The efficacy of aminosalicylates for the induction and maintenance of remission of UC is well established in the adult literature and these medications remain the first-line treatment for mild to moderate disease [18, 19]. Although there is very little pediatric UC data, oral 5-ASA formulations are recommended as the first-line induction therapy for mild to moderately active pediatric UC as well [20].

In a recent systematic review and meta-analysis, both oral and rectal preparations of 5-ASAs were found to have modest efficacy at inducing remission in mild-to-moderate UC compared to placebo with no statistically significant difference between the preparations [21]. There is no standardized dosage or frequency of dosing for rectal preparations in inducing remission of UC. In the most recent Cochrane Review, rectal 5-ASA was superior to rectal steroids for inducing remission of UC [22]. There is improved efficacy with combined rectal and oral 5-ASA therapy compared with oral 5-ASA therapy alone [23]. Although there is no standard dosing of oral 5-ASA for inducing remission, doses of 1.5–4.8 g/day have been shown to be effective depending on disease severity. The result of the ASCEND I and II trials show a statistically significant higher rate of mucosal healing in UC at 6 weeks with a dose of 4.8 g/day of delayed-release oral mesalazine over 2.4 g/day dosing [24]. However, a recent randomized control trial in pediatric UC patients showed equal effectiveness of high- and low-dose oral delayed-release mesalamine for achievement of clinical remission [25]. The reduction in fecal biomarkers, calprotectin and lactoferrin, was not statistically significant between the groups. Despite improved efficacy of combined oral and rectal 5-ASA therapy for inducing remission over oral 5-ASA alone, the remission rates are still significantly lower than with corticosteroids alone [22]. In UC, mesalamine has similar efficacy to sulfasalazine at equimolar doses.

Both oral and rectal mesalamine are more efficacious in preventing relapse of quiescent UC than placebo [19]. There are many randomized control trials that show topical 5-ASAs have comparable efficacy at preventing relapse of quiescent UC. On the other hand, in one recent meta-analysis, intermittent rectal mesalamine was superior to oral 5-ASAs with a number needed to treat (NNT) of 4 [23, 26]. In another recent meta-analysis, topical mesalamine was more effective at preventing relapse of quiescent UC compared to placebo with a NNT of 3 [27]. This study also showed a trend toward a greater effect size with continuous topical therapy compared with intermittent topical therapy. The analysis showed lower relapse rates when an overall higher total weekly dose of topical mesalamine was used, similar to the occurrence with higher doses of oral 5-ASA therapy for preventing relapse of quiescent UC. However, the majority of the patients in this study had only left-sided disease or proctitis.

In the adult population, oral 5-ASA has modest efficacy in maintaining remission of quiescent UC with good adherence but there is no standardized dosing regimen. Some of the more recent studies not only assessed efficacy in maintaining remission in UC, but also adherence to the prescribed treatment. In one recent study of MMX mesalamine at 2.4 g/day, there was only a 30% recurrence rate at 12 months for patients who were adherent to the medication more than 80% of the time, as compared to a 53% relapse rate at 12 months for patients who were less than 80% adherent to the medication regimen [28]. A meta-analysis showed that once-daily dosing of oral mesalamine was equally as effective as conventional dosing in preventing relapse in quiescent UC over 12 months of therapy [29, 30]. Although 5-ASA has proven to be effective in maintaining remission in quiescent ulcerative colitis, adherence must be considered when developing an individual’s treatment plan.

There are a few studies evaluating the efficacy of 5-ASA for the treatment and maintenance of remission in pediatric UC. There is one recent study on the efficacy of mesalamine 500 mg suppositories for the treatment of ulcerative proctitis in children. For the 49 patients enrolled, there was a statistically significant decrease in the disease activity index at 3 weeks. 41 patients had a mild or an unrelated adverse event [31]. Another recent pediatric study compared the efficacy of oral beclomethasone dipropionate (BDP) to oral 5-ASA in the treatment of mild to moderate UC in the pediatric population. The results of the study showed clinical remission was achieved after 4 weeks in 12 of 15 patients treated with BDP but only 5 of 15 patients treated with 5-ASA, thus showing BDP more efficacious at inducing remission in mild to moderate pediatric UC than 5-ASA [32].

In general, the preparation of 5-ASA used is dependent on the location and the severity of disease. In addition, in pediatrics, particularly in the younger age groups who potentially have greater difficulty in swallowing pills, the mode of delivery is also crucial. There are currently no 5-ASA liquid formulations. However, certain capsule formulations, namely Pentasa® and Colazal®, may be opened and the content emptied into foods such as yogurt and peanut butter. Data on the efficacy of this practice, however, have not been published to date.

Rectal formulations are usually a reasonable starting choice in patients with mild disease limited to the rectum or left colon [33]. Adherence needs to be considered when using these formulations. Patients with more extensive disease involving the transverse and ascending colon may require the addition of an oral preparation.

Dosing of oral 5-ASA in the pediatric population is variable, but the dosages usually fall in the range of 30–100 mg/kg/day. More recent guidelines established by ESPGHAN and the European Crohn’s and Colitis Organisation (ECCO) suggest a dose of 60–80 mg/kg/day in 2 daily doses up to 4.8 g daily for mesalazine, and 40–70 mg/kg/day in 2 divided doses with a maximum of 4 g per day for sulfasalazine. Higher doses have been used, although it is not evidence based. For rectal dosing, 25 mg/kg up to a maximum of 1 g may be used once daily [20].

The efficacy of 5-ASA in the induction and maintenance of remission in Crohn’s disease (CD) is controversial. Currently, their use in treatment of pediatric CD is limited and only recommended in selected patients with very mild disease [34]. In a recent Cochrane review consisting of adult studies, sulfasalazine showed only a modest effect over placebo in inducing remission in mild to moderate CD at a dose of 3-6 g/day [35]. It showed a 38% higher chance of inducing remission compared to placebo-treated patients. However, this effect was limited to patients with Crohn colitis. Sulfasalazine was 34% less effective at inducing remission than corticosteroids alone and it was less effective than combination therapy with corticosteroids and sulfasalazine. Two studies, the Trial of Adjunctive Sulfasalazine (TAS) in Crohn’s disease and the European Cooperative Crohn’s Disease Study (ECCDS), showed that sulfasalazine was not a useful adjunct to corticosteroid therapy in achieving remission [36, 37].

A recent systematic review and meta-analysis of randomized controlled trials that excluded the Crohn’s III trial data also suggests a modest effect of 5-ASA drugs inducing remission of active CD over placebo-treated patients with a NNT of 11 to prevent one patient’s disease remaining active [38]. The effect was based on a mean reduction in CDAI scores. Had the data from the Crohn’s III trial been available, the authors suspect there would have been no statistically significant difference between the 5-ASA treated group and the placebo-treated group. According to the latest Cochrane review, low-dose controlled-release mesalamine (1–2 g/day) was less effective at inducing remission in active CD compared to placebo-treated patients [35]. As with sulfasalazine, delayed-release mesalamine (2 g/day) was less efficacious than corticosteroids [39]. Trials evaluating higher doses of mesalamine (3–4.5 g/day) show inconsistent results. The majority of the studies show no difference in induction of remission in mild to moderately active CD relative to placebo [35]. Two of the studies showed statistically significant changes in CDAI scores, but they were found to be clinically insignificant. In a single trial, high dose mesalamine was less effective than budesonide [40]. Many of these studies were small and had several methodological weaknesses, which may limit the generalizability of the effects of mesalamine at inducing remission in mild to moderately active CD.

One pediatric study reviewed disease activity at diagnosis in 43 patients and compared the outcomes of single versus combination therapies. Ten of 25 patients in the mild group and 3 of 18 patients in the moderate to severe group received 5-ASA monotherapy immediately after diagnosis. These patients tended to have more exacerbations, shorter duration of the first remission, and longer total duration of systemic steroid use than patients receiving combination therapy, immunomodulators, or systemic steroids [41].

The role of 5-ASAs in maintaining remission in quiescent CD was also assessed in the review by Ford et al. No statistical significant benefit over placebo was found, although subgroup analysis of trials with low risk of bias showed mesalamine to be of benefit in preventing relapse with a NNT of 13 [38, 42]. This was the same result when a more conservative protocol analysis was completed, in which dropouts from individual studies were not considered treatment failures. There is one pediatric study evaluating maintenance of remission in CD patients after successful flare-up therapy with either nutrition or medications that showed that the relapse rate was similar with mesalazine and placebo [43].

Overall, evidence does not support the use of mesalamine for maintenance treatment in pediatric CD. Many gastroenterologists continue to use aminosalicylates in CD despite multiple studies showing at best a modest benefit over placebo [35]. The dosing of oral 5-ASA for pediatric CD is similar to that for pediatric UC with 50–80 mg/kg/day up to 4 g daily [34].

Surgical resection can induce remission in CD. However, endoscopic and clinical relapse of CD after surgical resection is common and has been reported to be as high as 75–90% and 20–30%, respectively, within 1 year [44, 45]. There is currently no standard therapy for preventing relapse post-operatively. Aminosalicylates in the postoperative setting have been extensively studied, but their effectiveness at preventing relapse after surgical resection remains controversial. In a systematic review and meta-analysis of 11 randomized controlled trials, the effect of mesalamine appears to be modest with a NNT of 13 compared to placebo or not treating after surgery [46]. In a Cochrane review, the effectiveness of mesalamine was even more modest with a NNT of 16–19 [47]. However, this effect seems to be limited to mesalamine only, as sulfasalazine demonstrated no advantage over the control therapy. There is heterogeneity in all of these studies including the dosage and preparation used, the length of treatment postsurgery, and the definition of remission. In a more recent network meta-analysis comparing different pharmacologic interventions in preventing relapse of CD after surgery, mesalamine was shown to reduce the risk of clinical relapse (relative risk or RR 0.60; 95% credible interval or Crl 0.37–0.88), but not endoscopic relapse (RR 0.67; 95% CrI 0.39–1.08) when compared to placebo [48].

Due to their structural similarity to aspirin, which has been shown to reduce the risk of CRC and adenomas in patients without IBD, it was believed that 5-ASAs had a similar effect on patients with a diagnosis of IBD [49]. However, more recent studies suggest that they may not provide much, if any, chemoprophylaxis for CRC. A population-based study including more than 8000 patients found that there was no protective effect of 5-ASA against CRC [50, 51]. This study evaluated the cumulative use of 5-ASA at 1, 5, and 7.5 years. Adherence to 5-ASA therapy was based on the frequency of prescription refills. It is possible that the cumulative use for longer than 7.5 years could be chemopreventive, but this has not been studied. In contrast, one small case-controlled study found that cumulative mesalamine doses decreased the risk of CRC in patients with IBD [52]. There are also several studies that have observed a significant chemopreventive effect of mesalamine compounds, especially at doses of >1.2 g/day. However, these studies been criticized because of the design, outcomes measured, and variables controlled for [53]. A more recent meta-analysis evaluating the nonreferral IBD patients suggested no protective effect of 5-ASA on CRC in IBD [54]. These results are, however, limited by the heterogeneity of the studies included. A chemopreventive effect was not seen in patients who received sulfasalazine regardless of setting (referral versus nonreferral).

As noted above, the exact mechanism of action of 5-ASA in the treatment of IBD is unknown, and the same can be said regarding chemoprophylaxis. One retrospective cohort study attempted to determine where in the dysplasia-carcinoma sequence they would exert their protective effect. The study identified patients with UC with no dysplasia, indefinite dysplasia, or flat low-grade dysplasia (LGD) and followed them for the development of high-grade dysplasia (HGD) or CRC. The data suggest that if mesalamine has any chemopreventive effect, it may act early in the neoplastic process before the development of LGD [53]. There are many in vivo and in vitro studies currently looking at the anti-inflammatory and antineoplastic effects on different proposed mechanism of action pathways, including inhibition of cyclooxygenase activity, enhanced apoptosis through inhibition of NF-κB and MAP kinases, improvement in the DNA replication process, inhibition of reactive oxygen species, and downregulation of oncogenes and transcription factors [49, 55]. 5-ASA is now thought to be involved in inhibition of protein synthesis, which may contribute to its anti-inflammatory and antineoplastic properties [56].

Sulfasalazine (SASP) therapy is usually accompanied with more side effects than the 5-ASA formulations due to the sulfapyridine moiety [2]. Up to 80–90% of patients who cannot tolerate sulfasalazine tolerate 5-ASA preparations [57]. In addition, patients who experience adverse reactions to a particular 5-ASA formulation often tolerate a different preparation.

Side effects of 5-ASA are listed in Table 25.2. The most common side effects of both SASP and 5-ASA are nausea, abdominal pain, diarrhea, dyspepsia, rash, and fever [58, 59]. Some of these effects, such as diarrhea, can be mitigated by a gradual increase in the dose [60]. Rare, but more serious side effects, include interstitial nephritis, pancreatitis, pericarditis, pneumonitis, hepatitis, neutropenia, and rarely, worsening colitis [57–59]. The risk of interstitial nephritis and pancreatitis is higher with 5-ASA, while the risk of hepatitis is higher with SASP. Agranulocytosis, hemolytic anemia, and oligospermia have also been reported with SASP [59].