Treatment of Ulcerative Colitis

Wojciech Blonski; Anna M. Buchner; Gary R. Lichtenstein


Curr Opin Gastroenterol. 2014;30(1):84-96. 

In This Article

Aminosalicylates (5-aminosalicylic Acid, Mesalamine)

First-line medications used to induce and maintain remission in patients with mild-to-moderately active ulcerative colitis are oral formulations of 5-aminosalicylic acid (5-ASA) (Table 1).[6]

A recently published Cochrane meta-analysis of 48 randomized controlled trials (RCTs) of parallel design evaluated the efficacy, dose–response and safety of oral 5-ASA formulations vs. placebo, sulfasalazine (SASP)/(5-ASA linked to sulfur molecule) or other oral 5-ASA formulations in induction of remission in patients with mild-to-moderately active ulcerative colitis with a minimum 4-week duration of induction treatment.[7] 5-ASA was superior to placebo in inducing complete global or clinical remission with the greatest benefit demonstrated for Multi-Matrix System (MMX) mesalamine and increasing dose of 5-ASA over 2 g daily, in inducing global or clinical improvement (including remission) that was dose-dependent and in inducing complete endoscopic remission with the greatest efficacy for daily doses greater than 3 g.[7] No difference was observed between oral 5-ASA formulations and SASP with respect to the failure to induce complete global or clinical remission and failure to induce global or clinical improvement (including remission).[7] There was a trend toward superiority of 5-ASA over SASP in inducing endoscopic improvement (including remission).[7] There was no difference between formulations of 5-ASA such as balsalazide, pentose, olsalazine and MMX mesalamine, and 5-ASA micropellets when compared with Asacol, Claversal and Salofalk in failure to induce complete global or clinical remission or global/clinical improvement or between once daily and twice or thrice daily dosing of 5-ASA in inducing clinical response or remission.[7] Comparison of high vs. low dose of 5-ASA suggested a benefit for higher dose of Pentasa 4 g/daily over 2.25 g daily in patients with moderate ulcerative colitis.[7] Although no difference was observed between Asacol 4.8 g daily vs. 2.4 g daily in achieving global clinical remission or improvement,[7] pooled data from the Assessing the Safety and Clinical Efficacy of New Dose (ASCEND) I and ASCEND II trials indicate that the higher dose of Asacol was associated with significantly higher rates of mucosal healing at week 6 in moderate ulcerative colitis (80 vs. 68%, P = 0.012) but not in mild ulcerative colitis (84 vs. 88%, P = 0.765) when compared with lower dose.[8] Mucosal healing was also strongly associated with clinical response to therapy and quality of life at the end of both trials.[8] Data from the ASCEND III trial suggested that patients with moderately active ulcerative colitis who previously were treated with multiple ulcerative colitis medications (P = 0.01), corticosteroids (P = 0.05), oral mesalamine (P = 0.07) or rectal therapies (P = 0.06) may benefit from higher Asacol dose.[9] There was a suggestion that addition of rectal mesalamine for 4 to 8-week treatment with oral mesalamine 4 g daily may result in greater remission rates when compared with 8-week immunotherapy with oral mesalamine (64 vs. 43%, P = 0.03),[10] and patients treated with combination therapy have higher concentrations of 5-ASA in the distal colonic mucosa.[11,12]

Overall, 5-ASA formulations were generally well-tolerated and common adverse events included headache, nausea, abdominal pain or cramping, nasopharyngitis or symptoms of upper respiratory infection, rash, anorexia or loss of appetite, flatulence or gas, dizziness and fever.[7]

A recently published Cochrane meta-analysis analyzed the data from 38 RCTs (8127 patients) of parallel design comparing the efficacy and safety of oral 5-ASA vs. placebo, SASP and other oral 5-ASA comparator in maintaining remission of ulcerative colitis.[13] The minimum treatment duration was 6 months and the primary outcome was failure to maintain clinical or endoscopic remission.[13] 5-ASA was found to be superior to placebo in maintaining clinical or endoscopic remission with dose-dependent effect.[13] Overall, no difference in efficacy was observed in maintaining remission between once daily vs. twice or thrice daily 5-ASA dosing with exception of benefit effect of once daily vs. twice daily dosing of Pentasa.[13] Patients adhere to both dosing regimens equally.[13] The maintenance efficacy increased with daily dose only for balsalazide 4 vs. 2 g and Salofalk granules 3 vs. 1.5 g.[13] Of note, Asacol 2.4 daily vs. 1.2 g daily was associated with longer duration of remission with a mean number of days in remission of 175 vs. 129, respectively (P < 0.001).[14]

Common adverse events included flatulence, abdominal pain, nausea, diarrhea, headache, dyspepsia and nasopharyngitis. It was suggested that there may be a bias favoring SASP because of the fact that the majority of trials included patients with known tolerance to SASP thus potentially minimizing SASP-related adverse events.[13]

It is generally recommended to initiate induction treatment with SASP and change to 5-ASA in case of intolerance, as oral 5-ASA formulations are more expensive than SASP.

It remains uncertain whether combination therapy with oral and rectal 5-ASA has any therapeutic advantage over immunotherapy with oral 5-ASA and more data are needed to make any definitive recommendation. Maintenance therapy with SASP should be advocated because of statistically significant superiority over 5-ASA formulations.[13] However, it should be also noted that the safety profile of SASP might be biased because of inclusion of patients with known tolerance to this agent. Male infertility has been associated with SASP but not with 5-ASA; thus, in patients concerned about fertility, the preferred agent would be 5-ASA.