PEDIATRIC-ONSET INFLAMMATORY BOWEL DISEASE: FROM PATHOPHYSIOLOGY TO NEW STRATEGIES FOR THERAPY CHOICE AND MONITORING

Introduzione: La terapia con anticorpi monoclonali anti-tumor necrosis factor (TNF) ha portato a una rivoluzione nella terapia delle malattie infiammatorie croniche intestinali (MICI), tuttavia una percentuale non trascurabile di pazienti non risponde alla terapia. Vi sono evidenze in costante aumento che suggeriscono che il fallimento terapeutico pu\uf2 essere dovuto a livelli ematici inadeguati di farmaco e/o alla comparsa di anticorpi anti-farmaco. appearance of anti-infliximab antibodies (AIA). I dati riguardanti il monitoraggio terapeutico dell'infliximab (IFX) nei bambini sono tuttavia ancora incompleti. Metodi: Abbiamo studiato 49 pazienti pediatrici (et\ue0 media 14.4) affetti da MICI (Malattia di Crohn 34, rettocolite ulcerosa 15) trattati con IFX. Sono stati raccolti campioni di siero a 6, 14, 22 e 54 settimane di terapia, prima delle infusioni di IFX. I livelli di IFX e di AIA sono stati misurati mediante test ELISA e posti in relazione con l'attivit\ue0 clinica di malattia misurata mediante score clinici (PCDAI/PUCAI) Risultati: Il 76.3% e il 73.9% dei pazienti ha ottenuto la remissione clinica, definita come uno score clinico 3.11 (p-value = 3.0x10-5, sensitivity 89%, specificity 80%). I valori ematici di AIA sono risultati inversamente correlati con i livelli di IFX (p = 0.00088) e con il rischio di reazioni avverse (p = 0.018). Conclusioni: La misurazione dei livelli ematici di infliximab pre-infusione alla fine dell'induzione \ue8 associata con la probabilit\ue0 di remissione duratura nei pazienti pediatrici affetti da MICI.Background: Anti-tumor necrosis factor monoclonal antibodies have lead to a revolution in the treatment of inflammatory bowel diseases (IBD), yet a sizable proportion of patients do not respond to therapy. There is increasing evidence suggesting that treatment failure may be associated with inadequate blood drug levels and/or the appearance of anti-infliximab antibodies (AIA). Data regarding therapeutic drug monitoring of infliximab (IFX) in children however are still incomplete. Methods: We studied 49 pediatric (median age 14.4) IBD patients (Crohn\u2019s disease 34, ulcerative colitis 15) treated with IFX. Serum samples were collected at 6, 14, 22 and 54 weeks, before IFX infusions. IFX and AIA were measured using ELISA assays. Disease activity was determined by PUCAI or PCDAI. Results: Clinical remission, defined as a clinical score 3.11 (p-value = 3.0x10-5, sensitivity 89%, specificity 80%). AIA concentrations were inversely correlated with IFX concentrations (p-value = 0.00088) and with adverse reactions (p-value = 0.018). Conclusions: Measurement of IFX trough levels at the end of induction therapy (week 14) is associated with sustained long-term response in pediatric patients with IBD

An adolescent with an altered state of mind

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Subcutaneous panniculitis-like T-cell lymphoma presenting with diffuse cutaneous edema in a 2-year-old child

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Altered pattern of tumor necrosis factor-Alpha production in peripheral blood monocytes from Crohn's disease basic study

AIM: To evaluate the inflammatory state in Crohn's disease (CD) patients and correlate it with genetic background and microbial spreading. METHODS: By means of flow cytometry, production of tumor necrosis factor-alpha (TNF-\u3b1) was measured in peripheral blood monocytes from patients suffering from CD, ulcerative colitis (UC) and in healthy subjects after stimulation of the NOD2 and TLR pathways. CD patients were genotyped for the three most common NOD2 variants (R702W, G908R and L1007Pfs*2) and basal production of TNF-\u3b1 was correlated to NOD2 genotype. Also, production of TNF-\u3b1 was correlated to plasmatic levels of LPS Binding Protein (LBP), soluble (s) CD14 and to the activity state of the disease. RESULTS: The patients with CD were characterized by a significantly higher monocyte basal expression of TNF-\u3b1 compared with healthy subjects and UC patients, and after stimulation with Pam3CSK4 (ligand of TLR2/1) and MDP-L18 (ligand of NOD2) this difference was maintained, while other microbial stimuli (LPS, ligand of TLR4 and PolyI:C, ligand of TLR3) induced massive activation in CD monocytes as well as in UC and in healthy control cells. There was no significant difference in the production of TNF-\u3b1 between patients who carried CD-associated heterozygous or homozygous variants in NOD2 and patients with wild type NOD2 genotype. Although serum LBP levels have been shown to correlate positively with the state of activity of the disease, TNF-\u3b1 production did not show a clear correlation with either LBP or sCD14 levels in plasma. Moreover, no clear correlation was seen between TNF-\u3b1 production and activity indices in either CD or UC. CONCLUSION: Peripheral monocytes from CD express higher basal and stimulated TNF-\u3b1 than controls, regardless of NOD2 genotype and without a clear correlation with disease activity

Candidate Biomarkers for the Detection of Serious Infections in Children: A Prospective Clinical Study

Serious bacterial infections (SBI) in children are associated with considerable morbidity and mortality, and their early identification remains challenging. The role of laboratory tests in this setting is still debated, and new biomarkers are needed. This prospective, observational, single-center study aims to evaluate the diagnostic role of blood biomarkers in detecting SBI in children presenting with signs of systemic inflammatory response syndrome (SIRS). A panel of biomarkers was performed, including C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), absolute neutrophil count (ANC), interleukin (IL)-6, IL-8, IL-10, human terminal complement complex (C5b-9), Plasmalemma-Vesicle-associated protein 1 (PV-1), Intercellular Adhesion Molecule-1 (ICAM-1), and Phospholipase A2 (PLA2). Among 103 patients (median age 2.9 years, 60% males), 39 had a diagnosis of SBI (38%). Significant predictors of SBI were CRP (p = 0.001) and ICAM-1 (p = 0.043). WBC (p = 0.035), ANC (p = 0.012) and ANC/WBC ratio (p = 0.015) were also significantly associated with SBI in children without pre-existing neutropenia. ROC curves, however, revealed suboptimal performance for all variables. Nevertheless, a model that combined CRP and ANC/WBC ratio had more in-depth diagnostic accuracy than either of the two variables. Overall, this study confirms the limited usefulness of blood biomarkers for the early diagnosis of SBI. WBC, ANC, ANC/WBC ratio, CRP, and ICAM-1 showed the best, albeit moderate, diagnostic accuracy

Multicentric Case-Control Study on Azathioprine Dose and Pharmacokinetics in Early-onset Pediatric Inflammatory Bowel Disease

BACKGROUND: Early-onset inflammatory bowel disease (IBD) is generally aggressive, with a high probability of complications and need of surgery. Despite the introduction of highly effective biological drugs, treatment with azathioprine continues to be important even for early-onset IBD; however, in these patients azathioprine response seems to be reduced. This study evaluated azathioprine doses, metabolite concentrations, and their associations with patients' age in children with IBD treated at 6 tertiary pediatric referral centers. METHODS: Azathioprine doses, metabolites, and clinical effects were assessed after at least 3 months of therapy in 17 early-onset (age 12 and <18 yrs, controls) patients with IBD. Azathioprine dose was titrated on therapeutic efficacy (response and adverse effects). Azathioprine metabolites and thiopurine methyltransferase activity were determined by high-performance liquid chromatography with ultra violet-vis detection (HPLC-UV) methods. RESULTS: Frequency of patients in remission was similar among early-onset and control groups, respectively (82% and 84%, P value = 0.72). Early-onset patients required higher doses of azathioprine (median 2.7 versus 2.0 mg\ub7kg\ub7d, P value = 1.1 7 10). Different doses resulted in comparable azathioprine active thioguanine nucleotide metabolite concentrations (median 263 versus 366 pmol/8 7 10 erythrocytes, P value = 0.41) and methylmercaptopurine nucleotide concentrations (median 1455 versus 1532 pmol/8 7 10 erythrocytes, P value = 0.60). Lower ratios between thioguanine nucleotide metabolites and azathioprine doses were found in early-onset patients (median 98 versus 184 pmol/8 7 10 erythrocytes\ub7mg\ub7kg\ub7d, P value = 0.017). Interestingly, early-onset patients presented also higher thiopurine methyltransferase activity (median 476 versus 350 nmol methylmercaptopurine/mg hemoglobin/h, P-value = 0.046). CONCLUSIONS: This study demonstrated that patients with early-onset IBD present increased inactivating azathioprine metabolism, likely because of elevated activity of the enzyme thiopurine methyltransferase

Allattamento al seno: Scienza e conformismo

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Renin-Angiotensin System Blockade for Diabetic Nephropathy Prevention

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Bilateral Finger Swelling in an Adolescent

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A pneumonia that does not improve

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