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ID PMID Title PublicationDate abstract
34700130 Nitidine chloride inhibits fibroblast like synoviocytes-mediated rheumatoid synovial infla 2021 Dec OBJECTIVE: Nitidine chloride (NC), a natural small molecular compound from traditional Chinese herbal medicine zanthoxylum nitidum, has been shown to exhibit anti-tumor effect. However, its role in autoimmune diseases such as rheumatoid arthritis (RA) is unknown. Here, we investigate the effect of NC in controlling fibroblast-like synoviocytes (FLS)-mediated synovial inflammation and joint destruction in RA and further explore its underlying mechanism(s). METHODS: FLSs were separated from synovial tissues obtained from patients with RA. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression was measured using quantitative RT-PCR. ELISA was used to measure the levels of cytokines and MMPs. Cell proliferation was detected using EdU incorporation. Migration and invasion were evaluated by Boyden chamber assay. RNA sequencing analysis was used to identify the target of NC. Collagen-induced arthritis (CIA) model was used to evaluate the in vivo effect of NC. RESULTS: NC treatment reduced the proliferation, migration, invasion, and lamellipodia formation but not apoptosis of RA FLSs. We also demonstrated the inhibitory effect of NC on TNF-α-induced expression and secretion of IL-6, IL-8, CCL-2, MMP-1 and MMP-13. Furthermore, we identified KCNH1, a gene that encodes ether-à-go-go-1 channel, as a novel targeting gene of NC in RA FLSs. KCNH1 expression was increased in FLSs and synovial tissues from patients with RA compared to healthy controls. KCNH1 knockdown or NC treatment decreased the TNF-α-induced phosphorylation of AKT. Interestingly, NC treatment ameliorated the severity of arthritis and reduced synovial KCNH1 expression in mice with CIA. CONCLUSIONS: Our data demonstrate that NC treatment inhibits aggressive and inflammatory actions of RA FLSs by targeting KCNH1 and sequential inhibition of AKT phosphorylation. Our findings suggest that NC might control FLS-mediated rheumatoid synovial inflammation and joint destruction, and be a novel therapeutic agent for RA.
32475196 Assessment of discordance of treatment satisfaction between patients with rheumatoid arthr 2021 Mar OBJECTIVES: To assess discordance in overall treatment satisfaction between patients with rheumatoid arthritis (RA) and their physicians. METHODS: This was a multicenter, cross-sectional, observational study of patients with RA (in low disease activity or remission) and their board-certified treating physicians in Japan; 202 patient-physician pairs were analyzed. Treatment satisfaction and perceptions were assessed using a structured questionnaire. RESULTS: Using a two-level ('satisfied' or 'unsatisfied') assessment of satisfaction, 195 patients (96.5%) and 190 physicians (94.1%) answered 'satisfied' with a high level of concordance (184 pairs, 91.1%). Using a four-level assessment, the ratio of 'satisfied' to 'somewhat satisfied' was higher in patients (66.3%/30.2%) than physicians (43.6%/50.5%). Satisfaction with treatment outcomes (e.g. joint conditions, subjective symptoms) was generally high in patients and physicians; relatively less satisfaction was reported for medication cost, especially among patients. Shared treatment decision-making was reported in ≥96% of patient-physician pairs. The most common 'most important' treatment target differed between patients ('Have a social life without worrying about RA') and physicians ('Prevent joint damage, deformity, and joint swelling'). CONCLUSIONS: Treatment satisfaction and concordance were high between patients in low activity/remission and physicians. Some differences between patients and physicians were reported in satisfaction for specific treatment outcomes and important treatment targets.
33916798 Peripheral Blood from Rheumatoid Arthritis Patients Shows Decreased T(reg) CD25 Expression 2021 Apr 3 Rheumatoid arthritis (RA) is a common autoimmune disease characterized by immune cell infiltration of the synovium, leading to the loss of cartilage, bone, and joint function. Although regulatory T (T(reg)) cells are thought to modulate the initiation and progression of RA, a consensus has yet to be reached regarding the function and composition of T(reg) cells in RA patients. To address these discrepancies, we analyzed not only the total T(reg) frequency but also that of T(reg) subpopulations in the peripheral blood of RA patients and healthy controls by flow cytometry. We found that the total T(reg) population was not significantly different between RA and control subjects. However, the effector T(reg) cell subgroup, defined as CD45RA(-)CD25(hi), showed markedly decreased frequency in RA patients. In addition, the total T(reg) population from RA patients showed a significant decline in the expression of CD25. Both the naïve and effector T(reg) subgroups also showed marked reduction of CD25 expression in RA patients compared to controls. These data suggest that the decreased frequency of effector T(reg) cells and overall reduction of CD25 expression in T(reg) cells in the peripheral blood may be evidence of altered T(reg) homeostasis associated with RA pathogenesis.
33183071 Preclinical discovery and development of adalimumab for the treatment of rheumatoid arthri 2021 Mar Introduction: Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by progressive joint disorders with significant pain and stiffness. In the past, RA was a difficult -to-treat ailment, but nowadays with the advent of biologics and better treatment strategies, disease remission is an achievable goal. Tumor necrosis factor α (TNFα) inhibitors were the first category of biologics to emerge with adalimumab being the first fully human TNFα.Areas covered: the authors provide an overview of the historical events that led to the discovery of TNFα inhibitors and more specifically the drug adalimumab. Several key trials are presented regarding the safety of the drug as well as its successful journey, but there is also a narrative description of the drug's future after patent expiration.Expert opinion: Adalimumab is a fully human TNFα inhibitor with a fairly rapid onset of action. It has a generally good safety and efficacy profile. Clinicians must be aware of the possible side effects and treat them in a timely manner or discontinue the drug where appropriate. Due to the success of the bio-originator adalimumab, a multitude of biosimilars have emerged but not, thus far, for all of the indications of the bio-originator.
34529695 Platelet indices parameters in the new disease activity score of rheumatoid arthritis with 2021 BACKGROUND: Platelet indices (PIs) are platelet parameters that are correlated with platelet activity. Despite being widely available, inexpensive, and feasible; their use in clinical settings is limited. Recently, we developed a new score (EgyDAS), which relies on PIs and assesses disease activity in rheumatoid arthritis (RA). OBJECTIVES: This study explored the practicability and validity of EgyDAS in RA with ankle involvement, considering that ankle is neglected in the commonly used DAS28 score. METHODS: This comparative case-control study included 2-groups of RA patients, group1 (control): without and group 2: with ankle involvement. RESULTS: Ankle involvement in RA showed no gender or age differences, however, it was associated with higher platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet distribution width (PDW), visual analogue scale (VAS), tender joint count (TJC), and lower hemoglobin (Hb) and mean platelet volume (MPV). DAS28 categorized a higher proportion of patients to have high disease activity compared with EgyDAS; moreover, it did not detect those in remission in group 2 patients. Highly significant differences in the 2-scores were observed between the two groups. Further analyses revealed superiority of EgyDAS in assessing disease activity in group 2 patients. Finally, both scores were found correlated together in the study groups. CONCLUSIONS: Over or underestimation of RA disease activity could occur when using DAS28. PIs were found correlated with ankle involvement in RA. PIs and EgyDAS are the best tools to assess disease activity in RA patients with ankle involvement. However, the study recommended the use of both scores together.
33504535 Neglected Achilles tendon rupture associated with rheumatoid arthritis: a case report and 2021 Jan 27 We report a case about a 69-year-old man, suffering from rheumatoid arthritis, diagnosed with a neglected Achilles tendon rupture. Considering the large Achilles tendon gap and the bad quality of the autologous tendons caused by rheumatoid disease, a reconstruction using an Achilles tendon with calcaneus bone block allograft was performed, with excellent clinical and functional outcomes.
33645241 Statin use and mortality in rheumatoid arthritis: an incident user cohort study. 2021 Mar BACKGROUND: Patients with rheumatoid arthritis (RA) have higher rates of mortality attributed to the inflammatory nature and the associated burden of cardiovascular complications. Previous research indicates that treatment with statin therapy may play a role in reducing the mortality rate of RA patients, but similar evidence in U.S. patients is lacking. OBJECTIVE: To assess the association between statin use and overall mortality among RA patients in the United States. METHODS: A population-based study of RA patients with incident statin use was conducted. Patients aged ≥ 18 years with a diagnosis of RA between January 2007 and December 2015 were included and reviewed for the use of statin medication. Time stratified propensity score matching was used to adequately balance the comparison groups. Logistic regression and Cox proportional hazard models were used to estimate the association. RESULTS: 19,614 people fulfilled the inclusion criteria for the study out of which 2,089 were statin users. There were 1,883 statin users that were matched to 1,883 statin nonusers. Baseline characteristics were well balanced across the 2 groups after matching. The hazards ratio for all-cause mortality in patients with RA for statin users was 0.72 (95% CI = 0.56-0.91; P = 0.008) compared with statin nonusers. CONCLUSIONS: Compared with no use of statins, current statin use is associated with 28% lower risk of mortality in RA patients. Decision makers and providers should consider and support integration of these results into the current clinical guidelines for delivering quality health care to RA patients. DISCLOSURES: No outside funding supported this study. The authors received no financial support for the research, authorship, and/or publication of this article. The authors have no affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this manuscript.
33887899 Pro-angiogenic effect of exosomal microRNA-103a in mice with rheumatoid arthritis via the 2021 Mar Rheumatoid arthritis (RA) is characterized by inflammation of the synovial membrane, accompanied by hyperplasia and neo-angiogenesis, which promote local inflammation. Macrophage-derived exosomes have been reported to enhance inflammation and the immune response. In the present study, we identified a novel exosomal microRNA (miR)-103a, which aids in the regulation of inflammation and angiogenesis in mice with RA, and attempted to identify the underlying mechanism. Initially, a mouse model of RA was established. Thereafter, exosomes were isolated from macrophage RAW264.7 cells and evaluated through transmission electron microscopy and nanoparticle tracking analysis. After prediction and verification of the target genes of miR-103a, RT-qPCR was used to assess miR-103a and HNF4A expression in mice with RA. High expression of miR-103a and low expression of HNF4A were observed in mice with RA, thus, miR-103a was found to target and downregulate HNF4A. Exosomal miR-103a promoted inflammation and angiogenesis in mice with RA which was accompanied by an increase in the levels of factors associated with inflammation and angiogenesis. However, an opposite trend was observed upon HNF4A elevation. Exosomal miR-103a was also found to activate the JAK/STAT3 signaling pathway. In conclusion, exosomal miR-103a inhibited the expression of HNF4A to activate the JAK/STAT3 signaling pathway, thereby exacerbating RA in mice.
33272191 Development of (186/188)Re-Chitosan as an Effective Therapeutic Agent for Rheumatoid Arthr 2021 BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory chronic disease characterized by inflammation, pain, swelling and disability, and radiosynovectomy is one of the disease treatment lines. In this study, the possibility of providing rhenium-186/rhenium-188 chitosan radiopharmaceuticals, optimization of conditions for their production and bio-distribution are reported. OBJECTIVE: In order to build perrhenic acid for labeling, natural rhenium was exposed to radiation. Radionuclidic and radiochemical purities of (186/188Re)-NaReO4 were examined by gamma spectroscopy and paper chromatography methods, respectively. METHODS: Labeling of chitosan with rhenium was done in different acidic situations. The radiochemical purity 186/188Re-chitosan was applied by radio thin layer chromatography (RTLC). Lastly, the bio-distribution of the radiolabeled chitosan was studied in various organs after intra articular injection of the complex to lab rats. Gamma spectrometry confirmed the high rhenium radionuclidic purity. Chromatography results showed that perrhenic acid was produced with purity greater than 97% and rhenium chitosan labeling was done over 98% in pH = 3. Dissection results showed a high bio-distribution of 186/188Re-chitosan after injection into the joint with no leakage to surrounding organs. CONCLUSION: According to the results, there is a possibility of labeling rhenium with chitosan in very high radiochemical purity. Regarding the high retention of these radiopharmaceuticals in joints with no leakage to surrounding organs, 186/188Re-chitosan can be applied as new radiosynovectomy drugs for rheumatoid arthritis treatment.
32550719 Tocotrienol regulates osteoclastogenesis in rheumatoid arthritis. 2021 Mar BACKGROUND/AIMS: The present study aimed to investigate whether tocotrienol regulates interleukin 17 (IL-17)-induced osteoclastogenesis in rheumatoid arthritis (RA). METHODS: We evaluated the effect of tocotrienol on IL-17-induced receptor activator of nuclear factor kappa B ligand (RANKL) production using RA fibroblast-like synoviocyte (FLS), together with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Osteoclast differentiation was confirmed after culturing IL-17-treated RA FLS and Th17 cells with tocotrienol and monocytes. We analyzed the suppressive effect of tocotrienol on Th17 cells percentage or Th17-cytokine levels among peripheral blood mononuclear cells using flow cytometry. RESULTS: We found that IL-17 stimulated FLS to produce RANKL and tocotrienol decreased this IL-17-induced RANKL production. Tocotrienol decreased the IL-17-induced activation of mammalian target of rapamycin, extracellular signal-regulated kinase, and inhibitor of kappa B-alpha. When monocytes were incubated with IL-17, RANKL, IL-17-treated FLS or Th17 cells, osteoclasts were differentiated and tocotrienol decreased this osteoclast differentiation. Tocotrienol reduced Th17 cell differentiation and the production of IL-17 and sRANKL; however, tocotrienol did not affect Treg cell differentiation. CONCLUSION: Tocotrienol inhibited IL-17- activated RANKL production in RA FLS and IL-17-activated osteoclast formation. In addition, tocotrienol reduced Th17 differentiation. Therefore, tocotrienol could be a new therapeutic choice to treat bone destructive processes in RA.
33338916 A nuclear factor kappa B reporter cell line used to evaluate ex vivo the net inflammatory 2021 Feb BACKGROUND: The overall clinical outcome of inflammatory conditions is the result of the balance between pro-inflammatory and anti-inflammatory mediators. Because nuclear factor kappa B (NF-ĸB) is at the bottom of many inflammatory conditions, methods to evaluate the net effect of inflammation modulators on this master regulator have been conceptualized for years. METHODS: Using an ex vivo NF-ĸB reporter cell line-based assay, plasma samples of patients with rheumatoid arthritis (n = 27), psoriasis (n = 15), or severe coronavirus disease-19 (COVID-19) (n = 21) were investigated for NF-ĸB activation compared to plasma samples from 9 healthy volunteers. RESULTS: When separated by C-reactive protein (CRP) threshold levels, samples of patients exhibiting increased CRP levels (≥5 mg/l) activated NF-ĸB more efficiently than samples from patients with levels below 5 mg/l (P = 0.0001) or healthy controls (P = 0.04). Overall, there was a moderate association of CRP levels with NF-ĸB activation (Spearman r = 0.66; p < 0.0001). Plasma from COVID-19 patients activated NF-ĸB more efficiently (mean 2.4-fold compared to untreated reporter cells) than samples from any other condition (healthy controls, 1.8-fold, P = 0.0025; rheumatoid arthritis, 1.7-fold, P < 0.0001; psoriasis, 1.7-fold, P < 0.0001). In contrast, effects of rheumatoid arthritis, psoriasis, or healthy volunteer samples did not differ. CONCLUSION: This study shows that a NF-ĸB reporter cell line can be used to evaluate the net inflammatory effect of clinical plasma samples. Patients with chronic but stable rheumatoid arthritis or psoriasis do not exhibit increased plasma levels of NF-ĸB-activating compounds as opposed to COVID-19 patients with high inflammatory burden.
33338006 Methotrexate in Italian patients wiTh Rheumatoid Arthritis (MITRA study): an observational 2021 Sep OBJECTIVES: To assess the delay between the disease onset and the beginning of methotrexate (MTX) treatment in RA patients and to evaluate the Italian rheumatologists' adherence to the EULAR 2013 recommendations. METHODS: MITRA is an Italian multicentre observational study carried out on DMARD-naïve RA patients recruited in an 18-month period starting from 2015. The data related to the patients' characteristics at baseline will be presented. RESULTS: 332 patients from 13 Italian centres were recruited: the median delay between the onset of symptoms and the beginning of MTX was 197 days (102-431); in 20% of patients a treatment with DMARDs was started within the first 90 days from the onset of symptoms. The clinical target selected was DAS28 remission in 64.2% of cases and low disease activity in 35.8%. Among patients in DAS28 high disease activity, 92.6% received a control visit which was rescheduled within the first 3 months, similarly to those in DAS28 moderate disease activity (91.6%). A DMARD monotherapy was prescribed in 319 patients, while a combined therapy of DMARDs was preferred in 13 cases; 282 patients were treated with MTX. Glucocorticoids were prescribed in 229 patients: the median dosage was of 5 mg (IQR 5-7.5) of prednisone equivalent/day. CONCLUSIONS: Diagnostic delay in RA patients continues to be longer than expected. The choice of low disease activity as a target is still very frequent and tight control does not seem to be based on disease activity. This paper offers a realistic and detailed picture of the clinical practice among Italian rheumatologists.
34244381 Diabetes mellitus and cardiovascular risk management in patients with rheumatoid arthritis 2021 Jul AIM: The objective was to examine the prevalence of atherosclerotic cardiovascular disease (ASCVD) and its risk factors among patients with RA with diabetes mellitus (RA-DM) and patients with RA without diabetes mellitus (RAwoDM), and to evaluate lipid and blood pressure (BP) goal attainment in RA-DM and RAwoDM in primary and secondary prevention. METHODS: The cohort was derived from the Survey of Cardiovascular Disease Risk Factors in Patients with Rheumatoid Arthritis from 53 centres/19 countries/3 continents during 2014-2019. We evaluated the prevalence of cardiovascular disease (CVD) among RA-DM and RAwoDM. The study population was divided into those with and without ASCVD, and within these groups we compared risk factors and CVD preventive treatment between RA-DM and RAwoDM. RESULTS: The study population comprised of 10 543 patients with RA, of whom 1381 (13%) had DM. ASCVD was present in 26.7% in RA-DM compared with 11.6% RAwoDM (p<0.001). The proportion of patients with a diagnosis of hypertension, hyperlipidaemia and use of lipid-lowering or antihypertensive agents was higher among RA-DM than RAwoDM (p<0.001 for all). The majority of patients with ASCVD did not reach the lipid goal of low-density lipoprotein cholesterol <1.8 mmol/L. The lipid goal attainment was statistically and clinically significantly higher in RA-DM compared with RAwoDM both for patients with and without ASCVD. The systolic BP target of <140 mm Hg was reached by the majority of patients, and there were no statistically nor clinically significant differences in attainment of BP targets between RA-DM and RAwoDM. CONCLUSION: CVD preventive medication use and prevalence of ASCVD were higher in RA-DM than in RAwoDM, and lipid goals were also more frequently obtained in RA-DM. Lessons may be learnt from CVD prevention programmes in DM to clinically benefit patients with RA .
33562353 Dietary Quality Associated with Self-Reported Diabetes, Osteoarthritis, and Rheumatoid Art 2021 Feb 7 BACKGROUND: To date, few studies have compared the dietary quality of US adults with diabetes mellitus (DM), osteoarthritis (OA), and rheumatoid arthritis (RA) by age groups. METHODS: This study used cross-sectional data from adult participants from National Health and Nutrition Examination Survey 2011-2016 to identify dietary quality measured by Healthy Eating Index (HEI)-2015 total and component scores and self-reported disease status for DM, OA, and RA. Associations between the disease status and HEI-2015 total/component scores among younger adults aged 20-59 years (n = 7988) and older adults aged 60 years and older (n = 3780) were examined using logistic regression models. These accounted for the complex survey design and were adjusted for self-reported disease status, sex, race/ethnicity, education levels, income status, weight status, physical activity levels, and smoking status. RESULTS: Among younger adults, 7% had DM, 7% had OA, and 3% had RA. Among older adults, 20% had DM, 32% had OA, and 6% had RA. Moderate added sugar intake was associated with diabetes in all adults. Excess sodium intake was associated with DM among younger adults. Inadequate seafood and plant protein intake was associated with RA among younger adults, while a poor overall dietary pattern was associated with RA among older adults. CONCLUSIONS: The dietary quality of US adults varied by self-reported DM, OA, and RA status, and each varied by age group.
33269650 Triple osteotomy for erosive first metatarsal in a patient with rheumatoid arthritis: a ca 2021 Jan Recently, over the half of the patients with rheumatoid arthritis achieved clinical remission with beneficial effects of disease modifying anti-rheumatic drugs, including biological disease modifying anti-rheumatic drugs. Because the patients in remission should have no/reduced progression of joint damage, there is a trend towards joint-preserving surgery in the treatment of rheumatoid forefoot deformities. Here we report a 76-year-old woman with rheumatoid arthritis developed a severe forefoot deformity including a large bony erosion of the first metatarsal head. She showed near remission for rheumatoid arthritis without having clinically active synovitis in her MTP joints. To preserving her metatarsophalangeal joint, a double first metatarsal osteotomy was planned to remove the bony erosion and simultaneously correct the hallux valgus. Thirty-month follow-up demonstrated excellent radiographical and patient-reported outcomes. To the best of our knowledge, this is the first case of a double first metatarsal osteotomy to remove the bony erosion and simultaneously correct the hallux valgus in a patient with rheumatoid arthritis with a large erosion of the first metatarsal head.
32353185 Factors Associated With Time to Pregnancy in Women With Axial Spondyloarthritis: A Registr 2021 Aug OBJECTIVE: The present study was undertaken to study time to pregnancy (TTP) and factors associated with TTP in women with axial spondyloarthritis (SpA) compared to women with rheumatoid arthritis (RA). METHODS: We included 274 women with axial SpA and 317 women with RA from the Norwegian nationwide registry RevNatus. For all the women, we had retrospectively collected data on TTP, and a subgroup also had prospectively collected data. We compared TTP in women with axial SpA to women with RA using Kaplan-Meier plots and a log rank test. To identify factors associated with TTP, we used Cox proportional hazards regression. RESULTS: TTP exceeded 12 months in 21% of women with axial SpA. In the subgroup followed prospectively, 32% had TTP that exceeded 12 months. Longer TTP was associated with older age, nulliparity, and longer disease duration, with hazard ratios of 0.97 (95% confidence interval [95% CI] 0.94-1.00), 0.66 (95% CI 0.50-0.88), and 0.94 (95% CI 0.91-0.98), respectively. Disease activity, medication, and self-reported health-related quality of life were not associated with TTP. We found no statistically significant differences between axial SpA and RA in regard to TTP. CONCLUSION: In women with axial SpA, longer TTP was associated with older age, nulliparity, and longer disease duration.
33844458 Nonserious Infections in Patients With Rheumatoid Arthritis: Results From the British Soci 2021 Oct OBJECTIVE: To describe the frequency and predictors of nonserious infections (NSI) and compare incidence across biologic agents within the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA). METHODS: The BSRBR-RA is a prospective observational cohort study. An NSI was defined as an infection that did not require hospitalization or intravenous therapy. Infections were captured from clinician questionnaires and patient diaries. Individuals were considered "at risk" from the date of initiation of biologic treatment for up to 3 years. Drug exposure was defined by agent: tumor necrosis factor inhibitor (TNFi), interleukin-6 (IL-6) inhibitor, B cell depletion (rituximab), or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) alone. A multiple-failure Cox model was used with multivariable adjustment. Missing data were addressed using multiple imputation. RESULTS: There were 17,304 NSI in 8,145 patients, with an event rate of 27.0 per person per year (95% confidence interval [95% CI] 26.6-27.4). Increasing age, female sex, comorbidity burden, glucocorticoid therapy, higher Disease Activity Score in 28 joints, and higher Health Assessment Questionnaire disability index were associated with an increased risk of NSI. There was a significant reduction in NSI risk with csDMARDs compared to biologic treatments. Compared to TNFi, IL-6 inhibition and rituximab were associated with a higher NSI risk (adjusted hazard ratio 1.45 [95% CI 1.29-1.63] and adjusted hazard ratio 1.28 [95% CI 1.14-1.45], respectively), while the csDMARD cohort had a lower risk (adjusted hazard ratio 0.64 [95% CI 0.59-0.70]). Within the TNFi class, adalimumab was associated with a higher NSI risk than etanercept (adjusted hazard ratio 1.11 [95% CI 1.05-1.17]). CONCLUSION: NSI occur frequently in RA, and predictors mirror those reported with serious infections. All biologics are associated with a greater risk of NSI, with differences observed between agents. While unmeasured confounding must be considered, the magnitude of effect is large, and a relationship between NSI and targeted immunomodulatory therapy likely exists.
34013458 Synergistic and receptor-mediated targeting of arthritic joints via intra-articular inject 2021 Dec Intra-articular drug delivery represents a tempting strategy for local treatment of rheumatoid arthritis. Targeting drugs to inflamed joints bypasses systemic-related side effects. Albeit, rapid drug clearance and short joint residence limit intra-articular administration. Herein, injectable smart hydrogels comprising free/nanoencapsulated leflunomide (LEF) were developed. Nanostructured lipid carriers (NLCs), 200-300 nm, were coated with either chondroitin sulfate (CHS), hyaluronic acid (HA), or chitosan (CS) to provide joint targetability. Coated NLCs were incorporated in either hyaluronic/pluronic (HP) or chitosan/β-glycerophosphate (CS/βGP) hydrogels. Optimized systems ensured convenient gelation time (14-100 s), injectability (5-15 s), formulation-dependent mechanical strength, and extended LEF release up to 51 days. In vivo intra-articular injection in induced arthritis rat model revealed that rats treated with HA-coated NLCs showed the fastest recovery. Histopathological examination demonstrated perfect joint healing in case of HA-coated LEF-NLCs in CS/βGP thermogel manifested as minor erosion of subchondral bone, improved intensity of extracellular matrix, cartilage thickness, and chondrocyte number. Both HA- and CHS-coated NLCs reduced TNF-α level 4-5-fold relative to positive control. The feat would be achieved via active targeting to CD44 receptors overexpressed in the articular tissue, limiting chondrocyte apoptosis together with innate synergistic targetability by promoting chondrocyte proliferation and neovascularization, inhibiting the production of pro-inflammatory cytokines, thus enhancing cartilaginous tissue repair.
34036479 Interplay of Microbiota and Citrullination in the Immunopathogenesis of Rheumatoid Arthrit 2022 Feb Microbiota is a balanced ecosystem that has important functions to the host health including development, defense, digestion, and absorption of dietary fibers and minerals, vitamin synthesizes, protection, and training the host immune system. On the other hand, its dysbiosis is linked to many human diseases such as rheumatoid arthritis (RA). The RA is an inflammatory autoimmune disorder caused by genetic and environmental factors; microbiota may be considered as a risk environmental factor for it. Citrullination is a post-translation modification (PMT) that converts the amino acid arginine to amino acid citrulline in certain proteins. These citrullinated proteins are recognized as a foreign antigen by the immune system resulting in the upregulation of inflammatory action such as in RA. The current work highlights the effect of both gut and oral microbiota dysbiosis on the development of RA, as well as discusses how the alteration in microbiota composition leads to the overgrowth of some bacterial species that entangled in RA pathogenicity. The evidence suggested that some oral and gut microbial species such as Porphyromonas gingivalis and Prevotella copri, respectively, contribute to RA pathogenesis. During dysbiosis, these bacteria can mediate the citrullination of either human or bacteria proteins to trigger an immune response that leads to the generation of autoantibodies.
33307367 Metabolomic and transcriptomic analyses of the anti-rheumatoid arthritis potential of xylo 2021 Jan Xylopic acid (XA), a diterpene kaurene and the major active ingredient of the African spice Xylopia aethiopica (Annonaceae), is reported to possess anti-inflammatory and analgesic properties. Here, we investigated the therapeutic potential of XA for rheumatoid arthritis (RA), a debilitating autoimmune inflammatory disease characterized by joint damage, in the complete Freund's adjuvant (CFA)-induced arthritis model in rats. We synthesized bioinspired reconstituted high-density lipoprotein (rHDL) nanoparticles loaded with purified XA crystals (rHDL/XA) that passively accumulate in inflamed joints of CFA-induced arthritic rats. Treatment with rHDL/XA minimized mononuclear cell infiltration of CFA-induced arthritic sites and ameliorated disease burden. Metabolomic and transcriptomic analyses revealed that the major molecular pathways perturbed following CFA-induced arthritis correlated with amino acid and lipid metabolism, which were restored to normal states by rHDL/XA treatment. This work demonstrates the anti-RA potential of XA in a nanoformulation and uncovers its underlying therapeutic mechanisms at the transcript and metabolite levels.