Drug Survival on First Biologic Therapy Among Late-Onset Rheumatoid Arthritis Patients Compared to Early-Onset Patients: A Population-Based Cohort Study.

INTRODUCTION: Rheumatoid arthritis (RA) patients can be divided according to the age of disease onset and classified as late-onset RA ≥ 60 years old or early-onset RA < 60 years old. Current treatment guidelines do not stipulate any preference regarding the biologic that should be used first in the late-onset group. This study aims to compare the drug survival times on first biological treatment between late and early-onset RA patients. METHODS: This is a population based cohort study using the medical records of Leumit healthcare services. We included all eligible RA patients between 2000 and 2017. RA patients were divided into late- and early-onset RA groups and compared according to drug survival time on the first biological therapy. RESULTS: The final cohort included 3814 RA patients, 2807 (73.6%) of whom had early-onset RA. Overall, biologic disease-modifying anti-rheumatic drugs (bDMARDs) were used more often among early-onset compared to late-onset patients (16.9% vs. 7.8%, p < 0.001). Among early-onset patients, etanercept was associated with the longest drug survival time on the first biologic, and adalimumab and infliximab were associated with the longest drug survival times among late-onset patients. No differences were observed in drug survival times between late and early-onset patients on the first bDMARD, except for abatacept and golimumab with longer drug survival time among early-onset patients. CONCLUSION: Late-onset RA patients were treated with biologics to a lesser extent than early-onset patients, but no differences were observed in drug survival times at the first bDMARD between the two groups.

Challenges in the Timely Diagnosis of Behcet's Disease.

Behcet's disease (BD) is a chronic, multi-systemic inflammatory disorder mainly characterized by recurrent oral and genital ulcers, skin lesions, and uveitis. As no pathognomonic laboratory test exists for BD, the diagnosis relies solely on clinical features. Over the years, great efforts have been invested in creating clinical diagnostic and classification criteria. The international study group criteria introduced in 1990 were the first true multinational set of criteria. Despite improving the ability to diagnose BD, these criteria still have limitations, including the inability to diagnose patients presenting without oral ulcers or presenting with rare manifestations of the disease. This led to the introduction of the international criteria for BD in 2013, which improved the sensitivity with minimal compromise on specificity. Despite the efforts made and as our understanding of the clinical manifestations of BD and genetic pathogenesis continue to evolve, efforts should be made to further enhance the currently accepted international classification criteria, perhaps by incorporating genetic testing (e.g., family history or HLA typing) as well as ethnic group-specific features.

A very rare cause of blue finger: A case-based review.

Introduction: Cryofibrinogen is an abnormal, cold-insoluble protein composed of a combination of fibrinogen, fibrin, and fibronectin. Cryofibrinogenemia can be essential (e.g. primary) or secondary to various conditions. While low levels of cryofibrinogen can be seen in asymptomatic healthy individuals without evidence of clinical features typical of cryofibrinogenemia, cryofibrinogenemia associated with clinical features is considered very rare. The clinical features of cryofibrinogenemia ranges from skin manifestations, including Raynaud's phenomenon and livedo reticularis, to more severe organ-threatening manifestations such as tissue ischemia and gangrene. Case description: We report a case of a 48-year-old male who presented with blue finger and palpable purpura on his distal extremities. Laboratory workup was positive for anti-nuclear antibodies, anti-double-stranded DNA, anti-ribonucleoprotein, and rheumatoid factor, while antineutrophil cytoplasmic antibodies and cryoglobulins were negative. Testing for hypercoagulable states and infectious etiologies was unrevealing. Later, angiographic computed tomography showed multiple pulmonary embolisms and disruption of blood flow to the left fifth digit. As the aforementioned workup could not explain the presence of the thrombus by a thromboembolic cause, a search for an in situ cause other than antiphospholipid syndrome was initiated and concentrated mainly on cryofibrinogenemia. Blood samples collected using prewarmed anticoagulant containing tubes were sent to central lab familiar with performing the test. Two weeks later, a positive result for the presence of cryofibrinogen confirmed the diagnosis of cryofibrinogenemia. Due to the presence of multiple signs compatible with mixed connective tissue disease, he was diagnosed with cryofibrinogenemia secondary to mixed connective tissue disease, and treatment with prednisone, low-molecular-weight heparin, prostacyclin and hydroxychloroquine was initiaed with favorable outcome. Conclusion: Cryofibrinogenemia is a rare and underdiagnosed condition. Clinicians should be aware of this cryopathy especially in the cases of Raynaud's phenomenon and ischemic ulcers not explained by other causes. Precautions must be taken during the diagnostic process, and therapy should be given as soon as possible.

Neurosarcoidosis: The Presentation, Diagnosis and Treatment Review of Two Cases.

Sarcoidosis is a chronic granulomatous disease of unknown cause characterized by the presence of non-caseating granulomas. The disease can affect any organ including the nervous system. Neurosarcoidosis occurs in about 5% patients with sarcoidosis. The clinical presentation of neurosarcoidosis is varied, and it can involve the brain, spinal cord and peripheral nervous system, separately or in different combinations. The diagnosis of neurosarcoidosis is challenging, as biopsies from the nervous system are not readily available. Anti-TNFα agents are becoming one of the cornerstone treatments for neurosarcoidosis. In this case-based review, we discuss two cases of neurosarcoidosis with different clinical presentations. The first patient presented with confusion, while the second presented with walking difficulty and neurogenic bladder. Both patients were treated with methylprednisolone pulse therapy with rapid, but non-complete, improvement. Therefore, infliximab was initiated in both cases with subsequent improvement in the clinical manifestations and imaging findings, emphasizing the effectiveness and safety of infliximab in cases of severe neurosarcoidosis. In conclusion, the goal of neurosarcoidosis management is to prevent organ system damage and minimize the toxic cumulative adverse effects of glucocorticoid use. In this case-based review we discuss the various presentations, the diagnosis and the treatment of neurosarcoidosis.

Prednisone and Its Active Metabolite Prednisolone Attenuate Lipid Accumulation in Macrophages.

BACKGROUND: Synthetic forms of glucocorticoids (GCs; eg, prednisone, prednisolone) are anti-inflammatory drugs that are widely used in clinical practice. The role of GCs in cardiovascular diseases, including atherosclerosis, is highly controversial, and their impact on macrophage foam cell formation is still unknown. We investigated the effects of prednisone and prednisolone on macrophage oxidative stress and lipid metabolism. METHODS AND RESULTS: C57BL/6 mice were intraperitoneally injected with prednisone or prednisolone (5 mg/kg) for 4 weeks, followed by lipid metabolism analyses in the aorta and peritoneal macrophages. We also analyzed the effect of serum samples obtained from 9 healthy human volunteers before and after oral administration of prednisone (20 mg for 5 days) on J774A.1 macrophage atherogenicity. Finally, J774A.1 macrophages, human monocyte-derived macrophages, and fibroblasts were incubated with increasing concentrations (0-200 ng/mL) of prednisone or prednisolone, followed by determination of cellular oxidative status, and triglyceride and cholesterol metabolism. Prednisone and prednisolone treatment resulted in a significant reduction in triglyceride and cholesterol accumulation in macrophages, as observed in vivo, ex vivo, and in vitro. These effects were associated with GCs' inhibitory effect on triglyceride- and cholesterol-biosynthesis rates, through downregulation of diacylglycerol acyltransferase 1 and HMG-CoA reductase expression. Glucocorticoid-induced reduction of cellular lipid accumulation was mediated by the GC receptors on the macrophages, because the GC-receptor antagonist (RU486) abolished these effects. In fibroblasts, unlike macrophages, GCs showed no effects. CONCLUSION: Prednisone and prednisolone exhibit antiatherogenic activity by protecting macrophages from lipid accumulation and foam cell formation.

Soybean Oil Modulates the Gut Microbiota Associated with Atherogenic Biomarkers.

During the last few decades there has been a staggering rise in human consumption of soybean-oil (SO). The microbiome and specific taxa composing it are dramatically affected by diet; specifically, by high-fat diets. Increasing evidence indicates the association between dysbiosis and health or disease state, including cardiovascular diseases (CVD) and atherosclerosis pathogenesis in human and animal models. To investigate the effects of high SO intake, C57BL/6 mice were orally supplemented with SO-based emulsion (SOE) for one month, followed by analyses of atherosclerosis-related biomarkers and microbiota profiling by 16S rRNA gene sequencing of fecal DNA. SOE-supplementation caused compositional changes to 64 taxa, including enrichment in Bacteroidetes, Mucispirillum, Prevotella and Ruminococcus, and decreased Firmicutes. These changes were previously associated with atherosclerosis in numerous studies. Among the shifted taxa, 40 significantly correlated with at least one atherosclerosis-related biomarker (FDR < 0.05), while 13 taxa positively correlated with the average of all biomarkers. These microbial alterations also caused a microbial-derived metabolic-pathways shift, including enrichment in different amino-acid metabolic-pathways known to be implicated in CVD. In conclusion, our results demonstrate dysbiosis following SOE supplementation associated with atherosclerosis-related biomarkers. These findings point to the microbiome as a possible mediator to CVD, and it may be implemented into non-invasive diagnostic tools or as potential therapeutic strategies.

Exogenous (Pomegranate Juice) or Endogenous (Paraoxonase1) Antioxidants Decrease Triacylglycerol Accumulation in Mouse Cardiovascular Disease-Related Tissues.

The polyphenol-rich pomegranate juice (PJ) and the high-density lipoprotein (HDL)-associated paraoxonase1 (PON1) are known as potent atheroprotective antioxidants, but their effects on other tissues related to cardiovascular disease (CVD) remain unknown. The current study aimed to investigate the effects of treating mice with PJ or recombinant PON1 (rePON1) on the oxidation and lipid status of CVD-related tissues: serum, aorta, heart, liver, kidney, visceral, and subcutaneous adipose tissues (VAT and SAT). Both PJ consumption and rePON1 injection decreased the serum levels of thiobarbituric acid-reactive substances (16% and 19%) and triacylglycerols (TAG, 24% and 27%), while only rePON1 increased the levels of thiol groups (35%) and decreased serum cholesterol (15%). Both PJ and rePON1 significantly decreased aortic cholesterol (38% and 32%) and TAG (62% and 58%) contents in association with downregulation of the key TAG biosynthetic enzyme diacylglycerol O-acyltransferase 1 (DGAT1, 71% and 65%), while only PJ decreased aortic lipid peroxides (47%). Substantial TAG-lowering effects of both PJ and rePON1 were observed also in the heart (31% and 42%), liver (34% and 42%), and kidney (42% and 57%). In both VAT and SAT, rePON1 decreased the levels of lipid peroxides (28% and 25%), while PJ decreased the TAG content (22% and 18%). Ex vivo incubation of SAT with serum derived from mice that consumed PJ or injected with rePON1 decreased SAT lipid peroxides (35% or 28%) and TAG mass (12% or 10%). These novel findings highlight potent TAG-lowering properties of exogenous (PJ) and endogenous (PON1) antioxidants in tissues associated with CVD.

Supplementation with linoleic acid-rich soybean oil stimulates macrophage foam cell formation via increased oxidative stress and diacylglycerol acyltransferase1-mediated triglyceride biosynthesis.

During the last decades there has been a staggering rise in human consumption of soybean oil (SO) and its major polyunsaturated fatty acid linoleic acid (LA). The role of SO or LA in cardiovascular diseases is highly controversial, and their impact on macrophage foam cell formation, the hallmark of early atherogenesis, is unclear. To investigate the effects of high SO or LA intake on macrophage lipid metabolism and the related mechanisms of action, C57BL/6 mice were orally supplemented with increasing levels of SO-based emulsion or equivalent levels of purified LA for 1 month, followed by analyses of lipid accumulation and peroxidation in aortas, serum and in peritoneal macrophages (MPM) of the mice. Lipid peroxidation and triglyceride mass in aortas from SO or LA supplemented mice were dose-dependently and significantly increased. In MPM from SO or LA supplemented mice, lipid peroxides were significantly increased and a marked accumulation of cellular triglycerides was found in accordance with enhanced triglyceride biosynthesis rate and overexpression of diacylglycerol acyltransferase1 (DGAT1), the key enzyme in triglyceride biosynthesis. In cultured J774A.1 macrophages treated with SO or LA, triglyceride accumulated via increased oxidative stress and a p38 mitogen-activated protein kinase (MAPK)-mediated overexpression of DGAT1. Accordingly, anti-oxidants (pomegranate polyphenols), inhibition of p38 MAPK (by SB202190) or DGAT1 (by oleanolic acid), all significantly attenuated SO or LA-induced macrophage triglyceride accumulation. These findings reveal novel mechanisms by which supplementation with SO or LA stimulate macrophage foam cell formation, suggesting a pro-atherogenic role for overconsumption of SO or LA. © 2016 BioFactors, 43(1):100-116, 2017.