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BACKGROUND: Empirical evidence for effective patient-researcher collaboration in basic research is lacking. This study aims to explore good working models and impact of patient involvement in basic rheumatology research and to identify barriers and facilitators. METHOD: A responsive evaluation of a three years' participatory research project in a basic and translational laboratory research setting. Several working models for patient involvement were piloted and adapted if considered necessary. The study comprised surveys, interviews, training days, meeting reports, Q-sort exercises and field notes, and regular reflective team sessions with participant involvement. A qualitative analysis using thematic coding focused on impact, barriers and facilitators. RESULTS: Thirteen patient research partners (PRPs) and fifteen basic researchers participated. PRPs experienced basic research as fascinating though complex to understand. Their initial role was mostly listening and asking questions. After several meetings equal and more meaningful relationships emerged. Researchers' motivation increased by listening to patient stories. They learned about disease impact on daily life and to speak in understandable language. This enabled PRPs to learn about research and the pathogenesis of their disease. It inspired them to stay involved over a longer period. After three years, both parties preferred 1:1 contacts over collaboration in team meetings. A common language and respectful communication were important facilitators. Limitations were the complexity of disease processes for patients and the time commitment for researchers. Impact was reported as a sincere dialogue with multiple advantages for patients and researchers, and to a lesser extent than expected on the research process and outcomes. CONCLUSION: Patient involvement contributes to motivating young scientists in performing basic research projects. Patients and researchers valued the benefits of long-term one-on-one collaboration. These benefits outweigh the lack of direct impact on basic research goals and performance. A plain language summary of the abstract is available (as) online Additional file 1.
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OBJECTIVE: To evaluate the short-term effects of use of the dr. Bart app, compared to usual care, on the number of secondary health care consultations and clinical outcomes in people with knee/hip OA in the Netherlands. METHOD: A randomized controlled design involving participants ≥50 years with self-reported knee and/or hip OA recruited from the community. The number of secondary health care consultations (primary outcome) and secondary outcomes were assessed at baseline, 3 and 6 months via online questionnaires. Data were analyzed using longitudinal mixed models, corrected for baseline values. Due to the design of this study, blinding of participants and researchers was not possible. RESULTS: In total, 427 eligible participants were allocated to either the dr. Bart group (n = 214) or usual care (n = 213). We found no difference between groups in the number of secondary (i.e., orthopaedic surgeon, rheumatologist, or physician assistant) health care consultations (incidence rate ratio (IRR) 1.20 (95% CI: 0.67; 2.19)). We found positive treatment effects of the dr. Bart app on symptoms (2.6 (95% CI: 0.4; 4.9)), pain (3.5 (95% CI: 0.9; 6.0)), and activities of daily living (2.9 (95% CI: 0.2; 5.6)) on a 0-100 scale, higher score indicating less complaints, but not in any other secondary outcome. CONCLUSION: The dr. Bart app did not change the number of secondary health care consultations compared to usual care. However, we found small positive effects (not clinically relevant) on pain, symptoms, and activities of daily living in people with knee/hip OA. TRIAL REGISTRATION: Dutch Trial Register (Trial Number NTR6693/NL6505) (https://www.trialregister.nl/trial/6505).
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Atividades Cotidianas , Aplicativos Móveis , Osteoartrite do Quadril/terapia , Osteoartrite do Joelho/terapia , Atenção Primária à Saúde/estatística & dados numéricos , Atenção Secundária à Saúde/estatística & dados numéricos , Autogestão , Idoso , Feminino , Clínicos Gerais , Objetivos , Comportamentos Relacionados com a Saúde , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Motivação , Países Baixos , Cirurgiões Ortopédicos , Osteoartrite do Quadril/fisiopatologia , Osteoartrite do Joelho/fisiopatologia , Medição da Dor , Fisioterapeutas , ReumatologistasRESUMO
OBJECTIVE: To explore the associations between different histologically assessed, inflammatory synovial characteristics and subsequent clinical and structural aspects in knee osteoarthritis (OA). DESIGN: Knee OA patients, ranging in stage from early to advanced, were recruited from three different ongoing studies. Synovial tissue biopsies were taken and histologically assessed for six features (four inflammatory related aspects, fibrosis and fibrin deposition). Clinical aspects (WOMAC pain, functioning and stiffness and SF-36 vitality) and structural aspects (Kellgren and Lawrence (KL)-grade, joint space narrowing (JSN; 0-3) and osteophytes (0-3), and reception of total knee replacement (TKR)) were repeatedly assessed during follow-up. Associations between histology and clinical and structural aspects were analysed using linear mixed model analyses and cox proportional hazards analysis. RESULTS: Biopsies of 83 patients (median complaint duration: 5 [2-8] years) were analysed. Follow-up was a median of 1.4 [0.8-2.7] years for clinical and 1.8 [0.2-5.2] years for structural aspects. Fibrosis and fibrin deposition were inversely correlated with the inflammatory features. A higher fibrosis score was associated with a lower scores for KL-grade, JSN and osteophytes, while higher scores for perivascular oedema, synovial lining thickness and vascularisation were associated with higher scores for structural aspects during follow-up. No associations were found between each of the histological features and any of the clinical aspects or the chance for TKR during follow-up. CONCLUSIONS: Inflammatory related histological aspects are associated with subsequent increased radiological severity in knee OA, while fibrosis seems to protect against this, providing a potential therapeutic target for OA treatment.
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Articulação do Joelho/patologia , Osteoartrite do Joelho/patologia , Adulto , Idoso , Artroplastia do Joelho/estatística & dados numéricos , Artroscopia , Biópsia , Progressão da Doença , Feminino , Fibrose , Humanos , Articulação do Joelho/diagnóstico por imagem , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/cirurgia , Estudos Prospectivos , Radiografia , Índice de Gravidade de Doença , Membrana Sinovial/patologiaRESUMO
OBJECTIVES: Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures. DESIGN: Hand OA patients, ≥50 years, with pain ≥5 (scale 0-10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0-3). RESULTS: Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference -7% (95%CI -31-17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant. CONCLUSIONS: We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA. CLINICAL TRIAL REGISTRATION NUMBER: NTR4574 (Dutch Trial Register).
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Articulação da Mão , Inflamação/metabolismo , Osteoartrite/radioterapia , Idoso , Proteína C-Reativa/metabolismo , Relação Dose-Resposta à Radiação , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Inflamação/diagnóstico , Inflamação/radioterapia , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico , Osteoartrite/metabolismo , Qualidade de Vida , Dosagem Radioterapêutica , Estudos Retrospectivos , Membrana Sinovial/diagnóstico por imagem , Resultado do Tratamento , Ultrassonografia DopplerRESUMO
Interstitial lung disease (ILD) is the primary cause of death in patients with systemic sclerosis (SSc). It is thought that chronic inflammation is a key component in SSc-ILD. Treatment, such as cyclophosphamide (CYC), targets this inflammation. We hypothesized that treatment with CYC might be more effective in the inflammatory phase. Therefore, we analyzed whether the extent of inflammation, as assessed by the proportion of ground glass compared to fibrosis, SSc disease duration, the extent of ILD, or baseline diffusion capacity of the lungs (DLCO) < 60%, modifies the effect of intravenous CYC pulse therapy (750 mg/m2) on pulmonary function (as measured by FVC, DLCO) in SSc-ILD patients, after 12, 24, and 36 months. Consecutive patients with SSc-ILD receiving CYC pulses between 2003 and 2015 were included. Pulmonary function tests were performed at 0, 6, 12, 24, and 36 months. There were 75 patients included. Forced vital capacity (FVC) (86% of predicted) and DLCO (42% of predicted) were stable after 12, 24 and 36 months of follow-up (p > 0.05). Forty-four patients completed 12 cycles of CYC. For the extent of ILD, proportion of ground glass compared to fibrosis, SSc disease duration, and baseline DLCO, there were no differences (all p > 0.05) in the course of FVC and DLCO. Treatment with CYC followed by maintenance therapy stabilizes pulmonary function in patients with SSc-ILD over a 3-year period. The extent of ILD, proportion of ground glass, SSc disease duration, and baseline DLCO < 60% did not influence the effect of CYC on pulmonary function.
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Ciclofosfamida/administração & dosagem , Imunossupressores/administração & dosagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/fisiopatologia , Escleroderma Sistêmico/complicações , Administração Intravenosa , Idoso , Ciclofosfamida/efeitos adversos , Feminino , Humanos , Imunossupressores/efeitos adversos , Inflamação/fisiopatologia , Estimativa de Kaplan-Meier , Modelos Lineares , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: Knowledge about the nature and impact of symptoms faced by patients with systemic sclerosis (SSc) is needed to identify targets for research and treatment. The aim of this study was to assess and compare the frequency and impact on everyday activities of SSc symptoms among patients from five European countries. METHODS: European patients with SSc were invited through announcements by patient associations to complete an online survey. The survey included items assessing the frequency of 40 SSc symptoms and the impact on daily activities, if present. Chi-square tests were utilised to assess the differences in frequency and impact of symptoms across countries. RESULTS: In total, 537 patients were included from France (n=111), the Netherlands (n=229), Spain (n=61), Switzerland (n=50), and the United Kingdom (n=86). Symptoms experienced by ≥ 70% of patients in all countries were fatigue, Raynaud's phenomenon, joint pain, and muscle pain. Twenty symptoms were experienced by ≥ 50% of patients in all countries. Thirty symptoms had an impact on daily activities in ≥ 50% of patients who reported that the symptom was present in all countries. There were significant differences among countries in the prevalence of 17 out of 40 symptoms. Furthermore, in 24 out of 40 symptoms significant differences in the proportion of patients reporting impact of a specific symptom on everyday activities were observed. CONCLUSIONS: European patients with SSc experience a broad range of symptoms that have an impact on everyday activities. International research initiatives should target common SSc symptoms cooperatively. Further research is needed to better understand the differences in SSc symptoms among countries.
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Atividades Cotidianas , Limitação da Mobilidade , Esclerodermia Difusa/fisiopatologia , Esclerodermia Limitada/fisiopatologia , Idoso , Artralgia/etiologia , Efeitos Psicossociais da Doença , Fadiga/etiologia , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Países Baixos , Doença de Raynaud/etiologia , Esclerodermia Difusa/complicações , Esclerodermia Limitada/complicações , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/fisiopatologia , Índice de Gravidade de Doença , Espanha , Inquéritos e Questionários , Suíça , Reino UnidoRESUMO
OBJECTIVE: To describe health care utilization (HCU) and predict analgesic use and health professional (HP) contact at baseline and 2 years in individuals with early symptomatic hip and/or knee osteoarthritis (OA). DESIGN: Baseline and two-year data on HCU of the 1002 participants from the multi-centre Cohort Hip & Cohort Knee study were used. Six forms of health care services were described: analgesic use, supplement use, contact with a General Practitioner (GP), contact with a HP, contact in secondary care, and alternative medicine use. Multivariable logistic regression was performed in order to identify predisposing, enabling and disease-related variables that predict analgesic use and HP contact at 2 years; treatment modalities of first choice in early OA. RESULTS: For the hip (n=170), the knee (n=414) and the hip and knee (n=418) group analgesic use (38%, 29% and 47%, respectively), contact with a GP (32%, 38% and 36%, respectively) and contact with a HP (26%, 18% and 20%, respectively), were reported most often at baseline. Contact with a GP significantly decreased, supplement use increased (to about one third), and other treatment modalities remained stable at 2 years. In all three groups, analgesic use at baseline was the strongest predictor for analgesic use at 2 years, whereas contact with a HP at baseline was the strongest predictor of contact with a HP after 2 years. Belonging to a first generation minority was a predisposing risk factor [Odds Ratio (95%-CI), 8.72 (1.55-48.97)] for analgesic use in the hip and knee group. CONCLUSIONS: In early OA, familiarity with HCU and other predisposing factors are, apart from disease-related factors strongly associated with HCU at 2 years. Further research is necessary to examine whether our findings reflect sub-optimal management of early OA in terms of efficacy and equity.
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Atenção à Saúde/estatística & dados numéricos , Osteoartrite do Quadril/terapia , Osteoartrite do Joelho/terapia , Idoso , Analgésicos/administração & dosagem , Terapias Complementares/estatística & dados numéricos , Suplementos Nutricionais/estatística & dados numéricos , Uso de Medicamentos/estatística & dados numéricos , Escolaridade , Medicina de Família e Comunidade/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Osteoartrite do Quadril/epidemiologia , Osteoartrite do Joelho/epidemiologia , Prevalência , Relações Profissional-PacienteRESUMO
OBJECTIVE: Systemic sclerosis (SSc) is associated with a significant reduction in life expectancy. A simple prognostic model to predict 5-year survival in SSc was developed in 1999 in 280 patients, but it has not been validated in other patients. The predictions of a prognostic model are usually less accurate in other patients, especially from other centres or countries. A study was undertaken to validate the prognostic model to predict 5-year survival in SSc in other centres throughout Europe. METHODS: A European multicentre cohort of patients with SSc diagnosed before 2002 was established. Patients with SSc according to the preliminary American College of Rheumatology classification criteria were eligible for the study when they were followed for at least 5 years or shorter if they died. The primary outcome was 5-year survival after diagnosis of SSc. The predefined prognostic model uses the following baseline variables: age, gender, presence of urine protein, erythrocyte sedimentation rate (ESR) and carbon monoxide diffusing capacity (DLCO). RESULTS: Data were available for 1049 patients, 119 (11%) of whom died within 5 years after diagnosis. Of the patients, 85% were female, the mean (SD) age at diagnosis was 50 (14) years and 30% were classified as having diffuse cutaneous SSc. The prognostic model with age (OR 1.03), male gender (OR 1.93), urine protein (OR 2.29), elevated ESR (1.89) and low DLCO (OR 1.94) had an area under the receiver operating characteristic curve of 0.78. Death occurred in 12 (2.2%) of 509 patients with no risk factors, 45 (13%) of 349 patients with one risk factor, 55 (33%) of 168 patients with two risk factors and 7 (30%) of 23 patients with three risk factors. CONCLUSION: A simple prognostic model using three disease factors to predict 5-year survival at diagnosis in SSc showed reasonable performance upon validation in a European multicentre study.
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Escleroderma Sistêmico/mortalidade , Adulto , Fatores Etários , Idoso , Sedimentação Sanguínea , Métodos Epidemiológicos , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteinúria/etiologia , Proteinúria/mortalidade , Capacidade de Difusão Pulmonar , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/diagnóstico , Fatores SexuaisRESUMO
OBJECTIVE: Insufficient data are available on the efficacy of combined conservative interventions recommended by treatment guidelines for knee/hip osteoarthritis (OA). The aims of this observational cohort study were (i) to estimate the results of an evidence-based 12-week tailored multimodal conservative treatment protocol for patients with knee/hip OA and (ii) to identify predictors for response. METHODS: After obtaining data on previous OA-related interventions, multimodal treatment was offered to patients with knee and/or hip OA at a specialized outpatient clinic. Treatment with analgesics was tailored using a numeric rating scale (NRS) for pain, aiming for NRS ≤ 4. The following outcome measures were assessed: (i) the proportion of patients fulfilling OMERACT-OARSI (Outcome Measures in Rheumatoid Arthritis Clinical Trials/Osteoarthritis Research Society International) responder criteria and (ii) the proportion of patients with NRS pain ≤ 4 after 12 weeks. RESULTS: A total of 183 out of 299 patients was included. OMERACT-OARSI responder criteria were fulfilled at 12 weeks in 47% of patients; 39% reached NRS pain ≤ 4. The only independent predictor for response was the number of previously used non-steroidal anti-inflammatory drugs (NSAIDs). The majority of patients had not been exposed adequately to conservative treatment modalities for knee and/or hip OA in the past (81%). CONCLUSION: Evidence-based multimodal conservative treatment using a standardized protocol for knee and/or hip OA is feasible and successful in 47% of patients. In general, response could not be predicted. Basic first-line recommended conservative treatment options have not been used adequately prior to referral to secondary care in the vast majority of patients.
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Analgésicos/uso terapêutico , Suplementos Nutricionais , Osteoartrite do Quadril/terapia , Osteoartrite do Joelho/terapia , Dor/tratamento farmacológico , Modalidades de Fisioterapia , Condroitina/administração & dosagem , Estudos de Coortes , Medicina Baseada em Evidências , Feminino , Glucosamina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/complicações , Osteoartrite do Quadril/fisiopatologia , Osteoartrite do Joelho/complicações , Osteoartrite do Joelho/fisiopatologia , Dor/etiologia , Dor/fisiopatologia , Medição da Dor , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVES: We have developed an instrument that provides the physician structured information about medication use and patients' (non-)adherence. This study aimed to determine the effectiveness of this instrument on adherence and medication beliefs in outpatients with rheumatoid arthritis (RA). METHODS: In this within-subject controlled prospective cohort study, 50 outpatients were assessed during three consecutive visits to their rheumatologist. At these three points in time, patients' adherence, medication beliefs, satisfaction about information about medication, and physical functioning were measured using validated self-report questionnaires. An intervention was scheduled during the second visit. The intervention consisted of a written report informing the physician about medication use and adherence to medication for each patient. The effectiveness of the intervention was evaluated by comparing outcome measures at the third visit to the same measures assessed prior to the intervention. RESULTS: At baseline, 30% of the patients (n = 50) were non-adherent. No significant changes in adherence were found between the first and second visit prior to the intervention. Adherence did not change after the intervention, compared to both of the adherence assessments prior to the intervention. Beliefs about medication, patients' satisfaction about information on medication, and physical functioning were also not significantly altered. CONCLUSION: Supplying the rheumatologist a report with information about medication use and adherence did not change adherence or patients' beliefs about medication. Further research is necessary to ensure effective support for adherence for individual patients with RA.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Cooperação do Paciente , Relações Médico-Paciente , Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Comunicação , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Exercise testing can be used (i) to evaluate functional limitations of systemic sclerosis (SSc) and (ii) to study whether the inflammatory and oxidative systems are activated after a physical stimulus. The aim of this study was to determine exercise-induced inflammatory and oxidative responses in SSc compared with healthy subjects. METHODS: Eleven patients with SSc and pulmonary involvement and 10 healthy subjects underwent maximal cardiopulmonary exercise testing (CPET). Physiological responses were followed continuously during cycling. Blood samples were taken at rest, during and after maximal exercise to measure inflammatory and oxidative markers. RESULTS: In nine of the 11 SSc patients, cardiocirculatory limitation and gas exchange impairment limited exercise capacity. Basal inflammatory cells, interleukin (IL)-6, and oxidative stress were increased in SSc compared to healthy subjects and intensified after exercise. Basal and exercise-induced inflammation and oxidative stress were correlated with the modified Rodnan skin score. CONCLUSIONS: Although exercise capacity is impaired in patients with SSc, physical activity intensifies the already increased basal levels of systemic inflammation and oxidative stress. These data support the concept of a role for systemic inflammation and oxidative stress in the ongoing systemic effects of SSc.
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Teste de Esforço/métodos , Mediadores da Inflamação/sangue , Resistência Física/fisiologia , Espécies Reativas de Oxigênio/sangue , Escleroderma Sistêmico/diagnóstico , Adulto , Fatores Etários , Idoso , Análise Química do Sangue , Estudos de Casos e Controles , Tolerância ao Exercício/fisiologia , Feminino , Seguimentos , Volume Expiratório Forçado , Humanos , Interleucina-6/sangue , Leucocitose/fisiopatologia , Peroxidação de Lipídeos/fisiologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Valores de Referência , Medição de Risco , Escleroderma Sistêmico/sangue , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
BACKGROUND: It has been suggested that the T-cell attracting and profibrotic chemokine CCL18 might play a role in the pathogenesis of systemic sclerosis (SSc). However, it is unclear what underlies the higher CCL18 levels in SSc. The aim of our study was to determine whether Toll-like receptor (TLR)-mediated stimulation of monocytes and dendritic cells (DCs) contributes to the higher levels of CCL18 in SSc. METHODS: CCL18 levels were measured in 40 patients with SSc, primary Raynaud's phenomenon (RP) and healthy controls. The presence of TLR4 agonists in the circulation of SSc patients was investigated using TLR4 transgenic Chinese hamster ovary (CHO) cells. CCL18 and interleukin (IL)-10 secretion by monocytes/macrophages and monocyte-derived DCs (moDCs) was measured in the supernatant. The indirect effect of lipopolysaccharide (LPS)-stimulated moDCs on CCL18 secretion by monocytes/macrophages was investigated using a transwell system. RESULTS: CCL18 levels were significantly elevated in SSc patients compared to patients with RP and healthy controls. SSc sera strongly induced CD25 expression on CHO cells genetically modified to express TLR4 but not on those expressing CD14 only. By contrast, serum from systemic lupus erythematosus (SLE) patients or healthy individuals did not have an effect. Neither monocytes/macrophages nor moDCs from SSc patients secreted higher levels of CCL18 compared to healthy controls. However, moDCs matured with the TLR4 ligand LPS from patients with SSc did secrete significantly higher amounts of IL-10 compared to those from healthy counterparts, which were IL-10 dependent. CONCLUSIONS: Our results suggest that elevated CCL18 levels in SSc are not caused by an intrinsically enhanced CCL18 secretion by monocytes/macrophages but are, at least partly, orchestrated by an enhanced IL-10 secretion by TLR4-stimulated DCs. These observations suggest a role for TLR4 ligands and DCs in the pathogenesis of SSc, a topic that warrants further investigation.
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Quimiocinas CC/metabolismo , Células Dendríticas/imunologia , Interleucina-10/imunologia , Doença de Raynaud/imunologia , Escleroderma Sistêmico/imunologia , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Quimiocinas CC/genética , Cricetinae , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Humanos , Interleucina-10/metabolismo , Masculino , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Probabilidade , Doença de Raynaud/sangue , Doença de Raynaud/fisiopatologia , Valores de Referência , Escleroderma Sistêmico/sangue , Escleroderma Sistêmico/fisiopatologia , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Receptor 4 Toll-Like/agonistasRESUMO
The aim of this study was to investigate the possible role of STAT4 gene in the genetic predisposition to systemic sclerosis (SSc) susceptibility or clinical phenotype. A total of 1317 SSc patients [896 with limited cutaneous SSc (lcSSc) and 421 with diffuse cutaneous SSc (dcSSc)] and 3113 healthy controls, from an initial case-control set of Spanish Caucasian ancestry and five independent cohorts of European ancestry (The Netherlands, Germany, Sweden, Italy and USA), were included in the study. The rs7574865 polymorphism was selected as STAT4 genetic marker. We observed that the rs7574865 T allele was significantly associated with susceptibility to lcSSc in the Spanish population [P = 1.9 x 10(-5) odds ratio (OR) 1.61 95% confidence intervals (CI) 1.29-1.99], but not with dcSSc (P = 0.41 OR 0.84 95% CI 0.59-1.21). Additionally, a dosage effect was observed showing individuals with rs7574865 TT genotype higher risk for lcSSc (OR 3.34, P = 1.02 x 10(-7) 95% CI 2.11-5.31). The association of the rs7574865 T allele with lcSSc was confirmed in all the replication cohorts with different effect sizes (OR ranging between 1.15 and 1.86), as well as the lack of association of STAT4 with dcSSc. A meta-analysis to test the overall effect of the rs7574865 polymorphism showed a strong risk effect of the T allele for lcSSc susceptibility (pooled OR 1.54 95% CI 1.36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype.
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Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fator de Transcrição STAT4/genética , Escleroderma Sistêmico/genética , População Branca/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/patologia , População Branca/etnologiaRESUMO
BACKGROUND: Detailed information is lacking on effectiveness of methotrexate (MTX) in sclerotic skin diseases, side-effects, and duration of remission after discontinuation. OBJECTIVES: To determine effectiveness, side-effects and period of remission gained by use of MTX in sclerotic skin diseases. METHODS: All patients with a sclerotic skin disease who were treated with MTX (group A) or MTX with corticosteroids (CS) (group B) between 1995 and 2007 were evaluated. Detailed information was collected on dosage and duration of MTX treatment, concomitant immunosuppressive medication and CS treatment, effectiveness, side-effects, duration of the remission period, and time until restart. RESULTS: Fifty-eight patients (A, n = 47; B, n = 11) were evaluated. Clinical assessment revealed that 38 patients (81%) treated with MTX and 11 patients (100%) treated with MTX + CS showed improvement of sclerotic skin. After one treatment course 51% of the patients treated with MTX and 73% treated with MTX + CS reached remission status with a median follow-up time of 55 and 58 months. Patients showing relapse still responded to a second and even to a third course of MTX. Patients who showed a relapse had received a lower cumulative dose, due to a shorter period of treatment with MTX in the first course. Serious side-effects were seen in six patients (10%). CONCLUSIONS: MTX was an effective treatment for various sclerotic skin diseases with a long period of remission and relatively low toxicity. Patients showing relapse still responded to a second and third course of MTX.
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Antimetabólitos Antineoplásicos/uso terapêutico , Metotrexato/uso terapêutico , Esclerodermia Localizada/tratamento farmacológico , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: High-density lipoprotein (HDL) antiatherogenic functions seem to be diminished during inflammatory conditions such as rheumatoid arthritis (RA). The aim of this study was to investigate the effects of tumour necrosis factor (TNF) inhibition on the antioxidative capacity of HDL in RA. METHODS: Plasma lipids and paraoxonase (PON-1) activity were investigated in 45 RA patients, before and during 6 months of anti-TNF therapy. In addition, HDL was isolated and tested for its ability to inhibit copper-induced oxidation of low-density lipoprotein in vitro. RESULTS: Plasma HDL concentrations did not change considerably after 6 months of therapy. However, stable increases of PON-1 activities were observed throughout the same period (p<0.03). The increases were more obvious when related to HDL or apolipoprotein AI concentrations. HDL total antioxidative capacity significantly improved 6 months after the initiation of anti-TNF therapy (p = 0.015). The initial improvement of PON-1 activity paralleled a decrease in the inflammatory status, whereas specific TNF blockade was likely to be responsible for the long-term effects. CONCLUSIONS: Anti-TNF therapy with infliximab has beneficial effects on lipids through changes in HDL antioxidative capacity, which might be clinically relevant and contribute to the reported protective effect of anti-TNF on cardiovascular morbidity in RA. This emphasises the importance of HDL antiatherogenic capacity for cardiovascular risk in chronic inflammatory conditions.
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Anticorpos Monoclonais/uso terapêutico , Antioxidantes/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , HDL-Colesterol/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Idoso , Antioxidantes/análise , Antioxidantes/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Arildialquilfosfatase/análise , Arildialquilfosfatase/sangue , Arildialquilfosfatase/metabolismo , Biomarcadores/análise , Sedimentação Sanguínea , Hidrolases de Éster Carboxílico/análise , Hidrolases de Éster Carboxílico/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Doença Crônica , Cobre/farmacologia , Esquema de Medicação , Feminino , Seguimentos , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Oxirredução , Estatísticas não Paramétricas , Estimulação QuímicaRESUMO
OBJECTIVES: Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype. METHODS: An initial case-control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay. RESULTS: Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes. CONCLUSIONS: Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.
Assuntos
Receptores de Interleucina/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Tumour necrosis factor alpha (TNFalpha) neutralising antibody constructs are increasingly being used to treat rheumatoid arthritis (RA). OBJECTIVE: To determine potential differences in clinical responses, soluble drug levels and antibody formation between patients with RA receiving infliximab and adalimumab. METHODS: 69 patients with RA fulfilling the 1987 American College of Rheumatology criteria and about to start treatment with infliximab or adalimumab, were enrolled consecutively. All patients had active disease (28-joint count Disease Activity Score >3.2). Infliximab was given intravenously at 3 mg/kg at baseline and after 2, 6 and 14 weeks. Adalimumab was administered as 40 mg biweekly subcutaneously. Concomitant drug treatment was monitored and continued at constant dosage during the study. All serum samples were tested for infliximab/adalimumab levels and anti-infliximab/anti-adalimumab antibodies. RESULTS: 35 patients received infliximab, 34 received adalimumab. At 6 months, 15 (43%), 6 (17%) and 14 (40%) of the infliximab-treated patients fulfilled the EULAR criteria for good, moderate and non-responders, respectively, whereas the corresponding figures for adalimumab-treated patients were 16 (47%), 8 (24%) and 10 (29%). Clinical responses correlated with the levels of S-infliximab/adalimumab and the formation of anti-infliximab/anti-adalimumab antibodies. CONCLUSION: The clinical response to two anti-TNFalpha biological agents closely follows the trough drug levels and the presence of antibodies directed against the drugs. Further studies that focus on the underlying pathways leading to antibody formation are warranted to predict immunogenicity of these expensive biological agents and treatment outcomes.
Assuntos
Anticorpos Anti-Idiotípicos/biossíntese , Anticorpos Monoclonais/imunologia , Artrite Reumatoide/sangue , Adalimumab , Idoso , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Radioimunoensaio/métodos , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: To conduct a replication study to investigate whether the -945 CTGF genetic variant is associated with systemic sclerosis (SSc) susceptibility or specific SSc phenotype. METHODS: The study population comprised 1180 patients with SSc and 1784 healthy controls from seven independent case-control sets of European ancestry (Spanish, French, Dutch, German, British, Swedish and North American). The -945 CTGF genetic variant was genotyped using a Taqman 5' allelic discrimination assay. RESULTS: An independent association study showed in all the case-control cohorts no association of the CTGF -945 polymorphism with SSc susceptibility. These findings were confirmed by a meta-analysis giving a pooled OR = 1.12 (95% CI 0.99 to 1.25), p = 0.06. Investigation of the possible contribution of the -945 CTGF genetic variant to SSc phenotype showed that stratification according to SSc subtypes (limited or diffuse), selective autoantibodies (anti-topoisomerase I or anticentromere) or pulmonary involvement reached no statistically significant skewing. CONCLUSION: The results do not confirm previous findings and suggest that the CTGF -945 promoter polymorphism does not play a major role in SSc susceptibility or clinical phenotype.