RESUMO
OBJECTIVES: To explore the association between serum S100A8/9 (calprotectin), clinical and ultrasound (US) assessment in juvenile idiopathic arthritis (JIA) patients. METHODS: A total of 30 well-characterised consecutive patients (18 female) with non-systemic JIA and 20 age-matched healthy controls were included. Serum and plasma samples obtained the same day of the clinical and sonographical assessment were tested for calprotectin levels by ELISA. Clinical status was defined using Wallace criteria. Ultrasonographic B-mode and power Doppler (PD) assessment of 44 joints for each subject was performed. RESULTS: Clinically active disease was present in 14 patients, while 16 patients were active according to US evaluation. We found no differences in the serum/plasma calprotectin levels in clinically active disease group [29.6 (5.4-198.1) ng/ml; 12.6 (2.8-65.8) ng/ml] as compared with inactive disease group [24.8 (14.1-204.3); 12.7 (3.4-65.1)] (p=0.73; p=0.29). There was also no difference between US active disease [29.8 (5.4-204.3); 12.9 (2.8-65.8)] and US inactive disease [24.8 (12.1-197.1); 11.7 (3.4-44.2)] with regard to the serum/plasma calprotectin levels (p=0.83; p=1.0). Serum/plasma calprotectin levels correlated moderately with C-reactive protein (CRP) (Spearman r=0.44, p=0.01; Spearman r=0.56, p=0.0021). CONCLUSIONS: To our knowledge, this is the first study to simultaneously examine the correlation between serum/plasma calprotectin levels, clinical and US assessment in JIA. Calprotectin was not associated with the disease status in JIA patients with low number of active joints and its levels were moderately correlated with CRP. Our preliminary study needs to be extended with a larger number of patients.
Assuntos
Artrite Juvenil , Complexo Antígeno L1 Leucocitário , Artrite Juvenil/diagnóstico por imagem , Biomarcadores , Proteína C-Reativa/metabolismo , Calgranulina A , Calgranulina B , Feminino , Humanos , Ultrassonografia , Ultrassonografia DopplerRESUMO
Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic diseases in children. Recently, the management of JIA has substantially changed, thanks to the availability of new treatment options, represented by biological drugs or biologics. These drugs modulate the specific mechanisms of the immune systems, such as TNF-α, IL-1 and IL-6 signaling, or lymphocyte activation and/or functioning. In this review, we provide a comprehensive discussion on the current recommendations and clinical evidence regarding the use of the available biologics in the treatment of JIA; moreover, the main pharmacokinetic and pharmacodynamic aspects of any specific biologic drug have been summarized.
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Artrite Juvenil/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Artrite Juvenil/metabolismo , Artrite Juvenil/patologia , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacocinética , Doenças Hematológicas/etiologia , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoAssuntos
Fibroma/diagnóstico , Articulações dos Dedos/diagnóstico por imagem , Radiografia/métodos , Ultrassonografia/métodos , Artrite Juvenil/diagnóstico , Criança , Diagnóstico Diferencial , Erros de Diagnóstico/prevenção & controle , Fibroma/fisiopatologia , Fibroma/terapia , Humanos , MasculinoRESUMO
The aim of this study is to retrospectively analyze 10-year drug survival of first-line TNF inhibitor (TNFi) in rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and juvenile idiopathic arthritis (JIA) patients, comparing withdrawal rates and discontinuation pattern between adult- and juvenile-onset populations. RA, AS, PsA, and JIA patients treated with infliximab, etanercept, or adalimumab as first TNFi between 1999 and 2015 were extracted from a local registry. Drug survival up to 10-year follow-up was evaluated by the Kaplan-Meier method and compared according to age (adult vs juvenile onset), TNFi agent, and discontinuation reason by a stratified log-rank test. Three hundred sixty JIA (205 etanercept, 66 adalimumab, and 89 infliximab) and 951 (607 RA, 188 AS, and 156 PsA) adult patients (464 infliximab, 262 adalimumab, and 225 etanercept) were included. After exclusion of systemic-onset JIA (18.5%), overall 10-year retention rate was 31.8%, with no difference between adult- and juvenile-onset patients (32.1 and 30.2%, respectively; HR 0.938 [95% CI 0.782-1.125]). Etanercept showed the highest drug survival in adult-onset population (p < 0.0001 vs both monoclonal antibodies) and infliximab the lowest in juvenile-onset population (p = 0.005 vs adalimumab and p < 0.0001 vs etanercept). Inefficacy was the most frequent reason for TNFi withdrawal in adult population (29.75%) with a significantly higher risk of discontinuation than in juvenile-onset subgroup (HR 1.390 [95% CI 1.060-1.824]). Serious infections and malignancies caused TNFi withdrawal only in adult whereas gastrointestinal, neuropsychiatric, and ocular complications quite only in juvenile patients. Despite a similar 10-year drug survival, adult- and juvenile-onset subpopulations showed a significantly different pattern of TNFi reasons for discontinuation.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Psoriásica/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/efeitos adversos , Adalimumab/uso terapêutico , Adulto , Idoso , Antirreumáticos/efeitos adversos , Produtos Biológicos/efeitos adversos , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Feminino , Humanos , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Canakinumab is a human anti-interleukin-1ß (IL-1ß) monoclonal antibody neutralizing IL-1ß-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA). METHODS: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197. RESULTS: Microarray analysis identified 984 probe sets differentially expressed (≥2-fold difference; P < 0.05) in patients versus controls. Over 50% of patients with ≥50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving ≥50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (≥2-fold difference; P < 0.05) on day 3 versus baseline, including IL-1ß, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (≥8-fold decline; P < 0.0001) and remained suppressed. IL-18 declined on day 57 (≥1.5-fold decline, P ≤ 0.002). CONCLUSIONS: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Interleucina-18/biossíntese , Interleucina-6/biossíntese , Transcriptoma/efeitos dos fármacos , Adolescente , Anticorpos Monoclonais Humanizados , Criança , Pré-Escolar , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Humanos , Imunoensaio , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Adulto JovemRESUMO
BACKGROUND: Data from routine clinical practice are needed to further define the efficacy and safety of biologic medications in children with juvenile idiopathic arthritis (JIA). The aim of this analysis was to investigate the disease status, reasons for discontinuation and adverse events in Italian JIA patients treated with etanercept (ETN). METHODS: In 2013, all centers of the Italian Pediatric Rheumatology Study Group were asked to make a census of patients given ETN after January 2000. Patients were classified in three groups: group 1 = patients still taking ETN; group 2 = patients discontinued from ETN for any reasons; group 3 = patients lost to follow-up while receiving ETN. All three groups received a retrospective assessment; patients in group 1 also underwent a cross-sectional assessment. RESULTS: 1038 patients were enrolled by 23 centers: 422 (40.7%) were in group 1, 462 (44.5%) in group 2, and 154 (14.8%) in group 3. Median duration of ETN therapy was 2.5 years. At cross-sectional assessment, 41.8% to 48.6% of patients in group 1 met formal criteria for inactive disease, whereas 52.4% of patients in group 2 and 55.8% of patients in group 3 were judged in clinical remission by their caring physician at last visit. A relatively greater proportion of patients with systemic arthritis were discontinued or lost to follow-up. Parent evaluations at cross-sectional visit in group 1 showed that 52.4% of patients had normal physical function, very few had impairment in quality of life, 51.2% had no pain, 76% had no morning stiffness, and 82.7% of parents were satisfied with their child's illness outcome. Clinically significant adverse events were reported for 27.8% of patients and ETN was discontinued for side effects in 9.5%. The most common adverse events were new onset or recurrent uveitis (10.2%), infections (6.6%), injection site reactions (4.4%), and neuropsychiatric (3.1%), gastrointestinal (2.4%), and hematological disorders (2.1%). Ten patients developed an inflammatory bowel disease and 2 had a malignancy. One patient died of a fulminant streptococcal sepsis. CONCLUSIONS: Around half of the patients achieved complete disease quiescence under treatment with ETN. The medication was overall well tolerated, as only one quarter of patients experienced clinically significant adverse events and less than 10% had treatment discontinued for toxicity.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Etanercepte/uso terapêutico , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Substituição de Medicamentos , Feminino , Humanos , Masculino , Metotrexato/uso terapêutico , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND/AIMS: To evaluate retrospectively the long-term efficacy of rituximab in patients with severe juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: Eight patients (15 eyes) with severe and longstanding JIA uveitis, who had an inadequate response in controlling uveitis to one or more biologic agents including tumour necrosis factor blockers and abatacept, received rituximab therapy. Rituximab was given at a dose of 1000â mg per infusion on days 1 and 15 and then every 6â months. Clinical responses to treatment, including decrease in uveitis activity, visual acuity changes, reduction of concomitant local and systemic corticosteroid and/or immunosuppressants, and occurrence of adverse events, were assessed. RESULTS: Eight patients with a mean±SD age of 22.8±5.5â years were treated. The mean ocular disease duration was 17.7â years; the mean±SD follow-up time on rituximab was 44.75±4.9â months; and the mean number of rituximab infusions received was 8.75 (range 6-12). All patients achieved complete control of uveitis, but in two patients rituximab was discontinued due to inefficacy in treating arthritis. The decrease in uveitis activity was evident 4-5 months after the first infusion. Systemic corticosteroids and immunosuppressants used in association with rituximab were discontinued in five patients at the end of follow-up. None of the patients experienced visual worsening during the follow-up. No drug-related complications were encountered. CONCLUSIONS: Rituximab may be a promising effective treatment option for refractory uveitis associated with JIA leading to long-term quiescence of uveitis, particularly for patients who have not previously responded to other biologic therapies.
Assuntos
Artrite Juvenil/complicações , Rituximab/administração & dosagem , Uveíte/tratamento farmacológico , Acuidade Visual/fisiologia , Adolescente , Adulto , Artrite Juvenil/diagnóstico , Artrite Juvenil/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Fatores Imunológicos/administração & dosagem , Infusões Intravenosas , Masculino , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Uveíte/diagnóstico , Uveíte/etiologia , Adulto JovemRESUMO
OBJECTIVE: The efficacy and safety of abatacept in patients with juvenile idiopathic arthritis (JIA) who experienced an inadequate response to disease-modifying antirheumatic drugs were previously established in a phase III study that included a 4-month open-label lead-in period, a 6-month double-blind withdrawal period, and a long-term extension (LTE) phase. The aim of this study was to present the safety, efficacy, and patient-reported outcomes of abatacept treatment (10 mg/kg every 4 weeks) during the LTE phase, for up to 7 years of followup. METHODS: Patients enrolled in the phase III trial could enter the open-label LTE phase if they had not achieved a response to treatment at month 4 or if they had received abatacept or placebo during the double-blind period. RESULTS: One hundred fifty-three (80.5%) of 190 patients entered the LTE phase, and 69 patients (36.3%) completed it. The overall incidence rate (events per 100 patient-years) of adverse events decreased during the LTE phase (433.61 events during the short-term phase [combined lead-in and double-blind periods] versus 132.39 events during the LTE phase). Similar results were observed for serious adverse events (6.82 versus 5.60), serious infections (1.13 versus 1.72), malignancies (1.12 versus 0), and autoimmune events (2.26 versus 1.18). American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) responses, Pedi 70 responses, and clinically inactive disease status were maintained throughout the LTE phase in patients who continued to receive therapy. Improvements in the Child Health Questionnaire physical and psychosocial summary scores were maintained over time. CONCLUSION: Long-term abatacept treatment for up to 7 years was associated with consistent safety, sustained efficacy, and quality-of-life benefits in patients with JIA.
Assuntos
Abatacepte/efeitos adversos , Abatacepte/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/psicologia , Qualidade de Vida/psicologia , Atividades Cotidianas/psicologia , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Criança , Método Duplo-Cego , Feminino , Humanos , Estudos Longitudinais , Masculino , Psicologia , Autorrelato , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Abatacept (ABA), a selective T cell costimulation modulator that binds to CD80 and CD86 on antigen-presenting cells, was investigated for its antiinflammatory effect in treating severe chronic uveitis associated with juvenile idiopathic arthritis (JIA). METHODS: Our retrospective study was conducted by members of the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC). Patients with JIA who are receiving ABA treatment for active uveitis were included. In all patients, uveitis had been refractory to previous topical and systemic corticosteroids, immunosuppressives, and at least 1 tumor necrosis factor-α inhibitor. A standardized protocol was used to document uveitis (MIWGUC) and arthritis. Baseline visit and visits at 3, 6, 9, and 12 months before and after ABA start were evaluated. Primary outcome measure was defined as achievement of uveitis inactivity; secondary outcome measures were tapering of corticosteroid and/or immunosuppressive treatment, and occurrence of complications. RESULTS: In all, 21 patients (16 female) with active uveitis (n = 21) and arthritis (n = 18) were included (mean age 11.8 ± 3.6 yrs). In 7 of 18 patients with active arthritis at baseline, inactivity was achieved following ABA treatment. Uveitis inactivity was achieved in 11 patients, but recurred later in 8 of them, and remained active in another 10 cases. Systemic corticosteroids or immunosuppression were tapered in 3 patients, but uveitis recurred in all of them during further followup. Ocular complications secondary to uveitis were present in 17 patients at baseline, while 3 patients developed new ocular complications during followup. CONCLUSION: A sustained response to ABA was uncommon in patients with severe and refractory uveitis.
Assuntos
Abatacepte/uso terapêutico , Artrite Juvenil/complicações , Imunossupressores/uso terapêutico , Uveíte/tratamento farmacológico , Adolescente , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Uveíte/complicaçõesRESUMO
OBJECTIVE: To investigate the impact of tocilizumab treatment on growth and growth-related laboratory parameters in patients with systemic juvenile idiopathic arthritis (JIA) enrolled in a phase III clinical trial. METHODS: Patients with systemic JIA ages 2-17 years (n = 112) received tocilizumab in a 12-week, randomized, placebo-controlled period and a long-term open-label extension. Height velocity and standard deviation (SD) score; levels of insulin-like growth factor 1 (IGF-1), osteocalcin (OC), and C-telopeptide of type I collagen (CTX-I); and Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) were measured in a post hoc analysis of 83 patients who never received growth hormone and did not reach Tanner stage 5 by the end of the first year of treatment. RESULTS: Patients had stunted growth at baseline (mean height SD score -2.2). During tocilizumab treatment, males (73%) and females (83%) experienced above-normal mean height velocities of 6.6 cm/year (P < 0.0001 versus World Health Organization norms). Mean height SD score increases during year 1 (0.29) and year 2 (0.31) were significant (both P < 0.0001). The mean SD score for IGF-1 levels increased significantly (-0.2 for year 1 and -0.1 for year 2 versus -1.0 at baseline; both P < 0.0001). Mean OC and CTX-I levels (both P < 0.0001) and the OC:CTX-I ratio (P = 0.014) significantly increased from baseline to year 2. In multiple regression analysis, first-year height velocity had a significant inverse relationship to JADAS-71 at year 1, age, mean glucocorticoid dosage during the year, and height SD score at baseline. CONCLUSION: Our findings indicate that during treatment with tocilizumab, patients with systemic JIA experience significant catch-up growth, normalization of IGF-1 levels, and bone balance improvement favoring bone formation.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Desenvolvimento Infantil/efeitos dos fármacos , Colágeno Tipo I/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Osteocalcina/sangue , Peptídeos/sangue , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
PURPOSE: To evaluate the long-term efficacy of golimumab in patients with severe recalcitrant uveitis who had inadequate response to previous biologics. METHODS: Retrospective study (13 patients with JIA, 4 with HLA-B27-associated uveitis). Indication for treatment was active uveitis despite biologics. Golimumab dosing was 50 mg monthly/subcutaneously. MAIN OUTCOME MEASURES: uveitis activity, visual acuity improvement, reduction of systemic therapy (corticosteroids/immunosuppressants), adverse events. RESULTS: Of 17 patients (34 affected eyes), response to golimumab was seen in 14 patients; at last visit uveitis was inactive in 12 patients. Three patients were nonresponders. Mean follow-up time on golimumab was 21.9 months. Visual acuity remained stable in 26 eyes, improved in 7, and worsened in 1. Mean systemic prednisolone dose before and after golimumab was 12.5-3.5 mg/day. One patient developed pulmonary infection. CONCLUSIONS: Golimumab may be a promising new therapeutic option for severe uveitis patients who have not responded to other biologics.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Uveíte/tratamento farmacológico , Adolescente , Adulto , Artrite Juvenil/complicações , Artrite Juvenil/imunologia , Doenças Autoimunes , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Antígeno HLA-B27/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/diagnóstico , Uveíte/imunologia , Adulto JovemAssuntos
Síndromes Periódicas Associadas à Criopirina/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Adolescente , Adulto , Pré-Escolar , Síndromes Periódicas Associadas à Criopirina/tratamento farmacológico , Síndromes Periódicas Associadas à Criopirina/imunologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Imunossupressores/uso terapêutico , Itália , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate safety and efficacy of adalimumab (ADA) and infliximab (IFX) for the treatment of juvenile idiopathic arthritis-related anterior uveitis (JIA-AU). METHODS: Starting January 2007, patients with JIA-AU treated with IFX and ADA were managed by a standard protocol and data were entered into the National Italian Registry (NIR). At baseline, all patients were refractory to standard immunosuppressive treatment and/or were corticosteroid-dependent. Data recorded every 3 months included uveitis course, number/type of ocular complications, drug-related adverse events (AE), treatment change or withdrawal, and laboratory measures. Data of patients treated for at least 1 year were retrieved from the NIR and analyzed using descriptive statistics. Treatment efficacy was based on change in uveitis course and in number of ocular complications. RESULTS: Up to December 2009, data for 108 patients with JIA-AU treated with anti-tumor necrosis factor-α agents were recorded in the NIR and data from 91, with at least 12 months' followup, were included in the study. Forty-eight patients were treated with IFX, 43 with ADA. Forty-seven patients (55.3%) achieved remission of AU, 28 (32.9%) had recurrent AU, and 10 (11.8%) maintained a chronic course. A higher remission rate was observed with ADA (67.4% vs 42.8% with IFX; p = 0.025). Ocular complications decreased from 0.47 to 0.32 per subject. Five patients experienced resolution of structural complications. No patient reported serious AE; 8 (8.8%) experienced 11 minor AE (9 with IFX, 2 with ADA). CONCLUSION: IFX and ADA appear to be effective and safe for treatment of refractory JIA-related uveitis, with a better performance of ADA in the medium-term period.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Uveíte/tratamento farmacológico , Adalimumab , Adolescente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Juvenil/complicações , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Infliximab , Itália , Masculino , Sistema de Registros , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte/complicaçõesRESUMO
The tumor necrosis factor alpha (TNFα) inhibitors have been used with good clinical results in the treatment of juvenile idiopathic arthritis (JIA). Anti TNFα therapy is generally well tolerated. Besides the site injection reactions, other various cutaneous manifestations have been encountered as adverse events. Here, we report four young patients receiving treatment with anti-TNFα (infliximab, adalimumab, and etanercept) for JIA developing different skin manifestations more than 1 year after the initiation of therapy. They underwent a dermatological exam. All four patients were ACR-Ped 30 responders to anti-TNF drugs. The first patient developed cutaneous vasculitis, the second one had lichen planus manifestations, while the third and the fourth developed psoriatic palmoplantar pustulosis accompanied by plaque-type psoriasis localized to the scalp. None of the patients had a personal or family history of dermatological diseases. In the first two patients, skin lesions healed with topical treatment after the discontinuation of anti-TNF agent, while psoriatic lesions did not resolve despite discontinuation of the drug and dermatological treatment. TNF inhibition can be both anti-inflammatory and pro-inflammatory. Cutaneous manifestations could be considered as a paradoxical adverse event of the anti-TNF-alpha treatment not only in rheumatoid arthritis but also in juvenile idiopathic arthritis.
Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais/efeitos adversos , Artrite Juvenil/patologia , Imunoglobulina G/administração & dosagem , Imunoterapia , Receptores do Fator de Necrose Tumoral/administração & dosagem , Pele/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Corticosteroides/uso terapêutico , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite Juvenil/imunologia , Etanercepte , Feminino , Seguimentos , Humanos , Imunoglobulina G/efeitos adversos , Infliximab , Líquen Plano/etiologia , Líquen Plano/prevenção & controle , Masculino , Psoríase/etiologia , Psoríase/prevenção & controle , Vasculite Leucocitoclástica Cutânea/etiologia , Vasculite Leucocitoclástica Cutânea/prevenção & controle , Adulto JovemRESUMO
OBJECTIVE: With the increasing use of etanercept for juvenile idiopathic arthritis (JIA) new possible adverse events are reported including new autoimmune diseases. Our purpose was to examine if the incidence of inflammatory bowel disease (IBD) in patients with JIA using etanercept is higher than in the healthy age-matched population. We give the clinical characteristics of the IBD in patients with JIA using etanercept. METHODS: The national JIA registries for etanercept of The Netherlands, Germany, Finland, Denmark, and Italy were searched for patients with JIA and IBD. The total number of patient-years was used to calculate incidence. The physicians of the identified patients were asked to give clinical details. RESULTS: Thirteen cases of IBD in JIA patients were identified in the registries between 1999 and 2008. The IBD incidence in JIA patients while using etanercept was 362 per 100,000 patient-years under etanercept, about 43 times higher than in the general pediatric population. Clinical presentation of IBD in JIA patients using etanercept was similar to that in non-JIA patients. The median time between onset of JIA and onset of IBD was 6 years and 10 months. The time between the start of etanercept and the first appearance of IBD symptoms was between 9 days and 4.5 years. CONCLUSION: The incidence of IBD in JIA patients using etanercept seems to be markedly increased, analyzing data from European registries. This incidence of IBD in the etanercept registries cannot be compared to the incidence of IBD in JIA patients using other treatment without etanercept, because such registries do not exist yet in all European countries. These findings are in keeping with a report of 8 new IBD cases occurring in French children with JIA using etanercept. These findings illustrate the need for large international disease-specific registries focused on outcome and pharmacovigilance.
Assuntos
Artrite Juvenil/tratamento farmacológico , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/epidemiologia , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Criança , Pré-Escolar , Dinamarca/epidemiologia , Etanercepte , Feminino , Finlândia/epidemiologia , Alemanha/epidemiologia , Humanos , Incidência , Lactente , Itália/epidemiologia , Masculino , Países Baixos/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: Rituximab (RTX), a chimeric mAb directed against the B-cell marker CD20, was investigated for its anti-inflammatory effect in treating refractory uveitis associated with JIA. METHODS: Case series, retrospective multicentre. JIA patients with severe uveitis with vision-threatening complications (n = 10) and with insidious onset. All patients were treated with RTX for active uveitis refractory to topical and systemic CSs, immunosuppressives and at least one of the TNF-α inhibitors. All had active arthritis. Uveitis and arthritis course were assessed before and after RTX treatment. RESULTS: After one RTX cycle (mean follow-up 11 months, range 7-18 months), uveitis inactivity was achieved in seven oligoarthritis patients (ANAâº, HLA-B27â») for a prolonged period of time (mean 7.5 months, range 6-9 months). Therefore, CSs and immunosuppression could be spared. In three of four patients responding to RTX, uveitis recurred thereafter, and RTX re-treatment led to inactivity again. In another three patients (ANA⺠polyarthritis, n = 1; ANA⺠HLA-B27⺠oligo- or polyarthritis, n = 2) uveitis activity persisted after RTX therapy. In seven patients, arthritis improved or was inactive after RTX treatment (PedACR30/50/70). CONCLUSION: RTX may represent a rescue therapy option for severe JIA-associated uveitis refractory to CSs, immunosuppression and TNF-α inhibitors.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Imunossupressores/uso terapêutico , Uveíte Anterior/tratamento farmacológico , Adolescente , Artrite Juvenil/complicações , Artrite Juvenil/diagnóstico , Criança , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Glucocorticoides/uso terapêutico , Humanos , Estudos Retrospectivos , Rituximab , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Uveíte Anterior/complicações , Uveíte Anterior/diagnóstico , Adulto JovemRESUMO
OBJECTIVE: We previously documented that abatacept was effective and safe in patients with juvenile idiopathic arthritis (JIA) who had not previously achieved a satisfactory clinical response with disease-modifying antirheumatic drugs or tumor necrosis factor blockade. Here, we report results from the long-term extension (LTE) phase of that study. METHODS: This report describes the long-term, open-label extension phase of a double-blind, randomized, controlled withdrawal trial in 190 patients with JIA ages 6-17 years. Children were treated with 10 mg/kg abatacept administered intravenously every 4 weeks, with or without methotrexate. Efficacy results were based on data derived from the 153 patients who entered the open-label LTE phase and reflect >or=21 months (589 days) of treatment. Safety results include all available open-label data as of May 7, 2008. RESULTS: Of the 190 enrolled patients, 153 entered the LTE. By day 589, 90%, 88%, 75%, 57%, and 39% of patients treated with abatacept during the double-blind and LTE phases achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30), Pedi 50, Pedi 70, Pedi 90, and Pedi 100 criteria for improvement, respectively. Similar response rates were observed by day 589 among patients previously treated with placebo. Among patients who had not achieved an ACR Pedi 30 response at the end of the open-label lead-in phase and who proceeded directly into the LTE, 73%, 64%, 46%, 18%, and 5% achieved ACR Pedi 30, Pedi 50, Pedi 70, Pedi 90, and Pedi 100 responses, respectively, by day 589 of the LTE. No cases of tuberculosis and no malignancies were reported during the LTE. Pneumonia developed in 3 patients, and multiple sclerosis developed in 1 patient. CONCLUSION: Abatacept provided clinically significant and durable efficacy in patients with JIA, including those who did not initially achieve an ACR Pedi 30 response during the initial 4-month open-label lead-in phase.
Assuntos
Artrite Juvenil/tratamento farmacológico , Imunoconjugados/efeitos adversos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Abatacepte , Adolescente , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Criança , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Humanos , Imunoconjugados/uso terapêutico , Metotrexato/uso terapêutico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. METHODS: Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. RESULTS: Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. CONCLUSIONS: Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Metotrexato/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Adolescente , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Some children with juvenile idiopathic arthritis either do not respond, or are intolerant to, treatment with disease-modifying antirheumatic drugs, including anti-tumour necrosis factor (TNF) drugs. We aimed to assess the safety and efficacy of abatacept, a selective T-cell costimulation modulator, in children with juvenile idiopathic arthritis who had failed previous treatments. METHODS: We did a double-blind, randomised controlled withdrawal trial between February, 2004, and June, 2006. We enrolled 190 patients aged 6-17 years, from 45 centres, who had a history of active juvenile idiopathic arthritis; at least five active joints; and an inadequate response to, or intolerance to, at least one disease-modifying antirheumatic drug. All 190 patients were given 10 mg/kg of abatacept intravenously in the open-label period of 4 months. Of the 170 patients who completed this lead-in course, 47 did not respond to the treatment according to predefined American College of Rheumatology (ACR) paediatric criteria and were excluded. Of the patients who did respond to abatacept, 60 were randomly assigned to receive 10 mg/kg of abatacept at 28-day intervals for 6 months, or until a flare of the arthritis, and 62 were randomly assigned to receive placebo at the same dose and timing. The primary endpoint was time to flare of arthritis. Flare was defined as worsening of 30% or more in at least three of six core variables, with at least 30% improvement in no more than one variable. We analysed all patients who were treated as per protocol. This trial is registered, number NCT00095173. FINDINGS: Flares of arthritis occurred in 33 of 62 (53%) patients who were given placebo and 12 of 60 (20%) abatacept patients during the double-blind treatment (p=0.0003). Median time to flare of arthritis was 6 months for patients given placebo (insufficient events to calculate IQR); insufficient events had occurred in the abatacept group for median time to flare to be assessed (p=0.0002). The risk of flare in patients who continued abatacept was less than a third of that for controls during that double-blind period (hazard ratio 0.31, 95% CI 0.16-0.95). During the double-blind period, the frequency of adverse events did not differ in the two treatment groups. Adverse events were recorded in 37 abatacept recipients (62%) and 34 (55%) placebo recipients (p=0.47); only two serious adverse events were reported, both in controls (p=0.50). INTERPRETATION: Selective modulation of T-cell costimulation with abatacept is a rational alternative treatment for children with juvenile idiopathic arthritis. FUNDING: Bristol-Myers Squibb.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Imunoconjugados/uso terapêutico , Abatacepte , Adolescente , Antirreumáticos/efeitos adversos , Artrite Juvenil/classificação , Criança , Método Duplo-Cego , Feminino , Humanos , Imunoconjugados/efeitos adversos , Infusões Intravenosas , Masculino , Amplitude de Movimento Articular , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: To investigate the genetic contribution of cytokine gene polymorphisms (interleukin 1 (IL1) and tumour necrosis factor alpha (TNFalpha)) on disease phenotype and on response to TNF-blocking agents in a population of patients with juvenile idiopathic arthritis (JIA). METHODS: A cohort of 107 consecutive patients with JIA who were receiving treatment with anti-TNF agents was enrolled in this study. Analysis of genetic polymorphisms for IL1B +3954, IL1RA +2018, TNFalpha -238 and TNFalpha -308 was performed by enzyme-linked oligo sorbent assay, and compared with those obtained from 630 healthy Caucasians and 263 adult patients with rheumatoid arthritis. Relevant demographic, clinical and laboratory data were collected from clinical charts and entered into a customised database, and chi(2) analysis was performed to compare cytokine polymorphisms with disease type according to the International League of Associations for Rheumatology criteria, presence of uveitis, rheumatoid factor and anti-nuclear antibody positivity, erosive disease, frequency of adverse effects to anti-TNF and clinical response after 3 months. RESULTS: The T/T genotype of the IL1B +3954 polymorphism was absent in patients with JIA and present in 5% of controls (p = 0.015). No significant correlation was found between the studied polymorphisms and clinical or laboratory variables considered. Clinical response to TNF inhibitors at 3 months was not associated with the genetic polymorphisms considered. CONCLUSION: In our cohort, the absence of the rare IL1B +3954 gene polymorphism was associated with JIA, but without specificity to particular disease phenotypes. The TNF and IL1 gene polymorphism studied did not seem to be associated with response to anti-TNF treatment.