Biomarker Of Disease Activity Research Articles

Elevated unphosphorylated STAT1 and IRF9 in T and B cells of primary sjögren's syndrome: Novel biomarkers for disease activity and subsets

ObjectivesAutoreactive B cells and interferon (IFN) signature are hallmarks of primary sjögren's syndrome (pSS), but how IFN signaling pathways influence autoantibody production and clinical manifestations remain unclear. More detailed studies hold promise for improved diagnostic methodologies and personalized treatment. MethodsWe analyzed peripheral blood T and B cell subsets from 34 pSS patients and 38 healthy donors (HDs) at baseline and upon stimulation regarding their expression levels of type I and II IFN signaling molecules (STAT1/2, IRF1, IRF9). Additionally, we investigated how the levels of these molecules correlated with serological and clinical characteristics and performed ROC analysis. ResultsPatients showed elevated IFN pathway molecules, including STAT1, STAT2 and IRF9 among most T and B cell subsets. We found a reduced ratio of phosphorylated STAT1 and STAT2 in patients in comparison to HDs, although B cells from patients were highly responsive by increased phosphorylation upon IFN stimulation. Correlation matrices showed further interrelations between STAT1, IRF1 and IRF9 in pSS. Levels of STAT1 and IRF9 in T and B cells correlated with the IFN type I marker Siglec-1 (CD169) on monocytes.High levels of STAT1 and IRF9 within pSS B cells were significantly associated with hypergammaglobulinemia as well as anti-SSA/anti-SSB autoantibodies. Elevated STAT1 levels were found in patients with extraglandular disease and could serve as a biomarker for this subgroup (p < 0.01). Notably, IRF9 levels in T and B cells correlated with EULAR Sjögren's syndrome disease activity index (ESSDAI). ConclusionHere, we provide evidence that in active pSS patients, enhanced IFN signaling incl. unphosphorylated STAT1 and STAT2 with IRFs entertain chronic T and B cell activation. Furthermore, increased STAT1 levels candidate as biomarker of extraglandular disease, while IRF9 levels can serve as biomarker for disease activity.

Serum sclerostin as a biomarker of disease activity in ankylosing spondylitis in correlation with radiographic imaging

BackgroundThe wingless signaling pathway of bone development is inhibited by sclerostin, which may contribute to the etiology of ankylosing spondylitis.AimThe study aimed to evaluate serum sclerostin levels in ankylosing spondylitis patients and investigate how it correlated with radiographic damage using the Spondylo-arthritis Research Consortium of Canada index (SPARCC), disease activity, and functional impairment.ResultsThis cross-sectional case–control study revealed a significantly lower mean serum sclerostin (11.28 ng/ml) in AS patients compared with controls (101.25 ng/ml). Serum sclerostin levels showed a significant negative correlation with each of Bath Ankylosing Spondylitis Metrology Index (BASMI) (p = 0.043), sacroiliac joints SPARCC, spine SPARCC, and overall SPARCC scores (p = 0.012, p = 0.036, and p = 0.007). The detection of AS, serum sclerostin levels ≤ 20 ng/ml showed 100% sensitivity and specificity.ConclusionSerum sclerostin had good discriminating power between ankylosing spondylitis cases and healthy control individuals and was correlated with subclinical activity status on magnetic resonance imaging.

#1089 Urinary Protein Biomarkers for Assessing Disease Activity and Chronicity in IgA Nephropathy

Abstract Background and Objectives IgA nephropathy (IgAN) is a progressive kidney disease characterized by the mesangial deposition of galactose-deficient IgA1, leading to kidney damage and may eventually lead to end-stage kidney disease. Current treatment decisions for IgAN patients rely on the degree of proteinuria. However, this is a non-specific parameter that can be the result of inflammatory disease activity and/or chronic glomerular damage. In this study, we employed the Olink proximity extension assay to comprehensively analyze the urinary proteome of IgAN patients. Our goal was to identify biomarkers capable of distinguishing between IgAN disease activity and disease chronicity. Method Urine samples were collected from 41 IgAN patients and 41 age- and eGFR-matched controls. Patient characteristics are shown in Table 1. Using Olink Proteomics, we measured 276 proteins in urine, from the inflammation, organ damage, and cardiometabolic panels. Comparisons were made between IgAN patients and controls, as well as between those with mild (eGFR ≥ 60 ml/min/1.73 m2 and uPCR &amp;lt; 100 mg/mmol) and active IgAN (eGFR ≥ 60 ml/min/1.73 m2 and uPCR ≥ 100 mg/mmol) to identify biomarkers for disease activity. Additionally, we compared IgAN patients with eGFR ≥ 60 ml/min/1.73 m2 to those with eGFR ≤ 30 ml/min/1.73 m2 to identify biomarkers associated with disease chronicity. Mann-Whitney U tests were used for group comparisons. Correction for multiple testing was performed using the Benjamini-Hochberg procedure. Disease activity and chronicity scores were calculated by averaging the z-scores of the identified biomarkers. Results L-Selectin (SELL), leukocyte inhibitory factor (LIF), interleukin-6 (IL-6), and carbonic anhydrase 1 (CA1) were most prominently elevated in IgAN patients compared to controls (Fig. 1A). SELL and CA1 were also markedly elevated in the active versus mild IgAN patients, and were therefore selected as biomarkers of disease activity (Fig. 1B). Contactin 2 (CNTN2) and chemokine (C-C motif) ligand 25 (CCL25) were most prominently elevated in IgAN patients with eGFR ≤ 30 ml/min/1.73 m2, and were selected as biomarkers of disease chronicity (Fig. 1C). We plotted the disease activity and chronicity scores calculated from the identified biomarkers to distinguish the different IgAN disease stages (Fig. 1D). Conclusion This study identified urine biomarkers indicative of IgAN disease activity and chronicity. Calculating an activity and chronicity score using these biomarkers offers a new approach to distinguish between inflammatory disease activity and chronicity, providing an alternative to proteinuria for guiding treatment decisions in IgAN patients. Validation of these biomarkers, and the scores calculated from them, in a larger cohort of IgAN patients is currently underway.

#887 Complement biomarkers in IgA nephropathy and IgA vasculitis with renal involvement: can urine rather than blood be the answer?

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Dysregulation of the complement system is considered a part of the pathogenesis and can occur both in the circulation and locally in the kidney. Despite this, most studies have focused on complement biomarkers in the blood, rather than in urine. Our aim was to evaluate a wide range of complement-related proteins in blood and urine at diagnosis and their association with disease activity in biopsy findings, proteinuria, and outcome. We added PTX-3, a protein expressed in activated endothelial cells, which can be both produced by and activate mesangial cells in IgAN and has a function in all three complement pathways. Adult-onset IgA vasculitis with renal involvement (IgAVN) shares many similarities with IgAN and cannot currently be distinguished by kidney biopsy or any established biomarker. We therefore also aimed to compare the same biomarkers between these two disorders. Method In a Swedish cohort of 96 patients with IgAN (n = 65) and IgAVN (n = 31), who had been followed prospectively for a median of 10.8 years, we performed the following analysis in plasma and urine in samples stored at the time of kidney biopsy. Analyses in plasma (p-) included C3bc, C4c, C5b-9, MASP2, MASP3, MAP1, FCN 1-3, MBL, CL11 and PTX-3 and in urine (u-) C3bc, C4c, C5b-9, MASP3, FCN2, FCN3, MBL and PTX-3. An in-house developed sandwich ELISA was used for all analyses. Kidney biopsies were classified according to the Oxford MEST-C score, describing (simplified for this small cohort) the presence vs absence (1 vs 0) of mesangial proliferation (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C). Severe outcome was defined by a combination of an eGFR slope &amp;gt; 2.5 ml/min/1.73 m2 per year or end stage kidney disease. For statistical analysis, Mann-Whitney U test was performed for comparison between independent groups, Chi squared test and Fisher's test for categorical variables and Spearman's ranks test for correlation analysis. Median values are presented without IQR for this abstract. Results Urine samples were available in 59 patients (IgAN n = 39, IgAVN n = 20). Patients with detectable u-MBL (28.9%) and u-C5b-9 (27.1%) had higher levels of proteinuria than those with undetectable levels (1.5 g/d vs 0.71g/d; p = 0.009 and 2.3 g/d vs 0.7 g/d respectively; p &amp;lt; 0.001). Lower eGFR (71 ml/min/1.73 m2 vs 88 ml/min/1.73 m2; p = 0.034) were observed if u-C5b-9 was measurable. Detectable levels of u-PTX-3 and u-MBL were more often found in the presence of M1 vs M0 (53% vs 20%; p = 0.022 and 47% vs 12.5%; p = 0.011), E1 vs E0 (55% vs 14%; p = 0.001 and 40% vs 11%; p = 0.020) and C1 vs C0 (56% vs 11%; p = 0.003 and 44% vs 11%; p = 0.012). No differences in proteinuria or eGFR were seen in patients with or without detectable u-PTX-3. The degree of proteinuria was positively correlated to the levels of u-C3bc (r = 0.33; p = 0.011) and u-C4c (r = 0.39; p &amp;lt; 0.001). U-C4c levels were higher in patients with M1 vs M0 (54.4 Au/mL vs 23.8 Au/mL; p = 0.037) and T1 vs T0 (53.2 Au/mL vs 23.8 Au/mL; p = 0.034). Concerning the analyses in plasma (n = 95), lower p-MASP3 and p-CL11 levels were correlated with lower eGFR (r = 0.29; p = 0.004 and r = 0.31, p = 0.002). Moreover, lower p-MASP3 levels were detected in patients with E1 vs E0 (2918 ng/mL vs 3404 ng/mL; p = 0.002) and C1 vs C0 (3053 ng/mL vs 3427 ng/mL; p = 0.015). Both p-C5b-9 (13.3 Au/mL vs 8.2 Au/mL; p = 0.001) and p-FCN 1 (395 ng/mL vs 289 ng/mL; p = 0.001) were higher in patients with C1 vs C0. No single complement-related protein was associated with severe outcome, and no statistically significant differences in plasma or urine levels between patients with IgAN and IgAVN were observed. Conclusion Increased urinary levels of MBL and PTX-3 could be potential biomarkers of disease activity in both IgAN and IgAVN, whereas excretion of C5b-9 might be more unspecific and associated with chronic damage. However, these results need to be confirmed in larger and more ethnically diverse cohorts. The impact of treatment on these potential biomarkers for disease activity need to be evaluated in longitudinal studies.

Serum Proteomic Profiles of Patients with Chronic Recurrent Multifocal Osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disease characterized by sterile bone inflammation; however, its pathophysiology is poorly understood. Thus, this study aimed to characterize the serum proteomic profiles of patients with CRMO to better understand the molecular mechanisms underpinning CRMO pathogenesis. Proteomic profiling of the sera collected from 11 patients with CRMO (five patients were in active phase, six were in inactive phase) was conducted using liquid chromatography-mass spectrometry. Sera from four children without inflammatory diseases were used as controls. Pathway analysis was performed to identify the upregulated and downregulated proteins in patients with active CRMO. Compared with the control group, 19 and 41 proteins were upregulated and downregulated, respectively, in patients with active CRMO. Pathway and process enrichment analyses revealed that axon guidance was the most enriched category of upregulated proteins in patients with active CRMO, followed by neutrophil degranulation and mitogen-activated protein kinase cascade regulation. In comparison to patients with inactive CRMO, 36 proteins, including 11 keratin proteins, were upregulated and highly enriched in the intermediate filament organization category. Rho GTPase pathway-related proteins were downregulated in ibuprofen-treated patients. Proteomic analysis identified upregulated proteins in the sera of patients with acute CRMO. These proteins can be used as biomarkers for disease diagnosis and activity. Furthermore, we anticipate that this study will contribute to a deeper understanding of the pathophysiology of CRMO, which, in turn, will contribute to the discovery of potential novel therapeutic targets.

Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect clinical and radiographic disease activity in multiple sclerosis

The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.

Red blood cell distribution width as a surrogate biomarker of damage and disease activity in patients with systemic lupus erythematosus.

Red blood cell distribution width (RDW) is a measure of variability in mean corpuscular volume. Alterations in RDW can be observed in a variety of human disorders, including inflammatory, cardiovascular, and hepatic or renal diseases. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect virtually any organ in the body. In this work, our objective was to analyse how a complete characterisation of disease characteristics in a large series of patients with SLE is related to RDW values. 284 patients with SLE and 181 age- and sex-matched healthy controls were recruited. Complete blood count including RDW was assessed. Multivariable analysis was performed to analyse the relationship between RDW and SLE disease characteristics, including composite scores of disease activity and damage. After multivariable adjustment, RDW was higher in patients with SLE compared to controls (beta coefficient 0.8 [95% confidence interval: 0.3-1] %, p=0.003). Several disease characteristics, such as the presence of extractable nuclear antibodies and antiphospholipid syndrome, and the use of prednisone and azathioprine, were significantly associated with higher levels of RDW after adjustment for confounders. Of note, cumulative disease damage and disease activity scores were associated with higher RDW values after controlling for covariates. RDW may serve as a surrogate biomarker of accrual disease damage and activity in patients with SLE.

Osteopontin as a Biomarker in Interstitial Lung Diseases.

Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75-1.51] ng/mL versus 0.81 [0.65-0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80-1.72] ng/mL versus 0.99 [0.66-1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.

Altered cerebrospinal fluid neurofilament light chain but not neurogranin levels are associated with response to ocrelizumab treatment in relapsing remitting multiple sclerosis: a preliminary study.

Ocrelizumab is a CD20-targeting monoclonal antibody used for treatment of multiple sclerosis (MS). Serum and cerebrospinal fluid (CSF) neurofilament light chain (NFL) levels are reduced in MS patients under ocrelizumab treatment indicating a preventive action against neuro-axonal degeneration. Our aim, in this preliminary study, was to explore the impact of ocrelizumab treatment on synaptic integrity through assessment of neurogranin levels. Thirteen relapsing-remitting multiple sclerosis (RRMS) patients resistant to first-line immunomodulating agents were enrolled and followed up for 24 months under ocrelizumab treatment. Disease activity was monitored by periodic EDSS, MSSS and cranial-spinal MRI assessments. No evidence of disease (NEDA)-3 activity was determined and CSF levels of NFL (marker of neuro-axonal integrity) and neurogranin (marker of synaptic integrity) were measured by ELISA at baseline and 12-month ocrelizumab treatment. Seven RRMS patients, who preserved NEDA-3 status during 24-month follow-up showed ≥30% NFL level decrease, whereas six patients with stable/increased NFL levels displayed relapse, MRI lesion or disability progression. Although most RRMS patients exhibited increased CSF levels of neurogranin under ocrelizumab treatment, patients with and without neurogranin level increase did not differ in terms of clinical features and NEDA-3 status. Baseline neurogranin levels negatively correlated with baseline EDSS scores. Our results confirm that NFL effectively monitors treatment response of RRMS patients under ocrelizumab treatment. Neurogranin does not appear to exhibit a similar benefit in screening of RRMS disease activity. Nevertheless, lower neurogranin levels are associated with increased disability in RRMS indicating a potential disease activity biomarker function.

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Neutrophils-derived Parameters as Cost-effective Inflammatory, Disease Activity Marker in Systemic Lupus Erythematosus (SLE) and Role in Prediction of Lupus Nephritis

Introduction: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease with various clinical manifestations and approximately 50% of the SLE patients develop lupus nephritis (LN), which increases the risk of renal failure, cardiovascular diseases and overall survival. Objectives: Evaluation of neutrophil-derived parameters (Neut-X, Neut-Y and Neut-Z) as an inflammatory, disease activity marker and as a predictor of nephritis in SLE patients. Material and Methods: In this cross-sectional study, 3 ml K3EDTA blood was taken from 110 SLE patients presented in Department of Clinical Immunology to evaluate neutrophil-derived parameters in Sysmex XT2000i haematology analyser and their correlation with other inflammatory biomarkers like, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as well as SLE disease activity index-2000 (SLEDAI-2K). 24-hours urine protein levels were also estimated as a marker of renal involvement. Records of renal biopsy were available in 73 SLE patients, who belonged to different morphologic classification of LN. Results: After performing bivariate Spearman correlation analysis (SPSS software, version 26.0), Neut-X (measures cytoplasmic granularity by side scattering) and Neut-Z (vector sum of Neut-X and Neut-Y) showed a significant positive correlation ( r &gt; 0.200, P &lt; .05) with ESR, CRP and SLEDAI-2K while Neut-Y (measures nucleic acid content by sideward fluorescence) showed a significant negative correlation ( r &gt; 0.200, P &lt; .05) with ESR and CRP. Receiver-operating characteristic curve analysis was used to evaluate diagnostic value of 24-hour urine protein and predictive values of neutrophil-derived parameters for renal involvement in SLE patients. Among neutrophil-derived parameters, Neut-X was found to be the best predictor of renal dysfunction with highest AUC of 0.710 (95% CI: 0.604-0.816; cut-off: 1344.50; sensitivity: 84.7%; specificity: 50%) followed by Neut-Z with AUC of 0.707 (95% CI: 0.600-0.813; cut-off: 1403.67; sensitivity: 87.5%; specificity: 50%). Conclusion: Our study shows that neutrophil-derived parameters may be used as novel cost-effective, non-invasive biomarker of disease activity as well as for predicting renal involvement in SLE patients.

Targeted metabolomics combined with machine learning to identify and validate new biomarkers for early SLE diagnosis and disease activity

BackgroundThe early diagnosis of systemic lupus erythematosus (SLE) and the assessment of disease activity progression remain a great challenge. Targeted metabolomics has great potential to identify new biomarkers of SLE. MethodsSerum from 44 healthy participants and 89 SLE patients were analyzed using HM400 high-throughput targeted metabolomics. Machine learning (ML) with seven learning models and trained the model several times iteratively selected the two best prediction model in a competitive way, which were independent validated by enzyme-linked immunosorbent (ELISA) with 90 SLE patients. ResultsIn this study, 146 differential metabolites, most of them organic acids, amino acids, and bile acids, were detected between patients with initial SLE and healthy participants, and 8 potential biomarkers were found by intersection of ML and statistics (area under the curve [AUC] > 0.95) showing a significant positive correlation with clinical indicators. In addition, we identified and validated 2 potential biomarkers for SLE classification (P < 0.05, AUC > 0.775; N-Methyl-L-glutamic acid, L-2-aminobutyric acid) showing a significant correlation with the SLE Disease Activity Index. These differential metabolites were mainly involved in metabolic pathways, amino acid biosynthesis, 2-oxocarboxylic acid metabolism and other pathways. ConclusionThis study indicated that the tricarboxylic acid cycle might be associated with SLE drug therapy. We identified 8 diagnostic models biomarkers and 2 biomarkers that could be used to identify initial SLE and distinguish different activity degree, which will promote the development of new tools for the diagnosis and evaluation of SLE.

Points to consider for unmet needs in axial spondyloarthritis. Proceedings of the French spondyloarthritis taskforce workshop

The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, for implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.

MicroRNA-5196 as an Accurate Biomarker of Disease Activity and Response to Treatment in Rheumatoid Arthritis

Objective: Methods: One hundred patients divided into two groups’ 50 responders and 50 non responders with 50 healthy individuals were studied. The serum expression ofmiRNA-5196 was detected by using real-time polymerase chain reaction. Results: miRNA-5196 expression was significantly higher in rheumatoid arthritis patients versus control group P &lt;0.05. Sub-group of patients into responders and non-responders showed that miRNA-5196 expression higher in non-responders than responders.miRNA-5196 expression related with response to TNF-α inhibitor and disease activity in patients with rheumatoid arthritis. Conclusion: miRNA-5196 may consider as a valid target for monitoring progression of RA disease and response to TNF-α inhibitor therapy.

Soluble CD27 is an intrathecal biomarker of T-cell-mediated lesion activity in multiple sclerosis

ObjectiveSoluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis.MethodsProtein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features.ResultsWe demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions.InterpretationOur results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes.

Morphological Differentiation of Corneal Inflammatory Cells: Proposal of Pragmatic Protocol.

Corneal confocal microscopy is a noninvasive imaging technique to analyze corneal nerve fibers and corneal inflammatory cells (CICs). The amount of CICs is a potential biomarker of disease activity in chronic autoinflammatory diseases. To date, there are no standardized criteria for the morphological characterization of CICs. The aim was to establish a protocol for a standardized morphological classification of CICs based on a literature search and to test this protocol for applicability and reliability. A systematic review of the literature about definitions of CICs was conducted. Existing morphological descriptions were translated into a structured algorithm and applied by raters. Subsequently, the protocol was optimized by reducing and defining the criteria of the cell types. The optimized algorithm was applied by 4 raters. The interrater reliability was calculated using Fleiss kappa (K). A systematic review of the literature revealed no uniform morphological criteria for the differentiation of the individual cell types in CICs. Our first protocol achieved only a low level of agreement between 3 raters (K = 0.09; 1062 rated cells). Our revised protocol was able to achieve a higher interrater reliability with 3 (K = 0.64; 471 rated cells) and 4 (K = 0.61; 628 rated cells) raters. The indirect use of criteria from the literature leads to a high error rate. By clearly defining the individual cell types and standardizing the protocol, reproducible results were obtained, allowing the introduction of this protocol for the future evaluation of CICs in the corneal confocal microscopy.

Serum and urine interferon-inducible protein 10, galectin-9, and SIGLEC-1 as biomarkers of disease activity in systemic lupus erythematosus

Serum and urine interferon-inducible protein 10, galectin-9, and SIGLEC-1 as biomarkers of disease activity in systemic lupus erythematosus

The proportion of CD161 on CD56+ NK cells in peripheral circulation associates with clinical features and disease activity of primary Sjögren's syndrome.

The purpose of this study was to examine the proportion of CD161 on CD56+ natural killer (NK) cells in peripheral blood of primary Sjögren's syndrome (pSS) and investigate its clinical relevance of pSS. The proportion of CD56+ NK cells and CD161 on CD56+ NK cells was detected by flow cytometry in 31 pSS patients and 29 healthy controls (HCs). The correlations between the proportion of CD161+CD56+ NK cells and clinical features and disease activity of pSS were further analyzed. Meanwhile, we drew the receiver operating characteristic curve to evaluate the diagnostic value of CD161+CD56+ NK cells in pSS. In addition, we evaluated the differences in the effects of CD161+ cells and CD161- cells in peripheral blood on the function of CD56+ NK cells in 5 pSS patients. The proportion of CD56+ NK cells and CD161+CD56+ NK cells decreased markedly in pSS patients compared to HCs. The correlation analysis showed that the proportion of CD161+CD56+ NK cells negatively correlated with white blood cells, Immunoglobulin A (IgA), IgM, IgG, European League Against Rheumatism Sjogren's Syndrome Patient Reported Index andEuropean League Against Rheumatism Sjogren's Syndrome Disease Activity Index, and positively correlated with complement C4. The proportion of CD161+CD56+ NK cells in pSS patients with decayed tooth, fatigue, arthralgia, skin involvement, primary biliary cirrhosis, interstitial lung disease, anti-SSA/Ro60 positive, anti-SSB positive and high IgG was lower than that in negative patients. Furthermore, compared with inactive patients, the proportion of CD161+CD56+ NK cells decreased obviously in active patients. The area under the curve was 0.7375 (p = .0016), the results indicated that CD161+CD56+ NK cells had certain diagnostic values for pSS. In addition, the proportion of CD86, HLA-DR, Ki67, FasL, TNF-α, and IFN-γ on CD161+CD56+ NK cells was lower than that on CD161-CD56+ NK cells in the peripheral blood of pSS patients. This study suggested that the proportion of CD56+ NK cells and CD161+CD56+ NK cells decreased significantly in pSS patients, and the proportion of CD161+CD56+ NK cells negatively associated with the clinical features and disease activity of pSS patients. CD161 expression inhibited the function of CD56+ NK cells in peripheral blood of pSS patients. The CD161+CD56+ NK cells may present as a potential target for therapy and a biomarker of disease activity in pSS.

Alpha Calcitonin Gene-related Peptide, Neuropeptide Y, and Substance P as Biomarkers for Diagnosis and Disease Activity and Severity in Multiple Sclerosis.

Alpha calcitonin gene-related peptide (aCGRP), neuropeptide Y (NPY), and substance P (SP) are neuropeptides that have emerged recently as potent immunomodulatory factors with potential as novel biomarkers and therapeutic targets in multiple sclerosis (MS). The study aimed to detect serum levels of aCGRP, NPY, and SP in MS patients versus healthy controls and their association with disease activity and severity. Serum levels were measured in MS patients and age and sex-matched healthy controls using ELISA. We included 67 MS patients: 61 relapsing-remitting MS (RR-MS) and 6 progressive MS (PR-MS), and 67 healthy controls. Serum NPY level was found to be lower in MS patients than in healthy controls (p < 0.001). Serum aCGRP level was higher in PR-MS compared to RR-MS (p = 0.007) and healthy controls (p = 0.001), and it positively correlated with EDSS (r = 0.270, p = 0.028). Serum NPY level was significantly higher in RR-MS and PR-MS than in healthy controls (p < 0.001 and p = 0.001, respectively), and it was lower in patients with mild or moderate/severe disease than in healthy controls (p < 0.001). Significant inverse correlations were found between SP level and MS disease duration (r = -0.279, p = 0.022) and duration of current DMT (r = -0.315, p = 0.042). Lower serum levels of NPY were revealed in MS patients compared to healthy controls. Since serum levels of aCGRP are significantly associated with disease activity and severity, it is a potential disease progression marker.

Serum Levels of S100A8/A9 as a Biomarker of Disease Activity in Patients with IgA Vasculitis.

S100A8/A9 protein is a well-known marker of disease activity or severity in many autoimmune and autoinflammatory diseases, but there have not been many studies about the role of S100A8/A9 in IgA vasculitis (IgAV). The aim of our study was to evaluate S100A8/A9 as a possible biomarker of activity in IgAV. We measured the serum levels of S100A8/A9 in pediatric patients with IgA vasculitis at the onset of the disease, after three months, and after six months. We compared these levels between patients with active disease, remission, and a control group, and assessed their correlation with disease activity and other markers of inflammation. Patients with active disease had significantly higher levels of serum S100A8/A9 (median ± SD) than those in the control group at the beginning of the disease (5740 ± 3157 ng/mL vs. 1447 ± 858.3 ng/mL; p < 0.0001), but also three months and six months after disease onset (p < 0.001). There was a positive correlation between S100A8/A9 serum levels and disease activity (p = 0.0003). Patients with active disease had significantly higher levels of S100A8/A9 than those in remission three months after disease onset (p = 0.0260). There was a correlation between S100A8/A9 and C-reactive protein, the C3 component of complement, ferritin, and fibrinogen. Serum levels of S100A8/A9 were also higher in patients with greater skin areas covered with rash. We demonstrated that serum levels of S100A8/A9 correlated well with disease activity and other biomarkers of inflammation in children with IgAV. According to our results, serum S100A8/A9 may be a good indicator of active disease in IgAV.