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ID PMID Title PublicationDate abstract
35432722 Dose-Dependent Efficacy of Umbelliferone and Gelatin-Coated ZnO/ZnS Core-Shell Nanoparticl 2022 Rheumatoid arthritis (RA) is a well-known autoimmune disorder that affects 1% of the global population. Zinc (Zn) is crucial for bone homeostasis, when compared with normal human bone, Zn level found to be decreased in RA patients and collagen-induced arthritis (CIA) rats. Notably, Zn-based medicinal products play a prominent role in reducing disease symptoms and acute side effects of patients with bone-related diseases. In this study, we report the clinical efficiency of gelatin- (Gel-) coated ZnO-ZnS core-shell nanoparticles (CSNPs) with umbelliferon (Uf) drug (Uf-Gel-ZnO-ZnS CSNPs) on the normal and CIA-induced Wistar rats. The formed ZnO-ZnS CSNPs are spherical in shape, with an average particle diameter of 150 ± 7 nm. It showed strong cytocompatibility when tested on L929 and foreskin fibroblasts (BJ) cells by MTT assay. While comparing with free Uf, various doses (2.5 and 5 mg) of Uf-Gel-ZnO-ZnS CSNPs showed strong inhibition of CIA by attenuated proinflammatory cytokines such as interleukin-1β, IL-6, PEG2, and IL-17. The Uf-Gel-ZnO-ZnS CSNPs show more effectiveness in reducing joint swelling and also increase the level of antioxidant enzymes. In addition, CSNPs significantly reduced the infiltration of inflammatory cells in the knee joint. Thus, the current study concludes that Uf-Gel-ZnO-ZnS CSNPs feasibly reduce the incidence of arthritis in a dose-dependent manner by attenuation of inflammation.
35203042 Triptolide inhibits cell growth and inflammatory response of fibroblast-like synoviocytes 2022 May Triptolide (TPL) is an active component derived from Tripterygium wilfordii Hook F (TwHF) with therapeutic potential for rheumatoid arthritis (RA). However, the underlying mechanism of TPL is remains under-studied. Competing endogenous RNA (ceRNA) networks may participate in the response to TPL in RA. Herein, we sought to identify a TPL response-related ceRNA axis. A circular RNA (circRNA)-microRNA (miRNA)-mRNA ceRNA axis associated with the TPL response was constructed according to our previous study. Modulatory mechanisms of the ceRNA axis were ascertained through a series of experimentations. The clinical relevance of the ceRNA axis was also determined using computational models. Here, we found that TPL had excellent clinical effect on RA and promising therapeutic efficacy in experimental animals. The ceRNA axis of hsa-circ-0003353 (circ0003353), miR-31-5p, and CDK1 was identified as a candidate biomarker for the response of RA patients to TPL. TPL inhibited the viability, proliferation, and cell cycle entry of RA-fibroblast-like synoviocytes (FLSs), as well as the production of cytokines. Overexpression of circ0003353 abolished the inhibitory effects of TPL on RA-FLSs. Mechanistically, circ0003353 sponged miR-31-5p that inversely targeted CDK1 and manipulated the p21/Cyclin B axis. Additionally, consecutive rescue experiments indicated that the inhibitory impacts of TPL on RA-FLSs were dependent on the circ0003353/miR-31-5p/CDK1 axis. Molecular docking was also applied to predict the specific binding sites and binding capacity of TPL to related targets. In conclusion, the present study demonstrated that TPL repressed the cell growth and inflammatory response of RA-FLSs by mediating the expression of the circ0003353/miR-31-5p/CDK1 axis. This novel ceRNA axis may serve as a biomarker for screening RA patients who respond to TPL treatment, which holds potential applications in the diagnosis and therapy of RA.
35296317 Chrysoeriol suppresses hyperproliferation of rheumatoid arthritis fibroblast-like synovioc 2022 Mar 16 BACKGROUND: Fibroblast-like synoviocytes (FLS) have cancer cell-like characteristics, such as abnormal proliferation and resistance to apoptosis, and play a pathogenic role in rheumatoid arthritis (RA). Hyperproliferation of RA-FLS that can be triggered by the activation of interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling destructs cartilage and bone in RA patients. Chrysoeriol is a flavone found in medicinal herbs such as Chrysanthemi Indici Flos (the dried capitulum of Chrysanthemum indicum L.). These herbs are commonly used in treating RA. Chrysoeriol has been shown to exert anti-inflammatory effects and inhibit STAT3 signaling in our previous studies. This study aimed to determine whether chrysoeriol inhibits hyperproliferation of RA-FLS, and whether inhibiting STAT3 signaling is one of the underlying mechanisms. METHODS: IL-6/soluble IL-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS were used to evaluate the effects of chrysoeriol. CCK-8 assay and crystal violet staining were used to examine cell proliferation. Annexin V-FITC/PI double staining was used to detect cell apoptosis. Western blotting was employed to determine protein levels. RESULTS: Chrysoeriol suppressed hyperproliferation of, and evoked apoptosis in, IL-6/sIL-6R-stimulated RA-FLS. The apoptotic effect of chrysoeriol was verified by its ability to cleave caspase-3 and caspase-9. Mechanistic studies revealed that chrysoeriol inhibited activation/phosphorylation of Janus kinase 2 (JAK2, Tyr1007/1008) and STAT3 (Tyr705); decreased STAT3 nuclear level and down-regulated protein levels of Bcl-2 and Mcl-1 that are transcriptionally regulated by STAT3. Over-activation of STAT3 significantly diminished anti-proliferative effects of chrysoeriol in IL-6/sIL-6R-stimulated RA-FLS. CONCLUSIONS: We for the first time demonstrated that chrysoeriol suppresses hyperproliferation of RA-FLS, and suppression of JAK2/STAT3 signaling contributes to the underlying mechanisms. This study provides pharmacological and chemical justifications for the traditional use of chrysoeriol-containing herbs in treating RA, and provides a pharmacological basis for developing chrysoeriol into a novel anti-RA agent.
33053261 Outcomes and Quality of Care in Rheumatoid Arthritis With or Without Video Telemedicine Fo 2022 Mar OBJECTIVE: Telemedicine has been proposed to improve access to care in rheumatology, but few studies of telerheumatology have been published. The objective of this study was to evaluate outcomes and quality of care for rheumatoid arthritis (RA) in patients seen by video telemedicine follow-up compared to in-person only. METHODS: Individuals in the Alaska Tribal Health System with a diagnosis of RA were recruited when seeing a rheumatologist either in-person or by video telemedicine, both of which were offered as part of usual follow-up care. At baseline, participants completed the Routine Assessment of Patient Index Data 3 (RAPID3) questionnaire and a telemedicine perception survey and agreed to medical record review. Participants repeated surveys by telephone at 6 and 12 months, and medical record abstraction was performed at 12 months for quality measures. RESULTS: At the 12-month outcome assessment, 63 of 122 RA patients (52%) had ever used telemedicine for RA. In univariate analysis, functional status improved over 12 months in the telemedicine group. In multivariate analysis, RAPID3 score and functional status were associated with telemedicine group (higher), with no statistically significant change over the 12-month period. The only quality measure that differed between groups at 12 months in univariate analysis was the proportion of visits in which disease activity was documented (higher in the in-person group, 40% versus 25%; P = 0.02), but this was not significant after multivariate analysis. CONCLUSION: In short-term follow-up, there was no significant difference in most outcome and quality measures in patients with RA who incorporated telemedicine follow-up in their care compared to in-person only.
34973077 Effect of dose adjustments on the efficacy and safety of tofacitinib in patients with rheu 2022 Apr INTRODUCTION/OBJECTIVES: We assess the impact of switching versus staying on the same tofacitinib dose on efficacy and safety in patients with rheumatoid arthritis (RA). METHODS: ORAL Sequel was an open-label, long-term extension study of patients with RA receiving tofacitinib 5 or 10 mg BID for up to 9.5 years. Tofacitinib doses could be switched during the study at investigator discretion. In this post hoc analysis, data from ORAL Sequel were stratified into four groups: 5 → 10 mg BID (Dose-up); 5 mg BID (Stay-on 5); 10 → 5 mg BID (Dose-down); and 10 mg BID (Stay-on 10). Efficacy assessments over 12 months included: change from baseline in 4-component Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28), and DAS28 minimum clinically important difference, remission, and low disease activity (LDA) rates. Safety was assessed for the study duration. RESULTS: Generally, DAS28 improvements and minimum clinically important difference rates were significantly greater (p < 0.05) in Dose-up versus Stay-on 5 up to month 12. DAS28 remission rates were significantly greater in Dose-up versus Stay-on 5 at month 12. Change from baseline in DAS28 was similar in Dose-down and Stay-on 10. No significant differences in DAS28 LDA rates were observed between groups. Safety data were similar overall across the four groups. CONCLUSION: In patients with RA receiving open-label tofacitinib, this analysis found that some benefited from increasing dose from 5 to 10 mg BID and did not find that reducing dose from 10 to 5 mg BID affected efficacy or that dose switching in either direction affected safety. STUDY REGISTRATION: ClinicalTrials.gov number NCT00413699. Registered December 20, 2006. https://clinicaltrials.gov/ct2/show/NCT00413699 Key Points • This post hoc analysis of data from the long-term extension study, ORAL Sequel, assessed the impact of dose switching between tofacitinib 5 and 10 mg twice daily (BID), at the investigator's discretion, on efficacy and safety in patients with rheumatoid arthritis (RA). • Dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months versus staying on 5 mg BID, and dosing down from 10 to 5 mg BID was not generally associated with a significant loss of efficacy. • Safety outcomes were generally consistent across dose groups and did not change markedly after switching dose in either direction. • These findings can help to inform physicians on what may be expected in terms of efficacy and safety when adjusting tofacitinib dose according to clinical need. The recommended tofacitinib dosage for the treatment of RA in most jurisdictions is 5 mg BID.
35451978 Sleep Disturbance and Quality of Life in Rheumatoid Arthritis: Prospective mHealth Study. 2022 Apr 22 BACKGROUND: Sleep disturbances and poor health-related quality of life (HRQoL) are common in people with rheumatoid arthritis (RA). Sleep disturbances, such as less total sleep time, more waking periods after sleep onset, and higher levels of nonrestorative sleep, may be a driver of HRQoL. However, understanding whether these sleep disturbances reduce HRQoL has, to date, been challenging because of the need to collect complex time-varying data at high resolution. Such data collection is now made possible by the widespread availability and use of mobile health (mHealth) technologies. OBJECTIVE: This mHealth study aimed to test whether sleep disturbance (both absolute values and variability) causes poor HRQoL. METHODS: The quality of life, sleep, and RA study was a prospective mHealth study of adults with RA. Participants completed a baseline questionnaire, wore a triaxial accelerometer for 30 days to objectively assess sleep, and provided daily reports via a smartphone app that assessed sleep (Consensus Sleep Diary), pain, fatigue, mood, and other symptoms. Participants completed the World Health Organization Quality of Life-Brief (WHOQoL-BREF) questionnaire every 10 days. Multilevel modeling tested the relationship between sleep variables and the WHOQoL-BREF domains (physical, psychological, environmental, and social). RESULTS: Of the 268 recruited participants, 254 were included in the analysis. Across all WHOQoL-BREF domains, participants' scores were lower than the population average. Consensus Sleep Diary sleep parameters predicted the WHOQoL-BREF domain scores. For example, for each hour increase in the total time asleep physical domain scores increased by 1.11 points (β=1.11, 95% CI 0.07-2.15) and social domain scores increased by 1.65 points. These associations were not explained by sociodemographic and lifestyle factors, disease activity, medication use, anxiety levels, sleep quality, or clinical sleep disorders. However, these changes were attenuated and no longer significant when pain, fatigue, and mood were included in the model. Increased variability in total time asleep was associated with poorer physical and psychological domain scores, independent of all covariates. There was no association between actigraphy-measured sleep and WHOQoL-BREF. CONCLUSIONS: Optimizing total sleep time, increasing sleep efficiency, decreasing sleep onset latency, and reducing variability in total sleep time could improve HRQoL in people with RA.
35426113 Janus Kinase Inhibitors: Next-Generation Treatment for Uveitis. 2022 May A large proportion of patients with visual impairment secondary to non-infectious uveitis may require DMARDs. Although these are highly effective, some patients may require alternatives to the currently available immunomodulators due to an inadequate response or undesirable side effects. Janus Kinase Inhibitors (JAKi) are already approved for several autoimmune diseases in rheumatology, gastroenterology and dermatology. To date, JAKi have been studied in phase 3 trials in various types of uveitis. Mechanism of Action: JAKi work by inhibiting the phosphorylation of Janus kinases, which are transmembrane proteins. This blocks the activation of transcription factors, which in turn downregulates cytokine expression and inflammatory mediators. JAKi represent an extremely effective novel therapeutic approach in rheumatology, gastroenterology and dermatology. They have already been approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and atopic eczema. In earlier comparative studies with conventional biologics, a better therapeutic response was reported in some cases. Several published case reports report reduced cortisone levels in patients with uveitis who had responded poorly to conventional and biological DMARDs. Approval studies are under way for JIA-associated and ANA-positive anterior uveitis. In summary, JAKi represent an innovative treatment option for patients with non-infectious uveitis in whom DMARDs are contraindicated or ineffective.
35417796 The role of B cells and their interactions with stromal cells in the context of inflammato 2022 Jun Interactions between B cells and stromal cells have essential functions in immune cell development and responses. During chronic inflammation, the pro-inflammatory microenvironment leads to changes in stromal cells, which acquire a pathogenic phenotype specific to each organ and disease. B cells are recruited to the site of inflammation and interact with these pathogenic stromal cells contributing to the disease's severity. In addition to producing autoantibodies, B cells contribute to the pathogenesis of autoimmune inflammatory diseases by serving as professional antigen-presenting cells, producing cytokines, and through additional mechanisms. This review describes the role of B cells and their interactions with stromal cells in chronic inflammation, with a focus on human disease, using three selected autoimmune inflammatory diseases: rheumatoid arthritis, systemic lupus erythematosus and multiple sclerosis. Understanding B cells roles and their interaction with stromal cells will help develop new therapeutic options for the treatment of autoimmune diseases.
35075294 Regulation of activated T cell survival in rheumatic autoimmune diseases. 2022 Apr Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections. Here, we review the molecular mechanisms that limit the duration of immune responses in health and discuss the factors that alter such regulation in the setting of systemic lupus erythematosus and rheumatoid arthritis. We highlight defects that could contribute to the development and progression of autoimmune disease and describe how chronic inflammation can alter the regulation of activated lymphocyte survival, promoting its perpetuation. These concepts might contribute to the understanding of the mechanisms that underlie the chronicity of inflammation in the context of autoimmunity.
35360114 Salivary Microbiota and Host-Inflammatory Responses in Periodontitis Affected Individuals 2022 OBJECTIVES: Periodontitis and rheumatoid arthritis (RA) are two widespread chronic inflammatory diseases with a previously suggested association. The objective of the current study was to compare the oral microbial composition and host´s inflammatory mediator profile of saliva samples obtained from subjects with periodontitis, with and without RA, as well as to predict biomarkers, of bacterial pathogens and/or inflammatory mediators, for classification of samples associated with periodontitis and RA. METHODS: Salivary samples were obtained from 53 patients with periodontitis and RA and 48 non-RA with chronic periodontitis. The microbial composition was identified using 16S rRNA gene sequencing and compared across periodontitis patients with and without RA. Levels of inflammatory mediators were determined using a multiplex bead assay, compared between the groups and correlated to the microbial profile. The achieved data was analysed using PCoA, DESeq2 and two machine learning algorithms, OPLS-DA and sPLS-DA. RESULTS: Differential abundance DESeq2 analyses showed that the four most highly enriched (log2 FC >20) amplicon sequence variants (ASVs) in the non-RA periodontitis group included Alloprevotella sp., Prevotella sp., Haemophilus sp., and Actinomyces sp. whereas Granulicatella sp., Veillonella sp., Megasphaera sp., and Fusobacterium nucleatum were the most highly enriched ASVs (log2 FC >20) in the RA group. OPLS-DA with log2 FC analyses demonstrated that the top ASVs with the highest importance included Vampirovibrio sp. having a positive correlation with non-RA group, and seven ASVs belonging to Sphingomonas insulae, Sphingobium sp., Novosphingobium aromaticivorans, Delftia acidovorans, Aquabacterium spp. and Sphingomonas echinoides with a positive correlation with RA group. Among the detected inflammatory mediators in saliva samples, TWEAK/TNFSF12, IL-35, IFN-α2, pentraxin-3, gp130/sIL6Rb, sIL-6Ra, IL-19 and sTNF-R1 were found to be significantly increased in patients with periodontitis and RA compared to non-RA group with periodontitis. Moreover, correlations between ASVs and inflammatory mediators using sPLS-DA analysis revealed that TWEAK/TNFSF12, pentraxin-3 and IL-19 were positively correlated with the ASVs Sphingobium sp., Acidovorax delafieldii, Novosphingobium sp., and Aquabacterium sp. CONCLUSION: Our results suggest that the combination of microbes and host inflammatory mediators could be more efficient to be used as a predictable biomarker associated with periodontitis and RA, as compared to microbes and inflammatory mediators alone.
35464401 Pathological Osteoclasts and Precursor Macrophages in Inflammatory Arthritis. 2022 Macrophages comprise a variety of subsets with diverse biological functions, including inflammation, tissue repair, regeneration, and fibrosis. In the bone marrow, macrophages differentiate into multinucleated osteoclasts, which have a unique bone-destroying capacity and play key roles in physiological bone remodelling. In contrast, osteoclasts are also involved in inflammatory bone erosion in arthritis and it has been unclear whether the osteoclasts in different tissue settings arise from similar monocytoid precursors and share similar phenotypes. Rapid progresses in the sequencing technologies have provided many important insights regarding the heterogeneity of different types of osteoclasts. The application of single-cell RNA sequencing (scRNA-seq) to the osteoclast precursor-containing macrophages enabled to identify the specific subpopulation differentiating into pathological mature osteoclasts in joints. Furthermore, an intravital imaging technology using two-photon microscopy has succeeded in visualizing the real-time dynamics of immune cells in the synovial microenvironment. These technologies together contributed to characterize the unique macrophages in the inflamed synovium, termed "arthritis-associated osteoclastogenic macrophages (AtoMs)", causing the pathological bone destruction in inflammatory arthritis. Here, we review and discuss how novel technologies help to better understand the role of macrophages in inflammatory arthritis, especially focusing of osteoclastogenesis at the pannus-bone interface.
34625404 Serious infections in patients with rheumatoid arthritis and psoriatic arthritis treated w 2022 Mar OBJECTIVES: To estimate the incidence of serious infections (SIs) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with tumour necrosis factor inhibitor (TNFi), and compare risk of SIs between patients with RA and PsA. METHODS: We included patients with RA and PsA from the NORwegian-Disease Modifying Anti-Rheumatic Drug registry starting TNFi treatment. Crude incidence rates (IRs) and IR ratio for SIs were calculated. The risk of SIs in patients with RA and PsA was compared using adjusted Cox-regression models. RESULTS: A total of 3169 TNFi treatment courses (RA/PsA: 1778/1391) were identified in 2359 patients. Patients with RA were significantly older with more extensive use of co-medication. The crude IRs for SIs were 4.17 (95% CI 3.52 to 4.95) in patients with RA and 2.16 (95% CI 1.66 to 2.81) in patients with PsA. Compared with the patients with RA, patients with PsA had a lower risk of SIs (HR 0.59, 95% CI 0.41 to 0.85, p=0.004) in complete set analysis. The reduced risk in PsA versus RA remained significant after multiple adjustments and consistent across strata based on age, gender and disease status. CONCLUSIONS: Compared with patients with RA, the risk of SIs was significantly lower in patients with PsA during TNFi exposure.
35143591 Interleukin-17 contributes to Ross River virus-induced arthritis and myositis. 2022 Feb Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17-producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.
35529852 SOX4 and RELA Function as Transcriptional Partners to Regulate the Expression of TNF- Resp 2022 SOX4 belongs to the group C of the SOX transcription factor family. It is a critical mediator of tumor necrosis factor alpha (TNF)-induced transformation of fibroblast-like s-ynoviocytes (FLS) in arthritis. In this study we investigated the genome wide association between the DNA binding and transcriptional activities of SOX4 and the NF-kappaB signaling transcription factor RELA/p65 downstream of TNF signaling. We used ChIP-seq assays in mouse FLS to compare the global DNA binding profiles of SOX4 and RELA. RNA-seq of TNF-induced wildtype and SoxC-knockout FLS was used to identify the SOX4-dependent and independent aspects of the TNF-regulated transcriptome. We found that SOX4 and RELA physically interact with each other on the chromatin. Interestingly, ChIP-seq assays revealed that 70.4% of SOX4 peak summits were within 50bp of the RELA peak summits suggesting that both proteins bind in close-proximity on regulatory sequences, enabling them to co-operatively regulate gene expression. By integrating the ChIP-seq results with RNA-seq from SoxC-knockout FLS we identified a set of TNF-responsive genes that are targets of the RELA-SOX4 transcriptional complex. These TNF-responsive and RELA-SOX4-depenedent genes included inflammation mediators, histone remodeling enzymes and components of the AP-1 signaling pathway. We also identified an autoregulatory mode of SoxC gene expression that involves a TNF-mediated switch from RELA binding to SOX4 binding in the 3' UTR of Sox4 and Sox11 genes. In conclusion, our results show that SOX4 and RELA together orchestrate a multimodal regulation of gene expression downstream of TNF signaling. Their interdependent activities play a pivotal role in the transformation of FLS in arthritis and in the inflammatory pathology of diverse tissues where RELA and SOX4 are co-expressed.
35202652 The naturally occurring flavonoid nobiletin reverses methotrexate resistance via inhibitio 2022 Apr Methotrexate (MTX) is the first-line treatment for rheumatoid arthritis (RA). However, after long-term treatment, some patients develop resistance. P-glycoprotein (P-gp), as an indispensable drug transporter, is essential for mediating this MTX resistance. In addition, nobiletin (NOB), a naturally occurring polymethoxylated flavonoid, has also been shown to reverse P-gp-mediated MTX resistance in RA groups; however, the precise role of NOB in this process is still unclear. Here, we administered MTX and NOB alone or in combination to collagen II-induced arthritic (CIA) mice and evaluated disease severity using the arthritis index, synovial histopathological changes, immunohistochemistry, and P-gp expression. In addition, we used conventional RNA-seq to identify targets and possible pathways through which NOB reverses MTX-induced drug resistance. We found that NOB in combination with MTX could enhance its performance in synovial tissue and decrease P-gp expression in CIA mice compared to MTX treatment alone. In vitro, in MTX-resistant fibroblast-like synoviocytes from CIA cells (CIA-FLS/MTX), we show that NOB treatment downregulated the PI3K/AKT/HIF-1α pathway, thereby reducing the synthesis of the P-gp protein. In addition, NOB significantly inhibited glycolysis and metabolic activity of CIA-FLS/MTX cells, which could reduce the production of ATP and block P-gp, ultimately decreasing the efflux of MTX and maintaining its anti-RA effects. In conclusion, this study shows that NOB overcomes MTX resistance in CIA-FLS/MTX cells through the PI3K/AKT/HIF-1α pathway, simultaneously influencing metabolic processes and inhibiting P-gp-induced drug efflux.
34690249 Gingival crevicular fluid microRNA associations with periodontitis. 2022 Jan 19 PURPOSE: The present study was performed to assess the associations of gingival crevicular fluid (GCF) microRNAs miR-140-3p, miR-145-5p, miR-146a-5p, and miR-195-5p with periodontitis (PD) and to evaluate the possible influence of rheumatoid arthritis (RA) in this context. METHOD: GCF samples were collected from 134 individuals with PD and 76 periodontally healthy individuals, with or without RA. After miRNA extraction from GCF, the levels of miR-140-3p, miR-145-5p, miR-146a-5p, and miR-195-5p were assessed using RT-qPCR. RESULTS: MiR-146a-5p levels were significantly lower among the patients with PD than among the healthy individuals (P < 0.001) and negatively correlated with PD severity based on PD stage and periodontal outcome parameters (P < 0.05). Patients with severe PD had higher GCF levels of miR-140-3p and miR-145-5p than did periodontally healthy individuals (P < 0.05). Significant AUC values for diagnosis of severe PD were revealed for miR-140-3p (AUC = 0.614, P = 0.022), miR-145-5p (AUC = 0.621, P = 0.016) and miR-146a-5p (AUC = 0.702, P < 0.001). Combination of the aforementioned miRNAs increased the diagnostic performance (AUC = 0.709, P < 0.001). CONCLUSION: It was demonstrated that miR-140-3p, miR-145-5p and miR-146a-5p were associated with PD and would be potentially effective for GCF-based non-invasive periodontitis diagnostics in patients with and without RA.
34890543 The immunomodulatory effect of koumine on B cells under dependent and independent response 2022 Jan 5 Dysregulated activation of polyclonal B cells and production of pathogenic antibodies are involved in the development of rheumatoid arthritis (RA). Therefore, targeted B cell therapy is effective against RA. Gelsemium elegans (Gardn. & Champ.) Benth., a toxic plant widely distributed in Southeast Asia, has been used for treating rheumatoid pain, neuropathic pain, spasticity, skin ulcers, and cancers for many years in traditional Chinese medicine. Koumine, an alkaloid monomer from Gelsemium elegans Benth., exerts therapeutic effects against RA. However, whether koumine affects B cells remains unknown. In this study, the effect of koumine on B cells under T cell-independent (TI) and T cell-dependent (TD) immune responses is investigated in vitro and in vivo. Mouse primary B cells were obtained by immunomagnetic bead sorting, and immunomodulatory effects of koumine on the activation, proliferation, and differentiation of B cells were determined in TI and TD models induced by lipopolysaccharide (LPS) and anti-CD40 antibodies in vitro, respectively. The humoral immune responses of TI and TD were established using NP-AECM-FICOLL and NP-CGG in C57BL/6J mice, respectively. We found that koumine inhibited B cell differentiation in the TI model and inhibited B cell activation and proliferation in the TD model in vitro. Koumine also inhibited antibody secretion in TI immune response, TD initial immune response, and in TD secondary immune response. Our results reveal that koumine has a direct and indirect immune regulatory effect on B cells, showing that it can directly inhibit the differentiation and secretion of autoantibodies after abnormal activation of B cells, and indirectly inhibit the activation and proliferation of TD B cells to reduce the secretion of antibodies. It may be an important mechanism for its anti-RA effect in mice, providing a rationale and laboratory data support for the application of koumine in anti-human RA therapy.
34980566 Treating-to-target in rheumatology: Theory and practice. 2022 Mar Despite its inclusion in current treatment recommendations, adherence to the treat-to-target strategy (T2T) is still poor. Among the issues are the definition(s) of target, especially the caveats of the patient global assessment (PGA), included in all recommended definitions of remission. The PGA is poorly related to inflammation, especially at low levels of disease activity, rather being a measure of the disease impact. Up to 60% of all patients otherwise in remission still score PGA at >1 and as high as 10. These patients (PGA-near-remission) are exposed to overtreatment if current recommendations are strictly followed and will continue to endure significant impact, unless adjuvant measures are implemented. A proposed method to overcome both these risks is to systematically pursue two targets: one focused on the disease process (the biological target) and another focused on the symptoms and impact (the impact target), the dual-target strategy. Candidate instruments to define each of these targets are discussed.
35064701 Inter-alpha-trypsin inhibitor heavy chain 4: A serologic marker relating to disease risk, 2022 Mar OBJECTIVE: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) regulates immunity and inflammation, but its clinical role in rheumatoid arthritis (RA) patients remains unclear. Hence, this study was conducted to explore the association of circulating ITIH4 with disease risk, clinical features, inflammatory cytokines, and treatment outcomes of RA. METHODS: After the enrollment of 93 active RA patients and 50 health controls (HCs), their serum ITIH4 level was analyzed by enzyme-linked immunosorbent assay (ELISA). For RA patients only, serum ITIH4 level at week (W) 6 and W12 after treatment was also analyzed. Besides, serum tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, and IL-17A at baseline of RA patients were also detected by ELISA. RESULTS: ITIH4 was downregulated in RA patients (151.1 (interquartile range (IQR): 106.2-213.5) ng/mL) than in HCs (306.8 (IQR: 238.9-435.1) ng/mL) (p < 0.001). Furthermore, ITIH4 was negatively related to C-reactive protein (CRP) (r(s)  = -0.358, p < 0.001) and 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) (r(s)  = -0.253, p = 0.014) in RA patients, but not correlated with other clinical features (all p > 0.05). Besides, ITIH4 was negatively linked with TNF-α (r(s)  = -0.337, p = 0.001), IL-6 (r(s)  = -0.221, p = 0.033), and IL-17A (r(s)  = -0.368, p < 0.001) in RA patients, but not correlated with IL-1β (r(s)  = -0.195, p = 0.061). Moreover, ITIH4 was gradually elevated in RA patients from baseline to W12 after treatment (p < 0.001). Additionally, the increment of ITIH4 at W6 and W12 was linked with treatment response and remission in RA patients (all p < 0.05). CONCLUSION: Circulating ITIH4 possesses clinical utility in monitoring disease risk, inflammation, disease activity, and treatment outcomes of RA.
35132461 Perioperative management of disease-modifying antirheumatic drugs for patients undergoing 2022 Apr BACKGROUND: In preparation for surgery, patients being treated with disease-modifying antirheumatic drugs (DMARDs) are recommended to either continue or withhold therapy perioperatively. Some of these drugs have known effects against bone healing, hence the importance of adequately managing them before and after surgery. OBJECTIVE: We aim to assess the current evidence for managing conventional synthetic and/or biologic DMARDs in the perioperative period for elective spine surgery. METHODS: A systematic review of four databases was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The included manuscripts were methodically scrutinized for quality, postoperative infections, wound healing characteristics, bone fusion rates, and clinical outcomes. RESULTS: Six studies were identified describing the management of conventional synthetic and/or biologic DMARDs. There were 294 DMARD-treated patients described undergoing various spine surgeries such as craniovertebral junction fusions. Three of the studies involved exclusive continuation of DMARDs in the perioperative window; one study involved exclusive discontinuation of DMARDs in the perioperative window; and two studies involved continuation or discontinuation of DMARDs perioperatively. Of patients that continued DMARDs in the perioperative period, 13/50 patients (26.0%) had postoperative surgical site infections or wound dehiscence, 2/19 patients (10.5%) had delayed wound healing, and 32/213 patients (15.0%) had secondary revision surgeries. A fusion rate of 14/19 (73.6%) was described in only one study for patients continuing DMARDs perioperatively. CONCLUSIONS: The available published data may suggest a higher risk of wound healing concerns and lower than average bone fusion, although this may be under-reported given the current state of the literature.