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ID PMID Title PublicationDate abstract
28107661 Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamet 2017 Apr The transcription factor NF-kB plays a pivotal role in the pathogenesis of rheumatoid arthritis. Here we attempt to slow arthritis progression by co-delivering the glucocorticoid dexamethasone (Dex) and small-interfering RNA targeting NF-kB p65 using our previously developed polymeric hybrid micelle system. These micelles contain two similar amphiphilic copolymers: polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). The hybrid micelles loaded with Dex and siRNA effectively inhibited NF-kB signaling in murine macrophages more efficiently than micelles containing either Dex or siRNA on their own. In addition, the co-delivery system was able to switch macrophages from the M1 to M2 state. Injecting hybrid micelles containing Dex and siRNA into mice with collagen-induced arthritis led the therapeutic agents to accumulate in inflamed joints and reduce inflammation, without damaging renal or liver function. Thus, blocking NF-kB activation in inflammatory tissue using micelle-based co-delivery may provide a new approach for treating inflammatory disease.
28352356 Investigation of the effect of phlomisoside F on complete Freund's adjuvant-induced arthri 2017 Feb Phlomis younghusbandii Mukerjee (Labiatae) has been reported to be effective in the treatment of rheumatoid arthritis (RA). In the present study, the anti-inflammatory and anti-arthritic effects of phlomisoside F (PF), isolated from P. younghusbandii Mukerjee (Labiatae), were investigated in male Wistar rats subjected to carrageen-induced paw edema and complete Freund's adjuvant (CFA)-induced arthritis. Arthritis scores were evaluated by a 5-point ordinal scale (scores 0-4). Expression levels of TNF-α, IL-1β, IL-6, IL-10, COX-2 and 5-LOX were determined via ELISA and western blot assays. Subsequent to establishing the edema and arthritis models, oral administration of PF (5, 10 and 20 mg/kg) significantly inhibited mean edema rate, compared with the control group in carrageenan-induced paw edema assay. In addition, administration of PF (5, 10 and 20 mg/kg/day) for 28 days markedly exhibited an anti-arthritic activity by offsetting the body weight loss, inhibiting the paw edema, reducing the arthritis scores and the indices of thymus and spleen, inhibiting the expression levels of TNF-α, IL-1β, IL-6, COX-2 and 5-LOX, and increasing the expression of IL-10, when compared with the respective control group in CFA-induced arthritis assay. In conclusion, PF is a valuable anti-arthritic constituent of P. younghusbandii, and the present study results suggest that this herb may be used in the treatment of RA.
28315676 The Major Histocompatibility Complex Class III Haplotype Ltab-Ncr3 Regulates Adjuvant-Indu 2017 May Rheumatoid arthritis is a complex disease associated with >100 risk loci, with the strongest association from the major histocompatibility complex (MHC) region. Here, we analyzed a new genetic association in the MHC class-III region (MHC-III) using adjuvant- and antigen-induced arthritis models. In addition, we used models for multiple sclerosis for comparison and dissected the MHC-III-mediated mechanisms of importance for antibody and T-cell responses to antigens. With the use of a panel of MHC-III recombinant inbred strains, we found that the 33-kb Ltab-Ncr3 haplotype in MHC-III was linked to the induction of arthritis with incomplete Freund's adjuvant, with similar effects in arthritis induced by several oil adjuvants (hexadecane, heptadecane, squalene, arlacel). Adoptive T-cell transfer experiment showed that this arthritis-protective effect operated during the priming of T cells by controlling their arthritogenicity. Interestingly, Ltab-Ncr3 did not regulate autoimmune diseases induced with tissue-specific antigens emulsified in adjuvant oils, such as collagen-induced arthritis or experimental autoimmune encephalomyelitis. No effect on antibody or T-cell response to tissue antigens in the Ltab-Ncr3 could be demonstrated. The finding that Ltab-Ncr3 is specific in regulating adjuvant-induced arthritis but not antigen-induced autoimmunity, and with unique effects on priming of autoreactive and arthritogenic T cells, provides new insight for understanding the regulation of autoimmune diseases.
28903427 Ginsenoside Rg1 attenuates adjuvant-induced arthritis in rats via modulation of PPAR-γ/NF 2017 Aug 15 Ginsenoside Rg1, the main active compound in Panax ginseng, has already been shown to have anti-inflammatory effects. However, the protective effects of Rg1 on rheumatoid arthritis (RA) remain unclear. The aim of the present study was to investigate the effects and mechanisms of Rg1 on adjuvant-induced arthritis (AIA) in rats. AIA rats were given Rg1 at doses of 5, 10, and 20 mg/kg intraperitoneally for 14 days to observe the anti-arthritic effects. The results showed that Rg1 significantly alleviated joint swelling and injuries. Rg1 can also significantly reduce the level of TNF-α and IL-6, increase PPAR-γ protein expression, inhibit IκBα phosphorylation and NF-κB nuclear translocation in the inflammatory joints of AIA rats and RAW264.7 cells stimulated by lipopolysaccharide (LPS). The results indicate that Rg1 has therapeutic effects on AIA rats, and the mechanism might be associated with its anti-inflammatory effects by up-regulating PPAR-γ and subsequent inhibition of NF-κB signal pathway.
29387048 Infectious Agents and Inflammation: The Role of Microbiota in Autoimmune Arthritis. 2017 In higher vertebrates, mucosal sites at the border between the internal and external environments, directly interact with bacteria, viruses, and fungi. Through co-evolution, hosts developed mechanisms of tolerance or ignorance toward some infectious agents, because hosts established "gain of function" interactions with symbiotic bacteria. Indeed, some bacteria assist hosts in different functions, among which are digestion of complex carbohydrates, and absorption and supply of vitamins. There is no doubt that microbiota modulate innate and acquired immune responses starting at birth. However, variations in quality and quantity of bacterial species interfere with the equilibrium between inflammation and tolerance. In fact, correlations between gut bacteria composition and the severity of inflammation were first described for inflammatory bowel diseases and later extended to other pathologies. The genetic background, environmental factors (e.g., stress or smoking), and diet can induce strong changes in the resident bacteria which can expose the intestinal epithelium to a variety of different metabolites, many of which have unknown functions and consequences. In addition, alterations in gut permeability may allow pathogens entry, thereby triggering infection and/or chronic inflammation. In this context, a local event occurring at a mucosal site may be the triggering cause of an autoimmune reaction that eventually involves distant sites or organs. Recently, several studies attributed a pathogenic role to altered oral microbiota in rheumatoid arthritis (RA) and to gut dysbiosis in spondyloarthritis (SpA). There is also growing evidence that different drugs, such as antibiotics and immunosuppressants, can influence and be influenced by the diversity and composition of microbiota in RA and SpA patients. Hence, in complex disorders such RA and SpA, not only the genetic background, gender, and immunologic context of the individual are relevant, but also the history of infections and the structure of the microbial community at mucosal sites should be considered. Here the role of the microbiota and infections in the initiation and progression of chronic arthritis is discussed, as well as how these factors can influence a patient's response to synthetic and biologic immunosuppressive therapy.
27748629 TNF-alpha antagonist induced lupus on three different agents. 2017 Mar Tumor necrosis factor alpha (TNF alpha) antagonists are biologic agents used in the management of inflammatory conditions such as rheumatoid arthritis, seronegative spondyloarthropathies and inflammatory bowel disease. These agents have been recently shown to cause a syndrome called anti-TNF induced lupus (ATIL), a rare condition which has similar clinical manifestations to idiopathic systemic lupus erythematosus (SLE). Given that extra-intestinal manifestations of inflammatory bowel disease include arthritis, it can be difficult to separate arthritis due to underlying disease from drug-induced arthritis. We present a case of a 28-year-old female with Crohn's disease, who developed disabling arthritis as a clinical manifestation of ATIL following treatment with three anti-TNF agents, namely infliximab, adalimumab and certolizumab.
28673091 Review of Primary Cutaneous Mucinoses in Nonlupus Connective Tissue Diseases. 2018 Jan/Feb Lichen myxedematosus is an idiopathic, cutaneous mucinosis with 2 clinicopathologic subsets. There is the generalised papular and sclerodermoid form, more properly termed scleromyxedema, and the localised papular form. We report the first case, to our knowledge, of lichen myxedematosus in association with rheumatoid arthritis as well as a case in association with dermatomyositis. An up-to-date literature review on cutaneous mucinoses and connective tissue diseases, excluding the common association of primary and secondary mucinoses with systemic lupus erythematosus, was also performed.
28178437 Gerald Loewi: A Major Contributor to the New Era of Rheumatology Thinking. 2017 Jan 30 Dr Gerald Loewi was Senior Research Scientist and Consultant Pathologist at the Medical Research Council (MRC) Rheumatism Research Unit at Taplow, England and subsequently the MRC Clinical Research Centre, Harrow, England. An immunologist with a background in pathology, he made major contributions to our understanding of the immunopathology of rheumatoid arthritis and other rheumatic disorders. With his colleagues, he developed a more sophisticated concept of what were initially thought to be primary autoimmune or degenerative diseases but are now recognized as much more complex disease processes. He was one of the first to initiate close collaboration between clinicians and scientists in rheumatology research and practice.
28235443 IL-6 Differs from TNF-α: Unpredicted Clinical Effects Caused by IL-6 Blockade in Psoriasi 2017 Mar IL-6 is a pleiotropic proinflammatory cytokine that is elevated in serum and skin lesions of patients with psoriasis. Anti-IL-6 therapies, however, which are effective for rheumatoid arthritis, are either ineffective for psoriasis or can induce new-onset psoriasis-like disease. Fritz et al. provide a potential explanation for these clinical observations by examining IL-17C-driven psoriasis-like disease in mice with an IL-6-deficient genetic background. These mice displayed slower onset skin disease initially, but then worsened over time, suggesting that a lack of IL-6 led to compensatory proinflammatory effects by other cytokines, which eventually worsened the psoriatic inflammation.
29469734 Clinical resolution of pemphigus vulgaris on rituximab. 2017 Sep 15 Although significant progress has been made for the treatment of pemphigus vulgaris (PV) with rituximab (RTX), a consensus remains to be determined for standard treatment protocol, regarding optimal dosing, infusion regimen, and use of concomitant immunotherapy to achieve safe, effective, and rapid clinical response. We describe a patient with pemphigus vulgaris treated with high dose rituximab with the rheumatoid arthritis protocol along with intravenous immunoglobulin therapy. This case provides evidence towards the growing body of research needed to modify and improve treatment for pemphigus using rituximab.
29422854 Reversible Cerebral Vasoconstriction Syndrome due to Atovaquone. 2017 Sep A 72-year-old Japanese woman with rheumatoid arthritis whose activity decreased with previous treatments had recurrent thunderclap headaches during an atovaquone regimen for the treatment of pneumocystis pneumonia. The recurrent headaches disappeared after discontinuation of the drug. Brain magnetic resonance images showed multiple cerebral vasoconstrictions of cerebral arteries with vasogenic cerebral white matter edema, which diminished several weeks later. We diagnosed the patient's headaches as reversible cerebral vasoconstriction syndrome due to atovaquone.
29354462 Arthroscopic Arthrodesis of the First Metatarsophalangeal Joint in Hallux Valgus Deformity 2017 Oct Arthrodesis of the first metatarsophalangeal joint is indicated for hallux valgus associated with degenerative changes, severe deformity, or rheumatoid arthritis and those for whom primary hallux valgus surgery has failed. Open approach requires extensive soft tissue dissection. The purpose of this Technical Note was to report the details of arthroscopic arthrodesis of the first metatarsophalangeal joint in severe and rigid hallux valgus deformity. This is a combination of endoscopic lateral release of the first metatarsophalangeal joint and arthroscopic arthrodesis of the joint. Endoscopic lateral release will convert the deformity into a flexible one and facilitate a subsequent arthrodesis procedure.
29622995 Increased arterial stiffness in rheumatoid arthritis and Its relation to disease activity: 2018 Mar BACKGROUND: Rheumatoid arthritis (RA) is associated with elevated plasma level of inflammatory markers. Chronic inflammation is known to predispose to endothelial dysfunction and increased arterial stiffness, which is an important marker of subclinical atherosclerosis and increased cardiovascular risk. OBJECTIVE: The aim is to test for the relationship between disease activity and arterial stiffness in RA patients. METHODS: The study included 90 RA patients, at different grades of disease activity and 45 healthy subjects, as a control group. Patients were subjected to full history taking and clinical examination, laboratory investigations including serum lipid profile and high sensitivity CRP (hs-CRP) measurements and plain x-rays of hands and feet. Modified Larsen method was used as radiographic scoring method. Disease activity score (DAS 28) was used for assessment of disease activity. Transthoracic echocardiography was performed to detect aortic stiffness parameters. Duplex ultrasound imaging of both common carotid arteries was performed to measure carotid stiffness parameters. RESULTS: The mean age of RA patients was 39.86 ± 9.39 years and most of them (83.3%) were females. RA patients had higher carotid stiffness index compared to control group patients (8.57 ± 4.83 vs 4.08 ± 1.13, p < .001). Very poor correlation was found between DAS-28 and aortic (r = 0.1, p = .28) as well as carotid (r = 0.05, p = .7) stiffness indices. No statistically significant correlation was found between hs-CRP and aortic stiffness index (r = 0.64, p = .55). Disease duration was significantly correlated to intima-media thickness (p < .01) as well as with other carotid stiffness parameters. Age also show a statistically significant positive correlation with carotid stiffness parameters. CONCLUSION: RA is associated with increased arterial stiffness, a well-recognized marker of cardiovascular risk. This is attributed to the inflammatory nature of the disease. It seems that the most important factors determining stiffness are patients' age and duration of illness.
29067495 Short-term application of tocilizumab during myocardial infarction (STAT-MI). 2018 Jan Acute myocardial infarction (MI) occurs when blood supply falls below critical levels and normal cellular maintenance mechanisms fail. Interleukin-6 (IL-6) is a proinflammatory cytokine released in MI and associated with poor clinical outcomes. Tocilizumab (TCZ) is a humanized monoclonal antibody against the IL-6 receptor. In a randomized, double-blinded, placebo controlled trial we assigned subjects admitted with MI a single TCZ dose of 162 mg subcutaneously vs. placebo in addition to standard of care medications and interventions. Primary outcome was a change in major adverse cardiac events (MACE) 30 days after enrollment. Secondary outcomes assessed changes in CRP 30 days after enrollment, changes in QT/QTc, and monitoring for trends in adverse events. Futility analysis was performed as subject enrollment slowed and no trends were noted in either the primary or secondary outcomes. Twenty-eight subjects were enrolled; 12 to TCZ and 16 to placebo. No statistically significant differences were noted between study arms regarding demographics, comorbidities, or medical/interventional therapies received. No statistically significant differences in MACE were observed. CRP increased after administration of TCZ but this was not statistically significant. No adverse events or safety signals were observed. Though futility analysis suggested that the primary outcome was not likely achievable as our recruitment slowed, we did not observe any adverse events or safety trends. Building on this information, future studies should be conducted to assess a true benefit from TCZ as adjunct therapy for MI. The work reported herein was performed under United States Air Force Surgeon General approved Clinical Investigation FKE20140029 and has been registered at ClinicalTrials.gov under identifier NCT02419937.
29029901 Spectrum of orocutaneous disease associations: Immune-mediated conditions. 2017 Nov There are a number of diseases that manifest both on the skin and the oral mucosa, and therefore the importance for dermatologists in clinical practice to be aware of these associations is paramount. In the following continuing medical education series, we outline orocutaneous disease associations with both immunologic and inflammatory etiologies.
28935290 Objectives and methodology of BIOBADASER phase iii. 2019 Jul OBJECTIVE: Describe the objectives, methods and results of the first year of the new version of the Spanish registry of adverse events involving biological therapies and synthetic drugs with an identifiable target in rheumatic diseases (BIOBADASER III). METHODOLOGY: Multicenter prospective registry of patients with rheumatic inflammatory diseases being treated with biological drugs or synthetic drugs with an identifiable target in rheumatology departments in Spain. The main objective of BIOBADASER Phase III is the registry and analysis of adverse events; moreover, a secondary objective was added consisting of assessing the effectiveness by means of the registry of activity indexes. Patients in the registry are evaluated at least once every year and whenever they experience an adverse event or a change in treatment. The collection of data for phase iii began on 17 December 2015. RESULTS: During the first year, 35 centers participated. The number of patients included in this new phase in December 2016 was 2,664. The mean age was 53.7 years and the median duration of treatment was 8.1 years. In all, 40.4% of the patients were diagnosed with rheumatoid arthritis. The most frequent adverse events were infections and infestations. CONCLUSIONS: BIOBADASER Phase III has been launched to adapt to a changing pharmacological environment, with the introduction of biosimilars and small molecules in the treatment of rheumatic diseases. This new stage is adapted to the changes in the reporting of adverse events and now includes information related to activity scores.
28386643 [Obesity and autoimmunity : Adipose tissue as an immune organ?]. 2017 May Adipose tissue possesses crucial immunological features in the development of comorbidities of obesity. Complex interactions between the metabolic system and cells of the immune system are the cause but are not fully understood. Autoimmune diseases might therefore be influenced by obesity. Epidemiological studies provide evidence of only a modest association between obesity and the development of rheumatoid arthritis and psoriatic arthritis. In obesity the course of inflammatory rheumatic diseases is aggravated, as subjectively measured by activity parameters; however, laboratory parameters show no differences and radiographic examinations reveal less bone destruction in obesity. Furthermore, there are indications for a poorer response to treatment especially with infliximab in patients with an increased body mass index (BMI). Weight loss has a positive effect on the course of joint diseases. Due to deficits in the currently available studies there is insufficient evidence to recommend individualization of treatment decisions based on the BMI.
28392572 An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T- 2018 Sep Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.
29423022 Comprehensive analysis of gene expression and DNA methylation datasets identify valuable b 2018 Jan 9 Rheumatoid arthritis (RA) represents a common systemic autoimmune disease which lays chronic and persistent pain on patients. The purpose of our study is to identify novel RA-related genes and biological processes/pathways. All the datasets of this study, including gene expression and DNA methylation datasets of RA and OA samples, were obtained from the free available database, i.e. Gene Expression Omnibus (GEO). We firstly identified the differentially expressed genes (DEGs) between RA and OA samples through the limma package of R programming software followed by the functional enrichment analysis in the Database for Annotation, Visualization and Integrated Discovery (DAVID) for the exploring of potential involved biological processes/pathways of DEGs. For DNA methylation datasets, we used the IMA package for their normalization and identification of differential methylation genes (DMGs) in RA compared with OA samples. Comprehensive analysis of DEGs and DMGs was also conducted for the identification of valuable RA-related biomarkers. As a result, we obtained 394 DEGs and 363 DMGs in RA samples with the thresholds of |log2fold change|> 1 and p-value < 0.05, and |delta beta|> 0.2 and p-value < 0.05 respectively. Functional analysis of DEGs obtained immune and inflammation associated biological processes/pathways. Besides, several valuable biomarkers of RA, including BCL11B, CCDC88C, FCRLA and APOL6, were identified through the integrated analysis of gene expression and DNA methylation datasets. Our study should be helpful for the development of novel drugs and therapeutic methods for RA.
29202589 Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive revie 2018 Jan Interstitial lung diseases (ILDs) are among the most serious complications associated with systemic rheumatic diseases, and lead to significant morbidity and mortality; they may also be the first manifestation of connective tissue diseases (CTDs). The aim of this narrative review is to summarise the data concerning the pathogenesis of CTD/ILD and its distinguishing features in different rheumatic diseseas. Areas covered: The pathogenesis, clinical aspects and treatment of ILD associated with rheumatic systemic diseases and CTDs were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1995 and February 2017 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: The management of CTD-ILD is challenging because of the lack of robust data regarding the treatments used, the heterogeneity of the diseases themselves, and the scarcity of well-defined outcome measures. Treatment decisions are often made clinically on the basis of functional, radiographic progression, and exacerbating factors such as age and the burden of comorbidities. Given the complexities of diagnosis and the paucity of treatment trials, the management of CTD patients with ILD requires multidisciplinary collaboration between rheumatologists and pulmonologists in CTD-ILD clinics.