RESUMEN
BACKGROUND AND AIMS: Rheumatoid arthritis (RA) manifests through various symptoms and systemic manifestations. Diagnosis involves serological markers like rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Past studies have shown the added value of likelihood ratios (LRs) in result interpretation. LRs can be combined with pretest probability to estimate posttest probability for RA. There is a lack of information on pretest probability. This study aimed to estimate pretest probabilities for RA. MATERIALS AND METHODS: This retrospective study included 133 consecutive RA patients and 651 consecutive disease controls presenting at a rheumatology outpatient clinic. Disease characteristics, risk factors associated with RA and laboratory parameters were documented for calculating pretest probabilities and LRs. RESULTS: Joint involvement, erosions, morning stiffness, and positive CRP, ESR tests significantly correlated with RA. Based on these factors, probabilities for RA were estimated. Besides, LRs for RA were established for RF and ACPA and combinations thereof. LRs increased with antibody levels and were highest for double high positivity. Posttest probabilities were estimated based on pretest probability and LR. CONCLUSION: By utilizing pretest probabilities for RA and LRs for RF and ACPA, posttest probabilities were estimated. Such approach enhances diagnostic accuracy, offering laboratory professionals and clinicians insights in the value of serological testing during the diagnostic process.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Factor Reumatoide , Humanos , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Factor Reumatoide/sangre , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anticuerpos Antiproteína Citrulinada/sangre , Masculino , Funciones de Verosimilitud , Probabilidad , Adulto , Autoanticuerpos/sangre , AncianoRESUMEN
The complement (C) system is implicated in the etiopathogenesis of rheumatoid arthritis (RA). However, there is a lack of studies characterizing all three C pathways in RA patients. This study aimed to evaluate the association between an in-depth examination of the C system and RA patient characteristics, focusing on disease activity and the presence of rheumatoid factor and anti-citrullinated protein autoantibodies (ACPA). In a cohort of 430 RA patients, functional assays of the three C pathways (classical, alternative, and lectin) and serum levels of their components were assessed. Components included C1q (classical); factor D and properdin (alternative); lectin (lectin); C1-inhibitor; C2, C4, and C4b (classical and lectin); C3, C3a, and C4b (common); and C5, C5a, and C9 (terminal). A multivariable linear regression analysis showed significant positive correlations between C-reactive protein and C system proteins and functional assays, especially in the terminal and common pathways. Disease activity, measured by scores with or without acute phase reactants, positively correlated with the classical pathway functional test and terminal pathway products. Conversely, rheumatoid factor or ACPA presence was associated with lower classical pathway values and decreased C3a and C4b levels, suggesting complement depletion. In conclusion, RA disease activity increases C molecules and functional complement assays, while rheumatoid factor or ACPA positivity is linked to C consumption. Our study offers a detailed analysis of the complement system's role in RA, potentially guiding the development of more targeted and effective treatment strategies.
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Artritis Reumatoide , Factor Reumatoide , Humanos , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Anciano , Factor Reumatoide/sangre , Adulto , Proteínas del Sistema Complemento/metabolismo , Proteínas del Sistema Complemento/inmunología , Anticuerpos Antiproteína Citrulinada/sangre , Vía Alternativa del Complemento , Activación de Complemento , Proteína C-Reactiva/metabolismo , Proteína C-Reactiva/análisis , Vía Clásica del ComplementoRESUMEN
The aim of the study was to investigate the features of the clinical picture of the disease in patients with ACPA-negative and ACPA-positive variants of rheumatoid arthritis. MATERIALS AND METHODS: : The study included patients with a reliable diagnosis of rheumatoid arthritis (RA) according to the criteria of ACR/EULAR 2010. Depending on the ACPA values, two groups of patients were recruited: ACPA-positive and ACPA-negative, comparable in gender, age, duration of the disease, and therapy. The nature of the onset and course of the disease and the activity of RA were evaluated (according to the DAS28, SDAI, CDAI indices). RESULTS AND DISCUSSION: : The study involved 79 patients with ACPA-negative variant of RA and 79 ACPA-positive patients. The age of patients (Me [IR] (in years)) with the ACPA(-) variant was 52 [39; 62]; with the ACPA(+) variant, 54 [42; 62]; the duration of the disease (in months) was 59 [23; 122] and 48 [17; 84], respectively. In ACPA(+) patients, a higher disease activity was determined (by the indices DAS 28crp, DAS28esr, SDAI, CDAI), higher values of C-reactive protein and erythrocyte sedimentation rate, and a greater number of painful and swollen joints (p < 0.05). According to the localization of the involved joints, arthritis of the proximal interphalangeal, metacarpal, wrist and shoulder joints was more often determined in ACPA(+) patients. Systemic manifestations of RA at the time of examination and in the anamnesis were statistically significantly more common in ACPA(+) (32.9%) than in ACPA(-) (17.7%) patients. Of the systemic manifestations, rheumatoid nodules were more common in ACPA(+) patients, whereas a tendency to a higher frequency of neuropathy, sclerites, and episcleritis was revealed in ACPA(-) patients. CONCLUSIONS: . In patients with ACPA(-) subtype, clinical signs of joint damage and the inflammatory component are less pronounced compared to ACPA(+). However, the mixed picture of manifestation, the less "bright" course of the disease, the absence of characteristic immunological biomarkers necessitate long-term and careful monitoring of this group of patients. At the same time, the subjective severity of the disease and dysfunction due to ankylosing joints do not differ from the ACPA(+) variant of RA.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Humanos , Artritis Reumatoide/inmunología , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Persona de Mediana Edad , Femenino , Masculino , Anticuerpos Antiproteína Citrulinada/sangre , Adulto , Índice de Severidad de la EnfermedadRESUMEN
The objective of this study was to assess the level of antibodies to carbamylated proteins and analyze the clinical and immunological associations in patients with ACPA-negative and ACPA-positive variants of rheumatoid arthritis. MATERIALS AND METHODS: . The study involved 150 patients with a reliable diagnosis of rheumatoid arthritis and 25 patients as healthy controls. Depending on ACPA values, two groups of patients were recruited: ACPA-positive (n = 75) and ACPA-negative (n = 75). RA activity was assessed by the DAS28 index. Determination of antibodies to carbamylated proteins was performed by enzyme-linked immunosorbent assay (BlueGene Biotech, China). Quantitative determination of ACPA in serum was performed by enzyme immunoassay using a commercial reagent kit (AxisShield, UK; upper limit of normal 5.0 U/mL; Orgentec, Germany; upper limit of normal 20.0 U/mL). RESULTS AND DISCUSSION: . Median anti-CarP in patients with RA was 126.2 [100.83; 157.41] ng/mL and was statistically significantly higher (p < 0.001) than in healthy controls (88.89 [70.53; 107.75] ng/mL). Among all patients with RA, 50 (33.3%) were anti-Carp-positive (22 (29.3%) in the ACPA(+) group and 28 (37.3%) in the ACPA(-) group), and one (2%) volunteer from healthy controls was anti-CarP(+) (p = 0.002). In ROC analysis performed to assess the diagnostic significance of anti-CarP for RA for all patients with RA, the area under the curve was 0.783 ± 0.047 with 95% CI: 0.691-0.874 (p < 0.001), with a cut-off point of 143 ng/mL, specificity 96%, sensitivity 36.7%. In the ACPA(+) RA group, the erosion count was statistically significantly higher (p = 0.044) in anti-CarP(+) patients than in anti-CarP(-) patients. A weak direct correlation between anti-CarP and DAS28 was found in the ACPA(-) RA group. CONCLUSIONS: . We studied the predictive value of anti-CarP as an auxiliary biomarker in ACPA(+) and ACPA(-) subtypes of RA. ACPA(+) anti-CarP(+) patients have a more "erosive" subtype of the disease than ACPA(+) anti-CarP(-) patients. In ACPA(-) patients, anti-CarP helps to identify a more erosive subtype of the disease, and among ACPA(-) patients it helps to reduce the proportion of seronegative patients. Further studies are required to determine the optimal standards for the laboratory diagnosis of anti-CarP and to clarify the diagnostic potential of these ABs as part of the differential diagnosis of arthritis in other rheumatic diseases.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Carbamilación de Proteína , Humanos , Artritis Reumatoide/inmunología , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Anticuerpos Antiproteína Citrulinada/sangre , Anticuerpos Antiproteína Citrulinada/inmunología , Adulto , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Estudios de Casos y ControlesRESUMEN
Early intervention has been the cornerstone of improving outcomes in patients with rheumatoid arthritis. Over the past decade, the boundaries have been pushed in an attempt to achieve effective prevention strategies in those who are at high risk of developing rheumatoid arthritis. Core risk factors including the presence of serum anti-citrullinated protein antibodies, arthralgia and subclinical inflammation on imaging are highly predictive of arthritis development. The influence of air pollution, diet and the role of microbiome on disease progression are less clear. In turn, therapeutic focus has shifted to an earlier pre-arthritis phase of the disease continuum where the clinically apparent arthritis may potentially be intercepted. Seven proof-of-concept interventional trials in at-risk individuals have been conducted so far. Whether true prevention of rheumatoid arthritis is possible remains elusive. Promising signals towards permanent disease modulation and improvement in symptom burden were seen with some immunomodulatory therapies, whilst others were unsuccessful. Long-term follow-up is required to ascertain a true effect. Looking forward, a better understanding of the natural history and underlying biological mechanisms of arthritis development and more accurate, validated risk stratification is needed.
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Artritis Reumatoide , Artritis Reumatoide/tratamiento farmacológico , Humanos , Factores de Riesgo , Progresión de la Enfermedad , Anticuerpos Antiproteína Citrulinada , Antirreumáticos/uso terapéuticoRESUMEN
OBJECTIVE: To investigate and compare trends in incidence rates (IRs) of seropositive and seronegative rheumatoid arthritis (RA) in Denmark using various data sources for serostatus definition. METHOD: This nationwide population-based cohort study was based on data from Danish healthcare and clinical quality registries between 2000 and 2018. Information on anti-cyclic citrullinated peptide and immunoglobulin M rheumatoid factor was obtained, and definitions of seropositivity according to the number of applied data sources were prespecified. Annual age- and sex-standardized IRs were calculated as the number of incident seropositive and seronegative cases, divided by the number of person-years (PY) in the general population in that given year. RESULTS: An increasing temporal trend in IR of seropositive RA and a decreasing trend in seronegative RA were observed. The IRs were higher for seropositive RA than for seronegative RA from 2009 onwards, with a widening of the IR gap between 2009 and 2016 regardless of the definition of seropositivity. When combining laboratory- and physician-reported autoantibody information and ICD-10 codes, the IR of seropositive RA in 2018 was approximately twice that of seronegative RA, at 19.0 and 9.0 per 100 000 PY, respectively. The level of antibody testing increased significantly during the study period. CONCLUSIONS: The IR of seropositive RA increased over time, whereas the IR of seronegative RA decreased. Temporal IR changes may be caused by a real change in the RA serology subtypes, an increase in autoantibody testing and availability, changes in registration practice over time, or a combination of these factors.
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Artritis Reumatoide , Sistema de Registros , Factor Reumatoide , Humanos , Artritis Reumatoide/epidemiología , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Artritis Reumatoide/diagnóstico , Dinamarca/epidemiología , Incidencia , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Factor Reumatoide/sangre , Estudios de Cohortes , Anticuerpos Antiproteína Citrulinada/sangre , Autoanticuerpos/sangre , Adulto JovenRESUMEN
OBJECTIVE: To identify differences in levels of serum biomarkers associated with atherosclerosis between anti-citrullinated protein antibodies (ACPA) positive groups. METHODS: Cross-sectional data were used from the Dutch Lifelines Cohort Study combined with data derived from RA risk and early RA studies conducted at the University Medical Center Groningen (UMCG). Serum biomarkers of inflammation, endothelial cell activation, tissue remodeling and adipokine, which were previously associated with atherosclerosis, were measured with Luminex in four ACPA positive groups with different characteristics: without joint complaints, with joint complaints, RA risk and early RA groups. RESULTS: Levels of C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor Receptor 1 (TNFR1) and vascular endothelial growth factor (VEGF) were significantly higher in the RA risk and early RA groups compared to the joint complaints and the no joint complaints groups. The difference remained statistically significant after correcting for renal function, smoking and hypertension in multivariate logistic regression analysis, with focus on ACPA positive with joint complaints group versus RA risk group: CRP OR = 2.67, p = 0.033; IL-6 OR = 3.73, p = 0.019; TNFR1 OR = 1.003, p < 0.001; VGEF OR = 8.59, p = 0.019. CONCLUSION: Individuals at risk for RA have higher levels of inflammatory markers and VEGF, which suggests that they might also have a risk of higher cardiovascular disease (CVD); however, this does not apply to individuals with ACPA positivity with self-reported joint complaints or without joint complaints only. Therefore, it is important that individuals with RA risk are referred to a rheumatologist to rule in or out arthritis/development of RA and discuss CVD risk.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Aterosclerosis , Biomarcadores , Proteína C-Reactiva , Interleucina-6 , Factor A de Crecimiento Endotelial Vascular , Humanos , Estudios Transversales , Anticuerpos Antiproteína Citrulinada/sangre , Biomarcadores/sangre , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Artritis Reumatoide/diagnóstico , Masculino , Persona de Mediana Edad , Femenino , Aterosclerosis/sangre , Aterosclerosis/inmunología , Factor A de Crecimiento Endotelial Vascular/sangre , Proteína C-Reactiva/análisis , Adulto , Interleucina-6/sangre , Factores de Riesgo , Anciano , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Países Bajos/epidemiologíaRESUMEN
Rheumatoid arthritis (RA) is prevalent in many Indigenous North American First Nations (FN) and tends to be seropositive, familial, and disabling, as well as associated with highly unfavorable outcomes such as early mortality. The risk of developing RA is based on a perfect storm of gene-environment interactions underpinning this risk. The gene-environment interactions include a high frequency of shared epitope encoding HLA alleles, particularly HLA-DRB1*1402, in the background population, and prevalent predisposing environmental factors such as smoking and periodontal disease. Together, these provide a compelling rationale for an RA prevention agenda in FN communities. Our research team has worked in partnership with several FN communities to prospectively follow the first-degree relatives of FN patients with RA, with the aim of better understanding the preclinical stages of RA in this population. We have focused on specific features of the anticitrullinated protein antibodies (ACPA) and other proteomic biomarkers as predictors of future development of RA. These studies have now led us to consider interventions having a favorable risk-benefit ratio if applied at a stage prior to a hypothetical "point of no return," when the autoimmunity potentially becomes irreversible. Based on a supportive mouse model and available human studies of curcumin, omega-3, and vitamin D supplements, we are undertaking studies where we screen communities using dried blood spot technology adapted for the detection of ACPA, and then enrolling ACPA-positive individuals in studies that use a combination of these supplements. These studies are guided by shared decision-making principles.
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Artritis Reumatoide , Humanos , Anticuerpos Antiproteína Citrulinada/sangre , Artritis Reumatoide/prevención & control , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Biomarcadores/sangre , Interacción Gen-Ambiente , Cadenas HLA-DRB1 , Indígenas NorteamericanosRESUMEN
Rheumatoid arthritis (RA) is a common autoimmune rheumatic disease that causes chronic synovitis, bone erosion, and joint destruction. The autoantigens in RA include a wide array of posttranslational modified proteins, such as citrullinated proteins catalyzed by peptidyl arginine deiminase4a. Pathogenic anti-citrullinated protein antibodies (ACPAs) directed against a variety of citrullinated epitopes are abundant both in plasma and synovial fluid of RA patients. ACPAs play an important role in the onset and progression of RA. Intensive and extensive studies are being conducted to unveil the mechanisms of RA pathogenesis and evaluate the efficacy of some investigative drugs. In this review, we focus on the formation and pathogenic function of ACPAs.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Humanos , Artritis Reumatoide/inmunología , Anticuerpos Antiproteína Citrulinada/inmunología , Autoantígenos/inmunología , Líquido Sinovial/inmunología , Líquido Sinovial/metabolismoAsunto(s)
Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Humanos , Artritis Reumatoide/inmunología , Anticuerpos Antiproteína Citrulinada/sangre , Antirreumáticos/uso terapéutico , Antirreumáticos/administración & dosificación , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Inhibidores del Factor de Necrosis Tumoral/administración & dosificación , FemeninoRESUMEN
Anti-citrullinated protein autoantibodies (ACPA) are diagnostic for rheumatoid arthritis (RA). The antigens recognized by these autoantibodies are produced by protein arginine deiminases (PADs), particularly PAD4. However, it remains unknown why and how PAD4 causes this aberrant citrullination in RA. Here, we report that poly-perforin pores are present on freshly isolated neutrophils from RA patients, but not on healthy donor neutrophils. Neutrophils with perforin pores also contained intracellular citrullinated proteins in the region adjacent to the pores. This response was replicated in vitro by treating neutrophils with purified perforin, which generated intense dots of anti-perforin immunofluorescence, calcium influx, and intracellular citrullination. Extensive neutrophil killing in Felty's syndrome, an aggressive form of RA, correlated with particularly high ACPA, and PAD4 autoantibodies. In contrast, other forms of death, including NETosis, apoptosis, and pyroptosis, produced minimal citrullination. We conclude that neutrophil targeting by perforin leading to intracellular citrullination takes place in patients with RA.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Citrulinación , Neutrófilos , Perforina , Arginina Deiminasa Proteína-Tipo 4 , Humanos , Neutrófilos/metabolismo , Neutrófilos/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/inmunología , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Anticuerpos Antiproteína Citrulinada/metabolismo , Anticuerpos Antiproteína Citrulinada/inmunología , Perforina/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Autoanticuerpos/inmunología , Desiminasas de la Arginina Proteica/metabolismo , Adulto , Síndrome de Felty/metabolismo , Síndrome de Felty/patología , Trampas Extracelulares/metabolismo , Citrulina/metabolismo , AncianoRESUMEN
Introduction: Polyarticular juvenile idiopathic arthritis (pJIA) is a childhood-onset autoimmune disease. Immune cells contribute to persistent inflammation observed in pJIA. Despite the crucial role of monocytes in arthritis, the precise involvement of classical monocytes in the pathogenesis of pJIA remains uncertain. Here, we aimed to uncover the transcriptomic patterns of classical monocytes in pJIA, focusing on their involvement in disease mechanism and heterogeneity. Methods: A total of 17 healthy subjects and 18 premenopausal women with pJIA according to ILAR criteria were included. Classical monocytes were isolated, and RNA sequencing was performed. Differential expression analysis was used to compare pJIA patients and healthy control group. Differentially expressed genes (DEGs) were identified, and gene set enrichment analysis (GSEA) was performed. Using unsupervised learning approach, patients were clustered in two groups based on their similarities at transcriptomic level. Subsequently, these clusters underwent a comparative analysis to reveal differences at the transcriptomic level. Results: We identified 440 DEGs in pJIA patients of which 360 were upregulated and 80 downregulated. GSEA highlighted TNF-α and IFN-γ response. Importantly, this analysis not only detected genes targeted by pJIA therapy but also identified new modulators of immuno-inflammation. PLAUR, IL1B, IL6, CDKN1A, PIM1, and ICAM1 were pointed as drivers of chronic hyperinflammation. Unsupervised learning approach revealed two clusters within pJIA, each exhibiting varying inflammation levels. Conclusion: These findings indicate the pivotal role of immuno-inflammation driven by classical monocytes in pJIA and reveals the existence of two subclusters within pJIA, regardless the positivity of rheumatoid factor and anti-CCP, paving the way to precision medicine.
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Artritis Juvenil , Perfilación de la Expresión Génica , Inflamación , Monocitos , Transcriptoma , Adulto , Niño , Femenino , Humanos , Anticuerpos Antiproteína Citrulinada , Artritis Juvenil/clasificación , Artritis Juvenil/genética , Artritis Juvenil/inmunología , Artritis Juvenil/patología , Estudios de Casos y Controles , Enfermedad Crónica , Análisis por Conglomerados , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/inmunología , Interferón gamma/inmunología , Monocitos/inmunología , Monocitos/metabolismo , Fenotipo , Medicina de Precisión , Premenopausia , Unión Proteica , Mapas de Interacción de Proteínas , Factor Reumatoide , Análisis de Secuencia de ARN , Transcriptoma/genética , Factor de Necrosis Tumoral alfa/inmunología , Aprendizaje Automático no SupervisadoRESUMEN
Since entering the stage 25 years ago as a highly specific serological biomarker for rheumatoid arthritis, anti-citrullinated protein antibodies (ACPAs) have been a topic of extensive research. This hallmark B cell response arises years before disease onset, displays interpatient autoantigen variability, and is associated with poor clinical outcomes. Technological and scientific advances have revealed broad clonal diversity and intriguing features including high levels of somatic hypermutation, variable-domain N-linked glycosylation, hapten-like peptide interactions, and clone-specific multireactivity to citrullinated, carbamylated and acetylated epitopes. ACPAs have been found in different isotypes and subclasses, in both circulation and tissue, and are secreted by both plasmablasts and long-lived plasma cells. Notably, although some disease-promoting features have been reported, results now demonstrate that certain monoclonal ACPAs therapeutically block arthritis and inflammation in mouse models. A wealth of functional studies using patient-derived polyclonal and monoclonal antibodies have provided evidence for pathogenic and protective effects of ACPAs in the context of arthritis. To understand the roles of ACPAs, one needs to consider their immunological properties by incorporating different facets such as rheumatoid arthritis B cell biology, environmental triggers and chronic antigen exposure. The emerging picture points to a complex role of citrulline-reactive autoantibodies, in which the diversity and dynamics of antibody clones could determine clinical progression and manifestations.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Citrulina , Humanos , Artritis Reumatoide/inmunología , Anticuerpos Antiproteína Citrulinada/inmunología , Anticuerpos Antiproteína Citrulinada/sangre , Animales , Citrulina/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Linfocitos B/inmunología , Autoantígenos/inmunología , Ratones , Biomarcadores/sangreRESUMEN
OBJECTIVES: To investigate the efficacy, safety, pharmacokinetics and pharmacodynamics of nipocalimab in participants with moderate to severe active rheumatoid arthritis (RA) and inadequate response or intolerance to ≥1 antitumour necrosis factor agent. METHODS: In this phase 2a study, participants with RA seropositive for anticitrullinated protein antibodies (ACPA) or rheumatoid factors were randomised 3:2 to nipocalimab (15 mg/kg intravenously every 2 weeks) or placebo from Weeks 0 to 10. Efficacy endpoints (primary endpoint: change from baseline in Disease Activity Score 28 using C reactive protein (DAS28-CRP) at Week 12) and patient-reported outcomes (PROs) were assessed through Week 12. Safety, pharmacokinetics and pharmacodynamics were assessed through Week 18. RESULTS: 53 participants were enrolled (nipocalimab/placebo, n=33/20). Although the primary endpoint did not reach statistical significance for nipocalimab versus placebo, a numerically higher change from baseline in DAS28-CRP at Week 12 was observed (least squares mean (95% CI): -1.03 (-1.66 to -0.40) vs -0.58 (-1.24 to 0.07)), with numerically higher improvements in all secondary efficacy outcomes and PROs. Serious adverse events were reported in three participants (burn infection, infusion-related reaction and deep vein thrombosis). Nipocalimab significantly and reversibly reduced serum immunoglobulin G, ACPA and circulating immune complex levels but not serum inflammatory markers, including CRP. ACPA reduction was associated with DAS28-CRP remission and 50% response rate in American College of Rheumatology (ACR) criteria; participants with a higher baseline ACPA had greater clinical improvement. CONCLUSIONS: Despite not achieving statistical significance in the primary endpoint, nipocalimab showed consistent, numerical efficacy benefits in participants with moderate to severe active RA, with greater benefit observed for participants with a higher baseline ACPA. TRIAL REGISTRATION NUMBER: NCT04991753.
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Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Reumatoide , Índice de Severidad de la Enfermedad , Humanos , Artritis Reumatoide/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Antirreumáticos/uso terapéutico , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anciano , Adulto , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Método Doble Ciego , Medición de Resultados Informados por el Paciente , Anticuerpos Antiproteína Citrulinada/sangreRESUMEN
OBJECTIVE: Rheumatoid arthritis can be classified according to ACPA and RF status. ACPA status may be associated with other pathophysiological differences, e.g., the cytokines driving inflammation. Obesity influences the course of RA, likely involving leptin; the exact mechanisms are not completely understood. This study investigates BMI influence on RA cytokine profiles and the possibility of predicting ACPA status and disease activity measured by Power-Doppler sonography (PDS). METHODS: Patients were examined using a multi-biomarker disease assay and PDS examination of wrists and MCP and PIP joints and stratified according to ACPA status and BMI, using prediction precision to determine BMI cutoff. Analysis was performed using elastic net regularization of logistic and multiple regression. We then attempted to predict ACPA status/PDS activity based on a bootstrap approach. RESULTS: A total of 120 measurements from 95 patients were performed. ACPA status prediction peaked at BMI 26 kg/m2, with AUC 0.82. PDS activity prediction had a mean average error of < 1.6 PDS points for all groups. In obese patients, cytokine profiles appear to align in ACPA-positive and -negative patients, with leptin playing a greater role in predicting PDS activity, but with some remaining differences. CONCLUSION: When stratified according to BMI, cytokine patterns can predict ACPA status and PDS activity in RA with a high degree of precision. This indicates that studies into the pathophysiology of RA should take BMI into account, to differentiate between disease- and obesity-associated phenomena. The underlying pathological processes of ACPA-negative and -positive RA appear different. Multi-cytokine evaluations may provide a deeper understanding of disease processes. Key Points ⢠A multi-cytokine approach combined with ultrasonography and modern mathematical methods can contribute to a deeper understanding of the relationship between systemic and joint inflammation. ⢠BMI influences cytokine profiles in rheumatoid arthritis and appears to "override" disease-specific processes. ⢠Using cytokines only, and adjusting for BMI, it is possible to predict the ACPA status and joint inflammation with considerable precision.
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Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Índice de Masa Corporal , Citocinas , Ultrasonografía Doppler , Humanos , Artritis Reumatoide/sangre , Artritis Reumatoide/diagnóstico por imagen , Artritis Reumatoide/inmunología , Femenino , Masculino , Persona de Mediana Edad , Anticuerpos Antiproteína Citrulinada/sangre , Citocinas/sangre , Anciano , Adulto , Biomarcadores/sangre , Obesidad/sangre , Obesidad/complicaciones , Índice de Severidad de la Enfermedad , Leptina/sangre , Articulación de la Muñeca/diagnóstico por imagenRESUMEN
OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic disease characterized by inflammatory synovitis, and genetic factors play the greatest role in RA. This study aimed to investigate the relationship between Toll-like receptor 10(TLR10) gene polymorphisms and susceptibility to RA. METHODS: A total of 271 patients with RA and an equal number of healthy controls were included, and the TLR10 rs2101521, rs10004195 and rs11725309 loci were genotyped by time-of-flight mass spectrometry. RESULTS: Compared with healthy controls, Individuals carrying the rs2101521 G allele had an increased risk of developing RA (P = 0.01; odds ratio (OR) = 1.367; 95 % confidence interval (CI): 1.076-1.736). Individuals with the rs2101521 GG genotype had a greater risk of RA (P = 0.01; OR = 1.816; 95 % CI: 1.161-2.984). Stratified analysis demonstrated a greater prevalence of positive anti-cyclic citrullinated peptide (CCP)antibody in patients carrying the rs2101521 G allele (P = 0.03). Additionally, patients with the rs11725309 CT genotype had elevated levels of C-reactive protein (CRP)(P = 0.007). CONCLUSION: In conclusion, TLR10 gene polymorphisms are associated with RA susceptibility.
Asunto(s)
Artritis Reumatoide , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 10 , Humanos , Artritis Reumatoide/genética , Masculino , Femenino , Persona de Mediana Edad , Receptor Toll-Like 10/genética , Adulto , Genotipo , Estudios de Casos y Controles , Proteína C-Reactiva/genética , Proteína C-Reactiva/análisis , Anticuerpos Antiproteína Citrulinada/sangre , Frecuencia de los GenesRESUMEN
Biosensors are unique analytical tools for the detection of biomarkers. Of these, autoantibodies against citrullinated proteins (ACPA) are useful for the differential diagnosis of rheumatoid arthritis (RA). The autoantibodies may be detected by immunoassay technology using synthetic cyclic citrullinated peptides (CCP), ie, anti-CCP. Recently, several biosensors have been developed for anti-CCP using CCP and mutated citrullinated vimentin (MCV) as recognition elements. In this review we highlight all currently available ACPA biosensor technology including those based on fluorescence, chemiluminescence, electrochemiluminescence (ECL), surface-enhanced Raman scattering (SERS)-based, surface plasmon resonance (SPR), lateral flow immunoassays (LFIA), and electrochemical. We explore various peptides as recognition elements, electrode modifiers and signal amplification systems thus providing new opportunities for next-generation biosensor design in RA.
Asunto(s)
Artritis Reumatoide , Técnicas Biosensibles , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/sangre , Artritis Reumatoide/inmunología , Humanos , Técnicas Biosensibles/métodos , Péptidos Cíclicos/inmunología , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Anticuerpos Antiproteína Citrulinada/sangre , Anticuerpos Antiproteína Citrulinada/inmunología , Inmunoensayo/métodosRESUMEN
The human microbiome exists throughout the body, and it is essential for maintaining various physiological processes, including immunity, and dysbiotic events, which are associated with autoimmunity. Peptidylarginine deiminase (PAD) enzymes can citrullinate self-proteins related to rheumatoid arthritis (RA) that induce the production of anti-citrullinated protein antibodies (ACPAs) and lead to inflammation and joint damage. The present investigation was carried out to demonstrate the expression of homologs of PADs or arginine deiminases (ADs) and citrullinated proteins in members of the human microbiota. To achieve the objective, we used 17 microbial strains and specific polyclonal antibodies (pAbs) of the synthetic peptide derived from residues 100-200 of human PAD2 (anti-PAD2 pAb), and the recombinant fragment of amino acids 326 and 611 of human PAD4 (anti-PAD4 pAb), a human anti-citrulline pAb, and affinity ACPAs of an RA patient. Western blot (WB), enzyme-linked immunosorbent assay (ELISA), elution, and a test with Griess reagent were used. This is a cross-sectional case-control study on patients diagnosed with RA and control subjects. Inferential statistics were applied using the non-parametric Kruskal-Wallis test and Mann-Whitney U test generated in the SPSS program. Some members of phyla Firmicutes and Proteobacteria harbor homologs of PADs/ADs and citrullinated antigens that are reactive to the ACPAs of RA patients. Microbial citrullinome and homolog enzymes of PADs/ADs are extensive in the human microbiome and are involved in the production of ACPAs. Our findings suggest a molecular link between microorganisms of a dysbiotic microbiota and RA pathogenesis.
Asunto(s)
Anticuerpos Antiproteína Citrulinada , Artritis Reumatoide , Citrulinación , Microbiota , Desiminasas de la Arginina Proteica , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Anticuerpos Antiproteína Citrulinada/inmunología , Anticuerpos Antiproteína Citrulinada/metabolismo , Artritis Reumatoide/inmunología , Artritis Reumatoide/microbiología , Estudios de Casos y Controles , Citrulina/metabolismo , Estudios Transversales , Hidrolasas/metabolismo , Arginina Deiminasa Proteína-Tipo 2/metabolismo , Arginina Deiminasa Proteína-Tipo 4/metabolismo , Desiminasas de la Arginina Proteica/metabolismo , Desiminasas de la Arginina Proteica/genéticaRESUMEN
BACKGROUND: Women are more likely to develop autoimmune diseases than men. Contribution from microchimerism (Mc) has been proposed, as women naturally acquire Mc from more sources than men because of pregnancy. Women with Rheumatoid Arthritis (RA) who lack RA-associated HLA alleles have been found to harbor Mc with RA-associated HLA alleles in higher amounts than healthy women in prior work. However, an immunological impact of Mc remains to be elucidated. OBJECTIVES: To test the hypothesis that Mc with RA-risk associated HLA alleles can result in the production of RA-associated autoantibodies, when host genetic risk is absent. METHODS: DBA/2 mice are unable to produce RA-specific anti-citrullinated autoantibodies (ACPAs) after immunization with the enzyme peptidyl arginine deiminase (PAD) in a previously developed model. DBA/2 females were mated with C57BL/6 males humanized to express HLA-DR4, which is associated with RA-risk and production of ACPAs, to evaluate DR4+ fetal Mc contribution. Next, DBA/2 females born of heterozygous DR4+/- mothers were evaluated for DR4+ Mc of maternal or littermate origin. Finally, DBA/2 females from DR4+/- mothers were crossed with DR4+ males, to evaluate the contribution of any Mc source to ACPA production. RESULTS: After PAD immunization, between 20 % and 43 % of DBA/2 females (otherwise unable to produce ACPAs) had detectable ACPAs (CCP2 kit) after exposure to sources of Mc with RA-associated HLA alleles, compared to 0 % of unmated/unexposed DBA/2 females. Further the microchimeric origin of the autoantibodies was confirmed by detecting a C57BL/6-specific immunoglobulin isotype in the DBA/2 response. CONCLUSION: Our study demonstrates that Mc cells can produce "autoantibodies" and points to a role of Mc in the biology of autoimmune diseases, including RA.
Asunto(s)
Artritis Reumatoide , Autoanticuerpos , Quimerismo , Ratones Endogámicos DBA , Artritis Reumatoide/inmunología , Animales , Ratones , Femenino , Autoanticuerpos/inmunología , Masculino , Humanos , Modelos Animales de Enfermedad , Alelos , Ratones Endogámicos C57BL , Anticuerpos Antiproteína Citrulinada/inmunología , EmbarazoRESUMEN
OBJECTIVES: The dysregulated immune response is one of the cardinal features of severe coronavirus disease 2019 (COVID-19). This study was conducted to clarify the occurrence of autoantibodies (AABs) associated with systemic autoimmune rheumatic diseases (SARDs) in hospitalized patients with a moderate, severe, and critical form of COVID-19. METHODS: The serum samples obtained from 176 hospitalized COVID-19 patients were investigated in this study, including patients with moderate (N = 90), severe (N = 50), and critical (N = 36) forms of COVID-19. Also, the serum samples collected from healthy subjects before the COVID-19 pandemic were used as controls (N = 176). The antinuclear antibodies (ANAs), antidouble-stranded DNA (anti-dsDNA), cytoplasmic-anti neutrophil cytoplasmic antibody (c-ANCA), perinuclear ANCA (p-ANCA), antiphospholipid antibodies (aPLs), and anticyclic citrullinated peptide (anti-CCP) occurrence was evaluated using a solid-phase enzyme-linked immunosorbent assay (ELISA). RESULTS: The results showed that the occurrence of ANAs, anti-dsDNA, anti-CCP, c-ANCA, and p-ANCA was significantly higher in the COVID-19 patients compared to serum obtained from healthy subjects (p < .0001, p < .0001, p < .0001, p < .05, and p < .001, respectively). The positive number of anti-CCP tests increased significantly in severe COVID-19 compared to the moderate group (p < .01). CONCLUSION: Our study further supports the development of autoantibodies related to systemic autoimmune rheumatologic diseases. To the best of our knowledge, this is the first study with a large sample size that reported the occurrence of anti-CCP in a severe form of COVID-19.