJ. In addition a tendency for an increase in the peak power output to peak oxygen consumption ratio (W peak/VO2 peak) was observed, which became significant in patients reaching an increase of plasma nitrite >30% (responders). CONCLUSIONS: BRJ administered for 1 week increases pulmonary NO production and the relative arginine bioavailability in patients with PAH, compared with placebo. An increase in the W peak/VO2 peak ratio was observed after BRJ ingestion in plasma nitrite responders. These findings indicate that supplementation with inorganic nitrate increase NO synthase-independent NO production from the nitrate-nitrite-NO pathway.

Plasma L-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction.

Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from L-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, L-arginine, L-ornithine, and L-citrulline were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma levels of ADMA and SDMA were higher, whereas L-arginine and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of L-arginine than patients with LVSD (p < 0.05). L-Arginine correlated to 6 min walking distance (6MWD) (r s = 0.58, p = 0.006) and L-arginine/ADMA correlated to WHO functional class (r s = -0.46, p = 0.043) in PAH. In conclusion, L-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, L-arginine correlated with 6MWD in PAH. L-arginine may provide useful information in differentiating PAH from LVSD.

Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension.

PURPOSE: Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine. METHODS: A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria. RESULTS: Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders. CONCLUSIONS: Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension.

OBJECTIVE: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. PATIENTS AND METHODS: ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min. RESULTS: A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45 min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60 min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. CONCLUSIONS: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

The association of fatigue, comorbidity burden, disease activity, disability and gross domestic product in patients with rheumatoid arthritis. Results from 34 countries participating in the Quest-RA program.

OBJECTIVES: The aim is to assess the prevalence of comorbidities and to further analyse to which degree fatigue can be explained by comorbidity burden, disease activity, disability and gross domestic product (GDP) in patients with rheumatoid arthritis (RA). METHODS: Nine thousands eight hundred seventy-four patients from 34 countries, 16 with high GDP (>24.000 US dollars [USD] per capita) and 18 low-GDP countries (<24.000 USD) participated in the Quantitative Standard monitoring of Patients with RA (QUEST-RA) study. The prevalence of 31 comorbid conditions, fatigue (0-10 cm visual analogue scale [VAS] [10=worst]), disease activity in 28 joints (DAS28), and physical disability (Health Assessment Questionnaire score [HAQ]) were assessed. Univariate and multivariate linear regression analyses were performed to assess the association between fatigue and comorbidities, disease activity, disability and GDP. RESULTS: Overall, patients reported a median of 2 comorbid conditions of which hypertension (31.5%), osteoporosis (17.6%), osteoarthritis (15.5%) and hyperlipidaemia (14.2%) were the most prevalent. The majority of comorbidities were more common in high-GDP countries. The median fatigue score was 4.4 (4.8 in low-GDP countries and 3.8 in high-GDP countries, p<0.001). In low-GDP countries 25.4% of the patients had a high level of fatigue (>6.6) compared with 23.0% in high-GDP countries (p<0.001). In univariate analysis, fatigue increased with increasing number of comorbidities, disease activity and disability in both high- and low-GDP countries. In multivariate analysis of all countries, these 3 variables explained 29.4% of the variability, whereas GDP was not significant. CONCLUSIONS: Fatigue is a widespread problem associated with high comorbidity burden, disease activity and disability regardless of GDP.

Effects of pharmacists' interventions on appropriateness of prescribing and evaluation of the instruments' (MAI, STOPP and STARTs') ability to predict hospitalization--analyses from a randomized controlled trial.

BACKGROUND: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. METHODS: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. RESULTS: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. CONCLUSION: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

Patient's global assessment of disease activity and patient's assessment of general health for rheumatoid arthritis activity assessment: are they equivalent?

OBJECTIVES: To assess (A) determinants of patient's global assessment of disease activity (PTGL) and patient's assessment of general health (GH) scores of rheumatoid arthritis (RA) patients; (B) whether they are equivalent as individual variables; and (C) whether they may be used interchangeably in calculating common RA activity assessment composite indices. METHODS: Data of 7023 patients from 30 countries in the Quantitative Standard Monitoring of Patients with RA (QUEST-RA) was analysed. PTGL and GH determinants were assessed by mixed-effects analyses of covariance models. PTGL and GH equivalence was determined by Bland-Altman 95% limits of agreement (BALOA) and Lin's coefficient of concordance (LCC). Concordance between PTGL and GH based Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI) and Routine Assessment of Patient Index Data 3 (RAPID3) indices were calculated using LCC, and the level of agreement in classifying RA activity in four states (remission, low, moderate, high) using κ statistics. RESULTS: Significant differences in relative and absolute contribution of RA and non-RA related variables in PTGL and GH ratings were noted. LCC of 0.64 and BALOA of -4.41 to 4.54 showed that PTGL and GH are not equivalent. There was excellent concordance (LCC 0.95-0.99) for PTGL and GH based DAS28, CDAI and RAPID3 indices, and >80% absolute agreement (κ statistics 0.75-0.84) in RA activity state classification for all three indices. CONCLUSIONS: PTGL and GH ratings differ in their determinants. Although they are individually not equivalent, they may be used interchangeably for calculating composite indices for RA activity assessment.

Acute haemodynamic response in relation to plasma vardenafil concentrations in patients with pulmonary hypertension.

AIMS: To evaluate the acute haemodynamic effects of a single oral dose of vardenafil and to study the drug concentration in relation to haemodynamic effects in patients with pulmonary hypertension (PH). METHODS: Sixteen patients with PH (aged 29-85\ years), received one single oral dose of vardenafil (5, 10 or 20 mg). The haemodynamic effect was assessed over a 60 min period. Vardenafil plasma concentrations were measured after 15, 30, 45 and 60 min using liquid chromatography-tandem mass spectrometry. RESULTS: At 60 min a reduction in mPAP with a median % decrease of -20.3% (range -48.3 to 3.0; P < 0.001) and an increase in cardiac output and the cardiac index with a median % change of 10.6% (range -25.0 to 88.1; P = 0.015) and 12.1% (range -24.0 to 94.4; P = 0.01) respectively was observed. The pulmonary vascular resistance (PVR) was reduced with a median % decrease of -28.9% (range -61.5 to -5.9; P < 0.001), and pulmonary selectivity was reflected by a median percent reduction of -16.9% (range -49.0 to 16.5; P = 0.002; n = 14) in the PVR/systemic vascular resistance ratio. There was a correlation between the plasma concentrations of vardenafil and change in mPAP (r = -0.579, P = 0.019) and between vardenafil concentrations and change in PVR (r = -0.662, P = 0.005). CONCLUSIONS: Vardenafil causes rapid changes in cardiopulmonary haemodynamics and there is a correlation between plasma vardenafil drug concentration and the acute changes in mPAP as well as PVR in patients with PH.

Increased plasma and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial hypertension.

BACKGROUND: Conflicting results on exhaled NO in pulmonary hypertension (PH) exist. Therefore, we analysed exhaled NO, as well as systemic and local nitrite, a possible alternative source of NO, in PH with regard to PH aetiology. METHODS: Exhaled NO at multiple flow-rates, as well as plasma and salivary nitrite and nitrate, was measured in 22 patients with PH and 21 healthy controls. Alveolar NO (Calv(NO) ) and bronchial flux (J'aw(NO) ) were calculated using the slope-intercept model. Patients with PH were subdivided into pulmonary arterial hypertension (PAH) and PH WHO Groups II-IV, according to the WHO clinical classification of PH. RESULTS: Exhaled NO was reduced at flow-rates in the range of 20-200 mL s(-1) in patients with PAH (n=13) vs. PH WHO Group II-IV (n=9) (P<0·05 all). Patients with PAH had higher Calv(NO) than healthy controls [2·61 (2·23, 3·36) vs. 1.97ppb (1·22, 2·49), P=0·03] and similar to PH WHO Group II-IV (P=0·51). Patients with PAH had lower J'aw(NO) than patients with PH WHO Group II-IV or healthy controls [430 (371, 702) vs. 807 (557, 993) or 731pLs(-1) (580, 818), P<0·05 both]. Subjects with PAH were characterized by higher levels of salivary and plasma nitrite than healthy controls (P<0·05 both). CONCLUSIONS: Patients with PAH have lower bronchial NO flux compared to healthy controls and patients with PH WHO Group II-IV along with elevated salivary and plasma nitrite compared to controls. This implies reduced bronchial NO synthase-derived NO formation in PAH. Increased alveolar NO levels were found in subjects with PH compared to controls, especially in subjects with PAH. This may reflect NO diffusion disturbances in the alveoli.

Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study.

INTRODUCTION: Work disability is a major consequence of rheumatoid arthritis (RA), associated not only with traditional disease activity variables, but also more significantly with demographic, functional, occupational, and societal variables. Recent reports suggest that the use of biologic agents offers potential for reduced work disability rates, but the conclusions are based on surrogate disease activity measures derived from studies primarily from Western countries. METHODS: The Quantitative Standard Monitoring of Patients with RA (QUEST-RA) multinational database of 8,039 patients in 86 sites in 32 countries, 16 with high gross domestic product (GDP) (>24K US dollars (USD) per capita) and 16 low-GDP countries (<11K USD), was analyzed for work and disability status at onset and over the course of RA and clinical status of patients who continued working or had stopped working in high-GDP versus low-GDP countries according to all RA Core Data Set measures. Associations of work disability status with RA Core Data Set variables and indices were analyzed using descriptive statistics and regression analyses. RESULTS: At the time of first symptoms, 86% of men (range 57%-100% among countries) and 64% (19%-87%) of women <65 years were working. More than one third (37%) of these patients reported subsequent work disability because of RA. Among 1,756 patients whose symptoms had begun during the 2000s, the probabilities of continuing to work were 80% (95% confidence interval (CI) 78%-82%) at 2 years and 68% (95% CI 65%-71%) at 5 years, with similar patterns in high-GDP and low-GDP countries. Patients who continued working versus stopped working had significantly better clinical status for all clinical status measures and patient self-report scores, with similar patterns in high-GDP and low-GDP countries. However, patients who had stopped working in high-GDP countries had better clinical status than patients who continued working in low-GDP countries. The most significant identifier of work disability in all subgroups was Health Assessment Questionnaire (HAQ) functional disability score. CONCLUSIONS: Work disability rates remain high among people with RA during this millennium. In low-GDP countries, people remain working with high levels of disability and disease activity. Cultural and economic differences between societies affect work disability as an outcome measure for RA.