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1.
Br J Clin Pharmacol ; 84(6): 1238-1249, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29436729

RESUMO

AIMS: Anti-CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions of anti-CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions. METHODS: We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid-dependent and steroid/calcineurin inhibitor-dependent disease) treated at a national referral centre over a 9-year period (400 treatments; follow-up 1-9 years). RESULTS: Infusion reactions were mainly absent in children with steroid-dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short-term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3-9 months following infusion, were similarly common in the two groups and resolved with targeted therapies [antibiotic, fluconazole, immunoglobulins (Igs), etc.]. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein-Barr virus and John Cunningham virus activation markers were occasionally observed. CONCLUSION: Overall, the toxicity of anti-CD20 monoclonal antibodies was limited to post-infusion side effects in children with more complex disease. The relatively safe profile of anti-CD20 antibodies supports their use as steroid-sparing agents in children with INS.

2.
Pharmacol Res Perspect ; 5(1): e00267, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28596831

RESUMO

Ofatumumab is an anti-CD20 humanized monoclonal antibody utilized in the treatment of several clinical conditions resistant to other treatments. In spite there was a general expectation that ofatumumab was less toxic compared to rituximab, side effects have been reported that resemble those of its anti-CD20 chimeric precursor. Here, we describe the first case of Ofatumumab associate lung injury occurring in a 14-year-old boy affected by nephrotic syndrome dependent to prednisone plus cyclosporine A who had been treated with the dose of drug utilized in nephrotic syndrome (1500 mg/173 m2). The patient developed the full blown picture of rituximab associated lung injury (RALI) after 45 days from ofatumumab infusion at the end of the steroid tapering: severe exertional dyspnea, mild fever and cyanosis, with CT scan showing diffuse ground glass areas in both lungs and DLCO (diffusing capacity of transfer factor of the lung for carbon monoxide) test suggestive for reduction of CO diffusion. Clinical outcome was good with rapid improvement and normalization of all parameters without any specific therapy. After 60 days, chest CT and CO diffusion tests were normal. In conclusion, we describe here the first case of acute pneumonitis associated with ofatumumab that presents the same clinical, laboratory, and radiology features of the lung injury reported for rituximab. Like RALI occurring in patients treated for nephrotic syndrome, this case had a mild clinical expression and recovered in a few months.

3.
Nephrol Dial Transplant ; 32(suppl_1): i7-i13, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28391333

RESUMO

Minimal change disease (MCD) is a pathological condition characterized by subtle glomerular lesions causing massive and reversible proteinuria that is usually steroid sensitive. Recurrence of symptoms of active disease following successful treatment (including proteinuria, oedema and oliguria) and steroid toxicity requires the use of other drugs to attain or maintain remission. Unresolved MCD is considered the initial step in the pathological pathway leading to focal and segmental glomerulosclerosis (FSGS). Historically, cyclophosphamide, chlorambucil, mycophenolate and calcineurin inhibitors have been utilized with success in MCD; however, the chronic nature of the disease and the toxicity of long-term use of these medications has pushed the development of new therapies. Synthetic corticotropin (adrenocorticotropic hormone) and anti-CD20 monoclonal antibodies, for example, are currently under investigation in clinical trials. In addition, these new interventions have dramatically impacted our understanding of the mechanisms of the disease. Phase II-IV clinical trials targeting new mechanisms and/or molecules are in progress. The list is long and includes drugs blocking the adaptive immune system (abatacept and anti-CD40 antibodies), as well as retinoids and the sialic acid precursor N-acetyl-D-mannosamine (ManNAc), two agents that affect the sieving properties of the glomerular basement membrane. Other drugs are being tested against FSGS and, if successful, could also be utilized against MCD. Clinical trials currently in progress should furnish a proper solution to what appears to be a solvable problem.


Assuntos
Ensaios Clínicos como Assunto/normas , Nefropatias/tratamento farmacológico , Proteinúria/tratamento farmacológico , Esteroides/uso terapêutico , Humanos , Nefropatias/complicações , Proteinúria/etiologia
6.
Clin Endocrinol (Oxf) ; 78(1): 79-85, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22724541

RESUMO

OBJECTIVE: It is still not known whether fat mass excess could exert a positive effect on bone. The aim of our study was to evaluate bone strength and quality in a group of overweight and obese children and adolescents by assessing bone geometry at metacarpal bones and ultrasound at phalangeal level. DESIGN AND PATIENTS: This is a cross sectional observational study performed in 123 subjects, aged 11.2 ± 2.9 years. MEASUREMENTS: Digitalized X-rays were evaluated at the level of the 2nd metacarpal bone for the determination of the outer (D) and inner (d) diameter, cortical area (CA), medullary endocortical area (EA), metacarpal index (MI) and bone strength (Bending Breaking Resistance Index; BBRI). A total of 98 subjects underwent amplitude dependent speed of sound (Ad-SOS) and bone transmission time (BTT) assessment by phalangeal ultrasonography. RESULTS: SDs for each measured parameter were as follows: Males: D = -0.71 ± 0.95, d = -0·29 ± 0.86, CA = -0.69 ± 0.69, EA = -0.32 ± 0.79, Ad-SOS = -1.14 ± 0.91, BTT = -1.17 ± 1.11 and BBRI (417 ± 151 vs 495 ± 174 mm(3) ) were all significantly lower than in controls (P < 0.05). Females: D = -1.03 ± 1.06, d = -0.38 ± 0.92, CA = -0.91 ± 0.72, EA = -0.46 ± 0.79, Ad-SOS = -1.08 ± 1.11, BTT = -0.97 ± 1.07 and BBRI (342 ± 117 vs 649 ± 318 mm(3) ) were all significantly lower than in controls (P < 0.05). CONCLUSIONS: Obese children show an unfavourable bone geometry and a bone of low quality and reduced strength compared to controls at a nonweight bearing skeletal site. This finding seems to support a detrimental effect of fat mass on bone and explain the frequent occurrence of wrist fractures in this group of children.


Assuntos
Densidade Óssea/fisiologia , Ossos Metacarpais/patologia , Obesidade/metabolismo , Obesidade/patologia , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino
7.
Horm Res Paediatr ; 77(2): 69-84, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22433947

RESUMO

Central diabetes insipidus (CDI) is the end result of a number of conditions that affect the hypothalamic-neurohypophyseal system. The known causes include germinoma/craniopharyngioma, Langerhans cell histiocytosis (LCH), local inflammatory, autoimmune or vascular diseases, trauma resulting from surgery or an accident, sarcoidosis, metastases and midline cerebral and cranial malformations. In rare cases, the underlying cause can be genetic defects in vasopressin synthesis that are inherited as autosomal dominant, autosomal recessive or X-linked recessive traits. The diagnosis of the underlying condition is challenging and raises several concerns for patients and parents as it requires long-term follow-up. Proper etiological diagnosis can be achieved via a series of steps that start with clinical observations and then progress to more sophisticated tools. Specifically, MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered a clear marker of neurohypophyseal functional integrity, together with the careful analysis of pituitary stalk shape and size, have provided the most striking findings contributing to the diagnosis and understanding of some forms of 'idiopathic' CDI. MRI STIR (short-inversion-time inversion recovery sequencing) is a promising technology for the early identification of LCH-dependent CDI.


Assuntos
Diabetes Insípido/diagnóstico , Diabetes Insípido/terapia , Adulto , Fatores Etários , Animais , Antidiuréticos/administração & dosagem , Antidiuréticos/efeitos adversos , Antidiuréticos/uso terapêutico , Criança , Desamino Arginina Vasopressina/administração & dosagem , Desamino Arginina Vasopressina/efeitos adversos , Desamino Arginina Vasopressina/uso terapêutico , Diabetes Insípido/etiologia , Diabetes Insípido/genética , Diabetes Insípido Nefrogênico/diagnóstico , Diabetes Insípido Nefrogênico/etiologia , Diabetes Insípido Nefrogênico/genética , Diabetes Insípido Nefrogênico/terapia , Diabetes Insípido Neurogênico/diagnóstico , Diabetes Insípido Neurogênico/etiologia , Diabetes Insípido Neurogênico/genética , Diabetes Insípido Neurogênico/terapia , Monitoramento de Medicamentos , Hidratação , Humanos , Lactente
8.
Clin Endocrinol (Oxf) ; 76(2): 161-76, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21955099

RESUMO

Magnetic resonance imaging (MRI) is the radiological examination method of choice for evaluating hypothalamo-pituitary-related endocrine disease and is considered essential in the assessment of patients with suspected hypothalamo-pituitary pathology. Physicians involved in the care of such patients have, in MRI, a valuable tool that can aid them in determining the pathogenesis of their patients' underlying pituitary conditions. Indeed, the use of MRI has led to an enormous increase in our knowledge of pituitary morphology, improving, in particular, the differential diagnosis of hypopituitarism. Specifically, MRI allows detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. MRI recognition of pituitary hyperintensity in the posterior part of the sella, now considered a marker of neurohypophyseal functional integrity, has been the most striking finding in the diagnosis and understanding of certain forms of 'idiopathic' and permanent growth hormone deficiency (GHD). Published data show a number of correlations between pituitary abnormalities as observed on MRI and a patient's endocrine profile. Indeed, several trends have emerged and have been confirmed: (i) a normal MRI or anterior pituitary hypoplasia generally indicates isolated growth hormone deficiency that is mostly transient and resolves upon adult height achievement; (ii) patients with multiple pituitary hormone deficiencies (MPHD) seldom show a normal pituitary gland; and (iii) the classic triad of ectopic posterior pituitary, pituitary stalk hypoplasia/agenesis and anterior pituitary hypoplasia is more frequently reported in MPHD patients and is generally associated with permanent GHD. Pituitary abnormalities have also been reported in patients with hypopituitarism carrying mutations in several genes encoding transcription factors. Establishing endocrine and MRI phenotypes is extremely useful for the selection and management of patients with hypopituitarism, both in terms of possible genetic counselling and in the early diagnosis of evolving anterior pituitary hormone deficiencies. Going forward, neuroimaging techniques are expected to progressively expand and improve our knowledge and understanding of pituitary diseases.


Assuntos
Hormônio do Crescimento/deficiência , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Doenças da Hipófise/diagnóstico , Animais , Diferenciação Celular , Humanos , Tamanho do Órgão , Hipófise/anatomia & histologia , Hipófise/embriologia , Diagnóstico Pré-Natal
9.
Eur J Endocrinol ; 165(3): 411-20, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21750044

RESUMO

OBJECTIVE: Controversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction. DESIGN: The study was conducted in a single Pediatric Endocrinology Research Unit. METHODS: Forty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed. RESULTS: Mean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, P<0.0001). Group 5 showed higher mean Posm and lower mean AVP at all time points (P<0.0001). Mean thirst score did not show a significantly different trend between the groups 1 and 2. Urine osmolality was above 750 mosm/kg in all but seven patients after osmotic challenge. CONCLUSIONS: Patients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.


Assuntos
Coristoma , Hipotálamo/fisiopatologia , Neuro-Hipófise , Displasia Septo-Óptica/fisiopatologia , Adolescente , Arginina Vasopressina/sangue , Arginina Vasopressina/deficiência , Feminino , Humanos , Hipopituitarismo/congênito , Hipopituitarismo/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Concentração Osmolar , Neuro-Hipófise/patologia , Neuro-Hipófise/fisiopatologia , Estudos Prospectivos , Solução Salina Hipertônica , Sede , Desequilíbrio Hidroeletrolítico/fisiopatologia
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