Maria Cristina Maggio

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.

The labyrinth of autoinflammatory disorders: a snapshot on the activity of a third-level center in Italy

Autoinflammatory disorders (AIDs) are a novel class of diseases elicited by mutations in genes regulating the homeostasis of innate immune complexes, named inflammasomes, which lead to uncontrolled oversecretion of the proinflammatory cytokine interleukin-1β. Protean inflammatory symptoms are variably associated with periodic fever, depicting multiple specific conditions. Childhood is usually the lifetime in which most hereditary AIDs start, though still a relevant number of patients may experience a delayed disease onset and receive a definite diagnosis during adulthood. As a major referral laboratory for patients with recurrent fevers, we have tested samples from 787 patients in the period September 2007–March 2014, with a total of 1,328 AID-related genes evaluated and a gene/patient ratio of 1.69. In this report, we describe our experience in the clinical approach to AIDs, highlight the most striking differences between child and adult-onset AIDs, and shed an eye-opening insight into their diagnostic process.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial

BACKGROUND Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. METHODS We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. FINDINGS Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. INTERPRETATION Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. FUNDING Italian Agency of Drug Evaluation.

Impaired GH Secretion in Patients with SHOX Deficiency and Efficacy of Recombinant Human GH Therapy

Background/Aims: Mutations of the short stature homeobox-containing (SHOX) gene on the pseudoautosomal region of the sex chromosomes cause short stature. GH treatment has been recently proposed to improve height in short patients with SHOX deficiency. The aim of this study was to evaluate GH secretion and analyze growth and safety of recombinant human GH (rhGH) therapy in short children and adolescents with SHOX deficiency. Patients and Design: We studied 16 patients (10 females; 9.7 ± 2.9 years old; height –2.46 ± 0.82 standard deviation score, SDS) with SHOX deficiency. All subjects underwent auxological evaluations, biochemical investigations, and were treated with rhGH (0.273 ± 0.053 mg/kg/week). Results: Impaired GH secretion was present in 37.5% of the studied subjects. Comparing baseline data with those at the last visit, we found that rhGH treatment improved growth velocity SDS (from –1.03 ± 1.44 to 2.77 ± 1.95; p = 0.001), height SDS (from –2.41 ± 0.71 to –1.81 ± 0.87; p < 0.001), and IGF-1 values (from –0.57 ± 1.23 to 0.63 ± 1.63 SDS, p = 0.010) without affecting body mass index SDS. Height SDS measured at the last visit was significantly correlated with chronological age (r = –0.618, p = 0.032), bone age (r = –0.582, p = 0.047) and height SDS (r = 0.938, p < 0.001) at the beginning of treatment. No adverse events were reported on rhGH therapy which was never discontinued. Conclusion: These data showed that impaired GH secretion is not uncommon in SHOX deficiency subjects, and that rhGH therapy may be effective in increasing height in most of these patients independent of their GH secretory status, without causing any adverse events of concern.

Evaluation of fitness levels of children with a diagnosis of acute leukemia and lymphoma after completion of chemotherapy and autologous hematopoietic stem cell transplantation

The aim of this study was to assess the fitness levels and possible deficits in physical performance in children with a diagnosis of childhood acute leukemia and lymphoma after 10 months of therapy ending through a specific test battery. A total of 58 subjects were enrolled in this study. The experimental group (EG) (7.55 ± 2.43 years; 41.8 ± 16.37 kg; 144.6 ± 10.21 cm) consisted of 18 children with diagnosed leukemia and lymphoma after completion of 10 months of therapy intervention and 40 healthy children who were enrolled in a control group (CG) (7.92 ± 1.78 years; 37.4 ± 12.37 kg; 140.6 ± 12.61 cm). A testing battery including the standing broad jump; the sit‐up test; the 4 × 10 m shuttle run test, and the hand grip strength test were administered to both groups. An unpaired t‐test was adopted to determine differences and the Pearson product moment was administered when appropriate. Results of the EG were generally lower when compared to the CG. Significant differences were identified for the standing broad jump (P < 0.05); 4 × 10 m shuttle run (P < 0.05); hand grip test DX (P < 0.05), and hand grip test SX (P < 0.05). No significant differences were found between the sit‐up tests. Pearson product moment correlation revealed a good interaction for all EG participants. Findings suggest that the proposed testing battery could be an appropriate tool to evaluate residual fitness levels in children with previous hematological malignancies. However, our results have to be confirmed with a larger number of participants with the same diagnosis of our EG.

Stevens-Johnson syndrome and cholestatic hepatitis induced by acute Epstein-Barr virus infection.

She arrived at our clinical division for the exanthema associated with the persistence of fever (4381C). She presented adequate auxological parameters (stature: 90 cm; weight: 13 kg; pubertal stage: PH1B1); pharynx hyperaemia, diffuse and confluent erythemato-pomphoid lesions with hitching; generalized angioedema more severe on the lips; and hepatomegaly. Haematological parameters revealed leukocytes: 10 620/mm; neutrophils/lymphocytes%: 59.8/33.6%; platelets: 342 000/mm; haemoglobin: 12 g/dl; alanine aminotransferase/aspartate aminotransferase: 67/276 IU/ml; g-glutamyl transferase: 201 IU/ml; erythrosedimentation rate (at first hour): 13; and Epstein–Barr virus (EBV) viral-capsid antigen IgM and IgG: positive.

Inhaled surfactant in the treatment of accidental talc powder inhalation: a new case report.

The use of talcum powder is incorrectly part of the traditional care of infants. Its acute aspiration is a very dangerous condition in childhood. Although the use of baby powder has been discouraged from many authors and the reports of its accidental inhalation have been ever more rare, sometimes new cases with several fatalities have been reported. We report on a patient in which accidental inhalation of baby powder induced severe respiratory difficulties. We also point out the benefits of surfactant administration. Surfactant contributed to the rapid improvement of the medical and radiological condition, preventing severe early and late complications and avoiding invasive approaches.

Gluten-Free Diet Impact on Leptin Levels in Asymptomatic Coeliac Adolescents: One Year of Follow-Up

Coeliac disease, daily more frequently diagnosed in our population, involves many organs also in oligosymptomatic patients and with an adequate nutritional regime. Possible endocrine implications include failure to thrive, pubertal delay and reproduction diseases due to deregulation of GH, FSH and LH secretion. Leptin, an adipose tissue hormone, can be decreased as well and its deficiency could be related to growth and puberty anomalies. We studied 14 asymptomatic coeliac patients in peripubertal age (7.5–13.8 years) and tested their leptin levels in order to correlate them with endocrine and anthropometric data. Before the diet was started leptinaemia (M±DS) was: 4.94 ± 5.53 ng/ml. In 10/14 patients (71%) leptinaemia was ≤2 DS for gender and age. In all the patients, after a period of 6–12 months of gluten-free diet, Leptin levels appreciably raised to 10.8 ± 7.9 ng/ml, with a significant correlation to the time of the diet. Leptinaemia was actually lower in patients with a severe mucosal atrophy, and in these patients it increased more significantly after the diet was started. The removal of gluten itself may reduce immunological hit to adipose tissue and the ‘malnutrition’ of adipocytes: leptin can hence increase despite no significant increase of body mass index occurs. This study could partially explain the correlation between body mass index, Coeliac disease and the deregulation of puberty and fertility, mainly in patients who started the diet late. It could also explain the reversibility of this alteration if the cause is removed.

Infliximab administration effective in the treatment of refractory Kawasaki Disease

Dear Sirs, Kawasaki Disease (KD) is a common vasculitis during the pediatric age. It involves little and medium caliber arteries. A risk of poor outcome is linked to the development of coronary artery aneurysms with sudden thrombo-embolic evolution (1). KD can present either in a classical (fulfilling all the American Reumatism Association (ARA) criteria) or an atypical or an incomplete form. Nowadays, the mainstay therapy for KD consists in high doses of IV administration of Immunoglobulins. Refractory cases, which do not respond to this kind of therapy, are demonstrated (2). Infliximab is a chimerical monoclonal antibody (IgG1) against Tumor Necrosis Factor (TNF) alpha. It belongs to biologic drugs, and it is properly used in the management of IBD, for adult patients in particular. We present a typical case of KD occurred in a 11 months old male child, who did not react both to IVIg administration and methyl prednisolone pulse therapy. A.A. was admitted after 4 days of continuous fever resistant to antibiotic therapy. Cutaneous rash, cheilitis, and conjunctivitis appeared after the fifth day of fever, and neck lymphadenopathy was also present. Phlogistic indexes were high: CrP (12 mg/dl), platelets (650,000/mm). Leucocitosis (WBC 22,000/mm) was present to total blood cell count. The first ultrasound cardiac evaluation showed no specific signs of coronaritis. Ultrasound abdominal evaluation revealed spread gall bladder and a target image of the bowel. A 2 gr/Kg intravenous Immunoglobulins administration was started, together with administration of salicylic acid at 80 mg/kg. The patient did not respond to therapy and fever persisted. A second dose of Ig was administered at the same amount. Ultrasound cardiac evaluation, performed after the first week of disease, showed two light coronary aneurisms. Patient s general conditions got worse. Hepatic serum transaminases also increased (three times normal values). So,methyl prednisolone iv pulse at 30 mg/ Kg was performed for three consecutive days. Fever persisted, CrP (18 mg/dl), platelets (1,400,000/mm), and white blood cells (45,000/ mm) raised. A second cardiac evaluation showed the patient was worsening. As a rescue therapy, Infliximab was started at 5 mg/Kg (3). The total infusion took 6 h and no adverse reaction occurred. The clinical response to Infliximab was excellent. Fever sharply decreased. Twenty-four h after the infusion, CrP (8 mg/dl), white blood cells (21,000), and hepatic serum transaminases (one time and half normal values) strongly decreased. Rash, cheilitis, and conjunctivitis disappeared. Ten days after the infusion, clinical remission persisted and finger desquamation was present to both hands and feet. CrP (0.4 mg/dl), white blood cells, and hepatic serum transaminases reached normal values. The patient was discharged after last cardiac ultrasound evaluation, which expressed a stopped disease, and he entered a strict surveillance follow-up program, ongoing the assumption of salicylic acid at 5 mg/ Kg as antiplatelets aggregation drug. Our report describes the use of Infliximab in the youngest patient affected by refractory KD as long as we know. KD is a reactive inflammatory condition, probably in genetic susceptible individuals (4), and TNF alpha and other pro-inflammatory cytokines may play an active role in its pathogenesis. In particular, patients with refractory KD, who are at significant risk for thromboembolic events because of their higher TNF alpha levels, may also benefit by Infliximab therapy, thanks to the new properties of the biologic drug recently reported by Danese et al. (5) and by Di Sabatino et al. (6). Indeed, Infliximab acts reducing the molecular expression of intestinal endothelial molecules vascular cell Pediatr Allergy Immunol 2010: 21: 1091–1092

Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome

TNFR‐associated periodic syndrome is an autoinflammatory disorder caused by autosomal‐dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR‐associated periodic syndrome biology is clear, particularly in the context of control of immune self‐tolerance. We investigated how TNF‐α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4+CD25− and regulatory CD4+CD25+ T cell functions in patients with TNFR‐associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR‐associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF‐κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR‐associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR‐associated periodic syndrome involving both CD4+ conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.