RESUMO
OBJECTIVES: The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs). METHODS: RESOLVE-1 is a Phase 3, randomised, double-blind, placebo-controlled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score. RESULTS: The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019. CONCLUSIONS: RESOLVE-1 is the first Phase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy.
Assuntos
Esclerodermia Difusa , Adolescente , Adulto , Ásia , Método Duplo-Cego , Europa (Continente) , Humanos , Israel , Esclerodermia Difusa/diagnóstico , Esclerodermia Difusa/tratamento farmacológico , Resultado do TratamentoRESUMO
OBJECTIVE: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). RESULTS: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSION: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care.
Assuntos
Esclerodermia Difusa , Escleroderma Sistêmico , Humanos , Esclerodermia Difusa/tratamento farmacológico , Agonistas de Receptores de Canabinoides/uso terapêutico , Resultado do Tratamento , Índice de Gravidade de Doença , Dronabinol/uso terapêutico , Pele , Escleroderma Sistêmico/tratamento farmacológicoRESUMO
BACKGROUND: The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II). OBJECTIVE: To investigate icatibant efficacy and safety in subjects with acute HAE attacks. METHODS: Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant. RESULTS: Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs. CONCLUSIONS: FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00912093.
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Angioedemas Hereditários/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Antagonistas de Receptor B2 da Bradicinina , Bradicinina/análogos & derivados , Adulto , Bradicinina/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Estimativa de Kaplan-Meier , MasculinoRESUMO
The objective of the study to review an experiential cohort of patients receiving IACS and review the associated literature. Review of 121 IACS in 61 patients with JIA. At 3-month intervals, injected joints were evaluated for swelling and range of motion, and the patient and parent were questioned regarding associated pain and morning stiffness. Data were analyzed by log-rank analysis according to injected corticosteroid preparation and its dosage. Adverse events were also recorded. A thorough literature search was done for the literature review. Mean duration of response was 12.5 months (52% of joints in remission at 1 year, 20% after 2 years, and 7% after 3 years). Response was longer with at least 1 mg/kg of corticosteroid, with the longest responses seen with triamcinolone hexacetonide (THA)>triamcinolone acetonide>methylprednisolone. Adverse events were cutaneous atrophy at three injections sites (2.5%), and transient Cushingoid habitus and increased appetite in two patients (3%). Review of the literature generated similar responses to those included herein. Thus, there have been several recommendations for IACS to be a major JIA treatment, and surveys now demonstrate a high level of usage by pediatric rheumatologists. In conclusion the use of IACS in JIA substantiated. THA at a dose of 1-1.5 mg/kg is ideal.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Glucocorticoides/uso terapêutico , Adolescente , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Apetite/efeitos dos fármacos , Artrite Juvenil/fisiopatologia , Atrofia/induzido quimicamente , Atrofia/patologia , Criança , Pré-Escolar , Estudos de Coortes , Síndrome de Cushing/induzido quimicamente , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Injeções Intra-Articulares , Masculino , Amplitude de Movimento Articular , Indução de Remissão , Estudos Retrospectivos , Pele/efeitos dos fármacos , Pele/patologiaAssuntos
Síndrome Antifosfolipídica/diagnóstico , Ruptura Cardíaca/patologia , Lúpus Eritematoso Sistêmico/diagnóstico , Infarto do Miocárdio/patologia , Músculos Papilares/patologia , Adolescente , Anticorpos Antinucleares/sangue , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Diagnóstico Diferencial , Ecocardiografia Transesofagiana , Ruptura Cardíaca/complicações , Hematúria/etiologia , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/etiologia , Prolapso da Valva Mitral/diagnóstico por imagem , Infarto do Miocárdio/complicações , Tempo de Protrombina , Edema Pulmonar/etiologia , Espondiloartropatias/complicações , Trombose/etiologia , Trombose/patologiaRESUMO
The objective was to derive dosing recommendations for the use of celecoxib in patients with juvenile rheumatoid arthritis (JRA) using pharmacokinetic (PK) and exposure-response data. PK and efficacy data from a randomized, double-blind, 12-week study of celecoxib dosed at 3 and 6 mg/kg twice a day (bid) as an investigational suspension formulation in 152 JRA patients aged 2 to 17 years, PK data from 36 adult RA patients, and relative bioavailability data in healthy adults comparing suspension or capsule sprinkles with the commercial capsule were analyzed. Typical oral clearance (L/h) values were 40% and 24% lower in patients weighing 10 and 25 kg, respectively, compared with a 70-kg patient. Longitudinal, logistic pharmacodynamic models incorporating linear effects of dose/area under the plasma concentration-time curve (AUC) over 0 to 12 hours (AUC(0-12)) suggested that the percentage of responders increased with celecoxib exposure. Systemic exposures (AUC) were similar for the suspension, capsule sprinkles, and intact capsule. Administration of a 50-mg bid capsule (or sprinkles) for patients weighing 10 to 25 kg and 100 mg bid for patients >25 kg was predicted to yield similar exposures and response rates as those observed in the JRA trial. Doses and dosage forms not studied in the JRA trial were approved based on the results of this analysis.
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Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/sangue , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Adolescente , Artrite Juvenil/metabolismo , Cápsulas/administração & dosagem , Celecoxib , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Pirazóis/farmacocinética , Sulfonamidas/farmacocinética , Suspensões/administração & dosagemRESUMO
OBJECTIVE: To evaluate efficacy and safety of CE-224,535, a selective P2X(7) receptor antagonist, versus placebo, in patients with active rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX). METHODS: In our phase IIA study (ClinicalTrials.gov no. NCT00628095; A6341009), patients aged ≥ 18 years with active RA were randomized to receive either CE-224,535 (500 mg bid) or placebo for 12 weeks; all patients continued a stable background dose of ≥ 7.5 mg MTX. RESULTS: The American College of Rheumatology 20% (ACR20) response rate (primary efficacy endpoint) was not significantly different from placebo for CE-224,535 (34.0% vs 36.2%; p = 0.591) at Week 12, or at any timepoint over the 12-week treatment period. There was no significant difference at Week 12 for the ACR20 response rate following subgroup analyses by age, sex, baseline disease activity, baseline duration of disease, geographic region, or concomitant use of steroids. ACR50/ACR70 response rates and change from baseline in Disease Activity Score 28-joint C-reactive protein (DAS28-3-CRP) and Health Assessment Questionnaire-Disability Index for CE-224,535 were not significant at Week 12 versus placebo. Treatment-emergent adverse events (AE) were reported by 62.3% (CE-224,535) and 55.3% (placebo) of patients; the most common AE were nausea (11.3%, CE-224,535; 4.3%, placebo) and diarrhea (7.5%, CE-224,535; 4.3%, placebo). The proportion of patients discontinuing due to an AE was 9.4% (CE-224,535) and 6.4% (placebo); no deaths were reported. Serious AE occurred in 3.8% (CE-224,535) and 2.1% (placebo) of patients; none was considered treatment-related. CONCLUSION: CE-224,535 was not efficacious, compared with placebo, for the treatment of RA in patients with an inadequate response to MTX. CE-224,535 demonstrated an acceptable safety and tolerability profile.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Benzamidas/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Uracila/análogos & derivados , Adulto , Idoso , Antirreumáticos/efeitos adversos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/fisiopatologia , Benzamidas/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Efeito Placebo , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Uracila/administração & dosagem , Uracila/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: We previously demonstrated that levels of fibrin d-dimer correlate with disease activity and response to therapies in systemic juvenile idiopathic arthritis (sJIA). We hypothesized that persistence of D-dimer elevation in the patterns previously described, but over a longer followup period, would signal poor outcome. METHODS: We studied 31 children identified from 2 centers. Subjects were assigned a risk category based on their first obtained D-dimer concentration. Risk categories were based on results of our initial study, where normalization of D-dimer in patients no longer taking immunosuppressive therapy predicted good short-term outcome, and persistent D-dimer elevation while taking immunosuppressives predicted bad outcome (radiographic abnormalities, joint replacement surgery, or poor functional class) or a severe systemic manifestation. Outcome was determined at the last followup visit, a minimum of 2 years after measurement of the initial d-dimer level. RESULTS: The 31 children were a mean 16.4 years old at an average of 8.8 years after their initial diagnosis. Ten children had a severe outcome during this period; all 10 had a study baseline risk category of "high." Of the 14 subjects who had a high risk category at study baseline, none had a mild outcome. CONCLUSION: Our study indicated that a paradigm of risk of severe disease based upon persistent elevation of fibrin d-dimer on first measurements (greater than a mean of 29 months in our initial study and at least 24 months in the additional subjects) is promising to predict poor longer-term outcome in sJIA. A larger prospective study is warranted to substantiate the preliminary data and assess the relative comparative value to other biomarkers and clinical endpoints.
Assuntos
Artrite Juvenil/sangue , Artrite Juvenil/diagnóstico , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Adolescente , Adulto , Artrite Juvenil/terapia , Artrografia , Biomarcadores/análise , Biomarcadores/sangue , Criança , Estudos de Coortes , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Regulação para Cima/imunologia , Adulto JovemRESUMO
OBJECTIVE: To compare the efficacy and safety of celecoxib and naproxen in children with juvenile rheumatoid arthritis (JRA). METHODS: In this multicenter, randomized, double-blind, noninferiority study, subjects with JRA were randomized to receive a target dose of celecoxib 3 mg/kg bid or 6 mg/kg bid, or a target dose of naproxen 7.5 mg/kg bid for 12 weeks (maximum allowed dose=600 mg total daily dose). The primary efficacy measure was the percentage of responders at Week 12 attaining the American College of Rheumatology pediatric 30% improvement criterion (ACR Pediatric-30). RESULTS: Both celecoxib doses were at least as effective as naproxen at Week 12 [ACR Pediatric-30 treatment differences: celecoxib 3 mg/kg bid-naproxen=1.36% (95% CI -13.08 to 15.80); celecoxib 6 mg/kg bid-naproxen=13.02% (95% CI -0.22 to 26.25)]. Celecoxib 6 mg/kg bid had a numerically higher response rate than celecoxib 3 mg/kg bid at all postrandomization visits and a numerically higher response rate than naproxen 7.5 mg/kg bid at Weeks 4, 8, and 12. Improvement in each ACR Pediatric-30 core set measure was comparable to or numerically higher for celecoxib 6 mg/kg bid than naproxen or celecoxib 3 mg/kg bid. Adverse event rates were similar for all treatment groups, except that gastrointestinal adverse events were more common in the naproxen group, although the difference was not statistically significant. CONCLUSION: Celecoxib 3 mg/kg bid and 6 mg/kg bid were at least as effective as naproxen 7.5 mg/kg bid in treating the signs and symptoms of JRA over 12 weeks. All treatments were generally well tolerated.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Naproxeno/administração & dosagem , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Adolescente , Anti-Inflamatórios não Esteroides/efeitos adversos , Celecoxib , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Naproxeno/efeitos adversos , Estudos Prospectivos , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos , Resultado do TratamentoRESUMO
OBJECTIVE: To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. METHODS: Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. RESULTS: By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550-treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04-0.06 mg/dl) were seen in all CP-690,550 treatment arms. CONCLUSION: Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted.
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Artrite Reumatoide/tratamento farmacológico , Janus Quinases/antagonistas & inibidores , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Artrite Reumatoide/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Creatinina/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Piperidinas , Resultado do TratamentoRESUMO
To determine the prevalence of anti-endothelial cell antibodies (AECA) in children with juvenile idiopathic arthritis (JIA) versus healthy control children. Twenty-eight children with active JIA were studied (ten each with polyarticular and oligoarticular disease, and eight with systemic onset disease). AECA were determined by a cell-based ELISA from samples obtained every 3 months over a 2 year period in each subject. These levels were compared against previously determined levels of von Willebrand factor antigen, fibrin d-dimer, and soluble forms of ICAM-1 and E-selectin, as well as clinical measures of disease activity. AECA were detected in 5/10 oligoarticular, 6/10 polyarticular, and 7/8 systemic JIA subjects and 0/14 controls. Mean levels of AECA were significantly higher in subjects with oligoarticular, and especially systemic disease as compared to polyarticular and control groups when analyzed by ANOVA. AECA are prevalent in JIA and are present more often and at higher levels in systemic disease.
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Artrite Juvenil/epidemiologia , Artrite Juvenil/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Células Endoteliais/imunologia , Adolescente , Especificidade de Anticorpos , Biomarcadores , Criança , Pré-Escolar , Humanos , Lactente , Estudos SoroepidemiológicosRESUMO
BACKGROUND & AIMS: The safety of selective cyclooxygenase-2 inhibitors in patients with ulcerative colitis in remission is unknown. METHODS: We performed a placebo-controlled pilot trial to evaluate the safety of celecoxib in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy. A total of 222 patients with ulcerative colitis in remission were randomized to receive oral celecoxib 200 mg or placebo twice daily for 14 days. Remission was defined as a total Mayo Clinic score of 2 points or less and an endoscopic score of 1 point or less. Disease exacerbation was defined as a total Mayo Clinic score of 5 points or more and an increase in the endoscopic score of 1 point or more. The primary analysis was disease exacerbation through day 14 among patients who underwent randomization, had at least 1 dose of study drug, and had both endoscopy and Mayo Clinic disease activity index scores at the baseline and final assessments. RESULTS: Three percent of patients in the celecoxib group experienced disease exacerbation through day 14, as compared with 4% in the placebo group (P = .719). Eleven percent of patients in each group experienced a bowel-related adverse event (P > .20). CONCLUSIONS: Therapy with celecoxib for up to 14 days did not have a greater relapse rate than placebo in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy.
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Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/fisiopatologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Adulto , Idoso , Artrite/tratamento farmacológico , Celecoxib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , RecidivaRESUMO
OBJECTIVE: To determine whether soluble forms of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and E-selectin correlate with clinical measures or other markers of endothelial activation in children with juvenile idiopathic arthritis (JIA) over time. METHODS: A total of 28 children with JIA were studied every 3 months over 2 years. At each interval, serum was tested for soluble (s)ICAM-1 and sE-selectin, plasma for fibrin d-dimer and von Willebrand factor (vWF), and the following clinical variables were recorded: erythrocyte sedimentation rate (ESR), physician and parent global assessments, swollen and limited joint counts, and functional assessment by Childhood Health Assessment Questionnaire. Concentrations of the adhesion molecules were also determined once in 30 age matched healthy children. RESULTS: Among all JIA subtypes, baseline sICAM-1 was elevated compared to controls; sE-selectin was higher in patients with systemic disease compared to other subtypes and controls. sE-selectin correlated with ESR, but there were no other correlations between concentrations of either adhesion molecule or any other clinical variables or vWF antigen. sICAM-1 was higher in those with elevated compared to normal d-dimer. There were no differences between mean sICAM-1 and sE-selectin before or during disease flare or improvement periods, except for an increase in sICAM-1 with flares in patients with systemic disease. CONCLUSION: sICAM-1 is elevated in children with active JIA. sE-selectin is only elevated in children with active systemic disease. Although some relationships were found between the adhesion molecules and other variables, they did not correlate with most variables, and did not parallel the disease course. Thus, we cannot recommend the routine use of these molecules as clinical biomarkers of disease activity. This study confirms that endothelial activation is key to the pathogenesis of JIA, especially in the systemic subtype.
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Artrite Juvenil/sangue , Selectina E/sangue , Endotélio Vascular/metabolismo , Molécula 1 de Adesão Intercelular/sangue , Adolescente , Artrite Juvenil/fisiopatologia , Biomarcadores/sangue , Criança , Pré-Escolar , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Nível de Saúde , Humanos , Lactente , Índice de Gravidade de Doença , Fator de von Willebrand/análiseRESUMO
OBJECTIVE: To determine serum levels of adhesion molecules ICAM-1, ICAM-3, VCAM-1, L-selectin, and E-selectin in children with a variety of pediatric rheumatic diseases and investigate their relationship to clinical disease activity. METHODS: Retrospective review of records of 18 children with rheumatic diseases who had banked sera available for study. Eight children had systemic lupus erythematosus (SLE), 2 mixed connective tissue disease, 4 dermatomyositis (DM), and 4 various forms of vasculitis. Levels of the soluble adhesion molecules were determined by sandwich ELISA. Levels were compared among patients with the various diagnoses and between patients with active vs inactive disease. Levels were also correlated with erythrocyte sedimentation rate in all patients; C3, C4, and total hemolytic complements and anti-dsDNA antibodies in SLE; and creatine phosphokinase, aldolase, and von Willebrand factor (vWF) antigen levels in DM. Levels also correlated with disease activity scores, which varied by diagnosis. RESULTS: A trend toward higher levels of sE-selectin was found in vasculitis vs other diagnoses (p = 0.08). sICAM-1 was higher in patients with active vs inactive disease (p = 0.05) across all diagnoses. L-selectin levels correlated with C4 complement levels in SLE patients (r = 0.76, p = 0.03), and there was a trend toward an inverse correlation between levels of sE-selectin and vWF (r = -0.93, p = 0.08). There was no direct correlation of the adhesion molecule levels with any of the disease activity scores. CONCLUSION: The small number of patients and retrospective design of this study mean that any results must be interpreted with caution. We conclude: (1) Elevated E-selectin levels in vasculitis likely reflect the high degree of endothelial activation and possibly overt vascular damage in those conditions. (2) The correlation of sL-selectin with C4 in SLE may indicate that downregulation of shedding of cell surface L-selectin is involved in continued adherence of leukocytes to endothelium, possibly causing further damage and immune complex deposition in this condition. (3) The trend toward inverse correlation between sE-selectin and vWF:Ag in DM is curious, but may show that the role of endothelium in the pathophysiology of this disease is different from those such as vasculitis. (4) Levels of sICAM- I may be a useful marker of active vs quiescent disease in general in the pediatric rheumatic diseases, although lack of correlation with disease activity indices may indicate that it is too insensitive to smaller differences in disease activity to be recommended for routine clinical use.
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Moléculas de Adesão Celular/sangue , Doenças Reumáticas/sangue , Adolescente , Adulto , Sedimentação Sanguínea , Criança , Pré-Escolar , Proteínas do Sistema Complemento , Dermatomiosite/sangue , Dermatomiosite/fisiopatologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Doença Mista do Tecido Conjuntivo/sangue , Doença Mista do Tecido Conjuntivo/fisiopatologia , Estudos Retrospectivos , Doenças Reumáticas/fisiopatologia , Índice de Gravidade de Doença , Vasculite/sangue , Vasculite/fisiopatologiaRESUMO
OBJECTIVE: To determine what sleep abnormalities may exist in children with juvenile rheumatoid arthritis (JRA). and their relationship to pain, dysfunction. and disease activity. METHODS: Twenty-five children with active JRA (11 pauciarticular, 9 polyarticular, 5 systemic) had their sleep assessed by parallel, validated patient and parent questionnaires (Sleep Self-Report, SSR, and Children's Sleep Habits Questionnaire, CSHQ). Disease activity was assessed by parent and physician global assessments (on a 5 point scale: 0 = no disease activity to 4 = very severe disease), erythrocyte sedimentation rate (ESR), and numbers of swollen and limited joints. Functional assessment was based on parental completion of the Juvenile Arthritis Functional Assessment Report (JAFAR). Pain was assessed by the average pain visual analog scale of the Varni Pediatric Pain Questionnaire. Results were compared to those from 45 healthy age and sex matched controls by Mann-Whitney U tests, and correlated with variables of JRA disease activity, function, and pain using Spearman correlations. RESULTS: Patients with JRA had higher total score on the CSHQ (p < 0.0001), as well as subscales assessing night wakings, parasomnias. sleep anxiety, sleep-disordered breathing, and morning wakening/daytime sleepiness (p < 0.0001-0.05). There were no correlations between CSHQ scores and JRA disease activity or pain variables, but the total score on the SSR did correlate with pain (r = 0.56, p = 0.005). CONCLUSION: We conclude that sleep abnormalities are common in children with JRA, and are multi-dimensional.
Assuntos
Artrite Juvenil/complicações , Dor/complicações , Transtornos do Sono-Vigília/etiologia , Ansiedade/epidemiologia , Ansiedade/etiologia , Ansiedade/fisiopatologia , Artrite Juvenil/patologia , Artrite Juvenil/fisiopatologia , Criança , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Dor/epidemiologia , Dor/fisiopatologia , Medição da Dor , Parassonias/epidemiologia , Parassonias/etiologia , Parassonias/fisiopatologia , Prevalência , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/etiologia , Síndromes da Apneia do Sono/fisiopatologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/etiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Transtornos do Sono-Vigília/epidemiologia , Transtornos do Sono-Vigília/fisiopatologia , Inquéritos e QuestionáriosRESUMO
E-selectin and intercellular adhesion molecule (ICAM)-1 are crucial to the inflammatory response in chronic inflammatory arthritis. Soluble (s) levels of these molecules in sera and synovial fluid (SF) correlate with some clinical parameters and synovial tissue expression of the same molecules in rheumatoid arthritis. Studies of sera from children with chronic inflammatory arthritis corroborate this information; corresponding SF data are relatively lacking. We thus studied SF sE-selectin and sICAM-1 in 28 children with active juvenile rheumatoid arthritis or a spondyloarthropathy. Levels were correlated with erythrocyte sedimentation rate (ESR), SF leukocyte counts, duration of disease, and duration of response to concomitant intra-articular corticosteroid injection. Levels were compared according to use of methotrexate and/or sulfasalazine. Synovial fluid sE-selectin correlated with ESR and SF leukocyte counts. There was a trend toward lower sICAM-1 in patients treated with sulfasalazine and/or methotrexate. We conclude that SF levels of sE-selectin accurately reflect intra-synovial inflammation. Soluble ICAM-1 levels may reflect the effects of disease-modifying agents.