The anti-inflammatory properties of ASA products are well recognized. Sulfasalazine, the first ASA product developed, was used in the 1940s to reduce joint inflammation in patients suffering from rheumatoid arthritis. Retrospectively, it was noted that patients with concomitant UC displayed improvement in their colitis (1). This observation led to numerous studies examining the efficacy of 5-ASA agents in the treatment of IBD.

ASA compounds like sulfasalazine contain a 5-ASA moiety linked to a carrier molecule, such as sulfapyridine, by an azo bond. This relationship was studied by Khan, who determined the 5-ASA moiety to be responsible for the therapeutic benefit seen in patients with IBD (2). The presence of a carrier protein prevents absorption of the drug in the stomach and small intestine. Once the intact sulfasalazine compound reaches the colon, the azo bond is cleaved by coloniform azo reductases, freeing the active 5-ASA from the carrier molecule. Mesalamine lacks the sulfapyridine moiety, thus increasing delivery of active 5-ASA to the small intestine. Asacol is mesalamine enveloped in an enteric coating that dissolves at a sustained pH of >7, thereby preventing absorption in the stomach and increasing delivery of the active drug to the terminal ileum. Furthermore, the development of topical foams and enemas has allowed for direct delivery of the active drug to inflamed colon.

Although the use of 5-ASA agents as first-line therapy for the induction and maintenance of remission in patients with mild-to-moderate UC is well established, the evidence supporting their use for the induction and maintenance of remission in mild-to-moderate CD is not as convincing.

Sulfasalazine, as the first ASA noted to reduce inflammation in colitis, has been studied extensively. In 1979, the National Cooperative Crohn’s Disease Study (NCCDS)
evaluated the effects of sulfasalazine, prednisone, and azathioprine in 569 patients. While initial analysis revealed a statistically significant response of active disease to 6 g/day of sulfasalazine compared to placebo, subgroup analysis determined that the benefit was limited to those patients with ileocolonic or colonic disease. Those with isolated small bowel disease obtained no benefit (3). Five years later, the European Cooperative Crohn’s Disease Study (ECCDS) published a study looking at improvements in the Crohn’s disease activity index (CDAI) of 452 patients randomized to receive sulfasalazine with or without 6-methylprednisolone. While 3 g/day of sulfasalazine proved to be beneficial in combination with 6-methylprednisolone, sulfasalazine alone showed no improvement (4).

The efficacy of mesalamine in CD has also been investigated in a number of randomized, placebo-controlled trials. Singleton et al. randomized 310 patients with active CD to receive either placebo or variable doses of Pentasa (1, 2, or 4 g/day) and then measured changes in the CDAI. Remission with 4 g/day of Pentasa versus placebo reached statistical significance, while patients with isolated small bowel disease showed a 93-point improvement in their CDAI compared to negligible change with placebo (5). However, there have been similarly designed trials that have failed to show the same therapeutic benefit exhibited in the Singleton study. Colombel et al. concluded that mesalamine (4 g/day) is less effective than budesonide (9 mg/day), and comparable to ciprofloxacin (1 g/day), for the induction and remission of active CD at both 8 and 16 weeks (6).

Although studies have shown sulfasalazine to be effective in the induction of isolated Crohn’s colitis, it has not been shown to maintain remission in patients with CD. These results were confirmed by the ECCDS (4), which followed 192 patients for 2 years, as well as the NCCDS (3). A smaller trial by Lennard-Jones et al. examined 43 patients over a 1-year period, with no significant difference in remission rates between the sulfasalazine and the placebo group (7).

The use of mesalamine in the maintenance of remission for CD has been well studied, with mixed results. Gisbert et al. performed a systematic review evaluating nine separate clinical trails, all of which exhibited great variation in the dose and duration of treatment with mesalamine. Overall, statistical benefit was shown in four of the nine trials (8). A multicenter, placebo-controlled trial by Gendre et al. followed 161 patients with CD for 2 years and found a significant benefit in patients receiving 2 g/day of Pentasa when initiated within 3 months of remission (9). In contrast, a Cochrane review evaluated seven placebo-controlled trials and found no evidence that 5-ASA preparations are superior to placebo for the maintenance of remission in patients with CD (10).

More recently, there has been a great deal of attention paid to the medical prevention of postsurgical recurrence in CD because of the high rates of recurrence. Although the results of studies evaluating the risk of postsurgical recurrence have been variable, ∼30% of all postresection patients will require further surgery within 10 years (11).

The use of sulfasalazine for the prevention of postsurgical recurrence has been shown to be no more effective than placebo (11). The results of studies evaluating the efficacy of mesalamine for the prevention of postsurgical recurrence have been mixed. For instance, a meta-analysis of 15 randomized controlled trials found a 13% reduction in postsurgical recurrence rates when compared to placebo (12). However, Lochs et al. followed 318 patients randomized to either placebo or mesalamine (4 g/day) after surgical resection. Overall, they found no statistically significant preventative effect for mesalamine given in the postsurgical setting (13).

In summary, the use of 5-ASA products for the treatment of mild-to-moderate CD may be a safe and effective choice. While sulfasalazine should be used only in patients with isolated colitis, mesalamine and its various formulations are available for patients who have small bowel and/or colonic involvement. The existing evidence on the use of sulfasalazine and mesalamine in the maintenance of remission or the prevention of postoperative recurrence does not support the use of these medications in these settings.

Steroids have been used in the treatment of inflammatory and autoimmune diseases for many years. Their use in the treatment of CD goes back to the 1970s, when 84% of IBD patients receiving steroids in Olmstead County, Minnesota, experienced some response (partial or complete remission) after 1 month of steroid therapy (14).

The effects of steroids are wide ranging and result from the activation of the glucocorticoid response element (GRE). Activated GREs decrease the production of inflammatory cytokines as well as inhibit proliferation and recruitment of inflammatory white blood cells (15).

Steroids, both systemic and nonsystemic, have been evaluated for efficacy in the treatment of CD. Budesonide is considered a nonsystemic steroid because of a high rate (80% to 90%) of first-pass metabolism in the liver (16), leading to fewer side effects when compared to systemic steroids. A recent 2008 Cochrane review compared the effectiveness of budesonide versus mesalamine or placebo in 12 separate studies. They determined that budesonide was superior to both placebo and mesalamine for induction of remission in CD (17). Appropriate dosing has also been examined in multiple studies, and 9 mg/day of budesonide has been shown to be superior to mesalamine for the induction of mild-to-moderate small bowel disease or right-sided colonic disease (18

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