Binding of Platelets to Lymphocytes: A Potential Anti-Inflammatory Therapy in Rheumatoid Arthritis.

Soluble factors released from platelets can modulate the immune response of leukocytes. We and others have recently found that T lymphocytes with bound platelets have reduced proliferation and IFN-γ and IL-17 production. Thus, we speculate that if we induce the binding of platelets to lymphocytes, we will be able to regulate the inflammatory response. When we cocultured platelets with lymphocytes at different ratios, we were able to increase the percentage of lymphocytes with bound platelets. The coculture of platelets with lymphocytes in the presence of stimulation decreased the production of IFN-γ and TNF-α, T cell proliferation, and the expression of CD25, PD-L1, and SLAM. However, this coculture increased CD39 expression. All of these effects were dependent on the dose of platelets and operated indistinctly with platelets from different healthy donors. When platelets were cocultured in the same compartment with lymphocytes, we observed less IFN-γ and TNF-α production and T lymphocyte proliferation than in cultures with platelets separated from lymphocytes by a 0.4-µm pore size filter. The binding of platelets to lymphocytes was blocked with anti-P-selectin Abs, and when this occurred we observed higher IFN-γ and TNF-α production than in nonblocked conditions. The cocultures of platelets with synovial fluid cells from rheumatoid arthritis patients reduced inflammatory cytokine production and increased IL-10 production. These results suggest that platelet binding to lymphocytes effectively regulates T lymphocyte function. This mechanism could be easily applied to reduce inflammatory responses.

Impact of ultrasonography on treatment decision in rheumatoid arthritis: the IMPULSAR study.

Ultrasonography (US) has shown to be more sensitive than physical examination for diagnosis and assessment of rheumatoid arthritis (RA). It is also a useful approach for accurate monitoring and intensive treatment adjustment. However, there is limited information concerning the impact of US on therapeutic decision-making in routine daily practice. A single-center cross-sectional study in routine daily practice was conducted to determine the percentage of patients with rheumatoid arthritis (RA) in which treatment decision was modified on the basis of results of musculoskeletal ultrasonography. All consecutive patients with RA visited for the control of their disease between September and November 2014 were included. Patients were visited by their attending rheumatologist, who made a therapeutic decision according to the results of physical examination and laboratory tests. Thereafter, a musculoskeletal ultrasound (US) was performed by an independent expert sonographer. According to US findings, a change in therapeutic decision was considered, and categorized as 'negative' (maintenance of the therapeutic attitude) or 'positive' (intensification or reduction of treatment). A total of 78 patients (83% women, mean age 63.3 years) were included. In 29 patients [32%, 95% confidence interval (CI) 26.5-48.9], a change in the therapeutic decision was made, which included intensification of treatment in 18 (62.1%) and reduction of treatment in 11 (37.9%). Change of treatment was more frequent in patients with intermediate disease activity (low and moderate) than in those in clinical remission or with high activity (41.4 vs. 25%), in men than in women (53.8 vs. 33.8%), and in the presence than in the absence of bone erosions (43.6 vs. 21.7%), although differences were not statistically significant. We conclude that in patients with RA, joint US is a relevant complementary tool for treatment decisions in daily practice, particularly in patients with intermediate disease activity.

Adalimumab regulates intracellular TNFα production in patients with rheumatoid arthritis.

INTRODUCTION: Adalimumab is a fully human anti-tumor necrosis factor α (anti-TNFα) monoclonal antibody that specifically blocks the interaction of TNFα with its receptors. It binds both soluble and transmembrane TNFα. We hypothesized that blocking these TNFα signals regulates the altered TNFα production in rheumatoid arthritis (RA) patients. METHODS: We compared, by flow cytometry, Toll-like receptor induction levels of membrane and intracellular TNFα in monocytes (iTNFα + CD14+ cells) from 12 patients before and after adalimumab treatment with those from 5 healthy donors. RESULTS: Before starting the treatment, the percentage of iTNFα+ CD14+ cells in the RA patients was significantly lower than that in healthy donors (mean ± SEM = 33.16 ± 4.82% vs 66.51 ± 2.4%, P < 0.001). When we added in vitro TNFα to healthy donor culture cells, levels of iTNFα+ CD14+ cells decreased, suggesting that the TNFα signal was responsible for the iTNFα+ CD14+ cell downregulation observed in the RA patients. After 2, 6 and 12 adalimumab injections, we observed significant blocking of membrane and soluble TNFα and a progressive increase in iTNFα+ CD14+ cells in ten patients with a good to moderate response as defined by the European League Against Rheumatism (EULAR) criteria. Levels of iTNFα+ CD14+ cells after 12 injections in these 10 patients were comparable to levels in healthy donors. In two patients, iTNFα+ CD14+ cell upregulation was not observed, and their EULAR-defined responses had not improved. The first patient developed antiadalimumab antibodies, explaining why adalimumab was not able to block membrane and soluble TNFα. In the second patient, adalimumab was discontinued because of adverse effects, which led to a decrease in iTNFα+ CD14+ cells to levels measured before treatment. CONCLUSIONS: Our findings suggest that adalimumab treatment in RA patients can return iTNFα levels to those of healthy donors. This effect was not observed in the presence of neutralizing antiadalimumab antibodies.

Rituximab-induced interleukin-15 reduction associated with clinical improvement in rheumatoid arthritis.

Rituximab therapy alters all aspects of B-cell participation in the disturbed immune response of rheumatoid arthritis patients. To determine the impact of B-cell depletion on other immune compartments, we analysed levels of soluble and surface interleukin-15 (IL-15) along with the frequency of IL-15-related subsets after rituximab treatment. We then studied the correlation of observed changes with clinical activity. Heparinized blood samples from 33 rheumatoid arthritis patients were collected on days 0, 30, 90 and 180 after each of three rituximab cycles. Serum cytokine levels were determined by ELISA. Interleukin-15 trans-presentation was analysed by cytometry. Flow cytometry with monoclonal antibodies was performed to analyse circulating cell subsets. Interleukin-15 was detected in the serum of 25 patients before initiating the treatment. Rituximab then progressively reduced serum IL-15 (138 ± 21 pg/ml at baseline, 48 ± 18 pg/ml after third cycle, P = 0·03) along with IL-17 (1197 ± 203 pg/ml at baseline, 623 ± 213 pg/ml after third cycle, P = 0·03) and tended to increase the frequency of circulating regulatory T cells (3·1 ± 1 cells/µl at baseline, 7·7 ± 2 cells/µl after third cycle). Rituximab also significantly decreased IL-15 trans-presentation on surface monocytes of patients negative for IL-15 serum (mean fluorescence intensity: 4·82 ± 1·30 at baseline, 1·42 ± 0·69 after third cycle P = 0·05). Reduction of serum IL-15 was associated with decrease in CD8(+)  CD45RO(+) /RA(+) ratio (1·17 ± 0·21 at baseline, 0·36 ± 0·06 at third cycle, P = 0·02). DAS28, erythrocyte sedimentation rate and C-reactive protein correlated significantly with CD8(+)  CD45RO(+) /RA(+) ratio (R = 0·323, R = 0·357, R = 0·369 respectively, P < 0·001). Our results suggest that sustained clinical improvement after rituximab treatment is associated with IL-15/memory T-cell-related mechanisms beyond circulating B cells.

Functional consequences of platelet binding to T lymphocytes in inflammation.

Expression of the scavenger receptor CD36 on lymphocytes is intriguing. We observed that a minor subpopulation of lymphocytes expressed CD36 on the cell surface. We investigated the source of CD36 and also the proliferation and cytokine production of these CD36(+) CD4(+) lymphocytes. Flow cytometry analysis and immunofluorescence microscopy showed that CD36(+) platelets were responsible for CD36 detection on lymphocytes. CD36 was then used as a tool to characterize lymphocytes with bound platelets. Activation-induced proliferation was lower in CD4(+) lymphocytes with bound platelets than lymphocytes without bound platelets. IL-17 and IFN-γ production was also reduced in lymphocytes with bound platelets. We then studied the presence of CD36(+) CD4(+) lymphocytes in RA patients. We observed that the percentage of CD4(+) lymphocytes with bound platelets was higher on RA patients than in healthy donors. RA patients with higher titers of anti-CCP, RF levels, and cardiovascular risk index presented a lower percentage of CD4(+) lymphocytes with bound platelets. These patients also had higher IL-17 and IFN-γ production. These results suggest that platelet-binding modifies lymphocyte function. This binding could be a regulatory mechanism in RA that confers a less severe phenotype.

[Validation of the Spanish version of the Primary Care Assessment Survey questionnaire]. / Validación de la versión en español del cuestionario PCAS para evaluar la atención primaria de salud.

OBJECTIVE: Adapt the Primary Care Assessment Survey (PCAS) questionnaire to the Spanish language and determine its validity and reliability in identifying strengths and weaknesses in primary health care (PHC). METHODS: Study of the adaptation and validation of a questionnaire-survey. The suitable sample selected was 244 users of PHC services. The users were over 18 years of age and had had at least two institutional visits prior to being included in the study. The variables used were access, continuity, comprehensiveness, integration, clinical interaction, interpersonal treatment, and trust. Participation was confirmed through analysis of the distribution of responses; participation and patterns of nonresponse; the construct, through exploratory factorial analysis, using principal component analysis and the varimax rotation; the criterion, through the Pearson product-moment correlation coefficient; and reliability using Cronbach's alfa and the intraclass correlation coefficient. RESULTS: The exploratory factorial analysis obtained 11 factors that explain 68.38% of the original variability. The criterion validity showed a sufficient correlation between the summary measure of the scale and the ad hoc variables Q33b (value of r x1x2 = 0.569; P = 0.01) and Q32 (value of r x1x2 = 0.600; P = 0.01). The scale obtained a coefficient of Cronbach's alfa of 0.94. The test-retest reliability (F [1 140] = 0.155 [P = 0.694]) demonstrated that the scale is stable over time. CONCLUSIONS: The psychometric properties of the adapted version of the PCAS questionnaire make it possible to state that it is a valid and reliable scale to evaluate primary care from a standpoint of ongoing care based on the physician-patient relationship.

Validación de la versión en español del cuestionario PCAS para evaluar la atención primaria de salud / Validation of the Spanish version of the Primary Care Assessment Survey questionnaire

OBJETIVO: Adaptar el cuestionario PCAS (del inglés Primary Care Assessment Survey) al idioma español y determinar su validez y su fiabilidad cuando se trata de identificar las debilidades y las fortalezas que se observan en la atención primaria de salud (APS). MÉTODOS: Estudio de adaptación y validación de un cuestionario-encuesta. Se seleccionó una muestra por conveniencia de 244 usuarios de servicios de APS, mayores de 18 años y con al menos dos visitas institucionales al momento de ser incluidos en el estudio. Se utilizaron las variables: accesibilidad, continuidad, integralidad, integración, interacción clínica, trato interpersonal y confianza. Se validaron la apariencia, mediante análisis de distribución de las respuestas, análisis de participación y patrones de no respuesta; el constructo, mediante análisis factorial exploratorio usando el método de componentes principales y rotación Varimax; el criterio, mediante el coeficiente de correlación de Pearson, y la fiabilidad, usando el alfa de Cronbach y el coeficiente de correlación intraclase. RESULTADOS: En el análisis factorial exploratorio se obtuvieron 11 factores que explicaron 68,38 por ciento de la variabilidad original. La validez de criterio mostró una correlación adecuada entre la medida resumen de la escala y las variables "ad hoc" Q33b (valor de r×1×2 = 0,569; P = 0,01) y Q32 (valor de r×1×2 = 0,600; P = 0,01). La escala obtuvo un coeficiente de alfa de Cronbach de 0,94. La fiabilidad test-retest (F [1,140] = 0,155 [P = 0,694]) demostró que la escala es estable en el tiempo. CONCLUSIONES: Las propiedades psicométricas de la versión adaptada del cuestionario PCAS permiten afirmar que se trata de una escala válida y fiable para evaluar la atención primaria desde un enfoque de continuidad asistencial basada en la relación médico-paciente.

OBJECTIVE: Adapt the Primary Care Assessment Survey (PCAS) questionnaire to the Spanish language and determine its validity and reliability in identifying strengths and weaknesses in primary health care (PHC). METHODS: Study of the adaptation and validation of a questionnaire-survey. The suitable sample selected was 244 users of PHC services. The users were over 18 years of age and had had at least two institutional visits prior to being included in the study. The variables used were access, continuity, comprehensiveness, integration, clinical interaction, interpersonal treatment, and trust. Participation was confirmed through analysis of the distribution of responses; participation and patterns of nonresponse; the construct, through exploratory factorial analysis, using principal component analysis and the varimax rotation; the criterion, through the Pearson product-moment correlation coefficient; and reliability using Cronbach's alfa and the intraclass correlation coefficient. RESULTS: The exploratory factorial analysis obtained 11 factors that explain 68.38 percent of the original variability. The criterion validity showed a sufficient correlation between the summary measure of the scale and the ad hoc variables Q33b (value of r x1x2 = 0.569; P = 0.01) and Q32 (value of r x1x2 = 0.600; P = 0.01). The scale obtained a coefficient of Cronbach's alfa of 0.94. The test-retest reliability (F [1 140] = 0.155 [P = 0.694]) demonstrated that the scale is stable over time. CONCLUSIONS: The psychometric properties of the adapted version of the PCAS questionnaire make it possible to state that it is a valid and reliable scale to evaluate primary care from a standpoint of ongoing care based on the physician-patient relationship.

Angina de pecho como forma de presentación clínica de la arteritis de Takaya / Angina pectoris as a clinical onset of Takayasu arteritis

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