Cost-effectiveness of hydroxychloroquine versus placebo for hand osteoarthritis: economic evaluation of the HERO trial

Background: An economic evaluation alongside the Hydroxychloroquine Effectiveness in Reducing symptoms of hand Osteoarthritis (HERO) trial was undertaken to assess the cost-effectiveness of hydroxychloroquine compared with placebo for symptomatic treatment of hand osteoarthritis for patients with at least moderate hand pain and inadequate response to current therapies. Methods: A trial-based cost–utility analysis was undertaken from the perspective of the UK National Health Service and Personal Social Services over a 12-month time horizon, using evidence from 248 participants included in the HERO trial, conducted in England. Patient-level data were collected prospectively over a 12-month period, using participant-completed questionnaires and investigator forms, to collect healthcare utilisation, costs and quality-adjusted life years (QALYs) using the EQ-5D-5L. The base-case analysis was conducted on an intention-to-treat basis and used multiple imputation methods to deal with missing data. Results were presented in terms of incremental cost-effectiveness ratios (incremental cost per QALY) and net health benefit, with uncertainty surrounding the findings explored using cost-effectiveness acceptability curves. Results: The base-case analysis estimated slightly lower costs on average (−£11.80; 95% confidence interval (CI) −£15.60 to −£8.00) and marginally fewer QALYs (−0.0052; 95% CI −0.0057 to −0.0047) for participants in the hydroxychloroquine group versus placebo group at 12 months. The resulting incremental cost-effectiveness ratio of £2,267 per QALY lost indicated that although costs were saved, health-related quality of life was lost. Even assuming symmetrical preferences regarding losses and gains for health benefits, the findings do not fall within the cost-effective region. Similar findings arose for analyses conducted from the societal perspective and using complete cases only. Conclusions: This economic evaluation indicates that hydroxychloroquine is unlikely to provide a cost-effective pain relief option for improving health-related quality of life in adult patients with moderate-to-severe hand osteoarthritis

Hydroxychloroquine Effectiveness in Reducing Symptoms of Hand Osteoarthritis: A Randomized Trial

Background: Synovitis is believed to play a role in producing symptoms in persons with hand osteoarthritis, but data on slow-acting anti-inflammatory treatments are sparse. Objective: To determine the effectiveness of hydroxychloroquine versus placebo as an analgesic treatment of hand osteoarthritis. Design: Randomized, double-blind, placebo-controlled clinical trial with 12-month follow-up. (ISRCTN registry number: ISRCTN91859104). Setting: 13 primary and secondary care centers in England. Participants: Of 316 patients screened, 248 participants (82% women; mean age, 62.7 years) with symptomatic (pain ≥4 on a 0- to 10-point visual analogue scale) and radiographic hand osteoarthritis were randomly assigned and 210 (84.7%) completed the 6-month primary end point. Intervention: Hydroxychloroquine (200 to 400 mg) or placebo (1:1) for 12 months with ongoing usual care. Measurements: The primary end point was average hand pain during the previous 2 weeks (on a 0- to 10-point numerical rating scale [NRS]) at 6 months. Secondary end points included self-reported pain and function, grip strength, quality of life, radiographic structural change, and adverse events. Baseline ultrasonography was done. Results: At 6 months, mean hand pain was 5.49 points in the placebo group and 5.66 points in the hydroxychloroquine group, with a treatment difference of −0.16 point (95% CI, −0.73 to 0.40 point) (P = 0.57). Results were robust to adjustments for adherence, missing data, and use of rescue medication. No significant treatment differences existed at 3, 6, or 12 months for any secondary outcomes. The percentage of participants with at least 1 joint with synovitis was 94% (134 of 143) on grayscale ultrasonography and 59% on power Doppler. Baseline structural damage or synovitis did not affect treatment response. Fifteen serious adverse events were reported (7 in the hydroxychloroquine group [3 defined as possibly related] and 8 in the placebo group). Limitation: Hydroxychloroquine dosage restrictions may have reduced efficacy. Conclusion: Hydroxychloroquine was no more effective than placebo for pain relief in patients with moderate to severe hand pain and radiographic osteoarthritis

Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity

Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and T-cell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glyco-lipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined.We have constructed two structural analogues of HER-2 glyco-lipopeptide (HER-GLP) by synthesizing a chimeric peptide made of one universal CD4(+) epitope (PADRE) and one HER-2 CD8(+) T-cell epitope (HER(420-429)). The C-terminal end of the resulting CD4-CD8 chimeric peptide was coupled to a tumor carbohydrate B-cell epitope, based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules. The resulting HER glyco-peptide (HER-GP) was then linked to a palmitic acid moiety, attached either at the N-terminal end (linear HER-GLP-1) or in the middle between the CD4+ and CD8+ T cell epitopes (branched HER-GLP-2). We have investigated the uptake, processing and cross-presentation pathways of the two HER-GLP vaccine constructs, and assessed whether the position of linkage of the lipid moiety would affect the B- and T-cell immunogenicity and protective efficacy. Immunization of mice revealed that the linear HER-GLP-1 induced a stronger and longer lasting HER(420-429)-specific IFN-gamma producing CD8(+) T cell response, while the branched HER-GLP-2 induced a stronger tumor-specific IgG response. The linear HER-GLP-1 was taken up easily by dendritic cells (DCs), induced stronger DCs maturation and produced a potent TLR- 2-dependent T-cell activation. The linear and branched HER-GLP molecules appeared to follow two different cross-presentation pathways. While regression of established tumors was induced by both linear HER-GLP-1 and branched HER-GLP-2, the inhibition of tumor growth was significantly higher in HER-GLP-1 immunized mice (p<0.005).These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers

Antitumor activity of a self-adjuvanting glyco-lipopeptide vaccine bearing B cell, CD4+ and CD8+ T cell epitopes

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Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment