Therapy of Extensive Disease

Mildly active extensive (extending proximal to splenic flexure) colitis is usually best treated first with oral 5-ASA. Sulfasalazine, the original 5-ASA preparation, is a prodrug that releases 5-ASA after cleavage by bacterial action on the diazo bond with sulfapyridine. However, the sulfapyridine moiety has little anti-inflammatory activity, and it causes adverse effects in up to 40% of patients. Most patients who experience adverse effects from sulfasalazine will tolerate oral 5-ASA preparations. The adverse effects from sulfa-pyridine can be dose related, and this prevents use of high doses of sulfasalazine, usually to a maximum of 4 g daily. Therefore, it is not possible to deliver as high a dose of 5-ASA with sulfasalazine as with other oral 5-ASA preparations. Other available oral preparations of 5-ASA include the prodrugs, olsalazine (Dipentum) and balsalazide (Colazal), as well as the targeted delivery preparation of 5-ASA (Asacol), and the continuous delivery preparation of 5-ASA (Pentasa).

One of the oral 5-ASA preparations should be used as initial therapy for mildly active UC. We usually start one of the newer oral 5-ASA medications such as Asacol at a dose of 2.4 g/d, balsalazide (Colazal) at 6.75 g/d (contains 2.4 g of 5-ASA), or Pentasa at a dose of 2.5 g/d. If there is no symptomatic response in 10 to 14 days, the dose may be increased to 4.8 g/d of Asacol or 4.0 g/d of Pentasa (Sutherland et al, 2000; Eaden et al, 2000). Some patients may respond well, except for persistent urgency or occasional blood streaks with mucous on stools. This usually reflects persistent distal colon inflammation, and the addition of 5-ASA suppositories (Canasa) or enemas (Rowasa) at bedtime may control these lingering symptoms.

The newer oral 5-ASA medications are several times more expensive than sulfasalazine, and when cost of the medication is a limiting factor for a patient, sulfasalazine is a reasonable choice. Sulfasalazine may be started at 1 g daily with an increase in the dose by 1 g each day up to the target dose of 3 to 4 g/d, if tolerated. The complete blood count should be checked after a week to look for toxicity, especially leukopenia. However, there are several drawbacks to using sulfasalazine instead of one of the newer 5-ASA preparations. Sulfasalazine should not be used in patients with a history of sulfa allergy. Besides allergic reactions, some patients develop headaches, nausea, anorexia, and other dose-related adverse effects. Sulfasalazine may cause reversible male infertility, which does not occur with the other oral 5-ASA medications.

For moderate symptoms, we start high dose oral 5-ASA with Asacol at 4.8 g/d (may be available as 800 mg tablets) or Pentasa at 4.0 g/d (available as 500 mg capsules); if the symptoms do not improve in a week, prednisone should be started at 40 mg/d as a single morning dose. Once symptoms come under control, the prednisone can be tapered, with reductions by 10 mg/d each week down to a dose of 20 mg/d, and with reductions of 5 mg/d each 1 to 2 weeks thereafter until prednisone is discontinued. If there is initial improvement but then symptomatic worsening while tapering prednisone or within a few weeks of stopping, the dose of prednisone can be increased again until symptoms improve and then tapered more slowly. For the patient who again flares with the second prednisone taper, the pred-nisone may be increased to the dose that controlled the symptoms, with AZA 2 to 2.5 mg/kg/d or 6-MP 1 to 1.5 mg/kg/d added. The prednisone may again be tapered after another 2 months. For those not responding to prednisone, nicotine patches are a consideration, gradually increased to a dose of 21 mg/d. If major symptoms persist despite these measures, consideration should be given to surgery with proctocolectomy and IAP for the patient who is less than 65 years of age, or end-ileostomy for the obese or older patient and for those with anal sphincter incompetence.*

Severe colitis symptoms can be very disabling and life threatening with risks including toxic megacolon, sepsis, and perforation. Such flares may be induced by medications, such as antibiotics and nonsteroidal anti-inflammatory drugs, or by development of an idiosyncratic reaction to sulfasalazine or 5-ASA, even in the patient who has previously tolerated these drugs for months or years. Patients with severe flares usually require hospitalization and intravenous (IV) corticosteroids. Bowel rest may be used but there is no data to support that this hastens induction ofremission and patients will usually tolerate a liquid or low residue diet. With the possibility of an idiosyncratic reaction to sulfasalazine or 5-ASA, it is usually worthwhile to stop this drug for a while to make sure this is not the provoking agent. Stool cultures and assessment for Clostridium difficile toxin and ova and parasites should be undertaken simultaneously with ini

*Editor's Note: I am also concerned about IAP anastomosis in patients with severe co-existent irritable bowel syndrome.

tiation of the corticosteroids. Daily monitoring of the patient should include examination of the abdomen and plain films of the abdomen daily or on alternate days. If symptoms do not improve with 5 days of IV steroids, such as Solu-Medrol at doses of 60 mg over 24 hours up to 40 to 60 mg each 8 hours, then proctocolectomy or IV cyclosporine should be considered. Although surgery may be the best alternative, some patients are unwilling to proceed with surgery, and IV cyclosporine (2 to 4 mg/d) is a reasonable alternative for 7 to 10 days. Initial combined therapy with steroid and cyclosporine does not appear to be more advantageous than starting with steroids and later adding the cyclosporine, if needed. After the patient improves from the severe flare, AZA (2 to 2.5 mg/kg) or 6-MP (1 to 1.5 mg/kg)^ should be overlapped with oral cyclosporine (5 mg/kg/d) with intended blood levels of cyclosporine of 150 to 300 ng/mL for 3 to 6 months. While the patient is on cyclosporine, antibiotic prophylaxis for Pneumocystis carinii with trimethoprim 160 mg/sulfamethoxazole 800 mg (one double strength tablet) once daily should be given. For the patient who responds to this program, AZA or 6-MP should be continued for years. For some patients intolerant of AZA, 6-MP may be better tolerated (Boulton-Jones et al, 2000). Concomitant 5-ASA seemingly adds little to the immunomodulatory drug regimen. Initial use of IV cyclosporine without corticosteroids may be reasonable therapy for severe UC in the patient with a history of steroid-induced psychosis, avascular necrosis, or other severe side effects from corticosteroids.

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