Over the past few decades, since the introduction of histamine H(2)-receptor antagonists, proton-pump inhibitors, cyclo-oxygenase-2-selective anti-inflammatory drugs (coxibs), and eradication of Helicobacter pylori infection, the incidence of peptic ulcer disease and ulcer complications has decreased. There has, however, been an increase in ulcer bleeding, especially in elderly patients. At present, there are several management issues that need to be solved: how to manage H. pylori infection when eradication failure rates are high; how best to prevent ulcers developing and recurring in nonsteroidal anti-inflammatory drug (NSAID) and aspirin users; and how to treat non-NSAID, non-H. pylori-associated peptic ulcers. Looking for H. pylori infection, the overt or surreptitious use of NSAIDs and/or aspirin, and the possibility of an acid hypersecretory state are important diagnostic considerations that determine the therapeutic approach. Combined treatment with antisecretory therapy and antibiotics for 1-2 weeks is the first-line choice for H. pylori eradication therapy. For patients at risk of developing an ulcer or ulcer complications, it is important to choose carefully which anti-inflammatory drugs, nonselective NSAIDs or coxibs to use, based on a risk assessment of the patient, especially if the high-risk patient also requires aspirin. Testing for and eradicating H. pylori infection in patients is recommended before starting NSAID therapy, and for those currently taking NSAIDs, when there is a history of ulcers or ulcer complications. Understanding the pathophysiology and best treatment strategies for non-NSAID, non-H. pylori-associated peptic ulcers presents a challenge.

The impact of CYP2C19 polymorphisms on H. pylori eradication rates in studied populations appears clinically relevant in patients prescribed omeprazole as a component of their dual- or triple-drug therapy, whereas regimens that include lansoprazole or rabeprazole are unaffected. The choice of PPI and/or dose rather than CYP2C19 genotyping could be a more practical approach to assure the highest H. pylori eradication rates in clinical settings.

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Cyclooxygenase (COX) inhibitors remain a major class of drugs in rheumatology and their widespread use is expected to continue. The view that a prothrombotic effect explains the increase in myocardial infarction (MI) associated with both COX-2 selective and traditional NSAIDs (tNSAIDs) has been increasingly questioned. We review the evidence that prostanoids direct the immune response away from a Th1 response and that consequently inhibition of prostaglandin synthesis results in augmentation of the Th1 response by limiting prostanoid synthesis. Although the role of prostanoids as mediators of inflammation in the periphery is well understood, the systemic immunomodulatory role of prostanoids shifting the immune response away from a Th1 type is less appreciated. Atherosclerosis is an inflammatory arterial disease driven by a Th1 type immune response. Moreover, the vulnerable phenotype of atheroma is associated with the cellular Th1 immune response in contrast to the stable plaque phenotype associated with a Th2 type response. We propose a class effect of COX-2 selective and tNSAIDs, which results in augmentation of Th1-mediated atherogenesis/ production of pro-atherogenic cytokines associated with detrimental plaque remodeling, instability, rupture and embolization resulting in MI. Understanding of the Th1 mediated immunity, which underlies the cardiovascular, and the non-Th1, which underlies gastrointestinal adverse effects associated with the use of COX inhibitors, should lead to better risk assessment and the development of anti-inflammatory treatments with improved safety. Our explanation also emphasizes the pharmacological effects and consequences of immunomodulation in the inflammation associated with atherosclerosis and other Th1- as well as non-Th1-driven diseases.