Samuele Naviglio

Prevention of flare recurrences in childhood-refractory chronic uveitis: an open-label comparative study of adalimumab versus infliximab.

To compare the efficacy and safety of adalimumab versus infliximab in an open‐label prospective, comparative, multicenter cohort study of childhood noninfectious chronic uveitis.

Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling

Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys-Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys-Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non-eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms that chronic ulcerative colitis may be associated with Loeys-Dietz syndrome. This finding suggests that an alteration of transforming growth factor beta signaling may by itself predispose to inflammatory colitis in humans, and represent an invaluable model to understand inflammatory bowel diseases.

Innate and adaptive immunity in self-reported nonceliac gluten sensitivity versus celiac disease

BACKGROUND Immune mechanisms have been implicated in nonceliac gluten sensitivity (NCGS), a condition characterized by intestinal and/or extraintestinal symptoms caused by the ingestion of gluten in non-celiac/non-wheat allergic individuals. AIMS We investigated innate and adaptive immunity in self-reported NCGS versus celiac disease (CD). METHODS In the supernatants of ex vivo-cultured duodenal biopsies from 14 self-reported NCGS patients, 9 untreated and 10 treated CD patients, and 12 controls we detected innate cytokines - interleukin (IL)-15, tumor necrosis factor-α, IL-1β, IL-6, IL-12p70, IL-23, IL-27, IL-32α, thymic stromal lymphopoietin (TSLP), IFN-α-, adaptive cytokines - interferon (IFN)-γ, IL-17A, IL-4, IL-5, IL-10, IL-13-, chemokines - IL-8, CCL1, CCL2, CCL3, CCL4, CCL5, CXCL1, CXCL10-, granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). RESULTS Mucosal innate and adaptive cytokines, chemokines and growth factors did not differ between self-reported NCGS, treated CD and controls. On the contrary, IL-6, IL-15, IL-27, IFN-α, IFN-γ, IL-17A, IL-23, G-CSF, GM-CSF, IL-8, CCL1 and CCL4 were significantly higher in untreated CD than in self-reported NCGS, treated CD and controls, while TSLP was significantly lower in untreated CD than in self-reported NCGS, treated CD and controls. CONCLUSION In our hands, patients with self-reported NCGS showed no abnormalities of the mucosal immune response.

An adolescent with an altered state of mind

A 17 year old previously healthy adolescent presented to the emergency department with severe headache, vomiting, and an altered state of mind. His mother reported that he had returned home one hour before, looking confused and agitated; afterwards he mentioned a worsening headache and had vomited twice. On arrival at the emergency department he was conscious but drowsy and slow in answering simple questions. He reported frontal headache (8/10 on a visual analogue scale) and photophobia, and he was unable to stand unassisted. He was afebrile, his heart rate was 170 beats/min, and his blood pressure was 132/80 mm Hg. His pupils were mydriatic and poorly reactive to light. The remainder of the physical examination was unremarkable. He denied taking any drugs or medication, and a urine screen test was negative for cannabinoids, opioids, amphetamines, benzodiazepines, ethanol, and cocaine. Computed tomography of the brain and a basic set of blood tests were performed, and all results were normal. On further questioning by his parents he admitted having smoked “herbal incense” with friends in the afternoon, after which he reported having experienced visual and auditory hallucinations. ### 1. Which diagnosis does this story suggest? #### Short answer Acute intoxication by an emerging drug of misuse, probably a synthetic cannabinoid. Clues to the diagnosis include acute onset, otherwise unexplained, central nervous system and autonomic disturbances in a healthy young person with negative drug screening tests and a history of smoking herbal incense. #### Long answer The evaluation of an adolescent or young adult presenting to the emergency department with a change of mental status can be challenging. The differential diagnosis is extensive, comprising psychiatric conditions and medical conditions, including cerebrovascular events, unreported trauma, intoxication, carbon monoxide poisoning, …

The science of breastfeeding: time for a change?

Breastfeeding has always been a matter of considerable interest in medicine, and a great number of studies have been carried out to evaluate its effects. Yet not all of them seem to be equally relevant. Solid scientific evidence has incontrovertibly demonstrated the superiority of breastfeeding for infant nutrition over every other possible surrogate, not only for biological and nutritional outcomes, but also from a psychological and relational point of view. The list of potentially beneficial components of human milk is extensive: it contains growth factors, immunoglobulins, cytokines, antimicrobial compounds as well as factors promoting intestinal colonization by favourable microbes (1). Nevertheless, the list of its alleged beneficial effects has also grown disproportionately, brought on by a panoply of scientific or not-so-scientific studies that have ridden the wave of breastfeeding science and eventually made breastfeeding a panacea, with presumed effects even very distant in time from infancy. Some of these claims are probably even beyond the possibility of a demonstration. And after many years of enthusiastic support, some of them are beginning to undergo a process of critical revision and sometimes have been even disproved. Take the example of obesity. Searching on Pubmed for ‘breastfeeding AND obesity’ returns more than 1000 results with a steep increase in their number in the last 10 years. The Agency for Healthcare Research and Quality ‘Report on maternal and infant health outcomes in developed countries’ by Ip et al. (2), after examining a great amount of published data, concluded that there was ‘an association between a history of breastfeeding and a reduction in the risk of being overweight or obese in adolescence and adult life’. The next sentence was possibly overlooked: ‘One should be cautious in interpreting all these associations because of the possibility of residual confounding’. Furthermore, even the World Health Organization (WHO) systematic review and meta-analysis report on the long-term effects of breastfeeding, while also concluding for a protective effect on obesity, had found clear evidence of publication bias in the published literature (3). More recent studies have questioned the possibility of a protective effect on obesity. A randomized, controlled trial involving more than 13 000 children who were followed for more than 11 years did not find substantial evidence of a protective effect of breastfeeding on obesity (4). Even if this issue may still be considered open, we may ask ourselves: do we really need a more certain answer? We do not think so. If we focus our attention on the advantages of breastfeeding in infancy, we can see that they are generally clear cut and quite easy to demonstrate. Breastfeeding has been shown to be able to reduce morbidity and mortality in infancy, mainly decreasing the incidence of infectious diseases (2,3). It has been calculated that exclusive breastfeeding for 6 months and weaning after 1 year in developing countries could prevent 13% of the world’s childhood mortality (5). In preterms, it stimulates gastrointestinal growth and maturity, reducing the riskof sepsis andnecrotizing enterocolitis (6). In consideration of all the available evidences, the superiority of breastfeeding in infant nutrition canbealready considered an establishedmatter of fact, evenwithout looking for its remote effects on adult health. This is not even surprising if we think that human milk composition has been finely tuned for human nutrition by thousands years of evolutionary pressures. In this sense, its superiority may be considered to be a Articles in the series A Different View are edited by William Meadow (wlm1@uchicago.edu). We encourage you to offer your own different view either in response to A Different View you do not fully agree with, or on an unrelated topic. Send your article to Dr. Meadow (wlm1@uchicago.edu).

Role of the Long Non-Coding RNA Growth Arrest-Specific 5 in Glucocorticoid Response in Children with Inflammatory Bowel Disease

Glucocorticoids (GCs) are widely employed in inflammatory, autoimmune and neoplastic diseases, and, despite the introduction of novel therapies, remain the first‐line treatment for inducing remission in inflammatory bowel disease (IBD). Given the high incidence of suboptimal response, associated with a significant number of side‐effects, that are particularly severe in paediatric patients, the identification of subjects that are most likely to respond poorly to GCs is extremely important. Recent evidence suggests that the long non‐coding RNA (lncRNA) GAS5 could be a potential marker of GC resistance. To address this issue, we evaluated the association between the lncRNA GAS5 and the efficacy of steroids, in terms of inhibition of proliferation, in two cell lines derived from colon and ovarian cancers, to confirm the sensitivity and specificity of these lncRNAs. These cells showed a different sensitivity to GCs and revealed differential expression of GAS5 after treatment. GAS5 was up‐regulated in GC‐resistant cells and accumulated more in the cytoplasm compared to the nucleus in response to the drug. The functions of GAS5 were assessed by silencing, and we found that GAS5 knock‐down reduced the proliferation during GC treatment. Furthermore, for the first time, we measured GAS5 levels in 19 paediatric IBD patients at diagnosis and after the first cycle of GCs, and we demonstrated an up‐regulation of the lncRNA in patients with unfavourable steroid response. Our preliminary results indicate that GAS5 could be considered a novel pharmacogenomic marker useful for the personalization of GC therapy.

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

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-α) 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-α was correlated to NOD2 genotype. Also, production of TNF-α 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-α 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-α 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-α production did not show a clear correlation with either LBP or sCD14 levels in plasma. Moreover, no clear correlation was seen between TNF-α production and activity indices in either CD or UC. CONCLUSION Peripheral monocytes from CD express higher basal and stimulated TNF-α than controls, regardless of NOD2 genotype and without a clear correlation with disease activity.

Ocular Involvement in Children with Inflammatory Bowel Disease

Background: Data on ocular manifestations of inflammatory bowel disease (IBD) in children are limited. Some authors have reported a high prevalence of asymptomatic uveitis, yet the significance of these observations is unknown and there are no recommendations on which ophthalmologic follow-up should be offered. Methods: Children with IBD seen at a single referral center for pediatric gastroenterology were offered ophthalmologic evaluation as part of routine care for their disease. Ophthalmologic evaluation included review of ocular history as well as slit-lamp and fundoscopic examination. Medical records were also reviewed for previous ophthalmologic diagnoses or complaints. Results: Data from 94 children were included (52 boys; median age 13.4 yr). Forty-six patients had a diagnosis of Crohns disease, 46 ulcerative colitis, and 2 IBD unclassified. Intestinal disease was in clinical remission in 70% of the patients; fecal calprotectin was elevated in 64%. One patient with Crohns disease had a previous diagnosis of clinically manifest uveitis (overall uveitis prevalence: 1.06%; incidence rate: 0.3 per 100 patient-years). This patient was also the only one who was found to have asymptomatic uveitis at slit-lamp examination. A second patient had posterior subcapsular cataract associated with corticosteroid treatment. No signs of intraocular complications from previous unrecognized uveitis were observed in any patient. Conclusions: Children with IBD may have asymptomatic uveitis, yet its prevalence seems lower than previously reported, and it was not found in children without a previous diagnosis of clinically manifest uveitis. No ocular complications from prior unrecognized uveitis were observed.

Ex vivo response to mucosal bacteria and muramyl dipeptide in inflammatory bowel disease

AIM To evaluate how mucosal bacteria impact on the spontaneous and muramyl dipeptide (MDP)-induced inflammation in Crohn’s disease (CD) and ulcerative colitis (UC). METHODS Colonic mucosal biopsies were collected from children with active or remissive CD, UC and controls. Two tissue samples were taken from inflamed mucosal segments (in patients with active disease) or from non-inflamed mucosa [in patients in remission or in healthy controls (HC)]. Experiments were performed in the presence or absence of antibiotics, to assess whether the disease-associated microbiota can modulate the cytokine response ex vivo. For this purpose, each specimen was half-cut to compare spontaneous and MDP-induced inflammation in the presence of live bacteria (LB) or antibiotics. After 24 h of culture, an array of 17 cytokines was assessed in supernatants. Statistical analyses were performed to find significant differences in single cytokines or in patterns of cytokine response in the different groups. RESULTS We demonstrated that subjects with CD display a spontaneous production of inflammatory cytokines including granulocyte-colony stimulating factor (G-CSF), interleukin (IL) 6, IL8, IL10 and IL12, that was not significantly influenced by the addition of antibiotics. UC specimens also displayed a trend of increased spontaneous secretion of several cytokines, which however was not significant due to broader variability among patients. After the addition of antibiotics, spontaneous IL8 secretion was significantly higher in UC than in controls. In HC, a trend towards the weakening of spontaneous IL8 production was observed in the presence of live mucosal bacteria with respect to the presence of antibiotics. In contrast, in the presence of LB UC showed an increasing trend of spontaneous IL8 production, while MDP stimulation resulted in lower IL8 production in the presence of antibiotics. We also showed that subjects with CD seem to have a lowered production of IL8 in response to MDP in the presence of LB. Only with the addition of antibiotics, likely reducing the contribution of LB, multivariate statistical analysis could identify the combination of measures of G-CSF, tumor necrosis factor alpha, IL4 and IL17 as a good discriminator between CD and UC. CONCLUSION We showed that the presence of LB or antibiotics can significantly influence the inflammatory response ex vivo in inflammatory bowel diseases.

Isolated hypoplasia of abdominal wall muscles associated with fetal ascites

We report the case of an infant born after parvovirus B19‐induced fetal hydrops, who presented at birth with bilateral abdominal wall laxity, which was more evident on the flanks. Imaging exams revealed congenital hypoplasia of oblique abdominal muscles not associated with other anatomical abnormalities except for small liver calcifications. We review the medical literature and identify similar cases associated with fetal ascites. We propose that isolated hypoplasia of abdominal wall muscles can be associated with fetal ascites from various causes, and represents a separate condition from prune belly syndrome.