Treatment options for Crohn’s disease have been developing and expanding rapidly over the past 10 years. Multiple classes of medications are currently available to treat Crohn’s disease, including 5-aminosalicylates (5-ASA),  antibiotics,  glucocorticoids,  thiopurine immunosuppressives, methotrexate, tumor necrosis factor (TNF) alpha antagonists, and anti-integrin therapies. Goals of treatment have expanded beyond relief of symptoms to include maintenance of long-term remission,  avoidance of corticosteroids and their associated side effects, and prevention of disease complications such as fistulas,  strictures,  and abscesses. Additional aims of therapy are to avoid the need for surgical intervention, minimize the risk of colorectal cancer, and to maintain adequate nutrition and improve quality of life. The benefits of medications in achieving these outcomes must be balanced with the potential drawbacks, including the increased risks of serious infections, malignancies, and substantial financial burden for both individual patients and society. 

  Aminosalicylates
Sulfasalazine is composed of 5-aminosalicylic acid (5-ASA) linked to sulfapyridine by an azobond that is cleaved in the presence of colonic bacteria to release the active 5-ASA (mesalamine)  component.  Other 5-ASA formulations have various delayed-  and sustained-release formulations to promote absorption in targeted segments of the GI tract, typically aimed at the distal small bowel and/or colon.  The mechanism of action of 5-ASA is incompletely understood,  but thought to include topical anti-inflammatory properties, including inhibition of cytokine synthesis, free radical scavenging,  and impairment of white blood cell adhesion and function.

Aminosalicylates have been widely used with success for ulcerative colitis,  but evidence of benefit in Crohn’s disease is less compelling with studies demonstrating mixed results. Early studies of sulfasalazine demonstrated a modest benefit in inducing remission (but not maintaining remission) in patients with Crohn’s colitis, using a dose of approximately 1 gram per 15 kg of body weight. However, subsequent studies of mesalamine, including a 2004 meta-analysis showed only a modest and clinically insignificant treatment effect.

Subsequent to this, a Cochrane meta-analysis in 2010 showed a small benefit with sulfasalazine: it was more likely to induce remission than placebo (RR 1.38), with a benefit seen mostly in patients with disease confined to the colon.

Mesalamine was not more effective than placebo for inducing remission or response. Similarly, a 2011 meta-analysis of 22 randomized controlled trials showed a trend toward benefit of sulfasalazine over placebo for active Crohn’s disease (RR 0.83 of failure to achieve remission), but no clear benefit of mesalamine over placebo for the same purpose .  Neither sulfasalazine nor mesalamine was effective for preventing relapse of quiescent Crohn’s disease,  and neither has demonstrated a steroid-sparing effect.  Without clear evidence supporting its efficacy in Crohn’s disease, aminosalicylate therapy is not widely used or recommended at this time. However, sulfasalazine may have a role in treating mild- moderate Crohn’s colitis.

Adverse effects of sulfasalazine lead to discontinuation of the medication in about 20- 25 % of patients and are generally related to the sulfapyridine component. Idiosyncratic reactions include rash, hepatitis, pancreatitis, pneumonitis, agranulocytosis,  aplastic anemia,  lupus-like reactions, Stevens- Johnson syndrome, and allergic reactions to the sulfa moiety. Agranulocytosis typically occurs within the first 3 months of treatment and can rarely be fatal. Compete blood cell counts and liver function tests should be monitored frequently during the first 6 months of therapy. Dose related effects can include nausea, anorexia, dyspepsia, leukopenia, hemolytic anemia, and headache.  Sulfasalazine is also associated with oligospermia in men,  which is reversible after discontinuation. Folic acid supplementation is recommended during sulfasalazine treatment to prevent the effects of medication-induced folic acid deficiency .  Adverse effects of mesalamine are less common, but can include nausea, headache, diarrhea, pancreatitis, and pneumonitis.  Rarely,  patients can develop worsening of their colitis symptoms,  sometimes associated with fever and rash. Nephrotoxicity is also a rare side effect,  most often caused by acute or chronic interstitial nephritis with a risk of approximately 1 per 4,000 patients per year, and so renal function should be monitored periodically during
therapy. 

### R. A. Fausel , MD
T. L. Zisman , MD, MPH
Division of Gastroenterology, University of Washington Medical Center , 1959 NE Pacific Street, Box 356424 , Seattle , WA 98195 , USA

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