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ID PMID Title PublicationDate abstract
31912462 Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis 2020 Mar INTRODUCTION: The Janus kinase (JAK) inhibitor therapeutic class has shown significant clinical benefit in the treatment of rheumatoid arthritis (RA). We sought to gain insight into the mode of action and immunological effects of filgotinib, a JAK1 selective inhibitor, in active RA by analyzing secreted and cell-based biomarkers key to RA pathophysiology in two phase 2b trials of filgotinib in active RA. METHODS: Immune cell subsets and 34 serum biomarkers were analyzed longitudinally over 12 weeks using blood samples collected from patients with active RA receiving filgotinib (100 or 200 mg once daily) or placebo (PBO) in the two phase 2b trials (DARWIN 1, on a background of methotrexate, and DARWIN 2, as monotherapy). RESULTS: Consistently across both studies, filgotinib treatment decreased multiple immune response biomarkers that have key roles in RA for immune response, and decreased markers that promote matrix degradation, angiogenesis, leukocyte adhesion, and recruitment. Filgotinib did not significantly modulate T and natural killer (NK) lymphoid subsets, but slightly increased B cell numbers after 12 weeks. Multiple correlations were observed for changes in biomarkers with disease activity score 28-CRP. MIP1β showed modest predictivity at baseline for ACR50 response at 12 weeks in the 100 mg filgotinib dose across both studies (AUROC, 0.65 and 0.67, p < 0.05). CONCLUSIONS: Filgotinib regulates biomarkers from multiple pathways, indicative of direct and indirect network effects on the immune system and the stromal response. These effects were not associated with reductions of major circulating lymphoid populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01888874, NCT01894516.
32043773 In Reply. 2020 Feb This letter to the editor is in response to the letter from Brugu's and colleagues regarding the Warner et al. study of sicca syndrome induced by immune checkpoint inhibitor therapy.
33456084 Baricitinib for the treatment of rheumatoid arthritis. 2020 Rheumatoid arthritis (RA) is a common inflammatory disease with several implications on health, disability and economy. Conventional treatment for RA centers on anti-inflammatory drugs and specific targeting of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6). Baricitinib is a novel, Food and Drug Administration (FDA) approved, once daily oral drug that is effective in combination with current treatment and results in significantly reduced symptoms with good safety profile. Further studies are required to find rare side effects and evaluate the long term efficacy in disease modulation and patient symptom reduction. This is a comprehensive review of the literature on baricitinib for the treatment of RA. This review provides an update on the pathophysiology, diagnosis and conventional treatment of RA, then proceeds to introduce baricitinib and the data that exists to support or refute its use in RA. The presented study also indicated clinical trials confirming the effectiveness of baricitinib in this indication.
33614673 JAK Inhibitors and Modulation of B Cell Immune Responses in Rheumatoid Arthritis. 2020 Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disease that can lead to joint destruction, functional disability and substantial comorbidity due to the involvement of multiple organs and systems. B cells have several important roles in RA pathogenesis, namely through autoantibody production, antigen presentation, T cell activation, cytokine release and ectopic lymphoid neogenesis. The success of B cell depletion therapy with rituximab, a monoclonal antibody directed against CD20 expressed by B cells, has further supported B cell intervention in RA development. Despite the efficacy of synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs) in the treatment of RA, few patients reach sustained remission and refractory disease is a concern that needs critical evaluation and close monitoring. Janus kinase (JAK) inhibitors or JAKi are a new class of oral medications recently approved for the treatment of RA. JAK inhibitors suppress the activity of one or more of the JAK family of tyrosine kinases, thus interfering with the JAK-Signal Transducer and Activator of Transcription (STAT) signaling pathway. To date, there are five JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib) approved in the USA, Europe and/ or Japan for RA treatment. Evidence from the literature indicates that JAK inhibitors interfere with B cell functions. In this review, the main results obtained in clinical trials, pharmacokinetic, in vitro and in vivo studies concerning the effects of JAK inhibitors on B cell immune responses in RA are summarized.
32629762 Peptidyl Arginine Deiminase Type 4 Gene Promoter Hypo-Methylation in Rheumatoid Arthritis. 2020 Jun 30 Protein citrullination is carried out by peptidylarginine deiminase type 4 (PAD4) enzyme. As a consequence of this process, post-translationally modified proteins are formed that become antigens for anti-citrullinated protein antibodies (ACPA). The study aimed at identifying whether the PADI4 gene is subject to epigenetic regulation through methylation of its promoter region, whether the degree of methylation differs in healthy individuals vs. rheumatoid arthritis (RA) patients and changes in correlation with ACPA, anti-PAD4 and disease activity. A total of 125 RA patients and 30 healthy controls were enrolled. Quantitative real-time methylation-specific PCR was used to analyze the methylation status. ACPA and anti-PAD4 antibodies were determined in serum by enzyme-linked immunosorbent immunoassay. The differences were observed in the degree of PADI4 gene promoter methylation between RA patients and HC, along with an upward trend for the methylation in RA, which was inversely proportional to the disease activity. A weak or modest negative correlation between the degree of PADI4 gene methylation and anti-PAD4, disease activity score (DAS28) and ACPA level has been found. The elevated methylation is associated with lower disease activity, lower levels of ACPA and aPAD4. The methylation degree in this area is growing up during effective treatment and might play a role in the RA pathophysiology and therefore could be a future therapeutic target.
32571732 Systematic Review of the Impact of Drugs on Diffuse Interstitial Lung Disease Associated w 2020 Jun 19 OBJECTIVE: To review the available evidence on the impact of rheumatoid arthritis (RA) treatments in associated diffuse interstitial lung disease (ILD). METHODS: Systematic review of studies evaluating the impact of pharmacological treatment in patients with RA and ILD. A bibliographic search in MEDLINE, EMBASE and Cochrane, a selection of articles and the methodological quality assessment (FLC 3.0 OSTEBA) and grading of the level of evidence (SING) of the selected articles were performed. RESULTS: 1,720 references were identified in primary search and 7 in manual or indirect. Forty-three articles were included: 7 systematic reviews, 2 randomized clinical trials, 5 cohort studies, 8 case-control studies and 21 case series. Methotrexate (MTX) and leflunomide (LEF) do not increase incidence, complications or mortality due to ILD. Although the results are not uniform, anti-TNF have often had worse outcomes in incidence, progression and mortality due to ILD than MTX, LEF, abatacept (ABA) and rituximab (RTX). The evidence found is scarce for JAK kinase and antifibrotic inhibitors, and controversial for IL-6 inhibitors. CONCLUSIONS: There is no evidence that MTX or LEF worsens the prognosis of patients with AR-EPID. RTX and ABA seem to have better results than other biologicals, such as anti-TNF, often achieving stabilization and, in some cases, the improvement of ILD in patients with RA.
32565704 Analysis of subgingival microbiome of periodontal disease and rheumatoid arthritis in Chin 2020 Jul OBJECTIVE: Periodontitis (PD) and rheumatoid arthritis (RA) share similar pathogenesis. Evidences indicated that oral bacteria play an important role in the etiology of both diseases. For example, Porphyromonas gingvialis connect the two diseases through immune responses. We designed this study to compare bacterial diversity in RA, PD and healthy subjects and to investigate whether there are other oral bacteria play an potential role in linking the two diseases. METHODS: This study included 3 groups of Chinese participants who visited Sichuan Provincial People's Hospital during August 2018 and March 2019. Subgingival plaques were collected from RA group (n = 54), PD group (n = 45) and normal group (n = 44). Illumina MiSeq was used to compare the composition of subgingival microbiota and analyze correlations between oral bacteria and both diseases. RESULTS: Alpha diversity Analysis reflected similar microbiome profile in RA, PD and healthy groups. But we found Treponema was significantly more abundant in the PD and RA groups than healthy group at each taxonomic level from the phylum down to the genus level. Porphyromonas, Prevotella, and Veilonella were significantly more abundant in RA while Streptococcus, Gemella, Planobacterium were verified the opposite results. CONCLUSIONS: We found no significant group differences referent to either microbial diversity or richness. But we picked out Spirochaetes which may link the two diseases. Upper/lower regulation of some microbia in RA may remind us a direction to explore the role they play in pathogenesis.
32322118 The impact of obesity on inflammatory markers used in the assessment of disease activity i 2020 INTRODUCTION: Obesity is known to be associated with elevated levels of inflammatory markers. The aim of the study was to assess the confounding effect of obesity on the levels of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in patients with rheumatoid arthritis (RA) in low disease activity state or remission as indicated by clinical disease activity index (CDAI). MATERIAL AND METHODS: Adult RA patients with CDAI less than 10 were divided into two groups: obese and non-obese, based on body mass index. Relevant exclusions were applied to eliminate causes of raised inflammatory markers other than obesity. The difference of CRP and ESR levels between the obese and non-obese groups was analyzed. RESULTS: Obese patients with RA (n = 85) had higher CRP and ESR than non-obese patients (n = 66) (p-values 0.008 and 0.000005, respectively). In addition, obese females with RA had significantly higher CRP and ESR as compared to non-obese females. However, the difference was not significant in males. Twenty-one obese (24.7%) and two non-obese RA patients (3%) had elevated CRP (difference of approximately 22% [24.7 minus 3]). Forty obese (47%) and 16 non-obese RA patients (24.2%) had elevated ESR (difference of approximately 23% [47 minus 24.2]). Thus, obesity was the attributable cause of falsely elevated CRP and ESR in 22% and 23% of patients, respectively. CONCLUSIONS: About one-fifth of patients with RA, who are actually in low disease activity, may have elevated inflammatory markers, primarily because of obesity. Therefore, elevated CRP and ESR in obese patients with RA should be interpreted with caution because it may lead to unnecessary overtreatment.
32318979 Biologic Disease-Modifying Antirheumatic Drug Prescription Patterns for Rheumatoid Arthrit 2020 Jun INTRODUCTION: Some patients with rheumatoid arthritis (RA) using tumor necrosis factor inhibitors (TNFi) experience inefficacy or lack of tolerability and hence switch to another TNFi (cycling) or to a therapy with another mode of action (switching). This study examined patient characteristics, prescribing patterns and treatment practice for RA in the United States. METHODS: Data were from the Adelphi Disease Specific Programme (Q2-Q3 2016). Rheumatologists completed a survey and patient record forms for adult patients with RA who had received ≥ 1 targeted therapy. Patients were grouped by class of first-used targeted therapy, and monotherapy vs. combination therapy. TNFi patients who received ≥ 1 targeted therapy were classified as cyclers or switchers. Univariate analyses compared patient characteristics and physician factors across the analysis groups. RESULTS: Overall, 631 patients received ≥ 1 targeted therapy; 535 were prescribed a TNFi as first targeted therapy, 53 a nonTNFi biologic disease-modifying antirheumatic drug (bDMARD), and 43 tofacitinib. Of 577 patients with known conventional synthetic (cs) DMARD status, 18.7% were prescribed monotherapy and 81.3% combination therapy. Combination therapy patients received significantly more concomitant medications prior to initiation of first targeted therapy than monotherapy patients (P < 0.05). The top reason for physicians to prescribe first use targeted therapy was strong overall efficacy (79.9%). Of 163 patients who progressed to second targeted therapy, 60.7% were cyclers. A lower proportion of cyclers persisted on their first use targeted therapy versus switchers (P = 0.03). The main reason physicians gave for switching patients at this stage was worsening condition (46.6%). CONCLUSIONS: Most patients were prescribed a TNFi as their first targeted therapy; over half then cycled to another TNFi. This suggests other factors may influence second use targeted treatment choice and highlights the need for greater understanding of outcomes associated with subsequent treatment choices and potential benefits of switching.
34240035 Rheumatoid arthritis-associated lung disease in black Africans: Descriptive study of 28 ca 2020 BACKGROUND: Several studies have shown that lung disease is a common extra-articular manifestation of rheumatoid arthritis (RA). OBJECTIVES: To describe the lung manifestations in the RA population in Lomé, Togo. METHODS: The study was conducted from October 2018 to July 2019 at the pulmonology unit of the Sylvanus Olympio University teaching hospital, in collaboration with rheumatology centres in Lomé, Togo. Patients meeting the American College of Rheumatology criteria for RA were prospectively enrolled. They underwent clinical examination, spirometry, a 6-minute walk test (6MWT) and a chest X-ray (CXR). All information collected and surveys gathered were subjected to statistical analysis. RESULTS: Twenty-four out of 28 patients were women (85.7%). The mean (standard deviation (SD)) duration of illness was 4.1 (2.8) years. Thirteen patients out of 28 (46.4%) had respiratory symptoms. On CXR, interstitial lung disease was the only pleuropulmonary lesion (17.8%). Spirometry was abnormal in 25% of cases, with a predominance of restrictive ventilatory disorder (21.4%). The 6MWT was abnormal in 25% of patients. A total of 20 patients (71.4%) had at least one lung manifestation. We noted that there were significantly more patients with respiratory symptoms and no radiographical abnormalities than those with both respiratory symptoms and radiographical abnormalities (p=0.013). CONCLUSION: Lung changes affect a significant proportion of RA patients in Lomé. Studies conducted with appropriate respiratory investigations and combining cardiovascular explorations will bring us closer to an understanding of the effects of RA-associated lung disease.
33344774 Rheumatoid arthritis increases the risk of pleural empyema. 2020 BACKGROUND: Rheumatoid arthritis (RA) can lead to various pulmonary manifestations. Evidence shows the possible association between RA and pleural empyema. METHODS: We conducted a retrospective cohort study to investigate the risk of pleural empyema in patients with RA. The RA group (n = 29,061) included newly diagnosed adult patients between 2000 and 2012. The comparison group (n = 1,16,244) included individuals without RA at a 1:4 ratio of frequency matched by age, gender, and diagnosis year. The occurrence of pleural empyema was monitored until the end of 2013. RESULTS: Patients with RA had a higher risk of developing pleural empyema than those without RA (23.6 vs 1.82 per 10,000 person-years, adjusted hazard ratio = 11.0, 95% confidence interval [CI] = 8.90-13.5). Furthermore, intensive care unit admission rates of pleural empyema were 37.7% in the RA group and 37.2% in the comparison group (adjusted odds ratio [OR] = 1.02, 95% CI = 0.66-1.57). The 30-day mortality rates of pleural empyema were 11.2% in the RA group and 10.9% in the comparison group (adjusted OR = 1.01, 95% CI = 0.51-1.88). CONCLUSION: Patients with RA are at a greater risk of developing pleural empyema than those without RA.
32982367 JAK Inhibitors in Rheumatoid Arthritis: An Evidence-Based Review on the Emerging Clinical 2020 Janus kinase (JAK) Inhibitors are the latest drug class of disease-modifying medication to emerge for the treatment of rheumatoid arthritis (RA). They are a small molecule-targeted treatment and are the first oral option to compare favourably to existing biologic disease-modifying anti-rheumatic drugs (DMARDs). Tofacitinib, baricitinib and upadacitinib are the first 3 JAK inhibitors to become commercially available in the field and are the core focus of this review. To date, they have demonstrated comparable efficacy to tumour necrosis factor (TNF) inhibitors in terms of American College of Rheumatology (ACR) response rates and disease activity (DAS28) scores with similar cost to the benchmark adalimumab. This narrative review article aims to synthesise and distil the key available trial data on JAK inhibitor efficacy and safety, along with their place in the ACR and European League Against Rheumatism (EULAR) guidelines for RA. The novel mechanism of action of the JAK/STAT pathway is highlighted along with the potential effects of modulating each pathway. The rapid onset of action, role in attenuation of central pain processing and effect on structural damage and radiographic progression are also all examined in detail. We also explore the latest meta-analyses and comparative performance of each of the 3 available JAKs in an effort to determine which is most efficacious and which has the most favourable safety profile. Post marketing concerns regarding thromboembolism risk and herpes zoster infection are also discussed. Additionally, we review the cost-benefit analyses of the available JAK inhibitors and address some of the pharmacoeconomic considerations for real-world practice in the UK and US by detailing the raw acquisition cost and the value they provide in comparison to the benchmark biologic adalimumab and the anchor DMARD methotrexate.
32494263 Fatty liver in Pakistani cohort with rheumatoid arthritis. 2020 May OBJECTIVE: To determine the frequency of fatty liver (non-alcoholic) disease, Framingham 10-year cardiovascular risk score in rheumatoid arthritis patients. METHODS: This study was conducted from September 1(st) to March 19, 2019, at Rheumatology OPD, Central Park Medical College Lahore. One hundred ninety two seropositive rheumatoid arthritis patients were recruited. Demographic details were noted, BP, BMI, smoking habits, and waist circumference were noted, then sent to radiology department for ultrasound scan of abdomen by an expert radiologist. On next day 10 ml blood was taken by phlebotomist for lipid profile and fasting blood sugar levels, after availability of results 10-years Framingham cardiovascular risk score was calculated. RESULTS: Females were (81.3%) mean age of (45.4) years, fatty liver was present in n=39 (20.3%). In positive cases comorbid like metabolic syndrome was present (71.8%), diabetes mellitus (33.3%), hypertension (59%) FRS score (intermediate to high in (33.3%), history of hakeem/desi medication use (51.3%), while on regression analysis all study parameters except DMARD's had significant association with fatty liver (p<0.05). CONCLUSION: Nonalcoholic fatty liver disease is very widely prevalent in rheumatoid arthritis patients. As in general population, it is multifactorial in origin and needs careful monitoring and treatment.
32292473 Study on the evaluation of rheumatoid arthritis via doppler ultrasonography and anti-cycli 2020 Mar OBJECTIVE: This study aims to discuss the value of ultrasonic analysis and anti-cyclic citrullinated peptide (CCP) antibody analysis in evaluating the state of rheumatoid arthritis (RA). METHODS: This study was conducted during March 2016 to December 2016. Total 82 patients with RA who sought treatment in the Affiliated Hospital of Hebei University were included in this study. Data on ultrasonic and anti-CCP antibody, ESR, and RF were collected and compared. The RA patients were divided into two groups of mild disease activity (DAS28 ≤ 3.2) and moderate-severe disease activity (DAS28 > 3.2) to compare the changes in synovial thickness of joints. The changes of joint ultrasonography were also compared between positive and negative anti-CCP antibodies group. RESULTS: It is found that the number of patients suffering from joint involvement in the negative anti-CCP antibody group was larger than that of the anti-CCP positive antibody group (P <0.05); the thickness of the synovium of joints of patients in the group with moderate-severe disease activity evaluated via ultrasonography was significantly larger than that of the group with mild disease activity (P <0.05). CONCLUSION: It is possible to observe the degree of disease activity dynamically by combining ultrasonography with anti-CCP antibody and make a better assessment of patients to facilitate treatment.
32211348 Role of Chemokines and Chemokine Receptors in Rheumatoid Arthritis. 2020 Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases and a prototypic inflammatory disease, affecting the small joints of the hands and feet. Chemokines and chemokine receptors play a critical role in RA pathogenesis via immune cells recruitment. Several chemokines and chemokine receptors are abundant in the peripheral blood and in the local inflamed joints of RA. Furthermore, synthetic and biologics disease modifying anti rheumatic drugs have been reported to affect chemokines expression. Thus, many studies have focused on targeting chemokines and chemokine receptors, where some have shown positive promising results. However, most of the chemokine blockers in human trials of RA treatment displayed some failures that can be attributed to several reasons in their structures and binding affinities. Nevertheless, targeting chemokines will continue to be under development, in order to improve their therapeutic potentials in RA and other autoimmune diseases. In this review we provide an up-to-date knowledge regarding the role of chemokines and chemokine receptors in RA with an emphasis on their activities on immune cells. We also discussed the effects of drugs targeting those molecules in RA. This knowledge might provide impetus for developing new therapeutic modalities to treat this chronic disease.
31907670 Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-ana 2020 Jan 6 PURPOSE: Fenebrutinib (GDC-0853), a Bruton's tyrosine kinase (BTK) inhibitor was investigated in a Phase 2 clinical trial in patients with rheumatoid arthritis (RA). Our aim was to apply a model-informed drug development (MIDD) approach to examine the totality of available clinical efficacy data. METHODS: Population pharmacokinetics (popPK) modeling, exposure-response (E-R) analysis, and model-based meta-analysis (MBMA) of fenebrutinib were performed based on the Phase 2 data. RESULTS: PopPK of fenebrutinib after oral administration was described using a 3-compartment model with linear elimination and a flexible absorption transit compartment model. Healthy subjects had a 52% higher apparent clearance than patients. E-R analyses based on longitudinal ACR20, ACR50, and ACR70 and DAS28 (CRP) data modeled fenebrutinib effect with an E(max) function, and an efficacy plateau was achieved within the exposure range obtained in the Phase 2 clinical trial. Based on literature data, a summary-level clinical efficacy database was constructed, and MBMA determined ACR20, ACR50, and ACR70 responder rates in the placebo and adalimumab arms of the Phase 2 clinical trial were found to be consistent with historical data for these treatments. CONCLUSIONS: Our multi-pronged approach applied MIDD to maximize knowledge extraction of efficacy data and enabled robust interpretation from a Phase 2 clinical trial.
32153766 Severe heterotopic ossification post total knee arthroplasty in a patient with rheumatoid 2020 Mar Stiffness following total knee arthroplasty (TKA) can be a devastating complication to the patient by limiting his function. Various causes have been reported in the literature, including heterotopic ossification (HO). HO is one of the rarely reported complication of TKA characterized by deposition of bone cells in non-skeletal tissue. This is a case of 32-year-old female known to have rheumatoid arthritis with history of TKA 4-years-ago complaining of right knee pain and restricted range of motion. She was later found to have HO and was treated with a revision TKA. In conclusion, the incidence and outcome of HO following total knee replacement in patients with RA remains underexplored topic in the literature.
32765264 Validation of the General Medication Adherence Scale in Pakistani Patients With Rheumatoid 2020 OBJECTIVE: The aim was to validate the Urdu version of General Medication Adherence Scale (GMAS) in patients with rheumatoid arthritis disease. METHODS: A 2-month (March-April 2019) cross-sectional study was conducted in randomly selected out-patients with rheumatoid arthritis. The sample size was calculated using item-subject ratio of 1:20. The scale was evaluated for factorial, concrete, concurrent, and known group validities. Concrete validity was established by correlating scores of EQ-5D quality of life scale and GMAS adherence score. Concurrent validity was established by correlating the GMAS adherence score with pill count. Analyses for sensitivity were also conducted. Cut-off value was determined through receiver operator curve (ROC), and test-retest method was used to analyze internal consistency and reliability. Data were analyzed through IBM SPSS, IBM AMOS, and MedCalc software. The Urdu version of EQ-5D quality of life questionnaire was used with permission from developers (#ID20884). The study was approved by an ethics committee (#NOV:15). RESULTS: A total of 351 responses were analyzed. The response rate was 98%. Reliability was in acceptable range, i.e., Cronbach α = 0.797. Factorial validity was established by calculation of satisfactory fit indices. Correlation coefficients for concrete and concurrent validities were ρ = 0.687, p < 0.01 and ρ = 0.779, p < 0.01, respectively. Known group validity was established as significant association of adherence score with insurance and illness duration (p < 0.05) that were reported. Sensitivity of the scale was 94%. Most patients had high adherence (N = 159, 45.3%). CONCLUSION: The Urdu version of GMAS demonstrated adequate internal consistency and was validated. These results indicate that it is an appropriate tool to measure medication adherence in Pakistani patients with rheumatoid arthritis.
30677505 Translocation of dead or alive bacteria from mucosa to joints and epiphyseal bone-marrow: 2020 Jan The recent demonstration that DNA from several mucosal bacteria, including Prevotella spp, could be found in numerous tissues (mesenteric lymph nodes, spleen, serum, liver, lung, eye and ankle joints), either in HLA-B27 rats with or without arthritis, or control rats without HLA-B27, could be a revolution in our understanding of spondyloarthritis and close disorders, including rheumatoid arthritis. Indeed, similar translocations of dead or alive bacteria or fungi from mucosa to joints, could contribute to the onset and flares of inflammatory rheumatisms. This state of the art article addresses six questions revived by this finding: 1-How does this bacterial DNA or living bacteria traffic from mucosa to joints? 2-Can some mucosal bacteria remain alive in those tissues, including joints? 3-Could bacteria from the gut microbiota ('self-bacteria') protect the host cells from invasion by more pathogenic bacteria (like dog-shepherds protect from wolves)? 4-Does the composition of the joint or bone marrow microbiota depends on local metabolism, which might differ from gut metabolism? 5-Could bacterial antigens from mucosal microbiota be sufficient to trigger trained immunity of presenting cells in joints, or does such phenomenon (with lasting epigenetic changes of presenting cells) require intra-cellular infection of presenting cells or their ancestors? 6-In which subsets of cells could living bacteria preferentially persist for a long period in the joint area? Transient or dormant infections within bone-marrow mesenchymal stem cells leading to trained immunity of some of their daughter cells in joints or enthesis, lasting after clearance or the invader, is an attractive hypothesis to test.
33360828 DiR-labeled tolerogenic dendritic cells for targeted imaging in collagen- induced arthriti 2021 Feb Tolerogenic dendritic cells (tolDCs) are immunosuppressive cells and play an important role in rheumatoid arthritis (RA) as immunotherapeutic tools. We aimed to investigate whether allogeneic tolDCs (allo-tolDCs) and autologous tolDCs (auto-tolDCs) had long-time tolerogenic potential in vivo and improve arthritis in collagen-induced arthritis (CIA) rats. TolDCs were induced by NF-κB Decoy ODN, and loaded with Bovine Type II collagen (CII- loaded tolDCs) and identified by flow cytometry, and labeled with DiR and injected into CIA rats. The biodistribution of DiR-labeled tolDCs was monitored by IVIS imaging at different time points. Major organs were harvested and analyzed by ex-in vivo cell imaging. The tolDCs were successfully constructed, along with expressing low levels of CD80 and CD86 compared to DCs. The fluorescent signals of all DiR (+) groups were observed at least 25 days, and as long as 35 days. DiR (+) CII- loaded allo-and auto-tolDCs at post injection mainly distributed in the chest and abdomen and gradually moved to limb joints over time. The allo- and auto-tolDCs decreased the expression of IFN-γ and IL-2 in CIA rats with different severity compared to CIA rats without tolDCs treatment, while significantly increased the expression of IL-4 and IL-10. Additionally, these tolDCs ameliorated the ankle joints injury in CIA rats with different severity. The both allo- and auto-tolDCs showed long-time tolerogenic potential in vivo and ameliorated arthritis in CIA rats with different severity.