Suppression of nitrosative stress and inflammation of the knee joint synovium in collagen type ii-induced rheumatoid arthritis by the inhibition of glycogen synthase kinase-3ß / Supresión del estrés nitrosativo e inflamación de la sinovial de la articulación de la rodilla en la artritis reumatoide inducida por colágeno tipo ii mediante la inhibición de la glucógeno sintasa quinasa-3 ß

SUMMARY: Rheumatoid arthritis (RA), an inflammatory autoimmune disease that causes cartilage degradation and tissue destruction, can affect synovial joints such as the knee joint. The link between the nitrosative stress enzyme inducible nitric oxide synthase (iNOS) and the cytokine interleukin-1 (IL-1β) in RA-induced knee joint synovial membrane damage with and without the incorporation of the GSK3β inhibitor TDZD-8 has never been studied. As a result, we used active immunization method with collagen type II (COII) for twenty one days to induce RA in rats. TDZD-8 (1 mg/kg; i.p.) was given daily into matched immunized rats for three weeks after day 21 (COII+TDZD-8). Blood and tissue samples were taken 42 days after immunization. A dramatic increase in rheumatoid factor (RF) blood levels, as well as considerable synovial tissue damage and inflammatory cell infiltration of the synovial membrane, were used to validate the onset of RA following COII immunization. COII immunization increased tissue levels of iNOS protein and IL- 1β mRNA and protein expression, which TDZD-8 suppressed considerably (p<0.0001). Furthermore, there was a significantly (p<0.001) positive correlation between iNOS, inflammatory biomarkers, and RF. We concluded that TDZD-8 reduced RA-induced IL-1β -iNOS axis-mediated arthritis in the rat knee joint synovium.

RESUMEN: La artritis reumatoide (AR), es una enfermedad autoinmune inflamatoria que causa la degradación del cartílago y la destrucción del tejido, pudiendo afectar las articulaciones sinoviales, como la articulación de la rodilla. No se ha estudiado el vínculo entre la óxido nítrico sintasa inducible por la enzima del estrés nitrosativo (iNOS) y la citocina interleucina-1 (IL-1β) en el daño de la membrana sinovial de la articulación de la rodilla provocado por AR con y sin la incorporación del inhibidor de GSK3β TDZD-8. Utilizamos el método de inmunización activa con colágeno tipo II (COII) durante veintiún días para inducir AR en ratas. Se administró TDZD-8 (1 mg/kg; i.p.) diariamente a ratas inmunizadas emparejadas durante tres semanas después del día 21 (COII+TDZD- 8). Se tomaron muestras de sangre y tejido 42 días después de la inmunización. Se observó un gran aumento de los niveles sanguíneos del factor reumatoideo (FR), así como un daño considerable del tejido sinovial e infiltración de células inflamatorias en la membrana sinovial, para validar la aparición de la AR después de la inmunización con COII. La inmunización con COII aumentó los niveles tisulares de la proteína iNOS y la expresión de proteína y ARNm de IL-1β, que TDZD-8 suprimió considerablemente (p<0,0001). Además, hubo una correlación positiva significativa (p<0,001) entre iNOS, biomarcadores inflamatorios y FR. Concluimos que TDZD- 8 redujo la artritis mediada por el eje IL-1β-iNOS inducida por la AR en la sinovial de la articulación de la rodilla de rata.

Respuesta immune humoral asociada a las vacunas contra SARS-CoV-2 en pacientes con artritis reumatoidea: datos del registro SAR-CoVAC / Humoral immune response associated to the vaccines against SARS-CoV-2 in patients with rheumatic arthritis: data from the SAR-CoVAC registry

Introducción: la artritis reumatoidea (AR) y los tratamientos indicados para su manejo pueden afectar la respuesta a la vacuna para SARS-CoV-2. Sin embargo, aún no se cuenta con datos locales. Objetivos: evaluar la respuesta humoral de la vacuna para SARS-CoV-2 y su seguridad en esta población. Materiales y métodos: estudio observacional. Se incluyeron pacientes ≥18 años, con AR ACR/EULAR 2010 que recibieron la vacunación para SARS-CoV-2. Detección de IgG anti-proteína S (kit COVIDAR). Resultados: se incluyeron 120 pacientes con AR. El 24,4% recibió tratamiento con glucocorticoides, 50,9% drogas biológicas y 13,3% inhibidores de JAK (janus kinases). El 6% había tenido infección por SARS-CoV-2 previamente. La vacuna más utilizada en la primera dosis fue Sputnik V (52,9%). El 25% recibió esquemas heterólogos. Luego de la primera dosis, el 59% presentó una prueba no reactiva o indeterminada, y un 18% luego de la segunda dosis. La aplicación de esquemas homólogos de vacuna Sinopharm (63,6% vs 13,3%, p<0,0001), y el uso de abatacept (27,3% vs 5,1%, p=0,005) y rituximab (18,2% vs 0%, p=0,001) al momento de la vacunación se asociaron a un resultado no reactivo o indeterminado. Conclusiones: similar a lo reportado en otras poblaciones internacionales, en esta cohorte, dos de cada 10 pacientes no desarrollaron anticuerpos. Una menor respuesta se asoció con la vacuna Sinopharm y al tratamiento con abatacept y rituximab.

Introduction: rheumatoid arthritis (RA) and its treatments can affect the response to the SARS-CoV-2 vaccine. However, we still do not have local data. Objectives: to evaluate the humoral response of the SARS-CoV-2 vaccine and its safety in this population. Materials and methods: observational study. Patients ≥18 years of age, with RA ACR/EULAR 2010 who had received vaccination for SARS-CoV-2 were included. Detection of anti-protein S IgG (COVIDAR Kit). Results: a total of 120 patients with RA were included. A quarter was receiving glucocorticoids, 50.9% biological drugs and 13.3% JAK inhibitors (janus kinases). Only 6% had a history SARS-CoV-2 infection. The most used vaccine was Sputnik V (52.9%) and 25% received mixed regimenes. After the first dose, 59% had a non-reactive or indeterminate test, and after the second, 18% were still having this result. The application of homologous Sinopharm vaccine regimen (63.6% vs 13.3%, p<0.0001) and the use of abatacept (27.3% vs 5.1%, p=0.005) and rituximab (18.2% vs 0%, p=0.001) at vaccination was associated with a non-reactive or indeterminate result. Conclusions: similar to other international populations, in this cohort, two out of 10 patients did not develop antibodies. A lower response was associated with the Sinopharm vaccine and treatment with abatacept and rituximab.

Gynecological/Obstetric Background and Rheumatoid Arthritis: A Cross-sectional Study in Brazilian Patients / Antecedentes ginecológicos/obstétricos e artrite reumatoide: Um estudo transversal em pacientes brasileiros

Abstract Objective To study a sample of rheumatoid arthritis (RA) patients for their gynecological/obstetric history and compare them to controls to determine their influences on number of pregnancies, menarche, menopause and reproductive years following RA onset. Methods This is a cross-sectional study of 122 RA patients and 126 controls. Patients and controls were questioned about age of menarche, age of menopause, number of pregnancies and abortions. Reproductive years were calculated as the difference between age at menopause and age at menarche. For comparison, we used the Mann-Whitney, unpaired t, chi-squared, and Spearman tests. The adopted significance was 5%. Results In the RA patients with disease beginning in the postmenopausal years, the period of reproductive years (age at menopause - age of menarche) showed a positive correlation with age at disease onset (rho=0.46; 95% confidence interval [CI]=0.20- 0.55 with p=0.0008). The number of pregnancies was higher in patients with postmenopausal disease onset when compared with those with premenopausal disease onset (median of 3 with interquartile range [IQR]=2-4 versus median of 2 with IQR=1-3; p=0.009), and RA patients had more pregnancies than controls (p=0.0002). Conclusion The present study shows that, in our population, the duration of reproductive years and the number of pregnancies are linked to the onset of RA.

Resumo Objetivo Estudar uma amostra de pacientes com artrite reumatoide (AR), com investigação da história ginecológica e obstétrica, comparando-a com controles, visando conhecer suas influências no número de gestações, menarcas, menopausa e anos reprodutivos no início da AR. Métodos Trata-se de um estudo transversal de 122 pacientes com AR e 126 controles. Pacientes e controles foram questionados sobre idade da menarca, idade da menopausa, número de gestações e abortos. Os anos reprodutivos foram calculados com a diferença entre a idade da menopausa e a idade da menarca. Para comparação, foram utilizados Mann Whitney, Teste t não pareados, Teste qui-quadrado e teste de Spearman. A significância adotada foi de 5%. Resultados Nas pacientes comAR e início da doença na pós-menopausa, o período de anos reprodutivos (idade da menopausa - idade da menarca) apresentou correlação positiva com a idade de início da doença (rho=0,46; intervalo de confiança de 95% [IC95%]=0,20-0,55 com p=0,0008). O número de gestações foi maior nas pacientes cominício da doença no período pós-menopausa quando comparadas às pacientes em pré-menopausa (mediana de 3 comintervalo interquartil [IIQ]=2-4 versusmediana de 2 com IIQ=1-3; p=0,009). Nas pacientes com AR, foi observado ummaior número de gestações do que no grupo controle (p=0,0002). Conclusão O presente estudo mostra que, em nossa população, a diminuição dos anos reprodutivos e o alto número de gestações estão relacionados ao surgimento da AR.

Depresión e inflamación: ¿Una relación más allá del azar? / Depression and inflammation: a relationship beyond random?

El tratamiento actual de la depresión mayor, una condición de alta prevalencia a nivel mundial, aún no resulta satisfactorio por las significativas tasas de falta de respuesta o de síntomas residuales. Esto, entre otras razones, ha motivado a la búsqueda de nuevos modelos de comprensión de los procesos biológicos que están a la base de esta enfermedad, con el propósito de encontrar mejores estrategias terapéuticas, al menos desde el punto de vista farmacológico. Se examinan algunas correspondencias entre los fenómenos clínicos y la articulación de los sistemas inmune, nervioso y endocrino, y se revisa algunas relaciones entre depresión y enfermedades inflamatorias sistémicas.

The current treatment of major depression, a condition of high prevalence worldwide, is still unsatisfactory due to the elevated rates of non-response or residual symptoms. This, among other reasons, has motivated the search for new models of understanding the biological processes that could better explain this disease, with the purpose of finding better therapeutic strategies, at least from the pharmacological point of view. Some correspondences between clinical phenomena and the interplay of the immune, nervous and endocrine systems are examined. Also, some relationships between depression and systemic inflammatory diseases are reviewed.

Predicción del riesgo coronario en la Artritis Reumatoide mediante variables asociadas a su actividad inmunológica / Prediction of coronary risk in Rheumatoid Arthritis by variables associated with its immunological activity

Introducción: el pronóstico del riesgo coronario a partir de la actividad en la artritis reumatoide constituye un problema aún vigente. Objetivos: evaluar la capacidad predictiva de factor reumatoide, proteína C reactiva, C3-C4 complemento, y el índice de actividad de la enfermedad empleándose 28 articulaciones sobre el riesgo coronario en esta enfermedad Métodos: se realizó un estudio longitudinal-prospectivo en una muestra de 50 pacientes. Los niveles séricos de: factor reumatoide, proteína c reactiva, C3, C4 complemento, lipoproteína(a), apolipoproteínas B y A1 fueron determinados por método inmunoturbidimétrico, mientras Colesterol total, colesterol de lioproteína de baja y alta densidad colesterol por ensayo enzimocolorimétrico. La velocidad de sedimentación globular fue determinada por método de Westergreen. El riesgo coronario se definió según valores deseables, o no, de los indicadores: lipoproteína (a), cocientes Apolipoproteína B/Apolipoproteína A1, colesterol de lipoproteína de baja densidad/colesterol de lipoproteína de alta densidad, Apolipoproteína B/colesterol de lipoproteína de baja densidad e índice aterogénico. Se empleó el programa estadístico SPSS, versión 18.0 para el análisis. Resultados: el perfil de actividad inmunoinflamatoria de la captación mostró adecuada capacidad predictiva sobre el riesgo coronario [regresión logística: Test de Hosmer y Lemeshow: (p= 0,54), porciento global de predicción correcta: 64 y 90 por ciento, al primer y tercer mes]. Las variables C3 complemento, C4 complemento e índice de actividad de la enfermedad contribuyeron a la predicción directa del riesgo coronario según cocientes Apolipoproteína B/Apolipoproteína A1, colesterol de lipoproteína de baja densidad/colesterol de lipoproteína de alta densidad e índice aterogénico (p asociada al Odds ratio ≤ 0,05). Los marcadores del metabolismo lipoproteico estudiados, excepto el cociente Apolipoproteína B/colesterol de lipoproteína de baja densidad, correspondientes al mes y tercer mes de seguimiento fueron pronosticados a partir de C4, C3 complemento, índice de actividad de la enfermedad y proteína C reactiva al momento de la captación (regresión lineal: R2 con p asociada ≤ 0,05). El factor reumatoide no contribuyó a la predicción longitudinal del riesgo coronario estudiado. Conclusiones: se demostró la utilidad del perfil de marcadores de actividad de la artritis reumatoide analizados en la predicción del riesgo coronario(AU)

Introduction: the prognosis of coronary risk from the activity in rheumatoid arthritis is still a problem. Objectives: to evaluate the predictive capacity of rheumatoid factor, C-reactive protein, C3-C4 complement, and the activity index of the disease using 28 joints on coronary risk in this disease Methods: a longitudinal-prospective study was carried out in a sample of 50 patients. The serum levels of: rheumatoid factor, c-reactive protein, C3, C4 complement, lipoprotein (a), apolipoproteins B and A1 were determined by immunoturbidimetric method, while total cholesterol, low-density lipoprotein cholesterol and high-density cholesterol by enzyme-correlated assay. The erythrocyte sedimentation rate was determined by the Westergreen method. Coronary risk was defined according to desirable values, or not, of the indicators: lipoprotein (a), Apolipoprotein B / Apolipoprotein A1 ratios, low density lipoprotein cholesterol / high density lipoprotein cholesterol, Apolipoprotein B / low lipoprotein cholesterol density and atherogenic index. The statistical program SPSS, version 18.0 was used for the analysis. Results: the profile of immunoinflammatory activity of the uptake showed adequate predictive capacity on coronary risk [logistic regression: Hosmer and Lemeshow test: (p = 0.54), overall percentage of correct prediction: 64 and 90 percent, to the first and third month]. The variables C3 complement, C4 complement and index of disease activity contributed to the direct prediction of coronary risk according to the Apolipoprotein B / Apolipoprotein A1, low density lipoprotein cholesterol / high density lipoprotein cholesterol and atherogenic index (p associated with Odds ratio ≤ 0.05). The lipoprotein metabolism markers studied, except for the Apolipoprotein B / low density lipoprotein cholesterol ratio, corresponding to the month and third month of follow-up were predicted from C4, C3 complement, disease activity index and C-reactive protein at the time of the uptake (linear regression: R2 with associated p≤0.05). The rheumatoid factor did not contribute to the longitudinal prediction of coronary risk studied. Conclusions: the usefulness of the profile of activity markers of rheumatoid arthritis analyzed in the prediction of coronary risk was demonstrated(AU)

Efecto antiiflamatorio de la fracción flavonoide de Lepechinia meyenii (Walp.) Epling (salvia) sobre leucocitos de pacientes con artritis reumatoide / Anti-Inflammatory Effect of The Flavonoid Fraction of Lepechinia meyenii (Walp.) Epling (SAGE) on Leukocytes of Patients With Rheumatoid Arthritis

RESUMEN Objetivos . Evaluar el efecto antiinflamatorio de la fracción flavonoide de Lepechinia meyenii (Walp.) Epling sobre leucocitos de pacientes con artritis reumatoide (AR). Materiales y métodos. Se recolectaron plantas de la especie Lepechinia meyenii (Walp.) Epling extrayendo diferentes fracciones flavonoides por cromatografía de columna y de capa fina. Se evaluó la producción de anión superóxido mediante la técnica de ensayo reducción nitroblue tetrazolium, en neutrófilos obtenidos de sangre de pacientes con AR, separados en tres grupos: control negativo, que consistió de neutrófilos (5x105 células), control positivo, formado por neutrófilos activados con PMA (phorbol myristate acetate) (150 ng/mL) y los tratamientos, formados por neutrófilos activados y tratados con diferentes concentraciones de la fracción flavonoide LM8 (60, 120 y 180 ug/mL). La expresión de genes proinflamatorios se estudió por RTqPCR, en leucocitos mononucleares obtenidos de pacientes con AR separados en tres grupos: control negativo, que consistió de leucocitos mononucleares (5x105 células), control positivo formado por leucocitos mononucleares activados con fitohemaglutinina (PHA) (150 ug/mL) y el tratamiento formado por leucocitos mononucleares activados y tratados con la fracción flavonoide LM8 (120 ug/mL). Resultados . Se purificaron varias fracciones flavonoides, resultando la fracción LM8 con el mejor efecto inmunomodulador. Dicha fracción disminuyó la producción de anión superóxido en una manera dependiente de la concentración. Por otro lado, disminuyó la expresión de TNFα, IL8 e IL17 en leucocitos mononucleares. Conclusiones. Estos resultados son alentadores respecto al efecto inmunomodulador de esta planta medicinal peruana y justifican continuar su estudio para una posible aplicación clínica.

ABSTRACT Objectives. to assess the anti-inflammatory effect of the flavonoid fraction of Lepechinia meyenii (Walp.) Epling on leukocytes of patients with rheumatoid arthritis (RA). Materials and Methods. Plants of the species Lepechinia meyenii (Walp.) Epling were collected and then different flavonoid fractions were extracted by column and thin layer chromatography. The superoxide anion production was evaluated by means of the reduction of nitroblue tetrazolium assay technique in neutrophils obtained from the blood of patients with RA, divided into three groups: negative control, which consisted of neutrophils (5x105 cells); positive control, made up of PMA (phorbol myristate acetate)-activated neutrophils (150 ng/mL), and the treatments, comprised of neutrophils activated and treated with different concentrations of the flavonoid fraction LM8 (60, 120, and 180 ug/mL). The expression of pro- inflammatory genes was studied by RTqPCR in mononuclear leukocytes obtained from patients with RA, divided into three groups: negative control, which consisted of mononuclear leukocytes (5x105 cells); positive control, made up of phytohaemagglutinin (PHA) (150 ug/ml)-activated mononuclear leukocytes, and the treatment, comprised of mononuclear leukocytes activated and treated with the flavonoid fraction LM8 (120 ug/mL). Results. Several flavonoid fractions were purified, with fraction LM8 showing the best immunomodulating effect. Said fraction diminished the superoxide anion production dependent on concentration. On the other hand, it diminished the expression of TNFα, IL8, and IL17 in mononuclear leukocytes. Conclusions. These results are encouraging in terms of the immunomodulating effect of this Peruvian medicinal plant and justify the continuation of their study for a potential clinical application.

Smoking promotes exacerbated inflammatory features in dendritic cells of Chilean rheumatoid arthritis patients / El tabaco exacerba características inflamatorias en células dendríticas de pacientes chilenos con artritis reumatoide

ABSTRACT Background: The dual potential to promote tolerance or inflammation when facing self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. There is an association between smoking and DCs maturation in patients with rheumatoid arthritis (RA). However, ethnicity is a key factor in autoimmune disorders. Aim: To evaluate phenotypic and functional alterations of DCs obtained from Chilean patients with RA as compared to healthy controls (HC). In second term, to compare the inflammatory behaviour of DCs between smoker and non-smoker patients. Material and Methods: Monocyte-derived DCs and T-cells were obtained from blood samples isolated from 30 HC and 32 RA-patients, 14 of which were currently smokers and 18 non-smokers. Several maturation surface markers were evaluated in DCs, including HLA-DR, CD40, CD80, CD83 and CD86. Furthermore, autologous co-cultures of DCs and T-cells were carried out and then T-cell proliferation, and expansion of Th1, Th17 and Tregs were analysed. Results: Compared with HC, RA-patients displayed increased HLA-DR expression in DCs, which was manifested mainly in patients with moderate-to- high disease activity scores (DAS28). Furthermore, RA-patients presented a stronger Th17-expansion and a correlation between DAS28 and Th1-expansion. Both effects were mainly observed in patients in remission or with a low DAS28. Moreover, smoker RA-patients displayed enhanced HLA-DR and CD83 expression in DCs as well as an exacerbated Th17-expansion and a correlation between DAS28 and Th1-expansion. Conclusions: These findings suggest that smoking enhances the inflammatory behaviour of DCs and the consequent Th1 and Th17-mediated response in patients with RA

Introducción: El potencial dual que poseen para promover tolerancia o inflamación ante antígenos propios, hace de las células dendríticas (CDs) actores fundamentales en el desarrollo de autoinmunidad. Existe una asociación entre fumar y la maduración de las CDs en pacientes con artritis reumatoide (AR). No obstante, la etnicidad es un factor clave a considerar en desórdenes autoinmunes. Objetivos: Comparar las alteraciones fenotípicas y funcionales de las CDs obtenidas desde pacientes Chilenos con AR y controles sanos (CS). Además, analizamos las diferencias en el comportamiento inflamatorio que existe entre las CDs obtenidas de pacientes fumadores y CS. Materiales y Métodos: Se obtuvieron CDs derivadas de monocitos y células T desde muestras de sangre aisladas de 30 CS y 32 pacientes con AR, 14 de los cuales eran fumadores y 18 no fumadores. Se evaluaron marcadores de maduración en la superficie de las CDs: HLA-DR, CD40, CD80, CD83 y CD86. Además, se realizaron co-cultivos autólogos de células T y CDs, analizando la proliferación de células T, y la expansión de células Th1, Th17 y Tregs. Resultados: En comparación con los CS, los pacientes AR mostraron un aumento de la expresión de HLA-DR en las CDs, principalmente en los individuos con DAS28 moderado-alto. Los pacientes con AR presentaron una mayor expansión de células Th17 y una correlación entre el DAS28 y la expansión de células Th1, ambos efectos manifestados principalmente en los individuos con un DAS28 bajo o en remisión. Además, los pacientes con AR fumadores mostraron un aumento en la expresión de HLA-DR y CD83 en las CDs y una expansión de células Th17 exacerbada así como una correlación entre el DAS28 y la expansión de células Th1. Conclusiones: Nuestros resultados sugieren que fumar favorece el comportamiento inflamatorio de las CDs y en consecuencia la inducción de respuestas mediadas por células Th1 y Th17 en los pacientes Chilenos con AR.

Prevalence of thyroid autoantibodies in patients with systematic autoimmune rheumatic diseases. Cross-sectional study

ABSTRACT BACKGROUND: Thyroid autoimmunity is more common in patients with rheumatic diseases than in healthy populations. The degree of association seems subject to influence from patients' geographical location. Here, we aimed to ascertain the prevalence of thyroid autoantibodies in a cohort of patients with systemic rheumatic disease and the degree of association between its presence and inflammatory activity. DESIGN AND SETTING: Cross-sectional observational study in a rheumatology unit. METHODS: 301 patients with systemic lupus erythematosus (SLE), 210 with rheumatoid arthritis (RA), 58 with scleroderma (SSc) and 80 with spondyloarthritis (SpA) were studied regarding thyroid function (TSH and T4), anti-thyroglobulin (TgAb) and anti-thyroperoxidase (TPOab) and compared with 141 healthy controls. Disease activity in patients with rheumatic disease was assessed through appropriate indexes. RESULTS: There were more antithyroid antibodies in SLE patients with hypothyroidism (P = 0.01; odds ratio, OR 2.7; 95% confidence interval, CI: 1.20-6.26) and in those without hypothyroidism (P = 0.06; OR 2.4; 95% CI: 1.28-4.55) than in controls. SSc patients also showed: P = 0.03 both with antithyroid antibodies and hypothyroidism (OR 3.4; 95% CI: 1.06-10.80) and without hypothyroidism (OR 3.1; 95% CI: 1.11-0.13). RA and SpA patients had the same prevalence as controls (P not significant). Presence of autoantibodies with and without hypothyroidism was not associated with the activity or functional indexes evaluated. CONCLUSION: SLE and SSc were associated with higher prevalence of thyroid autoantibodies in patients with and without hypothyroidism, unlike SpA and RA. There was no link between thyroid autoantibody presence and disease activity or functional impairment.

Correlation between cellular expression of complement regulatory proteins with depletion and repopulation of B-lymphocytes in peripheral blood of patients with rheumatoid arthritis treated with rituximab / Correlação entre expressão celular de proteínas reguladoras do complemento com a depleção e repopulação de linfócitos B no sangue periférico de pacientes com artrite reumatoide tratada com rituximabe

Abstract Objectives: To correlate the basal expression of complement regulatory proteins (CRPs) CD55, CD59, CD35, and CD46 in B-lymphocytes from the peripheral blood of a cohort of 10 patients with rheumatoid arthritis (RA) initiating treatment with rituximab (RTX) with depletion and time repopulation of such cells. Methods: Ten patients with RA received two infusions of 1 g of RTX with an interval of 14 days. Immunophenotypic analysis for the detection of CD55, CD59, CD35, and CD46 on B-lymphocytes was carried out immediately before the first infusion. The population of B-lymphocytes was analyzed by means of basal CD19 expression and after 1, 2, and 6 months after the infusion of RTX, and then quarterly until clinical relapse. Depletion of B-lymphocytes in peripheral blood was defined as a CD19 expression <0.005 × 109/L. Results: Ten women with a median of 49 years and a baseline DAS28 = 5.6 were evaluated; 9 were seropositive for rheumatoid factor. Five patients showed a repopulation of B-lymphocytes after 2 months, and the other five after 6 months. There was a correlation between the basal expression of CD46 and the time of repopulation (correlation coefficient = −0.733, p = 0.0016). A similar trend was observed with CD35, but without statistical significance (correction coefficient = −0.522, p = 0.12). Conclusion: The increased CD46 expression was predictive of a faster repopulation of B-lymphocytes in patients treated with RTX. Studies involving a larger number of patients will be needed to confirm the utility of basal expression of CRPs as a predictor of clinical response.

Resumo Objetivos: Correlacionar a expressão basal das proteínas reguladoras do complemento (PRC) CD55, CD59, CD35 e CD46 nos linfócitos B do sangue periférico de uma coorte de 10 pacientes com artrite reumatoide (AR) iniciando tratamento com rituximabe (RTX) com a depleção e tempo de repopulação dessas células. Métodos: Dez pacientes com AR receberam duas infusões de 1 g de RTX com intervalo de 14 dias. Análises imunofenotípicas para detecção de CD55, CD59, CD35 e CD46 nos linfócitos B foram feitas imediatamente antes da primeira infusão. A população de linfócitos B foi analisada por meio da expressão de CD19 basal e após um, dois e seis meses após a infusão de RTX e então trimestralmente até a recaída clínica. Depleção de linfócitos B no sangue periférico foi definida como expressão de CD19 < 0,005 × 109/l. Resultados: Dez mulheres com mediana de 49 anos e DAS 28 basal de 5,6 foram avaliadas; nove eram soropositivas para o fator reumatoide. Cinco pacientes apresentaram repopulação de linfócitos B após dois meses e as outras cinco aos seis meses. Houve correlação entre a expressão basal de CD46 e o tempo de repopulação (coeficiente de correlação -0,733, p = 0,0016). Tendência semelhante foi observada com CD35, porém sem significância estatística (coeficiente de correção 0,522, p = 0,12). Conclusão: Expressão aumentada de CD46 foi preditora de repopulação mais rápida de linfócitos B em pacientes tratados com RTX. Estudos com um número maior de pacientes serão necessários para confirmar a utilidade da expressão basal das PRC como preditora de resposta clínica.

Intestinal parasites infection: protective effect in rheumatoid arthritis? / Parasitoses intestinais: efeito protetor na artrite reumatoide?

Abstract Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, with a progressive course, characterized by chronic synovitis that may evolve with deformities and functional disability, and whose early treatment minimizes joint damage. Its etiopathogenesis is not fully elucidated but comprises immunologic responses mediated by T helper cells (Th1). An apparent minor severity of RA in patients from regions with lower income could be associated with a higher prevalence of gut parasites, especially helminths. Strictly, a shift in the immune response toward the predominance of T helper cells (Th2), due to the chronic exposure to helminths, could modulate negatively the inflammation in RA patients, resulting in lower severity/joint injury. The interaction between the immunological responses of parasitic helminths in rheumatoid arthritis patients is the purpose of this paper.

Resumo A artrite reumatoide (AR) é uma doença inflamatória autoimune, sistêmica, de curso progressivo, caracterizada por exuberante sinovite crônica, que pode gerar deformidades e incapacidade funcional, cujo tratamento precoce minimiza o dano às juntas. Sua etiopatogenia ainda não está completamente elucidada, mas compreende respostas imunológicas com a participação de células T auxiliares (Th1). Uma aparente menor gravidade da AR em pacientes de regiões com menor renda poderia estar associada a maior prevalência de parasitoses intestinais, especialmente as helmintíases. A rigor, um desvio na resposta imune para o predomínio de células T auxiliares (Th2), decorrente da exposição crônica a helmintos, modularia negativamente a inflamação em doentes com AR, e levaria a menor gravidade e dano articular. A revisão de aspectos da influência da reposta imunológica nas parasitoses intestinais, especialmente as helmintíases, em pacientes com artrite reumatoide é o objetivo desse trabalho.

Independence of carbohydrate-deficient isoforms of transferrin and cyclic citrullinated peptides in rheumatoid arthritis / Independência de isoformas de transferrina deficiente em carboidrato e peptídeos citrulinados cíclicos na artrite reumatoide

ABSTRACT Objective: The aim of this study was to assess the relationship between the two types of posttranslational modifications of proteins in RA: glycosylation on the example of carbohydrate-deficient transferrin and citrullination by means of autoantibodies to cyclic citrullinated peptides. Methods: The study was carried out in 50 RA patients. CDT was measured using N Latex CDT immunonephelometric test, the results were presented in absolute and relative units. Anti-CCP were measured using the chemiluminescent method and rheumatoid factor by immunoturbidimetric method. Results: 80% of RA patients were positive for anti-CCP, 70% for RF and 62% for both, anti-CCP and RF. The level of %CDT was significantly elevated, but absolute CDT level was not changed. The mean absolute CDT concentration was higher in anti-CCP positive patients than that in anti-CCP negative. CDT (absolute and relative concentration) did not correlate with anti-CCP and RF. However, serum RF significantly correlated with anti-CCP. %CDT did not correlate with anti-CCP, but absolute level correlated with anti-CCP only in anti-CCP negative and RF negative patients. CDT did not correlate with RF, but solely with anti-CCP in anti-CCP negative patients. Anti-CCP correlated with DAS 28 only in anti-CCP negative RA, but CDT (absolute and relative units) correlated with DAS 28 in all patients and in anti-CCP positive RA. Conclusions: These results suggest that the changes in CDT and anti-CCP concentrations are not associated with oneself and indicate on the independence of these posttranslational modifications in rheumatoid arthritis. Only the alterations in transferrin glycosylation reflected the activity of RA.

RESUMO Objetivo: Avaliar a relação entre os dois tipos de modificações pós-translacionais de proteínas na AR: glicosilação no caso da transferrina deficiente em carboidrato (TDC) e citrulinação por meio dos anticorpos no caso do antipeptídeo citrulinado cíclico (anti-CCP). Métodos: O estudo foi feito em 50 pacientes com AR. A TDC foi medida com o teste imunonefelométrico N Latex CDT e os resultados foram apresentados em unidades absolutas e relativas. O anti-CCP foi mensurado com o método quimioluminescente e o fator reumatoide (FR) pelo método imunoturbidimétrico. Resultados: Dos pacientes com AR, 80% foram positivos para anti-CCP, 70% para FR e 62% para ambos (anti-CCP e FR). A percentagem de transferrina total (%TDC) esteve significativamente elevada, mas o nível absoluto de TDC não esteve alterado. A concentração média de TDC absoluta foi maior nos pacientes anti-CCP positivos do que naqueles anti-CCP negativos. A TDC (concentração absoluta e relativa) não se correlacionou com o anti-CCP e o FR. No entanto, o FR sérico se correlacionou significativamente com o anti-CCP. O percentual de TDC não se correlacionou com o anti-CCP, mas seu nível absoluto se correlacionou com o anti-CCP apenas em pacientes FR negativos e anti-CCP negativos. A TDC não se correlacionou com o FR, somente com o anti-CCP em pacientes anti-CCP negativos. O anti-CCP se correlacionou com o DAS 28 apenas nos pacientes com AR anti-CCP negativos, mas a TDC (unidades absolutas e relativas) se correlacionou com o DAS 28 quando considerados todos os pacientes com AR e em pacientes com AR anti-CCP positivos. Conclusões: Esses resultados sugerem que as alterações na TDC e as concentrações de anti-CCP não estão associadas e indicam a independência dessas modificações pós-translacionais na artrite reumatoide. Apenas as alterações na glicosilação da transferrina refletem a atividade da AR.

Unbalanced expression of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of rheumatoid arthritis / Expressão não equilibrada do receptor de hidrocarboneto arílico nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ do sangue periférico na artrite reumatoide

ABSTRACT Objective: The goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of patients with rheumatoid arthritis. Methods: Flow cytometry was applied to determine the proportion of AhR positive cells in CCR6+CD4+T, CD4+CD25+T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real-time PCR. Results: The percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23 ± 10.71)% vs. (18.83 ± 7.32)%, p < 0.01]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71 ± 1.63) vs. (2.00 ± 1.27), p = 0.002; (2.62 ± 2.08) vs. (0.62 ± 0.29), p < 0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4+CD25+T cells was significantly lower than that from controls [17.90 (6.10 ± 80.10)% vs. (52.49 ± 19.18)%, p < 0.01]; In healthy controls, the percentage of AhR positive cells in CD4+CD25+T cells was significantly higher than that in CCR6+CD4+T cells, and was also significantly higher than that in PBMCs [(52.49 ± 19.18)% vs. (23.18 ± 5.62)% vs. (18.06 ± 7.80)%, X 2 = 24.03, p < 0.01]; in RA patients, the percentage of AhR positive cells in CCR6+CD4+T cells was significantly increased than that in CD4+CD25+T cells and PBMCs [(46.02 ± 14.68)% vs. 17.90 (6.10 ± 80.10)% vs. (34.22 ± 10.33)%, X 2 = 38.29, p < 0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6+CD4+T and CD4+CD25+T cells. Conclusion: AhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood.

RESUMO Objetivo: Analisar o papel do receptor de hidrocarboneto arílico (AhR) nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ no sangue periférico de pacientes com artrite reumatoide (AR). Métodos: Foi aplicada citometria de fluxo para determinar a proporção de células AhR positivas em linfócitos CCR6+ CD4+ e CD4+ CD25+ do sangue periférico e células mononucleares periféricas de cada indivíduo. Os níveis de expressão relativa de ácido ribonucleico mensageiro (do inglês ribonucleic acid, RNAm,) de AhR e RNAm de enzima de primeiro estágio essencial para o AhR (CYP1A1) foram testados por reação em cadeia de polimerase (do inglês polymerase chain reaction, PCR,) em tempo real. Resultados: A percentagem de células AhR positivas nas células mononucleares do sangue periférico foi maior no grupo com AR do que nos indivíduos saudáveis [(35,23 ± 10,71)% vs. (18,83 ± 7,32)%, (p < 0,01)]. Os níveis de expressão de AhR e CYP1A1 estavam aumentados em pacientes com AR quando comparados com os controles [(3,71 ± 1,63) vs. (2,00 ± 1,27), p = 0,002; (2,62 ± 2,08) vs. (0,62 ± 0,29), p < 0,01, respectivamente]. Em pacientes com AR, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente inferior à dos controles [17,90 (6,10 ± 80,10)]% vs. (52,49 ± 19,18)%, p < 0,01]; em controles saudáveis, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente mais elevada do que nos linfócitos T CCR6+ CD4+ e também foi significativamente maior do que nas células mononucleares do sangue periférico (do inglês peripheral blood mononuclear cells, PBMC,) [(52,49 ± 19,18)% vs. (23,18 ± 5,62)% vs. (18,06 ± 7,80)%, X 2 = 24,03, p < 0,01]; em pacientes com AR, a percentagem de células AHR positivas nos linfócitos T CCR6+ CD4+ era significativamente maior em comparação com os linfócitos T CD4+ CD25+ e PBMC (46,02 ± 14,68)% vs. [17,90 (6,10 ± 80.10)]% vs. (34,22 ± 10,33)%, X2 = 38,29, p < 0,01]; no entanto, não foi encontrada correlação estatisticamente significativa entre os dados clínicos e células AhR positivas em linfócitos T CCR6+ CD4+ e CD4+ CD25+. Conclusão: O Ahr pode participar do progresso patológico da AR ao controlar a diferenciação de linfócitos Th17 e Treg no sangue periférico.

Anti-CCP antibodies are not a marker of severity in established rheumatoid arthritis: a magnetic resonance imaging study / O anti-CCP não é um marcador de gravidade da artrite reumatoide estabelecida: um estudo de ressonância magnética

ABSTRACT Introduction: The presence of anti-CCP is an important prognostic tool of rheumatoid arthritis (RA). But research is still ongoing on its relationship with disease activity and functional capacity. Objectives: To study the relationship between anti-CCP and disease activity, functional capacity and structural damage indexes, by means of conventional radiography (CR) and magnetic resonance imaging (MRI), in cases of established RA. Methods: Cross-sectional study with RA patients with 1–10 disease duration. Participants underwent clinical evaluation with anti-CCP. Disease activity was assessed using the Clinical Disease Activity Index (CDAI), and functional capacity through the Health Assessment Questionnaire (HAQ). CR analysis was carried out by the Sharp van der Heijde index (SvdH), and MRI analysis by RAMRIS (Rheumatoid Arthritis Magnetic Resonance Image Scoring). Results: We evaluated 56 patients, with a median (IqR) age of 55 (47.5–60) years; 50 (89.3%) participants were female and 37 (66.1%) were positive for anti-CCP. Medians (IqR) of CDAI, HAQ, SvdH and RAMRIS were 14.75 (5.42–24.97) 1.06 (0.28–1.75), 2 (0–8) and 15 (7–35), respectively. There was no association between anti-CCP and CDAI, HAQ and SvdH and RAMRIS scores. Conclusion: Our results have not established an association of anti-CCP with the severity of disease. To date, we cannot corroborate anti-CCP as a prognostic tool in patients with established RA.

RESUMO Introdução: A presença do anti-CCP constitui importante ferramenta prognóstica da artrite reumatoide (AR), mas ainda se investiga sua relação com a atividade da doença e a a capacidade funcional. Objetivos: Estudar a relação do anti-CCP com os índices de atividade da doença, de capacidade funcional e de dano estrutural, por meio de radiografia convencional (RC) e de ressonância magnética (RM), em AR estabelecida. Métodos: Estudo transversal com pacientes com AR, com um a 10 anos de doença. Os participantes foram submetidos à avaliação clínica com pesquisa do anti-CCP. A atividade de doença foi avaliada por meio do Clinical Disease Activity Index (CDAI) e a capacidade funcional por meio do Health Assessment Questionnaire (HAQ). A análise da RC foi feita pelo índice de Sharp van der Heijde (SmvH) e da RM pelo Sistema de Pontuação de Imagem por Ressonância Magnética na Artrite Reumatoide (RAMRIS, Rheumatoid Arthritis Magnetic Resonance Image Scoring). Resultados: Foram avaliados 56 pacientes, com mediana (IIq) de 55 (47,5-60,0) anos, 50 (89,3%) do sexo feminino e 37 (66,1%) anti-CCP positivos. As medianas (IIq) do CDAI, do HAQ, de SmvH e do RAMRIS foram de 14,75 (5,42-24,97), 1,06 (0,28-1,75), 2 (0-8) e 15 (7-35), respectivamente. Não houve associação do anti-CCP com o CDAI, com o HAQ e com os escores SmvH e RAMRIS. Conclusão: Nossos resultados não estabeleceram a associação do anti-CCP com a gravidade da doença. Até o momento, não podemos corroborar o anti-CCP como uma ferramenta prognóstica em AR estabelecida.

Reactivation of cutaneous and mucocutaneous tegumentary leishmaniasis in rheumatoid arthritis patients: an emerging problem?

ABSTRACT Rheumatoid arthritis (RA) is a chronic condition that is frequent in patients living in tropical areas exposed to leishmaniasis. RA therapy involves immunosuppressant drugs such as methotrexate (MTX), monoclonal antibodies (mAbs) and prednisone. We report an unusual presentation of cutaneous (CL) or mucocutaneous leishmaniasis (ML) in RA patients from an endemic area of leishmaniasis. A 51-year-old woman noted a cutaneous ulcer on her left ankle during MTX and prednisone RA therapy. Initially diagnosed as a venous stasis ulcer, the aspirate of the injury revealed the presence of Leishmania DNA. A 73-year-old woman presenting non-ulcerated, infiltrated and painful erythematous nodules inside her nostrils while receiving MTX, anti-TNF mAb, and prednisone for RA, had also the aspirate of injuries showing the presence of Leishmania DNA. Both patients healed after the therapy with liposomal amphotericin. The RA therapy has changed to low-dose prednisone, without further reactivation episodes. Both cases suggest that CL or ML can reactivate after administration of an immunosuppressant for RA treatment. Therefore, immunosuppressive treatments for RA should be carefully prescribed in patients from endemic areas or with a history of CL and ML.

Posible papel de Porphyromonas gingivalis en el desarrollo de la artritis reumatoide / Possible role of Porphyromonas gingivalis in the develpment of rheumatoid arthritis

Varios estudios han sugerido una asociación entre la periodontitissevera, la prevalencia de la bacteria Porphyromonas gingivalis y el desarrollo de artritis reumatoide. Como fundamento de esta relación, se ha observado que esta bacteria secreta una enzima, peptidil-arginina deiminasa, que es capaz de citrulinar proteínas del hospedero y así favorecer una respuesta autoinmune. Sin embargo, debido a la heterogeneidad de diseños experimentales, selección de pacientes y valoración de los desenlaces, los resultados no han mostrado la reproducibilidad deseada. Asimismo, observaciones recientes apuntan a que la actividad enzimática podría ser generada por otras especies bacterianas, lo que hace más compleja su relación. Sin embargo, por otro lado, algunos estudios sugieren que el tratamiento periodontal puede limitar el desarrollo de la artritis reumatoide.

Various studies have suggested a link between severe periodontitis,the prevalence of Porphyromonas gingivalis, and the development ofrheumatoid arthritis. As evidence of this relationship, P. gingivalis hasbeen found to secrete an enzyme, peptidyl arginine deiminase, which isable to citrullinate host proteins and thus help activate an autoimmuneresponse. However, due to the heterogeneity of experimental designs,patient selection, and assessment of clinical outcomes, the results havenot shown the desired reproducibility. Furthermore, recent fi ndingsindicate that the enzymatic activity may be produced by other species ofbacteria, which suggests the relationship is more complex. However, anumber of studies have shown that periodontal treatment could inhibitthe development of rheumatoid arthritis.

IL33 in rheumatoid arthritis: potential contribution to pathogenesis / Ação da IL33 na artrite reumatoide: contribuição para a fisiopatalogia

ABSTRACT A better understanding of the inflammatory mechanisms of rheumatoid arthritis and the development of biological therapy revolutionized its treatment, enabling an interference in the synovitis – structural damage – functional disability cycle. Interleukin 33 was recently described as a new member of the interleukin-1 family, whose common feature is its pro-inflammatory activity. Its involvement in the pathogenesis of a variety of diseases, including autoimmune diseases, raises the interest in the possible relationship with rheumatoid arthritis. Its action has been evaluated in experimental models of arthritis as well as in serum, synovial fluid and membrane of patients with rheumatoid arthritis. It has been shown that the administration of interleukin-33 exacerbates collagen-induced arthritis in experimental models, and a positive correlation between cytokine concentrations in serum and synovial fluid of patients with rheumatoid arthritis and disease activity was found. This review discusses evidence for the role of interleukin-33 with a focus on rheumatoid arthritis.

RESUMO A melhor compreensão dos mecanismos inflamatórios da artrite reumatoide e o desenvolvimento da terapia biológica revolucionaram o tratamento da doença, permitindo uma interferência no ciclo sinovite–dano estrutural–incapacidade funcional. A interleucina 33 foi recentemente descrita como um novo membro da família da interleucina 1, cuja característica comum é a atividade pró-inflamatória. Por estar envolvida na patogênese de uma grande variedade de doenças, incluindo doenças autoimunes, a interleucina 33 começa a ser estudada na doença reumatoide. Ela tem sido avaliada em modelos experimentais de artrite, no soro, no líquido e membrana sinoviais de pacientes com artrite reumatoide. Demonstrou-se que a administração da interleucina 33 exacerba a artrite induzida por colágeno em modelos experimentais, e concentrações dessa citocina no soro e no líquido sinovial de pacientes com artrite reumatoide correlacionaram-se positivamente com a atividade da doença. Esse manuscrito apresenta a interleucina 33 e discute as evidências do seu papel em diferentes doenças, com ênfase na artrite reumatoide.

Overlap between systemic sclerosis and rheumatoid arthritis: a distinct clinical entity? / Sobreposição de esclerose sistêmica e artrite reumatoide: uma entidade clínica distinta?

ABSTRACT Introduction: Systemic sclerosis (SSc) is an autoimmune disease of the connective tissue characterized by the triad of vascular injury, autoimmunity (cellular and humoral) and tissue fibrosis. It is estimated that musculoskeletal pain is a common complaint of patients with SSc, ranging from 40 to 80%, and mainly in patients with early diffuse disease. Arthritis, clinically observed, may be a feature seen in the presentation of SSc, often leading to early diagnostic errors with rheumatoid arthritis (RA). In the course of the disease, arthritis is observed in 24–97% of patients with SSc. Objectives: To correlate the occurrence or nonoccurrence of arthritis in patients with SSc of the Midwest region of Brazil with possible distinct clinical and laboratory manifestations observed in three groups of patients. To report the frequency of true association between systemic sclerosis and rheumatoid arthritis in patients with clinically and radiologically observed synovitis. Methods: Sixty-one SSc patients were subsequently assessed every 3 months within 1 year, in order to clinically observe the occurrence of synovitis and its patterns of progression. Patients were divided into 3 groups: 41 patients with SSc without arthritis, 16 SSc patients with arthritis and 4 patients with overlap of SSc and RA. All patients underwent a radiological examination of the hands at the end of the study. Results: Among all patients evaluated, we found a female predominance (98.7%), mean age of 50.94 years, white color (49.2%), limited form of the disease (47.6%), time of diagnosis between 5 and 10 years (47.6%) and duration of the disease of 8.30 years. Among all patients, 14 (22.9%) had positive rheumatoid factor (RF), while among those with positive RF, only 10 patients had arthritis during one-year follow-up. The antibody anticitrulline (anti-CCP) test was performed in 24 patients, being positive in 4 of them (16.7%), with positivity being observed only in patients with SSc/RA overlap. Comparing the clinical manifestations among the groups of patients, there was a higher incidence of gastritis and cardiac valvulopathy in patients with SSc and arthritis, but not in the others. In the group of patients with SSc/RA overlap and in patients with SSc and arthritis a significant reduction in quality of life was observed, measured by HAQ index, especially in patients with arthritis present during clinical evaluation. We found radiographic changes in 42.6% of patients with SSc. However, in patients with synovitis, radiological changes consistent with rheumatoid arthritis were found in 50% of patients. Conclusions: While the frequency of clinical arthritis observed in patients with systemic sclerosis was 32.8%, the true overlap between of SSc and RA was 6.6% in this study. We also observed the frequency of positive anti-CCP in 20% of patients with arthritis versus no patients with SSc without arthritis.

RESUMO Introdução: A esclerose sistêmica (ES) é uma enfermidade do tecido conjuntivo de caráter autoimune caracterizada pela tríade de injúria vascular, autoimunidade (celular e humoral) e fibrose tecidual. Estima-se que a dor musculoesquelética seja uma queixa frequente dos pacientes com ES, que oscila entre 40% e 80%, e principalmente em pacientes com doença difusa precoce. A artrite, clinicamente observada, pode ser uma característica observada na apresentação da ES, frequentemente leva a erros diagnósticos iniciais com artrite reumatoide (AR). No curso da enfermidade, a artrite é observada em 24% a 97% dos pacientes com ES. Objetivos: Correlacionar a ocorrência ou não de artrite em pacientes com ES da região Centro-Oeste do Brasil com possíveis manifestações clínicas e laboratoriais distintas observadas em três grupos de pacientes. Relatar a frequência de verdadeira associação entre esclerose sistêmica e artrite reumatoide em pacientes com sinovite clínica e radiologicamente observada. Métodos: Foram avaliados 61 pacientes portadores de ES subsequentemente a cada três meses durante um ano, para fins de se constatar clinicamente a ocorrência de sinovite e padrões de evolução. Os pacientes foram divididos em três grupos: 41 com ES sem artrite, 16 com ES com artrite e quatro com sobreposição entre ES e AR. Todos os pacientes foram submetidos a exame radiológicos das mãos no fim do estudo. Resultados: Dentre todos os pacientes avaliados, encontrou-se predomínio feminino (98,7%), idade média de 50,94 anos, cor branca (49,2%), forma limitada da doença (47,6%), tempo de diagnóstico entre cinco e 10 anos (47,6%) e tempo de evolução da doença de 8,30 anos. Entre todos os pacientes, 14 (22,9%) apresentavam fator reumatoide (FR) positivo, embora entre aqueles com FR positivo apenas 10 apresentaram artrite durante o seguimento de um ano. O anticorpo anticitrulina (anti- CCP) foi feito em 24 pacientes, com positividade em quatro deles (16,7%), observada somente nos pacientes com sobreposição ES/AR. Na comparação das manifestações clínicas entre os grupos de pacientes, observou-se a maior ocorrência de gastrite e valvulopatia cardíaca em pacientes com ES e artrite, mas não nos demais grupos. No grupo de pacientes com overlap ES/AR e nos pacientes com ES e artrite observou-se redução importante de qualidade de vida, medida pelo índice HAQ, sobretudo nos pacientes com artrite presente no momento da avaliação clínica. Encontramos alterações radiográficas em 42,6% dos pacientes com ES. Contudo, nos pacientes com sinovite, encontraram-se alterações radiológicas compatíveis com artrite reumatoide em 50%. Conclusões: Enquanto a frequência de artrite clínica observada em pacientes com esclerose sistêmica foi de 32,8%, a verdadeira sobreposição entre ES e AR foi de 6,6% neste estudo. Observou-se ainda a frequência de anti-CCP positivo em 20% dos pacientes com artrite contra nenhum paciente com ES sem artrite.

Familial autoimmunity and polyautoimmunity in 60 Brazilian Midwest patients with systemic sclerosis / Autoimunidade familial e poliautoimunidade em 60 pacientes portadores de esclerose sistêmica da região Centro-Oeste do Brasil

ABSTRACT Introduction: Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, characterized by a triad of vascular injury, autoimmunity and tissue fibrosis. It is known that a positive family history is the greatest risk factor already identified for the development of SSc in a given individual. Preliminary observation of a high prevalence of polyautoimmunity and of familial autoimmunity in SSc patients support the idea that different autoimmune phenotypes may share common susceptibility variants. Objectives: To describe the frequency of familial autoimmunity and polyautoimmunity in 60 SSc patients in the Midwest region of Brazil, as well as to report the main autoimmune diseases observed in this association of comorbidities. Methods: A cross-sectional study with recruitment of 60 consecutive patients selected at the Rheumatology Department, University Hospital, Medicine School, Federal University of Mato Grosso do Sul (FMUFMS), as well as interviews of their relatives during the period from February 2013 to March 2014. Results: A frequency of 43.3% of polyautoimmunity and of 51.7% of familial autoimmunity in SSc patients was found. Patients with the presence of polyautoimmunity and familial autoimmunity presented primarily the diffuse form of SSc, but this indicator did not reach statistical significance. The autoimmune diseases most frequently observed in polyautoimmunity patients were: Hashimoto's thyroiditis (53.8%), Sjögren's syndrome (38.5%), and inflammatory myopathy (11.5%). The main autoimmune diseases observed in SSc patients' relatives were: Hashimoto's thyroiditis (32.3%), rheumatoid arthritis (22.6%), and SLE (22.6%). The presence of more than one autoimmune disease in SSc patients did not correlate with disease severity or activity. Conclusions: From the high prevalence of coexisting autoimmune diseases found in SSc patients, we stress the importance of the concept of shared autoimmunity, in order to promote a continued vigilance and promptly diagnose other possible autoimmune disease in patients, or in their kin.

RESUMO Introdução: A esclerose sistêmica (ES) é uma enfermidade do tecido conjuntivo de etiologia desconhecida, caracterizada pela tríade de injúria vascular, autoimunidade e fibrose tecidual. Sabe-se que uma história familiar positiva representa o maior fator de risco já identificado para o desenvolvimento da ES em um determinado indivíduo. Observação prévia de alta prevalência de poliautoimunidade e de autoimunidade familiar em pacientes com ES reforça a ideia de que fenótipos autoimunes distintos podem dividir variantes comuns de susceptibilidade. Objetivos: Descrever a frequência de autoimunidade familiar e de poliautoimunidade em 60 pacientes com ES da região Centro-Oeste do Brasil, bem como relatar as principais doenças autoimunes observadas nessa associação de comorbidades. Métodos: Estudo transversal com recrutamento de 60 pacientes consecutivos, selecionados no Serviço de Reumatologia do Hospital Universitário da Faculdade de Medicina da Universidade Federal de Mato Grosso do Sul (FMUFMS), bem como entrevista de seus parentes, de fevereiro de 2013 a março de 2014. Resultados: Foi encontrada uma frequência de 43,3% de poliautoimunidade e de 51,7% de autoimunidade familiar nos pacientes com ES. Os pacientes com presença de poliautoimunidade e de autoimunidade familiar eram principalmente da forma difusa de ES, porém esse índice não atingiu significância estatística. As doenças autoimunes mais comumente observadas nos pacientes com poliautoimunidade foram: tireoidite de Hashimoto (53,8%), síndrome de Sjögren (38,5%) e miopatia inflamatória (11,5%). As principais doenças autoimunes observadas nos parentes dos pacientes com ES foram: tireoidite de Hashimoto (32,3%), artrite reumatoide (22,6%) e LES (22,6%). A presença de mais de uma enfermidade autoimune em pacientes com ES não se correlacionou com maior gravidade ou atividade da doença. Conclusões: A partir da alta prevalência encontrada de doenças autoimunes coexistentes em pacientes com ES, salientamos a importância do conceito de autoimunidade compartilhada, de forma a promover uma vigilância constante e diagnosticar prontamente uma possível outra doença autoimune nos pacientes ou em seus parentes.

The role of KIR2DL3/HLA-C*0802 in Brazilian patients with rheumatoid vasculitis

OBJECTIVES: Rheumatoid arthritis is a polygenically controlled systemic autoimmune disease. Rheumatoid vasculitis is an important extra-articular phenotype of rheumatoid arthritis that can result in deep cutaneous ulcers. The objective of this study was to establish a correlation between the frequency of major histocompatibility complex class I/II alleles and killer immunoglobulin-like receptor genotypes in patients with cutaneous rheumatoid vasculitis. METHODS: Using the Scott & Bacon 1984 criteria to diagnose rheumatoid vasculitis and after excluding any other causes such as diabetes, atherosclerosis, adverse drug reactions, infection, and smoking, patients who met the criteria were selected. All of the selected rheumatoid vasculitis patients presented deep cutaneous ulcers. Identification of the major histocompatibility complex class I/II and killer immunoglobulin-like receptor genotypes was performed by polymerase chain reaction assays of samples collected from the 23 rheumatoid vasculitis patients as well as from 80 controls (40 non-rheumatoid vasculitis RA control patients and 40 healthy volunteers). RESULTS: An association between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and cutaneous lesions in rheumatoid vasculitis patients and a correlation between the inhibitor KIR2DL3 and the HLA-C*0802 ligand in rheumatoid vasculitis patients were found. CONCLUSION: An association was found between the presence of the HLA-DRB1*1402 and HLA-DRB1*0101 alleles and the development of cutaneous lesions in rheumatoid vasculitis patients. Additionally, the HLA-C*0802 ligand protects these individuals from developing cutaneous lesions. .

The use of Mycobacterium tuberculosis HspX and GlcB proteins to identify latent tuberculosis in rheumatoid arthritis patients

Rheumatoid arthritis (RA) is an autoimmune disease characterised by the destruction of articular cartilage and bone damage. The chronic treatment of RA patients causes a higher susceptibility to infectious diseases such as tuberculosis (TB); one-third of the world’s population is latently infected (LTBI) with Mycobacterium tuberculosis (Mtb). The tuberculin skin test is used to identify individuals LTBI, but many studies have shown that this test is not suitable for RA patients. The goal of this work was to test the specific cellular immune responses to the Mtb malate synthase (GlcB) and heat shock protein X (HspX) antigens of RA patients and to correlate those responses with LTBI status. The T-helper (Th)1, Th17 and Treg-specific immune responses to the GlcB and HspX Mtb antigens were analysed in RA patients candidates for tumour necrosis factor-α blocker treatment. Our results demonstrated that LTBI RA patients had Th1-specific immune responses to GlcB and HspX. Patients were followed up over two years and 14.3% developed active TB. After the development of active TB, RA patients had increased numbers of Th17 and Treg cells, similar to TB patients. These results demonstrate that a GlcB and HspX antigen assay can be used as a diagnostic test to identify LTBI RA patients.