Using 5-ASAs and Steroids for UC Treatment

Miguel Regueiro, MD: Ellen, I want to transition into specific therapies and talk about 5-ASA [5-aminosalicylic acid] and steroids. To go back to the basics of ulcerative colitis [UC], how do you use those in your practice?

Ellen J. Scherl, MD: Just as a segue from the guidelines, most of us don’t practice algorithmic medicine. Even if the patients fit into the algorithms, they often don’t want to. One challenge in ulcerative colitis is that we overutilize mesalamines and steroids. We’ll talk about how we position in the first line, but I’d like to break this into the era of symptom control and then move into the era of disease modification. 5-ASAs, mesalamines, were introduced in the 1940s with sulfasalazine from our rheumatology colleagues, who said it works in rheumatoid arthritis; you may want to try it in your patient with colitis. That was the first introduction.

In the 1980s, we started to talk about sulfur pyridine free, so we could do dose escalation. For induction failures, the range is between 20% and 50% with rectal administration and up to 70% to 90% with oral; for moderate to severe, this may not be the drug of choice. For maintenance, 40% to 60% of patients fail to maintain remission in 6 months to a year…. If a patient isn’t induced and maintained in remission, they’re going to continue to flare and have progression of disease, and they’re not going to understand this. Mesalamine has a limited role in more moderate to severe patients. By using it prolonged we delay the onset and introduction of effective therapies. What’s the mechanism of action? Nobody knows. NF-kappa-B? The mechanism of action is the same. It’s the delivery system that makes the difference.

Not only is disease activity a more of a problem than active disease medications, but you want to get the active medication to the site of active disease. Yes, topicals work, but not that well. There are adverse events like nausea, diarrhea, headaches, and intolerance, where patients can get worse. What about steroids? Steroid were a big introduction as disease modification in 1950. Philip Hench got the Nobel Prize for introducing life-altering medications, mostly in rheumatoid arthritis. We jumped on the bandwagon. Ten years later, it was recognized that these medicines don’t alter. We had to come up with disease medications that are steroid-sparing, such as 6-MP [6-mercaptopurine] and the thiopurines.

Steroids are a major problem for us. The mechanism of action is the corticoid receptors, but it doesn’t matter. The adverse events are vascular necrosis, glaucoma—all the things that would never allow it to be passed by the FDA. In terms of the thiopurines, maintenance of failure rates with immunomodulators can be up to 60% in ulcerative colitis. It doesn’t change the natural progression or alter the rate of colectomy. And again, there adverse events like infection. We know from the SAPPHIRE registry and from European data that there’s an increased incidence with skin cancers and other solid tumor cancers, as well as lymphoma. Even the NF-kappa life-threatening lymphomas occur only in patients with immunomodulators with or without anti–TNF [tumor necrosis factor]. These immunomodulators, we’re beginning to recognize, are no longer where we should be. That’s the era of symptom control.

You asked me to talk about disease modification in terms of TNF. TNF changed the way we look at disease. The SONIC trial made us understand that it’s not just treating symptoms; we need to treat the disease itself. At the end of 26 weeks, I consider SONIC to be a pivotal trial, it showed that infliximab and azathioprine worked as steroid-free remission in 70%, infliximab in nearly 60%, and azathioprine vs placebo was only 28%. This spearheaded the whole concept that treating symptoms alone as not good enough because these patients had elevated CRP [C-reactive protein] or endoscopic inflammation. SONIC led to STRIDE. What about patient-reported outcomes? Do we need something more? The consensus was that you need fecal calprotectin and CRP.

Then the…trial showed that 45% of patients achieved mucosal healing if you dose escalated from adalimumab every other week to every week based on fecal current CRP, whereas only 30% had mucosal healing if you dose escalated on symptom control. TNF has been a pivotal step in understanding mucosal healing and disease progression reversal. Now we move into the era of STRIDE-II, when we talk about quality of life. Marla Dubinsky and I have talked about STRIDE-III, maybe with intestinal ultrasound. We must do better educating ourselves and our patients in terms of progression of disease. That’s where I see it.

Miguel Regueiro, MD: That’s great. You took us through the first year of treatment for ulcerative colitis. To reiterate a point, 5-ASA is still in about 30% to 40% of UC, which is appropriate for milder patients who have a response. Your point is that we can’t linger on steroids, that’s not acceptable. Thiopurine data and ulcerative colitis is fairly poor, and you outline some of the adverse events and the first biologics anti-TNF. You did a great job at outlining those studies.

Transcript Edited for Clarity