Joint Inflammation Research Articles

Mesenchymal Stem Cell-Based Biomimetic Liposome for Targeted Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disorder that severely compromises joint health. The primary therapeutic strategy for advanced RA aims to inhibit joint inflammation. However, the nonspecific distribution of pharmacological agents has limited therapeutic efficacy and heightens the risks associated with RA treatment. To address this issue, we developed mesenchymal stem cell (MSC)-based biomimetic liposomes, termed MSCsome, which were composed of a fusion between MSC membranes and liposomes. MSC some with relatively simple preparation method effectively enhanced the targeting efficiency of drug to diseased joints. Interaction between lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 enhanced the affinity of the MSCsome for polarized macrophages, thereby improving its targeting capability to affected joints. The effective targeted delivery facilitated drug accumulation in joints, resulting in the significant inhibition of the inflammation, as well as protection and repair of the cartilage. In conclusion, this study introduced MSCsome as a promising approach for the effective treatment of advanced RA, providing a novel perspective on targeted drug delivery therapy for inflammatory diseases.

UNRAVELING THE GENETIC AND EPIGENETIC LANDSCAPE OF RHEUMATOID ARTHRITIS: A COMPREHENSIVE REVIEW OF PATHOGENESIS, DIAGNOSIS, AND THERAPEUTIC IMPLICATIONS

This exhaustive review delves into the genetic and epigenetic foundations of Rheumatoid Arthritis (RA), a multifaceted autoimmune disorder characterized by persistent joint inflammation. We discuss the findings of genome-wide association studies (GWAS) that have uncovered numerous genetic loci associated with RA, emphasizing the substantial impact of HLA variants on disease susceptibility and severity. The review also explores epigenetic mechanisms such as DNA methylation, histone modifications, and the regulatory role of microRNAs, all of which influence gene expression and immune response in RA. The involvement of inflammasomes in mediating inflammatory responses emphasizes potential therapeutic targets. Furthermore, the application of artificial intelligence for analyzing intricate genetic data presents promising opportunities for advancing diagnosis and treatment strategies. This article underscores the critical need for integrating multi-omics data. It emphasizes the significance of collaborative research in the field of RA, highlighting the importance of your work in this area.

Single-Cell Multi-Dimensional data analysis reveals the role of ARL4C in driving rheumatoid arthritis progression and Macrophage polarization dynamics

Rheumatoid arthritis (RA) is an enduring autoimmune inflammatory condition distinguished by continual joint inflammation, hyperplasia of the synovium, erosion of bone, and deterioration of cartilage.Fibroblast-like synoviocytes (FLSs) exhibiting “tumor-like” traits are central to this mechanism.ADP-ribosylation factor-like 4c (ARL4C) functions as a Ras-like small GTP-binding protein, significantly impacting tumor migration, invasion, and proliferation.However, it remains uncertain if ARL4C participates in the stimulation of RA FLSs exhibiting “tumor-like” features, thereby fostering the advancement of RA. In our investigation, we unveiled, for the inaugural instance, via the amalgamated scrutiny of single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk-seq) datasets, that activated fibroblast-like synoviocytes (FLSs) showcase high expression of ARL4C, and the ARL4C protein expression in FLSs derived from RA patients significantly surpasses that observed in individuals with osteoarthritis (OA) and traumatic injury (trauma).Silencing of the ARL4C gene markedly impeded the proliferation of RA FLSs by hindered the transition of cells from the G0/G1 phase to the S phase, and intensified cell apoptosis and diminished the migratory and invasive capabilities. Co-culture of ARL4C gene-silenced RA FLSs with monocytes/macrophages significantly inhibited the polarization of monocytes/macrophages toward M1 and the repolarization of M2 to M1.Furthermore, intra-articular injection of shARL4C significantly alleviated synovial inflammation and cartilage erosion in collagen-induced arthritis (CIA) rats.In conclusion, our discoveries propose that ARL4C assumes a central role in the synovial inflammation, cartilage degradation, and bone erosion associated with RA by triggering the PI3K/AKT and MAPK signaling pathways within RA FLSs.ARL4C holds promise as a prospective target for the development of pharmaceutical agents targeting FLSs, with the aim of addressing RA.

Exploring Potential Bioactive Components of Persea americana for the Treatment of Rheumatoid Arthritis through Network Pharmacology.

Rheumatoid arthritis (RA) is a chronic autoimmune disease character-ized by inflammation and joint destruction, leading to significant disability and reduced quality of life. Current treatment options for RA have limitations, highlighting the need for novel therapeu-tic approaches. In this study, we employed network pharmacology methods to identify potential bioactive compounds from Persea Americana (avocado) for the treatment of RA. We collected information on the phytoconstituents of avocados from the IMPPAT database and used Data Warrior software to filter out 64 plant constituents based on ADMET criteria. Target genes associated with avocado compounds were identified using the Bindingdb web server, resulting in 209 genes from Persea Americana. Protein-protein interaction (PPI) network analysis was performed using Cytoscape software to identify key genes and pro-teins involved in RA. Protein-drug interactions were analyzed, and ten avocado constituents with high binding affinity were identified. Our network pharmacology analysis revealed that avocado constituents, particularly Luteolin, have the potential to be developed as novel therapeutics for RA. The PPI network analysis identified key genes and proteins associated with RA, providing insights into the molecular mechanisms of the disease. The high binding affinity observed between Luteolin and PTGS2, a protein involved in joint inflammation, suggests its potential effectiveness in mitigating RA-related inflammation. Our study highlights the potential of avocado constituents, particularly Luteolin, as promising therapeutics for the treatment of rheumatoid arthritis (RA). Through network pharma-cology analysis, we identified key target genes and proteins associated with RA, shedding light on the underlying molecular mechanisms of the disease.

Identification of formulation parameters that affect the analgesic efficacy of ProGel-Dex – A thermoresponsive polymeric dexamethasone prodrug for chronic arthritis pain relief

The relief of joint pain is one of the main objectives in the clinical management of arthritis. Although significant strides have been made in improving management of rheumatoid and related forms of inflammatory arthritis, there are still major unmet needs for therapies that selectively provide potent, sustained and safe joint pain relief, especially among patients with osteoarthritis (OA), the most common form of arthritis. We have recently developed ProGel-Dex, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive dexamethasone (Dex) prodrug, which forms a hydrogel upon intra-articular administration and provides sustained improvement in pain-related behavior and inflammation in rodent models of arthritis. The focus of the present study was to investigate the impact of ProGel-Dex formulation parameters on its physicochemical properties and in vivo efficacy. The results of this study provide essential knowledge for the future design of ProGel-Dex that can provide more effective, sustained and safe relief of joint pain and inflammation.

Rational formulation of saponin and dexamethasone for the synergistic treatment of rheumatoid arthritis in vivo

Rheumatoid arthritis (RA) is a common autoimmune disease, and the abnormal proliferation of fibroblast-like synoviocytes (FLSs) in inflamed joints plays a key role in the pathogenesis of RA, which has become an important therapeutic target for RA treatment. This work reported a facilely formulated nanoparticle from saponin (Sap) and dexamethasone (Dex) in precise ratio, affording the resultant Dex@Sap nanoparticles. Benefiting from the enlargement of vascular endothelial cell gap at the inflammation site and intra-articular injection, Dex@Sap could accumulate at the inflamed joints to inhibit excessive proliferation of FLSs and mediate cell apoptosis, achieving symptomatic relief and efficient RA treatment, while reducing the amount of drug needed as well as the occurrence of adverse reactions. Typical AKT (also known as protein kinase B, PKB)/mTOR (mammalian target of rapamycin) pathway was observed to be inhibited, and the mitochondria-mediated intracellular reactive oxygen species (ROS) level was also upregulated by Dex@Sap. Further in vivo evaluations demonstrated that Dex@Sap could significantly alleviate RA-induced inflammatory response and the expression of pro-inflammatory cytokines to cure joint damage in collagen-induced arthritis mice and rats. This work provides a clinically promising nanomedicine to synergistically treat RA.

Impact of E. muris infection on B. burgdorferi-induced joint pathology in mice.

Tick-borne infections are increasing in the United States and around the world. The most common tick-borne disease in the United States is Lyme disease caused by infection with the spirochete Borrelia burgdorferi (Bb), and pathogenesis varies from subclinical to severe. Bb infection is transmitted by Ixodes ticks, which can carry multiple other microbial pathogens, including Ehrlichia species. To address how the simultaneous inoculation of a distinct pathogen impacted the course of Bb-induced disease, we used C57BL/6 (B6) mice which are susceptible to Bb infection but develop only mild joint pathology. While infection of B6 mice with Bb alone resulted in minimal inflammatory responses, mice co-infected with both Bb and the obligate intracellular pathogen Ehrlichia muris (Em) displayed hematologic changes, inflammatory cytokine production, and emergency myelopoiesis similar to what was observed in mice infected only with Em. Moreover, infection of B6 mice with Bb alone resulted in no detectable joint inflammation, whereas mice co-infected with both Em and Bb exhibited significant inflammation of the ankle joint. Our findings support the concept that co-infection with Ehrlichia can exacerbate inflammation, resulting in more severe Bb-induced disease.

Spine and Sacroiliac Joint Involvement in Newly Diagnosed Patients With Inflammatory Bowel Disease: Clinical and MRI Findings From a Population-Based Cohort.

In patients with inflammatory bowel disease (IBD), co-occurring spondyloarthritis (SpA) leads to poorer outcomes and impaired quality of life, highlighting the importance of early detection and effective treatment. This is the first study to assess the prevalence and distribution of axial symptoms and magnetic resonance imaging (MRI)-detected involvement of the spine and sacroiliac joints (SIJs) in early IBD. Newly diagnosed patients with IBD from a prospective, population-based cohort were consecutively recruited. Rheumatological interview, clinical, ultrasound, and MRI assessment for SIJ and spine inflammatory and structural lesions were made using validated scoring methods and consensus definitions of axial SpA (axSpA). Of 110 patients (ulcerative colitis: 70, Crohn's disease: 40, mean age of 42 years, and 40% male), 48 (44.9%) reported back and/or buttock pain, and 10 (9.1%) had inflammatory back pain. Seventeen (16.7%) patients had MRI findings indicative of axSpA; only 10 of these patients had axial symptoms. Inflammatory MRI lesions were present in SIJs and the spine of 27 (26.5%) and 30 (30.3%) patients, respectively. The Assessment of SpondyloArthritis International Society classification criteria for axSpA were met in 11 (10%) cases. MRI findings typical of axSpA were associated with peripheral joint and entheseal inflammation detected by ultrasound ( P = 0.04). No differences in clinical or imaging findings were found between patients with ulcerative colitis and Crohn's disease. One-in-6 newly diagnosed patients with IBD had MRI findings indicative of axSpA. As 40% of these patients were asymptomatic, this suggests that axSpA is underdiagnosed in early IBD. Multidisciplinary collaboration is essential to ensure early detection of axial inflammation and to enable optimal therapy preventing future structural damage and disability.

Detection of synovial inflammation in the sacroiliac joint space through intravoxel incoherent motion imaging: an alternative to contrast agents.

We investigated the diagnostic accuracy of simplified intravoxel incoherent motion (IVIM) imaging for detecting synovial inflammation in the sacroiliac joint (SIJ) in a population with active sacroiliitis. In accordance with the Assessment of Spondyloarthritis International Society criteria, 86 SIJs of 46 patients with active sacroiliitis were included in this retrospective study conducted between November 2020 and January 2022. Based on T1-weighted post-gadolinium images, the SIJs were divided into two groups: synovial inflammation positive (SIP) (n = 28) and synovial inflammation negative (SIN) (n = 58). Synovial areas in the SIJ space were independently and blindly reviewed for the presence of inflammation by two radiologists with differing levels of expertise in radiology. Using four b values, apparent diffusion coefficient (ADC)= ADC (0, 800) and the simplified 3T IVIM method parameters true diffusion coefficient (D1)= ADC (50, 800), D= ADC (400, 800), f1= f (0, 50, 800), f2= f (0, 400, 800), pseudodiffusion coefficient (D*)= D* (0, 50, 400, 800), ADClow = ADC (0, 50), and ADCdiff= ADClow - D were generated voxel by voxel for each patient. The IVIM and ADC parameters at the SIN and SIP joints were compared. The D parameter was significantly increased in SIP areas (1.23 ± 0.34 × 10-3 mm2/s) compared with SIN areas (1.02 ± 0.16 × 10-3 mm2/s) (P = 0.004). Conversely, the D* parameter was significantly decreased in SIP areas (21.78 ± 3.77 × 10-3 mm2/s) compared with SIN areas (16.19 ± 4.58 × 10-3 mm2/s) (P < 0.001). When the optimal cut-off value of 1.11 × 10-3 mm2/s was selected, the sensitivity for the D value was 71% and the specificity was 72% [area under the curve (AUC): 0.716)]. When the optimal cut-off value of 21.06 × 10-3 mm2/s was selected, the sensitivity for the D* value was 78.6%, and the specificity was 79.3% (AUC: 0.829). The interclass correlation coefficient was excellent for f1, f2 D*, D, and ADCdiff, good for ADClow and D1, but reasonable for ADC. The presence of synovial inflammation in the SIJ can be evaluated with high sensitivity and specificity using only four b values through the simplified IVIM method without the need for a contrast agent. IVIM imaging is a technique that allows us to gain insights into tissue perfusion without the administration of contrast agents, utilizing diffusion-weighted images. In this study, for the first time, we demonstrated the potential of detecting synovial inflammation in the SIJ using IVIM, specifically through the pseudodiffusion (D*) parameter, without the need for contrast agents.

Radiosynovectomy for hemophilic arthropathies. Analysis of opportunities and prospects

Introduction. A characteristic symptom of hemophilia is joint hemorrhage (hemarthroses).Aim: to evaluate the possibilities of radiosynovectomy in hemophilic arthropathies.Main findings. Radiosynovectomy (RSE) or radiosynoviorthesis (RSO) is a technique that achieves a long-lasting effect in chronic synovitis and hemophilic arthropathy. It consists of intra-articular injection of radiopharmaceuticals (RFLP) in the form of colloidal solutions, macroaggregates or microspheres containing radioactive isotopes, which are rapidly phagocytized by the covering cells of the synovial membrane. After such capture, the synovial sheath is subjected to intensive “internal” irradiation, which results in superficial fibrosis of synovial tissue and persistent suppression of joint inflammation.

Modulation of the K/BxN arthritis mouse model and the effector functions of human fibroblast-like synoviocytes by liver X receptors.

The role of liver X receptors (LXR) in rheumatoid arthritis (RA) remains controversial. We studied the effect of LXR agonists on fibroblast-like synoviocytes (FLS) from RA patients and the K/BxN arthritis model in LXRα and β double-deficient (Nr1h2/3-/-) mice. Two synthetic LXR agonists, GW3965 and T0901317, were used to activate LXRs and investigate their effects on cell growth, proliferation and matrix metalloproteinases, and chemokine production in cultured FLS from RA patients. The murine model K/BxN serum transfer of inflammatory arthritis in Nr1h2/3-/- animals was used to investigate the role of LXRs on joint inflammation in vivo. LXR agonists inhibited the FLS proliferative capacity in response to TNF, the chemokine-induced migration, the collagenase activity in FLS supernatant and FLS CXCL12 production. In the K/BxN mouse model, Nr1h2/3-/- animals showed aggravated arthritis, histological inflammation, and joint destruction, as well as an increase in synovial metalloproteases and expression of proinflammatory mediators such as IL-1β and CCL2 in joints compared with wild type animals. Taken together, these data underscore the importance of LXRs in modulating the joint inflammatory response and highlight them as potential therapeutic targets in RA.

Critical evaluation of the current role of SYSADOA in the management of osteoarthritis (literature review)

Background. Osteoarthritis is a common chronic disease characterized by progressive degradation of all joint components and inflammation. The priority issue in the management of OA is sear­ching for drugs that simultaneously relieve symptoms, modify the course of the disease, and are safe for use. Symptoma­tic slow-ac­ting drugs (SYSADOA) are of considerable interest due to their potential to slow cartilage degeneration and potential osteoarthritis di­sease mo­difying effect. The purpose of the study was to ana­lyze current literature data on several types of SYSADOA, their biological role, mecha­nisms of effect on joints, effectiveness and safetye. ­Materials and methods. An analytical review of literature data was conducted using the ana­lysis of scientific databases PubMed, Web of Science, Scopus, Google Scholar for the period 2005–2024, the search was conducted using the keywords “osteoarthritis”, “SYSADOA”, “DMOAD”, “effectiveness”, “safety”. Results. Glucosamine salts (GA) and chondroitin sulfate (CS) are the most stu­died slow-acting drugs and have positive biological effects on joint tissues. Prescription salts of GA and CS have effect of pain relieve and joint function improvement as separate agents and also potentiate the effect in combination. Studies revealed limiting of cartilage volume loss and joint space narrowing – a potential DMOAD effect of these drugs. GA salts and CS drugs are safe, as they have no difference in the frequency of side effects compared to placebo. The quality of drugs largely depends on the type of raw materials and technological production process, which are not standardized now. Conclusions. The role of SYSADOA in the treatment of OA has not been definitively determined, and studies on the effectiveness of drugs such as SYSADOA and the study of their DMOAD effect are still ongoing. Further stu­dies should focus on the use of pharmacological class SYSADOA that have been properly purified and quality strictly supervised.

How to Distinguish Non-Inflammatory from Inflammatory Pain in RA?

Managing non-inflammatory pain in rheumatoid arthritis (RA) can be a huge burden for the rheumatologist. Pain that persists despite optimal RA treatment is extremely challenging for patient and physician alike. Here, we outline the latest research relevant to distinguishing non-inflammatory from inflammatory RA pain and review the current understanding of its neurobiology and management. Nociplastic pain is a recently introduced term by the international pain community. Its definition encompasses the non-inflammatory pain of RA and describes pain that is not driven by inflamed joints or compromised nerves, but that is instead driven by a functional reorganisation of the central nervous system (CNS). Insights from all areas of nociplastic pain research, including fibromyalgia, support a personalised pain management approach for non-inflammatory pain of RA, with evidence-based guidelines favouring use of non-pharmacological interventions. Future developments include novel CNS targeting pharmacotherapeutic approaches to treat nociplastic pain.

Immune cell activity during anti-TNF treatment in patients with psoriasis and psoriatic arthritis.

Psoriasis is a chronic, inflammatory skin disease characterized by a dysregulated immune response and systemic inflammation. Up to one-third of patients with psoriasis have psoriatic arthritis (PsA). Targeted treatment with antibodies neutralizing tumor necrosis factor (TNF) can ameliorate both diseases. We here explored the impact of long-term infliximab treatment on the composition and activity status of circulating immune cells involved in chronic skin and joint inflammation. Immune cells were analyzed by multicolor flow cytometry. We measured markers of immune activation in peripheral blood mononuclear cell (PBMC) populations in 24 infliximab-treated patients with psoriasis/psoriatic arthritis compared to 32 healthy controls. We observed a significant decrease in the frequency of both peripheral natural killer (NK) cells and their subset CD56dimCD16+ NK cells in PsA compared to healthy controls and patients with psoriasis. The latter had a strong positive correlation with PASI in these patients, while CD56brightCD16- NK cells were negatively correlated with PASI. In addition, we observed an upregulation of CD69+ intermediate CD14+CD16+ and CD69+ classical CD14+CD16- monocytes in PsA and increased activity of CD38+ intermediate CD14+CD16+ monocytes in patients with psoriasis. Compared to healthy controls, psoriasis patients demonstrated shifts of the three B cell subsets with a decrease in transitional CD27-CD38high B cells. Our exploratory study indicates a preserved pathophysiological process including continuous systemic inflammation despite clinical stability of the patients treated with infliximab.

Clinical trial of arthroscopic debridement combined with functional exercise in the treatment of advanced knee osteoarthritis: A retrospective observational study.

Advanced knee osteoarthritis (KOA) impacts both knees, resulting in pain, deformity, and substantial restrictions in joint mobility. This study aims to examine the effectiveness of combining arthroscopic debridement with functional exercise in treating advanced KOA. A total of 296patients diagnosed with advanced KOA were divided into two groups: the observation group (n= 152) received arthroscopic debridement combined with functional exercise, while the control group (n= 144) underwent arthroscopic debridement only. The study compared and observed the outcomes between the two groups. There were no significant differences in knee joint function, inflammation level, and oxidative stress between the two groups before treatment (P> 0.05). Following treatment for six months, the observation group exhibited significantly lower visual analog scale (VAS) score, tissue inhibitors of metalloproteinase-1 (TIMP-1), tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), matrix metalloproteinase-3 (MMP-3), and malondialdehyde (MDA) levels compared to the control group (P< 0.05). Meanwhile, the observation group showed significantly higher levels of Lysholm score, hospital for special surgery (HSS) score, range of motion (ROM) of knee, peak torque (PT) and total work (TW) for knee extension and flexion, superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione (GSH) compared to the control group (P< 0.05). Besides, the effective treatment rate in the observation group was notably higher than that in the control group (80.92% vs. 69.44%, P< 0.05). The combination of arthroscopic debridement with functional exercise is an effective treatment for advanced KOA. This approach not only enhances the function and strength of knee joint and reduces inflammatory response but also boosts the body's antioxidant capacity. The treatment exhibits encouraging outcomes and warrants broad implementation.

A case-control study of the association of toxoplasmosis with antirheumatic therapy in rheumatoid arthritis

Background &amp; Objective: Toxoplasmosis is a globally prevalent opportunistic zoonotic infection. Rheumatoid arthritis (RA) is an autoimmune disease which is manifested as joint inflammation, pain, stiffness, and swelling. The patients may contract toxoplasmosis, especially when receiving antirheumatic immunosuppressive therapy. However conflicting results have been reported on toxoplasmosis in RA patients. We aimed to evaluate Toxoplasma gondii positivity and associated risk factors in patients with RA in Duhok province, Iraq, and to assess the role of antirheumatic therapy in toxoplasmosis and the possibility of its reactivation. Methodology: This case-control study was carried out in Duhok, Kurdistan Region, Iraq, from February 2022 to June 2023. A total of 88 RA patients, with and without concurrent antirheumatic therapy, were recruited. The diagnosis of RA was according to the 2010 American College of Rheumatology/European League. RA-patients were categorized into three groups: Group 1 - no-therapy (n = 14); Group 2 - conventional therapy (n = 49) and Group 3 - biologics in combination with conventional medications (n = 25). Healthy subjects (n = 61) were also selected as controls. Plasma samples obtained from the participants were screened for T. gondii infection using Human anti-Toxoplasma gondii antibody IgG. IgG positive samples were tested utilizing human anti-Toxoplasma gondii antibody IgM ELISA Kit and the avidity T. gondii IgG ELISA kit was used to determine the state of infection. Results: Of the 88 RA patients, with or without antirheumatic therapy, 76 (86.36%) were females and 12 (13.64%) were males. Patients on therapy (n = 74) received several conventional antirheumatic drugs of which methotrexate was the most frequently used one (86.36%). Among biological therapies, etanercept, a TNF-alpha inhibitor, was mostly used (13.51%). The toxoplasmosis was significantly less in the older age group (&gt; 50 y) compared to individuals under 30 y. Gender had no significant effect. Toxoplasma IgG positivity was found to be significantly higher in the three groups of RA patients in comparison with healthy controls. Further assessment of anti-Toxoplasma IgM positivity and Toxoplasma IgG avidity results to identify the state of T. gondii infection in anti-Toxoplasma IgG positive subjects revealed that the frequency of reactivation of toxoplasmosis in RA patient groups was not significantly different from that of the control counterparts. Conclusion: The study showed higher seroprevalence of anti-Toxoplasma antibodies in patients with RA irrespective of therapy; therefore, we could consider toxoplasmosis interaction with RA in the pathogenesis of both diseases. This seroprevalence was higher in younger age groups, but with no significant role of gender, duration of disease, duration of therapy and its type. No significant difference was noted in rates of reactivation of latent T. gondii infection among RA patients and healthy controls. Abbreviations: CI - Confidence interval; O - Odds ratio; RA - Rheumatoid arthritis; SD - Standard deviation; T. gondii - Toxoplasma gondii; TNF - Tumor necrosis factor. Keywords: Autoimmune disease; Rheumatoid arthritis; Antirheumatic drugs; Toxoplasma gondii; Toxoplasma seroprevalence; Toxoplasma IgG avidity. Citation: Abdullah RG, Eassa SH, Mohammad FK. A case-control study of the association of toxoplasmosis with antirheumatic therapy in rheumatoid arthritis. Anaesth, pain intensive care 2024;28(4):674−680; DOI: 10.35975/apic.v28i4.2510 Received: May 14, 2024; Reviewed: June 28, 2024; Accepted: June 28, 2024

Estimation of interleukin-6 level and atherogenic indices as predictors of severity of rheumatoid arthritis in Iraqi patients

Background &amp; Objective: Rheumatoid Arthritis (RA) is an inflammatory illness that causes joint degeneration and inflammation of the synovial membrane, leading to significant disability over time. Interleukin-6 (IL-6) is a widely distributed pro-inflammatory cytokine that has a variety of roles in several pathophysiologic systems, most notably in the RA development. The purpose of this study was to assess the blood levels of IL-6 and the severity and activity of RA in patients, and to assess the association of atherogenic indices with IL-6 as a predictor of severity in RA disease. Methodology: This study was a case control observational study involving 300 participants diagnosed with RA by the rheumatologists in accordance with American College of Rheumatologists (ACR)/ European League Against Rheumatism (EULAR) 2010 criteria. Serum levels of IL-6, CRP, RF and ACPA were measured by using ELISA technique. While, lipid profile was determined with spectrophotometry. Receiver operating curve (ROC) was used to study the opportunity of using atherogenic indices and IL-6 as diagnostic tools for RA. Results: The results indicated a higher IL-6 level in RA patients in comparison to the control group, e.g., 28.55 (18.76-41.07) pg/mLvs 10.19 (6.11-12.50) pg/ml. High atherogenic index of plasma (AIP) risk &gt; 0.24 in RA patients parameters (GDF-15, IL-6), the lipid profile parameters and atherogenic indices (TC, TG, VLDL-C, LDL-C, CRI-I, CRI-II, AIP, and AC) were compared with moderate atherogenic risk (AIP &lt; 0.24) in RA patients. While a significant decrease was recorded in the HDL-C and BMI levels, it had significantly high atherogenic risk (AIP &gt; 0.24) compared with moderate atherogenic risk (AIP &lt; 0.24) in RA patients. The ROC results analysis showed that the top 5 highly sensitive predictors for RA, e.g., CRI-I, AC, AIP, CRI-II followed by IL-6, have a relatively good sensitivity and specificities for predictors for RA. Conclusion: Increase in interleukin-6 may indicate the activity and severity of the disease. This biomarker could be helpful for early disease detection. The results showed a higher IL-6 in RA patients as well as increased dyslipidemia and atherogenicity in RA patients. Elevation of serum IL-6 and atherogenic indices are the best predictors for RA patients with a higher risk of atherosclerosis than other biomarkers. There is an important correlation between atherogenic indices parameters and the immunological biomarkers IL-6 indicating a significant role of the inflammation in the incidence of atherogenic indices in RA. Abbreviations: AUC- Area Under Curve; ACPA - Anti Cyclic Citrullinated Peptide Antibodies; CRP- C-Reactive Protein; ESR- Erythrocyte Sedimentation Rate; RF- Rheumatoid Factor; BMI- Body Mass Index; GDF-15 -Growth Differentiation Factor-15; DAS28-CRP- Disease Activity Score-28-C-Reactive Protein; TC- Total Cholesterol; TG- Triglyceride; HDL-C -High Density Lipoprotein Cholesterol; LDL-C -Low Density Lipoprotein Cholesterol; VLDL-C-Very Low Density Lipoprotein Cholesterol; AC-Atherogenic Coefficient; AIP-Atherogenic Index of Plasma; CR-I, CR-II- Castelli’s Risk Indexes. Keywords: Rheumatoid Arthritis, Interleukin-6, Atherogenic Indices. Citation: Abdulridha GAO, Hussein MA, Majeed SR. Estimation of interleukin-6 level and atherogenic indices as predictors of severity of rheumatoid arthritis in Iraqi patients. Anaesth. pain intensive care 2024;28(4):700−705; DOI: 10.35975/apic.v28i4.2400. Received: February 26, 2024; Reviewed: April 16, 2024; Accepted: July 09, 2024

The mode of action of IL-23 in experimental inflammatory arthritic pain and disease

ObjectivesWe have previously reported using gene-deficient mice that the interleukin (IL)-23p19 subunit is required for the development of innate immune-driven arthritic pain and disease. We aimed to explore here, using a number of in vivo approaches, how the IL-23p19 subunit can mechanistically control arthritic pain and disease in a T- and B- lymphocyte-independent manner.MethodsWe used the zymosan-induced arthritis (ZIA) model in wild-type and Il23p19−/− mice, by a radiation chimera approach, and by single cell RNAseq and qPCR analyses, to identify the IL23p19-expressing and IL-23-responding cell type(s) in the inflamed joints. This model was also utilized to investigate the efficacy of IL-23p19 subunit blockade with a neutralizing monoclonal antibody (mAb). A novel IL-23-driven arthritis model was established, allowing the identification of putative downstream mediators of IL-23 in the control of pain and disease. Pain and arthritis were assessed by relative static weight distribution and histology, respectively.ResultsWe present evidence that (i) IL-23p19+ non-bone marrow-derived macrophages are required for the development of ZIA pain and disease, (ii) prophylactic and therapeutic blockade of the IL-23p19 subunit ameliorate ZIA pain and disease and (iii) systemically administered IL-23 can induce arthritic pain and disease in a manner dependent on TNF, GM-CSF, CCL17 and cyclooxygenase activity, but independently of lymphocytes, CGRP, NGF and substance P.ConclusionsThe data presented should aid IL-23 targeting both in the choice of inflammatory disease to be treated and the design of clinical trials.

The immune landscape of the inflamed joint defined by spectral flow cytometry.

Cellular phenotype and function are altered in different microenvironments. For targeted therapies it is important to understand site-specific cellular adaptations. Juvenile Idiopathic Arthritis (JIA) is characterised by autoimmune joint inflammation, with frequent inadequate treatment responses. To comprehensively assess the inflammatory immune landscape, we designed a 37-parameter spectral flow cytometry panel delineating mononuclear cells from JIA synovial fluid (SF) of autoimmune inflamed joints, compared to JIA and healthy control blood. Synovial monocytes and NK cells (CD56bright) lack Fc-receptor CD16, suggesting antibody-mediated targeting may be ineffective. B cells and DCs, both in small frequencies in SF, undergo maturation with high 4-1BB, CD71, CD39 expression, supporting T cell activation. SF effector and regulatory T cells were highly active with newly described co-receptor combinations that may alter function, and suggestion of metabolic reprogramming via CD71, TNFR2 and PD-1. Most SF effector phenotypes, as well as an identified CD4-Foxp3+ T cell population, were restricted to the inflamed joint, yet specific SF-predominant CD4+Foxp3+ Treg subpopulations were increased in blood of active but not inactive JIA, suggesting possible recirculation and loss of immunoregulation at distal sites. This first comprehensive dataset of the site-specific inflammatory landscape at protein level will inform functional studies and the development of targeted therapeutics to restore immunoregulatory balance and achieve remission in JIA.

Acupuncture for rehabilitation after total knee arthroplasty: A systematic review and network meta-analysis

Background: The increasing interest in acupuncture for promoting post-operative rehabilitation has encouraged its use in rehabilitation after total knee arthroplasty (TKA), but its effectiveness remains controversial. Objective: This study aims to assess the efficacy of different models of acupuncture-related therapies on pain relief, motor function, inflammation, and overall rehabilitation of the knee after TKA. Methods: Databases PubMed, Embase, Cochrane, Web of Science, Scopus, and Clinicaltrials.gov were searched to screen eligible randomized controlled trials (RCTs). All RCTs that used acupuncture/moxibustion on TKA patients were included by two researchers independently after rigorous quality evaluation, with data extracted. The statistics were performed by using R 4.2.3 and Stata 17. Results: The network meta-analysis incorporated 28 RCTs, with 21 of them conducted in Chinese mainland and Taiwan region. Evidence of the relation of several common acupuncture /moxibustion treatments was shown by the network meta-analysis (NMA). The results of NMA showed that electroacupuncture was the preferred therapy for soothing pain symptoms (standardized mean difference=0.58, 95% CI=0.36 to 0.81). Auricular acupressure was the best treatment to improve the knee motor function. Electroacupuncture was superior to special acupuncture in relieving knee joint stiffness and inflammation. Conclusion: Acupuncture intervention, especially electroacupuncture, can effectively alleviate pain, improve motion, reduce stiffness, and decrease inflammation in post-TKA patients, with no serious adverse events.