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Boston, MA, United States

Ciccia F.,University of Palermo | Rizzo A.,Cervello | Triolo G.,University of Palermo
Current Opinion in Rheumatology | Year: 2016

Purpose of review Subclinical gut inflammation has been described in a significant proportion of patients with ankylosing spondylitis (AS), up to 10% of them developing it during the time of clinically overt inflammatory bowel disease. Histologic, immunologic, and intestinal microbiota alterations characterize the AS gut. Recent findings Microbial dysbiosis as well as alterations of innate immune responses have been demonstrated in the gut of AS. Furthermore, a growing body of evidence suggests that the gut of AS patients may be actively involved in the pathogenesis of AS through the production of proinflammatory cytokines, such as IL-23p19, and the differentiation of potentially pathogenic innate lymphoid cells producing IL-22 and IL-17. Finally, a strong correlation between the presence of subclinical gut inflammation and the degree of spine inflammation have been also proved in AS. Summary Subclinical gut inflammation and innate immune responses in AS may be considered a possible consequence of microbial dysbiosis. Relationships between cause and effect remain, however, to be answered. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.


Fries W.,Messina University | Cottone M.,Cervello | Cascio A.,Messina University
Alimentary Pharmacology and Therapeutics | Year: 2013

Background Recently, there have been increasingly frequent reports on the occurrence of macrophage activation syndrome (MAS) in patients with inflammatory bowel disease (IBD). Clinically, MAS is characterized mainly by fever, hepatosplenomegaly, cytopenia, and elevated circulating ferritin and CD25. Mortality, even if diagnosed rapidly, is high. Aim To identify all reports on MAS in IBD and to establish data on triggering agents, immunosuppression leading to MAS, and mortality. Methods A language unrestricted search on Pubmed and Scopus relating to the past 30 years was carried out by matching the following search-terms: h(a)emophagocytic lymphohistiocytosis OR h(a)emophagocytic lymphohistiocytic syndrome OR macrophage activation syndrome OR opportunistic infections OR cytomegalovirus OR Epstein-Barr virus AND Crohn's disease OR ulcerative colitis OR inflammatory bowel disease(s). Results Fifty cases were identified with an overall mortality of 30%. Virus-related MAS associated with cytomegalovirus or Epstein-Barr virus infections represents the main type of MAS, but in isolated cases bacterial infections precipitated the syndrome. In four cases (8%), a lymphoma was present at the time of MAS diagnosis or developed shortly thereafter. Thiopurine monotherapy was given before MAS onset in 56% of the patients, whereas multiple immunosuppression, including biologics, was administered to 24%. Conclusions In IBD patients, the syndrome appears to be triggered by infections, but genetic susceptibility may contribute to its development. Since immunosuppressive therapy represents the backbone of therapeutic interventions in IBD, with the risk of new, or the reactivation of latent infections, even more frequent cases of macrophage activation syndrome may be expected. © 2013 Blackwell Publishing Ltd.


Lanzuolo C.,Dulbecco Telethon Institute | Lanzuolo C.,CNR Institute of Neurobiology and Molecular Medicine | Sardo F.L.,Dulbecco Telethon Institute | Diamantini A.,Cervello | Orlando V.,Dulbecco Telethon Institute
PLoS Genetics | Year: 2011

Polycomb group (PcG) proteins are part of a conserved cell memory system that conveys epigenetic inheritance of silenced transcriptional states through cell division. Despite the considerable amount of information about PcG mechanisms controlling gene silencing, how PcG proteins maintain repressive chromatin during epigenome duplication is still unclear. Here we identified a specific time window, the early S phase, in which PcG proteins are recruited at BX-C PRE target sites in concomitance with H3K27me3 repressive mark deposition. Notably, these events precede and are uncoupled from PRE replication timing, which occurs in late S phase when most epigenetic signatures are reduced. These findings shed light on one of the key mechanisms for PcG-mediated epigenetic inheritance during S phase, suggesting a conserved model in which the PcG-dependent H3K27me3 mark is inherited by dilution and not by de novo methylation occurring at the time of replication. © 2011 Lanzuolo et al.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.4.2-1 | Award Amount: 7.63M | Year: 2011

-thalassaemia major is one of the most severe forms of chronic congenital anaemia. The recommended treatment consists in regular blood transfusions combined with chelating therapy to remove harmful iron accumulation in the body. The use of deferoxamine, the first chelating agent only available for subcutaneous administration is limited due to toxicity and the lack of compliance, despite its satisfactory therapeutic effects. An oral iron chelating agent, deferiprone, was authorised in Europe in August 1999 and recommended for the treatment of iron overload in patients with thalassaemia major when deferoxamine is contraindicated or inadequate. Despite a wide experience of the administration of deferiprone for thalassaemic patients, limited data are available on its use in children below 10 years and the need for additional data in this age subset was clearly indicated in the 2009 priority list approved by the Paediatric Committee at the European Medicines Agency (PDCO). In addition, according to the recent scientific advancements and in consideration of the anticipated benefit of this chelator in controlling cardiac iron overload, studies evaluating the effects of the deferiprone in all the paediatric ages and in all transfusion-dependent chronic congenital anaemia (including Sickle Cell Diseases) were also considered a critical therapeutic need. The DEEP project, in line with these premises, has been funded with the specific aim to produce a new oral liquid formulation of deferiprone suitable for the paediatric use and to provide evidences for the use of this chelator as first line therapy in the whole paediatric population (from 1 month to 18 years) affected by transfusion-dependent chronic anaemia. The condition under study in the DEEP project is rare. This poses special difficulties in the conduct of the studies due to the small patient population and the need to involve a large number of recruiting centres . However, being dedicated to develop an orphan drug, DEEP has been also recognised in the context of IRDiRC, the International Rare Diseases Research Consortium devoted to repurpose/develop 200 new drugs for Rare Diseases by the end of 2020. Main features of the DEEP project are: -The innovative design of the clinical studies including pharmacokinetic modelling for the definition of the most appropriate dosage of deferiprone in younger children, the cardiac MRI T2* evaluation as primary endpoint, a three years safety study aimed at evaluating deferiprone, in monotherapy or in combination, in the real worlds setting and, for the first time, a comparative efficacy-safety trial to compare the two existing oral chelators: deferiprone and deferasirox. -The DEEP Consortium including European and non-European Countries from the Mediterranean region where the transfusion-dependent congenital anaemia, in particular -thalassemia major, is particularly widespread: the collaboration within a multinational and multicultural network makes the Project extremely challenging due to many different ethical, methodological and social approaches to be explored and positively addressed.


Fiorino G.,center | Girolomoni G.,University of Verona | Lapadula G.,University of Bari | Orlando A.,Cervello | And 2 more authors.
Autoimmunity Reviews | Year: 2014

Biological agents are widely used in rheumatology, dermatology and inflammatory bowel disease. Evidence about their efficacy and safety has been strengthened for all those therapeutic indications over the last decade. Biosimilar agents are monoclonal antibodies similar to previously approved biologics. In the European Union, they have been approved for all the indications in the management of immune-mediated inflammatory diseases (IMIDs), although data only in rheumatoid arthritis and ankylosing spondylitis are currently available. Direct evidence on efficacy, safety, and immunogenicity of biosimilars is mandatory in psoriasis, psoriatic arthritis, and inflammatory bowel disease, as well as in children. Based on the current evidence in the literature, we present the joint official position of the Italian Societies of Rheumatology, Dermatology and Inflammatory Bowel Disease on the use of biosimilars in IMIDs. © 2014 Elsevier B.V.

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