Do NSAIDs, Antibiotics, Infection, or Stress Cause IBD Flare-ups?

David A. Johnson, MD, FACG, FASGE, FACP


September 08, 2009

Do NSAIDs, Antibiotics, Infections, or Stress Trigger Flares in IBD?

Singh S, Graff LA, Bernstein CN
Am J Gastroenterol. 2009;104:1298-1313

The spectrum of disease activity associated with inflammatory bowel disease (IBD) ranges from chronically active disease, to intermittent flares, to long-term quiescence. Because IBD flare-ups may cause numerous negative effects, including adverse patient outcomes as well as direct and indirect costs, the determinants of relapse are of great clinical interest. Although a number of plausible triggers have been suggested, the evidence to support many of these potential triggers remains scant, and no specifically defined variables have been identified. Similarly, physician counseling of and recommendations to IBD patients concerning how to avoid exacerbations are not supported by a strong evidence base. A recent clinical review by Singh and colleagues[1] provides an excellent summary of the evidence pertaining to the well-reported potential triggers of IBD flares. My comments represent a synthesis of the evidence as reported by the Singh review and include the study's bottom line recommendation for each potential trigger.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Scientific Hypothesis for Causality

NSAIDs have an inhibitory effect on the protective prostaglandins, and they uncouple mitochondrial oxidative phosphorylation in the mucosal enterocytes. Both of these factors can lead to increased mucosal permeability and progressive mucosal disruption. The uncoupling of mitochondrial phosphorylation leads to a reduction in intracellular adenosine triphosphate levels. This, in turn, causes loss of cytoskeletal control over tight junctions, which leads to increased mucosal permeability. Either increased permeability or mucosal breaks might enhance mucosal susceptibility to damage from exposure to a number of bacteria and possible toxins (eg, bile salts and hydrolytic or proteolytic digestive enzymes). Clinical data from case series have suggested that NSAIDs may be related to a flare of IBD activity. Accordingly, many IBD patients are counseled to avoid NSAIDs despite many having a need for these agents as treatment of IBD-related arthropathy.

Evidence of Contribution to IBD Flares

Although several studies report an association between NSAIDs and flares of IBD, these studies have significant methodologic flaws and should not be considered as definitive proof of association. Additionally, there is a possible publication bias against studies that report no impact of NSAIDs on IBD flares. A randomized, placebo-controlled trial of NSAIDs in IBD patients as well as funnel-plot analysis to evaluate the existing trials for bias would contribute to a better understanding of the role NSAIDs play in IBD flares.

Best Recommendation

In the absence of definite proof of a causal association, the use of NSAIDs for IBD-related arthropathy seems to be justified. Furthermore, there are no data to recommend the avoidance of episodic use for other indications (eg, headache and muscular strains). Because NSAID use carries a well-recognized risk for gastrointestinal mucosal damage and renal complications, the use of these agents should always be justified by a risk-benefit analysis for each patient.

Antibiotics Use and Enteric Infections

Scientific Hypothesis for Causality

The use of antibiotics may cause changes in the indigenous bowel flora that may lead either to overgrowth of potentially injurious organisms (eg, Clostridium difficile) or suppression of protective microbes. It is believed that such changes in the intestinal microbial flora may have a pivotal role in the pathogenesis of IBD. C difficile or other enteric infections can cause symptoms in any patient. Yet, the increased incidence of C difficile infection both in the general population and in IBD patients has focused attention on this organism as a potential trigger for the exacerbation of IBD. Additionally, there has been speculation as to whether other enteric infections (eg, protozoa, enteropathogenic bacteria and viruses, and helminthes) may play a causal role in IBD flares.

Evidence of Contribution to IBD Flares

Although the concept that antibiotics may contribute to alterations in microbial flora is reasonable, there is no convincing evidence that antibiotics directly trigger a flare of IBD. Additionally, no specific enteric infection has been identified as a causal factor of IBD exacerbations. Clearly, there has been an increase in the rates of C difficile infection in IBD patients, but this rate of increase has paralleled that of the population of non-IBD patients.

Best Recommendation

It is apparent that C difficile is associated with IBD and may predispose to the disease, but it is unlikely that C difficile infection causes IBD flares. Nonetheless, because C difficile and other enteric infections can cause symptoms indistinguishable from IBD flares, enteric infections should be a differential concern in all patients suspected of having an IBD exacerbation. Specifically, testing for C difficile infection should be undertaken in all symptomatic IBD patients -- even those who do not have the typical exposure risks, such as a recent hospitalization or the use of either antibiotics or immunomodulatory drugs -- because these risk factors are absent in one third or more of IBD patients who have C difficile infection.

Systemic Infections

Scientific Hypothesis for Causality

Because systemic infections evoke a host inflammatory response, it is conceivable that the release of inflammatory cytokines may affect constitutional symptoms or indirectly affect the trafficking of inflammatory cells to the intestine. Observational studies have noted a significant association between infections (eg, upper respiratory, urinary, or gastrointestinal) and a subsequent flare of IBD.

Evidence of Contribution to IBD Flares

Overall, the evidence base is weak to support a causal link between systemic infection and flare of IBD. It was suggested that IBD-affected tissues may have a related mucosal permeability defect that might, in fact, predispose to the development of systemic infections.

Best Recommendation

Although the relationship for causality is weak, many IBD patients are on immunosuppressant or immunomodulatory drugs and accordingly are more susceptible to infections. Appropriate preventive care, including vaccinations, is particularly key for these patients irrespective of their age.


Scientific Hypothesis for Causality

The physiologic response to stress involves a complex cascade of processes involving the hypothalamus-pituitary-adrenal axis as well as the autonomic nervous system axis. This response can affect immune and inflammatory functions. The release of neuropeptides and proinflammatory mediators may contribute to increased mucosal permeability, which, in turn, may contribute to increased intestinal inflammation.

Evidence of Contribution to IBD Flares

Although the majority of studies evaluating the association of stressful events and flare of IBD suggest a relationship, the definitive answer is yet unknown because the pertinent studies are methodologically problematic. Confusion remains as to how to measure and standardize subjective perceptions for stress as well as how to account for the potential buffering of stress factors.

Best Recommendation

It seems appropriate that IBD patients should be screened for stress levels that warrant interventions in an effort to minimize the effect of stress on gastrointestinal health and to improve overall well-being. However, the value of these interventions specific to prevention of an IBD flare remains speculative.



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