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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 -
Journal of Autoimmunity Dec 2023Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive polyarthritis that leads to cartilage and bone damage. Pre-clinical RA is a... (Review)
Review
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by progressive polyarthritis that leads to cartilage and bone damage. Pre-clinical RA is a prolonged state before clinical arthritis and RA develop, in which autoantibodies (antibodies against citrullinated proteins, rheumatoid factors) can be present due to the breakdown of immunologic self-tolerance. As early treatment initiation before the onset of polyarthritis may achieve sustained remission, optimize clinical outcomes, and even prevent RA progression, the pre-clinical RA stage is showing the prospect to be the window of opportunity for RA treatment. Growing evidence has shown the role of the gut microbiota in inducing systemic inflammation and polyarthritis via multiple mechanisms, which may involve molecular mimicry, impaired intestinal barrier function, gut microbiota-derived metabolites mediated immune regulation, modulation of the gut microbiota's effect on immune cells, intestinal epithelial cells autophagy, and the interaction between the microbiome and human leukocyte antigen alleles as well as microRNAs. Since gut microbiota alterations in pre-clinical RA have been reported, potential therapies for modifying the gut microbiota in pre-clinical RA, including natural products, antibiotic therapy, fecal microbiota transplantation, probiotics, microRNAs therapy, vitamin D supplementation, autophagy inducer-based treatment, prebiotics, and diet, holds great promise for the successful treatment and even prevention of RA via altering ongoing inflammation. In this review, we summarized current studies that include pathogenesis of gut microbiota in RA progression and promising therapeutic strategies to provide novel ideas for the management of pre-clinical RA and possibly preventing arthritis progression.
Topics: Humans; Gastrointestinal Microbiome; Arthritis, Rheumatoid; Autoimmune Diseases; Inflammation; MicroRNAs
PubMed: 36931952
DOI: 10.1016/j.jaut.2023.103001 -
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 -
RMD Open Oct 2023To estimate the effects of Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi), other biologic(b) or conventional synthetic(cs) disease-modifying... (Observational Study)
Observational Study
Risk of major adverse cardiovascular events in patients with rheumatoid arthritis treated with conventional synthetic, biologic and targeted synthetic disease-modifying antirheumatic drugs: observational data from the German RABBIT register.
OBJECTIVE
To estimate the effects of Janus kinase inhibitors (JAKi), tumour necrosis factor inhibitors (TNFi), other biologic(b) or conventional synthetic(cs) disease-modifying antirheumatic drugs (DMARDs) on the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA).
METHODS
Cohort study analysing episodes of DMARD-treatment initiated between January 2017 and April 2022 in the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy. Incidence rates (IRs) per 100 patient-years with 95% CIs were calculated for overall patients and those with cardiovascular risk (age ≥50 years and ≥1 cardiovascular risk factor). MACE risk was estimated as HRs by inverse probability of treatment weight-adjusted Andersen-Gill models.
RESULTS
A total of 154 MACE occurred among 14 203 treatment episodes (21 218 patient-years). IRs were 0.68 (0.47; 0.95), 0.62 (0.45; 0.83), 0.76 (0.53; 1.06) and 0.95 (0.68; 1.29) for JAKi, TNFi, bDMARDs and csDMARDs, respectively. IRs were higher in cardiovascular risk patients. Adjusted HRs (95% CI) comparing JAKi, bDMARDs and csDMARDs with TNFi were 0.89 (0.52 to 1.52), 0.76 (0.45; to1.27) and 1.36 (0.85 to 2.19) in overall, and 0.74 (0.41 to 1.31), 0.75 (0.45 to 1.27) and 1.21 (0.74 to 1.98) in cardiovascular risk patients. HRs were not increased in patients ≥65 years, with cardiovascular history or smokers, and also not when using csDMARD as reference instead of TNFi. IRs for baricitinib, tofacitinib and upadacitinib were 0.49 (0.25 to 0.85), 0.98 (0.58 to 1.55) and 0.53 (0.15 to 1.36), respectively.
CONCLUSION
In this German observational cohort study, MACE did not occur more frequently with JAKi compared with other DMARDs. However, individual JAKis showed different unadjusted IRs.
Topics: Humans; Middle Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Cardiovascular Diseases; Cohort Studies; Janus Kinase Inhibitors
PubMed: 37880180
DOI: 10.1136/rmdopen-2023-003489 -
Enfermedades Infecciosas Y... Apr 2024Infection of a native joint, commonly referred to as septic arthritis, is a medical emergency because of the risk of joint destruction and subsequent sequelae. Its...
Infection of a native joint, commonly referred to as septic arthritis, is a medical emergency because of the risk of joint destruction and subsequent sequelae. Its diagnosis requires a high level of suspicion. These guidelines for the diagnosis and treatment of septic arthritis in children and adults are intended for use by any physician caring for patients with suspected or confirmed septic arthritis. They have been developed by a multidisciplinary panel with representatives from the Bone and Joint Infections Study Group (GEIO) belonging to the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Paediatric Infections (SEIP) and the Spanish Society of Orthopaedic Surgery and Traumatology (SECOT), and two rheumatologists. The recommendations are based on evidence derived from a systematic literature review and, failing that, on the opinion of the experts who prepared these guidelines. A detailed description of the background, methods, summary of evidence, the rationale supporting each recommendation, and gaps in knowledge can be found online in the complete document.
Topics: Adult; Humans; Child; Arthritis, Infectious; Disease Progression; Anti-Bacterial Agents
PubMed: 37919201
DOI: 10.1016/j.eimce.2023.07.007 -
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 -
PloS One 2023To study the joint distribution and clinical picture of rheumatoid arthritis (RA) at the initial presentation in seropositive (anti-citrullinated protein antibody (ACPA)...
OBJECTIVES
To study the joint distribution and clinical picture of rheumatoid arthritis (RA) at the initial presentation in seropositive (anti-citrullinated protein antibody (ACPA) and/or rheumatoid factor (RF) positive) and negative patients and the effect of duration of symptoms on the clinical picture.
METHODS
Data of patients who received reimbursement for DMARDs for newly diagnosed RA in 1/2019 to 9/2021 were extracted from the national databases. Joint counts, presence of symmetrical swelling, other disease activity measures, and patient reported outcomes (PROs) were compared in seropositive and negative patients. Regression analyses were applied to compare clinical variables in patients with duration of symptoms of <3, 3-6, and >6 months, adjusted for age, sex, and seropositivity.
RESULTS
Data of 1816 ACPA and RF-tested patients were included. Symmetrical swelling was present in 75% of patients. Seronegative versus positive patients had higher value for all disease activity measures and PROs including median swollen joint count (SJC46 10 versus 5) and DAS28 (4.7 versus 3.7), (p<0.001). Patients diagnosed in <3 months had higher median pain VAS (62 versus 52 and 50, p<0.001) and HAQ (1.1 versus 0.9 and 0.75, p = 0.002) compared to those with a duration of symptoms of 3-6 and >6 months. Patients diagnosed >6 months were ACPA-positive more frequently (77% versus 70% in other groups, p = 0.045).
CONCLUSION
Incident RA presents mainly as symmetric arthritis. Seronegative patients have higher disease burden at the initial presentation. Patients experiencing more severe pain and decreased functional ability are diagnosed earlier, regardless of ACPA- status.
Topics: Humans; Male; Female; Adult; Middle Aged; Aged; Arthritis, Rheumatoid; Severity of Illness Index; Pain; Joints; Antirheumatic Agents
PubMed: 37410796
DOI: 10.1371/journal.pone.0287707 -
Clinical Infectious Diseases : An... Oct 2023Over the last several decades, periprosthetic joint infection (PJI) has been increasing in incidence and is occurring in more complex patients. While there have been...
Over the last several decades, periprosthetic joint infection (PJI) has been increasing in incidence and is occurring in more complex patients. While there have been advances in both surgical and medical treatment strategies, there remain important gaps in our understanding. Here, we share our current approaches to the diagnosis and management of PJI, focusing on frequent clinical challenges and collaborative interdisciplinary care. The more detailed review including diagnosis, surgical considerations, and a detailed antimicrobial discussion is presented in the online version.
Topics: Humans; Prosthesis-Related Infections; Arthritis, Infectious
PubMed: 37796054
DOI: 10.1093/cid/ciad457 -
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 -
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