Peptic ulcers begin when acid digestive juices damage the protective mucus lining of the stomach or duodenum. The bacterium H. pylori plays a significant role in the disease. In the 1970s, the only treatments were a diet and antacids - or surgery. Since then dramatic progress has been made through medicines to block acid formation and antibiotics that destroy H. pylori.
A peptic (or gastric/duodenal) ulcer is damage to the inner surface of the stomach or duodenum, resulting in loss of tissue and inflammation. The defect in the protective lining of the stomach and duodenum may be superficial or become deeply erosive if untreated.
Ulcers begin when acidic digestive juices damage the protective mucus lining, exposing the underlying tissue to a bacterium called Helicobacter pylori. H. pylori has the exceptional ability to survive in the acid environment of the stomach and was first discovered in 1982.
A second type of ulcer may occur in people who have to take non-steroidal anti-inflammatory medicines (NSAIDs). Unfortunately, these medicines cause reduced synthesis of mucus which normally protects the inner wall of stomach and duodenum. H. pylori infection is the cause of 95 per cent of duodenal and 80 per cent of gastric ulcers, with NSAIDs being responsible for most of the rest.
Peptic ulcer disease is extremely common and in developed countries the annual incidence is one to three per 1.000 of the population. It affects about one in ten men and one in 15 women in Europe at some stage in their lives. Some 250,000 hospital admissions annually are due to the disease. Complications of ulcers still claim the life of some 25,000 people each year in the EU.
Duodenal ulcers are most common in the age group 45-64 and are twice as common in men as in women, while gastric ulcers become more common with age and affect as many women as men. H. pylori infection is commonly acquired in childhood and is strongly correlated with age. In Europe, prevalence rates for H. pylori infection range from approximately 30 to 60 per cent.
Epidemiological research indicates that smokers are more prone to developing duodenal ulcers than people who refrain from smoking and that those who take certain types of analgesics frequently for a long period of time are more likely to develop stomach ulcers. As socio-economic conditions have improved greatly in recent decades, there has been a decrease in the prevalence of peptic ulcers. Still, a lot of upper gastrointestinal (GI) endoscopies, which is the procedure used to diagnose peptic ulcers and related diseases, are performed all over Europe.
Progress in developing medicines to treat and prevent recurrence of peptic ulcers has been dramatic. In the 1970s, peptic ulcer disease condemned a patient to dietary restrictions and antacids for a lifetime. Symptom relief, when achieved, was short-lived. Therefore, surgery, which removed parts or all of the stomach, was often the only effective remedy.
Some 25 years ago, histamine was discovered to play a major role in stimulating gastric acid and pepsin secretion, through receptors that differed from histamine H₁ receptors in the rest of the body. This enabled the development of selective H₂ receptor blockers. The medicines in this category generally are well tolerated and remain valuable treatments.
The second important advance was the discovery that inhibition of the enzyme that pumps acid into the stomach was also highly effective. Proton Pump Inhibitors (PPIs) have since become one of the world’s biggest-selling medicines. PPIs act faster than H₂ receptor blockers and are generally well tolerated.
The third major advance came with clinical studies that showed that the elimination of H. pylori by treatment with antibiotics and a PPI prevented recurrences. A great variety of eradication therapy regimens involving a PPI and a combination of two antibiotics (triple therapy) have been developed and are effective in eradicating H. pylori in 90 per cent or more of cases. These regimens are generally taken for seven or 14 days. The development of antibiotic-resistant strains of H. pylori is the main concern with this approach.
The development of effective medicines during the last 30 years has greatly reduced the recurrence rate of peptic ulcers and made operations much less frequent. Surgery is still required for certain serious or life-threatening complications of peptic ulcers and may be considered if medications are not working.
Research into PPIs has now become less intense, although research continues to explore some molecules in Phase 3 trials for non-erosive oesophageal reflux disease. There is a reversible acid pump inhibitor under Phase 2 study in acid-related GI disease and there are new approaches to H. pylori eradication, in Phase 2 studies.
The prostaglandin system plays an important role to strengthen the resistance of the inner lining of the stomach against injury. In particular, critically ill patients are at great risk of developing stress-related gastric mucosal lesions. It is hypothesised that prostaglandin levels are low in the gastric mucosa in patients with stress ulcers and research is being undertaken to find new cytoprotective compounds that are effective agents in increasing prostaglandin levels in such cases.
Clinical research is still ongoing to evaluate whether combination products including non-steroidal anti-inflammatory drugs (NSAIDs) and acid-reducing agents are effective in reducing the rate of development of NSAID-associated ulcers in patients who require long-term daily use of such NSAIDs.
Recently, a team of university researchers have found a new substance which is active against H. pylori and also reduces the activity of the stomach enzyme pepsin, which is believed to be involved in ulceration.
In chronic peptic ulcer induced by H. pylori infection, activated white blood cells produce several pro-inflammatory and anti-inflammatory cytokines. In fact, levels of pro-inflammatory and anti-inflammatory cytokines are elevated in gastric mucosa infected with H. pylori. Various forms of cytokines are also considered to play an important role in the pathogenesis of peptic ulcer and gastric cancer.
However, it is still unclear whether pro-inflammatory or anti-inflammatory cytokines are associated with the pathogenesis of the disorder. Research is underway to clarify the association between various forms of interleukins and the susceptibility to gastrointestinal disease development.
Lastly, as peptic ulcers usually have an infectious cause, it is logical that a vaccine-based approach be tried to eradicate it. Two European companies are collaborating to develop such a vaccine, and this has now completed Phase 2 trials. Meanwhile, in the United States, there was completion of Phase 1 trials of a vaccine directed against H. pylori.
Peptic ulcers can be seen as an area in which the development of new medicines over the past twenty years has been spectacularly successful in improving outcomes. With the improvements now achievable with the medications currently available, the somewhat slower pace of new development can be taken as a sign of a job well done.