Bingham CO, 3rd. The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation. The Journal of Rheumatology Supplement. Schneider M, Kruger K.
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Diagnostic utility of oxidative damage markers for early rheumatoid arthritis in non-smokers and negative anti-CCP patients. Melguizo 1 , V. Navarro 2,3 , B. Santos 1 , T. Arrobas 1,4 C. Navarro 2 , C. Clinical Biochemistry Department. University Hospital Virgen Macarena. Spain 2. Spain 3. Department of Rheumatology.
Leiden University Medical Center. The Netherlands 4. Besides the development of new markers and diagnostic criteria for rheumatoid arthritis RA , many patients are still diagnosed after several years of symptoms. Oxidative stress markers are already increased at an early stage of RA. Our aim was to evaluate the additional diagnostic value of these markers.
A case-control study was performed. Controls were selected from patient's relatives and matched by gender, age, and current smoking habit. Sixty-five RA patients without treatment and 65 healthy controls were included.
The same results were obtained in the subgroups of patients who smoke or not, and in anti-CCP positive or negative. The diagnosis performance of traditional markers showed good specificity but low sensitivity. Key words. Lipid hydroperoxide. Carbonyl protein. Rheumatoid arthritis.
Se incluyeron sesenta y cinco pacientes con AR sin tratamiento y 65 controles sanos. Los mismos resultados se obtuvieron en los subgrupos de pacientes que fuman o no, y en anti-CCP positivos o negativos.
Palabras clave. Artritis reumatoide. Despite the development of new specific markers and diagnostic criteria 1 , there is still an unacceptable delay in the diagnosis of RA, related to permanent disability.
Moreover, smoking is the most important environmental factor involved in RA pathogenesis 2,3 and a source of free radicals 4 , causing oxidative stress which is defined as the imbalance between the oxidative and anti-oxidative pathways of the body. Furthermore, it has been shown that oxidative stress is related with the emergence and development of RA 5,6 and it may act even before the onset of the disease 7,8. Therefore, our hypothesis is that oxidative damage markers could be useful to diagnose RA patients in an early stage.
The aim of this study was to assess the additional diagnostic value of oxidative damage markers in diagnosing RA combined with the traditional biochemical markers in patients with recent-onset RA. Secondly, we compared the accuracy of oxidative damage markers based on the smoking habit and the presence or absence of anti-CCP.
A case-control study was performed January - February , according to the local regulations and the Declaration of Helsinki. Written informed consent was obtained before the inclusion from every enrolled subject. Individuals included in this study were selected from the Early Arthritis Office at the Rheumatology Department. Demographic characteristics, smoking habit, disease related variables in patients and blood samples into heparinized and non-heparinized tubes were collected at one visit in all individuals.
Proteins were precipitated, a chromogen was added to the supernatant, detecting the resulting compound by an ultraviolet detector. The intra and inter-assay coefficient of variation CV were 4. The intra and inter-assay CV were 4. For descriptive purpose, median and interquartile range IQR in case of normality or mean and standard deviation SD in case of non-normality for continuous variables were used. Relative percent frequencies were used for categorical variables.
The Wilcoxon matched-pairs signed-ranks and the McNemar tests were used to compare continuous and dichotomous variables between case and control groups, respectively. Binary logistic regression models were used for the analysis in which RA diagnosis was the dependent variable and the traditional- and oxidative stress markers were included as independent variables. Sensitivity and specificity were calculated using ROC curves. No statistical significant differences between patients and controls were found regarding gender and smoking habit never, ever or current Table 1.
These results are the same whether patients are divided into subgroups with respect to smoking or anti-CCP antibodies positive or negative when compared with the healthy control group Table 1. No significant differences in the classic markers of RA among patients according to sex were found data not shown.
Diagnostics performance of different variables and logistic regression models for diagnostic of RA are shown in table 2.
The shared epitope showed significant differences between patients and controls table 1 , but did not provide diagnostic utility. Due to the contradictory results of MDA, this was not used to build logistic regression models. In the subgroup of smokers, sensitivity, specificity and area under the ROC curve did not increase when markers of oxidative damage were added to the model Table 2. In this study, we assessed the additional diagnostic value of oxidative stress markers for diagnosing patients with RA, in addition to avoiding the influence of the treatment have been selected patients who have no DMARD, glucocorticoid or antioxidant treatment.
The classical markers showed the expected diagnosis performance for a sample of patients with early RA 1 , where the addition of anti-CCP has not led to significant improvements in sensitivity 10, Due to the contradictory results of MDA 14 , was not used to build logistic regression models because it showed no diagnostic accuracy and also showed very low area under the roc curve Table 2.
When the three classical markers and oxidative damage biomarkers were added into the same model, diagnostic accuracy in recent-onset RA patients increased, especially due to sensitivity raise. A similar but reinforced behavior of oxidative damage biomarkers was observed in case of negative anti-CCP and non-smoking habit.
Thus, good sensitivity and specificity was observed when using together traditional markers and LOOH, especially in negative anti-CCP or non-smokers patients. Based on our initial hypothesis, these results show that oxidative damage markers can help to early diagnosis of RA when sensitivity is required or anti-CCP antibodies are negative.
Other studies reported results in the same way but they only focused on sensitivity and specificity and included patients with DMARD or steroids which have an antioxidant effect or were not in an early stage of the disease The most important strengths of our study are that all patients had not received any antioxidant treatment and had a recent onset of the disease.
Furthermore, due to the observed effect in non-smokers, it appears that oxidative stress contributes to the development of the disease as an independent factor of tobacco consumption. This result is consistent with our previous work 14 in which we reported an interaction between tobacco and oxidative stress with an increase risk of RA development. Moreover, recent studies associated smoking to the emergence of anti-CCP 16 , but not RF 17 , in patients with a specific HLA-DR shared epitope background, suggesting an etiology role of tobacco restricted to this risk genetic factor In our group, there are significant differences in the shared epitope but showed no diagnostic utility.
In our patients, the addition of LOOH and CP to classical biomarkers increased significantly diagnostic accuracy in non-smokers while provide no useful information in smokers. These results appear to reflect the association between anti-CCP and smoking in the disease. The results of this study are limited by relative small sample size, because of the difficulty to recruit patients without previously DMARD or glucocorticoid treatment. However control sample is representative of the population actually at risk of having the disease, not of the general population because of study design Another limitation of the study is the lack of standardization of methods of measurement of various markers, although the methods were the same for patients and controls.
The separately or combined addition of these two oxidative damage markers to the traditional disease markers RF, Anti-CCP, CRP improved the diagnosis of RA, especially in the cases that sensitivity is required in order to discard the disease in negative anti-CCP patients or non-smokers.
Therefore, although the results of this study provide new evidence for including oxidative damage markers, LOOH and CP, as new tools to be included in the diagnostic process or early RA, further studies with larger numbers of individuals are needed to confirm them. The authors would like to thank all participants who took part in this study.
We also thank Mr. Christian Leyva Prado, Mrs. Fernando Fabiani Romero for their technical support. Ann Rheum Dis ; Smoking as a trigger for inflammatory rheumatic diseases. Curr Opin Rheumatol ; Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Lupus ; Intracellular oxidative activation in synovial fluid neutrophils from patients with rheumatoid arthritis but not from other arthritis patients.
J Rheumatol ; Plasma total antioxidant capacity, lipid peroxidation, and erythrocyte antioxidant enzyme activities in patients with rheumatoid arthritis and osteoarthritis. Clin Biochem ; Antioxidant micronutrients and risk of rheumatoid arthritis in a cohort of older women. Am J Epidemiol ; Serum concentrations of alpha tocopherol, beta carotene, and retinol preceding the diagnosis of rheumatoid arthritis and systemic lupus erythematosus.
Ann Intern Med ; Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis. The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor in South Africans with early rheumatoid arthritis. Clinical Rheumatology ; Paraoxonase and arylesterase levels in rheumatoid arthritis. Clin Rheumatol ; Serum protein oxidation in patients with rheumatoid arthritis and effects of infliximab therapy.
Clin Chim Acta ; Interaction between oxidative stress and smoking is associated with rheumatoid arthritis.
2015, Número 1
Paula A. Correa, Gabriel J. Maldonado-Cocco, Juan Manuel Anaya. The specificity and sensitivity of anti-cyclic citrullinated peptide antibodies anti-CCP was examined in Latin-American patients with rheumatoid arthritis RA. Of the 69 patients with established RA, 36 were reexamined 2 years later. HLA genotypes were established by first, PCR sequence amplification using sequence-specific primers and then, complete sequencing of the product.
2015, Number 1
Key words:. Bingham CO, 3rd. The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation. The Journal of Rheumatology Supplement. Schneider M, Kruger K. Deutsches Arzteblatt International. Rheumatoid arthritis and swine influenza vaccine: a case report.