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RMD Open Jun 2024The International Map of Axial Spondyloarthritis (IMAS) is a global initiative aimed to assess the impact and burden of axial spondyloarthritis (axSpA) and identify the...
BACKGROUND
The International Map of Axial Spondyloarthritis (IMAS) is a global initiative aimed to assess the impact and burden of axial spondyloarthritis (axSpA) and identify the unmet needs from the patient's perspective.
METHOD
IMAS is a collaboration between the Axial Spondyloarthritis International Federation (ASIF), the University of Seville, Novartis Pharma AG and steered by a scientific committee. IMAS collected information through an online cross-sectional survey (2017-2022) from unselected patients with axSpA from Europe, Asia, North America, Latin America and Africa who completed a comprehensive questionnaire containing over 120 items.
RESULTS
5557 patients with axSpA participated in IMAS. Mean age was 43.9 ±12.8 years, 55.4% were female, 46.2% had a university education and 51.0% were employed. The mean diagnostic delay was 7.4 ±9.0 years (median: 4.0), and the mean symptom duration was 17.1 ±13.3 years. 75.0% of patients had active disease (Bath Ankylosing Spondylitis Disease Activity Index ≥4), and 59.4% reported poor mental health (12-item General Health Questionnaire ≥3). In the year before the survey, patients had visited primary care physicians 4.6 times and the rheumatologist 3.6 times. 78.6% had taken non-steroidal anti-inflammatory drug ever, 48.8% biological disease-modifying antirheumatic drugs and 43.6% conventional synthetic disease-modifying antirheumatic drugs. Patients's greatest fear was disease progression (55.9%), while the greatest hope was to be able to relieve pain (54.2%).
CONCLUSIONS
IMAS shows the global profile of patients with axSpA, highlighting unmet needs, lengthy delays in diagnosis and high burden of disease in patients with axSpA worldwide. This global information will enable more detailed investigations to obtain evidence on the critical issues that matter to patients around the world to improve their care and quality of life.
Topics: Humans; Male; Female; Adult; Cross-Sectional Studies; Middle Aged; Axial Spondyloarthritis; Quality of Life; Surveys and Questionnaires; Cost of Illness; Global Health; Severity of Illness Index
PubMed: 38851236
DOI: 10.1136/rmdopen-2023-003504 -
Therapeutic Advances in Musculoskeletal... 2024Radiographic axial spondyloarthritis (r-axSpA), formerly known as ankylosing spondylitis (AS), is a chronic, inflammatory rheumatic disease associated with symptoms such...
BACKGROUND
Radiographic axial spondyloarthritis (r-axSpA), formerly known as ankylosing spondylitis (AS), is a chronic, inflammatory rheumatic disease associated with symptoms such as inflammatory back pain, morning stiffness, and arthritis. First-line recommendations for patients with AS include treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for reducing pain and stiffness.
OBJECTIVES
The objective of our study is to evaluate the efficacy and short-term NSAID-sparing effect of secukinumab in patients with AS currently treated with NSAIDs.
DESIGN
We assessed the clinical Assessment of SpondyloArthritis International Society (ASAS20) response to secukinumab and evaluated the extent to which the use of concomitant NSAID can be reduced between weeks 4 and 12 in r-axSpA patients treated with secukinumab 150 mg compared with placebo.
METHODS
ASTRUM was a prospective 24-week randomized controlled trial of adult patients with active r-axSpA [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ⩾4] who had a documented inadequate response to ⩾2 NSAIDs. Patients were randomized (1:1:1) to initiate treatment with subcutaneous secukinumab 150 mg from either week 0 (group 1), week 4 (group 2), or week 16 (group 3). From week 4 onward, tapering of NSAIDs was allowed in all groups.
RESULTS
This study included 211 patients ( = 71, 70, and 70 in groups 1, 2, and 3, respectively). ASAS20 response at week 12 for pooled groups 1 and 2 group 3 was 51.1% 44.3% ( = 0.35). A higher proportion of patients in groups 1 and 2 achieved ASAS40 and BASDAI50 and showed improvements in other secondary clinical outcomes as compared to group 3 at week 16. More patients in groups 1 and 2 group 3 stopped their NSAID intake from baseline through week 16.
CONCLUSION
Treatment with secukinumab improved clinical outcomes and showed a short-term NSAID-sparing effect in patients with r-axSpA, even though the primary endpoint was not met.
TRIAL REGISTRATION
ClinicalTrials.gov; NCT02763046, EudraCT 2015-004575-74.
PubMed: 38846755
DOI: 10.1177/1759720X241255486 -
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