Arthritis Research & Therapy

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Estimated time-to-evolution in the validation cohort. Survival estimates as calculated by the Turnbull's method, in the validation cohort; T0 = blood draw
Distribution of categorized proteins in the validation cohort. Distribution of cases with high or low validated protein levels in preclinical systemic sclerosis patients who did evolve (progressors) or who did not (non-progressors) into definite systemic sclerosis. Dicothomization was performed as described in the main text; for endostatin risk is associated with high serum levels; for the basic fibroblast growth factor (FGF) and platelet-activating factor acetylhydrolase subunit beta (PAFAH1B2) risk is associated with low serum levels; clusterization made on the basis of serum concentrations
  • Chiara BellocchiChiara Bellocchi
  • Shervin AssassiShervin Assassi
  • Marka LyonsMarka Lyons
  • [...]
  • Lorenzo BerettaLorenzo Beretta
Background The study of molecular mechanisms characterizing disease progression may be relevant to get insights into systemic sclerosis (SSc) pathogenesis and to intercept patients at very early stage. We aimed at investigating the proteomic profile of preclinical systemic sclerosis (PreSSc) via a discovery/validation two-step approach. Methods SOMAcan aptamer-based analysis was performed on a serum sample of 13 PreSSc (discovery cohort) according to 2001 LeRoy and Medsger criteria (characterized solely by Raynaud phenomenon plus a positive nailfold capillaroscopy and SSc-specific antibodies without any other sign of definite disease) and 8 healthy controls (HCs) age, gender, and ethnicity matched. Prospective data were available up to 4±0.6 years to determine the progression to definite SSc according to the EULAR/ACR 2013 classification criteria. In proteins with relative fluorescence units (RFU) > |1.5|-fold vs HCs values, univariate analysis was conducted via bootstrap aggregating models to determine the predicting accuracy (progression vs non-progression) of categorized baseline protein values. Gene Ontologies (GO terms) and Reactome terms of significant proteins at the adjusted 0.05 threshold were explored. Significant proteins from the discovery cohort were finally validated via ELISAs in an independent validation cohort of 50 PreSSc with clinical prospective data up to 5 years. Time-to-event analysis for interval-censored data was used to evaluate disease progression. Results In the discovery cohort, 286 out of 1306 proteins analyzed via SomaScan, were differentially expressed versus HCs. Ten proteins were significantly associated with disease progression; analysis through GO and Reactome showed differentially enriched pathways involving angiogenesis, endothelial cell chemotaxis, and endothelial cell chemotaxis to fibroblast growth factor (FGF). In the validation cohort, endostatin (HR=10.23, CI95=2.2–47.59, p =0.003) was strongly associated with disease progression, as well as bFGF (HR=0.84, CI95=0.709-0.996, p =0.045) and PAF-AHβ (HR=0.372, CI95=0.171–0.809, p =0.013) Conclusions A distinct protein profile characterized PreSSc from HCs and proteins associated with hypoxia, vasculopathy, and fibrosis regulation are linked with the progression from preclinical to definite SSc. These proteins, in particular endostatin, can be regarded both as markers of severity and molecules with pathogenetic significance as well as therapeutic targets.
 
Flow diagram illustrating the participant eligibility and sample size for final analysis
Average a physical function (HAQ score) and b HRQoL (EQ-5D score) of HKOA participants at baseline and in each follow-up wave (EpiDoC 2, 3, and 4). Data labels are mean (standard deviation). PA, physical activity. Sample size not consistent due to missing values: physical function EpiDoC2—all (n = 953), no (n = 751), frequent (n = 62), very frequent (n = 140); physical function EpiDoC3—all (n = 728), no (n = 567), frequent (n = 50), very frequent (n = 111); physical function EpiDoC4—all (n = 408), no (n = 297), frequent (n = 36), very frequent (n = 75); HRQoL EpiDoC1—all (n = 1073), no (n = 845), frequent (n = 67), very frequent (n = 161); HRQoL EpiDoC2—all (n = 959), no (n = 748), frequent (n = 61), very frequent (n = 141); HRQoL EpiDoC3—all (n = 719), no (n = 559), frequent (n = 50), very frequent (n = 110); HRQoL EpiDoC4—all (n = 405), no (n = 293), frequent (n = 37), very frequent (n = 75). Kruskal–Wallis test for the difference between physical activity categories: HAQ—EpiDoC 1 (p < 0.001), EpiDoC 2 (p < 0.001), EpiDoC 3 (p < 0.001), EpiDoC 4 (p = 0.005); EQ-5D—EpiDoC 1 (p < 0.001), EpiDoC 2 (p < 0.001), EpiDoC 3 (p < 0.001), EpiDoC 4 (p = 0.134)
Estimates and 95% confidence intervals (95% CIs) of the association between physical activity frequency and a physical function and b HRQoL. PA, physical activity. Shapes indicate different models: diamonds for model 1, triangles for model 2, squares for model 3, and circles for model 4. All models are adjusted for years from baseline. Model 1 shows the crude effect of physical activity frequency. Model 2 was adjusted for sex, age group, and education level. Model 3 was further adjusted for body mass index. Model 4 was further adjusted for multimorbidity, hospitalizations, clinical severity, and unmanageable pain levels. Non-frequent physical activity was set as the reference in all models. Sample sizes (number of participants): physical function—model 1 (n = 1086), model 2 (n = 1086), model 3 (n = 1051), model 4 (n = 907); HRQoL—model 1 (n = 1084), model 2 (n = 1084), model 3 (n = 1050), model 4 (n = 907)
Hip and knee osteoarthritis (HKOA) is a chronic disease characterized by joint pain that leads to reduced physical function and health-related quality of life (HRQoL). At present, no cure is available. Clinical trials indicate that people with HKOA benefit from physical activity in several health-related outcomes. However, few studies have evaluated the long-term positive effect of regular physical activity. This study analyzed participants with HKOA from a nationwide population-based cohort (EpiDoC Cohort) to assess the impact of physical activity on patients’ physical function and HRQoL over a long-term follow-up. The regular weekly frequency of intentional physical activity was self-reported as non-frequent (0 times/week), frequent (1–2 times/week), or very frequent (≥ 3 times/week). This study followed 1086 participants over a mean period of 4.7 ± 3.4 years, during which 6.3% and 14.9% of participants reported frequent and very frequent physical activity, respectively. Using linear mixed models, we found that frequent ( β = − 0.101 [− 0.187, − 0.016]; β = 0.039 [− 0.002, 0.080]) and very frequent physical activity ( β = − 0.061 [− 0.118, − 0.004]; β = 0.057 [0.029, 0.084]) were associated with improved physical function and HRQoL over time, respectively, when compared with non-frequent exercise, adjusting for years to baseline, sex, age, years of education, body mass index, multimorbidity, hospitalizations, clinical severity, and unmanageable pain levels. These findings raise awareness of the importance of maintaining exercise/physical activity long term to optimize HRQoL and physical function. Further studies must address barriers and facilitators to improve the adoption of regular physical activity among citizens with HKOA.
 
  • Ilari Mäki-OpasIlari Mäki-Opas
  • Mari HämäläinenMari Hämäläinen
  • Eeva MoilanenEeva Moilanen
  • Morena ScoteceMorena Scotece
Background Systemic sclerosis is a rheumatoid disease best known for its fibrotic skin manifestations called scleroderma. Alternatively activated (M2-type) macrophages are normally involved in the resolution of inflammation and wound healing but also in fibrosing diseases such as scleroderma. TRPA1 is a non-selective cation channel, activation of which causes pain and neurogenic inflammation. In the present study, we investigated the role of TRPA1 in bleomycin-induced skin fibrosis mimicking scleroderma. Methods Wild type and TRPA1-deficient mice were challenged with intradermal bleomycin injections to induce a scleroderma-mimicking disease. Macrophages were investigated in vitro to evaluate the underlying mechanisms. Results Bleomycin induced dermal thickening and collagen accumulation in wild type mice and that was significantly attenuated in TRPA1-deficient animals. Accordingly, the expression of collagens 1A1, 1A2, and 3A1 as well as pro-fibrotic factors TGF-beta, CTGF, fibronectin-1 and YKL-40, and M2 macrophage markers Arg1 and MRC1 were lower in TRPA1-deficient than wild type mice. Furthermore, bleomycin was discovered to significantly enhance M2-marker expression particularly in the presence of IL-4 in wild type macrophages in vitro, but not in macrophages harvested from TRPA1-deficient mice. IL-4-induced PPARγ-expression in macrophages was increased by bleomycin, providing a possible mechanism behind the phenomenon. Conclusions In conclusion, the results indicate that interfering TRPA1 attenuates fibrotic and inflammatory responses in bleomycin-induced scleroderma. Therefore, TRPA1-blocking treatment could potentially alleviate M2 macrophage driven diseases like systemic sclerosis and scleroderma.
 
  • Minxi LaoMinxi Lao
  • Peiyin DaiPeiyin Dai
  • Guangxi LuoGuangxi Luo
  • [...]
  • Dongying ChenDongying Chen
Objectives To evaluate the safety, efficacy, and maternal and fetal outcomes of assisted reproductive therapy (ART) in systemic lupus erythematosus (SLE). Methods Patients from three tertiary hospitals from Guangzhou, China followed-up from 2013 to 2022 were included retrospectively. Patients with planned or unplanned natural pregnancy were chosen as controls. ART procedure and pregnancy outcomes were recorded and compared. Results A total of 322 ART cycles in 142 women were analyzed. Sixty-six intrauterine pregnancies out of 72 clinical pregnancies yielded 65 live infants, including 5 pairs of twins. The clinical pregnancy rate was 46.5% (66/142). The mean age at the first clinical pregnancy was 34.0 ± 3.8 years. The median (interquartile range, IQR) disease course was 42.5 (25, 84.8) months. Twenty-seven (40.9%) of them had a history of adverse pregnancy. Primary infertility occurred in 20 (30.3%) patients. Obstruction of fallopian tubes (17/66, 25.8%) and premature ovarian failure (9/66, 13.6%) were the leading causes for infertility. Ovulation induction therapy (OIT) were conducted in 60 (83.3%) pregnancies, and no ovarian hyperstimulation syndrome (OHSS) or thrombosis was observed. The leading maternal adverse pregnancy outcomes (APOs) included premature delivery (21/66, 31.8%), gestational diabetes mellitus (GDM) (15/66, 22.7%), and disease flares (10/66, 15.2%). Spontaneous premature delivery (9/21, 42.9%) and preterm premature rupture of membranes (PPROM) (6/21, 28.6%) were the leading causes for premature delivery. Preeclampsia (19.0% vs 0%, P = 0.012) increased in premature delivery. Infants delivered prematurely were likely to be low-birth-weight (LBW)/very-low-birth-weight (VLBW) (81.0% vs 7.7%, P < 0.001). Disease flares were mild (4/10, 40.0%) or moderate (5/10, 50.0%), and developed during the second (3/10, 30.0%) or third (6/10, 60.0%) trimester with favorable outcomes. Fetal loss in ART (6/66, 9.1%) was primarily attributed to early spontaneous abortion (n = 5). The average delivery time was 36.8 ± 2.1 weeks of gestation. The average birth weight was 2653.5 ± 578.6 g. LBW infants accounted for 30.8% (20/65). No neonatal death or neonatal lupus occurred. The incidence of adverse pregnancy outcomes did not increase in patients with ART compared with planned pregnancy and reduced significantly compared with an unplanned pregnancy. Conclusion The safety and efficacy of ART is assured in lupus patients with stable disease. Maternal and fetal APOs are comparable with planned pregnancy, with a relatively high incidence of premature delivery, GDM, and LBW infants.
 
Hyperspectral imaging (HSI) heatmap. A HSI oxyHb image from a patient with systemic sclerosis-Raynaud phenomenon (SSc-RP). Red: higher oxyHb [arbitrary units (AU)]; blue: lower oxyHb (AU). The region of interest (ROI) on the palmar side of the hand and fingertips is indicated by an opaque gray circle
Baseline comparison of oxyhemoglobin, deoxyhemoglobin, and O2 saturation parameters in SSc-RP patients and HC. Prior to the cold challenge, there were no statistically significant differences noted at baseline in oxyHb between SSc-RP and healthy controls (HCs) (A), but SSc-RP had greater levels of deoxyHb (B) and lower levels of O2 sat compared to HC (C) (p < 0.05). No significance (ns), *p < 0.05, **p < 0.01
Representative images at baseline and 0, 10, and 20 min following cold challenge for SSc-RP and HC. HSI captures oxyHb and O2 sat gross visual changes in the fingertips during RP activity induced by cold water challenge. Hyperspectral images and the gross appearance of the hands were different between SSc-RP and HC with heatmaps for SSc-RP patients with more blue pixels for oxyHb and O2 sat, and more red pixels for deoxyHb, that correlates with visible fingertip pallor during RP activity induced by cold water challenge. Blue pixels for oxyHb and O2 sat and red pixels for deoxyHb were rare in HC images. Red: higher oxyHb [arbitrary units (AU)]; blue: lower oxyHb (AU)
Comparison of oxyhemoglobin, deoxyhemoglobin, and O2 saturation parameters in SSc-RP patient and HC at baseline (prior to cold provocation) and post-cold provocation. After cold provocation, systemic sclerosis (SSc) patients had a threefold greater decline in oxyHb (A) and O2 sat (C) and minimal change in deoxyHb (B) from baseline (prior to cold provocation) to “time point 0” (immediately after cold provocation). Significant changes were observed in subsequent time points (10- and 20-min post-cold provocation) in oxyHb, O2 sat, and deoxyHb compared to HC. Mixed effects model. No significance (ns), *p < 0.05, **p < 0.01
Background/purpose Lack of robust, feasible, and quantitative outcomes impedes Raynaud phenomenon (RP) clinical trials in systemic sclerosis (SSc) patients. Hyperspectral imaging (HSI) non-invasively measures oxygenated and deoxygenated hemoglobin (oxyHb and deoxyHb) concentrations and oxygen saturation (O2 sat) in the skin and depicts data as oxygenation heatmaps. This study explored the potential role of HSI in quantifying SSc-RP disease severity and activity. Methods Patients with SSc-RP (n = 13) and healthy control participants (HC; n = 12) were prospectively recruited in the clinic setting. Using a hand-held camera, bilateral hand HSI (HyperMed™, Waltham, MA) was performed in a temperature-controlled room (22 °C). OxyHb, deoxyHb, and O2 sat values were calculated for 78-mm² regions of interest for the ventral fingertips and palm (for normalization). Subjects underwent a cold provocation challenge (gloved hand submersion in 15 °C water bath for 1 min), and repeated HSI was performed at 0, 10, and 20 min. Patients completed two patient-reported outcome (PRO) instruments: the Raynaud Condition Score (RCS) and the Cochin Hand Function Scale (CHFS) for symptom burden assessment. Statistical analyses were performed using the Mann-Whitney U test and a mixed effects model (Stata, College Station, TX). Results Ninety-two percent of participants were women in their 40s. For SSc-RP patients, 69% had limited cutaneous SSc, the mean ± SD SSc duration was 11 ± 5 years, and 38% had prior digital ulcers—none currently. Baseline deoxyHb was higher, and O2 sat was lower, in SSc patients versus HC (p < 0.05). SSc patients had a greater decline in oxyHb and O2 sat from baseline to time 0 (after cold challenge) with distinct rewarming oxyHb, O2 sat, and deoxyHb trajectories versus HCs (p < 0.01). There were no significant correlations between oxyHb, deoxyHb, and O2 sat level changes following cold challenge and RCS or CHFS scores. Conclusion Hyperspectral imaging is a feasible approach for SSc-RP quantification in the clinic setting. The RCS and CHFS values did not correlate with HSI parameters. Our data suggest that HSI technology for the assessment of SSc-RP at baseline and in response to cold provocation is a potential quantitative measure for SSc-RP severity and activity, though longitudinal studies that assess sensitivity to change are needed.
 
Representative pulmonary artery involvement images. The main pulmonary artery widened and vessel wall thickness (white arrows in A). The right main pulmonary artery vessel wall thickness and stenosis (white empty arrows in A). Stenosis of the right upper pulmonary artery (white arrows in B). Occlusion of the right upper pulmonary artery (white arrows in C). Occlusion of the right main pulmonary artery (white arrows in D). Dilation of the pulmonary artery (white arrows in E)
Distribution of pulmonary artery involvement in patients with Takayasu arteritis. A The heat map depicting the number of main pulmonary artery, lobar pulmonary artery and segment pulmonary artery. B The number of pulmonary segments involved for each case. The X-axis is the number of affected pulmonary artery segments, and the Y-axis is the number of affected patients with Takayasu arteritis
Clustering of the vascular involvement in the 65 patients with Takayasu arteritis pulmonary artery involvement (TAK-PAI). A The dendrogram on the bottom shows the clustering of the 26 vascular territories assessed in the cohort of 65 patients with TAK-PAI. The color map at the center indicates involvement (red) or noninvolvement (yellow) of the 26 vascular territories in each of the 65 patients. X-axis denotes different vessels and Y-axis denotes different patients. In the heatmap, negative four to four is the degree of vascular involvement and is normalized. B Prevalence of pulmonary artery involvement by cluster analysis. Heatmaps of the arteries indicated the percent of patients in each cluster with pulmonary artery involvement. A darker red indicates that a higher percentage of patients in the cluster have involvement of the pulmonary artery
Cumulative incidence of events. A Cumulative incidence of events in TAK with PAI and TAK without PAI. B Cumulative incidence of events in five cluster. C Cumulative incidence of events in Cluster1 and non-Cluster1. D All-cause mortality rate in TAK with PAI and TAK without PAI
Predictors of TAK with PAI
Objective To investigate the clinical characteristics and the site of pulmonary involvement in Takayasu arteritis (TAK) patients with pulmonary artery involvement (PAI). Methods We retrospectively investigated data of 141 TAK patients. The clinical and image data of the patients with and without PAI were analyzed and compared. The patients were followed up. The major outcome was all-cause mortality. The minor outcome was exacerbation or new occurrence of PAI, which leads to disease progression events. Results For the 141 TAK patients considered, PAI was detected in 65 (46.1%) patients. TAK patients with PAI had a significantly higher cumulative incidence of events than those without PAI ( P < 0.001). The frequencies of the following were significantly higher in TAK with PAI than those in TAK without PAI: disease duration [median 96 months (IQR: 24–174) vs. median 42 months (IQR: 6–120); P = 0.012], hemoptysis (10.8% vs. 1.32%; P = 0.040), oppression in the chest (40.0% vs. 21.1%; P = 0.014), fever (23.1% vs. 9.21%; P = 0.024), Mycobacterium tuberculosis infection (21.5% vs. 6.57%; P = 0.010), pulmonary hypertension (PAH) (21.5% vs. 2.6%; P < 0.001), pulmonary infarction (41.5% vs. 0 %; P < 0.001), and hypoxemia (18.5% vs. 1.3%; P < 0.001). Multivariate logistic regression analysis of data of TAK patients with symptom presentation showed that oppression in the chest (OR: 2.304; 95% CI: 1.024–5.183; P = 0.044) and thoracic aorta involvement (OR: 2.819; 95% CI: 1.165–6.833; P = 0.022) were associated with PAI. The cluster analysis performed for data of TAK patients with PAI revealed that the cluster characterized as the upper lobe of the right lung (Cluster1) had the worst prognosis. Conclusion In TAK, PAI is associated with thoracic aorta involvement. In TAK patients with PAI, the involvement of the upper lobe of the right lung is characterized with the worst prognosis.
 
ASDAS low disease activity and ASDAS inactive disease after 2 years of follow-up depending on the presence of Achilles enthesitis on physical examination
Background Enthesitis represents one of the most important peripheral musculoskeletal manifestations in patients with axial spondyloarthritis (axSpA). However, studies specifically evaluating Achilles tendon enthesitis and its impact over time are scarce. The objectives of this study were to evaluate the impact of Achilles’ tendon enthesitis found at baseline during physical examination on the outcome measures after 2 years of follow-up in patients with ankylosing spondylitis (AS). Methods This was an observational and prospective study conducted during 2 years of follow-up in the REGISPONSER-AS registry. Linear regression models adjusted for age, body mass index (BMI), and anti-TNF intake were conducted to evaluate the association between the presence of Achilles enthesitis at baseline and the patient-reported outcome (PRO) scores at baseline. The impact of this feature on PROs over 2 years of follow-up was evaluated using mixed models for repeated measures adjusted for age, BMI, and anti-TNF intake. Results Among the 749 patients included, 46 patients (6.1%) showed Achilles’ tendon enthesitis during physical examination at the baseline study visit. Patients with Achilles enthesitis had an increase in the global VAS score, BASDAI, mBASDAI, ASDAS-CRP, and BASFI scores in comparison with patients without this feature. In addition, the mean global VAS, BASDAI, and ASDAS-CRP scores were significantly higher among patients with Achilles enthesitis over the 2 years of follow-up after adjusting for age, BMI, and current anti-TNF intake. The percentage of patients achieving ASDAS low disease activity (ASDAS < 2.1) after 2 years of follow-up was 15.9% and 31.5% for patients with and without Achilles enthesitis, respectively (p = 0.030). Conclusions In patients with AS, the presence of Achilles’ tendon enthesitis was associated with worse scores on the outcome measures after 2 years of follow-up, leading to a lower probability of achieving low disease activity.
 
Resting cardiovascular measures taken at the endpoint in males (top) and females (bottom), including heart rate (A, C) and blood pressure (B, D). Blood pressure measures were statistically different for all hypertensive animals, with no differences due to the surgical group. Bars indicate p < 0.05 between the groups. Data are presented as mean ± 95% confidence interval
Representative images of joint histology. Black arrows indicate osteophyte formation, and white arrows point out regions of subchondral bone remodeling. Scale bar = 1 mm
Quantitative histological results for male (left) and female (right) tibial region in the medial joint compartment. A In males, minimum cartilage thickness decreased with MCLT+MMT compared to sham in both hypertensive and normotensive animals. B In females, decreased cartilage thickness due to MCLT+MMT only occurred in hypertensive animals. C The ratio of the bone area associated with the subchondral bone plate to the total area of bone and trabecular bone in the subchondral space (“bone area ratio”) increased in hypertensive-MCLT+MMT males compared to normotensive-MCLT+MMT males. D Hypertensive-MCLT+MMT females also had an increased bone area ratio; however, this was compared to hypertensive-sham animals. E, F Osteophyte areas increased due to MCLT+MMT in both strains and sexes. Bars represent p < 0.05 between the groups. Data are presented as mean ± 95% confidence interval
Results of semi-quantitative histological scoring for males (left) and females (right). All OARSI scores were determined based on the tibial region of the joint. A In males, medial compartment OARSI scores increased in both normotensive-MCLT+MMT and hypertensive-MCLT+MMT animals compared to their sham controls. B In females, this increase in medial compartment OARSI scores for the MCLT+MMT groups was also observed. C, D Lateral compartment OARSI scores did not change in any group. E In males, low-grade synovitis was present in both MCLT+MMT groups. F In females, low-grade synovitis was present in both MCLT+MMT groups, with hypertensive-MCLT+MMT animals having higher synovitis scores than normotensive-MCLT+MMT animals. Bars represent p < 0.05 the between groups. Black dots represent the outliers of the boxplots, while colored dots represent the individual data points. Data are presented as median and interquartile range
Cardiovascular responses to chemical stimulation of vagal afferents with 1-phenylbiguanide (PBG) in males (top) and females (bottom). A In males, heart rate responses were increased in the hypertensive-MCLT+MMT group compared to normotensive-MCLT+MMT; this decrease was not statistically significant in the male sham groups. B In males, blood pressure responses to PBG were enhanced with hypertension, regardless of the surgical group. C No differences were seen in female heart responses to PBG; however, D hypertension resulted in larger blood pressure drops with PBG administration in the MCLT+MMT surgical groups. This difference was not statistically significant in the sham surgical group. Bars indicate p < 0.05 between the groups. Data are presented as mean ± 95% confidence interval
Background Hypertension is a common comorbidity of osteoarthritis (OA) with known autonomic dysregulation; thus, the autonomic nervous system may provide a shared underlying mechanism. The objective of this study was to examine the role of the autonomic nervous system in a preclinical model of OA and hypertension. Methods Experiments were conducted in spontaneously hypertensive rats and a normotensive control strain, including male and female rats. OA was surgically induced via medial meniscus transection with skin incision used as a sham control ( n = 7–8/strain/sex/surgery). Tactile sensitivity, anxiety-related behavior, and serum corticosterone were measured at baseline then bi-weekly across 8 weeks. At weeks 9–10, cardiovascular responses to a chemical vagal nerve agonist were determined to indirectly evaluate vagus nerve function. The joint structure was assessed via grading of histological sections. Results In males, OA resulted in thinner cartilage in both hypertensive (OA vs. non-OA p < 0.001) and normotensive (OA vs. non-OA p < 0.001). Only females with comorbid hypertension and OA displayed thinner cartilage ( p = 0.013). Male hypertensive OA animals had increased calcified subchondral bone compared to normotensive OA animals ( p = 0.043) while female hypertensive OA animals had increased calcified subchondral bone compared to hypertensive sham animals ( p < 0.001). All MCLT+MMT groups developed low-grade synovitis; interestingly, hypertensive OA females had higher synovitis scores than normotensive OA females ( p = 0.046). Additionally, hypertension led to larger drops in blood pressure with vagal activation in both OA (hypertensive vs. normotensive p = 0.018) and sham (hypertensive vs. normotensive p < 0.001) male animals. In females, this trend held true only in OA animals (normotensive vs. hypertensive p = 0.005). Conclusion These data provide preliminary evidence that hypertension influences OA progression and encourages further study into the autonomic nervous system as a possible mechanism.
 
Cellular composition of different PRP products and corresponding donor blood samples. a Proportion of leukocytes (CD45⁺), b granulocytes (CD45⁺FSC/SSC NGr⁺), c lymphocytes and monocytes (CD45⁺FSC/SSC NGr⁻), d monocytes (CD45⁺CD14⁺), e B cells (CD45⁺CD14⁻CD19⁺CD3⁻), f T cells (CD45⁺CD14⁻LyCD19⁻CD3⁺), g NK cells (CD45⁺CD14⁻CD19⁻CD3⁻CD56⁺), h CD4⁺ T helper cells (CD45⁺CD14⁻CD19⁻CD3⁺CD4⁺CD8⁻), and i CD8⁺ cytotoxic T cells (CD45⁺CD14⁻CD19⁻CD3⁺CD4⁻CD8⁺) in donor blood compared to PRP samples. Abbreviations: NK cells, natural killer cells; PRP, platelet-rich plasma
Cytokine profile of different PRP products and corresponding donor blood samples. a Concentrations of IFN-γ, b TNF-α, c IL-1β, d IL-2, e IL-6, f IL-8, g IL-4, h IL-10, and i IL-13 in donor blood compared to PRP samples. Abbreviations: IFN-γ, interferon γ; TNF-α, tumor necrosis factor α; IL-1β, interleukin 1β; IL-2, interleukin 2; IL-4, interleukin 4; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IL-13, interleukin 13; PRP, platelet-rich plasma
2D and 3D cell cultures of primary human chondrocytes exposed to a pro-inflammatory environment. a Population doublings dependent on IFN-γ and b TNF-α at indicated concentrations, c metabolic activity dependent on IFN-γ and d TNF-α at indicated concentrations, e lactate dehydrogenase (LDH) release dependent on IFN-γ and f TNF-α at indicated concentrations, fold change in mRNA expression relative to control of gACAN, hCOL1A1, and iCOL2A1 and delta threshold cycles of jMMP3, kMMP9, and lMMP13 dependent on IFN-γ and TNF-α treatment, respectively. Abbreviations: PD, population doublings; CTRL, control; rel, relative; IFN-γ, interferon γ; TNF-α, tumor necrosis factor α; LDH, lactate dehydrogenase; ACAN, aggrecan; COL1A1, collagen type 1A1; COL2A1, collagen type 2A1; MMP3, matrix metalloproteinase 3; MMP9, matrix metalloproteinase 9; MMP13, matrix metalloproteinase 13; ∆CT, delta cycle threshold
Objective Platelet-rich plasma (PRP) therapy is increasingly popular to treat musculoskeletal diseases, including tendinopathies and osteoarthritis (OA). To date, it remains unclear to which extent PRP compositions are determined by the immune cell and cytokine profile of individuals or by the preparation method. To investigate this, we compared leukocyte and cytokine distributions of different PRP products to donor blood samples and assessed the effect of pro-inflammatory cytokines on chondrocytes. Design For each of three PRP preparations (ACP®, Angel™, and nSTRIDE® APS), products were derived using whole blood samples from twelve healthy donors. The cellular composition of PRP products was analyzed by flow cytometry using DURAClone antibody panels (DURAClone IM Phenotyping Basic and DURAClone IM T Cell Subsets). The MESO QuickPlex SQ 120 system was used to assess cytokine profiles (V-PLEX Proinflammatory Panel 1 Human Kit, Meso Scale Discovery). Primary human chondrocyte 2D and 3D in vitro cultures were exposed to recombinant IFN-γ and TNF-α. Proliferation and chondrogenic differentiation were quantitatively assessed. Results All three PRP products showed elevated portions of leukocytes compared to baseline levels in donor blood. Furthermore, the pro-inflammatory cytokines IFN-γ and TNF-α were significantly increased in nSTRIDE® APS samples compared to donor blood and other PRP products. The characteristics of all other cytokines and immune cells from the donor blood, including pro-inflammatory T cell subsets, were maintained in all PRP products. Chondrocyte proliferation was impaired by IFN-γ and enhanced by TNF-α treatment. Differentiation and cartilage formation were compromised upon treatment with both cytokines, resulting in altered messenger ribonucleic acid (mRNA) expression of collagen type 1A1 ( COL1A1 ), COL2A1 , and aggrecan ( ACAN ) as well as reduced proteoglycan content. Conclusions Individuals with elevated levels of cells with pro-inflammatory properties maintain these in the final PRP products. The concentration of pro-inflammatory cytokines strongly varies between PRP products. These observations may help to unravel the previously described heterogeneous response to PRP in OA therapy, especially as IFN-γ and TNF-α impacted primary chondrocyte proliferation and their characteristic gene expression profile. Both the individual’s immune profile and the concentration method appear to impact the final PRP product. Trial registration This study was prospectively registered in the Deutsches Register Klinischer Studien (DRKS) on 4 November 2021 (registration number DRKS00026175).
 
Genome-wide DNA methylation patterns in IgG4-RD patients. A Graphical overview of the study design. B Distribution of methylation beta values in B cells, CD4+ T cells, and salivary gland tissues of IgG4-RD patients and controls. C Number of hypomethylation and hypermethylation probes in B cells, CD4+ T cells, and salivary gland tissues of IgG4-RD patients compared with controls
Overlapped DNA methylation profiles in B cells, CD4⁺ T cells, and salivary gland tissues of IgG4-RD patients. A Venn diagram showing overlapped differentially methylated CpG sites in B cells, CD4⁺ T cells, and salivary gland tissues of IgG4-RD patients. B Delta beta values of overlapped differentially methylated genes and CpG sites in B cells, CD4⁺ T cells, and salivary gland tissues of IgG4-RD patients. C The methylation rate of MBP and HLA-DQB2 in B cells, CD4+ T cells, and salivary gland tissues of IgG4-RD patients compared with controls through pyrosequencing. D Immunohistochemistry staining of MBP in salivary gland tissues of two IgG4-RD patients and two controls (scale: 50μm)
DNA methylation status in B cells and CD4⁺ T cells of IgG4-RD patients. A Distribution of DMPs in B cells of IgG4-RD patients. B Significant GO categories in B cells of IgG4-RD patients. C Distribution of DMPs in CD4⁺ T cells of IgG4-RD patients. D Significant GO categories in CD4⁺ T cells of IgG4-RD patients
DNA methylation status in salivary gland tissues of IgG4-RD patients. A Principal components analysis of DMPs. Ellipses show the 95% confidence interval for the distribution of each group. Each dot represents an individual patient. B Supervised hierarchical clustering of DNA methylation in salivary gland tissues of IgG4-RD patients. C Distribution of DMPs in salivary gland tissues of IgG4-RD patients. D KEGG pathway analysis of DMPs in salivary gland tissues of IgG4-RD patients. E Significant GO categories in salivary gland tissues of IgG4-RD patients
Enrichment of DMR-related genes in salivary gland tissues of IgG4-RD patients. A KEGG pathway analysis of DMR-related genes in salivary gland tissues of IgG4-RD patients. B Significant GO categories of DMR-related genes in salivary gland tissues of IgG4-RD patients
Objectives Immunoglobulin-G4-related disease (IgG4-RD) is a distinct systemic autoimmune-mediated disease manifesting as chronic inflammation and tissue fibrosis. Since the role of DNA methylation in the pathogenesis of IgG4-RD is still unclear, we conduct this study to investigate epigenetic modifications in IgG4-RD. Methods A genome-wide DNA methylation study was conducted with B cells, CD4⁺ T cells, and salivary gland tissues from IgG4-RD patients and matched controls by using the Illumina HumanMethylation 850K BeadChip. We further performed pyrosequencing and immunohistochemistry assays to validate the methylation status of some targets of interest. Results We identified differentially methylated CpG sites including 44 hypomethylated and 166 hypermethylated differentially methylated probes (DMPs) in B cells and 260 hypomethylated and 112 hypermethylated DMPs in CD4⁺ T cells from 10 IgG4-RD patients compared with 10 healthy controls. We also identified 36945 hypomethylated and 78380 hypermethylated DMPs in salivary gland tissues of 4 IgG4-RD patients compared with 4 controls. DPM2 (cg21181453), IQCK (cg10266221), and ABCC13 (cg05699681, cg04985582) were hypermethylated and MBP (cg18455083) was hypomethylated in B cells, CD4⁺ T cells, and salivary gland tissues of IgG4-RD patients. We also observed the hypomethylated HLA-DQB2 in CD4⁺ T cells from IgG4-RD patients. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DMPs in salivary gland tissues of IgG4-RD patients revealed enrichment of pathways involved in the regulation of immune cell responses and fibrosis. Conclusion This is the first DNA methylation study in peripheral B cells, CD4⁺ T cells, and salivary gland tissues from IgG4-RD patients. Our findings highlighted the role of epigenetic modification of DNA methylation and identified several genes and pathways possibly involved in IgG4-RD pathogenesis.
 
Distinctive blood plasma metabolomic profile in BD. A Pathway enrichment analysis showed pathway perturbation in BD compared to HC. The X-axis indicates pathway impact values (from pathway topology analysis), and the Y-axis indicates p-values (from pathway enrichment analysis). The node color is based on its p-value and the node radius is determined based on pathway impact. B Volcano plot for compounds altered in BD compared to that in HC. The p-value is calculated based on the Mann-Whitney test. Red and blue indicate a 1.5-fold increase and decrease, respectively, in BD. ChemRICH analysis of BD compared with HC (C) and DC (D). The node color scale represents the ratio of an increased (red) or decreased (blue) compound. The node size means the total number of metabolites in each cluster
Identification of BD metabolic biomarker in plasma. A Score scatter plot of PLS-DA for BD with HC and DC. B 999 times permutation plot for PLS-DA (C) ROC analysis. AUC values of 13 metabolites’ composite ranged from 0.810 to 0.966. D Box and whisker plots presented relative abundances of BD-unique metabolites. The box indicates the interquartile range, and the whisker indicates the minimum and maximum values for all data (Mann-Whitney test, *p < 0.05, **p < 0.01)
Characteristics of PBMC lipidome in BD. A Volcano plot for compounds altered in BD compared to HC. The p-value is calculated based on the Mann-Whitney test. Red and blue indicate a 1.5-fold increase and decrease, respectively, in BD. ChemRICH analysis of BD compared with HC (B) and DC (C). The node color scale represents the ratio of an increased (red) or decreased (blue) compound. The node size means the total number of lipids in each cluster
Discovery of unique PBMC biomarkers in BD. A Score scatter plot of PLS-DA for BD with HC and DC. B 999 times permutation plot for PLS-DA (C) ROC analysis. AUC values of 10 lipid composites ranged from 0.900 to 0.950. D Box and whisker plots presented relative abundances of BD-unique lipids. The box indicates the interquartile range, and the whisker indicates the minimum and maximum values for all data (Mann-Whitney test, *p < 0.05)
Metabolic signature according to disease activity. OPLS-based shared and unique structure (SUS) plot with p (corr) values of plasma (A) and PBMCs (D). The compounds in the upper region (red) showed a gradual increase with stage transition. Spearman rank analysis identified metabolites with patterns corresponding to the remission-relapse transition in plasma (B) and PBMCs (E). Box and whisker plots show compounds with upregulation in both remission and relapse compared to HC in plasma (C) and PBMCs (F) (Mann-Whitney test, *p < 0.05, **p < 0.01)
Background Behçet’s disease (BD) is a systemic inflammatory disease that involves various organs. The clinical manifestation-based diagnosis of BD is a time-consuming process, which makes it difficult to distinguish from patients with similar symptoms. Moreover, an authentic biomarker has not been developed for accurate diagnosis yet. Our current study investigated the unique metabolic signatures of BD and explored biomarkers for precise diagnosis based on an untargeted metabolomic approach. Methods Integrative metabolomic and lipidomic profiling was performed on plasma samples of BD patients ( n = 40), healthy controls (HCs, n = 18), and disease controls (DCs, n = 17) using GC-TOF MS and LC-Orbitrap MS. Additionally, the lipid profiles of 66 peripheral blood mononuclear cells (PBMCs) were analyzed from 29 BD patients, 18 HCs, and 19 DCs. Results Plasma metabolic dysfunction in BD was determined in carbohydrate, hydroxy fatty acid, and polyunsaturated fatty acid metabolisms. A plasma biomarker panel with 13 compounds was constructed, which simultaneously distinguished BD from HC and DC (AUCs ranged from 0.810 to 0.966). Dysregulated PBMC metabolome was signatured by a significant elevation in lysophosphatidylcholines (LPCs) and ether-linked lysophosphatidylethanolamines (EtherLPEs). Ten PBMC-derived lipid composites showed good discrimination power (AUCs ranged from 0.900 to 0.973). Correlation analysis revealed a potential association between disease activity and the metabolites of plasma and PBMC, including sphingosine-1 phosphate and EtherLPE 18:2. Conclusions We identified metabolic biomarkers from plasma PBMC, which selectively discriminated BD from healthy control and patients with similar symptoms (recurrent mouth ulcers with/without genital ulcers). The strong correlation was determined between the BD activity and the lipid molecules. These findings may lead to the development for diagnostic and prognostic biomarkers based on a better understanding of the BD pathomechanism.
 
Osteoarthritis (OA) is a common and prevalent degenerative joint disease characterized by degradation of the articular cartilage. However, none of disease-modifying OA drugs is approved currently. Teriparatide (PTH (1-34)) might stimulate chondrocyte proliferation and cartilage regeneration via some uncertain mechanisms. Relevant therapies of PTH (1-34) on OA with such effects have recently gained increasing interest, but have not become widespread practice. Thus, we launch this systematic review (SR) to update the latest evidence accordingly. A comprehensive literature search was conducted in PubMed, Web of Science, MEDLINE, the Cochrane Library, and Embase from their inception to February 2022. Studies investigating the effects of the PTH (1-34) on OA were obtained. The quality assessment and descriptive summary were made of all included studies. Overall, 307 records were identified, and 33 studies were included. In vivo studies (n = 22) concluded that PTH (1-34) slowed progression of OA by alleviating cartilage degeneration and aberrant remodeling of subchondral bone (SCB). Moreover, PTH (1-34) exhibited repair of cartilage and SCB, analgesic, and anti-inflammatory effects. In vitro studies (n = 11) concluded that PTH (1-34) was important for chondrocytes via increasing the proliferation and matrix synthesis but preventing apoptosis or hypertrophy. All included studies were assessed with low or unclear risk of bias in methodological quality. The SR demonstrated that PTH (1-34) could alleviate the progression of OA. Moreover, PTH (1-34) had beneficial effects on osteoporotic OA (OPOA) models, which might be a therapeutic option for OA and OPOA treatment.
 
Flow diagram elaborating the details of the design and execution of the study
Spearman’s correlation between A age and plasma vitamin D levels, B age and SLEDAI-2K, C plasma vitamin D levels and SLEDAI-2K, D Galectin-9 and SLEDAI-2K, E anti dsDNA and plasma vitamin D and F Galectin-9 and SLEDAI-2K
Abstract Background and objectives Data on the association of vitamin D levels and clinical phenotype and disease activity in systemic lupus erythematosus (SLE) is controversial. Further, the optimal dose of oral vitamin D supplementation in SLE is not clear. Thus, the present study was designed to determine the association of plasma vitamin D levels with clinical phenotype, disease variables and serology in a large, cohort of SLE from South Asia and to evaluate the short-term effect of two different dosage regimens of oral vitamin D supplementation on disease flares and plasma vitamin D levels. Methods This is a two-phase study. Phase I was a cross-sectional analytical study of patients from north (26.85° N) and south India (11.94° N). Plasma 25-hydroxyvitamin-D(25(OH)D) was measured, and its association with demography, serology, disease activity, Galectin-9 and CXCL-10 was analysed. In phase II, patients with SLEDAI-2KG
 
Differentially expressed genes in GCA, TAK, and old and young HCs. A Numbers and B lists of (a) upregulated and (b) downregulated genes in GCA compared with that in TAK and old HCs and (c) upregulated genes in older subjects (GCA vs. TAK and old vs. young HCs). C Top 10 (a) upregulated and (b) downregulated pathways in GCA compared with that in TAK and old HCs and upregulated pathways in older subjects (GCA vs. TAK and old vs. young HCs). Orange, blue, and green: P < 0.05. GCA, giant cell arteritis; TAK, Takayasu arteritis; HC, healthy control
Relative immune cell subsets using CIBERSORT analysis in LVV and HCs. Results of the CIBERSORT analysis in LVV and HCs. A Patients with treatment-naive GCA, those with treatment-naive TAK, and old and young HCs. B The top 10 dysregulated genes in GCA defining M0-like monocytes, Tregs, Tfh cells, and B cells. Red, upregulated; blue, downregulated genes. LVV, large-vessel vasculitis; GCA, giant cell arteritis; TAK, Takayasu arteritis; HC, healthy control; CIBERSORT, cell-type identification by estimating relative subsets of RNA transcripts; NK, natural killer; FC, fold-change
Longitudinal analysis for the proportion of estimated subsets in LVV. The average proportion of estimated subsets was calculated using CIBERSORT analysis. A Patients with treatment-naive GCA, remission with prednisolone monotherapy, remission and relapse with prednisolone and tocilizumab treatment, treatment-naive patients with TAK, and HCs. B Treatment-naive patients with GCA after 6 weeks of treatment without relapse and with future relapse. LVV, large-vessel vasculitis; GCA, giant cell arteritis; TAK, Takayasu arteritis; HC, healthy control; PSL, prednisolone; TCZ, tocilizumab; CIBERSORT, cell-type identification by estimating relative subsets of RNA transcripts
Background Giant cell arteritis (GCA) is a primary large-vessel vasculitis (LVV) of unknown origin. Its management is a challenge due to the late onset of disease symptoms and frequent relapse; therefore, clarifying the pathophysiology of GCA is essential to improving treatment. This study aimed to identify the transition of molecular signatures in immune cells relevant to GCA pathogenesis by analyzing longitudinal transcriptome data in patients. Methods We analyzed the whole blood transcriptome of treatment-naive patients with GCA, patients with Takayasu arteritis (TAK), age-matched, old healthy controls (HCs), and young HCs. Characteristic genes for GCA were identified, and the longitudinal transition of those genes was analyzed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). Results Repeated measures analysis of variance revealed 739 differentially expressed genes among all patients and HCs. Of the 739 genes, 15 were characteristically upregulated and 36 were downregulated in patients with GCA compared to those with TAK and HCs. Pathway enrichment analysis showed that downregulated genes in GCA were associated with B cell activation. CIBERSORT analysis revealed that upregulation of “M0-macrophages” and downregulation of B cells were characteristic of GCA. Upregulation of “M0-macrophages” reflects the activation of monocytes in GCA toward M0-like phenotypes, which persisted under 6 weeks of treatment. Combined treatment with prednisolone and an interleukin-6 receptor antagonist normalized molecular profiles more efficiently than prednisolone monotherapy. Conclusions Gene signatures of monocyte activation and B cell inactivation were characteristic of GCA and associated with treatment response.
 
The role of the SIRT family in maintaining chondrocyte function. A SIRT in maintaining ECM homeostasis. B SIRT in regulating chondrocyte metabolism. C SIRT in preventing chondrocyte senescence. D SIRT in decreasing chondrocyte apoptosis and enhancing chondrocyte autophagy. Abbreviations: SIRT, sirtuins; SIRT1, sirtuin 1; SIRT2, sirtuin 2; SIRT3, sirtuin 3; SIRT4, sirtuin 4; SIRT5, sirtuin 5; SIRT6, sirtuin 6; SIRT7, sirtuin 7; ECM, extracellular matrix; Col2, type 2 collagen; HA, hyaluronan; MMP-13, matrix metalloproteinase-13; SOX9, SRY-Box transcription factor 9; FOXO4, forkhead box O-4; HAS2, hyaluronan synthase 2; Runx2, Runt-Related Transcription Factor 2; NAMPT, nicotinamide phosphoribosyltransferase; HIF-2α, hypoxia-inducible factor-2α; LOX-1, lectin-like oxidized low-density lipoprotein receptor-1; NF-κB, nuclear factor-κB; Mak, protein lysine malonylation; IL-1β, interleukin-1β; IL-6, interleukin-6; IL-8, interleukin-8; Bcl-2, B-cell lymphoma-2; Bax, Bcl-2-associated X; ER, endoplasmic reticulum; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; NAD + , nicotinamide adenine dinucleotide; p-AMPK, phospho-adenosine monophosphate-activated protein kinase; MFN2, mitofusin-2; FOXO1, forkhead box O-1; ATGs, autophagy-related proteins
The role of the SIRT family in mediating mitochondrial quality control in chondrocytes. SIRT1 can deacetylate PGC-1α, and then coactivate the transcription of NRF-1 or NRF-2, enhancing TFAM expression, which this process promotes mitochondrial biogenesis. SIRT3 could deacetylate OPA1 to promote mitochondrial dynamics, deacetylate Parkin to contribute to mitophagy, and elevate the level of GSH to reduce ROS to maintain mitochondrial homeostasis in chondrocytes. Abbreviations: SIRT, sirtuins; SIRT1, sirtuin 1; SIRT3, sirtuin 3; SIRT6, sirtuin 6; p-AMPK, phospho-adenosine monophosphate-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor Coactivator-1α; NRF-1, nuclear respiratory factor 1; NRF-2, nuclear respiratory factor 2; TFAM, mitochondrial transcription factor A; NAD⁺, nicotinamide adenine dinucleotide; OPA1, optic atrophy-1; MFN1, mitofusin-1; MFN2, mitofusin-2; DRP1, dynamin-related protein 1; PINK1:, PTEN-induced putative kinase-1; GSH, glutathione; ROS, reactive oxygen species
Osteoarthritis (OA) is mainly characterized by the progressive destruction of articular cartilage. Mounting studies have revealed that disruption of extracellular matrix (ECM) homeostasis, aberrant chondrocyte metabolism, an increase in the number of senescent chondrocytes and abnormal activation of cell death such as chondrocyte apoptosis and autophagy, are the crucial steps in OA development. Additionally, mitochondrial dysfunction also participates in the abovementioned processes and is the key element of OA pathogenesis. Sirtuin (SIRT) is a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that can actively participate and primarily regulate chondrocyte function in OA pathophysiological processes. Some members of the SIRT family located in mitochondria can regulate mitochondrial function and mediate mitochondrial homeostasis via deacetylation to protect chondrocytes. In addition, SIRT can maintain ECM homeostasis, regulate chondrocyte metabolism, inhibit chondrocyte apoptosis and autophagy, and prevent chondrocyte senescence in cartilage by exerting its deacetylation activity. However, the molecular mechanism of the SIRT family against the onset and development of OA remains poorly elucidated. In this review, we will discuss the potential protective role of SIRT in the progression of OA and summarize several sirtuin-activating molecules as well as their potential therapeutic applications for OA.
 
Background Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice. Methods In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated. Results Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity. Conclusions Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.
 
Background Psoriatic arthritis (PsA) patient data from two phase 3 secukinumab trials (FUTURE 1, 5) were analysed to quantify the prevalence and extent of pre-existing radiographic damage (RD) at baseline; investigate the association of RD with swollen/tender joint counts (SJC/TJC) at baseline; and investigate the extent to which RD at baseline correlated with response to secukinumab. Methods Pooled data (N = 1554) provided baseline radiographic bone erosion and joint space narrowing (JSN) scores at pre-specified locations per the van der Heijde-modified total Sharp score (vdH-mTSS) for PsA and swollen and tender joint scores in the same joints at multiple visits. Overall patient RD and individual joints RD bone erosion and JSN scores were assessed. The association between joint activity (tenderness, swelling) and vdH-mTSS was assessed at the overall patient-level and individual joint tender, swollen scores (yes/no) and RD joint JSN and bone erosion scores at the individual joint-level. Treatment response was assessed using SJC/TJC at weeks 16 and 52 and the proportion of patients achieving minimal disease activity (MDA) over all assessments within 1 year from FUTURE 5 alone. Results A substantial prevalence of pre-existing RD with higher prevalence of erosion than JSN was observed (86% and 60% of patients had positive erosion and JSN scores, respectively); higher RD prevalence was associated with longer time since PsA diagnosis. Joint activity was weakly associated with RD at baseline at the patient-level (Pearson’s coefficients: range 0.12–0.18), but strongly associated at the individual joint-level, with a higher probability of tender/swollen joints to associate with higher JSN/erosion scores: all 42 analysed joints showed statistical significance at the 0.05 level (unadjusted) for the relationship between joint tenderness (yes/no) and its JSN score, all but one for tenderness and bone erosion scores, and all but 2 for swollen and JSN scores and for swollen and bone erosion score. Secukinumab (150/300 mg), reduced TJC and SJC across all values of baseline erosion and JSN scores at weeks 16 and 52. Patients with higher levels of RD were less likely to achieve zero tender/zero swollen joint status and had lower chance of achieving MDA. Conclusions PsA patients showed substantial prevalence of RD at baseline that correlated with time since diagnosis, but patient’s individual joint activity was strongly associated with pre-existing RD at those joints. Patients with the highest RD at baseline had a reduced likelihood of achieving zero joint count status.
 
Background The infrapatellar fat pad (IFP) is the largest adipose deposit in the knee; however, its contributions to the homeostasis of this organ remain undefined. To determine the influence of the IFP and its associated synovium (IFP/synovium complex or IFP/SC) on joint health, this study evaluated the progression of osteoarthritis (OA) following excision of this unit in a rodent model of naturally-occurring disease. Methods Male Dunkin-Hartley guinea pigs ( n =18) received surgical removal of the IFP in one knee at 3 months of age; contralateral knees received sham surgery as matched internal controls. Mobility and gait assessments were performed prior to IFP/SC removal and monthly thereafter. Animals were harvested at 7 months of age. Ten set of these knees were processed for microcomputed tomography (microCT), histopathology, transcript expression analyses, and immunohistochemistry (IHC); 8 sets of knees were dedicated to microCT and biomechanical testing (material properties of knee joints tissues and anterior drawer laxity). Results Fibrous connective tissue (FCT) developed in place of the native adipose depot. Gait demonstrated no significant differences between IFP/SC removal and contralateral hindlimbs. MicroCT OA scores were improved in knees containing the FCT. Quantitatively, IFP/SC-containing knees had more osteophyte development and increased trabecular volume bone mineral density (vBMD) in femora and tibiae. Histopathology confirmed maintenance of articular cartilage structure, proteoglycan content, and chondrocyte cellularity in FCT-containing knees. Transcript analyses revealed decreased expression of adipose-related molecules and select inflammatory mediators in FCTs compared to IFP/SCs. This was verified via IHC for two key inflammatory agents. The medial articular cartilage in knees with native IFP/SCs showed an increase in equilibrium modulus, which correlated with increased amounts of magnesium and phosphorus. Discussion/conclusion Formation of the FCT resulted in reduced OA-associated changes in both bone and cartilage. This benefit may be associated with: a decrease in inflammatory mediators at transcript and protein levels; and/or improved biomechanical properties. Thus, the IFP/SC may play a role in the pathogenesis of knee OA in this strain, with removal prior to disease onset appearing to have short-term benefits.
 
of joint involvement in patients with uncontrolled gout treated with pegloticase (biweekly 8 mg infusion) plus oral methotrexate (15 mg/week) for up to 52 weeks (light blue bar; 52 weeks [26 infusions] in 8 patients, 24 weeks [12 infusions] in 2 patients). Data represent mean values and error bars represent standard error. Weeks 64 and 76 represent the 3- and 6-month post-treatment follow-up visits, respectively. BL, baseline (last measurement prior to the first pegloticase infusion). Reproduced from Annals of the Rheumatic Diseases 80 (Suppl 1) 2021 with permission from BMJ Publishing Group Ltd
of patient-reported HAQ outcomes during and after pegloticase + methotrexate treatment (light blue bar; 52 weeks in 8 patients, 24 weeks in 2 patients; A). Patient and physician Global Assessments of Gout are also shown (B). Data represent mean values and error bars represent standard error. Weeks 64 and 76 represent the 3- and 6-month post-treatment follow-up visits, respectively. Part A reproduced from Annals of the Rheumatic Diseases 80 (Suppl 1) 2021 with permission from BMJ Publishing Group Ltd
Clinical and patient-reported measures (A–C) and coincident DECT imaging (D) in a 44-year-old man with uncontrolled gout who underwent pegloticase + methotrexate co-therapy for 52 weeks. Marked improvements in quality of life measures were observed as urate load decreased. Left knee joint urate volume decreased from 22.6 cm³ at baseline to 3.1, 1.2, and 0.2 cm³ at weeks 24, 36, and 52, respectively (urate depicted in green). Lateral femoral condyle bone erosion (arrows) decreased in size and showed evidence of healing with increased sclerosis and new bone formation. DECT, dual-energy computed tomography; BL, baseline; HAQ, Health Assessment Questionnaire; DI, disability index. Part D reproduced from Annals of the Rheumatic Diseases 80 (Suppl 1) 2021 with permission from BMJ Publishing Group Ltd
Background Uncontrolled/refractory gout patients are recalcitrant/intolerant to oral urate-lowering therapies (ULTs), experiencing frequent gout flares, functionally limiting tophi, and low quality of life. Pegloticase lowers urate, but anti-pegloticase antibodies limit urate-lowering efficacy and increase infusion reaction (IR) risk. Immunomodulator + pegloticase co-administration may improve treatment response rates, with 79% of MIRROR open-label trial (MIRROR-OL, pegloticase + oral methotrexate) participants meeting 6-month response criteria. Exploratory outcomes from MIRROR-OL are described here. Methods Adults with uncontrolled gout (serum urate [SU] ≥ 6 mg/dL and ULT-intolerance/recalcitrance or functionally limiting tophi) were included. Oral methotrexate (15 mg/week) was administered 4 weeks before and during pegloticase treatment (biweekly 8 mg infusion, ≤ 52 weeks). Exploratory outcomes included change from baseline (CFB) in number of affected joints, Health Assessment Questionnaires (HAQs), and Gout Global Assessments. Results Fourteen patients received ≥ 1 pegloticase infusion, with 13 included in 52-week analyses (1 enrolled before treatment-extension amendment, exited at 24 weeks). Three patients prematurely exited due to SU rise; 10 completed 52-week evaluations (8 completed 52 weeks of co-therapy, 2 completed 24 weeks [met treatment goals]). At 52 weeks, SU averaged 1.1 ± 2.5 mg/dL, with improvements in HAQ pain and health (CFB: − 33.6 and − 0.7, respectively), Patient and Physician Global Assessments (CFB: − 4.6 and − 5.7, respectively), and joint involvement (CFB: − 5.6, − 8.4, − 6.0 tender, swollen, tophi-affected joints, respectively). Two patients underwent dual-energy computed tomography, showing concomitant monosodium urate volume reductions. All patients had ≥ 1 AE, with 92.9% experiencing acute flare. One mild IR (“cough”) occurred and no new safety signals were identified. Conclusion Pegloticase + methotrexate co-therapy resulted in sustained SU-lowering with meaningful improvements in clinical measures, urate burden, and patient-reported outcomes. Trial registration ClinicalTrials.gov (NCT03635957)
 
Background Interstitial lung disease, a common extra-articular complication of connective tissue disease, is characterized by progressive and irreversible pulmonary inflammation and fibrosis, which causes significant mortality. IL-22 shows a potential in regulating chronic inflammation and possibly plays an anti-fibrotic role by protecting epithelial cells. However, the detailed effects and underlying mechanisms are still unclear. In this study, we explored the impact of IL-22 on pulmonary fibrosis both in vivo and in vitro . Methods To induce pulmonary fibrosis, wild-type mice and IL-22 knockout mice were intratracheally injected with bleomycin followed by treatments with recombinant IL-22 or IL-17A neutralizing antibody. We investigated the role of IL-22 on bleomycin-induced pulmonary fibrosis and the mechanism in the possible interaction between IL-22 and IL-17A. Fibrosis-related genes were detected using RT-qPCR, western blot, and immunofluorescence. Inflammatory and fibrotic changes were assessed based on histological features. We also used A549 human alveolar epithelial cells, NIH/3T3 mouse fibroblast cells, and primary mouse lung fibroblasts to study the impact of IL-22 on fibrosis in vitro . Results IL-22 knockout mice showed aggravated pulmonary fibrosis compared with wild-type mice, and injection of recombinant IL-22 decreased the severe fibrotic manifestations in IL-22 knockout mice. In cell culture assays, IL-22 decreased protein levels of Collagen I in A549 cells, NIH/3T3 cells, and primary mouse lung fibroblasts. IL-22 also reduced the protein level of Collagen I in NIH/3T3 cells which were co-cultured with T cells. Mechanistically, IL-22 reduced the Th17 cell proportion and IL-17A mRNA level in lung tissues, and treatment with an IL-17A neutralizing antibody alleviated the severe pulmonary fibrosis in IL-22 knockout mice. The IL-17A neutralizing antibody also reduced Collagen I expression in NIH/3T3 cells in vitro . Knockdown of IL-17A with siRNAs or administration of IL-22 in NIH/3T3 cells and MLFs decreased expression of Collagen I, an effect blocked by concurrent use of recombinant IL-17A. Conclusions IL-22 mediated an anti-fibrogenesis effect in the bleomycin-induced pulmonary fibrosis model and this effect was associated with inhibition of IL-17A.
 
Background Rheumatoid arthritis patients usually suffer from arthritic chronic pain. However, due to an incomplete understanding of the mechanisms underlying autoimmune disorders, the management of arthritic pain is unsatisfactory. Here, we investigated the analgesic effect and underlying mechanism of the natural flavonoid naringenin (NAR) in collagen-induced arthritis (CIA) pain. Methods NAR was injected (i.p.) once per day for 42 days after initial immunization, and rats were sacrificed on the 28th (the 21st day after final immunization, PID 21) and 42nd days (PID 35). The inflammatory factors, central sensitization indicators, and CRMP2 phosphorylation, as well as the anti-rheumatoid activity and analgesic effect of NAR, were further investigated. Results We found that NAR decreased the arthritis score and paw swelling, as well as the mechanical and thermal pain. The immunofluorescence results also showed a dose dependent effect of NAR on reducing the expressions of spinal cFos, IBA-1, and GFAP on the 28th (PID 21) and 42nd day (PID 35). NAR decreased the phosphorylation of CRMP2 S522 and the expression of the kinase CDK5 in the spinal dorsal horn, but pCRMP2 Y479 was unchanged. In addition, CRMP2 was co-localized with NEUN, but not IBA-1 or GFAP, indicating the involvement of neural CRMP2 phosphorylation in CIA-related pain. Finally, CRMP2 S522 phosphorylation selective inhibitor (S)-lacosamide also alleviated arthritic pain. Conclusions Taken together, our results demonstrate that NAR alleviates inflammation and chronic pain in CIA model, which might be related to its inhibition of neuronal CRMP2 S522 phosphorylation, potentially mitigating the central sensitization. Our study provide evidence for the potential use of NAR as non-opioid-dependent analgesia in arthritic pain.
 
ROC curves for antibodies to dsDNA (model 1), dsDNA + U 1 RNP (model 2), and dsDNA + U 1 RNP + Ro60 (model 3) in SLE. The composite ROC curve of the three antibodies provides an AUC of 0.943
ROC curves for four different models of autoantibody combinations in SSc: CENP-B alone (model 1); CENP-B + RNA pol III (model 2); CENP-B + RNA pol III + U 1 RNP (model 3); CENP-B + RNA pol III + U 1 RNP + Scl70 (model 4). The ROC curve of the four combined antibodies gives an AUC of 0.958
ROC curves for six different models of autoantibody combinations in autoimmune myositis: Jo1 alone (model 1); Jo1 + HMGCR (model 2); Jo1+ HMGCR + MDA5 (model 3); Jo1+ HMGCR + MDA5 + NXP2 (model 4); Jo1 + HMGCR + MDA5 + NXP2 + TIF1γ (model 5); Jo1 + HMGCR + MDA5 + NXP2 + TIF1γ + Ro52 (model 6). The ROC curve of the six combined antibodies provides a global AUC of 0.813
Background In patients affected by connective tissue diseases (CTDs), the identification of wide autoantibody profiles may prove useful in early diagnosis, in the evaluation of prognosis (risk stratification), and in predicting response to therapy. The aim of the present study was to evaluate the utility of multiparametric autoantibody analysis performed by a new fully automated particle-based multi-analyte technology (PMAT) digital system in a large multicenter cohort of CTD patients and controls. Methods Serum samples from 787 patients with CTD (166 systemic lupus erythematosus; 133 systemic sclerosis; 279 Sjögren’s syndrome; 106 idiopathic inflammatory myopathies; 103 undifferentiated CTD), 339 patients with other disorders (disease controls) (118 infectious diseases, 110 organ-specific autoimmune diseases, 111 other rheumatic diseases), and 121 healthy subjects were collected in 13 rheumatologic centers of the FIRMA group. Sera were analyzed with the Aptiva-PMAT instrument (Inova Diagnostics) for a panel of 29 autoantibodies. Results Multiparametric logistic regression showed that enlarged antibody profiles have a higher diagnostic efficiency than that of individual antibodies or of antibodies that constitute classification criteria for a given disease and that probability of disease increases with multiple positive autoantibodies. Conclusions This is the first study that analyzes the clinical and diagnostic impact of autoantibody profiling in CTD. The results obtained with the new Aptiva-PMAT method may open interesting perspectives in the diagnosis and sub-classification of patients with autoimmune rheumatic diseases.
 
Time course of biomarkers in response to TNF-α inhibitor therapy. A Type I collagen formation, PRO-C1; B type III collagen formation, PRO-C3; C type IV collagen turnover, PRO-C4; D type VI collagen formation, PRO-C6; E type III collagen degradation, C3M; F type IV collagen degradation, C4M; G type VI collagen degradation, C6M; H type VII collagen degradation, C7M; I type X collagen degradation, C10C; J C-reactive metabolite, CRPM; K elastin degradation, EL-NE; L citrullination and degradation of vimentin, VICM; and M C-reactive protein, CRP. Time course is shown as median ± 95% CI. *p<0.05 **p<0.01, ***p<0.001, ****p<0.0001
Background/purpose: In axial spondyloarthritis (axSpA) inflammation of the sacroiliac joints and spine is associated with local extracellular matrix (ECM) remodeling of affected tissues. We aimed to investigate the association of ECM metabolites with treatment response in axSpA patients treated with TNF-α inhibitory therapy for 46 weeks. Methods: In a prospective clinical study of axSpA patients (n=55) initiating a TNF inhibitor (infliximab, etanercept, or adalimumab), serum concentrations of formation of type I (PRO-C1), type III (PRO-C3), and type VI (PRO-C6) collagen; turnover of type IV collagen (PRO-C4), and matrix-metalloproteinase (MMP)-degraded type III (C3M) collagen, MMP-degraded type IV (C4M), type VI (C6M), and type VII (C7M) collagen, and cathepsin-degraded type X collagen (C10C), MMP-mediated metabolite of C-reactive protein (CRPM), citrullinated vimentin (VICM), and neutrophil elastase-degraded elastin (EL-NE) were measured at baseline, week 2, week 22, and week 46. Results: Patients were mostly males (82%), HLA-B27 positive (84%), with a median age of 40 years (IQR: 32-48), disease duration of 5.5 years (IQR: 2-10), and a baseline Ankylosing Spondylitis Disease Activity Score (ASDAS) of 3.9 (IQR: 3.0-4.5). Compared to baseline, PRO-C1 levels were significantly increased after two weeks of treatment, C6M levels were significantly decreased after two and 22 weeks (repeated measures ANOVA, p=0.0014 and p=0.0015, respectively), EL-NE levels were significantly decreased after 2 weeks (p=0.0008), VICM levels were significantly decreased after two and 22 weeks (p=0.0163 and p=0.0374, respectively), and CRP were significantly decreased after two and 22 weeks (both p=0.0001). Baseline levels of PRO-C1, PRO-C3, C6M, VICM, and CRP were all associated with ASDAS clinically important and major improvement after 22 weeks (ΔASDAS ≥1.1) (Mann-Whitney test, p=0.006, p=0.008, p<0.001, <0.001, <0.001, respectively), while C6M, VICM and CRP levels were associated with ASDAS clinically important and major improvement after 46 weeks (ΔASDAS ≥2.0) (p=0.002, p=0.044, and p<0.001, respectively). PRO-C1 and C6M levels were associated with a Bath AS Disease Activity Score (BASDAI) response to TNF-inhibitory therapy after 22 weeks (Mann-Whitney test, p=0.020 and p=0.049, respectively). Baseline levels of PRO-C4 and C6M were correlated with the total SPARCC MRI Spine and Sacroiliac Joint Inflammation score (Spearman's Rho ρ=0.279, p=0.043 and ρ=0.496, p=0.0002, respectively). Conclusions: Extracellular matrix metabolites were associated with ASDAS response, MRI inflammation, and clinical treatment response during TNF-inhibitory treatment in patients with axSpA.
 
Selection of eligible patients from the CorEvitas RA registry who initiated treatment between January 2010 and December 2019. *Laboratory monitoring is not mandated in this observational registry; see the “Methods” section. CRP, C-reactive protein; Hb, hemoglobin; IL-6Ri, interleukin-6 receptor inhibitor; JAKi, Janus kinase inhibitor; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitor
Assessment of change in Hb level: crude mean (± SD) change in Hb level from baseline to month 6 (A). Adjusted mean change (beta coefficient ± 95% CI) in Hb level from baseline to month 6, comparing IL-6Ri with TNFi and JAKi separately (B). Proportions of patients with low month 6 Hb level, proportions who changed from normal baseline to low month 6 Hb level, and proportions who changed from low baseline to normal month 6 Hb level (C). Odds of having a low month 6 Hb level, changing from normal baseline to low month 6 Hb level, or changing from low baseline to normal month 6 Hb level, comparing IL-6Ri with TNFi and JAKi separately (D). *p < 0.01; **p < 0.001. Low Hb was defined as < 12 g/dL (women) or < 13 g/dL (men). Adjusted model covariates were baseline Hb, age, duration of rheumatoid arthritis, morning stiffness duration, sex, current smoker status, prior use of one conventional synthetic disease-modifying anti-rheumatic drug, prior use of a non-TNFi biologic disease-modifying anti-rheumatic drug, white race, cyclic citrullinated peptide antibody positivity, combination therapy with methotrexate, and CDAI (baseline CDAI and 6-month CDAI). BL, baseline; CDAI, Clinical Disease Activity Index; CI, confidence interval; Hb, hemoglobin; IL-6Ri, interleukin-6 receptor inhibitor; JAKi, Janus kinase inhibitor; M, month; OR, odds ratio; SD, standard deviation; TNFi, tumor necrosis factor inhibitor
Proportion of patients with an increase or no change, mild decrease, or moderate/worse decrease in Hb level at month 6, with adjusted OR and 95% CI comparing IL-6Ri with TNFi and JAKi separately. *p < 0.001. The OR reported are from adjusted analyses. Adjusted model covariates were baseline Hb, age, duration of rheumatoid arthritis, morning stiffness duration, sex, current smoker status, prior use of one conventional synthetic disease-modifying anti-rheumatic drug, prior use of a non-TNFi biologic disease-modifying anti-rheumatic drug, white race, cyclic citrullinated peptide antibody positivity, and combination therapy with methotrexate. CI, confidence interval; Hb, hemoglobin; IL-6Ri, interleukin-6 receptor inhibitor; JAKi, Janus kinase inhibitor; OR, odds ratio; TNFi, tumor necrosis factor inhibitor
Assessment of change in CRP level: crude mean (± SD) change in CRP level from baseline to month 6 (A). Adjusted mean change (beta coefficient ± 95% CI) in CRP level from baseline to month 6, comparing IL-6Ri with TNFi and JAKi separately (B). Proportions of patients with high month 6 CRP level, proportions who changed from normal baseline to high month 6 CRP level, and proportions who changed from high baseline to normal month 6 CRP level (C). Odds of having a high month 6 CRP level, changing from normal baseline to high month 6 CRP level, or changing from high baseline to normal month 6 CRP level, comparing IL-6Ri with TNFi and JAKi separately (D). *p < 0.05; **p < 0.01; ***p < 0.001. High CRP was defined as ≥ 0.8 mg/dL. Adjusted model covariates were baseline CRP, age, duration of rheumatoid arthritis, EuroQol-5 Dimension score, Health Assessment Questionnaire score, sex, prior use of ≥ 2 TNFi, white race, history of hyperlipidemia, and CDAI (baseline CDAI and 6-month CDAI). BL, baseline; CDAI, Clinical Disease Activity Index; CI, confidence interval; CRP, C-reactive protein; IL-6Ri, interleukin-6 receptor inhibitor; JAKi, Janus kinase inhibitor; M, month; OR, odds ratio; SD, standard deviation; TNFi, tumor necrosis factor inhibitor
Proportion of patients with CRP level ≤ 0.3 mg/dL at month 6. CRP, C-reactive protein; IL-6Ri, interleukin-6 receptor inhibitor; JAKi, Janus kinase inhibitor; TNFi, tumor necrosis factor inhibitor
Background To evaluate the effects of tumor necrosis factor inhibitors (TNFi), interleukin-6 receptor inhibitors (IL-6Ri), and Janus kinase inhibitors (JAKi) on hemoglobin (Hb) and C-reactive protein (CRP) levels in adults enrolled in CorEvitas (formerly Corrona), a large US rheumatoid arthritis (RA) registry. Methods Patients who initiated TNFi, IL-6Ri, or JAKi treatment during or after January 2010, had Hb and CRP measurements at baseline and 6-month follow-up (± 3 months) and had continued therapy at least until that follow-up, through March 2020, were included in the analysis. Changes in Hb and CRP were assessed at month 6. Abnormal Hb was defined as < 12 g/dL (women) or < 13 g/dL (men); abnormal CRP was ≥ 0.8 mg/dL. Differences in Hb and CRP levels were evaluated using multivariable regression. Results Of 2772 patients (TNFi, 65%; IL-6Ri, 17%; JAKi, 17%) evaluated, 1044 (38%) had abnormal Hb or CRP at initiation; an additional 252 (9%) had both abnormal Hb and CRP. At month 6, the IL-6Ri group had a greater Hb increase than the TNFi (mean difference in effect on Hb: 0.28 g/dL; 95% CI 0.19–0.38) and JAKi (mean difference in effect on Hb: 0.47 g/dL; 95% CI 0.35–0.58) groups, regardless of baseline Hb status (both p < 0.001). The CRP decrease at month 6 was greater with IL-6Ri compared with TNFi and JAKi, regardless of baseline CRP status (both p < 0.05). Conclusion These real-world results align with the mechanism of IL-6R inhibition and may inform treatment decisions for patients with RA.
 
Effects of anti-MYL6 antibody on NET formation and actin rearrangement induced by PMA. a Peripheral blood neutrophils from healthy volunteers were stimulated by 20 nM PMA with 0.5 μg/mL anti-human MYL6 polyclonal antibody or rabbit IgG as a control for 4 h at 37°C. After rinsing with PBS, the samples were mounted with a mounting solution containing DAPI. Bar, 100 μm. b NETs were induced in peripheral blood neutrophils by PMA with or without anti-MYL6 antibody as above. Before and 1 h after incubation, the samples were fixed with 4% paraformaldehyde for 15 min and permeated with 0.5% Triton X-100 for 5 min at RT. Thereafter, the samples were reacted with 1:100 dilution of anti-β-actin mAb (mouse IgG1) at 4°C overnight. After rinsing with PBS, the samples were next reacted with 4 μg/mL Alexa Fluor 488-conjugated goat anti-mouse IgG1 antibody and 100 nM Acti-stain 555 phalloidin for 1 h at RT in the dark. Cells were finally mounted with the mounting solution containing DAPI. Anti-β-actin antibody recognizes G-actin, whereas phalloidin binds specifically to F-actin. Bar, 10 μm
Anti-MYL6 antibody in AAV patients. Anti-MYL6 antibody in sera of 59 patients with MPA was determined by ELISA. As AAV controls, 15 patients with GPA and 18 patients with EGPA were included. The cutoff OD value of this ELISA was determined as 0.482 (mean+1.5 SD) using nine HC samples
Comparison of clinical parameters between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. Clinical parameters, including BUN, Cr, CRP, and BVAS (total score), were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients
Comparison of nine BVAS evaluation items between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. BVAS evaluation items, including general, cutaneous, mucous membranes/eyes, ENT, chest, cardiovascular, abdominal, renal, and nervous system scores, were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients
Background Neutrophil extracellular traps (NETs) are critically involved in microscopic polyangiitis (MPA) pathogenesis, and some patients with MPA possess anti-NET antibody (ANETA). Anti-myosin light chain 6 (MYL6) antibody is an ANETA that affects NETs. This study aimed to determine the significance of anti-MYL6 antibody in MPA. Methods The influence of anti-MYL6 antibody on NET formation and actin rearrangement necessary for NET formation was assessed by fluorescent staining. An enzyme-linked immunosorbent assay was established to detect serum anti-MYL6 antibody, and the prevalence of this antibody in MPA was determined. Furthermore, the disease activity and response to remission-induction therapy of MPA were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. Results Anti-MYL6 antibody disrupted G-actin polymerization into F-actin, suppressing phorbol 12-myristate 13-acetate-induced NET formation. Serum anti-MYL6 antibody was detected in 7 of 59 patients with MPA. The Birmingham vasculitis activity score (BVAS) of anti-MYL6 antibody-positive MPA patients was significantly lower than anti-MYL6 antibody-negative MPA patients. Among the nine BVAS evaluation items, the cutaneous, cardiovascular, and nervous system scores of anti-MYL6 antibody-positive MPA patients were significantly lower than anti-MYL6 antibody-negative MPA patients, although other items, including the renal and chest scores, were equivalent between the two groups. The proportion of patients with remission 6 months after initiation of remission-induction therapy in anti-MYL6 antibody-positive MPA patients was significantly higher than in anti-MYL6 antibody-negative MPA patients. Conclusions Collective findings suggested that anti-MYL6 antibody disrupted actin rearrangement necessary for NET formation and could reduce the disease activity of MPA.
 
Background Bone marrow-derived mesenchymal stem cells (BMSCs) are general progenitor cells of osteoblasts and adipocytes and they are characterized as a fundamental mediator for bone formation. The current research studied the molecular mechanisms underlying circRNA-regulated BMSC osteogenic differentiation. Methods Next-generation sequencing (NGS) was employed to study abnormal circRNA and mRNA expression in BMSCs before and after osteogenic differentiation induction. Bioinformatics analysis and luciferase reporting analysis were employed to confirm correlations among miRNA, circRNA, and mRNA. RT-qPCR, ALP staining, and alizarin red staining illustrated the osteogenic differentiation ability of BMSCs. Results Data showed that circ- Iqsec1 expression increased during BMSC osteogenic differentiation. circ- Iqsec1 downregulation reduced BMSC osteogenic differentiation ability. The present investigation discovered that Satb2 played a role during BMSC osteogenic differentiation. Satb2 downregulation decreased BMSC osteogenic differentiation ability. Bioinformatics and luciferase data showed that miR-187-3p linked circ- Iqsec1 and Satb2 . miR-187-3p downregulation or Satb2 overexpression restored the osteogenic differentiation capability of BMSCs post silencing circ- Iqsec1 in in vivo and in vitro experiments. Satb2 upregulation restored osteogenic differentiation capability of BMSCs post miR-187-3p overexpression. Conclusion Taken together, our study found that circ- Iqsec1 induced BMSC osteogenic differentiation through the miR-187-3p/ Satb2 signaling pathway.
 
A Therapy survival of patients treated with Benepali® (n=83) and B therapy survival of Benepali® in comparison to Enbrel® in patients matched by the number of bDMARD treatment courses in the past, JIA category, sex, ANA positivity, and disease duration at treatment start (± 3 years)
A–FA Course of cJADAS-10, B Physician Global Assessment (PhGA), C Number of joints with active arthritis, D Patients overall well-being (NRS 0-10), E Pain (NRS 0-19), and F HAQ values over time (predicted means with 95% confidence intervals estimated by generalized linear mixed models, p-value for change in parameters over 24 months)
Background To analyze therapy adherence, safety, and outcome in adult patients with juvenile idiopathic arthritis (JIA) treated with the etanercept biosimilar Benepali ® (Biogen Inc, Cambridge, USA). Methods Data from the prospective registry, JuMBO (Juvenile arthritis MTX/Biologics long-term Observation), were used for the analysis. JuMBO is a long-term observational cohort study. It follows adult patients with JIA who were formerly included in the national JIA biologic register (BiKeR Registry). Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in JIA patients treated with disease-modifying anti-rheumatic drugs (DMARDs). Results Eighty-three patients from the German JuMBO registry were treated with Benepali ® . Of these, 74% had switched from Enbrel ® (Pfizer Inc., NYC, USA) the originator of etanercept to Benepali ® for cost reasons. Therapy survival of patients treated with Benepali ® in comparison to Enbrel ® in patients matched by significant parameters was comparable. Adverse events (AE) were reported in 25.3% and serious adverse events (SAE) in 9.6% of patients. Physicians rated no SAE causative related to Benepali ® . The majority of SAEs were surgical/medical procedures and there was only one infection. All efficacy parameters (cJADAS-10, Physician Global Assessment, number of joints with active arthritis, patients’ overall well-being, pain, and HAQ) demonstrated improvement over 24 months ( p -values were not significant). 9.6% of patients permanently discontinued Benepali® because of an AE. Conclusions Tolerability and effectiveness of the biosimilar Benepali ® were satisfactory and therapy survival was comparable to the originator. Further data on therapy with biologics and biosimilars such as Benepali ® must be collected by registries such as BiKeR and JuMBO in order to optimize therapy and patient outcomes and to reduce costs in the health system in the long term.
 
Flowchart of participant recruitment
Scattergram showing fasting blood glucose at baseline and ΔKOOS based on prevalence of central sensitization
Background: Although cross-sectional and cohort data suggest that higher serum blood glucose levels in patients with knee osteoarthritis (KOA) are associated with more severe knee symptoms, little is known about the longitudinal relationship between serum blood glucose and knee symptoms, particularly considering central sensitization (CS) comorbidity, which also worsens knee symptoms. Methods: We evaluated the longitudinal relationship between serum blood glucose and knee symptoms by dividing the cohort of patients with KOA into those with and without CS. We hypothesized that higher serum blood glucose levels would worsen knee symptoms. A total of 297 participants (mean age: 59.6 years; females: 211; average BMI: 23.7 kg/m2) were enrolled in this study. At baseline, plain radiographs of the bilateral knee joints were evaluated according to the Kellgren-Lawrence grade (KLG). All participants exhibited at least a KLG ≥ 2 in each knee. At baseline, fasting blood glucose (FBG) and Central Sensitization Inventory-9 (CSI-9) were evaluated; ≥ 10 points on the CSI-9 was defined as CS+. Knee injury and Osteoarthritis Outcome Score (KOOS) was evaluated at baseline and at 1-year follow-up; the change in KOOS (ΔKOOS) was calculated by subtracting the KOOS at baseline from that at the 1-year follow-up. Multiple linear regression analysis was conducted with ΔKOOS as the dependent variable and FBG at baseline as the independent variable, adjusted for age, sex, BMI, and CSI-9 at baseline. Results: Of the 297 subjects, 48 (16.2 %) were defined as CS+. In the CS - group, there was no association between FBG levels at baseline and ΔKOOS. In contrast, FBG at baseline was negatively associated with ΔKOOS pain (B = - 0.448; p = 0.003), ADL (B = - 0.438; p = 0.003), and sports (B = - 0.706; p = 0.007). Conclusions: In patients with radiographic KOA and CS, higher blood glucose levels were associated with deteriorated knee symptoms during the 1-year follow-up. Healthcare providers should pay attention to controlling blood glucose, particularly in patients with KOA and concurrent CS, to mitigate their knee symptoms. Study design: Retrospective cohort study (evidence level: III).
 
Overview of the present study design. BCAC, Breast Cancer Association Consortium; IVW, inverse variance weighted; MR-PRESSO, Mendelian randomization pleiotropy residual sum and outlier; OCAC, the Ovarian Cancer Association Consortium; SNP, single-nucleotide polymorphism
Associations of genetic liability to rheumatoid arthritis with risk of overall cancer and 22 site-specific cancers in European individuals in the UK Biobank and FinnGen studies. CI, confidence interval; OR, odds ratio
Associations of genetic liability to rheumatoid arthritis with risk of female-specific cancers in European individuals in the UK Biobank, FinnGen, and international consortia. BCAC Breast Cancer Association Consortium; CI, confidence interval; OCAC, the Ovarian Cancer Association Consortium; OR, odds ratio
Associations of genetic liability to rheumatoid arthritis with risk of 12 site-specific cancers in East Asian individuals in the Biobank Japan. CI, confidence interval; OR, odds ratio
Background The associations of rheumatoid arthritis (RA) with risk of site-specific cancers beyond lymphohematopoietic cancer have been scarcely explored. We conducted a Mendelian randomization investigation of the associations of RA with site-specific cancers in European and East Asian populations. Methods Independent genetic variants strongly associated with RA in European and East Asian populations were selected as instrumental variables from genome-wide association studies of 58,284 European individuals (14,361 cases and 43,923 controls) and 22,515 East Asian individuals (4873 cases and 17,642 controls), respectively. The associations of genetic variants with overall and 22 site-specific cancers were extracted from the UK Biobank study ( n = 367,561), the FinnGen study ( n = 260,405), Biobank Japan ( n = 212,453), and international consortia. The associations for one outcome from different data sources were combined by meta-analysis. Results In the European population, the combined odds ratios per 1-unit increase in log odds of genetic liability to RA were 1.06 (95% confidence interval [CI] 1.03–1.10) for head and neck cancer, 1.06 (95% CI 1.02–1.10) for cervical cancer, 0.92 (95% CI 0.87–0.96) for testicular cancer, and 0.94 (95% CI 0.90–0.98) for multiple myeloma. In the East Asian population, the corresponding odds ratios were 1.17 (95% CI 1.06–1.29) for pancreatic cancer, 0.91 (95% CI 0.88–0.94) for breast cancer, and 0.90 (95% CI 0.84–0.96) for ovarian cancer. There were suggestive associations for breast and ovarian cancer and overall cancer in the European population. No other associations were observed. Conclusion This study suggests that RA may play a role in the development of several site-specific cancers.
 
Background Lupus nephritis (LN) is an inflammatory disease of the kidneys affecting patients with systemic lupus erythematosus. Current immunosuppressive and cytotoxic therapies are associated with serious side effects and fail to protect 20–40% of LN patients from end-stage renal disease. In this study, we investigated whether a small heat shock protein, HSPB5, can reduce kidney inflammation and the clinical manifestations of the disease in NZB/W F1 mice. Furthermore, we investigated whether HSPB5 can enhance the effects of methylprednisolone, a standard-of-care drug in LN, in an endotoxemia mouse model. Methods NZB/W F1 mice were treated with HSPB5, methylprednisolone, or vehicle from 23 to 38 weeks of age. Disease progression was evaluated by weekly proteinuria scores. At the end of the study, the blood, urine, spleens, and kidneys were collected for the assessment of proteinuria, blood urea nitrogen, kidney histology, serum IL-6 and anti-dsDNA levels, immune cell populations, and their phenotypes, as well as the transcript levels of proinflammatory chemokine/cytokines in the kidneys. HSPB5 was also evaluated in combination with methylprednisolone in a lipopolysaccharide-induced endotoxemia mouse model; serum IL-6 levels were measured at 24 h post-endotoxemia induction. Results HSPB5 significantly reduced terminal proteinuria and BUN and substantially improved kidney pathology. Similar trends, although to a lower extent, were observed with methylprednisolone treatment. Serum IL-6 levels and kidney expression of BAFF, IL-6, IFNγ, MCP-1 (CCL2), and KIM-1 were reduced, whereas nephrin expression was significantly preserved compared to vehicle-treated mice. Lastly, splenic Tregs and Bregs were significantly induced with HSPB5 treatment. HSPB5 in combination with methylprednisolone also significantly reduced serum IL-6 levels in endotoxemia mice. Conclusions HSPB5 treatment reduces kidney inflammation and injury, providing therapeutic benefits in NZB/W F1 mice. Given that HSPB5 enhances the anti-inflammatory effects of methylprednisolone, there is a strong interest to develop HSBP5 as a therapeutic for the treatment of LN.
 
Background Takayasu arteritis (TAK) is characterized by pro-inflammatory M1 macrophage infiltration and increased interferon (IFN)-γ expression in vascular lesions. IFN-γ is a key cytokine involved in M1 polarization. Macrophage polarization is accompanied by metabolic changes. However, the metabolic regulation mechanism of IFN-γ in M1 macrophage polarization in TAK remains unclear. Methods Immunohistochemistry and immunofluorescence were employed to observe the expression of IFN-γ, PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, the rate-limiting enzyme in glycolysis), and macrophage surface markers in the vascular tissue. Monocyte-derived macrophages from patients with TAK were cultured to examine the role of PFKFB3 in IFN-γ-induced M1 macrophage polarization. Seahorse analysis was used to detect the alterations in glucose metabolism during this process. Quantitative reverse transcription PCR, flow cytometry, and western blot were used to confirm the phenotypes of macrophages and related signaling pathways. Results In the vascular adventitia of patients with TAK, an increase in PFKFB3 accompanied by IFN-γ expression was observed in M1 macrophages. In vitro, IFN-γ successfully induced macrophage differentiation into the M1 phenotype, which was manifested as an increase in CD80 and HLA-DR markers and the pro-inflammatory cytokines IL-6 and TNF-α. During this process, PFKFB3 expression and glycolysis levels were significantly increased. However, glycolysis and M1 polarization induced by IFN-γ were suppressed by a PFKFB3 inhibitor. In addition, JAK2/STAT1 phosphorylation was also enhanced in macrophages stimulated by IFN-γ. The effects of IFN-γ on macrophages, including the expression of PFKFB3, glycolysis, and M1 polarization, were also inhibited by the JAK inhibitor tofacitinib or STAT1 inhibitor fludarabine. Conclusion PFKFB3-mediated glycolysis promotes IFN-γ-induced M1 polarization through the JAK2/STAT1 signaling pathway, indicating that PFKFB3 plays an important role in M1 polarization mediated by IFN-γ; thus, PFKFB3 is a potential intervention target in TAK.
 
Output of neural network trained to detect joints in the hands
Flow diagram regarding study identification and selection [32]. *Reason 1: not investigating radiographic scoring; reason 2: not using machine learning; reason 3: using a different imaging modality; reason 4: lacked sufficient information for analysis
Using a convolutional neural network (CNN), joints are identified from the input radiograph and the score for each joint is assigned
Rheumatoid arthritis is an autoimmune condition that predominantly affects the synovial joints, causing joint destruction, pain, and disability. Historically, the standard for measuring the long-term efficacy of disease-modifying antirheumatic drugs has been the assessment of plain radiographs with scoring techniques that quantify joint damage. However, with significant improvements in therapy, current radiographic scoring systems may no longer be fit for purpose for the milder spectrum of disease seen today. We argue that artificial intelligence is an apt solution to further improve upon radiographic scoring, as it can readily learn to recognize subtle patterns in imaging data to not only improve efficiency, but can also increase the sensitivity to variation in mild disease. Current work in the area demonstrates the feasibility of automating scoring but is yet to take full advantage of the strengths of artificial intelligence. By fully leveraging the power of artificial intelligence, faster and more sensitive scoring could enable the ongoing development of effective treatments for patients with rheumatoid arthritis.
 
Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A 2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and μCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.
 
The composition of salivary gland epithelial cell subpopulations was based on scRNA-seq analyses. a The subsets of salivary gland epithelial cells clustered by tSNE and UMAP methods. b The proportions of the different salivary gland epithelial cell subpopulations in different samples. c Violin plot comparing expression levels of CFTR gene in ionocytes and other subsets. The colored area of the violin plot represents the expression values distribution. d Feature plot showing the expression pattern of CFTR gene in the salivary gland epithelial cell subpopulations
Representative HE-stained and immunofluorescent stained slices for non-SjS and SjS group. Images are × 200 (scale bars, 50 μm) except immunofluorescent stained sections in b, which are × 100 (scale bars, 50 μm). Red staining shows CFTR localization and blue DAPI staining shows cell nuclei. a Matched slides of labial gland section were stained with hematoxylin and eosin (HE) and the dashed box in b indicates the section as in a. b DAPI staining of labial gland section for non-SjS and SjS group; magnification, × 100. c The white solid box in b represents the magnified region in the images. White arrowheads point to the expression of CFTR. d Comparison of the mean of CFTR expression between non-SjS (n = 44) and SjS (n = 36) groups. Error bars represent SD. p values are based on Mann–Whitney U test
The correlation of CFTR expression in SjS patients with and without dry mouth. Comparing the average CFTR expression across SjS patients with non-dry mouth (n = 9) and dry mouth (n = 25) groups reveals that CFTR is lower in SjS patients with a system of dry mouth. Error bars represent SEM. p values are based on Mann–Whitney U test
Introduction The autoimmune exocrinopathy, Sjögren’s syndrome (SjS), is associated with secretory defects in salivary glands. The cystic fibrosis transmembrane conductance regulator (CFTR) of the chloride channel is a master regulator of fluid secretion, but its role in SjS has not been investigated. Our research found a link between CFTR and SjS at the genetic and protein levels, as well as through clinical data. Methods We used single-cell RNA sequencing to identify the presence of CFTR in glandular epithelial cells of the human salivary gland (scRNA-seq) and confirmed the difference using immunofluorescence tests in labial glands and clinical data statistics from 44 non-SjS and 36 SjS patients. Results The changes of CFTR expression in salivary glands of SjS patients was assessed at both mRNA and protein levels. According to the scRNA-seq analyses, CFTR was the hallmark gene of ionocytes. We firstly identified that SjS had a lower level of CFTR expression in the labial glands than non-SjS at mRNA level. Using immunofluorescence assays, we also found that CFTR expression was decreased in SjS patients compared to non-SjS. The results of the clinical statistics revealed that CFTR expression was adversely correlated with feelings of dry mouth, lymphocyte infiltration in the labial glands, and certain autoantibodies in serum (antinuclear antibody, anti-Ro/SSA, and anti-La/SSB antibodies). Conclusion Those findings above proved an obviously downregulated expression of CFTR in salivary glands of SjS patients and its clinical significance. Dysfunction in CFTR or ionocytes may contribute to SjS pathogenesis and represents a promising therapeutic target.
 
Patient disposition. csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; HR-pQCT, high-resolution peripheral quantitative computed tomography
Adjusted mean change from baseline in bone erosion depth of the 2–3 metacarpal heads at 6 months. Assessed by HR-pQCT (primary endpoint, full analysis set). Error bars represent 95% CI. Numerators reflect the number of patients with available data on erosion parameters, and denominators, the number of bone erosions. P value is the statistical difference in the csDMARDs plus denosumab vs csDMARD therapy alone group. For adjusted mean as the primary endpoint, a linear mixed effect model analysis was performed using treatment group, sex, anti-CCP antibody (positive vs negative), and baseline DAS28-ESR as fixed effects; patients as random effects; and baseline values as covariates. CCP, cyclic citrullinated peptide; CI, confidence interval; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; DAS28-ESR, Disease Activity Score in 28 joints for rheumatoid arthritis with erythrocyte sedimentation rate as fixed effects; HR-pQCT, high-resolution peripheral quantitative computed tomography
Background This exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT). Methods In this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety. Results In total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2–3 metacarpal heads at 6 months was − 0.57 mm (− 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs − 0.22 mm (− 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: − 0.35 mm [− 1.00, 0.31]; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2–3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%). Conclusions Although the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture. Trial registration University Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018
 
Sugiyama et al. recently described in “Latent class analysis of 216 patients with adult-onset Still’s disease,” baseline characteristics, laboratory tests, treatment, relapse, and death of adult-onset Still’s disease (AOSD) patients from a Japanese hospital. They identified two subgroups: Class 1 (n=155) with a younger age and typical symptoms of AOSD and Class 2 (n=61) with older patients and fewer typical symptoms of AOSD. In 2022, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, an established X-linked disease associated with a somatic mutation in UBA1, is considered as a differential diagnosis for AOSD particularly in elderly. These patients from Class 2 could benefit from more explorations for mild myelodysplasia and VEXAS.
 
Histological and immunohistochemical evaluation of transverse sections near MCP3 through the extensor tendon. A HE-stained transverse section from the level indicated in B. T, extensor tendon; S, skin; O, location of ossa digitorum of the distal phalanx (removed from tissue block). C An enlargement of the HE-stained transverse section indicated by the C-box in A. T, extensor tendon. D Enlargements of adjacent transverse sections indicated by the D-boxes in A, with immunohistochemical staining for CD68, CD55 and cadherin-11. Arrows in panel D1: dorsal to the extensor tendon, a thin layer of tissue with expression of CD68, CD55 and cadherin-11 was present. Arrow in panel D2: in the tissue at the palmar aspect of the tendon some scattered macrophages were detected. There was no cadherin-11 expression, while CD55 was widely expressed, consistent with scattered fibroblasts
Example MR-image of extensor tenosynovitis at MCP 4 (arrow) and flexor tenosynovitis at MCP 3 (arrowhead), illustrating the oval shape of flexor tenosynovitis and the more flattened shape of extensor tenosynovitis. Axial T1-weighted fat-suppressed image after administration of gadolinium contrast (T1FS Gd) at the level of the MCPs of the right hand of a 40-year old female patient
Patterns of extensor tendons and their connecting fibrous bands on the dorsum of the hand based on anatomical literature, showing the most common pattern (A) and one of the many anatomical variations (B). Figures are based on data presented in Supplementary Tables S1 and S2. A The most common pattern, where the index finger has a single extensor digitorum communis tendon (in dark grey) and a single extensor indices tendon (in lighter grey) that inserts at the MCP-joint ulnar to the extensor digitorum communis. The middle finger has a single extensor digitorum communis. The ring finger originates as a single extensor digitorum communis tendon that diverges into two tendons midsubstance that again merge into one right before insertion at the MCP-joint. The little finger has a single extensor digitorum communis and a double extensor digiti minimi with double insertion at the MCP-joint. The fibrous bands are present in the 2nd, 3rd and 4th intermetacarpal spaces. B In this variation, the index finger has a single extensor digitorum communis tendon and a double extensor indices tendon (in lighter grey) that inserts at the MCP-joint ulnar to the extensor digitorum communis. The middle finger has a double extensor digitorum communis and the ring finger a single extensor digitorum communis tendon. The little finger has a single extensor digiti minimi and an absent extensor digitorum communis. The fibrous band in the second intermetacarpal space is absent and has a Y-shape in the third and fourth intermetacarpal space (y-subtype)
Proposal for updating anatomical textbook images of the extensor tendons of the hand based on published MRI data [8] (MCP 2-5) and on current histological findings (MCP 3). Blue represents tendon sheaths at the level of the wrist. Transparent blue represents presence of tenosynovial tissue at the MCP extensor tendons. The proximal and distal borders fade in and out on purpose, to illustrate that the area where tenosynovial tissue originates and 'ends' could not be deduced from this study
MRI-detected inflammation around the extensor tendons of metacarpophalangeal (MCP-) joints is prevalent in RA and poses a markedly increased risk of RA development when present in arthralgia patients. Such inflammation is called ‘peritendinitis’ since anatomy literature reports no presence of a tenosynovial sheath at these tendons. However, the presence or absence of tenosynovium at these extensor tendons has never been studied. Therefore, an anatomical and histological study of extensor tendons at the MCP-joints of three embalmed human hands was performed. Immunohistochemical staining showed the presence of markers for synovial macrophages and fibroblast-like synoviocytes bordering a natural dorsal space next to the extensor tendon, suggesting the presence of a synovial lining. This implies that contrast-enhancement on MRI around extensor tendons at MCP-joints observed in early RA and pre-RA likely represents tenosynovitis and that inflammation of this synovial tissue is an early feature of RA.
 
Study design. i AAV diagnosis (cohorts 1 and 2). ii AAV relapse (cohort 2). i CW-D-UVB at diagnosis was calculated using the participant's location and date of symptom onset if known, or the date of diagnosis minus 77 days. Seventy-seven days represents the undefined prodromal period [36] informed by the RKD registry analysis (see supplementary material). ii In this prospective n-of-1 component, each participant was a 'case' during period(s) of disease relapse and a 'control' during period(s) of remission [37]. The case window started at the date of relapse diagnosis minus 30 days (to account for the diagnostic delay) and ended 135 days later (see Additional file 1: Supplementary Methods). To improve the statistical power, 5 control dates were identified per patient, where possible
AAV relapse. a Latitude (degrees), b average winter vitD-UVB (kJ/m 2 ), c average winter CW-D-UVB (kJ/m 2 ) and d average annual vitD-UVB (kJ/ m 2 ) stratified by disease activity (active vs. remission) in the entire cohort 2
Background The aetiology of ANCA-associated vasculitis (AAV) and triggers of relapse are poorly understood. Vitamin D (vitD) is an important immunomodulator, potentially responsible for the observed latitudinal differences between granulomatous and non-granulomatous AAV phenotypes. A narrow ultraviolet B spectrum induces vitD synthesis (vitD-UVB) via the skin. We hypothesised that prolonged periods of low ambient UVB (and by extension vitD deficiency) are associated with the granulomatous form of the disease and an increased risk of AAV relapse. Methods Patients with AAV recruited to the Irish Rare Kidney Disease (RKD) ( n = 439) and UKIVAS ( n = 1961) registries were studied. Exposure variables comprised latitude and measures of ambient vitD-UVB, including cumulative weighted UVB dose (CW-D-UVB), a well-validated vitD proxy. An n -of-1 study design was used to examine the relapse risk using only the RKD dataset. Multi-level models and logistic regression were used to examine the effect of predictors on AAV relapse risk, phenotype and serotype. Results Residential latitude was positively correlated (OR 1.41, 95% CI 1.14–1.74, p = 0.002) and average vitD-UVB negatively correlated (0.82, 0.70–0.99, p = 0.04) with relapse risk, with a stronger effect when restricting to winter measurements (0.71, 0.57–0.89, p = 0.002). However, these associations were not restricted to granulomatous phenotypes. We observed no clear relationship between latitude, vitD-UVB or CW-D-UVB and AAV phenotype or serotype. Conclusion Our findings suggest that low winter ambient UVB and prolonged vitD status contribute to AAV relapse risk across all phenotypes. However, the development of a granulomatous phenotype does not appear to be directly vitD-mediated. Further research is needed to determine whether sufficient vitD status would reduce relapse propensity in AAV.
 
CONSORT diagram showing flow of patients through the ZEBRA 1 sub-study. The diagram provides a summary of the flow of patients through the ZEBRA 1 sub-study including screened cases and 13 patients randomised
Representative primary and secondary endpoint data for ZEBRA 1 sub-study. A Endpoint data for serum VCAM-1 and eGFR in ZEBRA 1. Upper panels show the serum VCAM-1 levels at baseline, 26 weeks, and 52 weeks for the patients in placebo and zibotentan groups. Mean and SD are indicated. There was no apparent difference between treatment groups. The lower panel shows that eGFR (ml/min/1.73m2) decreased in the placebo arm and increased in the zibotentan arm at 52 weeks. B Candidate CKD-SSc urinary biomarker data for ZEBRA 1. Secondary endpoint data for candidate urinary biomarkers of SSc-CKD identified in a previous cohort study [8]. For urinary ICAM-1 to creatinine ratio, there is no difference between treatment groups or timepoints. For MCP-1 to creatinine ratio, the placebo group shows increasing level at 52 weeks compared to a numerical reduction for the zibotentan group although distribution of data is wide as shown by SD for each time point
Endpoint data for ZEBRA 1 trial at baseline, 26 weeks, and 52 weeks
Background We report results from a phase II randomised placebo-controlled trial assessing zibotentan, a highly selective endothelin receptor antagonist (ERA), in chronic kidney disease (CKD) secondary to systemic sclerosis (SSc). Methods This trial included three sub-studies: ZEBRA 1—a randomised placebo-controlled, double-blind trial of zibotentan in SSc patients with CKD2 or CKD3 (and glomerular filtration rate (GFR) >45 ml/min) over 26 weeks; ZEBRA 2A—a 26-week placebo-controlled, single-blind trial of zibotentan in scleroderma renal crisis patients not requiring dialysis; and ZEBRA 2B—an open label pharmacokinetic study of zibotentan in patients on haemodialysis. Results Sixteen patients were screened for ZEBRA 1. Of these, 6 patients were randomised to zibotentan and 7 to placebo. In ZEBRA 1, there were 47 non-serious adverse events (AE) during the trial. Twenty-seven occurred in the placebo group and 20 in the zibotentan group. One serious adverse event (SAE) occurred during ZEBRA1, in the placebo arm. Descriptive statistics did not suggest an effect of study drug on serum sVCAM1. Estimated GFR numerically declined in patients treated with placebo at 26 weeks and 52 weeks. In contrast, average eGFR increased in zibotentan-treated cases. The 4 patients in ZEBRA 2A experienced 8 non-serious AEs, distributed equally between placebo and zibotentan. There was one SAE each in placebo and zibotentan groups, both unrelated to study medication. ZEBRA 2B recruited 8 patients, 6 completed first dosing, and 2 completed a second dosing visit. Pharmacokinetic analysis confirmed zibotentan levels within the therapeutic range. Three patients experienced 3 non-serious AEs. One SAE occurred and was unrelated to study drug. Conclusions Zibotentan was generally well-tolerated. ZEBRA 1 did not show any effect of zibotentan on serum sVCAM-1 but was associated with numerical improvement in eGFR at 26 weeks that was more marked at 52 weeks. ZEBRA 2B suggested a feasible dose regimen for haemodialysis patients. Trial registration EudraCT no: 2013-003200-39 (first posted January 28, 2014) ClinicalTrials.gov Identifier: NCT02047708 Sponsor protocol number: 13/0077
 
With great interest, we read the comment by Gilbert and Wicks on our recent publication [1] testing the accuracy and usability of Ada’s symptom checker among medical students.
 
With great interest, we have read the recent article “The risk of malignancy in patients with IgG4-related disease: a systematic review and meta-analysis” by Yu et al. While we have a great appreciation for the work conducted by the authors there are some methodological issues need to be considered. First, the period of articles included in the study, almost before 2013, implied that most follow-up days in these articles were earlier than the established date of a unified definition of IgG4-RD, 2011. Thus, it may lead to misclassification bias in the study. Second, IgG4-RD is a fibrous-inflammatory process that often involves multiple organs; however, malignant tumors related to IgG4-RD proposed in the study were only confined to four diseases. Therefore, we suggest adding subgroup analysis for more malignancies depending on the prevalence of IgG4-RD involved organs to ensure better clinical practice. Third, the causation between IgG4-RD and malignancy remains obscure currently. The time course for development in different malignancies varies significantly so that we cannot infer that malignancies discovered after IgG4-RD are directly relevant. With problems mentioned above, we recommend solutions to make this article more convincing.
 
Current understanding of IL-23 biology, with its link to other pro-inflammatory cytokines, for example, IL-17 and granulocyte macrophage-colony stimulating factor (GM-CSF), is primarily focused on T lymphocyte-mediated inflammation/autoimmunity. Pain is a significant symptom associated with many musculoskeletal conditions leading to functional impairment and poor quality of life. While the role of IL-23 in arthritis has been studied in mouse models of adaptive immune-mediated arthritis using targeted approaches (e.g., monoclonal antibody (mAb) neutralization), the literature on IL-23 and arthritis pain is limited. Encouragingly, the anti-IL-23p19 mAb, guselkumab, reduces pain in psoriatic arthritis patients. Recent evidence has suggested a new biology for IL-23, whereby IL-23 is required in models of innate immune-mediated arthritis and its associated pain with its action being linked to a GM-CSF-dependent pathway (the so-called GM-CSF➔CCL17 pathway). This Commentary discusses the current understanding of potential cytokine networks involving IL-23 in arthritis pain and provides a rationale for future clinical studies targeting IL-23p19 in arthritis pain.
 
Background Psoriatic Arthritis (PsA) is an immune-mediated disease with heterogenous symptoms indicating differences in the underlying immunopathogenesis. The primary objective of the study explored the dynamic mechanisms and interplay between immune cell subtypes constituting the immune response driving PsA to evaluate possible differences in immune cellular phenotypes, and secondary examined associations between emerging immune cellular phenotypes and disease outcomes. Methods Peripheral blood was collected from 70 PsA patients. Frequencies of nine immune cell subtypes were determined by multicolor flow cytometry. The interplay between immune cells were examined with principal component analysis (PCA) to establish immune cellular phenotypes. Disease characteristics, Disease Activity in Psoriatic Arthritis (DAPSA) and Psoriasis Area Severity Index (PASI) were retrieved to examine associations to individual cellular phenotypes. Results Four components were identified using PCA resembling four immune cellular phenotypes. Component 1, explaining 25.6% of the variance with contribution from T-helper 17 cells (Th17), memory T regulatory cells (mTregs), dendritic cells and monocytes, was associated with longer disease duration and higher DAPSA. Component 2, driven by Th1, naïve Tregs and mTregs, was associated with shorter disease duration. Component 3 was driven by both Th1, Th17 and CD8+ T cells, while component 4 was characterized by a reverse correlation between CD8+ T cells and natural killer cells. Conclusion Four immune cellular phenotypes of PsA were suggested at baseline demonstrating complex immune cellular mechanisms in PsA implying the possibility of improving PsA patient stratification based on both clinical and immune cellular phenotypes.
 
NP tissues from IDD patients showed decreased miR-217 expression. A Graph depicting the scatter plot of miRNA expression profiles between IDD patients and the control group (The axes represent expression fold in the IDD or control group. Genes were considered to be differentially expressed if they had an absolute log2-fold change of >2. Red dots indicate no difference between IDD and controls; green dots indicate more than a twofold increase; blue dots indicate more than a twofold decrease). B Heatmaps of 21 miRNAs that were found to be differentially expressed. C The volcano graph depicts the difference in miRNA expression levels between patients with IDD and healthy individuals in the control group. The purple dots on the right represent miRNAs that were upregulated, and the red dots on the left represent miRNAs that were downregulated. miR-217 is indicated. D The expression of miR-217 in human nucleus pulposus tissues was determined using qRT–PCR. E The expression of miR-217 in human nucleus pulposus cells was determined using qRT–PCR. F FISH analysis was performed on individuals with IDD as well as on the control group. Scale bar = 50 μm. G IDD Pfirrmann scores were shown to be negatively associated with miR-217 expression levels (r = −0.896, ***P < 0.001). H Methylation of the miR-217 promoter region. I Comparison of the methylation status of IDD patients (n=18) and controls (n=11). IDD, intervertebral disc degeneration; miR, microRNA; FC, fold change; DAPI, 4′,6-diamidino-2-phenylindole. ***P < 0.001
NP cell phenotypes when miR-217 was overexpressed or silenced. A Cy3 was employed to detect miR-217 mimics or inhibitor transfected and cultured NP cells, scale bar = 20 μm. B EdU assay was used to evaluate the proliferation of NP cells that were transfected with different treatments. Scale bar = 100 μm. C FCM was used to determine the apoptosis of NP cells. D, E Immunofluorescence was used to determine the Col II and MMP13 levels. F Western blotting was used to determine the levels of Col II, Aggrecan, MMP13, and ADAMT5. n=3. IDD, intervertebral disc degeneration; miR, microRNA; PBS, phosphate-buffered saline; DAPI, 4′,6-diamidino-2-phenylindole; FCM, flow cytometry; Col II, type II collagen; MMP, matrix metalloprotein; ADAMTS, a disintegrin-like and metalloproteinase with thrombospondin motifs; NP, nucleus pulposus; EdU, 5-ethynyl-2′-deoxyuridine
FBXO21 is directly targeted by miR-217 and is a regulator of IDD. A Gene ontology analysis showing the highest enrichment scores of the downregulated GO terms, including those involved in imaginal disc-derived wing margin morphogenesis, ECM structural constituent, and extracellular region. B Heatmap of all differentially expressed mRNAs between the sample with IDD and the paired controls. C The target of miR-217 was verified by Cytoscape. D Venn diagram displaying miR-217, computationally predicted to target FBXO21 by different algorithms. E The mRNA 3′UTR of FBXO21 and the putative miR-217 binding site sequence have high sequence conservation and complementarity with miR-217. F The wild- or mutant-type FBXO21 3′UTR reporter plasmid was either cotransfected with miR-217 mimics or inhibitor into cultured NP cells. As the 3′-UTR of wild-type FBXO21 contains miR-217 binding sites, the translation of firefly luciferase was inhibited in the miR-217 mimics group. Thus, by measuring the luciferase activity, it can be determined FBXO21 is the target gene of the miR-217. G, H The expression level of FBXO21 was evaluated by western blotting and qRT–PCR. n = 3. IDD, intervertebral disc degeneration; miR, microRNA; NP, nucleus pulposus; GO, gene ontology; mut, mutant; WT, wild type; FBXO21, F-box only protein 21. ***P < 0.001
MiR-217 is involved in IDD via the FBXO21/ERK axis. A, B The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene set enrichment analyses (GSEA) identified the ERK signalling pathway as the most significantly enriched pathway in intervertebral disc degeneration. C Western blot analysis revealed that miR-217 overexpression or silencing affected the expression patterns of FBXO21, ERK, pERK, Col II, Aggrecan, MMP3, MMP13, and ADAMT5. D Western blot analysis was used to determine the expression levels of FBXO21, Col II, Aggrecan, MMP13, and ADAMT5. Overexpression of FBXO21 effectively reversed the effects of miR-217 overexpression. E Coimmunoprecipitation revealed high-affinity physical interactions between FBXO21 and ERK. IDD, intervertebral disc degeneration; miR, microRNA; Col II, type II collagen; MMP, matrix metalloprotein; ADAMTS, a disintegrin-like and metalloproteinase with thrombospondin motifs; KEGG, Kyoto Encyclopedia of Genes and Genomes; FBXO21, F-box only protein 21; ERK, extracellular regulated protein kinases
MiR-217 upregulation prevented IDD development. A Injections of agomiR-217, antagomiR-217, or their negative controls were performed 3, 7, 14, and 21 days after surgery. B Time-dependent fluorescence images of mice treated for 24 and 72 h with agomiR-217, antagomiR-217, or their negative controls labelled by Cy3. Blue to red indicates low to high intensity of the fluorescence signal. C X-ray examination of intervertebral disc degeneration. The DHI was tested after 12 weeks of treatment with different agents. D Histological findings 12 weeks after IDD surgery. In the negative control group, there was a decrease in the number of NP cells, which were replaced by cells with a more fibroblast-like phenotype. However, there was an increase in the number of NP cells in the group treated with agomiR-217 compared to the group treated with antagomiR-217 or negative controls. Moreover, the histology scores were evaluated. E, F MMP13 and Col II immunostaining in IDD models with different treatments. Scale bar = 20 μm. G FCM was used to evaluate apoptotic activity in the intervertebral disc; scale bar = 200 μm. IDD, intervertebral disc degeneration; NC, negative control; miR, microRNA; Col II, type II collagen; MMP, matrix metalloprotein; FCM, flow cytometry. ***P < 0.001
Background Numerous potential therapeutic alternatives for intervertebral disc degeneration (IDD) have been investigated, the most promising of which are based on biological variables such as microRNAs (miRNAs). Therefore, we verified the hypothesis that miRNAs modulate IDD by affecting the FBXO21-ERK signalling pathway. Methods Microarray and quantitative real-time polymerase chain reaction (RT–qPCR) tests were used to examine the expression profiles of miRNAs in nucleus pulposus (NP) cells between patients with IDD and controls. Western blotting and luciferase reporter assays were used to identify the miRNA targets. Results Microarray and RT–qPCR assays confirmed that the expression level of miR-217 was significantly decreased in degenerative NP cells. CpG islands were predicted in the miR-217 promoter region. The IDD group had considerably higher methylation than the control group. Gain- and loss-of-function experiments revealed that miR-217 mimics inhibited apoptosis and extracellular matrix (ECM) breakdown in NP cells. Bioinformatic analyses and luciferase assays were used to determine the connection between miR-217 and FBXO21. In vitro tests revealed that miR-217 mimics inhibited the expression of FBXO21, pERK, MMP13, and ADAMTS5 proteins, successfully protecting the ECM from degradation. Additionally, in vivo investigation using the IDD mouse model demonstrated that the miR-217 agonist may sufficiently promote NP cell proliferation, decrease apoptosis, promote ECM synthesis, and suppress the expression of matrix-degrading enzymes in NP cells. Conclusions Overexpression of miR-217 inhibits IDD via FBXO21/ERK regulation. Trial registration This study was performed in strict accordance with the NIH guidelines for the care and use of laboratory animals (NIH Publication No. 85-23 Rev. 1985) and was approved by the human research ethics committee of Wuhan University Renmin Hospital (Approval No. RMHREC-D-2020-391), and written informed consent was obtained from each participant.
 
Background Non-neuropsychiatric systemic lupus erythematosus (non-NPSLE) has been confirmed to have subtle changes in brain structure before the appearance of obvious neuropsychiatric symptoms. Previous literature mainly focuses on brain structure loss in non-NPSLE; however, the results are heterogeneous, and the impact of structural changes on the topological structure of patients’ brain networks remains to be determined. In this study, we combined neuroimaging and network analysis methods to evaluate the changes in cortical thickness and its structural covariance networks (SCNs) in patients with non-NPSLE. Methods We compare the cortical thickness of non-NPSLE patients ( N =108) and healthy controls (HCs, N =88) using both surface-based morphometry (SBM) and regions of interest (ROI) methods, respectively. After that, we analyzed the correlation between the abnormal cortical thickness results found in the ROI method and a series of clinical features. Finally, we constructed the SCNs of two groups using the regional cortical thickness and analyzed the abnormal SCNs of non-NPSLE. Results By SBM method, we found that cortical thickness of 34 clusters in the non-NPSLE group was thinner than that in the HC group. ROI method based on Destrieux atlas showed that cortical thickness of 57 regions in the non-NPSLE group was thinner than that in the HC group and related to the course of disease, autoantibodies, the cumulative amount of immunosuppressive agents, and cognitive psychological scale. In the SCN analysis, the cortical thickness SCNs of the non-NPSLE group did not follow the small-world attribute at a few densities, and the global clustering coefficient appeared to increase. The area under the curve analysis showed that there were significant differences between the two groups in clustering coefficient, degree, betweenness, and local efficiency. There are a total of seven hubs for non-NPSLE, and five hubs in HCs, the two groups do not share a common hub distribution. Conclusion Extensive and obvious reduction in cortical thickness and abnormal topological organization of SCNs are observed in non-NPSLE patients. The observed abnormalities may not only be the realization of brain damage caused by the disease, but also the contribution of the compensatory changes within the nervous system.
 
Background Intra-articular injection is indicated for mild or moderate osteoarthritis (OA). However, the superiority of cell-based injection and the role of diverse cell sources are still unclear. This study aimed to compare the therapeutic effect of intra-articular injection with mesenchymal stem cells (MSCs) and cell-free methods for OA treatment. Methods A literature search of published scientific data was carried out from PubMed, MEDLINE, Embase, Cochrane Library, Web of Science, and China National Knowledge Internet (CNKI). Randomized controlled trials (RCTs) compared the efficacy and safety of MSC and cell-free intra-articular injection treatments for OA with at least 6-month follow-up. Results Dual network meta-analysis validated the therapeutic advantages of MSC treatments (VAS, Bayesian: 90% versus 10% and SUCRA: 94.9% versus 5.1%; WOMAC total, Bayesian: 83% versus 17% and SUCRA: 90.1% versus 9.9%) but also suggested a potential negative safety induced by cell injection (adverse events, Bayesian: 100% versus 0% and SUCRA: 98.2% versus 1.8%). For the MSC source aspect, adipose mesenchymal stem cells (ADMSCs) and umbilical cord mesenchymal stem cells (UBMSCs) showed a better curative effect on pain relief and function improvement compared with bone marrow mesenchymal stem cells (BMMSCs). Conclusion Intra-articular injection of MSCs is associated with more effective pain alleviation and function improvement than cell-free OA treatment. However, the potential complications induced by MSCs should be emphasized. A comparative analysis of the MSC sources showed that ADMSCs and UBMSCs exerted a better anti-arthritic efficacy than BMMSCs. Graphical Abstract Schematic illustration of MSC-based intra-articular injection for treating OA. Three major MSCs (UBMSCs, ADMSCs, and BMMSCs) are extracted and expanded in vitro. Subsequently, the amplified MSCs are concentrated and injected into the knee joint to treat OA.