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ID PMID Title PublicationDate abstract
35245865 Disease status in human and experimental arthritis, and response to TNF blockade, is assoc 2022 Apr Splice variants of CD74 differentially modulate the activity of cathepsin L (CTSL). As CD74 and CTSL participate in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA), we determined whether splice variants of CD74 could be biomarkers of disease activity. Gene expression was measured in mice with collagen-induced arthritis using quantitative PCR (qPCR). In vitro studies using murine macrophage/DC-lineage cells determined the relative influence of macrophage phenotype on isoform expression and the potential to produce CTSL in response to TNF. CD74 splice variants were measured in human RA synovium and RA patients' monocytes. In arthritic mice, the expression of the p41 CD74 isoform was significantly higher in severely affected paws compared with unaffected paws or the paws of naïve mice; the p41 isoform significantly correlated with the expression of TNF in arthritic paws. Compared with M2-like macrophages, M1-like macrophages expressed increased levels of CD74 and had higher expression, secretion and activity of CTSL. RA patients that responded to TNF blockade had significantly higher expression levels of CD74 in circulating monocytes after treatment, compared with non-responders. The expression of the human CD74 isoform a was significantly higher in RA synovia, compared with osteoarthritis synovia, and was associated with CSTL enzymatic activity. This study is the first to demonstrate differential expression of the CD74 p41 isoform in an auto-immune disorder and in response to therapy. The differential expression of CD74 splice variants indicates an association, and potentially a mechanistic role, in the pathogenesis of RA.
34971867 STAT3/HIF-1α/fascin-1 axis promotes RA FLSs migration and invasion ability under hypoxia. 2022 Feb Rheumatoid arthritis (RA) synovium was identified as "tumor-like" tissues because of the hypoxic microenvironment, significant cell proliferation, and invasion phenotypes. It was reported that hypoxia promoted tumor aggressiveness via up-regulated expression of fascin-1 in cancer. However, the role of fascin-1 in RA synovial hyperplasia and joint injury progression remains unknown. In the current study, we first identified that both fascin-1 and HIF-1α were highly expressed in the RA synovium, in which they were widely colocalized, compared to osteoarthritis(OA). As well, levels of fascin-1 in RA fibroblast-like synoviocytes(FLSs) were found significantly higher than those in OA FLSs. Further, it was demonstrated that the mRNA and protein levels of fascin-1 in RA FLSs were up-regulated in hypoxia (3 % O(2)) and experimental hypoxia induced by cobalt chloride. Mechanistically, the HIF-1α-mediated hypoxia environment activated the gene expression of the fascin-1 protein, which in turn promoted the migration and invasion of RA FLSs. Accordingly, the restoration of FLSs migration and invasion was observed following siRNA-mediated silencing of fascin-1 and HIF-1α expression. Notably, under the experimental hypoxia, we found that the expression levels of fascin-1, HIF-1α, and p-STAT3 were increased in a time-dependent manner, and fascin-1and HIF-1α expressions were dependent on p-STAT3. Our results indicated that hypoxia-induced fascin-1 up-regulation promoted RA FLSs migration and invasion through the STAT3/HIF-1α/fascin-1 axis, which might represent a novel therapeutic target for the treatment of RA.
35614190 Pinolenic acid exhibits anti-inflammatory and anti-atherogenic effects in peripheral blood 2022 May 25 Pinolenic acid (PNLA), an omega-6 polyunsaturated fatty acid from pine nuts, has anti-inflammatory and anti-atherogenic effects. We aimed to investigate the direct anti-inflammatory effect and anti-atherogenic effects of PNLA on activated purified CD14 monocytes from peripheral blood of patients with rheumatoid arthritis (RA) in vitro. Flow cytometry was used to assess the proportions of CD14 monocytes expressing TNF-α, IL-6, IL-1β, and IL-8 in purified monocytes from patients with RA after lipopolysaccharide (LPS) stimulation with/without PNLA pre-treatment. The whole genomic transcriptome (WGT) profile of PNLA-treated, and LPS-activated monocytes from patients with active RA was investigated by RNA-sequencing. PNLA reduced percentage of monocytes expressing cytokines: TNF-α by 23% (p = 0.048), IL-6 by 25% (p = 0.011), IL-1β by 23% (p = 0.050), IL-8 by 20% (p = 0.066). Pathway analysis identified upstream activation of peroxisome proliferator-activated receptors (PPARs), sirtuin3, and let7 miRNA, and KLF15, which are anti-inflammatory and antioxidative. In contrast, DAP3, LIF and STAT3, which are involved in TNF-α, and IL-6 signal transduction, were inhibited. Canonical Pathway analysis showed that PNLA inhibited oxidative phosphorylation (p = 9.14E-09) and mitochondrial dysfunction (p = 4.18E-08), while the sirtuin (SIRTs) signalling pathway was activated (p = 8.89E-06) which interfere with the pathophysiological process of atherosclerosis. Many miRNAs were modulated by PNLA suggesting potential post-transcriptional regulation of metabolic and immune response that has not been described previously. Multiple miRNAs target pyruvate dehydrogenase kinase-4 (PDK4), single-immunoglobulin interleukin-1 receptor molecule (SIGIRR), mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) and acetyl-CoA acyltranferase2 (ACAA2); genes implicated in regulation of lipid and cell metabolism, inflammation, and mitochondrial dysfunction. PNLA has potential anti-atherogenic and immune-metabolic effects on monocytes that are pathogenic in RA and atherosclerosis. Dietary PNLA supplementation regulates key miRNAs that are involved in metabolic, mitochondrial, and inflammatory pathways.
35077015 Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiat 2022 Jun OBJECTIVE: Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysine-specific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis. METHODS: LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxia-inducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated. RESULTS: In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis. CONCLUSION: LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.
34397169 Predictors of Rheumatic Immune-Related Adverse Events and De Novo Inflammatory Arthritis A 2022 Mar OBJECTIVE: To identify predictors of rheumatic immune-related adverse events (irAEs) following immune checkpoint inhibitor (ICI) treatment for cancer. METHODS: We performed a case-control study to predict the occurrence of rheumatic irAEs in cancer patients who initiated ICI treatment at Mass General Brigham and the Dana-Farber Cancer Institute between 2011 and 2020. We screened for the presence of rheumatic irAEs by reviewing the medical records of patients evaluated by rheumatologists or those prescribed nonglucocorticoid immunomodulatory drugs after the time of ICI initiation (baseline). Review of medical records confirmed the presence of rheumatic irAEs and the indications necessitating immunomodulatory drug treatment. Controls were defined as patients who did not experience rheumatic irAEs, did not have preexisting rheumatic disease, did not have a clinical evaluation by a rheumatologist after ICI treatment, did not receive an immunomodulatory drug after ICI, did not receive systemic glucocorticoids after ICI, and survived at least 6 months after the initial ICI treatment. We used logistic regression to estimate the odds ratios (ORs) (with 95% confidence intervals [95% CIs]) for the risk of a rheumatic irAE in the presence of various baseline predictors. RESULTS: A total of 8,028 ICI recipients were identified (mean age 65.5 years, 43.1% female, 31.8% with lung cancer). After ICI initiation, 404 patients (5.0%) were evaluated by rheumatologists, and 475 patients (5.9%) received an immunomodulatory drug to treat any irAEs. There were 226 confirmed rheumatic irAE cases (2.8%) and 118 de novo inflammatory arthritis cases (1.5%). Rheumatic diseases (either preexisting rheumatic diseases or rheumatic irAEs) were a common indication for immunomodulatory drug use (27.9%). Baseline predictors of rheumatic irAEs included melanoma (multivariable OR 4.06 [95% CI 2.54-6.51]) and genitourinary (GU) cancer (OR 2.22 [95% CI 1.39-3.54]), both relative to patients with lung cancer; combination ICI treatment (OR 2.35 [95% CI 1.48-3.74]), relative to patients receiving programmed death 1 inhibitor monotherapy; autoimmune disease (OR 2.04 [95% CI 1.45-2.85]) and recent glucocorticoid use (OR 2.13 [95% CI 1.51-2.98]), relative to patients not receiving a glucocorticoid, compared to the 2,312 controls without rheumatic irAEs. Predictors of de novo inflammatory arthritis were similar to those of rheumatic irAEs. CONCLUSION: We identified novel predictors of rheumatic irAE development in cancer patients, including baseline presence of melanoma, baseline presence of GU tract cancer, preexisting autoimmune disease, receiving or having received combination ICI treatment, and receiving or having received glucocorticoids. The proportion of cancer patients experiencing rheumatic irAEs may be even higher than was reported in the present study, since we used stringent criteria to identify cases of rheumatic irAEs. Our findings could be used to identify cancer patients at risk of developing rheumatic irAEs and de novo inflammatory arthritis and may help further elucidate the pathogenesis of rheumatic irAEs in patients with cancer who are receiving ICI treatment.
35094004 Distal Renal Tubular Acidosis Associated with Autoimmune Diseases: Reports of 3 Cases and 2022 Jan 30 BACKGROUND Distal renal tubular acidosis (dRTA) is a defect in the urinary acidification process that limits the elimination of protons [H+] by alpha intercalated cells in the collecting tubules, with consequent metabolic acidosis with a normal plasma anion gap. The relationship between this tubulopathy and immune-mediated diseases like Sjögren syndrome, rheumatoid arthritis, autoimmune hepatitis, primary biliary cirrhosis, systemic lupus erythematosus, and thyroiditis is well known. Further, the pathophysiological mechanisms are diverse, but, unfortunately, many are not yet fully understood. We report 3 cases of dRTA in patients with different autoimmune diseases and review the pathophysiological mechanisms already described. CASE REPORT The first case involved a 29-year-old woman with autoimmune hepatitis. She had metabolic acidosis with persistent hypokalemia, and a kidney stone was also identified. The second case involved a 67-year-old woman diagnosed with rheumatoid arthritis. She had metabolic acidosis with hypokalemia. The third case involved a 30-year-old woman with Sjögren syndrome and persistent metabolic acidosis. In addition to the presence of metabolic acidosis with a normal plasma anion gap, all 3 patients exhibited urine with a supraphysiologic pH (above 5.3). CONCLUSIONS Autoimmune diseases may be associated with deficits in urinary acidification with consequent metabolic acidosis and, therefore, systemic repercussions. This association must be remembered and researched because correct diagnosis and treatment will serve to reduce complications.
35175701 [Meloxicam clinical effects]. 2022 Pain syndromes, acute and chronic, against the background of inflammatory diseases (such as osteoarthritis (OA)), degenerative-dystrophic changes (involutive process, trauma) or systemic diseases (rheumatoid arthritis, etc.) dictate a steady increase in the intake of nonsteroidal anti-inflammatory drugs (NSAIDs). The choice of the most «safe NSAID» is based on the assessment of the toxicity index (the ratio when blocking cyclooxygenase (COX)) and the development of relative risks (the benefit/risk ratio). As well as those adverse events that can be detected with individual sensitivity to a specific NSAIDs, taking into account the anamnesis of previous diseases and intolerance to NSAIDs, existing chronic diseases (gastrointestinal tract, cardiovascular system, type 2 diabetes mellitus), limiting the appointment of NSAIDs. Considering these circumstances, the NSAID meloxicam (Amelotex) can be recommended for the treatment of various genesis pain syndromes. A number of studies have demonstrated the efficacy and safety of meloxicam with different methods of its administration (per oral (p/o), intramuscularly (i/m)) in the treatment of pain syndrome in the lower back, with OA, etc. Recent studies concern intravenous (i/v) meloxicam (30 mg) administration with moderate and severe postoperative pain syndrome. Today, the most commonly pain therapy scheme using meloxicam includes step-by-step administration of injectable and oral forms: meloxicam i/m (1.5 ml) for 3-5 days, followed by a transition to p/o (7.5-15 mg) intake for 14 days, or complex therapy with meloxicam (Amelotex), with muscle relaxant and B vitamins.
35255954 Single-cell transcriptomics of popliteal lymphatic vessels and peripheral veins reveals al 2022 Mar 7 BACKGROUND: Lymphatic dysfunction exists in tumor necrosis factor transgenic (TNF-Tg) mice and rheumatoid arthritis (RA) patients. While joint-draining TNF-Tg popliteal lymphatic vessels (PLVs) have deficits in contractility during end-stage arthritis, the nature of lymphatic muscle cells (LMCs) and their TNF-altered transcriptome remain unknown. Thus, we performed single-cell RNA-sequencing (scRNAseq) on TNF-Tg LMCs in PLVs efferent to inflamed joints versus wild-type (WT) controls. METHODS: Single-cell suspensions of PLVs were sorted for smooth muscle cells (SMCs), which was validated by Cspg4-Cre;tdTomato reporter gene expression. Single-cell RNA-seq was performed on a 10x Genomics platform and analyzed using the Seurat R package. Uniform Manifold Approximation and Projections (UMAPs) and Ingenuity Pathway Analysis software were used to assess cell clusters and functional genomics in WT vs. TNF-Tg populations. RESULTS: Fluorescent imaging of Cspg4-Cre;tdTomato vessels demonstrated dim PLVs and strong reporter gene expression in the adjacent superficial saphenous vein, which was corroborated by flow cytometry of LMCs and vascular smooth muscle cells (VSMCs) from these vessels. Due to their unique morphology, these populations could also be readily detected by scatter analysis of cells from non-fluorescent mice. Bioinformatics analysis of flow sorted WT and TNF-Tg cells identified 20 unique cell clusters that together were 22.4% LMCs, 15.0% VSMCs, and 62.6% non-muscle cells of 8879 total cells. LMCs and M2-macrophages were decreased, while inflammatory monocytes were increased in TNF-Tg lower limb vasculature. SMC populations were defined by Cald1, Tpm1, and Pdgfrb expression and were enriched in myofibroblast-like gene expression. TNF-Tg LMCs exhibited enhanced functional genomics associated with cell death, phagocyte recruitment, and joint inflammation. Among the most prominent TNF-induced genes in SMCs were Mmp3, Cxcl12, and Ccl19, and the most downregulated genes were Zbtb16, Galnt15, and Apod. CONCLUSIONS: Single-cell RNA-seq can be used to investigate functional genomics of lower limb vasculature in mice. Our findings confirm the inflammatory transcriptome of TNF-Tg vessels and altered gene expression in SMC populations. This study further supports a potential role of mesenchymal stromal cells in inflammatory-erosive arthritis pathogenesis, and warrants future studies to define the effects of this TNF-altered transcriptome on PLV function and joint homeostasis.
35254128 Interleukin-17 Contributes to Chikungunya Virus-Induced Disease. 2022 Apr 26 Alphaviral arthritides caused by mosquito-borne arboviruses such as chikungunya virus (CHIKV) can persist for months after the initial acute disease. Here, we investigated the contribution of interleukin-17 (IL-17), a cytokine involved in chronic autoimmune arthropathies such as rheumatoid arthritis, to the development of alphaviral arthropathy. Sera from CHIKV-infected patients who displayed both acute and chronic disease showed high levels of IL-17, IL-6, IL-21, IL-22, and IL-23, especially during the chronic phase of disease. We sought to validate these findings using a mouse model of CHIKV infection and disease using wild-type and IL-17A-deficient mice. Mice were infected with CHIKV, and joint and muscle tissues were harvested at designated time points. Tissue infiltrates were examined by immunohistochemistry, and tissue mRNA and protein expression of cytokines was assessed. Joint and muscle pathology was assessed using histology. CHIKV-infected mice lacking IL-17A showed reduced tissue inflammation and neutrophil infiltration, compared to wild-type mice. These investigations showed a role for IL-17 in the acute phase of CHIKV infection and also during the postacute disease resolution phase. IMPORTANCE CHIKV has been prevalent in Africa, Asia, and the Indian Ocean Islands for decades. There are currently no clinically approved vaccines or specific antiviral drugs targeting CHIKV. The upregulation of IL-17 detected in CHIKV disease patients and the reduced disease seen in IL-17-deficient mice suggest a correlation between IL-17 signaling pathways and CHIKV-induced arthritic inflammation. With an established role in contributing to the pathogenesis of immune-mediated diseases, such as psoriatic arthritis and rheumatoid arthritis, IL-17 signaling plays an important role in alphavirus arthritides.
31994915 Inhibition of glycogen synthase kinase-3β protects against collagen type II-induced arthr 2022 Jun MicroRNAs have been implicated in the pathogenesis of rheumatoid arthritis (RA) and their syntheses are modulated by glycogen synthase kinase-3β (GSK-3β). Therefore, we hypothesised that the GSK-3β inhibitor, TDZD-8 can protect against collagen-induced arthritis (CIA) via downregulating miR155 and miR-24 expression. Rats were randomly allocated into four groups (n = 6) as follows: Control, Control + TDZD-8 (1 mg/kg), CIA, and CIA + TDZD-8. Rats were sacrificed after 6 weeks. We observed in the model group (CIA) significant (p<.05) increase in arthritis score and serum levels of RA biomarkers, which were significantly (p < .05) inhibited by TDZD-8. TDZD-8 also significantly (p<.05) inhibited CIA-induced synovial tissue levels of miR155, miR-24, and inflammation. In addition, a significant (p<.05) modulation of biomarkers of survival (Bcl-2) and apoptosis (cleaved caspase-3) by TDZD-8 was observed. Thus, TDZD-8 protects against CIA in rats for a period of 6 weeks, which is associated with the inhibition of miR155/24 and inflammation, and apoptosis augmentation.
34798945 Cardiovascular Health in Pediatric Rheumatologic Diseases. 2022 Feb Cardiovascular disease risk is evident during childhood for patients with juvenile systemic lupus erythematosus, juvenile dermatomyositis, and juvenile idiopathic arthritis. The American Heart Association defines cardiovascular health as a positive health construct reflecting the sum of protective factors against cardiovascular disease. Disease-related factors such as chronic inflammation and endothelial dysfunction increase cardiovascular disease risk directly and through bidirectional relationships with poor cardiovascular health factors. Pharmacologic and nonpharmacologic interventions to improve cardiovascular health and long-term cardiovascular outcomes in children with rheumatic disease are needed.
34838728 Crystallographic landscape provides molecular insights into the modes of action of diverse 2022 Feb ROR-γt, the master regulator of Th-17 cells, is activated by the binding of small molecules at its orthosteric site, followed by the recruitment of co-activators or co-repressors in the ligand binding domain (LBD). Th-17 cells provide immune-dependent protection against cancers and pathogens. Their dysregulation causes inflammation and is therefore implicated in various autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and psoriasis. Consequently, there is enormous interest in the development of ROR-γt modulators, both agonist and inverse-agonists. Here, we review advances in the development of ROR-γt modulators that have been made over the past decade, focusing on the rich crystallography landscape for ROR-γt co-crystals that has delineated the relationship between the binding patterns of modulators and the resulting biological activities.
35450396 The Impact of Curcumin on the Inflammatory Profile of SW982 Cells in a Rheumatoid Arthriti 2022 Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases, affecting approximately 1% of the total global population. Curcumin, a natural polyphenol is a substance that could potentially mitigate the course of this disease. To evaluate curcumin's anti-inflammatory impact on synoviocytes in the RA model, a set of experiments was conducted on SW982 cells, stimulated by IL-1β, IL-6, or TNF-α to emulate inflammation. During the research, the curcumin effect was evaluated by measuring cell survivability, expression of MMP1 gene, subcellular localization of P70S6K1 protein, and its phosphorylated form and amount of produced IL-6 and TNF-α. Results of conducted experiments presented a positive impact of curcumin on synoviocytes in the RA model, by reducing SW982 cells' survivability, decreasing levels of MMP1 gene expression and TNF-α protein production, which altogether confirm beneficial effects of the curcumin therapy in a RA in vitro model.
35007215 Sex Differences in End-Stage Ankle Arthritis and Following Total Ankle Replacement or Ankl 2022 Feb 2 BACKGROUND: We investigated the influence of sex on patient-reported outcomes preoperatively and following total ankle replacement and ankle arthrodesis. METHODS: Patients who had undergone total ankle replacement or ankle arthrodesis for the treatment of end-stage ankle arthritis and who had ≥2 years of follow-up were identified from the Canadian Orthopaedic Foot and Ankle Society Prospective Ankle Reconstruction Database. Standard surgical techniques and implantation methods were followed, and STAR, Hintegra, Mobility, and Agility prostheses were used. Data were collected on patient demographics, revisions, secondary procedures, complications, Ankle Osteoarthritis Scale (AOS) scores, Short Form-36 (SF-36) scores, and expectations and satisfaction. Statistical analyses included 3-way repeated-measures analysis of variance (ANOVA) and multiple linear regression models controlling for inflammatory arthritis, age, preoperative scores, and surgery type. RESULTS: The study included 872 patients: 629 who had undergone total ankle replacement (316 men, 313 women) and 243 who had undergone ankle arthrodesis (154 men, 89 women). The mean duration of follow-up (and standard deviation) was 4.9 ± 2.4 and 4.0 ± 1.9 years for the total ankle replacement and ankle arthrodesis groups, respectively. Men were older than women (p ≤ 0.001). In both the total ankle replacement and ankle arthrodesis groups, women had higher AOS pain scores (i.e., more pain) than men preoperatively (p < 0.05). Pain was reduced significantly in both sexes postoperatively (p < 0.05), with no significant difference between sexes. In both the total ankle replacement and ankle arthrodesis groups, women had higher AOS disability scores (i.e., more disability) and lower SF-36 Physical Component Summary (PCS) scores (i.e., worse function) than men both preoperatively and postoperatively (p < 0.001). Postoperatively, AOS disability and SF-36 PCS scores improved significantly from baseline in both sexes (p < 0.001). After controlling for covariates, sex was not a significant predictor of postoperative SF-36 MCS (Mental Component Summary), AOS pain, or AOS disability scores (p > 0.05) but explained 0.5% of variance in SF-36 PCS scores (p = 0.03). Sex did not significantly influence preoperative expectations or postoperative satisfaction. When patients with inflammatory arthritis were excluded, preoperative and postoperative outcome measures, expectations, and satisfaction were similar. CONCLUSIONS: Men and women with end-stage ankle arthritis benefited from total ankle replacement and ankle arthrodesis with similar magnitudes of improvement. Small differences in pain and function between men and women undergoing total ankle replacement and ankle arthrodesis mostly disappeared when controlling for potential confounding variables. Both total ankle replacement and ankle arthrodesis remain good options for men and women with end-stage ankle arthritis. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
35197330 A Pathogenic Th17/CD38(+) Macrophage Feedback Loop Drives Inflammatory Arthritis through T 2022 Mar 15 The pathobiology of rheumatoid inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis, involves the interplay between innate and adaptive immune components and resident synoviocytes. Single-cell analyses of patient samples and relevant mouse models have characterized many cellular subsets in RA. However, the impact of interactions between cell types is not fully understood. In this study, we temporally profiled murine arthritic synovial isolates at the single-cell level to identify perturbations similar to those found in human RA. Notably, murine macrophage subtypes like those found in RA patients were expanded in arthritis and linked to promoting the function of Th17 cells in the joint. In vitro experiments identified a capacity for murine macrophages to maintain the functionality and expansion of Th17 cells. Reciprocally, murine Th17 cell-derived TNF-α induced CD38(+) macrophages that enhanced Th17 functionality. Murine synovial CD38(+) macrophages were expanded during arthritis, and their depletion or blockade via TNF-α neutralization alleviated disease while reducing IL-17A-producing cells. These findings identify a cellular feedback loop that promotes Th17 cell pathogenicity through TNF-α to drive inflammatory arthritis.
35514962 B Cell Characteristics at Baseline Predict Vaccination Response in RTX Treated Patients. 2022 BACKGROUND: Vaccination is considered as most efficient strategy in controlling SARS-CoV-2 pandemic spread. Nevertheless, patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) are at increased risk to fail humoral and cellular responses upon vaccination. The ability to predict vaccination responses is essential to guide adequate safety and optimal protection in these patients. METHODS: B- and T- cell data before vaccination were evaluated for characteristics predicting vaccine responses in altogether 15 patients with autoimmune inflammatory rheumatic diseases receiving RTX. Eleven patients with rheumatoid arthritis (RA) on other therapies, 11 kidney transplant recipients (KTR) on regular immunosuppression and 15 healthy controls (HC) served as controls. A multidimensional analysis of B cell subsets via UMAP algorithm and a correlation matrix were performed in order to identify predictive markers of response in patients under RTX therapy. RESULTS: Significant differences regarding absolute B cell counts and specific subset distribution pattern between the groups were identified at baseline. In this context, the majority of B cells from vaccination responders of the RTX group (RTX IgG+) were naïve and transitional B cells, whereas vaccination non-responders (RTX IgG-) carried preferentially plasmablasts and double negative (CD27-IgD-) B cells. Moreover, there was a positive correlation between neutralizing antibodies and B cells expressing HLA-DR and CXCR5 as well as an inverse correlation with CD95 expression and CD21low expression by B cells among vaccination responders. SUMMARY: Substantial repopulation of the naïve B cell compartment after RTX therapy appeared to be essential for an adequate vaccination response, which seem to require the additional capability of antigen presentation and germinal center formation. Moreover, expression of exhaustion markers represent negative predictors of vaccination responses.
34051316 Diagnosing muscle disease in a cohort of classic dermatomyositis patients seen at a rheuma 2022 Mar BACKGROUND: Existing criteria to improve the probability of capturing dermatomyositis (DM) include muscle biopsy but little is known about whether less invasive diagnostic procedures may be just as useful. OBJECTIVE: We aimed to determine whether skin biopsy, electromyography, or magnetic resonance imaging of the involved muscle could be done in lieu of muscle biopsy. METHODS: Two hundred and seventy-five patients were reviewed to investigate the presence of cutaneous and muscle disease, their timing in relation to diagnosis, and results of skin biopsies, muscle biopsies, magnetic resonance imaging, and electromyography. RESULTS: Of the cases with findings consistent with DM on muscle biopsy, 65% were in agreement with diagnostic features on electromyography or magnetic resonance imaging. Results of skin and muscle biopsies supported DM in 67% of patients who underwent both procedures. LIMITATIONS: A limited number of patients had muscle biopsies. CONCLUSION: In the presence of DM-specific skin findings, less invasive procedures may be sufficient to diagnose DM and guide its management.
35364376 The enhanced mitochondrial dysfunction by cantleyoside confines inflammatory response and 2022 May OBJECTIVE: Cantleyoside (CA) is a kind of iridoid glycosides in Pterocephalus hookeri (C. B. Clarke) Höeck. The purpose of this study was to investigate the effects of CA on human rheumatoid arthritis fibroblast synovial cells (HFLS-RA). METHODS: Cell proliferation of HFLS-RA was assessed by CCK-8. ELISA was used to detect cytokines NO, TNF-α, IL-1β/6, MCP-1, MMP-1/3/9 and metabolism-related ATPase activities and ATP levels. JC-1, DCFH-DA, Fluo-3 AM and Calcein AM probes were used to detect mitochondrial membrane potential (MMP), reactive oxygen species (ROS), Ca(2+) and mitochondrial permeability conversion pore (MPTP), respectively. Isolated mitochondria assay was used to detect mitochondrial swelling. Oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and real-time ATP production were measured using a Seahorse analyzer. Apoptosis was detected by TUNEL and Hoechst staining. Western blot was used to detect the expressions of AMPK/p-AMPK, Sirt 1, IκBα, NF-κB p65/p-NF-κB p65, Bcl-2 and Bax. Cytoplasmic nuclear isolation was also performed to detect the translocation of NF-κB. RESULTS: CA significantly suppressed cell proliferation and the levels of NO, TNF-α, IL-1β/6, MCP-1 and MMP-1/3/9 in HFLS-RA. In addition, CA promoted the apoptosis of HFLS-RA by increasing TUNEL and Hoechst positive cells and the ratio of Bax/Bcl-2. Inhibition of energy metabolism in HFLS-RA by CA reduced OCR, ECAR and real-time ATP generation rate. Importantly, CA promoted p-AMPK and Sirt 1 expression, inhibited IκBα degradation to reduce p-NF-κB and translocation. CONCLUSION: The results suggest that CA activates the AMPK/Sirt 1/NF-κB pathway by promoting mitochondrial dysfunction, thereby exerting anti-inflammatory and pro-apoptotic effects.
34264363 [Answering epidemiologic rheumatologic questions by cooperation with the large population- 2022 Mar This article presents how, based on the availability of new imaging methods and medications, objectives regarding the rheumatic disease axial spondyloarthritis (axSpA) have developed over the course of more than two decades into a rheumatologic research group. During recent years, cooperation with the Study of Health in Pomerania (SHIP) cohort has given rise to new fundamental aspects. This involved intensive cooperation between the Ruhr University Bochum (Rheumazentrum Ruhrgebiet) and the Greifswald University Hospital (Community Medicine research collective). The design of the SHIP cohort was published 10 years ago and the cohort approach presented in the Bundesgesundheitsblatt, which also described central methodologic questions in detail. In 2014, a cooperation project between the Ruhr Rheumatology Center/Ruhr University Bochum and the SHIP Department of Clinical and Epidemiologic Research (Klinisch-Epidemiologische Forschung, KEF; SHIP-KEF) was established, which has already resulted in publication of interesting results in high-ranking journals. In order to stress the potential of such corporations, important contents thereof are presented herein, with a focus on MRI and consideration of historical aspects.
35034001 COVID-19 Vaccination Uptake Among Individuals With Immune-mediated Inflammatory Diseases i 2022 May OBJECTIVE: We assessed coronavirus disease 2019 (COVID-19) vaccine uptake among individuals with immune-mediated inflammatory diseases (IMIDs) and the Ontario general population. METHODS: We studied all residents aged ≥ 16 years who were alive and enrolled in the Ontario Health Insurance Plan as of December 14, 2020, when vaccination commenced (n = 12,435,914). Individuals with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), psoriasis (PsO), and inflammatory bowel disease (IBD) were identified using established disease-specific case definitions applied to health administrative data. Vaccination status was extracted from the provincial COVaxON registry. Weekly cumulative proportions of first and second doses up until October 3, 2021, were expressed as the vaccinated percentage of each disease group, compared to the general Ontario population, and stratified by age. RESULTS: By October 3, 2021, the cumulative percentage with at least 1 dose was 82.1% for the general population, 88.9% for those with RA, 87.4% for AS, 90.6% for PsA, 87.3% for PsO, and 87.0% for IBD. There was also a higher total cumulative percentage with 2 doses among IMIDs (83.8-88.2%) vs the general population (77.9%). The difference was also evident when stratifying by age. Individuals with IMIDs in the youngest age group initially had earlier uptake than the general population but remain the lowest age group with 2 doses (70.6% in the general population vs. 73.7-79.2% across IMID groups). CONCLUSION: While implementation of COVID-19 vaccination programs has differed globally, these Canadian estimates are the first to reassuringly show higher COVID-19 vaccine uptake among individuals with IMIDs.