Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome in pediatric Inflammatory Bowel Disease: clinical characteristics and outcomes.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS) in children with inflammatory bowel disease (IBD) has been reported only anecdotally. This study aimed at describing the clinical features and outcomes of children diagnosed with both IBD and HLH/MAS. Data on IBD and HLH/MAS characteristics, biochemical, microbiological and genetic assessments, treatments, and outcomes were collected from the Italian Pediatric IBD Registry and presented using descriptive statistics. Out of 4643 patients with IBD, 18 (0.4%) were diagnosed with HLH/MAS, including 12 with ulcerative colitis and 6 with Crohn disease. Among the 18 patients, 7 (39%) had early-onset IBD, but the median age at HLH/MAS diagnosis was 14.0 years (IQR 11.9-16.0). Half of the patients had active IBD at HLH/MAS diagnosis, 11 (61%) patients were on thiopurines, and 6 (33%) were on anti-TNF biologics. An infectious trigger was identified in 15 (83%) patients. One (5%) patients was diagnosed with XIAP deficiency. All patients discontinued thiopurines and 5 (83.3%) discontinued anti-TNF biologics; 16 (80%) patients received steroids for HLH/MAS. Three (17%) patients had a relapse of HLH/MAS. No patient developed lymphoma or died during a median follow-up of 2.7 years (IQR 0.8-4.4). Conclusions: HLH/MAS mainly affects children with early-onset IBD but primarily develops during adolescence, following an infection while on immunosuppressant treatment. Although the prognosis is generally favorable, it is crucial to investigate an underlying immune deficiency.

Dual biological therapy and small molecules in pediatric inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) including Crohn's disease (CD), ulcerative colitis (UC) and inflammatory bowel disease unclassified (IBD-U) are chronic inflammatory disorders which can affect the gastrointestinal tract. Anti-tumor necrosis factors antibodies (anti-TNFα) such as infliximab (IFX) and adalimumab (ADA) are the first line biological therapy for severe or complicated IBDs in pediatric age. Second line therapeutic options as vedolizumab (VDZ) and ustekinumab (UST) are currently used off-label in pediatric age. Furthermore, despite optimization of biologics, a great proportion of patients may fail to respond to biologic agents (up to 30%) or lose response over the time (around 50%) hence these patients may be left without another valid therapeutic option. Consequently, several efforts have been made in the last years in order to develop new drugs and to contrive new therapeutic strategies. Small molecule drugs (SMDs) and combination therapy with either two biologic agents or with a SMD and a biological agent have recently been proposed. Data on safety and efficacy of these new therapeutic options are limited. The objective of the present review is to summarize the most up-to-date available literature in pediatric IBD.

Barrier Impairment and Type 2 Inflammation in Allergic Diseases: The Pediatric Perspective.

Allergic diseases represent a global burden. Although the patho-physiological mechanisms are still poorly understood, epithelial barrier dysfunction and Th2 inflammatory response play a pivotal role. Barrier dysfunction, characterized by a loss of differentiation, reduced junctional integrity, and altered innate defence, underpins the pathogenesis of allergic diseases. Epithelial barrier impairment may be a potential therapeutic target for new treatment strategies Up now, monoclonal antibodies and new molecules targeting specific pathways of the immune response have been developed, and others are under investigation, both for adult and paediatric populations, which are affected by atopic dermatitis (AD), asthma, allergic rhinitis (AR), chronic rhinosinusitis with nasal polyps (CRSwNP), or eosinophilic esophagitis (EoE). In children affected by severe asthma biologics targeting IgE, IL-5 and against IL-4 and IL-13 receptors are already available, and they have also been applied in CRSwNP. In severe AD Dupilumab, a biologic which inhibits both IL-4 and IL-13, the most important cytokines involved in inflammation response, has been approved for treatment of patients over 12 years. While a biological approach has already shown great efficacy on the treatment of severe atopic conditions, early intervention to restore epithelial barrier integrity, and function may prevent the inflammatory response and the development of the atopic march.