Severe Arthritis Research Articles

Poster 161: Consequence Athletes with Anterior Shoulder Instability: Consider Latarjet

Objectives:The Latarjet procedure has been shown to be effective in treating recurrent shoulder instability, especially in the setting of glenoid bone loss and after failed previous Bankart repair. Several studies have additionally shown a significant reduction in recurrent instability rates when compared to Bankart repair in contact athletes when the Latarjet procedure is performed in a primary setting. We have identified an additional population of patients that provides greater challenges beyond the common athlete including those involved in contact sports. Termed “consequence athletes,” these patients are defined as athletes who perform in high risk, uncontrolled environments for whom an injury is likely to threaten life or livelihood. This population includes elite military forces, law enforcement and federal agents, motocross, elite skiers/snowboarders, whitewater kayak and rafters, and rock climbers. The purpose of this study is to evaluate minimum 2-year outcomes of primary Latarjet procedure in consequence athletes with anterior shoulder instability.Methods:Consequence athletes who underwent open Latarjet by one of the three sports medicine trained senior surgeons between August 2006 and January 2018 were retrospectively reviewed from prospectively collected data. Minimum 24 follow up was obtained on all patients. Those younger than 18 at follow up, history of concomitant or prior remplissage procedure, glenoid reconstruction with allograft, severe glenohumeral arthritis, or hyperlaxity were excluded. Glenoid bone loss (GBL) was evaluated on preoperative MRI and the cohort divided into GBL 0-14% and ≥15%. Patient-reported outcome scores (PROs) were collected and included the American Shoulder and Elbow Surgeons (ASES) score, Single Numeric Assessment Evaluation (SANE) score, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, Short Form–12 (SF-12) Physical Component Summary (PCS), and numeric rating scale (NRS) for pain score (0 - 10, 10 = worst pain). Postoperative patient satisfaction (1 - 10, 10 = very satisfied) was evaluated. Complications and revision surgeries were recorded. Failure was defined as a postoperative dislocation or a revision surgery.Results:Sixty-five consequence athletes were included (54 males, 11 females). The mean age at surgery was 28.5 ± 8.7 years (range 15.8-56.4). The most frequent professions included 17 skiers (26.2%), 17 rock climbers (26.2%), 10 snowboarders (15.4%), 9 white water kayakers/rafters (13.8%), and 8 federal agents/military (12.3%). Primary latarjet was performed in 30 (46.2%) without prior history of soft tissue stabilization procedures. Mean GBL was 13.7%; 27 (41.5%) had 0-14% GBL and 32 (49.2%) had ≥15% GBL. Significant improvement in PROs at minimum 2-year follow was demonstrated for SANE (57.9 ± 24.5 to 91.0 ± 9.5), SF12 PCS (45.5 ± 8.7 to 54.4 ± 7.1), ASES pain (41.5 ± 9.7 to 47.4 ± 5.3), ASES function (31.8 ± 12.6 to 46.2 ± 6.8), ASES total (73.0 ± 19.8 to 93.7 ± 10.0), and quickDASH (27.0 ± 14.0 to 10.0 ± 28.8). Median patient satisfaction was 10. One patient sustained a recurrent dislocation (1.5%), 2 (3%) patients underwent revision surgery. There was no significant correlation between PROs and GBL, number of previous dislocations, or prior soft tissue stabilization procedures.Conclusions:The latarjet procedure a reliable and safe treatment for shoulder instability in the high demand “consequence athlete” population with a post-operative dislocation rate of 1.5% and revision rate of 3%. Significant improvement in PROs was demonstrated for SANE, SF12 PCS, ASES, and DASH with median patient satisfaction score of 10. These findings support treatment of this population with the latarjet procedure, even in the setting of minimal preoperative GBL, where a recurrent instability event could be catastrophic to the individual patient or those working or participating along with them.

Poster 215: Application of Machine Learning for Predicting Opioid Use After Arthroscopic Meniscal Surgery

Objectives:To identify predictive factors for continued opioid prescriptions after arthroscopic meniscal resection or repair and develop a predictive machine learning model.Methods:Patients undergoing arthroscopic meniscal surgery between August 2013 and February 2017 at a single institution were retrospectively identified. Patient demographic variables were recorded including age, sex, body mass index, and history of chronic opioid usage (> 1 month). Procedural details were recorded such as concomitant procedures, primary versus revision, and whether a partial debridement or a repair was performed. Intraoperative arthritis severity was measured using the Outerbridge Classification. Types of opioid medications prescribed and in which months were documented. For primary analysis, we used a multivariate Cox-Regression model. We then created a naïve Bayesian model, a machine learning classifier that utilizes Bayes’ theorem with an assumption of independence between the variables collected. The model randomly selected 70% of the sample to be trained on while 30% were tested.Results:A total of 735 patient were reviewed. Postoperative opioid refills occurred in 98 patients (16.9%). Using multivariate logistic modeling, independent risk factors for opioid refills included Male sex, larger BMI, chronic preoperative opioid use while meniscus resection demonstrated decreased likelihood of refills. Concomitant procedures, revisions, and presence of arthritis graded by the Outerbridge classification were not significant predictors of opioid refills. The Naïve Bayesian model for extended postoperative opioid use demonstrated good fit with our cohort with an area under the curve of 0.79, sensitivity of 94.5%, PPV of 83%, and a detection rate of 78.2%.Conclusions:After arthroscopic meniscus surgery, preoperative opioid consumption had the strongest association with sustained opioid use >1 month. Intraoperative arthritis was not an independent risk factor for continued refills. A novel machine learning algorithm performed with high accuracy and predictive ability to identify patients filling additional narcotic prescriptions after surgery.Figure 1.Cumulative hazard curve for the risk of using opioids up until 1 year postoperatively.Table 1.Multivariate logistic regression model for postoperative opioid refills.

An Objective Computational Method to Quantify Ankle Osteoarthritis From Low-Dose Weightbearing Computed Tomography.

The treatment of ankle osteoarthritis (OA) varies depending on the severity and distribution of the associated joint degeneration. Disease staging is typically based on subjective grading of appearance on conventional plain radiographs, with reported subpar reproducibility and reliability. The purpose of this study was to develop and describe computational methods to objectively quantify radiographic changes associated with ankle OA apparent on low-dose weightbearing CT (WBCT). Two patients with ankle OA and 1 healthy control who had all undergone WBCT of the foot and ankle were analyzed. The severity of OA in the ankle of each patient was scored using the Kellgren-Lawrence (KL) classification using plain radiographs. For each ankle, a volume of interest (VOI) was centered on the tibiotalar joint. Initial computation analysis used WBCT image intensity (Hounsfield units [HU]) profiles along lines perpendicular to the subchondral bone/cartilage interface of the distal tibia extending across the entire VOI. Graphical plots of the HU distributions were generated and recorded for each line. These plots were then used to calculate the joint space width (JSW) and HU contrast. The average JSW was 3.89 mm for the control ankle, 3.06 mm for mild arthritis (KL 2), and 1.57 mm for severe arthritis (KL 4). The average HU contrast was 72.31 for control, 62.69 for mild arthritis, and 33.98 for severe arthritis. The use of 4 projections at different locations throughout the joint allowed us to visualize specifically which quadrants have reduced joint space width and contrast. In this technique report, we describe a novel methodology for objective quantitative assessment of OA using JSW and HU contrast. Objective, software-based measurements are generally more reliable than subjective qualitative evaluations. This method may offer a starting point for the development of a more robust OA classification system or deeper understanding of the pathogenesis and response to ankle OA treatment.

Functional outcome of posterior cruciate ligament substituted total knee arthroplasty

Background and Aim: Total Knee Arthroplasty (TKA) is now most reliable treatment for severe arthritis. However, there is a need of a study to accurately assess and analyze the approach of a surgeon towards PCL and measure its outcome. We aimed to study clinical and functional outcome following posterior cruciate ligament substituted total knee arthroplasty.Material and Methods: Present research was carried out at Department of Orthopedics, Tertiary Care Institute of India where 50 patients were operated, 78 Total knee replacements done on 50 patients for the duration of two years. All patients were assessed clinically and functionally using the Oxford knee score. The preoperative medical evaluations of all patients were done to evaluate any potential complications that can be life-threatening or limb-threatening.Results: Most of the patients in study have excellent outcome 72% followed by good results of 14% after treatment. Out of 50 patients and 6 patient had post op suprapatellar fullness, which was relieved with medications for 3 weeks and 3 patients without no signs of immediate post-operative period, developed infection after 6 months followed which underwent staged revision total knee replacement.Conclusion: Post operatively, patients had pain free joint movements with correction of deformity. In patients with advanced osteoarthritis, gross varus deformity, fixed flexion deformity posterior cruciate ligament sacrificing total knee replacement will give greater mobility and function.

EE452 Efficacy and Cost Effectiveness of Biological Agents in Moderate to Severe Psoriatic Arthritis: A Meta-Analysis

Psoriatic arthritis (PsA) is a debilitating disease of the joints, if left untreated, irreversible damage would incur. A substantial percentage of medical expenses come directly from biologics. The objective of this study is to analyze the efficacy and cost-effectiveness of biologics in moderate to severe PsA patients in Taiwan.

Functional outcome of mild and moderate residual varus in posterior stabilized total knee arthroplasty in primary osteoarthritis knee: a prospective study

<p><strong>Background: </strong>Total knee arthroplasty (TKA) is one of the most commonly done orthopaedic surgical procedures for treating severe arthritis of the knee joint caused by osteoarthritis or inflammatory arthritis. The current clinical investigation, done at the Sanjay Gandhi Institute of Trauma and Orthopaedics in Bengaluru, provided the short-term functional result of mild and moderate residual varus in posterior stabilized TKA. The aim was to evaluate the efficacy of mild and moderate residual varus in total knee replacement for primary OA knee in terms of pain relief, range of motion and stability of the joint. <strong></strong></p><p><strong>Methods: </strong>30 total knee replacements were performed. All patients were examined pre- and post-operatively using the knee society clinical and functional score. The average pre-op KSS knee score was 38.7, with a functional score of 23.3. The most common reason for TKR was osteoarthritis. The follow-up time ranged from 6 to 12 months.<strong></strong></p><p><strong>Results: </strong>By the knee society clinical, functional score method, 96.6% of our patients received an outstanding assessment after scoring 80 points or higher. The mean post-operative KSS knee score is 86.57, and the knee society functional score is 92. 92% of patients had little/no pain after surgery, and walking ability increased and was unlimited in 80% of patients.<strong></strong></p><p><strong>Conclusions: </strong>After a short term follow up of 1 year in a research population of 30 with pre-operative osteo arthritis of the knee, with post-operative mild to moderate varus alignment showed better clinical results. <strong></strong></p>

The Effect of Triptolide Combined With Crocin on Arthritis in Mice: From Side Effect Attenuation to Therapy.

Clinical use of triptolide (TP) is restricted due to severe toxicity. This study assessed the protective effect of crocin (CR) as a natural antioxidant against TP-induced toxicity in bovine collagen type II-induced arthritis (CIA) in mice. The mice in the CIA model group showed macroscopic signs of severe arthritis. The anti-arthritis effects in the control, TP + CR, and TP groups were evaluated through assessment of foot volume, arthritis score, and proinflammatory cytokines, and collagen antibody assay. Crocin reduced TP-induced toxicity, as evidenced by evaluation of survival rate, body weight, visceral index, hepatic and renal functions, histopathologic analyses, and antioxidant enzyme activities. Transcriptome sequencing resulted in identification of 76 differentially expressed genes (DEGs) associated with hepatotoxicity between the TP and TP + CR groups. Of these, Three DEGs (Cyp1a2,Gsta4, and Gstp1) were validated using quantitative real-time PCR analysis. In conclusion, CR protected CIA mice from TP-induced toxicity through modulation of the cytochrome P450 and glutathione metabolism pathways.

The Antifungal Itraconazole Is a Potent Inhibitor of Chikungunya Virus Replication.

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disabling disease that can cause long-term severe arthritis. Since the last large CHIKV outbreak in 2015, the reemergence of the virus represents a serious public health concern. The morbidity associated with viral infection emphasizes the need for the development of specific anti-CHIKV drugs. Herein, we describe the development and characterization of a CHIKV reporter replicon cell line and its use in replicon-based screenings. We tested 960 compounds from MMV/DNDi Open Box libraries and identified four candidates with interesting antiviral activities, which were confirmed in viral infection assays employing CHIKV-nanoluc and BHK-21 cells. The most noteworthy compound identified was itraconazole (ITZ), an orally available, safe, and cheap antifungal, that showed high selectivity indexes of >312 and >294 in both replicon-based and viral infection assays, respectively. The antiviral activity of this molecule has been described against positive-sense single stranded RNA viruses (+ssRNA) and was related to cholesterol metabolism that could affect the formation of the replication organelles. Although its precise mechanism of action against CHIKV still needs to be elucidated, our results demonstrate that ITZ is a potent inhibitor of the viral replication that could be repurposed as a broad-spectrum antiviral.

Angiotensin II type 2 receptor pharmacological agonist, C21, reduces the inflammation and pain hypersensitivity in mice with joint inflammatory pain

Primary and secondary hyperalgesia develop in response to chronic joint inflammation due to peripheral and central mechanisms. Synovial macrophage and spinal microglia are involved in pain sensitization in arthritis. The level of angiotensin II type 2 receptor (AT2R) is related to the severity of arthritis. This study aimed to determine the role of AT2R in primary and secondary hyperalgesia in joint inflammatory pain in mice. After intra-articular CFA injection, primary hyperalgesia in the ipsilateral knee joint was measured by pressure application meter and gait analysis, secondary hypersensitivity in ipsilateral hind-paw was measured by von-Frey and Hargreaves tests following a combination of global AT2R-deficient (Agtr2-/-) mice and AT2R pharmacological agonist C21. Synovial macrophage and spinal microglia were collected for flow cytometry. Morphological reconstruction of microglia was detected by immunostaining. AT2R expression was investigated by quantitative polymerase chain reaction and western blot. Neuronal hyperactivity was evaluated by c-Fos and CGRP immunostaining. We found that pain hypersensitivity and synovial inflammation in Agtr2-/- mice were significantly exacerbated compared with wild-type mice; conversely, systemically administrated C21 attenuated both of the symptoms. Additionally, spinal microglia were activated, and an abundant increase of spinal AT2R was expressed on activated microglia in response to peripheral joint inflammation. Intrathecally-administrated C21 reversed the secondary hypersensitivity, accompanied by alleviation of spinal microglial activation, spinal neuronal hyperactivity, and calcitonin gene-related peptide content. These findings revealed a beneficial role of AT2R activating stimulation against pain hypersensitivity in joint inflammatory pain via direct modulation of synovial macrophage and spinal microglial activity.

Ethanolic Extracts of leaves of Alstonia scholaris Linn. Modulates Chronic Inflammatory Immune Response in FCA Induced Arthritis

AIM- The aim of the present investigation is scientifically establishing the anti-arthritic activity of selected medicinal plant so that we are able to come up with a more effective and potent bioactive phytoconstituents with less side effects in comparison with existing synthetic drugs. MATERIAL & METHODS- The leaves of Alstonia scholaris were collected from campus of College of Pharmacy. All the plant materials were taxonomically identified by Dr. Gyanendra Tiwari, Senior Scientist, KNK College of Horticulture. All the plant materials were dried under shade and subjected to coarse powder for extraction process. Accurately weighed quantity of leaf powder of Alstonia scholaris were extracted using 95 % ethanol by soxhlet apparatus for 72 h. The ethanolic extracts were dried under the reduced pressure to get crude ethanolic extracts. The Wistar albino rats were divided into 10 groups of six animals in each. For the induction of chronic inflammatory response, FCA (0.1 ml) was injected through intra-articular injection in left ankle joint of rats on 0 day. The severity of adjuvant arthritis was quantified by measuring the volume of the hind paw using Plethysmograph. Body weight was measured of all groups at zero days before immunization and at 21st day after treatments over by using a single pan weighing balance. RESULTS- The preliminary phytochemical analysis revealed that different active constituent present in different extracts such as carbohydrates, proteins, amino acids, fat, oils, steroids, terpenoids, glycosides, alkaloids, tannins and other phenolics compounds. The assessment made on the 21st day showed that the A. scholaris treatments at both doses (low and high) had moderately significant and highly significant effect and reduced (p< 0.01& p<0.001) the adjuvant-induced lesions in the respective treatment groups as compared with the arthritis control group. However, standard, A. scholaris had highly significant effects (p<0.001) in recovery of RBCs and haemoglobin. They also showed highly significant effects on decrease in WBCs and ESR treated groups, also showed moderately significant effects as compared to arthritic group. CONCLUSION- Besides from the obvious therapeutic importance, these components would be useful in understanding the mechanism of diseases with higher levels of cellular and molecular level. These components could serve as lead molecules for development of prospective anti-arthritic agents. Keywords: Anti-arthritic agent, Lead molecules, Alstonia scholaris, Shronic inflammatory response, Synthetic drugs, Plethysmograph

The Prominent Role of Hematopoietic Peptidyl Arginine Deiminase 4 in Arthritis: Collagen- and Granulocyte Colony-Stimulating Factor-Induced Arthritis Model in C57BL/6 Mice.

Genome-wide association studies have connected PADI4, encoding peptidylarginine deiminase 4 (PAD4), with rheumatoid arthritis (RA). PAD4 promotes neutrophil extracellular trap (NET) formation. This study was undertaken to investigate the origin of PAD4 and the importance of NET formation in a C57BL/6 mouse model of arthritis. To permit the effective use of C57BL/6 mice in the collagen-induced arthritis (CIA) model, we introduced the administration of granulocyte colony-stimulating factor (G-CSF) for 4 consecutive days in conjunction with the booster immunization on day 21. Mice with global Padi4 deficiency (Padi4-/- ) and mice with hematopoietic lineage-specific Padi4 deficiency (Padi4Vav1Cre/+ ) were evaluated in the model. G-CSF significantly increased the incidence and severity of CIA. G-CSF-treated mice showed elevated citrullinated histone H3 (Cit-H3) levels in plasma, while vehicle-treated mice did not. Immunofluorescence microscopy revealed deposition of Cit-H3 in synovial tissue in G-CSF-treated mice. Padi4-/- mice developed less severe arthritis and had lower levels of serum interleukin-6 and plasma Cit-H3, lower levels of Cit-H4 in synovial tissue, and less bone erosion on micro-computed tomography than Padi4+/+ mice in the G-CSF-modified CIA model. Similarly, Padi4Vav1Cre/+ mice developed less severe arthritis, compared with Padi4fl/fl mice, and presented the same phenotype as Padi4-/- mice. We succeeded in developing an arthritis model suitable for use in C57BL/6 mice that is fully compliant with high animal welfare standards. We observed a >90% incidence of arthritis in male mice and detectable NET markers. This model, with some features consistent with human RA, demonstrates that hematopoietic PAD4 is an important contributor to arthritis development and may prove useful in future RA research.

Are SMAD2/4/7 genetic variants associated with rheumatoid arthritis susceptibility and severity?

SMADs play one of the key roles in the TGFβ signalling pathway. Therefore, through their involvement in the immune response as well as in the fibrosis process, these proteins appear to take on one of the essential functions in the pathogenesis of autoimmune connective tissue diseases such as RA. This study aimed to investigate the association of selected SNPs in SMAD2/4/7 with RA risk in the Caucasian population and disease course in RA patients. The study was conducted on 647 patients with established RA and 496 unrelated healthy controls (HCs). All patients fulfilled the American College of Rheumatology Diagnostic classification criteria for RA (ACR 1987). The analysis has been conducted using TaqMan genotyping assay. Transcript-inferred pathogenicity score (TraP-score) has been evaluated by TrapScore. PredictSNP.2 has been used to predict the effect of amino acid substitutions. The present study revealed in SMAD4 a significantly higher frequency of AG rs12456284 (under codominant model OR=0.62 p=0.027 and overdominant model OR=0.59 p=0.016) and GA rs10502913 (under codominant model OR=0.65 p=0.050 and overdominant OR=0.64 p=0.033) genotypes in healthy subjects in comparison to RA patients. Additionally, very strong LD has been noted between these two genetic variants (D'=0.95 r2=0.90). Moreover, bioinformatic analysis classified rs12456284 as deleterious change with 94% prediction accuracy. SMAD2 rs1792666 and SMAD7 rs3736242 showed to have the highest association with disease course. SMAD4 rs10502913, SMAD7 rs3736242, and SMAD7 rs4464148 were associated with the concentration of creatinine. Our results suggested that rs12456284 and rs10502913 in SMAD4 may have a potential protective effect against RA. Particularly, SMAD2 rs1792666 and SMAD7 rs3736242 seem to be significantly associated with diseases course in RA patients in the Caucasian population.

A promising drug combination of mangiferin and glycyrrhizic acid ameliorates disease severity of rheumatoid arthritis by reversing the disturbance of thermogenesis and energy metabolism

BackgroundActivation of immune system in rheumatoid arthritis (RA) consumes amount of energy, and the energy metabolic signals may be a potential target for RA therapy. Baihu-Guizhi decoction (BHGZD) achieves satisfactory therapeutic effects in RA in clinics by recovering the adjacent articular cartilage and bone destruction, and abnormal articular temperature. However, its pharmacological material basis and molecular mechanisms have not been fully elucidated. PurposeThis study focused on exploring the potential acting mechanism of BHGZD against RA, and identifying its main bioactive compounds (BACs) of the combination of mangiferin and glycyrrhizic acid. MethodsKey putative targets of BHGZD acting on adjuvant-induced arthritis (AIA)-M rats were screened by the transcriptomic profiling of the whole blood cells and synovium tissues collected from rats in normal control, AIA-M model and AIA-M-BHGZD treatment groups. Then, BACs of BHGZD against RA were identified using Ultra Performance Liquid Chromatography-Mass spectrum/Mass spectrum, molecular docking, surface plasmon resonance and pharmacokinetic analysis. In vivo experiments based on AIA-M rats and in vitro experiments based on 3T3-L1 preadipocytes were performed to verify the pharmacological effects of BACs against RA and the corresponding mechanisms. ResultsPKA-ADCY5-PPARγ-PGC 1α-UCP1-PRDM16 signal axis was demonstrated to be the candidate targets of BHGZD against RA and was involved in maintaining the balance of thermogenesis and energy metabolism, according to the transcriptional regulatory network analysis based on “herbs-putative targets-disease interaction network”. Then, mangiferin from Rhizoma Anemarrhenae and glycyrrhizic acid from Radix Glycytthizae were identified as the main BACs of BHGZD against RA due to their highly accumulation in the blood in vivo, strong binding affinities with the two candidate targets of BHGZD against RA-ADCY5 and PPARγ, as well as the in vivo and in vitro strong regulation effects on energy metabolism disturbance. ConclusionsThese findings offer evidence that the combination of mangiferin and glycyrrhizic acid from BHGZD may be a promising candidate drug for RA therapy, and also provide an important reference for the development and modernization of traditional Chinese formulae.

Comparison of the Efficacy of Aspirin with Rivaroxaban in Postoperative DVT Prophylaxis after Hip Arthroplasty

Background: Patients suffering from severe hip arthritis and osteonecrosis are increasingly turning to total hip arthroplasty (THA) as a treatment option, according to recent research. If deep vein thrombosis (DVT) is not treated properly, it can result in a life-threatening pulmonary embolism as well as other potentially life-threatening consequences (PE). Aim: To compare the efficacy of aspirin with rivaroxaban in postoperative dvt prophylaxis after hip arthroplasty in patients at tertiary care hospital, Karachi Methodology: The College of Physicians and Surgeons of Pakistan approved this study prior to its completion. The Department of Orthopedics at JPMC, Karachi, chose those who had complete hip arthroplasty for the study. The school's ethical committee approved the study before it could begin. Before participating in the trial, all patients signed an informed consent form granting them permission to do so. Results: Patients from JPMC Karachi's Department of Orthopedics were included in the study. They were aged 49 to 75. Travel time to the hospital was an average of 58.878.19 years. They were aged 49 to 75. For every month, hour, and day spent in hospital, there are 14.416.14. Eighty people used aspirin, 32(40%) were 40-60 and 48(60%) were 61-75. In the rivaroxaban group, 40 patients (50%) were 40-60, and (61-75). The aspirin group had 80 patients, 38 male (47%) and 42 female (42%) (52.5%). One hundred and twenty-five patients (68.8%) were on rivaroxaban (31.2%). Conclusions: People who have a spontaneous venous thromboembolism should not be given long-term thromboprophylaxis after taking oral anticoagulants until more research is done. It is very important to figure out what DVY risk factors are in order to come up with preventative measures that are both safe and affordable. People can live longer if they get an early diagnosis and get treatment quickly, so they can live longer. High-quality, large-scale studies must be done before a conclusion can be drawn. Keywords: DVY risk, thromboembolism, thromboprophylaxis, arthroplasty

Transcriptomic profiling revealed the role of apigenin-4′-O-α-L-rhamnoside in inhibiting the activation of rheumatoid arthritis fibroblast-like synoviocytes via MAPK signaling pathway

BackgroundActivated fibroblast-like synoviocyte (FLS) played a significant role in the pathogenesis and progression of rheumatoid arthritis (RA). Apigenin-4′-O-α-L-rhamnoside showed remarkable effects against RA, however, no relevant studies on pharmacology of apigenin-4′-O-α-L-rhamnoside yet, the effects and underlying molecular mechanism of apigenin-4′-O-α-L-rhamnoside on RA are still unclear. PurposeThis study aimed to investigate the therapeutic effects and mechanisms of apigenin-4′-O-α-L-rhamnoside on RA-FLS cells by transcriptomic analysis. MethodsIn vitro, RA-FLS cell viability and migration were measured by CCK-8 and scratch assays, respectively. The effects of apigenin-4′-O-α-L-rhamnoside on inflammatory levels of MMP-1, MMP-3, RANKL and TNF-α in RA-FLS cells were detected using ELISA kits. High-throughput transcriptome analysis was performed to screen the key genes and related pathways of apigenin-4′-O-α-L-rhamnoside inhibit RA-FLSs, and the result of which were validated by RT-qPCR and western blot. Furthermore, in vivo, we also evaluated the effects of apigenin-4′-O-α-L-rhamnoside in rat with CIA. ResultsApigenin-4′-O-α-L-rhamnoside significantly suppressed RA-FLS migration, exerted remarkable inhibiting effects on the expression levels on MMP-1, MMP3, RANKL and TNF-α in RA-FLS cells. It seemed that MAPK signaling pathway might be closely related to the pathogenesis of RA by down-regulated relevant core targets (MAPK1, HRAS, ATF-2, p38 and JNK). Moreover, apigenin-4′-O-α-L-rhamnoside attenuated the severity of arthritis in CIA rat. ConclusionApigenin-4′-O-α-L-rhamnoside inhibited pro-inflammatory cytokine, chemokine and MMPs factors production of RA-FLS by targeting the MAPK signaling pathway, which provided a scientific basis for potential application in the treatment of RA.

Rho-GTPase dependent leukocyte interaction generates pro-inflammatory thymic Tregs and causes arthritis

Conditional mutation of protein geranylgeranyltransferase type I (GGTase-I) in macrophages (GLC) activates Rho-GTPases and causes arthritis in mice. Knocking out Rag1 in GLC mice alleviates arthritis which indicates that lymphocytes are required for arthritis development in those mice. To study GLC dependent changes in the adaptive immunity, we isolated CD4+ T cells from GLC mice (CD4+GLCs). Spleen and joint draining lymph nodes (dLN) CD4+GLCs exhibited high expression of Cdc42 and Rac1, which repressed the caudal HOXA proteins and activated the mechanosensory complex to facilitate migration. These CDC42/RAC1 rich CD4+GLCs presented a complete signature of GARP+NRP1+IKZF2+FOXP3+ regulatory T cells (Tregs) of thymic origin. Activation of the β-catenin/Lef1 axis promoted a pro-inflammatory Th1 phenotype of Tregs, which was strongly associated with arthritis severity. Knockout of Cdc42 in macrophages of GLC mice affected CD4+ cell biology and triggered development of non-thymic Tregs. Knockout of Rac1 and RhoA had no such effects on CD4+ cells although it alleviated arthritis in GLC mice. Disrupting macrophage and T cell interaction with CTLA4 fusion protein reduced the Th1-driven inflammation and enrichment of thymic Tregs into dLNs. Antigen challenge reinforced the CD4+GLC phenotype in non-arthritic heterozygote GLC mice and increased accumulation of Rho-GTPase expressing thymic Tregs in dLNs. Our study demonstrates an unexpected role of macrophages in stimulating the development of pro-inflammatory thymic Tregs and reveal activation of Rho-GTPases behind their arthritogenic phenotype.

A matched comparison of cementless unicompartmental and total knee replacement outcomes based on the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.

Background and purposeThe main treatments for severe medial compartment knee arthritis are unicompartmental (UKR) and total knee replacement (TKR). UKRs have higher revision rates, particularly for aseptic loosening, therefore the cementless version was introduced. We compared the outcomes of matched cementless UKRs and TKRs.Patients and methodsThe National Joint Registry was linked to the English Hospital Episode Statistics and Patient Reported Outcome Measures (PROMs) databases. 10,552 cementless UKRs and 10,552 TKRs were propensity matched and regression analysis used to compare revision/reoperation risks. 6-month PROMs were compared. UKR results were stratified by surgeon caseload into low- (< 10 UKRs/year), medium- (10 to < 30 UKRs/year), and high-volume (≥ 30 UKRs/year).Results8-year cementless UKR revision survival for the 3 respective caseloads were 90% (95% CI 87–93), 93% (CI 91–95), and 96% (CI 94–97). 8-year reoperation survivals were 76% (CI 71–80), 81% (CI 78–85), and 84% (CI 82–86) respectively. For TKR the 8-year implant survivals for revision and reoperation were 96% (CI 95–97) and 81% (CI 80–83). The HRs for the 3 caseload groups compared with TKR for revision were 2.0 (CI 1.3–2.9), 2.0 (CI 1.6–2.7), and 1.0 (CI 0.8–1.3) and for reoperation were 1.2 (CI 1.0–1.4), 0.9 (CI 0.8–1.0), and 0.6 (CI 0.5–0.7). 6-month Oxford Knee Score (OKS) (39 vs. 37) and EQ-5D (0.80 vs. 0.77) were higher (p < 0.001) for the cementless UKR.InterpretationCementless UKRs have higher revision and reoperation rates than TKR for low-volume UKR surgeons, similar reoperation but higher revision rates for mid-volume surgeons, and lower reoperation and similar revision rates for high-volume surgeons. Cementless UKR also had better PROMs.

POS0287 A PHASE III, RANDOMISED, DOUBLE-BLIND, ACTIVE-CONTROLLED CLINICAL TRIAL TO COMPARE BAT1806/BIIB800, A PROPOSED TOCILIZUMAB BIOSIMILAR, WITH TOCILIZUMAB REFERENCE PRODUCT IN SUBJECTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS WITH AN INADEQUATE RESPONSE TO METHOTREXATE THERAPY

BackgroundBAT1806/BIIB800 is a proposed biosimilar to reference tocilizumab (TCZ). A Phase III randomised, double-blind, active-controlled clinical trial was conducted as part of a biosimilar development programme.ObjectivesTo evaluate the efficacy, pharmacokinetics (PK), safety and immunogenicity of BAT1806/BIIB800 in comparison with EU-sourced TCZ in subjects with moderate to severe rheumatoid arthritis with inadequate response to methotrexate (MTX).MethodsThe study was conducted at 55 centres in China and Europe, between June 2018 and January 2021. Eligible subjects were randomised in a 2:1:1 ratio to one of three treatment groups: (1) BAT1806/BIIB800 up to Week 48, (2) TCZ up to Week 48, or (3) TCZ up to Week 24, followed by BAT1806/BIIB800 from Week 24 to Week 48, administered intravenously every 4 weeks at a dose of 8mg/kg. The primary endpoint was the proportion of subjects achieving an ACR20 response at timepoints pre-specified to meet the requirements of different Regulatory Agencies: Week 12, for EMA; Week 24, for FDA and NMPA. Equivalence margins applied to differences in ACR20 response rates in the BAT1806/BIIB800 and TCZ treatment groups were pre-specified as follows: +/- 14.5% for EMA (95% confidence interval (CI)); -12.0%,15% for FDA (90% CI); +/- 13.6% for NMPA (95% CI). Secondary endpoints included pharmacokinetics, safety and immunogenicity.The ICH E9(R1) estimands framework including intercurrent events (related or unrelated to the COVID19 pandemic) was implemented for the ACR20 evaluation. A logistic regression model including ‘region’ (China and Eastern Europe) and ‘previous biologic or targeted synthetic DMARD use’ (Yes/No) as captured in Interactive Web Response System as stratification factors was utilised to assess equivalence for the primary endpoint. The difference in response rates was estimated and corresponding confidence intervals were derived to assess equivalence for the primary endpoint. This abstract presents results up to Week 24.ResultsIn total, 621 subjects were randomised to receive BAT1806/BIIB800 (N=312), TCZ (N=155), or TCZ followed by BAT1806/BIIB800 (N=154). The groups were comparable in terms of baseline demographics and disease characteristics, including age, gender, disease activity and disease duration. The estimated proportions of subjects achieving an ACR20 response in the BAT1806/BIIB800 vs. the TCZ groups, respectively, were 68.97% vs. 64.82% at Week 12 and 69.89% vs. 67.94% at Week 24. The estimated difference between ACR response rates was 4.15% (95% CI -3.63, 11.93) at week 12, and 1.94% (90% CI -4.04, 7.92; 95% CI -5.18, 9.07) at Week 24. The CIs for the estimated differences between the treatment groups were within the pre-defined equivalence margins (Figure 1). The treatment groups were comparable in terms of serum trough levels, incidence of TEAEs and ADA/NAb positivity (Table 1).Table 1.Safety and Immunogenicity up to Week 24, and Pharmacokinetics at Week 24TCZ (N =309) n (%)BAT1806/BIIB800 (N=312) n (%)TEAE196 (63.4)201 (64.4)Related TEAE151 (48.9)148 (47.4)Serious TEAE13 (4.2)11 (3.5)Related Serious TEAE7 (2.3)2 (0.6)Fatal TEAE1 (0.3)3 (1.0)ADA positive a42 (13.6%)64 (20.5%)NAb positive a42 (13.6%)63 (20.2%)PK, n271276Serum trough level (ug/mL), mean (SD)15.4 (17.1)15.8 (12.3)Serum trough level (ug/mL), geometric mean (CV%)12.3 (140.3)12.9 (121.3)Below limit of quantification, n (%)43 (15.9)28 (10.1)TEAE, treatment emergent adverse eventsa subjects with ≥1 ADA/NAb positive results up to week 24ConclusionBAT1806/BIIB800 has demonstrated equivalent efficacy at Week 12 and Week 24 and a similar PK, safety and immunogenicity profile as reference tocilizumab up to Week 24.Disclosure of InterestsXiaomei Leng: None declared, Piotr Leszczynski: None declared, Sławomir Jeka: None declared, Shengyun Liu: None declared, Huaxiang Liu: None declared, Malgorzata Miakisz: None declared, Jieruo Gu: None declared, Lali Kilasonia Speakers bureau: Sandoz, Amgen, Takeda, Mykola Stanislavchuk Speakers bureau: Pfizer, Orion, Boehringer Ingelheim, Xiaolei Yang Shareholder of: Employee of the Bio-thera Solutions Ltd. with shares as a part of Stock incentive plan., Employee of: Employee of the Bio-thera Solutions Ltd., Yinbo Zhou Shareholder of: Employee of Bio-thera Solutions Ltd. with share as part of Stock incentive plan, Employee of: Employee of Bio-thera Solutions Ltd., Qingfeng Dong Shareholder of: Employee of Bio-thera Solutions Ltd. with shares as part of Stock incentive plan, Employee of: Employee of Bio-thera Solutions Ltd., Marian Mitroiu Shareholder of: Employee of Biogen and may hold stocks, Employee of: Employee of Biogen, Janet Addison Shareholder of: Employee of Biogen and holds stock in Biogen, Employee of: Employee of Biogen, Xiaofeng Zeng: None declared

POS0666 A MULTINATIONAL, PROSPECTIVE, OBSERVATIONAL STUDY IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING BARICITINIB, TARGETED SYNTHETIC OR BIOLOGIC DISEASE-MODIFYING THERAPIES: 12 MONTH TIME TO DISCONTINUATION, EFFECTIVENESS AND PATIENT REPORTED OUTCOME DATA FROM THE EUROPEAN COHORT

BackgroundBaricitinib (BARI), an oral selective JAK 1/2 inhibitor, is approved for treating adults with moderate to severe active rheumatoid arthritis (RA). RA-BE-REAL is a 3-year, multinational, prospective, observational study of adult patients with RA evaluating time to discontinuation of initial RA treatment for all causes (excluding sustained clinical response) over 24 months (M).ObjectivesThis analysis reports time to discontinuation in the European (France, Germany, Italy, Spain, UK) subgroup, treated with either BARI, biologic (b) disease-modifying anti-rheumatic drugs (DMARDs) or any other targeted synthetic (ts)DMARDs, as well as, the effectiveness of RA treatment, at 12M.MethodsIn the two cohorts, patients were initiated with BARI 2-mg or 4-mg (cohort A), or any bDMARD or tsDMARD (b/tsDMARDs; cohort B). Treatment initiation and changes are at the discretion of the patient or physician. Response rates for remission, low disease activity (LDA), moderate disease activity (MDA) or high disease activity (HDA) were determined using the Clinical Disease Activity Index (CDAI) at 12M. Quality of life using the EQ-5D-5L and patient reported outcome (PRO) measures for pain (pain visual analogue scale; VAS) and physical functioning (Health Assessment Questionnaire Disability Index; HAQ-DI) were also assessed at 12M. This pre-specified interim analysis reports descriptive 12M data using summary statistics, without any inferential testing.ResultsThis analysis involved 1073 adult RA patients with a mean age (standard deviation; SD) of 59.1 (13.2) (cohort A) and 57.0 (13.9) yrs (cohort B), respectively, and a mean disease duration (SD) of 10.0 (9.1) (cohort A) and 8.9 (9.6) yrs (cohort B), respectively. At baseline, 50.9% of patients in cohort A and 31.2% in cohort B initiated treatment as a monotherapy. At 12M, 26.7% of patients in cohort A and 44.1% of patients in cohort B had discontinued treatment. The most common reason for discontinuation in both cohorts was primary non-response. At 12M, 24.1% of patients in cohort A and 16.6% in cohort B achieved CDAI remission (Figure 1). The mean CDAI reduction was -14.5 and -12.0, respectively in cohorts A and B. Mean reductions from baseline in physician global assessment (PhGA) and in patient global assessment (PGA) were -3.4 and -2.5, respectively in cohort A and -3.0 and -2.1, respectively in cohort B. Improvements from baseline in EQ-5D-5L, HAQ-DI, and pain (VAS) were reported in both cohorts at 12M. The mean pain (VAS) reduction from baseline was -24.6 and -19.3 in cohort A and cohort B, respectively.Figure 1.Percentage of pts in cohorts A and B achieving remission and LDA at 12MConclusionThe majority of BARI-treated patients were in remission or had low disease activity and continued treatment at 12M.Table 1.Disease activity and patient reported outcomes at baseline and 12MCohort A BaricitinibCohort B b/tsDMARDsBaseline12MCFBBaseline12MCFBCDAI24.0 (11.7)9.1 (8.2)-14.5 (12.4)23.8 (12.4)10.7 (9.8)-12.0 (12.6)SJC5.2 (4.8)1.3 (2.4)-3.9 (4.8)4.7 (4.9)1.3 (2.8)-3.0 (4.6)TJC7.3 (6.1)2.2 (3.6)-4.7 (6.0)7.8 (6.5)3.0 (4.8)-4.0 (6.1)PhGA5.6 (2.0)2.3 (2.1)-3.4 (2.5)5.5 (2.1)2.5 (2.1)-3.0 (2.6)PGA5.9 (2.3)3.4 (2.5)-2.5 (2.9)5.8 (2.4)3.8 (2.6)-2.1 (3.0)HAQ-DI1.4 (0.7)1.0 (0.8)-0.4 (0.6)1.3 (0.7)1.0 (0.8)-0.3 (0.6)Pain (VAS)59 (23.1)33.2 (26.2)-24.6 (28.7)56.5 (24.3)36.6 (26.5)-19.3 (30.4)EQ-5D-5L0.5 (0.3)0.7 (0.2)0.1 (0.3)0.5 (0.3)0.7 (0.2)0.1 (0.3)Values represent observed mean (SD)b/tsDMARDs; biologic/targeted synthetic disease-modifying anti-rheumatic drugs, CFB; change from baseline, CDAI; clinical disease activity index, SJC; swollen joint count, TJC; tender joint count, P(h)GA; patient (physician) global assessment of disease activity, HAQ-DI; health assessment questionnaire disability index, VAS; visual analogue scale (mm), EQ-5D-5L; European quality of life 5 dimensions 5 levelsDisclosure of InterestsRieke Alten Speakers bureau: Eli Lilly and Company, Pfizer, Galapagos, Consultant of: Eli Lilly and Company, Pfizer, Galapagos, Grant/research support from: Eli Lilly and Company, Pfizer, Galapagos, Gerd Rüdiger Burmester Speakers bureau: Amgen, AbbVie, BMS, Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche, Sanofi, Consultant of: Amgen, AbbVie, BMS, Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche, Sanofi, Marco Matucci Cerinic Speakers bureau: Biogen, Eli Lilly and Company, Grant/research support from: Actelion, Biogen, Novartis, MSD, Andrew Ostor Consultant of: AbbVie, BMS, Roche, Janssen, Eli Lilly and Company, Novartis, Pfizer, UCB, Gilead, Paradigm, Liliana Zaremba-Pechmann: None declared, Marta Herrera Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Kathy Gibson Speakers bureau: UCB, Consultant of: Janssen, Novartis, Grant/research support from: Novartis, Employee of: Eli Lilly and Company, Tamas Treuer Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Jens Gerwien Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Bruno Fautrel Consultant of: AbbVie, Biogen, BMS, Celgene, Janssen, Eli Lilly and Company, Medac, MSD, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi-Aventis, SOBI, UCB, Grant/research support from: AbbVie, MSD, Pfizer, Eli Lilly and Company

POS0239 RISK OF VENOUS THROMBOEMBOLIC EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AGED ≥50 YEARS WITH ≥1 CARDIOVASCULAR RISK FACTOR: RESULTS FROM A PHASE 3b/4 RANDOMISED STUDY OF TOFACITINIB VS TUMOUR NECROSIS FACTOR INHIBITORS

POS0239 RISK OF VENOUS THROMBOEMBOLIC EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AGED ≥50 YEARS WITH ≥1 CARDIOVASCULAR RISK FACTOR: RESULTS FROM A PHASE 3b/4 RANDOMISED STUDY OF TOFACITINIB VS TUMOUR NECROSIS FACTOR INHIBITORS