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1.
Pediatr Rheumatol Online J ; 17(1): 66, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31575380

RESUMO

BACKGROUND: JIA-associated uveitis (JIAU) is a serious, sight-threatening disease with significant long-term complications and risk of blindness, even with improved contemporary treatments. The MIWGUC was set up in order to propose specific JIAU activity and response items and to validate their applicability for clinical outcome studies. METHODS: The group consists of 8 paediatric rheumatologists and 7 ophthalmologists. A consensus meeting took place on November 2015 in Barcelona (Spain) with the objective of validating the previously proposed measures. The validation process was based on the results of a prospective open, international, multi-centre, cohort study designed to validate the outcome measures proposed by the initial MIWGUC group meeting in 2012. The meeting used the same Delphi and nominal group technique as previously described in the first paper from the MIWGUC group (Arthritis Care Res 64:1365-72, 2012). Patients were included with a diagnosis of JIA, aged less than 18 years, and with active uveitis or an uveitis flare which required treatment with a disease-modifying anti-rheumatic drug. The proposed outcome measures for uveitis were collected by an ophthalmologist and for arthritis by a paediatric rheumatologist. Patient reported outcome measures were also measured. RESULTS: A total of 82 patients were enrolled into the validation cohort. Fifty four percent (n = 44) had persistent oligoarthritis followed by rheumatoid factor negative polyarthritis (n = 15, 18%). The mean uveitis disease duration was 3.3 years (SD 3.0). Bilateral eye involvement was reported in 65 (79.3%) patients. The main findings are that the most significant changes, from baseline to 6 months, are found in the AC activity measures of cells and flare. These measures correlate with the presence of pre-existing structural complications and this has implications for the reporting of trials using a single measure as a primary outcome. We also found that visual analogue scales of disease activity showed significant change when reported by the ophthalmologist, rheumatologist and families. The measures formed three relatively distinct groups. The first group of measures comprised uveitis activity, ocular damage and the ophthalmologists' VAS. The second comprised patient reported outcomes including disruption to school attendance. The third group consisted of the rheumatologists' VAS and the joint score. CONCLUSIONS: We propose distinctive and clinically significant measures of disease activity, severity and damage for JIAU. This effort is the initial step for developing a comprehensive outcome measures for JIAU, which incorporates the perspectives of rheumatologists, ophthalmologists, patients and families.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31421019

RESUMO

OBJECTIVE: To evaluate safety and effectiveness of adalimumab (ADA) in polyarticular-course juvenile idiopathic arthritis (pcJIA) in the STRIVE registry (NCT00783510). METHODS: STRIVE enrolled patients with pcJIA into 2 arms based on treatment with methotrexate (MTX) alone or ADA with/without MTX (ADA±MTX). Adverse events (AEs) per 100 patient-years (PY) of observation time were analyzed by registry arm. Patients who entered the registry within 4 weeks of starting MTX or ADA±MTX, defined as new users, were evaluated for change in disease activity assessed by the C-reactive protein-based 27-joint Juvenile Arthritis Disease Activity Score (JADAS27CRP ). RESULTS: At the 7-year cut-off date (June 1, 2016), data from 838 patients were available (MTX-arm, N=301; ADA±MTX-arm, N=537). The most common AEs were nausea (10.3%), sinusitis (4.7%), and vomiting (4.3%) in the MTX-arm and arthritis (3.9%), upper respiratory tract infection (3.5%), sinusitis, tonsillitis, and injection site pain (3.0% each) in the ADA±MTX-arm. Rates of serious infection were 1.5 events/100 PY in the MTX-arm and 2.0 events/100 PY in the ADA±MTX-arm. AE and serious AE rates were similar in patients receiving ADA with versus without MTX. No deaths or malignancies were reported. New users in the ADA±MTX-arm showed a trend toward lower mean JADAS27CRP compared with new users in the MTX-arm in the first year of STRIVE. CONCLUSIONS: The STRIVE registry 7-year interim results support that ADA±MTX is well tolerated by most children. Registry median (interquartile range) ADA exposure was 2.47 (1.0-3.6) years, with 42% of patients continuing ADA at the 7-year cut-off date.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31412128

RESUMO

OBJECTIVES: To investigate the courses and outcomes of pregnancies involving JIA patients who were exposed to DMARDs. METHODS: In the Juvenile arthritis MTX/Biologics long-term Observation study, pregnant patients or male patients with pregnant partners were identified. Standardized patient interviews were conducted, and the course and outcome of pregnancy were assessed. Prospectively collected physician- and patient-reported data were also considered in the analysis. RESULTS: The study sample included 152 pregnancies in 98 women with JIA and 39 pregnancies involving 21 male patients as partners. The majority of patients had polyarticular-onset/-course JIA (61%). The average age of patients at first pregnancy was 24.1 (4.5) years, and their mean disease duration was 13.8 (5.9) years. Patients had been exposed to DMARDs for 9.5 (5.6) years, and 90% of these patients had received biologics before. Half of the pregnancies occurred during DMARD exposure, mostly with etanercept. Significant differences in pregnancy outcomes between DMARD-exposed and -unexposed pregnancies were not observed. Spontaneous abortion (13.1%) and congenital anomaly (3.6%) rates were not suggestive of increased risk compared with expected background rates. However, the rates of premature birth (12.3%) and caesarean section (37.7%) were slightly above those in the German birthing population. The disease activity of female patients remained relatively stable in pregnancy, with mean cJADAS-10 scores of 5.3, 7.1 and 5.6 in each trimester, respectively. CONCLUSION: Young adults with JIA often become pregnant or become fathers of children while still being treated with DMARDs. Data suggest no increased risk of major adverse pregnancy outcomes.

5.
Arthritis Rheumatol ; 71(10): 1756-1765, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31131995

RESUMO

OBJECTIVE: Inflamed tissue is characterized by low availability of oxygen and nutrients. Yet CD4+ T helper lymphocytes persist over time in such tissue and probably contribute to the chronicity of inflammation. This study was undertaken to analyze the metabolic adaptation of these cells to the inflamed environment. METHODS: Synovial and blood CD4+ T cells isolated ex vivo from patients with juvenile idiopathic arthritis (JIA) and murine CD4+ T cells were either stimulated once or stimulated repeatedly. Their dependency on particular metabolic pathways for survival was then analyzed using pharmacologic inhibitors. The role of the transcription factor Twist 1 was investigated by determining lactate production and oxygen consumption in Twist1-sufficient and Twist1-deficient murine T cells. The dependency of these murine cells on particular metabolic pathways was analyzed using pharmacologic inhibitors. RESULTS: Programmed death 1 (PD-1)+ T helper cells in synovial fluid samples from patients with JIA survived via fatty acid oxidation (mean ± SEM survival of 3.4 ± 2.85% in the presence of etomoxir versus 60 ± 7.08% in the absence of etomoxir on day 4 of culture) (P < 0.0002; n = 6) and expressed the E-box-binding transcription factor TWIST1 (2-14-fold increased expression) (P = 0.0156 versus PD-1- T helper cells; n = 6). Repeatedly restimulated murine T helper cells, which expressed Twist1 as well, needed Twist1 to survive via fatty acid oxidation. In addition, Twist1 protected the cells against reactive oxygen species. CONCLUSION: Our findings indicate that TWIST1 is a master regulator of metabolic adaptation of T helper cells to chronic inflammation and a target for their selective therapeutic elimination.

6.
J Rheumatol ; 46(9): 1117-1126, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30824645

RESUMO

OBJECTIVE: To determine whether neutropenia is associated with increased risk for infection in patients with systemic juvenile idiopathic arthritis (sJIA) and polyarticular-course juvenile idiopathic arthritis (pcJIA) treated with tocilizumab (TCZ). METHODS: Data up to Week 104 from 2 phase III trials of intravenous TCZ in sJIA (n = 112; ClinicalTrials.gov, NCT00642460) and pcJIA (n = 188; ClinicalTrials.gov, NCT00988221) were pooled. Worst common toxicity criteria grade and lowest observed absolute neutrophil count (ANC) were identified for each patient. Associations between patient characteristics and lowest observed ANC were tested using univariate regression analysis. Infection and serious infection rates per 100 patient-years (PY) in periods associated with grades 1/2 and 3/4 neutrophil counts were compared with rates associated with normal neutrophil counts. RESULTS: ANC decreased to grade ≥ 3 in 25.0% and 5.9% of sJIA and pcJIA patients, respectively, and decreases were transient. Young age (p = 0.047) and methotrexate use (p = 0.012) were positively associated with neutropenia in patients with sJIA but not in patients with pcJIA. The rate of serious infections in patients with sJIA (10.9/100 PY; 95% CI 6.8-16.5) tended to be higher than in patients with pcJIA (5.2/100 PY; 95% CI 3-8.5). No increase in rates of serious or nonserious infections was observed during periods of neutropenia in either trial. CONCLUSION: Patients with JIA treated with TCZ experienced transient neutropenia that was not associated with an increased number of infections.

7.
Pediatr Rheumatol Online J ; 17(1): 6, 2019 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744659

RESUMO

BACKGROUND: Regular school sports can help adolescents achieve the recommended amount of daily physical activity and provide knowledge, attitudes and behavioral skills that are needed in order to adopt and maintain a physically active lifestyle. Furthermore, it reaches all children including those that are at risk for engaging in more sedentary types of behavior. Since adolescents with juvenile idiopathic arthritis (JIA) are less involved in physical and social activities than their healthy peers, the objectives were to (1) estimate the prevalence of participation in school sports among patients with JIA; (2) determine the correlates associated with school sports absenteeism; and (3) investigate whether attendance in school sports has changed in the era of biologics. METHODS: Data from schoolchildren with JIA recorded in the German National Paediatric Rheumatologic Database (NPRD) in the years 2000 to 2015 were considered for the analyses. Data from the year 2015 were inspected to analyze correlates of school sports absenteeism. Whether school sports participation had changed between 2000 and 2015 was determined using linear mixed models. RESULTS: During the 15-year period, the participation rates in school sports were determined in 23,016 patients. The proportion of patients who participated in school sports almost always steadily increased from 31% in 2000 to 64% in 2015 (ß = 0.017, 95% confidence interval (CI) 0.015, 0.020), whereas the exemption rate simultaneously decreased from 44% in 2000 to 16% in 2015 [ß = - 0.009, 95% CI -0.011, - 0.007]. In 2015, the data from 5879 patients (mean age 13.1 ± 3.3 years, female 65%, disease duration 5.9 ± 4.0 years, persistent oligoarthritis 37%) were available for evaluation. Full exemption from school sports (in 16.1% of cases) was associated with functional limitations, disease activity and any use of DMARDs, intra-articular glucocorticoid injections or physiotherapy. CONCLUSIONS: School sports attendance among children and adolescents with JIA has increased significantly over the past 15 years. Possible explanations include improved functional ability probably due to better treatment options. The integration of patients with child acceptable symptom states who have previously been fully exempted from school sports needs to be addressed in the future.


Assuntos
Artrite Juvenil/reabilitação , Participação do Paciente/tendências , Instituições Acadêmicas/tendências , Esportes/tendências , Absenteísmo , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Bases de Dados Factuais , Feminino , Alemanha , Humanos , Estilo de Vida , Masculino , Prevalência , Estudos Prospectivos
8.
Rheumatology (Oxford) ; 58(7): 1188-1195, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668879

RESUMO

OBJECTIVES: To provide an overview of the paediatric rheumatology (PR) services in Europe, describe current delivery of care and training, set standards for care, identify unmet needs and inform future specialist service provision. METHODS: An online survey was developed and presented to national coordinating centres of the Paediatric Rheumatology International Trials Organisation (PRINTO) (country survey) and to individual PR centres (centre and disease surveys) as a part of the European Union (EU) Single Hub and Access point for paediatric Rheumatology in Europe project. The survey contained components covering the organization of PR care, composition of teams, education, health care and research facilities and assessment of needs. RESULTS: Response rates were 29/35 (83%) for country surveys and 164/288 (57%) for centre surveys. Across the EU, approximately one paediatric rheumatologist is available per million population. In all EU member states there is good access to specialist care and medications, although biologic drug availability is worse in Eastern European countries. PR education is widely available for physicians but is insufficient for allied health professionals. The ability to participate in clinical trials is generally high. Important gaps were identified, including lack of standardized clinical guidelines/recommendations and insufficient adolescent transition management planning. CONCLUSION: This study provides a comprehensive description of current specialist PR service provision across Europe and did not reveal any major differences between EU member states. Rarity, chronicity and complexity of diseases are major challenges to PR care. Future work should facilitate the development, dissemination and implementation of standards of care, treatment and service recommendations to further improve patient-centred health care across Europe.

9.
Rheumatology (Oxford) ; 58(6): 975-986, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590748

RESUMO

OBJECTIVE: To define predictors for the 2-year outcome in terms of achieving inactivity, subsequent uveitis reactivation and occurrence of uveitis-related complications of JIA-associated uveitis. METHODS: Demographic and clinical parameters and serum samples of JIA-associated uveitis patients enrolled in ICON at ⩽1 year of JIA diagnosis were collected at study enrolment, every 3 months during the first year and subsequently every 6 months. Predictors for the 2-year outcome were evaluated by linear mixed models. RESULTS: Of 954 JIA patients included, uveitis occurred in 106 up to the first 2-year follow-up, with 98 of them having complete ophthalmological documentation. In 81.8% and 80.0% of patients, uveitis inactivity was achieved at the 1- and 2-year follow-up after uveitis onset, respectively. JIA onset after the age of 5 years, no use of topical corticosteroids, and adalimumab treatment were significantly associated with an inactive uveitis for at least 6 months (n = 57). Correlates for subsequent uveitis reactivation (n = 16, 30.2%) were age at uveitis onset ⩽5 years and active disease (clinical Juvenile Arthritis Disease Activity Score >4.5). Uveitis-related complications were present in 29.8% of patients at first uveitis documentation and in 30.7% and 32.8% at 1- and 2-year follow-up, respectively. Older age at JIA onset, short duration between JIA and uveitis onset, high anterior chamber (AC) cell grades, poor visual acuity, and topical steroid use at first uveitis documentation correlated with uveitis-related complications. CONCLUSION: In addition to demographic risk factors, JIA disease and uveitis activity scores and adalimumab are significant predictors for the 2-year outcome of JIA-associated uveitis patients.

10.
Arthritis Res Ther ; 20(1): 276, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545399

RESUMO

OBJECTIVE: The objective was to evaluate the 25(OH) vitamin D (25(OH)D) status of patients with juvenile idiopathic arthritis (JIA) and determine whether the 25(OH)D level is associated with disease activity and the course of JIA. METHODS: Patients ≤ 16 years of age with recently diagnosed JIA (< 12 months) were enrolled in the inception cohort of patients with newly diagnosed JIA (ICON), an ongoing prospective observational, controlled multicenter study started in 2010. Clinical and laboratory parameters were ascertained quarterly during the first year and half-yearly thereafter. Of the 954 enrolled patients, 360 patients with two blood samples taken during the first 2 years after inclusion and with follow up of 3 years were selected. The serum 25(OH)D levels were determined and compared with those of subjects from the general population after matching for age, sex, migration status and the month of blood-drawing. RESULTS: Nearly half of the patients had a deficient 25(OH)D level (< 20 ng/ml) in the first serum sample and a quarter had a deficient level in both samples. Disease activity and the risk of developing JIA-associated uveitis were inversely correlated with the 25(OH)D level (ß = - 0.20, 95% CI - 0.37; 0.03, hazard ratio 0.95, 95% CI 0.91; 0.99, respectively). CONCLUSION: In this study, 25(OH)D deficiency was common and associated with higher disease activity and risk of developing JIA-associated uveitis. Further studies are needed to substantiate these results and determine whether correcting 25(OH)D deficiency is beneficial in JIA.


Assuntos
Artrite Juvenil/sangue , Uveíte/sangue , Deficiência de Vitamina D/sangue , Vitamina D/sangue , Adolescente , Artrite Juvenil/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Prospectivos , Valores de Referência , Medição de Risco , Fatores de Risco , Uveíte/diagnóstico , Deficiência de Vitamina D/diagnóstico
11.
Arthritis Res Ther ; 20(1): 285, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587248

RESUMO

BACKGROUND: The availability of methotrexate and the introduction of multiple biological agents have revolutionized the treatment of juvenile idiopathic arthritis (JIA). Several international and national drug registries have been implemented to accurately monitor the long-term safety/efficacy of these agents. This report aims to present the combined data coming from Pharmachild/PRINTO registry and the national registries from Germany (BiKeR) and Sweden. METHODS: Descriptive statistics was used for demographic, clinical data, drug exposure, adverse events (AEs) and events of special interest (ESIs). For the Swedish register, AE data were not available. RESULTS: Data from a total of 15,284 patients were reported: 8274 (54%) from the Pharmachild registry and 3990 (26%) and 3020 (20%) from the German and the Swedish registries, respectively. Pharmachild children showed a younger age (median of 5.4 versus 7.6 years) at JIA onset and shorter disease duration at last available visit (5.3 versus 6.1-6.8) when compared with the other registries. The most frequent JIA category was the rheumatoid factor-negative polyarthritis (range of 24.6-29.9%). Methotrexate (61-84%) and etanercept (24%-61.8%) were the most frequently used synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs), respectively. There was a wide variability in glucocorticoid use (16.7-42.1%). Serious AEs were present in 572 (6.9%) patients in Pharmachild versus 297 (7.4%) in BiKeR. Infection and infestations were the most frequent AEs (29.4-30.1%) followed by gastrointestinal disorders (11.5-19.6%). The most frequent ESIs were infections (75.3-89%). CONCLUSIONS: This article is the first attempt to present a very large sample of data on JIA patients from different national and international registries and represents the first proposal for data merging as the most powerful tool for future analysis of safety and effectiveness of immunosuppressive therapies in JIA. REGISTRY REGISTRATION: The Pharmachild registry is registered at ClinicalTrials.gov ( NCT01399281 ) and at the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) ( http://www.encepp.eu/encepp/viewResource.htm?id=19362 ). The BiKeR registry is registered at ENCePP ( http://www.encepp.eu/encepp/viewResource.htm?id=20591 ).


Assuntos
Artrite Juvenil/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Farmacovigilância , Sistema de Registros/estatística & dados numéricos , Medicamentos Sintéticos/uso terapêutico , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Juvenil/diagnóstico , Produtos Biológicos/efeitos adversos , Criança , Pré-Escolar , Monitoramento de Medicamentos , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Estudos Prospectivos , Estudos Retrospectivos , Medicamentos Sintéticos/efeitos adversos , Resultado do Tratamento
12.
Trials ; 19(1): 629, 2018 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-30428891

RESUMO

BACKGROUND: This cluster-randomised monocentric controlled trial focuses on improving the uptake symptoms of mental health care in adolescents with chronic medical conditions who have been identified by screening to have depression or anxiety. The study aims to determine the efficacy of motivational interviewing (MI) delivered by trained physicians to increase 12- to 20-year-old adolescents' utilisation of psychological health care for symptoms of anxiety or depression. METHODS/DESIGN: In this single-centre approach, n = 1,000 adolescents will be screened (using PHQ-9 and GAD-7), and adolescents with results indicative of anxiety or depressive symptoms (n = 162) will be advised to seek psychological health care in clusters from treating physicians in specialised outpatient departments. Participants who screen positive will receive either two sessions of MI or treatment as usual (TAU; regarded as the typical daily clinical practice), which is focused on recommending them to seek psychological health care for further evaluation. MI efficacy will be compared to the current TAU as the control condition. The primary outcome is the utilisation rate of psychological health care after counselling by an MI-trained physician vs. an untrained physician. Additionally, reasons for not claiming psychological support and changes in disease-related parameters will be evaluated in a 6-month follow-up session. DISCUSSION: This trial will evaluate the feasibility of MI as a way to improve the utilisation of mental health-care services by adolescents who need further support other than that provided by standard care for chronic diseases. Physicians offering MI to adolescents may serve as a model for optimising health-care management in daily clinical practice, which may improve adolescents' long-term well-being by improving adherence to medical treatment and preventing negative lifelong consequences into adulthood. TRIAL REGISTRATION: German Trials Register (DRKS), DRKS00014043 . Registered on 26 April 2018. Düsseldorf University study ID: 2017114504.

13.
Artigo em Inglês | MEDLINE | ID: mdl-30044538

RESUMO

OBJECTIVES: To study JIA long-term outcomes in relation to the time of biological (b)DMARD initiation. METHODS: Outcomes of JIA patients prospectively followed by the BiKeR/JuMBO registers were analyzed with regard to i) drug-free remission and inactive disease, ii) functional status and quality of life, iii) surgery. To analyze the influence of early bDMARD therapy on outcomes, patients were assigned to three groups based on the time from symptom onset to bDMARD start (G1: ≤2 years, G2: >2-≤5 years, G3: >5 years). Propensity score-adjusted outcome differences were analyzed by multinomial logistic regression analyses among the groups. RESULTS: A total of 701 JIA patients were observed for 9.1±3.7 years. At the last follow-up (disease duration 14.3±6.1 years), 11.7% of patients were in drug-free remission, 40.0% had inactive disease. More than half reported no functional limitation, while 5% had undergone arthroplasty and 3% eye surgery. At the 10-year time point, patients in G1 (n=108) were significantly more likely to be in drug-free remission than those who began treatment later (G2: n=199; G3: n=259): 18.5%, 10.1%, 4.9%. Patients in G1 had significantly lower disease activity (cJADAS-10=4.9), a better overall well-being (18.2% patient global=0) and higher functional status (59.2% HAQ=0) compared to patients in G3 (7.1, 8.4%, 43.7%, respectively). G1 patients required arthroplasty significantly less frequently than G3 patients and had significantly lower disease activity over time than patients in both G2 and G3. CONCLUSION: Early DMARD treatment is associated with better disease control and outcomes, which supports the concept of a 'window of opportunity' for JIA. This article is protected by copyright. All rights reserved.

14.
Arthritis Res Ther ; 20(1): 106, 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848349

RESUMO

BACKGROUND: Achieving the best possible health-related quality of life (HRQoL) for a patient is an important treatment goal in juvenile idiopathic arthritis (JIA). We investigated the 36-month trajectories of HRQoL in children with JIA compared with healthy peers and identified the predictors of an unfavorable HRQoL. METHODS: Patients with a recent JIA diagnosis were enrolled in the German inception cohort study ICON. As a peer group, friends of patients of the same age and sex were asked to cooperate. Children were prospectively followed and regularly questioned about their HRQoL using the Pediatric Quality of Life Inventory 4.0 (PedsQL). Disease activity was assessed by the clinical Juvenile Arthritis Disease Activity Score (cJADAS-10), and the burden of the child's chronic illness on their family was assessed by the Family Burden Questionnaire (FaBel). Linear mixed models were used to compare the HRQoL of the patients and their peers. Associations between the health status of a patient at enrollment and an unfavorable HRQoL (PedsQL total < 79.3) at their 3-year follow-up (FU) were analyzed by logistic regression. RESULTS: Data from 953 patients (median symptom duration 6 months, mean age 7.9 years) and 491 healthy peers (aged 8.4 years) were analyzed. During 3 years of FU, the disease activity and HRQoL of the patients improved significantly (cJADAS-10 from 9.8 (6.2) to 2.7 (3.6) and PedsQL total score from 71.7 (18.2) to 87.3 (13.9)). While the HRQoL of the patients varied among the several JIA categories at the time of enrollment, no significant differences were found at the 3-year FU. After 36 months, the HRQoL of the patients had largely converged with that of their healthy peers. JIA patients had a psychosocial health status comparable with their healthy peers, whereas a small significant mean difference remained in physical health (5.8, 95% confidence interval (CI) 4.1-7.6). Up to the 36-month FU, three-quarters of JIA patients attained a favorable HRQoL (PedsQL ≥ 79.3) which was achieved by 90% of the peers. A higher family burden, higher pain level, and lower well-being at enrollment were associated with an unfavorable HRQoL. CONCLUSIONS: Under current therapeutic conditions, an HRQoL corresponding with that of healthy children is a realistic treatment goal in JIA.

15.
Arthritis Rheumatol ; 70(10): 1685-1694, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29732713

RESUMO

OBJECTIVE: To analyze the prognostic value of demographic, clinical, and therapeutic factors and laboratory biomarkers and to assess their role in predicting uveitis occurrence in patients with juvenile idiopathic arthritis (JIA). METHODS: Patients with JIA were enrolled within the first year after JIA diagnosis. Demographic and clinical parameters were documented. Serum samples were collected at study enrollment, at 3-month follow-up visits within the first year, and then every 6 months. A multivariable Cox regression analysis was performed to evaluate the impact of demographic, clinical, laboratory, and therapeutic parameters on uveitis onset. RESULTS: We included 954 JIA patients (67.2% female, 54.2% antinuclear antibody [ANA] positive, mean ± SD age at onset 7.1 ± 4.6 years). Uveitis occurred in 133 patients (observation period 44.5 months). Young age at JIA onset and ANA positivity were significantly associated with the onset of uveitis (both P < 0.001). Treatment of arthritis with methotrexate alone (hazard ratio [HR] 0.18 [95% confidence interval (95% CI) 0.12-0.29], P < 0.001) or combined with etanercept (HR 0.10 [95% CI 0.04-0.23], P < 0.001) or adalimumab (HR 0.09 [95% CI 0.01-0.61], P = 0.014) reduced the risk of uveitis onset and the occurrence of uveitis-related complications. Predictors of uveitis onset included elevated erythrocyte sedimentation rate at baseline (HR 2.36 [95% CI 1.38-4.02], P = 0.002) and continuing moderate or high disease activity during follow-up as measured by the 10-joint clinical Juvenile Arthritis Disease Activity Score (HR 4.30 [95% CI 2.51-7.37], P < 0.001). Additionally, S100A12 levels ≥250 ng/ml at baseline were significantly associated with the risk of uveitis (HR 2.10 [95% CI 1.15-3.85], P = 0.016). CONCLUSION: Apart from demographic risk factors and treatment modalities, JIA disease activity scores and laboratory biomarkers could be used to better define the group of JIA patients at high risk of uveitis onset.

16.
Arthritis Rheumatol ; 70(8): 1319-1330, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29609200

RESUMO

OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 × 10-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA.

17.
Rheumatol Int ; 38(Suppl 1): 211-218, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29637325

RESUMO

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the German language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. The participating centres were asked to collect demographic and clinical data along the JAMAR questionnaire in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach's alpha, interscale correlations, test-retest reliability, and construct validity (convergent and discriminant validity). A total of 319 JIA patients (2.8% systemic, 36.7% oligoarticular, 23.5% RF negative polyarthritis, and 37% other categories) and 100 healthy children were enrolled in eight centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the German version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practice and in clinical research.


Assuntos
Artrite Juvenil/diagnóstico , Avaliação da Deficiência , Medidas de Resultados Relatados pelo Paciente , Reumatologia/métodos , Adolescente , Idade de Início , Artrite Juvenil/fisiopatologia , Artrite Juvenil/psicologia , Artrite Juvenil/terapia , Estudos de Casos e Controles , Criança , Pré-Escolar , Características Culturais , Feminino , Alemanha , Nível de Saúde , Humanos , Masculino , Pais/psicologia , Pacientes/psicologia , Valor Preditivo dos Testes , Prognóstico , Psicometria , Qualidade de Vida , Reprodutibilidade dos Testes , Tradução
18.
Arthritis Rheumatol ; 70(7): 1155-1165, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29513936

RESUMO

OBJECTIVE: Uveitis is a visually debilitating disorder that affects up to 30% of children with the most common forms of juvenile idiopathic arthritis (JIA). The disease mechanisms predisposing only a subgroup of children to uveitis are unknown. This study was undertaken to identify genetic susceptibility loci for uveitis in JIA, using a genome-wide association study in 522 children with JIA. METHODS: Two cohorts of JIA patients with ophthalmologic follow-up data were genotyped. Data were then imputed using a genome-wide imputation reference panel, and an HLA-specific reference panel was used for imputing amino acids and HLA types in the major histocompatibility complex (MHC). After imputation, genome-wide and MHC-specific analyses were performed, and a reverse immunology approach was utilized to model antigen presentation at 13 common HLA-DRß1 alleles. RESULTS: Presence of the amino acid serine at position 11 (serine 11) in HLA-DRß1 was associated with an increased risk of uveitis in JIA patients (odds ratio [OR] 2.60, P = 5.43 × 10-10 ) and was specific to girls (Pfemales = 7.61 × 10-10 versus Pmales = 0.18). Serine 11 resides in the YST motif in the peptide-binding groove of HLA-DRß1; all 3 amino acids in this motif are in perfect linkage disequilibrium and show identical association with disease. Quantitative prediction of binding affinity revealed that HLA-DRß1 alleles with the YST motif could be distinguished on the basis of discernable peptide-binding preferences. CONCLUSION: These findings highlight a genetically distinct, sexually dimorphic feature of JIA with uveitis as compared to JIA without uveitis. The association could be indicative of the potential involvement of antigen presentation by HLA-DRß1 in the development of uveitis in JIA. The results of this study may advance our progress toward improved treatments for, and possible prevention of, the sight-threatening complications of uveitis in children with JIA.

19.
Ann Rheum Dis ; 77(7): 996-1002, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29453217

RESUMO

OBJECTIVES: To determine the reasons of methotrexate (MTX) discontinuation, frequency of adverse events (AE) and whether the time in inactive disease before MTX withdrawal disease is associated with the risk of disease flare. METHODS: Patients with juvenile idiopathic arthritis (JIA) beginning treatment with MTX were prospectively observed in the national JIA biologic register Biologika in der Kinderrheumatologie/Biologics in Paediatric Rheumatology and its follow-up register Juvenile arthritis Methotrexate/Biologics long-term Observation. Inactive disease was defined by a clinical Juvenile Arthritis Disease Activity Score ≤1, flare after MTX discontinuation by reoccurrence of at least moderate disease activity or restart of treatment with a disease-modifying antirheumatic drug . RESULTS: MTX treatment was initiated in 1514 patients after a mean disease duration of 2.1 years (SD=2.8). 40% of the patients experienced oligoarticular onset of JIA. MTX was discontinued in 982 (64.9%) patients. Ineffectiveness (36.9%) and achieving inactive disease (32.1%) were the most common reasons. Among the latter (n=316), 184 (58.2%) patients experienced a flare on follow-up. The likelihood of a flare was a function of time in inactive disease prior to MTX discontinuation (HR 0.95; 95% CI 0.92 to 0.97). Patients with inactive disease for longer than 12 months had a significantly lower flare rate (58 of 119, 48.7%; HR 0.48; 95% CI 0.34 to 0.69). The most frequently reported AE was MTX intolerance, including nausea, aversion and vomiting, accounting for 441 events (13.0 events/100 exposure years) in 307 (20.3%) patients. CONCLUSIONS: Patients who spent at least 12 months in inactive disease before MTX discontinuation had a significantly lower flare rate.

20.
Arthritis Rheumatol ; 70(7): 1144-1154, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29481737

RESUMO

OBJECTIVE: To investigate the pharmacokinetics, effectiveness, and safety of subcutaneous (SC) abatacept treatment over 24 months in patients with polyarticular-course juvenile idiopathic arthritis (JIA). METHODS: In this phase III, open-label, international, multicenter, single-arm study, patients with polyarticular JIA (cohort 1, ages 6-17 years and cohort 2, ages 2-5 years) in whom treatment with ≥1 disease-modifying antirheumatic drug was unsuccessful received weight-tiered SC abatacept weekly: 10 to <25 kg (50 mg), 25 to <50 kg (87.5 mg), ≥50 kg (125 mg). Patients who had met the JIA-American College of Rheumatology 30% improvement criteria (achieved a JIA-ACR 30 response) at month 4 were given the option to continue SC abatacept to month 24. The primary end point was the abatacept steady-state serum trough concentration (Cminss ) in cohort 1 at month 4. Other outcome measures included JIA-ACR 30, 50, 70, 90, 100, and inactive disease status, the median Juvenile Arthritis Disease Activity Score in 71 joints using the C-reactive protein level (JADAS-71-CRP) over time, safety, and immunogenicity. RESULTS: The median abatacept Cminss at month 4 (primary end point) and at month 24 was above the target therapeutic exposure (10 µg/ml) in both cohorts. The percentage of patients who had achieved JIA-ACR 30, 50, 70, 90, or 100 responses or had inactive disease responses at month 4 (intent-to-treat population) was 83.2%, 72.8%, 52.6%, 28.3%, 14.5%, and 30.1%, respectively, in cohort 1 (n = 173) and 89.1%, 84.8%, 73.9%, 58.7%, 41.3%, and 50.0%, respectively, in cohort 2 (n = 46); the responses were maintained to month 24. The median (interquartile range) JADAS-71-CRP improved from baseline to month 4: cohort 1, from 21.0 (13.5, 30.3) to 4.6 (2.1, 9.4); cohort 2, from 18.1 (14.0, 23.1) to 2.1 (0.3, 4.4). Improvements were sustained to month 24, at which time 27 of 173 patients (cohort 1) and 11 of 22 patients (cohort 2) had achieved JADAS-71-CRP remission. No unexpected adverse events were reported; 4 of 172 patients (2.3%) in cohort 1 and 4 of 46 (8.7%) in cohort 2 developed anti-abatacept antibodies, with no clinical effects. CONCLUSION: Weight-stratified SC abatacept yielded target therapeutic exposures across age and weight groups, was well tolerated, and improved polyarticular JIA symptoms over 24 months.

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