NSAIDs inflammatory bowel disease

The NSAIDs have a number of commonalities. Although not all NSAIDs are approved by the FDA for the whole range of rheumatic diseases, most are probably effective in rheumatoid arthritis, seronegative spondyloarthropathies (eg, psoriatic arthritis and arthritis associated with inflammatory bowel disease), osteoarthritis, localized musculoskeletal syndromes (eg, sprains and strains, low back pain), and gout (except tolmetin, which appears to be ineffective in gout). 

Two other aspects of gastrointestinal toxicity have yet to be studied. First, the use of COX-2 inhibitors in patients with inflammatory bowel disease, in whom it is likely that COX-2 activity is upregulated (92) and in whom traditional NSAIDs may exacerbate the disease. Experimental colitis has been induced both in COX-2-deficient mice and in rats treated with COX-2-selective inhibitors (93). However, in healthy volunteers, rofecoxib did not alter intestinal permeability, in contrast to indometacin, which increased it (94). Studies in patients with inflammatory bowel disease are necessary before considering COX-2 selective inhibitors to be safe in these patients (95). 

The causal connection between NSAIDs and large bowel inflammation needs to be confirmed by appropriate epidemiological studies. Many publications have associated NSAID and colonic inflammation (SEDA-10, 77) (SEDA-15, 95), but the differential diagnosis between colonic inflammation arising de novo and exacerbation of underlying inflammatory bowel disease can be difficult, and the role of NSAIDs in aggravating ulcerative colitis or Crohn s disease or other inflammatory bowel disease is controversial (SEDA-10, 76) (SEDA-15, 95). A case-control study showed no association between appendi-cectomy for acute appendicitis and the use of NSAIDs (SEDA-22, 111). 

The evidence that NSAIDs can cause exacerbation of inflammatory bowel disease is at best scanty (SEDA-10, 76) (SEDA-15, 92) (SEDA-17, 102). In the few studies in which drugs as a cause of relapse of chronic inflammatory bowel disease have been investigated, NSAIDs have not been shown to be major contributors. 

However, well-documented published series of patients with quiescent inflammatory bowel disease whose colitis became active shortly after they were given NSAIDs... 

Two studies of the possible association between NSAIDs and the onset or exacerbation of inflammatory bowel disease have given contrasting results. In the first study (139) the authors interviewed 60 patients (mean age 42 years) with either Crohn s disease or ulcerative colitis who required admission to hospital owing to symptoms of their disease, and 62 matched controls (mean age 46 years) with irritable bowel syndrome who did not require hospitalization. Patients were asked about their use of NSAIDs and the relation in time and duration to the exacerbation or onset of the inflammatory bowel disease. There was an association with the use of NSAIDs in 31% of the patients with inflammatory bowel disease, but in only 2% of those with irritable bowel syndrome. Compared with patients with irritable bowel syndrome the odds ratio (OR) for an exacerbation or new onset of symptoms of inflammatory bowel disease after recent use of NSAIDs (defined as use within 1 month of symptom exacerbation or onset of disease) was 20 (95% Cl = 2.6, 160). 

In contrast, the second study (140) showed that the use of NSAIDs was not associated with a higher incidence of active inflammatory bowel disease. The authors retrospectively examined the records of 192 outpatients with inflammatory bowel disease 112 with Crohn s disease (mean age 53 years) and 80 with ulcerative colitis (mean age 61 years). The use of NSAIDs was more common in patients with inactive inflammatory bowel disease than in those with active disease. Of 40 patients with active Crohn s disease, three were using NSAIDs compared with 14 of 72 with inactive disease. Of 58 patients with active ulcerative cohtis, eight were using NSAIDs compared with five of 21 patients with ulcerative colitis in remission. 

Despite the clinical importance of the problem, we lack a firm answer to the question of whether patients with inflammatory bowel disease should refrain from using NSAIDs. 

ESR erythrocyte sedimentation rate IBD inflammatory bowel disease NSAID nonsteroidal anti-inflammatory drug TPMT thiopurine S-methyltransferase TNF-a tumor necrosis factor-alpha... 

In summary, the true association between most dietary factors and risk of colon cancer is unclear. The protective effects of fiber, calcium, and a diet low in fat are not completely known at this time. Lifestyle factors such as NSAID use and hormone replacement use appear to decrease the risk of colorectal cancer, but questions remain about how to best use these agents. Obesity and alcohol use appear to increase risk of colon cancer, but their association is not well defined. Genetic and clinical risk factors such as inflammatory bowel disease are weU known risks for colon cancer. 

Figure 7.38 An entire subclass of NSAID prodrugs has been designed for treating chronic inflammatory bowel disease. These possess a central azo group and are not substantially metabolized until they reach the intestines. There bacteria, which are rich in nitroreductase enzymes, metabolize the azo bond, breaking it to form 5-aminosalicylicacid which is the active drug that combats the inflammation. An example is the symmetrical compound olsalazine which releases two molecules of the active amine on metabolic reduction.

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