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ID PMID Title PublicationDate abstract
29500270 How MHC molecules grab citrullinated peptides to foster rheumatoid arthritis. 2018 Mar 2 The molecular immunologist's dream is to elucidate a fundamental biochemical process that explains the basis of an affliction that affects millions of people, and that, precisely understood, might yield a rational approach to diagnosis, prevention, or therapy. In this issue of JBC, Ting et al. report proteomic, biochemical, and structural analyses that better explain how the antigen-presenting HLA-DR4 molecules bind citrullinated peptides to provoke rheumatoid arthritis (RA), a chronic autoimmune disease that affects 0.5-1% of the population.
29417936 Rheumatoid arthritis. 2018 Feb 8 Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.
30187662 Matrix metalloprotease 3 is associated with sarcopenia in rheumatoid arthritis - results f 2018 Nov AIM: Patients with rheumatoid arthritis (RA) show lower muscle mass and a higher prevalence of sarcopenia than healthy individuals. Correlations between sarcopenia and disease activity, physical function, laboratory data and body composition at baseline were investigated in a prospective, observational study (CHIKARA study) of RA patients. METHODS: Body composition was measured using a bioelectrical impedance analyzer. Parameters were compared between sarcopenia and non-sarcopenia groups, and correlations between sarcopenia and Disease Activity Score of 28 joints - erythrocyte sedimentation rate (DAS28-ESR), modified health assessment questionnaire, treatment, and laboratory data, including matrix metalloproteinase 3 (MMP3), were investigated. RESULTS: The participants were 100 patients with RA (women, 78%; mean age, 66.1 years). Mean disease duration was 5.5 years, DAS28-ESR was 3.55 and the prevalence of sarcopenia was 28%. Median C-reactive protein (CRP) and MMP3 were significantly higher in the sarcopenia group (0.21 mg/dL and 103.4 ng/mL) than in the non-sarcopenia group (0.11 mg/dL and 70.3 ng/mL). Sarcopenia was negatively correlated with weight, body mass index (BMI), muscle mass, body fat mass, estimated bone mass and basal metabolic rate, and positively correlated with Steinbrocker stage, CRP and MMP3 on univariate analyses. BMI, body fat mass and MMP3 were independently associated with sarcopenia on multivariate logistic regression analysis. When MMP3 was ≥ 90.7 ng/mL, the odds ratio for sarcopenia was increased 3.1-fold compared with < 90.7 ng/mL (P = 0.018). CONCLUSION: The prevalence of sarcopenia was 28% in patients with RA whose disease activity was mild. Low BMI, high fat mass and high MMP3 were independently associated with sarcopenia. MMP3 might be a useful marker for sarcopenia in patients with RA.
29544539 Pain sensitivity at rest and during muscle contraction in persons with rheumatoid arthriti 2018 Mar 15 BACKGROUND: We aimed to explore pressure pain sensitivity and the function of segmental and plurisegmental exercise-induced hypoalgesia (EIH) in persons with rheumatoid arthritis (RA) compared with healthy control subjects (HC). METHODS: Forty-six participants with RA (43 female, 3 male) and 20 HC (16 female, 4 male) participated in the study. Pressure pain thresholds, suprathreshold pressure pain at rest, and segmental and plurisegmental EIH during standardised submaximal contractions were assessed by algometry. Assessments of EIH were made by performing algometry alternately at the contracting (30% of the individual maximum) right m. quadriceps and the resting left m. deltoideus. RESULTS: Participants with RA had higher sensitivity to pressure pain (RA, 318 kPa; HC, 487 kPa; p < 0.001), suprathreshold pressure pain 4/10 (RA, 433 kPa; HC, 638 kPa; p = 0.001) and suprathreshold pressure pain 7/10 (RA, 620 kPa; HC, 851 kPa; p = 0.002) than HC. Segmental EIH (RA, 0.99 vs 1.27; p < 0.001; HC, 0.89 vs 1.10; p = 0.016) and plurisegmental EIH (RA, 0.95 vs 1.36; p < 0.001; HC, 0.87 vs 1.31; p < 0.001) increased significantly during static muscle contraction in both groups alike (p > 0.05). CONCLUSIONS: Our results indicate a generally increased pain sensitivity but normal function of EIH among persons with RA and offer one possible explanation for pain reduction observed in this group of patients following clinical exercise programmes. TRIAL REGISTRATION: ISRCTN registry, ISRCTN25539102 . Retrospectively registered on 4 March 2011.
29337196 Nicorandil and theophylline can protect experimental rats against complete Freund's adjuva 2018 Mar 5 Signaling pathways are interesting fields of study of pathogenesis and treatment trials. We elucidated the possible protective effects of nicorandil (15mg/kg/day) and theophylline (20mg/kg/day) on experimentally-induced RA, focusing on the role of JAK (Janus Kinase) / STAT (Signal Transducer and Activator of Transcription) / RANKL (Receptor Activator of Nuclear factor-Kappa B Ligand) / cytokine signaling pathway. Four sets of experiments were performed. First, effect of test agents on normal animals was evaluated. Second, effect of test agents was evaluated on Complete Freund's Adjuvant (CFA; 0.3ml, s.c.)-induced RA to investigate anti-arthritic effect. Third, effect of test agents was evaluated on growth hormone (GH; 2mg/kg/day, s.c.)-induced stimulation of JAK/STAT/RANKL/cytokine signaling pathway to investigate the role of this signaling pathway in their anti-arthritic effect. Fourth, the effect of test agents was performed on CFA/GH-induced RA. To fulfill this purpose, serum anti-citrullinated peptide antibody (ACPA), interleukin-6 (IL-6), and cartilage oligomeric matrix protein (COMP), together with tissue JAK2, STAT3, RANKL, inducible and endothelial nitric oxide synthases (iNOS and eNOS) as well as macrophage inflammatory protein (MIP(1α)) were estimated using ELISA, Western blotting and PCR techniques, confirmed by a histopathological study. Test agents significantly corrected JAK2, STAT3, RANKL and IL-6 values in animals receiving GH. Additionally, test agents could correct ACPA, IL-6, COMP, JAK2, STAT3, RANKL, iNOS, eNOS and MIP(1α) levels compared with the respective CFA or CFA/GH controls. These results conclude that nicorandil and theophylline have good anti-arthritic effects related to modulation of JAK/STAT/RANKL signaling pathway. Further clinical trials are claimed.
28833093 Multifaceted role of IL-21 in rheumatoid arthritis: Current understanding and future persp 2018 May Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder designated with hyperplastic synovium, bone destruction and cartilage degradation. Current therapies involve targeting major cytokines and inflammatory mediators involved in RA to alleviate the pain and provide a temporary relief. Interleukin 21 (IL-21), a recently identified cytokine is known to possess a versatile role in modulating the cells of the RA synovium. Over the past decade, the pleiotropic role of IL-21 in RA pathogenesis has been implicated in several aspects. T helper 17 (Th17) and follicular T helper cells (Tfh), being the key immunomodulators of the RA synovium secrete high amounts of IL-21 during disease progression. Several studies have provided experimental evidences elucidating the multifaceted role of IL-21 in RA disease progression. IL-21 has the potential to activate T cells, B cells, monocytes/macrophages and synovial fibroblasts in RA pathogenesis through activation of JAK-STAT, MAPK and PI3K/Akt signaling pathways. Till date, therapies targeting Th17 cells and its inflammatory cytokines have been under investigation and are subjected to various clinical trials. This review showcases the role of IL-21 in RA pathogenesis and recent reports implicating its function in various immune cells, major signaling pathways, and in promoting osteoclastogenesis.
30035658 Dual role of acid-sensing ion channels 3 in rheumatoid arthritis: destruction or protectio 2018 Aug Acid-sensing ion channels (ASIC) are voltage-independent cationic channels that open in response to decrease in extracellular pH. Amongst different subtypes, ASIC3 has received much attention in joint inflammatory conditions including rheumatoid arthritis. There have been a number of studies showing that there is an increase in expression of ASIC3 on nerve afferents supplying joints in response to inflammatory stimulus. Accordingly, a number of selective as well as nonselective ASIC3 inhibitors have shown potential in attenuating pain and inflammation in animal models of rheumatoid arthritis. On the other hand, there have been studies showing that ASIC3 may exert protective effects in joint inflammation. ASIC(-/-) animals, without ASIC3 genes, exhibit more joint inflammation and destruction in comparison to ASIC(+/+) animals. The present review discusses the dual nature of ASIC3 in joint inflammation with possible mechanisms.
29380036 TYMS polymorphisms and responsiveness to or toxicity of methotrexate in rheumatoid arthrit 2018 Nov OBJECTIVE: The aim of this study was to investigate whether the thymidylate synthase (TYMS) 2R/3R and 6 bp I/D polymorphisms can predict the response to or toxicity of methotrexate (MTX) in patients with rheumatoid arthritis (RA). METHODS: We conducted a meta-analysis of studies on the association between the TYMS 2R/3R and 6 bp I/D polymorphisms and non-responsiveness to or toxicity of MTX in RA patients. RESULTS: A total of 11 studies involving 1613 patients were considered. Meta-analysis showed no association between the TYMS 2R/3R 3R allele and non-responsiveness to MTX therapy (odds ratio [OR] = 1.087, confidence interval [CI] = 0.682-1.731, p = 0.726). The meta-analysis indicated that there was no association between the TYMS 6 bp I/D D allele and non-responsiveness to MTX therapy (OR = 0.688, 95% CI = 0.281-1.683, p = 0.413). Meta-analysis revealed that the TYMS 2R/3R polymorphism was not associated with MTX toxicity, except for in a co-dominant model, and the TYMS 6 bp I/D polymorphism was not associated with MTX toxicity in all genetic models. CONCLUSIONS: This meta-analysis demonstrates that the TYMS 2R/3R and 6 bp I/D polymorphisms may not be associated with non-responsiveness to or toxicity of MTX therapy in RA patients.
29791439 Multi-biomarker disease activity score as a predictor of disease relapse in patients with 2018 OBJECTIVE: Successfully stopping or reducing treatment for patients with rheumatoid arthritis (RA) in low disease activity (LDA) may improve cost-effectiveness of care. We evaluated the multi-biomarker disease activity (MBDA) score as a predictor of disease relapse after discontinuation of TNF inhibitor (TNFi) treatment. METHODS: 439 RA patients who were randomized to stop TNFi treatment in the POET study were analyzed post-hoc. Three indicators of disease relapse were assessed over 12 months: 1) restarting TNFi treatment, 2) escalation of any DMARD therapy and 3) physician-reported flare. MBDA score was assessed at baseline. Associations between MBDA score and disease relapse were examined using univariate analysis and multivariate logistic regression. RESULTS: At baseline, 50.1%, 35.3% and 14.6% of patients had low (<30), moderate (30-44) or high (>44) MBDA scores. Within 12 months, 49.9% of patients had restarted TNFi medication, 59.0% had escalation of any DMARD and 57.2% had ≥1 physician-reported flare. MBDA score was associated with each indicator of relapse. At least one indicator of relapse was observed in 59.5%, 68.4% and 81.3% of patients with low, moderate or high MBDA scores, respectively (P = 0.004). Adjusted for baseline DAS28-ESR, disease duration, BMI and erosions, high MBDA scores were associated with increased risk for restarting TNFi treatment (OR = 1.85, 95% CI 1.00-3.40), DMARD escalation (OR = 1.99, 95% CI 1.01-3.94) and physician-reported flare (OR = 2.00, 95% 1.06-3.77). CONCLUSION: For RA patients with stable LDA who stopped TNFi, a high baseline MBDA score was independently predictive of disease relapse within 12 months. The MBDA score may be useful for identifying patients at risk of relapse after TNFi discontinuation.
29217620 Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis trea 2018 Apr OBJECTIVE: To study the risk of a second malignant neoplasm (SMN) and mortality in patients with rheumatoid arthritis (RA) with a history of a primary cancer diagnosis and treated with biological disease-modifying antirheumatic drugs (bDMARD). METHODS: Among patients with RA (n=15 286) registered in the DANBIO Register during 2000-2011, 1678 had a primary cancer according to the Danish Cancer Registry. HRs for SMN and death were calculated. RESULTS: During follow-up there were 279 patients with RA contributing person-years to the bDMARDs use before their primary cancer diagnosis, 220 to the only after, 92 to the both before and after, while 1203 patients with RA contributed to the non-use strata. Ever use of bDMARDs was associated with a HR of 1.11 (95% CI 0.74 to 1.67) for developing a SMN compared with non-use (cancer site adjusted). The HR for death associated with bDMARD use before the primary cancer diagnosis was increased 1.53 (95% CI 1.13 to 2.09). After further adjustment for extent of the primary cancer, the HR for death was 1.20 (95% CI 0.88 to 1.63) for bDMARDs use before cancer, 1.36 (95% CI 0.78 to 2.39) for bDMARD use only after cancer and 1.22 (95% CI 0.70 to 2.13) for use both before and after the cancer. CONCLUSIONS: Among patients with RA with a history of cancer, treatment with bDMARDs was not associated with increased risk of SMN. No clear conclusion can be drawn regarding mortality in bDMARD-treated patients with RA.
30091955 Identification of Key Genes and Pathways in Rheumatoid Arthritis Gene Expression Profile b 2018 Apr OBJECTIVE: The aim of this study was to identify potential key candidate genes and uncover their potential mechanisms in rheumatoid arthritis. MATERIALS AND METHODS: The gene expression profiles of GSE12021, GSE55457, GSE55584 and GSE55235 were downloaded from the gene expression omnibus database, including 45 rheumatoid arthritis and 29 normal samples. The differentially expressed genes between the two types of samples were identified with the Linear Models for Microarray Analysis package using R language. The gene ontology functional and pathway enrichment analyses of differentially-expressed genes were performed using the database for annotation, visualization and integrated discovery software followed by the construction of a protein-protein interaction network. In addition, hub gene identification and gene ontology functional and pathway enrichment analyses of the modules were performed. RESULTS: The differentially expressed genes were mainly involved in immune response, inflammatory response, chemokine-mediated signaling pathway for rheumatoid arthritis patients. The top hub genes such as interleukin 6, jun proto-oncogene, chemokine receptor 5, epidermal growth factor receptor, were identified from the protein-protein interaction network. Sub-networks revealed hub genes were involved in significant pathways, including chemokine signaling pathway, cytokine-cytokine receptor interaction, tumor necrosis factor signaling pathway. The seed node gene is toll-like receptor 7 and growth arrest and deoxyribonucleic-acid -damage-inducible beta in the model-1 and model-2 by module analysis, respectively. CONCLUSION: These hub genes may be used as potential targets for rheumatoid arthritis diagnosis and treatment.
30146748 CD39 positive regulatory T cell frequency as a biomarker of treatment response to methotre 2018 Aug AIM: Nearly one-third of patients with rheumatoid arthritis (RA) do not respond to Methotrexate (MTX), the first-line therapy in RA. CD39, an ectonucleotidase highly expressed on regulatory T cells (Tregs), is responsible for production of adenosine, an important anti-inflammatory mediator of MTX action. Higher expression of CD39 on Tregs improves their suppressive capacity. Therefore, we aimed to study the role of CD39(+) Treg frequency as a biomarker for MTX treatment response in RA. METHODS: Patients with active RA who were naive to disease-modifying anti-rheumatic drugs were enrolled. Frequencies of CD39(+) Tregs (CD4(+) CD25(+) FoxP3(+) CD39(+) cells) and CD4(+) CD25(+) CD39(+) cells were determined by flow cytometry in peripheral blood before the start of therapy. After 4 months of MTX monotherapy, patients were classified into responders (European League Against Rheumatism [EULAR] good/moderate response) and non-responders (EULAR no response). All samples were genotyped for single nucleotide polymorphisms (SNPs) rs11188513 and rs7071836 in the ENTPD1 (CD39) gene. RESULTS: After 4 months of MTX monotherapy, 54 patients were classified as responders and 16 as non-responders. The baseline CD39(+) Treg and CD4(+) CD25(+) CD39(+) cell frequencies were significantly higher in the responder group as compared with the non-responder group (P < 0.05 and P < 0.01, respectively). AA genotype at SNP rs7071836 was associated with poor response to MTX (P < 0.05; odds ratio = 5.67; 95% CI = 1.12-28.75). CONCLUSION: Higher frequencies of CD39(+) Tregs and CD4(+) CD25(+) CD39(+) cells in the peripheral blood are associated with response to MTX in RA and hence, these could be considered as potential biomarkers for prediction of response to MTX treatment.
29427625 Extracellular vesicles: A new therapeutic strategy for joint conditions. 2018 Jul Extracellular vesicles (EVs) are attracting increasing interest since they might represent a more convenient therapeutic tool with respect to their cells of origin. In the last years much time and effort have been expended to determine the biological properties of EVs from mesenchymal stem cells (MSCs) and other sources. The immunoregulatory, anti-inflammatory and regenerative properties of MSC EVs have been demonstrated in in vitro studies and animal models of rheumatoid arthritis or osteoarthritis. This cell-free approach has been proposed as a possible better alternative to MSC therapy in autoimmune conditions and tissue regeneration. In addition, EVs show great potential as biomarkers of disease or delivery systems for active molecules. The standardization of isolation and characterization methods is a key step for the development of EV research. A better understanding of EV mechanisms of action and efficacy is required to establish the potential therapeutic applications of this new approach in joint conditions.
29787569 Association between IL-6 production in synovial explants from rheumatoid arthritis patient 2018 INTRODUCTION: The need for biomarkers which can predict disease course and treatment response in rheumatoid arthritis (RA) is evident. We explored whether clinical and imaging responses to biologic disease modifying anti-rheumatic drug treatment (bDMARD) were associated with the individual's mediator production in explants obtained at baseline. METHODS: RA Patients were evaluated by disease activity score 28 joint C-reactive protein (DAS 28-)), colour Doppler ultrasound (CDUS) and 3 Tesla RA magnetic resonance imaging scores (RAMRIS). Explants were established from synovectomies from a needle arthroscopic procedure prior to initiation of bDMARD. Explants were incubated with the bDMARD in question, and the productions of interleukin-6 (IL-6), monocyte chemo-attractive protein-1 (MCP-1) and macrophage inflammatory protein-1-beta (MIP-1b) were measured by multiplex immunoassays. The changes in clinical and imaging variables following a minimum of 3 months bDMARD treatment were compared to the baseline explant results. Mixed models and Spearman's rank correlations were performed. P-values below 0.05 were considered statistically significant. RESULTS: 16 patients were included. IL-6 production in bDMARD-treated explants was significantly higher among clinical non-responders compared to responders (P = 0.04), and a lack of suppression of IL-6 by the bDMARDS correlated to a high DAS-28 (ρ = 0.57, P = 0.03), CDUS (ρ = 0.53, P = 0.04) and bone marrow oedema (ρ = 0.56, P = 0.03) at follow-up. No clinical association was found with explant MCP-1 production. MIP-1b could not be assessed due to a large number of samples below the detection limit. CONCLUSIONS: Synovial explants appear to deliver a disease-relevant output testing which when carried out in advance of bDMARD treatment can potentially pave the road for a more patient tailored treatment approach with better treatment effects.
30309835 Tailored, Therapist-Guided Internet-Based Cognitive Behavioral Therapy Compared to Care as 2018 Oct 11 BACKGROUND: Internet-based cognitive behavioral therapy can aid patients with rheumatoid arthritis with elevated levels of distress to enhance their quality of life. However, implementation is currently lacking and there is little evidence available on the (cost-) effectiveness of different treatment strategies. OBJECTIVE: Cost-benefit ratios are necessary for informing stakeholders and motivating them to implement effective treatment strategies for improving health-related quality of life (HRQoL) of patients with rheumatoid arthritis. A cost-effectiveness study from a societal perspective was conducted alongside a randomized controlled trial on a tailored, therapist-guided internet-based cognitive behavioral therapy (ICBT) intervention for patients with rheumatoid arthritis with elevated levels of distress as an addition to care as usual (CAU). METHODS: Data were collected at baseline or preintervention, 6 months or postintervention, and every 3 months thereafter during the 1-year follow-up. Effects were measured in terms of quality-adjusted life years (QALYs) and costs from a societal perspective, including health care sector costs (health care use, medication, and intervention costs), patient travel costs for health care use, and costs associated with loss of labor. RESULTS: The intervention improved the quality of life compared with only CAU (Δ QALYs=0.059), but at a higher cost (Δ=€4211). However, this increased cost substantially reduced when medication costs were left out of the equation (Δ=€1863). Of all, 93% (930/1000) of the simulated incremental cost-effectiveness ratios were in the north-east quadrant, indicating a high probability that the intervention was effective in improving HRQoL, but at a greater monetary cost for society compared with only CAU. CONCLUSIONS: A tailored and guided ICBT intervention as an addition to CAU for patients with rheumatoid arthritis with elevated levels of distress was effective in improving quality of life. Consequently, implementation of ICBT into standard health care for patients with rheumatoid arthritis is recommended. However, further studies on cost reductions in this population are warranted. TRIAL REGISTRATION: Nederlands Trial Register NTR2100; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2100 (Archived by WebCite at http://www.webcitation.org/724t9pvr2).
28805018 Pain Catastrophizing, Subjective Outcomes, and Inflammatory Assessments Including Ultrasou 2018 May OBJECTIVE: Pain catastrophizing is conceptualized as a negative cognitive-affective response to anticipated or actual pain and has been associated with important pain-related outcomes. The objective of this prospective study of established rheumatoid arthritis (RA) patients was to explore how pain catastrophizing was related to patient-reported outcomes (PROs), composite scores, and assessments of inflammatory activity. METHODS: RA patients starting biologic disease-modifying antirheumatic drugs were examined at baseline and after 1, 2, 3, 6, and 12 months with PROs (joint pain/patient's global visual analog scale [VAS], modified Health Assessment Questionnaire, Rheumatoid Arthritis Impact of Disease score), clinical and laboratory assessments (tender/swollen joint count, assessor's global VAS, erythrocyte sedimentation rate/C-reactive protein [CRP] level), ultrasound (US) (gray scale [GS]/power Doppler [PD] of 36 joints and 4 tendons), and pain catastrophizing. The composite scores for Disease Activity Score in 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index were calculated. Statistical calculations included independent samples t-test, paired samples t-test, one-way analysis of variance, Pearson's correlations, and linear and logistic regression. RESULTS: Of 209 patients included, 152 (72.7%) completed 12-month followup. Pain catastrophizing, PROs, and clinical and inflammatory assessments decreased significantly (P < 0.001). Pain catastrophizing was strongly correlated with the PROs and composite scores (P < 0.001) but not with the inflammatory parameters (swollen joint count, CRP level, and GS/PD US). Patients with higher levels of pain catastrophizing had higher PROs and composite scores during the study (P < 0.001) but not inflammatory assessments. Baseline pain catastrophizing was negatively associated with achievement of remission at 6 and 12 months (P < 0.05). CONCLUSION: Pain catastrophizing was strongly associated with PROs and composite measures, but not with markers of inflammation. High levels of pain catastrophizing reduced the likelihood of achieving composite score remission and should be a factor to consider in a treat-to-target strategy.
29998824 Prevention of the progressive biochemical cartilage destruction under methotrexate therapy 2019 Mar OBJECTIVES: The aim of the study was to investigate biochemical cartilage composition under methotrexate (MTX) therapy and to intra-individually assess the impact of inflammation severity on cartilage composition by using dGEMRIC MRI in patients with early rheumatoid arthritis (eRA). METHODS: dGEMRIC of MCP joints of the index and middle finger of 28 patients from the AthroMark cohort were examined prior to MTX-therapy as well as after 3 and 6 month. OMERACT RA MRI score and clinical parameters (CRP and DAS28) were registered at any time point. Each patient's second and third MCP joints were dichotomised into the joint with more severe synovitis versus the joint with less severe synovitis according to the RAMRIS synovitis subscore. RESULTS: MCP joints with more severe synovitis ('bad joints') demonstrated significantly lower dGEMRIC values compared to MCP joints with less severe synovitis ('good joints') at time-points 0 and 3 months (p=0.002; p=0.019, respectively). After 6 months of MTX therapy no significant difference of dGEMRIC index was found between good and bad joint (p=0.086). CONCLUSIONS: Under MTX therapy, biochemical cartilage integrity remains stable; no further cartilage destruction occurred if patients were treated early in the course of the disease. In addition, six months of MTX therapy triggered an alignment of dGEMRIC index of MCP joints with initially severe synovitis and less severe synovitis in an intra-individual assessment. This underlines the importance of an early treatment in eRA to reduce further cartilage damage of the inflamed joints.
28703442 Measurement of absolute copy number variation of Glutathione S-Transferase M1 gene by digi 2018 Mar BACKGROUND: The investigation of copy number variations (CNVs) analysis of candidate genes is currently an important research area in modulating human diseases. We aimed to quantify CNVs in glutathione S-transferase M1 (GSTM1) gene and determine its genetic contribution in Tunisian rheumatoid arthritis (RA) and its subsets through an innovative technique for quantification. METHODS: A total of 165 RA cases and 102 healthy controls were included in the study. Using a recently powerful approach of digital droplet PCR (ddPCR), we quantified GSTM1 gene to determine the presence of no, one, or multiple copy number (CN) at high levels of sensitivity and specificity. Odds ratio and Fisher exact test were performed to estimate the association risk for GSTM1CNVs in RA. RESULTS: Copy number identified by ddPCR was 0, 1, and 2 copies per diploid genome. A high frequency of '0' copy was revealed with 54% in RA patients. The deletion ('0' copy) of GSTM1 was found to be a significant risk factor for anti-cyclic citrullinated peptide (anti-CCP) positive RA (OR=4.16, CI(95%) =[1.17-14.7]). In addition, a lack of association was found when comparing between the CNVs of RA patients and those of controls. CONCLUSION: This study highlights the powerful accuracy of ddPCR for the quantification of CNVs and suggests that the variation in the CN of GSTM1 is associated with anti-CCP positivity in RA. However, it does not indicate a specific role in the susceptibility to the disease in our Tunisian sample.
30074882 Prediction of Real-World Drug Effectiveness Prelaunch: Case Study in Rheumatoid Arthritis. 2018 Aug BACKGROUND: Decision makers often need to assess the real-world effectiveness of new drugs prelaunch, when phase II/III randomized controlled trials (RCTs) but no other data are available. OBJECTIVE: To develop a method to predict drug effectiveness prelaunch and to apply it in a case study in rheumatoid arthritis (RA). METHODS: The approach 1) identifies a market-approved treatment ( S) currently used in a target population similar to that of the new drug ( N); 2) quantifies the impact of treatment, prognostic factors, and effect modifiers on clinical outcome; 3) determines the characteristics of patients likely to receive N in routine care; and 4) predicts treatment outcome in simulated patients with these characteristics. Sources of evidence include expert opinion, RCTs, and observational studies. The framework relies on generalized linear models. RESULTS: The case study assessed the effectiveness of tocilizumab (TCZ), a biologic disease-modifying antirheumatic drug (DMARD), combined with conventional DMARDs, compared to conventional DMARDs alone. Rituximab (RTX) combined with conventional DMARDs was identified as treatment S. Individual participant data from 2 RCTs and 2 national registries were analyzed. The model predicted the 6-month changes in the Disease Activity Score 28 (DAS28) accurately: the mean change was -2.101 (standard deviation [SD] = 1.494) in the simulated patients receiving TCZ and conventional DMARDs compared to -1.873 (SD = 1.220) in retrospectively assessed observational data. It was -0.792 (SD = 1.499) in registry patients treated with conventional DMARDs. CONCLUSION: The approach performed well in the RA case study, but further work is required to better define its strengths and limitations.
30324535 Clinical immunity in bone and joints. 2019 Jan The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.