Anna Raper

Systemic and Vascular Inflammation in Patients With Moderate to Severe Psoriasis as Measured by [18F]-Fluorodeoxyglucose Positron Emission Tomography –Computed Tomography (FDG-PET/CT): A Pilot Study

OBJECTIVE To evaluate the feasibility of using [18F]-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT) to detect and quantify systemic inflammation in patients with psoriasis. DESIGN Case series with a nested case-control study. SETTING Referral dermatology and preventive cardiology practices. PARTICIPANTS Six patients with psoriasis affecting more than 10% of their body surface area and 4 controls age and sex matched to 4 of the patients with psoriasis for a nested case-control study. MAIN OUTCOME MEASURES The FDG uptake in the liver, musculoskeletal structures, and aorta measured by mean standardized uptake value, a measure of FDG tracer uptake by macrophages and other inflammatory cells. RESULTS FDG-PET/CT identified numerous foci of inflammation in 6 patients with psoriasis within the skin, liver, joints, tendons, and aorta. Inflammation in the joints was observed in a patient with psoriatic arthritis as well as in 1 patient with no history of joint disease or joint symptoms. In a nested case-control study, FDG-PET/CT imaging demonstrated increased vascular inflammation in multiple segments of the aorta compared with controls. These findings persisted after adjustment for traditional cardiovascular risk factors in multivariate analysis (mean β = 0.33; P < .001). Patients with psoriasis further demonstrated increased hepatic inflammation after adjusting for cardiovascular risk factors (β = 0.18; P < .001), but the association was no longer significant when adjusted for alcohol intake (β = -0.25; P = .07). CONCLUSION FDG-PET/CT is a sensitive tool for identifying inflammation and can be used to identify clinically observed inflammation in the skin and subclinical inflammation in the blood vessels, joints, and liver of patients with psoriasis.

Abnormal lipoprotein particles and cholesterol efflux capacity in patients with psoriasis

OBJECTIVES Psoriasis is a Th-1/17 mediated inflammatory disease associated with increased risk of cardiovascular disease (CVD). Inflammation may modulate lipoprotein particle number and directly impair HDL functions, in particular reverse cholesterol transport (RCT). We sought to study how chronic in vivo inflammation modulates lipoprotein particle composition using nuclear magnetic resonance spectroscopy (NMR) and HDL efflux in psoriasis. METHODS AND RESULTS We prospectively enrolled a consecutive sample of patients with psoriasis (n = 122) and compared lipoprotein and metabolic risk factors to patients without psoriasis (n = 134). Fasting lipids, insulin, glucose were measured by standard assays, and lipoprotein concentration and size were measured by NMR. In a random subset (n = 100 each group), HDL efflux capacity was quantified using a validated ex vivo system involving the incubation of macrophages with apolipoprotein B-depleted serum from patients. Traditional lipid concentrations were similar in both groups except for HDL concentration which was lower in psoriasis (43 mg/dl (36-58) vs 50 (42-62), p < 0.01). However, NMR showed an atherogenic profile in psoriasis similar to that observed in diabetes, with significant increase in LDL particle concentration [1210.5 (1002-1498) vs 1115 (935-1291), p = 0.02] with decrease in LDL size [20.6 (20.3-21.1) vs 21.3 (20.6-21.1), p < 0.001] beyond CV risk factors and HOMA-IR (p = 0.001). Finally, HDL efflux capacity was lower in psoriasis compared to controls in fully adjusted models (beta -0.14, p = 0.001). CONCLUSIONS These data support a more atherogenic lipoprotein profile by NMR and decreased HDL efflux capacity in psoriasis patients compared to controls beyond CVD risk factors. The abnormal lipoprotein particle composition and HDL efflux capacity in psoriasis may provide a link between psoriasis and CVD.

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1.

Individual plasmacytoid dendritic cells are major contributors to the production of multiple innate cytokines in an organ-specific manner during viral infection.

Abstract Plasmacytoid dendritic cells (pDCs) are an important source of IFN-α/β in response to a variety of viruses in vivo, including murine cytomegalovirus (MCMV). However, the respective contributions of various infected organs, and within these of pDCs, conventional dendritic cells and other cells, to the systemic production of IFN-α/β or other innate cytokines during viral infections in vivo is largely unknown. Whether a specialization of pDC subsets in the production of different patterns of innate cytokines exists in vivo in response to a viral infection has not been investigated. Here, by analyzing for the first time directly ex vivo, at the single-cell level, the simultaneous production of up to three cytokines in pDCs isolated from MCMV-infected mice, we show that (i) pDCs are the quasi-exclusive source of IFN-α/β, IL-12 and tumor necrosis factor (TNF)-α, early during MCMV infection, in two immunocompetent mouse lines and with two viral strains, (ii) pDC activation for IFN-α/β production is organ specific and (iii) a significant proportion of pDCs simultaneously produce IFN-α/β, TNF-α and IL-12, although TNF-α and IFN-α/β appear more often co-expressed with one another than each of them with IL-12. Altogether, these results show a broad and non-redundant role of pDCs in early innate detection of, and defense against, viral infection. The data also show differences in the responsiveness of pDCs from different tissues and suggest distinct molecular requirements for pDC production of various cytokines. These observations must be taken into account when designing new antiviral vaccination strategies aimed at harnessing pDC responses.

Negative regulation of leucocyte functions by CD33-related siglecs

The siglecs (sialic acid-binding Ig-like lectins) are a family of transmembrane receptors expressed in the haemopoietic, immune and nervous systems. The CD33-related siglecs are a distinct subset mostly expressed in the innate immune system where they can function as inhibitory receptors by suppressing the signalling mediated by receptors coupled with ITAMs (immunoreceptor tyrosine-based activation motifs). CD33-related siglecs contain ITIMs (immunoreceptor tyrosine-based inhibitory motifs) that recruit and activate SHP-1 [SH2 (Src homology 2) domain-containing phosphatase-1] and SHP-2. In addition, the ITIMs of CD33-related siglecs can suppress siglec-dependent adhesion of sialylated ligands and mediate endocytosis. Siglec-H is a recently characterized murine CD33-related endocytic receptor that lacks intrinsic tyrosine-based signalling motifs and is expressed selectively on PDCs (plasmacytoid dendritic cells). Siglec-H depends on DAP12 (DNAX-activating protein of 12 kDa) for surface expression and cross-linking with anti-siglec-H antibodies can selectively inhibit interferon-alpha production by PDCs following TLR9 (Toll-like receptor 9) ligation. Thus CD33-related siglecs are able to mediate diverse inhibitory functions of leucocytes in the innate immune system via both ITIM-dependent and -independent pathways.

The impact of psoriasis on 10-year Framingham risk

Psoriasis is a chronic inflammatory skin disease, and when severe, may be a risk factor for major adverse cardiac events (MACE) including myocardial infarction1, stroke and cardiovascular (CV) death. Indeed, recent studies evaluating the risk of MACE with IL-12/23 inhibitors in randomized trials emphasize the need for efforts at decreasing the risk of cardiovascular disease in psoriasis patients. 2. Risk stratification and treatment goals for cholesterol and blood pressure in psoriasis remains understudied, and the Framingham Risk score (FRS) for CV risk may underestimate long term risk of MACE in psoriasis patients. The Adult Treatment Panel for lipid management recommends that providers consider emerging risk factors when deciding on lipid treatment but does not provide specific guidelines. We described an initial estimate of this excess attributable risk of severe psoriasis on MACE3 and herein describe how this AR may affect FRS in psoriasis. We consecutively enrolled patients (n=138), and calculated FRS before and after adding the AR of psoriasis (6.2%)3, and estimated the reclassification rate by examining patients moved from a lower risk category to a higher risk category. Patients with psoriasis were relatively young with higher than expected tobacco use, alcohol use, body mass index and lipids (Table 1). Nonetheless, their risk for MACE by FRS was low (<10%) (male mean FRS 7.4 ± 7.75, female 5.9 ± 5.86), attributable to their young age. After considering the estimated AR, (mean FRS 13.36 ± 7.10, male 13.92 ± 7.77, female 12.48 ± 5.86), the majority of patients were re-classified to a higher-risk category: 73% (95% CI 61.5%–82.3%) of low risk patients were reclassified as intermediate, and 53% (95% CI 36.4%–64.1%) of intermediate risk patients were reclassified as high risk (Table 2). These findings suggest that adding the estimated AR of psoriasis on MACE to the FRS results in clinically important changes in prevention strategies3. Table 1 Demographic characteristics of study sample Table 2 Category of risk before and after adding psoriasis attributable risk with treatment goals Due to the young age of our population, the majority of patients were in the low risk category, which would not warrant aggressive risk reduction strategies. However, when considering an AR estimate of MACE, the majority of our patients were reclassified into the intermediate risk category which would warrant change in treatment plans and goals for over 60% of our patients (Table 2), an important finding in this population potentially at higher risk for CV disease with increased subclinical vascular inflammation4. We recognize this proof of concept study is limited by the generalizability of UK data to a US population. However, guidelines for identifying CVD risk factors are similar. Secondly, our AR was derived in severe psoriasis defined by treatment with systemic therapy or phototherapy; similarly, over 80% of our patients had been exposed to these therapies permitting this estimate to be applicable in this proof of concept study. The major implication of these findings is that patients with psoriasis may warrant more aggressive control of established CV risk factors. Measures to decrease CV risk include lifestyle and dietary education through targeted counseling. The percentage of these patients requiring drug interventions such as statins and anti-hypertensive is unknown but likely to be small. Finally, this illustration provides a quantitative approach for CV risk estimation in psoriasis, an approach gaining acceptance in the care of patients with rheumatoid arthritis5.

Treatment of Familial Hypercholesterolemia: Is There a Need Beyond Statin Therapy?

Familial hypercholesterolemia (FH) is a genetic lipid disorder that is characterized by severely elevated cholesterol levels and premature cardiovascular disease. Both the heterozygous and homozygous forms of FH require aggressive cholesterol-lowering therapy. Statins alone frequently do not lower these patients’ cholesterol to therapeutic levels, and some patients are intolerant to statins. Combination or monotherapy with other current pharmacotherapies are options, but even with these some FH patients do not meet their low-density lipoprotein (LDL) cholesterol goals. In the cases of statin intolerance, LDL apheresis may be another treatment option. There are currently several novel therapies in development for LDL lowering that target either production or catabolism of LDL, plaque regression, and potentially gene transfer. We conclude that there is a need beyond statins for patients with FH, especially in cases of statin intolerance, and when even the highest doses of statin do not get patients to goal cholesterol levels.

Long-term clinical results of microsomal triglyceride transfer protein inhibitor use in a patient with homozygous familial hypercholesterolemia

We report the case of a 49-year-old woman with homozygous familial hypercholesterolemia and a complicated cardiovascular history, treated for 5 years with a microsomal triglyceride transfer protein inhibitor in addition to her other lipid-lowering therapy.

A novel approach to measuring macrophage-specific reverse cholesterol transport in vivo in humans

Reverse cholesterol transport (RCT) is thought to be an atheroprotective function of HDL, and macrophage-specific RCT in mice is inversely associated with atherosclerosis. We developed a novel method using 3H-cholesterol nanoparticles to selectively trace macrophage-specific RCT in vivo in humans. Use of 3H-cholesterol nanoparticles was initially tested in mice to assess the distribution of tracer and response to interventions known to increase RCT. Thirty healthy subjects received 3H-cholesterol nanoparticles intravenously, followed by blood and stool sample collection. Tracer counts were assessed in plasma, nonHDL, HDL, and fecal fractions. Data were analyzed by using multicompartmental modeling. Administration of 3H-cholesterol nanoparticles preferentially labeled macrophages of the reticuloendothelial system in mice, and counts were increased in mice treated with a liver X receptor agonist or reconstituted HDL, as compared with controls. In humans, tracer disappeared from plasma rapidly after injection of nanoparticles, followed by reappearance in HDL and nonHDL fractions. Counts present as free cholesterol increased rapidly and linearly in the first 240 min after nadir; counts in cholesteryl ester increased steadily over time. Estimates of fractional transfer rates of key RCT steps were obtained. These results support the use of 3H-cholesterol nanoparticles as a feasible approach for the measurement of macrophage RCT in vivo in humans.

ELEVATED ENDOTHELIAL CELL, PLATELET AND T-CELL MICROPARTICLES IN PSORIASIS MAY PROVIDE NOVEL LINK TO ATHEROSCLEROSIS

Severe psoriasis is a risk factor for cardiovascular (CV) disease beyond traditional risk factors; however, the mechanism remains unknown. Recent findings suggest that cell membrane vesicles, or microparticles, which are released upon cell activation or apoptosis, are associated with CV disease and