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2.
Artigo em Inglês | MEDLINE | ID: mdl-31876783

RESUMO

In recent years, monogenic causes of immune dysregulation syndromes, with variable phenotypes, have been documented. Mutations in the lipopolysaccharide-responsive beige-like anchor (LRBA) protein are associated with common variable immunodeficiency, autoimmunity, chronic enteropathy, and immune dysregulation disorders. The LRBA protein prevents degradation of cytotoxic T-lymphocyte antigen 4 (CTLA4) protein, thus inhibiting immune responses. Both LRBA and CTLA4 deficiencies usually present with immune dysregulation, mostly characterized by autoimmunity and lymphoproliferation. In this report, we describe a patient with an atypical clinical onset of LRBA deficiency and the patient's response to abatacept, a fusion protein-drug that mimics the action of CTLA4.

3.
Br J Haematol ; 187(4): 502-508, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31309545

RESUMO

Autoimmune lymphoproliferative syndrome (ALPS) is a congenital disorder that results in an apoptosis impairment of lymphocytes, leading to chronic lymphoproliferation and autoimmunity, mainly autoimmune cytopenias. FAS gene defects are often responsible for the disease, the phenotype of which can vary from asymptomatic/mild forms to severe disease. More rarely, defects are associated to  other genes involved in apoptosis pathway, such as CASP10. Few data are available on CASP10-mutated patients. To date, two CASP10 mutations have been recognized as pathogenic (I406L and L258F) and others have been reported with controversial result on their pathogenicity (V410l, Y446C) or are known to be polymorphic variants (L522l). In this study, we evaluated apoptosis function in patients with an ALPS/ALPS-like phenotype carrying CASP10 variants. Molecular findings were obtained by next generation sequencing analysis of genes involved in immune dysregulation syndromes. Functional studies were performed after inducing apoptosis by FAS-ligand/TRIAL stimulation and analysing cell death and the function of CASP10, CASP8 and PARP proteins. We identified 6 patients with an ALPS (n = 2) or ALPS-like (n = 4) phenotype, carrying I406L (n = 1),V410l (n = 2),Y446C (n = 1) heterozygous CASP10 variants or the L522l polymorphisms (n = 2) associated with another polymorphic homozygote variant on CASP8 or a compound heterozygous mutation on TNFRSF13C. Apoptosis was impaired in all patients showing that such variants may play a role in the development of clinical phenotype.

8.
Exp Clin Transplant ; 2017 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-28969530

RESUMO

Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Although reduced intensity conditioning regimens seem to be related to better outcomes, a standard regimen for dyskeratosis congenita has never been defined. Here, we report a successful long-term outcome of an 8-year-old girl with dyskeratosis congenita who received 2 consecutive allogeneic hematopoietic stem cell transplants from different unrelated donors, because of rejection after the first one, both conditioned with fludarabine-based reduced intensity conditioning regimen. The second transplant was complicated by severe hemorrhagic cystitis and acute grade IV graft-versus-host disease in the early phase and mild chronic graft-versus-host disease and ureteral stenosis in the late phase. This experience confirms that dyskeratosis congenita is at high risk for transplant-related morbidity but that a fludarabine-based reduced intensity conditioning regimen is a safe and feasible option as a preparative regimen, as shown here in a second transplant after first graft rejection. To reduce the risk of graft-versus-host disease, more effective prophylaxis schedules should be chosen in cases of unrelated donor, and haploidentical hematopoietic stem cell transplant with in vitro α/ ß + and CD19+ depletion should be considered.

9.
J Chemother ; 29(1): 42-44, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25748533

RESUMO

This case report indicates the usefulness of voriconazole for the treatment of central nervous system (CNS) aspergillosis, also in paediatrics. However, it also confirms the need for therapeutic drug monitoring (TDM), especially in younger children that may require very high dosages in order to achieve plasma and cerebrospinal fluid (CSF) therapeutic concentrations.


Assuntos
Antifúngicos/administração & dosagem , Neuroaspergilose/tratamento farmacológico , Voriconazol/administração & dosagem , Antifúngicos/líquido cefalorraquidiano , Antineoplásicos/uso terapêutico , Feminino , Humanos , Hospedeiro Imunocomprometido , Lactente , Neuroaspergilose/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Voriconazol/líquido cefalorraquidiano
10.
Arthritis Care Res (Hoboken) ; 69(5): 677-686, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27564918

RESUMO

OBJECTIVE: To evaluate the demographic, disease activity, disability, and health-related quality of life (HRQOL) differences between children with juvenile idiopathic arthritis (JIA) and their healthy peers, and between children with JIA with and without clinical temporomandibular joint (TMJ) involvement and its determinants. METHODS: This study is based on a cross-sectional cohort of 3,343 children with JIA and 3,409 healthy peers, enrolled in the Pediatric Rheumatology International Trials Organisation HRQOL study or in the methotrexate trial. Potential determinants of TMJ involvement included demographic, disease activity, disability, and HRQOL measures selected through univariate and multivariable logistic regression. RESULTS: Clinical TMJ involvement was observed in 387 of 3,343 children with JIA (11.6%). Children with TMJ involvement, compared to those without, more often had polyarticular disease course (95% versus 70%), higher Juvenile Arthritis Disease Activity Score (odds ratio [OR] 4.6), more disability, and lower HRQOL. Children with TMJ involvement experienced clearly more disability and lower HRQOL compared to their healthy peers. The multivariable analysis showed that cervical spine involvement (OR 4.6), disease duration >4.4 years (OR 2.8), and having more disability (Childhood Health Assessment Questionnaire Disability Index >0.625) (OR 1.6) were the most important determinants for TMJ involvement. CONCLUSION: Clinical TMJ involvement in JIA is associated with higher disease activity, higher disability, and impaired HRQOL. Our findings indicate the need for dedicated clinical and imaging evaluation of TMJ arthritis, especially in children with cervical spine involvement, polyarticular course, and longer disease duration.


Assuntos
Artrite Juvenil/complicações , Avaliação da Deficiência , Qualidade de Vida , Índice de Gravidade de Doença , Transtornos da Articulação Temporomandibular/psicologia , Adolescente , Artrite Juvenil/fisiopatologia , Artrite Juvenil/psicologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Razão de Chances , Ensaios Clínicos Controlados Aleatórios como Assunto , Articulação Temporomandibular/fisiopatologia , Transtornos da Articulação Temporomandibular/etiologia , Transtornos da Articulação Temporomandibular/fisiopatologia
11.
Br J Haematol ; 175(3): 490-495, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27447678

RESUMO

Mycophenolate mofetil (MMF) has been shown to be effective in children with immune thrombocytopenia (ITP) and Evans syndrome (ES), but data from larger series and details on the timing of the response are lacking. We evaluated 56 children treated with MMF for ITP (n = 40) or ES (n = 16), which was primary or secondary to autoimmune lymphoproliferative syndrome -related syndrome (ARS). Thirty-five of the 54 evaluable patients (65%) achieved a partial (18%) or complete (46%) response after a median (range) of 20 (7-137) and 37 (7-192) d, respectively. ITP and ES patients responded in 58% and 81% of cases (P = not significant, ns), with complete response in 32% and 81% (P = 0·01), respectively. 60% and 73% of children with primary disease and ARS responded (P = ns) with complete response in 34% and 68% of cases (P = 0·01), respectively. Six of 35 (17%) children relapsed after a median of 283 d (range 189-1036). Limited toxicity was observed in four patients. The median durations of treatment and follow-up were seven and 12·7 months, respectively. This is the largest reported cohort of patients treated with MMF for ITP/ES. The results show that MMF is effective and safe and provides a relatively quick response, suggesting that it has a potential role as an alternative to more aggressive and expensive second/further-line treatments.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Antibióticos Antineoplásicos/uso terapêutico , Ácido Micofenólico/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Trombocitopenia/tratamento farmacológico , Adolescente , Anemia Hemolítica Autoimune/diagnóstico , Antibióticos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Itália , Masculino , Ácido Micofenólico/efeitos adversos , Razão de Chances , Púrpura Trombocitopênica Idiopática/diagnóstico , Recidiva , Retratamento , Estudos Retrospectivos , Trombocitopenia/diagnóstico , Resultado do Tratamento
12.
Arthritis Rheumatol ; 68(6): 1540-50, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26749157

RESUMO

OBJECTIVE: To estimate the placebo effect in juvenile idiopathic arthritis (JIA) through a meta-analysis of phase III clinical trials with placebo comparator. METHODS: A systematic literature search was carried out up to December 2014. For parallel design studies the outcome was evaluated as a single 1-dimensional (1-D) variable or as a composite score; outcomes of withdrawal studies were evaluated only as composite scores. RESULTS: We included 26 of 224 trials (12%). In trials with parallel study design and a 1-D outcome, the placebo effect was 0.35 (95% confidence interval [95% CI] 0.27-0.43). Among trials with parallel study design and a composite score outcome, the placebo rate response was higher in trials that included patients with nonsystemic JIA (0.35 [95% CI 0.29-0.42]) than in trials that included only patients with systemic JIA (0.17 [95% CI 0.10-0.30]). In the withdrawal design trials, the percentages of patients receiving placebo who had disease flares during the double-blind phase were lower in trials that included patients with nonsystemic JIA (0.55 [95% CI 0.47-0.64]) than in trials that included only patients with systemic JIA (0.68 [95% CI 0.33-0.90]). CONCLUSION: In trials with a parallel study design a sizable number of patients seem to benefit from a placebo effect, although this effect is smaller in patients with systemic JIA. In trials with a withdrawal design the inverse placebo effect is similar among the different JIA categories. This placebo effect should be considered when evaluating the effectiveness of proposed interventions and for future calculations of sample size.


Assuntos
Artrite Juvenil/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Efeito Placebo , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos
13.
JIMD Rep ; 26: 37-43, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26238250

RESUMO

Pearson syndrome (PS) is a very rare and often fatal multisystemic mitochondrial disorder involving the liver, kidney, pancreas, and hematopoietic and central nervous system. It is characterized principally by a transfusion-dependent anemia that usually improves over time, a tendency to develop severe infections, and a high mortality rate. We describe a group of 11 PS patients diagnosed in Italy in the period 1993-2014. The analysis of this reasonably sized cohort of patients contributes to the clinical profile of the disease and highlights a rough incidence of 1 case/million newborns. Furthermore, it seems that some biochemical parameters like increased serum alanine and urinary fumaric acid can help to address an early diagnosis.

14.
Br J Haematol ; 171(2): 247-253, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26058843

RESUMO

The management of refractory autoimmune cytopenias in childhood is challenging due to the lack of established evidence on escalating treatments. The long-term efficacy of immunosuppressive drugs was evaluated in children with refractory autoimmune cytopenias referred to the Haematology Unit of the Gaslini Children's Hospital between 2001 and 2014. Patients were grouped into three categories: autoimmune lymphoproliferative syndrome (ALPS), ALPS-related syndrome (at least one absolute/primary additional criterion for ALPS) and primary autoimmune cytopenia (PAC, cytopenia with no other immunological symptoms/signs). Fifty-eight children (aged 1-16 years) entered the study: 12 were categorized with ALPS, 24 were ALPS-related and 22 had PAC. Five didn't receive treatment. Fifty-three were initially treated with steroids/intravenous immunoglobulin. Fourteen responded, whereas 39 did not. Of these 39 patients, 34 (87%) received mycophenolate mofetil (MMF) as second/further-line treatment and 22 (65%) responded. Within these 34 subjects, ALPS patients responded better (11/11, 100%) than the two other groups pooled together (11/23, 48%; P = 0·002). Sirolimus was given as second/further-line treatment to 16 children, and 12 (75%) responded, including 8 who previously failed MMF therapy. Median follow-up was 3·46 years. MMF and Sirolimus were well-tolerated and enabled partial/complete and sustained remission in most children. These drugs may be successfully and safely used in children with refractory autoimmune cytopenias with or without ALPS/ALPS-related disorders and may represent a valid second/further line option.

16.
Ann Rheum Dis ; 72(9): 1503-9, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23100607

RESUMO

OBJECTIVES: To evaluate therapeutic approaches and response to therapy in juvenile systemic lupus erythematosus (SLE) with renal involvement in a large prospective international cohort from four geographic areas. METHODS: New onset and flared patients with active renal disease (proteinuria ≥0.5 g/24 h) were enrolled in 2001-2004. Therapeutic approaches and disease activity parameters were analysed at baseline, 6, 12 and 24 months. Response was assessed by the PRINTO/ACR criteria. RESULTS: 218/557 (79.8% female subjects, 117 new onset and 101 flared) patients with active renal disease were identified; 66 patients were lost to follow-up and 11 died. Mean age at disease onset for new onset group was higher than for flared group (13.1 vs 10.2 years, p<0.0001). At baseline, both groups had similar renal activity with similar median doses of corticosteroids (1.0-0.76 mg/kg/day). Cyclophosphamide (43.1%) and azathioprine (22%) were the most common immunosuppressive drugs. At baseline, South American patients received higher doses of corticosteroids than in other areas in new onset (median 1.16 vs 0.8-1 mg/kg/day) while cyclophosphamide use was similar in all four regions in the new onset group. There were no differences regarding the use of azathioprine or mycophenolate mofetil worldwide. PRINTO 70 response was reached in a greater percentage of new onset versus flared patients (74.8% vs 53.3%; p=0.005) at 6 months while at 24 months ACR 90 was reached by 69.9% and 56.1%, respectively. CONCLUSIONS: New onset and flared juvenile SLE improved similarly over 24 months with minimal differences in therapeutic approaches worldwide.


Assuntos
Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Glucocorticoides/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Adolescente , Idade de Início , Estudos de Coortes , Quimioterapia Combinada , Feminino , Nível de Saúde , Humanos , Cooperação Internacional , Nefrite Lúpica/epidemiologia , Nefrite Lúpica/patologia , Nefrite Lúpica/urina , Masculino , Estudos Prospectivos , Proteinúria/patologia , Recidiva , Índice de Gravidade de Doença , Resultado do Tratamento
17.
J Rheumatol ; 40(2): 192-200, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23204218

RESUMO

OBJECTIVE: To evaluate the rate of inactive disease in children with juvenile idiopathic arthritis (JIA) treated with etanercept, and to identify clinical characteristics associated with attainment of inactive disease. METHODS: Clinical charts of patients who were given etanercept between January 2002 and January 2011 were evaluated retrospectively. For each patient, all visits from initiation of etanercept to the last followup evaluation in which the patient was still receiving etanercept were examined to establish whether the patient had reached the state of inactive disease and to identify the first visit in which inactive disease was documented. Clinical characteristics associated with achievement of inactive disease were determined through univariate analyses and Cox regression procedures. RESULTS: A total of 173 patients who received etanercept for a median of 2.2 years (range 0.5-10.5 yrs) were studied. Eighty-seven patients (50.3%) achieved inactive disease after a median of 0.6 years (range 0.1-2.5 yrs) of therapy. At last followup evaluation, 85 patients (49.1%) still had inactive disease and 70 (40.5%) were in clinical remission on medication. The probability of achievement of inactive disease after 6, 12, and 24 months of therapy was 24%, 46% and 57%, respectively. On Cox regression analysis, the attainment of inactive disease was associated with lack of wrist involvement and an age at disease onset < 3.6 years. CONCLUSION: Around half of our patients with JIA treated with etanercept achieved a state of inactive disease. Children who lacked wrist involvement and were younger at disease onset had a greater likelihood of achieving inactive disease.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Imunoglobulina G/uso terapêutico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Indução de Remissão , Adolescente , Fatores Etários , Antirreumáticos/administração & dosagem , Antirreumáticos/efeitos adversos , Artrite Juvenil/fisiopatologia , Criança , Etanercepte , Feminino , Seguimentos , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Masculino , Modelos de Riscos Proporcionais , Receptores do Fator de Necrose Tumoral/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento , Punho/fisiopatologia
18.
Ann Rheum Dis ; 72(5): 686-93, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22736096

RESUMO

OBJECTIVES: To develop data-driven criteria for clinically inactive disease on and off therapy for juvenile dermatomyositis (JDM). METHODS: The Paediatric Rheumatology International Trials Organisation (PRINTO) database contains 275 patients with active JDM evaluated prospectively up to 24 months. Thirty-eight patients off therapy at 24 months were defined as clinically inactive and included in the reference group. These were compared with a random sample of 76 patients who had active disease at study baseline. Individual measures of muscle strength/endurance, muscle enzymes, physician's and parent's global disease activity/damage evaluations, inactive disease criteria derived from the literature and other ad hoc criteria were evaluated for sensitivity, specificity and Cohen's κ agreement. RESULTS: The individual measures that best characterised inactive disease (sensitivity and specificity >0.8 and Cohen's κ >0.8) were manual muscle testing (MMT) ≥78, physician global assessment of muscle activity=0, physician global assessment of overall disease activity (PhyGloVAS) ≤0.2, Childhood Myositis Assessment Scale (CMAS) ≥48, Disease Activity Score ≤3 and Myositis Disease Activity Assessment Visual Analogue Scale ≤0.2. The best combination of variables to classify a patient as being in a state of inactive disease on or off therapy is at least three of four of the following criteria: creatine kinase ≤150, CMAS ≥48, MMT ≥78 and PhyGloVAS ≤0.2. After 24 months, 30/31 patients (96.8%) were inactive off therapy and 69/145 (47.6%) were inactive on therapy. CONCLUSION: PRINTO established data-driven criteria with clearly evidence-based cut-off values to identify JDM patients with clinically inactive disease. These criteria can be used in clinical trials, in research and in clinical practice.


Assuntos
Bases de Dados Factuais/normas , Dermatomiosite/diagnóstico , Dermatomiosite/tratamento farmacológico , Medicina Baseada em Evidências/normas , Reumatologia/normas , Corticosteroides/uso terapêutico , Criança , Pré-Escolar , Bases de Dados Factuais/estatística & dados numéricos , Medicina Baseada em Evidências/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Estudos Longitudinais , Masculino , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Padrões de Referência , Reumatologia/estatística & dados numéricos , Sensibilidade e Especificidade
19.
Arthritis Rheum ; 59(8): 1120-7, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18668599

RESUMO

OBJECTIVE: To develop and validate a definition of minimal disease activity (MDA) in patients with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts of JIA patients followed over a 16-year period were reviewed to identify visits with high disease activity and MDA, defined on the basis of therapeutic decisions made by the attending physician. For each JIA activity measure recorded at the time of the visit, the cutoff value that best identified states of MDA was calculated by means of the area under the receiver operating characteristic curve analysis. A definition of MDA for oligoarthritis and polyarthritis was set up after testing the relative power of each variable in a multivariate analysis. Validation procedures included assessment of discriminant and construct validity. RESULTS: The definition that resulted from the analyses led to establish that a state of MDA could be defined as the presence of a physician global assessment < or =2.5 cm and a swollen joint count of 0 in patients with oligoarthritis; and as the presence of a physician global assessment < or =3.4 cm, a parent global assessment < or =2.1 cm, and a swollen joint count < or =1 in patients with polyarthritis. Validation procedures demonstrated that the MDA definition had good discriminant and construct validity in the context of both observational studies and controlled trials. CONCLUSION: We developed a preliminary definition of MDA in patients with JIA that represents a useful treatment target state and is proposed for inclusion as an outcome measure in future observational studies and clinical trials in patients with JIA.


Assuntos
Artrite Juvenil/patologia , Artrite Juvenil/fisiopatologia , Articulações/patologia , Índice de Gravidade de Doença , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Análise Multivariada , Curva ROC , Reprodutibilidade dos Testes
20.
Pediatr Rheumatol Online J ; 5: 23, 2007 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-18072960

RESUMO

OBJECTIVE: To investigate concordance between physicians and parents in rating the degree of functional ability of children with juvenile idiopathic arthritis (JIA). METHODS: The attending physician and a parent were asked to rate independently the level of physical functioning of 155 patients with disease duration >/= 5 years on a 6-point scale ranging from 1 = no disability (i.e. the child can do without difficulty all activities that children of his/her age can do) to 6 = severe disability (i.e. all activities are difficult for the child). At study visit, measures of JIA activity and damage were assessed. Agreement was evaluated with weighted kappa (<0.40 = poor agreement; 0.41-0.60 = moderate agreement; 0.61-0.80 = substantial agreement; >0.80 excellent agreement). Physician/parent evaluations were divided in 3 groups: 1) concordance; 2) parent over-rating = parent assessment over-rated relative to physician assessment; 3) physician over-rating = physician assessment over-rated relative to parent assessment. Factors affecting concordance/discordance were evaluated by means of Kruskal-Wallis or Chi-square/Fisher exact test. RESULTS: Concordance, parent over-rating and physician over-rating were observed in 107 (69%), 29 (18.7%) and 19 (12.3%) evaluations, respectively. Kappa value was 0.69. Parent over-rating was associated with greater intensity of pain (p = 0.01) and higher Childhood Health Assessment Questionnaire (C-HAQ) score (p = 0.004), whereas physician over-rating was associated with more severe joint disease (p = 0.04 to <0.001), higher C-reactive protein (p = 0.03) higher frequency of Steinbrocker functional class = II (p < 0.001), and greater articular damage, as measured with the Juvenile Arthritis Damage Index (p < 0.001). CONCLUSION: Physicians and parents revealed fair concordance in rating functional ability of children with JIA. Parent over-rating was associated with greater child's pain and worse C-HAQ score, whereas physician over-rating was associated with greater severity of joint inflammation and damage.

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