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Journal of Translational Medicine Sep 2023Rheumatoid arthritis (RA) is a chronic inflammatory illness that mostly affects the joints of the hands and feet and can reduce life expectancy by an average of 3 to...
INTRODUCTION
Rheumatoid arthritis (RA) is a chronic inflammatory illness that mostly affects the joints of the hands and feet and can reduce life expectancy by an average of 3 to 10 years. Although tremendous progress has been achieved in the treatment of RA, a large minority of patients continue to respond poorly to existing medications, owing in part to a lack of appropriate therapeutic targets.
METHODS
To find therapeutic targets for RA, a Mendelian randomization (MR) was performed. Cis-expression quantitative trait loci (cis-eQTL, exposure) data were obtained from the eQTLGen Consortium (sample size 31,684). Summary statistics for RA (outcome) were obtained from two largest independent cohorts: sample sizes of 97,173 (22,350 cases and 74,823 controls) and 269,377 (8279 cases and 261,098), respectively. Colocalisation analysis was used to test whether RA risk and gene expression were driven by common SNPs. Drug prediction and molecular docking was further used to validate the medicinal value of drug targets.
RESULTS
Seven drug targets were significant in both cohorts in MR analysis and supported by localization. PheWAS at the gene level showed only ATP2A1 associated with other traits. These genes are strongly associated with immune function in terms of biological significance. Molecular docking showed excellent binding for drugs and proteins with available structural data.
CONCLUSION
This study identifies seven potential drug targets for RA. Drugs designed to target these genes have a higher chance of success in clinical trials and is expected to help prioritise RA drug development and save on drug development costs.
Topics: Humans; Mendelian Randomization Analysis; Molecular Docking Simulation; Arthritis, Rheumatoid; Drug Delivery Systems; Drug Development
PubMed: 37697373
DOI: 10.1186/s12967-023-04474-z -
Clinical and Experimental Rheumatology Nov 2023Axial spondyloarthritides (axSpA) are a group of systemic autoimmune diseases, characterised by an inflammatory involvement of the axial skeleton, which, in the earlier... (Review)
Review
Axial spondyloarthritides (axSpA) are a group of systemic autoimmune diseases, characterised by an inflammatory involvement of the axial skeleton, which, in the earlier phases, cannot be detected by conventional radiology, but only by magnetic resonance imaging, thus defining the so-called non-radiographic axSpA (nr-axSpA). The initial osteitis then tends to complicate into bone reabsorption and aberrant bone deposition, which then determines the ankylosis of the axial skeleton in the latest phases of the disease.Peripheral joints may also be affected, enthesitis being its more characteristic manifestation. The radiographic form corresponds to ankylosing spondylitis which, with psoriatic arthritis, is the best-known subtype of SpA. AxSpA are rarely associated to laboratory abnormalities and are usually complicated by the presence of both extra-articular manifestations (particularly acute anterior uveitis, psoriasis and inflamatory bowel disease) and comorbidities, with a subsequent higher risk for patients of an impaired quality of life.In this paper we reviewed the literature on axSpA of 2021 and 2022 (Medline search of articles published from 1st January 2021 to 31st December 2022).
Topics: Humans; Spondylarthritis; Quality of Life; Spondylitis, Ankylosing; Arthritis, Psoriatic; Psoriasis
PubMed: 37965699
DOI: 10.55563/clinexprheumatol/9fhz98 -
Science Immunology Jul 2023Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell...
Immune checkpoint inhibitor (ICI) therapies used to treat cancer, such as anti-PD-1 antibodies, can induce autoimmune conditions in some individuals. The T cell mechanisms mediating such iatrogenic autoimmunity and their overlap with spontaneous autoimmune diseases remain unclear. Here, we compared T cells from the joints of 20 patients with an inflammatory arthritis induced by ICI therapy (ICI-arthritis) with two archetypal autoimmune arthritides, rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Single-cell transcriptomic and antigen receptor repertoire analyses highlighted clonal expansion of an activated effector CD8 T cell population in the joints and blood of patients with ICI-arthritis. These cells were identified as CD38CD127 CD8 T cells and were uniquely enriched in ICI-arthritis joints compared with RA and PsA and also displayed an elevated interferon signature. In vitro, type I interferon induced CD8 T cells to acquire the ICI-associated CD38 phenotype and enhanced cytotoxic function. In a cohort of patients with advanced melanoma, ICI therapy markedly expanded circulating CD38CD127 T cells, which were frequently bound by the therapeutic anti-PD-1 drug. In patients with ICI-arthritis, drug-bound CD8 T cells in circulation showed marked clonal overlap with drug-bound CD8 T cells from synovial fluid. These results suggest that ICI therapy directly targets CD8 T cells in patients who develop ICI-arthritis and induces an autoimmune pathology that is distinct from prototypical spontaneous autoimmune arthritides.
Topics: Humans; Arthritis, Psoriatic; Arthritis, Rheumatoid; CD8-Positive T-Lymphocytes; Synovial Fluid; T-Lymphocytes, Cytotoxic
PubMed: 37506196
DOI: 10.1126/sciimmunol.add1591 -
La Tunisie Medicale Jun 2023Juvenile idiopathic arthritis (JIA), as a chronic condition, is associated with significant disease- and treatment-related morbidity, thus impacting children's quality... (Review)
Review
Juvenile idiopathic arthritis (JIA), as a chronic condition, is associated with significant disease- and treatment-related morbidity, thus impacting children's quality of life. In order to optimize JIA management and to ensure the best possible care and outcome for children with rheumatic diseases, dedicated disease activity and damage assessment tools are essential. In recent years, there has been a concerted and important international effort to develop and validate disease activity and outcome instruments specific to JIA. This update aims to describe the main outcome measures currently used in JIA patients. These outcome measures include composite disease activity score, measures of physical function, measures of health related quality of life, clinical measures of damage and the assessment of Parent and child reported outcomes (PCROs).
Topics: Child; Humans; Arthritis, Juvenile; Quality of Life; Outcome Assessment, Health Care; Severity of Illness Index
PubMed: 38372552
DOI: No ID Found -
RMD Open Aug 2023To identify the best evidence on the efficacy of non-pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases...
Efficacy of non-pharmacological interventions: a systematic review informing the 2023 EULAR recommendations for the management of fatigue in people with inflammatory rheumatic and musculoskeletal diseases.
OBJECTIVE
To identify the best evidence on the efficacy of non-pharmacological interventions in reducing fatigue in people with inflammatory rheumatic and musculoskeletal diseases (I-RMDs) and to summarise their safety in the identified studies to inform European Alliance of Associations for Rheumatology recommendations for the management of fatigue in people with I-RMDs.
METHODS
Systematic review of randomised controlled trials (RCTs) including adults with I-RMDs conducted according to the Cochrane Handbook. Search strategy ran in Medline, Embase, Cochrane Library, CINAHL Complete, PEDro, OTseeker and PsycINFO. Assessment of risk of bias, data extraction and synthesis were performed by two reviewers independently. Data were pooled in meta-analyses.
RESULTS
From a total of 4150 records, 454 were selected for full-text review, 82 fulfilled the inclusion criteria and 55 RCTs were included in meta-analyses. Physical activity or exercise was efficacious in reducing fatigue in rheumatoid arthritis (RA) (standardised mean differences (SMD)=-0.23, 95% CI=-0.37 to -0.1), systemic lupus erythematosus (SLE) (SMD=-0.54, 95% CI=-1.07 to -0.01) and spondyloarthritis (SMD=-0.94, 95% CI=-1.23 to -0.66); reduction of fatigue was not significant in Sjögren's syndrome (SMD=-0.83, 95% CI=-2.13 to 0.47) and systemic sclerosis (SMD=-0.66, 95% CI=-1.33 to 0.02). Psychoeducational interventions were efficacious in reducing fatigue in RA (SMD=-0.32, 95% CI=-0.48 to -0.16), but not in SLE (SMD=-0.19, 95% CI=-0.46 to 0.09). Follow-up models in consultations (SMD=-0.05, 95% CI=-0.29 to 0.20) and multicomponent interventions (SMD=-0.20, 95% CI=-0.53 to 0.14) did not show significant reductions of fatigue in RA. The results of RCTs not included in the meta-analysis suggest that several other non-pharmacological interventions may provide a reduction of fatigue, with reassuring safety results.
CONCLUSIONS
Physica activity or exercise and psychoeducational interventions are efficacious and safe for managing fatigue in people with I-RMDs.
Topics: Adult; Humans; Arthritis, Rheumatoid; Exercise; Lupus Erythematosus, Systemic; Musculoskeletal Diseases; Rheumatology
PubMed: 37604639
DOI: 10.1136/rmdopen-2023-003350 -
Frontiers in Endocrinology 2023The aim of this study was to determine causal associations between inflammatory arthritis and eye diseases (disorders of sclera, cornea, iris, and ciliary body [DSCIC]...
OBJECTIVES
The aim of this study was to determine causal associations between inflammatory arthritis and eye diseases (disorders of sclera, cornea, iris, and ciliary body [DSCIC] and disorders of choroid and retina [DCR]).
METHODS
Genome-wide association studies' summary data of rheumatoid arthritis (RA) from a large-scale meta-analysis were used to identify genetically predicted RA. UK Biobank source data predicted ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA). Furthermore, data from the FinnGen Biobank were used to identify genetically predicted eye diseases. Two-sample Mendelian randomization analysis was used to assess the causal relationship between inflammatory arthritis and eye diseases in the European population. Inverse-variance weighting (IVW) was used as the primary method, while MR-Egger, weighted median, and MR-PRESSO outlier test were used to detect heterogeneity and pleiotropy.
RESULTS
Genetically determined RA was indeed observed to have a causal effect on DSCIC (odds ratio [OR] = 1.084, = 2.353 × 10) and DCR (OR = 1.151, = 1.584 × 10). AS was causally associated with DSCIC (OR = 1.068, < 2.024 × 10). In addition, PsA was also found to have a causal association with an increased risk of 17.9% for the development of DSCIC (OR = 1.179, = 0.003). On the flip side, DSCIC increased the risk of JIA (OR = 2.276, = 0.003).
CONCLUSION
Our study provided genetic evidence for the causal associations of RA, AS, and PsA with an increased risk of DSCIC, and a causal association between RA and DCR was also identified. In addition, DSCIC greatly increased the risk of JIA.
Topics: Humans; Arthritis, Psoriatic; Arthritis, Rheumatoid; Eye Diseases; Genome-Wide Association Study; Mendelian Randomization Analysis; Retinal Diseases; Spondylitis, Ankylosing
PubMed: 37876547
DOI: 10.3389/fendo.2023.1251167 -
Immunological Reviews Sep 2023Immune checkpoint inhibitors are now an established treatment in the management of a range of cancers. Their success means that their use is likely to increase in future... (Review)
Review
Immune checkpoint inhibitors are now an established treatment in the management of a range of cancers. Their success means that their use is likely to increase in future in terms of the numbers of patients treated, the indications and the range of immune checkpoints targeted. They function by counteracting immune evasion by the tumor but, as a consequence, can breach self-tolerance at other sites leading to a range of immune-related adverse events. Included among these complications are a range of rheumatologic complications, including inflammatory arthritis and keratoconjunctivitis sicca. These superficially resemble immune-mediated rheumatic diseases (IMRDs) such as rheumatoid arthritis and Sjogren's disease but preliminary studies suggest they are clinically and immunologically distinct entities. However, there appear to be common processes that predispose to the development of both that may inform preventative interventions and predictive tools. Both groups of conditions highlight the centrality of immune checkpoints in controlling tolerance and how it can be restored. Here we will discuss some of these commonalities and differences between rheumatic irAEs and IMRDs.
Topics: Humans; Autoimmunity; Neoplasms; Rheumatic Diseases; Arthritis; Immunotherapy
PubMed: 37435963
DOI: 10.1111/imr.13242 -
International Journal of Molecular... Jun 2023Arthritis has a high prevalence globally and includes over 100 types, the most common of which are rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis...
Arthritis has a high prevalence globally and includes over 100 types, the most common of which are rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PsA), and inflammatory arthritis [...].
Topics: Humans; Arthritis, Psoriatic; Synovial Fluid; Arthritis, Rheumatoid; Osteoarthritis
PubMed: 37373313
DOI: 10.3390/ijms241210166 -
International Journal of Molecular... Sep 2023Rheumatoid arthritis (RA) and osteoarthritis (OA) have a significant impact on the quality of life of patients around the world, causing significant pain and disability.... (Review)
Review
Rheumatoid arthritis (RA) and osteoarthritis (OA) have a significant impact on the quality of life of patients around the world, causing significant pain and disability. Furthermore, the drugs used to treat these conditions frequently have side effects that add to the patient's burden. Photobiomodulation (PBM) has emerged as a promising treatment approach in recent years. PBM effectively reduces inflammation by utilizing near-infrared light emitted by lasers or LEDs. In contrast to photothermal effects, PBM causes a photobiological response in cells, which regulates their functional response to light and reduces inflammation. PBM's anti-inflammatory properties and beneficial effects in arthritis treatment have been reported in numerous studies, including animal experiments and clinical trials. PBM's effectiveness in arthritis treatment has been extensively researched in arthritis-specific cells. Despite the positive results of PBM treatment, questions about specific parameters such as wavelength, dose, power density, irradiation time, and treatment site remain. The goal of this comprehensive review is to systematically summarize the mechanisms of PBM in arthritis treatment, the development of animal arthritis models, and the anti-inflammatory and joint function recovery effects seen in these models. The review also goes over the evaluation methods used in clinical trials. Overall, this review provides valuable insights for researchers investigating PBM treatment for arthritis, providing important references for parameters, model techniques, and evaluation methods in future studies.
Topics: Animals; Humans; Low-Level Light Therapy; Quality of Life; Inflammation; Arthritis, Rheumatoid; Osteoarthritis
PubMed: 37762594
DOI: 10.3390/ijms241814293 -
Biomedical Journal Feb 2024Nod-like receptors (NLRs) are innate immune receptors that play a key role in sensing components from pathogens and from damaged cells or organelles. NLRs form signaling... (Review)
Review
Nod-like receptors (NLRs) are innate immune receptors that play a key role in sensing components from pathogens and from damaged cells or organelles. NLRs form signaling complexes that can lead to activation of transcription factors or effector caspases - by means of inflammasome activation -Inflammatory arthritis (IA) culminating in promoting inflammation. An increasing body of research supports the role of NLRs in driving pathogenesis of IA, a collection of diseases that include rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis, and pediatric arthritis. In this review, we briefly discuss the main drivers of IA diseases and dive into the evidence for - and against - various NLRs in driving these diseases. We also review the studies examining the use of NLR and inflammasome inhibitors as potential therapies for IA.
Topics: Humans; Child; Arthritis, Psoriatic; Inflammasomes; NLR Proteins; Arthritis, Rheumatoid; Spondylitis, Ankylosing
PubMed: 37598797
DOI: 10.1016/j.bj.2023.100655