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1.
Lancet ; 398(10315): 1984-1996, 2021 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-34767764

RESUMO

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA). METHODS: This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434. FINDINGS: Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study. INTERPRETATION: The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. FUNDING: Pfizer.


Assuntos
Artrite Juvenil/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Piperidinas/uso terapêutico , Pirimidinas/uso terapêutico , Administração Oral , Adolescente , Criança , Pré-Escolar , Humanos , Resultado do Tratamento
2.
Rheumatology (Oxford) ; 60(10): 4568-4580, 2021 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33506875

RESUMO

OBJECTIVES: To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). METHODS: In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or <30 kg, respectively. Primary end points were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with i.v. tocilizumab (i.v.-TCZ) in sJIA and pJIA. RESULTS: Study participants were 51 sJIA patients and 52 pJIA patients aged 1-17 years who received s.c.-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. CONCLUSION: s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Injeções Subcutâneas , Masculino , Resultado do Tratamento
3.
Pediatr Dermatol ; 32(4): e140-4, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25845414

RESUMO

Tumor necrosis factor α (TNF-α) antagonists are used in the treatment of numerous autoimmune conditions. Adalimumab is the first monoclonal antibody to TNF-α and is used to treat juvenile idiopathic arthritis. A growing body of literature associates anti-TNF-α therapies with several adverse dermatologic manifestations, including drug-induced lupus erythematosus (LE). We describe a case of cutaneous LE in a 16-year-old girl treated with adalimumab for juvenile idiopathic arthritis. The temporal association between her presenting symptoms and adalimumab initiation and gradual improvement after stopping biologic therapy suggest adalimumab-induced cutaneous LE. With increasing use of anti-TNF therapies in children, the potential for drug-induced LE should not be overlooked.


Assuntos
Adalimumab/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Lúpus Eritematoso Cutâneo/induzido quimicamente , Adolescente , Biópsia , Feminino , Humanos , Lúpus Eritematoso Cutâneo/patologia , Pele/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
4.
Pediatr Rheumatol Online J ; 22(1): 88, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39375683

RESUMO

BACKGROUND: Chronic anterior uveitis (CAU) carries a significant risk for eye complications and vision loss. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) introduced consensus treatment plans (CTPs) to standardize treatment for CAU and facilitate future comparative effectiveness studies. Two CTPs were developed to address: 1) initiation of methotrexate (MTX) in patients with CAU naïve to steroid-sparing therapy, and 2) initiation of a TNF inhibitor (TNFi) in patients with severe uveitis or uveitis refractory to MTX. We evaluated implementation of the uveitis CTPs using existing CARRA Registry infrastructure and assessed feasibility of the CTPs for comparative effectiveness research. METHODS: This prospective observational cohort study was conducted at nine pilot sites between February 2020 and August 2022. Patients with JIA-associated CAU (JIA-U) were treated according to either the MTX or TNFi CTP. Uveitis activity and medication use were recorded at 0, 3, and 6 months. We assessed patient enrollment rates, CTP arm selection, uveitis control, and quality of data collection. We also evaluated CTP arm selection in a retrospective cohort of similar JIA-U patients enrolled in the CARRA Registry during the same study period. RESULTS: Seventeen patients were included in the pilot cohort. Eight were treated with the MTX CTP (4 oral MTX, 4 subcutaneous MTX), and 9 with the TNFi CTP (9 received standard-dose adalimumab, none selected high-dose adalimumab or infliximab). Uveitis was controlled in 13 of 17 patients by 6 months. Query of the CARRA-wide Registry identified 42 patients with JIA-U who were treated according to the MTX or TNFi CTPs. Among these, 26 were treated with MTX (8 oral, 18 subcutaneous) and 16 with TNFi (12 standard dose adalimumab, 2 high dose adalimumab, and 2 infliximab). CONCLUSION: Both the MTX and TNFi uveitis CTPs can practically be implemented in clinical settings and are currently being utilized across Registry sites. However, in patients starting TNFi therapy, all pilot study participants and most patients across the CARRA Registry were treated with a standard dose of adalimumab. This consensus on the treatment approach underscores its broad acceptance but also limits the applicability of the uveitis TNFi CTP for comparative effectiveness research.


Assuntos
Estudos de Viabilidade , Metotrexato , Inibidores do Fator de Necrose Tumoral , Humanos , Metotrexato/uso terapêutico , Feminino , Masculino , Criança , Estudos Prospectivos , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Projetos Piloto , Adolescente , Uveíte Anterior/tratamento farmacológico , Sistema de Registros , Consenso , Uveíte/tratamento farmacológico , Antirreumáticos/uso terapêutico , Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Pesquisa Comparativa da Efetividade
5.
Artigo em Inglês | MEDLINE | ID: mdl-39135452

RESUMO

OBJECTIVE: Examine levels of candidate blood-based biomarkers (CBB) in juvenile idiopathic arthritis (JIA) treated with tofacitinib. METHODS: JIA patients who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBB (S100A8/9, S100A12, IL-18, SAA, resistin, VEGF, Angiopoietin-1, Angiopoietin-2, MMP8, MMP2, TIMP1, Leptin, CXCL9, sIL2R, ICAM-1, sTNFr, IL-6, IL-23, MCP1, CCL18, and CCL20). Association of CBB with JIA response to treatment from baseline to week 18 were assessed. RESULTS: This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. There were 35% (50/143) of patients with a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement while 90/121/137 (63%/85%/96%) achieved JIA-ACR70/50/30 improvement at wk18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in JADAS-27 or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with wk18 improvement in JADAS-27 and JIA-ACR90 response, after adjusting for age, sex, JIA disease duration and baseline resistin [(r2 0.79, SE, 0.070, p<0.01 and OR(95%CI) = 1.134(1.018, 1.264)]. HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (p=0.0097). CONCLUSION: Among the CBB included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

6.
Pediatr Rheumatol Online J ; 21(1): 61, 2023 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-37353795

RESUMO

BACKGROUND: Childhood-onset Systemic Lupus Erythematosus (cSLE) is an autoimmune disease associated with fatigue, mood symptoms, and pain. Fortunately, these symptoms are potentially modifiable with psychological intervention such as cognitive-behavioral therapy (CBT). The Treatment and Education Approach for Childhood-onset Lupus (TEACH) program is a CBT intervention developed to target these symptoms for adolescents and young adults with cSLE. This pilot randomized controlled trial (RCT) aims to determine the feasibility and effect of TEACH for youth with cSLE. Adjustments to the study protocol following the COVID-19 pandemic are also described. METHODS: This two-arm multisite RCT will explore the feasibility (primary outcome) and effect (secondary outcome) of a remotely delivered TEACH protocol. Participants will be randomized to a six-week remotely delivered TEACH program plus medical treatment as usual (TAU) or TAU alone. We will include patients ages 12-22 years presenting to rheumatology clinics from six sites. Validated measures of fatigue, depressive symptoms, and pain will be obtained at baseline and approximately eight and 20 weeks later. Protocol adjustments were also made due to the COVID-19 pandemic, in collaboration with the investigative team, which included patients and caregivers. CONCLUSIONS: Findings from this multi-site RCT aim to document the feasibility of TEACH and provide an estimate of effect of a remotely delivered TEACH protocol on fatigue, depression, and pain symptoms in youth with cSLE as compared to standard medical treatment alone. This findings may positively impact clinical care for patients with cSLE. CLINICAL TRIALS: gov registration: NCT04335643.


Assuntos
COVID-19 , Lúpus Eritematoso Sistêmico , Adolescente , Criança , Humanos , Adulto Jovem , Fadiga , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/terapia , Lúpus Eritematoso Sistêmico/psicologia , Dor , Projetos Piloto
7.
Ann Med ; 54(1): 1839-1850, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35786149

RESUMO

Systemic juvenile idiopathic arthritis (SJIA) is a rare disease with distinct features not seen in other categories of juvenile idiopathic arthritis. In recent years, advances in the understanding of disease immunopathogenesis have led to improved targeted therapies with significant improvement in patient outcomes. Despite these advances, there remain subsets of SJIA with refractory disease and severe disease-associated complications. This review highlights existing options for treatment of refractory SJIA and explores potential future therapeutics for refractory disease.Key Points:Despite targeted Interleukin IL-1 and IL-6 inhibitors a subset of SJIA remains refractory to therapy. About 1 in 7 SJIA patients will be refractory to targeted IL-1 or IL-6 therapy.There is no current agreed upon definition for refractory SJIA and we propose in this review that refractory SJIA is presence of active systemic or arthritic features despite treatment with anti-IL-1 or anti-IL-6 therapy or disease requiring glucocorticoids for control beyond 6 months.SJIA disease associated complications include presence of associated macrophage activation syndrome (MAS), interstitial lung disease (ILD) or amyloidosis and management of each differs.Refractory SJIA treatment options currently include additional conventional synthetic disease modifying anti-rheumatic drugs (csDMARDS), biologic (bDMARDS), combination biologic therapy, targeted synthetic (tsDMARDS) or other immunomodulatory therapies.


Assuntos
Artrite Juvenil , Síndrome de Ativação Macrofágica , Artrite Juvenil/complicações , Artrite Juvenil/tratamento farmacológico , Terapia Combinada , Glucocorticoides/uso terapêutico , Humanos , Síndrome de Ativação Macrofágica/complicações , Síndrome de Ativação Macrofágica/etiologia
8.
Front Pediatr ; 8: 436, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32850549

RESUMO

Juvenile dermatomyositis (JDM) is a multisystem vasculopathy that infrequently presents with acute complications (1). We report here the case of a 12-year-old girl with JDM who developed Thrombotic Thrombocytopenic purpura (TTP) and Purtscher's retinopathy. This is the second pediatric case of JDM with TTP and Purtscher's retinopathy in the literature. The diagnosis of JDM was based on her clinical presentation (fever, myalgia, proximal muscle weakness, characteristic skin rash and elevated muscle enzymes) (2). Despite improvement of rash, fever and weakness with corticosteroids and intravenous Immunoglobulins (IVIG), the patient developed retinopathy, thrombocytopenia, hemolytic anemia, renal failure, and pulmonary edema within 1 week of initial treatment. A clinical diagnosis of TTP and Purtscher's retinopathy was made and her ADAMTS13 activity was found to be low. Regardless of aggressive treatment with pulse steroid therapy, IVIG, plasmapheresis along with multiple infusions of Fresh Frozen plasma (FFP), her condition deteriorated. In view of her worsening condition, she received one dose of Rituximab and within 48 h, her hematological and retinal involvements improved. Rituximab was given at the same dose once weekly thereafter for 4 total doses. Her disease process was halted, and retinopathy improved significantly in 48 h and continued to gradually improve over 3 weeks of maintenance therapy with cyclosporine, methotrexate, and IVIG and then stabilized. This report documents the association of TTP and Purtscher's retinopathy with JDM, emphasizing that early recognition and prompt treatment with rituximab along with the current standard of care treatment i.e., Vincristine, corticosteroids and plasmapheresis could be of potential benefit in controlling disease activity.

9.
Pediatr Rheumatol Online J ; 18(1): 80, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066778

RESUMO

BACKGROUND: Heme oxygenase-1 (HMOX1) catalyzes the metabolism of heme into carbon monoxide, ferrous iron, and biliverdin. Through biliverdin reductase, biliverdin becomes bilirubin. HMOX1-deficiency is a rare autosomal recessive disorder with hallmark features of direct antibody negative hemolytic anemia with normal bilirubin, hyperinflammation and features similar to macrophage activation syndrome. Clinical findings have included asplenia, nephritis, hepatitis, and vasculitis. Pulmonary features and evaluation of the immune response have been limited. CASE PRESENTATION: We present a young boy who presented with chronic respiratory failure due to nonspecific interstitial pneumonia following a chronic history of infection-triggered recurrent hyperinflammatory flares. Episodes included hemolysis without hyperbilirubinemia, immunodeficiency, hepatomegaly with mild transaminitis, asplenia, leukocytosis, thrombocytosis, joint pain and features of macrophage activation with negative autoimmune serologies. Lung biopsy revealed cholesterol granulomas. He was found post-mortem by whole exome sequencing to have a compound heterozygous paternal frame shift a paternal frame shift HMOX1 c.264_269delCTGG (p.L89Sfs*24) and maternal splice donor HMOX1 (c.636 + 2 T > A) consistent with HMOX1 deficiency. Western blot analysis confirmed lack of HMOX1 protein upon oxidant stimulation of the patient cells. CONCLUSIONS: Here, we describe a phenotype expansion for HMOX1-deficiency to include not only asplenia and hepatomegaly, but also interstitial lung disease with cholesterol granulomas and inflammatory flares with hemophagocytosis present in the bone marrow.


Assuntos
Anemia Hemolítica Congênita , Anemia Hemolítica , Transtornos do Crescimento , Heme Oxigenase-1/deficiência , Hepatomegalia/diagnóstico por imagem , Distúrbios do Metabolismo do Ferro , Insuficiência Respiratória , Baço , Anemia Hemolítica/diagnóstico , Anemia Hemolítica/genética , Anemia Hemolítica Congênita/sangue , Anemia Hemolítica Congênita/diagnóstico , Anemia Hemolítica Congênita/fisiopatologia , Anemia Hemolítica Congênita/terapia , Bilirrubina/sangue , Exame de Medula Óssea/métodos , Criança , Deterioração Clínica , Cuidados Críticos/métodos , Diagnóstico , Evolução Fatal , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Heme Oxigenase-1/genética , Humanos , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/fisiopatologia , Ativação de Macrófagos , Masculino , Nefrite/diagnóstico , Nefrite/etiologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/etiologia , Baço/diagnóstico por imagem , Baço/patologia
10.
Arthritis Care Res (Hoboken) ; 72(10): 1420-1430, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31421019

RESUMO

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


Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Sistema de Registros , Adolescente , Artrite Juvenil/complicações , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Uveíte/tratamento farmacológico , Uveíte/etiologia
11.
Pediatr Rheumatol Online J ; 17(1): 48, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331351

RESUMO

BACKGROUND: We describe a Childhood Arthritis and Rheumatology Research Alliance (CARRA) survey of North American pediatric rheumatologists that assesses physician attitudes on withdrawal of medications in systemic juvenile idiopathic arthritis (SJIA). METHODS: A REDCap anonymous electronic survey was distributed to 100 random CARRA JIA workgroup physician-voting members. The survey had three broad sections including: A) demographic information; B) physicians' opinions on clinical inactive disease (CID) in SJIA and C) existing practices for withdrawing medications in SJIA. RESULTS: The survey had an 86% response rate. 88 and 93% of participants agreed with the current criteria for CID and clinical remission on medications (CRM) respectively. 78% thought it necessary to meet CRM before tapering medications except steroids. 76% use CARRA SJIA consensus treatment plans always or the majority of the time. All participants weaned steroids first in SJIA patients on combination therapy, 47% waited > 6 months before tapering additional medications. 35% each tapered methotrexate over > 6 months and 2-6 months; however, 39% preferred tapering anakinra, canakinumab and tocilizumab more quickly over 2-6 months and favored spacing the dosing interval for canakinumab and tocilizumab. When patients are on combination therapy with methotrexate and biologics, 58% preferred tapering methotrexate first while others considered patient/family preference and adverse effects to guide their choice. CONCLUSION: Most CARRA members surveyed use published consensus treatment plans for SJIA and agree with validated definitions of CID and CRM. There was agreement with tapering steroids first in SJIA. There was considerable variability with tapering decisions of all other medications.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Atitude do Pessoal de Saúde , Desprescrições , Reumatologistas , Corticosteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Juvenil/fisiopatologia , Tomada de Decisão Clínica , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Metotrexato/uso terapêutico , Inquéritos e Questionários
13.
Arthritis Rheumatol ; 68(10): 2514-26, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27111558

RESUMO

OBJECTIVE: To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons. RESULTS: In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n = 48) or GPA (n = 183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil. CONCLUSION: Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.


Assuntos
Granulomatose com Poliangiite/fisiopatologia , Hemorragia/fisiopatologia , Falência Renal Crônica/fisiopatologia , Pneumopatias/fisiopatologia , Poliangiite Microscópica/fisiopatologia , Síndrome Nefrótica/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Adolescente , Corticosteroides/uso terapêutico , Distribuição por Idade , Anticorpos Anticitoplasma de Neutrófilos , Ásia/epidemiologia , Azatioprina/uso terapêutico , Canadá/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Europa (Continente)/epidemiologia , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/terapia , Hemorragia/etiologia , Humanos , Imunossupressores/uso terapêutico , Lactente , Falência Renal Crônica/etiologia , Falência Renal Crônica/terapia , Pneumopatias/etiologia , Masculino , Metotrexato/uso terapêutico , Poliangiite Microscópica/complicações , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/terapia , Ácido Micofenólico/uso terapêutico , Síndrome Nefrótica/etiologia , Oxigenoterapia , Plasmaferese , Proteinúria/etiologia , Diálise Renal , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Rituximab/uso terapêutico , Estados Unidos/epidemiologia
14.
Arthritis Care Res (Hoboken) ; 67(4): 529-37, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25331530

RESUMO

OBJECTIVE: Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP. METHODS: Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution. RESULTS: Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively. CONCLUSION: The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry.


Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Antirreumáticos/efeitos adversos , Artrite Juvenil/tratamento farmacológico , Médicos , Vigilância da População/métodos , Reumatologia/métodos , Adolescente , Sistemas de Notificação de Reações Adversas a Medicamentos/tendências , Artrite Juvenil/diagnóstico , Artrite Juvenil/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino , Médicos/tendências , Projetos de Pesquisa/tendências , Reumatologia/tendências
15.
Artigo em Inglês | MEDLINE | ID: mdl-25057265

RESUMO

BACKGROUND: This study aimed to assess long-term safety and developmental data on juvenile idiopathic arthritis (JIA) patients treated in routine clinical practice with celecoxib or nonselective nonsteroidal anti-inflammatory drugs (nsNSAIDs). METHODS: Children aged ≥2 to <18 years with rheumatoid-factor-positive or -negative polyarthritis, persistent or extended oligoarthritis, or systemic arthritis were enrolled into this prospective, observational, multicenter standard-of-care registry. Eligible patients were newly or recently prescribed (≤6 months) an nsNSAID or celecoxib. Enrolled patients were followed to the end of the study, whether they remained on the original NSAID, switched, or discontinued therapy altogether. All adverse events (AEs) regardless of severity were captured in the database. RESULTS: A total of 274 patients (nsNSAID, n = 219; celecoxib, n = 55) were observed for 410 patient-years of observation. Naproxen, meloxicam, and nabumetone were the most frequently used nsNSAIDs. At baseline, the celecoxib group was older, had a numerically longer median time since diagnosis, and a numerically higher proportion of patients with a history of gastrointestinal-related NSAID intolerance. AEs reported were those frequently observed with NSAID treatment and were similar across groups (nsNSAIDs: 52.0%; celecoxib: 52.9%). Twelve unique patients experienced a total of 18 serious AEs; the most frequent were infections, and none was attributed to NSAID use. CONCLUSIONS: The safety profile of celecoxib and nsNSAIDs appears similar overall. The results from this registry, ongoing pharmacovigilance, and the phase 3 trial that led to the approval of celecoxib for children with JIA provide evidence that the benefit-risk for celecoxib treatment in JIA remains positive. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00688545.


Assuntos
Anti-Inflamatórios não Esteroides , Artrite Juvenil/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Pirazóis/efeitos adversos , Sulfonamidas/efeitos adversos , Adolescente , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/classificação , Celecoxib , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Masculino , Conduta do Tratamento Medicamentoso , Segurança do Paciente , Pirazóis/administração & dosagem , Sistema de Registros , Sulfonamidas/administração & dosagem , Tempo , Estados Unidos
16.
J Rheumatol ; 39(5): 1088-94, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22337238

RESUMO

OBJECTIVE: There are no validated tools for measuring disease activity in pediatric vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is a valid disease activity tool in adult vasculitis. Version 3 (BVAS v.3) correlates well with physician's global assessment (PGA), treatment decision, and C-reactive protein in adults. The utility of BVAS v.3 in pediatric vasculitis is not known. We assessed the association of BVAS v.3 scores with PGA, treatment decision, and erythrocyte sedimentation rate (ESR) at diagnosis in pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: Children with AAV diagnosed between 2004 and 2010 at all ARChiVe centers were eligible. BVAS v.3 scores were calculated with a standardized online tool (www.vasculitis.org). Spearman's rank correlation coefficient (r(s)) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR. RESULTS: A total of 152 patients were included. The physician diagnosis of these patients was predominantly granulomatosis with polyangiitis (n = 99). The median BVAS v.3 score was 18.0 (range 0-40). The BVAS v.3 correlations were r(s) = 0.379 (95% CI 0.233 to 0.509) with PGA, r(s) = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and r(s) = 0.403 (95% CI 0.253 to 0.533) with ESR. CONCLUSION: Applied to children with AAV, BVAS v.3 had a weak correlation with PGA and moderate correlation with both ESR and treatment decision. Prospective evaluation of BVAS v.3 and/or pediatric-specific modifications to BVAS v.3 may be required before it can be formalized as a disease activity assessment tool in pediatric AAV.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/imunologia , Sistema de Registros/normas , Índice de Gravidade de Doença , Vasculite/diagnóstico , Vasculite/fisiopatologia , Adulto , Fatores Etários , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Criança , Estudos de Coortes , Feminino , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/imunologia , Granulomatose com Poliangiite/fisiopatologia , Humanos , Masculino , Pediatria/normas , Reprodutibilidade dos Testes , Estudos Retrospectivos , Reumatologia/normas , Vasculite/imunologia
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