A novel, fixed-dose calcipotriol and betamethasone dipropionate cream for the topical treatment of plaque psoriasis: Direct and indirect evidence from phase 3 trials discussed at the 30th EADV Congress 2021.

Four posters about the novel, fixed-dose calcipotriol and betamethasone dipropionate cream (CAL/BDP cream) based on Poly-Aphron Dispersion (PAD) Technology were presented at the 30th European Academy of Dermatology and Venereology (EADV) Congress 2021 and are summarized here. CAL/BDP cream was compared in two randomized, phase 3 trials to vehicle and active comparator (CAL/BDP gel/topical suspension [TS]) in adults with plaque psoriasis (NCT03802344 and NCT03308799). Pooled data from both trials demonstrated significant greater efficacy in favour of CAL/BDP cream for all efficacy endpoints, including PGA treatment success, mPASI, and mPASI75 compared to CAL/BDP gel/TS. CAL/BDP cream was well tolerated and comparable to CAL/BDP gel/TS with no adverse drug reactions with a frequency >1%. In the NCT03308799 study, CAL/BDP cream demonstrated a substantial improvement in the proportion of participants achieving a minimum 4-point improvement on the peak pruritus numeric rating scale (NRS) score compared with vehicle at Weeks 1, 4 and 8. CAL/BDP cream also improved quality of life (QoL), as assessed through the Dermatology Life Quality Index (DLQI), and the EQ-VAS at Week 8 compared with active comparator. Treatment convenience of CAL/BDP cream, as measured by the Psoriasis Treatment Convenience Scale, was superior to CAL/BDP gel/TS at all studied timepoints, including questions addressing formulation's greasiness and overall treatment satisfaction. Finally, an indirect comparison following the Bucher's method of adjusted indirect comparison and the difference-in-differences method was conducted to compare CAL/BDP cream and CAL/BDP foam, as both therapies have been compared to CAL/BDP gel/TS. Indirect evidence showed that treatment with CAL/BDP cream was associated with a trend for greater QoL improvement than CAL/BDP foam when DLQI improvement was assessed at the recommended treatment duration of 8 weeks for CAL/BDP cream and 4 weeks for CAL/BDP foam. CAL/BDP cream was statistically superior versus CAL/BDP foam in four out of five treatment satisfaction domains.

Efficacy, quality of life, and treatment satisfaction: an indirect comparison of calcipotriol/betamethasone dipropionate cream versus foam for treatment of psoriasis.

OBJECTIVE: To assess how the use of calcipotriol and betamethasone dipropionate (Cal/BDP) cream impacted efficacy, patients' quality of life (QoL), and treatment satisfaction versus Cal/BDP foam. METHODS: Data from clinical trials of Cal/BDP cream and foam were analyzed, by applying the common anchor Cal/BDP gel. Efficacy was assessed by Physician Global Assessment (PGA) treatment success and ≥75% reduction in Psoriasis Area and Severity Index (PASI75 response); QoL by Dermatology Life Quality Index (DLQI); treatment satisfaction by Psoriasis Treatment Convenience Scale (PTCS) and Topical Product Usability Questionnaire (TPUQ). RESULTS: Treatment with Cal/BDP cream was on par with foam on PGA treatment success (risk ratio (RR) for Cal/BDP cream versus foam: 0.80; 95%CI: 0.56, 1.14; p = .21) and PASI75 response (RR for Cal/BDP cream vs. foam: 0.85; 95%CI: 0.64, 1.13; p = .27) when assessed at the treatment duration of 8 weeks for Cal/BDP cream and 4 weeks for Cal/BDP foam. Treatment with Cal/BDP cream was associated with significantly greater treatment satisfaction versus foam on the domains: overall treatment satisfaction (p = .01), "ease of application" (p < .001), "lack of greasiness" (p < .001), "moisturizing effect" (p = .01), and almost significantly greater improvement on the domain "easily incorporated into daily routine" (p = .07). Furthermore, there was a trend for greater DLQI improvement with cream versus foam when assessed at recommended treatment duration [mean difference (MD) for Cal/BDP cream vs. foam: -1.00; 95%CI: -2.20, 0.20; p = .10]. CONCLUSIONS: Indirect comparison analyses showed that Cal/BDP cream significantly improves treatment satisfaction and tends to improve QoL versus foam. Cal/BDP cream is on par with foam on efficacy.

Occurrence, mortality and cost of brain disorders in Denmark: a population-based cohort study.

OBJECTIVES: To examine the occurrence of brain disorders (ie, neurological and mental disorders) in Denmark and mortality and cost of illness among affected persons. DESIGN: Matched cohort study. SETTING: We obtained routinely collected registry data on all Danish residents during 1995-2015. PARTICIPANTS: We identified all persons alive on 1 January 2015 with a diagnosis of 25 specific brain disorders (prevalent cohort) and all persons with an incident diagnosis during 2011-2015 (incident cohort). Each person was matched on age and sex with 10 persons from the general population without the brain disorder of interest. PRIMARY AND SECONDARY OUTCOME MEASURES: Prevalence and incidence of hospital-diagnosed brain disorders, 1-year absolute and relative mortality, and attributable direct and indirect costs of illness compared with the corresponding matched cohorts. RESULTS: We identified 1 075 081 persons with at least one prevalent brain disorder (any brain disorder) on 1 January 2015, corresponding to 18.9% of the Danish population. The incidence rate of any brain disorder during 2011-2015 was 1349 per 100 000 person-years (95% CI 1345 to 1353). One-year mortality after diagnosis was increased in persons with any brain disorder (HR 4.7, 95% CI 4.7 to 4.8) and in persons in every group of specific brain disorders compared with the matched cohort from the general population. The total attributable direct costs of brain disorders in 2015 were €5.2 billion and total attributable indirect costs were €11.2 billion. Traumatic brain injury, stress-related disorders, depression and stroke were the most common brain disorders. Attributable costs were highest for depression, dementia, stress-related disorders and stroke. CONCLUSIONS: One in five Danish residents alive on 1 January 2015 had been diagnosed with at least one brain disorder, and mortality was five times higher in persons with any diagnosed brain disorder than in the general population. We found high attributable direct and indirect costs of brain disorders.

Correlations of fatigue in Danish patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis.

OBJECTIVE: To describe fatigue in relation to disease-specific and socioeconomic factors and to test possible correlations between fatigue and work impairment, quality of life, pain, sleep, depression, and physical functioning in people with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). METHODS: A questionnaire-based cross-sectional survey collecting patient characteristics such as disease characteristics, socioeconomic factors and patient-reported outcomes (PROs) from patients with RA, PsA and axSpA in Denmark. PRO scales included the FACIT-Fatigue sub-scale, Work Productivity and Activity Impairment scale (WPAI), EuroQol (EQ-5D), Medical Outcomes Study Sleep Scale (MOS), Major Depression Inventory (MDI), and Health Assessment Questionnaire (HAQ). Respondents were recruited via routine visits to the outpatient rheumatology clinic; information on diagnosis, treatment and disease activity was collected from medical journals by trained nurses. RESULTS: 487 patients participated in the study. Fatigue was more present in women, experienced patients, and patients who changed medication in the past 12 months, who were unemployed, who had less education, and who had lower household income. There was no statistically significant difference between mean fatigue in the three diagnostic groups (p = 0.08). Fatigue correlated with all included PROs (Pearson correlation coefficients, p<0.0001). Stratifying for diagnosis and adjusting for socioeconomic factors did not change the conclusion. CONCLUSION: In a stable, representative group of patients with RA, PsA and axSpA, we found significant correlations between fatigue and work impairment, quality of life, pain, sleep, depression and physical functioning. Fatigue cannot be perceived as a single problem, but rather as a symptom that affects broadly.

Societal costs attributable to Crohn's disease and ulcerative colitis within the first 5 years after diagnosis: a Danish nationwide cost-of-illness study 2002-2016.

Objective: There is little information on cost-of-illness among patients diagnosed with Crohn's disease (CD) and ulcerative colitis (UC) in Denmark. The objective of this study was to estimate the average 5-year societal costs attributable to CD or UC patients in Denmark with incidence in 2003-2015, including costs related to health care, prescription medicine, home care and production loss.Materials and methods: A national register-based, cost-of-illness study was conducted using an incidence-based approach to estimate societal costs. Incident patients with CD or UC were identified in the National Patient Registry and matched with a non-IBD control from the general population on age and sex. Attributable costs were estimated applying a difference-in-difference approach, where the total costs among individuals in the control group were subtracted from the total costs among patients.Results: CD and UC incidence fluctuated but was approximately 14 and 31 per 100,000 person years, respectively. The average attributable costs were highest the first year after diagnosis, with costs equalling €12,919 per CD patient and €6,501 per UC patient. Hospital admission accounted for 36% in the CD population and 31% in the UC population, the first year after diagnosis. Production loss exceeded all other costs the third-year after diagnosis (CD population: 52%; UC population: 83%).Conclusions: We found that the societal costs attributable to incident CD and UC patients are substantial compared with the general population, primarily consisting of hospital admission costs and production loss. Appropriate treatment at the right time may be beneficial from a societal perspective.

Quality of life and patient preferences among Danish patients with ulcerative colitis - results from a survey study.

Objective: To explore health-related quality of life (HRQoL) and assess preferences for medical treatment attributes to obtain information of the relative importance of the different attributes in a Danish population with ulcerative colitis (UC).Methods: We used data from an online survey collected in March 2018 among people with self-reported UC. A total of 302 eligible respondents answered the HRQoL questionnaires (EuroQol-5 Dimensions (EQ-5D-5L) and the Short Inflammatory Bowel Disease Questionnaire (SIBDQ)), and 212 also completed the discrete choice experiment (DCE). The probability of choosing an alternative from a number of choices in the DCE was estimated using a conditional logit model.Results: The respondents had an average SIBDQ score of 4.5 and an HRQoL score of 0.77, applying the EQ-5D-5L questionnaire. HRQoL correlated with disease severity, and the respondents had lower HRQoL than did a gender- and age-matched subset of the Danish population. The most important medical treatment attribute was efficacy within eight weeks. Additionally, respondents stated a preference for avoiding taking steroids, for fast onset of effect and for oral formulations.Conclusions: HRQoL correlates with disease severity, and patients with UC have lower HRQoL than the general population. The most important treatment attribute was efficacy, but patients also would like to avoid steroids, value fast onset of effect and prefer oral formulations.

Societal costs of venous thromboembolism and subsequent major bleeding events: a national register-based study.

AIMS: Detailed evidence on the societal costs of venous thromboembolism (VTE), i.e. deep vein thrombosis (DVT) and pulmonary embolism (PE), and of subsequent major bleeding events, e.g. intracranial and gastrointestinal bleedings, is limited. The objective was to estimate the average 3-year societal event costs attributable to VTE and subsequent major bleedings in Denmark. METHODS AND RESULTS: Based on nationwide Danish registers, each incident patient diagnosed with VTE in the period from 2004 to 2016 was identified and matched with four non-VTE patients by nearest-neighbour propensity score matching. For bleeding patients, the reference cohort was VTE patients without bleedings. Event costs in terms of VTE, DVT, PE, and major bleedings in VTE patients were measured by the 'difference-in-actual-cost' method within 3 years after the incidence. Societal costs included healthcare costs (primary care, hospital, and prescription medicine), municipality home care services, and production loss. The study population included 74 137 VTE incident patients (DVT: 43 099; PE: 31 038), and 4887 VTE patients with a major bleeding within 3 years from VTE diagnosis. The 3-year attributable societal VTE event costs were 40 024 EUR (DVT: 34 509 EUR; PE: 50 083 EUR) with 53% of these costs appearing in the first incident year. Similar results for major bleedings were 51 168 EUR with 46% of these costs appearing in the first incident year. CONCLUSION: The societal costs of VTE and subsequent major bleedings are substantial and ought to be considered. Estimated costs of events may be informative in evaluating the impact of preventive interventions targeting VTE and subsequent major bleedings.

Severity of fatigue in people with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis - Results of a cross-sectional study.

BACKGROUND: Despite improvements in treatment for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (axSpA), several key unmet needs remain, such as fatigue. The objective of this study was to describe the severity of fatigue, disease characteristics and socioeconomic factors in people with RA, PsA and axSpA. METHODS: The study was designed as a cross-sectional survey collecting patient characteristics such as disease characteristics, socioeconomic factors and fatigue in people with RA, PsA and axSpA in Denmark. Respondents were consecutively recruited for the study over a six-month period in 2018 via routine visits to outpatient rheumatology clinics. Study nurses collected information on diagnosis, current disease-related treatment and disease activity from medical journals. People were invited to complete a questionnaire related to socioeconomic factors and containing the FACIT-Fatigue subscale. Descriptive statistics were analyzed using SAS. RESULTS: We invited 633 people to participate, and 488 (77%) completed the questionnaire. Women constituted 62% of respondents, and the mean age was 53.5 years. Respondents had on average been diagnosed between 11 and 15 years ago. Overall, 79% had no changes to their disease-related treatment during the past year, and the average disease activity as indicated by DAS28 for RA and PsA was 2.48 and 2.36, respectively, and BASDAI for axSpA was 28.40. Fatigue was present in all three diagnoses (mean: 34.31). The mean fatigue score varied from respondents answering that they suffered from no or little fatigue (mean: 45.48) to extreme fatigue (mean: 10.11). Analyses demonstrated that the respondents were not considerably different from nonrespondents, and the study population is considered representative compared with Danish RA and axSpA patients in the Danish National Rheumatology Registry, the DANBIO database. CONCLUSION: We found that the majority of the study population were fatigued (61%). They had low disease activity and few disease-related treatment changes.

Societal costs due to meningococcal disease: a national registry-based study.

PURPOSE: Limited detailed evidence exists on the societal costs of meningococcal disease. The objective of this study was to estimate the average 5-year societal cost of events attributable to meningococcal disease in Denmark. METHODS: The study was based on the nationwide Danish registries. Incident patients diagnosed with meningococcal disease were identified and each matched with two controls, using direct matching on age, gender, and level of education. Siblings constituted a secondary control population where one patient was matched with one sibling control without meningococcal disease. Costs related to health care in the primary and secondary sectors, prescription medicine, municipality home care services and costs of production loss, ie, estimated loss of yearly earnings, were included (1997-2015). RESULTS: The incidence of meningococcal disease fluctuated between 1980 and 2015. The average attributable societal costs were highest the first year after diagnosis, with costs equaling USD 18,920 per event in the primary study population (matched controls) and USD 16,169 in the secondary study population (sibling controls). Hospital admission costs accounted for 65% and production loss for 30%; however, having a lifetime perspective and including loss due to premature death further increase the costs of meningococcal disease events. CONCLUSION: The costs of meningococcal disease are substantial, and the estimated costs of event may be informative in evaluating the impact of preventive interventions targeting meningococcal disease.

Spinal pain and co-occurrence with stress and general well-being among young adolescents: a study within the Danish National Birth Cohort.

This study aims to describe the patterns in low back, mid back, and neck pain complaints in young adolescents from the Danish National Birth Cohort (DNBC) and to investigate the co-occurrence of spinal pain and stress and general well-being, respectively. Cross-sectional data from the 11-year follow-up of DNBC were used. As part of a web-based survey, a total of 45,371 young adolescents between 10 and 14 years old completed the Young Spine Questionnaire, the Stress in Children Questionnaire, and a one-item question on general well-being. Associations between spinal pain and, respectively, stress and general well-being were estimated by means of multiple logistic regression models. Almost one fifth of boys and one quarter of girls reported spinal pain. Compared with adolescents who reported no stress, adolescents reporting medium and high values of stress had odds ratios (OR) of 2.19 (95% CI 2.08-2.30) and 4.73 (95% CI 4.28-5.23), respectively, of reporting spinal pain (adjusted for age, gender, and maternal education). Adolescents who reported poor general well-being had an OR of 2.50 (95% CI 2.31-2.72) for reporting spinal pain compared to adolescents with good general well-being. CONCLUSION: Spinal pain is a common complaint among young adolescents and co-occurs with stress and poor general well-being. The mutual dependency between the factors remained to be explained. What is Known: • The prevalence of spinal pain increases rapidly during childhood and adolescence, but different measurement instruments result in great variation in the estimates of spinal pain in children and adolescents. • Some studies have shown that different psychosocial measures are associated with spinal pain in children and adolescents. What is New: • Spinal pain, as measured by the newly developed and validated Young Spine Questionnaire, is a common complaint in young adolescents aged 10-14 years. • Spinal pain in young adolescents co-occurs with stress and poor general well-being.

Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis.

BACKGROUND: The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear. METHODS: Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, 'active' placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library's CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life. RESULTS: A total of 131 randomised placebo-controlled trials enrolling a total of 27,422 participants were included. None of the trials used 'active' placebo or no intervention as control intervention. All trials had high risk of bias. SSRIs significantly reduced the Hamilton Depression Rating Scale (HDRS) at end of treatment (mean difference -1.94 HDRS points; 95% CI -2.50 to -1.37; P < 0.00001; 49 trials; Trial Sequential Analysis-adjusted CI -2.70 to -1.18); Bayes factor below predefined threshold (2.01*10-23). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious adverse events (OR 1.37; 95% CI 1.08 to 1.75; P = 0.009; 44 trials; Trial Sequential Analysis-adjusted CI 1.03 to 1.89). This corresponds to 31/1000 SSRI participants will experience a serious adverse event compared with 22/1000 control participants. SSRIs also significantly increased the number of non-serious adverse events. There were almost no data on suicidal behaviour, quality of life, and long-term effects. CONCLUSIONS: SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42013004420.

Can positional MRI predict dynamic changes in the medial plantar arch? An exploratory pilot study.

BACKGROUND: Positional MRI (pMRI) allows for three-dimensional visual assessment of navicular position. In this exploratory pilot study pMRI was validated against a stretch sensor device, which measures movement of the medial plantar arch. We hypothesized that a combined pMRI measure incorporating both vertical and medial displacement of the navicular bone induced by loading would be correlated with corresponding stretch sensor measurements. METHODS: 10 voluntary participants were included in the study. Both pMRI and subsequent stretch sensor measurements were performed in a) supine, b) standing and c) standing position with addition of 10 % body weight during static loading of the foot. Stretch sensor measurements were also performed during barefoot walking. RESULTS: The total change in navicular position measured by pMRI was 10.3 mm (CI: 7.0 to 13.5 mm). No further displacement occurred when adding 10 % bodyweight (mean difference: 0.7 mm (CI: -0.7 to 2.0 mm), P = 0.29). The total navicular displacement correlated with stretch sensor measurement under static loading conditions (Spearman's rho = 0.66, P = 0.04) but not with measurements during walking (Spearman's rho = 0.58, P = 0.08). CONCLUSIONS: Total navicular bone displacements determined by pMRI showed concurrent validity with stretch sensor measurements but only so under static loading conditions. Although assessment of total navicular displacement by combining concomitant vertical and medial navicular bone movements would appear advantageous compared to monoplanar measurement the combined measure did not seem to predict dynamic changes of the medial foot arch during walking, which are among several possible factors depending on different walking patterns.

Sonographic measurements of the achilles tendon, plantar fascia, and heel fat pad are reliable: A test-retest intra- and intertester study.

PURPOSE: To determine intra- and interobserver reliability and precision of sonographic (US) scanning in measuring thickness of the Achilles tendon, plantar fascia, and heel fat pad in patients with heel pain. METHODS: Seventeen consecutive patients referred with heel pain were included. Two evaluators blinded to the diagnosis performed independently US scanning of both feet without any dialogue with the patient. The examiner left the room, and the next examiner entered. All patients had two US scans performed by each examiner. Two months later, the US images were randomly presented to the evaluators for measurements. Reliability and agreement were assessed by calculation of intraclass correlation coefficient (ICC), 95% limits of agreement (LOA), and typical error (TE). LOA was calculated as a percentage of the mean thickness of each structure to obtain a unitless parameter. RESULTS: We found excellent intratester reliability (ICC 0.78-0.98) and good intertester reliability using one measurement (ICC 0.72-0.91) and excellent (ICC 0.85-0.95) when using average of two measurements. The intratester agreements were good with LOA: 9.5-23.4% and TE: 3.4-8.4%. The intertester agreements were acceptable using one measurement with LOA: 16.1-36.4%, and better using two measurements with LOA: 14.4-33.2%. CONCLUSIONS: US is a reliable technique of measurement in the daily clinic, and one single measurement is sufficient. In research, we recommend that the same observer performs the US measurements, if one single scanning is preferred; if more researchers are involved, the average measurement of two US scans is recommended. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:480-486, 2016.

Navicular bone position determined by positional MRI: a reproducibility study.

OBJECTIVE: To examine intraobserver, interobserver and between-day reproducibility of positional MRI for evaluation of navicular bone height (NVH) and medial navicular position (MNP). MATERIALS AND METHODS: Positional MRI (pMRI) of the foot was performed on ten healthy participants (0.25 T G-scanner). Scanning was performed in supine and standing position, respectively. Two radiologists evaluated the images in a blinded manner. Reliability and agreement were assessed by calculation of intraclass correlation coefficient (ICC) and 95 % limits of agreement as a percentage of the mean (LOA%). RESULTS: Intraobserver and interobserver reliability was "substantial" in both supine and standing position (ICC 0.86-0.98) and showed good agreement (LOA% 4.9-14.7 %). Between-day reliability of navicular height and medial navicular position in standing position remained substantial (ICC 0.85-0.92) with adequate agreement (LOA% 8.3-19.8 %). In supine position between-day reliability was "moderate" for NVH (ICC 0.72) and "slight" for MNP (ICC 0.39). Agreement remained adequate between-days for MNP in supine position (LOA% 17.7 %), but it was less than adequate for NVH in supine position (LOA% 24.2 %). CONCLUSION: Navicular height and medial navicular position can be measured by pMRI in a very reproducible manner within and between observers. Increased measurement variation is observed between-days in supine position, which may be due to small positional differences or other unknown biomechanical factors.