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)

Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis.

BACKGROUND: Circulating IgA anti-citrullinated protein antibodies (ACPA) associate with more active disease, but a previous study implied that salivary IgA ACPA is related to a less severe disease. Therefore, we aimed to characterize the IgA ACPA response in the saliva and serum in relation to clinical picture and risk factors among patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 196) and healthy blood donors (n = 101), included in the cross-sectional study "Secretory ACPA in Rheumatoid Arthritis" (SARA), were analyzed for ACPA of IgA isotype, and for subclasses IgA1 and IgA2 ACPA in paired saliva and serum samples using modified enzyme-linked immunosorbent assays (ELISA) targeting reactivity to a cyclic citrullinated peptide (anti-CCP). Cutoff levels for positive tests were set at the 99th percentile for blood donors. Antibody levels were related to clinical characteristics, radiographic damage, smoking habits, and carriage of HLA-DRB1/shared epitope (SE). RESULTS: IgA ACPA in the saliva was found in 12% of RA patients, IgA1 occurred in 10%, and IgA2 in 9%. In serum, IgA ACPA was found in 45% of the patients, IgA1 in 44%, and IgA2 in 39%. Levels of IgA ACPA in the saliva correlated significantly with serum levels of IgA (r = 0.455). The presence of salivary IgA ACPA was associated with a higher erythrocyte sedimentation rate (ESR), 28-joint disease activity score, tender joint count, and patient global assessment at the time of sampling. None of the antibodies was associated with smoking, SE, or radiographic damage. CONCLUSION: Salivary IgA ACPAs were detected in a subset of RA patients in association with higher disease activity. This suggests that mucosal ACPA responses in the oral cavity may contribute to disease-promoting processes in RA.

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.

The efficacy and safety of warming acupuncture and moxibustion on rheumatoid arthritis: A protocol for a systematic review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA), as an autoimmune disease, can eventually lead to joint deformity and loss of function, seriously reduce the quality of life of patients and increase economic burden. As a traditional Chinese therapy, warming acupuncture and moxibustion is safe, economical, and has few side effects. At present, some studies have shown that warming acupuncture and moxibustion has a certain effect on RA, but there is no evidence of evidence-based medicine. The purpose of this study was to evaluate the efficacy and safety of warming acupuncture and moxibustion in the treatment of rheumatoid arthritis. METHOD: Randomized controlled trials of warming acupuncture and moxibustion treating RA will be searched in the databases including PubMed, EMBASE, the Cochrane library, Web of science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), and China biomedical literature database (CBM) from inception to July, 2020. In addition, Baidu, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain the gray literature and relevant data that have not yet been published. Two qualified researchers will extract data and assess the risk of bias from included studies independently. Statistical analysis is performed in RevMan 5.3 software. RESULTS: The primary outcome is symptom evaluation including morning stiffness, pain, and joint swelling. The number of joints affected by RA, Rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), anti-cyclic peptide containing citrulline (A-CCP), and adverse effects, will be evaluated as secondary outcomes. CONCLUSIONS: This study will compare the efficacy and safety of warming acupuncture and moxibustion with common acupuncture in the treatment of RA, providing reliable evidence for clinical application. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/C8RY9.

Vasculitis reumatoide: estudio de 41 casos / Rheumatoid vasculitis: study of 41 cases

OBJETIVO: Analizar las características clínicas, tratamiento y evolución de la vasculitis reumatoide. MÉTODOS: Estudio retrospectivo (1975-2017). Pacientes con vasculitis reumatoide diagnosticados en 2 servicios de reumatología. RESULTADOS: Se incluyó a 41 pacientes: 17 (41,5%) varones y 24 (58,5%) mujeres; con una edad media al diagnóstico de 67 ± 9 años y una duración de la artritis reumatoide de 10 ± 8,3 años. La artritis fue erosiva en 33 (80%) pacientes. Tanto el factor reumatoide como los anticuerpos antipéptido citrulinados fueron positivos en todos los casos. Los síntomas constitucionales se presentaron en 30 pacientes (73%) y las manifestaciones extrarticulares en 17 (41%). Las manifestaciones clínicas más frecuentes fueron: cutáneas 28 (68%) y neuropatía periférica 26 (63%). Todos los pacientes fueron tratados con glucocorticoides. En 24 pacientes (58%) se asoció a un inmunosupresor y 5 (12%) pacientes fueron tratados con fármacos biológicos. La mortalidad a los 2 años de seguimiento fue del 33%. Las principales causas de muerte fueron: la infección y la progresión de la vasculitis reumatoide. La frecuencia de la vasculitis reumatoide disminuyó en la última década. CONCLUSIONES: Las manifestaciones clínicas de la vasculitis reumatoide en España son similares a las descritas. La frecuencia disminuye; sin embargo, el cuadro clínico y la gravedad se mantienen invariables

AIM: To describe the clinical manifestations, evolution and treatment of patients with rheumatoid vasculitis. METHODS: Retrospective study (1975-2017) of all patients diagnosed with rheumatoid vasculitis in 2 Rheumatology Services. RESULTS: A total of 41 patients were included, 17 (41.5%) males and 24 (58.5%) females; mean age at diagnosis: 67 ± 9 years; duration of rheumatoid arthritis: 10 ± 8.3 years. Most patients had erosive disease, 33 (80%). Rheumatoid factor and anticitrullinated antibodies were positive in all patients. Constitutional symptoms were present in 30 (73%) patients and extra-articular manifestations in 17 (41%) patients. The clinical manifestations of rheumatoid vasculitis were mainly: cutaneous 28 (68%), and polyneuritis 26 (63%). All patients were treated with glucocorticoids. An immunosuppressant was associated in 24 (58.5%) patients. Five (12%) patients were treated with the association of glucocorticoids and a biologic treatment. The mortality after 2years of follow-up was 33%, the most common causes being infection and progression of the vasculitis. The frequency of rheumatoid vasculitis has decreased over the last decade. CONCLUSION: The clinical manifestations of rheumatoid vasculitis were similar to previous studies. The frequency of rheumatoid vasculitis seems to decrease. However, the clinical picture and severity remains invariable

A budget impact analysis for making treatment decisions based on anti-cyclic citrullinated peptide (anti-CCP) testing in rheumatoid arthritis.

Aim: Given that rheumatoid arthritis (RA) patients with high anti-citrullinated protein antibodies (ACPA) titer values respond well to abatacept, the aim of this study was to estimate the annual budget impact of anti-cyclic citrullinated peptide (anti-CCP) testing and treatment selection based on anti-CCP test results.Materials and methods: Budget impact analysis was conducted for patients with moderate-to-severe RA on biologic or Janus kinase inhibitor (JAKi) treatment from a hypothetical US commercial payer perspective. The following market scenarios were compared: (1) 90% of target patients receive anti-CCP testing and the results of anti-CCP testing do not impact the treatment selection; (2) 100% of target patients receive anti-CCP testing and the results of anti-CCP testing have an impact on treatment selection such that an increased proportion of patients with high titer of ACPA receive abatacept. A hypothetical assumption was made that the use of abatacept would be increased by 2% in Scenario 2 versus 1. Scenario analyses were conducted by varying the target population and rebate rates.Results: In a hypothetical health plan with one million insured adults, 2,181 patients would be on a biologic or JAKi treatment for moderate-to-severe RA. In Scenario 1, the anti-CCP test cost was $186,155 and annual treatment cost was $101,854,295, totaling to $102,040,450. In Scenario 2, the anti-CCP test cost increased by $20,684 and treatment cost increased by $160,467, totaling an overall budget increase of $181,151. This was equivalent to a per member per month (PMPM) increase of $0.015. The budget impact results were consistently negligible across the scenario analyses.Limitations: The analysis only considered testing and medication costs. Some parameters used in the analysis, such as the rebate rates, are not generalizable and health plan-specific.Conclusions: Testing RA patients to learn their ACPA status and increasing use of abatacept among high-titer ACPA patients result in a small increase in the total budget (<2 cents PMPM).

Effects of Bifidobacterium animalis subsp. lactis HN019 on ligature-induced periodontitis in rats with experimental rheumatoid arthritis.

The purpose of this study was to evaluate the effects of systemic administration of the probiotic Bifidobacterium animalis subsp. lactis HN019 (HN019) on ligature-induced periodontitis in rats with experimental rheumatoid arthritis (RA). 28 rats were divided into four groups (n=7): RA (rheumatoid arthritis), RA/PROB (probiotic), RA/EP (experimental periodontitis) and RA/EP/PROB. From day zero, HN019 was added daily to the water of the PROB groups animals until the end of the experiment. From day seven, RA was induced. On day 28, in EP groups, ligatures were positioned around mandibular first molars and remained in position for 11 days, in order to induce periodontitis. The animals were euthanised on day 39. Microtomographic, histomorphometric, immunoenzymatic and microbiological analyses were performed. Data were statistically analysed (P<0.05). Group RA/EP/PROB presented reduced alveolar bone loss, tumour necrosis factor-α and interleukin (IL)-6 levels and increased IL-17 levels when compared with group RA/EP. There were no significant differences regarding connective tissue attachment level and IL-10 levels between groups RA/EP and RA/EP/PROB. Group RA/PROB showed decreased anti-citrullinated protein antibodies levels when compared with groups RA and RA/EP. Group RA/EP/PROB presented a higher rate of aerobic/anaerobic bacteria than group RA/EP. Systemic administration of HN019 promoted a protective effect against periodontal tissue destruction, decreasing both bone loss and inflammatory mediators and increasing the proportion of bacteria compatible with periodontal health, in rats with experimental RA and EP.

Artritis reumatoide, diagnóstico, evolución y tratamiento / Rheumatoid arthritis, diagnosis, evolution and treatment

La artritis reumatoide es la enfermedad inflamatoria más común en adultos con una alta prevalencia en la población general, invocando para su diagnóstico la presencia de al menos cuatro criterios de los orientados por el Colegio Americano de Reumatología, teniendo un papel protagónico en los últimos años la presencia de anticuerpos anti proteína citrulinada, así como los estudios de imágenes, que ayudan al diagnóstico de la artritis reumatoide temprana en el curso de los dos primeros años de evolución y sus orientaciones terapéuticas adecuadas, aspecto fundamental en la actualidad para evitar las lesiones erosivas irreversibles, que resultan en un marcado compromiso de la calidad de vida de los pacientes que la sufren, elementos que revisamos en este artículo de opinión(AU)

Rheumatoid arthritis is the most common inflammatory disease in adults with a high prevalence in the general population, invoking for its diagnosis the presence of at least four criteria of those guided by the American College of Rheumatology, having a leading role in recent years the presence of anti-citrullinated protein antibodies, as well as imaging studies, which help the diagnosis of early rheumatoid arthritis in the course of the first two years of evolution and its appropriate therapeutic orientations, a fundamental aspect nowadays to avoid irreversible erosive lesions , which result in a marked commitment to the quality of life of patients who suffer from it, elements that we review in this opinion article(AU)

Use of a Citrullinated Peptide Panel for Detection of Anti-Citrullinated Protein Antibodies by Enzyme-Linked Immunosorbent Assay.

Anti-citrullinated protein antibodies (ACPA)s are a hallmark of rheumatoid arthritis (RA) and are essential for serological diagnosis of RA.ACPAs are not specific for a single citrullinated target; in fact, several citrullinated ACPA target proteins have been described. As a consequence, ACPAs are primarily detected by enzyme-linked immunosorbent assays, where several citrullinated peptides are used as target antigens.This chapter focuses on the detection of ACPAs using a recently developed peptide panel in enzyme-linked immunosorbent assays.

Number of individual ACPA reactivities in synovial fluid immune complexes, but not serum anti-CCP2 levels, associate with inflammation and joint destruction in rheumatoid arthritis.

INTRODUCTION: Individual patients with rheumatoid arthritis (RA) show divergent specific anti-citrullinated protein/peptide antibodies (ACPA) patterns, but hitherto no individual ACPA specificity has consistently been linked to RA pathogenesis. ACPA are also implicated in immune complexes (IC)-associated joint pathology, but until now, there has been no method to investigate the role of individual ACPA in RA IC formation and IC-associated pathogenesis. METHODS: We have developed a new technique based on IC binding to C1q-coated magnetic beads to purify and solubilise circulating IC in sera and synovial fluids (SF) from 77 patients with RA. This was combined with measurement of 19 individual ACPA in serum, SF and in the IC fractions from serum and SF. We investigated whether occurrence of individual ACPA as well as number of ACPA in these compartments was related to clinical and laboratory measures of disease activity and inflammation. RESULTS: The majority of individual ACPA reactivities were enriched in SF as compared with in serum, and levels of ACPA in IC were regulated independently of levels in serum and SF. No individual ACPA reactivity in any compartment showed a dominating association to clinical and laboratory measures of disease activity and severity. Instead, the number of individual ACPA reactivities in the IC fraction from SF associated with a number of markers of joint destruction and inflammation. CONCLUSIONS: Our data highlight the polyclonality of ACPA in joint IC and the possibility that a broad ACPA repertoire in synovial fluid IC might drive the local inflammatory and matrix-degrading processes in joints, in analogy with antibody-induced rodent arthritis models.

Exposure to passive smoking and rheumatoid arthritis risk: results from the Swedish EIRA study.

INTRODUCTION: Smoking has consistently been associated with increased risk of developing rheumatoid arthritis (RA). The aim of this study was to estimate the influence of passive smoking on the risk of developing anti-cyclic citrullinated peptide antibodies (ACPA)-positive and ACPA-negative RA. METHODS: A population-based case-control study using incident cases of RA was performed in Sweden, and the study population in this report was restricted to include never-smokers (589 cases, 1764 controls). The incidence of RA among never-smokers who had been exposed to passive smoking was compared with that of never-smokers who had never been exposed, by calculating the OR with a 95% CI employing logistic regression. RESULTS: No association was observed between exposure to passive smoking and RA risk (OR 1.0, 95% CI 0.8 to 1.2 for ACPA-positive RA, and OR 0.9, 95% CI 0.7 to 1.2, for ACPA-negative RA). No suggestion of a trend between duration of passive smoking and RA risk was observed. DISCUSSIONS: No association was observed between exposure to passive smoking and RA risk, which may be explained by a threshold below which no association between smoke exposure and RA occurs.

A Treat-to-Target Strategy Preserves Work Capacity in a Rheumatoid Arthritis Inception Cohort Treated With Combination Conventional DMARD Therapy.

OBJECTIVES: Quantification of work disability in patients with early rheumatoid arthritis (RA) receiving conventional DMARDs according to a treat-to-target strategy. METHODS: This is a retrospective cohort analysis of RA patients who received combination conventional DMARDs, escalated to achieve DAS28(ESR) remission and completed an annual work and arthritis questionnaire. Random effect mixed modeling was used to assess associations between average hours worked per week (HWPW), and baseline prognostic factors. HWPW were compared with matched population averages. Cox proportional hazards modeling was employed to evaluate associations between permanent loss of employment and treatment response, disease and demographic factors. RESULTS: Work data from 135 patients working at baseline and 137 working at any point followed for up to 14 years (range 1-14) were available for analysis. The mean age was 45 years, 70% were female, and 70% and 68% were seropositive for rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP), respectively. Men worked more hours than women; there was a highly significant association between working hours lost and increasing age (0.28 hours, P = 0.04) and female gender (11.92 hours, P < 0.001). HWPW were maintained over the study time comparable to the general population (loss of 0.78 vs. 0.24 HWPW). EULAR good responders at 6 months were more likely to be working at 10 years compared to those with moderate/no response. Permanent loss of employment and baseline age were strongly associated for anti-CCP positive participants (P = 0.04). CONCLUSIONS: Treat-to-target combination conventional DMARD therapy maintains work capacity, particularly in good responders, comparable to the general population. Improving treatment response in moderate/no responders early in disease may increase work retention.