Inflammatory bowel disease:An archetype disorder of outer environment sensor systems

The pathogenesis of the two inflammatory bowel disease(IBD) phenotypes ulcerative colitis(UC) and Crohn' s disease(CD) has remained elusive,thus frustrating attempts at defining a cure.IBD often presents as a complex inflammatory process wherein colon lesions(UC) or widespread ulceration and fissure(CD) might be accompanied by ancillary extra-intestinal manifestations involving the eye,skin,joints or liver,but also by full-blown "autoimmune" disorders from psoriasis and multiple sclerosis to rheumatoid arthritis;attempts at unraveling a link or a hierarchical order in these entities have proven almost fruitless.More recently,the input of genetics has suggested that the IBDs might be multiorgan inflammatory processes,elicited by a large number of low-penetrance susceptibility genes,with environmental factors needed to induce full-blown disease.At a noteworthy exception to this rule,the description of the nucleotide-oligomerization domain(NOD) gene mutations in CD came at the beginning of the 2000s:the NOD-LRR are part of a highly conserved microbial sensor system which respond to bacterial peptidoglycans by mounting an inflammatory response.At least in Caucasian patients,the prevalently loss-of-function mutation of NOD permitted to unexpectedly define CD as an immune deficiency state,and upon its recent description in apparently unrelated disorders such as the Blau syndrome(a granulomatous pediatric syndrome),and perhaps in psoriasis and chronic obstructive pulmonary disorders,has contributed to revolutionize our view of IBD and CD in particular.The latter affection,together with psoriasis and chronic pulmonary disease can now be included into a newly identified category named "barrier organ disease",wherein a barrier organ is defined as a large mucosal or epithelial surface with an abundant metagenomic microbial population and an underneath reactive tissue,the whole structure being in contact with the outer environment and capable to react to it.Personalized treatments and empowerment of research across different disease phenotypes should be the advantages of this novel mindset.

Inflammatory bowel diseases: Current problems and future tasks

Current knowledge on inflammatory bowel disease(IBD)is mainly endorsed by controlled trials and epidemiologic studies. Yet,we seldom look at the messages from real-world practice. Among a patient population followed since2008,we looked at an unselected sample of 64 IBD patients [26 Crohn's disease(CD) and 38 ulcerative colitis(UC)] who had been seen as out-patients in the last year.Inducing remission,mesalamines(86% for UC/69% for CD/33%-16% as MMX formulation) prevailed as prescrip-tions; steroids(55%/19% for UC/CD) ranked second.Prescription of third-party drugs(antibiotics,NSAIDs,biologics) and adherence,were issues in the maintenance.34% of CD,and 23% of UC patients showed accompany-ing immunologic diseases: CD-associated familiar psoriasis(4:9) ranked first. Main Message. The association between IBD(CD mainly) and psoriasis,now found in our practice,matches current basic science gathering IBD together with psoriasis(and perhaps chronic respiratory disease) under the comprehensive term "barrier organ disease" wherein an epithelial surface with sensor system srules contacts between outer antigens and a reactive underneath tissue,with the balance between inflammation and quiescence kept at any time by mucosal permeability.IBD is thus viewed as a polyfactorial/polygenic/syndromic disorder,embedded into a galaxy of immune conditions offering multiple points of attack. This mindset of splitting the IBDs into pathogenic categories may allow overcoming the uniformly targeting of a single cytokine by biological drugs,in favor of demarcating the boundaries between different disease-subtype-specific indications,and paving the way to future personalized strategies.

Individually administered or co-prescribed thiopurines and mesalamines for inflammatory bowel disease

Data from both basic research and clinical experience continue to suggest that mesalamines and thiopurines are effective and efficient for the maintenance of remission ofinflammatory bowel diseases.Several decades following the formalization of their indications,attention on these two drugs has been fostered by recent achievements.Demonstration of the ability of mesalamine to activate a colonocyte differentiation factor has shed light on its chemopreventive effects on colorectal cancer;in addition to their anti-proliferative efficacy,thiopurines have been shown to be specific regulators of apoptosis.The two drugs are often coadministered in clinical practice.Recent advancements have shown that mesalamines exert a positive synergism in this context,insofar as they can inhibit sidemethylation of thiopurines and hasten the function of the main immunosuppressive pathways.Considering that up to 40% of patients cannot tolerate thiopurines,such renovated targets have stimulated efforts to improve compliance by research on the toxicity mechanisms.The definition of genetic polymorphisms in the enzymes of thiopurine metabolism,and the uncovering of synergistic drug interactions,such as that with allopurinol,are just two of the results of such efforts.Interaction between basic research and clinical practice has continued to inform indications and refine the prescriptions of mesalamines and thiopurines;these have not been restrained(they have been implemented in some cases)by the advent of the novel biological molecules with anti-cytokine activity.