Clinical effectiveness of biologics in clinical practice

TNF inhibitors are currently considered both effective and cost-effective in patients with active rheumatoid arthritis (RA), particularly in patients who have not responded fully to methotrexate. There is substantial doubt about the cost-effectiveness of TNF inhibitors as initial treatment for active RA. New data from the National Data Bank for Rheumatic Diseases now question the current consensus in methotrexate failures. The data suggest that in routine clinical practice TNF inhibitors provide only modest incremental benefits over best conventional therapy. If confirmed, these observational studies suggest that the economic argument underpinning the widespread use of TNF inhibitors in established RA is unsustainable.     

Spiropiperidine CCR5 antagonists

A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed.     

Extensive expansion of primary human gamma delta T cells generates cytotoxic effector memory cells that can be labeled with Feraheme for cellular MRI

Gamma delta T cells (GDTc) comprise a small subset of cytolytic T cells shown to kill malignant cells in vitro and in vivo. We have developed a novel protocol to expand GDTc from human blood whereby GDTc were initially expanded in the presence of alpha beta T cells (ABTc) that were then depleted prior to use. We achieved clinically relevant expansions of up to 18,485-fold total GDTc, with 18,849-fold expansion of the Vδ1 GDTc subset over 21 days. ABTc depletion yielded 88.1 ± 4.2 % GDTc purity, and GDTc continued to expand after separation. Immunophenotyping revealed that expanded GDTc were mostly CD27-CD45RA- and CD27-CD45RA+ effector memory cells. GDTc cytotoxicity against PC-3M prostate cancer, U87 glioblastoma and EM-2 leukemia cells was confirmed. Both expanded Vδ1 and Vδ2 GDTc were cytotoxic to PC-3M in a T cell antigen receptor- and CD18-dependent manner. We are the first to label GDTc with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles for cellular MRI. Using protamine sulfate and magnetofection, we achieved up to 40 % labeling with clinically approved Feraheme (Ferumoxytol), as determined by enumeration of Perls’ Prussian blue-stained cytospins. Electron microscopy at 2,800× magnification verified the presence of internalized clusters of iron oxide; however, high iron uptake correlated negatively with cell viability. We found improved USPIO uptake later in culture. MRI of GDTc in agarose phantoms was performed at 3 Tesla. The signal-to-noise ratios for unlabeled and labeled cells were 56 and 21, respectively. Thus, Feraheme-labeled GDTc could be readily detected in vitro via MRI.     

Association between the Number of Injuries Sustained and 12-Month Disability Outcomes: Evidence from the Injury-VIBES Study

Objective

To determine associations between the number of injuries sustained and three measures of disability 12-months post-injury for hospitalised patients.

Methods

Data from 27,840 adult (18+ years) participants, hospitalised for injury, were extracted for analysis from the Validating and Improving injury Burden Estimates (Injury-VIBES) Study. Modified Poisson and linear regression analyses were used to estimate relative risks and mean differences, respectively, for a range of outcomes (Glasgow Outcome Scale-Extended, GOS-E; EQ-5D and 12-item Short Form health survey physical and mental component summary scores, PCS-12 and MCS-12) according to the number of injuries sustained, adjusted for age, sex and contributing study.

Findings

More than half (54%) of patients had an injury to more than one ICD-10 body region and 62% had sustained more than one Global Burden of Disease injury type. The adjusted relative risk of a poor functional recovery (GOS-E<7) and of reporting problems on each of the items of the EQ-5D increased by 5–10% for each additional injury type, or body region, injured. Adjusted mean PCS-12 and MCS-12 scores worsened with each additional injury type, or body region, injured by 1.3–1.5 points and 0.5 points, respectively.

Conclusions

Consistent and strong relationships exist between the number of injury types and body regions injured and 12-month functional and health status outcomes. Existing composite measures of anatomical injury severity such as the NISS or ISS, which use up to three diagnoses only, may be insufficient for characterising or accounting for multiple injuries in disability studies. Future studies should consider the impact of multiple injuries to avoid under-estimation of injury burden.