Abstract and Introduction
Abstract
Background Aspirin has detrimental effects on the gastrointestinal tract mucosa and may play a role in the aetiology of inflammatory bowel disease.
Aim To investigate if the regular use of aspirin is associated with the development of Crohn's disease (CD) and ulcerative colitis (UC) using, for the first time, a prospective cohort study design.
Methods A total of 135 780 men and women in Europe, aged 30–74 years, were recruited into the European Prospective Investigation into Cancer and Nutrition study. Participants completed questionnaires at baseline detailing their regular aspirin use and were then followed up to identify those who developed either incident CD or UC. Each case was matched with four controls and odds ratios (OR) were calculated, adjusting for cigarette smoking. Potential interactions between aspirin and smoking were assessed.
Results A total of 35 participants developed CD and a further 84 were diagnosed with UC. Regular aspirin intake was positively associated with the risk of developing CD (OR = 6.14, 95% CI = 1.76–21.35). In those who took aspirin and smoked there was no detectable increased risk of CD (OR = 0.30, 95% CI = 0.03–3.08). No association was found between regular aspirin use and UC (OR = 1.29, 95% CI = 0.67–2.46).
Conclusions A strong positive association between regular aspirin use and CD, but not UC, was observed. The data suggest that regular aspirin use should be measured in epidemiological work on CD. If such findings are consistent in other work then aspirin may affect the development of CD in a middle-aged to elderly population.
Introduction
Ulcerative colitis (UC) and Crohn's disease (CD) are the two major forms of inflammatory bowel diseases (IBD). Patients often need to take medications lifelong, have an impaired quality of life and are at an increased risk of complications including colorectal cancer. In the West the prevalence of UC and CD is 120-200/100 000 and 50-200/100 000, respectively, whilst the annual expenditure on drugs in 2009 used to treat IBD was estimated at U$ 5 billion worldwide.
The aetiology of inflammatory bowel disease is unknown, although the initiation and maintenance of inflammation of the gastrointestinal tract probably involves environmental, genetic and immunological factors. A possible causative risk factor for IBD, for which there are plausible biological mechanisms, are the nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin. The adverse effects of NSAIDs, on the gastrointestinal mucosa include erosions, ulceration, inflammation, perforation and bleeding. These may be mediated by the acidic and lipophilic properties of NSAIDs allowing them to act as detergents, which disrupts lipid cell membranes. NSAIDs can also dissipate the mitochondrial H electrochemical gradient which is required for ATP generation, leading to an uncoupling of mitochondrial oxidative phosphorylation causing cell death. Lastly, NSAIDs affect prostaglandin synthesis, which leads to effects on inflammatory processes, mesenteric blood flow and cell growth. Aspirin irreversibly inhibits the cyclooxygenase (COX) enzyme, preventing prostaglandin synthesis by acetylating a serine residue causing steric blockage of the COX active-site channel. This leads to impaired production of the prostaglandin precursor, prostaglandin H2 (PGH2), altering the production of downstream prostaglandins. This includes inhibition of prostaglandin E2 (PGE2) production which has anti-inflammatory effects such as inhibition of TNF-α, IL-1, 5-lipooxygenase and leukotrienes. Similarly, inhibition of prostaglandin D2 (PGD2) prevents a novel mechanism involved in mesenteric vasodilatation in those with IBD.
The experimental data on how aspirin may be involved in the aetiology of IBD needs to be supported by epidemiological data in which patients presenting with new IBD are shown to be prescribed NSAIDs more frequently than controls. To date, three epidemiological case-control studies have reported positive associations between NSAIDs and the development of new IBD with the odds ratios varying between 1.75 and 20.3. However, a methodological problem with these investigations may be significant recall bias for NSAID use in patients who are possibly taking these drugs to alleviate their symptoms including abdominal pain and arthalgia prior to the diagnosis. This would lead to a spurious over-estimation of any potential aetiological effects of aspirin. To eliminate such recall biases, a prospective cohort study design is required. Such work would help clarify that aspirin/NSAIDs were truly taken before the onset of symptoms and are therefore likely to be involved in aetiology. The aim of this investigation was to perform the first prospective investigation of aspirin and IBD, in a large multi-centre European cohort study, to help provide information on the aetiology of both CD and UC.