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The relation between Helicobacter pylori and nonsteroidal anti-inflammatory drugs

  • Jamie Barkin
    Correspondence
    Requests for reprints should be addressed to Jamie Barkin, MD, Division of Gastroenterology, University of Miami, Mount Sinai Medical Center, 4300 Alton Road, Suite G-22, Miami, Florida 33140
    Affiliations
    Division of Gastroenterology, University of Miami School of Medicine, Mount Sinai Medical Center, Miami, Florida, USA
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Open AccessPublished:August 16, 2004DOI:https://doi.org/10.1016/S0002-9343(98)00277-0

      Abstract

      Both infection with Helicobacter pylori and use of nonsteroidal anti-inflammatory drugs (NSAIDs) can result in gastritis and ulcers. H. pylori has been identified as a major etiologic factor in the development of peptic ulcer disease; however, its relationship to NSAID-associated toxicity is less well characterized. Several studies have suggested that NSAID use does not increase susceptibility to H. pylori, and the converse has also been suggested, namely, that H. pylori does not exacerbate NSAID-associated injury. H. pylori itself may stimulate production of gastric prostaglandins, which may have a role in ulcer healing. More carefully controlled studies may be better able to elucidate the individual and synergistic mechanisms involved in ulceration induced by H. pylori and NSAIDs. Recent studies have suggested that elimination of H. pylori before NSAID treatment decreases ulcer occurrence. Therefore, at this time, eradication of H. pylori should be considered only in certain high-risk patients, i.e., those with a history of gastroduodenal ulcers.
      Gastrointestinal (GI) ulceration and its resulting complications have long been associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs). With an increase in the availability and use of these drugs, NSAID-associated gastropathy has become a significant source of morbidity and mortality, and its treatment has become a major economic concern. In attempts to quantitate and characterize the scale of the problem, many epidemiologic studies have identified factors that increase the risk of these events. In nearly all studies, increasing age has been shown to be a significant risk factor.
      • Fries J.F.
      • Miller S.R.
      • Spitz P.W.
      • et al.
      Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use.
      ,
      • Henry D.
      • Dobson A.
      • Turner C.
      Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs.
      With nearly half of the NSAIDs being prescribed for persons >60 years of age, there is significant risk of toxicity in this population.
      Identification of Helicobacter pylori as the primary etiologic factor in the development of peptic ulcer disease and the observation that the incidence of H. pylori also increases with age
      • Dooley C.P.
      • Cohen H.
      • Fitzgibbons P.L.
      • et al.
      Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons.
      have raised the question of a possible synergistic relation between the presence of H. pylori infection and NSAID use in the development of gastropathy.
      Despite numerous studies, this question has not yet been satisfactorily resolved; a brief survey of the literature will show that the data are not particularly convincing for or against this hypothesis. Since half of all NSAID prescriptions are for a population not only considered at increased risk for NSAID-associated gastropathy but who also have >60% prevalence of H. pylori, it is not clear if the individual effects of the 2 variables can in fact be distinguished.

      Confounding factors in H. pylori–NSAID studies

      When considering the studies that have analyzed the relation between H. pylori and NSAID-induced gastropathy, it becomes clear that there are many factors that have not been—and in some cases could not have been—controlled that may significantly affect the outcome.
      The use of one particular NSAID may convey a different risk factor than does another NSAID; several studies have determined that the various NSAIDs have different relative risks for GI complications that in some cases may be dose dependent.
      • Henry D.
      • Lim L.L.-Y.
      • García Rodríguez L.A.
      • et al.
      Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs results of a collaborative meta-analysis.
      The toxicity of an NSAID seems to be related to its ability to inhibit cyclo-oxygenase-1 (COX-1) compared with its ability to inhibit cyclo-oxygenase-2 (COX-2), as indicated by the observation that the increase in the relative risk of individual NSAIDs in a meta-analysis
      • Henry D.
      • Lim L.L.-Y.
      • García Rodríguez L.A.
      • et al.
      Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs results of a collaborative meta-analysis.
      parallels the increase in potency against COX-1.
      • Mitchell J.A.
      • Akarasereenont P.
      • Thiemermann C.
      • et al.
      Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.
      In addition, specific host factors, other than age, may contribute to outcome but have not often been considered. An example is the decrease in gastric and duodenal mucosal blood flow that occurs during NSAID use, which may be exacerbated by factors such as smoking and H. pylori; these latter factors, however, alter mucosal blood flow in the absence of NSAID use.
      • Taha A.S.
      • Angerson W.
      • Nakshabendi I.
      • et al.
      Gastric and duodenal mucosal blood flow in patients receiving non-steroidal anti-inflammatory drugs influence of age, smoking, ulceration and Helicobacter pylori.
      For H. pylori, specific gene expression results in variability in the pathogenicity of various strains.
      • Figura N.
      Identifiable Helicobacter pylori strains or factors important in the development of duodenal ulcer disease.
      ,
      • Mobley H.L.
      Helicobacter pylori factors associated with disease development.
      In clinical trials, there is usually no characterization of the strains with respect to this pathogenicity. Consequently, this pathogenic variability can provide an uncontrolled variable when comparing studies, since the prevalence rates of the different strains may vary depending on geographic location.
      The accurate determination of the presence of H. pylori is critical to the outcome of these studies, yet the choice of diagnostic test can provide an added variable. Currently, there are 3 basic means for determining the presence of H. pylori: (1) serologic testing; (2) the urease breath test; and (3) endoscopy with biopsy, utilizing culture, histologic assessment, or a rapid urease test. Evaluation of the biopsy specimen provides the most reliable method, but since it requires an invasive technique, it is used primarily in patients already requiring endoscopy. Serologic testing is widely used, and although it has been shown to be reasonably accurate in predicting the H. pylori status of patients who have not been treated for this organism,
      • Cutler A.F.
      • Havstad S.
      • Ma C.K.
      • et al.
      Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection.
      it may not be as useful a method during or directly after treatment, since the decrease in H. pylori–specific immunoglobulin is time dependent over a period as long as 6–12 months.
      • Cutler A.
      • Schubert A.
      • Schubert T.
      Role of Helicobacter pylori serology in evaluating treatment success.
      ,
      • Perez-Perez G.I.
      • Cutler A.F.
      • Blaser M.J.
      Value of serology as a noninvasive method for evaluating the efficacy of treatment of Helicobacter pylori infection.
      Furthermore, both the specificity and the sensitivity varies among the several serologic test systems, with the possibility that the specificity is compromised in the presence of NSAIDs.
      • Taha A.S.
      • Boothman P.
      • Nakshabendi I.
      • et al.
      Diagnostic tests for Helicobacter pyloricomparison and influence of non-steroidal anti-inflammatory drugs.
      ,
      • Taha A.S.
      • Reid J.
      • Boothman P.
      • et al.
      Serological diagnosis of Helicobacter pylori—evaluation of four tests in the presence or absence of non-steroidal anti-inflammatory drugs.
      In one study, 23% of the patients who tested positive by serology were shown to be negative by the rapid urease test.
      • Hawkey G.M.
      • Everitt S.
      • Pearson G.M.
      • et al.
      Non-steroidal anti-inflammatory drugs and Helicobacter pylori as independent risk factors for peptic ulcer bleeding.
      The urease breath test, although highly sensitive and specific, requires specialized equipment and is more difficult to perform, and hence is not readily available. A new approach may combine the specificity and sensitivity of the invasive technique with the ease and availability of the serologic method. The polymerase chain reaction (PCR) is a molecular biology technique that can not only detect the presence of H. pylori using gastric juice and oral secretions, but should also be able to distinguish between isolates of different pathogenicities.
      • Westblom T.U.
      • Phadnis S.
      • Yang P.
      • Czinn S.J.
      Diagnosis of Helicobacter pylori infection by means of a polymerase chain reaction assay for gastric juice aspirates.
      ,
      • Westblom T.U.
      Molecular diagnosis of Helicobacter pylori.
      However, this assay has not yet become widely used in clinical studies.
      Another important variable in endoscopic studies is lack of a standard definition for standard terminology; the distinctions among evaluated criteria such as gastritis, erosions, submucosal hemorrhage, and even ulcers may vary from place to place. In a similar manner, what needs to be determined are appropriate endpoints for studies, i.e., are the studies looking at peptic ulcer disease, gastritis, mucosal hemorrhage, or endoscopic ulcers. An observed interaction between H. pylori and NSAIDs may depend on the endpoint chosen and the methodology employed.
      With the above caveats in mind, what do the studies actually show?

      NSAID use does not increase susceptibility to H. pylori

      Although mucosal injury, such as occurs with NSAID use, might be expected to result in increased susceptibility to H. pylori colonization, several studies have shown that such an interaction does not occur.
      • Caselli M.
      • Pazzi P.
      • LaCorte R.
      • et al.
      Campylobacter-like organisms, nonsteroidal anti-inflammatory drugs and gastric lesions in patients with rheumatoid arthritis.
      ,
      • Shallcross T.M.
      • Rathbone B.J.
      • Wyatt J.I.
      • Heatley R.V.
      Helicobacter pylori associated chronic gastritis and peptic ulceration in patients taking non-steroidal anti-inflammatory drugs.
      ,
      • Graham D.Y.
      • Lidsky M.D.
      • Cox A.M.
      • et al.
      Long-term nonsteroidal antiinflammatory drug use and Helicobacter pylori infection.
      ,
      • Loeb D.S.
      • Talley N.J.
      • Ahlquist D.A.
      • et al.
      Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury the role of Helicobacter pylori.
      ,
      • Santucci L.
      • Fiorucci S.
      • Patoia L.
      • et al.
      Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens.
      If anything, there appears to be a negative correlation between the use of NSAIDs and the incidence of H. pylori. Several studies have determined that there is a lower incidence of H. pylori in patients taking NSAIDs.
      • Caselli M.
      • Pazzi P.
      • LaCorte R.
      • et al.
      Campylobacter-like organisms, nonsteroidal anti-inflammatory drugs and gastric lesions in patients with rheumatoid arthritis.
      ,
      • Taha A.S.
      • Nakshabendi I.
      • Lee F.D.
      • et al.
      Chemical gastritis and Helicobacter pylori related gastritis in patients receiving non-steroidal anti-inflammatory drugs comparison and correlation with peptic ulceration.
      ,
      • Laine L.
      • Marin-Sorensen M.
      • Weinstein W.M.
      Nonsteroidal antiinflammatory drug-associated gastric ulcers do not require Helicobacter pylori for their development.
      One study determined that there may even be toxic effects on the H. pylori, at least with the use of aspirin.
      • Caselli M.
      • Pazzi P.
      • LaCorte R.
      • et al.
      Campylobacter-like organisms, nonsteroidal anti-inflammatory drugs and gastric lesions in patients with rheumatoid arthritis.
      The minimum inhibitory concentration (MIC) for aspirin against H. pylori was in the range that is clinically relevant. The MICs for 2 other NSAIDs, diclofenac and ketoprofen, although lower than their peak plasma concentrations, could conceivably be reached in vivo in the milieu of the gastric mucosal surface as the drugs dissociate and become absorbed.

      H. pylori gastritis and NSAID-induced gastritis are mutually exclusive

      Whereas H. pylori is associated with a chronic, histologic gastritis,
      • Dooley C.P.
      • Cohen H.
      • Fitzgibbons P.L.
      • et al.
      Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons.
      use of NSAIDs gives rise to a reactive or chemical gastritis that is also observed with other drugs or under the condition of bile reflux.
      • Taha A.S.
      • Nakshabendi I.
      • Lee F.D.
      • et al.
      Chemical gastritis and Helicobacter pylori related gastritis in patients receiving non-steroidal anti-inflammatory drugs comparison and correlation with peptic ulceration.
      ,
      • Quinn C.M.
      • Bjarnason I.
      • Price A.B.
      Gastritis in patients on non-steroidal anti-inflammatory drugs.
      ,
      • McCarthy C.J.
      • McDermott M.
      • Hourihane D.
      • O’Morain C.
      Chemical gastritis induced by naproxen in the absence of Helicobacter pylori infection.
      This reactive gastritis may be histologically distinguished from that caused by H. pylori by the presence of foveolar hyperplasia and muscle fibers in the lamina propria, as well as edema and vasodilation.
      • Taha A.S.
      • Nakshabendi I.
      • Lee F.D.
      • et al.
      Chemical gastritis and Helicobacter pylori related gastritis in patients receiving non-steroidal anti-inflammatory drugs comparison and correlation with peptic ulceration.
      In studies involving NSAID users who were also positive for H. pylori, it was shown that the 2 types of gastritis can arise from their respective causes independently of the presence of the other cause, that both types result in ulceration, and that there does not appear to be exacerbation of histologic gastritis by NSAIDs.
      • Shallcross T.M.
      • Rathbone B.J.
      • Wyatt J.I.
      • Heatley R.V.
      Helicobacter pylori associated chronic gastritis and peptic ulceration in patients taking non-steroidal anti-inflammatory drugs.
      ,
      • Taha A.S.
      • Nakshabendi I.
      • Lee F.D.
      • et al.
      Chemical gastritis and Helicobacter pylori related gastritis in patients receiving non-steroidal anti-inflammatory drugs comparison and correlation with peptic ulceration.
      ,
      • Quinn C.M.
      • Bjarnason I.
      • Price A.B.
      Gastritis in patients on non-steroidal anti-inflammatory drugs.
      ,
      • Laine L.
      • Cominelli F.
      • Sloane R.
      • et al.
      Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production a controlled double-blind trial.
      In what may be a consequence of an observed reduction of incidence of H. pylori in NSAID users, some studies have shown a lower incidence of chronic gastritis in NSAID users than in nonusers.
      • Shallcross T.M.
      • Rathbone B.J.
      • Wyatt J.I.
      • Heatley R.V.
      Helicobacter pylori associated chronic gastritis and peptic ulceration in patients taking non-steroidal anti-inflammatory drugs.
      ,
      • Laine L.
      • Marin-Sorensen M.
      • Weinstein W.M.
      Nonsteroidal antiinflammatory drug-associated gastric ulcers do not require Helicobacter pylori for their development.

      H. pylori does not exacerbate NSAID-associated mucosal injury

      Several studies that utilized the Lanza endoscopy scoring system to quantitate mucosal injury as an endpoint determined that the presence of H. pylori had no effect on NSAID-associated gastroduodenal mucosal injury or adaptation to such injury. A study by Lanza et al
      • Lanza F.L.
      • Evans D.G.
      • Graham D.Y.
      Effect of Helicobacter pylori infection on the severity of gastroduodenal mucosal injury after the acute administration of naproxen or aspirin to normal volunteers.
      showed that in younger patients (<45 years) with no prior history of peptic ulcer disease, those who were serologically positive for H. pylori did not have any greater mucosal injury after 7 days of naproxen or aspirin treatment than did patients who were serologically negative. The concern of this study is that although the risk of NSAID-associated gastropathy is considered to be greatest during early treatment, short-term NSAID studies have been shown to be poor predictors of long-term complications. However, longer studies arrived at conclusions similar to those of the Lanza study.
      In several 4-week studies, there was no statistical difference in the degree of gastric mucosal damage between H. pylori–positive and H. pylori–negative patients taking NSAIDs or placebo.
      • Laine L.
      • Cominelli F.
      • Sloane R.
      • et al.
      Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production a controlled double-blind trial.
      ,
      • Goggin P.M.
      • Collins D.A.
      • Jazrawi R.P.
      • et al.
      Prevalence of Helicobacter pylori infection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis.
      ,
      • Thillainayagam A.V.
      • Tabaqchali S.
      • Warrington S.J.
      • Farthing M.J.
      Interrelationships between Helicobacter pylori infection, nonsteroidal antiinflammatory drugs and gastroduodenal disease a prospective study in healthy volunteers.
      ,
      • Lipscomb G.R.
      • Wallis N.
      • Armstrong G.
      • et al.
      Influence of Helicobacter pylori on gastric mucosal adaptation to naproxen in man.
      In one of these studies in which naproxen was used in a healthy patient population whose mean age was 29.6 years and who had no history of peptic ulcer disease, the investigators also determined that there were no significant differences in mucosal blood flow between the H. pylori–positive and H. pylori–negative groups. They further observed no difference in the degree of gastric mucosal adaptation to naproxen between the groups, as indicated by significant reductions in median damage score in both groups by day 28 compared with day 1.
      • Lipscomb G.R.
      • Wallis N.
      • Armstrong G.
      • et al.
      Influence of Helicobacter pylori on gastric mucosal adaptation to naproxen in man.
      Similar results were obtained in a 6-month study that compared an asymptomatic patient population >40 years of age who were taking a variety of NSAIDs for rheumatoid arthritis with healthy age-matched controls who were not taking NSAIDs.
      • Loeb D.S.
      • Talley N.J.
      • Ahlquist D.A.
      • et al.
      Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury the role of Helicobacter pylori.
      They found no difference in H. pylori prevalence between the 2 study groups, and the presence of H. pylori could not be correlated with severity of mucosal injury.
      Another study that did not specifically state a time frame but indicated long-term exposure to NSAIDs reported a significantly lower percentage of patients with gastric hemorrhages and a quantifiably lower percentage with gastric mucosal erosions in H. pylori–positive NSAID users (32% and 34%, respectively) than in H. pylori–negative NSAID users (61% and 57%, respectively).
      • Graham D.Y.
      • Lidsky M.D.
      • Cox A.M.
      • et al.
      Long-term nonsteroidal antiinflammatory drug use and Helicobacter pylori infection.
      Two recent studies on the enhancement of ulcer healing by the proton pump inhibitor omeprazole suggest that the presence of H. pylori is a positive prognostic factor for ulcer healing.
      • Hawkey C.J.
      • Karrasch J.A.
      • Szczepanski L.
      • et al.
      Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group.
      ,
      Yeomans ND, Tulassay Z, Juhász L, et al. for the Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) Study Group
      A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.
      In both studies, the success rate of omeprazole, as well as of ranitidine in one of the studies, was greater in H. pylori–positive patients than in H. pylori–negative patients; the presence of H. pylori was assessed by the rapid urease test.
      Although it is unlikely that H. pylori conveys protection against NSAID injury, these data may point to a possible explanation for the reported lack of significant synergism between NSAIDs and H. pylori: H. pylori induces an increase in mucosal prostaglandins.
      • Laine L.
      • Cominelli F.
      • Sloane R.
      • et al.
      Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production a controlled double-blind trial.
      ,
      • Hudson N.
      • Balsitis M.
      • Filipowicz F.
      • Hawkey C.J.
      Effect of Helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs.
      The studies discussed above contrast with 2 studies that indicated an exacerbation of NSAID toxicity in the presence of H. pylori.
      • Santucci L.
      • Fiorucci S.
      • Patoia L.
      • et al.
      Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens.
      ,
      • Heresbach D.
      • Raoul J.L.
      • Bretagne J.F.
      • et al.
      Helicobacter pylori a risk and severity factor of non-steroidal anti-inflammatory drug induced gastropathy.
      However, one of these studies suggested that the additive effect between H. pylori and NSAIDs may occur in cases in which the NSAID is one that already has an increased risk of gastric toxicity.
      • Santucci L.
      • Fiorucci S.
      • Patoia L.
      • et al.
      Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens.
      The other study was a prospective study that included groups of patients already presenting with moderate-to-severe mucosal injury, including bleeding,
      • Heresbach D.
      • Raoul J.L.
      • Bretagne J.F.
      • et al.
      Helicobacter pylori a risk and severity factor of non-steroidal anti-inflammatory drug induced gastropathy.
      and this preselection may thus present a built-in sampling bias.

      H. pylori and NSAIDs are both associated with ulcerogenesis

      Numerous studies have determined that both H. pylori and NSAIDs are independent risk factors for the development of ulcers. However, similar to what has been observed for gastric mucosal injury, there are currently no convincing studies suggesting that these factors are additive or synergistic when endoscopically detected ulcers are used as an endpoint.
      In a prospective study by Kim and Graham,
      • Kim J.G.
      • Graham D.Y.
      The Misoprostol Study Group
      Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy.
      there was no significant difference between the percentage of H. pylori–positive long-term NSAID users who developed gastroduodenal ulcers (50%) and the percentage of H. pylori–negative long-term NSAID users who developed ulcers (50%). Although serology was the method of H. pylori analysis, if anything the use of this method might actually have overestimated the H. pylori–positive population.
      Two studies did report a higher incidence of gastric or duodenal ulcers in H. pylori–positive NSAID users than in H. pylori–negative users.
      • Li E.K.M.
      • Sung J.J.Y.
      • Suen R.
      • et al.
      Helicobacter pylori infection increases the risk of peptic ulcers in chronic users of non-steroidal anti-inflammatory drugs.
      ,
      • Pilotto A.
      • Franceschi M.
      • Leandro G.
      • et al.
      The effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly.
      The findings from these studies only support the idea that H. pylori is a risk factor for ulcers; the studies should not suggest any additive or synergistic relation, since control groups of non-NSAID users were not included. The same conclusion was reached by Greenberg
      • Greenberg P.D.
      • Albert C.M.
      • Ridker P.M.
      • et al.
      Helicobacter pylori as a risk factor for peptic ulcers in patients taking low-dose aspirin.
      in a prospective, nested, case-controlled study of patients taking acetylsalicylic acid. He found that H. pylori was a risk factor for ulceration in patients taking aspirin or placebo.
      The only recent study that shows a positive correlation between H. pylori and increased risk of NSAID-induced ulcers is based on eradication of H. pylori using triple therapy: bismuth subcitrate, tetracycline, and metronidazole.
      • Chan F.K.
      • Sung J.J.
      • Chung S.C.
      • et al.
      Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.
      In this study, 26% of the patients on naproxen who were also H. pylori positive developed ulcers, compared with only 3% of the patients in whom H. pylori was successfully eradicated before NSAID therapy. The uncertainty in this study deals with the use of bismuth, which can accumulate in the GI system and has other effects on the GI mucosa, including stimulation of prostaglandin synthesis that can be maintained during and beyond the duration of treatment.
      • Mertz-Nielsen A.
      • Steenberg P.
      • Neumark T.
      • et al.
      Colloidal bismuth subcitrate causes sustained release of gastric mucosal prostaglandin E2.
      (Cf. H. pylori eradication may be of benefit in NSAID users, this article.)

      H. pylori and NSAIDs both are risk factors for ulcer complications

      Ulcer complications, especially bleeding, are the major cause of morbidity and mortality in patients with peptic ulcer disease. Several studies have addressed the question of whether H. pylori, NSAIDs, or the combination presents a greater risk for upper GI bleeds. Although most of these studies did show that H. pylori and NSAIDs are risk factors for upper GI bleeding, there is still no consensus on whether H. pylori exacerbates NSAID-associated bleeds. Most studies have shown that H. pylori and NSAIDs are independent risk factors that do not seem to have an additive or synergistic effect
      • Hawkey G.M.
      • Everitt S.
      • Pearson G.M.
      • et al.
      Non-steroidal anti-inflammatory drugs and Helicobacter pylori as independent risk factors for peptic ulcer bleeding.
      ,
      • Pilotto A.
      • Leandro G.
      • Di Mario F.
      • et al.
      Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly a case control study.
      ,
      • Labenz J.
      • Tillenburg B.
      • Stolte M.
      • et al.
      Ulcer healing by eradicating Helicobacter pylori.
      ; several studies have suggested that NSAIDs themselves are the primary risk factor.
      • Hawkey G.M.
      • Everitt S.
      • Pearson G.M.
      • et al.
      Non-steroidal anti-inflammatory drugs and Helicobacter pylori as independent risk factors for peptic ulcer bleeding.
      ,
      • Pilotto A.
      • Leandro G.
      • Di Mario F.
      • et al.
      Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly a case control study.
      ,
      • Al-Assi M.T.
      • Genta R.M.
      • Karttunen T.J.
      • Graham D.Y.
      Ulcer site and complications relation to Helicobacter pylori infection and NSAID use.
      Al-Assi et al
      • Al-Assi M.T.
      • Genta R.M.
      • Karttunen T.J.
      • Graham D.Y.
      Ulcer site and complications relation to Helicobacter pylori infection and NSAID use.
      recently suggested that NSAID use may in fact exacerbate H. pylori–induced ulcers and their complications. This suggestion is based on data obtained during the Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA) study, which showed that a prior history of peptic ulcer disease and/or gastrointestinal bleeding was a primary risk factor for NSAID-associated bleeds, although H. pylori itself was not studied as a potentially confounding factor.
      • Silverstein F.E.
      • Graham D.Y.
      • Senior J.R.
      • et al.
      Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial.
      ,
      • Simon L.S.
      • Hatoum H.T.
      • Bittman R.M.
      • et al.
      Risk factors for serious nonsteroidal-induced gastrointestinal complications regression analysis of the MUCOSA trial.
      Only one study has so far suggested that H. pylori increases the risk for NSAID-induced bleeding. This study compared the presence of H. pylori, assayed by serology or the urease breath test, in NSAID patients with, and in those without, bleeding peptic ulcers and determined that the presence of H. pylori is associated with a 2-fold increase in risk for bleeding peptic ulcer among NSAID users.
      • Aalykke C.
      • Lauritsen J.M.
      • Hallas J.
      • et al.
      Helicobacter pylori—a risk factor in NSAID-related bleeding peptic ulcer a prospective case control study.

      H. pylori is associated with increased mucosal prostaglandin production

      As previously mentioned, the incidence of NSAID-associated gastric mucosa injury appears to be lower in the presence of H. pylori. The apparent association between H. pylori and increased levels of mucosal prostaglandin production may provide a possible explanation, since prostaglandins are important mediators of mucosal protection and ulcer healing.
      Although an early study
      • Taha A.S.
      • McLaughlin S.
      • Holland P.J.
      • et al.
      Effect on gastric and duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis.
      found a correlation between increased prostaglandin levels and gastritis regardless of H. pylori status, more recent studies have determined that higher prostaglandin production occurs in H. pylori–positive patients.
      • Laine L.
      • Cominelli F.
      • Sloane R.
      • et al.
      Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production a controlled double-blind trial.
      ,
      • Hudson N.
      • Balsitis M.
      • Filipowicz F.
      • Hawkey C.J.
      Effect of Helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs.
      Furthermore, the decrease in mucosal prostaglandin production associated with some NSAIDs, such as naproxen,
      • Laine L.
      • Cominelli F.
      • Sloane R.
      • et al.
      Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production a controlled double-blind trial.
      ,
      • Taha A.S.
      • McLaughlin S.
      • Holland P.J.
      • et al.
      Effect on gastric and duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis.
      ,
      • Laine L.
      • Sloane R.
      • Ferretti M.
      • Cominelli F.
      A randomized, double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production.
      is ameliorated by the presence of H. pylori
      • Laine L.
      • Cominelli F.
      • Sloane R.
      • et al.
      Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production a controlled double-blind trial.
      ,
      • Hudson N.
      • Balsitis M.
      • Filipowicz F.
      • Hawkey C.J.
      Effect of Helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs.
      ; i.e., the level of prostaglandin synthesis in NSAID users who are histologically positive for H. pylori is approximately equivalent to that of control subjects.

      H. pylori eradication may be of benefit in NSAID users

      Two studies have addressed the question of whether H. pylori eradication is beneficial to NSAID users. Bianchi Porro et al
      • Bianchi Porro G.
      • Parente F.
      • Imbesi V.
      • et al.
      Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users response to omeprazole dual therapy.
      used the combination of amoxicillin and omeprazole in long-term NSAID users with H. pylori and determined that the presence of H. pylori did not significantly affect the rate of ulcer healing. However, in the 6-month follow-up after cessation of omeprazole therapy and after ulcer healing, there was a quantitatively higher rate (not significant) of ulcer recurrence in an H. pylori–positive group (46%) compared with the H. pylori–negative (27%) or H. pylori–eradicated (31%) groups. These data not only suggest that a combination of H. pylori and NSAIDs may be more damaging to the gastric mucosa than NSAIDs alone, but also indirectly suggest that H. pylori eradication may be of benefit in patients requiring NSAIDs.
      The second study, by Chan et al,
      • Chan F.K.
      • Sung J.J.
      • Chung S.C.
      • et al.
      Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.
      found that eradication of H. pylori using a triple therapy (bismuth subcitrate, tetracycline, and metronidazole) before NSAID administration significantly decreased the occurrence of NSAID-associated ulcers. In this study, 12 of 47 H. pylori– positive patients (26%) developed gastric and/or duodenal ulcers after 8 weeks of naproxen administration. This was significantly (p = 0.01) greater than the 7% of patients (3 of 45) who developed NSAID-associated ulcers in the H. pylori–eradication group. The difference becomes even more significant (p = 0.002) if it is considered that 2 of the 3 ulcers in the eradication group were in patients in whom eradication therapy failed; the overall percentage of successful eradication was 89%. However, as stated previously, the use of bismuth in this study may provide an additional uncontrolled protective factor.
      It is important to note that neither of these studies indicate any adverse effects of eradicating H. pylori, and indeed, there may be benefits. However, it has been suggested that H. pylori may be an innocent bystander to NSAID-induced injury,
      • Berkelhammer C.
      Helicobacter pylori and ulcer in patients taking NSAIDs.
      and if this proves to be the case, eradication may not necessarily predict a better outcome during NSAID use.

      Summary

      Although broad generalizations may be possible regarding the effects of both H. pylori and NSAIDs on the upper GI tract, the available data do not unequivocally suggest an interaction between these 2 ulcerogenic agents or suggest specific mechanisms of protection or pathogenesis. What needs to be obtained is a consensus on the specific questions to be addressed and on the specific studies, i.e., endpoints, patient populations, and appropriate methodology, that should be initiated to more clearly determine the relationship between these 2 agents of GI pathogenesis.
      However, given that the eradication of H. pylori before initiation of NSAID therapy maybe beneficial, it may be prudent to consider such a course, as recommended in the NIH consensus report,
      NIH Consensus Conference: Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. Helicobacter pylori in peptic ulcer disease.
      in patients determined to be at high risk for a complication of NSAID use, i.e., those patients with a history of gastroduodenal ulcers.

      References

        • Fries J.F.
        • Miller S.R.
        • Spitz P.W.
        • et al.
        Toward an epidemiology of gastropathy associated with nonsteroidal antiinflammatory drug use.
        Gastroenterology. 1989; 96: 647-655
        • Henry D.
        • Dobson A.
        • Turner C.
        Variability in the risk of major gastrointestinal complications from nonaspirin nonsteroidal anti-inflammatory drugs.
        Gastroenterology. 1993; 105: 1078-1088
        • Dooley C.P.
        • Cohen H.
        • Fitzgibbons P.L.
        • et al.
        Prevalence of Helicobacter pylori infection and histologic gastritis in asymptomatic persons.
        N Engl J Med. 1989; 321: 1562-1566
        • Henry D.
        • Lim L.L.-Y.
        • García Rodríguez L.A.
        • et al.
        Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs.
        BMJ. 1996; 312: 1563-1566
        • Mitchell J.A.
        • Akarasereenont P.
        • Thiemermann C.
        • et al.
        Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.
        Proc Natl Acad Sci USA. 1993; 90: 11693-11697
        • Taha A.S.
        • Angerson W.
        • Nakshabendi I.
        • et al.
        Gastric and duodenal mucosal blood flow in patients receiving non-steroidal anti-inflammatory drugs influence of age, smoking, ulceration and Helicobacter pylori.
        Aliment Pharmacol Ther. 1993; 7: 41-45
        • Figura N.
        Identifiable Helicobacter pylori strains or factors important in the development of duodenal ulcer disease.
        Helicobacter. 1997; 2: S3-S12
        • Mobley H.L.
        Helicobacter pylori factors associated with disease development.
        Gastroenterology. 1997; 113: S21-S28
        • Cutler A.F.
        • Havstad S.
        • Ma C.K.
        • et al.
        Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection.
        Gastroenterology. 1995; 109: 136-141
        • Cutler A.
        • Schubert A.
        • Schubert T.
        Role of Helicobacter pylori serology in evaluating treatment success.
        Dig Dis Sci. 1993; 38: 2262-2266
        • Perez-Perez G.I.
        • Cutler A.F.
        • Blaser M.J.
        Value of serology as a noninvasive method for evaluating the efficacy of treatment of Helicobacter pylori infection.
        Clin Infect Dis. 1997; 25: 1038-1043
        • Taha A.S.
        • Boothman P.
        • Nakshabendi I.
        • et al.
        Diagnostic tests for Helicobacter pylori.
        J Clin Pathol. 1992; 45: 709-712
        • Taha A.S.
        • Reid J.
        • Boothman P.
        • et al.
        Serological diagnosis of Helicobacter pylori—evaluation of four tests in the presence or absence of non-steroidal anti-inflammatory drugs.
        Gut. 1993; 34: 461-465
        • Hawkey G.M.
        • Everitt S.
        • Pearson G.M.
        • et al.
        Non-steroidal anti-inflammatory drugs and Helicobacter pylori as independent risk factors for peptic ulcer bleeding.
        Gastroenterology. 1997; 112 (Abstr.): A144
        • Westblom T.U.
        • Phadnis S.
        • Yang P.
        • Czinn S.J.
        Diagnosis of Helicobacter pylori infection by means of a polymerase chain reaction assay for gastric juice aspirates.
        Clin Infect Dis. 1993; 16: 367-371
        • Westblom T.U.
        Molecular diagnosis of Helicobacter pylori.
        Immunol Invest. 1997; 26: 163-174
        • Caselli M.
        • Pazzi P.
        • LaCorte R.
        • et al.
        Campylobacter-like organisms, nonsteroidal anti-inflammatory drugs and gastric lesions in patients with rheumatoid arthritis.
        Digestion. 1989; 44: 101-104
        • Shallcross T.M.
        • Rathbone B.J.
        • Wyatt J.I.
        • Heatley R.V.
        Helicobacter pylori associated chronic gastritis and peptic ulceration in patients taking non-steroidal anti-inflammatory drugs.
        Aliment Pharmacol Ther. 1990; 4: 515-522
        • Graham D.Y.
        • Lidsky M.D.
        • Cox A.M.
        • et al.
        Long-term nonsteroidal antiinflammatory drug use and Helicobacter pylori infection.
        Gastroenterology. 1991; 100: 1653-1657
        • Loeb D.S.
        • Talley N.J.
        • Ahlquist D.A.
        • et al.
        Long-term nonsteroidal anti-inflammatory drug use and gastroduodenal injury.
        Gastroenterology. 1992; 102: 1899-1905
        • Santucci L.
        • Fiorucci S.
        • Patoia L.
        • et al.
        Severe gastric mucosal damage induced by NSAIDs in healthy subjects is associated with Helicobacter pylori infection and high levels of serum pepsinogens.
        Dig Dis Sci. 1995; 40: 2074-2080
        • Taha A.S.
        • Nakshabendi I.
        • Lee F.D.
        • et al.
        Chemical gastritis and Helicobacter pylori related gastritis in patients receiving non-steroidal anti-inflammatory drugs.
        J Clin Pathol. 1992; 45: 135-139
        • Laine L.
        • Marin-Sorensen M.
        • Weinstein W.M.
        Nonsteroidal antiinflammatory drug-associated gastric ulcers do not require Helicobacter pylori for their development.
        Am J Gastroenterol. 1992; 87: 1398-1402
        • Quinn C.M.
        • Bjarnason I.
        • Price A.B.
        Gastritis in patients on non-steroidal anti-inflammatory drugs.
        Histopathology. 1993; 23: 341-348
        • McCarthy C.J.
        • McDermott M.
        • Hourihane D.
        • O’Morain C.
        Chemical gastritis induced by naproxen in the absence of Helicobacter pylori infection.
        J Clin Pathol. 1995; 48: 61-63
        • Laine L.
        • Cominelli F.
        • Sloane R.
        • et al.
        Interaction of NSAIDs and Helicobacter pylori on gastrointestinal injury and prostaglandin production.
        Aliment Pharmacol Ther. 1995; 9: 127-135
        • Lanza F.L.
        • Evans D.G.
        • Graham D.Y.
        Effect of Helicobacter pylori infection on the severity of gastroduodenal mucosal injury after the acute administration of naproxen or aspirin to normal volunteers.
        Am J Gastroenterol. 1991; 86: 735-737
        • Goggin P.M.
        • Collins D.A.
        • Jazrawi R.P.
        • et al.
        Prevalence of Helicobacter pylori infection and its effect on symptoms and non-steroidal anti-inflammatory drug induced gastrointestinal damage in patients with rheumatoid arthritis.
        Gut. 1993; 34: 1677-1680
        • Thillainayagam A.V.
        • Tabaqchali S.
        • Warrington S.J.
        • Farthing M.J.
        Interrelationships between Helicobacter pylori infection, nonsteroidal antiinflammatory drugs and gastroduodenal disease.
        Dig Dis Sci. 1994; 39: 1085-1089
        • Lipscomb G.R.
        • Wallis N.
        • Armstrong G.
        • et al.
        Influence of Helicobacter pylori on gastric mucosal adaptation to naproxen in man.
        Dig Dis Sci. 1996; 41: 1583-1588
        • Hawkey C.J.
        • Karrasch J.A.
        • Szczepanski L.
        • et al.
        Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group.
        N Engl J Med. 1998; 338: 727-734
        • Yeomans ND, Tulassay Z, Juhász L, et al. for the Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) Study Group
        A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs.
        N Engl J Med. 1998; 338: 719-726
        • Hudson N.
        • Balsitis M.
        • Filipowicz F.
        • Hawkey C.J.
        Effect of Helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs.
        Gut. 1993; 34: 748-751
        • Heresbach D.
        • Raoul J.L.
        • Bretagne J.F.
        • et al.
        Helicobacter pylori.
        Gut. 1992; 33: 1608-1611
        • Kim J.G.
        • Graham D.Y.
        • The Misoprostol Study Group
        Helicobacter pylori infection and development of gastric or duodenal ulcer in arthritic patients receiving chronic NSAID therapy.
        Am J Gastroenterol. 1994; 89: 203-207
        • Li E.K.M.
        • Sung J.J.Y.
        • Suen R.
        • et al.
        Helicobacter pylori infection increases the risk of peptic ulcers in chronic users of non-steroidal anti-inflammatory drugs.
        Scand J Rheumatol. 1996; 25: 42-46
        • Pilotto A.
        • Franceschi M.
        • Leandro G.
        • et al.
        The effect of Helicobacter pylori infection on NSAID-related gastroduodenal damage in the elderly.
        Eur J Gastroenterol Hepatol. 1997; 9: 951-956
        • Greenberg P.D.
        • Albert C.M.
        • Ridker P.M.
        • et al.
        Helicobacter pylori as a risk factor for peptic ulcers in patients taking low-dose aspirin.
        Gastroenterology. 1997; 112 (Abstr.): A133
        • Chan F.K.
        • Sung J.J.
        • Chung S.C.
        • et al.
        Randomised trial of eradication of Helicobacter pylori before non-steroidal anti-inflammatory drug therapy to prevent peptic ulcers.
        Lancet. 1997; 350: 975-979
        • Mertz-Nielsen A.
        • Steenberg P.
        • Neumark T.
        • et al.
        Colloidal bismuth subcitrate causes sustained release of gastric mucosal prostaglandin E2.
        Aliment Pharmacol Ther. 1991; 5: 127-133
        • Pilotto A.
        • Leandro G.
        • Di Mario F.
        • et al.
        Role of Helicobacter pylori infection on upper gastrointestinal bleeding in the elderly.
        Dig Dis Sci. 1997; 42: 586-591
        • Labenz J.
        • Tillenburg B.
        • Stolte M.
        • et al.
        Ulcer healing by eradicating Helicobacter pylori.
        Gastroenterology. 1995; 108 (Abstr.): A140
        • Al-Assi M.T.
        • Genta R.M.
        • Karttunen T.J.
        • Graham D.Y.
        Ulcer site and complications.
        Endoscopy. 1996; 28: 229-233
        • Silverstein F.E.
        • Graham D.Y.
        • Senior J.R.
        • et al.
        Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs. A randomized, double-blind, placebo-controlled trial.
        Ann Intern Med. 1995; 123: 241-249
        • Simon L.S.
        • Hatoum H.T.
        • Bittman R.M.
        • et al.
        Risk factors for serious nonsteroidal-induced gastrointestinal complications.
        Fam Med. 1996; 28: 204-210
        • Aalykke C.
        • Lauritsen J.M.
        • Hallas J.
        • et al.
        Helicobacter pylori—a risk factor in NSAID-related bleeding peptic ulcer.
        Gastroenterology. 1997; 112 (Abstr.): A51
        • Taha A.S.
        • McLaughlin S.
        • Holland P.J.
        • et al.
        Effect on gastric and duodenal mucosal prostaglandins of repeated intake of therapeutic doses of naproxen and etodolac in rheumatoid arthritis.
        Ann Rheum Dis. 1990; 49: 354-358
        • Laine L.
        • Sloane R.
        • Ferretti M.
        • Cominelli F.
        A randomized, double-blind comparison of placebo, etodolac, and naproxen on gastrointestinal injury and prostaglandin production.
        Gastrointest Endosc. 1995; 42: 428-433
        • Bianchi Porro G.
        • Parente F.
        • Imbesi V.
        • et al.
        Role of Helicobacter pylori in ulcer healing and recurrence of gastric and duodenal ulcers in longterm NSAID users.
        Gut. 1996; 39: 22-26
        • Berkelhammer C.
        Helicobacter pylori and ulcer in patients taking NSAIDs.
        JAMA. 1995; 273 (Letter): 376
      1. NIH Consensus Conference: Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. Helicobacter pylori in peptic ulcer disease.
        JAMA. 1994; 272: 65-69