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1.
JCI Insight ; 5(6)2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32213704

RESUMO

Systemic juvenile idiopathic arthritis (sJIA) begins with fever, rash, and high-grade systemic inflammation but commonly progresses to a persistent afebrile arthritis. The basis for this transition is unknown. To evaluate a role for lymphocyte polarization, we characterized T cells from patients with acute and chronic sJIA using flow cytometry, mass cytometry, and RNA sequencing. Acute and chronic sJIA each featured an expanded population of activated Tregs uncommon in healthy controls or in children with nonsystemic JIA. In acute sJIA, Tregs expressed IL-17A and a gene expression signature reflecting Th17 polarization. In chronic sJIA, the Th17 transcriptional signature was identified in T effector cells (Teffs), although expression of IL-17A at the protein level remained rare. Th17 polarization was abrogated in patients responding to IL-1 blockade. These findings identify evolving Th17 polarization in sJIA that begins in Tregs and progresses to Teffs, likely reflecting the impact of the cytokine milieu and consistent with a biphasic model of disease pathogenesis. The results support T cells as a potential treatment target in sJIA.

2.
Ann Rheum Dis ; 79(2): 225-231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31707357

RESUMO

OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS. METHODS: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis. RESULTS: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes. CONCLUSIONS: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.

3.
Neurol Neuroimmunol Neuroinflamm ; 6(3): e560, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31044148

RESUMO

Objective: To highlight a novel, treatable syndrome, we report 4 patients with CNS-isolated inflammation associated with familial hemophagocytic lymphohistiocytosis (FHL) gene mutations (CNS-FHL). Methods: Retrospective chart review. Results: Patients with CNS-FHL are characterized by chronic inflammation restricted to the CNS that is not attributable to any previously described neuroinflammatory etiology and have germline mutations in known FHL-associated genes with no signs of systemic inflammation. Hematopoietic stem cell transplantation (HCT) can be well tolerated and effective in achieving or maintaining disease remission in patients with CNS-FHL. Conclusions: Early and accurate diagnosis followed by treatment with HCT can reduce morbidity and mortality in CNS-FHL, a novel, treatable syndrome. Classification of evidence: This study provides Class IV evidence that HCT is well tolerated and effective in treating CNS-FHL.

4.
J Am Heart Assoc ; 8(11): e011319, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-31130036

RESUMO

Background Accurate prediction of coronary artery aneurysms ( CAAs ) in patients with Kawasaki disease remains challenging in North American cohorts. We sought to develop and validate a risk model for CAA prediction. Methods and Results A binary outcome of CAA was defined as left anterior descending or right coronary artery Z score ≥2.5 at 2 to 8 weeks after fever onset in a development cohort (n=903) and a validation cohort (n=185) of patients with Kawasaki disease. Associations of baseline clinical, laboratory, and echocardiographic variables with later CAA were assessed in the development cohort using logistic regression. Discrimination (c statistic) and calibration (Hosmer-Lemeshow) of the final model were evaluated. A practical risk score assigning points to each variable in the final model was created based on model coefficients from the development cohort. Predictors of CAAs at 2 to 8 weeks were baseline Z score of left anterior descending or right coronary artery ≥2.0, age <6 months, Asian race, and C-reactive protein ≥13 mg/ dL (c=0.82 in the development cohort, c=0.93 in the validation cohort). The CAA risk score assigned 2 points for baseline Z score of left anterior descending or right coronary artery ≥2.0 and 1 point for each of the other variables, with creation of low- (0-1), moderate- (2), and high- (3-5) risk groups. The odds of CAA s were 16-fold greater in the high- versus the low-risk groups in the development cohort (odds ratio, 16.4; 95% CI , 9.71-27.7 [ P<0.001]), and >40-fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8-180 [ P<0.001]). Conclusions Our risk model for CAA in Kawasaki disease consisting of baseline demographic, laboratory, and echocardiographic variables had excellent predictive utility and should undergo prospective testing.

5.
Pediatr Rheumatol Online J ; 17(1): 7, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30764840

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) were historically thought to be distinct entities, often managed in isolation. In fact, these conditions are closely related. A collaborative approach, which incorporates expertise from subspecialties that previously treated HLH/MAS independently, is needed. We leveraged quality improvement (QI) techniques in the form of an Evidence-Based Guideline (EBG) to build consensus across disciplines on the diagnosis and treatment of HLH/MAS. METHODS: A multidisciplinary work group was convened that met monthly to develop the HLH/MAS EBG. Literature review and expert opinion were used to develop a management strategy for HLH/MAS. The EBG was implemented, and quality metrics were selected to monitor outcomes. RESULTS: An HLH/MAS clinical team was formed with representatives from subspecialties involved in the care of patients with HLH/MAS. Broad entry criteria for the HLH/MAS EBG were established and included fever and ferritin ≥500 ng/mL. The rheumatology team was identified as the "gate-keeper," charged with overseeing the diagnostic evaluation recommended in the EBG. First-line medications were recommended based on the acuity of illness and risk of concurrent infection. Quality metrics to be tracked prospectively based on time to initiation of treatment and clinical response were selected. CONCLUSION: HLH/MAS are increasingly considered to be a spectrum of related conditions, and joint management across subspecialties could improve patient outcomes. Our experience in creating a multidisciplinary approach to HLH/MAS management can serve as a model for care at other institutions.


Assuntos
Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Algoritmos , Consenso , Citocinas/sangue , Diagnóstico Diferencial , Medicina Baseada em Evidências/métodos , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/terapia , Guias de Prática Clínica como Assunto , Melhoria de Qualidade
7.
Arthritis Care Res (Hoboken) ; 70(7): 1052-1057, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29073349

RESUMO

OBJECTIVE: Several studies revealed the efficacy of glucocorticoids on prevention of coronary artery lesions (CALs) in Kawasaki disease (KD) patients. However, impacts of different doses of glucocorticoids on clinical outcomes of KD remain unknown. METHODS: Using the Japanese Diagnosis Procedure Combination inpatient database, we evaluated KD patients who were treated with normal-dose (prednisolone 0.5-4.0 mg/kg/day) or high-dose (methylprednisolone 10-40 mg/kg/day) glucocorticoids. We investigated risks of CALs and readmission, total hospitalization cost, and length of hospital stay in the acute phase of KD using propensity score matching, stabilized propensity-score inverse probability of treatment weighting, and instrumental variable methods. RESULTS: We identified a total of 3,220 patients with KD who were treated with normal-dose (n = 2,453) or high-dose (n = 767) glucocorticoids in addition to intravenous immunoglobulin. One-to-one propensity-matched analyses with 744 pairs demonstrated no significant differences between the normal-dose and the high-dose groups in risk of CALs (risk ratio [RR] 0.83, 95% confidence interval [95% CI] 0.49, 1.40) and risk of readmissions (RR 0.85, 95% CI 0.65, 1.11). Stabilized propensity-score inverse probability weighting and instrumental variable analyses showed similar results to the propensity score matching analyses. CONCLUSION: Risks of CALs and readmissions and total hospitalization costs were similar between the normal-dose and the high-dose glucocorticoids groups for patients with KD, whereas total length of hospital stay was shorter in the high-dose group than that in the normal-dose group.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/tratamento farmacológico , Glucocorticoides/administração & dosagem , Metilprednisolona/administração & dosagem , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Pré-Escolar , Doença da Artéria Coronariana/epidemiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Prednisolona/administração & dosagem , Distribuição Aleatória
8.
J Am Heart Assoc ; 6(6)2017 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-28566299

RESUMO

BACKGROUND: Accurate risk prediction of coronary artery aneurysms (CAAs) in North American children with Kawasaki disease remains a clinical challenge. We sought to determine the predictive utility of baseline coronary dimensions adjusted for body surface area (z scores) for future CAAs in Kawasaki disease and explored the extent to which addition of established Japanese risk scores to baseline coronary artery z scores improved discrimination for CAA development. METHODS AND RESULTS: We explored the relationships of CAA with baseline z scores; with Kobayashi, Sano, Egami, and Harada risk scores; and with the combination of baseline z scores and risk scores. We defined CAA as a maximum z score (zMax) ≥2.5 of the left anterior descending or right coronary artery at 4 to 8 weeks of illness. Of 261 patients, 77 patients (29%) had a baseline zMax ≥2.0. CAAs occurred in 15 patients (6%). CAAs were strongly associated with baseline zMax ≥2.0 versus <2.0 (12 [16%] versus 3 [2%], respectively, P<0.001). Baseline zMax ≥2.0 had a C statistic of 0.77, good sensitivity (80%), and excellent negative predictive value (98%). None of the risk scores alone had adequate discrimination. When high-risk status per the Japanese risk scores was added to models containing baseline zMax ≥2.0, none were significantly better than baseline zMax ≥2.0 alone. CONCLUSIONS: In a North American center, baseline zMax ≥2.0 in children with Kawasaki disease demonstrated high predictive utility for later development of CAA. Future studies should validate the utility of our findings.


Assuntos
Aneurisma Coronário/etiologia , Vasos Coronários/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Ecocardiografia , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico por imagem , Fatores Etários , Pré-Escolar , Aneurisma Coronário/diagnóstico , Feminino , Humanos , Imunossupressores/uso terapêutico , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , América do Norte , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco
9.
Clin Rheumatol ; 36(2): 413-419, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27987089

RESUMO

Several studies revealed the epidemiology of Kawasaki disease-related hospitalizations among children in the USA and other countries. However, disparities of developing coronary artery aneurysms by race/ethnicity, patient socioeconomic status, and geographic locations remain unknown in the USA. Hospital discharge record data of patients with Kawasaki disease aged 19 years or younger were obtained from the 2003, 2006, 2009, and 2012 Kid's Inpatient Database. The data were weighted to estimate the annual hospitalization rates with respect to age, gender, and race/ethnicity in the USA. Multivariable logistic regression was conducted to ascertain the factors associated with the development of coronary artery aneurysms. Total annual hospitalization rates of Kawasaki disease showed a decreasing trend, ranging from 6.54 per 100,000 children in 2003 to 6.11 per 100,000 children in 2012 (p < 0.001). The proportions of coronary artery aneurysms among patients with Kawasaki disease ranged from 2.25 to 3.20%. Factor associated with the development of coronary artery aneurysms was hospitals in West (OR 2.15, 95% CI 1.42-3.26). Race/ethnicity, health insurance status, and household income were not associated with the development of coronary artery aneurysms. Total hospitalization rates of Kawasaki disease showed a decreasing trend. Children admitted to hospitals in West region were more likely to develop coronary artery aneurysms.


Assuntos
Aneurisma Coronário/epidemiologia , Aneurisma Coronário/terapia , Hospitalização/estatística & dados numéricos , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/terapia , Pediatria , Adolescente , Criança , Pré-Escolar , Vasos Coronários/patologia , Coleta de Dados , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Alta do Paciente , Resultado do Tratamento , Estados Unidos
10.
Pediatr Rheumatol Online J ; 14(1): 67, 2016 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-27964737

RESUMO

BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ("unaided"), versus after use of the DDSS ("aided"). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p < 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an "open book" approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists' ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086.


Assuntos
Técnicas de Apoio para a Decisão , Medicina Baseada em Evidências , Doenças Reumáticas/diagnóstico , Software , Criança , Erros de Diagnóstico/prevenção & controle , Humanos
11.
Clin Rheumatol ; 35(11): 2749-2756, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27596741

RESUMO

At the national level, IgA vasculitis-related hospitalizations among children in the USA are scarce. Furthermore, nationwide epidemiology and hospital course of children with IgA vasculitis have not been fully described in the USA, and disparities by race/ethnicity remain unknown. Hospital discharge records of patients aged 19 years or younger were obtained from the 2003, 2006, 2009, and 2012 Kids' Inpatient Database, and they were weighted to estimate the annual hospitalization rates with respect to age, gender, and race/ethnicity in the USA. Annual hospitalization rates were calculated using weighted case estimates and US census data. Negative binomial regression was used to ascertain the factors associated with length of hospital stay. Total annual hospitalization rates showed a significant decreasing trend, ranging from 2.45 per 100,000 children in 2003 to 1.89 per 100,000 children in 2012 (p < 0.001). The peak ages of the hospitalized children with IgA vasculitis were 2 and 7 years, and male-to-female ratios were 1.38-1.44. Factors associated with length of hospital stay were patients' ages (10-14 and 15-19 years), race/ethnicity (Hispanic, Asian, and Pacific Islander), comorbid electrolyte abnormality, GI hemorrhage, intussusception, renal symptoms, and GI symptoms. The annual hospitalization rates for IgA vasculitis are declining in the USA across multiple age groups. GI and renal manifestations are associated with increased length of hospital stay.


Assuntos
Hospitalização/estatística & dados numéricos , Imunoglobulina A , Vasculite/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Tempo de Internação , Masculino , Estados Unidos/epidemiologia , Vasculite/terapia , Adulto Jovem
12.
Arthritis Rheumatol ; 68(7): 1758-68, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26815131

RESUMO

OBJECTIVE: Treg cell-mediated suppression of Teff cells is impaired in juvenile idiopathic arthritis (JIA); however, the basis for this dysfunction is incompletely understood. Animal models of autoimmunity and immunodeficiency demonstrate that a diverse Treg cell repertoire is essential to maintain Treg cell function. The present study was undertaken to investigate the Treg and Teff cell repertoires in JIA. METHODS: Treg cells (CD4+CD25+CD127(low) ) and Teff cells (CD4+CD25-) were isolated from peripheral blood and synovial fluid obtained from JIA patients, healthy controls, and children with Lyme arthritis. Treg cell function was measured in suppressive assays. The T cell receptor ß chain (TRB) was amplified by multiplex polymerase chain reaction and next-generation sequencing was performed, with amplicons sequenced using an Illumina HiSeq platform. Data were analyzed using ImmunoSEQ, International ImMunoGeneTics system, and the Immunoglobulin Analysis Tools. RESULTS: Compared to findings in controls, the JIA peripheral blood Treg cell repertoire was restricted, and clonotypic expansions were found in both blood and synovial fluid Treg cells. Skewed usage and pairing of TRB variable and joining genes, including overuse of gene segments that have been associated with other autoimmune conditions, was observed. JIA patients shared a substantial portion of synovial fluid Treg cell clonotypes that were private to JIA and not identified in Lyme arthritis. CONCLUSION: We identified restriction and clonotypic expansions in the JIA Treg cell repertoire with sharing of Treg cell clonotypes across patients. These findings suggest that abnormalities in the Treg cell repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA.


Assuntos
Artrite Juvenil/imunologia , Linfócitos T Reguladores/fisiologia , Adolescente , Artrite Juvenil/sangue , Células Cultivadas , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Líquido Sinovial/citologia , Subpopulações de Linfócitos T/fisiologia
13.
Rheum Dis Clin North Am ; 41(1): 63-73, viii, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25399940

RESUMO

Kawasaki disease (KD) is the archetypal pediatric vasculitis, exemplifying the unique aspects and challenges of vascular inflammation in children. The condition is almost unheard of in adults, is closely associated with infections, and is self-limited, with fever resolving after an average of 12 days even without treatment. Yet KD is also a potentially fatal disease and the most common cause of acquired heart disease in the developed world. Unraveling of the developmental, immunologic, and genetic secrets of Kawasaki disease promises to improve our understanding of vasculitis in particular, and perhaps also to provide a window on the fundamental mysteries of inflammatory diseases in general.


Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/terapia , Criança , Pré-Escolar , Aneurisma Coronário/etiologia , Humanos , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico
14.
J Am Heart Assoc ; 3(6): e001483, 2014 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-25380671

RESUMO

BACKGROUND: Multicenter studies on idiopathic or viral pericarditis and pericardial effusion (PPE) have not been reported in children. Colchicine use for PPE in adults is supported. We explored epidemiology and management for inpatient hospitalizations for PPE in US children and risk factors for readmission. METHODS AND RESULTS: We analyzed patients in the Pediatric Health Information System database for (1) a code for PPE; (2) absence of codes for underlying systemic disease (eg, neoplastic, cardiac, rheumatologic, renal); (3) age ≥30 days and <21 years; and (4) discharge between January 1, 2007, and December 31, 2012, from 38 hospitals contributing complete data for each year of the study period. Among 11 364 hospitalizations with PPE codes during the study period, 543 (4.8%) met entry criteria for idiopathic or viral PPE. Significantly more boys were noted, especially among adolescents. No temporal trends were noted. Median age was 14.5 years (interquartile range 7.3 to 16.6 years); 78 patients (14.4%) underwent pericardiocentesis, 13 (2.4%) underwent pericardiotomy, and 11 (2.0%) underwent pericardiectomy; 157 (28.9%) had an intensive care unit stay, including 2.0% with tamponade. Median hospitalization was 3 days (interquartile range 2 to 4 days). Medications used at initial admission were nonsteroidal anti-inflammatory drugs (71.3%), corticosteroids (22.7%), aspirin (7.0%), and colchicine (3.9%). Readmissions within 1 year of initial admission occurred in 46 of 447 patients (10.3%), mostly in the first 3 months. No independent predictors of readmission were noted, but our statistical power was limited. Practice variation was noted in medical management and pericardiocentesis. CONCLUSIONS: Our report provides the first large multicenter description of idiopathic or viral PPE in children. Idiopathic or viral PPE is most common in male adolescents and is treated infrequently with colchicine.


Assuntos
Anti-Inflamatórios/uso terapêutico , Imunossupressores/uso terapêutico , Derrame Pericárdico/epidemiologia , Derrame Pericárdico/terapia , Pericardiectomia , Pericardiocentese , Pericardite/epidemiologia , Pericardite/terapia , Adolescente , Distribuição por Idade , Fatores Etários , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Humanos , Lactente , Pacientes Internados , Tempo de Internação , Masculino , Readmissão do Paciente , Derrame Pericárdico/diagnóstico , Derrame Pericárdico/virologia , Pericardite/diagnóstico , Pericardite/virologia , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
15.
Artigo em Inglês | MEDLINE | ID: mdl-25249820

RESUMO

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is the most common cause of non-infectious joint inflammation in children. Synovial inflammation results in pain, swelling and stiffness. Animal and adult human studies indicate that localized joint-associated inflammation may produce generalized changes in pain sensitivity. The aim was to characterize pain sensitivity in children with JIA to mechanical and thermal stimulus modalities using quantitative sensory testing (QST) at an affected inflamed joint, and compare to children in clinical remission. Generalized hypersensitivity was evaluated by comparing QST measures at the thenar eminence between JIA and healthy control children. METHODS: 60 children aged 7-17 years with JIA participated. QST assessed sensory detection threshold and pain threshold at two sites: (1) affected joint (clinically active or inactive), (2) contralateral thenar eminence. Joint site included finger, wrist, knee and ankle. Clinical status was measured using objective and subjective markers of disease severity. Questionnaires assessed pain intensity and frequency, functional disability, anxiety, pain catastrophization and fatigue. QST data collected from joints were compared within JIA patients: active vs. inactive inflammation; and data from the contralateral thenar eminence were compared between JIA and healthy control cohorts in Europe [EU, (n = 151)] and the US (n = 92). Statistical analyses were performed using Kruskal-Wallis with Dunn's post-hoc comparison, Mann-Whitney or Fisher's exact test, where appropriate. RESULTS: Overall, children with JIA reported low pain scores and low degrees of functional disability. Sensory detection thresholds and pain thresholds were similar in "active" compared to "inactive" joints. Despite this, children with JIA had generalized hypersensitivity at the thenar eminence when compared to healthy children for pressure (vs. EU p < 0.001), light touch (vs. EU p < 0.001), cold (vs EU, p < 0.01; vs US, p < 0.001) and heat pain (vs EU, p < 0.05; vs US p < 0.001). CONCLUSIONS: JIA is associated with increased sensitivity to painful mechanical and thermal stimuli, even in absence of pain reports, or markers of disease activity. Future research investigating mechanisms underlying pain hypersensitivity in JIA is warranted; this will in turn guide pharmacologic and non-pharmacologic interventions to prevent or reverse these processes.


Assuntos
Artralgia/epidemiologia , Artrite Juvenil/fisiopatologia , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Transtornos Somatoformes/epidemiologia , Adolescente , Artralgia/etiologia , Artrite Juvenil/complicações , Estudos de Casos e Controles , Criança , Estudos de Coortes , Avaliação da Deficiência , Feminino , Humanos , Masculino , Medição da Dor , Estimulação Física , Prevalência , Limiar Sensorial/fisiologia , Transtornos Somatoformes/etiologia
16.
J Rheumatol ; 41(6): 1163-70, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24786928

RESUMO

OBJECTIVE: To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). METHODS: Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. RESULTS: Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. CONCLUSION: Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Metotrexato/uso terapêutico , Prednisolona/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Criança , Pré-Escolar , Progressão da Doença , Método Duplo-Cego , Quimioterapia Combinada , Etanercepte , Feminino , Humanos , Masculino , Indução de Remissão , Resultado do Tratamento
17.
Pediatr Rheumatol Online J ; 11(1): 42, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24180594

RESUMO

BACKGROUND: The significance of hypergammaglobulinemia as a marker of immune activation is unknown, as a differential diagnosis for hypergammaglobulinemia in children has not been adequately established. The goal of this study was to identify conditions associated with hypergammaglobulinemia in children, with the hypothesis that elevated immunoglobulin levels may precede or predict the development of autoimmune conditions. METHODS: We reviewed the medical records for all children with IgG level ≥2000 mg/dL treated at a tertiary care children's hospital from January 1, 2000 through December 31, 2009. We compared clinical and laboratory features of these patients, and developed an algorithm to predict the likelihood of underlying autoimmunity based on these characteristics. RESULTS: After excluding children who had received IVIG, a total of 442 patients with hypergammaglobulinemia were identified. Of these, nearly half had autoimmune conditions, most frequently systemic lupus erythematosus and lupus-related disorders. Autoimmune gastrointestinal disorders such as inflammatory bowel disease were also common. Infectious diseases were the next largest category of diseases, followed with much less frequency by malignant, drug-related, and other conditions. In comparison with non-autoimmune conditions, patients with autoimmune disease had higher IgG levels, lower white blood cell counts, lower hemoglobin values, and lower C-reactive protein (CRP) levels. Multivariable logistic regression confirmed that CRP (P = 0.002), white blood cell count (P < 0.001), hemoglobin (P = 0.015), and female gender (P < 0.001) are independent risk factors for autoimmune disease in patients with high IgG levels. CONCLUSIONS: In a cohort of pediatric patients at a tertiary care children's hospital, hypergammaglobulinemia was most commonly associated with autoimmune diseases. In female patients with hypergammaglobulinemia, the presence of leukopenia, anemia, and normal CRP was 95% predictive of underlying autoimmune disease.

18.
EMBO Mol Med ; 5(2): 210-20, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23281308

RESUMO

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97-1 and 0.95-1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease.


Assuntos
Biomarcadores/urina , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/urina , Animais , Estudos de Casos e Controles , Criança , Pré-Escolar , Proteínas Contráteis/urina , Feminino , Filaminas , Humanos , Lactente , Masculino , Espectrometria de Massas , Metaloendopeptidases/urina , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/urina , Proteômica
19.
Pediatrics ; 130(5): e1190-7, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23071213

RESUMO

BACKGROUND AND OBJECTIVES: Little information is available concerning the natural history and optimal treatment of chronic nonbacterial osteomyelitis (CNO). We conducted a retrospective review to assess the clinical characteristics and treatment responses of a large cohort of pediatric CNO patients. METHODS: Children diagnosed with CNO at 3 tertiary care centers in the United States between 1985 and 2009 were identified. Their charts were reviewed, and clinical, laboratory, histopathologic, and radiologic data were extracted. RESULTS: Seventy children with CNO (67% female patients) were identified. Median age at onset was 9.6 years (range 3-17), and median follow-up was 1.8 years (range 0-13). Half of the patients had comorbid autoimmune diseases, and 49% had a family history of autoimmunity. Patients with comorbid autoimmune diseases had more bone lesions (P < .001), higher erythrocyte sedimentation rate (P < .05), and higher use of second line therapy (P = .02). Treatment response to nonsteroidal antiinflammatory drugs (NSAIDs), sulfasalazine, methotrexate, tumor necrosis factor α inhibitors, and corticosteroids was evaluated. The only significant predictor of a positive treatment response was the agent used (P < .0001). Estimated probability of response was 57% for NSAIDs, 66% for sulfasalazine, 91% for methotrexate, 91% for tumor necrosis factor α inhibitors, and 95% for corticosteroids. CONCLUSIONS: In a US cohort of 70 children with CNO, coexisting autoimmunity was a risk factor for multifocal involvement and treatment with immunosuppressive agents. Disease-modifying antirheumatic drugs and biologics were more likely to lead to clinical improvement than NSAIDs.


Assuntos
Osteomielite , Adolescente , Anti-Inflamatórios/uso terapêutico , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Imunossupressores/uso terapêutico , Masculino , Osteomielite/diagnóstico , Osteomielite/tratamento farmacológico , Osteomielite/imunologia , Estudos Retrospectivos
20.
Nat Rev Rheumatol ; 8(10): 570-2, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22986458

RESUMO

In the absence of definitive diagnostic tests, several schemes for the classification of paediatric vasculitis have been devised and periodically updated, but are these revisions necessary and useful?


Assuntos
Vasculite/classificação , Criança , Humanos , Pediatria/normas , Reumatologia/normas
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