RA Response Research Articles

Toward pre-treatment prediction of biologic DMARD response in RA.

Toward pre-treatment prediction of biologic DMARD response in RA.

OA15 Drivers of change in four and two component disease activity scores after etanercept treatment, in a multi-centre cohort of patients with established rheumatoid arthritis

Abstract Background/Aims Treatment response in RA is measured by different disease activity scores (DAS28). The widely used 4 component (4C) DAS28 does not always correlate with synovitis, and a new 2 component version (2C) DAS28 has been developed to address this problem. Here, we use multivariable linear regression models to identify drives of change (Δ) in 4C and 2C DAS28 after 3 months on the anti-TNF drug etanercept (ETN). Methods Using data from the Biologics in RA Genetics and Genomics Study Syndicate (BRAGGSS), we identified patients treated with originator or biosimilar ETN (N = 773). Differences between the follow-up (FU) and baseline (BL) DAS28, adjusted for baseline, serve as outcome variables. Multiple imputation by chained equations was used to impute missing data, and models were internally validated via bootstrapping. Table 1 shows the baseline statistics, and model parameters for the included covariates. Results We found that 15.8% (95% CI: 11 - 20.6%) of the variance in Δ4C was explained by the baseline DAS28, compared to 26.3% (95% CI: 20.9 - 31.7%) for the Δ2C. Age of onset, HAQ score and concurrent DMARD treatment were significantly associated with both ΔDAS28 scores. Δ4C-DAS28 was additionally associated with first biologic use, seropositivity for either rheumatoid factor or anti-citrullinated peptide antibodies, and the Hospital Anxiety and Depression Scale-Anxiety score. The only additional predictor significantly associated with Δ2C-DAS28 was weight. After adjusting for baseline DAS28, the additional clinical covariates only explained 7.6% (IQR: 7.3 - 7.8%), and 2.3% (IQR: 2.0 - 2.6%) of the variance for the 4C- and 2C-DAS28, respectively. Conclusion ΔDAS28 is heavily influenced by the baseline DAS28, and additional clinical covariates explain little to none of the additional variance. Notably, known factors associated with treatment response, such as seropositivity and previous unsuccessful treatments, were only significant for the 4C-DAS28. This suggests that the 4C DAS and 2C DAS capture different aspects of RA disease progression. Further association studies are required to find other reliable predictors for ΔDAS28, which may include biological markers of response. Significant covariates identified here should be considered as potential confounding factors. Disclosure M. Stadler: None. S. Ling: None. N. Nair: None. J. Isaacs: None. K. Hyrich: None. A. Morgan: None. G. Wilson: None. D. Plant: None. J. Bowes: None. A. Barton: None.

OA27 Sustainability of response between upadacitinib and adalimumab in patients with rheumatoid arthritis: results through 3 years from the SELECT-COMPARE trial

Abstract Background/Aims A greater proportion of patients with RA and inadequate response to methotrexate (MTX) receiving upadacitinib (UPA), achieved REM/LDA compared with adalimumab (ADA), both with background MTX, through 26 weeks in the phase 3, SELECT-COMPARE trial. Here we assessed sustainability of response over 3 years. Methods SELECT-COMPARE included a 26-week, double-blind, placebo (PBO)-controlled period, a 48-week, double-blind active comparator-controlled period, and an ongoing long-term extension for up to 10 years. Patients on background MTX received UPA 15 mg once daily, PBO, or ADA 40 mg every other week. Patients not achieving at least 20% improvements in tender/swollen joint counts (Weeks 14-22) or LDA (CDAI ≤10 at Week 26) were rescued from UPA to ADA or PBO/ADA to UPA. This post hoc analysis evaluated clinical REM (CDAI ≤2.8; SDAI ≤3.3), LDA (CDAI ≤10; SDAI ≤11), and DAS28(CRP) <2.6/≤3.2 at first occurrence (prior to treatment switch [rescue]), and over 3 years following initial response in patients randomized to UPA or ADA. For those patients who achieved REM/LDA, Kaplan-Meier was used to define time from when the response was first achieved to the earliest date at which the response was lost at two consecutive visits, discontinuation of study drug, or losing response at the time of rescue. Predictive ability of time to CDAI REM/LDA was assessed using Harrell’s concordance (c)-index (range: 0 [all predictions wrong] to 1.0 [perfect predictive ability]). Non-responder imputation was used for missing data. Results Through 3 years, a significantly higher proportion of patients receiving UPA + MTX vs ADA + MTX achieved CDAI REM (47% vs 35%, P = 0.001) as well as CDAI LDA (70% vs 60%, P = 0.001). At 30 months after first occurrence of response, CDAI REM/LDA was sustained in 19%/42% of patients randomized to UPA and 10%/30% of patients randomized to ADA. Time to initial clinical response did not appear to be predictive of sustained disease control. C-index for CDAI REM/LDA was 0.50/0.60 on UPA vs 0.49/0.56 on ADA. Through last follow-up visit, 37%/58% of patients receiving UPA and 27%/48% on ADA remained in CDAI REM/LDA, respectively. Of patients who lost CDAI REM, 68% on UPA and 55% on ADA remained in LDA. Roughly similar proportions on UPA and ADA recaptured CDAI REM/LDA (UPA, 40%/17%; ADA, 48%/19%). Similar results were observed for REM/LDA based on SDAI and for DAS28(CRP) <2.6/≤3.2. Conclusion Among patients with inadequate response to MTX, a higher proportion receiving UPA + MTX achieved remission or LDA across disease activity measures vs ADA + MTX. UPA-treated patients demonstrated a consistently higher sustained response rate over 3 years compared to those receiving ADA. Furthermore, significant proportions of patients who lost response on either UPA or ADA were able to recapture remission or LDA. Disclosure M.H. Buch: Consultancies; M.H.B. has received consulting fees/meeting support from AbbVie, Boehringer Ingleheim, Eli Lilly, Merck-Serono, and Sanofi. Grants/research support; M.H.B. has received research grants from Pfizer, Gilead, and UCB. P. Nash: Honoraria; P.N. has received honoraria for lectures and advice from AbbVie, BMS, Pfizer, Gilead/Galapagos, Sanofi, Celgene, Novartis, Lilly, Janssen, UCB, Samsung, MSD, Roche. Grants/research support; P.N. has received research funding for clinical trials. A. Kavanaugh: Consultancies; A.K. has provided expert advice to AbbVie Inc., Amgen, Astra-Zeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, and UCB. Grants/research support; A.K. has has received grants/research support. B. Combe: Consultancies; B.C. has received consulting fees from AbbVie, BMS, Celltrion, Gilead, Galapagos, Janssen, Eli Lilly, MSD, Pfizer, Roche Chugai. L. Bessette: Consultancies; L.B. has received consulting fees from Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis. Sandoz, Gilead, Fresenius Kabi, and Teva. Member of speakers’ bureau; L.B. has served as a speaker for Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis. Sandoz, Gilead, Fresenius Kabi, and Teva. Grants/research support; L.B. has received grants/research support from Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Eli Lilly, Novartis. Sandoz, Gilead, Fresenius Kabi, and Teva. I. Song: Shareholder/stock ownership; IH.S. is an employee of AbbVie and may hold stock or options. T. Shaw: Shareholder/stock ownership; T.S. is an employee of AbbVie and may hold stock or options. Y. Song: Shareholder/stock ownership; Y.S. is an employee of AbbVie and may hold stock or options. J.L. Suboticki: Shareholder/stock ownership; J.L.S is an employee of AbbVie and may hold stock or options. R. Fleischmann: Consultancies; R.F. is a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, and UCB. Grants/research support; R.F. has received grant/research support from AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Janssen, Novartis, Pfizer, UCB, Regeneron, Roche,Sanofi-Aventis.

酸雨对中国陆地生态系统土壤呼吸影响的整合分析

PDF HTML阅读 XML下载 导出引用 引用提醒 酸雨对中国陆地生态系统土壤呼吸影响的整合分析 DOI: 10.5846/stxb202110202959 作者: 作者单位: 作者简介: 通讯作者: 中图分类号: 基金项目: 国家自然科学基金项目（31901296）；广东省基础与应用基础研究基金项目（2021A1515010652）；广州市基础研究计划项目（202102020289） Effects of acid rain on soil respiration in Chinese terrestrial ecosystems: A meta-analysis Author: Affiliation: Fund Project: This work was supported by the National Natural Science Foundation of China (31901296), the Guangdong Basic and Applied Basic Research Foundation (2021A1515010652), and the Guangzhou Basic Research Program (2021000031). 摘要 | 图/表 | 访问统计 | 参考文献 | 相似文献 | 引证文献 | 资源附件 | 文章评论 摘要:通过整合分析（Meta-analysis）国内外公开发表的81篇模拟酸雨实验论文的2683条有效观测数据，量化了酸雨对中国3个主要陆地生态系统（森林、草地和农田）土壤呼吸（Rs）及其组分（自养呼吸（Ra）、异养呼吸（Rh））的影响。结果表明，酸雨显著降低了Rs （-9.6%）、Rh （-7.7%）和Ra （-11.7%）；酸雨pH越低，Rs及其组分的降幅越大；野外实验对Rh和Ra的负效应大于温室实验。酸雨对Rs的负效应在农田最大（-14.7%），草地次之（-10.8%），森林最小（-8.0%）；森林Rh、Ra对酸雨的响应与Rs一致，不同林型间差异不显著；草地Rh和Ra在酸雨处理下分别显著降低和增加。Rs、Rh与土壤pH显著正相关，与土壤有机碳（SOC）显著负相关；Rh和Ra分别与地上和地下生物量显著正相关。酸雨对Rs和Ra的负效应随纬度的增加而减弱，随年平均温的升高而增强，对Rs的正效应随年平均降水的降低而增强。研究表明，酸雨不仅降低了土壤pH，抑制了植物生长，减少了植物向土壤的碳输入，还降低了微生物活性，减少了Rh，导致SOC分解降低，因而未显著改变土壤碳库。研究结果将为全球变化背景下我国陆地生态系统的碳预算提供科学借鉴。 Abstract:Anthropogenic activities over the last four decades have increased depositions of sulfur dioxide (SO2) and nitrogen oxides (NOx) by three to five fold in China, which resulted in a serious problem of acid rain with adverse effects on terrestrial carbon cycle. Soil respiration (Rs) as the second largest flux for the most terrestrial carbon cycle, and its two components (i.e., autotrophic respiration (Ra) and heterotrophic respiration (Rh)) are extremely sensitive to anthropogenic acid rain due to its detrimental effects on plant growth and soil microbes. Although numerous ecosystem-level manipulative experiments were conducted to explore the underlying mechanisms how acid rain affected Rs, a quantitative synthesis of previous studies on the effects of acid rain on Rs and its two components across different terrestrial ecosystems was scarce. By conducting a meta-analysis of 2683 observations from 81 independent experimental studies, we quantified the directions and magnitudes of the responses of Rs, Ra, and Rh to simulated acid rain (SAR) in three major terrestrial ecosystems (i.e., forest, grassland, farmland) in China. Across all the experimental studies, our results showed that SAR significantly reduced Rs (-9.6%), Rh (-11.7%) and Ra (-11.7%), and the degree of reduction was proportional to the pH of SAR. The negative effects of SAR on Rh and Ra were greater in field experiment than that in pot experiment due to the differences in the intensity of SAR and experimental duration. Among different terrestrial ecosystem types, the negative effect of SAR on Rs was the most negative in farmland ecosystems (-14.7%), followed by grassland (-10.8%) and forest (-8.0%) ecosystems. The responses of Rh and Ra to SAR in forest ecosystems were consistent with that of Rs, and there were no significant differences among different forest types (i.e., coniferous forest, coniferous and broadleaved mixed forest and broadleaved forest). In grassland ecosystems, the response to SAR was negative for Rh, but positive for Ra. Linear-regression analysis showed that Rs and Rh were positively correlated with soil pH, but negatively correlated with soil organic carbon (SOC). Rh and Ra were positively correlated with aboveground biomass (AGB) and belowground biomass (BGB), respectively. Meta-regression analysis indicated that the negative effects of SAR on Rs and Ra were decreased with the increase of latitude, and increased with the increase of mean annual temperature (MAT), whereas the positive effect of SAR on Rs increased with a decrease in mean annual precipitation (MAP). Based on this meta-analysis, we found that SAR not only reduced soil pH, inhibited plant growth, and thus reduced plant carbon input to soil, but also inhibited microbial activities, reduced Rh, and SOC decomposition rate. Therefore, anthropogenic acid rain significantly altered the input and output of SOC, but did not significantly change the content of SOC in terrestrial ecosystems. These results will provide scientific basis for assessing the carbon budget of the Chinese terrestrial ecosystems in response to global change. 参考文献 相似文献 引证文献

Formation of extracellular traps by circulating neutrophils and monocytes in rheumatoid arthritis patients: a study of new citrullinated autoantigen

Detection of subcellular structures containing typical citrullinated rheumatoid autoantigens in a single compartment presents a special interest, due to importance of anticitrulline autoantibodies for the autoimmune response in RA. Neutrophil and monocyte extracellular traps (NETs and ETs, respectively) may be considered such candidate structures. Our objective was to assess ability of blood neutrophils and monocytes from RA patients to generate NETs and ETs spontaneously and after in vitro induction.32 patients with verified RA and 30 healthy volunteers as controls were included into the study. Circulating neutrophils and monocytes were isolated with one-step density gradient centrifugation using three layers of ficoll-amidotrizoate gradient. Composition of isolated cellular fractions, their viability, and non-specific activation were evaluated microscopically using Trypan Blue exclusion test, as well as Nitro-Blue Tetrazolium test. The NETs were induced by phorbol-12-myristate-13-acetate, and ETs by bacterial LPS. Spontaneous and induced formation of extracellular traps was assessed using fluorescence microscopy. Neutrophil and monocyte fractions contained minute percentages of impurities and low extents of activated and dead cells. Spontaneous NET and ET formation in RA patients was significantly increased comparing to healthy controls. Neutrophils from ACPA-positive RA patients were found to have higher frequency of NET formation, compared to ACPA-negative RA patients. The monocytes did not demonstrate such differences between these subgroups. There were no substantial morphological differences in NETs and ETs patterns between the individuals from both groups. Induced extracellular trap production in RA was significantly higher compared to healthy controls. The level of myeloperoxidase-specific fluorescence in ETs was considerably lower than in NETs. NETs could probably be considered as a source of citrulline autoantigen participating in autoantibody production and stimulation of inflammatory autoimmune responses in RA, whereas ETs may play less important role in this process.

IL-33 Gene Polymorphisms as Potential Biomarkers of Disease Susceptibility and Response to TNF Inhibitors in Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients.

ObjectiveRheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) belong to inflammatory rheumatic diseases, the group of conditions of unknown etiology. However, a strong genetic component in their pathogenesis has been well established. A dysregulation of cytokine networks plays an important role in the development of inflammatory arthritis. Interleukin 33 (IL-33) is a recently identified member of the IL-1 family. To date, the significance of IL-33 in inflammatory arthritis has been poorly studied. This research aimed to investigate the potential of IL-33 gene polymorphisms to serve as biomarkers for disease susceptibility and TNF inhibitor response in RA, AS, and PsA patients.Materials and MethodsIn total, 735 patients diagnosed with RA, AS, and PsA and 229 healthy individuals were enrolled in the study. Genotyping for three single nucleotide polymorphisms (SNPs) within the IL-33 gene, namely, rs16924159 (A/G), rs10975519 (T/C), and rs7044343 (C/T), was performed using polymerase chain reaction amplification employing LightSNiP assays.ResultsIn the present study, the IL-33 rs10975519 CC genotype was associated with a decreased risk of developing RA in females, while the IL-33 rs16924159 polymorphism was associated with the efficacy of anti-TNF therapy and clinical parameters for RA and AS patients. The IL-33 rs16924159 AA genotype correlated with higher disease activity and worse clinical outcomes in RA patients treated with TNF inhibitors, and AS patients carrying the IL-33 rs16924159 AA genotype had higher disease activity and a worse response to anti-TNF therapy. That indicates a deleterious role of the IL-33 rs16924159 AA genotype in the context of RA, as well as AS.ConclusionsThe obtained results suggest that IL-33 gene polymorphisms might be potential candidate biomarkers of disease susceptibility and anti-TNF treatment response in patients with inflammatory rheumatic diseases.

Effects of fire on soil respiration and its components in a Dahurian larch (Larix gmelinii) forest in northeast China: Implications for forest ecosystem carbon cycling

Fire plays a critical part in regulating soil carbon (C) budgets in forest ecosystems. However, few studies have focused on the effects of fire on soil respiration (Rs) and its heterotrophic (Rh) and autotrophic (Ra) components. In this study, we examined the response of Rs, Rh, and Ra to fire and the driving factors that affect Rs after a fire disturbance in a Dahurian larch (Larix gmelinii) forest in northeastern China. Fire disturbance significantly increased Rh by approximately 24% and significantly reduced Ra by approximately 66% in burned plots compared to unburned plots. The ratio of Rh to Rs significantly increased from 0.57 in the unburned plots to 0.79 in the burned plots. Fire disturbance also led to cumulative Rs C efflux increasing by approximately 10% and 28% during the growing season and the period of spring freeze–thaw cycles (FTC) in the burned plots. Furthermore, using structural equation modelling, we showed that T5 (soil temperature at 5 cm depth) was the main abiotic factor affecting Rs in both unburned and burned plots. Fine root biomass (FR) was the dominant biotic driver of Rs in the control plots, whereas microbial biomass carbon (MBC) was the dominant biotic driver of Rs in burned plots. Our findings demonstrated a significant discrepancy in the response of Rs components to fire disturbance. Forest fires can cause considerable losses of soil C in a cold temperate forest ecosystem, which suggests that proactive management of forest regeneration should be carried out after forest fire disturbances.

POS0631 COMPARATIVE EFFICACY OF COMBINATION THERAPY WITH BIOLOGIC OR TARGET SYNTHETIC DRUGS FOR RHEUMATOID ARTHRITIS: A BAYESIAN NETWORK META-ANALYSIS

Background:Biologic agents and small molecules have shown long term benefit when added in patients with active RA non-responders to conventional DMARDs treatment (1). In head-to-head trials only adalimumab was compared to other drugs in combination with methotrexate, with some evidence of superiority but no data on multiple comparisons have been reported (2). The availability of biosimilar agents led in clinical practice to prefer mainly the cheaper one, so the choice of the most effective treatment remains a clinical unmet need (3).Objectives:To assess the relative efficacy of different therapeutic strategies for achieving ACR50 response at 24 weeks of treatment in patients with active RA, based on direct and indirect evidence.Methods:We performed systematic reviews of MEDLINE, EMBASE, and Cochrane Library databases, searching for all published phase 3 Randomised Controlled Trials (RCTs) comparing adalimumab originator to its biosimilars, abatacept, baricitinib, certolizumab pegol, tofacitinib or upadacitinib, combined to MTX, in patients with active RA inadequate responders to previous conventional DMARDs. American College of Rheumatology (ACR) 50% response at 24 weeks of treatment had to be evaluated both in adalimumab branch and in examined drug branch. Bayesian fixed-effect network meta-analysis was performed to combine the direct and indirect evidence using the WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK).Results:Eleven RCTs evaluating 6’004 patients were included in the analysis, namely originator (1) and biosimilars (2) adalimumab, abatacept (3), baricitinib (4), certolizumab pegol (5), tofacitinib (6) and upadacitinib (7). Convergence was reached at n.100’000 iterations. Upadacitinib seems to be more effective than both originator and biosimilar adalimumab in achieving ACR 50 (OR 1.65 95% CI 1.25-2.14 and OR 1.22 95%CI 1.10-2.18; see Figure 1). Similarly, tofacitinib was more effective of originator adalimumab (OR 1.25 95%CI 1.01-155). Upadacitinib was ranked first among treatments with a probability of being the agent more likely to induce ACR 50 response of 86.3%. In this regard tofacitinib had a probability of 4.8%, hence it was ranked second among treatments.Figure 1.Caterpillar plot OR for ACR50 at 24 weeks (originator [1] and biosimilars [2] adalimumab; abatacept [3]; baricitinib [4]; certolizumab pegol [5]; tofacitinib [6]; upadacitinib [7]).Conclusion:Although patients with active RA and inadequate response to MTX have different therapeutic combination of biologics or small molecules options, the best relative efficacy in terms of ACR50 response after 24 weeks of treatment is for upadacitinib 15 mg/day.

The synergistic efficacy of hydroxychloroquine with methotrexate is accompanied by increased erythrocyte mean corpuscular volume.

ObjectivesTo determine whether concomitant HCQ modulates the increase in erythrocyte mean corpuscular volume (MCV) caused by MTX therapy, and whether this is associated with improved clinical response in RA.MethodsA retrospective observational analysis was conducted on two independent hospital datasets of biologic-naïve, early-RA patients who started oral MTX. Baseline characteristics, DAS28-ESR and monthly MCV after starting MTX were obtained. Conventional and machine-learning statistical approaches were applied to the discovery cohort (Cohort 1, 655 patients) and results validated using Cohort 2 (225 patients).ResultsHCQ therapy with MTX was associated with a 2-fold increase in the likelihood of response defined in this study as clinical remission or low disease activity at 6 months (P <0.001). The improved clinical outcome of combination HCQ and MTX therapy was associated with an accelerated rise in MCV from 2 months after commencing therapy. The increase in MCV at 3 months was equivalent to the contemporaneous reduction in the DAS (DAS28-ESR) in predicting clinical response at 6 months. Using latent class mixed modelling, five trajectories of MCV change over 6 months from baseline were identified. The odds ratio of response to treatment was 16.2 (95% CI 5.7, 46.4, P <0.001) in those receiving combination therapy classified within the MCV elevation >5 fl class, which contained the most patients, compared with MTX alone.ConclusionOur data provide mechanistic insight into the synergistic clinical benefit of concomitant HCQ with MTX, boosting the rise in MCV, which could serve as a companion biomarker of treatment response.

Elicitation of Rheumatologist Preferences for the Treatment of Patients with Rheumatoid Arthritis After the Failure of a First Conventional Synthetic Disease-Modifying Anti-Rheumatic Agent.

IntroductionRheumatoid arthritis (RA) clinical guidelines do not provide strong recommendations for the choice of disease-modifying anti-rheumatic drugs (DMARD) in patients with an inadequate response to methotrexate (MTX), and only limited evidence is available on factors influencing rheumatologist treatment decisions. We aimed to describe therapeutic preferences after the failure of a first-line strategy of MTX in simulated cases of patients with RA.MethodsFictional but realistic case-vignettes (n = 64) of patients with RA and an inadequate response to MTX were developed with a combination of RA-poor prognostic factors and comorbidities. Physicians were presented with eight vignettes and chose the most and least appropriate therapeutic option from the following six options randomly proposed 3 by 3: (1) replacing MTX with another csDMARD; (2) combining MTX with one or more csDMARDs; (3) adding a bDMARD of either TNF inhibitors (TNFi), tocilizumab (TCZ), abatacept (ABA), or rituximab (RTZ). A total of 1605 complete case vignettes were produced and randomly assigned to a representative sample of French rheumatologists. For each vignette, whenever a treatment was preferred, one point was incremented for this treatment; if this treatment was the least desired, one point was removed. Preferences were elicited using a normalized best–worst score.ResultsTwo hundred and four French rheumatologists participated in the study with each vignette being assessed 20–28 times for a completion rate of 94%. TNFi was the first-choice strategy (80% of vignettes), except in cases with a history of infection and pulmonary comorbidity, where ABA was the first preference (85%). TCZ came third in 83% of the cases. Other options were never preferred and repeatedly yielded negative scores.ConclusionsWe observed a conservative trend with TNFi as the main therapeutic choice for patients with RA and inadequate response to MTX. Preference for bDMARD-based strategies increased with the number of RA-poor prognosis factors, whereas an increase in the number of comorbidities resulted in an increased preference for ABA. Understanding clinical decision-making will be particularly important as the therapeutic landscape for RA continues to evolve.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00311-1.

The association between increased body mass index and response to conventional synthetic disease-modifying anti-rheumatic drug treatment in rheumatoid arthritis: results from the METEOR database.

Few data exist on the association between increased BMI and response to conventional synthetic DMARDs (csDMARDs) in RA. We aimed to explore the association between increased (overweight or obese) BMI on csDMARD prescribing, MTX dose and disease activity over 12 months. Participants in an international RA database were stratified into early (<1 year post-diagnosis) and established RA. EULAR response, 28-joint DAS (DAS28) remission and treatments were recorded at baseline, 6 months and 12 months. Increased BMI was explored in early and established RA as predictors of good EULAR response, DAS28 remission, number of csDMARDs and MTX dose, using logistic and linear regression. Data from 1313 patients, 44.3% with early RA, were examined. In early RA, increased BMI was not significantly associated with remission. In established RA, obese patients on monotherapy were significantly less likely to achieve good EULAR response or DAS28 remission at 6 months and more likely to be treated with combination csDMARDs compared with normal BMI. In patients taking MTX, overweight and obese patients with early and established RA were exposed to higher MTX doses (mono- and combination therapy), with a mean dose of 20 mg/week, compared with 15 mg/week in those of normal BMI. We observed that compared with patients with normal BMI, overweight and obese individuals experienced more intensive csDMARD exposures. Similar response rates were observed in early RA but increased BMI was associated with reduced response in established RA. Optimization of targeted RA treatment remains important, particularly in those with increased BMI where response in established disease may be attenuated.

A study on machining performance of wire electric discharge grinding (WEDG) process during machining of tungsten alloy micro-tools

In this experimental study, tungsten alloy micro-tools of high aspect ratio are machined through wire electric discharge grinding (WEDG) method using the step machining technique on a hybrid micro-electro-discharge machine to achieve high productivity and finish. Tungsten alloy micro-tools are widely used in the fabrication of miniature products. The precise and economical machining of the tungsten material with an optimum level of accuracy and surface properties is a challenge because of its exceptional characteristics like hot hardness, high strength, low wear, and corrosion rate. The material removal rate (MRR) and surface roughness (Ra) responses are studied during machining of micro-tools, selecting the variability of applied voltage, circuit capacitance, and spindle speed during machining for a constant-aspect-ratio micro-tool. Both voltage and capacitance are found to be influencing parameters for MRR and surface roughness. Higher voltage and capacitance values tend to increase MRR and roughness values on the machined micro-tool. Further, the parametric conditions are also identified for higher MRRs and lower surface roughness (Ra) values after employing the hybrid Taguchi design of experimentation methodology. Surface topography of the machined surface studied by energy-dispersive spectroscopy (EDS) reveals the presence of pyrolytic carbon and oxygen elements. Field emission scanning electron microscopy (FESEM) images show a little waviness across the machined surface. A mathematical model is developed to evaluate the correlation among governing parameters for machining response and validated by confirmation experiments. The machining procedure can be further developed to fabricate more predominant fluted micro-tools for difficult-to-machine tungsten material.

Gut microbiome could predict drug response in RA.

Gut microbiome could predict drug response in RA.

Rheumatoid arthritis CD14+ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease.

IntroductionThis study investigates the metabolic activity of circulating monocytes and their impact on pro‐inflammatory responses in RA and explores whether this phenotype is already primed for inflammation before clinical manifestations of disease.MethodsBlood was collected and CD14+ monocytes isolated from healthy control donors (HC), individuals at‐risk (IAR) and RA patients. Monocyte frequency in blood and synovial tissue was assessed by flow cytometry. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT‐PCR, Western blot, migration assays, Seahorse‐XFe‐technology, mitotracker assays and transmission electron microscopy. Transcriptomic analysis was performed on HC, IAR and RA synovial tissue.ResultsCD14+ monocytes from RA patients are hyper‐inflammatory following stimulation, with significantly higher expression of cytokines/chemokines than those from HC. LPS‐induced RA monocyte migratory capacity is consistent with increased monocyte frequency in RA synovial tissue. RA CD14+ monocytes show enhanced mitochondrial respiration, biogenesis and alterations in mitochondrial morphology. Furthermore, RA monocytes display increased levels of key glycolytic enzymes HIF1α, HK2 and PFKFB3 and demonstrate a reliance on glucose consumption, blockade of which abrogates pro‐inflammatory mediator responses. Blockade of STAT3 activation inhibits this forced glycolytic flux resulting in metabolic reprogramming and resolution of inflammation. Interestingly, this highly activated monocytic phenotype is evident in IAR of developing disease, in addition to an enhanced monocyte gene signature observed in synovial tissue from IAR.ConclusionRA CD14+ monocytes are metabolically re‐programmed for sustained induction of pro‐inflammatory responses, with STAT3 identified as a molecular regulator of metabolic dysfunction. This phenotype precedes clinical disease onset and may represent a potential pathway for therapeutic targeting early in disease.

Usefulness of Cytokine Gene Polymorphisms for the Therapeutic Choice in Japanese Patients with Rheumatoid Arthritis.

BackgroundRheumatoid arthritis (RA) is characterized by systemic synovitis with bone erosion and joint cartilage degradation. Although the analysis of polymorphisms in cytokine-encoding genes is important or understanding the pathophysiology of RA and selecting appropriate treatment for it, few studies have examined such single-nucleotide polymorphisms (SNPs) specifically in Japanese patients. This study was established to investigate the associations between polymorphisms in cytokine-encoding genes, autoantibodies and therapeutic responses in Japanese RA patients.MethodsThe subjects in this study consisted of 100 RA patients and 50 healthy controls. We extracted data on sex, age, disease duration, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and therapeutic responses, including to methotrexate (MTX) and biological disease-modifying antirheumatic drugs (DMARDs). Genomic DNA was isolated from peripheral blood, which was genotyped for IL-10, TNF-α, TGF-β1, and IFN-γ polymorphisms.ResultsRegarding IL-10 (−592 C/A and −819 C/T), significant decreases in the frequencies of the IL-10 (−592) CC genotype and (−819) CC genotype were found in RA patients compared with the levels in controls. For IFN-γ (+874 T/A), a significant decrease in the frequency of the TT genotype was found in RA patients compared with that in controls. Regarding TGF-β1 (+869 T/C), patients with positivity for anti-CCP antibody had a significantly lower frequency of the CC genotype than those with negativity for it. Furthermore, the IL-10 (−592) CC genotype and (−819) CC genotype might be related to the biological DMARD-response.ConclusionOur results suggest that the analysis of polymorphisms in cytokine-encoding genes may be useful when selecting treatment for Japanese RA patients.

Differential Influence of No-Tillage and Precipitation Pulses on Soil Heterotrophic and Autotrophic Respiration of Summer Maize in the North China Plain

It is important to strengthen the studies on the response of soil respiration components to tillage practices and natural precipitation in cropland. Therefore, soil heterotrophic respiration (RH) and autotrophic (RA) respiration were monitored by a root exclusion method in the North China Plain (NCP). The tillage practices included no-tillage (NT) and conventional tillage (CT), and the study periods were the summer maize growth stages in 2018 and 2019. RH, RA, soil water content and temperature were measured continuously for 113 days by an automatic sampling and analysis system. The soil RH values on bright days and rain-affected days were higher under NT in 2018 (14.22 and 15.06 g CO2 m−2 d−1, respectively) than in 2019 (8.25 and 13.30 g CO2 m−2 d−1, respectively). However, the RA values on bright days and rain-affected days were lower under NT in 2018 (4.74 and 4.97 g CO2 m−2 d−1, respectively) than in 2019 (5.67 and 6.93 g CO2 m−2 d−1, respectively). Moreover, NT decreased RH but increased RA compared to CT in 2019. Compared to bright days, the largest increase in both RH and RA after rain pulses was under CT in 2019 (6.75 and 1.80 g CO2 m−2 d−1, respectively). Soil water content and soil temperature were higher in 2018 than in 2019. Moreover, NT increased soil water content and decreased soil temperature on bright days compared to CT in 2019. Furthermore, soil temperature accounted for more variations in RH on bright days and rain-affected days, but soil water content had a greater influence on RA on bright days. However, after precipitation, higher soil water content decreased RA under NT in 2018, while soil water content was positively related to RA under CT in 2019. This study determined the differential response of RH and RA to tillage practices and natural precipitation pulses, and we confirmed that excessively dry soil increases soil carbon loss after rain events in the NCP.

Selective impairment of slowly adapting type 1 mechanoreceptors in mice following vincristine treatment

Loss of the sense of touch in fingertips and toes is one of the earliest sensory dysfunctions in patients receiving chemotherapy with anti-cancer drugs such as vincristine. However, mechanisms underlying this chemotherapy-induced sensory dysfunction is incompletely understood. Whisker hair follicles are tactile organs in non-primate mammals which are functionally equivalent to human fingertips. Here we used mouse whisker hair follicles as a model system and applied the pressure-clamped single-fiber recording technique to explore how vincristine treatment affect mechanoreceptors in whisker hair follicles. We showed that in vivo treatment of mice with vincristine impaired whisker tactile behavioral responses. The pressure-clamped single-fiber recordings made from whisker hair follicle afferent nerves showed that mechanical stimulations evoked three types of mechanical responses, rapidly adapting response (RA), slowly adapting type 1 response (SA1) and slowly adapting type 2 response (SA2). Vincristine treatment significantly reduced SA1 responses but did not significantly affect RA and SA2 responses. Our findings suggest that SA1 mechanoreceptors were selectively impaired by vincristine leading to the impairment of in vivo whisker tactile behavioral responses.

Does periodontitis affect the treatment response of biologics in the treatment of rheumatoid arthritis?

BackgroundRheumatoid arthritis (RA) and periodontitis (PD) have been suggested to share many clinical and pathological features. However, few reports have investigated the relationship between the degree of PD and the treatment response to RA.This study aimed to examine the relationship between the extent of PD and the treatment response to biologics in RA patients using FDG-PET/CT.MethodsSixty RA patients (male, n = 14; female, n = 46; average age, 58.3 years) treated with biologic agents were included in this study. FDG-PET/CT was performed at baseline and 6 months after the initiation of biological therapy. The maximum standardized uptake value (SUVmax) was used as a representative value for the assessment of the FDG uptake in periodontal tissue and joints including the bilateral shoulders, elbows, wrists, hip, knees, and ankle joints. The Disease Activity Score (DAS) 28-CRP and the following clinical parameters were assessed: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide antibody (ACPA), rheumatoid factor (RF), and matrix metalloproteinase 3 (MMP-3). The relationship between the treatment response of RA and the baseline SUVmax of the periodontal tissue was evaluated.ResultsThe baseline periodontal SUVmax was related to patient age (r = 0.302, p = 0.009) and the ACPA level (r = 0.265, p = 0.025). The DAS28-CRP, CRP, ESR, MMP-3, and joint SUVmax values were significantly decreased after 6 months of biological therapy. However, the mean periodontal SUVmax, ACPA, and RF showed no significant changes after treatment. There was a significantly negative correlation between the baseline periodontal SUVmax and the treatment response of DAS28-CRP (r = − 0.369, p = 0.004).ConclusionThere was a negative correlation between the extent of PD at baseline and the treatment response of RA patients who received biological therapy. The evaluation of the periodontal condition is considered to be an essential part for the management of RA.

Global Transcriptomic Responses of Roseithermus sacchariphilus Strain RA in Media Supplemented with Beechwood Xylan.

The majority of the members in order Rhodothermales are underexplored prokaryotic extremophiles. Roseithermus, a new genus within Rhodothermales, was first described in 2019. Roseithermus sacchariphilus is the only species in this genus. The current report aims to evaluate the transcriptomic responses of R. sacchariphilus strain RA when cultivated on beechwood xylan. Strain RA doubled its growth in Marine Broth (MB) containing xylan compared to Marine Broth (MB) alone. Strain RA harbors 54 potential glycosyl hydrolases (GHs) that are affiliated with 30 families, including cellulases (families GH 3, 5, 9, and 44) and hemicellulases (GH 2, 10, 16, 29, 31,43, 51, 53, 67, 78, 92, 106, 113, 130, and 154). The majority of these GHs were upregulated when the cells were grown in MB containing xylan medium and enzymatic activities for xylanase, endoglucanase, β-xylosidase, and β-glucosidase were elevated. Interestingly, with the introduction of xylan, five out of six cellulolytic genes were upregulated. Furthermore, approximately 1122 genes equivalent to one-third of the total genes for strain RA were upregulated. These upregulated genes were mostly involved in transportation, chemotaxis, and membrane components synthesis.

Effects of grazing exclusion on soil respiration components in an alpine meadow on the north-eastern Qinghai-Tibet Plateau

Grazing exclusion has been widely used to restore degraded grasslands worldwide. Total soil respiration (Rs) (consisting of heterotrophic respiration (Rh, microbes and soil fauna respiration) and autotrophic respiration (Ra, plant root and their symbionts respiration)) play a critical role in the global carbon (C) balance. Quantifying Rs, Rh and Ra in relation to different grazing exclusion durations is vital to better understanding the impact of grassland management on global C cycling. However, how Rs and its components respond to different grazing exclusion durations remain unclear. Therefore, in this study, a trenching method was used to separate the Ra and Rh in an alpine meadow with different grazing exclusion durations (0, 4, 7, 10 and 12 years) on the north-eastern Qinghai-Tibet Plateau. Our results demonstrated that the growing season Rs, Rh and Ra showed nonlinear (hump-shaped) response patterns with the length of grazing exclusion, with a peak point at the 7-year grazing exclusion. Meanwhile, grazing exclusion treatments significantly increased the Rs, Rh and Ra compared to the grazed site. Grazing exclusion substantially increased the soil respiration temperature sensitivity (Q10) values of Rs, Rh and Ra. Moreover, the Q10 values of Ra and Rh showed hump-shaped response patterns with the length of grazing exclusion, with a threshold of 7 years grazing exclusion. The annual Ra/Rs ratio ranged from 53% to 69% during the growing season, indicating that changes in soil respiration were mainly determined by changes in autotrophic respiration. In addition, soil temperature could better explain Rh (R2 = 0.89–0.94) than Ra (R2 = 0.84–0.9). Our research highlights the nonlinear response of Rs, Rh and Ra to the length of grazing exclusion, and suggests that different grazing exclusion durations should be considered for better evaluating the impact of grassland management on global C cycling on the north-eastern Qinghai-Tibet Plateau.