Potent in vitro activity of curcumin and quercetin co-encapsulated in nanovesicles without hyaluronan against Aspergillus and Candida isolates

The rapid emergence of resistance to classical antifungals has increased the interest in novel antifungal compounds. Curcumin and quercetin are two natural plant-derived bioactive molecules shown to promote wound healing in injured tissues. In this study, we investigated the in vitro susceptibility of several Aspergillus and Candida isolates to curcumin and quercetin encapsulated in nanovesicles with and without hyaluronan and elucidated the efficacy of these nanovesicles as topical drug delivery systems. Antifungal susceptibility testing performed according to the CLSI guidelines indicated that curcumin-quercetin co-encapsulated in nanovesicles without hyaluronan (CUR-QUE-NV-WH) had stronger activity against Candida isolates than fluconazole. Furthermore, CUR-QUE-NV-WH showed efficacy against fluconazole-resistant Candida isolates as evidenced by MICs at least two times lower than those of fluconazole. Examination of skin permeation profiles using an in vitro Franz diffusion cell system revealed that curcumin and quercetin delivered by nanovesicles were released and accumulated in the skin; however, only quercetin could penetrate through the skin layers. Collectively, our results demonstrate that CUR-QUE-NV-WH has potent antifungal activity against Candida isolates and might be a topical treatment, which warrants its further investigation as a novel antifungal agent.     

Anti-inflammatory effects of intravenous methotrexate associated with lipid nanoemulsions on antigen-induced arthritis

OBJECTIVE:To test the hypothesis that intravenous use of methotrexate associated with lipid nanoemulsions can achieve superior anti-inflammatory effects in the joints of rabbits with antigen-induced arthritis compared with commercial methotrexate.METHODS:Arthritis was induced in New Zealand rabbits sensitized with methylated bovine serum albumin and subsequently intra-articularly injected with the antigen. A nanoemulsion of methotrexate labeled with ³H-cholesteryl ether (4 mg/kg methotrexate) was then intravenously injected into four rabbits to determine the plasma decaying curves and the biodistribution of the methotrexate nanoemulsion by radioactive counting. Additionally, the pharmacokinetics of the methotrexate nanoemulsion were determined by high-pressure liquid chromatography. Twenty-four hours after arthritis induction, the animals were allocated into three groups, with intravenous injection with saline solution (n=9), methotrexate nanoemulsion (0.5 µmol/kg methotrexate, n=7), or commercial methotrexate (0.5 µmol/kg, n=4). The rabbits were sacrificed 24 h afterward. Synovial fluid was then collected for protein leakage and cell content analyses and synovial membranes were collected for histopathological analysis.RESULTS:The methotrexate nanoemulsion was taken up mainly by the liver and the uptake by arthritic joints was two-fold greater than that by control joints. The methotrexate nanoemulsion treatment reduced leukocyte influx into the synovial fluid by nearly 65%; in particular, mononuclear and polymorphonuclear cells were reduced by 47 and 72%, respectively. In contrast, cell influx was unaffected following treatment with commercial methotrexate. Protein leakage into the arthritic knees of the rabbits was also more limited following methotrexate nanoemulsion treatment than following commercial methotrexate treatment.CONCLUSIONS:The intravenous methotrexate nanoemulsion showed anti-inflammatory effects on the synovia of arthritic joints that were clearly superior to the effects of a commercial methotrexate preparation. This result is conceivably due to greater methotrexate uptake by the joints when the drug is associated with a nanoemulsion.     

The skin tissue is adversely affected by TNF-alpha blockers in patients with chronic inflammatory arthritis: a 5-year prospective analysis

OBJECTIVE:

We evaluated the incidence of and the main risk factors associated with cutaneous adverse events in patients with chronic inflammatory arthritis following anti-TNF-α therapy.

METHODS:

A total of 257 patients with active arthritis who were taking TNF-α blockers, including 158 patients with rheumatoid arthritis, 87 with ankylosing spondylitis and 12 with psoriatic arthritis, were enrolled in a 5-year prospective analysis. Patients with overlapping or other rheumatic diseases were excluded. Anthropometric, socioeconomic, demographic and clinical data were evaluated, including the Disease Activity Score-28, Bath Ankylosing Spondylitis Disease Activity Index and Psoriasis Area Severity Index. Skin conditions were evaluated by two dermatology experts, and in doubtful cases, skin lesion biopsies were performed. Associations between adverse cutaneous events and clinical, demographic and epidemiological variables were determined using the chi-square test, and logistic regression analyses were performed to identify risk factors. The significance level was set at p<0.05.

RESULTS:

After 60 months of follow-up, 71 adverse events (73.85/1000 patient-years) were observed, of which allergic and immune-mediated phenomena were the most frequent events, followed by infectious conditions involving bacterial (47.1%), parasitic (23.5%), fungal (20.6%) and viral (8.8%) agents.

CONCLUSION:

The skin is significantly affected by adverse reactions resulting from the use of TNF-α blockers, and the main risk factors for cutaneous events were advanced age, female sex, a diagnosis of rheumatoid arthritis, disease activity and the use of infliximab.     

Macrophage activation syndrome in a child with systemic juvenile rheumatoid arthritis

Macrophage activation syndrome (MAS) is a rare and potentially fatal complication of rheumatic disorders in children. We describe a 13-month-old boy in whom MAS developed as a complication of systemic juvenile rheumatoid arthritis (S-JRA). He suffered from fever and generalized rash followed by multiple joints swelling for four months before admission. Physical examination revealed cervical lymphadenopathy and hepatosplenomegaly. Laboratory findings were: abnormal liver enzymes, increased triglyceride and ferritin levels, coagulopathies resembling disseminated intravascular coagulation, anemia and thrombocytopenia. Hyperplasia of hemophagocytic macrophages was remarkable in his bone marrow. Methylprednisolone and cyclosporin therapy resulted in clinical and laboratory improvements. This is the third case of MAS associated with S-JRA in Koreans, and the first one, in which hemophagocytic macrophages were proven in bone marrow.     

Ⅱ型胶原诱导的类风湿关节炎模型的制作

Ⅱ型胶原诱导的类风湿关节炎模型CIA模型是目前最为理想的类风湿关节炎动物模型。受诸多因素影响，模型制作难度较大，成功率不高。结合参考国内外大量文献，本室多年研究经验，从动物品系的选择，胶原的配制和准备，注射的部位和方法，评价的指标等方面为CIA模型的制作提供了参考。     

The genetic pathogenesis,diagnosis and therapeutic insight of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease that causes chronic inflammation of the joints. RA is a heterogeneous disorder caused by an abnormal autoimmune response triggered by the complex interactions of genetic and environmental factors that contribute to RA etiology. However, its underlying pathogenic mechanisms are yet to be fully understood. In this review, I provide an overview of the pathogenesis, diagnosis and therapeutic insight in the clinical management of RA in light of the recent updates to classification criteria and recent discoveries of genetic loci associated with susceptibility for RA.     

Diagnostic performances of anti-cyclic citrullinated peptides antibody and antifilaggrin antibody in Korean patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology. We studied the diagnostic performances of anti-cyclic citrullinated peptides antibody (anti-CCP) assay and recombinant anti-citrullinated filaggrin antibody (AFA) assay by enzyme linked immunosorbent assay (ELISA) in patients with RA in Korea. Diagnostic performances of the anti-CCP assay and AFA assay were compared with that of rheumatoid factor (RF) latex fixation test. RF, anti-CCP, and AFA assays were performed in 324 RA patients, 251 control patients, and 286 healthy subjects. The optimal cut off values of each assay were determined at the maximal point of area under the curve by receiver-operator characteristics (ROC) curve. Sensitivity (72.8%) and specificity (92.0%) of anti-CCP were better than those of AFA (70.3%, 70.5%), respectively. The diagnostic performance of RF showed a sensitivity of 80.6% and a specificity of 78.5%. Anti-CCP and AFA showed positivity in 23.8% and 17.3% of seronegative RA patients, respectively. In conclusion, we consider that anti-CCP could be very useful serological assay for the diagnosis of RA, because anti-CCP revealed higher diagnostic specificity than RF and AFA at the optimal cut off values and could be performed by easy, convenient ELISA method.     

类风湿性关节炎患者外周血细胞内IFN-γ和IL-4的三色流式分析

目的　用全血在单个细胞水平上研究类风湿性关节炎 (RA)患者TH1 TH2 细胞因子分泌模式及其与疾病活动程度的关系。方法　用三色流式细胞术检测RA患者外周血细胞内细胞因子IFN γ和IL 4的表达情况。结果　RA患者外周血IFN γ 细胞百分率及IFN γ /IL 4 细胞比值比健康人明显增高 ,IFN γ /IL 4 比值与患者Stoke指数呈正相关 (r=0 .86 10 ,P <0 .0 1)。结论　RA患者外周血中细胞因子分泌模式朝TH1 偏移 ,IFN γ /IL 4 比值与疾病活动性相关 ,TH1 TH2 平衡在RA发病机理及疾病进程中起重要作用     

Bucillamine-induced pemphigus vulgaris in a patient with rheumatoid arthritis and polymyositis overlap syndrome

Bucillamine is a disease modifying anti-rheumatic drug, structurally similar to D-penicillamine. Although D-penicillamine-induced pemphigus has been not infrequently demonstrated, pemphigus associated with bucillamine was rarely reported. We describe a patient complicating pemphigus vulgaris after bucillamine treatment in rheumatoid arthritis (RA) and polymyositis (PM) overlap syndrome. PM and RA overlap syndrome was diagnosed three years ago and bucillamine was administrated for 20 months. Skin lesions including erythematous flaccid blisters on her chest, axillae, and back were occurred and were compatible with pemphigus vulgaris by typical pathology. Withdrawal from bucillamine and prednisolone treatment made rapid improvement of pemphigus lesions.     

血清抗肽酰基精氨酸脱亚氨酶4抗体检测在类风湿关节炎诊断中的意义

目的比较类风湿关节炎(rheumatoid arthritis,RA)患者血清中抗肽酰基精氨酸脱亚氨酶4(PADI4)抗体水平和其它风湿病组及正常对照组间的差异,以评估其在RA诊断中的价值。方法采用酶联免疫吸附法(enzyme-linked immunosorbentassay,ELISA)检测患者血清中抗PADI4抗体水平,并研究其与RA患者DAS28评分、抗CCP抗体、抗角蛋白抗体(anti-keratinantibody,AKA)、类风湿因子(rheumatoid factor,RF)等指标的相关性。结果RA患者血清中抗PADI4抗体阳性率为47%,明显高于其它风湿性疾病患者和健康对照组(P<0.05)。抗PADI4抗体对RA诊断的敏感性为43%,特异性为92%。相关性分析显示抗PADI4抗体水平与DAS28评分、抗CCP抗体无相关性(r=-0.025,P=0.82;r=-0.058,P=0.60)。RF阴性患者PADI4抗体阳性50%;AKA阴性的患者PADI4抗体阳性43%;抗CCP抗体阴性的患者抗PADI4抗体阳性60%。结论RA患者血清中抗PADI4抗体有较高的诊断价值,特别有助于RF、抗CCP...     

类风湿关节炎滑膜组织及关节液中DcR3表达的研究

目的:观察研究人诱骗受体3(DcR3)在类风湿关节炎(RA)关节液及滑膜组织中的表达及其与滑膜炎性病变程度的相关性.方法:用免疫组织化学的方法对12例RA患者、6例骨关节炎(OA)患者及4例无关节病变的骨折患者滑膜组织中DcR3的表达进行描述分析,并对DcR3表达情况与RA患者滑膜炎性病变程度相关性进行分析.同时用ELISA的方法检测了26例RA及19例OA患者关节液中DcR3的表达.结果:DcR3在RA滑膜组织主要分布于血管翳周围炎性细胞及部分滑膜细胞中,DcR3阳性细胞数约为72％.OA滑膜组织细胞中DcR3也呈现少量的阳性表达,但与RA比较阳性程度较弱,阳性细胞数量较少:对DcR3表达与RA滑膜炎性程度的相关性分析发现,DcR3与RA滑膜炎性程度呈正相关(r=0.832,P＜0.01),同时发现RA患者关节液中表达也明显高于OA患者.结论:DcR3在RA滑膜组织炎性细胞及滑膜细胞上的异常表达可能是其参与RA滑膜炎及滑膜组织侵袭等病理过程,从而导致滑膜损伤的一个重要机制.     

Increased risk of depression in patients with rheumatoid arthritis: a seven-year population-based cohort study

OBJECTIVE:

Rheumatoid arthritis (RA) is a costly and crippling autoimmune disease that can lead to the development of depression, contributing to suboptimal clinical outcomes. However, no longitudinal studies have identified an association between rheumatoid arthritis and subsequent depression. This study aimed to investigate the incidence and risk factors of depression among RA patients in Taiwan.

METHODS:

Using Taiwan''s National Health Insurance Research Database, we identified 3,698 newly diagnosed RA patients aged 18 years or older, together with 7,396 subjects without RA matched by sex, age and index date, between 2000 and 2004. The incidence of depression and the risk factors among RA cases were evaluated using Cox proportional-hazard regression.

RESULTS:

The incidence of depression was 1.74-fold greater in the RA cohort than in the non-RA cohort (11.80 versus 6.89 per 1,000 person-years; p<0.01). Multivariate analysis showed that RA subjects who were female, were older, or had comorbidities such as stroke, chronic kidney disease, or cancer had a significantly greater risk of depression compared with those without these conditions.

CONCLUSION:

This population-based cohort study showed a strong relationship between RA and a subsequent risk of depression. The findings could be beneficial to healthcare providers for identifying individuals with a higher predisposition for depression, thereby possibly facilitating the provision of an appropriate rehabilitation intervention after RA onset to support the patient''s adaptation.     

Maillard Reaction,mitochondria and oxidative stress: Potential role of antioxidants

Glycation and oxidative stress are two important processes known to play a key role in complications of many disease processes. Oxidative stress, either via increasing reactive oxygen species (ROS), or by depleting the antioxidants may modulate the genesis of early glycated proteins in vivo. Maillard Reactions, occur in vivo as well as in vitro and are associated with the chronic complications of diabetes, aging and age-related diseases. Hyperglycaemia causes the autoxidation of glucose, glycation of proteins, and the activation of polyol metabolism. These changes facilitate the generation of reactive oxygen species and decrease the activity of antioxidant enzymes such as Cu,Zn-superoxide dismutase, resulting in a remarkable increase of oxidative stress. A large body of evidence indicates that mitochondria alteration is involved and plays a central role in various oxidative stress-related diseases. The damaged mitochondria produce more ROS (increase oxidative stress) and less ATP (cellular energy) than normal mitochondria. As they are damaged, they cannot burn or use glucose or lipid and cannot provide cell with ATP. Further, glucose, amino acids and lipid will not be correctly used and will accumulate outside the mitochondria; they will undergo more glycation (as observed in diabetes, obesity, HIV infection and lipodystrophia). The objective of this paper is to discuss how to stop the vicious circle established between oxidative stress, Maillard Reaction and mitochondria. The potential application of some antioxidants to reduce glycation phenomenon and to increase the antioxidant defence system by targeting mitochondria will be discussed. Food and pharmaceutical companies share the same challenge, they must act now, urgently and energetically.     

Macrophage activation syndrome in juvenile rheumatoid arthritis successfully treated with cyclosporine A: a case report

Macrophage activation syndrome (MAS) is one of the serious complications of juvenile rheumatoid arthritis (JRA) and recently, cyclosporine A has been found to be effective in patients with corticosteroid-resistant MAS. A 29-yr-old male was admitted with high fever and jaundice for one month. He was diagnosed as juvenile arthritis 16 yr ago. Physical and laboratory results showed hepatosplenomegaly, high fever, pancytopenia and impaired liver and renal function tests, elevated triglyceride and serum ferritin levels. Bone marrow biopsy showed hyperplasia of histiocytes with active hemophagocytosis. He was diagnosed as MAS associated with juvenile rheumatoid arthritis and managed with high-dose corticosteroids initially, but clinical symptoms and laboratory findings did not improve immediately. Finally, he completely recovered after treatment with cyclosporine A (3 mg/kg/day).     

Cyclophilin A may contribute to the inflammatory processes in rheumatoid arthritis through induction of matrix degrading enzymes and inflammatory cytokines from macrophages

Cyclophilin A (CypA) levels increase in the sera and synovial fluids of rheumatoid arthritis (RA) patients, but the cell types expressing CypA and the function of CypA in the pathogenesis of RA are not known yet. Immunohistochemistry analyses revealed high level CypA staining in the macrophages in the lining layers of human RA and osteoarthritis synovium. Low level CypA staining was also detected in endothelial cells, lymphocytes, and smooth muscle cells in RA synovium. Further investigation of the CypA function using monocyte/macrophage cell lines revealed that CypA induced expression of cytokine/chemokines such as TNF-alpha, IL-8, MCP-1, and IL-1beta and matrix metalloproteinase (MMP)-9 through a pathway that is dependent on NFkappaB activation. Furthermore, MMP-9 staining pattern overlapped with that of CypA in both RA and OA synovium. Our data suggest that CypA may stimulate macrophages to degrade joint cartilage via MMP-9 expression and promote inflammation via pro-inflammatory cytokine secretion.     

Etanercept-induced systemic lupus erythematosus in a patient with rheumatoid arthritis

Tumor necrosis factor (TNF) is known to play a critical role in the pathogenesis of rheumatoid arthritis (RA). Etanercept is a recombinant soluble fusion protein of TNF alpha type II receptor and IgG, which acts as a specific TNF-alpha antagonist. Anti-TNF-alpha therapy has been an important advance in the treatment of RA. However, induction of autoantibodies in some proportion of patients treated with TNF alpha inhibitors raised concerns for development of systemic autoimmune diseases such as systemic lupus erythematosus (SLE). Although new autoantibody formation is common with anti-TNF alpha therapy, there are only rare reports of overt SLE, most of which manifested without major organ involvement and resolved shortly after discontinuation of the therapy. We describe a 55-yr-old Korean woman who developed overt life threatening SLE complicated by pneumonia and tuberculosis following etanercept treatment for RA. This case is to our knowledge, the first report of etanercept-induced SLE in Korea.     

Non-coding RNA network associated with obesity and rheumatoid arthritis

Obesity causes epigenetic alterations mediated by non-coding RNAs (ncRNAs) that increase susceptibility to autoimmune and inflammatory pathways. Obese individuals with rheumatoid arthritis (RA) are particularly affected, with worse clinical outcomes and treatment responses. In order to identify micro RNAs (miRNAs) and long ncRNAs (lncRNAs) that may influence RA development, progression, treatment efficacy, and clinical outcomes in obese individuals, we systematically screened PubMed, Web of Science, and Scopus databases for articles on these topics, published in the last decade. We ended up with 38 of initially 1110 documents and found that both obesity and RA share dysregulated expression of miR-21, miR-143, miR-146a, miR-155 miRNAs, H19, and HOTAIR lncRNAs (all but H19, up-regulated). With one exception (H19 and BMI in brown fat tissue), they correlated positively with clinical measures and disease activity. H19 and HOTAIR regulate 24 miRNAs, some differentially expressed in the investigated diseases. Both regulate miR-143-3p. We also investigated eleven GWAS-identified SNVs found in exonic lncRNA regions (there were none in exonic miRNA genes). Eight were associated with RA and three with obesity-related traits, seven change binding sites for miRNAs, especially on LINC01184 and GATA3-AS1, four were associated with gene expression in adipocytes (including LINC01184) and two may also change the secondary structure of ENSG00000284825 and LINC02656. These ncRNAs compose a unique regulatory network in obese RA patients, compiled for the first time in this review, which we suggest as future therapeutic targets in these simultaneous conditions.     

Ultrasonographic findings of the shoulder in patients with rheumatoid arthritis and comparison with physical examination

The objectives of this study were: 1) to identify the ultrasonographic (US) abnormalities and 2) to compare the findings of physical examination with US findings in rheumatoid arthritis (RA) patients with shoulder pain. We studied 30 RA patients. Physical examination was performed systemically as follows: 1) area of tenderness; 2) range of passive and active shoulder motion; 3) impingement tests; 4) maneuvers for determining the location of the tendon lesions. US investigations included the biceps, the supraspinatus, infraspinatus, and subscapularis tendons; the subacromial-subdeltoid bursa; and the glenohumeral and acromioclavicular joints. Thirty RA patients with 35 painful and 25 non-painful shoulders were examined. The range of motion affected the most by shoulder pain was abduction. The most frequent US finding of shoulder joint was effusion in the long head of the biceps tendon. Among the rotator cuff tendons, subscapularis was the most frequently involved. Tendon tear was also common among non-painful shoulders. Physical examination used for the diagnosis of shoulder pain had low sensitivity and specificity for detecting abnormalities in the rheumatoid shoulder joint. In conclusion, US abnormalities showed frequent tendon tears in our RA patients. Physical examination had low sensitivity and specificity for detecting rotator cuff tear in the rheumatoid shoulder joint.     

云南地区汉族人群PSMB8、PSMB9及TAP2基因多态性与类风湿关节炎的关联研究

目的 研究云南汉族人群中PSMB8、PSMB9及TAP2基因多态性与类风湿关节炎(rheumatoid arthritis,RA)的相关性.方法 应用聚合酶链反应-限制性片段长度多态性法对177例RA患者及288名健康对照PSMB8基因的rs2071543、rs55745125、rs138635403位点和PSMB9基因的rs17587多态性位点进行基因分型,应用多聚酶链反应扩增阻碍系统法对TAP2基因的rs2228396多态性位点进行基因分型.计算基因型及等位基因频率.采用Epi Info 7软件计算上述多态位点在RA组及正常对照组之间的比值比(OR值).结果 rs138635403及rs17587位点的等位基因及基因型频率在RA组和对照组间差异有统计学意义(P＜0.05),其中RA组rs17587的GG基因型频率(0.672)高于对照组(0.524)(OR=1.862,95％CI:1.261～2.749).结论 云南汉族人群PSMB9基因的rs17587位点多态性与RA存在关联.     

Contrasting diagnosis performance of forced oscillation and spirometry in patients with rheumatoid arthritis and respiratory symptoms

OBJECTIVES:

Pulmonary involvement in rheumatoid arthritis is directly responsible for 10% to 20% of all mortality. The best way to improve the prognosis is early detection and treatment. The forced oscillation technique is easy to perform and offers a detailed exam, which may be helpful in the early detection of respiratory changes. This study was undertaken to (1) evaluate the clinical potential of the forced oscillation technique in the detection of early respiratory alterations in rheumatoid arthritis patients with respiratory complaints and (2) to compare the sensitivity of forced oscillation technique and spirometric parameters.

METHODS:

A total of 40 individuals were analyzed: 20 healthy and 20 with rheumatoid arthritis (90% with respiratory complaints). The clinical usefulness of the parameters was evaluated by investigating the sensibility, the specificity and the area under the receiver operating characteristic curve. ClinicalTrials.gov: NCT01641705.

RESULTS:

The early adverse respiratory effects of rheumatoid arthritis were adequately detected by the forced oscillation technique parameters, and a high accuracy for clinical use was obtained (AUC>0.9, Se = 80%, Sp = 95%). The use of spirometric parameters did not obtain an appropriate accuracy for clinical use. The diagnostic performance of the forced oscillation technique parameters was significantly higher than that of spirometry.

CONCLUSIONS:

The results of the present study provide substantial evidence that the forced oscillation technique can contribute to the easy identification of initial respiratory abnormalities in rheumatoid arthritis patients that are not detectable by spirometric exams. Therefore, we believe that the forced oscillation technique can be used as a complementary exam that may help to improve the treatment of breathing disorders in rheumatoid arthritis patients.