Medical Management of Ulcerative Colitis Conrad Beckett Bradford Royal Infirmary M62 Course March 2006

Aims of medical therapy Treat acute attacks Maintain remission

What is the evidence base? What’s new?

Treatment options 5-Aminosalicylates Steroids Azathioprine Cyclosporin Infliximab New therapies

Topical Therapy 5-ASA vs. steroid enemas Effective in inducing remission (1). 5-ASA more effective than topical steroids (2). Cyclosporin enemas used in resistant proctitis.

Oral 5-ASA 5-ASA are effective in the induction and maintenance of remission in UC (3)[Grade A]. ASCEND 11 found that 4.8g/day is better than 2.4g/day in treating moderately active UC (4). Paoluzi et al. found that 2.4g/day no more effective in preventing recurrence than 1.2g/day (5).

Oral 5-ASA (2) Adherence to therapy vital to emphasize as x5 increase in relapse rate when compliance <80% (6). Adding topical 5-ASA to oral 5-ASA therapy can also help in frequently relapsing disease (7).

Oral 5-ASA (3) Regular 5-ASA may reduce risk of colorectal cancer in patients with UC (8). The case-control study found that 5-ASA use reduced CRC risk by 81%. Regular hospital visits also reduced risk. A family history of sporadic CRC increased risk five fold. May help with patient compliance.

Steroids Remain standard therapy for inducing remission in moderate/severe UC [grade A]. Trials conducted >40 years ago (10,11). No evidence to support their use in maintenance of remission [grade A]. ? Any benefit from more than 40mg (12).

Azathioprine Until recently, relatively weak Grade C evidence (13,14). The azathioprine withdrawal study provided stronger evidence (15) [Grade A]. A recent study by Ardizzone has strengthened the evidence for its use in inducing remission of steroid dependent UC (16). 53% vs. 21% in remission and steroid free at 6/12 when compared to 5-ASA.

Cyclosporin No RCT data. Use based on the Lichtiger study where 75% short-term response in severe UC (18). At best, 55% avoid surgery at 3 years. Significant side-effect profile. Lower dose, 2mg/kg may be better tolerated (19).

Infliximab ACT 1&2 have demonstrated its efficacy in the induction and maintenance of remission in UC (Rutgeerts et al. NEJM 2005;353: ). Significantly better than placebo in inducing and maintaining remission in moderate to severe UC. Sig. more treated patients were able to achieve steroid free remission. Improved quality of life scores.

Infliximab (2) Also studied as a single infusion as rescue therapy in acute severe UC (20). Significantly fewer patients in the Infliximab treated group had a colectomy (29% vs. 67%). No serious side-effects. Follow-up only 3 months.

Infliximab vs. Cyclosporin No trial evidence as to which to use first as rescue therapy when IV steroids fail. Both have a significant side-effect profile. Infliximab is a simpler single infusion. No long-term data on Infliximab in UC. Neither increase surgical complications. Half-life of Infliximab >> CyA.

Treatment algorithm for UC Acute Severe Colectomy Cyclosporin Infliximab IV Steroids 5 ASA Oral Steroids AZA dependent refractory ModerateSevere RemissionRescue ACT patientsJarnerot patients Infliximab

When to intervene? The Oxford study demonstrated that at day 3 of IV hydrocortisone, if BO x 8/day BO x 3-8 with CRP>45mg/l 85% would require colectomy. If > 3 stools (with blood) a day at day 7, there was a 60% chance of continuous symptoms and 40% chance of colectomy.

Summary High dose 5-ASA more effective in inducing remission in moderate UC. 5-ASA compliance vital in maintaining remission. 5-ASA may have a role in reducing CRC risk. Strengthening evidence for Azathioprine. Consider Infliximab or Cyclosporin promptly as rescue therapy when no response to IV steroids. JOINT CARE! As surgery will be the best treatment for some patients.