David T. Rubin, MD, on Positioning Therapies for Crohn Disease

Gastroenterologists should remember that careful assessment of risk for progression, early treatment, and a treat-to-target approach remain critical in helping patients with Crohn disease achieve the best possible outcomes, David T. Rubin, MD, FACG, said at the Advances in Inflammatory Bowel Diseases virtual regional meeting on September 30.

Dr Rubin is the Joseph B Kirsner Professor of Medicine and chief of the Section of Gastroenterology, Hepatology, and Nutrition at the University of Chicago.

He acknowledged that the growing list of therapies for Crohn disease is a benefit, “but it adds complexity to the process of choosing therapies and determining the right one for each patient.”

First, Dr Rubin stated, “make sure you understand the patient’s overall risk for progression to poor outcomes, including surgery, recurrent or repeat surgeries, hospitalization, short bowel syndrome, or other disabilities” that can develop in this condition. Understanding that risk is essential in guiding the caregiver to the appropriate therapies for each patient.

In general, a patient diagnosed with Crohn disease at more than 30 years old, who does not have perianal or severe rectal disease, has superficial ulcers, has had no prior surgical resection, and does not present with stricturing or penetrating disease behavior can be classified as low risk. However, patients diagnosed when younger than 30 years old, who have more extensive bowel involvement, perianal disease, penetrating disease, deep ulcers, and a history of prior surgery should be considered at high risk of disease progression.

The first steps, Dr Rubin explained, are to use this risk stratification to guide treatment. “Assess the patient’s inflammatory status and prognosis, the current and prior disease burden, comorbidities, and any disease- and therapy-related complications,” he said. “This will better identify low- and high-risk patients. Perform initial treatment for patients in remission as well as those not in remission. For the low-risk patient, the initial treatment may be budesonide, or even no treatment for those who have mild nonprogressive Crohn disease, with ongoing monitoring. “It’s important for patients with normal labs and who have stood the test of time to know that it’s unlikely this disease will progress,” he said. Minimal or no treatment are also options for patients who show only incidental ileitis on colonoscopy.”

In both high-risk patients and those who do not respond to low-risk treatment, the key is to use treatments to control inflammatory process and prevent progression, Dr Rubin continued. “Most available therapies have been studied in such patients because they are at the highest risk for poor outcomes.”

Start by positioning based on disease-related factors, he said. How sick is the patient in front of you? What is the risk for poor outcomes? “Remember we are clearly defining different phases: induction and maintenance. We may need more intensive therapy for induction that can be de-escalated during the maintenance phase.”

Dr Rubin added, “It’s also appropriate to consider whether surgery is the first treatment for someone newly diagnosed with Crohn’s. Obviously, somebody who presents with a penetrating complication or bowel obstruction would be someone in whom surgery would be appropriate for the first treatment.” He noted that a randomized clinical trial found that patients who had surgery at the time of diagnosis with Crohn disease and those who were treated with infliximab had similar quality of life and clinical remission rates.

“It’s obviously a hard thing to recommend surgery to someone at the time of diagnosis who doesn’t have a penetrating complication or obstruction, but it is something to keep in mind,” he advised.

Choosing therapies should also account for factors such as the patient’s body mass index, whether the patient is male or female, has high C-reactive protein (CRP) or low albumin levels, and whether the patient has previously developed immunogenicity to a biologic, all of which can affect drug clearance and absorption. “Men clear anti-TNFs faster than women,” Dr Rubin explained. “The patient with low albumin may be leaking protein from their bowel, so they will clear the drug rapidly, and also is at higher risk because they are in that nutritional state.”

He further advised that organ-selective therapies be used before systemic therapies—such as budesonide before prednisone—and that comorbidities such as rheumatoid arthritis, psoriasis, and spondyloarthritis be considered, because some therapeutics are effective for both IBD and other autoimmune conditions, while others may be contraindicated.

While there are good data that support an exclusive enteral nutrition diet for Crohn disease in children and some positive data for adults as well, Dr Rubin noted that this diet is not palatable nor sustainable. A study conducted in Israel showed that a partial enteral diet, with a regular meal once a day based on the Crohn Disease Exclusion Diet, was better tolerated and demonstrated superior sustained remission and reduction of inflammation by week 12.

The best study of diet in Crohn disease, he said, was that led by James Lewis, MD, which compared the effectiveness of the Specific Carbohydrate Diet to the Mediterranean diet as treatment for Crohn's disease (CD) with mild to moderate symptoms. Patients achieved similar remission rates on both eating plans, but inflammation was not controlled based on CRP. The Mediterranean diet was found more palatable and easier to follow, Dr Rubin noted. “One of the takeaway messages here is that diet affects symptoms, and we knew that, but also that it might be used as an adjunctive approach to helping patients feel better.”

Dr Rubin reviewed several network meta-analyses and systematic reviews of trials that have helped clarify how to position the medical therapies available for Crohn disease. In one such analysis of 18 pivotal trials assessing induction therapy in biologic-naïve patients with moderate to severe Crohn disease, infliximab and adalimumab ranked the highest for inducing clinical remission and endoscopic improvement, outperforming certolizumab, vedolizumab, and ustekinumab. “In general, our colleagues agree that anti-TNFs are the strongest therapies when we need them,” he said.

Another meta-analysis compared the rates of clinical remission seen with the early use of anti-TNFs vs conventional step-up therapy and found that adult patients treated earlier in their disease course—less than 2 years—were 2 to 3 times twice as likely to be in clinical remission after 6-12 months, while children were 3 times more likely to sustain remission. “It’s important to keep in mind that you don’t want to be waiting to get patients on the right therapy. You need to treat them early to control their disease for many different reasons.”

“What if you start with an anti-TNF and the patient doesn’t respond or loses response?” Dr Rubin asked. “A meta-analysis of studies of ustekinumab vs vedolizumab among patients who had not responded to anti-TNFs found that ustekinumab was more effective in the maintenance phase but both agents were effective in inducing remission.”

Patients with perianal Crohn disease have a significantly impaired quality of life, he said.  Multiple studies of anti-TNFs have shown the benefit of combination therapy with an anti-TNF and ciprofloxacin for cessation of drainage and closure of fistulae. High serum trough concentrations of infliximab are associated with greater fistula healing, Dr Rubin said, while a trial of adalimumab combined with ciprofloxacin showed a 65% fistula response rate at week 12 and 53% at week 24.

“Controlling the risk of perineal sepsis as the fistula stops draining and inflammation is controlled is a very important concept,” Dr Rubin explained. “Even with uncomplicated perianal fistulae, I encourage using ciprofloxacin with infliximab in induction and possibly longer. I also use ciprofloxacin with other biologic therapies when treating patients with perianal disease.”

The newest approved therapy for Crohn disease, risankizumab, targets the p19 subunit of interleukin 23 (IL-23). The ADVANCE and MOTIVATE induction trials and the FORTIFY maintenance study yielded “quite significant” results, Dr Rubin stated. “This is a very positive -looking therapy with a safety profile that looks like ustekinumab. We believe IL-23 is more a tissue-specific cytokine and therefore inhibiting it affects the tissue is a more direct way that systemic immunosuppression.”

For the post-operative patient with Crohn disease, “It’s upon us to monitor and do our best to prevent recurrence,” Dr Rubin said. For low-risk patients, imidazole antibiotics are appropriate and thiopurines are more effective than mesalamine or no treatment but not effective to prevent severe endoscopic recurrence. High-risk patients should start medical therapy within 4 weeks post-op, usually an anti-TNF combined with an immunomodulator, and colonoscopy should be performed within 6 months, or 3 months for higher-risk patients, Dr Rubin advised.

He also urged clinicians to employ a treat-to-target approach with their patients. This includes conducting a baseline assessment of disease activity and severity; the benchmark establishment of targets that correlate with endoscopy; early reassessment of the target, usually within 6 weeks for most patients; and the adjustment of therapy as needed.          

Targets identified by the STRIDE 2 consensus Crohn disease include the absence of abdominal pain and altered bowel habits, and endoscopic/radiologic improvements. The consensus incorporates short-term targets such as normalization of CRP and fecal calprotectin and of growth in children, he explained. “Pay attention to objective targets to move forward. Be very intentional about it. I always think about what’s my target and when do I reassess it—usually at 6 weeks.”

Targeted synthetic small molecules offer new possibilities for management of Crohn disease, Dr Rubin said. Janus kinase inhibitors (JAKs) and sphingosine 1-phosphate receptor modulators (S1Ps) “allow oral delivery, get absorbed right away in the small bowel, have predictable pharmacokinetics, and present no immunogenicity problems.” They are fast-acting and offer the potential for novel treatment strategies.

Tofacitinib, the first JAK inhibitor to be approved for ulcerative colitis, has shown some positive results in Crohn disease in a real-world open-label study, although its phase 2 studies were negative.  Upadacitinib, also approved for ulcerative colitis, has proved effective in trials for moderate to severe Crohn disease with response as early as week 2, Dr Rubin explained. Both JAK inhibitors are approved for use in ulcerative colitis only if a patient has failed to respond to an anti-TNF.

Combination therapy using multiple biologics and small molecules may be on the horizon. The EXPLORER open-label study used vedolizumab, adalimumab, and methotrexate in combination to treat high-risk patients with Crohn disease who were biologic-naïve. Vedolizumab was continued for 104 weeks while adalimumab was stopped at 26 weeks and methotrexate at 34 weeks. Dr Rubin noted that about one-third of patients were in endoscopic remission at week 26 and 55% were in clinical remission. “This is certainly a possible approach to very high-risk patients.”

—Rebecca Mashaw

Reference:
Rubin, DT. Keynote: Positioning therapies for Crohn's disease. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. September 30, 2022. Virtual