Tasa de publicaciones de trabajos presentados sobre artritis reumatoidea en congresos de Reumatología / Publication rates of papers on rheumatoid arthritis submitted to Congresses of Rheumatology

Resumen Introducción: se publica una minoría de todos los trabajos presentados en los Congresos Argentinos de Reumatología (CAR). Objetivos: analizar los temas de estudio (TDE) de los trabajos sobre artritis reumatoidea (AR) presentados en los CAR y su tasa de publicación. Materiales y métodos: se analizaron todos los resúmenes sobre AR, como motivo primario de estudio, presentados en los CAR entre 2008 y 2017. Se agruparon según TDE, y se determinaron los TDE repetidos definidos como, al menos, dos estudios similares presentados sobre el mismo tema. Se determinó la tasa de publicación, el número de estudios similares por TDE, el número de centros participantes y el número de pacientes estudiados. Resultados: sobre 346 trabajos presentados, 51 (14,7%) fueron publicados. Se publicaron 14 (11,9%) de los 118 estudios sobre TDE repetidos versus 37 (16,2%) del resto de los TDE (p=0,4). Los trabajos sobre TDE repetidos no incluyeron más pacientes ni involucraron a un número mayor de centros. Se encontraron 13 TDE repetidos con al menos tres estudios similares y ningún estudio publicado. Conclusiones: solo una minoría de los trabajos sobre AR se publicó. Un tercio de los trabajos presentados en los CAR correspondió a TDE repetidos, que no mejoraron la tasa de publicación.

Abstract Introduction: only a few articles submitted to the Argentine Congress of Rheumatology (ACOR) are published. Objectives: to analyse the topics of study (TOS) and the publication rate of articles on rheumatoid arthritis (RA) submitted to the ACOR. Materials and methods: every abstract submitted to the ACOR between 2008 and 2017, whose primary research subject was RA, was analyzed and sorted according to TOS. Repeated TOS, defined as at least two similar studies on the same topic, were identified. The publication rate and the number of similar studies according to TOS, participating centers, and patients were determined. Results: out of 346 articles submitted, 51 (14.7%) were published. Fourteen (11.9%) of the 118 studies on repeated TOS were published vs. 37 (16.2%) of the rest of the TOS (p: 0.4). The articles on repeated TOS neither included more patients nor involved a higher number of centers. Thirteen repeated TOS with at least three similar studies, but no published articles were identified. Conclusions: only a few articles on RA were published. One third of the studies submitted to the ACOR are repeated TOS, a fact that does not improve the publication rate.

Consecuencias de la artritis reumatoide en la articulación temporomandibular y su manejo odontológico / Consequences of rheumatoid arthritis in the temporomandibular joint and its dental management

Introducción: la artritis reumatoide es parte del grupo de las enfermedades autoinmunes con incidencia considerable sobre la población. Se caracteriza por la afección de las articulaciones del cuerpo que la padece; en mayor frecuencia se encuentra afectada la articulación temporomandibular por el complejo articular que ésta presenta; entre los signos y síntomas que comúnmente podemos encontrar en pacientes con este tipo de enfermedad son los chasquidos o ruidos articulares, dolor orofacial, pérdida o imposibilidad del movimiento de la mandíbula y cambios anatómicos localizados en el área de la articulación temporomandibular. Objetivo: describir las consecuencias que desencadena la artritis reumatoide sobre la articulación temporomandibular y cómo es para el odontólogo el manejo de estos pacientes en consulta, evaluar los tratamientos para cada caso sobre un correcto diagnóstico. Material y métodos: se realizó una revisión bibliográfica de artículos recientes sobre el tema, utilizando buscadores como SciELO, Elsevier y PubMed, siendo 30 las fuentes seleccionadas con idiomas en inglés y español. Resultados: esta enfermedad autoinmune se caracteriza por afectar múltiples articulaciones del cuerpo humano simétrica y bilateralmente incluyendo la articulación temporomandibular (ATM), lo cual conlleva al riesgo de desarrollar trastornos temporomandibulares (TTM). Es importante conocer los métodos para realizar un correcto diagnóstico oportuno de la ATM del paciente con artritis reumatoide (AR) con la finalidad de ofrecer un tratamiento conservador. Conclusión: los trastornos temporomandibulares desencadenantes de la artritis reumatoide son afecciones que se deben considerar para el buen manejo del paciente con este padecimiento, comprender y respaldar un diagnóstico clínico es de vital importancia para dar al paciente un tratamiento adecuado dependiendo el grado de complejidad en la que cada individuo se encuentra; conocer el manejo adecuado y encaminar al paciente a una mejor calidad de vida es clave en la consulta odontológica del día a día (AU)

Introduction: rheumatoid arthritis is part of the group of autoimmune diseases with considerable incidence in the population. It is characterized by the affection of the joints of the body that suffers from it; most frequently the temporomandibular joint is affected due to the articular complex that it presents; among the signs and symptoms that we can commonly find in patients with this type of disease are joint clicks or noises, orofacial pain, loss or impossibility of jaw movement and anatomical changes located in the temporomandibular joint area. Objective: to describe the consequences that rheumatoid arthritis triggers on the temporomandibular joint and how it is for the dentist to manage these patients in consultation, to evaluate the treatments for each case on a correct diagnosis. Material and methods: a bibliographic review of recent articles on the subject was carried out, using search engines such as SciELO, Elsevier and PubMed, with 30 sources selected in English and Spanish. Results: this autoimmune disease is characterized by affecting multiple joints of the human body symmetrical and bilaterally including the TMJ which leads to the risk of developing TMD. It is important to know the methods to make a correct diagnosis of the TMJ of the patient with RA in order to offer a conservative treatment. Conclusions: the temporomandibular disorders that trigger rheumatoid arthritis are conditions that should be considered for the proper management of the patient with this condition, understanding and supporting a clinical diagnosis is of vital importance to give the patient an adequate treatment depending on the degree of complexity in which each individual is; knowing the proper management and directing the patient to a better quality of life is key in the day-to-day dental practice (AU)

A rat model of rheumatoid arthritis: TDZD-8 is associated with the protection against the induction of the synovium knee joint IL-17A/GSK3beta/ROS/alpha-SMA axis of fibrosis / Un modelo de rata de artritis reumatoide: TDZD-8 está asociado con la protección contra la inducción del eje de fibrosis de la articulación sinovial de la rodilla IL-17A/GSK3ß/ROS/α-SMA

SUMMARY: Rheumatoid arthritis (RA) that affects the synovial knee joint causes swelling of the synovial membrane and tissue damage. Interleukin-17A (IL-17A) and the enzyme glycogen synthase kinase-3β (GSK3β) are involved in the pathogenesis of RA. The link between IL-17A, GSK3β, the oxidative stress, and the profibrogenic marker alpha-smooth muscle actin (α-SMA) with and without TDZD-8, GSK3β inhibitor has not been studied before. Consequently, active immunization of rats was performed to induce RA after three weeks using collagen type II (COII) injections. The treated group received daily injection of 1 mg/kg TDZD-8 for 21 days following the immunization protocol (COII+TDZD-8). Blood and synovium tissue samples were harvested at the end of the experiment. RA development was confirmed as corroborated by a substantial increase in blood levels of the highly specific autoantibody for RA, anti-citrullinated protein antibody as well as augmentation of reactive oxidative species (ROS) levels measured as lipid peroxidation. RA induction also increased synovium tissue levels of IL-17A and the profibrogenic marker, α-SMA. All these parameters seemed to be significantly (p<0.0001) ameliorated by TDZD-8. Additionally, a significant correlation between IL-17A, ROS, and α-SMA and biomarkers of RA was observed. Thus, knee joint synovium RA induction augmented IL-17A/GSK3β/ROS/α-SMA axis mediated arthritis in a rat model of RA, which was inhibited by TDZD-8.

La artritis reumatoide (AR) que afecta la articulación sinovial de la rodilla provoca inflamación de la membrana sinovial y daño tisular. La interleucina-17A (IL-17A) y la enzima glucógeno sintasa quinasa-3β (GSK3β) están involucradas en la patogenia de la AR. No se ha estudiadol vínculo entre IL-17A, GSK3β, el estrés oxidativo y el marcador profibrogénico actina de músculo liso alfa (α-SMA) con y sin inhibidor de TDZD-8, GSK3β. En consecuencia, se realizó una inmunización activa de ratas para inducir la AR después de tres semanas usando inyecciones de colágeno tipo II (COII). El grupo tratado recibió una inyección diaria de 1 µg/ kg de TDZD-8 durante 21 días siguiendo el protocolo de inmunización (COII+TDZD-8). Se recogieron muestras de sangre y tejido sinovial al final del experimento. El desarrollo de AR se confirmó como lo corroboró el aumento sustancial en los niveles sanguíneos del autoanticuerpo altamente específico para AR, el anticuerpo antiproteína citrulinada, así como el aumento de los niveles de especies oxidativas reactivas (ROS) medidos como peroxidación lipídica. La inducción de AR también aumentó los niveles de tejido sinovial de IL-17A y el marcador profibrogénico, α-SMA. Todos estos parámetros parecían mejorar significativamente (p<0,0001) con TDZD-8. Además, se observó una correlación significativa entre IL- 17A, ROS y α-SMA y biomarcadores de AR. Por lo tanto, la inducción de AR en la sinovial de la articulación de la rodilla aumentó la artritis mediada por el eje IL-17A/GSK3β/ROS/α-SMA en un modelo de rata de AR, que fue inhibida por TDZD-8.

Ansiedad, depresión y vulnerabilidad al estrés en personas con diagnóstico de artritis reumatoidea: un estudio exploratorio del Hospital de Clínicas de la Universidad Nacional de Asunción / Anxiety, depression, and vulnerability to stress in people diagnosed with rheumatoid arthritis: An exploratory study at the Hospital de Clínicas of the Universidad Nacional de Asunción

Antecedentes: Estudios observacionales han descrito una alta prevalencia de depresión y ansiedad en la artritis reumatoidea: los trastornos depresivos mayores se detectan en el 17 % de los pacientes con la patología, y la inflamación local y sistémica desempeña un papel importante en la ansiedad y la depresión. Objetivos: El objetivo general de esta investigación fue determinar la frecuencia de ansiedad, depresión y vulnerabilidad al estrés en pacientes con diagnóstico de artritis reumatoidea. Materiales y métodos: Este fue un estudio observacional, descriptivo de asociación cruzada y temporalmente prospectivo. El muestreo fue no probabilístico de casos consecutivos. Se incluyó a personas adultas con diagnóstico de artritis reumatoide que consultaron en el Departamento de Reumatología del Hospital de Clínicas, entre agosto y octubre del 2022. Para el diagnóstico psiquiátrico se utilizaron los siguientes instrumentos: Escala de Ansiedad Generalizada (GAD-7), Patient Health Questionnaire (PHQ-2) y Escala de Vulnerabilidad al Estrés de Smith y Miller. Resultados: Se incluyó a 36 pacientes, todas mujeres, con edades comprendidas entre los 20 y 77 años. El 27,8 % tenía depresión, según los puntos de corte del PHQ-2. El 22,2 % presentaba ansiedad, según los puntos de corte de GAD-7. En cuanto al estrés, el 22,2 % tenía vulnerabilidad a este y el 5,6 % era seriamente vulnerable. Conclusión: Depresión, ansiedad y vulnerabilidad al estrés son comorbilidades frecuentemente observadas en pacientes con artritis reumatoidea. Se requieren de intervenciones específicas de salud mental para abordar estas cuestiones y mejorar la calidad de vida de los pacientes afectados.

Background: Observational studies have described a high prevalence of depression and anxiety in rheumatoid arthritis: major depressive disorders are detected in 17 % of patients with the pathology, and local and systemic inflammation play an important role in anxiety and depression. Objectives: The overall objective of this research was to determine the frequency of anxiety, depression, and vulnerability to stress in patients diagnosed with rheumatoid arthritis. Materials and methods: This was an observational, descriptive, temporally prospective, cross-association study. Sampling was non-probabilistic of consecutive cases. We included adults with a diagnosis of rheumatoid arthritis who consulted at the Rheumatology Department of the Hospital de Clínicas between August and October 2022. The following instruments were used for psychiatric diagnosis: Generalized Anxiety Scale (GAD-7), Patient Health Questionnaire (PHQ-2) and Smith and Miller's Stress Vulnerability Scale. Results: Thirty-six patients, all women, aged between 20 and 77 years, were included in the study. The 27.8 % had depression, according to the cut-off points of the PHQ-2. Anxiety was present in 22.2 %, according to the GAD-7 cut-off points. Regarding stress, 22.2 % were vulnerable to stress and 5.6 % were seriously vulnerable. Conclusion: Depression, anxiety and vulnerability to stress are frequently observed comorbidities in patients with rheumatoid arthritis. Specific mental health interventions are required to address these issues and improve the quality of life of affected patients.

Acercamiento teórico al uso de la imagenología en el diagnóstico temprano de la artritis reumatoide / Theoretical approach to the use of imaging in the early diagnosis of rheumatoid arthritis

La artritis reumatoide es una enfermedad progresiva, con manifestaciones clásicas y tempranas como es la afectación de las articulaciones pequeñas de las manos y los tobillos. Se realizó una revisión bibliográfica de los documentos publicados entre 2017 y 2022. Se realizó una lectura preliminar de 37 artículos que cumplían con los criterios de inclusión, y finalmente se seleccionaron 23 artículos, de los cuales se tomó el contenido de mayor importancia. La ecografía es una técnica fiable y más sensible que la exploración clínica en el estudio de la enfermedad músculo-esquelética, pues permite una exploración multiplanar y dinámica, lo que resulta en un diagnóstico más exacto. La técnica Doppler constituye un complemento útil en el seguimiento de estos pacientes. Esta enfermedad es recurrente en las consultas de Reumatología, por tanto, en su valoración inicial, la utilidad de los medios diagnósticos, especialmente la ecografía, tiene gran importancia.

Rheumatoid arthritis is a progressive disease, with classic and early manifestations such as involvement of the small joints of the hands and ankles. We conducted a bibliographic review of the documents published between 2017 and 2022. A preliminary reading of 37 articles that met the inclusion criteria was carried out, and 23 articles were finally selected, from which the most important content was taken. Ultrasound is a more sensitive and reliable technique than clinical examination for the study of musculoskeletal disease, since it allows a multiplanar and dynamic examination, which results in a more accurate diagnosis. Doppler technique is a useful complement in the follow-up of these patients. This disease is recurrent in Rheumatology consultations, that's why in its initial assessment, the usefulness of diagnostic means, especially ultrasound, is of great importance.

Shared epitope classification methods according to Gregersen and de Vries allow adequate characterization of patients with rheumatoid arthritis in a Colombian population

Introduction: The most important genetic association in rheumatoid arthritis (RA) is presented with some alleles from the HLA-DRB1 gene that encode the shared epitope (SE). Objectives: To apply the SE classification methods of Gregersen, de Vries, Raychaudhuri, Mattey, and Tezenas du Montcel in a group of Colombian patients with RA and determine the most common HLA-DRB1 alleles in the population. Methods: RA diagnosis, genetic study of the HLA-DRB1 region using Luminex technology in 50 RA and 50 healthy subjects. For the classification analysis, Fisher's exact test and chi-squared test were applied. Tables were created to count the RA-related alleles. We used odds ratio to determine the risk between the presence of the shared epitope (SE) and anti-cyclic citrullinated peptides (Anti-CCP). Results: Gregersen and de Vries methods were suitable for the characterization of RA in this population (p = .006). The most prevalent HLA-DRB1 alleles in the RA group were 14:02,04:04, 08:02,04:05, and 10:01. High frequencies of the 07:01, 03:01,13:02,01:02, and 12:01 HLA-DRB1 alleles were found in the healthy population. HLA-DRB1 alleles with similar distribution in both populations were 04:07, 15:01, 11:01, 16:02, and 01:01. A high frequency of SE + was observed in Anti-CCP + individuals (63.15%); however, this was not statistically significant [OR2.4 (.63-9.01); p = .19]. Conclusion: The SE classification methods of Gregersen and de Vries were adequate in characterizing RA in a Colombian population group. An equivalence of 100% was verified between the susceptibility alleles defined by de Vries and the alleles assigned as SE according to Gregersen.

Introducción: La asociación genética más importante en artritis reumatoide (AR) se presenta con algunos alelos del gen HLA DRB1 que codifican el epítope compartido (EC). Objetivos: Aplicar los métodos de clasificación de EC de Gregersen et al., de Vries et al., Raychaudhuri et al., Mattey et al., y Tezenas du Montcel et al., en un grupo de pacientes colombianos con AR, y determinar los alelos HLA DRB1 más frecuentes en esta población. Métodos: Diagnóstico para AR, estudio genético de la región HLA DRB1 por tecnología Luminex® de 50 sujetos AR y 50 sanos. Para análisis comparativos de clasificaciones EC, se aplicaron las pruebas test exacto de Fisher y Chi-cuadrado y se realizaron tablas de conteos para los alelos relacionados con AR. Se estimó la razón de odds para determinar el riesgo entre la presencia de EC y los anticuerpos antipéptidos cíclicos citrulinados (anti-PCC). Resultados: Los métodos de Gregersen et al. y de Vries et al. fueron adecuados para la caracterización de AR en esta población (p = 0,006). Los alelos HLA DRB1 más prevalentes en el grupo AR fueron 14:02, 04:04, 08:02, 04:05 y 10:01. Se encontraron altas frecuencias de los alelos HLA DRB1 07:01, 03:01,13:02, 01:02 y 12:01 en población sana. Alelos HLA DRB1 con distribución similar en ambas poblaciones fueron: 04:07, 15:01, 11:01, 16:02 y 01:01. Se observó alta frecuencia de individuos EC+ en el grupo AR anti-PCC+ (63,15%); no obstante, sin asociación estadística (OR: 2,4 [0,63-9,01]; p = 0,19). Conclusión: Los métodos de clasificación para EC de Gregersen et al. y de Vries et al. fueron adecuados caracterizando AR en un grupo de población colombiana. Se corroboró equivalencia del 100% entre los alelos de susceptibilidad definidos por de Vries y los alelos asignados como EC según Gregersen et al.

Periodontite associada à artrite reumatoide: o papel das redes extracelulares de neutrófilos (NETs) / Periodontitis associated with rheumatoid arthritis: the role of neutrophil extracellular traps (NETs)

Introdução: As redes extracelulares de neutrófilos (NETs) são apontadas como um dos mecanismos relevantes na patogênese da periodontite e artrite reumatoide (AR). No entanto, permanece pouco compreendido a participação das NETs como mecanismo de ligação entre as duas doenças. Objetivos: 1) Investigar a concentração das NETs na saliva, no plasma e in vitro em indivíduos com AR e controles saudáveis e a associação com a periodontite e atividade da AR; 2) Avaliar o impacto do tratamento periodontal não cirúrgico na concentração das NETs na saliva e no plasma; 3) Investigar a associação entre a presença de polimorfismos de nucleotídeo único no gene codificador da enzima peptidil arginina deaminase 4 (PAD4) com a AR, a produção de NETs in vitro e a periodontite; 4) Sistematizar as evidências disponíveis na literatura sobre o efeito do tratamento periodontal não cirúrgico sobre os principais parâmetros clínicos e laboratoriais da AR e score de atividade da doença 28 (DAS28). Material e Métodos: Para atender aos objetivos 1 e 2, a concentração de NETs na saliva, no plasma e na cultura de neutrófilos isolados do sangue periférico foi determinada por meio da identificação do complexo mieloperoxidase (MPO)-DNA com o uso do kit PicoGreen®. Para atender ao objetivo 3 foi realizada a extração do DNA genômico das células mononucleares do sangue periférico de indivíduos com AR e controles e foi realizada a genotipagem para os polimorfismos de nucleotídeo único PADI4_89, PADI4_90, PADI4_92 e PADI_104. Para atender ao objetivo 4 foi realizada uma overview incluindo revisões sistemáticas que avaliaram o efeito do tratamento periodontal não cirúrgico sobre os parâmetros da AR. A busca foi realizada nas principais bases de dados, sem restrição de idioma ou data de publicação. Foi realizada ainda uma meta-análise incluindo dados dos estudos primários identificados nas revisões sistemáticas analisadas. Resultados: 1) e 2) Indivíduos com AR e com periodontite apresentaram maior concentração de NETs na saliva, no plasma e in vitro. O tratamento periodontal não cirúrgico reduziu a concentração de NETs na saliva e plasma de indivíduos com AR. 3) Não foi observada associação entre a presença de genótipos polimórficos e a AR. A presença de um haplótipo homozigoto para o polimorfismo foi associada a uma maior produção de NETs in vitro e piores parâmetros periodontais. 4) Foram incluídas na overview nove revisões sistemáticas. Os principais desfechos avaliados foram DAS28; proteína C-Reativa e/ou velocidade de hemossedimentação. A meta-análise mostrou que o tratamento periodontal não cirúrgico resultou em diminuição significativa do DAS28. Conclusão: A concentração das NETs na saliva, no plasma e na cultura de neutrófilos de sangue periférico está associada a AR e a periodontite, podendo representar o elo entre as duas doenças. O tratamento periodontal não cirúrgico leva à redução da atividade da AR. Polimorfismos no gene PADI4 estão associados a produção de NETs in vitro e à presença de periodontite.

Introduction: Neutrophil extracellular traps (NETs) are recognized as one of the relevant mechanisms in the pathogenesis of periodontitis and rheumatoid arthritis (RA). However, the participation of NETs as a linking mechanism between the two diseases remains poorly understood. Objectives: 1) To investigate the concentration of NETs in saliva, plasma, and in vitro in individuals with RA and healthy controls and the association of NETs with periodontitis and RA activity; 2) To evaluate the impact of non-surgical periodontal treatment on the concentration of NETs in saliva and plasma; 3) To investigate the association between the presence of single nucleotide polymorphisms in the gene coding for the enzyme peptidyl arginine deaminase 4 (PAD4) with RA, in vitro production of NETs, and periodontitis; 4) To systematize the evidence available in the literature on the effect of non-surgical periodontal treatment on the main clinical and laboratory parameters of RA and disease activity score 28 (DAS28). Material and Methods: To accomplish Objectives 1 and 2, the concentration of NETs in saliva, plasma, and culture of neutrophils isolated from peripheral blood was determined by identifying the myeloperoxidase (MPO)-DNA complex using the PicoGreen kit®. To accomplish Objective 3, genomic DNA was extracted from peripheral blood mononuclear cells of individuals with RA and healthy controls, and genotyping was performed for single nucleotide polymorphisms PADI4_89, PADI4_90, PADI4_92, and PADI_104. To accomplish the Objective 4, an overview, including systematic reviews that evaluated the effect of non-surgical periodontal treatment on RA parameters, was performed. The search was carried out in the main databases, with no restriction on language or date of publication. A meta- analysis, including data from the primary studies identified in the analyzed systematic reviews, was also performed. Results: For Objectives 1 and 2, individuals with RA and periodontitis showed a higher concentration of NETs in saliva, plasma, and in vitro. Non-surgical periodontal treatment reduced the concentration of NETs in saliva and plasma of individuals with RA. For Objective 3, no association between the presence of polymorphic genotypes and RA was observed. The presence of a homozygous haplotype for the polymorphism was associated with a higher production of NETs in vitro and worse periodontal parameters. For Objective 4, nine systematic reviews were included in the overview. The main outcomes evaluated were DAS28, C-Reactive protein, and/or erythrocyte sedimentation rate. The meta- analysis showed that non-surgical periodontal treatment resulted in a significant decrease in DAS28. Conclusion: The concentration of NETs in saliva, plasma and culture of peripheral blood neutrophils is associated with RA and periodontitis and may represent the link between the two diseases. Non-surgical periodontal treatment leads to reduced RA activity. Polymorphisms in the PADI4 gene are associated with the in vitro production of NETs and with presence of periodontitis.

Periodontitis in rheumatoid arthritis: a case-control study in a brazilian sample

To investigate the presence of periodontitis in RA patients comparing it with controls in a Brazilian sample. Methods: This is a case control study conducted in a public health rheumatologic center. One hundred and sixteen RA patients and 68 paired controls were compared for epidemiological data and presence of periodontal disease evaluated by number of remaining teeth, presence of bacterial plaque, bleeding on probing, probing depth and clinical level of gingival insertion. In addition, data on comorbidities was collected. Results: RA patients and controls have the same amount of teeth loss (P = 0.84). RA patients had more calculus (P = 0.02); dental plaques (P = 0.04); gingival recession (P = 0.02) and bleeding (P = 0.01). Although the number of individuals with periodontitis was higher in RA patients, the severity of periodontitis was similar in both groups (P = ns). Presence of diabetes and hypothyroidism also associated with periodontitis (P = 0.01 and 0.02 respectively). In a model of logistic regression built to assess the independence of association of RA and its comorbidities with periodontitis, only diabetes and RA remained independent. Conclusion: This case control study shows higher frequency of periodontitis in RA patients than controls

Expenditure of biological drugs for rheumatoid arthritis treatment in the Brazilian public health system

ABSTRACT OBJECTIVE This work aims to analyze the quantity and expenses related to biological drugs used for the treatment of rheumatoid arthritis (RA) in outpatient public care within the Brazilian Unified Health System (SUS). METHODS It is a cross-sectional descriptive study based on secondary data from a historical series, referring to the purchase, volume, and the number of patients treated with different biological drugs (infliximabe, etanercept, adalimumab, rituximab, abatacept, tocilizumab, golimumab, and certolizumab pegol) for RA treatment in outpatient care from 2012 to 2017. The data were extracted from the SUS Outpatient Information System database-SIA/SUS and included ten drugs used for RA treatment. The study assessed the quantity and expenditure of these drugs, the number of RA patients treated, and the expenditure by RA subtypes. The National Broad Consumer Price Index was used to adjust the expenditures for December 2017. RESULTS The Ministry of Health allocated approximately $500 million to provide about 2 million units of biological drugs for RA patients from 2012 to 2017. The supply of adalimumab 40 mg and etanercept 50 mg accounted for 68.3% of the total expenditure. The subtypes "other rheumatoid arthritis with rheumatoid factor" (ICD-10 M05.8), "rheumatoid arthritis without rheumatoid factor" (ICD-10 M06.0), and "Felty's syndrome" (M05. 0) represented 84.5% of the total expenditures. The proportion of patients treated with biological drugs increased by 33.0%. There was a significant 83.0% increase in the number of patients using biological drugs compared to the overall number of RA patients treated during the study period. CONCLUSIONS The results obtained allow us to draw a more recent profile of expenditure on RA treatment and indicate trends in the use of biological drugs for this condition, generating data that can support management decisions in public health policies.

Transferencia tendinosa del primer radial externo al cubital posterior: ¿mejora significativamente la corrección de la desviación radial en la muñeca reumática? / Extensor carpi radialis longus tendon transfer to extensor carpi ulnaris: Does it significantly improve the correction of radial deviation in the rheumatoid wrist?

Introducción: La artritis inflamatoria puede conducir al síndrome de caput ulnae con desviación radial de la muñeca y los meta-carpianos. El tratamiento es la artroplastia de rescate de la articulación radiocubital distal y la reubicación del tendón del extensor cubital del carpo (ECC). Sin embargo, puede ser débil para corregir la desviación. Clayton describió la transferencia del tendón del extensor radial largo del carpo (ERLC) al ECC. El objetivo de este estudio fue comparar la corrección de la desviación radial de los metacarpianos en pacientes operados con transferencia del ERLC al ECC o sin ella. Materiales y Métodos: Estudio de cohorte retrospectiva en pacientes con artritis reumatoide y síndrome de caput ulnae, sometidos a tenoplastia del ECC con ERLC o sin este procedimiento. Se formaron dos grupos: pacientes con transferencia (grupo A) y sin transferencia (grupo B). Se calculó la corrección del ángulo de Clayton comparando las medidas preoperatoria y del último control, y se compararon los resultados. Resultados: El seguimiento promedio fue de 28 meses. El ángulo de Clayton preoperatorio promedio era de 44,54° (DE ± 7,52) en el grupo A y 60,24° (DE ± 12,28) en el grupo B (p = 0,001). El promedio de corrección fue de 6,57° (DE ± 4,11) y 0,95° (DE ± 9,17), respectivamente (p = 0,026). Conclusiones: El nivel de corrección fue mayor en el grupo A. No obstante, si bien ambas técnicas lograron mejorar el ángulo, el grado de corrección podría estar supeditado a la magnitud del ángulo preoperatorio. Nivel de Evidencia: IV

Introduction: Inflammatory arthritis can lead to caput ulnae syndrome with radial deviation of the wrist and metacarpals. Treatment includes salvage arthroplasty of the distal radioulnar joint and relocation of the extensor carpi ulnaris (ECU) tendon. However, the ECU may be too weak to correct the deviation. To strengthen the ECU, Clayton described the transfer of the extensor carpi radialis longus (ECRL) tendon to the ECU. The aim of this work is to compare the correction of the radial deviation of the metacarpals in patients with and without transfer of the ECRL to the ECU. Materials and Methods: Retrospective cohort study. Patients with rheumatoid arthritis and caput ulnae syndrome, treated with ECU tenoplasty with or without ECRL, were included. The patients were divided into two groups: ECRL to ECU transfer (group A) and no transfer (Group B). The correction of the metacarpal-radial angle (Clayton's angle) was calculated by comparing the measurements before surgery and at end of follow-up, and the results obtained were compared. Results: The average follow-up was 28 months. The preoperative Clayton angle was on average 44.54° (SD ± 7.52) in group A and 60.24° (SD ± 12.28) in group B (p = 0.001). The correction average was 6.57° (SD ± 4.11) and 0.95° (SD ± 9.17) for group A and B respectively (p=0.026). Conclusions: The level of correction obtained was higher in group A. However, although both techniques managed to improve the angle, the degree of correction could be subject to the magnitude of the preoperative angle. Level of Evidence: IV

Role of Interleukin-36 in inflammatory joint diseases / 浙江大学学报·医学版

Interleukin (IL)-36 is a family of cytokines that belongs to the larger IL-1 superfamily. IL-36 agonist/antagonist binds to the interleukin-36 receptor involving in physiological inflammation regulation and pathogenesis of many inflammatory diseases. In inflammatory joint diseases, the expression of IL-36 changes, and some studies have initially explored the role of IL-36 in these diseases. In psoriatic arthritis, IL-36 signal mediates plasma cell and fibroblast-like synoviocyte crosstalk presenting IL-36 agonist/antagonist imbalance. In rheumatoid arthritis, IL-36 agonists induce fibroblast-like synoviocyte to produce pro-inflammatory factors, while IL-36 antagonist deficiency leads to lesion progression. In osteoarthritis, IL-36 agonists induce chondrocytes to produce catabolic enzymes and pro-inflammatory factors. This article reviews the expression and function of IL-36 in different inflammatory joint diseases to provide a reference for revealing their pathogenic mechanisms and discovering therapeutic targets.

The expression of long non-coding RNA human leukocyte antigen complex P5(lncRNA HCP5) in synovial tissue of patients with rheumatoid arthritis is up-regulated and correlated with immune cell infiltration / 细胞与分子免疫学杂志

Objective To identify the potential long non-coding RNA (lncRNA) expressed in rheumatoid arthritis (RA) synovium key to RA onset and investigate its association with immune cell infiltration. Methods RA synovium data were downloaded from the GEO database and normalized. The lncRNAs key to RA onset were identified using multiple machine learning methods. Infiltration of 22 immune cell populations in RA synovium was measured by cell-type identification by estimating relative subsets of RNA transcripts (CIBER-SORT). The relationship between the key lncRNA and infiltrating immune cells was analyzed. Finally, real-time quantitative PCR was applied to validate the expression of the key lncRNA in RA synovial cells. Results lncRNA human leukocyte antigen complex P5(HCP5) was identified as the key lncRNA associated with RA onset. Infiltration analysis revealed increased abundance of CD8+ T cells, γδ T cells, and M1 macrophages while decreased abundance of M2 macrophages in RA synovial tissue. Correlation analysis demonstrated that the lncRNA HCP5 expression was positively associated with the infiltration abundance of CD8+ T cells, γδ T cells, and M1 macrophages in RA synovial tissue. Furthermore,the expression of lncRNA HCP5 in RA synovial cells was up-regulated. Conclusion lncRNA HCP5 expression is up-regulated in RA synovial tissue and potentially associated with immune cells infiltration.

Treatment of rheumatoid arthritis by injection of sinomenine solid lipid nanoparticles under a fluorescence endoscopic laser confocal microscope / 中国中药杂志

A fluorescence endoscopic laser confocal microscope(FELCM) was used to direct the injection of sinomenine solid lipid nanoparticles(Sin-SLN) into the joint, and the in vitro effectiveness of Sin-SLN in the treatment of rheumatoid arthritis(RA) was evaluated. Sin-SLN was prepared with the emulsion evaporation-low temperature curing method. The Sin-SLN prepared under the optimal conditions showed the encapsulation efficiency of 64.79%±3.12%, the drug loading of 3.84%±0.28%, the average particle size of(215.27±4.21) nm, and the Zeta potential of(-32.67±0.84) mV. Moreover, the Sin-SLN demonstrated good stability after sto-rage for 30 days. The rabbit model of RA was established by the subcutaneous injection of ovalbumin and complete Freund's adjuvant. Five groups were designed, including a control group, a model group, a Sin(1.5 mg·kg~(-1)) group, a Sin-SLN(1.5 mg·kg~(-1)) group, and a dexamethasone(positive drug, 1.0 mg·kg~(-1), ig) group. The control group and the model group only received puncture treatment without drug injection. After drug administration, the local skin temperature and knee joint diameter were monitored every day. The knee joint diameter and the local skin temperature were lower in the drug administration groups than in the model group(P<0.05, P<0.01). FELCM recorded the morphological alterations of the cartilage of knee joint. The Sin-SLN group showed compact tissue structure and smooth surface of the cartilage. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the serum le-vels of interleukin-1(IL-1) and tumor necrosis factor-α(TNF-α). The findings revealed that the Sin-SLN group had lower IL-1 and TNF-α levels than the model group(P<0.05, P<0.01). Hematoxylin-eosin(HE) staining was employed to reveal the pathological changes of the synovial tissue, which were significantly mitigated in the Sin-SLN group. The prepared Sin-SLN had uniform particle size and high stability. Through joint injection administration, a drug reservoir was formed. Sin-SLN effectively alleviate joint swelling and cartilage damage of rabbit, down-regulated the expression of inflammatory cytokines, and inhibited the epithelial proliferation and inflammatory cell infiltration of the synovial tissue, demonstrating the efficacy in treating RA.

Mechanism of Gardeniae Fructus in ameliorating rheumatoid arthritis based on metabolomics and intestinal microbiota / 中国中药杂志

Rheumatoid arthritis(RA), a chronic autoimmune disease, is featured by persistent joint inflammation. The development of RA is associated with the disturbance of endogenous metabolites and intestinal microbiota. Gardeniae Fructus(GF), one of the commonly used medicinal food in China, is usually prescribed for the prevention and treatment of jaundice, inflammation, ache, fever, and skin ulcers. GF exerts an effect on ameliorating RA, the mechanism of which remains to be studied. In this study, ultra-perfor-mance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)-based serum non-target metabolomics and 16S rDNA high-throughput sequencing were employed to elucidate the mechanism of GF in ameliorating RA induced by complete Freund's adjuvant in rats. The results showed that GF alleviated the pathological conditions in adjuvant arthritis(AA) rats. The low-and high-dose GF lo-wered the serum levels of interleukin(IL)-6, tumor necrosis factor-α(TNF-α), IL-1β, and prostaglandin E2 in the rats(P<0.05, P<0.01). Pathways involved in metabolomics were mainly α-linolenic acid metabolism and glycerophospholipid metabolism. The results of 16S rDNA sequencing showed that the Streptococcus, Facklamia, Klebsiella, Enterococcus, and Kosakonia were the critical gut microorganisms for GF to treat AA in rats. Spearman correlation analysis showed that the three differential metabolites PE-NMe[18:1(9Z)/20:0], PC[20:1(11Z)/18:3(6Z,9Z,12Z)], and PC[20:0/18:4(6Z,9Z,12Z,15Z)] were correlated with the differential bacteria. In conclusion, GF may ameliorate RA by regulating the composition of intestinal microbiota, α-linolenic acid metabolism, and glycerophospholipid metabolism. The findings provide new ideas and data for elucidating the mechanism of GF in relieving RA.

Correlation between traditional Chinese medicine and reduced risk of readmission in rheumatoid arthritis patients with hypoproteinemia:a retrospective cohort study / 中国中药杂志

This study aimed to explore the correlation between traditional Chinese medicine(TCM) and reduced risk of readmission in patients having rheumatoid arthritis with hypoproteinemia(RA-H). A retrospective cohort study was conducted on 2 437 rheumatoid arthritis patients in the information system database of the First Affiliated Hospital of Anhui University of Chinese Medicine from 2014 to 2021, and 476 of them were found to have hypoproteinemia. The patients were divided into TCM users and non-TCM users by propensity score matching. Exposure was defined as the use of oral Chinese patent medicine or herbal decoction for ≥1 month. Cox regression analysis was performed to explore the risk factors of clinical indicators of rheumatoid arthritis. Additionally, the use of TCM during hospitalization was analyzed, and analysis of association rules was conducted to investigate the correlation between TCM, improvement of indicators and readmission of patients. Kaplan-Meier survival curve was plotted to compare the readmission rate of TCM users and non-TCM users. It was found the readmission rate of RA-H patients was significantly higher than that of RA patients. By propensity score matching, 232 RA-H patients were divided into TCM group(116 cases) and non-TCM group(116 cases). Compared with the conditions in the non-TCM group, the readmission rate of the TCM group was lowered(P<0.01), and the readmission rate of middle-aged and elderly patients was higher than that of young patients(P<0.01). Old age was a risk factor for readmission of RA-H patients, while TCM, albumin(ALB) and total protein(TP) were the protective factors. During hospitalization, the TCMs used for RA-H patients were mainly divided into types of activating blood and resolving stasis, relaxing sinew and dredging collaterals, clearing heat and detoxifying, and invigorating spleen and resolving dampness. The improvement of rheumatoid factor(RF), immunoglobulin G(IgG), erythrocyte sedimentation rate(ESR), C-reactive protein(CRP) and ALB was closely related to TCM. On the basis of western medicine treatment, the application of TCM could reduce the readmission rate of RA-H patients, and longer use of TCM indicated lower readmission rate.

IL-27: a novel cytokine mediating immune related diseases / 生理学报

Interleukin 27 (IL-27) is a pleiotropic cytokine that is involved in the regulation of the body's innate and adaptive immunity. Previous studies have shown that IL-27 mediates a variety of inflammatory responses in vivo. With the development of animal models and technical tools, several studies have shown that it is also closely associated with autoimmune diseases and other immune related diseases, and is considered as an important candidate for the treatment of viral disease, autoimmune diseases, tumors and obesity. Therefore, this paper reviews recent progress on the role of IL-27 in acquired immunodeficiency syndrome (AIDS), rheumatoid arthritis, tumors and obesity, with the aim of providing new ideas for the treatment of immune related diseases.

Osteoimmunology research in rheumatoid arthritis: From single-cell omics approach / 中华医学杂志(英文版)

Cellular immune responses as well as generalized and periarticular bone loss are the key pathogenic features of rheumatoid arthritis (RA). Under the pathological conditions of RA, dysregulated inflammation and immune processes tightly interact with skeletal system, resulting in pathological bone damage via inhibition of bone formation or induction of bone resorption. Single-cell omics technologies are revolutionary tools in the field of modern biological research.They enable the display of the state and function of cells in various environments from a single-cell resolution, thus making it conducive to identify the dysregulated molecular mechanisms of bone destruction in RA as well as the discovery of potential therapeutic targets and biomarkers. Here, we summarize the latest findings of single-cell omics technologies in osteoimmunology research in RA. These results suggest that single-cell omics have made significant contributions to transcriptomics and dynamics of specific cells involved in bone remodeling, providing a new direction for our understanding of cellular heterogeneity in the study of osteoimmunology in RA.

Berberine inhibits autophagy and promotes apoptosis of fibroblast-like synovial cells from rheumatoid arthritis patients through the ROS/mTOR signaling pathway / 南方医科大学学报

OBJECTIVE@#To evaluate the regulatory effect of berberine on autophagy and apoptosis balance of fibroblast-like synoviocytes (FLSs) from patients with in rheumatoid arthritis (RA) and explore the mechanism.@*METHODS@#The inhibitory effect of 10, 20, 30, 40, 50, 60, 70, and 80 μmol/L berberine on RA-FLS proliferation was assessed using CCK-8 method. Annexin V/PI and JC-1 immunofluorescence staining was used to analyze the effect of berberine (30 μmol/L) on apoptosis of 25 ng/mL TNF-α- induced RA-FLSs, and Western blotting was performed to detect the changes in the expression levels of autophagy- and apoptosis-related proteins. The cells were further treated with the autophagy inducer RAPA and the autophagy inhibitor chloroquine to observe the changes in autophagic flow by laser confocal detection of mCherry-EGFP-LC3B. RA-FLSs were treated with the reactive oxygen species (ROS) mimic H2O2 or the ROS inhibitor NAC, and the effects of berberine on ROS, mTOR and p-mTOR levels were observed.@*RESULTS@#The results of CCK-8 assay showed that berberine significantly inhibited the proliferation of RA-FLSs in a time- and concentration-dependent manner. Flow cytometry and JC-1 staining showed that berberine (30 μmol/L) significantly increased apoptosis rate (P < 0.01) and reduced the mitochondrial membrane potential of RA-FLSs (P < 0.05). Berberine treatment obviously decreased the ratios of Bcl-2/Bax (P < 0.05) and LC3B-II/I (P < 0.01) and increased the expression of p62 protein in the cells (P < 0.05). Detection of mCherry-EGFP-LC3B autophagy flow revealed obvious autophagy flow block in berberine-treated RA-FLSs. Berberine significantly reduced the level of ROS in TNF-α-induced RA-FLSs and upregulated the expression level of autophagy-related protein p-mTOR (P < 0.01); this effect was regulated by ROS level, and the combined use of RAPA significantly reduced the pro-apoptotic effect of berberine in RA-FLSs (P < 0.01).@*CONCLUSION@#Berberine can inhibit autophagy and promote apoptosis of RA-FLSs by regulating the ROS-mTOR pathway.

Silencing of SMAD family member 3 promotes M2 polarization of macrophages and the expression of SMAD7 in rheumatoid arthritis / 细胞与分子免疫学杂志

Objective To investigate the effect of SMAD family member 3(SMAD3) silenced by small interfering RNA (siRNA) on macrophage polarization and transforming growth factor β1 (TGF-β1)/ SMAD family signaling pathway in rheumatoid arthritis (RA). Methods RA macrophages co-cultured with rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) were used as a cell model. TGF-β1 was used to stimulate macrophages, and SMAD3-specific siRNA (si-SMAD3) and negative control siRNA (si-NC) were transfected into human RA macrophages co-cultured in TranswellTM chamber. The expression of SMAD3 mRNA was detected by real-time fluorescence quantitative PCR, and the expression of TGF-β1, SMAD3 and SMAD7 protein was detected by Western blot analysis. The contents of TGF-β1 and IL-23 in cell culture supernatant were determined by ELISA. Cell proliferation was detected by CCK-8 assay. TranswellTM chamber was used to measure cell migration. Results Compared with the model group and the si-NC group, the expression of TGF-β1, SMAD3 mRNA and protein in RA macrophages decreased significantly after silencing SMAD3. In addition, the secretion of IL-23 decreased significantly, and the cell proliferation activity and cell migration were inhibited, with high expression of SMAD7. Conclusion Knockdown of SMAD3 can promote M2 polarization and SMAD7 expression in RA macrophages.