Effect of Disease Activity on Organ Damage Progression in Systemic Lupus Erythematosus: University of Toronto Lupus Clinic Cohort.

OBJECTIVE: To examine the role of disease activity on organ damage over 5 years in patients with active systemic lupus erythematosus (SLE) despite standard of care. METHODS: This analysis of the University of Toronto Lupus Clinic cohort assessed organ damage [measured by Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)] in patients with active SLE [SLE Disease Activity Index 2000 (SLEDAI-2K) ≥ 6], using Cox proportional time-independent hazard models. Subgroup analyses were conducted in patients with SLEDAI-2K 6 or 7, 8 or 9, and ≥ 10 at baseline, and in the overall study population by steroid dose at study entry (< 7.5 vs ≥ 7.5 mg/day). RESULTS: Among the overall study population (n = 649), SDI progression was observed in 209 (32.2%) patients over the 5-year follow-up period. Mean SDI change in patients with a score > 0 was generally consistent across all SLEDAI-2K subgroups. Multivariable analyses identified age at study start (HR 1.03, P < 0.0001), steroid dose (HR 2.03, P < 0.0001), immunosuppressants (HR 1.44, P = 0.021), and SLEDAI-2K (subgroup analyses HR 1.64-2.03, P = 0.0017 to < 0.0001) as the greatest risk factors for SDI progression, while a study start date after the year 2000 had a protective effect on SDI progression compared with a start date prior to the year 2000 (HR 0.65, P = 0.0004). CONCLUSION: Patients within the higher SLEDAI-2K subgroups at study entry or receiving high doses of steroids were more likely to have organ damage progression.

Persistent Disease Activity Remains a Burden for Patients with Systemic Lupus Erythematosus.

OBJECTIVE: Persistent systemic lupus erythematosus (SLE) disease activity is associated with increased morbidity and mortality. In a multicenter cohort of patients with prevalent SLE, we described persistence, patterns, and predictors of change in disease activity over time. METHODS: Based on SLE Disease Activity Index (SLEDAI)-2K scores at cohort entry, patients were classified into 4 groups: low (score < 4; LOW), moderate (4 to < 6; MOD), moderately high (6 to ≤ 10; MHIGH), and very high (> 10; VHIGH). Multivariable linear and longitudinal mixed linear regression models were used to identify predictors of change over time in SLEDAI-2K. RESULTS: There were 2019 participants, with declining followup data over 5 years (1326, 580, 274, 186, and 148 patients, respectively). At cohort entry, mean (± SD) age was 42 (± 17) years, disease duration 11 (± 10) years, and 90% were female. The 4 groups included 44% LOW (n = 891), 20% MOD (n = 400), 22% MHIGH (n = 442), and 14% VHIGH (n = 286); therefore, 36% had clinically important SLE activity. The proportion of patients in the LOW group at entry who moved to a higher activity level varied from 30% (167/557) at 1 year, to 49% (41/83) at 3 years, and 54% (30/56) at 5 years. Among 181 patients with MOD to VHIGH entry activity and 3 years of followup, 116 (64.1%) remained active. In all analyses, only higher SLEDAI-2K at cohort entry remained a significant predictor of higher SLEDAI-2K in subsequent years. CONCLUSION: Higher SLEDAI-2K at study entry was the single major independent predictor of higher SLEDAI-2K over time, reflecting frequent persistence of active disease, even in patients with longstanding disease. This highlights gaps in the optimal treatment of SLE.

Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study.

To describe the characteristics of patients receiving belimumab, overall patterns of systemic lupus erythematosus (SLE) care, clinical outcomes, and changes in glucocorticoid dose following 6 months of therapy with belimumab, and healthcare resource utilization in belimumab users in Canadian clinical practice settings. Retrospective multicenter medical chart review study of adult patients with SLE who were prescribed belimumab as part of usual care and who received ≥8 infusions or 6 months of treatment. Primary endpoints included physician-determined overall clinical improvement from baseline, glucocorticoid use, and physician-determined SLE disease severity at Month 6. In total, 52 patients were included in the study. At belimumab initiation, 5.8/76.9/17.3% of patients had mild/moderate/severe SLE, respectively. Oral glucocorticoids were discontinued in 11.4% of patients and 59.1% received a lower dose at Month 6. At Month 6, 80.8/57.7/17.3% of patients had a physician-determined clinical improvement of ≥20/≥50/≥80%, respectively. Sixteen patients had a SLE Disease Activity Index-2K score at both baseline and Month 6, with a mean improvement of 2.6 ± 5.3 from 8.1 ± 3.2 at baseline. No formal disease assessment tool was utilized for 42.3% of study patients at baseline. This study provides the first real-world insights into belimumab use in Canada. It demonstrates significant reduction or discontinuation of glucocorticoid dose in 70.5% of patients and clinically significant improvement following 6 months' belimumab therapy. The high number of patients with no formal disease activity assessments highlights a key care gap in SLE treatment in the real-world setting.

Cost analysis of fixed-dose combination of dutasteride and tamsulosin compared with concomitant dutasteride and tamsulosin monotherapy in patients with benign prostatic hyperplasia in Canada.

INTRODUCTION: We estimate the lifetime cost of treatment for moderate/severe symptoms associated with benign prostatic hyperplasia (BPH) in a cohort of Canadian men aged 50 to 59, and we evaluate the costs of 2 daily bioequivalent treatment options: fixed-dose combination (FDC) of dutasteride (0.5 mg) and tamsulosin (0.4 mg), or concomitant administration of dutasteride (0.5 mg) and tamsulosin (0.4 mg) monotherapies. METHODS: The expected lifetime costs were estimated by modelling the incidence of acute urinary retention (AUR), BPH-related surgery and clinical progression over a patient's lifetime (up to 25 years). A model was developed to simulate clinical events over time, based on a discrete Markov process with 6 mutually exclusive health states and annual cycle length. RESULTS: The estimated lifetime budget cost for the cohort of 374 110 men aged 50 to 59 in Canada is between $6.35 billion and $7.60 billion, equivalent to between $16 979 and $20 315 per patient with moderate/severe symptoms associated with BPH. Costs are lower for FDC treatment, with the net difference in lifetime budget impact between the 2 treatment regimens at $1.25 billion. In this analysis, the true costs of BPH in Canada are underestimated for 2 main reasons: (1) to make the analysis tractable, it is restricted to a cohort aged 50 to 59, whereas BPH can affect all men; and (2) a closed cohort approach does not include the costs of new (incident) cases. CONCLUSION: Canadian clinical guidelines recommend the use of the combination of tamsulosin and dutasteride for men with moderate/severe symptoms associated with BPH and enlarged prostate volume. This analysis, using a representational patient group, suggests that the FDC is a more cost-effective treatment option for BPH.

Clinical, economic, and humanistic burden of asthma in Canada: a systematic review.

BACKGROUND: Asthma, one of the most common chronic respiratory diseases, affects about 3 million Canadians. The objective of this study is to provide a comprehensive evaluation of the published literature that reports on the clinical, economic, and humanistic burden of asthma in Canada. METHODS: A search of the PubMed, EMBASE, and EMCare databases was conducted to identify original research published between 2000 and 2011 on the burden of asthma in Canada. Controlled vocabulary with "asthma" as the main search concept was used. Searches were limited to articles written in English, involving human subjects and restricted to Canada. Articles were selected for inclusion based on predefined criteria like appropriate study design, disease state, and outcome measures. Key data elements, including year and type of research, number of study subjects, characteristics of study population, outcomes evaluated, results, and overall conclusions of the study, were abstracted and tabulated. RESULTS: Thirty-three of the 570 articles identified by the clinical and economic burden literature searches and 14 of the 309 articles identified by the humanistic burden literature searches met the requirements for inclusion in this review. The included studies highlighted the significant clinical burden of asthma and show high rates of healthcare resource utilization among asthma patients (hospitalizations, ED, physician visits, and prescription medication use). The economic burden is also high, with direct costs ranging from an average annual cost of $366 to $647 per patient and a total annual population-level cost ranging from ~ $46 million in British Columbia to ~ $141 million in Ontario. Indirect costs due to time loss from work, productivity loss, and functional impairment increase the overall burden. Although there is limited research on the humanistic burden of asthma, studies show a high (31%-50%) prevalence of psychological distress and diminished QoL among asthma patients relative to subjects without asthma. CONCLUSIONS: As new therapies for asthma become available, economic evaluations and assessment of clinical and humanistic burden will become increasingly important. This report provides a comprehensive resource for health technology assessment that will assist decision making on asthma treatment selection and management guidelines in Canada.

Cost-effectiveness of dutasteride-tamsulosin combination therapy for the treatment of symptomatic benign prostatic hyperplasia: A Canadian model based on the CombAT trial.

INTRODUCTION: Benign prostatic hyperplasia (BPH) is common in men 50 years old and older. The main treatment options are alpha-blockers (such as tamsulosin), which reduce symptoms, and 5-alpha reductase inhibitors (such as dutasteride), which reduce symptoms and slow disease progression. Clinical studies have demonstrated that dutasteride-tamsulosin combination therapy is more effective than either monotherapy to treat symptomatic BPH. We studied the cost-effectiveness in Canada of the dutasteride (0.5 mg/day) and tamsulosin (0.4 mg/day) combination compared with tamsulosin or dutasteride monotherapy. METHODS: A Markov model was developed which follows a cohort of male BPH patients ≥50 with moderate to severe lower urinary tract symptoms (LUTS). The model estimates costs to the Canadian health care system and outcomes (in terms of quality adjusted life years [QALYs]) at 10 years and over a patient's lifetime. The dutasteride-tamsulosin combination was compared to each of tamsulosin monotherapy and dutasteride monotherapy. RESULTS: Compared with tamsulosin, the combination was more costly and produced better patient outcomes. Over a lifetime, the incremental cost-effectiveness ratio was CAN$25 437 per QALY gained. At a willingness to pay CAN$50 000 per QALY, the probability of combination therapy being cost-effective was 99.6%. Compared with dutasteride, the combination therapy was the dominant option from year 2, offering improved patient outcomes at lower cost. The probability that combination therapy is more cost-effective than dutasteride was 99.8%. CONCLUSION: Combination therapy offers important clinical benefits for patients with symptomatic BPH, and there is a high probability that it is cost-effective in the Canadian health care system relative to either monotherapy.

The effect of dutasteride on the detection of prostate cancer: A set of meta-analyses.

BACKGROUND: Dutasteride has been shown to significantly improve symptoms of benign prostatic hyperplasia (BPH) and reduce clinical progression. Recent data from studies evaluating 5-alpha reductase inhibitors (5-ARIs) for the prevention of prostate cancer, however, suggest 5ARIs, including dutasteride, may be associated with increased incidence of Gleason 8-10 prostate tumours. This meta-analysis was undertaken to quantify the effect of dutasteride on detection of prostate cancer and high-grade prostate cancer. METHODS: Our meta-analysis includes data from GlaxoSmithKline-sponsored phase III randomized clinical trials (with a study duration of ≥2 years) evaluating the effect of dutasteride, alone or in combination with tamsulosin, to treat BPH or to reduce the risk of prostate cancer. The incidence of prostate cancer, including Gleason 7-10 and Gleason 8-10, for patients taking either dutasteride, dutasteride plus tamsulosin, tamsulosin alone, or placebo, were evaluated using the Mantel-Haenszel Risk Ratio (MHRR) method of conducting meta-analyses. RESULTS: The meta-analysis demonstrated that in a population with symptomatic BPH and/or at increased risk of prostate cancer, a statistically significant lower number of detectable prostate cancers was found in men taking dutasteride compared to control groups (MHRR: 0.66, 95% CI 0.52-0.85). In our analysis, there was no increased risk for Gleason 7-10 (MHRR: 0.83, 95% CI 0.56-1.21) or Gleason 8-10 prostate cancers (MHRR: 0.99, 95% CI 0.39-2.53) in men taking dutasteride over control groups. There were several limitations that need to be considered when interpreting these results. CONCLUSION: These data provide support for the continued use of dutasteride in the treatment of symptomatic BPH patients.

The effect of process parameters on audible acoustic emissions from high-shear granulation.

Product quality in high-shear granulation is easily compromised by minor changes in raw material properties or process conditions. It is desired to develop a process analytical technology (PAT) that can monitor the process in real-time and provide feedback for quality control. In this work, the application of audible acoustic emissions (AAEs) as a PAT tool was investigated. A condenser microphone was placed at the top of the air exhaust on a PMA-10 high-shear granulator to collect AAEs for a design of experiment (DOE) varying impeller speed, total binder volume and spray rate. The results showed the 10 Hz total power spectral densities (TPSDs) between 20 and 250 Hz were significantly affected by the changes in process conditions. Impeller speed and spray rate were shown to have statistically significant effects on granulation wetting, and impeller speed and total binder volume were significant in terms of process end-point. The DOE results were confirmed by a multivariate PLS model of the TPSDs. The scores plot showed separation based on impeller speed in the first component and spray rate in the second component. The findings support the use of AAEs to monitor changes in process conditions in real-time and achieve consistent product quality.

Low-surfactant microemulsions for enhanced topical delivery of poorly soluble drugs.

PURPOSE: To develop and characterize low-surfactant microemulsion (ME) gels to enhance topical delivery of poorly soluble drugs. METHOD: Five low surfactant ME formulations were manufactured following the construction of pseudo-ternary phase diagrams. The MEs were screened for their ability to dissolve a poorly soluble new chemical entity (Model Drug X). Various viscosity imparting agents like Carbopol 934, Colloidal Silica, HPMC K100M, Lubrajel NP, and Xanthan Gum were evaluated for the manufacture of these ME gels. Each ME gel was then further evaluated for physical stability, including assessing rheological profiles. In vitro release profiles were also determined and compared to a conventional ointment. RESULTS: Three of the five low surfactant MEs developed (ME1, ME4 and ME5) were capable of dissolving Model Drug X up to 14 fold higher than the conventional ointment formulation. ME1 and ME4 gels comprising Xanthan gum or Carbopol 934 were physically stable, while ME5 gel was stable only with Colloidal Silica. The ME5 gel with Colloidal Silica showed an irreversible increase in its elastic modulus when exposed to high temperature, indicating that the formulation would be less suitable for commercial use. The Xanthan Gum and Colloidal Silica gels yielded significantly higher release rates (8 - 10 fold) compared to a conventional ointment and formulations containing Carbopol 934. The significant difference in drug release rates between Xanthan Gum and Carbopol 934 indicated that choice of viscosity imparting agent played an important role in governing drug release from ME gels. CONCLUSION: ME gels were developed with low surfactant concentrations and improved formulation characteristics, which increased the solubility and subsequent release of a poorly soluble drug. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Audible acoustics in high-shear wet granulation: application of frequency filtering.

Previous work has shown analysis of audible acoustic emissions from high-shear wet granulation has potential as a technique for end-point detection. In this research, audible acoustic emissions (AEs) from three different formulations were studied to further develop this technique as a process analytical technology. Condenser microphones were attached to three different locations on a PMA-10 high-shear granulator (air exhaust, bowl and motor) to target different sound sources. Size, flowability and tablet break load data was collected to support formulator end-point ranges and interpretation of AE analysis. Each formulation had a unique total power spectral density (PSD) profile that was sensitive to granule formation and end-point. Analyzing total PSD in 10 Hz segments identified profiles with reduced run variability and distinct maxima and minima suitable for routine granulation monitoring and end-point control. A partial least squares discriminant analysis method was developed to automate selection of key 10 Hz frequency groups using variable importance to projection. The results support use of frequency refinement as a way forward in the development of acoustic emission analysis for granulation monitoring and end-point control.