Transcriptome analysis of ankylosing spondylitis patients before and after TNF-α inhibitor therapy reveals the pathways affected
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE141646 | GEO | 2019/12/10
REPOSITORIES: GEO
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Project description:Transcriptome analysis of ankylosing spondylitis patients before and after TNF-α inhibitor therapy reveals the pathways affected
| PRJNA594302 | ENA
Project description:Ankylosing spondylitis (AS) is a type of spondyloarthropathies, the diagnosis of which is often delayed. The lack of early diagnosis tools often delays the institution of appropriate therapy. This study aimed to investigate the systemic metabolic shifts associated with AS and TNF inhibitors treatment. Additionally, we aimed to define reliable serum biomarkers for the diagnosis. We employed an untargeted technique, ultra-performance liquid chromatography-mass spectroscopy (LC-MS), to analyze the serum metabolome of 32 AS individuals before and after 24-week TNF inhibitors treatment, as well as 40 health controls (HCs). Multivariate and univariate statistical analyses were used to profile the differential metabolites associated with AS and TNF inhibitors. A diagnostic panel was established with the least absolute shrinkage and selection operator (LASSO). The pathway analysis was also conducted. A total of 55 significantly differential metabolites were detected. We generated a diagnostic panel comprising five metabolites (L-glutamate, arachidonic acid, L-phenylalanine, PC (18:1(9Z)/18:1(9Z)), 1-palmitoylglycerol), capable of distinguishing HCs from AS with a high AUC of 0.998, (95%CI: 0.992-1.000). TNF inhibitors treatment could restore the equilibrium of 21 metabolites. The most involved pathways in AS were amino acid biosynthesis, glycolysis, glutaminolysis, fatty acids biosynthesis and choline metabolism. This study characterized the serum metabolomics signatures of AS and TNF inhibitor therapy. We developed a five-metabolites-based panel serving as a diagnostic tool to separate patients from HCs. This serum metabolomics study yielded new knowledge about the AS pathogenesis and the systemic effects of TNF inhibitors.
| S-EPMC7933516 | biostudies-literature
Project description:Background: Increased platelet count has been reported in ankylosing spondylitis (AS) patients, but its clinical significance is still largely elusive. The objective of this study was to evaluate the clinical role of platelet count in AS patients, especially its impact on treatment outcomes. Methods: A case-control study containing 35 AS patients receiving anti-tumor necrosis factor-α (anti-TNF-α) therapy and 45 healthy controls was performed, and AS patients were followed at least 6 months after anti-TNF-α therapy. A systematic review and meta-analysis of studies containing relevant data on outcomes of interest was also performed. Results: AS patients had significantly higher platelet count than controls (p = 0.0001), and the significantly increased platelet count in AS patients was confirmed in a meta-analysis of 14 studies involving 1,223 AS patients and 913 controls (mean difference = 39.61, 95% CI 27.89-51.34, p < 0.001). Besides, platelet count was significantly correlated with ESR (p < 0.001) and was moderately correlated with ASDAS-CRP score (p = 0.002). Moreover, anti-TNF-α therapy could reduce platelet count in AS patients at the first month and the effect was maintained through the treatment duration. In the prospective follow-up study of those 35 AS patients, those responders to anti-TNF-α therapy had significantly lower platelet count than nonresponders (p = 0.015). Logistic regression analysis suggested that lower platelet count was associated with higher possibility of achieving good response to anti-TNF-α therapy in AS patients (odds ratio = 2.26; 95% CI = 1.06-4.82; p = 0.035). Conclusion: This study suggested that platelet count was associated with inflammation severity and treatment outcomes in AS patients, and elevated platelet count was a promising biomarker of poorer response to anti-TNF-α therapy. The findings above need to be validated in more future studies.
| S-EPMC7741170 | biostudies-literature
Project description:ObjectiveGut dysbiosis contributes to multiple autoimmune diseases, including ankylosing spondylitis, which is commonly treated with tumor necrosis factor (TNF)-α inhibitors (TNFis). Because host TNF-α levels are considered to interact with gut microbiota, we aimed to systematically investigate the microbiota profile of ankylosing spondylitis patients with anti-TNF-α-based treatment and identify potential key bacteria.MethodsFecal samples were collected from 11 healthy controls and 24 ankylosing spondylitis patients before/after anti-TNF-α treatment, the microbiota profiles of which were evaluated by 16S ribosomal DNA amplicon sequencing and subsequent bioinformatic analysis.ResultsSignificantly different microbial compositions were observed in samples from ankylosing spondylitis patients compared with healthy controls, characterized by a lower abundance of short-chain fatty acid (SCFA)-producing bacteria. All patients exhibited a positive response after anti-TNF-α treatment, accompanied by a trend of restoration in the microbiota compositions and functional profile of ankylosing spondylitis patients to healthy controls. In particular, the abundance of SCFA-producing bacteria (e.g. Megamonsa and Lachnoclostridium ) was not only significantly lower in ankylosing spondylitis patients than in healthy controls and restored after anti-TNF-α treatment but also negatively correlated with disease severity (e.g. cor = -0.52, P = 8 × 10 -5 for Megamonsa ). In contrast, Bacilli and Haemophilus may contribute to ankylosing spondylitis onset and severity.ConclusionsMicrobiota dysbiosis in ankylosing spondylitis patients can be restored after anti-TNF-α treatment, possibly by impacting SCFA-producing bacteria.
| S-EPMC9351697 | biostudies-literature
Project description:BACKGROUND:Ankylosing spondylitis (AS) results from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the heritability of AS. METHODS:Using a candidate gene approach in this case-control study, 51 mainly functional single nucleotide polymorphisms (SNPs) in genes regulating inflammation were assessed in 709 patients with AS and 795 controls. Data on the patients with AS were obtained from the DANBIO registry where patients from all of Denmark are monitored in routine care during treatment with conventional and biologic disease modifying anti-rheumatic drugs (bDMARDs). The results were analyzed using logistic regression (adjusted for age and sex). RESULTS:Nine polymorphisms were associated with risk of AS (p?<?0.05). The polymorphisms were in genes regulating a: the TNF-? pathway (TNF -308 G?>?A (rs1800629), and?-?238 G?>?A (rs361525); TNFRSF1A -609 G?>?T (rs4149570), and PTPN22 1858 G?>?A (rs2476601)), b: the IL23/IL17 pathway (IL23R G?>?A (rs11209026), and IL18-137 G?>?C (rs187238)), or c: the NFkB pathway (TLR1 743 T?>?C (rs4833095), TLR4 T?>?C (rs1554973), and LY96-1625 C?>?G (rs11465996)). After Bonferroni correction the homozygous variant genotype of TLR1 743 T?>?C (rs4833095) (odds ratios (OR): 2.59, 95% confidence interval (CI): 1.48-4.51, p?=?0.04), and TNFRSF1A -609 G?>?T (rs4149570) (OR: 1.79, 95% CI: 1.31-2.41, p?=?0.01) were associated with increased risk of AS and the combined homozygous and heterozygous variant genotypes of TNF -308 G?>?A (rs1800629) (OR: 0.56, 95% CI: 0.44-0.72, p?=?0.0002) were associated with reduced risk of AS. CONCLUSION:We replicated associations between AS and the polymorphisms in TNF (rs1800629), TNFRSF1A (rs4149570), and IL23R (rs11209026). Furthermore, we identified novel risk loci in TNF (rs361525), IL18 (rs187238), TLR1 (rs4833095), TLR4 (rs1554973), and LY96 (rs11465996) that need validation in independent cohorts. The results suggest that genetically determined high activity of the TNF-?, IL23/IL17, and NFkB pathways increase risk of AS.
| S-EPMC6136164 | biostudies-literature
Project description:ObjectivesTo evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in ankylosing spondylitis (AS) patients treated with tumor necrosis factor-alpha (TNF-α) blocking therapy in daily clinical practice.MethodsConsecutive outpatients from the Groningen Leeuwarden AS (GLAS) cohort were included based on the availability of cervical and lumbar radiographs before start of TNF-α blocking therapy and after 2, 4, and/or 6 years of follow-up. Clinical data were assessed at the same time points. Radiographs were scored by two independent readers using the modified Stoke AS Spine Score (mSASSS). Spinal radiographic progression in relation to clinical assessments was analyzed using generalized estimating equations.Results176 AS patients were included, 58% had syndesmophytes at baseline. Median mSASSS increased significantly from 10.7 (IQR: 4.6-24.0) at baseline to 14.8 (IQR: 7.9-32.8) at 6 years. At the group level, spinal radiographic progression was linear with a mean progression rate of 1.3 mSASSS units per 2 years. Both spinal radiographic damage at baseline and radiographic progression were highly variable between AS patients. Male gender, older age, longer disease duration, higher BMI, longer smoking duration, high CRP, and high ASDAS were significantly associated with syndesmophytes at baseline. Significantly more radiographic progression was seen in patients with versus without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years) and in patients >40 versus ≤40 years of age (1.8 vs. 0.7 mSASSS units per 2 years). No longitudinal associations between radiographic progression and clinical assessments were found.ConclusionsThis prospective longitudinal observational cohort study in daily clinical practice shows overall slow and linear spinal radiographic progression in AS patients treated with TNF-α blocking therapy. At the individual level, progression was highly variable. Patients with syndesmophytes at baseline showed a 4-fold higher radiographic progression rate than patients without syndesmophytes.
| S-EPMC4400173 | biostudies-literature
Project description:ObjectivesAnkylosing spondylitis (AS) is challenging to diagnose in its early stages, and treatment options are limited.MethodsGEO2R analysis and weighted gene co-expression network analysis (WGCNA) were used to identify DEGs and key modules. Kyoto Encyclopedia of Genes and Genomes analysis and Protein-protein interactions were used to identify core genes. Receiver operating characteristic curve, chi-square and t-test were used to analyze the correlation between gene expression and clinicopathological characteristics. Gene expression was detected using Real-time polymerase chain reaction and western blotting.ResultsGEO2R analysis and WGCNA identified 1100 DEGs and brown module. The KEGG analysis revealed that 444 core genes were closely associated with specific pathways. PPIs demonstrated that a key module, consisting of 6 genes, was linked to the phagosome pathway. NCF4, identified as an effective biomarker, was selected for diagnosing AS. Bioinformatics analyses indicated that NCF4 could be associated with important clinical markers. RT-PCR and western blotting showed increased expression of NCF4 in AS, which decreased after anti-TNF therapy.ConclusionsAnti-TNF therapy may exert its therapeutic function by inhibiting NCF4 expression, hence controlling the phagosome pathway. NCF4 has the potential to function as a diagnostic and prognostic biomarker for AS.
| S-EPMC10483821 | biostudies-literature
Project description:BackgroundClinical characteristics and manifestations of psoriatic arthritis (PsA) have been extensively studied in western countries, yet data of Korean patients with PsA are very limited. We aimed to investigate the clinical traits of patients with PsA and dissect the characteristics of those with axial involvement.MethodsIn this observational study, we analyzed clinical data of 109 patients with PsA who were enrolled in the Korean College of Rheumatology Biologics and Targeted Therapy registry between December 2012 and March 2022 at the time point of initiating or switching to a biologic agent. Data from 2,221 patients with ankylosing spondylitis (AS) registered during the same period were also analyzed. We divided patients with PsA into patients with or without axial involvement and then added AS patients with psoriasis (total three subgroups) for comparative analyses.ResultsAsymmetric oligoarthritis was the most common clinical manifestation in patients with PsA, followed by symmetric polyarthritis and spondylitis. Our analysis indicated that methotrexate and sulfasalazine were the two most prescribed disease-modifying antirheumatic drugs for patients with PsA before starting biologic therapy. The patients with psoriatic spondylitis had more peripheral joint involvement (P = 0.016), less prior uveitis (P < 0.001), and lower human leukocyte antigen B27 (HLA-B27) positivity (P < 0.001) than the AS patients with psoriasis. Furthermore, syndesmophytes and radiographic sacroiliitis were prevalent among patients with PsA and AS patients with psoriasis who had the HLA-B27 gene.ConclusionOur study shows that the degree of peripheral arthritis is less severe in Korean patients with PsA who require biologics and reestablishes that psoriatic spondylitis is a common and important clinical pattern in Korean patients with PsA.Trial registrationClinicalTrials.gov Identifier: NCT01965132.
| S-EPMC9424747 | biostudies-literature
Project description:AimsThe target of this article was to reveal the role of tumor necrosis factors α (TNF-α) and Interleukin-10 (IL10) gene polymorphisms in ankylosing spondylitis (AS) development and explore the interaction between these two gene polymorphisms.MethodsThe genotyping of gene polymorphims was conducted using ABI Taqman assay method in 84 AS patients and 92 healthy people. Hardy-Weinberg equilibrium (HWE) was checked in the control group and the genotypes and alleles difference were compared with χ(2) test. Odds ratio (OR) with 95% confidence interval (CI) was calculated to identify the strength of association between gene polymorphism and disease. Meanwhile, multifactor dimensionality reduction (MDR) method was used to analysis the interaction between gene polymorphisms.ResultsThe genotypes CG+CC of the minor allele in IL10 rs1878672 in cases was obviously higher frequency than the controls (P=0.03) and the minor allele C was also associated with the increased risk of AS, compared with G allele (OR=2.05, 95% CI=1.08-3.89). Rs3024490 in IL10 also showed a significant correlation to the onset risk of AS (GG vs. TT: OR=3.03, 95% CI=1.04-8.87; G vs. T: OR=1.70, 95% CI=1.08-2.68). What's more, there was the interaction between TNF-α rs3093662 and IL10 rs3021094, rs3024490 polymorphisms in AS.ConclusionsIL10 rs1878672 and rs3024490 polymorphisms obviously increase the susceptibility to AS, but not TNF-α rs3093662. Both IL10 and TNF-α polymorphisms may affect the onset of AS.
| S-EPMC4713653 | biostudies-literature
Project description:BACKGROUND Ankylosing spondylitis (AS) is a chronic inflammatory disease that predominantly affects the axial skeleton. The ability of anti-TNF-α agents to reduce disease activity in patients with axial spondyloarthritis (axSpA), including AS, has been demonstrated in multiple randomized trials and several meta-analyses. Reports on the efficacy of rituximab in treatment of AS have described good results. We report on a patient with AS who failed anti-TNF-α therapy but showed good clinical improvement with rituximab therapy. CASE REPORT A 38-year-old male patient was diagnosed with AS and showed poor response to sulfasalazine and non-steroidal anti-inflammatory drugs (NSAIDs). Infliximab was initiated with marked improvement as per the Bath ankylosing spondylitis disease activity index (BASDAI). Due to disease flare, the patient was switched to etanercept. He subsequently acquired papillary thyroid cancer and etanercept was discontinued. He underwent a total thyroidectomy followed by radioiodine therapy. For his ongoing active disease, NSAIDs and sulfasalazine were resumed with a lack of response (BASDAI=7.1). Rituximab was started and resulted in significant improvement (BASDAI=2.3). CONCLUSIONS Rituximab can be a potential target therapy for patients who start to lose response to TNF-inhibitors or for those who develop solid malignancies. Further placebo-controlled studies are required.
| S-EPMC5315003 | biostudies-literature