Aminosalicylates

Aminosalicylates are anti-inflammatory medications mainly used to treat ulcerative colitis.

Benefit & risk (Crohn's disease)

Response and remission

  • Sulfasalazine 3-6g/d is effective in patients with ileo-colonic, colonic (but not ileal) Crohn’s disease (based on small patient numbers).
    • Overall, 40% enter remission c.f. 30% provided placebo at 4 months.
    • It is rarely used due to side-effects.
  • Mesalazine 4g/d is only marginally more effective than placebo in mild ileal or colonic Crohn’s disease, therefore rarely used.
  • Although often prescribed, there is no evidence that topical therapy is effective (or ineffective) to treat distal colonic Crohn’s disease.

Maintenance of remission

  • Although not recommended for maintenance of remission, meta-analyses have inconsistent results.
  • A 2005 Cochrane Database systematic review demonstrated possible benefit based on a “per protocol” but not intention to treat analysis.
  • A more recent (2007) meta-analysis demonstrated a small significant benefit (39.1% vs. 32.5%; NNT = 16).
  • One RCT showed treatment with pH 7-dependent mesalazine (2.4g/d Asacol™) was more effective (NNT = 5).

Prevention relapse post surgery

  • Meta-analysis of 6 studies comprising 1141 patients has demonstrated that 4g/d mesalazine reduces rate of endoscopic recurrence by 18% (NNT = 5.5) & clinical recurrence by 15% (NNT = 6.6); particularly following isolated small bowel resection.

Major side effects

  • Long term, 5ASA intolerance occurs in up to 15% of patients and can be associated with a flare in disease in 3%.
  • Headache, nausea, epigastric pain and diarrhoea are the most common side effects.
  • Rare, idiosyncratic side effects include Stevens Johnson syndrome, pancreatitis, agranulocytosis and alveolitis have been described.
  • Renal impairment (interstitial nephritis; nephrotic syndrome) is rare (0.3%/y) and usually reversible on stopping therapy.
  • National Formularly should be consulted to review adverse drug reactions and drug interactions.

Benefit & risk (ulcerative colitis)

Response

Aminosalicylates are effective (NNT is 6 for remission cf. placebo). There is no difference in efficacy between any of the mesalazine compounds for active UC. Doses of at least 2g/d should be used to induce remission in left sided and extensive colitis; once daily dosing is comparable to divided doses. Mesalazine is better tolerated and as effective as sulfasalazine. Balsalazide may be marginally more effective than mesalazine.

Response in proctitis

No benefit providing topical doses > 1g daily or divided daily doses. If patients choose (less optimal) oral therapy, mesalamine 3.6 g PO od is more effective than lower doses.

ECCO statement 11A (UC 2017)

A mesalamine 1-g suppository once daily is the preferred initial treatment for mild or moderately active proctitis [EL1]. Mesalamine foam or enemas are an alternative [EL1], but suppositories deliver the drug more effectively to the rectum and are better tolerated [EL3]. Topical mesalamine is more effective than topical steroids [EL1]. Combining topical mesalamine with oral mesalamine or topical steroids is more effective [EL2]

Left sided and extensive colitis

Provide mesalazine 1 g enema nocte & mesalamine >/=2 g PO od.

Mesalazine enemas are superior to steroid enemas, (though 3 trials have shown equivalence with beclomethasone dipropionate enemas). Foam and liquid preparations are equivalent; low volume enemas may be better tolerated. Once daily oral therapy is as effective as multi-day dosing and improves compliance, though has not been assessed with adjunctive topical therapy. Some but not all studies suggest greater benefit from higher doses (4.8 vs. 2.4 g/d).

Response times to mesalazine
  • No rectal bleeding by 7 days (MMX 4.8 g/d), 9 days (Asacol 4.8 g/d), or 16 days (Asacol 2.4 g/d)
  • Sustained complete remission 37-45 days (MMX 4.8 g/d)

Maintenance

Oral mesalamine is more effective than placebo at maintaining remission (NNT 6). Rectal 5-ASA is superior to placebo (OR 16.2, 95% CI 4.7-55.9 @ 1yr) and may be superior to oral 5-ASA in distal UC. The addition of intermittent rectal to regular oral 5-ASA provides added benefit. The choice of formulation depends on disease extent.

ECCO statement 12E (UC 2017)

Mesalamine compounds are the first-line maintenance treatment in patients responding to mesalamine or steroids [oral or rectal] [EL1]. Rectal mesalamine is first-line maintenance in proctitis and an alternative in left-sided colitis [EL1]. A combination of oral and rectal mesalamine may be used as second-line maintenance treatment [EL1]

At least 2 g oral 5-ASA is recommended for maintenance. There is no added benefit in providing rectal doses > 1g/d. Therapy should be provided once daily as it is equally effective as more frequent dosing and improves compliance. There is no difference between preparations.

ECCO statement 12F (UC 2017)

The effective dose of oral mesalamine to maintain remission is 2 g/day [EL1]. For rectal treatment, 3 g/week in divided doses may be sufficient. Once-daily administration of mesalamine is the preferred dosing regimen [EL2]. Although sulphasalazine is equally or slightly more effective [EL1], oral mesalamine preparations are preferred to reduce toxicity. All preparations of oral mesalamine are effective [EL1]

5-ASA maintenance should be continued long-term, to try reduce the risk of colon cancer (though well-powered long-term efficacy studies have not been undertaken).

ECCO statement 12K (UC 2017)

Mesalamine maintenance treatment should be continued long-term [EL3]; this may reduce the risk of colon cancer [EL3]

Cancer Prevention

5-ASAs are believed to lower colon cancer risk in IBD (OR 0.51, 95% CI 0.37-0.69), although only case-control and cohort study evidence is available. They should be used in patients at high risk (PSC, FHx CRC) and in those with risk based on duration, extent and activity. They should commence from the onset of disease.

ECCO statement 8J (UC 2017)

Chemoprevention with mesalamine compounds may reduce the incidence of colorectal cancer in ulcerative colitis [EL2]. There is insufficient evidence to recommend for or against chemoprevention with thiopurines

Major side effects

  • Long term, 5ASA intolerance occurs in up to 15% of patients and can be associated with a flare in disease in 3%.
  • Headache, nausea, epigastric pain and diarrhoea are the most common side effects.
  • Rare, idiosyncratic side effects include Stevens Johnson syndrome, pancreatitis, agranulocytosis and alveolitis have been described.
  • Renal impairment (interstitial nephritis; nephrotic syndrome) is rare (0.3%/y) and usually reversible on stopping therapy.
  • National Formularly should be consulted to review adverse drug reactions and drug interactions.
  • Renal impairment is idiosyncratic, associated with having IBD rather than taking mesalazine. Monitor creatinine and electrolytes in those with pre-existing renal disease or taking nephrotoxic drugs (e.g. every 3-6 months).

Monitoring required and optimization

  • Monitor FBC & creatinine at least 6-monthly.

Special situations

Pregnancy and lactation

  • Sulfasalazine is safe in pregnancy and lactation.
    • Provide folic acid >/= 2 mg/d preconception to minimize increased susceptibility to neural tube defects.
  • Mesalazine </= 3 g/d is safe in pregnancy and lactation (data unavailable for higher doses).
  • Meta-analyses report no increase or slight increase in congenital malformations, although latter cannot exclude confounding effect of active Crohn’s disease.

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