Inflammatory Arthritis Research Articles

Impaired adipocyte-mediated regulation of fibroblasts in inflammatory arthritis.

Impaired adipocyte-mediated regulation of fibroblasts in inflammatory arthritis.

Prevalence and Distribution of Musculoskeletal Symptoms in Cystic Fibrosis and Impacts on Daily Life.

Musculoskeletal problems are reported in the literature as a common problem for people with cystic fibrosis, with a range of aetiologies including an inflammatory arthritis. However, accurate data on the presentations and prevalence are lacking. The aim of this cohort study was to describe the scale and impact of musculoskeletal symptoms in CF. A collaboratively designed questionnaire was administered to adults attending two large UK CF centres. Data collected evaluated scale and impact of musculoskeletal symptoms. Results were obtained from 489 patients (response rate 59%). Of these, 49% reported that musculoskeletal symptoms impacted their activities of daily living in the previous year. Back pain was common, occurring in 44% of participants in the preceding week. The knee was the most commonly affected painful peripheral joint, with 26% of participants reporting knee pain within the last week rising to 50% within the last year. Early morning stiffness and joint swelling were markedly less common, suggesting that the majority of musculoskeletal pain in CF is not due to an inflammatory arthritis but is due to other factors. Musculoskeletal problems are common in CF and frequently affect activities of daily living. Symptoms of inflammatory arthritis occurred in only a small minority of individuals. A focused approach to characterising and clarifying the aetiology of musculoskeletal symptoms is needed to inform the management of these disabling symptoms.

IL33-induced neutrophil extracellular traps (NETs) mediate a positive feedback loop for synovial inflammation and NET amplification in rheumatoid arthritis.

This study investigated the mechanisms driving the induction and sustained presence of neutrophil extracellular traps (NETs) in the synovial microenvironment of rheumatoid arthritis (RA). Synovial tissue and fluid samples were collected from patients with RA and osteoarthritis (OA), and NET levels and cytokine concentrations were measured using a cytometric bead array and enzyme-linked immunosorbent assay (ELISA). The ability of interleukin-33 (IL-33) to induce NET formation was evaluated using quantitative assays, immunofluorescence staining, live-cell imaging, and electron microscopy. Coincubation experiments of NETs with fibroblast-like synovial cells (FLSs) were conducted, and a modified Transwell migration assay was designed to assess neutrophil migration. The role of IL-33 and NETs in RA progression was further investigated using a collagen antibody-induced arthritis (CAIA) mouse model. The results revealed an increase in NETs and IL-33 levels in the synovial fluid of RA patients, with a significant positive correlation between them. NET formation assays confirmed that IL-33 activates neutrophils to produce NETs and that neutrophils from RA patients exhibit increased responsiveness to IL-33 stimulation. Both in vitro and in vivo evidence has demonstrated that NETs stimulate FLSs to secrete IL-33 and the chemokine CXCL8 via Toll-like receptor 9, promoting further neutrophil recruitment and increasing NET production within the RA synovium. This study reveals a novel positive feedback loop involving NETs and FLSs that is mediated by IL-33 that increases NET accumulation in RA. Targeting IL-33 or NET formation and amplification may offer new therapeutic strategies for managing RA.

Sea Hare Hydrolysate Reduces PD‐L1 Levels in Cancer Cells and Mitigates Rheumatoid Arthritis Ina Collagen‐Induced Arthritis Mouse Model

ABSTRACTOur previous study highlighted the anticancer potential of sea hare hydrolysate (SHH), particularly its role in regulating macrophage polarization and inducing pyroptotic death in lung cancer cells through the inhibition of signal transducer and activator of transcription 3 (STAT3). These findings prompted us to investigate additional features of immune‐oncology (I‐O) agents or adjuvants, such as programmed cell death protein 1 (PD‐1)/programmed death ligand 1 (PD‐L1) inhibition and their association with rheumatoid arthritis (RA) risk, to explore the potential of SHH as an I‐O agent or adjuvant. In this study, we investigated the effects of SHH on PD‐L1 levels in various cancer cell types and assessed its effectiveness in treating RA, a common side effect of I‐O agents. Our results showed a marked reduction in PD‐L1 levels in multiple cancer cell lines and decreased PD‐1 and PD‐L1 levels in tumor‐associated macrophages. In a mouse model with collagen‐induced arthritis (CIA), SHH exhibited anti‐inflammatory effects comparable to methotrexate (MTX), a first‐line treatment for RA. Both the SHH and MTX groups had significantly lower arthritis scores and paw thickness compared to the CIA group. Additionally, SHH or MTX treatment effectively reduced elevated levels of anticollagen type II (CII) antibodies and proinflammatory cytokines (IL‐1β, IL‐6, and TNF‐α). Histopathological analysis revealed that SHH and MTX treatments notably mitigated arthritic inflammation, synovial hyperplasia, and loss of articular cartilage and bone. Micro‐CT scans showed reduced articular destruction in the SHH and MTX groups. These findings indicate that SHH treatment decreases PD‐L1 levels in cancer cells and reduces the severity of CIA by exerting anti‐inflammatory effects. Therefore, SHH holds promise as an I‐O agent without side effects such as exacerbation of RA.

TNFα-inhibitors cycling with golimumab as second drug in inflammatory arthritis patients: Data from the multicenter GO-REAL registry

Introduction/ObjectivesThere are still controversies about the efficacy of cycling to a second tumor necrosis factor inhibitor (TNFi) in patients with inflammatory arthritis. The aim of this study was to evaluate survival, persistence and effectiveness of golimumab (GLM) in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) with previous experience with other TNFi and to compare these results with TNFi naive patients. MethodsObservational cohort of consecutive patients with RA, PsA and axSpA who had started treatment with GLM according to medical indication. bDMARD naive and TNFi experienced patients were selected. ResultsA total of 147 (62.3%) bDMARD naive and 45 (19.1%) TNFi experienced patients were included. Patients were followed up for a total of 441.5 patients/year, 55 (28.6%) discontinued GLM, 42 (28.6%) and 13 (28.9%) in each group, respectively (p=0.967). The majority (63.6%) suspended due to inefficacy, followed by lack of access (23.6%) and adverse events (9.1%). Median GLM survival was 74.0 months (95% CI 57.0, 91.0) and 71.0 months (95% CI 37.0, 105.0), in the bDMARD naive and TNFi experienced patients, respectively (p=0.695). Drug persistence at 6, 12, 24 and 36 months was 92.8%, 88.1%, 76.1%, 65.4% and 93.1%, 77.4%, 74.2%, 68.5%, respectively. In the multivariable analysis, having public health insurance was associated with higher risk of drug discontinuation (HR 2.56, 95% CI 1.28–5.00, p=0.008). TNFi experienced patients did not show significantly higher risk of GLM suspension (HR 1.35, 95% CI 0.70–2.57, p=0.370). ConclusionIn this cohort, TNFi experienced patients had comparable survival and persistence of treatment with GLM. Having public health insurance was associated with lower drug retention rates.

Features Associated With Different Inflammatory Phenotypes of Calcium Pyrophosphate Deposition Disease: A Study Using Data From the International American College of Rheumatology/EULAR Calcium Pyrophosphate Deposition Classification Criteria Cohort.

The study objective was to examine the disease, demographic, and imaging features associated with different inflammatory phenotypes of calcium pyrophosphate deposition (CPPD) disease, ie, recurrent acute calcium pyrophosphate (CPP) crystal arthritis, chronic CPP crystal inflammatory arthritis, and crowned dens syndrome (CDS). Data from an international cohort (assembled from 25 sites in 7 countries for the development and validation of the 2023 CPPD classification criteria from the American College of Rheumatology/EULAR) that met the criteria were included. Three cross-sectional studies were conducted to determine the phenotypic characteristics of recurrent acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and CDS. Multivariable logistic regression analysis was used to calculate adjusted odds ratio (aOR) and 95% confidence interval (CI) to examine the association between potential risk factors and the inflammatory phenotype. Among the 618 people included (56% female; mean age [standard deviation] 74.0 [11.9] years), 602 (97.4%) had experienced acute CPP crystal arthritis, 332 (53.7%) had recurrent acute arthritis, 158 (25.6%) had persistent inflammatory arthritis, and 45 (7.3%) had had CDS. Recurrent acute CPP crystal arthritis associated with longer disease duration (aOR 2.88 [95% CI 2.00-4.14]). Chronic CPP crystal inflammatory arthritis was associated with acute wrist arthritis (aOR 2.92 [95% CI 1.81-4.73]), metacarpophalangeal joint osteoarthritis (aOR 1.87 [95% CI 1.17-2.97]), and scapho-trapezo-trapezoid (STT) joint osteoarthritis (aOR 1.83 [95% CI 1.15-2.91]), and it was negatively associated with either metabolic or familial risk for CPPD (aOR 0.60 [95% CI 0.37-0.96]). CDS was associated with male sex (aOR 2.35 [95% CI 1.21-4.59]), STT joint osteoarthritis (aOR 2.71 [95% CI 1.22-6.05]), and more joints affected with chondrocalcinosis (aOR 1.46 [95% CI 1.15-1.85]). CPPD disease encompasses acute and chronic inflammatory phenotypes, each with specific clinical and imaging features that need to be considered in the diagnostic workup.

Target Therapy in Chronic Arthritis: The Unmet Needs, State-of-the-Art on Dual Biologic Treatments, and Future Perspectives

Since the early 1990s, the introduction of biologic disease-modifying antirheumatic drugs (b-DMARDs) in managing rheumatological diseases has revolutionised the course of inflammatory chronic arthritis, improving the quality of life, slowing the radiographic progression, avoiding disability, preserving workability, and reducing mortality [...]

Understanding Gout – Pathogenesis, Diagnosis and Management

Gout is one of the most common types of inflammatory arthritis caused by accumulation of uric acid crystals within joints. It typically starts in the big toe with symptoms such as intense joint pain especially at night, swelling and redness. This sudden episode is also called a “flare” or an “attack”. Males are three times more likely to be affected with gout than females. Other key risk factors include obesity, hypertension, high alcohol and seafood intake. Diagnosis of gout is mostly clinical. Joint fluid analysis which shows urate crystals and ultrasound are used to confirm the diagnosis. An acute attack of gout can be relieved by anti-inflammatory agents like NSAIDs, Colchicine and Corticosteroids which is followed by long term management – uric acid lowering agents, lifestyle, weight and dietary management.

Optimizing Gout Treatment: A Comprehensive Review of Current and Emerging Uricosurics

Gout is the most common inflammatory arthritis, affecting approximately 5.1% of adults in the United States (US) population. Gout is a metabolic and autoinflammatory disease. Elevated uric acid pools lead to the precipitation of monosodium urate (MSU) crystals in and around joints, as well as other tissues, and the subsequent autoinflammatory response. Since elevated serum urate (SU) levels (hyperuricemia) correspond with gout severity, urate-lowering therapies (ULTs) are the cornerstone of gout treatment.ULTs include xanthine oxidoreductase inhibitors, uricosurics, less commonly used in the US but widely used in Europe and Asia, including benzbromarone, dotinurad, and probenecid (the only US Food and Drug Administration (FDA) approved uricosuric in the US), and uricases, including rasburicase and pegloticase (available only in the US).Over 90% of the daily load of uric acid filtered by the kidneys is reabsorbed through renal transporters. These urate transporters include uric acid transporter 1 (URAT1), glucose transporter 9, and organic anion transporters 1, 3, and 4 (OAT1, OAT3, OAT4). They are the target of approved and in-the-pipeline uricosurics.Any drug that increases renal excretion of uric acid, independently of the mechanism through which it exerts its effect, may be considered a uricosuric drug. This review discusses drugs that increase renal excretion of uric acid, either approved or in development, as well as off-label drugs with uricosuric properties.

Effects of employees living with an ‘arthritis’ on sickness absence and transitions out of employment: a comparative observational study in the UK

PurposeTo assess sickness absence and transitions from employment for employees with arthritis compared with employees without arthritis over time.MethodsWe use 10 waves of the UK Household Longitudinal Survey (2009–2019). The...

Testing the efficacy of WORK-ON: vocational rehabilitation for people with chronic inflammatory arthritis in Denmark—protocol for a randomised controlled trial

IntroductionAmong people with chronic inflammatory arthritis (IA), up to 40% lose their job in the first few years after diagnosis of this condition and are hence at high risk of...

Global, regional, and national burden of gout in elderly 1990–2021: an analysis for the global burden of disease study 2021

BackgroundGout, an inflammatory arthritis, disproportionately affects the elderly due to hyperuricemia, leading to significant health-related quality of life impairments and escalating healthcare costs. However, a comprehensive global analysis focusing on the elderly population is needed to inform effective interventions.MethodsUtilizing data from the Global Burden of Disease Study 2021, this study assessed the prevalence, incidence, and Years Lived with Disability (YLDs) of gout among individuals aged ≥ 55 years in 204 countries from 1990 to 2021. We also evaluated the impact of high body mass index (BMI) and kidney dysfunction as key risk factors.ResultsThe study identified 37,230,366 cases of gout globally among the elderly, with an age-standardized prevalence rate of 2505.4 per 100,000 population. There was a notable increase in prevalence with an Estimated Annual Percentage Change (EAPC) of 1.08. Similarly, the age-standardized incidence and YLD rates increased, with EAPCs of 0.83 and 1.06, respectively. High-income regions, particularly Australasia and High-income North America, exhibited the highest rates, while Central Latin America and the Caribbean reported the lowest. Males had a higher burden of gout than females. High BMI and kidney dysfunction were significant contributors to YLDs, with their impact more pronounced in regions with higher Socio-Demographic Index (SDI).ConclusionThe study found a growing gout burden among the elderly, with substantial regional and gender disparities. It underscores the urgent need for targeted public health interventions, particularly in high SDI regions, to address modifiable risk factors like high BMI and kidney dysfunction and to curb the rising trend of gout prevalence and disability.

Immune Checkpoint Inhibitor Associated Rheumatoid Arthritis.

Immune checkpoint inhibitors (ICI) have revolutionized cancer therapy over the past decade. Unfortunately, immune related adverse events (irAEs) are common, including rheumatologic adverse events. These rheumatologic irAEs include de novo rheumatoid arthritis-like presentations or flares of pre-existing rheumatoid arthritis, collectively called ICI-associated rheumatoid arthritis. In this article we review the different mechanisms of disease activity and management approaches including use of conventional (cs) DMARDs and biologic (b) DMARDs in this patient population. Other forms of ICI-induced inflammatory arthritis e.g., PMR-like or Spondylarthritis-type IA, are beyond the scope of this review. The heterogeneous presentations of inflammatory arthritis in patients receiving immune checkpoint inhibitors has made this a challenging area to study. Nonetheless, recent studies are providing better understanding on the mechanisms of de novo disease and flares in patients with rheumatoid arthritis. About half of patients with pre-existing rheumatoid arthritis flare after receiving checkpoint inhibitors. Persistent arthritis is often encountered in patients receiving combination immune checkpoint inhibitors. Outcomes on overall survival do not differ in rheumatoid arthritis patients receiving checkpoint inhibitors compared to their non-arthritis counterparts. Rheumatologist play a critical role in the management of active rheumatoid arthritis induced by checkpoint inhibitors. Collaboration with oncology colleagues will continue to be a crucial component in providing quality care to these patients. While the use of glucocorticoids is often the first line therapy for active inflammatory arthritic disease, we recommend earlier consideration of DMARDs just as we inverted the treatment pyramid several decades ago, for rheumatoid arthritis.

Hydroethanolic Extract of Polygonum aviculare L. Mediates the Anti-Inflammatory Activity in RAW 264.7 Murine Macrophages Through Induction of Heme Oxygenase-1 and Inhibition of Inducible Nitric Oxide Synthase

Polygonum aviculare L. (PAL), commonly known as knotgrass, has been utilized as a traditional folk medicine across Asian, African, Latin American and Middle Eastern countries to treat various inflammatory diseases, including arthritis and airway inflammation. Numerous medicinal herbs exert anti-inflammatory and antioxidative effects that are mediated through the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the inhibition of nuclear factor kappa B (NF-κB). However, the underlying molecular mechanisms linking the antioxidative and anti-inflammatory effects remain poorly understood. Heme oxygenase-1 (HO-1) is an antioxidant enzyme that catalyzes heme degradation, ultimately leading to the production of carbon monoxide (CO). Elevated levels of CO have been correlated with the decreased level of inducible nitric oxide synthase (iNOS). In this study, we examined whether HO-1 plays a key role in the relationship between the antioxidative and anti-inflammatory properties of PAL. The anti-inflammatory and antioxidative activities of PAL in an in vitro system were evaluated by determining NF-κB activity, antioxidant response element (ARE) activity, pro-inflammatory cytokine and protein levels, as well as antioxidant protein levels. To examine whether HO-1 inhibition interfered with the anti-inflammatory effect of PAL, we measured nitrite, reactive oxygen species, iNOS, and HO-1 levels in RAW 264.7 murine macrophages pre-treated with Tin protoporphyrin (SnPP, an HO-1 inhibitor). Our results demonstrated that PAL increased ARE activity and the Nrf2-regulated HO-1 level, exerting antioxidative activities in RAW 264.7 macrophages. Additionally, PAL reduced cyclooxygenase-2 (COX-2) and iNOS protein levels by inactivating NF-κB in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Further investigation using the HO-1 inhibitor revealed that HO-1 inhibition promoted iNOS expression, subsequently elevating nitric oxide (NO) generation in LPS-activated RAW 264.7 macrophages treated with PAL compared to those in the macrophages without the HO-1 inhibitor. Overall, our findings suggest that HO-1 induction by PAL may exert anti-inflammatory effects through the reduction of the iNOS protein level. Hence, this study paves the way for further investigation to understand molecular mechanisms underlying the antioxidative and anti-inflammatory activities of medicinal herbs.

“Motion Capture Suit Sign” for Immunotherapy-Induced Inflammatory Arthritis on 99mTc-MDP Bone Scintigraphy

Abstract We report the 99mTc-MDP bone scan of a 44-year-old man with a history of lung adenocarcinoma and recent multiple joint pain after completing pembrolizumab immunotherapy treatment. This interesting image of symmetric uptakes around bilateral joints throughout the skeleton resembles the ball sensors on a motion capture suit. Hence, we recommend naming this distinctive imaging appearance as the “motion capture suit” sign.

Recent advances in nuclear medicine and their role in inflammatory arthritis: focus on the emerging role of FAPI PET/CT

AbstractImaging molecular processes associated with inflammatory disease has been revolutionized by hybrid imaging using positron emission tomography/computed tomography (PET/CT). PET/CT visualizes metabolic activity as well as protein expression and provides a comprehensive whole-body evaluation. It has the potential to reveal inflammation prior to detection of structural changes in inflammatory joint diseases. FAP is a type II transmembrane glycoprotein overexpressed not only in the stroma of tumors but also in the fibrotic processes of certain immune-mediated disorders. The recent introduction of fibroblast activation protein inhibitors (FAPI) labeled by positron emitters and thus suitable for PET/CT allows to investigate FAP expression in vivo. This review will focus on the use of FAPI-PET/CT for the diagnosis and evaluation of treatment response in inflammatory joint diseases.

Allopurinol Adherence in US Patients With Gout

Background/Objective Gout is the most common inflammatory arthritis, and its morbidity can be substantially reduced through urate-lowering therapy. However, adherence to allopurinol—the most common urate-lowering therapy—is notoriously poor. Prior studies have not fully elucidated factors associated with allopurinol adherence, particularly psychosocial factors. Methods We used 2018–2021 data from the Medical Expenditure Panel Survey, a national longitudinal survey on health care expenditures and utilization. We calculated the medication possession ratio (MPR) for allopurinol for participants with gout and categorized each as follows: no allopurinol fills, low adherence (MPR ≤0.8), or high adherence (MPR >0.8) to allopurinol. We used multivariable logistic regression to identify factors associated with high adherence, using person-year as the unit of measure and accounting for clustering for participants who contributed more than 1 person-year. Results The analyses included 919 respondents (1453 person-years), representing a weighted total of 15,084,439 person-years. Across all years, 27.4% had no allopurinol fills, 37.4% had low adherence, and 35.2% had high adherence. In multivariable models for high adherence, Black race (odds ratio, 0.49; 95% confidence interval, 0.33–0.73, compared with White) and residence in the South US region (odds ratio, 0.54; 95% confidence interval, 0.35–0.82, compared with Northeast) were negatively associated with high adherence. Conclusions Black race and residing in the Southern US were associated with lower allopurinol adherence among gout patients. Interventions to improve adherence, particularly among Black patients in the South, are needed to maximize the potential benefits of allopurinol.

Retrospective analysis of hip arthroplasty in patients younger than 50 years in a single center.

To report on causes and treatment options of hip arthroplasty in younger population in a single center. Data was accessed retrospectively from hospital information system (HIS) and charts were reviewed. All patients younger than 50 years, who had hip arthroplasty for any indication during January 2020 to July 2023 time period at Lady Reading Hospital, Peshawar, were included in this study. We identified 61 patients, comprising of 33 male and 28 female patients. Mean age was 36.98 ± 7.792 years. Non-cemented hip arthroplasty was performed in 88.5% of patients. Avascular necrosis (49.2%) was the leading indication for hip arthroplasty in younger patients, followed by neglected fracture neck of femur (24.6%), inflammatory arthritis (3.2%), and other causes (23%). Metal on highly cross-linked polyethylene was the commonest bearing surface. Non-cemented hip arthroplasty was the commonest treatment method in younger population in this study.

Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis.

Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis. To pharmacologically disrupt the Pol II transcription cycle, we used two covalent inhibitors of the transcription factor II H-associated cyclin-dependent kinase 7 (CDK7), THZ1 and YKL-5-124. Both reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed preestablished inflammatory macrophage polarization. In mice, CDK7 inhibition ameliorated both acute and chronic progressive inflammatory arthritis. Lastly, CDK7 inhibition down-regulated a pathogenic gene expression signature in synovial explants from patients with rheumatoid arthritis. We propose that interfering with Pol II early elongation by targeting CDK7 represents a therapeutic opportunity for rheumatoid arthritis and other inflammatory diseases.

Utility of the 2019 EULAR/ACR SLE classification criteria for predicting mortality and hospitalisation: development and cross-validation of ominosity score

ObjectiveThe 2019 European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria score (≥20 points) has been associated with poor outcomes. We aimed...