Sulfasalazine has been suggested to exert its clinical effects through anti-inflammatory, immunosuppressive, and bacteriostatic mechanisms. Downregulation of the inflammatory response by sulfasalazine is mediated by inhibition of granulocyte functions including degranulation, chemotaxis, migration [2, 8], and superoxide production [9]. It also acts on several arachidonic acid metabolism pathways resulting in a net increase in prostaglandins which possess both anti-inflammatory and immunosuppressive effects, and a decrease in pro-inflammatory lipoxygenase [9] titers. Immunologically, sulfasalazine inhibits the activity of natural killer cells and T-cells [6, 8]. The sulfapyridine moiety has in vitro bactericidal activity in human blood [1, 10].

5-ASA has been shown to decrease leukotriene production, remove free radicals, and inhibit leukocyte chemotaxis in vitro and in vivo models. 5-ASA has also been postulated to inhibit the nuclear factor-kappa B pathway , decrease oxidative stress induced cell injury and apoptosis, increase heat shock protein response, decrease leukotriene production, and alter prostaglandin metabolism in colonic epithelial cells [3]. Patients with ulcerative colitis who are treated with 5-ASA have lower fecal concentrations of prostaglandin E2 [11].

The primary mechanism of action of 5-ASA may be activation of gamma-form peroxisome proliferator-activated receptors (PPAR-gamma) in colonic epithelial cells. These receptors play a role in inducing transcription in response to environmental cues, and are activated in vivo primarily by colonic bacteria. Evidence for PPAR-gamma involvement in ulcerative colitis is derived from the observation that heterozygote knock-out mice develop colonic inflammation. Interestingly, PPAR-gamma is known to have antiproliferative effects , while influencing differentiation and apoptosis. Cumulatively, these may protect against the development of colonic dysplasia and neoplasia in ulcerative colitis [3].

5-ASA is believed to act topically, in that direct mucosal contact is required for its therapeutic effect. Accordingly, 5-ASA is available in both oral and rectal preparations. Although oral therapy is more commonly used in clinical practice [12], rectal therapy is effective in treating left-sided disease [13]. As rectal administration cannot deliver drug reliably beyond the splenic flexure, this defines the proximal margin for primary rectal therapy [12]. However, rectal therapy may still augment the efficacy of oral 5-ASA in patients with more extensive disease [14]. Rectal therapy also delivers medication to the site of maximal inflammation, while limiting systemic absorption and associated side effects. However, uptake of rectal therapy may be limited by poor patient acceptance [12].

The proximal distribution of 5-ASA differs among suppositories, foams, and liquid enemas [12]. Suppositories deliver drug only to the rectum, as evidenced by scintigraphic studies [15, 16]. Foam preparations reach the sigmoid colon [16, 17], while enemas deliver medication up to the splenic flexure [12, 16, 18]. The proximal spread of an enema is dependent upon its volume [12] and viscosity [19]. All formulations of 5-ASA are equally effective in inducing remission [20], but foam based products offer more uniform colonic coating [21] and greater patient comfort [22] than liquid enema. Enema retention optimizes efficacy and is improved with greater viscosity [19] but reduced by disease severity (Fig. 38.2) [23].

The frequency of adverse events attributed to sulfasalazine and 5-ASA is highly variable in the literature, in part because of variations in dose, formulation, and event definition [7]. Adverse events are less common with 5-ASA than with sulfasalazine [7], likely from loss of the sulfapyridine moiety [3]. One review found no significant difference in the rate of adverse events between 5-ASA and placebo. A study that followed patients for 8 years reported drug-related adverse events in 20 % of patients treated with sulfasalazine versus 6.5 % of those treated with 5-ASA [45]. The most common adverse effects of sulfasalazine were dyspepsia, rash, and headache, in 62 %, 35 %, and 27 % of patients respectively [45]. Of note, 40 % of patients that were initially intolerant of sulfasalazine successfully underwent desensitization through a protocol of gradual dose escalation [45]. The overall rate of adverse effects with 5-ASA is 1.5 % in patients never exposed to sulfasalazine, 4 % in patients with prior sulfasalazine exposure, and 22 % in patients with prior sulfasalazine intolerance [45]. This overlap suggests that some intolerance to sulfasalazine can be attributed to 5-ASA [46]. Common adverse effects of 5-ASA include rash, diarrhea, headache, and fever, which occur in 37 %, 25 %, 17 % and 17 % of patients, respectively [45]. Other organ-specific adverse effects are summarized in Table 38.1.

The risk of colorectal cancer in patients with ulcerative colitis increases with duration of disease and the extent of inflammation. Additional risk factors in this population include concomitant primary sclerosing cholangitis, folate deficiency, and a family history of colorectal cancer [75, 76]. Currently, management of this risk involves colonoscopic surveillance and colectomy for dysplasia [77, 78]. This has prompted the search for more cost effective, less invasive methods for primary prevention [77].