ABSTRACT
Loss of the regulatory mechanisms that avoid excessive or constitutive activation of NF-κB may be associated with chronic inflammatory disorders, including rheumatoid arthritis (RA). After massive sequencing of 158 regulators of the NF-κB pathway in RA patients, we focused on a scarcely known gene, ASCC1, and showed that it potently inhibits the expression of NF-κB target genes (TRAIL, TNF-α, cIAP-1, IL8) and blocks activation of a NF-κB-luciferase reporter construct in five different human cell lines. Therefore, ASCC1 may contribute to avoiding a pathologic activation of this transcription factor. A truncated variant of ASCC1 (p.S78*) was found in RA patients and control individuals. Functional in vitro studies revealed that truncation abrogated the NF-κB inhibition capacity of ASCC1. In contrast with full-length protein, truncated ASCC1 did not reduce the transcriptional activation of NF-κB and the secretion of TNF-α in response to inflammatory stimuli. We analyzed the clinical impact of p.S78* variant in 433 patients with RA and found that heterozygous carriers of this variant needed more disease-modifying antirheumatic drugs, and more patients with this genotype needed treatment with corticoids and biologic agents. Moreover, the truncated allele-carrier group had lower rates of remission compared with the full-length variant carriers. Overall, our findings show for the first time, to our knowledge, that ASCC1 inhibits NF-κB activation and that a truncated and inactive variant of ASCC1 is associated with a more severe disease, which could have clinical value for assessing the progression and prognosis of RA.
Subject(s)
Arthritis, Rheumatoid/pathology , Carrier Proteins/physiology , NF-kappa B/antagonists & inhibitors , Transcriptional Activation/genetics , Aged , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/genetics , Base Sequence , Carrier Proteins/genetics , Cell Line, Tumor , Enzyme Activation , Female , Gene Expression Regulation , HEK293 Cells , HeLa Cells , Humans , Inhibitor of Apoptosis Proteins/biosynthesis , Interleukin-8/biosynthesis , MCF-7 Cells , Male , NF-kappa B/metabolism , Sequence Analysis, DNA , Signal Transduction/genetics , TNF-Related Apoptosis-Inducing Ligand/biosynthesis , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Fundamento y objetivo Identificación de factores presentes en la artritis de reciente comienzo que puedan ayudar a predecir el desarrollo o no de artritis reumatoide (AR). Descripción de las características clínicas de una cohorte de AR de inicio. Pacientes y método Cohorte de inicio prospectiva de 5 años de duración en 34 servicios de reumatología españoles formada por pacientes con oligoartritis y poliartritis de menos de 1 año de evolución no tratados previamente. A todos los pacientes se les realizó al inicio una valoración de la actividad inflamatoria, capacidad funcional y factores de riesgo de AR. Además se realizaron radiografías de manos y pies y determinaciones de factor reumatoide (FR) y de anticuerpos anti-CCP. Tras 3 años, se evaluó el diagnóstico definitivo y las variables que determinaron la evolución hacia AR. Resultados Se incluyó a 171 pacientes, de los que 161 (94,2%) acabaron cumpliendo criterios diagnósticos de AR, la mayoría (157; 97,5%) en la visita inicial. Los factores relacionados con el diagnóstico de AR fueron: el FR positivo (odds ratio [OR]=8,5; intervalo de confianza [IC] del 95%, 169,8), los anti-CCP (OR=8,5; IC del 95%, 0,9675,7) y el DAS28 (OR=1,9; IC del 95%, 1,13,3). El 65% de los pacientes presentaban erosiones en la visita basal. Conclusiones Tanto la extensión de la afección articular como tener un FR positivo y anticuerpos anti-CCP permiten predecir la evolución a AR. El daño radiológico, en muchos pacientes, ya está al inicio, por lo que es más importante un tratamiento contundente precoz que esperar a tener un diagnóstico de AR (AU)
Objective To identify factors present in recent onset arthritis that may help to predict rheumatoid arthritis (RA), and to describe a cohort of recent onset RA. Patients and method A 5 year prospective cohort of patients with early oligo and polyarthritis (< 1 year of evolution) from 34 rheumatology units, was studied. Sociodemographic, clinical features and RA risk factors were recorded. Rheumatoid factor (RF), anti-CCP determinations and radiographs of hands and feet were analyzed too. After three years, a diagnosis of certainty and the variables that determined the evolution to RA, were evaluated. Results One hundred and seventy one patients were included; 161 (94.2%) fulfilled RA diagnostic criteria; most of them (157; 97.5%) in the first visit. Factors associated with RA diagnosis were: positive RF, anti-CCP and DAS-28; 65% of the patients had radiological erosions in the first visit. Conclusions Positive RF, anti-CCP and the disease activity are predictive factors of RA. Radiological damage exists very early in most of patients, that's why it is more important to treat the disease aggressively instead than achieving an RA diagnosis of certainty (AU)
Subject(s)
Humans , Arthritis, Rheumatoid/epidemiology , Triage/methods , Risk Factors , Autoimmune Diseases/epidemiology , Early Diagnosis , Cohort StudiesABSTRACT
OBJECTIVE: To identify factors present in recent onset arthritis that may help to predict rheumatoid arthritis (RA), and to describe a cohort of recent onset RA. PATIENTS AND METHOD: A 5 year prospective cohort of patients with early oligo and polyarthritis (< 1 year of evolution) from 34 rheumatology units, was studied. Sociodemographic, clinical features and RA risk factors were recorded. Rheumatoid factor (RF), anti-CCP determinations and radiographs of hands and feet were analyzed too. After three years, a diagnosis of certainty and the variables that determined the evolution to RA, were evaluated. RESULTS: One hundred and seventy one patients were included; 161 (94.2%) fulfilled RA diagnostic criteria; most of them (157; 97.5%) in the first visit. Factors associated with RA diagnosis were: positive RF, anti-CCP and DAS-28; 65% of the patients had radiological erosions in the first visit. CONCLUSIONS: Positive RF, anti-CCP and the disease activity are predictive factors of RA. Radiological damage exists very early in most of patients, that's why it is more important to treat the disease aggressively instead than achieving an RA diagnosis of certainty.
ABSTRACT
The macrophage inhibitory factor (MIF) is a cytokine that has been implicated in several inflammatory and autoimmune diseases, including rheumatoid arthritis, systemic lupus, glomerulonephritis, and multiple sclerosis. In rheumatoid arthritis (RA), results ranging from lack of association of MIF polymorphisms with RA, to involvement in either severity or susceptibility to the disease have been reported in the past. We aimed at investigating the role of this gene in RA in the Spanish population. Two well-known MIF promoter polymorphisms were tested in 606 adult RA patients and 886 healthy controls: a single nucleotide polymorphism at -173G/C and a tetranucleotide repeat (CATT)(5-8) located at -794. We found a significant association of the allele -173C with RA (p = 0.01; odds ratio [OR] = 1.31; 95% confidence interval [CI] = 1.06-1.62). The -173C risk allele, previously reported to be transmitted in excess in patients with juvenile idiopathic arthritis, was significantly more frequent in early-onset adult RA patients than in healthy controls (p = 0.003; OR = 1.57; 95% CI = 1.14-2.15), whereas late-onset patients were not significantly different to controls (p = 0.6; OR = 1.09; 95% CI = 0.77-1.55). In conclusion, the -173C allele in the MIF promoter region is associated with increased RA predisposition, mainly in early-onset patients.
