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Arthritis Care & Research Jun 2024Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine...
OBJECTIVE
Low complement is associated with clinical systemic lupus erythematosus (SLE) disease activity and future organ damage. We studied the association of hydroxychloroquine (HCQ) whole blood levels with changes in complement.
METHODS
We performed two analyses on data prospectively collected from an SLE cohort. In the first (a "new starts on HCQ" analysis), we compared changes in complement between those starting hydroxychloroquine and those who did not. The second analysis evaluated the association between hydroxychloroquine whole blood levels and low complement in all cohort visits using conditional logistic regression.
RESULTS
In the "new starts on HCQ" analysis, a higher percentage of patients starting hydroxychloroquine (as reflected in HCQ blood levels>50) experienced a normalization of C4 compared to those who did not (23/57 (40%) vs. 9/56 (13%), p=0.011), as well as a significantly greater increase in both C3 and C4 (p=0.048 and p=0.017 respectively). In the "all cohort visits" analysis, there was a statistically significant higher probability of having normal C4 levels in visits with higher hydroxychloroquine whole blood levels (OR 1.8 to 2.6 depending on the levels). This relationship was most pronounced for whole blood hydroxychloroquine levels of 200ng/ml or more.
CONCLUSION
We observed significant improvement in complement levels when hydroxychloroquine was started and among those with higher whole blood levels of hydroxychloroquine, particularly with respect to C4. Modulating the pathogenic mechanisms that lead to complement consumption may be one mode by which hydroxychloroquine prevents poor outcomes in SLE.
PubMed: 38831658
DOI: 10.1002/acr.25381 -
Movement Disorders : Official Journal... Feb 2024Neuroinflammation might contribute to the pathogenesis of multiple systemic atrophy (MSA). However, specific alterations in the peripheral inflammatory and immune...
BACKGROUND
Neuroinflammation might contribute to the pathogenesis of multiple systemic atrophy (MSA). However, specific alterations in the peripheral inflammatory and immune profiles of patients with MSA remain unclear.
OBJECTIVES
To determine the peripheral inflammatory and immune profiles of patients with MSA and their potential value as biomarkers for facilitating clinical diagnosis and monitoring disease severity.
METHODS
This cross-sectional study included 235, 240, and 235 patients with MSA, patients with Parkinson's disease (PD), and healthy controls (HCs), respectively. Inflammatory and immune parameters were measured in peripheral blood, differences between groups were assessed, and clusters were analyzed. Associations between the parameters and clinical characteristics of MSA were assessed using Spearman and partial correlation analyses.
RESULTS
Significant differences were observed especially in monocytes, neutrophils-to-lymphocyte ratio (NLR) and neutrophils-to-lymphocyte ratio (MPV) between MSA patients and HCs (P < 0.01). Monocytes and uric acid (UA) levels were also significantly different between the MSA and PD patients (P < 0.05). The combination of NLR and MPV distinguished MSA-P patients from HCs (areas under the curve = 0.824). In addition, complement components C4 and C3 were significantly correlated with the Scale Outcomes in PD for Autonomic Symptoms and Wexner scale, whereas immunoglobulin G (IgG) was significantly correlated with scores of Unified Multiple System Atrophy Rating Scale (P < 0.05).
CONCLUSIONS
In MSA patients, monocytes, NLR and MPV might serve as potential diagnostic biomarkers, whereas MLR, C3, C4, and IgG significantly correlate with disease severity. © 2023 International Parkinson and Movement Disorder Society.
Topics: Humans; Multiple System Atrophy; Cross-Sectional Studies; Parkinson Disease; Biomarkers; Immunoglobulin G
PubMed: 38155513
DOI: 10.1002/mds.29674 -
Clinica Chimica Acta; International... Feb 2024The complement system is involved in numerous diseases, through diverse mechanisms and degree of activation. With the emergence of complement targeting therapeutic,...
INTRODUCTION
The complement system is involved in numerous diseases, through diverse mechanisms and degree of activation. With the emergence of complement targeting therapeutic, simple and accessible tools to evaluate the extent of complement activation are strongly needed.
METHODS
We evaluated two multiplex panels, measuring complement activation fragments (C4a, C3a, C5a, Bb, Ba, sC5b9) and intact components or regulators (C1q, C2, C3, C4, C5, FD, FP, FH, FI). The specificity of each measurement was assessed by using complement proteins depleted sera and plasma collected from patients with complement deficiencies. Normal values distribution was estimated using 124 plasma samples from healthy donors and complement activation profile was assessed in plasma collected from 31 patients with various complement-mediated disorders.
RESULTS
We observed good inter-assay variation. All tested protein deficiencies were accurately detected. We established assay-specific reference values for each analyte. Except for C3, C4 and C4a, the majority of the measurements were in good agreement with references methods or published data.
CONCLUSION
Our study substantiates the utility of the Complement Multiplex assay as a tool for measuring complement activation and deficiencies. Quantifying complement cleavage fragments in patients exhibiting classical or alternative pathway activation allowed evaluating the activation state of the whole cascade.
Topics: Humans; Complement System Proteins; Complement Activation; Biomarkers; Plasma
PubMed: 38176523
DOI: 10.1016/j.cca.2023.117750 -
International Immunopharmacology Sep 2023To explore the relationship between immunoglobulin A (IgA), complement C4, and liver fibrosis (L.F.) progression (LFP) in patients with chronic hepatitis B (CHB).
OBJECTIVE
To explore the relationship between immunoglobulin A (IgA), complement C4, and liver fibrosis (L.F.) progression (LFP) in patients with chronic hepatitis B (CHB).
METHODS
This is a retrospective cohort study of CHB patients who received liver biopsies. Relevant data, including demographics, clinical serum markers, and immunological results obtained during liver biopsies, were collected and analyzed to assess and verify the relationship between IgA, C4, and LFP.
RESULTS
This study included 1,938 CHB patients, of whom 132 received two liver biopsies (group 1). Thirty (22.7%) of these patients were diagnosed with LFP (increase in L.F. stage (Scheuer score F ≥ 1)). IgA (C-IgA) and C4 (C-C4) change values between the first and second biopsies were independent risk factors for LFP. IgA levels increased, and C4 levels decreased during the second liver puncture. The remaining 1,806 patients received one liver puncture (group 2). They were divided into the following subgroups: A (F ≤ 1), B (1 < F ≤ 3), and C (F > 3) to verify whether the same trend was observed by cross-sectional study. IgA levels were highest, and C4 levels were lowest in group C (IgA: C > B > A, p < 0.05; C4: C < B < A, p < 0.05).
CONCLUSIONS
The findings of this study suggest that serum IgA and C4 levels are independent risk factors for LFP that could serve as future targets for L.F. management and treatment.
Topics: Humans; Complement C4; Immunoglobulin A; Hepatitis B, Chronic; Retrospective Studies; Cross-Sectional Studies; Liver Cirrhosis; Liver; Biomarkers
PubMed: 37451022
DOI: 10.1016/j.intimp.2023.110604 -
Cells Aug 2023Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than...
INTRODUCTION
Upregulation of complement system factors are reported to be increased in polycystic ovary syndrome (PCOS) and may be due to obesity and insulin resistance rather than inherently due to PCOS. We directly compared complement factors from an obese, insulin-resistant PCOS population to a nonobese, non-insulin-resistant PCOS population in a proteomic analysis to investigate this.
METHODS
Plasma was collected from 234 women (137 with PCOS and 97 controls) from a biobank cohort and compared to a nonobese, non-insulin-resistant population (24 with PCOS and 24 controls). Slow off-rate modified aptamer (SOMA) scan plasma protein measurement was undertaken for the following complement system proteins: C1q, C1r, C2, C3, C3a, iC3b, C3b, C3d, C3adesArg, C4, C4a, C4b, C5, C5a, C5b-6 complex, C8, properdin, factor B, factor D, factor H, factor I, Mannose-binding protein C (MBL), complement decay-accelerating factor (DAF) and complement factor H-related protein 5 (CFHR5).
RESULTS
The alternative pathway of the complement system was overexpressed in both obese and nonobese PCOS, with increased C3 ( < 0.05) and properdin ( < 0.01); additionally, factor B increased in obese PCOS ( < 0.01). For inhibitors of this pathway, factor I was increased ( < 0.01) in both slim and obese PCOS, with an increase in CFHR5 and factor H in obese PCOS ( < 0.01). Complement factors iC3b, C3d and C5a, associated with an enhanced B cell response and inflammatory cytokine release, were increased in both slim and obese PCOS ( < 0.05). C3a and its product, C3adesArg, were both significantly elevated in nonobese PCOS (<0.01) but not altered in obese PCOS. Hyperandrogenemia correlated positively with properdin and iC3b in obese PCOS ( < 0.05) but not in nonobese PCOS. There was no association with insulin resistance. BMI correlated positively in both groups with factor B, factor H and C5a. Additionally, in obese PCOS, BMI correlated with C3d, factor D, factor I, CFHR5 and C5a ( < 0.05), and in nonobese PCOS, BMI correlated with properdin, iC3b, C3, C3adesArg, C3a, C4, C5, C5a and C1q. In obese controls, BMI correlated with C3, C3desArg, C3a, C3d, C4, factor I, factor B, C5a and C5, whilst in nonobese controls, BMI only correlated negatively with C1q. Comparison of nonobese and obese PCOS showed that properdin, C3b, iC3b, C4A, factor D, factor H and MBL differed.
CONCLUSION
The upregulation of the alternative complement pathway was seen in nonobese PCOS and was further exacerbated in obese PCOS, indicating that this is an inherent feature of the pathophysiology of PCOS that is worsened by obesity and is reflected in the differences between the nonobese and obese PCOS phenotypes. However, the increase in the complement proteins associated with activation was counterbalanced by upregulation of complement inhibitors; this was evident in both PCOS groups, suggesting that insults, such as a cardiovascular event or infection, that cause activation of complement pathways may be amplified in PCOS.
PubMed: 37566081
DOI: 10.3390/cells12152002 -
Journal of Veterinary Internal Medicine 2024High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy.
BACKGROUND
High concentrations of complement factors are presented in serum of animal epilepsy models and human patients with epilepsy.
OBJECTIVES
To determine whether complement dysregulation occurs in dogs with idiopathic epilepsy (IE).
ANIMALS
The study included 49 dogs with IE subgrouped into treatment (n = 19), and nontreatment (n = 30), and 29 healthy dogs.
METHODS
In this case-control study, the serum concentrations of the third (C3) and fourth (C4) components of the complement system were measured using a canine-specific ELISA kit.
RESULTS
Serum C3 and C4 concentrations were significantly higher in dogs with IE (C3, median; 4.901 [IQR; 3.915-6.673] mg/mL, P < .001; C4, 0.327 [0.134-0.557] mg/mL, P = .03) than in healthy control dogs (C3, 3.550 [3.075-4.191] mg/mL; C4, 0.267 [0.131-0.427] mg/mL). No significant differences were observed in serum C3 and C4 concentrations between dogs in the treatment (C3, median; 4.894 [IQR; 4.192-5.715] mg/mL; C4, 0.427 [0.143-0.586] mg/mL) and nontreatment groups (C3, 5.051 [3.702-7.132] mg/mL; C4, 0.258 [0.130-0.489] mg/mL). Dogs with a seizure frequency >3 times/month had significantly higher serum C3 (6.461 [4.695-8.735] mg/mL; P < .01) and C4 (0.451 [0.163-0.675] mg/mL; P = .01) concentrations than those with a seizure frequency ≤3 times/month (C3, 3.859 [3.464-5.142] mg/mL; C4, 0.161 [0.100-0.325] mg/mL).
CONCLUSIONS AND CLINICAL IMPORTANCE
Dysregulation of classical complement pathway was identified in IE dogs. Serum C3 and C4 concentrations could be diagnostic biomarkers for IE in dogs with higher seizure frequency.
Topics: Humans; Dogs; Animals; Complement C3; Complement C4; Case-Control Studies; Epilepsy; Seizures; Dog Diseases
PubMed: 38329151
DOI: 10.1111/jvim.17008 -
The Journal of Pharmacology and... Aug 2023Sutimlimab, a humanized monoclonal antibody targeting the classic complement pathway, is approved in the United States, Japan, and the European Union for the treatment... (Clinical Trial)
Clinical Trial
Sutimlimab, a humanized monoclonal antibody targeting the classic complement pathway, is approved in the United States, Japan, and the European Union for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome [hemoglobin (Hb) levels]. Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed. The pharmacokinetic (PK) characteristics of sutimlimab were best described by a two-compartment model with parallel linear and nonlinear clearance terms. Body weight was a significant covariate for the volume of distribution in the central compartment (V) and total body clearance of sutimlimab. Ethnicity (Japanese, non-Japanese) was a covariate on V and maximal nonlinear clearance. There were no PK differences between healthy participants and patients. After graphical exposure-response analysis for biomarkers, a pharmacokinetic-pharmacodynamic model was developed by integrating an indirect response/turnover model for Hb with a maximum effect (E) model, relating the Hb-elevating effect of sutimlimab to plasma exposure. Renal function and occurrence of blood transfusion were identified as covariates on Hb change from baseline. Simulations showed that E was attained with the approved dosing (6.5 g in patients <75 kg and 7.5 g in patients ≥75 kg), independent of covariate characteristics, and provided adequate sutimlimab exposure to maximize effects on Hb, bilirubin, and total complement component C4 levels. A change in Hb from baseline at steady state of 2.2 g/dl was projected, consistent with phase 3 study observations. SIGNIFICANCE STATEMENT: The final validated population pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) models confirm that the approved dosing regimen for sutimlimab (6.5 g in patients <75 kg and 7.5 g in patients ≥75 kg) is sufficient, without the need for further dose adjustments in populations of patients with cold agglutinin disease.
Topics: Adult; Humans; Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal, Humanized; Biomarkers; Body Weight
PubMed: 37164370
DOI: 10.1124/jpet.122.001511 -
The Journal of Allergy and Clinical... Aug 2023Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue...
Angioedema is generally readily recognizable clinically and is characterized by localized nonpitting edema involving subcutaneous, submucosal, or deep dermal tissue caused by increased vascular permeability and extravasation of intravascular fluid. It can occur via a variety of mechanisms. A number of clinical conditions (masqueraders) are occasionally mistaken for angioedema. Clinical classification of the various angioedema forms begins with noting the presence or absence of concurrent urticaria or wheals. Pathogenesis can be considered through two broad categories: mast cell-mediated with release of vasoactive mediators causing angioedema usually associated with urticaria or in the context of an anaphylactic reaction; and bradykinin (BK)-driven, in which increased vascular permeability is mediated by BK. BK-mediated angioedema does not occur with urticaria, nor does it respond to antiallergic medications. The various forms of hereditary angioedema are included in this category, requiring specific tests of C4 and C1 inhibitor level and function to confirm the diagnosis. Angiotensin converting enzyme inhibitors, which impair the degradation of BK, account for up to a third of all patients with angioedema presenting to the emergency department. Finally, angioedema may occur by yet unknown mechanisms; under this circumstance, it is difficult to manage.
Topics: Humans; Angioedema; Urticaria; Angioedemas, Hereditary; Complement C1 Inhibitor Protein; Bradykinin; Angiotensin-Converting Enzyme Inhibitors
PubMed: 37343921
DOI: 10.1016/j.jaip.2023.06.022 -
Ocular Immunology and Inflammation Apr 2024To study the role of the complement system's C3 and C4 fractions in the pathogenesis of different types of uveitis.
PURPOSE
To study the role of the complement system's C3 and C4 fractions in the pathogenesis of different types of uveitis.
METHODS
A prospective case-control study. 118 patients were enrolled. The control group comprised 60 patients who were otherwise healthy people undergoing cataract or pterygium surgery, whereas the uveitis patients group consisted of 58 people. The levels of C3 and C4 fractions in the blood and in the aqueous humor for both groups were evaluated and compared.
RESULTS
No statistically significant differences were found in the levels of the C3 and C4 fractions in the blood between the groups. However, a statistically significant difference was observed in the levels of C3 and C4 in the aqueous humor between the case and control groups, as C3 and C4 fractions were not detected in the control group. The analysis of the mean gradient between the C4 levels in the blood samples and in the aqueous samples did not reveal a statistically significant difference between the case and control groups. However, upon performing an analogous mean gradient analysis of C3 levels, a statistically significant elevation in the value of the mean gradient was observed in the case group as compared to the control group.
CONCLUSION
Our findings are in line with our initial hypothesis, that the complement system's C3 and C4 fractions may have a role in the pathogenesis of uveitis.
PubMed: 38588040
DOI: 10.1080/09273948.2024.2337838 -
Frontiers in Immunology 2023Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main... (Observational Study)
Observational Study
OBJECTIVES
Recent studies supported coagulation involvement in multiple sclerosis, an inflammatory-demyelinating and degenerative disease of the central nervous system. The main objectives of this observational study were to identify the most specific pro-coagulative/vascular factors for multiple sclerosis pathogenesis and to correlate them with brain hemodynamic abnormalities.
METHODS
We compared i) serum/plasma levels of complement(C)/coagulation/vascular factors, viral/microbiological assays, fat-soluble vitamins and lymphocyte count among people with multiple sclerosis sampled in a clinical remission (=30; 23F/7M, 40 ± 8.14 years) or a relapse (=30; 24F/6M, age 41 ± 10.74 years) and age/sex-matched controls (=30; 23F/7M, 40 ± 8.38 years); ii) brain hemodynamic metrics at dynamic susceptibility contrast-enhanced 3T-MRI during relapse and remission, and iii) laboratory data with MRI perfusion metrics and clinical features of people with multiple sclerosis. Two models by Partial Least Squares Discriminant Analysis were performed using two groups as input: (1) multiple sclerosis vs. controls, and (2) relapsing vs. remitting multiple sclerosis.
RESULTS
Compared to controls, multiple sclerosis patients had a higher Body-Mass-Index, Protein-C and activated-C9; and a lower activated-C4. Levels of Tissue-Factor, Tie-2 and P-Selectin/CD62P were lower in relapse compared to remission and HC, whereas Angiopoietin-I was higher in relapsing vs. remitting multiple sclerosis. A lower number of total lymphocytes was found in relapsing multiple sclerosis vs. remitting multiple sclerosis and controls. Cerebral-Blood-Volume was lower in normal-appearing white matter and left caudatum while Cerebral-Blood-Flow was inferior in bilateral putamen in relapsing versus remitting multiple sclerosis. The mean-transit-time of gadolinium-enhancing lesions negatively correlated with Tissue-Factor. The top-5 discriminating variables for model (1) were: EBV-EBNA-1 IgG, Body-Mass-Index, Protein-C, activated-C4 and Tissue-Factor whereas for model (2) were: Tissue-Factor, Angiopoietin-I, MCHC, Vitamin A and T-CD3.
CONCLUSION
Tissue-factor was one of the top-5 variables in the models discriminating either multiple sclerosis from controls or multiple sclerosis relapse from remission and correlated with mean-transit-time of gadolinium-enhancing lesions. Tissue-factor appears a promising pro-coagulative/vascular biomarker and a possible therapeutic target in relapsing-remitting multiple sclerosis.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT04380220.
Topics: Adult; Humans; Middle Aged; Gadolinium; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence; Thromboplastin
PubMed: 37583699
DOI: 10.3389/fimmu.2023.1226616