PUD is usually defined as a greater than 3- to 5-mm rupture of the gastric or duodenal mucosa, which is caused by an imbalance in factors that protect the gastric and duodenal mucosa and factors that can cause damage. In this study, we analyzed the prevalence trends of PUD at the global, regional and national levels from 1990 to 2019, along with PPIs medication use over the span of thirty years. The prevalence of PUD in 2019 was approximately 8.09 million worldwide, and this study exhibited continues increasing tendency in the number of prevalent. Similar to the results of other research reports [16, 17], the incidence of PUD showed a slight increase from 2006 to 2019, but the ASR showed a decreasing trend. However, in recent years, this downward trend has plateaued, which may be related to the fact that the main ulcer etiology has shifted in many countries from H. pylori infection to non-steroidal anti-inflammatory drug (NSAIDs) use . For PUD, which is a chronic disease, it is often necessary to take appropriate drugs for a long period of time, and its recurrent characteristics and potentially serious complications have a significant impact on the social economy and medical and health costs.
PUD may be attributed to many etiologies, such as H. pylori infection, NSAIDs use, gastric bypass surgery, smoking, selective serotonin reuptake inhibitor use, stress, lifestyle habits and genetic characteristics, which have been identified as the main risk factors [1, 2]. During the study period, especially in the first 20 years, the incidence of and mortality due to PUD showed significant decreasing trends, which were closely related to PPIs use and the widespread administration of anti-H. pylori treatment, which started in the late 1980s. In the last 10 years of the study period, the incidence of and mortality due to PUD showed relatively stable trends that did not decline with the further promotion of anti-H. pylori treatment. However, there was an increase in the use of NSAIDs, especially aspirin and other drugs, and these drugs often lead to serious complications in patients with PUD. In previous studies, especially in Australia, a country with an inexplicable history of H. pylori, H. pylori infection was associated with 70% to 90% of PUD cases [18, 19]. Although these values are lower in some other studies, H. pylori infection is still a key factor in the pathogenesis of PUD . Despite anti-inflammatory effect, NSAIDs are always used in antipyrexia and analgesic therapy, which makes NSAIDs as most commonly prescribed medicine . Targeting cyclooxygenases enzymes (COXs), NSAIDs are divided into non-selective NSAIDs and selective COX-2 inhibitors, such as aspirin and celecoxib repectively . However, NSAIDs could cause gastrointestinal adverse effects including ulcers, bleeding or perforation [21, 23]. Drugs such as aspirin and other NSAIDs account for approximately 10% of PUD cases. NSAIDs have a stronger correlation with duodenal ulcers than with gastric ulcers. In recent decades, the use of these drugs has increased dramatically [24, 25]. They account for approximately 5% to 10% of all prescription drugs each year and have shown an increasing trend . In general practice, the prevalence of NSAIDs use in patients over 65 years old is as high as 96% . A study from Norway indicated that approximately 7.3% of elderly patients over 60 years old took at least one NSAIDs prescription within one year period . Differ from aspirin, selective COX-2 inhibitors have a weaker association with PUD than nonselective NSAIDs, which suppress COX-1 activity to inhibit gastric mucosa repair [29, 30].
For sever obesity patients, bariatric surgery, such as Roux-en-Y gastric bypass (RYGBP) surgery and duodenal switch (DS) surgery, could be a proper therapy to reduce weight and comorbidities . Due to well-established procedure and nearly 70 years of surgical experience, RYGBP is considered as gold standard for bariatric surgery . Although overweight and related metabolic symptoms would be reduced after gastric bypass surgery, several complications still might influence the recovery of operated patients, such as marginal ulcer (MU). MU developed at or distal to gastroenteral anastomosis and occurs in approximately 5% of obese patients undergoing gastric bypass surgery [31, 33]. In patients with upper gastrointestinal symptoms after gastric bypass surgery, the incidence can reach 27% to 36%, indicating gastric bypass surgery history might contribute to the development of PUD [1, 34].
In the vast majority of GBD regions, the incidence of and mortality due to PUD showed significant downward trends with increasing SDI; this is closely related to the awareness of H. pylori treatment and the appropriate management of other chronic diseases. However, in some areas, this relationship is questionable, especially in the southern sub-Saharan African region. The cause of this phenomenon is still controversial and may be related to the epidemiological characteristics and risk factors for PUD in such countries and territories. Although the incidence of H. pylori infection had decreased as SDIs increased in these areas, in some countries, the infection rate remains very high. NSAIDs use rates in these areas were significantly lower than those in developed countries [35, 36]. Studies have also shown that the rates of severe PUD-related complications, such as perforation of the digestive tract, are high in these countries and territories and appear to be associated with Khat intake . When stratified by SDI, the incidence of PUD showed decreasing trends in different groups over time. The decrease was more obvious in low- and low-middle-SDI regions than in high-SDI regions, and the incidence of PUD tended to plateau in high-SDI regions; however, it was still far lower than those in low-SDI regions. PUD-related deaths decreased in all groups. In 2019, in different countries and regions, the prevalence of PUD generally decreased with increasing SDI, but in some Pacific islands, such as Kiribati and Vanuatu, the prevalence of PUD remained abnormally high. This may be related to the high H. pylori infection rate among and the ethnic characteristics of Pacific islanders. Some studies found that Maori and Pacific Island adults and children living in South Auckland had a high rate of infection with H. pylori compared to Europeans from the same area . Data showed that household crowding involving children in New Zealand contributed to 44% of H. pylori infections in Pacific Islanders, 36% in Maori people and 14% in Europeans [39, 40].
The age-standardized incidence rate showed an increasing annual trend with increasing age. This is different from the incidence rate of H. pylori. A multicenter cross-sectional study showed that the positive rate of H. pylori serum antibody increased linearly from the 30- to 39-year-old age group to the 60- to 69-year-old group, while the infection rates of H. pylori in people aged 20 to 29 and over 70 years old were low. The change in the H. pylori infection rate showed a trend of initially increasing and then decreasing with age . The consistent increase in the age-standardized incidence rate may be associated with an increased incidence of drug-related PUD in older people who are more likely to suffer from other chronic diseases and require other medications, such as NSAIDs. Studies have shown that the use of NSAIDs peaks at approximately 50 years old, and after 70 years old, the use of NSAIDs, especially aspirin, decreases, which is related to the increased incidence of NSAID-related adverse reactions in the elderly population [42, 43]. Estrogen can prevent ulcers by inhibiting the synthesis and release of gastrin and reducing the secretion of gastric acid. The decrease in estrogen levels in elderly females may be a protective factor for PUD  and may also cause a slight decrease in the growth trend of the age-standardized incidence rate in elderly women over 80 years old.
Regarding sex, at the end of the twentieth century, the incidence of and mortality due to PUD showed significant decreases, and the trends in males were more obvious than those in females. Over time, the decreasing trends of the age-standardized incidence and mortality rates became less steep, but the rates in males remained higher than those in females. PUD-related deaths and DALYs were significantly lower in females than in males. However, further analysis of PUD-related factors revealed that the incidence in females was slightly higher than that in males aged less than 20 years. In 2019, among the different GBD regions, the incidence rates of PUD in the Oceania, High-income Asia Pacific, Eastern Europe, East Asia and Central Asia regions were significantly higher in males than in females, while in other regions, there was no significant difference in the incidence between the sexes. In some regions, such as Western sub-Saharan Africa, the rate in females was significantly higher than that in males. However, the PUD-related death rate was higher in males than in females, except in Central sub-Saharan Africa. In West African countries, such as Ghana and Nigeria, the incidence of PUD in females accounted for approximately 54–57% . Research results have shown that there is a sex difference in the influence of acetic acid-induced gastric ulcer formation in rats. After the administration of certain interventions, the natural defensive mechanism in the gastric mucosa was adversely disturbed in male rats but activated in female rats . This phenomenon is similar to previous clinical and the current research results, although the specific mechanism is not completely clear.
There were increasing trends in the EAPCs in the age-standardized prevalence and DALY rates among only female patients in Eastern Europe (marginally increasing incidence and death rate trends) from 1990 to 2019, mainly due to the increase in the number of females in Russia and the Ukraine. In these two countries, especially in Siberia, the H. pylori infection rates were significantly higher than those in other regions. However, there were no differences in H. pylori infection rates between the sexes and among ethnicities [46, 47]. Therefore, the consistently increased risk of PUD among females in these areas may be related to factors such as drugs or bypass surgery [48, 49]. These reasons require further study to produce high-level evidence-based medical evidence.
The roles of anti-H. pylori therapy and acid suppression therapy in the treatment and prevention of PUD are clear. Identifying high-risk populations and preventing drug-related complications are particularly important at this stage. Anti-H. pylori treatment can reduce the incidence of PUD and reduce the risk of gastric cancer in high-risk groups. Similar to acid suppression therapy, it will not increase the economic burden of disease treatment. However, there is still some controversy regarding whether to administer anti-H. pylori treatment in all positive patients considering the extensive administration of antibiotics, as it may promote the production of other resistant bacteria, leading to the occurrence of Clostridium difficile-associated diarrhea, and increase the potential risk of cardiovascular disease [50, 51]. Acid suppressant drugs, mainly PPIs, seem to be the most effective class of gastroprotectants for the management of PUD . Especially in recent years, the risk factors for PUD have gradually changed from H. pylori infection to drug-related PUD, so treatment with PPIs has gradually increased in importance. Especially in patients with gastrointestinal bleeding, PPIs can significantly reduce the incidence of adverse outcomes. However, PPIs also have certain medication risks, such as an increased risk of fracture and the development of other infections. These risks still lack strong evidence, and the benefits of PPIs greatly outweigh their associated risks. The current controversy mainly concerns the durations and doses of PPIs and whether oral PPIs have the same effect as intravenous medication in maintenance treatment .
The study has some limitations. First, critical information about disease burden in some countries does not exist or was unavailable, making it difficult to illustrate and understand health trends. Second, compared with other chronic noncommunicable diseases with high mortality rates, the mortality rate associated with PUD is relatively low, but PUD has the characteristic of recurrence. The high prevalence rate also results in a high disease burden. However, compared with that of malignant tumors, diabetes, and cardiovascular and cerebrovascular diseases, evidence indicating that PUD should be considered a high-priority disease is lacking .