Bruce Sands, MD, on Redefining Combination Therapy in IBD

A hard look at the actual effectiveness of biologics in the treatment of inflammatory bowel disease (IBD) shows that many patients are not achieving remission from Crohn disease and ulcerative colitis (UC) with existing agents, Bruce Sands, MD, MS, said at the virtual regional meeting of Advances in Inflammatory Bowel Disease (AIBD) on September 11.

“We all realize that we’ve reached a plateau with the efficacy of our agents in the treatment of IBD,” he said.

Dr Sands is chief of the Dr Henry D Janowitz division of gastroenterology and the Dr Burrill B Crohn Professor of Medicine at the Icahn School of Medicine at Mount Sinai in New York.

Citing a study by Ryan Ungaro, MD, on the real effectiveness of biologics in IBD, he noted that at week 54 of various clinical trials of anti-tumor necrosis factor (TNF) agents, overall remission rates after 1 year range from around 17% to 36%. “Other agents aren’t much better,” he added, observing that a study of tofacitinib in UC showed just a 10% difference between the drug and placebo during induction.

“We’re leaving a lot of patients behind who simply aren’t achieving remission.”

In fact, there are examples in the history of IBD that also illustrate how combination therapies can help overcome these plateaus, Dr Sands pointed out, such as the combination of oral and topical 5-ASAs, and using enema and oral applications of mesalamine. “This gives credence to the notion that a combination of 2 different therapies or at least 2 modes of delivery can achieve better results” than a single drug or route of administration alone, he explained.

The SONIC trial compared infliximab monotherapy, thiopurine monotherapy, and the 2 agents in combination in anti-TNF naïve patients with Crohn disease, Dr Sands said, showed that steroid-free remission at week 26 months was clearly more achievable with the combination than either agent alone.

“The same story applies in the case of ulcerative colitis,” he noted, where the SUCCESS trial, also using infliximab, azathioprine, and a combination of the 2 showed the combination was more effective than either agent alone.

“It’s only recently we’ve begun to understand why combination therapy might work, at least with infliximab,” Dr Sands explained. A post hoc analysis of the exposure-response relationship “seems to suggest it’s all about the drug level of infliximab, and the effect of the azathioprine helps to boost those levels, not so much the combination or synergistic action.” In theory the same result could be achieved through a treat-to-target approach using infliximab alone, he said. The caveat is that this is a post-hoc analysis and this should be established through prospective trials.

Beyond 6 months, the efficacy of combination therapy using anti-TNFs and thiopurines is not as apparent, Dr Sands stated, citing a Danish study that illustrated this point.

“For other biologics other than anti-TNFs, there really is not evidence that combination therapy with a thiopurine or an immunomodulator is better than monotherapy with ustekinumab or vedolizumab alone,” he continued.

“We have examples of the failure of combination therapy and one notable failure is the in COMMIT study, where patients with Crohn disease were assigned to either infliximab and placebo or methotrexate and infliximab but notably all patients in both groups received concomitant steroids,” Dr Sands explained. At week 15, with patients off of steroids, there were very high rates of remission, “much higher than we’re used to seeing.” Neither duration of disease nor Crohn Disease Activity Index (CDAI) score did not appear to make a difference in remission rates. “This would suggest that there was not a benefit to combination therapy,” as the patients achieved these high rates of remission and maintained remission at 56-57% out to week 50.

“Increasingly confusing” is the meta-analysis of several studies showing that concomitant steroid therapy with anti-TNFs is not more effective than anti-TNF monotherapy in inducing remission in Crohn disease, Dr Sands noted. “This is all a little bit confusing, and I’d say the jury is still out” on whether combination therapy with anti-TNFs and steroids is superior to anti-TNFs in induction. “COMMIT says yes, this systematic review and meta-analysis says no, and the latter is a higher level of evidence, perhaps.”

Dr Sands noted that there are risks involved with some combination therapies, referencing the example of a French study highlighting a significant risk of lymphoma and serious opportunistic infections with the use of combination therapy.

“How can we optimize our existing combination therapies?” he asked. “One notion is we can actually step-down dose and improve safety of the thiopurine.” Patients in one study who stepped down did about as well as those who continued but better than those who stopped azathioprine. “Patients who stopped their azathioprine were more likely to have undetectable levels of infliximab at trough, and the presence of antibodies. If you do a sensitivity analysis, you don’t need full dosing of azathioprine to achieve the desired results.”

Patients who have experienced loss of response and immunogenicity to anti-TNFs do better with combination when changing to a second-line anti-TNF, Dr Sands stated. The combination of infliximab or adalimumab with azathioprine provides greater durability of response among patients with antidrug antibodies to a previous anti-TNF than simply changing to another anti-TNF monotherapy.

Dr Sands emphasized the importance of avoiding giving combination therapy to patients who are “excessively susceptible to the negative effects of the thiopurine or the anti-TNF.” For example, he said, young men who are seronegative for Epstein-Barr Virus (EBV) and who might contract EBV after beginning treatment with azathioprine “are at excessive risk of early post-mononucleosis lymphoma, so maybe methotrexate would be a better choice.”

Genetic testing for NUDT15 polymorphisms and TPMT mutations also offers the ability to target combination therapy to avoid adverse effects such as severe thiopurine-induced leukopenia or pancreatitis, he stated.

In the future, Dr Sands said, “we’ll be talking about different sorts of combinations, not with immune modulators, but maybe with multiple biologics. We have so many different biologic types now, and we can take the example of dermatology and rheumatology, where they have many types of agents and are combining them in new ways.” Further, new oral small molecule therapies, such as sphingosine 1-phosphate receptor modulators and Janus kinase inhibitors, offer new opportunities for combinations.

However, Dr Sands said, it’s important to approach new combinations with caution, pointing to the combination of etanercept and anakinra in rheumatoid arthritis, which presented the risk of serious infections.

“There may be an immunological price to pay for over suppressing the immune system with certain combinations.”

--Rebecca Mashaw

Sands BE. Redefining combination therapy. Presented at: Advances in Inflammatory Bowel Diseases regional meeting. September 11, 2021. Virtual