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ID PMID Title PublicationDate abstract
29148561 The role of IL-23 receptor signaling in inflammation-mediated erosive autoimmune arthritis 2018 Feb The IL-23/Th17 axis has been implicated in the development of autoimmune diseases, such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA). RA and PsA are heterogeneous diseases with substantial burden on patients. Increasing evidence suggests that the IL-23 signaling pathway may be involved in the development of autoimmunity and erosive joint damage. IL-23 can act either directly or indirectly on bone forming osteoblasts as well as on bone resorbing osteoclasts. As IL-23 regulates the activity of cells of the bone, it is conceivable that in addition to inflammation-mediated joint erosion, IL-23 may play a role in physiological bone remodeling. In this review, we focus on the role of IL-23 in autoimmune arthritis in patients and murine models, and provide an overview of IL-23 producing and responding cells in autoimmune arthritic joints. In addition, we discuss the role of IL-23 on bone forming osteoblasts and bone resorbing osteoclasts regarding inflammation-mediated joint damage and bone remodeling. At last, we briefly discuss the clinical implications of targeting this pathway for joint damage and systemic bone loss in autoimmune arthritis.
29773404 Large tibial geode, which developed several years after a left medial Oxford unicondylar k 2018 Aug BACKGROUND: Tibial geodes are rare, and usually reported in association with rheumatoid arthritis. This case study reported the rare occurrence of a tibial geode in association with a left unicondylar knee arthroplasty (UKA). The patient, a 55-year-old male, was initially pleased with his UKA, which was performed at another institution. However, just over one year after the operation he began experiencing pain and discomfort. He did not present to the current institution until he was six years after UKA. This pain was movement and weight bearing related, although he still managed to maintain an active lifestyle working as a builder. After several years of follow-up, a computed tomography (CT) scan showed a significant increase in size of the geode. METHODS: The patient initially did not want to undergo further surgery, as he was self-employed, but it was decided, in conjunction with the patient, that it was time to operate because the stability of the prothesis was in question. Transcortical and retrograde curettage of the geode was performed and one and a half femoral head allografts were used to fill the geode. RESULTS: Follow-up since the operation showed good infilling of the geode and bone remodelling, with resolution of symptoms at 12 months. CONCLUSIONS: This case report was the first to report a symptomatic tibial geode in close association with UKA, which did not lead to revision surgery to total knee arthroplasty (TKA), but instead was successfully treated with currettage and bone grafting.
30024562 Rheumatoid arthritis-like features in Hansen disease: A case report. 2018 Jul RATIONALE: Hansen disease is an infectious chronic disease with various clinical manifestations. Its joint performance may easily mimic rheumatoid arthritis. PATIENT CONCERNS: We report a case of a 57-year-old woman diagnosed with Hansen disease 10 years ago, who suffered from joints swelling, pain and joints deformities of both hands for 19 years. The skin on the hands showed rashes, thickening, desquamation and chapping, with both thenar muscles atrophy. She also had severe hypoalgesia of the whole body, and morning stiffness for one hour. DIAGNOSES: The final diagnosis was joint damage and peripheral neuropathy due to Hansen disease. INTERVENTIONS: The patient received neurotrophic treatment instead of anti-rheumatic treatment. OUTCOMES: At 1-year follow up, no further aggravation of joint swelling and pain was detected. LESSONS: The correct diagnosis of Hansen disease involving joints depends on the combination of medical history, careful physical examination, and laboratory examination.
29422077 Adiponectin aggravates bone erosion by promoting osteopontin production in synovial tissue 2018 Feb 8 BACKGROUND: We have previously reported that adiponectin (AD), an adipokine that is secreted by adipocytes, correlates well with progressive bone erosion in rheumatoid arthritis (RA). The exact mechanism of AD in promoting joint destruction remains unclear. Osteopontin (OPN) is required for osteoclast recruitment. We hypothesized that AD exacerbates bone erosion by inducing OPN expression in synovial tissue. This study aimed to evaluate a novel role for AD in RA. METHODS: The serum levels of AD and OPN were determined in 38 patients with RA, 40 patients with osteoarthritis (OA), and 20 healthy controls using enzyme-linked immunosorbent assay (ELISA). AD and OPN production were measured by double immunofluorescence in RA and OA synovial tissue. Quantitative real-time PCR and immunofluorescence were used to evaluate the mRNA and protein expression levels of OPN in RA synovial fibroblasts (RASFs) and OA synovial fibroblasts after pre-incubation with AD, respectively. Migration of the RAW264.7 osteoclast precursor cell line was assessed using the Transwell migration assay and co-culture system. Bone destruction and osteoclastogenesis were assessed by immunohistochemical staining, microcomputed tomography and tartrate-resistant acid phosphatase (TRAP) staining in AD-treated collagen-induced arthritis (CIA) mice with or without OPN silencing. The expression levels of OPN and integrin α(v)β(3) in the ankle joint tissues of the mice were examined by double immunofluorescence. RESULTS: Our results indicated that the AD and OPN expression levels increased noticeably and were associated with each other in the RA serum. The AD distribution was coincident with that of OPN in the RA synovial tissue. AD stimulation of RASFs increased OPN production in a dose-dependent manner. AD-treated RASFs promoted RAW264.7 cell migration, and the effect was blocked with a specific antibody against OPN. Silencing of OPN using lentiviral-OPN short hairpin RNA reduced the number of TRAP-positive osteoclasts and the extent of bone erosion in the AD-treated CIA mice. When bound to integrin α(v)β(3), OPN functions as a mediator of AD and osteoclasts. CONCLUSIONS: Our study provides new evidence of AD involvement in bone erosion. AD induces the expression of OPN, which recruits osteoclasts and initiates bone erosion. These data highlight AD as a novel target for RA treatment.
29577053 Hsa_circ_0001859 Regulates ATF2 Expression by Functioning as an MiR-204/211 Sponge in Huma 2018 BACKGROUND: circRNAs are part of the competitive endogenous RNA network, which putatively function as miRNA sponges and play a crucial role in the development of numerous diseases. However, studies of circRNAs in rheumatoid arthritis (RA) disease are limited. This work aims to identify the expression pattern of circRNAs in synovial tissues and their inflammatory regulation mechanism. METHODS: We first compared the mRNA expression in rheumatoid arthritis patients with that in healthy volunteers by GEO database mining to identify gene loci specifically expressed in synovial tissues. Functional enrichment algorithms were then used to draw the interactome diagram of circRNAs-miRNAs-mRNAs. Finally, loss-of-function and rescue assays of the candidate circRNAs were performed in vitro. RESULTS: A total of 29 differentially expressed circRNAs related to rheumatoid arthritis were discovered. Silencing of hsa_circ_0001859 suppressed ATF2 expression and decreased inflammatory activity in SW982 cells. Hsa_circ_0001859 could compete with ATF2 for miR-204/211. DISCUSSION: These findings indicate that hsa_circ_0001859 participates deeply in the process of chronic inflammatory disease in synovial tissue.
30289539 Switch or swap strategy in rheumatoid arthritis patients failing TNF inhibitors? Results o 2018 Oct 1 OBJECTIVE: To establish evidence-based and experts' opinion filtered statements on the optimal treatment choice between cycling (switch) and changing mode of action strategies (swap) in RA patients failing TNF inhibitors (TNFis). METHODS: The relevant question (switch vs swap) was rephrased into a research question according to the population, intervention, comparison and outcome (PICO) strategy, considering all the available scientific evidence published from the 2013 EULAR set of recommendations up to mid-January 2016. Final statements derived from the retrieved scientific evidence and experts' consensus, with eventual rephrasing through a Delphi method during a national consensus of Italian rheumatologists. RESULTS: From a total of 365 records, 12 studies were finally included. The final statements argued that, until head-to-head comparison data are available, switch and swap can be still considered suitable strategies in RA patients failing first TNFi, even though some data seem to lend more support to a different mode of action-targeted strategy. CONCLUSION: After failure of first TNFi course, switch and swap can be currently considered as alternative suitable approaches in RA patients.
30080871 Changes in bone density and bone turnover in patients with rheumatoid arthritis treated wi 2018 Data describing the effect of in vivo B cell depletion on general bone loss in patients with rheumatoid arthritis (RA) are limited. Given the pathogenetic role of B cells in RA, it is tempting to speculate that B cell depletion might have a beneficial effect on bone loss. We prospectively investigated the changes in bone mineral density (BMD), bone turnover, inflammation and disease activity before and after rituximab in 45 RA patients over a 12 month period, 36 patients of whom completed the study and were included in the analysis. There was no significant change in our primary endpoint; lumbar spine BMD after 12 months. However, we found a significant decrease in neck of femur (mean -0.017 g/cm2, 95% CI -0.030, -0.004 p = 0.011) and total femur BMD (mean -0.016 g/cm2, 95% CI -0.025, -0.007 p = 0.001). Additionally, there was a significant increase in procollagen type 1 amino-terminal propeptide (P1NP) and bone specific alkaline phosphatase (BAP); biomarkers of bone formation (median change from baseline to 12 months; P1NP 11.3 μg/L, 95% CI -1.1, 24.8 p = 0.025; BAP 2.5 μg/L, 95% CI 1.2, 3.6 p = 0.002), but no significant change in bone resorption or osteocyte markers. The fall in BMD occurred despite improvement in disease control. Post-menopausal women had the lowest mean lumbar spine, femoral and forearm BMD at baseline and after 12 months, additionally they had a higher level of bone turnover throughout the study. In conclusion, BMD was maintained at the lumbar spine and forearm, but fell at the femur sites. A high prevalence of vitamin D deficiency was observed and these patients had lower BMD and evidence of higher bone turnover.
29134891 Efficacy and safety of baricitinib in Japanese patients with rheumatoid arthritis: Subgrou 2018 Jul OBJECTIVES: To evaluate efficacy/safety of baricitinib for rheumatoid arthritis (RA) in Japanese subpopulations from four phase 3 studies, and assess whether results in these subpopulations are consistent with the overall study populations. METHODS: Subgroup analyses (394 patients) of four phase 3 randomized controlled trials: RA-BEGIN [no or limited treatment with disease-modifying antirheumatic drugs (DMARDs)], RA-BEAM [inadequate response (IR) to methotrexate], RA-BUILD [IR to conventional synthetic DMARDs (csDMARDs)], and RA-BEACON (IR to tumor necrosis factor inhibitors receiving csDMARDs). RESULTS: For American College of Rheumatology 20% improvement (ACR20) response rate, Japanese patients receiving baricitinib 4-mg showed similar improvement compared to methotrexate at Week 24 (72 versus 69%; RA-BEGIN), and greater improvement compared with placebo at Week 12 (67 versus 34%; RA-BEAM). Japanese patients receiving baricitinib 4-mg also showed greater improvement compared with placebo at Week 12 in RA-BUILD and RA-BEACON. Across all studies, baricitinib was well-tolerated, with no deaths and one malignancy. In RA-BEGIN and RA-BEAM, herpes zoster rates were higher for Japanese patients than for overall populations; all events were mild/moderate. CONCLUSION: Data for baricitinib, with/without methotrexate, in Japanese subpopulations across all stages of the RA treatment continuum accord with the efficacy/safety profile in overall study populations. Baricitinib appears to be similarly effective in Japanese patients.
30466479 Induction of chronic destructive arthritis in SCID mice by arthritogenic fibroblast-like s 2018 Nov 22 BACKGROUND: Fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) are autonomously activated to maintain inflammation and joint destruction in co-transplantation models. To elucidate inducing mechanisms involved in this altered behavior, the arthritogenic potential of FLSs from murine antigen-induced arthritis (AIA) were investigated in a transfer model. METHODS: FLSs were isolated, expanded in vitro, and transferred into knee joint cavities of severe combined immunodeficient (SCID) mice. Their arthritogenic capacity was assessed by monitoring joint swelling and evaluation of histological parameters 70 to 100 days after transfer. RESULTS: FLSs from AIA mice were able to transfer arthritis into recipient SCID mice. FLS transfer induced a chronic arthritis with recruitment of inflammatory cells and marked cartilage destruction. Long-lasting inflammation was not required for imprinting of arthritogenicity in FLSs since cells isolated from acute arthritic joints were fully competent to transfer arthritis. We also observed arthritogenic potential in FLSs isolated from contralateral non-arthritic joints in our monoarticular arthritis model. CONCLUSIONS: We show that the transformation of FLSs into arthritogenic cells occurs early in arthritis development. This challenges current hypotheses on the role of these cells in arthritis pathogenesis and opens up the way for further mechanistic studies.
31032592 [Therapeutic effects of Hedyotis diffusa Willd. on type II collagen-induced rheumatoid art 2018 Jun 8 OBJECTIVE: To investigate the therapeutic effects of Hedyotis diffusa Willd.on type Ⅱ collagen-induced rheumatoid arthritis in rats. METHODS: According to the random number table, 60 SD rats were divided into the normal control group (n=10, normal saline) and model group (n=50).The collagen-induced arthritis model was established with the injection of type Ⅱ collagen into the back in rats other than the normal group and evaluated by arthritis score, then the model rats were randomly divided into model group (normal saline), tripterygium wilfordii polyglycoside (GTW) 6 mg/kg group (daily dose:0.4 mg/kg), HD 3, 6, 12 g/kg groups (daily dose:3, 6 and 12 g/kg, respectively), with 10 rats in each group. The rats were treated with corresponding agents by intragastric administration.The arthritis index and the pain threshold of all rats at different time points were observed and measured weekly.After treated by intragastric administration for 28 days, all rats were killed to measure the changes of serum cytokine levels including interleukin 1β (IL-lβ), tumor necrosis factor a (TNF-a), prostaglandin (PGE(2)), receptor activator for nuclear factor-kappa B ligand (RANKL) and osteoprotegerin (OPG). RESULTS: Compared with the control group, the arthritis index and the serum levels of IL-lβ, TNF-a, PGE(2), RANKL, OPG and RANKL/OPG of the model group were increased significantly (P<0.05), the pain threshold of the model group was decreased significantly (P<0.05); compared with the model group, the arthritis index and the serum levels of IL-lβ, TNF-a, PGE(2), RANKL, OPG and RANKL/OPG of the GTW group, HD low-dose, medium-dose, high dose groups were decreased significantly (P<0.05), the pain threshold of the model group was increased significantly (P<0.05). CONCLUSIONS: Hedyotis diffusa Willd.can significantly reduce arthritis index and increase pain threshold, reduce the level of IL-lβ, TNF-a, PGE(2), RANKL, OPG, and RANKL/OPG, then can prevent CIA effectively.
29449498 Early Psoriatic Arthritis Versus Early Seronegative Rheumatoid Arthritis: Role of Dermosco 2018 May OBJECTIVE: Exclusion of psoriatic skin/nail lesions is important in differentiating early seronegative rheumatoid arthritis (ERA) from early polyarticular psoriatic arthritis (EPsA) and such manifestations may go unnoticed in atypical or minimally expressed cases. The aim of this study is to assess the usefulness of integrated rheumatological-dermatological evaluation in highlighting dermatological lesions missed on rheumatological examination and to investigate the role of ultrasonography (US) and dermoscopy in improving the recognition of subclinical psoriatic findings. METHODS: Patients with a new diagnosis of seropositive or seronegative ERA and EPsA with prevalent hands involvement were recruited. All were reassessed for the presence of psoriatic lesions during an integrated rheumatological-dermatological clinical evaluation and underwent hands US and proximal nailfold dermoscopy. RESULTS: Seventy-three consecutive subjects were included in the study: 25 with seropositive ERA, 23 with seronegative ERA, and 25 with EPsA. One-fourth of the subjects initially diagnosed as seronegative ERA presented cutaneous or nail psoriasis on integrated rheumatological-dermatological evaluation, thereby being reclassified as EPsA. The presence of at least 1 extrasynovial feature on hand US and dotted vessels on proximal nailfold dermoscopy was significantly associated with EPsA, with a sensitivity of 68.0% and 96.0% and a specificity of 88.1% and 83.3% for US and dermoscopy, respectively. When used together, specificity for PsA diagnosis raised to 90.5%. CONCLUSION: Integrated rheumatological-dermatological clinical evaluation may be helpful in identifying patients with EPsA misclassified as seronegative ERA. Additionally, US and dermoscopy may be used as supportive tools in identifying subclinical psoriatic features, which may come in handy in distinguishing EPsA from ERA.
28990193 Antimicrobial peptides as a possible interlink between periodontal diseases and its risk f 2018 Apr Antimicrobial peptides (AMPs) play a critical role in controlling innate and acquired immune responses. Local dysregulation of AMP is implicated in the pathogenesis of periodontal diseases as a response to periodontal pathogen challenge. Changes in AMP expression also characterize tobacco smoking, diabetes mellitus, obesity and rheumatoid arthritis, which are established risk factors of periodontal diseases, suggesting AMP may act as putative mechanistic links between these. The aim was to evaluate and summarize critically the current evidence pertaining to interrelationships between AMPs, periodontal diseases and selected periodontal disease risk factors. General and theme specific keywords were used to search the PUBMED database for studies relevant to AMP, periodontal diseases, smoking, diabetes mellitus, obesity and rheumatoid arthritis and critically reviewed. A total of 131 abstracts and 119 full text articles were screened for relevance; 13 studies were selected for inclusion after critical review. Local AMP dysregulation characteristic to periodontal diseases appears to occur within a broader landscape of complex systemic immune perturbations independently induced by smoking, metabolic and rheumatoid disease. The nature of these interactions and mechanistic pathways involved are inadequately understood. AMPs could be possible mechanistic interlinks between periodontal diseases and its risk factors. However, such evidence is very limited and more in vivo and in vitro studies are necessary to clarify the nature of such relationships. A greater understanding of AMPs as shared mediators is essential for unraveling their value as therapeutic or biomarker candidates.
29717033 An Outsourced Health-enhancing Physical Activity Program for People with Rheumatoid Arthri 2018 Aug OBJECTIVE: To describe changes of health-enhancing physical activity (HEPA), health perception, and functioning during the second year of a 2-year support program, determine aspects of adherence and response, and describe perceptions of the program. METHODS: Out of 220 individuals with rheumatoid arthritis (RA), 177 participated in the followup. Group support, strength training, and moderate-intensity aerobic activity were encouraged. Data collection included HEPA, perceived health, functioning, and perceptions of the program. Participants with unchanged/improved general health perception and at least 2 of aerobic capacity, grip strength, or timed standing were considered responders. RESULTS: Current and maintained HEPA decreased from 82% to 75% (p = 0.0141) and from 41% to 27% (p < 0.0001) during the second year. Minor declines in quality of life and activity limitation occurred (p = 0.0395 and 0.0038, respectively), while outcome expectations for benefits of physical activity increased (p = 0.0010 and 0.0186) and waist circumference tapered off (p = 0.0070). Strength training was performed on average 41 and 35 times among responders (n = 54) and nonresponders (n = 105), respectively (p = 0.2708); HEPA 194 and 171 days, respectively (p = 0.0828); and support group meetings 12 and 10 times, respectively (p = 0.0943). Strength training, aerobic activity, and short text message reminders were perceived as most valuable; step registration and the self-monitoring walk tests were less appreciated. CONCLUSION: About one-fourth of the originally sedentary individuals with RA sustained their new HEPA behaviors after 2 years and most improvements of health and functioning were sustained. Structured use of behavior change techniques and a second year to support maintenance with a reduced program might help patients with RA to sustain HEPA behavior.
28440680 Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: 2018 Jan OBJECTIVES: The objective of this study is to evaluate the efficacy and safety of long-term (64 weeks; 52-week extension of a 12-week study) baricitinib treatment in Japanese patients with active rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: Patients (N = 145) with active RA were randomized to placebo, 1mg, 2mg, 4mg, or 8mg baricitinib for the first 12 weeks. During the 52-week extension period, patients on 4mg or 8mg baricitinib remained on the same dose and all other patients were re-randomized to 4mg or 8mg baricitinib. Most patients on 8mg baricitinib were switched to 4mg by week 64 (protocol amendment); data analysis was based on the treatment group at the beginning of the extension period. RESULTS: Increases in the American College of Rheumatology (ACR) response rates (ACR20, ACR50, and ACR70) observed during the first 12 weeks were maintained during the extension period, accompanied by improvements in ACR core components. At week 64, a large proportion of patients (>40%) had low disease activity. Most treatment-related adverse events were mild or moderate; herpes zoster was the most common reason (11/27 patients) for discontinuation. CONCLUSIONS: The efficacy and safety profile of baricitinib was maintained during long-term treatment of Japanese patients with RA and background methotrexate therapy. Clinicaltrials.gov NCT01469013; Funding: Eli Lilly and Incyte.
29482351 Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheu 2018 Aug Major Objectives: To review the efficacy, safety, and economics of sarilumab, an interleukin-6 (IL-6) receptor antagonist, in the treatment of rheumatoid arthritis (RA). DATA SOURCES: PubMed (1966 to January 2018), Clinicaltrials.gov (January 2018), and Scopus (1970 to January 2018) were searched using sarilumab, Kevzara, REGN88, and SAR153191. STUDY SELECTION AND DATA EXTRACTION: Human studies published in peer-reviewed publications in English were the primary sources for efficacy and safety. DATA SYNTHESIS: Data from randomized, double-blind, controlled, published clinical studies weeks demonstrated statistically significantly higher American College of Rheumatology (ACR) 20, ACR50, and Disease Activity Score-28 (DAS28) remission response rates and improvements in DAS28 and Health Assessment Questionnaire-Disability Index scores for sarilumab monotherapy versus adalimumab monotherapy (P < 0.05) and for sarilumab versus placebo in patients receiving methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs); P < 0.05. The ACR20 and ACR50 response rates were, respectively, 56-72% and 35-46% for sarilumab, 58% and 30% for adalimumab, and 33-34% and 15-18% for placebo. DAS28 remission rates were 20-34% for sarilumab, 7% for adalimumab, and 7-10% for placebo. Sarilumab has a higher risk for neutropenia than tocilizumab, the other IL-6 inhibitor, but a lower risk for dyslipidemia, injection site reactions, and gastrointestinal perforation. The acquisition costs of sarilumab are expected to be similar to those of most other biologic DMARDs. CONCLUSION: Sarilumab is an alternative to biologic DMARDs or targeted synthetic DMARDs in patients with moderate to severely active RA who have not responded adequately to prior conventional synthetic DMARDs or tumor necrosis factor-α inhibitors.
30319661 The IL-20 Cytokine Family in Rheumatoid Arthritis and Spondyloarthritis. 2018 This review describes the IL-20 family of cytokines in rheumatoid arthritis (RA) and spondyloartrhitits (SpA) including psoriatic arthritis. The IL-20 receptor (R) cytokines IL-19, IL-20, and IL-24 are produced in both the peripheral blood and the synovial joint and are induced by Toll-like receptor ligands and autoantibody-associated immune complexes in monocytes. IL-19 seems to have anti-inflammatory functions in arthritis. In contrast, IL-20 and IL-24 increase the production of proinflammatory molecules such as monocyte chemoattractant protein 1 and are associated with bone degradation and radiographic progression. IL-22 is also associated with progression of bone erosions. This suggests that the IL-22RA1 subunit shared by IL-20, IL-22, and IL-24 is important for bone homeostasis. In line with this, the IL-22RA1 has been found on preosteoclasts in early RA. IL-26 is produced in high amounts by myofibroblasts and IL-26 stimulation of monocytes is an important inducer of Th17 cells in RA. This indicates a role for IL-26 as an important factor in the interactions between resident synovial cells and infiltrating leukocytes. Clinical trials that investigate inhibitors of IL-20 (fletikumab) and IL-22 (fezakinumab) in psoriasis and RA have been terminated. Instead, it seems that the strategy for modulating the IL-20 cytokine family should take the overlap in cellular sources and effector mechanisms into account. The redundancy encourages inhibition of more than one cytokine or one of the shared receptors. All IL-20 family members utilize the Janus kinase signaling pathway and are therefore potentially inhibited by drugs targeting these enzymes. Effects and adverse effects in ongoing clinical trials with inhibitors of IL-22 and the IL-22RA1 subunit and recombinant IL-22 fusion proteins will possibly provide important information about the IL-20 subfamily of cytokines in the future.
29426059 Brief Report: The Genetic Profile of Rheumatoid Factor-Positive Polyarticular Juvenile Idi 2018 Jun OBJECTIVE: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)-positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF-positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies. METHODS: Patients with RF-positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single-nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF-positive polyarticular JIA. RESULTS: As expected, the HLA region was strongly associated with RF-positive polyarticular JIA (P = 5.51 × 10(-31) ). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF-negative polyarticular JIA risk loci were associated with RF-positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF-positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF-negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF-positive polyarticular JIA was more similar to that of RA patients with age at onset 16-29 years than to that of RA patients with age at onset ≥70 years. CONCLUSION: RF-positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood-onset presentation of autoantibody-positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies.
29374666 Quality of life, sleep and rheumatoid arthritis (QUASAR): a protocol for a prospective UK 2018 Jan 26 INTRODUCTION: People with rheumatoid arthritis (RA) frequently report reduced health-related quality of life (HRQoL), the impact one's health has on physical, emotional and social well-being. There are likely numerous causes for poor HRQoL, but people with RA have identified sleep disturbances as a key contributor to their well-being. This study will identify sleep/wake rhythm-associated parameters that predict HRQoL in patients with RA. METHODS AND ANALYSIS: This prospective cohort study will recruit 350 people with RA, aged 18 years or older. Following completion of a paper-based baseline questionnaire, participants will record data on 10 symptoms including pain, fatigue and mood two times a day for 30 days using a study-specific mobile application (app). A triaxial accelerometer will continuously record daytime activity and estimate evening sleep parameters over the 30 days. Every 10 days following study initiation, participants will complete a questionnaire that measures disease specific (Arthritis Impact Measurement Scale 2-Short Form (AIMS2-SF)) and generic (WHOQOL-BREF) quality of life. A final questionnaire will be completed at 60 days after entering the study. The primary outcomes are the AIMS2-SF and WHOQOL-BREF. Structural equation modelling and latent trajectory models will be used to examine the relationship between sleep/wake rhythm-associated parameters and HRQoL, over time. ETHICS AND DISSEMINATION: Results from this study will be disseminated at regional and international conferences, in peer-reviewed journals and Patient and Public Engagement events, as appropriate.
30277570 NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. 2018 Nov Nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) gene polymorphism was reported to be associated with susceptibility, disease activity or anti-tumour necrosis factor (TNF) treatment response in rheumatoid arthritis (RA). However, the roles of NLRP3 inflammasome in the development of RA have not yet been elucidated fully. The present study aimed to study the role of NLRP3 inflammasome in RA. NLRP3 inflammasome activation in synovial tissues from RA and osteoarthritis (OA) patients were assessed by Western blot. Active caspase-1 in synovia was stained by a FAM-FLICA caspase-1 probe. Mice with collagen-induced arthritis (CIA) were treated with MCC950, a selective NLRP3 inhibitor, or vehicle for 2 weeks. The clinical score of arthritis, synovial inflammation and cartilage erosion were assessed. Proinflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The results showed that NLRP3 inflammasome was highly activated in both synovia from RA patients and CIA mice. Activation of NLRP3 inflammasome occurred mainly in the infiltrating monocyte/macrophages in synovia, but not in fibroblast-like synoviocytes. Treatment with MCC950 resulted in significantly less severe joints inflammation and bone destruction. NLRP3 inflammasome activation in the synovia was inhibited significantly by MCC950 with reduced production of interleukin (IL)-1β. The inhibition of NLRP3 inflammasome activation by MCC950 was confirmed further in a human monocytic cell line, THP-1. In conclusion, NLRP3 inflammasome is involved in the pathogenesis of RA. Targeting NLRP3 inflammasome with a small molecule inhibitor might be a novel therapeutic strategy for RA.
30518408 Association between autophagy and inflammation in patients with rheumatoid arthritis recei 2018 Dec 5 BACKGROUND: Increasing evidence indicates a pathogenic role of deregulated autophagy in rheumatoid arthritis (RA). We examined the relationship between autophagy and inflammatory parameters in patients with RA receiving biologic therapy. METHODS: In 72 patients with RA and 20 healthy control subjects (HC), autophagosome levels were determined by the mean fluorescence intensity (MFI) of autophagosomotropic dye incorporated into circulating immune cells, and p62 expression levels in immune cells were measured by flow cytometry. We used immunoblotting to examine protein expression of LC3-II and p62 in peripheral blood mononuclear cells. RESULTS: Patients with RA had significantly higher levels of autophagosome reflected by MFI of Cyto-ID in circulating lymphocytes, monocytes, and granulocytes (median values, 3.6, 11.6, and 64.8, respectively) compared with HC (1.9, 6.0, and 35.8; respectively) (all p < 0.001). p62 MFI levels in lymphocytes and granulocytes from patients with RA (17.1 and 8.6, respectively) were significantly lower than those in the corresponding cells from HC (20.2, p < 0.05; and 13.1, p < 0.001, respectively). Significantly higher levels of LC3-II protein expression in contrast to lower p62 protein levels were observed in patients with RA than in HC. The autophagosome levels in immune cells were significantly correlated with inflammatory parameters in patients with RA, and they were significantly decreased with disease remission after treatment with tumor necrosis factor-α inhibitors or interleukin-6 receptor inhibitor. CONCLUSIONS: Elevated autophagy with significant correlation to inflammation suggests the involvement of autophagy in RA pathogenesis. The effectiveness of biologic therapy might be partly related to the downregulation of autophagy expression.