Biologic agents for rheumatoid arthritis--negotiating the NICE technology appraisals

In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has provided guidance [technology appraisals (TAs) 130, 186, 195, 198 and 225] on the use of biologic drugs for the treatment of RA. This is based on an analysis of efficacy, safety and cost-effectiveness, and has resulted in a complex management pathway that restricts freedom to prescribe biologics according to their licensed indications. Specifically, TNF antagonists are the only class of biologics that can be used first line in DMARD-inadequate responders, and only in patients with a persistent 28-joint DAS score of ≥5.1. Alternative biologic agents are denied to those with contraindications to anti-TNF drugs and are also not supported following intolerance to TNF antagonists. Rituximab is the only class of biologic permitted after TNF antagonist inefficacy, in the absence of a contraindication to its use, whereas abatacept and tocilizumab are licensed and may be a more efficacious choice at this stage in some patient groups. Furthermore, for patients who demonstrate sequential inadequate responses, treatment is restricted to one TNF antagonist, rituximab and tocilizumab, whereas abatacept is only a permitted choice when rituximab is contraindicated or has been withdrawn because of an adverse event. In this review, we discuss the treatment algorithm published by NICE, and suggest alternatives where perceived deficiencies exist.     

Potency of myopic defocus in spectacle lens compensation

PURPOSE: Previous studies have shown that chick eyes compensate for positive or negative lenses worn for brief periods if the chicks are in darkness the remainder of the time. This study was undertaken to determine whether chicks can compensate for brief periods of lens wear if given unrestricted vision the remainder of the time. Previous studies have also shown that chick eyes alternately wearing positive and negative lenses for brief periods compensate for the positive lenses. The current study sought to determine whether brief periods of positive lens wear can outweigh daylong wearing of negative lenses. METHODS: Chicks wore +6 D or +10 D lenses for between 8 and 60 min/d, in two to six periods and wore either no lenses or negative lenses for the remainder of the 12-hour daylight period. Refraction and ultrasound biometry were performed before and after the 3-day-long experiments. RESULTS: Wearing positive lenses for as little as 12 min/d (six periods of 2 minutes) with unrestricted vision the remainder of the time caused eyes to become hyperopic and reduced the rate of ocular elongation. These effects also occurred when the scene viewed was beyond the far point of the lens-wearing eye and thus was myopically blurred. Even when chicks wore negative lenses for the entire day except for 8 minutes of wearing positive lenses, the eyes compensated for the positive lenses, as though the negative lenses had not been worn. When chicks wore binocular negative lenses for the entire day except for 8 minutes of wearing a positive lens on one eye and a plano lens on the other, the eye wearing the positive lens became less myopic than the eye wearing the plano lens. CONCLUSIONS: Brief periods of myopic defocus imposed by positive lenses prevent myopia caused by daylong wearing of negative lenses. This implies that periods of myopic and hyperopic defocus do not add linearly. If children are like chicks and if the hyperopic defocus of long daily periods of reading predisposes a child to myopia, regular, brief interruptions of reading might have use as a prophylaxis against progression of myopia.     

Abnormal activation of the social brain during face perception in autism

ASD involves a fundamental impairment in processing social-communicative information from faces. Several recent studies have challenged earlier findings that individuals with autism spectrum disorder (ASD) have no activation of the fusiform gyrus (fusiform face area, FFA) when viewing faces. In this study, we examined activation to faces in the broader network of face-processing modules that comprise what is known as the social brain. Using 3T functional resonance imaging, we measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing nonemotional faces. We replicated our original findings of significant activation of face identity-processing areas (FFA and inferior occipital gyrus, IOG) in ASD. However, in addition, we identified hypoactivation in a more widely distributed network of brain areas involved in face processing [including the right amygdala, inferior frontal cortex (IFC), superior temporal sulcus (STS), and face-related somatosensory and premotor cortex]. In ASD, we found functional correlations between a subgroup of areas in the social brain that belong to the mirror neuron system (IFC, STS) and other face-processing areas. The severity of the social symptoms measured by the Autism Diagnostic Observation Schedule was correlated with the right IFC cortical thickness and with functional activation in that area. When viewing faces, adults with ASD show atypical patterns of activation in regions forming the broader face-processing network and social brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging to the mirror neuron system are involved in the face-processing disturbances in ASD.     

Mapping the social and physical contexts of physical activity across adolescence using ecological momentary assessment

BACKGROUND: Research has sought to understand how environmental factors influence adolescent physical activity, yet little is known about where and with whom adolescents are physically active. PURPOSE: This study used electronic ecological momentary assessment (e.EMA) to map the social and physical contexts of exercise and walking across adolescence. Differences in physical activity contexts by gender, grade in school, day of the week, and season were examined. METHODS: Twice a year between 9th and 12th grade, 502 adolescents (51% female) of mixed ethnicity (55% White) participated in 4-day e.EMA intervals (Thursday-Sunday) where their primary activity (e.g., exercise, TV, homework), social company (e.g., friends, family, class), and physical location (e.g., home, school, outdoors) were assessed every 30 (+/-10) min during waking hours. RESULTS: Overall, greater proportions of exercise and walking were reported with friends, outdoors, and at school. However, boys were more likely to report exercising and walking in outdoor locations than girls. Exercising with classmates, family, and at school decreased across high school. Walking with family, friends, and outdoors also decreased. On weekdays compared to weekends, students reported a greater proportion of their exercise and walking at school. Students were more likely to report exercising and walking outdoors in the fall and the spring than in the winter. CONCLUSION: e.EMA showed that the social and physical contexts of adolescent exercise and walking vary as a function of gender, grade in school, day of the week, and season. Understanding the contexts of physical activity during the high school years can be helpful in designing interventions during adolescence.     

Effect of Plasma TNF-α on Filgrastim-Stimulated Hematopoiesis in Mice and Humans

Study Objective . To delineate possible explanations for a nonmonotone hematopoiesis, dose-response curve with filgrastim therapy after high-dose chemotherapy. Design . Sequential two-phase study. Settings . University teaching hospital and basic pharmaceutical sciences laboratory. Subjects . Thirty-nine patients with breast cancer or melanoma and 15 normal CF-1 male mice. Interventions . Serial blood samples were obtained from patients after high-dose chemotherapy to evaluate hematopoiesis and tumor necrosis factor-α (TNF-α) concentrations. Murine hematopoiesis was induced by filgrastim with or without coadministration of lipopolysaccharide. Measurements and Main Results . Detection of plasma TNF-α in patients corresponded to substantially slower recovery of granulocytes, erythrocytes, and platelets, and was directly proportional to the prescribed dosage of filgrastim. Lipopolysaccharide stimulated the secretion of TNF-α in mice and totally aberrated filgrastim-induced granulopoiesis. Conclusions . This in vivo evidence suggests that regulatory pathways involving endogenous cytokines may override the effect of recombinant cytokines.     

A Wearable Magnet-Based System to Assess Activity and Joint Flexion in Humans and Large Animals

Functional outcomes, such as joint flexion and gait, are important indicators of efficacy in musculoskeletal research. Current technologies that objectively assess these parameters, including visual tracking systems and force plates, are challenging to deploy in long-term translational and clinical studies. To that end, we developed a wearable device that measures both physical activity and joint flexion using a single integrated sensor and magnet system, and hypothesized that it could evaluate post-operative functional recovery in an unsupervised setting. To demonstrate the feasibility of measuring joint flexion, we first compared knee motion from the wearable device to that acquired from a motion capture system to confirm that knee flexion measurements during normal human gait, predicted via changes in magnetic field strength, closely correlated with data acquired by motion capture. Using this system, we then monitored a porcine cohort after bilateral stifle arthrotomy to investigate longitudinal changes in physical activity and joint flexion. We found that unsupervised activity declined immediately after surgery, with a return to pre-operative activity occurring over a period of 2 weeks. By providing objective, individualized data on locomotion and joint function, this magnet-based system will facilitate the in vivo assessment of novel therapeutics in translational orthopaedic research.     

Hypertension in response to chronic reductions in uterine perfusion in pregnant rats: effect of tumor necrosis factor-alpha blockade

Reductions in uterine perfusion pressure (RUPP) in pregnant rats is associated with increased tumor necrosis factor-alpha (TNF-alpha). This study was designed to determine the role of endogenous TNF-alpha in mediating changes in arterial pressure and endothelin-1 (ET-1) in RUPP rats. To achieve this goal we examined the effect of RUPP in the presence and absence of a TNF-alpha-soluble receptor, etanerecept (0.4 mg/kg). Mean arterial pressure increased from 102+/-1 mm Hg in normal pregnant (NP) rats to 134+/-3 mm Hg (P<0.05) in RUPP rats. Serum TNF-alpha increased to 40+/-7.6 pg/mL in RUPP rats (n=24) versus 14.8+/-3.3 pg/mL (n=16; P<0.05) in NP rats. Administration of etanerecept decreased TNF-alpha in RUPP rats (n=20) to 17.2+/-3 pg/mL and mean arterial pressure to 118+/-2 mm Hg (P<0.05). Tissue ET-1 decreased in etanerecept-treated RUPP rats compared with control RUPP rats. The direct effect of TNF-alpha blockade on endothelial activation in response to placental ischemia was examined in human umbilical vein endothelial cells. ET-1 secreted from human umbilical vein endothelial cells treated with RUPP serum was 59.2+16 pg/mg and decreased when etanerecept was added to the medium with RUPP serum (7.60+/-0.77 pg/mg), as well as in response to serum from etanerecept-treated RUPP rats (7.30+/-0.55 pg/mg; P<0.001). ET-1 secreted from human umbilical vein endothelial cells was 15.6+/-2 pg/mg when treated with NP serum. These data support the hypothesis that endogenous TNF-alpha is an important stimulus for ET-1 in response to placental ischemia and is important in mediating endothelial cell activation and hypertension during pregnancy.