Suitability of machine learning models for prediction of clinically defined Stage III/IV periodontitis from questionnaires and demographic data in Danish cohorts.

AIM: To evaluate if, and to what extent, machine learning models can capture clinically defined Stage III/IV periodontitis from self-report questionnaires and demographic data. MATERIALS AND METHODS: Self-reported measures of periodontitis, demographic data and clinically established Stage III/IV periodontitis status were extracted from two Danish population-based cohorts (The Copenhagen Aging and Midlife Biobank [CAMB] and The Danish Health Examination Survey [DANHES]) and used to develop cross-validated machine learning models for the prediction of clinically established Stage III/IV periodontitis. Models were trained using 10-fold cross-validations repeated three times on the CAMB dataset (n = 1476), and the resulting models were validated in the DANHES dataset (n = 3585). RESULTS: The prevalence of Stage III/IV periodontitis was 23.2% (n = 342) in the CAMB dataset and 9.3% (n = 335) in the DANHES dataset. For the prediction of clinically established Stage III/IV periodontitis in the CAMB cohort, models reached area under the receiver operating characteristics (AUROCs) of 0.67-0.69, sensitivities of 0.58-0.64 and specificities of 0.71-0.80. In the DANHES cohort, models derived from the CAMB cohort achieved AUROCs of 0.64-0.70, sensitivities of 0.44-0.63 and specificities of 0.75-0.84. CONCLUSIONS: Applying cross-validated machine learning algorithms to demographic data and self-reported measures of periodontitis resulted in models with modest capabilities for the prediction of Stage III/IV periodontitis in two Danish cohorts.

Prevalence of survey-based criteria for fibromyalgia and impact on hospital burden: a 7 year follow-up study from an outpatient clinic.

OBJECTIVES: To evaluate the prevalence of survey-based criteria for fibromyalgia (FM) among newly referred patients in a rheumatic outpatient clinic, and to compare the use of secondary healthcare services between survey-based FM and non-FM cases. METHOD: Newly referred patients to an outpatient clinic were screened for the fulfilment of the 2011 FM survey criteria during a 6 month period in 2013 in this observational cohort study. Demographic data were obtained at baseline. Patients' medical files were evaluated and comparisons between groups were made regarding the use of hospital healthcare facilities during the 7 year observation period. RESULTS: Out of 300 invited patients, 248 (83%) completed the questionnaire; 90 patients (36%) fulfilled survey-based criteria for FM at enrolment. FM cases were primarily women (80% vs 54% of non-FM cases), and received more medications (median 4 vs 3 drugs) and public economic support (62% vs 20%). At the 7 year follow-up, crude analyses showed that FM cases had a higher number of hospital courses (median 10 vs 8) and had undergone more invasive procedures (78% vs 60%). Neurologists (42% vs 28%), gastroenterologists (30% vs 13%), endocrinologists (40% vs 21%), pain specialists (13% vs 3%), psychiatrists (20% vs 7%), and abdominal surgeons (43% vs 30%) were consulted more often by FM than by non-FM cases. CONCLUSION: Fulfilment of FM survey criteria among newly referred patients to a rheumatic outpatient clinic is frequent. Our study findings show that FM continues to present a challenge for healthcare professionals as well as for patients. RESEARCH HIGHLIGHTS: ● Fulfilment of FM survey criteria among newly referred patients to a rheumatic outpatient clinic is frequent.● The burden on the secondary healthcare system for these patients is significant.● This study suggests the need for increased awareness about the diagnosis of FM among certain medical and surgical specialties.

Risk of periodontitis in patients with psoriasis and psoriatic arthritis.

BACKGROUND: Psoriasis and periodontitis are chronic inflammatory disorders with overlapping inflammatory pathways, but data on risk of periodontitis in psoriasis are scarce and a possible pathogenic link is poorly understood. OBJECTIVE: We investigated the association between psoriasis and periodontitis in a nationwide cohort study. METHODS: All Danish individuals aged ≥18 years between 1 January 1997 and 31 December 2011 (n = 5,470,428), including 54 210 and 6988 patients with mild and severe psoriasis, and 6428 with psoriatic arthritis, were linked through administrative registers. Incidence rate ratios (IRRs) were estimated by Poisson regression. RESULTS: Incidence rates of periodontitis per 10 000 person-years were 3.07 (3.03-3.12), 5.89 (1.07-6.84), 8.27 (5.50-12.45) and 11.12 (7.87-15.73) for the reference population, mild psoriasis, severe psoriasis and psoriatic arthritis respectively. Adjusted IRRs were (1.66; 1.43-1.94) for mild psoriasis, (2.24; 1.46-3.44) for severe psoriasis and (3.48; 2.46-4.92) for psoriatic arthritis. Similar results were found when a case-control design was applied. CONCLUSIONS: We found a significant psoriasis-associated increased risk of periodontitis, which was highest in patients with severe psoriasis and psoriatic arthritis.

Risk of self-harm and nonfatal suicide attempts, and completed suicide in patients with psoriasis: a population-based cohort study.

BACKGROUND: Psoriasis is a common inflammatory skin disease, and inflammation may affect suicidal behaviour. Current data on the incidence and risk of suicidal behaviour in patients with psoriasis are scarce. OBJECTIVES: We investigated the association between psoriasis and the risk of self-harm and suicide attempts and suicides. METHODS: All Danish patients aged ≥ 18 years with mild or severe psoriasis (cases) from 1 January 1997 to 31 December 2011 were matched on age, sex and calendar time 1 : 5 with healthy controls. The outcome was a diagnosis of self-harm or a nonfatal suicide attempt, or completed suicide. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) and confidence intervals (CIs) were estimated by Poisson regression models. RESULTS: The study cohort comprised 408 663 individuals, including 57 502 and 11 009 patients with mild and severe psoriasis, respectively. In total 280 cases of self-harm or suicide attempts, and 574 suicides occurred during follow-up. There was no increased risk of self-harm or suicide attempts in patients with mild psoriasis (IRR 1·01, 95% CI 0·17-2·01), but this risk was significantly increased in severe psoriasis (IRR 1·69, 95% CI 1·00-2·84). There was no increased risk of suicides in mild (IRR 1·05, 95% CI 0·84-1·32) or severe psoriasis (IRR 0·78, 95% CI 0·45-1·36). Similar results were found when suicides were confirmed by official forensic investigations, and when psoriasis was compared with atopic dermatitis. CONCLUSIONS: We found limited evidence to suggest an increased risk of self-harm and nonfatal suicide attempts in patients with psoriasis. Importantly, after adjustment for psoriatic arthritis this risk was no longer significantly increased. The risk of completed suicide was also not increased, regardless of psoriasis severity.

Association between psoriasis and inflammatory bowel disease: a Danish nationwide cohort study.

BACKGROUND: Psoriasis, Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders with overlapping genetic architecture. However, data on the frequency and risk of CD and UC in psoriasis are scarce and poorly understood. OBJECTIVES: To investigate the association between CD and UC in patients with psoriasis. METHODS: All Danish individuals aged ≥ 18 years between 1 January 1997 and 31 December 2012 were linked in nationwide registers. Psoriasis severity was defined in two models: hospital visits and medication. Incidence rates per 10 000 person-years were calculated, and incidence rate ratios (IRRs) were estimated by Poisson regression. RESULTS: In the total cohort (n = 5 554 100) there were 75 209 incident cases of psoriasis, 11 309 incident cases of CD and 30 310 incident cases of UC, during follow-up. The adjusted IRRs (95% confidence intervals) of CD were 1·28 (1·03-1·59), 2·56 (1·87-3·50), 2·85 (1·72-4·73) and 3·42 (2·36-4·95) in patients with mild psoriasis, severe psoriasis (hospital), severe psoriasis (medication) and psoriatic arthritis, respectively. Similarly, the adjusted IRRs of UC were 1·49 (1·32-1·68), 1·56 (1·22-2·00), 1·96 (1·36-2·83) and 2·43 (1·86-3·17), respectively. The 10-year incidence of CD was 2-5 per 1000 patients and of UC 7-11 per 1000 patients, depending on psoriasis severity and the presence of psoriatic arthritis. Additionally, an increased risk of incident psoriasis was found following CD or UC. CONCLUSIONS: We observed a psoriasis-associated increased risk of CD and UC, which was higher in severe psoriasis, and an increased risk of psoriasis in patients with inflammatory bowel disease. Increased focus on gastrointestinal symptoms in patients with psoriasis may be warranted.

Myocardial function and effects of biologic therapy in patients with severe psoriasis: a prospective echocardiographic study.

BACKGROUND: Psoriasis is a chronic inflammatory disease and is associated with cardiovascular events. Little is known about subclinical myocardial dysfunction and potential changes in myocardial function during anti-inflammatory treatment in these patients. We prospectively studied left ventricular function in patients with severe psoriasis who initiated biologic therapy. METHODS: Between November 1 2013 and May 31 2014 the study subjects underwent physical, laboratory and comprehensive echocardiographic examination at baseline and after 3 months of treatment. Pearson correlation coefficients and Student's t-test were applied to assess changes in diastolic function (defined as the E/e' ratio) and global longitudinal strain (GLS). RESULTS: Eighteen patients with severe psoriasis treated with biologic therapy with a mean follow-up of 85.6 ± 18.2 days were included. The patients had a baseline psoriasis area and severity index (PASI) of 12.0 ± 4.1 and normal left ventricular ejection fraction [(LVEF) 56.3 ± 3.8%], diastolic dysfunction (E/e' 8.1 ± 2.1) and GLS (-16.8 ± 2.1%). At follow-up, an improvement (baseline vs. follow-up) of PASI (12.0 ± 4.1 vs. 2.7 ± 3.1, P < 0.001), E/e' (8.1 ± 2.1 vs. 6.7 ± 1.9, P ≤ 0.001) and GLS (-16.8 ± 2.1 vs. -18.3 ± 2.3%, P < 0.001) were recorded. No changes were demonstrated in LVEF (56.3 ± 3.8 vs. 56.8 ± 3.3%, P = 0.31), body mass index (30.9 ± 5.7 vs. 31.0 ± 5.8 kg/m(2) , P = 0.90), mean arterial blood pressure (103.1 ± 8.5 vs. 103.7 ± 10.8 mmHg, P = 0.74). Likewise, no changes were seen in total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, estimated glomerular filtration rate and glycosylated haemoglobin. CONCLUSION: In patients with severe psoriasis treatment with biologic therapy was associated with improved PASI and amelioration of myocardial dysfunction.

Concomitant fibromyalgia in rheumatoid arthritis is associated with the more frequent use of biological therapy: a cross-sectional study.

OBJECTIVES: To compare the 28-joint Disease Activity Score (DAS28) and its components in patients with rheumatoid arthritis (RA) with and without concomitant fibromyalgia (FM), and to investigate the use of biological treatment in the two groups. METHOD: Questionnaires developed to diagnose FM were handed out among RA patients during their planned visits. Values for DAS28 were obtained from the DANBIO registry. Demographic data and data on patients' medical treatment, disease duration, serological and radiological status were retrieved from patients' files. The χ2 test and an unpaired t-test were applied to investigate group differences in the use of biological therapy, baseline characteristics, patient-reported outcomes, and DAS28 between groups when appropriate. RESULTS: Questionnaires were completed by 162 out of 264 (61%) patients. Twenty-five patients (15.4%) with concomitant FM were identified. No group differences were found regarding disease duration, age, gender, and serological status. Of the RA patients with concomitant FM, 64% were treated with biological therapy vs. 32% of RA patients without concomitant FM (p = 0.002). The mean DAS28 in the FM group was 4.4 compared to 2.9 in the non-FM group (p < 0.001). Elevated DAS28 in the FM group resulted from a high tender joint count (p = 0.003) and a high visual analogue scale (VAS)-global score (p < 0.001). Erosions were more frequent in the non-FM group (p = 0.04). CONCLUSIONS: Concomitant FM in patients with RA is associated with a higher DAS28 due to subjective parameters and with the more frequent use of biological treatments. This raises the question of whether the more frequent use of biologics in these patients is justified by inflammation, or is instead due to persistent pain and other centrally mediated symptoms.

Risk of psoriasis in patients with childhood asthma: a Danish nationwide cohort study.

BACKGROUND: Psoriasis and asthma are disorders driven by inflammation. Psoriasis may carry an increased risk of asthma, but the reverse relationship has not been investigated. OBJECTIVES: To investigate the risk of psoriasis in subjects with childhood asthma in a nationwide Danish cohort. METHODS: Data on all Danish individuals aged 6-14 years at study entry between 1 January 1997 and 31 December 2011 (n = 1,478,110) were linked at an individual level in nationwide registers. Incidence rates per 10,000 person-years were calculated, and incidence rate ratios (IRRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by Poisson regression models. RESULTS: There were 21,725 cases of childhood asthma and 6586 incident cases of psoriasis. There were 5697 and 889 incident cases of mild and severe psoriasis, respectively. The incidence rates of overall, mild and severe psoriasis were 4.49, 3.88 and 0.61 for the reference population, and 5.95, 5.18 and 0.83 for subjects with childhood asthma, respectively. The IRRs for overall, mild and severe psoriasis were 3.94 [95% confidence interval (CI) 2.16-7.17], 5.03 (95% CI 2.48-10.21) and 2.27 (95% CI 0.61-8.42) for patients with childhood asthma. CONCLUSIONS: Childhood asthma was associated with a significantly increased risk of psoriasis. Further studies are warranted to determine the clinical significance and effects of therapeutic interventions on this association.

Association between depression and risk of atrial fibrillation and stroke in patients with psoriasis: a Danish nationwide cohort study.

BACKGROUND: Psoriasis and depression are associated with atrial fibrillation (AF) and stroke, but the influence of depression on the risk of stroke and AF in patients with psoriasis has not been examined. OBJECTIVES: We investigated the impact of depression on the risk of stroke and AF in patients with psoriasis in a nationwide cohort. METHODS: Data on all Danish citizens aged ≥ 18 years between 1 January 1997 and 31 December 2011 (n = 5 251 888) were linked at the individual level in nationwide registers. Incidence rates (IRs) per 1000 person-years were calculated, and hazard ratios (HRs) adjusted for age, sex, concomitant medication and comorbidity were estimated by multivariate Cox regression models. RESULTS: There were 56,496 and 11,357 incident cases of mild and severe psoriasis, respectively. Incident depression occurred among 12,788 cases with mild and 3261 cases with severe psoriasis. IRs per 1000 patient-years of AF were 3·21, 5·02, 8·41, 5·39 and 7·41; and IRs of stroke were 2·62, 3·09, 6·71, 3·62 and 9·03 for the reference population, mild psoriasis without depression, mild psoriasis with depression, severe psoriasis without depression and severe psoriasis with depression, respectively. The respective HRs for new-onset AF were 1·14 [95% confidence interval (CI) 1·08-1·33], 1·19 (95% CI 1·06-1·33), 1·32 (95% CI 1·15-1·53) and 1·74 (95% CI 1.43-2·11), respectively. For stroke the HRs were 1·63 (95% CI 1·43-1·85) in patients with mild psoriasis and depression and 2·47 (95% CI 2·07-2·95) in patients with severe psoriasis and depression. CONCLUSIONS: In patients with psoriasis, depression is associated with an increased risk of incident AF and stroke.

T-wave morphology analysis of competitive athletes.

BACKGROUND: T-wave morphology has been shown to be more sensitive than QT and QTc interval to describe repolarization abnormalities. The electrocardiogram (ECG) performed in athletes may manifest abnormalities, including repolarization alterations. The aim of this study was to investigate the characteristics of T-wave morphology features in athletes. METHODS: Eighty male elite athletes, consisting of 40 Tour de France cyclists (age 27±5years), 40 soccer players (age 26±6years) and 40 healthy men (age 27±5years) were included. RESULTS: Sinus bradycardia, left ventricular (LV) hypertrophy, incomplete right bundle branch block and early repolarization were documented in 25 %, 20%, 13% and 14% of athletes, respectively. ECG criteria for LV hypertrophy in 12-lead ECG were more common in cyclists (35%) than in soccer players (5%), P<0.0001. Cyclists and soccer players had significantly longer RR interval, and repolarization features than the control group. CONCLUSIONS: T-wave morphology of athletes is different from non-athletes, depending of the sport. Decreased potassium current in cardiomyocytes associated with LVH may contribute to these changes.

'Short-term treatment with methotrexate does not affect microvascular endothelial function in patients with psoriasis'.

BACKGROUND: Psoriasis is associated with increased risk of cardiovascular disease (CVD), possibly due to chronic low-grade systemic inflammation. Systemic anti-inflammatory treatment might reduce the risk of CVD. OBJECTIVE: Our aim was to investigate if short-term treatment with methotrexate influences microvascular endothelial function (MEF), an early surrogate marker of atherosclerosis, in patients with psoriasis. METHODS: We prospectively studied a hospital cohort of patients with psoriasis. Measurements of MEF were performed with the Endo-PAT2000© device at baseline and after 8-10 weeks of treatment with methotrexate. At the same time points, we recorded anamnestic information, measured body mass index (BMI), waist and hip circumferences and blood pressure, and drew blood samples (lipid profile, HbA1 and hs-CRP). Psoriasis severity was evaluated by psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI). RESULTS: A total of 32 patients with psoriasis were included. Median age was 46 (range 18-82) years, and 50% were men. Twenty-seven patients completed the study. After 8-10 weeks, median PASI had decreased significantly by 6.2 (from 9.8 to 3.6), and DLQI had decreased by 7 (from 9 to 2). No significant changes were observed in MEF, expressed by reactive hyperaemia index and augmentation index. Also, we saw no significant changes in BMI, waist-hip ratio, blood pressure and blood samples. CONCLUSION: Short-term treatment with methotrexate did not affect MEF in patients with psoriasis. Further studies are warranted.

Cardiovascular function is better in veteran football players than age-matched untrained elderly healthy men.

The aim of the study was to determine whether lifelong football training may improve cardiovascular function, physical fitness, and body composition. Our subjects were 17 male veteran football players (VPG; 68.1 ± 2.1 years) and 26 healthy age-matched untrained men who served as a control group (CG; 68.2 ± 3.2 years). Examinations included measurements of cardiac function, microvascular endothelial function [reactive hyperemic index (RHI)], maximum oxygen uptake (VO2max), and body composition. In VPG, left ventricular (LV) end-diastolic volume was 20% larger (P < 0.01) and LV ejection fraction was higher (P < 0.001). Tissue Doppler imaging revealed an augmented LV longitudinal displacement, i.e., LV shortening of 21% (P < 0.001) and longitudinal 2D strain was 12% higher (P < 0.05), in VPG. In VPG, resting heart rate was lower (6 bpm, P < 0.05), and VO2max was higher (18%, P < 0.05). In addition, RHI was 21% higher (P < 0.05) in VPG. VPG also had lower body mass index (P < 0.05), body fat percentage, total body fat mass, android fat percentage, and gynoid fat percentage (all P < 0.01). Lifelong participation in football training is associated with better LV systolic function, physical fitness, microvascular function, and a healthier body composition. Overall, VPG have better cardiovascular function compared with CG, which may reduce their cardiovascular morbidity and mortality.

Risk of thromboembolism and fatal stroke in patients with psoriasis and nonvalvular atrial fibrillation: a Danish nationwide cohort study.

OBJECTIVES: Psoriasis is a chronic inflammatory disease that is associated with a prothrombotic state and cardiovascular disease, including atrial fibrillation and thromboembolism. We therefore evaluated the impact of psoriasis in patients with atrial fibrillation and the performance of the CHA2 DS2 VASc score in these patients. DESIGN, SETTING AND PARTICIPANTS: The study comprised all Danish patients hospitalized with nonvalvular atrial fibrillation in the period 1997-2011 (n = 99,357). Follow-up started 7 days from discharge and excluded subjects treated with anticoagulation. Poisson regression adjusted for CHA2 DS2 VASc score was used to estimate the incidence rate ratios and 95% confidence intervals. MAIN OUTCOME MEASURE: Hospitalization or death from thromboembolism. RESULTS: Mean follow-up was 3.5, 3.1, and 2.8 years for patients with no psoriasis, mild psoriasis and severe psoriasis, respectively. Patients with psoriasis were younger compared to patients without psoriasis, but CHA2DS2VASc score did not differ between the three groups. Thromboembolism rates per 100 patient-years (95% confidence intervals) were 4.8 (4.7-4.9), 4.8 (4.2-5.4) and 6.1 (5.0-7.5) for patients with no psoriasis, mild psoriasis and severe psoriasis, respectively. Importantly, the observed thromboembolism rates in patients with severe psoriasis were markedly higher (2.6- to3.4-fold) than predicted by the CHA2 DS2 VASc score. Relative to no psoriasis, incidence rate ratios were 0.99 (0.87-1.11) and 1.27 (1.02-1.57) for mild and severe psoriasis, respectively. Correspondingly, incidence rate ratios for fatal stroke were 0.97 (0.80-1.12) and 1.51 (1.12-2.05). CONCLUSIONS: In patients with nonvalvular atrial fibrillation not treated with oral anticoagulation, severe psoriasis was associated with increased risk of thromboembolism. In these patients, CHA2 DS2 VASc underestimated the risk of thromboembolism.

Nationwide population-based study of cause-specific death rates in patients with psoriasis.

BACKGROUND: Psoriasis is a common chronic disease, mediated by type 1 and 17 helper T cell-driven inflammation. Epidemiological studies have demonstrated a wide range of comorbidities and increased mortality rates. However, the current evidence on psoriasis-related mortality is limited and nationwide data have not been presented previously. METHODS: In a nationwide population-based cohort we evaluated all-cause and cause-specific death rates in patients with psoriasis as compared to the general population. RESULTS: The entire Danish population aged 18 and above, corresponding to a total of 5,458,627 individuals (50.7% female, 40.9 years ± 19.7), including 94,069 with mild psoriasis (53% female, 42.0 ± 17.0 years) and 28,253 with severe psoriasis (53.4% female, 43.0 ± 16.5 years), was included. A total of 884,661 deaths were recorded, including 10 916 in patients with mild psoriasis and 3699 in patients with severe psoriasis. The age at time of death varied by psoriasis status, i.e. 76.5 ± 14.0, 74.4 ± 12.8 and 72.0 ± 13.4 years, for the general population, mild psoriasis and severe psoriasis respectively. In general, the highest death rates were observed in patients with severe psoriasis. Overall death rates per 1000 patient years were 13.8 [confidence interval (CI) 13.8-13.8], 17.0 (CI 16.7-17.3) and 25.4 (CI 24.6-26.3) for the general population, patients with mild psoriasis and patients with severe psoriasis respectively. CONCLUSION: This nationwide population-based study of cause-specific death rates in patients with psoriasis demonstrated reduced lifespan and increased rates of all examined specific causes of death in patients with psoriasis compared to the general population.

Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort.

BACKGROUND: Psoriasis is a common disease and is associated with cardiovascular diseases. Systemic anti-inflammatory drugs may reduce risk of cardiovascular events. We therefore examined the rate of cardiovascular events, i.e. cardiovascular death, myocardial infarction and stroke, in patients with severe psoriasis treated with systemic anti-inflammatory drugs. METHODS: Individual-level linkage of administrative registries was used to perform a longitudinal nationwide cohort study. Time-dependent multivariable adjusted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular events associated with use of biological drugs, methotrexate, cyclosporine, retinoids and other antipsoriatic therapies, including topical treatments, phototherapy and climate therapy. RESULTS: A total of 6902 patients (9662 treatment exposures) with a maximum follow-up of 5 years were included. Incidence rates per 1000 patients-years for cardiovascular events were 4.16, 6.28, 6.08, 18.95 and 14.63 for biological drugs, methotrexate, cyclosporine, retinoid and other therapies respectively. Relative to other therapies, methotrexate (HR 0.53; CI 0.34-0.83) was associated with reduced risk of the composite endpoint and a comparable but non-significant protective effect was observed with biological drugs (HR 0.58; CI 0.30-1.10), whereas no protective effect was apparent with cyclosporine (HR 1.06; CI 0.26-4.27) and retinoids (HR 1.80; CI 1.03-2.96). Tumour necrosis factor inhibitors (HR 0.46; CI 0.22-0.98) were linked to reduced event rates, whereas the interleukin-12/23 inhibitor ustekinumab (HR 1.52; CI 0.47-4.94) was not. CONCLUSION: Systemic anti-inflammatory treatment with methotrexate was associated with significantly lower rates of cardiovascular events during long-term follow-up compared to patients treated with other antipsoriatic therapies. The treatment strategy in patients with severe psoriasis may have an impact on cardiovascular outcomes and randomized trials to evaluate the cardiovascular safety and efficacy of systemic antipsoriatic therapies are called for.

Clopidogrel bioactivation and risk of bleeding in patients cotreated with angiotensin-converting enzyme inhibitors after myocardial infarction: a proof-of-concept study.

Clopidogrel is an oral antiplatelet prodrug, the majority of which is hydrolyzed to an inactive metabolite by hepatic carboxylesterase 1 (CES1). Most angiotensin-converting enzyme inhibitors (ACEIs) are also metabolized by this enzyme. We examined the effects of ACEIs on clopidogrel bioactivation in vitro and linked the results with a pharmacoepidemiological study. In vitro, ACEIs inhibited CES1-mediated hydrolysis of a model substrate, and trandolapril and enalapril increased formation of clopidogrel active metabolite. In 70,934 patients with myocardial infarction, hazard ratios for clinically significant bleeding in ACEI-treated patients cotreated with or without clopidogrel were 1.10 (95% confidence interval (CI): 0.97-1.25, P = 0.124) and 0.90 (95% CI: 0.81-0.99, P = 0.025), respectively, as compared with patients who did not receive ACEIs. This difference was statistically significant (P = 0.002). We conclude that cotreatment with selected ACEIs and clopidogrel may increase the risk of bleeding. Combination of in vitro and pharmacoepidemiological studies may be a useful paradigm for assessment of drug-drug interactions.