Joint Destruction Research Articles

Charcot arthropathy and acro-osteolysis in a 5-year-old girl with hereditary sensory and autonomic neuropathy type II: A case report

Charcot neuropathic arthropathy is a destructive process that can occur in patients with neuropathy associated with medical diseases such as diabetes. A rare cause of neuropathic arthropathy is congenital insensitivity to pain (CIP) which includes varying degrees of sensory loss and lack of pain perception contributing to absent withdrawal responses. The clinical manifestations of CIP include delayed diagnosis of fractures, joint dislocations, acro-osteolysis, avascular necrosis, osteomyelitis, heterotopic ossification, and Charcot arthropathy. We herein report a case of Charcot arthropathy of ankle joints in a 5-year-old girl with CIP due to underlying hereditary sensory and autonomic neuropathy who had recurrent upper and lower limb fractures with acro-osteolysis. She had an inability to perceive pain from the first year of her life. She also had mild developmental delay. Family history was unremarkable. Blood count, liver and thyroid function tests, erythrocyte sedimentation rate, C-reactive protein, blood electrolytes, blood sugar and other laboratory tests were normal. Charcot neuropathic arthropathy in children is rare and can be a part of congenital diseases like CIP. A high degree of suspicion may lead to early detection and can prevent joint and bone destruction and deformities.

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.

Influence of the timing of biological treatment initiation on Juvenile Idiopathic Arthritis long-term outcomes

BackgroundJuvenile idiopathic arthritis (JIA) treatment is aimed at inducing remission to prevent joint destruction and disability. However, it is unclear what is the long-term impact on health-related outcomes of the timing of biological disease-modifying antirheumatic drug (bDMARD) initiation in JIA. Our aim was to evaluate the long-term impact of the time between JIA onset and the initiation of a bDMARD in achieving clinical remission, on physical disability and health-related quality of life (HRQoL).MethodsAdult JIA patients registered in the Rheumatic Diseases Portuguese Register (Reuma.pt) and ever treated with bDMARD were included. Data regarding socio-demographic, JIA-related characteristics, disease activity, physical disability (HAQ-DI), HRQoL (SF-36), and treatments were collected at the last visit. Patients were divided into 3 groups (≤ 2 years, 2–5 years, or > 5 years), according to the time from disease onset to bDMARD initiation. Regression models were obtained considering remission on/off medication, HAQ-DI, SF-36, and joint surgeries as outcomes and time from disease onset to bDMARD start as an independent variable.ResultsThree hundred sixty-one adult JIA patients were evaluated, with a median disease duration of 20.3 years (IQR 12.1; 30.2). 40.4% had active disease, 35.1% were in remission on medication, and 24.4% were in drug-free remission; 71% reported some degree of physical disability. Starting a bDMARD > 5 years after disease onset decreased the chance of achieving remission off medication (OR 0.24; 95% CI 0.06, 0.92; p = 0.038). Patients who started a bDMARD after 5 years of disease onset had a higher HAQ and worse scores in the physical component, vitality, and social function domains of SF-36, and more joint surgeries when compared to an earlier start.ConclusionLater initiation of bDMARDs in JIA is associated with a greater physical disability, worse HRQoL, and lower chance of drug-free remission in adulthood.

Identification of biomarkers in patients with rheumatoid arthritis responsive to DMARDs but with progressive bone erosion.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that may cause joint destruction and disability. The pharmacological treatment of RA aims at obtaining disease remission by effectively ceasing joint inflammation and arresting progressive bone erosions. Some patients present bone lesions accrual even after controlling joint inflammation with current therapies. Our study aimed to analyze lymphocyte subsets and levels of circulating cytokines in patients with RA with progressive bone erosions. We enrolled 20 patients with a diagnosis of RA and 12 healthy donors (HD). Patients with RA were divided into patients with bone erosions (RA-BE+) and without bone erosions (RA-BE-). Lymphocyte subsets in peripheral blood were evaluated by flow cytometry. Circulating cytokines levels were evaluated by protein array. The distribution of lymphocyte subsets was not able to separate HD from AR patients and RA-BE+ and RA-BE- in cluster analysis. We observed a significant expansion of CXCR5- PD1+ T peripheral helper cells (Tph cells) and a reduction in both total memory B cells and switched memory B cells in RA patients compared to HD. We observed an expansion in the frequency of total B cells in RA-BE+ patients compared to RA-BE- patients. Unsupervised hierarchical clustering analysis of 39 cytokines resulted in a fairly good separation of HD from RA patients but not of RA-BE+ patients from RA-BE- patients. RA-BE+ patients showed significantly higher levels of IL-11 and IL-17A than RA-BE- patients. We show that patients with progressive erosive disease are characterized by abnormalities in B cells and in cytokines with a proven role in bone reabsorption. Understanding the role played by B cells and the cytokine IL-11 and IL-17A in progressive erosive disease can help identify novel biomarkers of erosive disease and design treatment approaches aimed at halting joint damage in RA.

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.

Charcot Neuroarthropathy of the Foot and Ankle in the Acute Setting: An Illustrative Case Report and Targeted Review.

Charcot neuroarthropathy (CN) is a rare but serious sequela of diabetes and other diseases that cause peripheral neuropathy. It is most commonly characterized by degeneration of the foot and/or ankle joints leading to progressive deformity and altered weight-bearing. If left untreated, the deformities of CN lead to ulceration, infection, amputation, and even death. Because of the associated peripheral neuropathy and proprioception deficits that accompany CN, patients typically do not perceive the onset of joint destruction. Moreover, in the hands of the untrained clinician, the initial presentation of CN can easily be mistaken for infection, osteoarthritis, gout, or inflammatory arthropathy. Misdiagnosis can lead to the aforementioned serious sequelae of CN. Thus, an early accurate diagnosis and off-loading of the involved extremity, followed by prompt referral to a specialist trained in the care of CN are crucial to prevent the late-term sequelae of the disease. The purpose of this article was to create an opportunity for enhanced understanding between orthopedic surgeons and emergency physicians, to improve patient care through the optimization of diagnosis and early management of CN in the emergent setting.

DKK-1 and Its Influences on Bone Destruction: A Comparative Study in Collagen-Induced Arthritis Mice and Rheumatoid Arthritis Patients.

Dickkopf-1 (DKK-1) has been considered a master regulator of bone remodeling. As precursors of osteoclasts (OCs), myeloid-derived suppressor cells (MDSCs) were previously shown to participate in the process of bone destruction in rheumatoid arthritis (RA). However, the role of DKK-1 and MDSCs in RA is not yet fully understood. We investigated the relevance between the level of DKK-1 and the expression of MDSCs in different tissues and joint destruction in RA patients and collagen-induced arthritis (CIA) mouse models. Furthermore, the CIA mice were administered recombinant DKK-1 protein. The arthritis scores, bone destruction, and the percentage of MDSCs in the peripheral blood and spleen were monitored. In vitro, the differentiation of MDSCs into OCs was intervened with recombinant protein and inhibitor of DKK-1. The number of OCs differentiated and the protein expression of the Wnt/β-catenin signaling pathway were explored. The level of DKK-1 positively correlates with the frequency of MDSCs and bone erosion in RA patients and CIA mice. Strikingly, recombinant DKK-1 intervention significantly exacerbated arthritis scores and bone destruction, increasing the percentage of MDSCs in the peripheral blood and spleen in CIA mice. In vitro experiments showed that recombinant DKK-1 promoted the differentiation of MDSCs into OCs, reducing the expression of β-catenin and TCF4 and increasing the expression of CyclinD1. In contrast, the DKK-1 inhibitor had the opposite effect. Our findings highlight that DKK-1 promoted MDSCs expansion in RA and enhanced the differentiation of MDSCs into OCs via targeting the Wnt/β-catenin pathway, aggravating the bone destruction in RA.

Medermycin Inhibits TNFα-Promoted Inflammatory Reaction in Human Synovial Fibroblasts.

Synovial inflammation plays a crucial role in the destruction of joints and the experience of pain in osteoarthritis (OA). Emerging evidence suggests that certain antibiotic agents and their derivatives possess anti-inflammatory properties. Medermycin (MED) has been identified as a potent antibiotic, specifically active against Gram-positive bacteria. In this study, we aimed to investigate the impact of MED on TNFα-induced inflammatory reactions in a synovial cell line, SW-982, as well as primary human synovial fibroblasts (HSF) using RNA sequencing, rtRT-PCR, ELISA, and western blotting. Through the analysis of differentially expressed genes (DEGs), we identified a total of 1478 significantly upregulated genes in SW-982 cells stimulated with TNFα compared to the vehicle control. Among these upregulated genes, MED treatment led to a reduction in 1167 genes, including those encoding proinflammatory cytokines such as IL1B, IL6, and IL8. Pathway analysis revealed the enrichment of DEGs in the TNF and NFκB signaling pathway, further supporting the involvement of MED in modulating inflammatory responses. Subsequent experiments demonstrated that MED inhibited the expression of IL6 and IL8 at both the mRNA and protein levels in both SW982 cells and HSF. Additionally, MED treatment resulted in a reduction in p65 phosphorylation in both cell types, indicating its inhibitory effect on NFκB activation. Interestingly, MED also inhibited Akt phosphorylation in SW982 cells, but not in HSF. Overall, our findings suggest that MED suppresses TNFα-mediated inflammatory cytokine production and p65 phosphorylation. These results highlight the potential therapeutic value of MED in managing inflammatory conditions in OA. Further investigations utilizing articular chondrocytes and animal models of OA may provide valuable insights into the therapeutic potential of MED for this disease.

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.

Herbal Allies for Rheumatoid Arthritis: A Comprehensive Review of Natural Products

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting primarily the joints, producing discomfort, inflammation, and potentially damaging joint destruction. Rheumatoid arthritis affects people all around the world, and its prevalence and impact differ by place. The World Health Organisation (WHO) estimates that 0.5% to 1% of the global population has rheumatoid arthritis. To decrease the progression of rheumatoid arthritis, disease-modifying anti-rheumatic medications (DMARDs) such as methotrexate and sulfasalazine are used. TNF inhibitors and IL-6 inhibitors are two examples of biologic DMARDs that target specific immune system components. Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics help manage pain and inflammation while corticosteroids provide short-term relief during flares. Treatment strategies are tailored to the individual, and talking with a healthcare expert is essential for effective management. Herbal therapies are regarded to offer an advantage over synthetic pharmaceuticals for the treatment of rheumatoid arthritis due to their natural approach, potential symptom relief, holistic approach to health, and individualised therapy possibilities. However, scientific data supporting their effectiveness is sparse and variable, and their quality and safety can vary. Before adopting herbal therapies as part of a treatment plan, it is critical to check with a healthcare expert. Because of their natural chemicals with anti-inflammatory and analgesic characteristics, medicinal herbs may aid rheumatoid arthritis. However, further research is required to determine their efficacy, safety, and appropriate application.

Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.

Effect of Juanbi Qianggu Formula on biological behaviors of fibroblast-like synoviocytes in rheumatoid arthritis by regulating FGFR1 signaling pathway based on network pharmacology and cell function experiments

This study aimed to explore the molecular mechanism of Juanbi Qianggu Formula(JBQGF), an empirical formula formulated by the prestigious doctor in traditional Chinese medicine, in the treatment of rheumatoid arthritis based on network pharmacology and cell function experiments. The main active components and targets of JBQGF were obtained through Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP) and Encyclopedia of Traditional Chinese Medicine(ETCM), and the core targets underwent functional enrichment analysis and signaling pathway analysis. Cytoscape 3.6.0 was used to construct a visualized "active component-target-signaling pathway" network of JBQGF. After screening, nine potential pathways of JBQGF were obtained, mainly including G protein-coupled receptor signaling pathway and tyrosine kinase receptor signaling pathway. As previously indicated, the fibroblast growth factor receptor 1(FGFR1) signaling pathway was highly activated in active fibroblast-like synoviocytes(FLS) in rheumatoid arthritis, and cell and animal experiments demonstrated that inhibition of the FGFR1 signaling pathway could significantly reduce joint inflammation and joint destruction in collagen-induced arthritis(CIA) rats. In terms of the tyrosine kinase receptor signal transduction pathway, the analysis of its target genes revealed that FGFR1 might be a potential target of JBQGF for rheumatoid arthritis treatment. The biological effect of JBQGF by inhibiting FGFR1 phosphorylation was preliminarily verified by Western blot, Transwell invasion assay, and pannus erosion assay, thereby inhibiting matrix metalloproteinase 2(MMP2) and receptor activator of nuclear factor-κB ligand(RANKL) and suppressing the invasion of fibroblasts in rheumatoid arthritis and erosive effect of pannus bone. This study provides ideas for searching potential targets of rheumatoid arthritis treatment and TCM drugs through network pharmacology.

Schisandrin treatment suppresses the proliferation, migration, invasion, and inflammatory responses of fibroblast-like synoviocytes from rheumatoid arthritis patients and attenuates synovial inflammation and joint destruction in CIA mice.

Rheumatoid arthritis (RA) is a systemic autoimmune disease causing joint dysfunction. As disease-modifying anti-rheumatic drugs (DMARDs) have poor efficacy in 20% to 25% of RA patients, additional novel RA medications are urgently needed. Schisandrin (SCH) has multiple therapeutic effects. However, whether SCH is effective against RA remains unknown. To investigate how SCH affects the abnormal behaviours of RA fibroblast-like synoviocytes (FLSs) and further elucidate the underlying mechanism of SCH in RA FLSs and collagen-induced arthritis (CIA) mice. Cell Counting Kit-8 (CCK8) assays were used to characterize cell viability. EdU assays were performed to assess cell proliferation. Annexin V-APC/PI assays were used to determine apoptosis. Transwell chamber assays were used to measure cell migration and invasion in vitro. RT-qPCR was used to assess proinflammatory cytokine and MMP mRNA expression. Western blotting was used to detect protein expression. RNA sequencing was performed to explore the potential downstream targets of SCH. CIA model mice were used to assess the treatment efficacy of SCH in vivo. Treatments with SCH (50, 100, and 200 μΜ) inhibited RA FLSs proliferation, migration, invasion, and TNF-α-induced IL-6, IL-8, and CCL2 expression in a dose-dependent manner but did not affect RA FLSs viability or apoptosis. RNA sequencing and Reactome enrichment analysis indicated that SREBF1 might be the downstream target in SCH treatment. Furthermore, knockdown of SREBF1 exerted effects similar to those of SCH in inhibiting RA FLSs proliferation, migration, invasion, and TNF-α-induced expression of IL-6, IL-8, and CCL2. Both SCH treatment and SREBF1 knockdown decreased activation of the PI3K/AKT and NF-κB signalling pathways. Moreover, SCH ameliorated joint inflammation and cartilage and bone destruction in CIA model mice. SCH controls the pathogenic behaviours of RA FLSs by targeting SREBF1-mediated activation of the PI3K/AKT and NF-κB signalling pathways. Our data suggest that SCH inhibits FLS-mediated synovial inflammation and joint damage and that SCH might have therapeutic potential for RA.

Total Glucosides of Peony Alleviate Joint Destruction in Rabbits With Osteoarthritis

Objective Although many painkillers can be used to relieve the symptoms of osteoarthritis (OA), these drugs do not address joint bone degeneration and muscle wasting, highlighting the need for alternative treatments. This study evaluated the ability of various plant extracts to inhibit joint destruction, focusing on the total glucosides of peony (TGP) obtained from the normal Chinese medication white peony. Methods A rabbit OA model was established by anterior cruciate ligament resection (ACLT) and TGP treatment was initiated for 3 months. The morphologies of the skeletal muscle fibers, articular cartilage, and subchondral bone of the knee joint were histologically observed via X-ray and micro-computed tomography scan. Results TGP significantly reduced the histopathological changes associated with skeletal muscle atrophy and inflammation, and alleviated cartilage degeneration. In addition, TGP treatment significantly improved the bone density and microstructure of subchondral bone in rabbit knee joints compared with the model group. Conclusion The results suggested that TGP treatment may alleviate the progression of osteoarthritis and reduce the destruction of joint cartilage and bone in ACLT.

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.

Frequency of fimA Genotypes of P. gingivalis in Rheumatoid Arthritis Patients and Control group.

Rheumatoid arthritis (RA): Chronic inflammatory polyarthritis, an autoimmune response targeting citrullinated antigens, due to destructive synovial joint inflammation. Porphyromonas gingivalis, a gram-negative bacterium residing in the subgingival tissues of the oral cavity, has been implicated in the association with RA, mainly due to the identification of a bacterial enzyme known as peptidyl arginine deaminase (PAD). The presence of this enzyme in P. gingivalis suggests its potential role in RA development by generating citrullinated antigens. Aims: The association between P. gingivalis and the development of anticitrullinated peptide antibody (ACPA) and if its role as an environmental risk factor of RA. Methods: This case-control study involved a total 140 participants, collection of blood and gingival crevicular fluid (GCF) samples from the participants, various tests were conducted, Specific PCR primers targeting fimA genotypes of P. gingivalis were utilized to amplify the relevant genetic regions.Statistical analysis used: Statistical Package for the Social Sciences (SPSS) version 26, a T-test and Chi-square (χ^2) test were utilized. Results: The p-values for ESR, ACCP, and IL-17 were 0.0001, 0.02, and 0.0001, respectively, indicating strong statistical significance for RA patients. Among the RA patients with P. gingivalis infection and the RA patients without P. gingivalis infection the analysis did not reveal a statistically significant difference in mean of ACCP and all biomarkers between the two groups (p-value=1.000) Conclusions: No association between P. gingivalis and the development of ACPA, the rise in ESR levels as disease severity escalates underscores the potential practicality of using ESR as an indicator to evaluate disease activity in RA, a trend towards a higher occurrence of gum problems among RA patients especially in category of patients developed gum problems before the onset of RA.

CD64 as novel molecular imaging marker for the characterization of synovitis in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is one of the most prevalent and debilitating joint diseases worldwide. RA is characterized by synovial inflammation (synovitis), which is linked to the development of joint destruction. Magnetic resonance imaging and ultrasonography are widely being used to detect the presence and extent of synovitis. However, these techniques do not reveal the activation status of inflammatory cells such as macrophages that play a crucial role in synovitis and express CD64 (Fc gamma receptor (FcγR)I) which is considered as macrophage activation marker.ObjectivesWe aimed to investigate CD64 expression and its correlation with pro-inflammatory cytokines and pro-damaging factors in human-derived RA synovium. Furthermore, we aimed to set up a molecular imaging modality using a radiolabeled CD64-specific antibody as a novel imaging tracer that could be used to determine the extent and phenotype of synovitis using optical and nuclear imaging.MethodsFirst, we investigated CD64 expression in synovium of early- and late-stage RA patients and studied its correlation with the expression of pro-inflammatory and tissue-damaging factors. Next, we conjugated an anti-CD64 antibody with IRDye 800CW and diethylenetriamine penta-acetic acid (DTPA; used for 111In labeling) and tested its binding on cultured THP1 cells, ex vivo RA synovium explants and its imaging potential in SCID mice implanted with human RA synovium explants obtained from RA patients who underwent total joint replacement.ResultsWe showed that CD64 is expressed in synovium of early and late-stage RA patients and that FCGR1A/CD64 expression is strongly correlated with factors known to be involved in RA progression. Combined, this makes CD64 a useful marker for imaging the extent and phenotype of synovitis. We reported higher binding of the [111In]In-DTPA-IRDye 800CW anti-CD64 antibody to in vitro cultured THP1 monocytes and ex vivo RA synovium compared to isotype control. In human RA synovial explants implanted in SCID mice, the ratio of uptake of the antibody in synovium over blood was significantly higher when injected with anti-CD64 compared to isotype and injecting an excess of unlabeled antibody significantly reduced the antibody-binding associated signal, both indicating specific receptor binding.ConclusionTaken together, we successfully developed an optical and nuclear imaging modality to detect CD64 in human RA synovium in vivo.

1299 Puerperal Shoulder Pain: A Rare Case of Glenohumeral Joint Septic Arthritis

Abstract Introduction Native glenohumeral joint septic arthritis is a rare manifestation of an occult bacteraemia. Without urgent diagnosis and intervention, septic arthritis can lead to rapid cartilaginous and joint destruction. We report an unusual presentation of postpartum streptococcal glenohumeral arthritis. Case Description A fit and healthy 34-year-old woman gravida 2 para 3 developed unremitting shoulder pain, reduced range of movement and tachycardia day 1 postpartum after a vaginal delivery associated with a grade two perineal tear. Initial blood work revealed rising inflammatory markers, CRP 275, WCC 16.2. Initial radiographs showed no significant abnormality. T2 weighted MRI revealed a large glenohumeral joint effusion. All samples from joint aspirate grew Group B streptococcus (GBS), concordant with a high vaginal swab taken in the late third trimester. The patient underwent urgent arthroscopic washout and synovial sampling, growing GBS. Transthoracic echocardiogram revealed no imaging evidence of infective endocarditis. The patient was commenced on an appropriate 6-week intravenous antibiotic course and clinically improved. Physiotherapy and rehabilitation improved shoulder range of movements. Discussion There is a scarcity of orthopaedic complications reported with obstetric pathology. Atraumatic joint pain associated with physiological, or biochemical signs of infection should alert the diagnosing surgeon to consider septic arthritis. Haematogenous bacterial translocation can cause atypical presentations of septic arthritis. Routine biochemical parameters and arthrocentesis continues to prove to be the gold standard of diagnosis. A compilation of a case series detailing location, microorganism, complications, and effective treatment would prove useful to tailor management of these rare presentations.

Rituximab, but not other biologics, impairs humoral immunity in patients with rheumatoid arthritis-a study using CoVariant protein arrays.

RA is an autoimmune disease characterized by chronic inflammation and joint destruction. Biologics are crucial to achieving treat-to-target goals in patients with RA. The global spread and continuous variation of severe acute respiratory syndromecoronavirus 2(SARS-CoV-2) necessitate the monitoring of variant-specific humoral responses post-vaccination. The aim of this study was to investigate how different biologic treatments for vaccinated RA patients might affect their neutralizing antibodies against multiple SARS-CoV-2 variants. We recruited RA patients who had received three doses of conventional SARS-CoV-2 vaccines and were treated with various biologics, e.g. TNF inhibitor (etanercept), IL-6 inhibitor (tocilizumab), CTLA4-Ig (abatacept) or anti-CD20 (rituximab). Serum samples were used to profile the binding and neutralizing antibodies using our own SARS-CoV-2 variant (CoVariant) protein array, developed previously. Compared with healthy controls, only RA therapy with rituximab showed a reduction in neutralizing antibodies capable of targeting spike proteins in SARS-CoV-2 wild-type and most variants. This reduction was not observed in binding antibodies against SARS-CoV-2 wild-type or its variants. After receiving three doses of SARS-CoV-2 vaccination, RA patients who underwent rituximab treatment generated sufficient antibodies but exhibited lower neutralizing activities against wild-type and multiple variants, including current Omicron. Other biological DMARDs, e.g. TNF inhibitor, IL-6 inhibitor and CTLA4-Ig, did not show obvious inhibition.