Patrón genético y serológico en pacientes con diagnóstico de artritis reumatoide / Genetic and serological pattern in patients diagnosed with rheumatoid arthritis

Introducción: La artritis reumatoide es una enfermedad autoinmune de causas desconocidas en la que pueden influir distintas alteraciones genéticas. Se describen casos seropositivos con mayor riesgo de padecer manifestaciones extraarticulares y complicaciones de la enfermedad. Objetivo: Identificar la relación existente entre las alteraciones genéticas y la positividad de autoanticuerpos en pacientes con diagnóstico de artritis reumatoide. Métodos: Investigación básica, no experimental, transversal y descriptiva de un universo de 157 pacientes con diagnóstico de artritis reumatoide según los criterios del Colegio Americano de Reumatología. La muestra quedó conformada por 113 pacientes. Como parte del seguimiento de laboratorio de cada paciente se determinó anticuerpos tipo factor reumatoide y antipéptido citrulinado cíclico. Se realizó el estudio genético para identificar HLA-DR3 y HLA-DR4. Se utilizó la prueba no paramétrica de correlación de Pearson para determinar correlación entre el patrón genético y la seropositividad en estos pacientes. Resultados: Promedio de edad de 58,74 años con predominio de pacientes femeninas (72,57 por ciento). El 38,05 por ciento presentó al menos una comorbilidad asociada. El factor reumatoide fue positivo en el 60,18 por ciento de los pacientes, mientras que el antipéptido citrulinado cíclico positivo se identificó en el 41,59 %. Se halló alteraciones del patrón genético en el 66,37 por ciento de los pacientes; el HLA-DR4 estuvo presente de forma independiente en el 38,67 por ciento de los casos positivos y combinado con el HLA-DR3 en el 20,66 por ciento. Conclusión: Se identificó una correlación positiva considerable entre las alteraciones del patrón genético y la seropositividad. La presencia de alteraciones del patrón genético triplica el riesgo de seropositividad en los pacientes con artritis reumatoide(AU)

Introduction: Rheumatoid arthritis is an autoimmune disease of unknown causes in which the presence of different genetic alterations is invoked. Seropositive cases with a higher risk of appearance of extra-articular manifestations and complications of the disease are described. Objective: To identify the relationship between the presence of genetic alterations and autoantibody positivity in patients diagnosed with rheumatoid arthritis. Methods: Basic, non-experimental, cross-sectional and descriptive research with a universe of 157 patients diagnosed with rheumatoid arthritis according to the criteria of the American College of Rheumatology. The sample was made up of a total of 113 patients. As part of the laboratory follow-up of each patient, the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies was determined, and a genetic study was performed to identify the presence of HLA-DR3 and HLA-DR4. The nonparametric Pearson's correlation test was used to determine the correlation between the identification of HLA types and seropositivity in patients with rheumatoid arthritis. Results: Average age of 58.74 years with a predominance of female patients (72.57%). 38.05 percent presented at least one associated comorbidity. Rheumatoid factor was positive in 60.18 percent of the patients, while positive anti-cyclic citrullinated peptide was identified in 41.59 percent of the cases studied. Genetic pattern alterations were identified in 66.37 percent of the patients; HLA-DR4 was present independently in 38.67 percent of the positive cases and combined with HLA-DR3 in 20.66 percent. Conclusion: A considerable positive correlation was identified between alterations in the genetic pattern and seropositivity. The presence of genetic pattern alterations triples the risk of seropositivity in patients with rheumatoid arthritis(AU)

Serum Proteomic Profiling in Rheumatoid Arthritis by Antibody Suspension Bead Arrays.

The versatility of protein microarrays provides researchers with a wide variety of possibilities to address proteomic studies. Therefore, protein microarrays are becoming very useful tools to identify candidate biomarkers in human body fluids for disease states such as rheumatoid arthritis (RA). In RA serum, there is a high prevalence of rheumatoid factor (RF), which is an antibody with high specificity against Fc portion of IgG. The presence of RF, in particular RF-IgM, has the great potential to interfere with antibody-based immunoassays by nonspecifically binding capture antibodies. Because of this concern, we describe a procedure to reduce the interference of RF-IgM on RA serum protein profiling approaches based on multiplexed antibody suspension bead arrays.

Contributing factors of clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis patients with tightly controlled disease activity in clinical practice: a retrospective study.

OBJECTIVES: To determine whether specific parameters contribute to clinical outcomes at 1 year post-diagnosis in early rheumatoid arthritis (RA) patients under the 'treat-to-target' strategy in clinical practice. METHODS: We retrospectively analyzed 125 RA patients selected according to the following criteria; the patients' symptom duration was ≤6 months, and none had experience with DMARDs. We evaluated the patients' clinical disease activity at baseline and 1 year of treatment and the musculoskeletal ultrasound (MSUS)-detected synovitis activity at baseline. We performed an analysis to identify parameters that contribute to SDAI remission and the use of biologic/targeted synthetic (b/ts) DMARDs at 1 year post-diagnosis. RESULTS: Forty-seven patients received b/tsDMARDs therapy, and 58 patients achieved SDAI remission at 1 year post-diagnosis. Rheumatoid factor positivity, low patient's/evaluator's global assessment at baseline, and methotrexate use at 1 year post-diagnosis were associated with SDAI remission. The baseline clinical disease activity and MSUS scores were not associated with SDAI remission. Anti-cyclic citrullinated peptide antibody positivity/high titer and high swollen joint counts or the presence of severe synovial hypertrophy at baseline were associated with the use of b/tsDMARDs therapy. CONCLUSION: The value of the expected poor-prognosis factors may be diminished by intensive therapy within the 'windows of opportunity'.

Optical Biosensors for the Detection of Rheumatoid Arthritis (RA) Biomarkers: A Comprehensive Review.

A comprehensive review of optical biosensors for the detection of biomarkers associated with rheumatoid arthritis (RA) is presented here, including microRNAs (miRNAs), C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), interleukin-6 (IL-6) and histidine, which are biomarkers that enable RA detection and/or monitoring. An overview of the different optical biosensors (based on fluorescence, plasmon resonances, interferometry, surface-enhanced Raman spectroscopy (SERS) among other optical techniques) used to detect these biomarkers is given, describing their performance and main characteristics (limit of detection (LOD) and dynamic range), as well as the connection between the respective biomarker and rheumatoid arthritis. It has been observed that the relationship between the corresponding biomarker and rheumatoid arthritis tends to be obviated most of the time when explaining the mechanism of the optical biosensor, which forces the researcher to look for further information about the biomarker. This review work attempts to establish a clear association between optical sensors and rheumatoid arthritis biomarkers as well as to be an easy-to-use tool for the researchers working in this field.

Artrite reumatoide do tipo EORA com trombocitose significativa: relato de caso / Elderly-onset rheumatoid arthritis with significant thrombocytosis: a case report

Este relato teve como objetivo apresentar um caso de elderly onset rheumatoid arthritis associada à trombocitose reacional significativa. À admissão, o paciente apresentava quadro de poliartrite de pequenas e grandes articulações associado à rigidez matinal. Após exames solicitados, evidenciaram-se trombocitose de 1.697.000 cel./mm³ e anticorpos antipeptídeos citrulinados positivos, sendo diagnosticado com artrite reumatoide do tipo elderly onset rheumatoid arthritis.

This report aimed at presenting a case of elderly-onset rheumatoid arthritis associated with significant reactive thrombocytosis. On admission, the patient presented polyarthritis of small and large joints associated with morning stiffness. After the performance of the requested tests, thrombocytosis of 1,697,000 cells/mm3 and positive anti-CCP were evidenced, and the patient was diagnosed with elderly-onset rheumatoid arthritis.

Predicting Imaging Remission in Rheumatoid Arthritis: a Case-control Ultrasound Study.

BACKGROUND: To elucidate the achievement rates of imaging remission and to examine the characteristics associated with imaging remission status among patients with rheumatoid arthritis (RA) who have attained clinical remission. METHODS: Ninety-seven patients with RA patients who had attained clinical remission, defined by DAS28-ESR < 2.6 were enrolled. Power Doppler ultrasonography (PDUS) was performed on 16 joints and 2 tendons, including the first to third metacarpophalangeal, second and third proximal interphalangeal, radiocarpal (RC), second and third metatarsophalangeal joints, and extensor carpi ulnaris tendons. They were graded based on a dichotomous assessment. The clinical and laboratory data of patients who had attained imaging remission were compared to those of patients who had attained only clinical remission. RESULTS: The imaging remission rate was 51.5% in patients who had attained clinical remission. Forty-seven patients (48.5%) were PDUS positive. Power Doppler was detected most frequently in the right RC joint (n = 40). PDUS positive patients had higher evaluator global assessment (EGA) scores (P < 0.001) than PDUS negative patients. PDUS positive patients also had higher clinical disease activity index and simplified clinical disease activity index scores than PDUS negative patients. Patients who had attained imaging remission had lower pain scores and used nonsteroidal anti-inflammatory drugs less frequently. Patients who had attained imaging remission had higher rheumatoid factor (RF) and anti-cyclic citrullinated peptide levels. A low EGA score was found to be a predictor of imaging remission achievement among patients who had attained clinical remission. CONCLUSION: Only 51.5% of the patients with RA who had attained clinical remission were also in imaging remission. Patients who had attained imaging remission had lower EGA scores and higher RF levels than patients who had attained only clinical remission.

[Association of markers of rheumatoid arthritis in lupus. Is it a rhupus?] / Association des marqueurs de la polyarthrite rhumatoïde chez les lupiques. S'agit-il d'un rhupus?

Anti-citrullinated cyclic peptide antibodies (ACPA) were initially considered very specific for the diagnosis of rheumatoid arthritis (RA), and can predict the prognosis of the disease. However, these antibodies can be detected in other autoimmune diseases, including systemic lupus erythematosus (SLE), the most common manifestation of which is inflammatory arthritis, which is often found in early-stage rheumatoid arthritis. The aim of our study is to evaluate the prevalence of ACPA antibodies and to analyze the profiles of their associations with autoantibodies specific to lupus, in order to look for a possible rhupus overlap syndrome in our patients. This is a retrospective study, carried out at the immunology unit, at Blida University Hospital, Algeria, involving 96 lupus patients, diagnosed according to the criteria of the American college of rheumatology (ACR). ACPA have been identified by the ELISA technique. ACPA was positive in 14,56% of our patients, whereas anti-DNA, anti-Sm and rheumatoid factor (RF) autoantibodies were positive, respectively in 47.09%, 35.41%, and in 26.04% of our patients. In addition, the presence of ACPA with anti DNA was found in 12.5% of patients. Of the 14 with ACPA+, 57.14% had arthritis. Our results confirm that ACPA auto-antibodies do not represent a pathognomonic criterion of RA. This sometimes makes the differential diagnosis with lupus difficult especially at the beginning of the disease.

Exposure to ambient air pollution and autoantibody status in rheumatoid arthritis.

OBJECTIVE: To evaluate the relationship between air pollutant (AP) exposure and rheumatoid arthritis (RA) autoantibody status METHODS: We performed a cross sectional study utilizing enrollment data from participants in the Veterans Affairs rheumatoid arthritis registry. HLA-DRB1 shared epitope (SE), smoking, rheumatoid factor (RF), and anti-cyclic citrullinated peptide antibody (ACPA) status were collected. Mean exposure levels were obtained for AP (NO2, SO2, particulate matter [PM2.5, PM10], and ozone) from air quality monitoring stations at patients' residential zip codes in the year prior to enrollment. Multivariable logistic and ordinary least squares regression models were used to determine independent associations of AP with RA seropositivity and autoantibody concentration. RESULTS: The cohort included 557 veterans (90% male, 76% Caucasian), with mean age of 70 years and mean disease duration of 13 years. The majority were HLA-DRB1 SE, RF, and ACPA positive (73%, 79%, and 76%, respectively). In univariate models, PM2.5 exposure was associated with higher ACPA concentration (p = 0.009). Similarly, in multivariable regression models, PM2.5 exposure was independently associated with higher ACPA concentration (p = 0.037). Current smoking independently predicted RF and ACPA positivity and titers, while HLA-DRB1 SE alleles were associated with RF positivity and ACPA positivity and titers. CONCLUSIONS: In an elderly cohort of RA patients, fine particulate matter (PM2.5) exposure independently predicted higher ACPA concentration. Further study of fine particulate matter in the pathogenesis of RA is warranted. Key Points • A study that integrates both genetic and environmental exposure data, relative to RA autoantibody status. • Of different air pollutants measures, exposure to fine particulate matter (PM2.5) appears to be most closely linked to ACPA titers.

[Increased expression of LC3 in peripheral blood mononuclear cells is related to disease status in patients with rheumatoid arthritis].

Objective To detect the mRNA and protein expression of microtubule-associated protein 1 light chain 3 (LC3) in peripheral blood mononuclear cells (PBMCs) of patients with rheumatoid arthritis (RA), and to investigate its relationship with RA. Methods Twenty-two patients with RA and 16 healthy subjects with matching gender and age as controls were included in the study. PBMCs were isolated by density gradient centrifugation. The level of LC3 mRNA in PBMCs was detected by real-time fluorescent quantitative PCR. The protein level of LC3 in PBMCs was detected by Western blot analysis. The expression of LC3 protein in PBMCs was detected by immunofluorescence staining. Pearson analysis was used to analyze the correlation between LC3 expression and clinical parameters of RA patients. Results Compared with the normal control group, the levels of LC3 mRNA and protein in PBMCs of RA patients went up significantly, and the expression of LC3 significantly increased in PBMCs. The mRNA expression level of LC3 was obviously positively correlated with erythrocyte sedimentation rate (ESR, r=0.7480), 28 joint disease activity (DAS28, r=0.5016), C-reactive protein (CRP, r=0.6518), and rheumatoid factor (RF, r=0.7232). Conclusion The expression of LC3 is up-regulated in RA patients and is associated with ESR, DAS28, CRP and RF.

Kinetic Approach Extends the Analytical Measurement Range and Corrects Antigen Excess in Homogeneous Turbidimetric Immunoassays.

BACKGROUND: Homogeneous turbidimetric immunoassays are widely used in the clinical laboratory and offer short assay times, reduced reagent costs, and the potential for full automation. However, these assays have a limited analytical measurement range (AMR) above which antigen excess leads to falsely low estimates of the analyte concentration (i.e., the hook effect). Traditional methods for correction of antigen excess require sample dilution, compromising time and cost-efficiency. Therefore, novel methods that extend the AMR are needed. METHODS: A kinetic model of a generic homogeneous turbidimetric immunoassay was built and then parameterized using a genetic algorithm. Kinetic features that could be used to extend the AMR were identified and subsequently validated with clinical data from consecutive measurements of 2 homogeneous turbidimetric immunoassays: κ serum free light chain and rheumatoid factor. RESULTS: A novel kinetic parameter, the area under the curvature (AUCU), was derived that increases in proportion to the analyte concentration in a range beyond the AMR of conventional end point methods. When applied to clinical data, the AUCU method provided a log-linear calibration curve in the zone of antigen excess extending the AMR by >10-fold for 2 different immunoassays. CONCLUSIONS: The AUCU method detects and corrects antigen excess, extending the AMR in homogeneous turbidimetric immunoassays. The advantage of this method over conventional methods would be a reduction in the number of repeated samples, resulting in significant time and cost savings.

Correlation between Relative Expression of IL 17 and PERP in Rheumatoid Arthritis Patients and Disease Activity.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder. Decreased apoptosis is considered an important leading cause of autoimmune diseases. As IL17 and PERP can affect apoptosis process, they may contribute the pathogenesis and activity of RA. Objectives of this study were to investigate the possible correlation of IL 17 and PERP levels with RA pathogenesis and activity. Peripheral blood mononuclear cells (PBMCs) were isolated from fifty RA patients and fifty healthy subjects, RNA was extracted and subjected to real time PCR to detect the relative expression of IL17 and PERP. Results were correlated with RA disease activity parameters. Increased IL17 and decreased PERP mRNA expression levels were detected in patients as compared to the healthy controls (P˂0.001) and they were positively and inversely correlated with disease activity score for 28 joints (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF). A significant negative correlation between PERP and IL-17 mRNA expression levels was found (P ˂0.001). In conclusion, increased level of IL 17 and decreased level of PERP may constitute two major factors in the pathogenesis and activity of RA.

Determination of Rheumatoid Factors by ELISA.

IgM and IgA autoantibodies binding to IgG are called rheumatoid factors (RFs) and occur with high frequency in rheumatoid arthritis (RA) and with lower frequency in other autoimmune diseases. RFs have diagnostic and prognostic value in RA, but they also have a high potential to cause false positive reactions in other immunoassays, especially sandwich assays. For these reasons it is imperative to be able to measure RFs in serum samples from patients suspected of RA or other autoimmune diseases and in serum samples to be analyzed by sandwich immunoassay for various clinical parameters. Here, a simple ELISA for IgM and IgA RFs is described.

Alterações da proteína C reativa e fator reumatoide em cães naturalmente infectados por Leishmania spp / Changes in C-reactive protein and rheumatoid factor in dogs naturally infected by Leishmania spp

A leishmaniose visceral canina é uma zoonose considerada doença tropical de prioridade. A leishmaniose afeta vários sistemas do corpo dos cães, incluindo vísceras e pele. A proteína C reativa (PCR) e o fator reumatoide (FR) são exames realizados na medicina para detecção de inflamação e artrites em seres humanos, no entanto, há poucos trabalhos voltados para cães com leishmaniose que demonstrem as alterações ocorridas na PCR e FR. Este trabalho teve como objetivo demonstrar as alterações de PCR e FR e sua correlação com a hiperproteinemia e hiperalbuminemia, além da compararação com o desvio a esquerda presente no exame hematológico. O trabalho foi realizado no Hospital Veterinário do Centro Universitário da Grande Dourados/MS e Centro de Controle de Zoonoses, no qual foram avaliados 34 cães, de diversar raças e idade e submetidos a colheita de sangue venosa para realização de exames em imuno-látex, bioquímica sérica e hemograma, em cães naturalmente infectados por Leishmania spp. Foram utilizados somente cães positivos ao teste rápido DPP® para leishmaniose, juntamente com resultado positivo no exame parasitológico, depois de diagnosticados foram realizados exames hematológicos e bioquímicos. Quando realizado o teste para quantificação de FR em soro sanguíneo, para os 34 animais estudados, foi observado positividade em apenas 1 animal, enquanto que os cães foram positivos para a PCR em 38,23% dos casos estudados. Em casos de animais com leishmaniose é possível estabelecer níveis inflamatórios precocemente, enquanto que o FR demonstrou não ser um bom marcador para animais soropositivos para a doença.(AU)

Canine visceral leishmaniasis is a zoonosis considered a priority tropical disease. The disease affects various body systems of dogs, including viscera and skin. C-reactive protein (CRP) and rheumatoid factor (RF) are tests performed in medicine for the detection of inflammation and arthritis in humans, however, there are few studies aimed at dogs with leishmaniasis that demonstrate changes in CRP and RF. This work aimed to demonstrate the changes of CRP and RF and its correlation with hyperproteinemia and hyperalbuminemia, in addition to the comparison with the left deviation present in the hematological examination. The work was carried out at the Veterinary Hospital of the University Center of Grande Dourados/MS and Zoonoses Control Center, in which 34 dogs of different breeds and ages were submitted to venous blood collection for immuno-latex exams, Biochemistry and blood count in dogs naturally infected with Leishmania spp. Only dogs to the DPP® rapid test for leishmaniasis were used, together with a positive result in parasitological examination, after hematological and biochemical tests were performed. When the test for the quantification of FR in serum was performed, for the 34 animals studied, positivity was observed in only 1 animal, while the dogs were PCR positive in 38.23% of the cases studied. In cases of animals with leishmaniasis it is possible to establish inflammatory levels early, whereas the FR showed not to be a good marker for animals seropositive for the disease.(AU)

Diet Quality and Its Relationship with Antioxidant Status in Patients with Rheumatoid Arthritis.

A direct contribution towards destructive, proliferative synovitis in rheumatoid arthritis (RA) has been attributed to reactive oxygen species action. Some nutrients are considered to be capable of improving the oxidant/antioxidant status in RA; however the impact of diet composition on the antioxidant capacity of serum has not yet been studied in this disease. The aim of the study was to assess the relationship between diet quality and antioxidant status in patients with RA and healthy controls. Nutritional assessment was performed, and antioxidant status in serum, without and with deproteinization (TAS and DSAS, resp.), was determined in 82 RA and 87 healthy subjects. The diet of the RA group was low-energy and imbalanced. TAS and DSAS were significantly lower in RA patients than in controls. Antioxidant status significantly correlated with the supply of foods and nutrients influencing antioxidant and anti-inflammatory defense in RA; however, in this group, TAS was more sensitive to diet than DSAS. In healthy subjects, the nonprotein pool of serum antioxidants was more tightly linked to diet. These outcomes indicate the need to monitor diet quality of patients with RA and the usefulness of TAS measurements in this monitoring.

Therapeutic plasma exchange for hyperviscosity syndrome secondary to high rheumatoid factor.

Hyperviscosity syndrome (HVS) is most commonly associated with Waldenstrom's macroglobulinemia, where it may be life-threatening. HVS may also occur in autoimmune diseases; data pertaining to efficacy of therapeutic plasma exchange (TPE) in HVS arising in non-malignant gammopathy are limited. We report a case of 71-year-old female with erosive rheumatoid arthritis with profoundly elevated rheumatoid factor (57,400 IU/ml; normal <35) who presented with findings consistent with HVS: profound weakness, headache, epistaxis and plasma viscosity (8.5 centipoise). She was successfully treated with pulsed high-dose steroids and TPE. Her symptoms of HVS have not recurred and the plasma viscosity has remained less than 3 centipoise. Given a slow onset of non-specific symptoms, HVS may be missed, incurring high risk of adverse effect. In symptomatic patients with high RF activity, a high index of suspicion for HVS is necessary to ensure timely identification and treatment with TPE, a safe and effective therapy.

Adiposity in Juvenile Psoriatic Arthritis.

OBJECTIVE: Adult patients with psoriatic arthritis are at increased risk for obesity and metabolic syndrome, but data regarding adiposity in children with juvenile psoriatic arthritis (JPsA) are limited. Our study assessed adiposity in children with JPsA in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. METHODS: Patients with JPsA in the CARRA registry were divided into nonoverweight and overweight groups using recommendations from the US Centers for Disease Control, and differences in demographic and clinical characteristics between groups at baseline and after 1-year followup were assessed using chi-square test, Fisher's exact test, T test, or Mann-Whitney U test, as appropriate. The prevalence of overweight status in the JPsA registry patients was compared to rheumatoid factor-positive and -negative polyarticular juvenile idiopathic arthritis (RF+polyJIA; RF-polyJIA) registry cohorts and the US pediatric population, using a chi-square goodness-of-fit test. RESULTS: Overweight children represented 36.3% of this JPsA cohort (n = 320). Compared to nonoverweight children, they were significantly older at symptom onset and rheumatologist's first assessment, and scored significantly worse on patient/physician outcome measures. At 1-year followup, changes in body mass index were not associated with changes in clinical features or outcome measures. The prevalence of overweight and obesity in patients with JPsA was significantly higher than in RF+polyJIA patients, RF-polyJIA patients, and the US pediatric population. CONCLUSION: In this registry, almost 1 in 5 patients with JPsA were obese and more than one-third were overweight. This is significantly more than expected compared to the US pediatric population, and appropriate longterm followup of this JPsA subgroup is warranted.