-
RMD Open Nov 2023The inclusion of patient research partners (PRPs) in research projects is increasingly recognised and recommended in rheumatology. The level of involvement of PRPs in... (Review)
Review
OBJECTIVE
The inclusion of patient research partners (PRPs) in research projects is increasingly recognised and recommended in rheumatology. The level of involvement of PRPs in translational research in rheumatology remains unknown, while in randomised clinical trials (RCTs), it has been reported to be 2% in 2020. Therefore, we aimed to assess the involvement of PRPs in recent translational studies and RCTs in rheumatology.
METHODS
We conducted a scoping literature review of the 80 most recent articles (40 translational studies and 40 RCTs) from four target diseases: rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus and lower extremity osteoarthritis. We selected 20 papers from each disease, published up until 1 March 2023, in rheumatology and general scientific journals. In each paper, the extent of PRP involvement was assessed. Analyses were descriptive.
RESULTS
Of 40 translational studies, none reported PRP involvement. Of 40 RCTs, eight studies (20%) reported PRP involvement. These trials were mainly from Europe (75%) and North America (25%). Most of them (75%) were non-industry funded. The type of PRP involvement was reported in six of eight studies: six studies reported PRP participation in the study design or design of the intervention and two of them in the interpretation of the results. All the trials reporting the number of PRPs (75%), involved at least two PRPs.
CONCLUSION
Despite a worldwide movement advocating for increased patient involvement in research, PRPs in translational research and RCTs in rheumatology are significantly under-represented. This limited involvement of PRPs in research highlights a persistent gap between the existing recommendations and actual practice.
Topics: Humans; Rheumatology; Arthritis, Rheumatoid; Arthritis, Psoriatic; Patient Participation; Lupus Erythematosus, Systemic
PubMed: 37996123
DOI: 10.1136/rmdopen-2023-003566 -
International Journal of Biological... Apr 2024Hyaluronic acid (HA), a biodegradable, biocompatible and non-immunogenic therapeutic polymer is a key component of the cartilage extracellular matrix (ECM) and has been... (Review)
Review
Hyaluronic acid (HA), a biodegradable, biocompatible and non-immunogenic therapeutic polymer is a key component of the cartilage extracellular matrix (ECM) and has been widely used to manage two major types of arthritis, osteoarthritis (OA) and rheumatoid arthritis (RA). OA joints are characterized by lower concentrations of depolymerized (low molecular weight) HA, resulting in reduced physiological viscoelasticity, while in RA, the associated immune cells are over-expressed with various cell surface receptors such as CD44. Due to HA's inherent viscoelastic property and its ability to target CD44, there has been a surge of interest in developing HA-based systems to deliver various bioactives (drugs and biologics) and manage arthritis. Considering therapeutic benefits of HA in arthritis management and potential advantages of novel delivery systems, bioactive delivery through HA-based systems is beginning to display improved outcomes over bioactive only treatment. The benefits include enhanced bioactive uptake due to receptor-mediated targeting, prolonged retention of bioactives in the synovium, reduced expressions of proinflammatory mediators, enhanced cartilage regeneration, reduced drug toxicity due to sustained release, and improved and cost-effective treatment. This review provides an underlying rationale to prepare and use HA-based bioactive delivery systems for arthritis applications. With special emphasis given to preclinical/clinical results, this article reviews various bioactive-loaded HA-based particulate carriers (organic and inorganic), gels, scaffolds and polymer-drug conjugates that have been reported to treat and manage OA and RA. Furthermore, the review identifies several key challenges and provides valuable suggestions to address them. Various developments, strategies and suggestions described in this review may guide the formulation scientists to optimize HA-based bioactive delivery systems as an effective approach to manage and treat arthritis effectively.
Topics: Humans; Hyaluronic Acid; Osteoarthritis; Arthritis, Rheumatoid; Pharmaceutical Preparations; Polymers
PubMed: 38460633
DOI: 10.1016/j.ijbiomac.2024.130645 -
International Journal of Circumpolar... Dec 2023Advances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA... (Review)
Review
Advances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA have not achieved the high rates of treatment success observed in other populations. We review factors contributing to poor long-term outcomes for INA with RA. We conducted a narrative review of studies evaluating RA in INA supplemented with regional administrative health and clinical cohort data on clinical outcomes and health care utilisation. We discuss factors related to conducting research in INA populations including studies of RA prevention. NA with RA have a high burden of genetic and environmental predisposing risk factors that may impact disease phenotype, delayed or limited access to rheumatology care and advanced therapy. These factors may contribute to the observed increased rates of persistent synovitis, premature end-stage joint damage and mortality. Novel models of care delivery that are culturally sensitive and address challenges associated with providing speciality care to patients residing in remote communities with limited accessibility are needed. Progress in establishing respectful research partnerships with INA communities has created a foundation for ongoing initiatives to address care gaps including those aimed at RA prevention. This review highlights some of the challenges of diagnosing, treating, and ultimately perhaps preventing, RA in INA populations.
Topics: Humans; Arthritis, Rheumatoid; Longitudinal Studies; Population Groups; Indigenous Peoples; North America
PubMed: 36642913
DOI: 10.1080/22423982.2023.2166447 -
Immunity, Inflammation and Disease Oct 2023Naringenin is widely recognized for its notable attributes, including anti-inflammatory, anti-cancer, and immunomodulatory activities. However, its specific implications...
BACKGROUND
Naringenin is widely recognized for its notable attributes, including anti-inflammatory, anti-cancer, and immunomodulatory activities. However, its specific implications for rheumatoid arthritis (RA) and the underlying mechanisms remain to be explored. This study aimed to investigate the therapeutic efficacy and pharmacological mechanism of Naringenin in the treatment of collagen-induced arthritis (CIA).
METHODS
A CIA model was established in DBA/1 mice, and various doses of Naringenin were administered orally to assess its impact on RA. The study also involved lipopolysaccharides (LPS)-induced RAW264.7 cells to further evaluate the effects of Naringenin. Mechanistic studies were conducted to elucidate the signaling pathways involved in Naringenin's actions.
RESULTS
Naringenin significantly alleviated foot inflammation in DBA/1 CIA mice and attenuated the levels of pro-inflammatory cytokines in serum. It also enhanced antioxidant capacity in the CIA model. In vitro studies with LPS-induced RAW264.7 cells demonstrated that Naringenin attenuated pro-inflammatory cytokines and reactive oxygen species (ROS) levels. Mechanistic studies confirmed that Naringenin activated autophagy and increased autophagic flux. Blocking autophagy, either by silencing Atg5 or inhibiting autophagolysosome using chloroquine, effectively counteracted the impact of Naringenin on pro-inflammatory cytokines. Further exploration revealed that Naringenin activated the AMPK/ULK1 signaling pathway, and inhibition of AMPK reversed the initiation of autophagy and reduced pro-inflammatory cytokine secretion induced by Naringenin.
CONCLUSIONS
This study unveils a novel mechanism by which Naringenin may be used to treat RA. It demonstrates the therapeutic efficacy of Naringenin in a CIA model by reducing inflammation, modulating cytokine levels, and enhancing antioxidant capacity. Moreover, the activation of autophagy through the AMPK/ULK1 signaling pathway appears to play a critical role in Naringenin's anti-inflammatory effects. These findings suggest potential strategies for the development of anti-rheumatic medications based on Naringenin.
Topics: Mice; Animals; Arthritis, Experimental; AMP-Activated Protein Kinases; Antioxidants; Lipopolysaccharides; Mice, Inbred DBA; Arthritis, Rheumatoid; Macrophages; Cytokines; Inflammation; Anti-Inflammatory Agents; Autophagy
PubMed: 37904715
DOI: 10.1002/iid3.983 -
European Journal of Pharmacology Jun 2024Fibroblast-like synoviocytes (FLS) play an important role in rheumatoid arthritis (RA)-related swelling and bone damage. Therefore, novel targets for RA therapy in FLS...
Fibroblast-like synoviocytes (FLS) play an important role in rheumatoid arthritis (RA)-related swelling and bone damage. Therefore, novel targets for RA therapy in FLS are urgently discovered for improving pathologic phenomenon, especially joint damage and dyskinesia. Here, we suggested that pyruvate kinase M2 (PKM2) in FLS represented a pharmacological target for RA treatment by antimalarial drug artemisinin (ART). We demonstrated that ART selectively inhibited human RA-FLS and rat collagen-induced arthritis (CIA)-FLS proliferation and migration without observed toxic effects. In particular, the identification of targets revealed that PKM2 played a crucial role as a primary regulator of the cell cycle, leading to the heightened proliferation of RA-FLS. ART exhibited a direct interaction with PKM2, resulting in an allosteric modulation that enhances the lactylation modification of PKM2. This interaction further promoted the binding of p300, ultimately preventing the nuclear translocation of PKM2 and inducing cell cycle arrest at the S phase. In vivo, ART obviously suppressed RA-mediated synovial hyperplasia, bone damage and inflammatory response to further improve motor behavior in CIA-rats. Taken together, these findings indicate that directing interventions towards PKM2 in FLS could offer a hopeful avenue for pharmaceutical treatments of RA through the regulation of cell cycle via PKM2 lactylation.
Topics: Synoviocytes; Arthritis, Rheumatoid; Animals; Cell Proliferation; Humans; Rats; Fibroblasts; Pyruvate Kinase; Thyroid Hormone-Binding Proteins; Male; Thyroid Hormones; Arthritis, Experimental; Cell Movement; Molecular Targeted Therapy; Membrane Proteins; Carrier Proteins; Small Molecule Libraries
PubMed: 38570082
DOI: 10.1016/j.ejphar.2024.176551 -
Annals of the Rheumatic Diseases Apr 2024Erythropoietin (EPO) known as an erythrocyte-stimulating factor is increased in patients with rheumatoid arthritis (RA). Nevertheless, the function of EPO in the process...
OBJECTIVE
Erythropoietin (EPO) known as an erythrocyte-stimulating factor is increased in patients with rheumatoid arthritis (RA). Nevertheless, the function of EPO in the process of RA and relative mechanism needs to be further clarified.
METHODS
The level of EPO in serum and synovial fluid from patients with RA and healthy controls was determined by . Collagen-induced arthritis (CIA) mice were constructed to confirm the role of EPO on RA pathogenesis. Differentially expressed genes (DEGs) of EPO-treated fibroblast-like synoviocyte (FLS) were screened by transcriptome sequencing. The transcription factor of neuraminidase 3 (NEU3) of DEGs was verified by double luciferase reporting experiment, DNA pulldown, electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR (qPCR) assay.
RESULTS
The overexpression of EPO was confirmed in patients with RA, which was positively associated with Disease Activity Score 28-joint count. Additionally, EPO intervention could significantly aggravate the joint destruction in CIA models. The upregulation of NEU3 was screened and verified by transcriptome sequencing and qPCR in EPO-treated FLS, and signal transducer and activator of transcription 5 was screened and verified to be the specific transcription factor of NEU3. EPO upregulates NEU3 expression via activating the Janus kinase 2 (JAK2)-STAT5 signalling pathway through its receptor EPOR, thereby to promote the desialylation through enhancing the migration and invasion ability of FLS, which is verified by JAK2 inhibitor and NEU3 inhibitor.
CONCLUSION
EPO, as a proinflammatory factor, accelerates the process of RA through transcriptional upregulation of the expression of NEU3 by JAK2/STAT5 pathway.
Topics: Animals; Humans; Mice; Arthritis, Experimental; Arthritis, Rheumatoid; Cell Proliferation; Cells, Cultured; Erythropoietin; Fibroblasts; Neuraminidase; STAT5 Transcription Factor; Synovial Membrane; Synoviocytes
PubMed: 38272667
DOI: 10.1136/ard-2023-224852 -
Seminars in Arthritis and Rheumatism Apr 2024To elucidate the risk and temporal relationship of cardiovascular (CV) comorbidities in rheumatic diseases.
OBJECTIVES
To elucidate the risk and temporal relationship of cardiovascular (CV) comorbidities in rheumatic diseases.
METHODS
Patients in the FinnGen study diagnosed between 2000 and 2014 with seropositive (n = 2368) or seronegative (n = 916) rheumatoid arthritis (RA), ankylosing spondylitis (AS, n = 715), psoriatic arthritis (PsA, n = 923), systemic lupus erythematosus (SLE, n = 190), primary Sjogren's syndrome (pSS, n = 412) or gout (n = 2034) were identified from healthcare registries. Each patient was matched based on age, sex, and birth region with twenty controls without any rheumatic conditions. Overall risk ratios (RR) were calculated by comparing the prevalence of seven CV diseases between patients and controls. Logistic regression models were used for estimating odds ratios (OR) for CV comorbidities before and after the onset of rheumatic diseases.
RESULTS
The RR for 'any CVD' varied from 1.14 (95 % confidence interval [CI] 1.02-1.26) in PsA to 2.05 (95 % CI 1.67-2.52) in SLE. Patients with SLE or gout demonstrated over two-fold risks for several CV comorbidities. Among CV comorbidities, venous thromboembolism (VTE) showed the highest effect sizes in several rheumatic diseases. The ORs for CV comorbidities were highest within one year before and/or after the onset of the rheumatic disease. However, in gout the excess risk of CV disease was especially high before gout diagnosis.
CONCLUSIONS
The risk of CV comorbidities was elevated in all studied rheumatic diseases, with highest risks observed in SLE and gout. The risk for CV diseases was highest immediately before and/or after rheumatic disease diagnosis, highlighting the increased risk for CV comorbidities across all rheumatic diseases very early on the disease course.
Topics: Humans; Arthritis, Psoriatic; Rheumatic Diseases; Arthritis, Rheumatoid; Gout; Lupus Erythematosus, Systemic; Cardiovascular Diseases
PubMed: 38308930
DOI: 10.1016/j.semarthrit.2024.152382 -
JAMA Network Open Mar 2024Depression is among the most common comorbidities in rheumatoid arthritis (RA). There is a lack of data regarding the association of RA seropositivity and biologic...
IMPORTANCE
Depression is among the most common comorbidities in rheumatoid arthritis (RA). There is a lack of data regarding the association of RA seropositivity and biologic agents with depression risk among individuals with RA.
OBJECTIVE
To investigate the risk of depression following RA diagnosis among patients in South Korea.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included 38 487 patients with RA and a comparison group of 192 435 individuals matched 1:5 for age, sex, and index date. Data were from the Korean National Health Insurance Service database. Participants were enrolled from 2010 to 2017 and were followed up until 2019. Participants who had previously been diagnosed with depression or were diagnosed with depression within 1 year after the index date were excluded. Statistical analysis was performed in May 2023.
EXPOSURES
Seropositive RA (SPRA) was defined with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes M05 and enrollment in the Korean Rare and Intractable Diseases program. Seronegative RA (SNRA) was defined with ICD-10 codes M06 (excluding M06.1 and M06.4) and a prescription of any disease-modifying antirheumatic drugs (DMARDs) for 270 days or more.
MAIN OUTCOMES AND MEASURES
Newly diagnosed depression (ICD-10 codes F32 or F33).
RESULTS
The mean (SD) age of the total study population was 54.6 (12.1) years, and 163 926 individuals (71.0%) were female. During a median (IQR) follow-up of 4.1 (2.4-6.2) years, 27 063 participants (20 641 controls and 6422 with RA) developed depression. Participants with RA had a 1.66-fold higher risk of depression compared with controls (adjusted hazard ratio [aHR], 1.66 [95% CI, 1.61-1.71]). The SPRA group (aHR, 1.64 [95% CI, 1.58-1.69]) and the SNRA group (aHR, 1.73 [95% CI, 1.65-1.81]) were associated with an increased risk of depression compared with controls. Patients with RA who used biologic or targeted synthetic DMARDs (aHR, 1.33 [95% CI, 1.20-1.47]) had a lower risk of depression compared with patients with RA who did not use these medications (aHR, 1.69 [95% CI, 1.64-1.74]).
CONCLUSIONS AND RELEVANCE
This nationwide cohort study found that both SPRA and SNRA were associated with a significantly higher risk of depression. These results suggest the importance of early screening and intervention for mental health in patients with RA.
Topics: Humans; Female; Middle Aged; Male; Cohort Studies; Depression; Retrospective Studies; Arthritis, Rheumatoid; Antirheumatic Agents; Republic of Korea; Biological Products
PubMed: 38441894
DOI: 10.1001/jamanetworkopen.2024.1139 -
British Journal of Hospital Medicine... Jan 2024Management of joint infection is an evolving topic. This article reviews the literature on the management of native and prosthetic joint infection and suggests some... (Review)
Review
Management of joint infection is an evolving topic. This article reviews the literature on the management of native and prosthetic joint infection and suggests some areas of improvement in short- and long-term management which could lead to better patient outcomes. Surgical management is the mainstay of treatment for native or prosthetic knee infection and aspiration should only be used for diagnostic purposes. A multidisciplinary team approach and compliance with national guidelines, alongside referral networks and pooling of expertise, should be mandatory to improve patient outcomes.
Topics: Humans; Arthritis, Infectious; Knee Joint; Referral and Consultation
PubMed: 38300684
DOI: 10.12968/hmed.2023.0219 -
Arthritis Research & Therapy Feb 2024We report long-term, end-of-study program safety outcomes from 25 randomized clinical trials (RCTs) in adult patients with psoriasis (PsO), psoriatic arthritis (PsA), or...
Long-term safety of Ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of final safety data from 25 randomized clinical trials.
BACKGROUND
We report long-term, end-of-study program safety outcomes from 25 randomized clinical trials (RCTs) in adult patients with psoriasis (PsO), psoriatic arthritis (PsA), or axial spondyloarthritis (axSpA) [including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)] who received ≥ 1 dose of Ixekizumab (IXE) over 5 years (PsO) or up to 3 years (PsA, axSpA).
METHODS
This integrated safety analysis consists of data from patients who received any dose of IXE, across 25 RCTs (17 PsO, 4 PsA, 4 axSpA). Rates of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and selected adverse events (AEs) of interest were analyzed for all pooled studies by years of therapy and overall, through March 2022. Results were reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) overall and at successive year intervals.
RESULTS
Six thousand eight hundred ninety two adult patients with PsO, 1401 with PsA, and 932 with axSpA (including AS and nr-axSpA), with a cumulative IXE exposure of 22,371.1 PY were included. The most commonly reported TEAE across indications was nasopharyngitis (IRs per 100 PY: 8.8 (PsO), 9.0 (PsA), 8.4 (axSpA)). SAEs were reported by 969 patients with PsO (IR 5.4), 134 patients with PsA (IR 6.0), and 101 patients with axSpA (IR 4.8). Forty-five deaths were reported (PsO, n = 36, IR 0.2; PsA, n = 6, IR 0.3; axSpA, n = 3, IR 0.1). TEAEs did not increase during IXE exposure: IRs per 100 PY, PsO: 88.9 to 63.2 (year 0-1 to 4-5), PsA: 87 to 67.3 (year 0-1 to 2-3), axSpA: 82.1 to 55.4 (year 0-1 to > = 2). IRs per 100 PY of discontinuation from IXE due to AE were 2.9 (PsO), 5.1 (PsA), and 3.1 (axSpA). IRs per 100 PY of injection site reactions were 5.9 (PsO), 11.6 (PsA) and 7.4 (axSpA); Candida: 1.9 (PsO), 2.0 (PsA), and 1.2 (axSpA); depression, major adverse cerebro-cardiovascular events and malignancies: ≤ 1.6 across all indications. Adjudicated IRs per 100 PY of inflammatory bowel disease were ≤ 0.8 across indications (0.1 [PsO]; 0.1 [PsA]; 0.8 [axSpA]).
CONCLUSIONS
In this integrated safety analysis, consisting of over 22,000 PY of exposure, the long-term safety profile of IXE was found to be consistent with previous, earlier reports, with no new safety signals identified.
TRIAL REGISTRATION
NCT registration numbers for RCTs included in this integrated analysis can be found in Additional File 1.
Topics: Adult; Humans; Arthritis, Psoriatic; Non-Radiographic Axial Spondyloarthritis; Randomized Controlled Trials as Topic; Psoriasis; Spondylitis, Ankylosing; Antibodies, Monoclonal, Humanized
PubMed: 38347650
DOI: 10.1186/s13075-023-03257-7