**2. Epidemiology**

The incidence of peptic ulcer disease is tightly related to epidemiological changes in environmental factors, reflecting aging, prevalence of *Helicobacter pylori* infection and use of NSAIDs.

Non-steroidal anti-inflammatory drugs (NSAIDs) are estimated to be the most prescribed therapy worldwide (Clinard, 2001); unfortunately, chronic NSAIDs therapy may induce upper gastrointestinal injury, leading to symptoms such as dyspepsia, chest pain or heartburn or severe complications (i.e. gastroduodenal ulcers bleeding or perforation).

The incidence of GI injuries is significantly higher (about four fold) in patients receiving NSAIDs chronic therapy and 1-2.5 clinically significant adverse events were recorded for 100 patients treated/year; it was estimated that 20-40% of patients receiving chronic NSAIDs therapy present endoscopic finding of gastroduodenal mucosal injury (MacDonald, 1997; Ramey, 2005; Targownik 2006; Taha, 1996). All these evidences, lead to an increased mortality of patients receiving NSAIDs.

Moreover, these adverse event rates, resulting from observational studies, refer to general population receiving NSAIDs; when clinical studies evaluate high-risk categories, the relative risk for upper GI events significantly increase. Therefore, the available guidelines identify these high-risk categories of patients and try to outline possible specific management strategies for each category (Anon, 2000; Lanza, 2009; Moens, 2004; MacLean 2001).

Different guidelines identify various risk factors for the development of upper GI injury under NSAIDs therapy: age, previous history of an upper GI event, the need of high-dose NSAIDs, Helicobacter pylori infection, use of antiplatelet agents, use of warfarin or other anticoagulant agents, corticosteroids, selective serotonin re-uptake inhibitors (SSRI), and alendronate (Langman 1994; Garcia Rodriguez 1994; Papatheodoridis, 2006; Huang, 2002). On the other hand, GI risk factors in patients receiving coxibs are not well defined, with a significant lack of data: only a previous history of peptic disease or ulcer bleeding, presence of *Helicobacter pylori* infection and concomitant assumption of antiplatelet agents are considered independent risk factors (Lanas, 2005).

In order to minimize NSAID-related events, evidence-based guidelines suggest to prescribe coxibs or a gastroprotective agent combined to a nsNSAID to high risk patients (Lanza, 2009).

The first drug registered as a gastroprotective agent, in patients receiving NSAID, was misoprostol, a PG analogue. Clinical studies assessed the efficacy of misoprostol in reducing the onset of gastroduodenal injuries in patients receiving chronic NSAIDs therapy; however, misoprostolis poorly tolerable. Effective doses of misoprostol induce dyspepsia and are often associated to development of diarrhea and abdominal pain/bloating while low doses do not induce side effects but are ineffective as gastroprotection (Lanza, 1989; Targownik, 2008).

Other recent and effective therapies were developed in order to reduce upper GI symptoms and prevent complications: histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPI) have both demonstrated efficacy in NSAID-related GI side effects (Hawkey, 2005; Hooper, 2004; Rostom, 2002; Scheiman, 2006).

During chronic NSAIDs therapy, a significant amount of patients present with dyspeptic symptoms; however, development of GI symptoms is not predictive for development of NSAID-related injury (gastropathy or ulcers). Moreover, about 60% of patients with endoscopic findings of NSAID-related injury do not present GI symptoms until bleeding or perforation occur. Finally, only 10% of NSAID-related injury become symptomatic for hemorrhage (Somerville, 1986).
