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PURPOSE: Meaningful score differences (MSDs), as defined by recent FDA guidance, can improve the interpretation of outcome measure scores and score changes. Well-accepted methods for estimating MSDs typically rely on external anchor variables, but the applications of these methods are limited in children and adolescents with rheumatic diseases. This project explored multiple candidate anchors for the PROMIS® Pediatric measures of Physical Activity, Fatigue, Pain Interference, and Mobility for children with juvenile idiopathic arthritis (JIA) or systemic lupus erythematosus (SLE). METHODS: Longitudinal data were extracted from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Candidate anchors included patient-reported domain-specific global impressions of change (GIC) along with other parent- and clinician-reported variables. Prior to MSD estimation, the quality of the anchors was assessed using a priori criteria (correlation ≥0.30, n≥10, <10% missing). Anchors meeting criteria were used to calculate MSDs. RESULTS: Among 289 children with JIA and 47 with SLE, the GIC did not meet criteria inhalf of the scenarios. Other candidate anchors performed slightly better. The calculated MSDs varied by external anchor across measures, diagnoses, and direction of change (better vs worse). CONCLUSIONS: Many of the candidate external anchoring variables did not meet pre-specified criteria for calculating MSDs. Even for those that did, the choice of anchoring variable had a strong impact on the estimated MSD value and were different from other published values. As in adults, establishing pediatric MSDs requires selection of high-quality anchors, as changes in the variables used as anchors can impact MSD values and any subsequent score interpretations.
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BACKGROUND: The incidence of systemic lupus in children with discoid lupus is unknown. OBJECTIVE: This study assessed the baseline characteristics of patients with pediatric discoid lupus erythematosus (pDLE). METHODS: Medical records at 17 sites were reviewed for pediatric dermatology and rheumatology patients with discoid lupus erythematosus. The inclusion criteria were clinical and/or histopathologic diagnosis of discoid lupus erythematosus with an age at onset of <18 years. Baseline data were collected at the first documented visit. Outcomes included diagnosis of systemic lupus erythematosus (SLE) at the baseline visit using the 1997 American College of Rheumatology (primary) and the 2012 Systemic Lupus International Collaborating Clinics (secondary) criteria. RESULTS: Of the >1500 charts reviewed, 438 patients met the inclusion criteria. The cohort was predominantly female (72%) and racially/ethnically diverse. A diagnosis of SLE at the baseline visit (pDLE + SLE) was rendered in 162 (37%) patients using the American College of Rheumatology and in 181 (41%) patients using the Systemic Lupus International Collaborating Clinics criteria. Patients with pDLE + SLE were older at the time of rash onset (median, 12.9 vs 8.9 years; P < .001), with shorter time from discoid lupus erythematosus onset to diagnosis, compared with patients with pDLE-only (median, 2 vs 7 months; P < .001). Patients with pDLE + SLE were more likely to be female (P = .004), with generalized discoid lupus erythematosus and clinically aggressive disease, including end-organ involvement, positive serologies, and higher- titer levels of antinuclear antibodies (P < .001). LIMITATIONS: Retrospective study. CONCLUSION: A diagnosis of discoid lupus erythematosus in adolescence should prompt thorough screening for SLE.
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Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Adolescente , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Lúpus Eritematoso Discoide/diagnóstico , Lúpus Eritematoso Discoide/epidemiologia , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Estudos RetrospectivosRESUMO
PURPOSE: A key limitation to widespread adoption of patient-reported outcome (PRO) measures is the lack of interpretability of scores. We aim to identify clinical severity thresholds to distinguish categories of no problems, mild, moderate, and severe along the PROMIS® Pediatric T-score metric for measures of anxiety, mobility, fatigue, and depressive symptoms for use in populations with juvenile idiopathic arthritis (JIA) and childhood-onset systemic lupus erythematosus (cSLE). METHODS: We used a modified standard setting methodology from educational testing to identify clinical severity thresholds (clinical cut scores). Using item response theory-based parameters from PROMIS item banks, we developed a series of clinical vignettes that represented different severity or ability levels along the PROMIS Pediatric T-score metric. In stakeholder workshops, participants worked individually and together to reach consensus on clinical cut scores. Median cut-score placements were taken when consensus was not reached. Focus groups were recorded and qualitative analysis was conducted to identify decision-making processes. RESULTS: Nine adolescents (age 13-17 years) with JIA (33% female) and their caregivers, five adolescents (age 14-16 years) with cSLE (100% female) and their caregivers, and 12 pediatric rheumatologists (75% female) participated in bookmarking workshops. Placement of thresholds for bookmarks was highly similar across stakeholder groups (differences from 0 to 5 points on the PROMIS t-score metric) for all but one bookmark placement. CONCLUSION: This study resulted in clinical thresholds for severity categories for PROMIS Pediatric measures of anxiety, mobility, fatigue, and depressive symptoms, providing greater interpretability of scores in JIA and cSLE populations.
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Ansiedade/psicologia , Artrite Juvenil/psicologia , Artrite Juvenil/reabilitação , Depressão/psicologia , Lúpus Eritematoso Sistêmico/psicologia , Lúpus Eritematoso Sistêmico/reabilitação , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida/psicologia , Adolescente , Criança , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Children with discoid lupus erythematosus (DLE) are at risk for disfigurement and progression to systemic lupus erythematosus (SLE). Consensus is lacking regarding optimal care for children with DLE. OBJECTIVES: The aim of this study was to compare practice patterns among paediatric dermatologists/rheumatologists treating paediatric DLE. METHODS: An online survey was sent to 292 paediatric rheumatologists in the Childhood Arthritis and Rheumatology Research Alliance and 200 paediatric dermatologists in the Pediatric Dermatology Research Alliance. Consensus was defined as ≥ 70% agreement. RESULTS: Survey response rates were 38% (76 of 200) for dermatology and 21% (60 of 292) for rheumatology. Both specialties agreed that screening labs should include complete blood counts with differential, urinalysis, complement levels, erythrocyte sedimentation rate, antinuclear antibody and other autoantibodies, hepatic function and renal function/electrolytes. Both specialties agreed that arthritis or nephritis should prompt intensified evaluation for SLE. No other patient features achieved consensus as disease-modifying risk factors. Hydroxychloroquine was agreed upon as first-line systemic therapy, but consensus was lacking for second- or third-line treatment. CONCLUSIONS: We found few areas of consensus and significant practice differences between paediatric dermatologists and rheumatologists treating DLE. Knowledge gaps include risk factors for SLE, optimal screening and treatment of refractory skin disease.
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Dermatologia/estatística & dados numéricos , Lúpus Eritematoso Discoide/terapia , Lúpus Eritematoso Sistêmico/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Reumatologia/estatística & dados numéricos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Criança , Consenso , Dermatologistas/estatística & dados numéricos , Dermatologia/normas , Progressão da Doença , Humanos , Lúpus Eritematoso Discoide/diagnóstico , Lúpus Eritematoso Discoide/imunologia , Lúpus Eritematoso Discoide/patologia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Programas de Rastreamento/normas , Programas de Rastreamento/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Padrões de Prática Médica/normas , Reumatologistas/estatística & dados numéricos , Reumatologia/normas , Fatores de Risco , Inquéritos e Questionários/estatística & dados numéricosRESUMO
Objective The objective of this article is to describe and compare clinical features, treatment, and renal outcomes of children with membranous lupus nephritis (MLN), through analysis of a national multicenter registry. Methods Patients with pediatric systemic lupus erythematosus (SLE) and MLN from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry were included. Demographic, disease and medication-related data were collected between 2010 and 2014 from 59 CARRA Legacy Registry sites. Results A total of 132 individuals had MLN, either in isolation or in combination with proliferative LN. Seventy-four patients had pure MLN. The proportion of patients with daily corticosteroid treatment was similar among groups (96%, 91%, and 96%, for class III+V, IV+V, and V, respectively, p = 0.67). Proportion of individuals exposed to any disease-modifying antirheumatic drug (DMARD) or biologic was similar among the three groups (83%, 91%, 95% for class III+V, IV+V, and V, respectively, p = 0.189). Proportion of patients with decreased glomerular filtration rate (less than 90 ml/min/1.73 m2) was significantly different among groups (4%, 38%, and 4%, for class III+V, IV+V, and V, respectively, p < 0.0001). Conclusion This is the largest reported cohort of children with MLN. More research is needed to understand treatment practices for pediatric MLN, particularly decisions related to pharmacologic treatment of pure MLN. More work is also needed to identify prognostic factors and predictors of outcome for pediatric MLN. Future observational studies will be a first step toward understanding and formulating a standardized approach to treatment of pediatric membranous LN and allowing for the initiation of prospective comparative effectiveness studies and interventional trials.
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Antirreumáticos/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/epidemiologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/epidemiologia , Adolescente , Criança , Comportamento Cooperativo , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/complicações , Humanos , Rim/patologia , Estudos Longitudinais , Nefrite Lúpica/patologia , Masculino , Pediatria , Sistema de Registros , Sociedades Médicas , Estados UnidosRESUMO
OBJECTIVE: Statins reduce atherosclerosis and cardiovascular morbidity in the general population, but their efficacy and safety in children and adolescents with systemic lupus erythematosus (SLE) are unknown. This study was undertaken to determine the 3-year efficacy and safety of atorvastatin in preventing subclinical atherosclerosis progression in pediatric-onset SLE. METHODS: A total of 221 participants with pediatric SLE (ages 10-21 years) from 21 North American sites were enrolled in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus study, a randomized double-blind, placebo-controlled clinical trial, between August 2003 and November 2006 with 36-month followup. Participants were randomized to receive atorvastatin (n=113) or placebo (n=108) at 10 or 20 mg/day depending on weight, in addition to usual care. The primary end point was progression of mean-mean common carotid intima-media thickening (CIMT) measured by ultrasound. Secondary end points included other segment/wall-specific CIMT measures, lipid profile, high-sensitivity C-reactive protein (hsCRP) level, and SLE disease activity and damage outcomes. RESULTS: Progression of mean-mean common CIMT did not differ significantly between treatment groups (0.0010 mm/year for atorvastatin versus 0.0024 mm/year for placebo; P=0.24). The atorvastatin group achieved lower hsCRP (P=0.04), total cholesterol (P<0.001), and low-density lipoprotein (P<0.001) levels compared with placebo. In the placebo group, CIMT progressed significantly across all CIMT outcomes (0.0023-0.0144 mm/year; P<0.05). Serious adverse events and critical safety measures did not differ between groups. CONCLUSION: Our results indicate that routine statin use over 3 years has no significant effect on subclinical atherosclerosis progression in young SLE patients; however, further analyses may suggest subgroups that would benefit from targeted statin therapy. Atorvastatin was well tolerated without safety concerns.
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Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , Ácidos Heptanoicos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Pirróis/uso terapêutico , Adolescente , Aterosclerose/complicações , Aterosclerose/diagnóstico , Atorvastatina , Espessura Intima-Media Carotídea , Criança , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Lipídeos/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.
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Biomarcadores/sangue , Doenças Cardiovasculares , Lúpus Eritematoso Sistêmico , Adolescente , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Criança , Colesterol/sangue , Estudos Transversais , Método Duplo-Cego , Feminino , Humanos , Lipoproteína(a)/sangue , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Placebos , Fatores de Risco , Triglicerídeos/sangue , Adulto JovemRESUMO
An unusual case of central nervous system vasculitis in pediatric Wegener's granulomatosis, a rare disorder that infrequently presents during childhood, is reported. A 13-year-old girl with Wegener's granulomatosis, whose initial presentation resembled Henoch-Schonlein purpura, developed recurring seizures. MRI of the brain demonstrated multiple areas of increased signal in the occipital, parietal, and frontal lobes, consistent with central nervous system vasculitis. Although both peripheral and cranial neuropathies have been reported in patients with Wegener's granulomatosis, cerebral vasculitis is unusual, particularly in childhood. This case emphasizes the need to consider Wegener's granulomatosis in the differential diagnosis of both unexplained seizures and central nervous system vasculitis in children with systemic illness.
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Transtornos Cerebrovasculares/complicações , Granulomatose com Poliangiite/complicações , Vasculite/complicações , Adolescente , Encéfalo/patologia , Transtornos Cerebrovasculares/diagnóstico , Diagnóstico Diferencial , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/patologia , Humanos , Vasculite por IgA/diagnóstico , Rim/patologia , Imageamento por Ressonância Magnética , Convulsões/diagnóstico , Convulsões/etiologia , Vasculite/diagnósticoRESUMO
Antibodies against phospholipids (PL) and PL-binding proteins have been causally implicated in antiphospholipid syndrome (APS). Mutations in the fifth domain of the beta2-glycoprotein I (beta2GPI) protein, a putative PL-binding site, may play a critical role in APS pathogenesis. The purpose of this study was to identify associations between beta2GPI mutations and both antiphospholipid antibodies (aPL) and their associated clinical manifestations in a pediatric and adolescent cohort and to search for novel mutations. Genetic analysis of beta2GPI was performed in 58 youths with systemic lupus erythematosus (SLE) and/or aPL, to identify known polymorphisms at amino acids 247 and 306 as well as novel mutations in exon 7 of the beta2GPI gene, and their association with aPL-associated clinical manifestations. Our results demonstrate an association between substitution of Val for Leu at AA247 (L247V) of beta2GPI and both the development of aPL (P = 0.05) and aPL-associated clinical manifestations (P = 0.03) among pediatric patients. The odds ratio associated with risk of aPL-associated clinical manifestations for the homozygous VV polymorphism was 5.5 (CI 1.3-23, P = 0.03) for the overall cohort, and 4.75 (CI 0.66-55.49, P = 0.06) after adjusting for ethnicity. The association was not significant after stratifying for SLE versus non-SLE. Association between the VV genotype at amino acid 247 of beta2GPI and clinical disease supports a genetic cause for APS among children and adolescents. Neither novel exon 7 beta2GPI mutations or the previously described C306G polymorphism was identified in this pediatric cohort.
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Anticorpos Antifosfolipídeos/sangue , Glicoproteínas/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Síndrome Antifosfolipídica/genética , Síndrome Antifosfolipídica/imunologia , Sequência de Bases , Criança , Pré-Escolar , Estudos de Coortes , DNA Complementar/genética , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Masculino , Polimorfismo Genético , beta 2-Glicoproteína IRESUMO
Cross infection has become a serious risk to hospitalized patients. Potential sources of infection by anaesthetic apparatus and equipment and the danger arising from disregard of proper asepsis are discussed. Prophylactic and hygienic measures to minimize these hazards are reviewed. Since patients receiving intensive therapy are particularly are risk very high hygienic standards are a "must" in these units. The need for thoroughly and regularly checking all equipment for contamination is emphasized.
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Anestesia/efeitos adversos , Infecção Hospitalar/prevenção & controle , Desinfecção , Unidades de Terapia Intensiva , Esterilização , Anestesiologia/instrumentação , Bactérias/efeitos dos fármacos , Óxido de Etileno/farmacologia , Alemanha Ocidental , Humanos , Ácido Peracético/farmacologia , Fenóis/farmacologiaRESUMO
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) can be associated with significant morbidity in children and adolescents. Renal involvement in SLE appears to be more severe and more frequent in the pediatric age group, with the major predictors for poor outcome being the severity of histopathologic lesions, severity of renal impairment at diagnosis, and hypertension. In addition to currently recognized cardiovascular and pulmonary involvement, accelerated atherosclerosis is of increasing concern in young individuals with SLE, because of both disease effects and medication usage. Neuropsychiatric SLE seen in childhood ranges from subtle cognitive dysfunction to severe central nervous system involvement; however, there is controversy over the value of different diagnostic studies. APS in children may be associated with SLE, idiopathic, or associated with viral infections. Systemic anticoagulation is recommended for patients with thrombotic events, but long-term management has not been well studied in children.
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Síndrome Antifosfolipídica/patologia , Lúpus Eritematoso Sistêmico/patologia , Adolescente , Síndrome Antifosfolipídica/etiologia , Síndrome Antifosfolipídica/terapia , Criança , Pré-Escolar , Suscetibilidade a Doenças , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/terapiaRESUMO
HLA-DM (abbreviated DM) is an MHC-encoded glycoprotein that catalyzes the selective release of peptides, including class II-associated invariant chain peptides, from MHC class II molecules. To perform its function, DM must assemble in the endoplasmic reticulum (ER), travel to endosomes, and interact productively with class II molecules. We have described previously an EBV-transformed B cell line, 7.12.6, which displays a partial Ag presentation defect and expresses a mutated DM beta-chain with Cys79 replaced by Tyr. In this study, we show that HLA-DR molecules in 7.12.6 have a defect in peptide loading and accumulate class II-associated invariant chain peptides (CLIP). Peptide loading is restored by transfection of wild-type DMB. The mutant DM molecules exit the ER slowly and are degraded rapidly, resulting in greatly reduced levels of mutant DM in post-Golgi compartments. Whereas wild-type DM forms noncovalent alphabeta dimers, such dimers form inefficiently in 7.12.6; many mutant DM beta-chains instead form a disulfide-bonded dimer with DM alpha. Homodimers of DM beta are also detected in 7.12.6 and in the alpha-chain defective mutant, 2.2.93. We conclude that during folding of wild-type DM, the native conformation is stabilized by a conserved disulfide bond involving Cys79beta and by noncovalent contacts with DM alpha. Without these interactions, DM beta can form malfolded structures containing interchain disulfide bonds; malfolding is correlated with ER retention and accelerated degradation.
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Dissulfetos/metabolismo , Antígenos HLA-D/genética , Antígenos HLA-D/metabolismo , Mutagênese Sítio-Dirigida , Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/metabolismo , Transporte Biológico/genética , Linhagem Celular , Cisteína/genética , DNA Complementar/análise , Dimerização , Antígenos HLA-D/fisiologia , Antígeno HLA-DR3/genética , Antígeno HLA-DR3/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Peptídeos/genética , Peptídeos/imunologia , Peptídeos/metabolismo , Mutação Puntual , Ligação Proteica/genética , Análise de Sequência de DNA , Transfecção/imunologia , Tirosina/genéticaRESUMO
The HLA-DM locus encodes class II-like A and B chains and apparently regulates the antigen presentation function of conventional major histocompatibility complex (MHC) class II molecules. Here we describe the HLA-DMB mutations in three presentation defective B lymphoblastoid cells lines (B-LCL), 7.19.6, 10.6.6, and 10.78.6, which express DMB transcripts of abnormal length. Mutant 7.19.6 has a C-->T point mutation that introduces a 5' splice site into exon 3 of DMB. The independently derived mutants, 10.6.6 and 10.78.6, each harbor a G-->A mutation in exon 3 and also lack an identical downstream segment of RNA. Mapping of DMB intron/exon borders, using a genomic clone, revealed that the segment missing in mutants 10.6.6 and 10.78.6 represents the fourth exon of DMB; no mutations were found within exon 4 in either 10.6.6 or 10.78.6, however. In addition, the DMB gene was found to have a six exon genomic structure, typical of MHC class II B genes.
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Genes MHC da Classe II/genética , Antígenos HLA-D/genética , Antígenos de Histocompatibilidade Classe II , Sequência de Aminoácidos , Sequência de Bases , Clonagem Molecular , DNA Complementar/genética , Éxons/genética , Humanos , Íntrons/genética , Dados de Sequência Molecular , Mutação , Reação em Cadeia da Polimerase , Splicing de RNA , RNA Mensageiro/genética , DNA Polimerase Dirigida por RNA/metabolismo , Análise de Sequência de DNA , Transcrição GênicaRESUMO
OBJECTIVE: To evaluate the clinical features and outcome of antiphospholipid syndrome (APS) in children. STUDY DESIGN: Retrospective chart review of patients seen at the Children's Hospital of Philadelphia and Children's Seashore House Pediatric Rheumatology Center between 1988 and 1993. RESULTS: Nine patients with ages ranging from 8 months to 17 years are presented. Clinical features of five patients with primary APS, described in detail, were digital ischemia, stroke, chorea, Addison disease, and pulmonary vaso-occlusive disease. The four children with secondary APS had systemic lupus erythematosus. Clinical features of these patients include livedo reticularis, deep venous thrombosis, and pulmonary hypertension. Antiphospholipid titers, results of coagulation studies, and serologic findings did not predict outcome. CONCLUSION: APS in children has diverse clinical features similar to those in adults and should be considered in cases of unexplained vaso-occlusive disease.