Introduction: Few studies have evaluated the impact of delayed diagnosis of axial spondyloarthritis (axSpA) on the overall burden of disease. The objective of this review was to evaluate the available literature on the clinical, economic, and humanistic burden of delayed diagnosis in patients with axSpA. Methods: This systematic literature review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched the MEDLINE and Embase databases for Englishlanguage publications of original research articles (up to July 12, 2018) and conference abstracts (January 1, 2014, to July 12, 2018) reporting studies of adult patients with delayed diagnosis of axSpA associated with clinical,

BackgroundMetastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies.MethodsA systematic literature search identified two randomized trials as suitable for indirect comparison: the coBRIM trial of vemurafenib plus cobimetinib versus vemurafenib and the COMBI-v trial of dabrafenib plus trametinib versus vemurafenib. The comparison followed the method of Bucher et al. and analyzed both efficacy (overall survival [OS], progression-free survival [PFS], and overall response rate [ORR]) and safety outcomes (adverse events [AEs]).ResultsThe indirect comparison revealed similar efficacy outcomes between both therapies, with no statistically significant difference between therapies for OS (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.68 − 1.30), PFS (HR 1.05, 95% CI 0.79 − 1.40), or ORR (risk ratio [RR] 0.90, 95% CI 0.74 − 1.10). Dabrafenib plus trametinib differed significantly from vemurafenib plus cobimetinib with regard to the incidence of treatment-related AE (RR 0.92, 95% CI 0.87 − 0.97), any AE grade ≥3 (RR 0.71, 95% CI 0.60 − 0.85) or dose interruption/modification (RR 0.77, 95% CI 0.60 − 0.99). Several categories of AEs occurred significantly more frequently with vemurafenib plus cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib.ConclusionsThis indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus cobimetinib but was associated with reduced adverse events.

Background: Metastatic melanoma is an aggressive form of skin cancer with a high mortality rate and the fastest growing global incidence rate of all malignancies. The introduction of BRAF/MEK inhibitor combinations has yielded significant increases in PFS and OS for melanoma. However, at present, no direct comparisons between different BRAF/MEK combinations have been conducted. In light of this, an indirect treatment comparison was performed between two BRAF/MEK inhibitor combination therapies for metastatic melanoma, dabrafenib plus trametinib and vemurafenib plus cobimetinib, in order to understand the relative efficacy and toxicity profiles of these therapies. Several categories of AEs occurred significantly more frequently with vemurafenib plus cobimetinib, while some occurred significantly more frequently with dabrafenib plus trametinib. For severe AEs (grade 3 or above), four occurred significantly more frequently with vemurafenib plus cobimetinib and no severe AE occurred significantly more frequently with dabrafenib plus trametinib. Conclusions: This indirect treatment comparison suggested that dabrafenib plus trametinib had comparable efficacy to vemurafenib plus cobimetinib but was associated with reduced adverse events.

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GERAS is a prospective, non-interventional cohort study in AD patients and caregivers. The Zarit Burden Inventory (ZBI) and the EQ-5D were used to measure burden and HRQoL respectively. Spearman correlations were computed between EQ-5D, ZBI and T-IADL at baseline, 18-months and for change over 18-months. T-IADL and ZBI change scores were summarised by EQ-5D domain change category (better/stable/ worse). Results: 1495 caregivers were available at baseline [67 years (SD 12) and 64% female]. According to baseline patient severity, caregivers' EQ-5D health state values were 0.86, 0.85 and 0.82 and ZBI total scores were 25, 29 and 34 in mild, moderate and moderately severe/severe AD respectively. T-IADL increased from a mean of 79 hours (SD 89; median 60 hours) at baseline by a mean of 17 hours (SD 105; median 10 hours) over 18-months, and showed a stronger correlation with ZBI than with EQ-5D, although correlations were low for both (e.g. change scores 0.118 ZBI; 0.020 EQ-5D). Worsening within EQ-5D domains (mobility, self-care, usual activities, pain/ discomfort and anxiety/depression) was associated with the greatest increase in burden scores, although the majority of caregivers (68-90%) remained stable within each EQ-5D domain. Relative to these stable caregivers, larger increases in T-IADL over 18-months were associated with better ratings in mobility and usual activities but worsening in pain/discomfort. Larger increases in T-IADL were associated with both better and worse ratings in anxiety/depression [23.5 hours better (11%); 12.2 hours stable (68%); 24.8 hours worse (16%)]. ConClusions: EQ-5D health state values had low sensitivity to changes in caregiver time over an 18-month period. ZBI may better reflect the impact of caring for AD patients.