Manuela Pardeo

Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: Report of forty-six patients from an international multicenter series

OBJECTIVE To examine the safety and efficacy of the interleukin-1 (IL-1) receptor antagonist anakinra as first-line therapy for systemic juvenile idiopathic arthritis (JIA). METHODS Patients with systemic JIA receiving anakinra as part of initial disease-modifying antirheumatic drug (DMARD) therapy were identified from 11 centers in 4 countries. Medical records were abstracted using a standardized instrument, and resulting data were analyzed to characterize concomitant therapies, clinical course, adverse events, and predictors of outcome. RESULTS Among 46 patients meeting inclusion criteria, anakinra monotherapy was used in 10 patients (22%), while 67% received corticosteroids and 33% received additional DMARDs. Outcomes were evaluated at a median followup interval of 14.5 months. Fever and rash resolved within 1 month in >95% of patients, while C-reactive protein and ferritin normalized within this interval in >80% of patients. Active arthritis persisted at 1 month in 39% of patients, at 3 months in 27%, and at >6 months of followup in 11%. Approximately 60% of patients, including 8 of 10 receiving anakinra monotherapy, attained a complete response without escalation of therapy. Disease characteristics and treatment were similar in partial and complete responders, except that partial responders were markedly younger at onset (median age 5.2 years versus 10.2 years; P = 0.004). Associated adverse events included documented bacterial infection in 2 patients and hepatitis in 1 patient. Tachyphylaxis was not observed. CONCLUSION Anakinra as first-line therapy for systemic JIA was associated with rapid resolution of systemic symptoms and prevention of refractory arthritis in almost 90% of patients during the interval examined. These results justify further study of IL-1 inhibition as first-line, rather than rescue, therapy in systemic JIA.

Is serum Troponin T a useful marker of myocardial damage in newborn infants with perinatal asphyxia

Aim: To assess the correlation of echocardiographic signs of myocardial damage to serum cardiac troponin T (cTnT) concentrations in newborn infants with perinatal asphyxia.

Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis: results from a phase III trial.

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.

Safety and Efficacy of Etanercept in a Cohort of Patients with Juvenile Idiopathic Arthritis Under 4 Years of Age

Objective. To evaluate safety, tolerability, and efficacy of etanercept in a cohort of patients with juvenile idiopathic arthritis (JIA) under 4 years of age. Methods. Data were collected at every visit during treatment with etanercept in 25 children who began treatment at a mean age of 3 years (range 18–48 months). Safety endpoints included the incidence of any adverse events. Efficacy endpoints included the American College of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria for improvement. Results. Data from 25 patients with JIA treated with etanercept for a mean period of 23 months were analyzed. All patients received concomitant medications: 24 methotrexate, 3 cyclosporin A, and 10 corticosteroids. After the first 6 months of treatment, 15 (71.4%) patients achieved an ACR Pedi30 response and at the last observation 20 (80%) achieved ACR Pedi30. ACR Pedi50 and 70 responses were, respectively, 62% and 43% at 6 months and 72% and 64% at the last followup. Five patients (20%) discontinued etanercept for lack of efficacy. Two (8%) developed adverse events, both primary varicella zoster virus (VZV) infections (both not vaccinated). One was hospitalized because of a necrotizing fasciitis secondary to VZV infection. No cases of tuberculosis, opportunistic infections, or malignancies were reported. Conclusion. In our cohort of patients etanercept proved to be safe and efficacious in the majority of children. The response in toddlers was similar to that in older children. We observed only 1 case of severe infection that required hospitalization and stopped treatment temporarily.

Infliximab therapy in pediatric Takayasu’s arteritis: report of two cases

Takayasu arteritis (TA) is a chronic vasculitis of unknown etiology. Experience with anti-tumor necrosis factor alpha (anti-TNF) agents in difficult-to-treat patients with TA is limited and refers to adult patients. Here, we present two cases of pediatric TA treated with infliximab, in which clinical remission was observed. Anti-TNF treatment represents a useful therapy in pediatric Takayasu arteritis too, especially to avoid the risk of long-term corticosteroids toxicity.

A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0–2.0 mg/kg/day) among adults and 2–4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

Objectives To analyse the prevalence of CECR1 mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study. Methods Direct sequencing of CECR1 was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor. Results Biallelic homozygous or compound heterozygous CECR1 mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24 months (6 months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without CECR1 mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect. Conclusions DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes.

What do parents know about the malformations afflicting the hearts of their children

Traditionally, medical professionals have entrusted the parents of children with chronic illness with the task of imparting knowledge about the illness to the children. This practice assumes that parents understand the illness, and that they pass on their knowledge in a manner appropriate for the individual child. The aim of our study was to assess the knowledge that parents of children with a cardiac defect have about the malformation in the heart of their child. We sent a modified version of the Leuven questionnaire to 350 families. The questionnaire was filled in and sent back to our centre by 148 families. Parents showed a good knowledge of the name and anatomical characteristics of the cardiac disease suffered by their child. Parents with a child taking drugs were not very knowledgeable about the regime, side effects, and interaction with other drugs or food. Only one-quarter of the parents knew the definition of endocarditis, although almost two-fifths were aware that unexplained fever for more than 5 days was the most typical symptom. Less than half of the parents knew that endocarditis could recur. About two-fifths of parents knew the real possibility of their child being involved in competitive sports; but almost half of parents were unable to answer this question. The poor knowledge about particular aspects of the disease, treatment, and preventive measures revealed by our parents may have major consequences. The results of our study are relevant to general daily clinical practice.

Neurogenic stunned myocardium presenting as left ventricular hypertrabeculation in childhood: a variant of Takotsubo cardiomyopathy?

Objective: To report the first case of neurogenic stunned myocardium presenting with heart left ventricle noncompaction requiring intensive care in the perioperative period of tension tumor-induced hydrocephalus. Methods and Design: Case report and literature review. Our Institutional Review Board waived the need for consent. Patient: A 12-yr-old female with intracranial astrocytoma and hypertensive hydrocephalus presented with severe heart dysfunction and life-threatening ventricular ectopies intraoperatively. A severe heart failure developed requiring hemodynamic and ventilatory support for 10 days. Echocardiography showed a transient noncompaction aspect of the left ventricular wall, further confirmed by a cardiac magnetic resonance image. The noncompaction aspect lasted until 15 days postadmission, as was the case for the QT interval prolongation; no life-threatening ectopies were demonstrated on the subsequent Holter electrocardiogram monitoring. Conclusions: This report describes a unique presentation of myocardial stunning in association with an intracranial illness, namely, a hypertensive hydrocephalus complicating an intracranial neoplasm.

Neonatal emergencies associated with cardiac rhabdomyomas: an 8-year experience.

During the foetal-neonatal period, rhabdomyomas represent the majority of cardiac tumours and are closely associated with tuberous sclerosis. Cardiac rhabdomyomas may be completely asymptomatic and are incidentally discovered during an echocardiogram, or may cause cardiac dysfunctions requiring medical and/or surgical intervention. During foetal life and the early neonatal period, life-threatening conditions, mostly due to arrhythmias, cardiac failure or obstruction, do occur on rare occasions. We reviewed the medical records of all cases of cardiac rhabdomyomas diagnosed prenatally or postnatally over an 8-year period. The present study reviews 7 cases of life-threatening conditions. Arrhythmic episodes were described in 5 patients, and blood flow obstruction was reported in 2 cases. Antiarrhythmic agents successfully controlled the clinical and electrophysiological conditions. Obstructive conditions were associated with poor outcomes. In conclusion, when prenatal diagnosis of rhabdomyoma is made, appropriate planning at delivery for the management of potential haemodynamic complications may prevent adverse neonatal outcomes. The clinical outcome is more influenced by obstructive rather than by dysrhythmic complications. Appropriate antiarrhythmic treatment is of primary importance. In all cases discovered through prenatal and/or neonatal life-threatening conditions, an accurate follow-up should always be performed to anticipate the development of tuberous sclerosis.