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ID PMID Title PublicationDate abstract
31431998 Efficacy and safety of subcutaneous tocilizumab in rheumatoid arthritis over 1 year: a UK 2019 OBJECTIVE: The ACT-MOVE study assessed the real-world efficacy and safety of s.c. tocilizumab (TCZ-SC), provided as monotherapy or in combination with conventional synthetic DMARDs (csDMARDs) over 1 year, in patients with RA and an inadequate response to csDMARD therapy and/or first TNF inhibitor. METHODS: In this UK multicentre, open-label phase IIIb study, patients received TCZ-SC 162 mg once weekly for 52 weeks as monotherapy or with csDMARDs. Efficacy and safety were evaluated at baseline, weeks 2 and 4 and every 4 weeks thereafter up to week 52. RESULTS: Of 161 patients who received at least one dose of TCZ-SC, 21 (13.0%) received TCZ-SC alone and 140 (87.0%) TCZ-SC with a csDMARD(s). From baseline to week 52, there was a mean decrease in DAS28-ESR score among all patients (-3.68), and within monotherapy (-3.75) and combination therapy (-3.67) groups. The proportion of patients who achieved DAS28 clinical remission (DAS28-ESR <2.6) at week 52 was 75.4% (95% CI 66.8, 82.8). At the same time point, ≥80% of patients who remained on TCZ-SC achieved DAS28 clinical remission or had low disease activity (DAS28-ESR ≥2.6 and ≤3.2). Overall, 6.2% of patients had at least one serious adverse event (10.2/100 patient-years), and there was one death; 11.2% of patients discontinued owing to adverse events. CONCLUSION: TCZ-SC was effective and tolerated in a real-world setting over 1 year. The efficacy of TCZ-SC was similar whether given as monotherapy or with csDMARDs; its safety profile was consistent with that previously established. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT02046603.
29982743 The 70th anniversary of glucocorticoids in rheumatic diseases: the second youth of an old 2019 Apr 1 Seventy years ago, the first administration of cortisone in a patient with RA marked a milestone in the treatment of inflammatory diseases. However, the initial enthusiasm rapidly vanished as the administration of high doses for lengthy periods revealed worrisome adverse effects. It has taken several decades to overcome the (sometimes excessive) mistrust and to achieve a more differentiated evaluation of the benefit-risk profile and the adequate usage of glucocorticoids (GCs). Today, GCs remain indispensable for the treatment of many inflammatory conditions and their usefulness in RA as a disease-modifying low-dose co-medication is widely acknowledged. Recent studies show promising results concerning both traditional GCs and new formulations. Still, decades of relatively little scientific attention have resulted in a continuing lack of detailed evidence. Hence there is an ongoing need for further research regarding mechanisms of GC actions, the further optimization of treatment parameters for traditional GCs and new formulations.
30949048 Subantimicrobial Dose Doxycycline Worsens Chronic Arthritis-Induced Bone Microarchitectura 2019 Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease hallmarked by irreversible damage of cartilage and bone. Matrix metalloproteinases (MMPs) involved in connective tissue remodeling play an important role in this process. Numerous MMPs have been examined in humans and animals, but their functions are still not fully understood. Therefore, we investigated the role of MMPs in the K/BxN serum-transfer model of RA with the broad-spectrum MMP inhibitor subantimicrobial dose doxycycline (SDD) using complex in vivo and in vitro methodolgy. Methods: Chronic arthritis was induced by repetitive i.p. injections of K/BxN serum in C57BL/6J mice. SDD was administered daily in acidified drinking water (0.5 mg/mL, 80 mg/kg) during the 30 days experimental period. Mechanonociceptive threshold of the paw was evaluated by aesthesiometry, grasping ability by grid test, arthritis severity by scoring, neutrophil myeloperoxidase activity by luminescence, vascular hyperpermeability and MMP activity by fluorescence in vivo imaging and the latter also by gelatin zymography, bone structure by micro-computed tomography (micro-CT). Plasma concentrations of doxycycline were determined by liquid chromatography-mass spectrometry analysis. Results: K/BxN serum induced significant inflammatory signs, mechanical hyperalgesia, joint function impairment, increased myeloperoxidase activity and vascular hyperpermeability. Significant increase of MMP activity was also observed both in vivo and ex vivo with elevation of the 57-60, 75, and 92 kDa gelatinolytic isoforms in the arthritic ankle joints, but neither MMP activity nor any above described functional parameters were influenced by SDD. Most importantly, SDD significantly reduced bone mineral density in the distal tibia and enhanced the Euler number in the ankle. Arthritis-induced microarchitectural alterations demonstrating increased irregularity and cancellous bone remodeling, such as increased Euler number was significantly elevated by SDD in both regions. Conclusion: We showed increase of various MMP activities in the joints by in vivo fluorescence imaging together with ex vivo zymography, and investigated their functional significance using the broad-spectrum MMP inhibitor SDD in the translational RA model. This is the first demonstration that SDD worsens arthritis-induced bone microarchitectural alterations, but it appears to be independent of MMP inhibition.
31599078 The therapeutic effects of edaravone on collagen-induced arthritis in rats. 2020 Feb Current research suggests that synovial phagocytic cells remove excessive amounts of free oxygen radicals (reactive oxygen species [ROS]), thereby preventing damage to synovial tissues. Moreover, ROS may affect the expression of growth arrest and DNA damage inducible α (GADD45A), thus further promoting the activation of synovial fibroblasts. Male adult rats were assessed for progression of collagen-induced arthritis (CIA) using a macroscopic arthritis scoring system of the hind paws and by measuring the changes in the rat's body weight, and activity level before and after diagnosis of CIA. Rats were intraperitoneally injected twice daily with edaravone at doses of 3, 6, and 9 mL/kg. Samples were taken at 2, 4, and 6 weeks, respectively. Edaravone was found to significantly reduce macroscopic arthritis and microscopic pathology scores in CIA rats. The concentration of endothelial nitric oxide synthase-6, glutathione, and heme oxygenase-1 in the serum of rats decreased, as was the production of ROS around the synovium and inflammatory factors. Moreover, ROS-1 increased the expression of the nuclear factor-κB (NF-κB) p65 protein by altering the expression level of GADD45A, causing aggravation of tissue damage. Edaravone also significantly improved the physiological condition of CIA rats, including appetite, weight changes, and loss of fur, as well as limb mobility. We believe that edaravone acts to reduce the expression of NF-ĸB p65 by clearing ROS, which causes reduced expression of GADD45A, and subsequently reduces the level of apoptosis and inflammatory response proteins, thereby reducing the symptoms of CIA. We, therefore, propose that edaravone is an effective option for clinical treatment of rheumatic arthritis.
31392302 Protective effect of hydroxychloroquine on rheumatoid arthritis-associated atherosclerosis 2019 Jun BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease. We examined the effect of gut microbiota in a mouse model of RA that develops atherosclerosis. METHODS: We created three groups of K/BxN female mice that were positive for the anti-glucose-6-phosphate isomerase (GPI) antibody: control diet (CD), high fat diet (HFD), and HFD with hydroxychloroquine (HFD + HCQ). Serological tests were used to detect the serum levels of total cholesterol (TCHO), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), anti-GPI antibody titers, and serum cytokines. Atherosclerotic plaque was determined by histological analysis, and gut microbiota were determined by 16sV4 sequencing. RESULTS: Relative to mice given the CD, those receiving the HFD had increased serum levels of LDL-C, TCHO, and TG, decreased serum levels of HDL-C, increased atherosclerotic lesions in the aortic root, and altered gut microbiota. Addition of HCQ to HFD decreased the serum levels of LDL-C, TCHO, and TG, increased serum levels of HDL-C, and decreased the atherosclerotic lesions in the aortic root. Mice receiving HFD + HCQ also had the greatest bacterial diversity among the three experimental groups. Moreover, HCQ treatment significantly increased the abundance of Akkermansia and Parabacteroides, and decreased the abundance of Clostridium sensu stricto cluster 1, and therefore may be responsible for the reduced RA-associated atherosclerosis and dyslipidemia. CONCLUSION: Our mouse model of RA indicated that HFD increased ankle width and aggravated atherosclerosis and dyslipidemia, and that HCQ alleviated the dyslipidemia and atherosclerosis, but had no effect on ankle width.
31168413 Low rates of radiographic progression of structural joint damage over 2 years of baricitin 2019 OBJECTIVES: To evaluate radiographic progression of structural joint damage over 2 years in patients with rheumatoid arthritis from baricitinib clinical trials who were disease-modifying antirheumatic drug (DMARD)-naïve or had an inadequate response to conventional synthetic DMARDs (csDMARD-IR). METHODS: Patients had completed one of three phase III studies and entered a long-term extension (LTE) study, continuing on the same baricitinib dose as at originating study completion. At 52 weeks, DMARD-naïve patients receiving methotrexate (MTX) or combination therapy (baricitinib 4 mg+MTX) were switched to baricitinib 4 mg monotherapy (±MTX per investigator opinion); MTX-IR patients receiving adalimumab were switched to baricitinib 4 mg on background MTX. At 24 weeks, csDMARD-IR patients receiving placebo were switched to baricitinib 4 mg on background csDMARD. Radiographs at baseline, year 1 and year 2 were scored using the van der Heijde modified Total Sharp Score. Linear extrapolation was used for missing data. RESULTS: Of 2573 randomised patients, 2125 (82.6%) entered the LTE, of whom 1893 (89.1%) entered this analysis. At year 2, progression was significantly lower with initial baricitinib (monotherapy or combination therapy) versus initial MTX in DMARD-naïve patients (proportion with non-progression defined by ≤smallest detectable change (SDC): 87.3% baricitinib 4 mg+MTX; 70.6% MTX; p≤ 0.001). In MTX-IR patients, progression with initial baricitinib was significantly lower than with initial placebo and similar to initial adalimumab (≤SDC: 82.7% baricitinib 4 mg; 83.5% adalimumab; 70.6% placebo; p≤0.001). In csDMARD-IR patients, significant benefit was seen with baricitinib 4 mg (≤SDC: 87.2% vs 73.2% placebo; p≤0.01). CONCLUSIONS: Treatment with once-daily baricitinib resulted in low rates of radiographic progression for up to 2 years.
31357088 CD26 in autoimmune diseases: The other side of "moonlight protein". 2019 Oct Dipeptidyl peptidase 4 (DPP-4) is a serine protease, which has enzymatic activity to selectively clean the N-terminal dipeptide of peptides and proteins with proline or alanine in the second position. DPP-4 inhibitor has been widely used for the treatment of type 2 diabetes by increasing the level of the glucagon-like peptide-1 and decreasing the glucose level. DPP-4, also known as lymphocyte cell surface protein CD26, plays a core role of T cell immunity. Many roles of CD26 in other immune cells have been found. As a "moonlight protein", the effect of CD26 in autoimmune diseases has attracted more and more attention. The paper reviewed the function and potential effect of CD26 in autoimmune diseases, which shows CD26 may be a new target of autoimmune diseases deserved further study.
30783431 Downregulated MEG3 participates in rheumatoid arthritis via promoting proliferation of fib 2019 Mar Maternally expressed gene 3 (MEG3) in rheumatoid arthritis (RA) and its underlying mechanism were explored. Synovial tissues from 10 RA patients and 10 controls were collected to detect MEG3 expression in fibroblast-like synoviocytes (FLS). The relationship between MEG3 expression and TNF-α was analyzed. After MEG3 knockdown by lentivirus transfection, cell cycle, proliferation, apoptosis, invasion and secretion of inflammatory factors were detected. Furthermore, the effect of MEG3 on STAT3 and PI3K/AKT pathways was explored. MEG3 was downregulated in RA patients, and exogenous TNF-α treatment could decrease MEG3 expression. After transfection with lentivirus, downregulated MEG3 led to FLS proliferation and secretion of inflammatory cytokines, IL-6 and IL-8, improved the invasive ability and inhibited apoptosis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results revealed that downregulated MEG3 increased the expression levels of MMP2 and MMP9. Western blotting results showed that downregulated MEG3 activated STAT3 and PI3K/AKT pathways. Downregulated MEG3 was able to promote proliferation and invasion, and inhibit apoptosis of FLS via STAT3 pathway.
33405657 Fluorogenic Probe for Detecting Active Matrix Metalloproteinase-3 (MMP-3) in Plasma and Pe 2019 Jun 10 Diagnosis of patients with rheumatoid arthritis (RA) is essential for early and accurate drug treatment to protect the patient from joint bone erosion and relieve symptoms of the disease. In some cases, the RA patient's X-ray images and other clinical diagnostic methods are often difficult to distinguish from different diseases, such as gout, osteoarthritis, and other inflammatory conditions. Thus, methods for diagnosis of disease activity and real-time monitoring of therapeutic effect and accurate differentiation from other bone diseases are needed. In this article, we suggest a matrix metalloproteinase-3 (MMP-3)-specific protease-activated probe immobilized in vitro kit and cell staining for flow cytometry analysis as methods to support clinical diagnosis. To overcome interindividual differences, we used phorbol 12-myristate 13-acetate (PMA)-activated plasma from 269 RA patients, 49 osteoarthritis patients, and 30 healthy volunteers. The in vitro kit developed for PMA-activated plasma showed potential for identifying disease severity and distinguishing RA from other bone diseases. In particular, expression of active MMP-3 increased until the moderate disease activity and then sharply decreased at severe disease. We suggest an analysis of intracellular MMP-3-specific protease-activated probe staining by flow cytometry. Compared with anti-MMP-3 antibody staining, the results for active MMP-3 in neutrophils using the probe exactly matched the results obtained with the in vitro kit. We also confirmed that expression of active MMP-3 was mainly from neutrophils. Together, these results suggest that the MMP-3-specific protease-activated probe might be a promising noninvasive tool for accurate diagnosis of disease severity and differentiation from similar bone diseases as well as for monitoring therapeutic efficacy.
32440504 Genistein inhibits angiogenesis developed during rheumatoid arthritis through the IL-6/JAK 2020 May BACKGROUND: Angiogenesis plays an important role in the development of rheumatoid arthritis (RA), which increases the supply of nutrients, cytokines, and inflammatory cells to the synovial membrane. Genistein (GEN), a soy-derived isoflavone, has been validated that can effectively inhibit the angiogenesis of several tumours. We thus carried out a study in vitro to investigate the effect of GEN in vascular endothelial growth factor (VEGF) expression and angiogenesis induced by the inflammatory environment of RA. METHODS: MH7A cells were used to verify whether GEN can inhibit the expression of VEGF in MH7A cells under inflammatory conditions and demonstrate the mechanism. EA.hy926 ​cells were used to verify whether GEN can inhibit the migration and tube formation of vascular endothelial cells in inflammatory environment. RESULTS: GEN dose-dependently inhibited the expression and secretion of interleukin (IL)-6 and VEGF, as well as the nucleus translocation of Signal transducer and activator of transcription 3 (STAT3) in MH7A. Furthermore, GEN inhibited IL-6-induced vascular endothelial cell migration and tube formation in vitro. CONCLUSION: GEN inhibits IL-6-induced VEGF expression and angiogenesis partially through the Janus kinase 2 (JAK2)/STAT3 pathway in RA, which has provided a novel insight into the antiangiogenic activity of GEN in RA. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our study provides scientific guidance for the clinical translational research of GEN in the RA treatment.
31849542 Clinical Improvements as Predictors of Improvements in Patient-Reported Outcomes: Post Hoc 2019 BACKGROUND: In rheumatoid arthritis (RA), little is known about clinical responses to treatment as predictors of patient-reported outcome (PRO) changes. In this post hoc analysis, we examined the relationship between clinical outcomes at week 12 and PRO changes at week 24 in patients with RA. METHODS: In an open-label study, Latin American patients with moderate-to-severe RA and an inadequate response to methotrexate (MTX) were randomized to receive etanercept 50 mg/week plus MTX (ETN+MTX; n=281) or an additional conventional disease-modifying anti-rheumatic drug (DMARD) plus MTX (DMARD+MTX; n=142) for 24 weeks. The PROs included Health Assessment Questionnaire Disability Index (HAQ-DI), 36-item Short Form (SF-36), Physician and Patient Global Assessment scores (PGA, PtGA), Physician and Patient Satisfaction, and an activity impairment assessment. PRO changes at week 24 were calculated by week-12 improvements using the American College of Rheumatology criteria (ACR <20, ≥20 to <50, ≥50 to <70, and ≥70) and the 28-joint Disease Activity Scores (DAS28 ≥3.2, ≥2.6 to <3.2, and <2.6). Observed-cases data were analyzed using an ANCOVA model with linear contrast, adjusted for baseline PRO and ACR/DAS28 values. RESULTS: For both ETN+MTX- and DMARD+MTX-treated patients, there was a significant linear trend between week-12 changes in ACR and DAS28 responses and week-24 changes in HAQ-DI (P<0.001 for all), with numerical improvements generally favoring ETN+MTX. Similar relationships were observed for SF-36, PGA, PtGA, Physician Satisfaction, Patient Satisfaction, and activity impairment. CONCLUSIONS: In patients with RA, clinical response after 12 weeks of treatment with ETN+MTX or DMARD+MTX could be a predictor of week-24 response for several PROs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00848354.
31817071 Polymorphisms in TNF Receptor Superfamily 1B (TNFRSF1B:rs3397) are Linked to Mycobacterium 2019 Dec 4 We previously discovered that single nucleotide polymorphisms (SNPs) in PTPN2/22 (T-cell negative-regulators) occur in 78% of rheumatoid arthritis (RA), along with Mycobacterium avium paratuberculosis (MAP) infection in 33% of patients. In Crohn's disease, we reported that SNPs in TNFα and receptors (TNFRSF1A/TNFRSF1B) benefited intracellular MAP-survival, increased infection, and elevated inflammatory response mimicking the poor response to anti-TNFα treatment in some patients. Here, we studied the frequency and effects of SNPs in TNFα/TNFRSF1A/TNFRSF1B in RA including gene expression, MAP infection, and osteoporosis marker levels in blood (54 RA and 48 healthy controls). TNFα:rs1800629 (GA) was detected in 19/48 (40%) RA and 8/54 (15%) controls (p-value < 0.05, odds ratio (OR) = 3.6, 95% CI: 1.37-9.54). TNFRS1B:rs3397 (CT) was detected in 21/48 (44%) RA and 10/54 (19%) controls (p-value < 0.05, OR = 4.43, 95% CI: 1.73-11.33). In RA, rs3397 downregulated TNFRSF1B expression (CC > CT (0.34 ± 0.14) and CC > TT (0.27 ± 0.12)), compared to wildtype CC (0.51 ± 0.17), p-value < 0.05. MAP DNA was detected significantly in 17/48 (35.4%) RA compared to 11/54 (20.4%) controls (p-value < 0.05, OR = 2.14, 95% CI: 1.12-5.20). The average osteocalcin level was significantly lower (p-value < 0.05) in RA (2.70 ± 0.87 ng/mL), RA + MAP (0.60 ± 0.31 ng/mL), RA + TNFRSF1B:rs3397 (TT) (0.67 ± 0.35 ng/mL), compared to the healthy control (5.31 ± 1.39 ng/mL), and MAP-free RA (3.85 ± 1.31 ng/mL). Overall, rs3397 appears to downregulate TNFRSF1B, increase MAP infection, worsen inflammation, and cause osteocalcin deficiency and possibly osteoporosis in RA.
31388350 Efficacy of leflunomide combined with ligustrazine in the treatment of rheumatoid arthriti 2019 BACKGROUND: Leflunomide (LEF) is a first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA). However, there are still a few nonresponders. It is logical to suggest that employing combinations including LEF that produce synergistic effects in terms of pharmacological activity is a promising strategy to improve clinical outcomes. METHODS: We propose a novel approach for predicting LEF combinations through investigating the potential effects of drug targets on the disease signaling network. We first constructed an RA signaling network with disease-associated driver genes. Thousands of available FDA-approved and investigational compounds were then selected based on a drug-RA network, which was generated using an algorithm model named synergistic score that combines chemical structure, functional prediction and target pathway. We then validated our predicted combination in a prospective clinical trial. RESULTS: Ligustrazine (LIG), a key component of the Chinese herb Chuanxiong and an approved drug in China, ranked first according to synergistic score. In the clinical trial, after 48 weeks, the American College of Rheumatology (ACR) 20 response rate was significantly lower (P < 0.05) in the LEF group [58.8% (45.4%, 72.3%)] than in the LEF + LIG group [78.7% (68.5%, 89.0%)]. Consistently, the erosion score was lower in patients treated with LEF + LIG than in those treated with LEF (0.34 ± 0.20 vs 1.12 ± 0.30, P < 0.05). CONCLUSIONS: Our algorithm combines structure and target pathways into one model that predicted that the combination of LEF and LIG can reduce joint inflammation and attenuate bone erosion in RA patients. To our knowledge, this study is the first to apply this paradigm to evaluate drug combination hypotheses.
31057488 IgG Anti-ghrelin Immune Complexes Are Increased in Rheumatoid Arthritis Patients Under Bio 2019 Rheumatoid arthritis (RA) is a systemic autoimmune disease associated with increased risk of cardiovascular disease and metabolic alterations. The mechanisms underlying these alterations remain unclear. Ghrelin is a gastrointestinal hormone with potent effects on food intake, body weight, metabolism, and immune response. Recent studies reported the presence of anti-ghrelin autoantibodies in healthy subjects and the levels and affinity of these autoantibodies were altered in anorectic and obese individuals. In this cross-sectional study we analyzed anti-ghrelin autoantibodies in RA patients and evaluated its relationship with clinical, body-composition and metabolic parameters. Clinical measurements of RA patients included the disease activity score-28 (DAS-28), inflammatory biomarkers, autoantibodies (RF and anti-CCP), body composition, glucose and lipid profile. Serum ghrelin levels were measured by enzyme-linked immunosorbent assay (ELISA). Free and total anti-ghrelin autoantibodies quantification (IgG and IgA isotypes) was performed by in-house ELISA. RA patients had lower IgG anti-ghrelin autoantibodies levels and higher immune complexes percentage (IgG+ghrelin) compared to the control group, while the IgA anti-ghrelin autoantibodies showed no significant differences. In the bivariate analysis, the percentage of IgG anti-ghrelin immune complexes positively correlated with BMI and ghrelin whereas in the multivariate regression model, the variables associated were DAS-28, body weight, visceral fat, LDL-C and TG (R (2) = 0.72). The percentage of IgA anti-ghrelin immune complexes positively correlated with RF and anti-CCP and the multivariate regression model showed an association with RF and body fat percentage (R (2) = 0.22). Our study shows an increased percentage of IgG anti-ghrelin immune complexes in RA patients despite ghrelin levels were similar in both groups, suggesting an increase in the affinity of these autoantibodies toward ghrelin. The associations found in the multiple regression analysis for anti-ghrelin immune complexes support the previously reported functions of these natural autoantibodies as carriers and modulators of the stability and physiological effect of the hormone. However, in RA both the disease activity and the RF appear to influence the formation of these anti-ghrelin immune complexes.
30630509 The oncoprotein TBX3 is controlling severity in experimental arthritis. 2019 Jan 10 BACKGROUND: Development of autoimmune diseases is the result of a complex interplay between hereditary and environmental factors, with multiple genes contributing to the pathogenesis in human disease and in experimental models for disease. The T-box protein 3 is a transcriptional repressor essential during early embryonic development, in the formation of bone and additional organ systems, and in tumorigenesis. METHODS: With the aim to find novel genes important for autoimmune inflammation, we have performed genetic studies of collagen-induced arthritis (CIA), a mouse experimental model for rheumatoid arthritis. RESULTS: We showed that a small genetic fragment on mouse chromosome 5, including Tbx3 and three additional protein-coding genes, is linked to severe arthritis and high titers of anti-collagen antibodies. Gene expression studies have revealed differential expression of Tbx3 in B cells, where low expression was accompanied by a higher B cell response upon B cell receptor stimulation in vitro. Furthermore, we showed that serum TBX3 levels rise concomitantly with increasing severity of CIA. CONCLUSIONS: From these results, we suggest that TBX3 is a novel factor important for the regulation of gene transcription in the immune system and that genetic polymorphisms, resulting in lower expression of Tbx3, are contributing to a more severe form of CIA and high titers of autoantibodies. We also propose TBX3 as a putative diagnostic biomarker for rheumatoid arthritis.
30891131 Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of 2019 Mar 14 The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.
31517250 Prevalence and associated factors of subclinical atherosclerosis in rheumatoid arthritis a 2019 BACKGROUND: Rheumatoid arthritis (RA) is associated with a 5 to 10 years reduction in life expectancy due to premature atherosclerosis. This reduction is the consequence of traditional cardiovascular risk factors (TCRF) as well as systemic inflammation. The aim of the present study was to describe the prevalence and factors associated with subclinical atherosclerosis in RA at the University Hospital of Kinshasa (UHK). METHODS: Patients with a diagnosis of RA based on the 2010 ACR/EULAR criteria were included in this cross-sectional study from 1 June 2014 to 31 May 2015 at the UHK. RA disease activity was measured using the DAS28-ESR. Active RA was defined by a DAS 28 > 2.6. Severe RA was defined by the presence of extra-articular manifestation, joint erosions on X-rays or HAQ ≥0.5. An assessment of subclinical atherosclerosis was performed by the measurement of the carotid intima-media thickness (cIMT) using two-dimensional ultrasonography. Subclinical atherosclerosis was defined by a cIMT ≥0.9 mm. A diagnosis of atheroma plaque was retained when the cIMT was ≥1.5 mm. The association between subclinical atherosclerosis and potential risk factors was modeled using logistic regression analysis. RESULTS: We recruited 75 patients. The average age was 51.8 ± 14.6 years, with a sex ratio F/M of 4. The prevalence of subclinical atherosclerosis was 32%. In logistic regression being a woman of ≥55 years old (aOR 10.6, 95% CI [2.087-53.82], p = 0.028), DAS28-ESR > 2.6 (aOR 3.5,95% CI [1.55-10.38], p = 0.044), severe RA (aOR 32.6,95% CI [1.761-60.37],p = 0.035), high blood pressure (aOR 22.4,95% CI [5.04-99.41], p = 0.005) and obesity (aOR 32.3, 95% CI [2.606-40.73], p = 0.026) emerged as factors associated with subclinical atherosclerosis. CONCLUSION: Subclinical atherosclerosis is common in RA patients attending the UHK. It appears to be associated with RA disease activity and severity apart from traditional cardiovascular risk factors. These results suggest that early management of subclinical atherosclerosis targeting remaining RA disease activity and cardiovascular risk factors could slow down progression to clinical cardiovascular disease.
31488947 Serum Metabolomic Profiles of Rheumatoid Arthritis Patients With Acute-Onset Diffuse Inter 2019 OBJECTIVE: Acute-onset diffuse interstitial lung disease (AoDILD) includes acute exacerbation of interstitial lung disease (ILD), drug-induced ILD, and Pneumocystis pneumonia, and frequently occurs in patients with rheumatoid arthritis (RA). Since AoDILD causes a poor prognosis in RA, biomarkers for AoDILD were eagerly desired. Metabolomic analyses were extensively performed in cancer patients and successfully generated better diagnostic biomarkers. In the present study, serum metabolomic profiles of AoDILD in RA were investigated to generate better potential metabolomic biomarkers. METHODS: Serum samples of 10 RA patients with AoDILD were collected on admission and in a stable state, more than 3 months before the admission. Serum metabolomic analyses were conducted on the samples from these RA patients with AoDILD. RESULTS: Apparently distinct serum metabolomic profiles in AoDILD were not observed in univariate or hierarchical cluster analyses. Partial least squares-discriminant analysis (PLS-DA) was performed to select candidate metabolites based on variable importance in projection (VIP) scores. The PLS-DA model generated from the four metabolites with VIP scores more than 2.25 (mannosamine, alliin, kynurenine, and 2-hydroxybutyric acid) could successfully discriminate AoDILD from the stable condition (area under the curve: 0.962, 95% confidence interval: 0.778-1.000). CONCLUSION: It was demonstrated that metabolomic profiling was useful to generate better biomarkers in AoDILD.
31312786 The prevalence and types of discordance between physician perception and objective data fr 2019 BACKGROUND: Heterogeneity in assessments of rheumatoid arthritis (RA) disease remission, based on physician judgment and patient self-reports versus standardized measures, have previously been reported. This study explored the prevalence and types of discordance between physician perception versus objective data of RA disease activity in real-world clinical practice in the US. METHODS: Data were from the Adelphi RA Disease Specific Programme (DSP; January to March 2014), a cross-sectional survey of US rheumatologists and their patients. RA remission based on physician judgment versus Disease Activity Score in 28 joints (3)-erythrocyte sedimentation rate (DAS28(3)-ESR) and Clinical Disease Activity Index (CDAI) scores were compared using descriptive analyses; patient and physician factors associated with discordance were identified using bivariate and multivariate analyses. RESULTS: Of 101 rheumatologists participating (completing patient-record forms for 843 patients), 56.4% based assessment of remission on clinical judgment alone. Of 531 patients eligible for the discordance analysis, 49.7% were in remission based on rheumatologists' evaluation, and 30.7% were eligible based on DAS28(3)-ESR. Compared with DAS28(3)-ESR criteria, 25.8% of patients' disease remission was negatively discordant (overestimated remission) based on clinical perception. These patients were mostly administered biologic disease-modifying antirheumatic drugs and were without a treat-to-target strategy followed by their rheumatologist (P < 0.05). These patients were also more likely to have experienced a higher level of pain as well as increased joint inflammation and damage (e.g. destruction of cartilage, thinning of bone, and/or synovium inflammation) compared with concordant patients (P < 0.005). Conversely, 6.8% of rheumatologists were positively discordant (under estimated remission) versus the DAS28(3)-ESR. Sensitivity analysis indicated different levels of discordance using CDAI, with 35.6% negative discordance and 1.3% positive discordance of rheumatologist-assessed disease remission compared with objective data. CONCLUSION: There is discordance between RA remission as assessed by rheumatologist perception versus standardized measures among those in the US DSP sample. Our study identified the factors associated with the discordance which may inform strategies to enhance assessments of RA disease remission.
32647413 A Study on Association Between Protein Carbonyl and Anti-cyclic Citrullinated Peptide Anti 2020 Jul Redox state and immune mechanisms are two major factors implicated in rheumatoid arthritis (RA). Regarding some limitations of anti-cyclic citrullinated peptide (anti-CCP) antibody in RA diagnosis, recruiting another strong marker of oxidative stress could lead to more definitive diagnosis. To evaluate the potential of protein carbonyl content as a supplementary biomarker for RA. Eighty patients with RA attending the Research Center from 2015 to 2016 were recruited in this study. Smoker and alcoholic subjects, or those with any other systemic illness were excluded from the study. Demographic information and clinical data were collected. Numbers of swollen and tender joints were determined and RA disease activity was assessed. Serum samples were used for assessing protein carbonyl level, platelet count, and anti-CCP antibody values. Statistical analyses for significant differences were performed according to parametric (Student t test) and nonparametric (Mann-Whitney test) tests. The correlation was determined by Pearson coefficient. There was a significant correlation between protein carbonyl levels and anti-CCP antibodies in active RA (p value = 0.01), but not in remission phase (p value = 0.28). A significant positive correlation was observed between protein carbonyl levels and platelets count in active RA (p value = 0.001), but not in remission phase (p value = 0.85). Protein carbonyl could be considered as a future cost-effective supplementary biomarker, alongside anti-CCP antibody, in active RA diagnosis as it showed a significant positive correlation with anti-CCP antibody and platelet, two major mediators in the disease pathogenesis.