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ID PMID Title PublicationDate abstract
33236554 A Study of the Efficacy and Safety of Subcutaneous Injections of Tocilizumab in Adults wit 2020 Sep BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.
30635658 Mother-child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythe 2020 Jan The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.
31965234 [Neurological symptoms in a patient on anti-TNF therapy, methotrexate and prednisolone fo 2020 Mar A 78-year-old woman with rheumatoid arthritis on TNF-α inhibitor, methotrexate and prednisolone presented with severe but unspecific symptoms such as leg weakness, shivering, bifrontal headache, nausea and staggering. The broad range of differential diagnoses lead to intricate and time-consuming diagnostic procedures. Serology, magnetic resonance imaging and microbiological investigations represent important steps to make the final diagnosis of cerebral toxoplasmosis. Both diagnostic approach and therapy require close cooperation of different disciplines. Therapies of rheumatoid arthritis as well as of toxoplasmosis are based on a long-term treatment and could be associated with numerous harmful side effects. Continuous monitoring and permanent adjustment of therapy regimes are therefore mandatory.
31948411 Prevalence and incidence of bronchiectasis in Italy. 2020 Jan 16 BACKGROUND: The understanding of the epidemiology of bronchiectasis is still affected by major limitations with very few data published worldwide. The aim of this study was to estimate the epidemiological burden of bronchiectasis in Italy in the adult population followed-up by primary care physicians. METHODS: This study analyzed data coming from a large primary care database with 1,054,376 subjects in the period of time 2002-2015. Patients with bronchiectasis were selected by the use of International Statistical Classification of Diseases, 9th revision, Clinical Modification codes (ICD-9-CM). RESULTS: Patients with bronchiectasis were more likely to have a history of tuberculosis (0.47% vs. 0.06%, p < 0.0001), had higher rates of asthma (16.6% vs. 6.2%, p < 0.0001), COPD (23.3% vs. 6.4%, p < 0.0001) and rheumatoid arthritis (1.9% vs. 0.8%, p < 0.0001). The prevalence and incidence of bronchiectasis in primary care in Italy in 2015 were 163 per 100,000 population and 16.3 per 100,000 person-years, respectively. Prevalence and incidence increased with age and overall rates were highest in men over 75 years old. Prevalence and incidence computed after the exclusion of patients with a diagnosis of either asthma or COPD is 130 per 100,000 and 11.1 cases per 100,000 person-years, respectively. CONCLUSIONS: Bronchiectasis is not a rare condition in Italian adult population. Further studies are needed to confirm our results and provide a better insight on etiology of bronchiectasis in Italy. TRIAL REGISTRATION: not applicable.
31937287 Effectiveness of distal tibial osteotomy with distraction arthroplasty in varus ankle oste 2020 Jan 14 BACKGROUND: In highly active older individuals, end-stage ankle osteoarthritis has traditionally been treated using tibiotalar arthrodesis, which provides considerable pain relief. However, there is a loss of ankle joint movement and a risk of future arthrosis in the adjacent joints. Distraction arthroplasty is a simple method that allows joint cartilage repair; however, the results are currently mixed, with some reports showing improved pain scores and others showing no improvement. Distal tibial osteotomy (DTO) without fibular osteotomy is a type of joint preservation surgery that has garnered attention in recent years. However, to our knowledge, there are no reports on DTO with joint distraction using a circular external fixator. Therefore, the purpose of this study was to examine the effect of DTO with joint distraction using a circular external fixator for treating ankle osteoarthritis. METHODS: A total of 21 patients with medial ankle arthritis were examined. Arthroscopic synovectomy and a microfracture procedure were performed, followed by angled osteotomy and correction of the distal tibia; the ankle joint was then stabilized after its condition improved. An external fixator was used in all patients, and joint distraction of approximately 5.8 mm was performed. All patients were allowed full weight-bearing walking immediately after surgery. RESULTS: The anteroposterior and lateral mortise angle during weight-bearing, talar tilt angle, and anterior translation of the talus on ankle stress radiography were improved significantly (P < 0.05). Signal changes on magnetic resonance imaging also improved in all patients. Visual analog scale and American Orthopedic Foot & Ankle Society scores improved significantly (P < 0.05), and no severe complications were observed. CONCLUSION: DTO with joint distraction may be useful as a joint-preserving surgery for medial ankle osteoarthritis in older patients with high levels of physical activity. LEVEL OF EVIDENCE: Level IV, retrospective case series.
32561292 Role of JAK-STAT signaling in the pathogenic behavior of fibroblast-like synoviocytes in r 2020 Sep 5 Rheumatoid arthritis (RA) fibroblast-like synoviocytes (RA-FLS) play a crucial role in the pathogenesis of RA. RA-FLS display passive pro-inflammatory responses and self-directed aggressive responses, such as pro-inflammatory mediator production, reduced apoptosis and formation of a thickened synovial lining. Evidence suggests a role for Janus kinase (JAK)-signal transducer and transcriptional activator (STAT) signaling in the passive response but the aggressive behavior of RA-FLS is poorly understood. The pharmacologic effects of the novel JAK inhibitor, peficitinib, on cytokine-induced intracellular signaling and self-directed aggressive behavior of RA-FLS (e.g., increased expression of apoptosis-resistant genes and sodium nitroprusside-induced apoptosis) were investigated and compared with approved JAK inhibitors. RA-FLS assembly to form a lining-like structure and pro-inflammatory mediator production was investigated in three-dimensional (3D)-micromass culture. Peficitinib inhibited STAT3 phosphorylation in RA-FLS following induction by interferon (IFN)-α2b, IFN-γ, interleukin (IL)-6, oncostatin M, and leukemia inhibitory factor in a concentration-related manner, and was comparable to approved JAK inhibitors, tofacitinib and baricitinib. Peficitinib and tofacitinib suppressed autocrine phosphorylation of STAT3 and expression of apoptosis-resistant genes, and promoted cell death. In 3D-micromass culture, peficitinib reduced multi-layered RA-FLS cells to a thin monolayer, an effect less pronounced with tofacitinib. Both compounds attenuated production of vascular endothelial growth factor-A, matrix metalloproteinases, IL-6 and tumor necrosis factor superfamily-11. This study confirmed the pathogenic role of uncontrolled JAK-STAT signaling in the aggressive and passive responses of RA-FLS that are critical for RA progression. The novel JAK inhibitor peficitinib suppressed the pro-inflammatory behavior of RA-FLS, accelerated cell death and abrogated thickening of the synovium.
32598086 A77 1726, the active metabolite of the anti-rheumatoid arthritis drug leflunomide, inhibit 2020 Aug The newly reassorted IAV subtypes from zoonotic reservoirs respond poorly to current vaccines and antiviral therapy. There is an unmet need in developing novel antiviral drugs for better control of IAV infection. The cellular factors that are crucial for virus replication have been sought as novel molecular targets for antiviral therapy. Recent studies have shown that Janus kinases (JAK), JAK1, and JAK2, play an important role in IAV replication. Leflunomide is an anti-inflammatory drug primarily used for treating rheumatoid arthritis (RA). Prior studies suggest that A77 1726, the active metabolite of leflunomide, inhibits the activity of JAK1 and JAK3. Our current study aims to determine if A77 1726 can function as a JAK inhibitor to control IAV infection. Here, we report that A77 1726 inhibited the replication of three IAV subtypes（H5N1, H1N1, H9N2）in three cell types (chicken embryonic fibroblasts, A549, and MDCK). A77 1726 inhibited JAK1, JAK2, and STAT3 tyrosine phosphorylation. Similar observations were made with Ruxolitinib (Rux), a JAK-specific inhibitor. JAK2 overexpression enhanced H5N1 virus replication and compromised the antiviral activity of A77 1726. Leflunomide inhibited virus replication in the lungs of IAV-infected mice, alleviated their body weight loss, and prolonged their survival. Our study demonstrates for the first time the ability of A77 1726 to inhibit JAK2 activity and suggests that inhibition of JAK activity contributes to its antiviral activity.
31689108 Bioisosteric Development of Multitarget Nonsteroidal Anti-Inflammatory Drug-Carbonic Anhyd 2020 Mar 12 Multitarget nonsteroidal anti-inflammatory drug (NSAID)-carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending on the NSAID portion. A selection of derivatives were assayed in vitro to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated that the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative (5c) showed major antihyperalgesic action compared with the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multitarget compounds, which induce markedly improved pain relief compared with the parent NSAIDs.
32866644 Up-regulated DERL3 in fibroblast-like synoviocytes exacerbates inflammation of rheumatoid 2020 Nov Endoplasmic reticulum (ER) stress associated proteins contribute to the pathogenesis of rheumatoid arthritis (RA) through affecting synoviocyte proliferation and proinflammatory cytokine production. The role of DERL3, an ER-associated degradation component, in joint inflammation of RA was explored. Synovial tissues from RA and osteoarthritis (OA) patients were collected, and in RA synovial tissue, DERL3 showed up-regulation and significantly positive correlation with the expression of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-1. Immunofluorescence result suggested DERL3 was located in fibroblast-like synoviocytes (FLS). Among different inflammatory stimuli, DERL3 could be up-regulated by TNF-α stimulation in FLS. Under TNF-α stimulation, knocking down DERL3, the expression of IL-6, IL-8, MMP-1, MMP-13 was reduced and the activation of nuclear factor kappa B (NF-κB) signaling pathway was inhibited. In pristane-induced arthritis (PIA) rat model, Derl3 was up-regulated in synovial tissue and disease was attenuated after intraarticular injection of siDerl3. Overall, we conclude that TNF-α inducing DERL3 expression promotes the inflammation of FLS through activation of NF-κB signaling pathway, suggesting DERL3 plays important roles in the pathogenesis of RA and is a promising therapeutic target.
33013198 Increased Serum Interleukin-2 Levels Are Associated with Abnormal Peripheral Blood Natural 2020 OBJECTIVE: To investigate the relationship between serum interleukin-2 (IL-2) levels and disease activity, absolute numbers of peripheral lymphocyte subsets, autoantibodies, and associated cytokines in patients with rheumatoid arthritis (RA). METHODS: This study included 106 patients with RA, evaluated their disease activity (DAS28 score), and divided them into disease remission (DAS28 ≤ 2.6), low disease activity (DAS28 ≤ 3.2), and moderate-high disease activity (DAS28 > 3.2) groups. Flow cytometry was used to detect the absolute numbers of peripheral lymphocyte subpopulations and CD4+ T cell subsets in each group, and serum cytokine levels were measured using cytometric bead array. RESULTS: Serum IL-2 levels in RA patients were positively correlated with disease activity and rheumatoid factor titers (p < 0.001 and p = 0.045, respectively), and multiple regression analysis revealed that serum IL-2 levels were an independent factor affecting disease activity. Serum IL-2 levels were positively correlated with Th17/Treg ratios (p = 0.013). Compared with the remission group, peripheral lymphocyte and CD4+ T lymphocyte subsets in patients with active RA decreased to varying degrees; however, the numbers of peripheral natural killer (NK) cells were significantly higher in the moderate-high disease activity group than in the remission (p = 0.046) and low disease activity (p = 0.020) groups; the percentages of NK cells had the same trend. In addition, the number and percentage of NK cells were positively correlated with serum IL-2 levels (p = 0.018 and p = 0.006, respectively). CONCLUSIONS: In RA patients, serum IL-2 levels were not only correlated with patients' disease activity and autoantibody levels but were also involved in their Th17/Treg immune imbalance. In addition, in patients with active RA, NK cell levels were abnormally elevated, possibly due to high serum levels of IL-2.
32377535 Elevated Expression of the Long Noncoding RNA IFNG-AS1 in the Peripheral Blood from Patien 2020 Long noncoding RNAs (lncRNAs) have been increasingly recognized as key immune molecules that participate in the pathogenesis of autoimmune diseases. Previous studies have demonstrated that the lncRNA Ifng-AS1, a key scaffold that contributes to the transcription of IFN-γ, depends on T-bet for active transcription in Th1 cells. However, the effect of its human ortholog, IFNG-AS1, on the pathogenesis of rheumatoid arthritis (RA) remains unclear. In this study, we found that the transcript level of lncRNA IFNG-AS1 was increased in the peripheral blood of RA patients. IFNG, as a target gene of IFNG-AS1, was overexpressed and positively correlated with the transcript level of IFNG-AS1 in the RA patients. Our data also showed that the transcript level of T-bet was upregulated and positively correlated with IFNG-AS1 expression. T-bet regulated the transcription of IFNG-AS1 in human CD4(+) T cells in vitro. Furthermore, strong positive correlations were observed between the increased transcript level of IFNG-AS1 and the serum level of rheumatoid factor, the erythrocyte sedimentation rate, and the C-reactive protein in RA patients, and patients positive for anticyclic citrullinated peptide antibodies had increased levels of IFNG-AS1. Finally, receiver operating characteristic (ROC) curve analysis suggested that IFNG-AS1 might be a potential biomarker of RA. Taken together, our findings indicated that IFNG-AS1, guided by T-bet, is augmented in the peripheral blood of RA patients and may play a critical role in the pathogenesis of RA by regulating the expression of IFNG.
32278845 Outcomes of Acute Myocardial Infarction in Patients with Rheumatoid Arthritis. 2020 Oct BACKGROUND: There is a paucity of data on the outcomes of acute myocardial infarction in patients with rheumatoid arthritis in the contemporary era. METHODS: We queried the National Inpatient Sample database (2002-2016) for hospitalizations with acute myocardial infarction. We described the trends and outcomes of acute myocardial infarction-rheumatoid arthritis compared with acute myocardial infarction-no rheumatoid arthritis. RESULTS: The analysis included 9,359,546 hospitalizations with acute myocardial infarction, of whom 123,783 (1.3%) had rheumatoid arthritis. There was an increase in the number of hospitalizations with acute myocardial infarction-rheumatoid arthritis (P(trend) < .001). There was an observed downtrend in mortality rates for acute myocardial infarction-rheumatoid arthritis (5.8% in 2002 vs 5.2% in 2016, P(trend) = .01) corresponding to an increase in the utilization of percutaneous coronary intervention (P(trend) < .001). In the overall cohort of acute myocardial infarction, rheumatoid arthritis was independently associated with lower rate of in-hospital mortality (adjusted odds ratio 0.90; 95% confidence interval, 0.81-0.99, P = .03). Compared with ST-elevation myocardial infarction (STEMI)-no rheumatoid arthritis, STEMI-rheumatoid arthritis was associated with lower in-hospital mortality and cardiac arrest, while it was associated with higher discharges to nursing facilities. No difference in mortality was observed among non-ST-elevation myocardial infarction (NSTEMI)-rheumatoid arthritis and NSTEMI-no rheumatoid arthritis, while NSTEMI-rheumatoid arthritis was associated with lower cardiac arrest, cardiogenic shock, and hemodialysis, at the expense of higher bleeding events and discharges to nursing facilities. CONCLUSION: In this nationwide analysis, we found an increase in hospitalizations for acute myocardial infarction-rheumatoid arthritis. Among patients with acute myocardial infarction, rheumatoid arthritis was independently associated with lower in-hospital mortality, particularly in cases of STEMI.
32347340 Tocilizumab treatment in Felty's syndrome. 2020 Jul Felty's syndrome (FS) is a deforming disease, characterized by the triad of rheumatoid arthritis (RA), neutropenia, and splenomegaly. Currently, FS patients are treated mainly with immunosuppressants, such as methotrexate and glucocorticoids, which however are not suitable to some patients and may cause severe side effects. Here we report a clinical FS case that was treated with Tocilizumab (TCZ) successfully. The patient had symmetrical swelling and pain of multiple joints, deformity of elbow joints with obvious morning stiffness. Joint color Doppler ultrasound showed synovial hyperplasia and bone erosion of wrist and proximal interphalangeal joints and CT scan suggested splenomegaly. Further examination showed neutropenia and anemia, a high titer of anti-cyclic citrullinated peptide antibody, rheumatoid factor and anti-nuclear antibodies, positive p-ANCA, and elevated IgA and IgG. After treating with TCZ, the patient has been relieved of clinical symptoms. His spleen has recovered to normal size. The absolute neutrophil count (ANC) tended to be stable, and joint erosion did not deteriorate. We have reviewed the literatures on FS treatment with biological agents and found only a few reports using TNF-α antagonist and rituximab treating FS, but none with TCZ. So, it is the first time to report a successful FS case treated with TCZ. This case suggests that the TCZ may be a new choice for FS treatment, under the condition of closely monitoring the ANC.
32720470 Conversion of T Follicular Helper Cells to T Follicular Regulatory Cells by Interleukin-2 2021 Jan OBJECTIVE: This study was undertaken to identify characteristics of follicular regulatory T (Tfr) cells and elucidate the mechanisms by which follicular helper T (Tfh) cells convert to Tfr cells. We probed the phenotype of T helper cells in patients with systemic lupus erythematosus (SLE) and underlying transcriptional regulation using cytokine-induced STAT family factors. METHODS: Peripheral blood mononuclear cells from 41 patients with SLE and 26 healthy donors were used to sort out the memory Tfh cell subset, and Tfh cells were cultured under various conditions. The phenotype of T helper cells and underlying mechanisms of transcriptional regulation were probed using flow cytometry and quantitative polymerase chain reaction analyses. These analyses evaluated the expression of characteristic markers and phosphorylation of STATs. Chromatin immunoprecipitation was used to evaluate histone modifications. RESULTS: In patients with SLE, the proportion of CD4+CXCR5+FoxP3-PD-1(high) Tfh cells was increased (P < 0.01), whereas the proportion of CD4+CXCR5+CD45RA-FoxP3(high) activated Tfr cells was decreased (P < 0.05). Serum interleukin-2 (IL-2) levels were also reduced in patients with SLE. IL-2 induced conversion of memory Tfh cells to functional Tfr cells, which was characterized by CXCR5+Bcl-6+FoxP3(high) pSTAT3+pSTAT5+ cells. The loci of FOXP3 and BCL6 at STAT binding sites were marked by bivalent histone modifications. Following IL-2 stimulation, STAT3 and STAT5 selectively bound to FOXP3 and BCL6 gene loci accompanied by suppression of H3K27me3. Finally, IL-2 stimulation suppressed the generation of CD38+CD27(high) plasmablasts in Tfh and B cell coculture assays ex vivo. CONCLUSION: Impaired function of Tfr cells might be attributed to defective IL-2 production. Exogenous IL-2 restores the function of Tfr cells through the conversion of Tfh cells to Tfr cells in patients with SLE. Thus, restoring balance between Tfh and Tfr cells may provide new therapeutic approaches in SLE.
32546108 T follicular helper cell subsets: a potential key player in autoimmunity. 2021 Mar Follicular helper T (Tfh) cells are one of CD4+ helper T subsets which promote B cell maturation, activation and antigen-specific antibody production. Autoantibodies are hallmarks of autoimmune diseases, and crucial contributions of Tfh cells in development of these diseases are now evident. Deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. These days multiple researchers reported three subpopulations which has distinct effector functions in Tfh cells: Tfh1, Tfh2 and Tfh17 cells. In this review, we summarize the observed alterations in whole Tfh cells and subset distribution during autoimmune diseases.
31092710 Development and Validation of a MicroRNA Panel to Differentiate Between Patients with Rheu 2020 Feb OBJECTIVE: MicroRNA (miRNA) are short noncoding RNA that regulate genes and are both biomarkers and mediators of disease. We used small RNA (sRNA) sequencing and machine learning methodology to develop an miRNA panel to reliably differentiate between rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) and control subjects. METHODS: Plasma samples from 167 RA and 91 control subjects who frequency-matched for age, race, and sex were used for sRNA sequencing. TIGER was used to analyze miRNA. DESeq2 and random forest analyses were used to identify a prioritized list of miRNA differentially expressed in patients with RA. Prioritized miRNA were validated by quantitative PCR, and lasso and logistic regression were used to select the final panel of 6 miRNA that best differentiated RA from controls. The panel was validated in a separate cohort of 12 SLE, 32 RA, and 32 control subjects. Panel efficacy was assessed by area under the receiver operative characteristic curve (AUC) analyses. RESULTS: The final panel included miR-22-3p, miR-24-3p, miR-96-5p, miR-134-5p, miR-140-3p, and miR-627-5p. The panel differentiated RA from control subjects in discovery (AUC = 0.81) and validation cohorts (AUC = 0.71), seronegative RA (AUC = 0.84), RA remission (AUC = 0.85), and patients with SLE (AUC = 0.80) versus controls. Pathway analysis showed upstream regulators and targets of panel miRNA are associated with pathways implicated in RA pathogenesis. CONCLUSION: An miRNA panel identified by a bioinformatic approach differentiated between RA or SLE patients and control subjects. The panel may represent an autoimmunity signature, perhaps related to inflammatory arthritis, which is not dependent on active disease or seropositivity.
33362761 Th17/Treg-Related Transcriptional Factor Expression and Cytokine Profile in Patients With 2020 OBJECTIVES: The aim of our study was to determine whether there is a correlation between transcription factors expression and Th17/Treg ratio, cytokine profile in the RA phenotype as well as to identify transcription factors that could be a potential biomarker for RA. METHODS: The study was conducted on 45 patients with RA, 27 patients with OA and 46 healthy controls (HCs). Th17 and Treg frequency was determined by flow cytometry (15 patients with RA/OA and 15 subjects of HC). Gene expression was estimated by qPCR, and the serum cytokine levels were determined by ELISA. RESULTS: The percentage of Treg (CD4+CD25highCD127-) cells in RA patients was lower than in OA patients or HCs. Proportions of Th17 (CD4+CCR6+CXCR3-) cells were higher in RA and OA in comparison to HCs. STAT5 showed a very high expression in the blood of RA patients compared to healthy subjects. The expression of STAT5 and HELIOS was not detected in Th17 cells. A positive correlation between SMAD3 and STAT3 in RA patients was observed. Negative correlations between HIF-1A and SMAD2 in RA Treg cells and DAS-28 score were observed. The range of serum of IL-17 and IL-21 were higher in RA patients than in OA patients. Concentrations of serum IL-2 and IFN-γ were higher in RA and OA patients than in healthy subjects. Based on the ROC analysis, the diagnostic potential of the combination of HIF1A, SMAD3 and STAT3, was determined at AUC 0.95 for distinguishing RA patients from HCs. For distinguishing RA patients from OA patients the diagnostic potential of the combination of SMAD2, SMAD3, SMAD4 and STAT3, was determined at AUC 0.95. CONCLUSION: Based on our study, we conclude that SMAD3 and STAT3 could be potential diagnostic biomarkers for RA.
32816215 Characterization of Creatine Kinase Levels in Tofacitinib-Treated Patients with Ulcerative 2021 Aug BACKGROUND: Tofacitinib is an oral, small-molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Creatine kinase (CK) levels and CK-related adverse events (AEs) in tofacitinib-treated patients with UC were evaluated. METHODS: Data were analyzed for three UC cohorts: Induction (phase 2 and 3 induction studies); Maintenance (phase 3 maintenance study); Overall [patients who received tofacitinib 5 or 10 mg twice daily (b.d.) in phase 2, phase 3, or open-label, long-term extension studies; data at November 2017]. Clinical trial data for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis are presented for contextualization. RESULTS: Week 8 mean change from baseline CK with tofacitinib 10 mg b.d. induction therapy was 91.1 U/L (95% CI, 48.1-134.1) versus 19.2 U/L (8.5-29.9) with placebo. Among patients completing induction with 10 mg b.d. and re-randomized to 52 weeks of maintenance therapy, mean increases from induction baseline to the end of maintenance were 35.9 (8.1-63.7), 90.3 (51.9-128.7), and 115.6 U/L (91.6-139.7), with placebo, 5 and 10 mg b.d., respectively. The incidence rate (unique patients with events per 100 patient-years) for AEs of CK elevation in the tofacitinib-treated UC Overall cohort was 6.6 versus 2.2, 6.5, and 3.7 for tofacitinib-treated patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis, respectively. No serious AEs of CK elevation or AEs of myopathy occurred in UC studies. CONCLUSIONS: In patients with UC, CK elevations with tofacitinib appeared reversible and not associated with clinically significant AEs. UC findings were consistent with tofacitinib use in other inflammatory diseases. TRIAL REGISTRATION: NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612; NCT01262118; NCT01484561; NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01059864; NCT01164579; NCT00976599; NCT01359150; NCT02147587; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055; NCT00413699; NCT00661661; NCT01710046; NCT00678210; NCT01276639; NCT01309737; NCT01241591; NCT01186744; NCT01163253; NCT01877668; NCT01882439; NCT01976364.
32878994 National registry for patients with inflammatory rheumatic diseases (IRD) infected with SA 2020 Sep OBJECTIVES: Patients with inflammatory rheumatic diseases (IRD) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be at risk to develop a severe course of COVID-19. The influence of immunomodulating drugs on the course of COVID-19 is unknown. To gather knowledge about SARS-CoV-2 infections in patients with IRD, we established a registry shortly after the beginning of the pandemic in Germany. METHODS: Using an online questionnaire (www.COVID19-rheuma.de), a nationwide database was launched on 30 March 2020, with appropriate ethical and data protection approval to collect data of patients with IRD infected with SARS-CoV-2. In this registry, key clinical and epidemiological parameters-for example, diagnosis of IRD, antirheumatic therapies, comorbidities and course of the infection-are documented. RESULTS: Until 25 April 2020, data from 104 patients with IRD infected with SARS-CoV-2 were reported (40 males; 63 females; 1 diverse). Most of them (45%) were diagnosed with rheumatoid arthritis, 59% had one or more comorbidities and 42% were treated with biological disease-modifying antirheumatic drugs. Hospitalisation was reported in 32% of the patients. Two-thirds of the patients already recovered. Unfortunately, 6 patients had a fatal course. CONCLUSIONS: In a short time, a national registry for SARS-CoV2-infected patients with IRD was established. Within 4 weeks, 104 cases were documented. The registry enables to generate data rapidly in this emerging situation and to gain a better understanding of the course of SARS-CoV2-infection in patients with IRD, with a distinct focus on their immunomodulatory therapies. This knowledge is valuable for timely information of physicians and patients with IRD, and shall also serve for the development of guidance for the management of patients with IRD during this pandemic.
32117219 Targeting Extracellular Vesicles to the Arthritic Joint Using a Damaged Cartilage-Specific 2020 The targeted delivery of therapies to diseased tissues offers a safe opportunity to achieve optimal efficacy while limiting systemic exposure. These considerations apply to many disease indications but are especially relevant for rheumatoid arthritis (RA), as RA is a systemic autoimmune disease which affects multiple joints. We have identified an antibody that is specific to damaged arthritic cartilage (anti-ROS-CII) that can be used to deliver treatments specifically to arthritic joints, yielding augmented efficacy in experimental arthritis. In the current study, we demonstrate that scaffolds enriched with bioactive payloads can be delivered precisely to an inflamed joint and achieve superior efficacy outcomes consistent with the pharmacological properties of these payloads. As a scaffold, we have used extracellular vesicles (EVs) prepared from human neutrophils (PMNs), which possess intrinsic anti-inflammatory properties and the ability to penetrate inflamed arthritic cartilage. EV fortified with anti-ROS-CII (EV/anti-ROS-CII) retained anti-ROS-CII specificity and bound exclusively to the damaged cartilage. Following systemic administration, EV/anti-ROS-CII (a) exhibited the ability to localize specifically in the arthritic joint in vivo and (b) was able to specifically target single (viral IL-10 or anti-TNF) or combined (viral IL-10 and anti-TNF) anti-inflammatory treatments to the arthritic joint, which accelerated attenuation of clinical and synovial inflammation. Overall, this study demonstrates the attainability of targeting a pro-resolving biological scaffold to the arthritic joint. The potential of targeting scaffolds such as EV, nanoparticles, or a combination thereof alongside combined therapeutics is paramount for designing systemically administered broad-spectrum of anti-inflammatory treatments.