Sarcoidosis manifesting during treatment with secukinumab for psoriatic arthritis.

Sarcoidosis is a multisystem inflammatory disorder of uncertain aetiology. There are numerous case reports of sarcoidosis occurring during treatment with biological immunotherapies. Here, we describe the case of a 52-year-old woman with psoriatic arthritis who developed multisystem sarcoidosis while being treated with secukinumab (anti-interleukin-17A) therapy which, to our knowledge, is the first such case. We discuss existing literature and hypothesise that IL-17 blockade may precipitate the development of granulomatous disease.

Evading Capture by Residual Disease Monitoring: Extramedullary Manifestation of JAK2 V617F-Positive Primary Myelofibrosis After Allogeneic Stem Cell Transplantation.

Monitoring of the JAK2 V617F allele burden in myeloproliferative neoplasms after allogeneic stem cell transplantation is useful to determine levels of residual disease and has the potential to detect early relapse and guide subsequent clinical intervention. A case is described of a JAK2 V617F-positive primary myelofibrosis patient who underwent allogeneic stem cell transplantation. Prospective residual disease monitoring of the peripheral blood failed to detect an extramedullary manifestation of the disease, a periorbital myeloid sarcoma, arising nearly three years after transplant. This case serves to highlight a pitfall in residual disease monitoring for myeloproliferative neoplasm-associated mutations in the post-allogeneic stem cell transplantation setting.

Elevated uptake of plasma macromolecules by regions of arterial wall predisposed to plaque instability in a mouse model.

Atherosclerosis may be triggered by an elevated net transport of lipid-carrying macromolecules from plasma into the arterial wall. We hypothesised that whether lesions are of the thin-cap fibroatheroma (TCFA) type or are less fatty and more fibrous depends on the degree of elevation of transport, with greater uptake leading to the former. We further hypothesised that the degree of elevation can depend on haemodynamic wall shear stress characteristics and nitric oxide synthesis. Placing a tapered cuff around the carotid artery of apolipoprotein E -/- mice modifies patterns of shear stress and eNOS expression, and triggers lesion development at the upstream and downstream cuff margins; upstream but not downstream lesions resemble the TCFA. We measured wall uptake of a macromolecular tracer in the carotid artery of C57bl/6 mice after cuff placement. Uptake was elevated in the regions that develop lesions in hyperlipidaemic mice and was significantly more elevated where plaques of the TCFA type develop. Computational simulations and effects of reversing the cuff orientation indicated a role for solid as well as fluid mechanical stresses. Inhibiting NO synthesis abolished the difference in uptake between the upstream and downstream sites. The data support the hypothesis that excessively elevated wall uptake of plasma macromolecules initiates the development of the TCFA, suggest that such uptake can result from solid and fluid mechanical stresses, and are consistent with a role for NO synthesis. Modification of wall transport properties might form the basis of novel methods for reducing plaque rupture.

Classification of pathologic response to neoadjuvant therapy in esophageal and junctional cancer: assessment of existing measures and proposal of a novel 3-point standard.

OBJECTIVE: To assess existing measures of pathologic response to neoadjuvant therapy in esophageal and junctional cancer, and to recommend an optimum classification. BACKGROUND: Multimodal therapy is increasingly the standard of care for locally advanced esophageal cancer. Numerous measures of pathologic response have been studied; however, no international standardization exists and no measure is incorporated into the current American Joint Committee on Cancer staging system. METHODS: A total of 393 consecutive patients completing multimodal therapy were studied, all with prospectively recorded Mandard tumor regression grades (TRG). Seven other published methods of response were compared, and a novel 3-point TRG [TRG 1 (complete); TRG 2/3 (partial); TRG 4/5 (none/minimal)] was tested. Clinical and pathologic evidence of nodal regression was assessed in a consecutive subset of 200 comprehensively staged patients. RESULTS: All models had similar discriminatory and stratification power, and they predicted survival (P < 0.0001) on univariate analysis. Conversely, only the 3-point TRG (P = 0.042) along with ypN (P < 0.001) and ypT stage (P < 0.001) independently predicted survival. The median survival for TRG 1 was 71 months compared with 30 and 17 months for TRG 2/3 and TRG 4/5, respectively (P < 0.0001). Apparent complete nodal response (cN1 to ypN0) was seen in 64% of the TRG 1 group, 30% of the TRG 2/3 group, and 5% of the TRG 4/5 group (P < 0.0001). CONCLUSIONS: No existing response measure independently predicts outcome. A complete response (TRG 1) defines a unique cohort after neoadjuvant therapy, associated closely with nodal response, and overall survival. This classification merits consideration for standardization of treatment response, and for inclusion in staging nomenclature.

Endothelial microparticle release is stimulated in vitro by purified IgG from patients with the antiphospholipid syndrome.

IgG antiphospholipid antibodies (aPL) exert direct effects on various cell types, contributing to the pathogenesis of thrombosis and pregnancy morbidity in patients with the antiphospholipid syndrome (APS). Some IgG samples from these patients activate endothelial cells (EC) in vitro as judged by surface expression of adhesion molecules such as E-selectin, which can promote thrombosis. Endothelial microparticles (EMP), which themselves are potentially prothrombotic, are released by activated EC. Though elevated circulating EMP levels have been reported in patients with APS, it is not known whether these EMP are released due to a direct effect of aPL on the cells. We tested the effect of purified polyclonal IgG from patients with APS (APS-IgG) and healthy controls (HC-IgG) upon cultured human umbilical vein EC (HUVEC). HUVEC exposed to APS-IgG produced significantly more EMP than those exposed to HC-IgG (p=0.0036) and a greater proportion of these EMP carried surface E-selectin (6.2% ± 4.0 for APS-IgG vs. 3.4% ± 2.0 for HC IgG, p=0.0172). This study therefore demonstrates that purified polyclonal APS-IgG can drive EMP release. We propose that EMP generation may be a useful measure of aPL-mediated pathogenic effects upon EC.

High throughput en face mapping of arterial permeability using tile scanning confocal microscopy.

Elevated uptake of plasma macromolecules by the arterial wall has been implicated in the initiation of atherosclerosis. Here we describe a new method for mapping such uptake in laboratory animals. Albumin was labelled with a fluorescent dye and administered intravenously. After 10 min, the aorta was fixed in situ, excised and opened. En face confocal microscopy employing a computer-controlled stage was used to obtain contiguous tiles, each consisting of a stack of images of fluorescence emission at different depths in the wall. To obtain two-dimensional maps, intensities were summed in each column of voxels starting at the endothelial surface and extending 10 µm into the wall. Variation in the sensitivity of the system with time and in all three spatial directions was assessed and corrected using calibration standards and model specimens. In immature rabbits, uptake around aorto-intercostal branches was greatest in an arrowhead-shaped region around the downstream half of each ostium, and at its lateral margins. Uptake around branches in mature rabbits was more uniform; it was highest upstream of the ostium. Patches and streaks of high uptake were also seen at non-branch locations in the descending thoracic aorta. Transport was more uniform around branches in mice, except for small regions of high uptake at the ostial rim and at the leading edge of an intimal cushion upstream of the ostium, where lesions develop. The technique provides accurate quantification in three dimensions over large areas; it has high throughput, sensitivity and resolution and is suitable for widespread use.

Levels of circulating endothelial cells and colony-forming units are influenced by age and dyslipidemia.

BACKGROUND: The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults, and in children with familial hypercholesterolemia (FH). METHODS: Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony-forming units (CFUs), also known as endothelial progenitor cells. RESULTS: CEC number increased with age. Children with FH had elevated CECs as compared with healthy children, with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium-dependent vascular function, measured by flow-mediated dilatations, was positively associated with CFU number, even after adjustment for confounding risk variables. CONCLUSION: Levels of CECs increase and CFUs decrease with age. In childhood, before the onset of clinically detectable cardiovascular dysfunction, children with a major risk factor for atherosclerotic disease have levels of these indexes of vascular injury and repair approaching those seen in adults.

Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy.

Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.

Thrombin binding predicts the effects of sequence changes in a human monoclonal antiphospholipid antibody on its in vivo biologic actions.

The mechanisms by which antiphospholipid Abs (aPL) cause thrombosis are not fully understood. It is clear that binding to a number of phospholipid-associated Ags is important but it is difficult to identify which Ag-binding properties are most closely linked to the ability to cause biologic effects such as promotion of thrombosis and activation of endothelial cells. We have previously used an in vitro expression system to produce a panel of human monoclonal IgG molecules between which we engineered small differences in sequence leading to significant well-defined changes in binding properties. In this study, we assess the properties of five of these IgG molecules in assays of biologic function in vitro and in vivo. The i.p. injection of these IgG into mice subjected to a femoral vein pinch stimulus showed that only those IgG that showed strong binding to thrombin promoted in vivo venous thrombosis and leukocyte adherence. However, this finding did not hold true for the effects of these IgG on activation of cultured endothelial cells in vitro, where there was a less clear relationship between binding properties and biologic effects.