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30001781 Pharmacotherapy Pearls in Rheumatology for the Care of Older Adult Patients: Focus on Oral 2018 Aug Providing safe and effective pharmacotherapy to geriatric patients with rheumatologic disorders is challenging. Multidisciplinary care involving rheumatologists, primary care physicians, and other specialties can optimize benefit and reduce adverse outcomes. Oral disease-modifying antirheumatic drugs, including methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, and the small molecule inhibitors tofacitinib and apremilast have distinctive monitoring requirements and specific adverse reaction profiles. This article provides clinically relevant pearls for use of these interventions in older patients.
30042601 Satisfaction and discontent of Polish patients with biological therapy of rheumatic diseas 2018 OBJECTIVES: Biologics are medications widely applied in the management of inflammatory rheumatic diseases. The drugs were found to be effective but their application is associated with some disadvantages. Medication with biologics is relatively expensive, and in Poland, it is carried out in specialized centers. The study was designed to evaluate various aspects of satisfaction and dissatisfaction of Polish patients treated with biologics. MATERIAL AND METHODS: An anonymous questionnaire was distributed in 23 Polish rheumatological centers involved in the treatment; 1212 returned questionnaires were used for analysis. Responses were received from 606 patients with rheumatoid arthritis, 427 with ankylosing spondylitis, 117 psoriatic arthritis, and 62 adult patients with juvenile idiopathic arthritis (in whom administration of the drugs had been introduced before they were 18 years old). The investigated group constituted about one-fifth of all rheumatic patients on biologics in Poland. RESULTS: A beneficial or very beneficial influence of the medication on the state of physical health was found mostly in patients with rheumatoid arthritis (51.3 and 30.5%) and ankylosing spondylitis (51.0 and 36.8%). Family life was improved by the treatment especially in patients with ankylosing spondylitis (40.7 and 35.6% beneficial and very beneficial, respectively), sleep quality and sexual life mostly in those with ankylosing spondylitis (beneficial/very beneficial influence 41.5/38.4, and 38.7/23.9, respectively). There was a rather small influence of biological treatment on the financial situation of the patients. In general, satisfaction with the treatment was evaluated as positive or very positive in 88% of all investigated patients.In a significant part of the patients, transportation to the medical center was considered as a disadvantage of the treatment. About one-third of the patients considered laboratory and imaging tests to be done before initiation of the medication as a difficulty, and for about 40% waiting time for qualification for the medication was a significant disadvantage. The route of drug administration was without importance for 4/5 of the patients. CONCLUSIONS: Summing up, the results were similar in the patients suffering from various diseases although those with psoriatic arthritis felt the highest satisfaction (possibly due to the positive aesthetic effect), and those with ankylosing spondylitis had significant improvement in sexual life (probably due to younger age). Relatively low satisfaction was found in patients with juvenile idiopathic arthritis. There was a small influence of medication on financial status of the patients. Application of biologics has few disadvantages and most of them are associated with the organization of health services (waiting time for the tests, transportation to the medical centers).
30120096 Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX 2018 Dec OBJECTIVES: Neutrophil extracellular traps (NETs) act in various rheumatic diseases. Although NET formation was originally described as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)-dependent pathway, it appears that there are also NOX-independent pathways of NET release. Currently, no tools are available that can discriminate between both NET-forming pathways. We aimed to develop a serological method allowing the discrimination between NETs generated through NOX-dependent or NOX-independent pathways. METHODS: Histones from in vitro generated NOX-dependent and NOX-independent NETs were characterised with a panel of lupus-derived antibodies against N-terminal histone tails using immunofluorescence microscopy, western blot and ELISA. NETs in patients with NET-associated diseases, that is, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriatic arthritis (PsA) and sepsis, were characterised in sandwich ELISAs employing antibodies against myeloperoxidase (MPO) and N-terminal histone tails as detecting and capturing antibodies, respectively. Functional responses of endothelial cells to NOX-dependent and NOX-independent NETs were assessed as well. RESULTS: Neutrophil elastase cleaves the N-terminal tails of core histones during NOX-dependent, but not during NOX-independent NET formation. Consequently, the detection of MPO-histone complexes with antibodies against N-terminal histone tails allows discrimination between NETs formed through a NOX-dependent or NOX-independent manner. Characterisation of in vivo circulating NETs revealed the presence of NOX-independent NETs in RA, SLE and sepsis, but NOX-dependent NETs in PsA. NOX-independent NETs displayed an increased capacity to activate endothelial cells when compared with NOX-dependent NETs. CONCLUSIONS: These results indicate heterogeneity in NET-forming pathways in vivo and highlight the need for disease-specific strategies to prevent NET-mediated pathology.
30484025 Multiple microlithiasis in bilateral parotid glands as the initial clinical manifestation 2018 Sep We report a rare case of Sjögren's syndrome (SS) with multiple microliths in the bilateral parotid glands. A 41-year-old man presented to our department with mild pain in the region of the right parotid gland. The dental examination was negative except for the parotid regions. The right region was moderately swollen and the left mildly swollen. Plain radiography revealed multiple calculi in the bilateral parotid glands. Ultrasonography showed heterogenic parenchyma, with microliths and cystic lesions in the parotid glands and heterogenic echotexture in the submandibular glands. Immunologic tests and the Schirmer test confirmed the diagnosis of SS. As the patient had no classic symptoms of SS, the bilateral multiple microliths were the first sign, facilitating the final diagnosis. Early diagnosis of SS is highly relevant because the proper therapy can be initiated. Adequate follow-up and, especially, control of the disease activity by identifying the predictive factors, are the primary objectives of SS management, enabling personalized treatment of this malignant disease. This case is a good example of how detection of calcifications in the bilateral parotid glands by plain radiography can help diagnose SS at an early stage.
31534486 Clinical outcomes and complications following primary total elbow arthroplasty using the L 2019 Oct BACKGROUND: The Latitude total elbow arthroplasty (TEA) is an implant with limited published data on its performance and outcomes. The aim of this study was to report the short-term outcomes of the Latitude TEA as well as to describe the radiographic outcomes and complications. METHODS: The Latitude was implanted in 20 patients (23 elbows) in a linked configuration. Patients were recalled to clinic for the assessment of their range-of-motion and compared to preoperative values. Administration of functional outcome measures was also performed. RESULTS: Mean follow-up was 4.7 years (range, 1 to 7.5 years) with four elbows requiring revision. The flexion-extension arc improved from 86.6 to 101.3 (range, 76 to 126) postoperatively (p = 0.04). The average Disabilities of the Arm, Shoulder, and Hand score was 28.1 (range, 5.8 to 50.4) and the average Mayo Elbow Performance Score was 89.6 (range, 76 to 100), with 83% of elbows scoring in the good or excellent range. Radiolucencies were detected in 60% of patients and 31% of these lucencies progressed in size at the time of follow-up. CONCLUSIONS: The Latitude prosthesis provides patients with favorable clinical outcomes with improvements in their range-of-motion and a complication rate comparable to other elbow arthroplasty implants.
30572138 Novel autoantibodies in Sjögren's syndrome: A comprehensive review. 2019 Feb Sjögren's syndrome is a systemic autoimmune disease characterized by immune- mediated injury of exocrine glands, as well as a diverse array of extraglandular manifestations. B cell over-activation is a key feature of the disease, attested by the wide spectrum of autoantibodies detected in these patients. Up to date, anti- Ro/SSA and anti-La/SSB antibodies are traditional biomarkers for disease classification and diagnosis. On the other hand, the detection of novel autoantibodies in SS has increased in the last years, opening a window of opportunity to denote particular stages of the disease, to establish clinical phenotypes, and to predict long-term complications such as lymphoma. For instance, anti-SP-1, anti-CA6 and anti-PSP antibodies occur in an earlier stage than anti-Ro/La antibodies, and may identify a subset of primary Sjögren's syndrome patients with mild or incomplete disease, whereas anti-cofilin-1, anti- alpha-enolase and anti-RGI2 antibodies are potential biomarkers of MALT lymphoma. Antibody detection is also important to elucidate new aspects of SS pathophysiology, and in the future to permit a phenotype-specific patient approach. Herein we review the literature regarding new autoantibodies in SS and attempt to dissect their usefulness as diagnostic tools, pathogenic role, identification of clinical phenotypes and as predictors of an overlap syndrome.
30233813 Development of clinically apparent synovitis: a longitudinal study at the joint level duri 2018 INTRODUCTION: Subclinical inflammation, detected by MRI, in patients with arthralgia is predictive for development of inflammatory arthritis (IA). However, within patients that develop IA, the course of inflammation at the joint level during this transition is unknown. This longitudinal study assessed progression of inflammation at the joint level. METHODS: 350 joints (unilateral metacarpophalangeals (MCPs), wrist, metatarsophalangeal (MTP) joints) of 35 patients presenting with clinically suspect arthralgia (CSA) that progressed to IA were studied at presentation with CSA and subsequently when clinical synovitis was first identified at joint examination (median time interval 17 weeks). At both time points, subclinical inflammation (bone marrow oedema, synovitis, tenosynovitis) was evaluated with MRI and joint examination was performed. RESULTS: At presentation with CSA, 71 joints showed subclinical inflammation. During progression to IA, 20% of these joints had resolution of inflammation, 60% had persistent inflammation and 20% progressed to clinical synovitis. Of all joints that had developed clinical synovitis (n = 45), no prior subclinical inflammation was detected in 69%. Similar results were observed for anticitrullinated protein antibodies (ACPA)-positive and ACPA-negative patients. CONCLUSIONS: This longitudinal study demonstrated moderate correlations between joints with subclinical inflammation and joints that developed clinical synovitis. These data imply that IA development is a more systemic rather than a locally outgrowing process.
30225546 Differentiating Disease Flare From Infection: A Common Problem in Rheumatology. Do 18F-FDG 2018 Sep 17 PURPOSE OF REVIEW: Fever is common within rheumatology but it is often challenging to identify its source. To do so correctly is paramount in patients with an underlying inflammatory condition receiving immunosuppressive therapy. This review article looks at the available evidence and merits of both 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scans and new proposed biomarkers in determining the cause of fever within rheumatology. RECENT FINDINGS: 18F-FDG PET/CT scans are already an established tool in the detection and diagnosis of malignancy and are emerging for use in fever of unknown origin. More recently, they have been used to identify rheumatological causes of fever such as large vessel vasculitis and adult-onset Still's disease. Within these conditions, biomarkers such as procalcitonin and presepsin may help to differentiate endogenous from exogenous pyrogens. 18F-FDG PET/CT scanning shows promise in locating the source of pyrogens and may be superior to other conventional forms of imaging. As evidence and test availability increases, its use is likely to become commonplace in the diagnostic work-up of fever. Once a source is located, selected biomarkers may be used to confirm a cause.
29649576 Epigenetic alterations in primary Sjögren's syndrome - an overview. 2018 Nov Primary Sjögren's syndrome (pSS) is a chronic autoimmune rheumatic disease characterized by inflammation of exocrine glands, mainly salivary and lacrimal glands. In addition, pSS may affect multiple other organs resulting in systemic manifestations. Although the precise etiology of pSS remains elusive, pSS is considered to be a multi-factorial disease, where underlying genetic predisposition, environmental factors and epigenetic mechanisms contribute to disease development. Epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, may constitute a dynamic link between genome, environment and phenotypic manifestation by their modulating effects on gene expression. A growing body of studies reporting altered epigenetic landscapes in pSS suggests that epigenetic mechanisms play a role in the pathogenesis of pSS, and the reversible nature of epigenetic modifications suggests therapeutic strategies targeting epigenetic dysregulation in pSS. This article reviews our current understanding of epigenetic mechanisms in pSS and discusses implications for novel diagnostic and therapeutic approaches.
28811201 The unmet need in rheumatology: Reports from the targeted therapies meeting 2017. 2018 Jan The 19th annual international Targeted Therapies meeting brought together over 100 leading basic scientists and clinical researchers from around the world in the field of immunology, molecular biology and rheumatology and other specialties. During the meeting, breakout sessions were held consisting of 5 disease-specific groups with 20-40 experts assigned to each group based on clinical or scientific expertise. Specific groups included: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, systemic lupus erythematous, connective tissue diseases (e.g. Sjogren's syndrome, Systemic sclerosis, vasculitis including Bechet's and IgG4 related disease), and a basic science immunology group spanning all of the above clinical domains. In each group, experts were asked to consider and update previously identified unmet needs in 3 categorical areas: basic/translational science, clinical science and therapeutic development, and clinical care. Overall, similar primary unmet needs were identified within each disease foci, and several additional needs were identified since the time of last year's congress. Within translational/basic science, the need for better understanding the heterogeneity within each disease was highlighted so that predictive tools for therapeutic responses can be developed. Within clinical science and therapeutic trials, a strong focus was placed upon the need to identify pre-clinical states of disease allowing prevention in those at risk. The ability to cure remains perhaps the ultimate unmet need. Further, the need to develop new and affordable therapeutics, as well as to conduct strategic trials of currently approved therapies was again highlighted. Within the clinical care realm, improved co-morbidity management and patient-centered care were identified as unmet needs. Lastly, it was strongly felt there was a need to develop a scientific infrastructure for well-characterized, longitudinal cohorts paired with biobanks and mechanisms to support data-sharing. This infrastructure could facilitate many of the unmet needs identified within each disease area.
29755657 Regulatory effect of anti-gp130 functional mAb on IL-6 mediated RANKL and Wnt5a expression 2018 Apr 17 We investigated the effect on rheumatoid arthritis (RA) of an anti-gp130 monoclonal antibody (mAb) and its mechanism using RA fibroblast-like synoviocytes (FLS) and a collagen antibody-induced arthritis (CAIA) mouse model. We determined the interleukin 6 (IL-6), IL-6 receptor α (IL-6Rα), gp130, receptor activator of nuclear factor κB ligand (RANKL), matrix metalloproteinase 3 (MMP3), TIMP metallopeptidase inhibitor 1 (TIMP1), and Bcl-2 levels in RA and osteoarthritis (OA) serum and synovial fluid. RA FLS were cultured with or without IL-6/IL-6Rα; WNT5A and RANKL levels were detected. We generated an anti-gp130 mAb (M10) with higher affinity and specificity, blocked IL-6 signaling with it, and assessed its effects on the CAIA model, WNT5A and RANKL expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation. The IL-6 signaling system in patients with RA was increased; RANKL, MMP3, TIMP1, and Bcl-2 in RA bone were elevated. IL-6/IL-6Rα increased RA FLS WNT5A and RANKL expression. M10 ameliorated arthritis in the CAIA model, and inhibited RANKL, WNT5A, and Bcl-2 expression in RA FLS by blocking IL-6 signaling, likely via Janus kinase-STAT3 pathway downregulation. The IL-6-soluble IL-6Rα-gp130 complex is hyperactive in RA and OA. M10 may be the basis for a novel RA treatment drug.
30488000 Predicting achievement of the treatment targets at 6 months from 3-month response levels i 2018 OBJECTIVE: When initiating a new therapy in patients with rheumatoid arthritis (RA), current treatment recommendations suggest escalating therapy in case of poor clinical improvement by 3 months or if the treatment target has not been reached by 6 months. We investigated which disease activity improvement levels at 3 months predicted achievement of the treatment targets at 6 months in a real-life clinical setting. METHODS: We included 1610 patients with RA enrolled in the NOR-DMARD study between 2000 and 2012. Analyses were performed for the total group of patients and repeated for subgroups stratified by baseline disease activity, disease duration or treatment with methotrexate or a tumour necrosis factor inhibitor. We used a diagnostic test approach to explore the associations between 3-month response and 6-month outcome. RESULTS: Not achieving 50% improvement in Simplified Disease Activity Index (SDAI) by 3 months significantly decreased the likelihood of reaching remission at 6 months in all subgroups (negative likelihood ratios (LRs-) 0.15-0.36). Patients with high disease activity when initiating treatment were likely to fail reaching remission if they achieved less than SDAI 70% response by 3 months (LR- 0.25 and negative predictive value 0.98). Achieving a major response (SDAI 85%) at 3 months significantly increased the likelihood of reaching remission at 6 months (LRs+ 6.56). CONCLUSION: Levels of 3-month disease activity improvement can inform clinicians when deciding to continue or adjust ongoing therapy in a treat-to-target strategy aiming for remission or low disease activity within 6 months. The required levels of 3-month improvement varied with baseline disease activity.
29713281 The Effectiveness and Safety of Tripterygium wilfordii Hook. F Extracts in Rheumatoid Arth 2018 Objective: To conduct a meta-analysis of the effectiveness and safety of Tripterygium wilfordii Hook. F (TwHF) extracts for the treatment of rheumatoid arthritis (RA). Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, Medline, CNKI, SinoMed and WanFang Library till 12 July 2017. All included studies were analyzed with the use of the Review Manager 5.2 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Results: Fourteen randomized controlled trials (RCTs) were identified. TwHF extracts provided a statistically significant improvement in grip strength (GS), swelling joint count (SJC) and morning stiffness (MS) compared with placebo (P < 0.001). The meta-analysis showed significant differences between TwHF extract-treated group and the DMARDs group in GS, MS, C-reactive protein (CRP), and tender joint count (TJC) (P < 0.05), aside from ESR and SJC (P > 0.05). The pooled results also displayed significant differences between the combination of TwHF extracts with DMARDs and the DMARDs alone group in ESR, CRP, SJC, and TJC (P ≤ 0.05). For the safety analysis, two trials favored TwHF extract-treatment and one trial favored non-TWHF extract-treatment in AEs (P < 0.05). Eleven trials showed no statistically significant differences between TwHF extract-treated group and the DMARDs group (P > 0.05). Conclusions: The findings of this systematic review with meta-analysis indicate that TwHF extracts provides statistically significant and clinically important improvement in RA symptoms and has an acceptable safety profile.
29662880 Common Evaluations of Disease Activity in Rheumatoid Arthritis Reach Discordant Classifica 2018 OBJECTIVES: The classification of disease activity states in rheumatoid arthritis (RA) can be achieved through disease activity indices, such as the Disease Activity Score in 28 joints erythrocyte sedimentation rate (DAS28-ESR), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Subjective measurements, such as patient reported outcomes have been incorporated into several of these indices alongside more objective assessments, such as increases in the ESR and C-reactive protein. Moreover, while they use similar criteria, different indices weight these criteria to different extents. Therefore, the classifications based on each evaluation may not always be the same. We aim to compare the performance of the three indices and their individual components in two different populations. METHODS: Data from Dutch and Portuguese adherent centers were extracted from the METEOR database, a multinational collaboration on RA. We included a total of 24,605 visits from Dutch centers (from 5,870 patients) and 20,120 visits from Portuguese centers (from 3,185 patients). We compared the disease activity states as evaluated by the DAS28-ESR, CDAI, and SDAI across the two populations. In addition, we analyzed the individual components of each evaluation, including their respective contributions to the outcome, in each population. RESULTS: We found significant differences in the disease activity states classified with the DAS28-ESR between the two populations. SDAI and CDAI had more congruous results. While the proportion of visits to Dutch and Portuguese centers that were classified as "in remission" was very similar between the CDAI and SDAI, the DAS28-ESR gave discordant results. Dutch patients had lower ESRs, which is more heavily weighted in the DAS28-ESR. In addition, even though the mean physicians' global assessment values did not vary significantly for Dutch vs Portuguese physicians, we found that doctors at Portuguese centers overall scored the physician's global assessment lower than Dutch physicians for patient visits classified by disease activity state. CONCLUSION: While the CDAI and SDAI assigned disease activity states that were largely similar, the DAS28-ESR was often discordant across the two populations. Moreover, we found that physicians, more than patients, evaluated disease activity differently among the Portuguese and Dutch populations.
29588576 A 4-year non-randomized comparative phase-IV study of early rheumatoid arthritis: integrat 2018 BACKGROUND: While disease-modifying antirheumatic drugs (DMARDs) are a mainstay of therapy for rheumatoid arthritis (RA), some patients with early RA refuse DMARDs. In anthroposophic medicine (AM), a treatment strategy for early RA without DMARDs has been developed. Preliminary data suggest that RA symptoms and inflammatory markers can be reduced under AM, without DMARDs. PATIENTS AND METHODS: Two hundred and fifty-one self-selected patients aged 16-70 years, starting treatment for RA of <3 years duration, without prior DMARD therapy, participated in a prospective, non-randomized, comparative Phase IV study. C-patients were treated in clinics offering conventional therapy including DMARDs, while A-patients had chosen treatment in anthroposophic clinics, without DMARDs. Both groups received corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Primary outcomes were intensity of RA symptoms measured by self-rating on visual analog scales, C-reactive protein, radiological progression, study withdrawals, serious adverse events (SAE), and adverse drug reactions in months 0-48. RESULTS: The groups were similar in most baseline characteristics, while A-patients had longer disease duration (mean 15.1 vs 10.8 months, p<0.0001), slightly more bone destruction, and a much higher proportion of women (94.6% vs 69.7%, p<0.0001). In months 0-12, corticosteroids were used by 45.7% and 81.6% (p<0.0001) and NSAIDs by 52.8% and 68.5% (p=0.0191) of A- and C-patients, respectively. During follow-up, both groups not only had marked reduction of RA symptoms and C-reactive protein, but also some radiological disease progression. Also, 6.2% of A-patients needed DMARDs. Apart from adverse drug reactions (50.4% and 69.7% of A- and C-patients, respectively, p=0.0020), none of the primary outcomes showed any significant between-group difference. CONCLUSION: Study results suggest that for most patients preferring anthroposophic treatment, satisfactory results can be achieved without use of DMARDs and with less use of corticosteroids and NSAIDs than in conventional care. LIMITATION: Because of the non-randomized study design, with A-patients choosing anthroposophic treatment, one cannot infer how this treatment would have worked for C-patients.
29312834 Joint damage is amplified in rheumatoid arthritis patients with positive thyroid autoantib 2018 BACKGROUND: Autoimmune thyroid disease (AITD), which is characterized by an increased presence of thyroid autoantibodies (TAbs), such as antibodies against thyroid peroxidase (TPOAbs) and antibodies against thyroglobulin (TgAbs), has been reported to be associated with rheumatoid arthritis (RA) because AITD and RA both involve autoimmunity. However, few data are available on the incidence of TAbs in Chinese RA patients, and studies on the association between TAbs and joint damage as well as synovitis in RA patients remain sparse. Here, we aimed to evaluate the incidence of TAbs in a consecutive Chinese RA cohort and to investigate whether the elevated presence of TAbs is associated with joint damage and synovitis in RA patients. METHODS: A total of 125 hospitalized RA patients were consecutively recruited. Clinical data and available synovial tissues were collected at baseline, and TAbs and thyroid function were detected by chemiluminescent immunoassay. Patients who tested positive for TPOAbs or TgAbs were classified as the TAbs-positive group, and patients who tested positive for neither TPOAbs nor TgAbs were recruited as the TAbs-negative group. Disease activity was assessed using DAS28-ESR (the disease activity score in 28 joints and including the erythrocyte sedimentation rate). X-ray assessment of the hand/wrist was performed according to the Sharp/van der Heijde-modified Sharp score (mTSS), and patients with an mTSS score >10 were defined as having radiographic joint damage (RJD). Serial tissue sections were stained immunohistochemically for CD3, CD15, CD20, CD34, CD38, and CD68, and synovitis were assessed according to Krenn's synovitis score. RESULTS: A total of 44 (35%) patients were positive for either TPOAbs or TgAbs. Importantly, there was a significantly greater percentage of patients with RJD in the TAbs-positive group versus the TAbs-negative group (68% vs. 42%, p = 0.005). Compared with the TAbs-negative group, significantly more CD38-positive plasma cells infiltrated the TAbs-positive synovium, and a higher percentage of patients with high-grade synovitis were observed in the TAbs-positive group (5/8, 63% vs. 5/14, 36%). Moreover, RF positivity and disease activity indicators, including TJC28, DAS28-ESR, and CDAI, were significantly higher in the TAbs-positive group (all p < 0.05). Adjusted logistic regression analysis revealed that positive TAbs (OR 2.999, 95% CI [1.301-6.913]; p = 0.010) and disease duration (OR 1.013, 95% CI [1.006-1.019]; p < 0.001) were independently associated with RJD, and an odds ratio of 2.845 (95% CI [1.062-7.622]) was found for RJD in women with positive TAbs (n = 37) compared with those without TAbs (n = 59) (p = 0.038). CONCLUSION: Our data showed that joint destruction was amplified in RA patients with an elevated presence of TAbs, which supports the importance and necessity of TAbs and thyroid function screening and monitoring in RA patient management in clinical practice.
30783431 Downregulated MEG3 participates in rheumatoid arthritis via promoting proliferation of fib 2019 Mar Maternally expressed gene 3 (MEG3) in rheumatoid arthritis (RA) and its underlying mechanism were explored. Synovial tissues from 10 RA patients and 10 controls were collected to detect MEG3 expression in fibroblast-like synoviocytes (FLS). The relationship between MEG3 expression and TNF-α was analyzed. After MEG3 knockdown by lentivirus transfection, cell cycle, proliferation, apoptosis, invasion and secretion of inflammatory factors were detected. Furthermore, the effect of MEG3 on STAT3 and PI3K/AKT pathways was explored. MEG3 was downregulated in RA patients, and exogenous TNF-α treatment could decrease MEG3 expression. After transfection with lentivirus, downregulated MEG3 led to FLS proliferation and secretion of inflammatory cytokines, IL-6 and IL-8, improved the invasive ability and inhibited apoptosis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results revealed that downregulated MEG3 increased the expression levels of MMP2 and MMP9. Western blotting results showed that downregulated MEG3 activated STAT3 and PI3K/AKT pathways. Downregulated MEG3 was able to promote proliferation and invasion, and inhibit apoptosis of FLS via STAT3 pathway.
30201867 The Protective Effect of a Long-Acting and Multi-Target HM-3-Fc Fusion Protein in Rheumato 2018 Sep 10 Current treatment of rheumatoid arthritis (RA) is limited by relative shortage of treatment targets. HM-3 is a novel anti-RA polypeptide consisting of 18 amino acids with integrin αVβ3 and α5β1 as targets. Previous studies confirmed that HM-3 effectively inhibited the synovial angiogenesis and the inflammatory response. However, due to its short half-life, the anti-RA activity was achieved by frequent administration. To extend the half-life of HM-3, we designed a fusion protein with name HM-3-Fc, by combination of modified Fc segment of immunoglobulin 4 (IgG4) with HM-3 polypeptide. In vitro cell experiments demonstrated that HM-3-Fc inhibited the proliferation of splenic lymphocytes and reduced the release of TNF-α from macrophages. The pharmacodynamics studies on mice paw in Collagen-Induced Arthritis (CIA) model demonstrated that HM-3-Fc administered once in 5 days in the 50 and 25 mg/kg groups, or once in 7 days in the 25 mg/kg group showed a better protective effect within two weeks than the positive control adalimumab and HM-3 group. Preliminary pharmacokinetic studies in cynomolgus confirmed that the in vivo half-life of HM-3-Fc was 15.24 h in comparison with 1.32 min that of HM-3, which demonstrated that an Fc fusion can effectively increase the half-life of HM-3 and make it possible for further reduction of subcutaneous injection frequency. Fc-HM-3 is a long-acting active molecule for RA treatment.
32254445 Polypeptide nano-Se targeting inflammation and theranostic rheumatoid arthritis by anti-an 2018 Jun 7 Rheumatoid arthritis (RA) is a chronic autoimmune disease and there is a lack of effective treatments. Nitric oxide (NO) plays an important role in inflammatory diseases, but the exact mechanism is not clear. We selected ruthenium complexes [Ru(Phen)(2)(4idip)](ClO(4))(2) (Ru) to induce the generation of NO in cells. SeNPs-PEG-RGD@Ru (Se@RuNPs) were prepared by modifying selenium nanoparticles with PEG, RGD and Ru. Se@RuNPs can promote uptake by Human Umbilical Vein Endothelial Cells (HUVECs) and trace the internalization and biodistribution. Experiments showed that Se@RuNPs target the abundant neovascular network of inflammatory sites to induce NO and promote the apoptosis of HUVECs and inhibit the growth of new vessels in local tissue. Moreover, NO activates autophagy by modulating signaling pathways related to AMPKα and mTOR, increasing the flux of autophagy, inhibiting the activity of NF-κB-p65, and modulating the levels of inflammatory cytokines. The exact mechanism of the inflammatory response regulated by NO is revealed. Histopathological analysis showed that the Se@RuNPs effectively reduced synovitis, cartilage corrosion and inflammatory cytokine expression levels, achieving satisfactory therapeutic effects. These unexpected results provide an effective strategy for target treatment of RA.
29375576 M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocyte 2017 OBJECTIVES: We investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC) differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate OC differentiation in vitro. RESULTS: Forty RA patients and 20 healthy donors were included. Twenty-two patients (55%) were anticitrullinated protein antibody (ACPA) positive. The median M1/M2 ratio was 0.59 (0.31-1.11, interquartile range). There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated OC number in vitro in RA patients (ρ = 0.81, p < 0.001). The ACPA-positive patients had significantly higher M1/M2 ratios in vivo (p = 0.028) and significantly greater numbers of OCs in vitro (p = 0.005) than the ACPA-negative patients. Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to in vitro osteoclastogenesis. RA patients with M1/M2 ratios >1 (having relatively more M1 monocytes) had higher C-reactive protein and erythrocyte sedimentation rates than RA patients with M1/M2 ratios ≤1. M1-dominant monocytes in vitro produced higher concentrations of interleukin-6 upon stimulation with lipopolysaccharide than M2 monocytes. CONCLUSION: M1/M2 monocytes imbalance strongly contributes to osteoclastogenesis of RA patients. Our findings cast M1 and M2 monocyte subsets in a new light as a new target of treatments for RA to prevent progression of osteoclastic bone destruction.