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ID PMID Title PublicationDate abstract
32990025 Therapeutic Effect of Exogenous Regulatory T Cells on Collagen-induced Arthritis and Rheum 2020 Jan Regulatory T (Treg) cells have anti-inflammatory functions and heighten immune tolerance. The proportion and functions of Treg cells are perturbed in rheumatoid arthritis (RA), contributing to the excessive immune activation associated with this disease. We therefore hypothesized that supplementation with foreign Treg cells could be used to treat RA. To investigate the therapeutic effects of exogenous Treg cells on RA and its mechanism, we used human Treg cells to treat collagen-induced arthritis (CIA) in a rat model to observe whether exogenous Treg cells can treat the disease across species. Successful treatment would indicate that Treg cell transplantation in humans is more likely to affect RA. In the present study, human Treg cells were collected from healthy human peripheral blood and culture-expanded in vitro. Induced human Treg cells were injected into CIA rats via the tail vein. The rats' lymphocyte subtypes, cytokines, and Th1/Th2 ratios were measured using flow cytometry. In the rats, following injection of the human Treg cells, the severity of CIA was significantly reduced (P < 0.01), the proportion of endogenous Treg cells increased in the peripheral blood and spleen (P = 0.007 and P < 0.01, respectively), and the proportion of B cells decreased (P = 0.031). The IL-5 level, IL-6 level, and Th1/Th2 ratio in the peripheral blood were decreased (P = 0.013, 0.009, and 0.012, respectively). The culture-expanded human Treg cells were also cultured with synovial fibroblast cells from RA patients (RASFs). After coculture with Treg cells, RASFs showed reduced proliferation (P < 0.01) and increased apoptosis (P = 0.037). These results suggest that exogenous and induced Treg cells can produce a therapeutic effect in RA and CIA by increasing endogenous Treg cells and RASF apoptosis and reducing B cells, the Th1/Th2 ratio, and secretion levels of IL-5 and IL-6. Treg cell transplantation could serve as a therapy for RA that does not cause immune rejection.
32668112 RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. 2020 Jul 16 BACKGROUND: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown. METHODS: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings. RESULTS: Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis. CONCLUSIONS: Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).
31994328 Association between MRI findings and patient-reported outcomes in patients with rheumatoid 2020 Apr OBJECTIVE: To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse. METHODS: Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n = 70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests. RESULTS: Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P < .01), independent of clinical and radiographic measures, and was also associated with most of the hand-related HAQ items (P < .03). In multivariate models including MRI, SvH scores were not associated with PROs. MRI-assessed inflammation was not associated with PROs at remission or relapse. CONCLUSION: Magnetic resonance imaging-assessed wrist/hand damage, but not inflammation, in patients with established RA is associated with patient-reported physical impairment at remission and relapse. The amount of damage in the wrist/hand is associated with reduced hand function.
32304147 Association between SLCO1A2 genetic variation and methotrexate toxicity in human rheumatoi 2020 Aug Methotrexate (MTX), one of the important disease-modifying anti-rheumatic drugs, is the first-line drug for rheumatoid arthritis (RA) treatment. However, its adverse drug effects (ADEs) often lead to the abortion of MTX therapy. Human organic anion-transporting polypeptide 1A2 (OATP1A2, also referred as OATP-A or OATP1) encoded by SLCO1A2 gene is an important isoform of the solute carrier transporter (SLC) family. It is known to participate in the cellular uptake of MTX. In our previous study, we identified four OATP1A2 natural variants (E184K, D185N, T259P, and D288N) with impaired MTX uptake activity. This study aimed to evaluate the association of the SLCO1A2 genetic variations encoding these OATP1A2 variants and MTX-related toxicity in RA patients. A total of 60 RA patients were genotyped for these four polymorphisms (G550A, G553A, A775C, and G862A). The association between SLCO1A2 genetic variations and MTX toxicity was analyzed by binary logistic regression analysis. Single nucleotide polymorphisms (SNPs) analysis revealed that A775C and G862A SNPs were not detected in RA patients enrolled in this study, and the presence of 550AA genotype was associated with a high risk of MTX ADEs. Haplotype analysis revealed that H3 (H3 = AG) showed a high risk of MTX ADEs. Furthermore, there was a significant association of 550AA genotype and impaired MTX disposition, which might be the cause of the increased incidence of MTX ADEs in RA patients. Therefore, genetic variations in SLCO1A2 gene are risk factors for MTX toxicity and its information contributes to the prediction of MTX-related toxicity in RA treatment.
33088399 A new tool for early diagnosis of rheumatoid arthritis using combined biomarkers; synovial 2020 INTRODUCTION: rheumatoid arthritis (RA) is a common autoimmune disease with unknown etiology and pathogenesis. Biomarkers have the potential to aid in the clinical diagnosis of the disease, or to provide means of detecting early signs of the disease. Evaluating Melanoma associated antigen genes (MAGE-1) mRNA expression rate in synovial fluid cells and serum levels of anti-cyclic citrullinated peptides (anti-CCP) and rheumatoid factor (RF) for RA early diagnosis. METHODS: a total of 213 subjects were enrolled in the study, 135 RA patients and 78 normal subjects with traumatic knee joints (control group). Serum RF and anti-CCP were estimated quantitatively using ELISA. MAGE-1 mRNA expression rate was analyzed by RT-PCR. RESULTS: a significant increase in serum levels of RF IgM and anti-CCP in RA patients compared to the controls. A positively significant correlation was found between serum anti-CCP and RF IgM. The expression rate of MAGE-1 mRNA was 100% in RA patients versus the controls (0%). The specificity and the sensitivity of the three biomarkers was 100%. CONCLUSION: the high expression rate of MAGE-1 in synovial fluid cells of RA patients is encouraging its utilization as a diagnostic biomarker for RA. The combined use of MAGE-1 transcript in synovial fluid cells, serum RF and anti-CCP is recommended for improving early diagnostic ability of RA.
32803913 Interleukin-1 receptor-associated kinase gene polymorphisms contribute to rheumatoid arthr 2020 Dec AIM: Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting about 1% of world population. Three polymorphisms of Interleukin-1 receptor-associated kinase (IRAK1) gene, rs3027898, rs1059702 and rs1059703, are studied to associate with RA risk. However, the findings are inconclusive. Therefore, we performed a meta-analysis to derive a more precise estimation of the impact of the 3 polymorphisms on RA risk. METHOD: The strength of association between 3 polymorphisms and RA risk was assessed by calculating odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). RESULTS: Overall, for rs3027898 polymorphism, no association was observed in pooled analysis, but the stratified analysis suggested that rs3027898 CA genotype was associated with a reduced risk of RA in an Asian population (heterozygous model: OR = 0.79, 95% CI = 0.66-0.96, P = .018). Rs1059702 polymorphism was related with an increased RA risk (homozygous model: OR = 1.59, 95% CI = 1.19-2.13, P = .002, heterozygous model: OR = 1.49, 95% CI = 1.17-1.88, P = .001, and allele comparison model: OR = 1.35, 95% CI = 1.20-1.53, P < .001). Moreover, rs1059703 was also associated with an increased RA risk (dominant model: OR = 1.26, 95% CI = 1.07-1.49, P = .006), especially in Caucasian populations. CONCLUSION: These results indicated that all 3 Interleukin-1 receptor-associated kinase (IRAK1) gene polymorphisms, rs3027898, rs1059702 and rs1059703 were related to RA risk.
32113698 Effect of antiresorptive and bone forming treatments in bone erosions in rheumatoid arthri 2020 May 8 Rheumatoid arthritis (RA) is a chronic inflammatory disease that can cause joint destruction and marked disability. Early treatment with disease-modifying drugs, including biological therapy, is the principal treatment to prevent the structural damage associated with this entity. Some studies have indicated that concomitant treatment with antiresorptives, such as bisphosphonates or denosumab, could prevent erosive lesions in this process, and it has even been suggested that treatment with a bone forming agent, such as teriparatide, could revert previously established erosive lesions. In this article we review the evidence available on the efficacy of treatment with antiresorptives and bone forming agents in the prevention and/or treatment of bone erosions associated with RA.
31972421 A network pharmacology approach to explore the potential targets underlying the effect of 2020 Mar OBJECTIVE: To explore the potential targets underlying the effect of sinomenine (SIN) on rheumatoid arthritis (RA) by utilizing a network pharmacology approach. METHODS: SIN and its drug targets were identified using network analysis followed by experimental validation. First, the Pharmmapper, UniProt and GeneCards databases were mined for information relevant to the prediction of SIN targets and RA-related targets. Second, the SIN-target gene and SIN-RA target gene networks were created in Cytoscape software followed by the collection of the candidate targets of each component by R software. Eventually, the key targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. RESULTS: Sixty-seven potential targets of SIN and 3797 related targets involved in RA were subjected to network analysis, and the 20 intersection targets indicated the principal pathways linked to RA. Additionally, 16 key targets, which were linked to more than three genes, were determined to be crucial genes. GO analysis showed that 14 biological processes, 5 cellular components and 2 molecular functions were identified, when corrected by a P value ≤ 0.01. Seven related signaling pathways were identified by KEGG analysis, when corrected according to a Bonferroni P value ≤ 0.05. CONCLUSION: The present study explored the potential targets and signaling pathways of SIN during the treatment of RA, which may help to illustrate the mechanism (s) involved in the action of SIN and may provide a better understanding of its anti-rheumatoid arthritis effects in terms of inhibiting angiogenesis, synovial hyperplasia, and bone destruction.
32414400 The effect of nicotinamide adenine dinucleotide phosphate oxidase 4 on migration and invas 2020 May 15 BACKGROUND: Reactive oxygen species (ROS) regulate the migration and invasion of fibroblast-like synoviocytes (FLS), which are key effector cells in rheumatoid arthritis (RA) pathogenesis. Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) induces ROS generation and, consequently, enhances cell migration. Despite the important interrelationship between RA, FLS, and ROS, the effect of NOX4 on RA pathogenesis remains unclear. METHODS: FLS isolated from RA (n = 5) and osteoarthritis (OA, n = 5) patients were stimulated with recombinant interleukin 17 (IL-17; 10 ng/ml) and tumor necrosis factor alpha (TNF-α; 10 ng/ml) for 1 h. Cell migration, invasion, adhesion molecule expression, vascular endothelial growth factor (VEGF) secretion, and ROS expression were examined. The mRNA and protein levels of NOX4 were analyzed by RT-qPCR and western blotting, respectively. The NOX4 inhibitor GLX351322 and NOX4 siRNA were used to inhibit NOX4 to probe the effect of NOX4 on these cellular processes. RESULTS: Migration of RA FLS was increased 2.48-fold after stimulation with IL-17 and TNF-α, while no difference was observed for OA FLS. ROS expression increased in parallel with invasiveness of FLS following cytokine stimulation. When the expression of NOX was examined, NOX4 was significantly increased by 9.73-fold in RA FLS compared to unstimulated FLS. Following NOX4 inhibition, cytokine-induced vascular cell adhesion molecule 1 (VCAM1), VEGF, and migration and invasion capacity of RA FLS were markedly decreased to unstimulated levels. CONCLUSION: NOX4 is a key contributor to cytokine-enhanced migration and invasion via modulation of ROS, VCAM1, and VEGF in RA FLS.
32333475 PTPN22 gene polymorphism and susceptibility to rheumatoid arthritis (RA): Updated systemat 2020 Sep BACKGROUND: Several genome-wide association studies have revealed a genetic background with respect to susceptibility to rheumatoid arthritis (RA). Although several individual case-control studies have evaluated the role of protein tyrosine phosphatase non-receptor 22 (PTPN22) gene rs2476601 single nucleotide polymorphism (SNP) in conferring a risk for RA, the results have been conflicting. Hence, this meta-analysis was aimed to provide a solution for this issue. METHODS: To search for studies assessing the association between the PTPN22 gene rs2476601 SNP and the risk of RA, a systematic search was conducted in the main databases, including PubMed, Scopus and Web of Science, prior to December 2019. The odds ratio (OR) and corresponding 95% confidence interval (CI) was calculated to assess the possibility of association risk. RESULTS: The literature search identified 52 case-control studies. The pooled analysis detected significant positive association of rs2476601 in all genetic models, including dominant model (OR = 1.69, 95% CI = 1.55-1.84, P < 0.001), recessive model (OR = 2.50, 95% CI = 2.06-3.05, P < 0.001), allelic model (OR = 1.80, 95% CI = 1.60-2.2, P < 0.001), TT versus CC model (OR = 2.79, 95% CI = 2.28-3.41, P < 0.001) and CT versus CC model (OR = 1.59, 95% CI = 1.50-1.67, P < 0.001). Analyses based on population stratification indicated that rs2476601 SNP strongly increased the risk of RA in Caucasians and Africans under all genotype models. CONCLUSIONS: This meta-analysis reports that the PTPN22 gene rs2476601 SNP increases RA risk, especially in Caucasians and Africans.
32980634 Targeted silver nanoparticles for rheumatoid arthritis therapy via macrophage apoptosis an 2021 Jan Infiltration of inflammatory cells, especially the M1 macrophages that secrete various types of inflammation cytokines, play crucial roles in the pathogenesis of rheumatoid arthritis (RA). To relief synovial inflammation, M1 macrophages must be eliminated or switched to anti-inflammatory M2 phenotype. We herein developed folic acid modified silver nanoparticles (FA-AgNPs) that can actively deliver into M1 macrophages to synergistically induce M1 macrophages reduction and M2 macrophages polarization for effective RA treatment. The AgNPs was facilely prepared, PEGylated and modified with FA to realize M1 macrophages targeting delivery via folate receptor overexpressed on M1 macrophages surface. After entering cells, FA-AgNPs dissolved and released Ag(+) in response to intracellular glutathione (GSH), which is the key element to exert a series of anti-inflammatory functions, such as M1 macrophages apoptosis and reactive oxygen species (ROS) scavenging to facilitate M2 macrophages polarization, both of which contributed to RA treatment. This nano-system could passively accumulate into inflamed joints, permit potent anti-inflammatory activity, and impose strong therapeutic efficacy in mice RA models with high biosafety. After treatment, FA-AgNPs could be gradually cleared from the body mainly via feces without tissue accumulation, and did not show any appreciable long-term toxicity. This work declares the first example of using bio-active nanoparticles for RA treatment without loading any drugs, and highlights the potential of FA-AgNPs for targeted RA therapy via simultaneous M1 macrophage apoptosis and M1-to-M2 macrophages re-polarization.
32778419 Risk of Total Knee and Hip Arthroplasty in Patients With Rheumatoid Arthritis: A 12-Year R 2020 Dec BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory disease that causes the destruction of soft tissues and cartilage around joints. Owing to the widespread use of potent disease-modifying antirheumatic drugs, the need for total knee and hip arthroplasties (TKA and THA) has been reduced in patients with RA. However, the current association between RA and either THA or TKA has not been demonstrated in large-scale epidemiological studies. METHODS: We conducted a large-scale retrospective cohort study of patients diagnosed with RA during a 12-year period (2000-2012) in Taiwan. We recruited 32,949 patients with RA and 32,949 individually propensity score-matched non-RA controls. RESULTS: After adjusting for confounding factors, we found that the risk of THA or TKA was 4.02 times higher in patients with RA than in those without RA (95% confidence interval [CI], 3.77-4.52). The risk of THA or TKA was highest in patients with RA younger than 40 years (adjusted hazard ratio, 43.18; 95% CI, 16.01-116.47). Compared with non-RA patients, patients with RA were 4.82 times more likely to undergo THA (95% CI, 3.84-6.04), 3.85 times more likely to undergo TKA (95% CI, 3.48-4.25), and 19.06 times more likely to undergo both THA and TKA (95% CI, 8.90-40.80). CONCLUSION: These findings document a 4.02-fold greater long-term risk of undergoing THA or TKA in RA patients relative to non-RA patients in Taiwan.
33090382 A nomogram to predict recurrence of RA patients in clinical remission within one year. 2020 Oct OBJECTIVE: Some patients with rheumatoid arthritis (RA) will recur despite they have achieved clinical remission after treatment. The subclinical synovitis detected by ultrasonography (US) may be one of the main causes of the RA recurrence. The aim of this study is to establish a nomogram for predicting the outcome of RA patients with disease in clinical remission. PATIENTS AND METHODS: One hundred and sixty-seven RA patients who achieved clinical remission and were willing to receive a 1-year follow-up were included in this study. Their demographic, clinical, and laboratory characteristics were recorded at baseline. 7-joints ultrasound (US7) synovitis score (simplified from US7 score) were evaluated at baseline and at the end of follow-up (or when RA recurrence confirmed). All patients were divided into recurrence group and non-recurrence group after the follow-up. Multivariable regression was applied to link the predictors that were significant at p < 0.05 in the univariate analysis and the recurrence of RA patients in clinical remission, which was served as the basis of the nomogram. RESULTS: Fifty-one RA patients were included in the recurrence group and 116 patients in the non-recurrence group. All US7 synovitis scores in this study showed excellent reproducibility. Multivariable analysis revealed that high-titer positive anti-cyclic citrullinated peptide (anti-CCP), simplified clinical disease activity index (SDAI), baseline grayscale ultrasound (GSUS) score, and baseline power Doppler ultrasound (PDUS) score were the independent predictors for RA recurrence within 1 year. A nomogram incorporating the independent predictors was constructed to predict the risk of RA recurrence. The nomogram showed good discrimination (C-index=0.826) and good calibration. CONCLUSIONS: The nomogram incorporating anti-CCP, SDAI, and subclinical synovitis helps to achieve complete remission and reduces the risk of short-term recurrence of RA patients.
31314615 Muscle stiffness in rheumatoid arthritis is not altered or associated with muscle weakness 2020 Jul Objectives: To investigate muscle stiffness and strength in rheumatoid arthritis patients compared to healthy controls.Methods: A sample of 80 RA patients from three discrete groups: 1 - newly diagnosed treatment-naïve RA (n = 29), 2 - active RA for at least 1 year (n = 18) and 3 - in remission RA for at least 1 year (n = 33), was compared to 40 healthy controls. Shear wave velocity (SWV) was measured using shear wave elastography as a surrogate for tissue stiffness in multiple muscles. All participants performed isometric grip strength, timed get-up-and-go test, 30-s chair stand test and isokinetic knee extension/flexion (60°/s). The difference in SWV amongst the groups was tested using one-way ANOVA, and the correlation between SWV and muscle strength results were calculated using Pearson's coefficients.Results: The mean age ± SD was 61.2 ± 12.8 for RA patients and 61.5 ± 10.5 years for controls. SWV was not significantly different amongst the groups on all muscles (p > .05). In comparison to controls, the new and active RA groups showed a significantly lower isokinetic strength by -29% (p = .013) and -28% (p = .040), fewer chair stands by -28% (p = .001) and -44% (p < .001), longer walking times by -25% (p = .025) and -30% (p = .001), respectively, and weaker grip strength by -45% for both (p < .001). The muscle strength in the remission RA groups was not significantly lower, except in the isokinetic knee strength (-21%; p = .027). The correlations between SWE and the muscle assessment results were weak and insignificant (r < 0.30; p > .05).Conclusion: Significant muscle weakness was demonstrated in patients with RA disease. However, muscle stiffness was normal and not associated with muscle strength.
32752061 Food-Derived Nanoscopic Drug Delivery Systems for Treatment of Rheumatoid Arthritis. 2020 Jul 31 Rheumatoid arthritis (RA) is a severe systemic inflammatory disease with no cure at present. Recent developments in the understanding of inflammation and nanomaterial science have led to increased applications of nanostructured drug delivery systems in the treatment of RA. The present review summarizes novel fabrications of nanoscale drug carriers using food components as either the delivered drugs or carrier structures, in order to achieve safe, effective and convenient drug administration. Polyphenols and flavonoids are among the most frequently carried anti-RA therapeutics in the nanosystems. Fatty substances, polysaccharides, and peptides/proteins can function as structuring agents of the nanocarriers. Frequently used nanostructures include nanoemulsions, nanocapsules, liposomes, and various nanoparticles. Using these nanostructures has improved drug solubility, absorption, biodistribution, stability, targeted accumulation, and release. Joint vectorization, i.e., using a combination of bioactive molecules, can bring elevated therapeutic outcomes. Utilization of anti-arthritic chemicals that can self-assemble into nanostructures is a promising research orientation in this field.
31865066 Effects of daphnetin on the autophagy signaling pathway of fibroblast-like synoviocytes in 2020 Mar Daphnetin (DAP), an active ingredient extracted from Daphne odora, has pharmacological effects such as anti-inflammatory, antioxidation and anti-tumor properties. The current study aims to investigate the relationship between the anti-rheumatoid effect of DAP and the inhibition of both the PI3K/AKT/mTOR and autophagy signaling pathways. DAP inhibited the proliferation of CIA-FLS in a dose-dependent manner and induce apoptosis, accelerated the G1/G0 phase and inhibited the S phase. DAP reduced the phosphorylation of AKT and mTOR and the expression of Atg5, Beclin-1 and LC3-II/LC3-I in CIA-FLS induced by TNF-α. DAP also reduced the inflammatory response in CIA-FLS induced by TNF-α by inhibiting the cytokine expression of TNF-α, IL-6, TGF-β, IL-17, and INF-γ and promoting IL-10 expression. Overall, DAP inhibited the proliferation of CIA-FLS by down-regulating the PI3K/AKT/mTOR signaling pathway and inhibited autophagy in order to induces apoptosis, which may be potential therapeutic approach in treatment of RA.
32765497 Distinct Single Cell Gene Expression in Peripheral Blood Monocytes Correlates With Tumor N 2020 Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFNβ/α activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: "T1IFN undetectable (T1IFN ND) or IFNβ/α >1.3" (n = 9) and "T1IFN detectable but IFNβ/α ≤ 1.3" (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: "T1IFN ND," "T1IFN detected and IFNβ/α ≤ 1.3," and "IFNβ/α >1.3." Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFNβ/α >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ≤ 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFNβ/α>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFNβ/α >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.
32343882 Association of High Serum Interleukin-6 Levels With Severe Progression of Rheumatoid Arthr 2020 Sep OBJECTIVE: The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. This study was undertaken to investigate, by post hoc analysis, whether baseline IL-6 levels are predictive of sarilumab treatment responses in 2 phase III studies. METHODS: Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every 2 weeks (in the MONARCH trial; ClinicalTrials.gov identifier: NCT02332590) or sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks plus methotrexate (MTX) (n = 401, n = 396, and n = 397, respectively) (in the MOBILITY trial; ClinicalTrials.gov identifier: NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression. RESULTS: In MONARCH, patients with high baseline IL-6 levels (all ≥3 times the upper limit of normal; n = 100) had higher disease activity at baseline than those with low IL-6 levels (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high compared to those with low baseline IL-6 levels. In MOBILITY, compared to patients with low IL-6 levels (n = 397), patients with high IL-6 levels (n = 398) had higher disease activity and joint damage at baseline, were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo plus MTX compared to sarilumab 150 mg or 200 mg plus MTX. Baseline IL-6 and C-reactive protein levels were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles. CONCLUSION: IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 levels may be likely to benefit from sarilumab compared to adalimumab or MTX. Prospective validation is warranted to confirm the results of these post hoc analyses.
33623620 COVID-19 infection during autoimmune disease: study of 2 cases in Republic of Guinea. 2020 INTRODUCTION: Coronavirus is a virus that can target the respiratory, musculoskeletal systems with a cascade of inflammatory processes. The objective of this work is to establish the link between autoimmune diseases and a COVID-19 infection in Guinea. METHODS: Retrospective patient data were obtained from medical records. Informed consent was obtained under the direction of the national health security agency (ANSS). RESULTS: We report the case of two patients aged 52 and 64 years respectively, known to have rheumatoid arthritis (RA) and systemic scleroderma (SDS) admitted with clinical signs suggesting underlying infection with COVID-19. They were tested with RT-PCR, which was positive within hours. CONCLUSION: In view of the rapid clinical worsening of patients with COVID-19 infection and autoimmune diseases, increased surveillance should be undertaken with abstinence of any factors that might weaken the immunity of these patients.
32967471 State of the art: approved and emerging JAK inhibitors for rheumatoid arthritis. 2021 Feb INTRODUCTION: Rheumatoid arthritis (RA) is the most common autoimmune inflammatory arthritis in adults. In the past decade, many treatments have emerged to expand the therapeutic armamentarium of rheumatologists. Among emerging treatments, Janus Kinase inhibitors (JAKi) are promising in treating RA and several other inflammatory conditions, such as psoriatic arthritis (PsA). The JAK/STAT signaling pathway is located downstream certain cytokines receptors that are known to be involved in RA pathogenesis. So far, three JAKi are approved for the treatment of RA, while other JAKi, are under investigation. AREAS COVERED: Herein, the authors review those JAKi approved and emerging for the treatment of RA and provide their expert perspectives on the subject area. EXPERT OPINION: JAKi represent an interesting alternative to other DMARDs when MTX has failed. Long-term extension studies are still ongoing, but one can assume that most of the major safety concerns have already come out. Switching from one JAKi to another DMARD has been little studied, but in such cases, preferring a treatment which does not interfere with the JAK/STAT pathway seems to be a reasonable choice.