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Peptic Ulcer Disease Medications YouTube

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Peptic Ulcer Disease Medications YouTube

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This video gives an overview of the pharmacological management of peptic ulcer disease. For an overview of peptic ulcer disease, please take a look at the following video: https://youtu.be/VfBpKmzWzOQ For the slides please visit: http://www.letstalkmed.com/pharmacology-of-peptic-ulcer.html Feel free to fill out this questioneer about the quality of this video, we would be happy to hear from you!

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Abstract

OBJECTIVES:

Resistance to standard Helicobacter pylori (HP) treatment regimens has led to unsatisfactory cure rates in HP-infected patients. This study was designed to evaluate a novel four-drug regimen (three antibiotics and a proton pump inhibitor (PPI)) for eradication of HP infection in treatment-naive patients.

METHODS:

Patients with a diagnosis of HP gastritis or peptic ulcer disease confirmed using endoscopy and stool antigen testing were eligible for inclusion in this study. All patients underwent a washout period of 6 weeks from any prior antibiotic or PPI usage. Patients were then randomized to either levofloxacin, omeprazole, nitazoxanide, and doxycycline (LOAD) therapy for 7 days (LOAD-7) or 10 days (LOAD-10), including levofloxacin 250 mg with breakfast, omeprazole 40 mg before breakfast, nitazoxanide (Alina) 500 mg twice daily with meals and doxycycline 100 mg at dinner, or lansoprozole, amoxicillin, and clarithromycin (LAC) therapy for 10 days, which included lansoprozole 30 mg, amoxicillin 1 g with breakfast and dinner, and clarithromycin 500 mg with breakfast and dinner. HP eradication was confirmed by stool antigen testing at least 4 weeks after cessation of therapy.

RESULTS:

Intention-to-treat analysis revealed significant differences ( P<0.05) in the respective eradication rates of the LOAD therapies (88.9% (80/90) LOAD-10, 90% (81/90) LOAD-7, 89.4% (161/180) for combined LOAD) compared with those receiving LAC, 73.3% (66/90). There were no differences in adverse effects between the groups.

CONCLUSIONS:

This open-label, prospective trial demonstrates that LOAD is a highly active regimen for the treatment of HP in treatment-naive patients. A large randomized controlled trial is warranted to further evaluate the efficacy of this regimen.

INTRODUCTION

Helicobacter pylori (HP) is a small, Gram-negative spirochete inhabiting the mucous layer overlying the gastric epithelial cells in humans. It is the most common chronic human bacterial infection and the most common cause of gastritis, with incidence rates as high as 50% worldwide ( 1). Furthermore, according to the World Health Organization, HP is classified as a type 1 carcinogen and is the primary cause of peptic ulcer disease, gastric carcinoma, and mucosa-associated lymphoid tissue lymphomas ( 1, 2, 3, 4, 5, 6, 7).

Current guidelines from the American College of Gastroenterology and the European Helicobacter Study Group recommend either a clarithromycin-based triple therapy (a proton pump inhibitor (PPI) plus amoxicillin and clarithromycin) or a bismuth quadruple therapy (a PPI plus bismuth, metronidazole, and tetracycline) as a standard of care in the treatment of confirmed HP infections ( 4, 7). However, a study by Rokkas et al. ( 8), based on the Maastricht III guidelines, indicated that treatment with a PPI, amoxicillin, and clarithromycin regimen as first-line therapy will fail in ∼30% of patients on an intention-to-treat (ITT) basis, and treatment with PPI, bismuth, metronidazole, and tetracycline as second-line therapy will fail in another 30%, leaving ∼10% of the total patient population in need of an alternative regimen. Patient tolerability, adherence, and drug resistance rates play a major role in treatment selection and efficacy. Drug resistance has the greatest impact on clarithromycin therapy, with HP resistance rates ranging from 10 to 30% ( 2, 9, 10, 11), and actual cure rates for PPI, amoxicillin, and clarithromycin triple therapy consistently falling below 80% ( 5, 6, 8, 10, 12). In contrast, global resistance rates to metronidazole have been reported to range from 25 to 66%, but some investigators believe resistance might be overcome with increased doses of metronidazole ( 2, 4, 9, 10, 11, 12, 13). Unfortunately, this increase in dosage can lead to the potential for intolerable side effects and pill burden, thus affecting treatment tolerability and adherence ( 4).

In response to increasing rates of resistance with the aforementioned three- and four-drug regimens, newer treatment regimens aimed at eradicating the organism more effectively are increasing in popularity ( 1, 3, 5, 6, 7, 8, 9, 10, 12). This study evaluates a novel four-drug regimen, three antibiotics and a PPI, for the eradication of HP infection in treatment-naive patients.

METHODS

Study patients

Consecutive patients with dyspeptic symptoms undergoing upper endoscopy were recruited for study participation. To be included in the study, patients must have had HP-induced gastritis confirmed by endoscopy (four-quadrant stomach biopsy (antro-corpus-incisura); Caris Life Sciences, Irving, TX) and monoclonal stool antigen testing (Premier Platinum HPsA PLUS, Meridian Bioscience, Cincinnati, OH). Exclusion criteria were as follows: partial gastrectomy or gastric malignancy; active bleeding; age <20 years; pregnancy; prior HP treatment or infection; recent history and treatment for Clostridium difficile infection; current use of a PPI, H2 receptor antagonist, antacid, anticoagulant, or misoprostol; recent use of antibiotics (within 6 weeks), or allergy to any medication used in the study.

Study design

A randomized, open-label trial was conducted to compare the tolerability and efficacy of a novel four-drug regimen in eradicating HP gastritis. The study compared the LOAD regimen ( levofloxacin (Levaquin ®; Ortho-McNeil-Janssen Pharmaceuticals, Raritan, NJ), omeprazole (Prilosec ®; AstraZeneca Pharmaceuticals LP, Wilmington, DE), nitazoxanide ( Alinia ®; Romark Laboratories, LC, Tampa, FL), and doxycycline (Vibramycin ®; Pfizer, New York, NY)) with the current standard of care as represented by the LAC regimen ( lansoprazole (Prevacid ®; Takeda Pharmaceuticals North America, Deerfield, IL), amoxicillin (Amoxil ®; GlaxoSmithKline, Research Triangle Park, NC), and clarithromycin (Biaxin ®; Abbott Laboratories, Abbott Park, IL)). Before randomization, patients underwent a washout period of 6 weeks from any antibiotic or PPI use, and provided written informed consent before the initiation of therapy. Eligible patients were then randomized to either LOAD therapy for 7 days (LOAD-7) or 10 days (LOAD-10; levofloxacin 250 mg with breakfast, omeprazole 40 mg before breakfast, nitazoxanide 500 mg twice daily with meals, and doxycycline 100 mg at dinner) or LAC therapy for 10 days (lansoprozole 30 mg, amoxicillin 1 g with breakfast and dinner, clarithromycin 500 mg with breakfast and dinner). Randomization was performed in blocks of three, where the assignment of treatment was drawn in a blinded manner from an envelope. Patients were instructed to return to the clinic at least 4 weeks after the cessation of therapy for repeat stool antigen testing for HP. An ad hoc analysis of those initially meeting the definition of a "cure" (HP-negative by stool antigen at least 4 weeks after the cessation of therapy) was performed. These patients were asked to return to the clinic approximately 1 year later to test for HP recurrence (recrudescence or reinfection).

Outcome assessments

The primary efficacy outcome was measured as relative eradication rates between the three regimens, at least 4 weeks after the cessation of therapy, with patient tolerability and compliance addressed as secondary end points. At the cessation of HP therapy, all anti-secretory agents were discontinued and stool antigen testing for HP was performed at least 4 weeks after therapy to evaluate for complete eradication. Usage of a monoclonal antibody stool antigen test to assess HP eradication has been validated in a large meta-analysis and was approved by the United States Food and Drug Administration ( 14, 15). During the course of therapy, all patients were contacted by phone at least four times to assess for side effects and adherence. Helicobacter pylori recrudescence or reinfection was assessed using a ¹³ C-urea breath test (OAPI BreathTeK Otsuka Pharmaceutical, Rockville, MD) and stool antigen testing as previously described. Patients were instructed to discontinue any anti-secretory agent at least 2 weeks before follow-up testing.

The study protocol was approved by the institutional review board at Long Island Jewish Hospital-Forest Hills, and performed in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice Guidelines, and applicable local laws and regulations. Signed informed consent was obtained from each patient before study enrollment.

RESULTS

Clinical outcomes

In total, 653 patients ( N=653) were evaluated from a community referral base between February 2008 and January 2010. These patients reported symptoms of dyspepsia ( n=439, 67.2%), abdominal pain ( n=114, 17.5%), gastroesophageal reflux ( n=89, 13.6%), early satiety ( n=8, 1.2%), and loss of appetite ( n=3, 0.5%). Of these patients, 270 (41.3%) were enrolled with confirmed HP gastritis or non-bleeding peptic ulcers as documented by endoscopy (four-quadrant stomach biopsies) and stool antigen testing. Overall, 278 patients (42.6%) were excluded because of recent or ongoing usage of PPI, H ₂ receptor antagonist, bismuth, or antacid; 79 (12.1%) patients were excluded because of recent usage of nonsteroidal anti-inflammatory drugs, Cox-II inhibitors, or misoprostol; 24 (3.7%) patients were excluded because of recent antibiotic usage; and 2 (0.3%) declined to participate. Baseline characteristics and patient demographics are further elucidated in . Approximately two-thirds of those enrolled were of Asian descent; however, there was a broad distribution of patients representing the six distinct regions of the continent.

Table 1

No difference in patient adherence among LOAD-10, LOAD-7, and LAC regimens was detected. Overall, 94.4% (85/90), 96.7% (87/90), and 94.4% (85/90) of patients completed the LOAD-10, LOAD-7, and LAC regimens, respectively. In the LOAD-7 and LOAD-10 groups, eight patients discontinued therapy owing to gastrointestinal distress ( n=6), dizziness ( n=1), or palpitations ( n=1). Five patients in the LAC arm discontinued therapy secondary to a minor skin rash ( n=2) or gastrointestinal distress ( n=3). Follow-up data are unavailable for one patient in the LOAD-10 arm who left the country during treatment; this patient was therefore considered to be a treatment failure. As depicted in , ITT analysis in the patient population revealed that eradication rates were 88.9% (80/90) for LOAD-10, 90% (81/90) for LOAD-7, 89.4% (161/180) for combined LOAD regimen patients, and 73.3% (66/90) for LAC. There was no significant difference between LOAD-7 and LOAD-10 in eradication rates or adverse events. When compared with LAC in the ITT population, significant differences were detected between LOAD-7, LOAD-10, and combined LOAD therapy, P=0.013, P=0.006, and P=0.0001, respectively. Per protocol eradication rates comparing LOAD-7 and LOAD-10 patients with LAC-10 patients revealed respective cure rates of 93.6% (161/172) and 77.6% (66/85), P=0.0003 (). As depicted in here was no difference in reported adverse events between the groups.

Table 2

Although eradication of HP was of primary concern, recurrence (recrudescence or reinfection) data were collected on 218 "cures" ( n=152 LOAD, n=75 LOAD-7, and n=77 LOAD-10; n=66 LAC) at 1 year (range 12 to 14 months) after the completion of therapy using stool antigen and urea breath testing. Nine patients were lost to follow-up or refused retesting. The incidence of recurrence was 11.5% (25/218) for all patients, 9.2% (14/152) for LOAD, and 16.7% (11/66) for LAC, P=0.16.

Indistinguishable symptoms of recurrence made delineating between true recrudescence and reinfection difficult. Of note, 80% (20/25) of the patients who were HP positive 1 year later had traveled out of the country to areas of high HP prevalence (Asia and Latin America). Most of these, 15/25 (60%), had traveled to Asia: Bangladesh ( n=4), India ( n=3), Kazakhstan ( n=3), Nepal ( n=2), Turkey ( n=2), and Mongolia ( n=1).

DISCUSSION

HP resistance to metronidazole and clarithromycin in standard therapy has led to a decline in cure rates and increased the demand for a more efficacious, yet tolerable, therapy. Although there are few regional data regarding HP resistance in our community, previous studies indicate that, in New York and the Northeast region of the United States, antibiotic resistance ranges from 9 to 15% for clarithromycin and 5 to 31% for metronidazole, and is negligible to nonexistent for amoxicillin and tetracycline ( 2, 11). Fluoroquinolone resistance is of concern especially in areas of high fluoroquinolone use; unfortunately, regional data on HP resistance to this class of drugs are not available.

A meta-analyses including over 53,000 patients indicated the cure rate for the recommended first-line therapy is <80%, which is far below the desired 90% cure rate for any HP regimen ( 16, 17, 18). Rokkas et al. ( 8) highlight a greater concern-at least 10% of HP patients will fail standard first- and second-line regimens. In response to rising resistance rates, therapies including concomitant quadruple therapy and sequential therapy have emerged as alternatives to standard therapy ( 12, 18, 19, 20). Although sequential therapy is innovative, the regimen is also very complex, requiring mid-therapy transition from dual to triple therapy ( 18, 19, 20). Comparatively, concomitant quadruple therapy appears to be an effective, safe, and well-tolerated alternative to triple therapy and is less complex than sequential therapy ( 20).

Our study indicates that a unique four-drug regimen (LOAD) is potentially more efficacious than the standard of care (LAC) for the treatment of HP in a treatment-naive population. Overall, patients receiving LAC had an unsatisfactory cure rate of 73.3% ITT (77.6% per protocol); this outcome is similar to those reported by others ( 4, 8, 21, 22). On the other hand, the LOAD cure rate of 89.4% ITT (93.6% per protocol) meets the criteria that content experts deem acceptable ( 22, 23). Furthermore, there was a trend toward fewer patients receiving LOAD (9.2%) therapy having HP recurrence 1 year later as compared with those receiving LAC therapy (16.7%). Notably, a majority of those positive for HP 1 year later had traveled out of the United States to areas of known high HP prevalence; in addition, it is possible that noncompliance and antibiotic resistance had roles in disease recurrence. However, these results are in line with a meta-analysis by Niv and Hazazi ( 24) indicating much higher HP recurrence rates in developing countries.

The antibiotics used in this study (levofloxacin, doxycycline, and nitazoxanide) were selected because of ease of dosing (once or twice daily) and supportive data indicating these agents are highly active against HP ( 25, 26, 27). A pilot study in patients previously failing treatment successfully used a similar regimen LEND (levofloxacin, esomeprazole, nitazoxanide, and doxycycline) to achieve a comparable ITT eradication rate of 90% (27/30) ( 28).

Levofloxacin, a bactericidal fluoroquinolone antibiotic, has activity against HP due primarily to the drug's activity on bacterial DNA gyrase ( 29). Levofloxacin has been advocated for use in second- and third-line "rescue" regimens ( 4, 5, 6, 7, 8, 12, 30, 31). Unfortunately fluoroquinolone resistance, especially in patients who have routinely received a fluoroquinolone for other indications, is of particular concern ( 4, 12, 29). A lower dose of levofloxacin was used to aid in the tolerability of this four-drug regimen, however, as levofloxacin is a concentration-dependent agent, higher doses may increase eradication rates. Although the optimal dose of levofloxacin is yet to be determined, our study demonstrated efficacy using the lower dose of 250 mg once daily. Considering the LOAD regimen was well tolerated overall, an increase in levofloxacin dosage may be warranted.

Doxycycline, a tetracycline analog, has bacteriostatic properties through the inhibition of bacterial protein synthesis ( 32). The current literature indicates there is little to no resistance to this class ( 2, 9, 11), thus supporting the use of tetracyclines as superior alternatives for rescue therapies ( 33, 34). Although tetracycline is traditionally dosed four times a day, doxycycline offers the advantages of once- or twice-daily dosing and thus potentially improving compliance and tolerability ( 32). In our study, LOAD therapy takes advantage of the prolonged half-life of doxycycline by using a single 100 mg dose at dinner. Dosing doxycycline only once a day may help to increase tolerability while decreasing pill burden, but, as in the case with levofloxacin, it is possible that twice-daily dosing may improve clinical outcomes.

Nitazoxanide is a thiazolide antibiotic indicated for use in adults and children for the treatment of Cryptosporidium and Giardia infections. The bactericidal activity of nitazoxanide is a result of the drug's ability to prevent anaerobic energy metabolism via inhibition of the pyruvate oxidoreductase enzyme ( 35). Unlike metronidazole, nitazoxanide has been shown to be non-mutagenic for HP ( 35) and to possess anti-vacuolating toxin activity ( 36). In vitro studies indicate nitazoxanide is a potent agent against HP and other anaerobes, having activity against metronidazole-resistant strains ( 27, 36). In addition to the in vitro data, others have reported clinical success using nitazoxanide in a two-drug regimen combined with a PPI ( 27) or sucralfate 37 and a three-drug regimen with a PPI and amoxicillin ( 38). Clinical studies with nitazoxanide have used total daily doses ranging from 1,000 to 2,000 mg ( 27, 28, 37, 38) when given in combination with other antibiotics, a dose of 500 mg twice daily has been successful ( 28, 38). This lower dose of nitazoxanide is generally better tolerated and helps in regard to capping the total cost of therapy.

Current guidelines recommend a PPI as part of any standard therapy regimen in the treatment of HP ( 4, 7). PPIs enhance therapy by effectively increasing gastric pH, which serves to enhance the activity of the antibiotics and disrupt the acidic environment preferred by HP ( 39). Omeprazole was selected for use because at the time this study was initiated, it was the only generic option. Comparisons of the available PPIs in the treatment of HP have been reviewed elsewhere and are beyond the scope of this paper ( 40).

Although the data indicate LOAD therapy is statistically superior to the standard of care, this study has several limitations. Patients were enrolled from a single center, thus narrowing the population size and the applicability to larger populations. Although the population studied was diverse, approximately two-thirds of the patients were of Asian descent. However, the distribution of Asian patients was quite diverse as well, with patient representation from six distinct regions of the continent (South Asia, East Asia, Southeast Asia, the Middle East, Central Asia, and Russia). This unique global distribution of patients is primarily due to our location in New York, which is convenient to many ethnically distinct neighborhoods. Presumably, symptom improvement would follow HP eradication; unfortunately, in this study patients were not assessed for symptom improvement. Secondary to constraints in funding, we were unable to perform HP susceptibility and DNA testing for antibiotic resistance and differentiation of recrudescence and reinfection. Another limitation of the study is the use of a telephone survey to assess for compliance, which is probably not optimal; non-compliance may have been associated with treatment failures and recurrence. On the other hand, this type of less-stringent follow-up may serve as an indicator of expected clinical outcomes in community practice. Finally, patients receiving therapy were not blinded, potentially leaving a margin of error due to surveillance bias.

In summary, this prospective trial demonstrates that LOAD is a highly active and well-tolerated regimen for the treatment of HP infection in treatment-naive patients. The novel LOAD regimen combines three antibiotics with a PPI, offering the advantages of good tolerability, twice-a-day dosing, low pill burden (five per day), minimal in vitro HP resistance, and superior therapeutic outcomes as compared with a standard triple-therapy regimen. A large, randomized controlled clinical trial is warranted to confirm the therapeutic superiority of this regimen as a first- or second-line treatment option over the standard recommended therapies for HP eradication.

STUDY HIGHLIGHTS

Acknowledgments

We thank Matthew Bardin, PharmD, BCPS, for his guidance and technical assistance.

Notes

Guarantor of the article: P. Patrick Basu, MD.

Specific author contributions: Principal investigator, patient recruitment, patient evaluation, data collection, and manuscript preparation: Patrick Basu; data collection, patient evaluation, and manuscript preparation: Krishna Rayapudi; data collection and patient evaluation: Tommy Pacana and NV Krishnaswamy; manuscript preparation, background research, and statistics: Molly Flynn.

Financial support: None.

Potential competing interests: Patrick Basu has received educational grants from Salix Pharmaceuticals and Romark Labs, and serves on the advisory boards for Roche, Vertex, and Gilead. The other authors declare no conflict of interest.

References

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Premier Platinum HpSA® PLUS Prescribing Information Meridian Bioscience, Inc. Cincinnati, OH. February 2008.

Niv Y, Hazazi R. Helicobacter pylori recurrence in developed and developing countries: meta-analysis of ¹³C-urea breath test follow-up after eradication. Helicobacter. 2008;13:56-61.

Loo VG, Sherman P, Matlow AG. [Helicobacter pylori infection in a pediatric population: in vitro susceptibilities to omeprazole and eight antimicrobial agents. Antimicrob Agents Chemother. 1992;36:1133-1135. PMC free article]

Basu P, Rayapudi K, Esteves J. LEND (levofloxacin, esomeprazole, nitazoxanide and doxycycline) for the treatment of previously non-responsive Helicobacter pylori. Am J Gastroenterol. 2008;103 (suppl 1:S52.

Walker RC. Symposium on antimicrobial agents-part XIII: the fluoroquinolones. Mayo Clin Proc. 1999;74:1030-1037.

Smilack JD. Symposium on antimicrobial agents-part X: the tetracyclines. Mayo Clin Proc. 1999;74:727-729.

Stuppy WP. Dual therapy: nitazoxanide and sucralfate for the treatment of Helicobacter pylori. Am J Gastroenterol. 2010;105 (suppl 1:S45.

Campitelli E, Paszkiewich A, Ibarra D, et al. Efficacy of a nitazoxanide based regimen for Helicobacter pylori eradication. Am J Gastroenterol. 2008;103 (suppl 1:S44.

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A Randomized Study Comparing Levofloxacin, Omeprazole, Nitazoxanide, and Doxycycline versus Triple Therapy for the Eradication of Helicobacter pylori

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Resistance to standard Helicobacter pylori (HP) treatment regimens has led to unsatisfactory cure rates in HP-infected patients. This study was designed to evaluate a novel four-drug regimen (three antibiotics and a proton pump inhibitor (PPI)) for eradication of HP infection in treatment-naive patients.

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Abstract

An idiopathic peptic ulcer is defined as an ulcer with unknown cause or an ulcer that appears to arise spontaneously. The first step in treatment is to exclude common possible causes, including Helicobacter pylori infection, infection with other pathogens, ulcerogenic drugs, and uncommon diseases with upper gastrointestinal manifestations. When all known causes are excluded, a diagnosis of idiopathic peptic ulcer can be made. A patient whose peptic ulcer is idiopathic may have a higher risk for complicated ulcer disease, a poorer response to gastric acid suppressants, and a higher recurrence rate after treatment. Risk factors associated with this disease may include genetic predisposition, older age, chronic mesenteric ischemia, smoking, concomitant diseases, a higher American Society of Anesthesiologists score, and higher stress. Therefore, the diagnosis and management of emerging disease should systematically explore all known causes and treat underlying disease, while including regular endoscopic surveillance to confirm ulcer healing and the use of proton-pump inhibitors on a case-by-case basis.

Keywords: Idiopathic peptic ulcer, Helicobacter pylori infection, Endoscopy

INTRODUCTION

Helicobacter pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs) are common causes of peptic ulcer disease (PUD). However, in recent years, the global occurrence of non- H. pylori, non-NSAID PUD has increased. Management of this emerging disease is increasingly important. Although clinicians tend to describe non- H. pylori, non-NSAID PUD as idiopathic, the term "idiopathic" refers to a disease whose cause is not known or appears to arise spontaneously. Therefore, in addition to a missed diagnosis of H. pylori and the unrecognized use of NSAIDs/aspirin, a diagnosis of idiopathic peptic ulcer disease (IPUD) should also exclude all other recognized etiologies of PUD, which requires a systematic approach that considers all possible causes.

IS THE PROPORTION OR ABSOLUTE NUMBER OF IDIOPATHIC PEPTIC ULCERS INCREASING?

The management of PUD changed dramatically after the discovery of H. pylori as a major cause of chronic gastritis, peptic ulcer, and gastric cancer. Over half of the world's population is infected with H. pylori, especially in developing countries [ 1, 2]. Historically, H. pylori infection was found in 90% to 100% of patients with duodenal ulcer (DU) and 60% to 100% of patients with gastric ulcer (GU) [ 3]. A test-and-treat strategy for H. pylori infection has been adopted as first-line management for patients with PUD, while a screen-and-treat strategy for H. pylori infection in the asymptomatic population has been considered as an effective approach to decrease future risk of gastric cancer [ 4, 5]. These strategies have led to a continuous decline in the incidence of H. pylori-related peptic ulcers. Studies in Asia have also found that the incidence of H. pylori infection in younger patients has decreased [ 6- 10], probably due to improved sanitation and hygiene. Conversely, the global use of NSAIDs/aspirin is increasingly prevalent in an aging population and medical comorbidities are frequent. Thus, non- H. pylori PUD is relatively more common because of increased use of ulcerogenic drugs [ 11].

Graham [ 12] proposed a model to illustrate the changing proportion of H. pylori-positive and -negative ulcer disease. If the H. pylori prevalence were to decline from 80% to 40%, and the risk of PUD from causes other than H. pylori were to remain stable at about 250 per 100,000 persons, the total number of ulcers would decrease from 1,050 to 650 per 100,000 persons, but the proportion of H. pylori-negative PUD would increase from 24% to 38% [ 12]. Epidemiological studies have consistently reported an increasing proportion of H. pylori-negative PUD, especially in Asian countries. Studies in the 1990s in the United States found that only about 6% of DUs were not associated with H. pylori infection, particularly in Caucasians [ 13]. However, later studies contradicted these results. A study in Orlando, Florida, found that only 32% of DU patients were H. pylori-positive, and only 25% of bleeding ulcers were associated with H. pylori [ 14]. A larger scale study including 305 cases showed that ~35% of PUD was not associated with H. pylori or NSAIDs [ 15], while a multicenter French study found that about 21.6% of patients with PUD had neither H. pylori infection nor a history of using ulcerogenic drugs [ 16]. Thus, it appears that the incidence of idiopathic ulcer remains stable in Western countries, in contrast to the increasing trend in Asian countries in recent years () [ 15- 43].

In Asian countries, a study published in 1991 revealed that only 6% of DUs were H. pylori negative, and when ulcerogenic agents were excluded the incidence was as low as 0.3% [ 17]. In a 2006 Japanese study, DU was idiopathic in one third of cases [ 38], and the proportion of idiopathic ulcers was found to be as high as 40.6% in a Korean study conducted in 2007 [ 31]. The trend of increasing idiopathic ulcers appears to follow an exponential curve if we focus on large-scale studies with a study population > 300) () and exclude studies that included bleeding PUD (). As further evidence for the changing etiology, research conducted in Hong Kong found that only the absolute number of H. pylori-related bleeding ulcer was declining, while the number of H. pylori-negative bleeding ulcers remained stable [ 33, 44- 46]. Thus, the accumulated evidence supports the concept proposed by Graham [ 12]: non- H. pylori- and non-NSAIDs-related ulcer diseases are more likely to be found in older, sicker patients, are more resistant to acid suppression therapy, and are associated with a greater risk of bleeding and recurrence and a greater overall mortality rate as compared with traditional H. pylori-positive PUD [ 44, 45].

IDIOPATHIC PEPTIC ULCER DISEASE: A DIAGNOSIS OF EXCLUSION

Because IPUD is defined as PUD that arises without an identifiable cause, it is a diagnosis of exclusion. Possible etiologies to be excluded are shown in the (upper panel), which may include missed H. pylori infection, unidentified use of ulcerogenic medications, rare systemic diseases with upper gastrointestinal tract manifestations, hyperacidity of the stomach, and other rare infections involving the upper gastrointestinal tract.

Table 1.

Etiologies to be excluded

Missed diagnosis of Helicobacter pylori infection

Surreptitious usage of ulcerogenic medications (e.g., unrecognized nonsteroidal anti-inflammatory drugs, aspirin, and other ulcerogenic drugs)

Rare systemic diseases with upper gastrointestinal tract manifestations (e.g., Crohn's disease, mastocytosis, sarcoidosis, amyloidosis, eosinophilic gastroenteritis, and vasculitis)

Hyperacidity of the stomach (i.e., Zollinger-Ellison syndrome).

Other infections (e.g., Helicobacter heilmanii, cytomegalovirus, herpes simplex virus, tuberculosis, syphilis, and fungal infection)

Risk factors of idiopathic ulcer disease

Demographic risk factors (e.g., white race and older age)

Psychoactive substance use (e.g., tobacco use and alcohol)

Genetic risk factors (e.g., mucin genes and HLA-DQA1)

Comorbid diseases (e.g., liver cirrhosis, end-stage renal disease, diabetes mellitus, cerebrovascular accident, and malignancy)

Chronic mesenteric ischemia

Higher psychological stress

Incorrect diagnosis of H. pylori

There are several methods available to detect H. pylori infection. These methods are characterized according to whether a mucosal specimen is needed for analysis. Biopsy-based tests include histological evaluation, culture, polymerase chain reaction, and the rapid urease test (RUT). Alternatively, non-invasive methods may include the urea breath test (UBT), serology, and the stool antigen test (SAT). A meta-analysis has revealed the following pooled sensitivity and specificity for different methods: RUT 0.67 and 0.93; histology 0.70 and 0.90; culture 0.45 and 0.98; UBT 0.93 and 0.92; SAT 0.87 and 0.70; and serology 0.88 and 0.69 [ 46], respectively, which clearly demonstrates that each of the different tests has its own limitations, and a single negative test does not exclude H. pylori infection.

Current or recent use of antibiotics or proton pump inhibitors (PPIs) is known to influence the accuracy of H. pylori tests. Bacterial concentrations are decreased by these medications, leading to false-negative results. A number of studies have demonstrated a lower yield in testing for H. pylori infection in patients receiving antibiotic therapy. Borody et al. [ 17] showed that ~22% of H. pylori-negative DU patients were reported to have used antibiotics recently. Gisbert et al. [ 33] also found a lower prevalence of H. pylori in DU patients who had prior antibiotic therapy compared with those who did not (78% vs. 96%). In another study, the prevalence of H. pylori-negative DU was shown to be much lower when patients taking antibiotics within 4 weeks of testing were excluded [ 47]. In addition, the use of PPIs and histamine-2 receptor antagonists (H2RAs) can also cause false-negative results by reducing gastric acid secretion and inhibiting the growth of H. pylori. Approximately one-third of patients who remained positive for H. pylori infection had a negative UBT result while receiving PPIs [ 48]. The study even showed that the proportion of patients whose UBT results turned out to be positive after completion of PPIs therapy were 91% at 3 days, 97% at 7 days, and 100% at 14 days [ 48]. Chey et al. [ 49] also demonstrated that both PPIs and H2RAs could affect the sensitivity of UBT, with an equivocal or false-negative result of 61% and 18%, respectively.

RUT can also yield a false-negative result during an actively bleeding stage of PUD. Lee et al. [ 50] have found that the prevalence of H. pylori infection in patients presenting with bleeding DU was 72.7%, which was lower than the prevalence of 92.8% in those with non-bleeding peptic ulcers ( p < 0.05). The false-negative rate of RUT for bleeding ulcer has been reported to be up to 25% [ 50]. In another study, 55.1% of patients with bleeding ulcers with an initially negative RUT result were discovered to have a positive result at follow-up endoscopy [ 23]. Lee et al. [ 51] have demonstrated that the low sensitivity of RUT (61%) for diagnosis of H. pylori infection during bleeding peptic ulcer can be overcome by increasing the number of biopsies from the gastric antrum to 74% or from the gastric body to 73%. Some investigators speculate that these results reflect a buffering effect of serum albumin on the pH indicator of the RUT [ 52].

The location and number of biopsies taken are also important for the diagnostic accuracy of both RUTs and histological results [ 33, 45, 53, 54]. The distribution of H. pylori can be sporadic and variable in the stomach when intestinal metaplasia or atrophic gastritis develops. By histological examination, < 3% of antral biopsy specimens yielded a false-negative interpretation, compared with 6% to 9% of those from the corpus ( p = 0.02) [ 54]. Another study based on 1,000 biopsy specimens has shown that the area of H. pylori colonization was larger than the area of active chronic gastritis, suggesting that H. pylori colonization may precede the development of active chronic gastritis [ 53]. In the presence of atrophic gastritis or intestinal metaplasia, H. pylori is prone to disappear from the gastric mucosa with such a histological change [ 55]. Therefore, it is postulated that H. pylori may migrate proximally from the antrum to the corpus because of lack of acid in the atrophic antrum. A meta-analysis has suggested that the sensitivities of RUT and histology could be improved to 78% and 83%, respectively, if biopsies were taken from both the antrum and the corpus of the stomach [ 46].

Unrecognized use of ulcerogenic drugs

Surreptitious use of medications or lack of medication history with regard to ulcerogenic drugs may be of paramount importance when encountering H. pylori-negative PUD. By testing the blood for drugs, some studies have shown that a substantial number of users of ulcerogenic drugs cannot provide a correct description of their medication history [ 56, 57]. Using the platelet cyclo-oxygenase activity test, 12.7% more users of aspirin could be identified than the number obtained by clinical history alone. Sixty-six percent of NSAID users were actually taking aspirin, alone or in combination with other NSAIDS, and 59.3% of patients who claimed no (non-aspirin) NSAID use were actually using NSAIDs [ 57]. Blood salicylic acid concentrations revealed that about half of patients with intractable PUD who denied using aspirin were actually aspirin users [ 56]. Ong et al. [ 27] also found that when serum thromboxane B2 levels were checked, more than 30% of patients who were thought to have IPUD were found to have taken NSAIDs. Other possible non-NSAID, non-aspirin, ulcer-related drugs include steroids, potassium chloride, nitrogen-containing bisphosphonates, and some immunosuppressive medications [ 58, 59]. Visible gastric mucosal damage was found in 38% of patients who received alendronate as compared to 13% in the placebo group [ 59]. The results demonstrate that a valid review of medication history is mandatory before making the diagnosis of IPUD.

Excluding malignancies

Follow-up endoscopy is necessary in IPUD, especially in those patients who have alarming symptoms or recurrent ulcers, to determine whether there are secondary causes or undiscovered malignancies (). In fact, ~5% of endoscopically benign-appearing GUs are malignant [ 60, 61]. Endoscopic surveillance of the gastric pre-malignant condition has been useful in identifying early-stage malignancy at 3- to 6-month follow-up visits scheduled to confirm that the GU is healed [ 62, 63]. Although the optimal interval for endoscopic surveillance remains to be determined, repeat endoscopic biopsies, obtaining sufficient tissue involving submucosa, or targeted optical biopsy by image-enhanced endoscopy is a reasonable approach for IPUD [ 64].

Excluding rare etiologies

Rare etiologies for PUD may include unusual systemic diseases and unusual infectious pathogens. Uncommon systemic diseases, such as Crohn's disease (), mastocytosis, amyloidosis, sarcoidosis, vasculitis, eosinophilic gastroenteritis, and Zollinger-Ellison syndrome (), are possible sources of the upper gastrointestinal manifestations of PUD. Screening of the lower gastrointestinal tract for Crohn's disease and specific laboratory and radiological tests (such as repeated measurement of serum fasting gastrin, secretin stimulation test, quantification of gastric acid secretion, measurement of serum chromogranin A, radiological studies, and endoscopic ultrasound for Zollinger-Ellison syndrome) are needed to exclude these uncommon diseases. Rare infectious causes of PUD may include Helicobacter heilmanii, tuberculosis, syphilis, cytomegalovirus (), herpes simplex virus, and fungal infection ().

In summary, accurate diagnosis of classic IPUD requires a systematic approach as outlined in . Confirmation of H. pylori infection status of the stomach and duodenum by at least three parallel tests is recommended to decrease the risk of a false-negative result. Thorough review of medication history is important to identify the use of potential ulcerogenic drugs. Moreover, a complete histological study of a benign-appearing ulcerative lesion is crucial to rule out the possibility of malignancy. Repeat endoscopic biopsies, optical targeted biopsy, or obtaining tissues deeper than the mucosal layer may improve diagnostic accuracy. Zollinger-Ellison syndrome should always be kept in mind when encountering poorly-healed peptic ulcers. Finally, rare infectious agents should be considered in the differential diagnosis, especially in immunocompromised subjects.

Table 2.

Exclusion of Helicobacter pylori infection

History of use of ulcerogenic medication

Completeness of histopathology to rule out occult malignancy, inflammatory bowel disease or vasculitis

Exclusion of Zollinger-Ellison syndrome, including the measurement of serum levels of fasting gastrin and chromogranin A, basal and maximal gastric acid secretion, secretin test, and radiological studies

Exclusion of other infectious pathogens

RISK FACTORS AND THE CLINICAL COURSE OF CLASSICAL IPUD

Risk factors for classical IPUD may include demographic risk factors, use of psychoactive substances, genetic risk factors, comorbid diseases, chronic mesenteric ischemia, and higher psychological stress (, lower panel).

Demographic factors, such as being Caucasian and older age, are associated with IPUD. A greater prevalence of H. pylori-negative ulcers was found in whites than in non-whites in previous studies [ 13, 15]. In multi-racial studies, a greater prevalence of H. pylori-negative DUs was found in Malays and Chinese than in Indians [ 7, 65]. Molecular changes in gastric protective factors, such as mucin, are also hypothesized to be associated with risk of ulcers. The gastric protective layer, which prevents enzymatic attachment by gastric acid, pepsin, and other aggressive factors, is created by secreted mucin. Structural changes of membrane-bound mucin and glycan side-chain sialic acids are associated with protective efficiency against offending factors. Based on an immunochemical study of ulcer tissues, cytoplasmic MUC17 staining intensity was significantly lower in patients with IPUD than in those with H. pylori-related peptic ulcer [ 66]. In addition to genetic or epigenetic changes in the gastric mucin molecule, the HLA-DQA1*0102 allele was associated with increased risk of IPUD [ 67, 68]. Ethnic differences in the prevalence of H. pylori-negative PUD may correlate with different lifestyles or unknown genetic factors. Several studies in different areas have demonstrated that patients with IPUD are significantly older than those with PUD associated with H. pylori or NSAID use [ 23, 26, 27, 34, 69].

Older age was associated with a significantly lower level of prostaglandin concentration in the fundus, antrum, and post-bulbar duodenum [ 70]. Because prostaglandins protect the gastric mucosa from damage, diminished synthesis in elderly subjects makes their mucosa more susceptible to aggressive factors, followed by the ulcerogenic process. Moreover, older patients have higher risk for vascular disease, especially chronic mesenteric ischemia [ 71]. A combination of risk factors, including reduced blood flow, decreased production of prostaglandins by the stomach, a higher prevalence of concomitant diseases, and a higher American Society of Anesthesiologists score in the elderly render the mucosa more fragile and, thus, PUD is more likely to develop [ 16, 72, 73]. Cigarette smoking also increases xanthine oxidase activity, production of leukotrienes and nitric oxide, and neutrophil infiltration into the gastric mucosa [ 72]. An association between psychological stress and PUD has long been suggested. Two recent studies of Japanese victims of the Great East Japan Earthquake and Tsunami that occurred in 2011 have found that the incidence of PUD increased significantly after the psychological trauma [ 74, 75]. In the first 3 months after the earthquake, the incidence of PUD was increased 1.5 fold, and the incidence of bleeding PUD was increased 2.2 fold [ 74, 75]. Furthermore, after the earthquake, the proportion of IPUD doubled from 13% in 2010 to 24% in 2011 ( p < 0.05) [ 75]. A population-based study of 3,379 Danish adults in 1982 to 1983 revealed a greater incidence of ulcers among subjects in the highest tertile of stress scores (3.5%) than in those in the lowest tertile (1.6%; p < 0.01) and high psychological stress has been identified as an independent risk factor for PUD on multivariate analysis (odds ratio, 1.12 per point increment of stress index; 95% confidence interval [CI], 1.01 to 1.23; p = 0.03) [ 76].

The clinical course of IPUD remains poorly understood because of the heterogeneity of diagnostic methods and populations recruited for studies. Nevertheless, idiopathic ulcer disease tends to cause longer-lasting ulceration, a greater recurrence rate and mortality rate, and greater symptoms of dyspepsia. In addition, it is more refractory to treatment than H. pylori-positive ulcer disease [ 26, 77- 84]. Furthermore, IPUD is also more likely to present with hemorrhage, and multiple and larger ulcers [ 84]. After a bleeding episode, the risk of recurrent ulcer complications within 12 months was higher in patients with H. pylori-negative PUD than in those with H. pylori-related PUD after eradication therapy (13.4% vs. 2.5%, p < 0.001) [ 26]. In Hong Kong, a 7-year cohort study has shown that the cumulative incidence of recurrent bleeding from ulcers was higher in the H. pylori-negative ulcer cohort than in the positive cohort (42.3% vs. 11.2%, p < 0.0001), and more patients died in the H. pylori-negative ulcer cohort than in the H. pylori-positive ulcer cohort (87.6% vs. 37.3%, p < 0.0001) [ 84]. A randomized trial with a 2-year follow-up period consistently showed that the prognosis of H. pylori-negative ulcers was poorer [ 81]. The rates of recurrent ulcer or ulcer that has not healed (35% vs. 26%), and relapse of dyspepsia symptoms (16% vs. 7%) were higher in those with H. pylori-negative ulcers than in those with H. pylori-positive ulcers [ 81].

MANAGEMENT OF IDIOPATHIC PEPTIC ULCER DISEASE

As IPUD is increasingly encountered, whether we should modify the standard treatment of PUD, including short-term PPI therapy and once-off H. pylori eradication, is of clinical significance. Based on present knowledge regarding a poorer response to acid-suppressing therapy in IPUD than in H. pylori-positive ulcers, anti-secretory medication remains the mainstay of treatment [ 77]. In a Danish study, outcomes in PPI-treated patients with DU did not differ according to H. pylori status, which suggested that PPI therapy was effective in the prevention of recurrence of IPUD [ 81]. In contrast, another study from Hong Kong demonstrated that the risk of re-bleeding (2.9 per 100 person-years vs. 1.1 per 100 person-years, p < 0.001) and mortality (hazard ratio, 1.1; 95% CI, 0.6 to 1.7) were not reduced by gastro-protective agents in patients with bleeding IPUD [ 30]. Gillen et al. [ 85] found that H. pylori infection may potentiate the anti-secretory effect of PPIs. During PPI administration, median basal intragastric pH was higher in the H. pylori-positive (7.95) versus -negative (3.75) subjects ( p < 0.002) [ 85]. The poorer response to the anti-secretory therapy and altered gastric physiology of IPUD could indicate the necessity of longer duration and higher dose of acid-suppressing agents. Quan and Talley [ 45] have proposed a flow chart for the management of IPUD (). After excluding gastric H. pylori infection (by multiple testing with a parallel interpretation of results) and the use of common ulcerogenic medications, the diagnosis of clinical IPUD is made. PPIs administration for 4 to 8 weeks is recommended, and a longer duration of therapy may be needed for complicated ulcer (e.g., bleeding or perforated). Otherwise, patients with uncomplicated ulcer disease may wean off therapy with a wait-and-see strategy, or receive on-demand/maintenance PPI therapy if symptoms recur. Re-evaluation of IPUD by endoscopy should be considered. If healing is slow or absent, items listed in should be re-evaluated to confirm whether classic IPUD is the correct diagnosis.

CONCLUSIONS

An increase in the proportion of idiopathic ulcers has been confirmed worldwide, and peptic ulcer, once considered to be an infectious disease after the discovery of H. pylori, has gradually reverted to the original "no acid, no ulcer" theory. Given that the prognosis of IPUD is poorer than that of PUD associated with H. pylori or NSAIDs, careful evaluation of H. pylori infection by multiple parallel tests, detailed review of medication history, and thorough exclusion of other possible causes are of paramount importance before making the diagnosis of IPUD. Further well-designed clinical trials are needed to elucidate the natural history of IPUD, and to optimize the treatment strategy for this emerging disease.

Footnotes

No potential conflict of interest relevant to this article was reported.

REFERENCES

5. IARC Helicobacter pylori Working Group . Lyon (FR): International Agency for Research on Cancer; c2015. Helicobacter pylori eradication as a strategy for gastric cancer prevention (IARC Working Group Reports, No. 8) [Internet] [cited 2015 Jun 22]. Available from: http://www.iarc.fr/en/publications/pdfs-online/wrk/wrk8/index.php.

12. Graham DY, Large U.S. clinical trials report a high proportion of H. pylori negative duodenal ulcers at study entry as well as a high recurrence rate after cure of the infection: have we all been wrong? Gastroenterology. 1998;114(Suppl 1):A17.

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A systematic approach for the diagnosis and treatment of idiopathic peptic ulcers

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An idiopathic peptic ulcer is defined as an ulcer with unknown cause or an ulcer that appears to arise spontaneously. The first step in treatment is to exclude common possible causes, including Helicobacter pylori infection, infection with other pathogens, ...

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License this video for your hospital's health literacy or marketing initiatives: http://www.nucleushealth.com/ythealthliteracy This video, created by Nucleus Medical Media, describes common locations of stomach (or peptic) ulcers: esophageal ulcers located in your esophagus, gastric ulcers located in the antrum of your stomach, and duodenal ulcers located in the portion of your stomach connected to your small intestines.