NSAIDs are widely used to treat pain and rheumatic conditions, but they induce adverse events in different body systems, although the major, most frequent events occur in the upper and lower gastrointestinal (GI) tracts. Areas covered: This review is focused on damage caused by NSAIDs in the upper and lower GI tracts, the different mechanisms of damage and the GI-sparing NSAIDs designed to minimize adverse events based on understanding of these mechanisms. Expert commentary: Among the new NSAIDs, COX-2 selective inhibitors have been extensively investigated, and some were approved for human use. Celecoxib demonstrated its safety for the entire GI tract, compared to traditional NSAIDs. However, coxibs, like traditional NSAIDs, are toxic to the cardiovascular (CV) system. Other GI-sparing agents include nitric oxide-NSAIDs and phosphatidylcholine-associated NSAIDs. Testing in animal models and humans they showed GI advantages over the parent NSAID compounds, but none obtained regulatory approval or were further investigated. Hydrogen sulfide-releasing NSAIDs are currently under clinical development, and more data are needed before clinical use. Alternative therapies, such as modulating gut microbiota, are being explored. Currently, clinicians must continue prescribing traditional NSAIDs or coxibs, associated with/without proton pump inhibitor therapy, based on the presence of GI/CV risk factors.

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Background There are few large prospective cohort studies evaluating predictors of outcomes in acute pancreatitis. Objectives The purpose of this study was to determine the role of age and co-morbid disease in predicting major outcomes in acute pancreatitis. Methods Data points were collected according to a predefined electronic data collection form. Acute pancreatitis and its complications were defined according to the revised Atlanta classification. Univariable and multivariable analyses were conducted using Cox proportional hazard regression and multiple logistic regression. Results From June 2013–February 2015, 1655 adult patients were recruited from 23 centres across Spain. Co-morbid disease, obesity, open surgical necrosectomy within 30 days, and pancreatic necrosis were independently associated with both 30-day mortality and persistent organ failure ( p < 0.05 for all). Age was not associated with persistent organ failure, however the extreme of age (>85 years) was associated with mortality ( p < 0.05). Co-morbid disease and obesity were not independently associated with a prolonged length of stay or other markers of morbidity on adjusted analysis ( p > 0.05). Conclusion Comorbidity and obesity are important determinates of mortality and persistent organ failure in acute pancreatitis, but in the absence of organ failure they do not appear to independently contribute to morbidity. This has important implications for severity classification and predictive models of severity in acute pancreatitis.

As acute pancreatitis progresses to the severe form, a life-threatening systemic inflammation is triggered. Although the mechanisms involved in this process are not yet well understood, it has been proposed that circulating exosomes may be involved in the progression of inflammation from the pancreas to distant organs. Here, the inflammatory capacity and protein profile of plasma exosomes obtained during the first 24 h of hospitalization of patients diagnosed with acute pancreatitis were characterized and compared with the final severity of the disease. We found that the final severity of the disease strongly correlates with the inflammatory capacity of exosomes in the early stages of acute pancreatitis. Exosomes isolated from patients with mild pancreatitis had no effect on macrophages, while exosomes isolated from patients with severe pancreatitis triggered NFκB activation, TNFα and IL1β expression, and free radical generation. To delve deeper into the mechanism involved, we performed a proteomic analysis of the different exosomes that allowed us to identify different groups of proteins whose concentration was also correlated with the clinical classification of pancreatitis. In particular, an increase in the amount of S100A8 and S100A9 carried by exosomes of severe pancreatitis suggests that the mechanism of action of exosomes is mediated by the effect of these proteins on NADPH oxidase. This enzyme is activated by S100A8/S100A9, thus generating free radicals and promoting an inflammatory response. Along these lines, we observed that inhibition of this enzyme abolished all the proinflammatory effects of exosomes from severe pancreatitis. All this suggests that the systemic effects, and therefore the final severity of acute pancreatitis, are determined by the content of circulating exosomes generated in the early hours of the process.

The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.