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ID PMID Title PublicationDate abstract
30938274 Immunometabolism in rheumatoid arthritis. 2018 Sep Recent studies have revealed a relationship between cellular metabolism and cell function in immune cells. Cellular metabolism not only provides supplemental ATP, but also supports dynamic changes in cell proliferation and differentiation. For example, T cells exhibit subset-specific metabolic profiles, and require certain types of metabolism for their functions. Determining the metabolic profiles that support inflammatory immune responses may lead to novel treatment strategies for chronic inflammatory diseases such as rheumatoid arthritis (RA). However, the mechanisms by which metabolism modulates cell function have been unclear. Recent studies have begun to unveil unexpected non-metabolic functions for metabolic enzymes in the context of inflammation, including roles in signaling and gene regulation. Here we describe recent findings related to immunometabolism, the metabolome of RA patients, and the metabolically independent functions of glycolytic enzymes. We discuss how metabolic processes impact immune cells, especially T cells and fibroblast like synoviocytes, which are considered the orchestrators of autoimmune arthritis.
32185319 Canakinumab for refractory RA: a case report. 2018 Sep Rheumatoid arthritis is a common autoimmune disease leading often to joint destruction and reduced quality of life. We report a case of a young woman with rheumatoid arthritis with fever and rapid, destructive joint involvement verified with magnetic resonance imaging. She had failed therapy with methotrexate and leflunomide, anti-TNF, IL-6 inhibitor, B cell depletion and IL-1RA. Her laboratory results remained insignificant despite the aggressiveness of her disease. In this case, the patient only partly responded to anakinra but developed side effects, and therefore was switched to Canakinumab that led to sustained remission. There are no clear biomarkers or other clues in order to separate early in the beginning of the disease course if a polyarticular inflammatory spectrum can be IL-1β driven. The young age of the patient at onset of disease, its aggressive course, inflammatory fever without significant laboratory inflammatory markers but with polyarthritis affecting small joints, may raise the suspicion of an IL-1β-driven disease and alert the treating rheumatologist to the use of IL-1β inhibitors early in the disease course.
30190774 An elusive case of digital ischemia in a patient with Rheumatoid Arthritis. 2018 Jul Essential thrombocytosis (ET) has rarely been reported with autoimmune rheumatic disorders. We report a case of young female, diagnosed case of Rheumatoid arthritis (RA), who had been overlooked for her raised platelet counts. Later her symptoms of impending digital gangrene led to an active search for her thrombocytosis. JAK2 mutation came out to be positive and she was diagnosed as ET associated with RA. She was treated with Hydroxyurea and Aspirin, in addition to her RA treatment. Patient responded well to the treatment and her platelet counts have been gradually improved, however, she developed gangrene of toe, for which amputation of distal phalanx of toe and nail excision was done, later in the disease course.
30214869 Pericarditis-complicated takotsubo cardiomyopathy in a patient with rheumatoid arthritis. 2018 Aug A 64-year-old woman with medication-controlled rheumatoid arthritis (RA) was admitted to our hospital complaining of chest pains. An electrocardiogram showed elevated ST-segments in the inferior leads, and inverted T-waves in the left precordial leads. Left ventriculography demonstrated apical ballooning, and cardiac magnetic resonance imaging demonstrated apical ballooning of the left ventricle, and moderate pericardial effusion. The patient was diagnosed with takotsubo cardiomyopathy (TTC), complicated by pericarditis. In the literature, autoimmune disorders have been associated with TTC. We suggest that this patient's pericardial effusion was caused by TTC, and that her coexisting RA might have played a role in the etiology of the significant pericardial fluid accumulation.
28886220 Anti-inflammatory effects of polyphenols in arthritis. 2018 Mar Polyphenols have been extensively investigated with regard to their antioxidant, anti-inflammatory, and immunomodulant properties in many inflammatory chronic conditions. The aim of this review is to summarise how these compounds can modulate the inflammatory pathways which characterise the most prevalent arthropathies including osteoarthritis, rheumatoid arthritis and crystal-induced arthritis. Among polyphenols, epigallocatechin gallate, carnosol, hydroxytyrosol, curcumin, resveratrol, kaempferol and genistein have been the most widely investigated in arthritis. The most important results of the studies outlined in this article show how polyphenolic compounds are able to inhibit the expression and the release of a number of pro-inflammatory mediators and proteolytic enzymes, the activity of different transcriptional factors and the production of reactive oxygen species in vitro. Studies on animal models of rheumatoid arthritis, osteoarthritis and gout show interesting results in terms of reduced tissue damage, restored cartilage homeostasis, and decreased levels of uric acid, respectively. Despite the multiple protective effects of polyphenols, there are no dietary recommendations for patients affected by rheumatic diseases. Future studies, including intervention trials, should be conducted to determine the relevance of polyphenols consumption or supplementation in arthritis. © 2017 Society of Chemical Industry.
29868593 A Potential Benefit of "Balanced Diet" for Rheumatoid Arthritis. 2018 Although it is largely unknown how diet might modulate rheumatoid arthritis (RA), dietary interventions, including so-called "low-carbohydrate" diets, may be considered for RA patients because of the high incidence of cardiovascular comorbidity. However, it has been shown that restriction or skewed intake of particular nutrient may alter the components of the intestinal flora. Changes to the gut microbiota or dysbiosis may be relevant to the pathogenesis of RA because the gut microbiota is reported to regulate the T cell phenotype and T cell-mediated immunity. RA patients should be advised that a balanced diet that includes appropriate amounts of carbohydrate, especially dietary fiber, is important for maintaining the symbiosis of intestinal flora, which could be beneficial for preventing autoimmunity. The review attempts to focus current findings regarding the suggested relationship between diet-derived carbohydrate, gut microbiota, and the pathogenesis of RA.
30018955 The Role of Long Non-coding RNAs in the Pathogenesis of RA, SLE, and SS. 2018 Rheumatoid diseases are a group of systemic autoimmune diseases which affect multiple organs with largely unknown etiology. In the past decade, long non-coding RNAs (lncRNAs) have emerged as important regulators of biological processes and contribute deeply to immune cell development and immune responses. Substantial evidences have been accumulated showing that LncRNAs involved in the pathogenesis of the rheumatoid diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In this review, we summarize literature combined with bioinformatics methods to analyze the unique and common lncRNAs patterns in rheumatoid diseases and try to reveal the important function of lncRNAs in RA, SLE and SS.
29465367 Proprotein convertase enzyme FURIN is upregulated in primary Sjögren's syndrome. 2018 May OBJECTIVES: The proprotein convertase enzyme FURIN is a critical regulator of the anti-inflammatory TGFβ-1 cytokine and peripheral immune tolerance. In T cells, FURIN is co-regulated with IFN-γ and thus highly expressed in T helper 1 type cells. Previous studies have demonstrated that FURIN is upregulated in inflammatory conditions, including atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus. Here, we evaluated the levels of FURIN in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with primary Sjögren's syndrome (pSS) and in healthy controls. METHODS: FURIN plasma levels were determined by ELISA, and the mRNA expression in PBMCs was quantitated using qPCR. FURIN levels in the plasma were correlated with the clinical and demographic characteristics of the patients. RESULTS: FURIN was found to be significantly upregulated at both the protein and mRNA level in pSS patients compared to healthy controls. In pSS patients, high FURIN protein levels were significantly associated with elevated IFN-γ levels in the plasma as well as a longer duration of sicca symptoms in the eyes. pSS patients with high FURIN levels in their plasma showed a trend towards lower levels of serum beta-2 microglobulin, ESR and a lower systemic disease activity index ESSDAI. CONCLUSIONS: The proprotein convertase FURIN is significantly upregulated in pSS. Elevated FURIN levels associate with high levels of the Th1 type cytokine IFN-γ and long duration of dry eye symptoms. Patients with high FURIN levels show signs of lower disease activity suggesting that FURIN might have a protective role in pSS.
29687872 IKKε aggravates inflammatory response via activation of NF-κB in rheumatoid arthritis. 2018 Apr OBJECTIVE: Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease, whereas its cause still remains elusive. Typical pathological manifestations of RA include persistent synovitis and bone degeneration in the surrounding joints. Although the incidence of RA is high in population, currently there have been no effective cures for it. The purpose of this study is to investigate the therapeutic effects and main mechanism of IKKε (inhibitor of nuclear factor kappa-B kinase ε) in collagen II induced- Rheumatoid Arthritis (CIA) mice model. MATERIALS AND METHODS: IKKε-/- and wild-type (WT) littermate control mice were intraperitoneally injected with 5 mg/kg collagen II monoclonal antibody cocktail (Cab) for 5 days. After that, the nociception threshold and clinical rheumatoid arthritis articular damage score of mice were evaluated. After 5 days-CAb treatment, serum levels of a series of inflammatory cytokines including interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α) and interferon (IFN) were detected with enzyme-linked immunosorbent assay (ELISA) in both groups. Besides, Real-time reverse transcription polymerase chain reaction (Real-time RT-PCR) was used to evaluate the expression of these inflammatory cytokines in plantar tissues. In addition, Western blot was performed to investigate the protein levels of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B) signaling pathway. Moreover, WT mice receiving CAb were further applied with or without IKK inhibitor amlexanox (25 mg/kg) to investigate the expression of the above-mentioned inflammatory cytokines. RESULTS: Our work showed that IKKε-/- mice with CIA displayed less nociception and suppressed inflammatory response than WT mice. Meanwhile, the clinical rheumatoid arthritis articular damage scores were significantly decreased in IKKε-/- mice. The levels of TNF-α, IL-1β, IL-6 in serum and plantar tissues in IKKε-/- mice were significantly lower than those in WT mice. Besides, NF-κB expression in IKKε-/- mice was significantly decreased. Similarly, the same phenotype was observed in WT mice administrated with IKKε inhibitor amlexanox as that of IKKε-/- mice, indicating that inflammatory and nociception responses were remarkably decreased than those of the negative controls. CONCLUSIONS: IKKε plays an important role in promoting nociception and inflammatory response in CIA. Our research demonstrated that knockout of IKKε may serve as a new direction for clinical prevention and treatment of rheumatoid arthritis. IKKε inhibitor amlexanox may become a new drug for the treatment of rheumatoid arthritis.
29358281 Visualising the interaction of CD4 T cells and DCs in the evolution of inflammatory arthri 2018 Apr OBJECTIVES: Successful early intervention in rheumatoid arthritis (RA) with the aim of resetting immunological tolerance requires a clearer understanding of how specificity, cellular kinetics and spatial behaviour shape the evolution of articular T cell responses. We aimed to define initial seeding of articular CD4(+) T cell responses in early experimental arthritis, evaluating their dynamic behaviour and interactions with dendritic cells (DCs) in the inflamed articular environment. METHODS: Antigen-induced arthritis was used to model articular inflammation. Flow cytometry and PCR of T cell receptor (TCR) diversity genes allowed phenotypic analysis of infiltrating T cells. The dynamic interactions of T cells with joint residing DCs were visualised using intravital multiphoton microscopy. RESULTS: Initial recruitment of antigen-specific T cells into the joint was paralleled by accumulation of CD4(+) T cells with diverse antigen-receptor expression and ability to produce tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) on mitogenic restimulation. A proportion of this infiltrate demonstrated slower motility speeds and engaged for longer periods with articular DCs in vivo. Abatacept treatment did not disrupt these interactions but did reduce T cell expression of inducible costimulatory (ICOS) molecule. We also demonstrated that non-specific CD4(+) T cells could be recruited during these early articular events. CONCLUSIONS: We demonstrate that CD4(+) T cells engage with articular DCs supporting antigen specific T cell reactivation. This cellular dialogue can be targeted therapeutically to reduce local T cell activation.
29445306 Repository corticotropin injection in patients with rheumatoid arthritis resistant to biol 2018 INTRODUCTION: Although synthetic and biologic disease-modifying antirheumatic drugs are available, many patients with rheumatoid arthritis have a difficult-to-control disease and need other treatment options. Repository corticotropin injection (RCI) may alleviate symptoms and exacerbations in patients with refractory disease. METHODS: Nine patients with refractory rheumatoid arthritis were included in this study. Patients were maintained on their baseline therapies with a minimum of 7.5 mg prednisone daily. RCI was given daily at 40 U for 7 days. Patients who had an adequate disease response were given 40 U twice weekly through Week 12. For patients who had inadequate disease response, the dose was increased to 80 U daily for 7 days, followed by 80 U twice weekly through Week 12. RESULTS: The primary endpoint was >1.2 point reduction in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12. Secondary endpoints were improvements in Health Assessment Questionnaire-Disease Index and Functional Assessment of Chronic Illness Therapy scores. Six of the nine patients met the primary endpoint. The average change in DAS28-CRP from baseline to Week 12 was numerically greater with 40 U than with 80 U RCI. Functional Assessment of Chronic Illness Therapy and Health Assessment Questionnaire-Disease Index improved as early as Week 1, and the improvements remained throughout treatment. CONCLUSION: There was no association between cortisol levels and low-dose RCI response. No serious adverse events occurred. RCI produced a clinically meaningful reduction in markers of disease activity, improved health-related quality of life, and a favorable safety profile. The response rate to RCI was substantial and shows promise in this difficult-to-treat population.
35129928 2018 Jul Analgesics (including NSAIDs, paracetamol and opioids) are sometimes used on top of disease-modifying treatments for relief of pain and stiffness in people with rheumatoid arthritis (RA) whose symptom control is not adequate. The previous guideline recommended analgesics other than NSAIDs to reduce a person’s need for long term treatment with NSAIDs, and included cautionary recommendations about how and when NSAIDs should be used. However, the evidence on analgesia other than NSAIDs in the previous guideline was highly limited, meaning there is uncertainty about the effectiveness of different types of analgesia in rheumatoid arthritis. Given this uncertainty, the committee wished to update these recommendations to reflect the latest and most robust clinical evidence. The committee agreed to use the term NSAIDS to include both selective and non-selective COX II inhibitors.
30740246 From neuroimunomodulation to bioelectronic treatment of rheumatoid arthritis. 2018 May Neuronal stimulation is an emerging field in modern medicine to control organ function and reestablish physiological homeostasis during illness. The nervous system innervates most of the peripheral organs and provides a fine tune to control the immune system. Most of these studies have focused on vagus nerve stimulation and the physiological, cellular and molecular mechanisms regulating the immune system. Here, we review the new results revealing afferent vagal signaling pathways, immunomodulatory brain structures, spinal cord-dependent circuits, neural and non-neural cholinergic/catecholaminergic signals and their respective receptors contributing to neuromodulation of inflammation in rheumatoid arthritis. These new neuromodulatory networks and structures will allow the design of innovative bioelectronic or pharmacological approaches for safer and low-cost treatment of arthritis and related inflammatory disorders.
30023327 Enhanced Lymphatic Uptake of Leflunomide Loaded Nanolipid Carrier via Chylomicron Formatio 2018 Jun Purpose: The current study aims the lymphatic delivery of leflunomide loaded nanostructured lipid carriers (LNLC) for the treatment of rheumatoid arthritis, mainly focussed to enhance the lymphatic delivery via chylomicron formation, improved bioavailability and reduced systemic toxicity. Methods: Melt emulsification ultra-sonication method was used to formulate the nanostructured lipid carrier (NLC) containing leflunomide. Four batches were prepared by using various concentration of surfactants (tween 80 and poloxmer 188) and lipid mixtures (stearic acid and oleic acid). All the formulations were studied for various physiochemical properties Results: The formulation with increased concentration of lipid and surfactants showed highest entrapment efficiency (93.96 ± 0.47%) and better drug release (90.35%) at the end of 48 hrs. In vivo tests were carried out to determine the antiarthritic potential of the formulation in Sprague-dawley rats for a duration of 30d. The effect was evaluated by measuring the reduction in knee thickness. LNLC showed a marked reduction in inflammation compared to standard drug. Intestinal lymphatic uptake studies of LNLC were performed by intraduodenal administration and compared with leflunomide drug solution. The mesenteric lymph node was analysed by HPLC method and the concentration of drug was estimated. It showed that LNLC having highest uptake (40.34μg/ml) when compared with leflunomide drug solution (10.04μg/ml). Radiographic analysis and histopathological studies showed the formation of healthy cartilage after treatment period. Conclusion: The results suggested that LNLC has the potential to reduce the systemic toxicities associated with conventional therapy along with improved efficacy in the treatment of rheumatoid arthritis.
29901003 An Extensive Study of the Functional Polymorphisms of Kinin-Kallikrein System in Rheumatoi 2018 Mar OBJECTIVES: This study aims to examine the following functional polymorphisms in rheumatoid arthritis (RA) susceptibility: (i) the 587C>T of kininogen gene, (ii) the 287 bp Alu repeat insertion of angiotensin converting enzyme gene, (iii) the 9 bp insertion of bradykinin receptor 2 gene, (iv) the -58T>C of bradykinin receptor 2 gene, and (v) the -699G>C of bradykinin receptor 1 gene. PATIENTS AND METHODS: The study included 136 RA patients (27 males; 109 females; mean age 60.8 years; range 39 to 75 years) and 149 ethnic matching controls (30 males, 119 females; mean age 56.2 years; range 35 to 78 years). Polymerase chain reaction coupled with restriction assay was performed for 587C>T, -58T>C, and -699G>C. RESULTS: Rheumatoid arthritis patients and controls carried the wild type allele of 587C>T; therefore, produced the high molecular weight kininogen. No significant difference was observed in genotype or allele distribution of the studied functional polymorphisms between RA patients and controls. CONCLUSION: Kinin-kallikrein system related genes might not be major RA susceptibility loci.
31453131 A novel bioavailable hydrogenated curcuminoids formulation (CuroWhite™) improves symptom 2019 Oct Rheumatoid arthritis (RA) is an inflammatory disease that cause chronic pain, disability and joint destruction. The present placebo controlled randomized study aimed to evaluate the efficacy of a novel hydrogenated curcuminoid formulation-CuroWhite™, in rheumatoid arthritis (RA) patients. Twenty four RA patients were randomized in 1:1:1 ratio to receive 250 mg, 500 mg CuroWhite or placebo as one capsule a day, over a period of three months. Improvement in the ACR response, changes in disease activity assessed using the DAS 28 score, change in physical function assessed on change in ESR, CRP, RF values were evaluated before and after the study. Results suggested that patients who received CuroWhite both low and high doses reported statistically significant changes in their clinical symptoms towards end of the study when compared with placebo. There were significant changes in DAS28 (50-64%) VAS (63-72%) ESR (88-89%), CRP (31-45%) RF (80-84%) values and ACR response for CuroWhite groups in comparison with placebo. Thus, CuroWhite acts as the analgesic and anti-inflammatory product for management of RA by the reduction of the inflammatory action which was confirmed by improvement in ESR, CRP, VAS, RF, DAS-28 and ACR responses. CuroWhite was significantly effective against RA with highly safe without serious side effects and well tolerated.
29899668 Retrocalcaneal Bursitis Precedes or Accompanies Achilles Tendon Enthesitis in the Early Ph 2018 The consecutive reports and stored images of ultrasound examinations for 100 symptomatic ankles of 74 patients with rheumatoid arthritis (RA) were reviewed for the presence or absence of retrocalcaneal bursitis (RCB) and Achilles tendon enthesitis (ATE). The ankles were classified into 4 categories based on the presence or absence of RCB or ATE. The number of RCB(-)/ATE(-), RCB(+)/ATE(-), RCB(+)/ATE(+), and RCB(-)/ATE(+) ankles was 62, 16, 12, and 10, respectively. When classifying patients into early RA and established RA, the percentage of RCB(-)/ATE(+) ankles with early RA was significantly lower than that with established RA (P = .00595). The disease duration was significantly longer in the RCB(-)/ATE(+) ankles than in the RCB(+)/ATE(-) ankles (median [interquartile range]: 15.29 [8.69] months vs 3.6 [3.06] months, P = .0247). It was speculated that RCB precedes or accompanies ATE in the early phase of RA, which suggests that entheseal inflammation in RA arises from synovial tissues.
30733840 Crosstalk between Fas and S1P(1) signaling via NF-kB in osteoclasts controls bone destruct 2019 Nov Rheumatoid arthritis (RA) mainly affects various joints of the body, including the temporomandibular joint (TMJ), and it involves an infiltration of autoantibodies and inflammatory leukocytes into articular tissues and the synovium. Initially, the synovial lining tissue becomes engaged with several kinds of infiltrating cells, including osteoclasts, macrophages, lymphocytes, and plasma cells. Eventually, bone degradation occurs. In order to elucidate the best therapy for RA, a comprehensive study of RA pathogenesis needs to be completed. In this article, we discuss a Fas-deficient condition which develops into RA, with an emphasis on the role of sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling which induces the migration of osteoclast precursor cells. We describe that Fas/S1P(1) signaling via NF-κB activation in osteoclasts is a key factor in TMJ-RA severity and we discuss a strategy for blocking nuclear translocation of the p50 NF-κB subunit as a potential therapy for attenuating osteoclastogenesis.
29765444 Sequentiality of treatment in the rheumatoid arthritis drug programme in the years 2009-20 2018 Apr Approximately 1% of the population suffers from rheumatoid arthritis (RA) worldwide (0.45% in Poland). The therapy consists of the use of disease-modifying antirheumatic drugs (DMARDs). Biologics are used in the form of the drug programme. Analysis of the NHF database demonstrated the sequence of conversion between drugs and time spent in a single treatment. In 2009, the patients would start the following treatments: adalimumab 5.8%; etanercept 14.4%; infliximab 23.1%; leflunomide 53.6%; rituximab 3%. After the first year 16% of patients changed therapy or abstained, and in the second year this situation affected 65% of patients. The following percentages maintained the same treatment in the last 6 years: infliximab 4%; adalimumab 15%; etanercept 21%; leflunomide on prescription was continued by 70%. Patients remain too long on the same therapy when it is inefficient. Achieving remission or low disease activity (DAS28 < 2.6) should take place within 6 months of starting therapy.
30155252 Lymphoproliferative disorder in an elderly rheumatoid arthritis patient after longterm ora 2018 Sep Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is frequently reported in the literature; however, its pathophysiology has not been fully elucidated to date. We herein describe a case of MTX-LPD that occurred after long-term treatment with oral MTX in a 67-year-old Japanese woman with rheumatoid arthritis (RA) who presented with generalized lymphadenopathy of the neck. The patient had been diagnosed with RA 24 years earlier, and had been on oral MTX for 20 years. The patient noticed a mass on her neck, which prompted a visit to our hospital. The mass was confirmed as diffuse large B-cell lymphoma by biopsy. MTX treatment was discontinued, which resulted in a reduction in the size of the mass and improvement of the patient's symptoms. Therefore, clinicians must be aware of MTX-LPD as a differential diagnosis for patients with rheumatological conditions on long-term MTX therapy presenting with signs and symptoms suggestive of lymphoma.