Treating IBD Without TNFis and JAKs

Treating inflammatory bowel disease (IBD) without using biologics, such as tumor-necrosis-factor inhibitor (TNFi) agents, or small molecule therapeutics such as Janus-kinase (JAK) inhibitors, is possible, said David Rubin, MD, codirector of the Digestive Diseases Center at UChicago Medicine, at the virtual Advances in Inflammatory Bowel Disease (AIBD) 2020 regional meeting on July 25.

“But we have to define ‘treat,’” he added. “The goals of treatment remain the same: improve symptoms, induce remission, prevent relapse, and prevent complications.” 

In reviewing the literature about the therapeutic agents that were once widely used for treating Crohn disease (CD) and ulcerative colitis (UC), Dr Rubin said he found important reminders “for all of us about what we need to think about when we’re using these older treatments and how we can still make them work for our patients.”

The traditional treatment strategy for IBD is a step-up approach through traditional therapeutics. “There are a lot of difficulties in this in general, but the treat-to-target approach allows us to move through these steps in an effective way.”

CD and UC present varying challenges and concerns in treatment, Dr Rubin noted. He pointed out that while mesalamines should not be used for the treatment of CD, these agents have shown advantages in the treatment of UC, “including efficacy for induction of response is 50% to 70%; induction of remission is 15% to 40%; and an excellent safety profile.”

The National Cooperative Crohn disease study (NCCDS) revealed that in this form of IBD, sulfasalazine proved to be the best of the 5-ASAs for inducing response in active CD. Between 40% and 50% of patients responded to therapy at 1 g/15 kg per day, and more than 80% of patients with mild to moderate CD achieved remission with 4 g/day controlled-release capsules.

Dr Rubin noted that when choosing between oral and rectal administration of 5-ASAs, “there is a rationale that the delivery system makes a difference. It’s hard to get 5-ASA down to the distal colon orally.” He considers combination therapy of oral plus rectal administration may be most effective.

One of the fears concerning steroid use in IBD is that patients may develop adrenal insufficiency or crisis; however, Dr Rubin said, “This is rare. Doses of 5 mg or less do not seem to cause any adrenal problems.” Similarly, some physicians are fearful of relapse of disease after tapering patients off steroids, but again, he said, there is no evidence of this.

However, steroid dependence is an issue, he said. Steroid dependence is defined as the inability to reduce steroids below the equivalent of 10 mg/day of prednisolone or 3 mg/day of budesonide within 3 months of starting the therapy without recurrence of active disease, or the inability to avoid needing steroids for at least 90 days.

“The practical approach is to taper doses of corticosteroids over duration of the induction period or the duration of time for maintenance therapy to work,” Dr Rubin stated. “I think we’re tapering people much too long.” While useful, steroids are associated with worse outcomes, including mortality, infection, diabetes, and other comorbidities.

Thiopurines remain widely used, Dr Rubin noted. The combined therapy of anti-TNFs and thiopurine “prevents immunogenicity and increases efficacy” of the biologics, he stated.

With the advent of TPMT and NUDT15 testing, it is now possible to determine before beginning treatment if a patient is likely to have reduced capacity to process these therapeutic agents, making them even safer. However, risks of lymphoma and nonmelanoma skin cancer associated with these immunomodulators are described in the literature. "Nonetheless, they do have benefit."

There are many reasons why patients may not respond to a particular therapy, Dr Rubin stated, from “the drug just doesn’t work,” to intentional nonadherence by patients who fear the therapy to problems with patients being unable to afford a particular medication.

After the initial treatment phase, patients should be regularly assessed, targets adjusted, treatments altered as indicated, and then when the goal of remission is reached, monitoring must continue. “The best approach is to trust but verify,” he said.

--Rebecca Mashaw

Rubin, D. Clinical management of UC and CD: can we still treat IBD without the mAbs and the JAKs? Presented at: Advances in Inflammatory Bowel Disease 2020 regional, Chicago; July 25, 2020; virtual.