Treatment With Tofacitinib in Refractory Psoriatic Arthritis: A National Multicenter Study of the First 87 Patients in Clinical Practice.

OBJECTIVE: Tofacitinib (TOF) is the first Janus kinase (JAK) inhibitor approved for psoriatic arthritis (PsA). It has shown efficacy in patients refractory to anti-tumor necrosis factor-α in randomized controlled trials (RCTs). Our aim was to assess efficacy and safety of TOF in clinical practice. METHODS: This was an observational, open-label multicenter study of PsA patients treated with TOF due to inefficacy or adverse events of previous therapies. Outcome variables were efficacy, corticosteroid dose-sparing effect, retention rate, and safety. A comparative study of clinical features between our cohort of patients and those from the OPAL Beyond trial was performed. RESULTS: There were 87 patients (28 women/59 men), with a mean age of 52.8 ± 11.4 years. All patients were refractory to biologic disease-modifying antirheumatic drugs (DMARDs) and/or to conventional synthetic DMARDs plus apremilast. TOF was started at 5 mg twice daily after a mean follow-up of 12.3 ± 9.3 years from PsA diagnosis. At first month, Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) decreased from median 4.8 (IQR 4.1-5.4) to 3.7 (IQR 2.8-4.7, P < 0.01), Disease Activity Index for Psoriatic Arthritis from median 28 (IQR 18.4-34.1) to 15.5 (IQR 10.1-25.7, P < 0.01), and C-reactive protein from median 1.9 (IQR 0.3-5.0) to 0.5 (IQR 0.1-2.2) mg/dL (P < 0.01). Also, TOF led to a significant reduction in prednisone dose. Mild adverse effects were reported in 21 patients (24.13%), mainly gastrointestinal symptoms. TOF retention rate at Month 6 was 77% (95% CI 65.2-86.3). Patients in clinical practice were older with longer disease duration and received biologic agents more commonly than those in the OPAL Beyond trial. CONCLUSION: Data from clinical practice confirm that TOF seems to be effective, rapid, and relatively safe in refractory PsA despite clinical differences with patients in RCTs.

Phenol-Enriched Virgin Olive Oil Promotes Macrophage-Specific Reverse Cholesterol Transport In Vivo.

The intake of olive oil (OO) enriched with phenolic compounds (PCs) promotes ex vivo HDL-mediated macrophage cholesterol efflux in humans. We aimed to determine the effects of PC-enriched virgin OO on reverse cholesterol transport (RevCT) from macrophages to feces in vivo. Female C57BL/6 mice were given intragastric doses of refined OO (ROO) and a functional unrefined virgin OO enriched with its own PC (FVOO) for 14 days. Our experiments included two independent groups of mice that received intragastric doses of the phenolic extract (PE) used to prepare the FVOO and the vehicle solution (saline), as control, for 14 days. FVOO intake led to a significant increase in serum HDL cholesterol and its ability to induce macrophage cholesterol efflux in vitro when compared with ROO group. This was concomitant with the enhanced macrophage-derived [3H]cholesterol transport to feces in vivo. PE intake per se also increased HDL cholesterol levels and significantly promoted in vivo macrophage-to-feces RevCT rate when compared with saline group. PE upregulated the expression of the main macrophage transporter involved in macrophage cholesterol efflux, the ATP binding cassettea1. Our data provide direct evidence of the crucial role of OO PCs in the induction of macrophage-specific RevCT in vivo.

LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis: Insight From Mouse Models.

RATIONALE: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. OBJECTIVE: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. METHODS AND RESULTS: Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B-containing lipoproteins. CONCLUSIONS: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical Abstract: A graphical abstract is available for this article.

Vitamin B3 impairs reverse cholesterol transport in Apolipoprotein E-deficient mice.

INTRODUCTION: High Density Lipoproteins (HDL) are dysfunctional in hypercholesterolemia patients. The hypothesis was tested that nicotinamide (NAM) administration will influence HDL metabolism and reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT) in a murine model of hypercholesterolemia. METHODS: Apolipoprotein E-deficient (KOE) mice were challenged with a high-fat diet for 4 weeks. The effect of different doses of NAM on cholesterol metabolism, and the ability of HDL to promote m-RCT was assessed. RESULTS: The administration of NAM to KOE mice produced an increase (∼1.5-fold; P<0.05) in the plasma levels of cholesterol, which was mainly accounted for by the non-HDL fraction. NAM produced a [3H]-cholesterol plasma accumulation (∼1.5-fold) in the m-RCT setting. As revealed by kinetic analysis, the latter was mainly explained by an impaired clearance of circulating non-HDL (∼0.8-fold). The relative content of [3H]-tracer was lowered in the livers (∼0.6-fold) and feces (>0.5-fold) of NAM-treated mice. This finding was accompanied by a significant (or trend close to significance) up-regulation of the relative gene expression of Abcg5 and Abcg8 in the liver (Abcg5: 2.9-fold; P<0.05; Abcg8: 2.4-fold; P=0.06) and small intestine (Abcg5: 2.1-fold; P=0.15; Abcg8: 1.9-fold; P<0.05) of high-dose, NAM-treated mice. CONCLUSION: The data from this study show that the administration of NAM to KOE mice impaired m-RCT in vivo. This finding was partly due to a defective hepatic clearance of plasma non-HDL.

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice.

Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans.

LXR-dependent regulation of macrophage-specific reverse cholesterol transport is impaired in a model of genetic diabesity.

Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8.

Hepatic CD36 downregulation parallels steatosis improvement in morbidly obese undergoing bariatric surgery.

BACKGROUND: The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. OBJECTIVE: We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. MATERIALS AND METHODS: Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. RESULTS: RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA-IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (-40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (-80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman's r=0.92; P=0.001) and phospholipid (Spearman's r=0.76; P=0.04) contents in this tissue. CONCLUSIONS: For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery.