Progressive Joint Destruction Research Articles

OA04 Efficacy and safety of nipocalimab in patients with moderate to severe active rheumatoid arthritis: the multicenter, randomised, double-blinded, placebo-controlled phase 2a IRIS-RA study

Abstract Background/Aims Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with autoantibodies. Despite the use of targeted therapies, up to half of patients fail to achieve remission or low disease activity (LDA). Anti-citrullinated protein antibodies (ACPAs), key autoantibodies that predict progression of joint destruction in RA, are largely an immunoglobulin G (IgG) isotype. Nipocalimab is a high affinity, fully human, IgG1 monoclonal antibody that is designed to selectively block the neonatal Fc receptor (FcRn), preventing recirculation and thereby lowering IgG levels, potentially including ACPAs and other pathogenic antibodies. In this phase 2a proof-of-concept study (IRIS-RA; NCT04991753), we report the efficacy and safety of nipocalimab in patients with moderate to severe, active RA. Methods Eligible adult patients with moderate to severe RA (≥6 swollen/tender joints), positive for ACPA or rheumatoid factor, and ≥1 advanced therapies, were randomized 3:2 to receive intravenous 15 mg/kg nipocalimab or placebo every 2 weeks for 10 weeks. The primary endpoint was the change from baseline in the Disease Activity Score 28 using C-reactive protein (DAS28-CRP) at Week 12. Secondary endpoints included the proportion of patients who achieved ACR20, ACR50, ACR70, and ACR90 responses, DAS28-CRP remission, and change from baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 12. Results In total, 53 patients were enrolled (nipocalimab, n = 33; placebo, n = 20). Most patients were female (67.9%) and white (90.6%) with a median age of 59 (range, 26-74) years. Demographic and baseline disease characteristics were comparable between groups except higher CRP in placebo. At Week 12, patients treated with nipocalimab showed a numerically greater mean (standard deviation [SD]) change in DAS28-CRP score compared to the placebo group (-1.17 [1.34] vs -0.62 [0.96]; mean difference [95% confidence interval], -0.45 [-1.17-0.28]; p=0.224). A numerically higher proportion of patients achieved ACR20, ACR50, ACR70, and ACR90 responses compared to placebo. In the nipocalimab group, 7 (21.2%) patients achieved DAS28-CRP remission compared to 2 (10.0%) patients in the placebo group (treatment difference, 9.9% [-9.5-29.3%]; p=0.456). Similarly, patients in the nipocalimab group had a numerically greater mean (SD) improvement in HAQ-DI score (-0.27 [0.55] vs -0.11 [0.36], respectively). The proportion of patients with treatment-emergent adverse events (TEAEs) were 81.8% vs 60.0% in the nipocalimab vs placebo groups. In the nipocalimab group, 3 serious TEAEs were reported, including burn infection, infusion-related reaction, and deep-vein thrombosis. There were no TEAEs that led to death. Conclusion Treatment with nipocalimab resulted in consistent and numerically higher improvements across ACR20, ACR50, ACR70, and ACR90 responses, as well as DAS28-CRP, DAS28-CRP remission, and HAQ-DI, with acceptable safety profile. Nipocalimab showed activity in patients with moderate to severe RA and warrants further investigation to understand the predictors of nipocalimab response. Disclosure P.C. Taylor: Consultancies; AbbVie, Biogen, Eli Lilly, Fresenius, Galapagos, Gilead Sciences, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Inc, Sanofi, Aqtual, and UCB. Grants/research support; Galapagos. G. Schett: None. F. Ibrahim: Corporate appointments; Employee of Janssen Research & Development. B. Zhou: Corporate appointments; Employee of Janssen Research & Development. J. Leu: Corporate appointments; Employee of Janssen Research & Development. S. Liva: Corporate appointments; Employee of Janssen Research & Development. Q. Wang: Corporate appointments; Employee of Janssen Research & Development. R. Rojo Cella: Corporate appointments; Employee of Janssen Research & Development. C.S. Karyekar: Corporate appointments; Employee of Janssen Research & Development. K. Fei: Corporate appointments; Employee of Janssen Research & Development.

Advanced application of carbohydrate-based micro/nanoparticles for rheumatoid arthritis

Rheumatoid arthritis (RA) is a kind of synovitis and progressive joint destruction disease. Dysregulated immune cell activation, inflammatory cytokine overproduction, and subsequent reactive oxidative species (ROS) production contribute to the RA process. Carbohydrates, including cellulose, chitosan, alginate and dextran, are among the most abundant and important biomolecules in nature and are widely used in biomedicine. Carbohydrate-based micro/nanoparticles(M/NPs) as functional excipients have the ability to improve the bioavailability, solubility and stability of numerous drugs used in RA therapy. For on-demand therapy, smart reactive M/NPs have been developed to respond to a variety of chemical and physical stimuli, including light, temperature, enzymes, pH and ROS, alternating their physical and macroscopic properties, resulting in innovative new drug delivery systems. In particular, advanced products with targeted dextran or hyaluronic acid are exploiting multiple beneficial properties at the same time. In addition to those that respond, there are promising new derivatives in development with microenvironment and chronotherapy effects. In this review, we provide an overview of these recent developments and an outlook on how this class of agents will further shape the landscape of drug delivery for RA treatment.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA. The RESET-RA study is a randomized, double-blind, sham-controlled, multi-center, two-stage pivotal trial that enrolled patients with moderate-to-severe RA who were incomplete responders or intolerant to at least one biologic or targeted synthetic disease-modifying anti-rheumatic drug. A neuroimmune modulation device (SetPoint Medical, Valencia, CA) was implanted on the left cervical vagus nerve within the carotid sheath in all patients. Following post-surgical clearance, patients were randomly assigned (1:1) to active stimulation or non-active (control) stimulation for 1min once per day. A predefined blinded interim analysis was performed in patients enrolled in the study's initial stage (Stage 1) that included demographics, enrollment rates, device implantation rates, and safety of the surgical procedure, device, and stimulation over 12 weeks of treatment. Sixty patients were implanted during Stage 1 of the study. All device implant procedures were completed without intraoperative complications, infections, or surgical revisions. No unanticipated adverse events were reported during the perioperative period and at the end of 12 weeks of follow-up. No study discontinuations were due to adverse events, and no serious adverse events were related to the device or stimulation. Two serious adverse events were related to the implantation procedure: vocal cord paresis and prolonged hoarseness. These were reported in two patients and are known complications of surgical implantation procedures with vagus nerve stimulation devices. The adverse event of vocal cord paresis resolved after vocal cord augmentation injections with filler and speech therapy. The prolonged hoarseness had improved with speech therapy, but mild hoarseness persists. The surgical procedures for implantation of the novel neuroimmune modulation device for the treatment of RA were safe, and the device and its use were well tolerated. NCT04539964; August 31, 2020.

Identification of citrullinated α1-antitrypsin (A1AT) in saliva in a mouse model of rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA) is an autoimmune disease characterized by progressive joint destruction. Early diagnosis and treatment, before joint deformation or destruction occurs, are crucial. Identifying novel biomarkers for RA in saliva could potentially enable early detection of the disease, prior to its onset. MethodsWe conducted a comprehensive proteomic analysis of salivary proteins in a mouse model of RA. Proteins were identified using western blotting and enzyme-linked immunosorbent assay in the serum, saliva, and ankle joints of DBA/1JJmsSlc mice, a model of RA. Ankle joints and submandibular glands were stained with hematoxylin and eosin and immunostained, and the results were compared with those of control mice. ResultsCitrullinated alpha-1 antitrypsin (A1AT, 46 kDa) was commonly detected in the saliva, serum, and ankle joints of mice with severe RA and was confirmed through proteomic analysis. Western blotting showed a band corresponding to 46 kDa in the serum, saliva, and ankle joints. Immunostaining of the ankle joints with the A1AT antibody showed a strong positive signal in the synovium. ConclusionsIn DBA/1JJmsSlc mice, cyclic citrullinated peptide antibodies and A1AT may be involved in citrullination and contribute to the development and severity of RA, making them valuable treatment targets requiring further study.

Network analysis, in vivo, and in vitro experiments identified the mechanisms by which Piper longum L. [Piperaceae] alleviates cartilage destruction, joint inflammation, and arthritic pain.

Osteoarthritis (OA) is characterized by irreversible joint destruction, pain, and dysfunction. Piper longum L. [Piperaceae] (PL) is an East Asian herbal medicine with reported anti-inflammatory, analgesic, antioxidant, anti-stress, and anti-osteoporotic effects. This study aimed to evaluate the efficacy of PL in inhibiting pain and progressive joint destruction in OA based on its anti-inflammatory activity, and to explore its potential mechanisms using in vivo and in vitro models of OA. We predicted the potential hub targets and signaling pathways of PL through network analysis and molecular docking. Network analysis results showed that the possible hub targets of PL against OA were F2R, F3, MMP1, MMP2, MMP9, and PTGS2. The molecular docking results predicted strong binding affinities for the core compounds in PL: piperlongumine, piperlonguminine, and piperine. In vitro experiments showed that PL inhibited the expression of LPS-induced pro-inflammatory factors, such as F2R, F3, IL-1β, IL-6, IL-17A, MMP-1, MMP-2, MMP-3, MMP-9, MMP-13, NOS2, PTGS2, PGE2, and TNF-β. These mechanisms and effects were dose-dependent in vivo models. Furthermore, PL inhibited cartilage degradation in an OA-induced rat model. Thus, this study demonstrated that multiple components of PL may inhibit the multilayered pathology of OA by acting on multiple targets and pathways. These findings highlight the potential of PL as a disease-modifying OA drug candidate, which warrants further investigation.

Hsa-miR-21-5p reflects synovitis and tenosynovitis components of Musculoskeletal Ultrasonography Seven-joint Scores in Rheumatoid Arthritis Disease and Predicts the Disease Flare

Rheumatoid arthritis (RA) is characterized by progressive joint destruction with subsequent serious disability. Objective biomarkers of RA course progression are lacking, which necessitates the discovery of activity indicators and predictors of the disease outcome. Musculoskeletal Ultrasound Seven-joint Score (MSUS7) is proposed as a reliable technique to evaluate radiographic RA progression. Homo sapiens-microRNA-21-5p (hsa-miR-21-5p) plays an important role during joint remodeling and the pro-inflammatory process driving RA progression. We aimed to evaluate plasma hsa-miR-21-5p as a noninvasive RA activity biomarker and to investigate if hsa-miR-21-5p is linked to MSUS7 components in the context of RA activity. This cross-sectional study included 71 RA patients classified into inactive (n = 36) and active (n = 35) groups according to the Disease Activity Score 28-joint count with ESR (DAS28-ESR). Joints were assessed by MSUS7. Gray-scale ultrasound (GSUS) and power Doppler ultrasound (PDUS) were used to rate the synovitis, tenosynovitis, and erosion in the joints. Plasma hsa-miR-21-5p expression was measured by real-time PCR. The absolute count of regulatory T cell (Treg) was calculated after Treg frequency was assessed by flow cytometry. Results: Hsa-miR-21 expression was significantly up-regulated in the active RA group with a median fold change of 51.6 in comparison to the inactive cases with a median fold change of 7.7 (p < 0.001). Hsa-miR-21-5p was positively correlated with DAS28-ESR, C reactive protein (CRP), and rheumatoid factor (r = 0.7, p < 0.001, r = 0. 0.6, p < 0.001, and r = 0.4, p = 0.002, respectively), while negatively correlated with Treg absolute count (r = -0.4, p < 0.001). Hsa-miR-21-5p levels were correlated with synovitis and tenosynovitis in GSUS (r = 0.4, p < 0.001, r = 0.3, p = 0.025, respectively) and in PDUS (r = 0.5, p < 0.001 and 0.4, p = 0.001, respectively). The hsa-miR-21-5p accurately distinguished RA activity [AUC 0.933, 94.3% sensitivity, and 86.1% specificity]. Logistic regression analysis revealed hsa-miR-21-5p as an independent predictor for RA flare (OR = 1.228, p = 0.004). Hsa-miR-21-5p was linked to synovitis and tenosynovitis components of the MSUS7. Up-regulated hsa-miR-21-5p can be utilized as a predictor for RA disease flare.

Humoral factors in the formation of neuroosteoarthropathy in type 2 diabetes mellitus

BACKGROUND: Diabetic neuroosteoarthropathy is a severe and insufficiently studied complication of diabetes mellitus, which is characterized by progressive destruction of bones and joints against the background of neuropathy and leads to the formation of foot deformities of varying severity. The search for predictors of this pathology is extremely relevant, because will optimize therapy and reduce the risk of limb amputation.AIM: To compare the levels of advanced glycation end products and their receptors in the blood and bone tissue in patients with type 2 diabetes mellitus and diabetic neuroosteoarthropathy and in individuals without this complication in order to determine the possibility of using these parameters as early predictors of severe foot deformities in this category of patients.MATERIALS AND METHODS: During hospitalization for planned surgical treatment, venous blood and bone tissue samples were taken from patients with chronic (inactive) stage of DNOAP and patients with neuropathic foot ulcers.RESULTS: The study included 88 patients with type 2 diabetes mellitus and neuropathic form of diabetic foot syndrome, who were divided into 2 groups. Group 1 consisted of patients with chronic diabetic neuroosteoarthropathy, group 2 — patients with severe diabetic neuropathy without osteoarticular disorders. The study did not show statistically significant differences in the level of AGE in the blood serum of patients with DNOAP and without this complication, however, a significant increase in AGE receptors (RAGE) in bone tissue was recorded in the group of patients with DNOAP compared with the control. Patients with increased RAGE expression in bone had higher blood levels of AGE compared to the group without this complication, but this difference was not significant.CONCLUSION: For the first time, a study of AGEs and receptors for them in the blood serum and bone tissue in individuals with DNOAP and without this complication was carried out. The obtained results suggest that the determining factor in the rate of formation and the likelihood of recurrence of DNOAP in type 2 diabetes mellitus is not the content of AGEs in the blood, but the expression of their receptors in bone tissue.

The influence of the degree of activity of rheumatoid arthritis on the parameters of stable metabolites of nitric oxide

Rheumatoid arthritis (RA) is an immunoinflammatory disease characterized by progressive destruction of joints and damage to internal organs, which is based on disturbances in the humoral and cellular immune system [1,2]. In the absence of effective therapy, life expectancy in patients with RA is lower by 3 years in women and 7 years in men, primarily due to the high risk of developing comorbid diseases [5].

A Step in the Right Direction: Analyzing Differences in Demographics and Mortality in Operative Management of Charcot Neuroarthropathy

Category: Midfoot/Forefoot; Diabetes Introduction/Purpose: Charcot neuroarthropathy (CN) of the foot is a debilitating condition associated with diabetic neuropathy that involves progressive bone and joint destruction. Previous literature suggests the prevalence of CN is between 0.8%-8% in diabetic patients; however, CN diagnosis relies on skilled physician judgment, ultimately making management difficult. Physicians must account for the location, deformity, stage, and presence or absence of infection to appropriately treat CN. Correct diagnosis and treatment is essential to improving patients’ quality of life, but treatment varies with no definitive best-practice guidelines. Here, we provide demographic and all-cause mortality data for patients who underwent arthrodesis, exostectomy, minor amputations, and below-the-knee amputation (BKA), to evaluate the outcomes and characterize the populations managed with surgery for Charcot neuroarthropathy of the foot. Methods: Institutional review board approval was obtained. A database of all patients from 1/1/2000 to 1/31/2022 with CPT and ICD codes indicating a diagnosis of Charcot neuroarthropathy who underwent exostectomy, arthrodesis, and/or amputation was created from the electronic medical record. Demographic and mortality data was collected for the study sample, including date-of- birth, sex, race, and all-cause mortality. Procedure data was also collected, which included date, code, and description. Amputation patients were separated into major and minor; major include transtibial and trans-metatarsal, whereas minor include toe and metatarsal amputations. Descriptive statistics were conducted and single-factor ANOVA and Chi squared tests were used for analysis. Results: Of the 2,066 patients; 557 had arthrodesis, 493 had exostectomy, 681 had minor amputation, and 335 had major amputation. Average age was 58.17 ± 13.8 overall, and 54.8 ± 13.6, 55.0 ± 13.0, 61.6 ± 13.6, and 61.5 ± 13.4 years for arthrodesis, exostectomy, minor amputation, and major amputation, respectively. Females accounted for 56.6% of arthrodeses, 56.8% of exostectomies, 34.5% of minor amputations, and 28.4% of major amputations performed (p &lt; 0.001). Patients were predominantly white in each group and overall, 2.1% were tobacco smokers. Mortality was 10.6%, 11.4%, 33.8%, and 31.9% in the arthrodesis, exostectomy, minor amputation, and major amputation groups, respectively (Figure 1). Conclusion: This is the first report of significant sample size (&gt;2,000 patients) comparing both demographic and mortality between common surgical procedures for Charcot neuroarthropathy. Patients undergoing both minor and major amputations were more likely to be older and male compared to those undergoing less intensive operations. Most importantly, this data demonstrates that patients undergoing amputation have significantly worse mortality (33.8% and 31.9%) than those who undergo arthrodesis (10.6%) and exostectomy (11.4%). Future studies may include an analysis of cause-specific mortality for patients diagnosed with CN to evolve clinical and surgical management.

Nanocomposite hydrogel to deliver the immunomodulator lenalidomide and anti-inflammatory hesperidin locally to joints affected by rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disease characterized by inflammatory cell infiltration, neovascularization in the synovial tissue, and progressive joint destruction. The immunomodulatory drug lenalidomide and anti-inflammatory anti-oxidant hesperidin show therapeutic potential against the disease as two complementary drugs, but they also show poor oral bioavailability and solubility as well as a short time in circulation. To overcome these disadvantages, the two drugs were loaded into polymeric micelles in their native forms and also, they were conjugated to polyethylene glycol to create acid-activated prodrugs. Lastly, the micelles alone or with the prodrugs were formulated into an injectable hydrogel. Of all formulations, the hydrogel containing micelles and prodrugs led to the greatest drug uptake by Raw264.7 macrophages in culture and inhibition of angiogenesis in a chick chorioallantoic membrane assay. In rats with collagen-induced arthritis, the hydrogel released the two drugs in a sustained manner, preferentially in joints with acidic pH. They dampened inflammatory responses, mitigating bone injury. This biocompatible, pH-responsive formulation based on two complementary drugs may provide a new strategy for treating rheumatoid arthritis.

Clinical, radiographic and molecular characterization of two unrelated families with multicentric osteolysis, nodulosis, and arthropathy

BackgroundMulticentric osteolysis nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder characterized by marked progressive bone loss and joint destruction resulting in skeletal deformities. MONA is caused by MMP2 deficiency. Here we report clinical and molecular analyses of four patients in two families from Pakistan and Finland.MethodsClinical analyses including radiography were completed and blood samples were collected. The extracted DNA was subjected to whole-exome analysis or target gene sequencing. Segregation analyses were performed in the nuclear pedigree. Pathogenicity prediction scores for the selected variants and conservation analyses of affected amino acids were observed.ResultsThe phenotype in the four affected individuals was consistent with multicentric osteolysis or MONA, as the patients had multiple affected joints, osteolysis of hands and feet, immobility of knee joint and progressive bone loss. Long-term follow up of the patients revealed the progression of the disease. We found a novel MMP2 c.1336 + 2T > G homozygous splice donor variant segregating with the phenotype in the Pakistani family while a MMP2 missense variant c.1188 C > A, p.(Ser396Arg) was homozygous in both Finnish patients. In-silico analysis predicted that the splicing variant may eventually introduce a premature stop codon in MMP2. Molecular modeling for the p.(Ser396Arg) variant suggested that the change may disturb MMP2 collagen-binding region.ConclusionOur findings expand the genetic spectrum of Multicentric osteolysis nodulosis and arthropathy. We also suggest that the age of onset of this disorder may vary from childhood up to late adolescence and that a significant degree of intrafamilial variability may be present.

Characterization of a recombinant factor IX molecule fused to coagulation factor XIII-B subunit.

Severe haemophilia B (HB) is characterized by spontaneous bleeding episodes, mostly into joints. Recurrent bleeds lead to progressive joint destruction called haemophilic arthropathy. The current concept of prophylaxis aims at maintaining the FIX level >3-5IU/dL, which is effective at reducing the incidence of haemophilic arthropathy. Extended half-life FIX molecules make it easier to achieve these target trough levels compared to standard FIX concentrates. We previously reported that the fusion of a recombinant FIX (rFIX) to factor XIII-B (FXIIIB) subunit prolonged the half-life of the rFIX-LXa-FXIIIB fusion molecule in mice and rats 3.9- and 2.2-fold, respectively, compared with rFIX-WT. However, the mechanism behind the extended half-life was not known. Mass spectrometry and ITC were used to study interactions of rFIX-LXa-FXIIIB with albumin. Pharmacokinetic analyses in fibrinogen-KO and FcRn-KO mice were performed to evaluate the effect of albumin and fibrinogen on in-vivo half-life of rFIX-LXa-FXIIIB. Finally saphenous vein bleeding model was used to assess in-vivo haemostatic activity of rFIX-LXa-FXIIIB. We report here the key interactions that rFIX-LXa-FXIIIB may have in plasma are with fibrinogen and albumin which may mediate its prolonged half-life. In addition, using the saphenous vein bleeding model, we demonstrate that rFIX-FXIIIB elicits functional clot formation that is indistinguishable from that of rFIX-WT.

Administration of Recombinant TAPBPL Protein Ameliorates Collagen-Induced Arthritis in Mice.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease distinguished by synovial hyperplasia and a progressive destruction of joints. T cells are critical players in the pathogenesis of RA. We have previously identified a novel immune checkpoint molecule, TAPBPL, that inhibits T cell functions in vitro. As a model for human RA, we investigated the ability of the TAPBPL protein to ameliorate collagen type II (CII)-induced arthritis (CIA) in mice that were injected with recombinant TAPBPL or a control protein. The mice were analyzed for CIA development, immune cells, and their responses. We found that TAPBPL protein significantly decreased CIA incidence and reduced clinical and pathological arthritis scores, which were related to a lower number of activated CD4 T cells but a greater number of regulatory T cells (Tregs) in the spleen, and a reduction of Th1/Th17 inflammatory cytokines in the joints and serum. Importantly, TAPBPL protein inhibited CII-specific T cell growth and Th1 and Th17 cytokine expression and reduced the production of CII autoantibodies in the serum. Our results suggest that TAPBPL protein can ameliorate CIA in mice and has the potential to be used in the treatment of patients with RA.

Study of Association of Chromosomal Region 1Q21-23 with Rheumatoid Arthritis and Their Correlation with Severity of Disease.

The understanding of the pathophysiology of rheumatoid arthritis (RA) has taken a major step forward with the research of new illness-related genes and further deciphering the involved molecular. Gene variants like human leukocyte antigen (HLA)-DRB1 and PTPN22 1858T act as individual risk factors for RA. It also serves as a risk factor for the rate of progression of joint destruction and clinical manifestations in autoimmune diseases like RA. The focus of this study is to find out the association of chromosomal region 1q21-23 with RA and its connection with disease severity using the disease activity score (DAS) and distribution frequency of the prevalent alleles of such genes in an already recruited group of patients/controls of India, specifically Northwest Rajasthan. This was a case-control study wherein every patient of RA aged 16 years and above diagnosed with RA as per the 2010 American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) revised criteria for RA in Outpatient Department (OPD) and Inpatient Department (IPD) patients were included. Blood samples of the study population were drawn at Sardar Patel Medical College (SPMC), Bikaner (rheumatology OPD), along with the cooperation of Birla Institute of Technology and Science (BITS), Hyderabad (Department of Biological Sciences) from July 2009 to January 2012. A total of 100 controls (without any previous history of disease) and 135 cases were selected considering inclusion and exclusion criteria. Clinical data along with laboratory parameters like complete blood count, serum electrolytes (sodium, potassium, calcium, and chlorine ions), blood sugar, blood urea with serum creatinine, lactate dehydrogenase (LDH) isoenzymes assay, serum glutamic-oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) ratio, serum γ-glutamyl transferase (GGT) level, serum amylase, arterial blood gas (ABG), total serum proteins were evaluated and recorded from the patients. Our study showed control group has a mean age of 45.11 + 4.12 years. The case and control groups did not have significant differences in any of the clinical variables. 59% of cases show joint deformity. Allelic frequencies of the D1S498 polymorphism in cases were found significant in sizes 198, 204, 208, and 210, while it was found insignificant in sizes 192, 196, 200, 202, and 206. No correlation was found in allelic frequencies of the D1S318 polymorphism in cases and controls. Bigger cohort studies will allow better genomic elucidation of clinically defined intermediate phenotypes evaluated in RA patients by virtue of the autoimmune origin of the disease and its diverse symptoms in patients. Genetic-molecular studies can be a milestone for adopting effective personalized treatment for such progressively debilitating diseases. How to cite this article: Gauri LA, Meena MK, Singh U, et al. Study of Association of Chromosomal Region 1Q21-23 with Rheumatoid Arthritis and Their Correlation with Severity of Disease. J Assoc Physicians India 2023;71(9):28-32.

Neutrophil- and Platelet-to-Lymphocyte Ratios (NLR &amp; PLR) and Their Relation with Disease Activity in Rheumatoid Arthritis Patients

Abstract Background RA is the most common chronic inflammatory arthritis and is associated with progressive destruction of synovial joints and physical disability. It is a polygenic disease characterized by autoimmunity and systemic inflammation with progressive impairment of the joints, resulting in lifelong disability and increased mortality. Aim of the Work The aim of the study is to study the correlation between both of Neutrophil- and platelet-to-lymphocyte ratios (NLR&amp;PLR) and disease activity in RA patients. Patients and Methods Our cross-sectional case-control study enrolled 50 patients with RA, in addition to 30 healthy volunteers as a control group.All included patients were subjected to full history taking with special emphasis on history of RA, thorough clinical examination was done with special emphasis on musculoskeletal examination. Results When we compared RA patients with the controls, we found a highly statistically significant difference between them regarding NLR and PLR being higher in the RA group. In our study we found that both NLR and PLR has fair diagnostic value to discriminate between RA patients and controls using the ROC curve at a cut-off value of 2.58 and 151.05 respectively. In RA patients, highly statistically significant correlation was found between both NLR and PLR. In addition, statistically significant correlation was found between NLR with both VAS score and DAS28_ESR and also between PLR with ESR, VAS score and RF.PLR also correlated significantly with US7 score, PDUS synovitis and gray GSUS tenosynovitis. Conclusion NLR and PLR that can be obtained via CBC (which is convenient, inexpensive and fast), can serve as an additional useful marker for the diagnosis of RA. NLR and PLR has important value in the assessment of RA related disease activity. In contrast to traditional markers, they are less expensive and effective measure of inflammation that is not impacted by the cytokines influencing the ESR and CRP. US7 score is a simple and effective measure to detect subclinical synovitis in RA patients and to assess and follow up disease activity.

Identification of novel TACE inhibitors using DNN based- virtual screening, molecular dynamics and biological evaluation

Rheumatoid Arthritis (RA) is a well-known autoimmune inflammatory disease, distressing roughly 1% of the adult population throughout the globe. Many studies have suggested that overexpression of TNF-α, a pro-inflammatory cytokine, is responsible for the progression of RA. Furthermore, inhibition of the shedding rate of TNF-α is regulated by the TACE (TNF-α converting enzyme) protein and, hence is considered as an important therapeutic target for the prevention of progressive synovial joint destruction in rheumatoid arthritis. In the present study, we have proposed a deep neural network (DNN)-based workflow for the virtual screening of compounds towards the identification of potential inhibitors against the TACE proteins. Subsequently, a set of compounds were shortlisted, based on the molecular docking and subjected to the biological evaluation to validate the inhibitory activities of the screened compounds, determine the practical applicability of the DNN-based model, and strengthen the hypothesis. Out of seven, three compounds (BTB10246, BTB10247, and BTB10245) showed significant inhibition at 10 µM and 0.1 µM concentration. These three compounds also showed a stable and significant interaction potential against the TACE protein as compared with the re-docked complex system and can serve as a novel scaffold for further design of new molecules with improved inhibitory activities against TACE. Communicated by Ramaswamy H. Sarma

Mid-Term Outcomes of Arthroscopic Rotator Cuff Repair in Patients with Rheumatoid Arthritis.

The effectiveness of arthroscopic rotator cuff repair (ARCR) on rheumatoid arthritis (RA) patients remains a controversial topic. This study investigates the mid-term outcomes of ARCR in RA patients and identifies the factors influencing clinical efficacy. This retrospective study enrolled RA patients with small or medium rotator cuff tears (RCTs) between February 2014 and February 2019. Visual Analog Scale (VAS), American Shoulder and Elbow Surgeons (ASES), and Constant-Murley scores were collected at each follow-up time. Ultimately, magnetic resonance imaging (MRI) and X-ray were employed to assess rotator cuff integrity and progression of shoulder bone destruction, respectively. Statistical methods used two-way repeated-measures ANOVA or generalized estimation equations. A total of 157 patients were identified and divided into ARCR (n = 75) and conservative treatment (n = 82) groups. ARCR group continued to be divided into small tear (n = 35) and medium tear (n = 40) groups. At the final, all scores were better in ARCR group than in the conservative treatment group (p < 0.05). A radiographic evaluation of the final follow-up demonstrated that the progression rate in ARCR group (18.67%) was significantly lower than that of the conservative treatment group (39.02%, p < 0.05). In the comparison of the small tear and medium tear groups, all scores increased significantly after surgery (p < 0.05), and the final follow-up scores were better than preoperative scores (p < 0.05) but worse than those of the 6-month postoperative follow-up (p < 0.05). Comparison between the two groups revealed that all scores of the small tear group were significantly better than those of the medium tear group at 6-month postoperative follow-up (p < 0.05). Although the scores of small tear group remained better than those of the medium group at the final postoperative follow-up, the difference was not statistically significant (p > 0.05). Radiographic assessment of the final follow-up demonstrated that the progression rate in the small tear group (8.57%) was significantly lower than that in the medium group (27.50%, p < 0.05), and the retear rate of small tear group (14.29%) was significantly lower than that of the medium tear group (35.00%, p < 0.05). ARCR could effectively improve the quality of life for RA patients with small or medium RCTs, at least in the medium term. Despite the progression of joint destruction in some patients, postoperative retear rates were comparable to those in the general population. ARCR is more likely to benefit RA patients than conservative treatment.

Association of the Clinical and Radiographic Findings at Onset With Future Joint Destruction in Patients With Rheumatoid Arthritis.

Since inflammation can cause joint destruction in patients with rheumatoid arthritis (RA), it is assumed that joints that are symptomatic at onset are at higher risk of joint destruction; however, this theory remains controversial. This study aimed to investigate whether the progression of joint destruction in hands and feet could be predicted from the clinical and radiographic findings at onset. This study included 75 patients who visited our hospital within one year after the onset of RA with at least 12 months of follow-up. We examined the positive predictive value (PPV) and the sensitivity of the clinical findings (swelling, tenderness, and squeeze test) and joint destruction at onset for the progression of joint destruction. Sixty joints (45 metacarpophalangeal and proximal interphalangeal joints, 15 metatarsophalangeal joints) exhibited progressive structural destruction during the study course. Both the PPV and the sensitivity of the clinical findings for the progression of joint destruction were low; however, only the sensitivity of the squeeze test for the feet was high. The PPV of joint destruction at onset was higher than the clinical findings, and the sensitivity of joint destruction at onset was as high as the squeeze test for the feet. Conclusions: Regular follow-up with imaging is necessary regardless of symptoms and joint destruction at the onset. Adding the squeeze test for feet to routine clinical practice may help predict the risk of joint destruction for the feet.

CD5L aggravates rheumatoid arthritis progression via promoting synovial fibroblasts proliferation and activity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive cartilage erosion and joint destruction. Synovial fibroblasts (SFs) play a crucial role in the pathogenesis of RA. This study aims to explore the function and mechanism of CD5L during RA progression. We examined the levels of CD5L in synovial tissues and SFs. The collagen-induced arthritis (CIA) rat models were used to investigate the effect of CD5L on RA progression. We also investigated the effects of exogenous CD5L on the behavior and activity of RA synovial fibroblasts (RASFs). Our results showed that CD5L expression was significantly upregulated in synovium of RA patients and CIA-rats. Histology and Micro-CT analysis showed that synovial inflammation and bone destruction were more severe in CD5L-treated CIA rats compared with control rats. Correspondingly, CD5L blockade alleviated bone damage and synovial inflammation in CIA-rats. The exogenous CD5L treatment promoted RASFs proliferation invasion and proinflammatory cytokine production. Knockdown of CD5L receptor by siRNA significantly reversed the effect of CD5L treatment on RASFs. Moreover, we observed that CD5L treatment potentiated PI3K/Akt signaling in the RASFs. The promoted effects of CD5L on IL-6 and IL-8 expression were significantly reversed by PI3K/Akt signaling inhibitor. In conclusion, CD5L promote RA disease progression via activating RASFs. CD5L blocking is a potential therapeutic approach for RA patients.

Cartilage Damage Pathological Characteristics of Diabetic Neuropathic Osteoarthropathy.

Diabetic neuropathic osteoarthropathy (DNOAP) is a rare and easily missed complication for diabetes that leads to increased morbidity and mortality. DNOAP is characterized by progressive destruction of bone and joint, but its pathogenesis remains elusive. We herein aimed to investigate the pathological features and pathogenesis of the cartilages damage in DNOAP patients. The articular cartilages of eight patients with DNOAP and eight normal controls were included. Masson staining and safranine O/fixed green staining (S-O) were used to observe the histopathological characteristics of cartilage. The ultrastructure and morphology of chondrocytes were detected by electron microscopy and toluidine blue staining. Chondrocytes were isolated from DNOAP group and control group. The expression of receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and Aggrecan protein was evaluated by western blot. Reactive oxygen species (ROS) levels were measured using a 2',7'-dichlorofluorescin diacetate (DCFH-DA) probe. The percentage of apoptotic cells was determined by flow cytometry (FCM). The chondrocytes were cultured with different glucose concentrations to observe the expression of RANKL and OPG. Compared with the control group, the DNOAP group showed fewer chondrocytes, subchondral bone hyperplasia, and structural disorder, and a large number of osteoclasts formed in the subchondral bone area. Moreover, mitochondrial and endoplasmic reticulum swellings were observed in the DNOAP chondrocytes. The chromatin was partially broken and concentrated at the edge of nuclear membrane. The ROS fluorescence intensity of chondrocyte in DNOAP group was higher than that in normal control group (28.1 ± 2.3 vs. 11.9 ± 0.7; P < 0.05). The expression of RANKL, TNF-α, IL-1β, and IL-6 protein in DNOAP group was higher than that in normal control group, whereas OPG and Aggrecan protein were lower than that in normal control group (both P < 0.05). FCM showed that the apoptotic rate of chondrocyte in DNOAP group was higher than that in normal control group (P < 0.05). The RANKL/OPG ratio showed significant upward trend when the concentration of glucose was over than 15 mM. DNOAP patients tend to have severe destruction of articular cartilage and collapse of organelle structure including mitochondrion and endoplasm reticulum. Indicators of bone metabolism (RANKL and OPG) and inflammatory cytokines (IL-1β, IL-6, and TNF-α) play an important role in promoting the pathogenesis of DNOAP. The glucose concentration higher than 15 mM made the RANKL/OPG ratio change rapidly.