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ID PMID Title PublicationDate abstract
29572348 Novel Anti-Inflammatory Peptides Based on Chemokine-Glycosaminoglycan Interactions Reduce 2018 May 1 Inflammation is characterized by the infiltration of leukocytes from the circulation and into the inflamed area. Leukocytes are guided throughout this process by chemokines. These are basic proteins that interact with leukocytes to initiate their activation and extravasation via chemokine receptors. This is enabled through chemokine immobilization by glycosaminoglycans (GAGs) at the luminal endothelial surface of blood vessels. A specific stretch of basic amino acids on the chemokine, often at the C terminus, interacts with the negatively charged GAGs, which is considered an essential interaction for the chemokine function. Short-chain peptides based on this GAG-binding region of the chemokines CCL5, CXCL8, and CXCL12γ were synthesized using standard Fmoc chemistry. These peptides were found to bind to GAGs with high affinity, which translated into a reduction of leukocyte migration across a cultured human endothelial monolayer in response to chemokines. The leukocyte migration was inhibited upon removal of heparan sulfate from the endothelial surface and was found to reduce the ability of the chemokine and peptide to bind to endothelial cells in binding assays and to human rheumatoid arthritis tissue. The data suggest that the peptide competes with the wild-type chemokine for binding to GAGs such as HS and thereby reduces chemokine presentation and subsequent leukocyte migration. Furthermore, the lead peptide based on CXCL8 could reduce the disease severity and serum levels of the proinflammatory cytokine TNF-α in a murine Ag-induced arthritis model. Taken together, evidence is provided for interfering with the chemokine-GAG interaction as a relevant therapeutic approach.
30136282 Changes in anti-citrullinated protein antibody isotype levels in relation to disease activ 2018 Dec Rheumatoid arthritis (RA) is a chronic inflammatory disease where serum analysis of anti-citrullinated peptide/protein antibodies (ACPA) is an important diagnostic/prognostic tool. Levels and changes of ACPA in RA patients have been studied previously in relation to disease course and therapy response, but less is known regarding ACPA isotype changes in early RA. Hence, recent-onset RA patients (n = 231) were subjected to a 3-year clinical and radiological follow-up. Serum samples were serially collected and ACPA isotypes were analysed using the second-generation cyclic citrullinated peptide (CCP) as capture antigen. Changes in ACPA isotype levels and status were related to disease course and pharmacotherapy. At inclusion, 74% of the patients tested positive for ACPA IgG; 55% for immunoglobulin (Ig)A, 37% for secretory IgA (SIgA) and 35% for IgM. The proportion of positive patients decreased significantly at follow-up regarding ACPA SIgA, IgM and IgA. During the initial 3 months, reduction of the 28-joint disease activity score (DAS28) correlated with reduced levels of ACPA IgG (Rho = 0·242, P = 0·003), IgA (Rho = 0·260, P = 0·008), IgM (Rho = 0·457, P < 0·001) and SIgA (Rho = 0·402, P < 0·001). Levels of ACPA SIgA (P = 0·008) and IgM (P = 0·021) decreased significantly among patients with good response to treatment, which was not seen regarding ACPA IgA or IgG. Changes in ACPA isotype levels were not associated with radiographic damage. In conclusion, ACPA SIgA and IgM declined rapidly upon anti-rheumatic therapy and correlated with decreased disease activity in recent-onset RA. This may indicate that down-regulation of mucosal immunity to citrullinated proteins/peptides and recruitment of new B cells are key features of therapy responses in early RA.
29142030 Plasma MicroRNA Profiles in Patients with Early Rheumatoid Arthritis Responding to Adalimu 2018 Jan OBJECTIVE: The aim was to identify plasma (i.e., cell-free) microRNA (miRNA) predicting antitumor necrosis and/or methotrexate (MTX) treatment response in patients enrolled in an investigator-initiated, prospective, double-blinded, placebo-controlled trial (The OPERA study, NCT00660647). METHODS: We included 180 disease-modifying antirheumatic drug-naive patients with early rheumatoid arthritis (RA) randomized to adalimumab (ADA; n = 89) or placebo (n = 91) in combination with MTX. Plasma samples before and 3 months after treatment initiation were analyzed for 91 specific miRNA by quantitative reverse transcriptase-polymerase chain reaction on microfluidic dynamic arrays. A linear mixed-effects model was used to test for associations between pretreatment miRNA and changes in miRNA expression and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean (28 joints) remission at 3 and 12 months, applying false discovery rate correction for multiple testing. Using leave-one-out cross validation, we built predictive multivariate miRNA models and estimated classification performances using receiver-operating characteristics (ROC) curves. RESULTS: In the ADA group, a higher pretreatment level of miR-27a-3p was significantly associated with remission at 12 months. The level decreased in remitting patients between pretreatment and 3 months, and increased in nonremitting patients. No associations were found in the placebo group receiving only MTX. Two multivariate miRNA models were able to predict response to ADA treatment after 3 and 12 months, with 63% and 82% area under the ROC curves, respectively. CONCLUSION: We identified miR-27a-3p as a potential predictive biomarker of ACR/EULAR remission in patients with early RA treated with ADA in combination with MTX. We conclude that pretreatment plasma-miRNA profiles may be of predictive value, but the results need confirmation in independent cohorts.
30008457 Cardiovascular Disease Prevention in Rheumatoid Arthritis: Compliance with Diabetes Screen 2018 Oct OBJECTIVE: To evaluate compliance with diabetes screening guidelines for cardiovascular disease (CVD) prevention in rheumatoid arthritis (RA) compared to the general population. METHODS: We conducted the first longitudinal study of a population-based RA cohort including all prevalent RA cases in British Columbia between 1996 and 2006 and followed until 2010, with matched general population comparators. Using administrative data, we measured compliance with general population guidelines [i.e., testing plasma glucose (PG) at least once every 3 years after age 45] after excluding individuals with previous diabetes. Followup was divided into 3-year eligibility periods. Compliance was measured as the proportion of periods with ≥ 1 PG test performed. OR (95% CI) of compliance in RA (vs general population) was calculated using generalized estimating equation models, adjusting for age and sex. Mean compliance rate per patient was also calculated and compared using the Mann-Whitney U test. RESULTS: Analysis included 22,624 individuals with RA, contributing 48,724 three-year eligibility periods; and 22,579 people in a general population group, contributing 51,081 three-year eligibility periods. PG was measured in 72.3% (SD 37%) of the eligible time periods in the RA sample and in 70.4% (SD 38%) for the general population (OR 1.05, 95% CI 1.02-1.09, p < 0.0001). RA individuals met recommended screening guidelines in 71.4% of their eligible periods, compared to 70.6% (p < 0.001). Screening improved over time in RA relative to the general population. Family physicians ordered nearly all the PG tests. CONCLUSION: Compliance with general population guidelines for diabetes screening in RA was suboptimal, with little difference relative to the general population, despite a higher risk of CVD and diabetes.
30638679 Modulation of autoimmune arthritis by environmental 'hygiene' and commensal microbiota. 2019 May Observations in patients with autoimmune diseases and studies in animal models of autoimmunity have revealed that external environmental factors including exposure to microbes and the state of the host gut microbiota can influence susceptibility to autoimmunity and subsequent disease development. Mechanisms underlying these outcomes continue to be elucidated. These include deviation of the cytokine response and imbalance between pathogenic versus regulatory T cell subsets. Furthermore, specific commensal organisms are associated with enhanced severity of arthritis in susceptible individuals, while exposure to certain microbes or helminths can afford protection against this disease. In addition, the role of metabolites (e.g., short-chain fatty acids, tryptophan catabolites), produced either by the microbes themselves or from their action on dietary products, in modulation of arthritis is increasingly being realized. In this context, re-setting of the microbial dysbiosis in RA using prebiotics, probiotics, or fecal microbial transplant is emerging as a promising approach for the prevention and treatment of arthritis. It is hoped that advances in defining the interplay between gut microbiota, dietary products, and bioactive metabolites would help in the development of therapeutic regimen customized for the needs of individual patients in the near future.
29508096 Low-dose methotrexate in rheumatoid arthritis: a potential risk factor for bisphosphonate- 2018 Jun Bisphosphonate-induced osteonecrosis of the jaw [BIONJ] is a relatively new pathological condition which was first described in the year 2003. The prevalence of BIONJ in patients on oral formulations is around 0.05% within the first 3 years and increases up to 0.2% after 4 years of consumption. Proven systemic risk factors like anemia, uncontrolled diabetes, corticosteroid therapy, and chemotherapy in neoplastic diseases [e.g., high doses of methotrexate up to 30 mg daily] significantly increase the chances of acquiring BIONJ. We present three patients with osteoporosis and rheumatoid arthritis [RA] who consumed oral bisphosphonates [alendronate] for less than 1 year and developed BIONJ within 2 to 5 months of undergoing a traumatic dental procedure. The patients also gave a history of consuming low doses of methotrexate [disease-modifying anti-rheumatic drugs] up to 20 mg weekly for 4 to 10 years. No history of steroid consumption was given by any of the patients. This case series highlights the possibility of rheumatoid arthritis and low-dose methotrexate being potential risk factors for BIONJ. This may be on account of the synergistic effect of methotrexate and bisphosphonates and the pro-inflammatory state created by RA which increased the risk of acquiring BIONJ.
28696795 Decoy receptor 3 down-regulates centrosomal protein 70 kDa specifically in rheumatoid sy 2018 Mar OBJECTIVES: Decoy receptor 3 (DcR3) competitively binds to Fas ligand, lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpes virus entry mediator on T cells (LIGHT) and TNF-like ligand 1A (TL1A), thereby preventing their effects. Using a microarray assay, we previously newly identified centrosomal protein 70 kDa (CEP70) as one of the genes whose expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA-FLS) is reduced by DcR3. Here, we investigated the significance of DcR3 regulation of CEP70 for RA-FLS. METHODS: Synovial samples were obtained from RA patients who had never been treated with biologics and from osteoarthritis (OA) patients. CEP70 mRNA expression was quantified using RT-qPCR analysis. CEP70 protein expression was assessed using immunohistochemical and western blot analyses. RESULTS: CEP70 was expressed predominantly in the superficial lining layer in RA synovial tissue. CEP70 expression was dose-dependently downregulated by DcR3-Fc in RA-FLS but was not downregulated in OA-FLS. TL1A antibody prevented the DcR3-Fc inhibitory effects on CEP70 expression in RA-FLS. CONCLUSIONS: These results indicated that DcR3 reduces CEP70 expression in RA-FLS by binding to membrane-bound TL1A and may suppress RA-FLS proliferation. The reduction in CEP70 expression by DcR3/TL1A signaling may control the hyperplasia of RA synovium.
29850885 The ability of rheumatologists blinded to prior workup to diagnose rheumatoid arthritis on 2018 Sep 1 OBJECTIVES: We aimed to study the ability of board-certified rheumatologists, blinded to all prior diagnostic test results, to establish the presence/absence of an inflammatory rheumatic disease (IRD) or RA among polyarthralgia or arthritis patients, solely relying on clinical assessment. METHODS: We performed a prospective, examiner-blinded, cross-sectional study documenting the diagnostic work in four sequential steps (medical history, physical examination, musculoskeletal ultrasonography and laboratory tests) of board-certified rheumatologists in a convenience cohort of 100 patients referred for inpatient diagnostic workup to a tertiary care rheumatology centre. RESULTS: The ability to correctly identify patients with or without an IRD (diagnostic accuracy) increased from 27% after the clinical assessment to 53% after the ultrasonography and to 70% after taking laboratory test results into account. The corresponding values for correctly identifying patients with or without RA were 19, 42 and 60%, respectively. Therefore the diagnostic accuracy of solely clinical assessment for determining the diagnosis of IRD or RA compared with the diagnosis established by a consecutive thorough in-patient workup was only 27 and 19% in our cohort, respectively. Pretreatment with corticosteroids (in the prior 7 days) vs none did not alter these results substantially (20 vs 29% for IRD, 15% vs 20% for RA). CONCLUSION: Experienced rheumatologists, if deprived of information on prior external imaging and laboratory workup by blinding, were not able to correctly classify the majority of patients presenting with polyarthralgia or arthritis symptoms for inpatient workup, relying only on a brief symptom-focused medical history and physical examination.
28701065 Predictors of biologic discontinuation due to insufficient response in patients with rheum 2018 Mar OBJECTIVE: This study aimed to investigate predictors of biologic discontinuation due to insufficient response as a surrogate for relapse in patients with rheumatoid arthritis (RA) who achieved clinical remission with biologic treatment. METHODS: This study was performed based on data from a multicenter registry, and included 404 patients who achieved clinical remission within the first year of treatment with their first biologic. Cumulative retention rate of the first biologic was estimated using Kaplan-Meier curves, and the impact of patient characteristics on biologic discontinuation was assessed with Cox proportional hazards models. RESULTS: During follow-up, 50 patients discontinued their first biologic due to insufficient response. Overall discontinuation rates due to insufficient response after achieving remission were 6%, 11%, and 19% at 1, 2, and 5 years, respectively. Multivariate analysis revealed that concomitant glucocorticoids at achieving remission [hazard ratio (HR): 3.80, 95% confidence interval (CI): 1.89-7.64)] and a higher level of C-reactive protein (CRP) at achieving remission (HR: 1.47 per 1 mg/dL, 95% CI: 1.09-1.99) independently predict discontinuation due to insufficient response after achieving remission. CONCLUSION: Patients with RA who achieved remission with concomitant glucocorticoid treatment and a higher level of CRP are at high risk of subsequent biologic discontinuation due to insufficient response.
29336187 Efficacy and safety of sirukumab in Japanese patients with moderate to severe rheumatoid a 2018 Nov OBJECTIVE: To evaluate the efficacy and safety of sirukumab in Japanese patients with active rheumatoid arthritis (RA) uncontrolled by disease-modifying antirheumatic drugs. METHODS: This subgroup analysis based on a double-blind, placebo-controlled, 52-week phase 3 study (SIRROUND-D) assessed American College of Rheumatology (ACR) 20 response at week 16 and van der Heijde-modified Sharp score (vdH-S) at week 52 (coprimary endpoints). RESULTS: A total of 168 (Japanese)/1670 patients received sirukumab 50 mg/4 weeks (q4w, n = 58), 100 mg/every 2 weeks (q2w, n = 54), or placebo (n = 56) subcutaneously. Significantly more patients achieved ACR20 response at week 16 with sirukumab (50 mg q4w: 69.0%; 100mg q2w: 66.7%) vs. placebo (21.4%; p < .001). Median change from baseline in total vdH-S score at week 52 was significantly lower with sirukumab (50 mg q4w: 0.3, p = .024; 100 mg q2w: 0.0, p = .002) vs. placebo (1.3). Sirukumab consistently showed greater improvements in secondary endpoints at weeks 24 and 52. Nasopharyngitis, elevated liver enzymes, injection site erythema and upper respiratory tract infections were the common treatment-emergent adverse events (TEAEs). Incidences of TEAEs and serious AEs were consistent between sirukumab groups through week 52. CONCLUSION: Sirukumab showed clinically meaningful improvements consistent with significant improvements in the global study. No new safety signals were observed.
29453198 Targeting KCa1.1 Channels with a Scorpion Venom Peptide for the Therapy of Rat Models of R 2018 May Fibroblast-like synoviocytes (FLSs) are a key cell type involved in rheumatoid arthritis (RA) progression. We previously identified the KCa1.1 potassium channel (Maxi-K, BK, Slo 1, KCNMA1) as a regulator of FLSs and found that KCa1.1 inhibition reduces disease severity in RA animal models. However, systemic KCa1.1 block causes multiple side effects. In this study, we aimed to determine whether the KCa1.1 β1-3-specific venom peptide blocker iberiotoxin (IbTX) reduces disease severity in animal models of RA without inducing major side effects. We used immunohistochemistry to identify IbTX-sensitive KCa1.1 subunits in joints of rats with a model of RA. Patch-clamp and functional assays were used to determine whether IbTX can regulate FLSs through targeting KCa1.1. We then tested the efficacy of IbTX in ameliorating disease in two rat models of RA. Finally, we determined whether IbTX causes side effects including incontinence or tremors in rats, compared with those treated with the small-molecule KCa1.1 blocker paxilline. IbTX-sensitive subunits of KCa1.1 were expressed by FLSs in joints of rats with experimental arthritis. IbTX inhibited KCa1.1 channels expressed by FLSs from patients with RA and by FLSs from rat models of RA and reduced FLS invasiveness. IbTX significantly reduced disease severity in two rat models of RA. Unlike paxilline, IbTX did not induce tremors or incontinence in rats. Overall, IbTX inhibited KCa1.1 channels on FLSs and treated rat models of RA without inducing side effects associated with nonspecific KCa1.1 blockade and could become the basis for the development of a new treatment of RA.
30630786 Inhibitory effect of Saposhnikovia divaricate polysaccharide on fibroblast-like synoviocyt 2018 Nov To study the mechanism and inhibitory effect of Saposhnikovia divaricata polysaccharide (SDP) on fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis rat model. Rheumatoid arthritis rat model was established by the classical composite factors including wind, cold, damp plus biological agents. The synovial tissues were digested with trypsin to isolate FLS cells. The different dosage of SDP was applied in culture. The cell viability was evaluated by MTT assay and the apoptosis was determined by analytic flow cytometry. The expression change of p53 gene was monitored by RT-PCR method. The production of secretory inflammation factors TNF-α and IL-1β were determined by ELISA. The proliferative and apoptotic proteins such as Bcl-2, Bax, Caspase-3, MMP-1, MMP-3, P53 were measured by western blotting. Our data demonstrated that treatment with high concentration of SDP could enhance the expression of P53 at both mRNA (P<0.05) and protein (P<0.05) level, inhibit the secretion of TNF-α (P<0.05) and IL-1β (P<0.05). Simultaneously, the Bcl-2/Bax ratio and level of MMP-1, MMP-3 was significantly decreased, and apoptotic marker caspase-3 protein was increased. In addition, the FACS analysis consistently consolidated the apoptosis-inducing effect of SDP on RAFLS. SDP could significantly inhibit dysplasia of RAFLS via modulation of p53 expression and suppression of inflammatory factors, which suggested a potential therapeutic value for rheumatoid arthritis.
29724250 Does information on novel identified autoantibodies contribute to predicting the progressi 2018 May 3 BACKGROUND: The presence of autoantibodies is considered an important characteristic of rheumatoid arthritis (RA); therefore, both anticitrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are included in the 2010 classification criteria for rheumatoid arthritis (RA). However, a considerable number of RA patients lack both these autoantibodies. Recently, several novel autoantibodies have been identified but their value for the classification of RA patients is unclear. Therefore, we studied the value of novel autoantibodies using the presence of anticarbamylated protein (anti-CarP) antibodies as an example for predicting RA development in patients with undifferentiated arthritis (UA). METHODS: There were 1352 UA patients included in the Leiden Early Arthritis Clinic (EAC) cohort according to the 1987 criteria. When the 2010 criteria were used, there were 838 UA patients. Of these, we evaluated whether they fulfilled the 1987 or 2010 criteria after 1 year, respectively. Logistic regression analyses were performed with RA as outcome and ACPA, RF, and anti-CarP antibodies as predictors. Analyses were repeated after stratification for ACPA and RF. RESULTS: Thirty-three percent of the 1987-UA patients and 6% of the 2010-UA patients progressed to RA during the first year of follow-up. For the 1987-UA patients, anti-CarP antibodies were associated with progression to RA, an association which remained when a correction was made for the presence of ACPA and RF (odds ratio (OR) 1.7, 95% confidence interval (CI) 1.2-2.4). After stratification for ACPA and RF, anti-CarP antibodies were associated with progression to RA only for ACPA- and RF-negative patients (OR 2.1, 95% CI 1.3-3.7). For the 2010-UA patients, anti-CarP antibodies were associated with progression to RA; however, they were not when a correction was made for the presence of ACPA and RF (OR 0.8, 95% CI 0.3-2.1). CONCLUSIONS: Our finding that anti-CarP antibodies have no additional value when RA is defined according to the 2010 criteria might be inherent to the composition of the 2010 criteria and therefore might also apply to other novel autoantibodies. Potentially it would be interesting to evaluate other, non-autoantibody biomarkers.
29433546 A unique role for galectin-9 in angiogenesis and inflammatory arthritis. 2018 Feb 12 BACKGROUND: Galectin-9 (Gal-9) is a mammalian lectin secreted by endothelial cells that is highly expressed in rheumatoid arthritis synovial tissues and synovial fluid. Roles have been proposed for galectins in the regulation of inflammation and angiogenesis. Therefore, we examined the contribution of Gal-9 to angiogenesis and inflammation in arthritis. METHODS: To determine the role of Gal-9 in angiogenesis, we performed human dermal microvascular endothelial cell (HMVEC) chemotaxis, Matrigel tube formation, and mouse Matrigel plug angiogenesis assays. We also examined the role of signaling molecules in Gal-9-induced angiogenesis by using signaling inhibitors and small interfering RNA (siRNA). We performed monocyte (MN) migration assays in a modified Boyden chamber and assessed the arthritogenicity of Gal-9 by injecting Gal-9 into mouse knees. RESULTS: Gal-9 significantly increased HMVEC migration, which was decreased by inhibitors of extracellular signal-regulating kinases 1/2 (Erk1/2), p38, Janus kinase (Jnk), and phosphatidylinositol 3-kinase. Gal-9 HMVEC-induced tube formation was reduced by Erk1/2, p38, and Jnk inhibitors, and this was confirmed by siRNA knockdown. In mouse Matrigel plug assays, plugs containing Gal-9 induced significantly higher angiogenesis, which was attenuated by a Jnk inhibitor. Gal-9 also induced MN migration, and there was a marked increase in MN ingress when C57BL/6 mouse knees were injected with Gal-9 compared with the control, pointing to a proinflammatory role for Gal-9. CONCLUSIONS: Gal-9 mediates angiogenesis, increases MN migration in vitro, and induces acute inflammatory arthritis in mice, suggesting a novel role for Gal-9 in angiogenesis, joint inflammation, and possibly other inflammatory diseases.
30268355 Does inflammatory joint diseases affect the accuracy of infection biomarkers in patients w 2019 Mar BACKGROUND: The diagnosis of periprosthetic joint infections (PJI) in patients with inflammatory joint diseases (IJD) could be challenging. Several tests used for diagnosing PJI may be inaccurate due to baseline inflammatory characteristics of such diseases. We aimed to evaluate the accuracy of several infection biomarkers, in a specific subgroup of patients with PJI and IJD. METHODS: From January 2014 to August 2017, patients with resisting pain at the relevant site, following total knee arthroplasty were evaluated prospectively. A total of 38 patients were undergone revision arthroplasty. Patients were categorized in terms of MSIS criteria: Patients with PJI (Group 1, n = 17) and patients without PJI (Group 2, n = 21). Serum ESR, CRP, Procalcitonin, synovial cell count, percentage of neutrophils in synovial fluid, synovial CRP, Lactoferrin, ELA-2, Thiol - Disulphide levels, BPI and the Alpha defensin test results were obtained. The results of two groups were compared and the diagnostic accuracy of each variable was evaluated. RESULTS: There were 22 women, 16 men with a mean age of 67.8 ± 6.9 years. The differences were significant in all evaluated biomarkers in terms of PJI (p values of all biomarker were <0.001). Alpha defensin, Lactoferrin, ELA-2, BPI, Procalcitonin and synovial CRP were the most accurate tests with area under curve >0.90. CONCLUSIONS: Our results demonstrated that IJD may not affect the accuracy of infection biomarkers in patients with PJI. Alpha defensin test, Lactoferrin, ELA-2, BPI, Procalcitonin and synovial CRP can be used in the diagnosis of PJI in patients with IJD.
29155973 Tapering versus steady-state methotrexate in combination with tocilizumab for rheumatoid a 2018 Jan 1 OBJECTIVE: To explore whether tocilizumab + tapering MTX has comparable efficacy and safety vs tocilizumab + stable MTX in adult RA patients with inadequate response to MTX. METHODS: This randomized, placebo-controlled non-inferiority study involved patients with severe active RA [28-joint DAS (DAS28) >5.1] who had initiated tocilizumab + MTX at the study start. Patients received open-label tocilizumab (8 mg/kg i.v. every 4 weeks) and open-label MTX. At week 24, patients achieving good/moderate EULAR response were randomized to group A (double-blind MTX taper) or group B (double-blind MTX maintenance); both arms continued open-label tocilizumab. Primary analysis was the proportion of patients maintaining good/moderate EULAR response from week 24 to 60. RESULTS: The study stopped early due to low recruitment, although the predetermined non-inferiority criteria were still met; 427 patients were enrolled to the open-label phase at week 0. At week 24, EULAR good/moderate response was achieved in 272 individuals (64.4%) who were randomized, 136 in each arm (36% withdrew/were not eligible). Additionally, 45.0% achieved DAS28 ⩽3.2, 33.5% achieved remission (DAS28 <2.6) and 64.2% had a DAS28 change ⩾1.2. After week 24 randomization, the proportion of patients maintaining good/moderate EULAR response to week 60 was significantly greater for MTX taper vs stable MTX (76.5 vs 65.4%; P = 0.036), and since the lower limit of the 95% CI was >0.9, the pre-determined criteria for non-inferiority was fulfilled despite reduced recruitment. Safety analysis revealed no unexpected tocilizumab safety signals. CONCLUSIONS: Tapering MTX in patients with RA receiving tocilizumab was non-inferior to continuing stable MTX in maintaining a good/moderate EULAR response. There were no unexpected safety signals; tocilizumab and MTX therapy was generally well tolerated in both groups. Trial registration number: EudraCT 2011-005260-20.
29780382 Extracellular Purine Metabolism Is the Switchboard of Immunosuppressive Macrophages and a 2018 If misregulated, macrophage (Mϕ)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ(+)CD39(+)CD73(+) Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.
30324406 The persistence of golimumab compared to other tumour necrosis factor-α inhibitors in dai 2019 Feb To assess the persistence of golimumab and other tumour necrosis factor-α inhibitors (TNFis) in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) in Slovenia. We analysed prospectively the collected data of all patients treated with golimumab and other TNFis from 1 January 2010 to 31 July 2018 from the mandatory national BioRx.si registry. We assessed the treatment persistence stratified by treatment type, indication and prior exposure to bDMARDs using the Kaplan-Meier method and Cox proportional regression hazards' models adjusted for the well-appreciated confounders. We also assessed its effectiveness at 1 year after the initiation of therapy. During the 7-year observation period, 24 Slovenian rheumatologists from eight centres contributed data on 368, and 1654 patients treated for 849, and 3321 person-years with golimumab and other TNFis, respectively. The overall proportions of RA, AS and PsA patients being persistent on golimumab vs. other TNFis at 2 years after starting the therapy did not differ significantly and were 53%, 67% and 59% vs. 47%, 65% and 59%, respectively. The crude and adjusted hazard ratios for golimumab discontinuation did not differ significantly between bDMARD-naïve and bDMARD-experienced patients for any of the indications. In contrast, bDMARD-experienced AS and PsA patients treated with other TNFis were significantly more likely to discontinue treatment. The persistence of golimumab in patients with RA, AS and PsA in Slovenia was comparable with its persistence in more affluent Western European countries. We observed a better persistence of golimumab compared to other TNFis in bDMARD-experienced AS and PsA patients.
29750395 Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With 2018 Nov OBJECTIVE: It has been reported that ADAMTS-12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS-12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS-12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. METHODS: The collagen-induced arthritis (CIA) model was established in ADAMTS-12-deficient mice and their control littermates to determine the role of ADAMTS-12 in vivo. Micro-computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme-linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein-protein interaction assays were performed to detect the interactions of ADAMTS-12 and its various deletion mutants with connective tissue growth factor (CTGF). RESULTS: Deficiency of ADAMTS-12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS-12 caused enhanced osteoclastogenesis. In vitro and in vivo protein-protein interaction assays demonstrated that ADAMTS-12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS-12. In addition, deletion of ADAMTS-12 enhanced, while overexpression of ADMATS-12 reduced, CTGF-mediated inflammation. Furthermore, ADAMTS-12 regulation of inflammation was largely lost in CTGF-deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS-12-deficient CIA mouse model. CONCLUSION: This study provides evidence that ADAMTS-12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover.
29756256 Peptidylarginine deiminases and deiminated proteins at the epidermal barrier. 2018 Aug Deimination or citrullination is a post-translational modification catalysed by a family of calcium-dependent enzymes called peptidylarginine deiminases (PADs). It corresponds to the transformation of arginine residues within a peptide sequence into citrulline residues. Deimination induces a decreased net charge of targeted proteins; therefore, it alters their folding and changes intra- and intermolecular ionic interactions. Deimination is involved in several physiological processes (inflammation, gene regulation, etc.) and human diseases (rheumatoid arthritis, neurodegenerative diseases, cancer, etc.). Here, we describe the PADs expressed in the epidermis and their known substrates, focusing on their role in the epidermal barrier function.