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Ocular Immunology and Inflammation Jun 2024To evaluate the clinical characteristics, treatment outcomes and ocular complications in patients with HLA-B27-associated AU compared to those without HLA-B27.
PURPOSE
To evaluate the clinical characteristics, treatment outcomes and ocular complications in patients with HLA-B27-associated AU compared to those without HLA-B27.
METHODS
From the population-based data of all adult patients with AU during 2009-2020 ( = 413), 241 patients tested for HLA-B27 were included. Age of the initial onset, gender, etiology, course of uveitis, visual outcomes and complications were studied.
RESULTS
170 patients (71%) were HLA-B27+ and 71 (29%) HLA-B27-. Mean age at uveitis onset was 37 ± 13 in HLA-B27+ (95% CI, 35.4-39.3) and 43 ± 14 (95% CI, 40.3-46.4) in HLA-B27- patients ( = 0.001). Male:female ratio was 1.1:1 among HLA-B27+ and 0.58:1 ( = 0.024) in HLA-B27- patients. Most patients, 63% in HLA-B27+ and 68% in HLA-B27- had chronic uveitis. Recurrences were noted in 31% in HLA-B27+ group compared to 13%in HLA-B27-. 51% and 17% of HLA-B27+ and HLA-B27- patients, respectively, had systemic disease-associated uveitis. Etiology was Idiopathic in 44% and 69% of HLA-B27+ and HLA-B27- patients, respectively ( < 0.001). After the follow-up, +2 and -4 ETDRS letters changes were noted in HLA-B27+ and HLA-B27- patients ( = 0.005). Ocular complications developed in 43% and 47%, and surgical treatment of complications was required in 20% and 33% of patients in HLA-B27+ and HLA-B27- patients ( = 0.009). 1% (HLA-B27+) and 3% (HLA-B27-) developed visual impairment.
CONCLUSION
Our results highlight the differences in the age of uveitis onset, gender distribution, course of uveitis, etiology, and treatment outcomes in HLA-B27+ and HLA-B27-uveitis. HLA-B27 seems to be associated with younger age at uveitis onset, more recurrences, systemic diseases, and better treatment outcomes with less complications.
PubMed: 38842206
DOI: 10.1080/09273948.2024.2360593 -
The South African Journal of... 2024Ankylosing spondylitis (AS) is characterised as a chronic inflammatory disease of the axial skeleton. The force platform is an option for performing the postural... (Review)
Review
BACKGROUND
Ankylosing spondylitis (AS) is characterised as a chronic inflammatory disease of the axial skeleton. The force platform is an option for performing the postural assessment of these individuals.
OBJECTIVES
To review and evaluate the behaviour of the centre of pressure (CoP) variables during the postural control examination in patients with AS compared to a control group.
METHOD
A systematic review, registered in PROSPERO, that followed the PRISMA Statement. A search was carried out in the following databases: Medline, Web of Science, Embase, Scopus, and Scielo, from 1945 to 2023. Studies were selected that aimed to understand the use of the force platform for the assessment of postural control. The risk of bias assessment was performed using the AXIS tool.
RESULTS
Five studies were included, with a total of 247 participants. The assessment of risk of bias presented high scores in the AXIS tool. Patients with a diagnosis of AS presented increased thoracic kyphosis in most of the studies, as well as large displacements in the anteroposterior (AP) and mediolateral (ML) directions, and altered total mean velocity (TMV) and frequency, indicating worse postural stability. Regarding the functional status, the most used questionnaires were the Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI) and Bath Ankylosing Disease Activity Index (BASDAI).
CONCLUSION
Patients with ankylosing spondylitis present postural instability, verified by means of higher values of centre of posture variables.
CLINICAL IMPLICATIONS
Individuals with ankylosing spondylitis presented postural instability and balance deficit. Therefore, exercises for balance training and postural control are essential in the clinical management of these patients.
PubMed: 38841593
DOI: 10.4102/sajp.v80i1.1953 -
Nature Jun 2024Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments...
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments and high failure rates during drug development, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.
Topics: Female; Humans; Male; Anti-Inflammatory Agents; Cells, Cultured; Chromosomes, Human, Pair 21; Databases, Factual; Gene Expression Regulation; Genome-Wide Association Study; Genomics; Haplotypes; Inflammation; Inflammatory Bowel Diseases; Macrophages; Proto-Oncogene Protein c-ets-2; Reproducibility of Results; Tumor Necrosis Factors; Interleukin-23
PubMed: 38839969
DOI: 10.1038/s41586-024-07501-1 -
Internal Medicine (Tokyo, Japan) Jun 2024Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation (LP/L-IDD) are rare entities associated with the use of immunosuppressive drugs...
Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation (LP/L-IDD) are rare entities associated with the use of immunosuppressive drugs (ISD) for autoimmune conditions. Composite lymphomas, featuring both B-cell and T-cell lymphomas, are infrequent, and their occurrence as LP/L-IDD is rare. We herein report the case of a 70-year-old man with right pleural effusion and lymphadenopathy, who was treated with infliximab for sarcoidosis and ankylosing spondylitis. A biopsy revealed a composite lymphoma of DLBCL and PTCL-NOS. CHOP chemotherapy led to significant remission. This case report emphasizes the need to consider lymphoma in patients with autoimmune diseases such as sarcoidosis and ankylosing spondylitis, especially those treated with ISDs.
PubMed: 38839334
DOI: 10.2169/internalmedicine.3274-23 -
Acta Medica Philippina 2024Parturients with both ankylosing spondylitis (AS) and SARS-CoV-2 Infection (COVID-19) present unique challenges to anesthesiologists. Neuraxial analgesia for labor...
Parturients with both ankylosing spondylitis (AS) and SARS-CoV-2 Infection (COVID-19) present unique challenges to anesthesiologists. Neuraxial analgesia for labor remains the gold standard in obstetric patients. However, in patients with AS, this approach may be deemed difficult to impossible. Administration of systemic opioids for labor analgesia can be an option, bearing in mind the potential respiratory depressant effect to both the mother and the fetus, especially in the setting of concomitant COVID-19. This paper reports the successful management of such a patient using patient-controlled analgesia (PCA) with intravenous remifentanil.
PubMed: 38836085
DOI: 10.47895/amp.v58i9.8779 -
Frontiers in Medicine 2024Interleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R...
OBJECTIVE
Interleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS.
METHODS
The C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability.
RESULTS
According to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.996, = 5.12 × 10) and ukb-a-88 (OR: 0.994, 95% CI 0.993-0.996, = 6.25 × 10). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.997, = 1.25 × 10) and ukb-a-88 (OR: 0.995, 95% CI 0.994-0.997, = 7.81 × 10). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy.
CONCLUSION
This MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.
PubMed: 38835791
DOI: 10.3389/fmed.2024.1368346 -
Genetic associations in ankylosing spondylitis: circulating proteins as drug targets and biomarkers.Frontiers in Immunology 2024Ankylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or...
BACKGROUND
Ankylosing spondylitis (AS) is a complex condition with a significant genetic component. This study explored circulating proteins as potential genetic drug targets or biomarkers to prevent AS, addressing the need for innovative and safe treatments.
METHODS
We analyzed extensive data from protein quantitative trait loci (pQTLs) with up to 1,949 instrumental variables (IVs) and selected the top single-nucleotide polymorphism (SNP) associated with AS risk. Utilizing a two-sample Mendelian randomization (MR) approach, we assessed the causal relationships between identified proteins and AS risk. Colocalization analysis, functional enrichment, and construction of protein-protein interaction networks further supported these findings. We utilized phenome-wide MR (phenMR) analysis for broader validation and repurposing of drugs targeting these proteins. The Drug-Gene Interaction database (DGIdb) was employed to corroborate drug associations with potential therapeutic targets. Additionally, molecular docking (MD) techniques were applied to evaluate the interaction between target protein and four potential AS drugs identified from the DGIdb.
RESULTS
Our analysis identified 1,654 plasma proteins linked to AS, with 868 up-regulated and 786 down-regulated. 18 proteins (AGER, AIF1, ATF6B, C4A, CFB, CLIC1, COL11A2, ERAP1, HLA-DQA2, HSPA1L, IL23R, LILRB3, MAPK14, MICA, MICB, MPIG6B, TNXB, and VARS1) that show promise as therapeutic targets for AS or biomarkers, especially MAPK14, supported by evidence of colocalization. PhenMR analysis linked these proteins to AS and other diseases, while DGIdb analysis identified potential drugs related to MAPK14. MD analysis indicated strong binding affinities between MAPK14 and four potential AS drugs, suggesting effective target-drug interactions.
CONCLUSION
This study underscores the utility of MR analysis in AS research for identifying biomarkers and therapeutic drug targets. The involvement of Th17 cell differentiation-related proteins in AS pathogenesis is particularly notable. Clinical validation and further investigation are essential for future applications.
Topics: Spondylitis, Ankylosing; Humans; Biomarkers; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Protein Interaction Maps; Genetic Predisposition to Disease; Blood Proteins; Mendelian Randomization Analysis; Molecular Docking Simulation; Genome-Wide Association Study
PubMed: 38835753
DOI: 10.3389/fimmu.2024.1394438 -
Arthritis Research & Therapy Jun 2024Immune checkpoints have emerged as promising therapeutic targets for autoimmune diseases. However, the specific roles of immune checkpoints in the pathophysiology of...
Exploration of the combined role of immune checkpoints and immune cells in the diagnosis and treatment of ankylosing spondylitis: a preliminary study immune checkpoints in ankylosing spondylitis.
OBJECTIVE
Immune checkpoints have emerged as promising therapeutic targets for autoimmune diseases. However, the specific roles of immune checkpoints in the pathophysiology of ankylosing spondylitis (AS) remain unclear.
METHODS
Hip ligament samples were obtained from two patient groups: those with AS and femoral head deformity, and those with femoral head necrosis but without AS, undergoing hip arthroplasty. Label-Free Quantification (LFQ) Protein Park Analysis was used to identify the protein composition of the ligaments. Peripheral blood samples of 104 AS patients from public database were used to validate the expression of key proteins. KEGG, GO, and GSVA were employed to explore potential pathways regulated by immune checkpoints in AS progression. xCell was used to calculate cell infiltration levels, LASSO regression was applied to select key cells, and the correlation between immune checkpoints and immune cells was analyzed. Drug sensitivity analysis was conducted to identify potential therapeutic drugs targeting immune checkpoints in AS. The expression of key genes was validated through immunohistochemistry (IHC).
RESULTS
HLA-DMB and HLA-DPA1 were downregulated in the ligaments of AS and this has been validated through peripheral blood datasets and IHC. Significant differences in expression were observed in CD8 + Tcm, CD8 + T cells, CD8 + Tem, osteoblasts, Th1 cells, and CD8 + naive T cells in AS. The infiltration levels of CD8 + Tcm and CD8 + naive T cells were significantly positively correlated with the expression levels of HLA-DMB and HLA-DPA1. Immune cell selection using LASSO regression showed good predictive ability for AS, with AUC values of 0.98, 0.81, and 0.75 for the three prediction models, respectively. Furthermore, this study found that HLA-DMB and HLA-DPA1 are involved in Th17 cell differentiation, and both Th17 cell differentiation and the NF-kappa B signaling pathway are activated in the AS group. Drug sensitivity analysis showed that AS patients are more sensitive to drugs such as doramapimod and GSK269962A.
CONCLUSION
Immune checkpoints and immune cells could serve as avenues for exploring diagnostic and therapeutic strategies for AS.
Topics: Humans; Spondylitis, Ankylosing; Male; Female; Adult; Middle Aged; Immune Checkpoint Proteins
PubMed: 38835033
DOI: 10.1186/s13075-024-03341-6 -
RMD Open Jun 2024To assess the impact of bimekizumab on physical functioning, sleep, work productivity and overall health-related quality of life (HRQoL) in patients with... (Randomized Controlled Trial)
Randomized Controlled Trial
Improved physical functioning, sleep, work productivity and overall health-related quality of life with bimekizumab in patients with axial spondyloarthritis: results from two phase 3 studies.
OBJECTIVE
To assess the impact of bimekizumab on physical functioning, sleep, work productivity and overall health-related quality of life (HRQoL) in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA) in the phase 3 studies BE MOBILE 1 and 2.
METHODS
Patients were randomised to subcutaneous bimekizumab 160 mg or placebo every 4 weeks; from Week 16, all patients received bimekizumab 160 mg every 4 weeks. We report the following outcomes to Week 52: Bath Ankylosing Spondylitis Functional Index (BASFI), Medical Outcomes Study Sleep Scale Revised (MOS-Sleep-R) Index II, Work Productivity and Activity Impairment: axSpA (WPAI:axSpA), Short Form-36 Physical and Mental Component Summary (SF-36 PCS/MCS) and Ankylosing Spondylitis Quality of Life (ASQoL).
RESULTS
At Week 16, bimekizumab-randomised patients demonstrated significantly greater improvement from baseline versus placebo in BASFI, SF-36 PCS and ASQoL (p<0.001), and numerically greater improvements in MOS-Sleep-R Index II and WPAI:axSpA scores. Higher proportions of bimekizumab-randomised versus placebo-randomised patients at Week 16 achieved increasingly stringent thresholds for improvements in BASFI (0 to ≤4), and thresholds for meaningful improvements in SF-36 PCS (≥5-point increase from baseline) and ASQoL (≥4-point decrease from baseline). Responses were sustained or further improved to Week 52, where 60%-70% of bimekizumab-treated patients achieved BASFI ≤4 and meaningful improvements in SF-36 PCS and ASQoL, regardless of whether originally randomised to bimekizumab or placebo.
CONCLUSION
Bimekizumab treatment led to early improvements in physical function, sleep, work productivity and overall HRQoL at Week 16 in patients across the full axSpA disease spectrum. Improvements were sustained to Week 52.
TRIAL REGISTRATION NUMBERS
NCT03928704; NCT03928743.
Topics: Humans; Quality of Life; Male; Female; Adult; Middle Aged; Sleep; Treatment Outcome; Axial Spondyloarthritis; Severity of Illness Index; Physical Functional Performance; Double-Blind Method; Efficiency; Antibodies, Monoclonal, Humanized
PubMed: 38834351
DOI: 10.1136/rmdopen-2024-004202 -
Rheumatology (Oxford, England) Jun 2024The potential impact of ankylosing spondylitis (AS) on cancer risk remains unclear. This study seeks to investigate the relationship between AS and different types of...
OBJECTIVES
The potential impact of ankylosing spondylitis (AS) on cancer risk remains unclear. This study seeks to investigate the relationship between AS and different types of cancers.
METHODS
A literature search of the PubMed, Embase and Cochrane Library up to July 10th, 2023, was conducted. Two investigators selected eligible studies and extracted relevant data. The study used the random-effects model to explore the causality between AS and cancer, utilising relative risk (RR) as a measure for the study.
RESULTS
A total of 20 cohorts with >330 000 participants were included. The pooling analysis shows AS being associated with a higher risk of cancers (RR = 1.16, 95% CI : 1.07-1.26, p= 0.001, I2=70.60%). In the subgroup analysis, AS has a higher cancer risk in Asia, but this association is not significant in Europe. Individual investigations indicate that AS is associated with an increased risk of bone cancer (RR = 3.41, 95% CI : 1.45-7.99, p= 0.005, I2=0.00%), thyroid gland cancer (RR = 1.76, 95% CI : 1.29-2.40, p< 0.001, I2=13.70%), multiple myeloma (RR = 1.74, 95% CI : 1.42-2.15, p< 0.001, I2=27.20%), leukaemia (RR = 1.52, 95% CI : 1.27-1.82, p< 0.001, I2=0.00%), kidney cancer (RR = 1.45, 95% CI : 1.08-1.94, p= 0.014, I2=0.00%), prostate cancer (RR = 1.43, 95% CI : 1.17-1.74, p< 0.001, I2=82.80%), and non-Hodgkin's lymphoma (RR = 1.42, 95% CI : 1.17-1.73, p< 0.001, I2=0.00%). However, there is no significant correlation with connective tissue cancer, brain cancer, testicular and other male cancers, bladder cancer, female cancers, skin cancer, and cancers of the digestive system and respiratory system.
CONCLUSION
AS appears to be related to cancer development. The results highlighted the necessity for large-scale studies, considering influencing factors such as AS course, medication histories, and potential biases when examining cancer risk.
PubMed: 38830028
DOI: 10.1093/rheumatology/keae294