Abstract

Objectives. NSAID-induced gastroduodenal lesions are a frequent and potentially serious health problem in patients with rheumatic diseases. Helicobacter pylori (H. pylori) has also been recognized as a major risk factor for the development of ulcer disease. However, the role of H. pylori in the pathogenesis of NSAID-induced gastroduodenal lesions has remained controversial, and there is currently no clear consensus on the management of NSAID users who are infected with H. pylori.

Methods. To clarify this situation we have performed a systematic literature search to find randomized controlled trials comparing the efficacy of eradication in patients receiving NSAIDs to prevent ulcer development.

Results. Seven randomized controlled trials and one meta-analysis were identified. There were three papers on NSAID-naive patients. According to this data, NSAID-naive users benefit from testing for H. pylori infection and subsequent H. pylori eradication therapy prior to the initiation of NSAID. In contrast, H. pylori eradication alone does not protect chronic NSAID users with recent ulcer complications from further gastrointestinal (GI) events. To prevent recurrent ulcer bleeding long-term acid suppressive therapy is needed.

Conclusions. In conclusion, ulcer risk reduction after H. pylori eradication therapy is clearly more marked in patients beginning NSAID therapy than in patients who were already receiving and tolerating NSAID therapy. Thus, the management of H. pylori infection and the prevention of GI complications in NSAID users need to be individualized on the basis of recently published data.

Introduction

Helicobacter pylori (H. pylori) have been recognized as a major risk factor for the development of gastroduodenal ulcer disease. The lifetime risk of peptic ulcer in a person infected with H. pylori ranges from 3% in the United States to 25% in Japan [1]. Peptic ulcers may remain asymptomatic, cause different degrees of dyspepsia or cause severe complications such as bleeding and perforation. H. pylori are causally linked to a diverse spectrum of gastrointestinal (GI) diseases, including peptic ulcer disease (PUD), gastric cancer and gastric mucosa-associated lymphoid tissue (MALT) lymphoma [2]. Two prospective studies, both in high-risk populations of gastric cancer, have reported H. pylori infection as a definitive risk factor for the development of gastric cancer [3, 4]. In addition, the International Agency for Research on Cancer has categorized H. pylori as a group I carcinogen [5].

An infection with H. pylori can be diagnosed by both non-invasive and invasive methods. Non-invasive methods include the urea breath test, serological tests and stool antigen assays [6]. Invasive methods are mainly based on endoscopy and biopsies [7]. The selection of the most appropriate test to detect H. pylori depends on the clinical setting (Table 1) [8].

Table 1.

Characteristics of methods for detection of H. pylori

Method Indication Sensitivity (%) Specifity (%) 
Non-invasive    
    Urea breath test Diagnosis, follow-upa 95 100 
    Serological test Screening, diagnosisb 95 91 
    Stool antigen Diagnosis, follow-upc 89–96 96 
Invasive    
    Urease test Diagnosis 80–100         92–90 
    Histology Diagnosis 90 90 
    Culture Antibiotic sensitivity testing 80–90 95 
Method Indication Sensitivity (%) Specifity (%) 
Non-invasive    
    Urea breath test Diagnosis, follow-upa 95 100 
    Serological test Screening, diagnosisb 95 91 
    Stool antigen Diagnosis, follow-upc 89–96 96 
Invasive    
    Urease test Diagnosis 80–100         92–90 
    Histology Diagnosis 90 90 
    Culture Antibiotic sensitivity testing 80–90 95 

Adapted from Dzierzanowska-Fangrat K et al. [43]. aShould not be performed earlier than 4 weeks after eradication. bLocal validation is necessary. cShould not be performed earlier than 8 weeks after eradication.

In general, testing for H. pylori is recommended only if there is a reasonable option for treatment. Recommendations have been issued by the European Maastricht III Consensus (Table 2) [9].

Table 2.

Guideline for the treatment of H. pylori infection, according to the Maastricht III Consensus Report

Treatment is recommended Treatment is advised 
PUD Functional dyspepsia 
MALT Lymphoma PPI maintenance therapy 
Atrophic gastritis Use of NSAIDs 
Gastric cancer, including first-degree relative Iron deficiency anaemia 
Desire of the patient  
Treatment is recommended Treatment is advised 
PUD Functional dyspepsia 
MALT Lymphoma PPI maintenance therapy 
Atrophic gastritis Use of NSAIDs 
Gastric cancer, including first-degree relative Iron deficiency anaemia 
Desire of the patient  

Adapted from Malfertheiner et al. [9].

Effective anti-microbial therapy for eradication of H. pylori is available, but there is still no ideal treatment. Clinically relevant H. pylori eradication regimens must have cure rates of at least 80% without major side-effects and with minimal induction of bacterial resistance. Similar success rates have not been achieved with antibiotics alone. The so-called triple therapies, combinations of two antibiotics with one anti-secretory drug, twice daily for 7 days, have been evaluated in randomized trials [10]. The recommended first-line therapy is based on proton-pump inhibitors (PPI) in combination with 500 mg clarithromycin and either 1 g of amoxicillin or 400 mg of metronidazole, if the primary resistance to clarithromycin in the area is <15–20%. Following first-line treatment failure, 14-day PPI triple therapy employing alternative antibiotics or quadruple therapy could be used. The main anti-microbial agents used in those regimens are tetracycline, levofloxacin, rifabutin and bismuth.

Although chronic H. pylori infection is associated with gastric carcinoma, the effect of H. pylori treatment on prevention of gastric cancer development in chronic carriers is unknown. In a randomized controlled trial in a high-risk population in China, the incidence of gastric carcinoma was found to be similar in patients receiving H. pylori eradication and placebo over a period of 7.5 yrs. Only in a subgroup of H. pylori-positive participants without pre-cancerous lesions, H. pylori eradication led to a significant decrease of gastric cancer [11]. It is important in that context that there is some evidence for an association of use of NSAIDs with a decreased risk of gastric cancer in a dose-dependent manner [12].

However, NSAIDs are also well-established risk factors for the development of uncomplicated and complicated PUD [13]. In patients with rheumatic diseases, NSAID-induced gastroduodenal lesions are a frequent and potentially serious health problem. The incidence of NSAID gastropathy is in the range of 1.2–1.6% per year in patients with RA [14]. Evidence suggests that co-prescription of NSAIDs with PPIs reduce gastroduodenal lesions [15]. Simultaneously, the rate of acquisition of H. pylori has decreased substantially over recent decades in industrialized countries [1]. Hence, there may be uncertainty about the further development of the incidence of gastroduodenal ulcer diseases induced by H. pylori and NSAIDs.

The precise contribution of H. pylori to ulcerogenesis and to upper intestinal bleeding in NSAID users is not clear. Accordingly, the role of H. pylori eradication in the prevention of GI pathology is not well defined, despite the role of PPIs being well established [16]. There is, therefore, no good consensus on the optimal management of NSAID users who are infected with H. pylori.

To analyse this situation we have performed a systematic literature search to review all randomized controlled trials addressing this problem. Based on a critical review of the studies, proposals are made for clinical practice about indications for H. pylori eradication in patients who are already treated or who are about to be treated with NSAIDs with special regard to RA patients as a high-risk patient group.

Methods

Electronic searches of Medline, Embase and the Cochrane Library from 1966 to August 2006 were carried out using search terms for H. pylori, GI disease, eradication therapy and anti-inflammatory therapies. Medical Subject Heading terms were exploded where appropriate. All randomized controlled trials and meta-analyses of randomized controlled trials in any language comparing the efficacy of eradication in patients receiving NSAIDs to prevent ulcer development were included. A recursive hand search of the references of all articles reviewed and of the retrieved original studies was done to look for studies not identified by the computer search. A manual search of abstract submitted to the Digestive Disease Week between 1984 and 2006 was also performed. The following criteria were used to include published studies: first, they had to be randomized controlled trials investigating patients with H. pylori infection and NSAIDs treatment. Second, the H. pylori infection had to be confirmed by histology, culture, serology or urea breath test. Third, NSAID and PPI use had to be defined in duration and dosage of medication. Fourth, the trial profile had to compare eradication regimen vs placebo or vs PPI treatment.

Results

The literature search in the three databases generated 55 citations. Manual search did not yield any new studies. Of these, 47 studies were subsequently excluded because they did not allow adequate evaluation. No review articles were included. Altogether, seven randomized controlled trials and one meta-analysis were identified [17–24]. The main characteristics and major differences between these studies are presented in Table 3.

Table 3.

Major differences in the studies on H. pylori eradication for the prevention of NSAID-associated ulcers

 Chan et al. [17Hawkey et al. [18Pilotto et al. [19Chan et al. [20Chan et al. [21Labenz et al. [22Lai et al. [23
Baseline characteristics of the patients        
    Number of patient 92 279 66 400 100 660 140 
    Median age in years 62.5 54.9 75.4 67.5 62.5 54.7 58.2 
    Sex (M/F) 26/66 84/195 29/37 247/153 33/67 253/407 38/102 
    RA (%) 4.3 41.5 Not provided 4.6 (naproxen group) 100.0 14.6 (systemic inflammatory diseases) 35.0 
Major differences        
    Trial profile Triple therapy vs NSAID alone Triple therapy vs omeprazole Triple therapy vs pantoprazole Triple therapy vs omeprazole Triple therapy vs omeprazole Triple therapy plus 4 weeks omeprazole/placebo vs omeprazole plus 4 weeks omeprazole/placebo Triple therapy vs placebo 
    Prior NSAID use NSAID naive Chronic users Chronic users Chronic users incl. aspirin NSAID naive, concurrent use of aspirin are allowed NSAID naive, concurrent use of aspirin are allowed Chronic users 
    PPI use in the study No PPI used in both groups 20 mg omeprazole for 3 weeks in both groups 40 mg pantoprazole for 1 week (eradication) or for 1 month (control) 20 mg omeprazole for 8 weeks (eradication) or for 6 months (control) 20 mg omeprazole for 1 week in both groups 20 mg omeprazole for 1 week (eradication) followed by 4 weeks omeprazole/placebo or for 1 week omeprazole plus 4 weeks omeprazole (control/placebo) No PPI used in both groups 
    Exclusion of corticosteroid Yes Dose equivalent ≥10 mg prednisolone Not provided Yes Yes Dose equivalent ≥10 mg prednisolone Yes 
    Ulcer history Excluded Included Included Included Included Excluded Excluded 
    Dyspepsia Excluded Included Included Not provided Included Not provided Included 
    Schedule of endoscopy 2 months 1, 3 and 6 months 1 month Only in case of upper GI bleeding 6 months 5 weeks 12 weeks 
    Definition of ulcer >5 mm >3 mm >3 mm >5 mm >5 mm >3 mm >5 mm 
    NSAIDs used Naproxen Variable Diclofenac Naproxen or aspirin Diclofenac SR Diclofenac Variable 
    Eradication regimen 1-week bismuth triple therapy 1-week omeprazole triple therapy 1-week pantoprazole triple therapy 1-week bismuth triple therapy 1-week omeprazole triple therapy 1-week omeprazole triple therapy 2-weeks triple antibiotic therapy 
    Follow-up 2 months 6 months 1 month 6 months 6 months 5 weeks 3 months 
    End-points Primary: endoscopic ulcer Endoscopic ulcer or dyspepsia Gastroduodenal lesions Recurrent upper GI bleeding Primary: endoscopic ulcer/secondary: complicated ulcer Endoscopic ulcer Endoscopic ulcer 
Eradication rate        
    Intervention (%) 89* 66* 88.5* 92.0 90.0 83.3 77.6 
    Control (%) 0.0 14.0 51.6 8.5 6.0 16.8 0.0 
Endoscopic ulcer        
    Intervention (%) 7* 11.0 (endoscopy at 8 weeks)* 29* 8.6 (only naproxen group)* 9.8* 1.2 7.0 
    Control (%) 26.0 0.0 (endoscopy at 8 weeks) 9.0 2.0 (only naproxen group) 30.6 Omeprazole: 0.0, placebo 5.8* 8.5 
 Chan et al. [17Hawkey et al. [18Pilotto et al. [19Chan et al. [20Chan et al. [21Labenz et al. [22Lai et al. [23
Baseline characteristics of the patients        
    Number of patient 92 279 66 400 100 660 140 
    Median age in years 62.5 54.9 75.4 67.5 62.5 54.7 58.2 
    Sex (M/F) 26/66 84/195 29/37 247/153 33/67 253/407 38/102 
    RA (%) 4.3 41.5 Not provided 4.6 (naproxen group) 100.0 14.6 (systemic inflammatory diseases) 35.0 
Major differences        
    Trial profile Triple therapy vs NSAID alone Triple therapy vs omeprazole Triple therapy vs pantoprazole Triple therapy vs omeprazole Triple therapy vs omeprazole Triple therapy plus 4 weeks omeprazole/placebo vs omeprazole plus 4 weeks omeprazole/placebo Triple therapy vs placebo 
    Prior NSAID use NSAID naive Chronic users Chronic users Chronic users incl. aspirin NSAID naive, concurrent use of aspirin are allowed NSAID naive, concurrent use of aspirin are allowed Chronic users 
    PPI use in the study No PPI used in both groups 20 mg omeprazole for 3 weeks in both groups 40 mg pantoprazole for 1 week (eradication) or for 1 month (control) 20 mg omeprazole for 8 weeks (eradication) or for 6 months (control) 20 mg omeprazole for 1 week in both groups 20 mg omeprazole for 1 week (eradication) followed by 4 weeks omeprazole/placebo or for 1 week omeprazole plus 4 weeks omeprazole (control/placebo) No PPI used in both groups 
    Exclusion of corticosteroid Yes Dose equivalent ≥10 mg prednisolone Not provided Yes Yes Dose equivalent ≥10 mg prednisolone Yes 
    Ulcer history Excluded Included Included Included Included Excluded Excluded 
    Dyspepsia Excluded Included Included Not provided Included Not provided Included 
    Schedule of endoscopy 2 months 1, 3 and 6 months 1 month Only in case of upper GI bleeding 6 months 5 weeks 12 weeks 
    Definition of ulcer >5 mm >3 mm >3 mm >5 mm >5 mm >3 mm >5 mm 
    NSAIDs used Naproxen Variable Diclofenac Naproxen or aspirin Diclofenac SR Diclofenac Variable 
    Eradication regimen 1-week bismuth triple therapy 1-week omeprazole triple therapy 1-week pantoprazole triple therapy 1-week bismuth triple therapy 1-week omeprazole triple therapy 1-week omeprazole triple therapy 2-weeks triple antibiotic therapy 
    Follow-up 2 months 6 months 1 month 6 months 6 months 5 weeks 3 months 
    End-points Primary: endoscopic ulcer Endoscopic ulcer or dyspepsia Gastroduodenal lesions Recurrent upper GI bleeding Primary: endoscopic ulcer/secondary: complicated ulcer Endoscopic ulcer Endoscopic ulcer 
Eradication rate        
    Intervention (%) 89* 66* 88.5* 92.0 90.0 83.3 77.6 
    Control (%) 0.0 14.0 51.6 8.5 6.0 16.8 0.0 
Endoscopic ulcer        
    Intervention (%) 7* 11.0 (endoscopy at 8 weeks)* 29* 8.6 (only naproxen group)* 9.8* 1.2 7.0 
    Control (%) 26.0 0.0 (endoscopy at 8 weeks) 9.0 2.0 (only naproxen group) 30.6 Omeprazole: 0.0, placebo 5.8* 8.5 

*P ≤ 0.05.

NSAID-naive patients

There were three papers on NSAID-naive patients. According to these, NSAID-naive users benefit from testing for H. pylori infection and, if positive, H. pylori eradication therapy prior to the initiation of NSAID. In one trial, triple therapy was compared with NSAIDs alone without use of PPIs [17]. The other two studies compared triple therapy vs PPIs with different regimes [21, 22]. Notably, in two studies with RA patients, no corticosteroid use was allowed.

Chronic NSAID users

There were four papers looking at chronic NSAID users. Helicobacter pylori eradication alone did not protect chronic NSAID users with recent ulcer complications from further GI events. In two trials, triple therapy was compared with PPIs. In another one, triple therapy was tested against placebo [18–20, 23]. In the remainder, eradication therapy was compared with maintenance of PPI medication [19].

Study heterogeneity

Critical review of the studies revealed some heterogeneity in the design and the definitions used. For example, the definition of an ulcer varied almost 2-fold between studies from >3 mm to >5 mm on endoscopy. Clearly, a diameter of 3 mm will result in a higher prevalence and incidence of ulcers than a diameter of 5 mm. Similarly, there were different definitions for NSAID user as well as the types, doses, duration and their indications for NSAID use. The main confounding factors were the differences in the choice of the PPI, the obtained history of PUD and the regimes used for eradication of H. pylori. The eradication regimes were different in all studies. The regime most frequently used was 1-week triple therapy with PPI, while Chan et al. [17, 20] also used a 1-week bismuth triple therapy and Lai et al. [23] used a 2-weeks triple antibiotic therapy without PPIs. In all studies, the use of PPIs varied between no PPI use, 1-week use and 6 months use.

Nevertheless, the recent meta-analysis by Vergara et al. [24] showed a significant reduction of the ulcer risk for NSAID-naive patients receiving H. pylori eradication therapy [odds ratio (OR) = 0.26; 95% CI 0.14, 0.49] but not for chronic NSAID users (OR = 0.95; 95% CI 0.53, 1.72).

Discussion

Although the strategies to reduce the risk for PUD in patients with ongoing analgesic therapy are controversial, several conclusions can be drawn from the available data.

Role of H. pylori

The nature of the contribution of NSAIDs and H. pylori infection to the pathogenesis of PUD has not yet been elucidated. There are studies showing that the interaction between H. pylori and NSAIDs in ulcer development may be synergistic, additive, independent or antagonistic [25–30]. These conflicting data can be accounted for in part by the heterogeneity of study designs and by diversified host responses to H. pylori infection. Nevertheless, in the meta-analysis by Huang et al. [31], NSAID use and H. pylori infection were identified as independent risk factors for ulcer development which, in combination, seem to act in an additive manner. The presence of H. pylori infection was calculated to increase the risk of peptic ulcer in NSAID users by >3-fold (OR = 3.5). The prevalence of peptic ulcer in H. pylori-positive patients in that study was 53% and 21% in H. pylori-negative patients. These data suggest either that some patients with an H. pylori infection are prone to develop ulcers on exposure to NSAIDs, or that NSAIDs may worsen complications in patients with pre-existing H. pylori-induced ulcers.

Role of NSAIDs

Epidemiological studies have consistently shown that the risk of ulcer complications is substantially increased during the first 3 months of NSAID treatment [32]. Probably, initiation of NSAIDs aggravates PUD in susceptible patients, which will result in a group who can tolerate long-term NSAIDs, irrespective of their H. pylori status. A number of clinical factors have been identified which increase the risk of developing serious GI complications in NSAID users: age, concomitant medication (anti-coagulation, corticosteroid use), history of PUD and high-dose NSAID use [33]. Since NSAID-associated ulceration occurs asymptomatically, the actual frequency of gastroduodenal ulceration associated with NSAIDs is different from the number of patients who present with dyspepsia (cumulative incidence of endoscopic gastroduodenal ulcers: 25–30% after 3 months of NSAID therapy) [34]. Several mechanisms are associated with the development of PUD: in addition to certain local effects (topical injury, neutrophil adherence) the main mechanism of NSAIDs induced gastroduodenal complications is the inhibition of cyclo-oxygenase (COX)-1 and disruption of prostaglandin production [35]. Thus, NSAID use and H. pylori infection may impair the gastric mucosal defence by different mechanisms: H. pylori infection induces mucosal inflammation whereas NSAIDs inhibit the gastric prostaglandin synthesis.

Strategy in H. pylori-positive patients with NSAID use

Strategies that may prevent GI complications in H. pylori-positive patients with NSAID use include eradication of H. pylori infection and/or concurrent therapy with a PPI. Management of H. pylori-infected chronic NSAID users is believed to depend on the duration of NSAID use and the presence of risk factors (Table 4). An expert committee has recommended a treatment strategy stratified in different risk categories (Table 5).

Table 4.

Patient's individual risk factors

Chronic NSAID users   Risk factors 
Low risk No risk factors  Use of high dose or multiple NSAIDs 
   Age over 65 yrs 
   Comorbidity 
Moderate risk 1 or 2 risk factors   
High risk Multiple risk factors or Taking concomitant aspirin, corticosteroids or anti-coagulants 
Very high risk Multiple risk factors or History of ulcer bleeding 
Chronic NSAID users   Risk factors 
Low risk No risk factors  Use of high dose or multiple NSAIDs 
   Age over 65 yrs 
   Comorbidity 
Moderate risk 1 or 2 risk factors   
High risk Multiple risk factors or Taking concomitant aspirin, corticosteroids or anti-coagulants 
Very high risk Multiple risk factors or History of ulcer bleeding 

Adapted from Chan et al. [41].

Table 5.

Individualized strategy for patients with NSAID use

 Risk for ulcer complications H. pylori test-and-treat approach Long-term PPI therapy 
Naive NSAID users  Recommendation- evidence No 
Chronic NSAID users Very high risk Potential benefit Recommendation- evidence 
 High risk Potential benefit Recommendation 
 Moderate risk Potential benefit Potential benefit 
 Low risk No No 
 Risk for ulcer complications H. pylori test-and-treat approach Long-term PPI therapy 
Naive NSAID users  Recommendation- evidence No 
Chronic NSAID users Very high risk Potential benefit Recommendation- evidence 
 High risk Potential benefit Recommendation 
 Moderate risk Potential benefit Potential benefit 
 Low risk No No 

Adapted from Papatheodoridis et al. [42].

H. pylori eradication

In patients commencing NSAIDs, H. pylori eradication reduces the incidence of GI ulceration in patients who are about to start NSAID therapy but by itself is insufficient to prevent recurrent ulcer bleeding in chronic NSAID users with recent PUD. NSAID-naive users benefit from testing for H. pylori infection and, eradication therapy prior to the initiation of NSAID (test-and-treat approach). Chan et al. [21] showed a significant reduction in the incidence of peptic ulcers after H. pylori eradication in NSAID-naive patients with a history of PUD compared with a group with omeprazole and placebo antibiotics (peptic ulcers: 9.8% in the eradication group and 30.6% in the placebo group). In 1997, the same group had already shown that in NSAID-naive patients without a history of PUD, eradication of H. pylori before NSAID therapy does reduce the occurrence of NSAID-induced peptic ulcers (peptic ulcers: 7% in the eradication group and 26% in the NSAID group without eradication) [17]. The value of primary prophylaxis by eradication of H. pylori was also evaluated in a trial comparing four different interventions (three active vs one placebo group). The rate of ulcer development was significantly higher in the placebo group than in all actively treated patients, but there was no difference between the three arms (peptic ulcers: 1.2% in the eradication group and 5.8% in the placebo group) [22].

In contrast, H. pylori eradication alone does not protect chronic NSAID users with recent ulcer complications from further GI events. Furthermore, it has been shown that among chronic NSAID users with a history of ulcer bleeding, the eradication of H. pylori alone is not sufficient to prevent recurrent ulcer bleeding. However, patients receiving PPI maintenance in addition to NSAIDs (long-term PPI therapy) showed a significant reduction of recurrent bleeding compared with the patient who has had H. pylori eradication (probability of recurrent bleeding 4.4 vs 18.8%) [20]. Similar findings have been described by Hawkey et al. [18], who showed that curing H. pylori infection did not reduce the risk of ulcer in chronic NSAID users.

High-risk patients with RA often need anti-phlogistic therapy and they do have additional risk factors such as a concomitant medication with corticosteroids. Pilotto et al. [19] showed in a risk group with elderly patients that in the prevention of gastroduodenal damage, long-term PPI therapy is more effective than H. pylori eradication (peptic ulcers: 29% in the eradication group vs 9% in controls). In contrast, Lai et al. [23] failed to show a benefit of H. pylori eradication when no PPIs were taken concomitantly.

PPI prophylaxis

As discussed, PPI therapy is superior to the eradication of H. pylori for the secondary prevention of upper GI bleeding in H. pylori-infected patients who continue to take NSAIDs [20]. Any of the patients at high-risk for PUD, who need to continue taking NSAIDs, benefit from long-term PPI therapy (Fig. 1).

Fig. 1.

PPI use in NSAID therapy.

Fig. 1.

PPI use in NSAID therapy.

There has been a lot of controversy on the role of coxibs in the prevention of GI side-effects and the associated cardiovascular risk. Most data show that the GI risk is reduced by up to 50% in comparison with conventional NSAIDs, and that the cardiovascular risk is rather similar to conventional NSAIDs in subsets of patients with cardiovascular disease [36]. As mentioned previously, a history of ulcer bleeding is the single most important risk factor for NSAID-related ulcer complications, but the safety of COX-2 inhibitors in patients with a prior history of ulcer bleeding is not precisely known at present [37]. In a recently published study, Chan et al. [38] show that in patients at very high risk for recurrent ulcer bleeding, combination treatment with COX-2 inhibitor and PPI was more effective than COX-2 inhibitor alone.

Strategy in H. pylori-positive patients with NSAID use and RA

Withdrawal of NSAIDs or dose reduction is often not possible in patients with RA. Moreover, many of the patients with RA receive high-dose NSAID therapy with several concomitant medications such as corticosteroids, resulting in an increased risk for GI complications. These patients are at a very high risk for bleeding recurrence and it seems advisable to remove as many risk factors as possible. Many of the studies on NSAID use were conducted in RA patients [1, 21, 33, 35]; however, no detailed data are given regarding DMARDs or other concomitant medications. Corticosteroid use is a recognized independent risk factor for the development of gastric ulcers: an OR of 6.8 (95% CI 1.3–36.0) was found in one study, and 45% of the RA population with ulcers was H. pylori positive [39]. In addition, some DMARDs seem to have an interaction with H. pylori: use of SSZ may increase the incidence of gastric ulcers [40].

Conclusion

Ulcer risk reduction after H. pylori eradication therapy is clearly more marked in patients starting to commence NSAIDs than in patients who tolerate and were already receiving NSAID therapy. Thus, the management of H. pylori infection and the prevention of GI complications in NSAID users need to be individualized on the basis of recently published data.

graphic

Acknowledgements

We thank Prof. M. Gross, Munich, Germany, for providing Fig. 1.

Disclosure statement: W.E.S is a member of the Speakers Bureau and Advisory Board of AstraZeneca, Wedel, Germany. All other authors have declared no conflicts of interest.

References

1
Suerbaum
S
Michetti
P
Helicobacter pylori Infection
N Engl J Med
 , 
2002
, vol. 
347
 (pg. 
1175
-
86
)
2
Parsonnet
J
Friedman
GD
Vandersteen
DP
, et al.  . 
Helicobacter pylori infection and the risk of gastric carcinoma
N Engl J Med
 , 
1991
, vol. 
325
 (pg. 
1170
-
1
)
3
You
WC
Zhang
L
Gail
MH
, et al.  . 
Gastric dysplasia and gastric cancer: Helicobacter pylori, serum vitamin C, and other risk factors
J Natl Cancer Inst
 , 
2000
, vol. 
92
 (pg. 
1607
-
12
)
4
Uemura
N
Okamoto
S
Yamamoto
S
, et al.  . 
Helicobacter pylori infection and the development of gastric cancer
N Engl J Med
 , 
2001
, vol. 
345
 (pg. 
784
-
9
)
5
International Agency for Research on Cancer. Infection with Helicobacter pylori
In: Schistosomes, liver flukes, and Helicobacter pylori. IARC monographs on the evaluation of carcinogenic risks to humans. Lyon: International Agency for Research on Cancer
 , 
1994
, vol. 
61
 (pg. 
177
-
280
)
6
Vaira
D
Gatta
L
Ricci
C
Miglioli
M
Review article: diagnosis of Helicobacter pylori infection
Aliment Pharmacol Ther
 , 
2002
, vol. 
16
 
Suppl 1
(pg. 
16
-
23
)
7
Megraud
F
Advantages and disadvantages of current diagnosis tests for the detection of Helicobacter pylori
Scand J Gastroenterol Suppl
 , 
1996
, vol. 
215
 (pg. 
57
-
62
)
8
Howden
CW
Hunt
RH
Guidelines for the management of Helicobacter pylori infection. Ad Hoc Committee on Practice Parameters of the American College of Gastroenterology
Am J Gastroenterol
 , 
1998
, vol. 
93
 (pg. 
2330
-
8
)
9
Malfertheiner
P
Megraud
F
O’Morrain
C
, et al.  . 
Current concepts in the management of Helicobacter pylori infection – The Maastricht III Consensus Report
Gut
 , 
2007
, vol. 
56
 (pg. 
772
-
81
)
10
Malfertheiner
P
Bayerdorffer
E
Diete
U
, et al.  . 
The GU-MACH study: the effect of 1-week omeprazole triple therapy on Helicobacter pylori infection in patients with gastric ulcer
Aliment Pharmacol Ther
 , 
1999
, vol. 
13
 (pg. 
703
-
12
)
11
Wong
BC
Lam
SKL
Wong
WM
, et al.  . 
Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China
J Am Med Assoc
 , 
2004
, vol. 
291
 (pg. 
187
-
94
)
12
Wang
WH
Huang
JQ
Zheng
GF
Lam
SK
Karlberg
J
Wong
BC
Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis
J Natl Cancer Inst
 , 
2003
, vol. 
95
 (pg. 
1784
-
91
)
13
Chan
FKL
Leung
WK
Peptic-ulcer disease
Lancet
 , 
2002
, vol. 
360
 (pg. 
933
-
41
)
14
Fries
JF
Murtagh
KN
Bennett
M
Zatarain
E
Lingala
B
Bruce
B
The rise and decline of nonsteroidal antiinflammatory drug-associated gastropathy in rheumatoid arthritis
Arthritis Rheum
 , 
2004
, vol. 
50
 (pg. 
2433
-
40
)
15
Steen
KS
Nurmohamed
MT
Visman
I
, et al.  . 
Decreasing incidence of symptomatic gastrointestinal ulcers and ulcer complications in patients with rheumatoid arthritis
Ann Rheum Dis
 , 
2007
 
Aug 20; [Epub ahead of print]
16
Chan
FKL
NSAID-induced peptic ulcers and Helicobacter pylori infection
Drug Safety
 , 
2005
, vol. 
28
 (pg. 
287
-
300
)
17
Chan
FKL
Sung
JJY
Cung
SCS
, et al.  . 
Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers
Lancet
 , 
1997
, vol. 
350
 (pg. 
975
-
9
)
18
Hawkey
CJ
Tulassay
Z
Szczepanski
L
, et al.  . 
Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal anti-inflammatory drugs: HELP NSAIDs study
Lancet
 , 
1998
, vol. 
352
 (pg. 
1016
-
21
)
19
Pilotto
A
Di Mario
F
Franceschi
M
, et al.  . 
Pantoprazole versus one-week Helicobacter pylori eradication therapy for the prevention of acute NSAID-related gastroduodenal damage in elderly subjects
Aliment Pharmacol Ther
 , 
2000
, vol. 
14
 (pg. 
1077
-
82
)
20
Chan
FKL
Chung
SCS
Suen
BY
, et al.  . 
Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen
N Engl J Med
 , 
2001
, vol. 
344
 (pg. 
967
-
73
)
21
Chan
FKL
To
KF
Wu
JCY
, et al.  . 
Eradication of Helicobacter pylori and risk of peptic ulcers in patients starting long-term treatment with non-steroidal anti-inflammatory drugs: a randomised trial
Lancet
 , 
2002
, vol. 
359
 (pg. 
9
-
13
)
22
Labenz
J
Blum
AL
Bolten
WW
, et al.  . 
Primary prevention of diclofenac associated ulcers and dyspepsia by omeprazole or triple therapy in Helicobacter pylori positive patients: a randomised, double blind, placebo controlled, clinical trial
Gut
 , 
2002
, vol. 
51
 (pg. 
329
-
35
)
23
Lai
KC
Lau
CS
Ip
WY
, et al.  . 
Effect of treatment of Helicobacter pylori on the prevention of gastroduodenal ulcers in patients receiving long-term NSAIDs: a double-blind, placebo-controlled trial
Aliment Pharmacol Ther
 , 
2003
, vol. 
17
 (pg. 
799
-
805
)
24
Vergara
M
Catalan
M
Gisbert
JP
Calvet
X
Meta-analysis: role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users
Aliment Pharmacol Ther
 , 
2005
, vol. 
21
 (pg. 
1411
-
8
)
25
Labenz
J
Peitz
U
Kohl
H
, et al.  . 
Helicobacter pylori increases the risk of peptic ulcer bleeding: a case-control study
Ital J Gastroenterol Hepatol
 , 
1999
, vol. 
31
 (pg. 
110
-
5
)
26
Aalykke
C
Lauritsen
JM
Hallas
J
Reinholdt
S
Krogfelt
K
Lauritsen
K
Helicobacter pylori and risk of ulcer bleeding among users of nonsteroidal anti-inflammatory drugs: a case-control study
Gastroenterol
 , 
1999
, vol. 
116
 (pg. 
1305
-
9
)
27
Lanas
A
Fuentes
J
Benito
R
Serrano
P
Bajador
E
Sainz
R
Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin
Aliment Pharmacol Ther
 , 
2002
, vol. 
16
 (pg. 
779
-
86
)
28
Loeb
DS
Talley
NJ
Ahlquist
DA
Carpenter
HA
Zinsmeister
AR
Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury: the role of Helicobacter pylori infection
Gastroenterol
 , 
1992
, vol. 
102
 (pg. 
1899
-
905
)
29
Stack
WA
Atherton
JC
Hawkey
GM
Logan
RF
Hawkey
CJ
Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding
Aliment Pharmacol Ther
 , 
2002
, vol. 
16
 (pg. 
497
-
509
)
30
Pilotto
A
Leandro
G
Di Mario
F
Franceschi
M
Bozzola
L
Valerio
G
Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly: a case-control study
Digest Dis Sci
 , 
1997
, vol. 
42
 (pg. 
586
-
91
)
31
Huang
JQ
Sridhar
S
Hunt
RH
Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis
Lancet
 , 
2002
, vol. 
359
 (pg. 
14
-
22
)
32
Langman
MJ
Weil
J
Wainwright
P
, et al.  . 
Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs
Lancet
 , 
1994
, vol. 
343
 (pg. 
1075
-
8
)
33
Laine
L
Bombardier
C
Hawkey
CJ
, et al.  . 
Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis
Gastroenterol
 , 
2002
, vol. 
123
 (pg. 
1006
-
12
)
34
Hawkey
CJ
Laine
L
Simon
T
, et al.  . 
Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study
Gut
 , 
2003
, vol. 
52
 (pg. 
820
-
6
)
35
Bombardier
C
Laine
L
Reicin
A
, et al.  . 
Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis
N Engl J Med
 , 
2000
, vol. 
343
 (pg. 
1520
-
8
)
36
Borer
JS
Simon
LS
Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance
Arthritis Res Ther
 , 
2005
, vol. 
7
 
Suppl 4
(pg. 
S14
-
22
)
37
Garcia Rodriguez
LA
Jick
H
Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs
Lancet
 , 
1994
, vol. 
343
 (pg. 
769
-
72
)
38
Chan
FK
Wong
VW
Suen
BY
, et al.  . 
Combination of cyclo-oxgenase-2 inhibitor and a proton-pump inhibitor for prevention of recurrent ulcer bleeding in patients at very high risk: a double-blind, randomised trial
Lancet
 , 
2007
, vol. 
369
 (pg. 
1621
-
6
)
39
Voutilainen
M
Sokka
T
Juhola
M
Farkkila
M
Hannonen
P
Nonsteroidal anti-inflammatory drug-associated upper gastrointestinal lesions in rheumatoid arthritis patients. Relationships to gastric histology, Helicobacter pylori infection, and other risk factors for peptic ulcer
Scand J Gastroenterol
 , 
1998
, vol. 
33
 (pg. 
811
-
6
)
40
Taha
AS
Sturrock
RD
Russel
RH
Helicobacter pylori and peptic ulcers in rheumatoid arthritis patients receiving gold, sulfasalazine, and nonsteroidal anti-inflammatory drugs
Am J Gastroenterol
 , 
1991
, vol. 
87
 (pg. 
1732
-
5
)
41
Chan
FKL
Non-steroidal anti-inflammatory drugs and proton-pump inhibitors vs. Cylo-oxygenase-2 selective inhibitors in reducing the risk of recurrent ulcer bleeding in patients with arthritis
Aliment Pharmacol Ther
 , 
2005
, vol. 
21
 
Suppl 1
(pg. 
5
-
6
)
42
Papatheodoridis
GV
Archimandritis
AJ
Role of Helicobacter pylori eradication in aspirin or non-steroidal anti-inflammatory drug users
World J Gastroenterol
 , 
2005
, vol. 
11
 (pg. 
3811
-
6
)
43
Dzierzanowska-Fangrat
K
Lehours
P
Megraud
F
, et al.  . 
Diagnosis of Helicobacter pylori infection
Helicobacter
 , 
2006
, vol. 
11
 
Suppl 1
(pg. 
6
-
13
)

Comments

0 Comments