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Rheumatology Advance Access published online on May 13, 2008
Rheumatology, doi:10.1093/rheumatology/ken123
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Use of NSAIDs and infection with Helicobacter pylori—what does the rheumatologist need to know?

U. Kiltz1, J. Zochling1, W. E. Schmidt2 and J. Braun1

1Rheumazentrum Ruhrgebiet, St. Josefs Hospital, Landgrafenstr, Herne and 2Department of Medicine I, St. Josef Hospital, Ruhr-University of Bochum Medical School, Bochum, Germany.

Correspondence to: U. Kiltz, Rheumazentrum Ruhrgebiet, St. Josefs Hospital, Landgrafenstr. 15, 44652 Herne, Germany. E-mail: kiltz{at}rheumazentrum-ruhrgbiet.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
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.

KEY WORDS: Non-steroidal anti-inflammatory drugs, Helicobacter pylori, Eradication, Gastroduodenal lesions, Rheumatoid arthritis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 Acknowledgements
 References
 
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].


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  		TABLE 1. Characteristics of methods for detection of H. pylori

 
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].


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  		TABLE 2. Guideline for the treatment of H. pylori infection, according to the Maastricht III Consensus Report

 
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
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Results
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 Acknowledgements
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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
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 Introduction
 Methods
 Results
Discussion
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 Acknowledgements
 References
 
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.


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  		TABLE 3. Major differences in the studies on H. pylori eradication for the prevention of NSAID-associated ulcers

 
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
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 Discussion
Conclusion
 Acknowledgements
 References
 
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).


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  		TABLE 4. Patient's individual risk factors

 

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  		TABLE 5. Individualized strategy for patients with NSAID use

 
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).


Figure 1
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  		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
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
Acknowledgements
 References
 
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.

Formula


   Acknowledgements
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 Acknowledgements
References
 
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
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Submitted 2 July 2007; revised version accepted 22 February 2008.
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