ORLANDO – Prescribing optimal therapy for a patient with inflammatory bowel disease can be challenging under ordinary circumstances, but add an extra-intestinal manifestation and the complexity grows greater still. Until more evidence-based findings emerge to help guide and individualize systemic or combination therapy, one of the advantages of biologics – their ability to target the intestine – can be a drawback when patients present with other manifestations.

To highlight the challenges and propose management strategies, Corey A. Siegel, MD, presented the case of a 45-year-old man seeking care 8 years after a diagnosis of ileocolonic Crohn’s disease. Seven years earlier, after the patient failed 5-aminosalicylic acid medication and prednisone therapy, clinicians prescribed infliximab (Remicade, Janssen) monotherapy. He experienced a “great response,” Dr. Siegel said at the Advances in Inflammatory Bowel Diseases meeting.

“Unfortunately, he had a real-life delayed hypersensitivity reaction 2 years ago with no drug present at trough and good antibodies, equal to 12 on a drug tolerant assay,” added Dr. Siegel, director of the Inflammatory Bowel Disease Center at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., and moderator of a case discussion panel session. So physicians initiated combination therapy with adalimumab (Humira, AbbVie) and methotrexate, but the patient “never felt as good as he did on infliximab, even with weekly dosing.”

A colonoscopy 9 months ago revealed mild to mildly active ileal and ascending colon disease. “So he still has residual disease present, even with weekly dosing of adalimumab,” Dr. Siegel explained. At the time, clinicians prescribed vedolizumab (Entyvio, Takeda) and the patient reported IBD symptom improvement. “He was doing better but not fantastic, and now his joints were bothering him, and they never bothered him before.” The man reported joint pain in his hands, knees, and hips. A more recent, follow-up colonoscopy revealed improvement, although mildly active disease was still present.

Do we need to dose-optimize vedolizumab or is it time to move on here? Dr. Siegel asked an expert panel: Bruce E. Sands, MD, David T. Rubin, MD, and Gary L. Lichtenstein, MD.

“This is a difficult question,” said Dr. Sands, professor of medicine and gastroenterology at the Icahn School of Medicine at Mount Sinai, New York. Dose escalation to every 4 weeks can recapture some patients with symptoms from active inflammation in the gut, he said. However, “vedolizumab is really a gut-focused, immune system modulating agent that really is not going to do anything to target peripheral inflammation. So if his arthralgias are driven by peripheral inflammation, obviously this patient would do better with something that has more systemic effect.”

Instead of considering a third anti–tumor necrosis factor (anti-TNF) agent when the patient has already not responded fully to others in that class, Dr. Sands suggested ustekinumab (Stelara, Janssen). “It could be that ustekinumab would be a better choice versus dose escalation of vedolizumab, unless you add something to the dose-escalated vedolizumab to treat the arthralgias like celecoxib.”

Next, Dr. Siegel asked if the arthralgias are truly extra-intestinal manifestations of inflammatory bowel disease “or is it what my patients are telling me – what they see all over the Internet – that vedolizumab causes arthralgias or arthropathies?

“That is an important question,” said Dr. Rubin, section chief of gastroenterology, hepatology, and nutrition at the University of Chicago. “My question back to you is when did the joint pain start – right after vedolizumab was initiated? Right after steroids were tapered? Or after the patient was on stable dosing for some time?”

The arthralgias seemed to start right after the patient started vedolizumab, Dr. Siegel said. But when clinicians inquired a little further, the patient reported “it was when he came off the adalimumab that things really started.”

“One of the things to recognize is not all arthropathies parallel disease activity,” said Gary Lichtenstein, MD, director of the Inflammatory Bowel Disease Center at the University of Pennsylvania in Philadelphia. There are two types we see in IBD, and one parallels and one does not parallel disease activity. The patient could also have a concomitant condition such as rheumatoid arthritis, he added, “so partnering with someone more savvy in examining joints and more knowledgeable, like a rheumatologist, might be an important thing to look at.”

It could be that systemically active infliximab and adalimumab with methotrexate were essentially covering up an extra-intestinal manifestation that was later uncovered with the selective mechanism of vedolizumab, Dr. Rubin said. “If that’s true, I don’t think I would give him more vedolizumab to treat his joint pain – that certainly wouldn’t do it. I would make sure his disease is responding from mucosal view, then I would add methotrexate or even consider sulfasalazine.”

This is distinct then from thinking the vedolizumab caused the joint pain, Dr. Rubin said, because that would imply a drug reaction that needs the drug to be discontinued. “Despite some descriptions of this we don’t have a clear association, and in fact the GEMINI series does not suggest it happens that way, it was not different than placebo, which is why I asked about the prednisone, which is another way to trigger some of this.”

A meeting attendee said that the patient did very well with infliximab, and asked “can we ever go back?”

“Probably not easily,” Dr. Sands said. “For someone with a bona fide delayed hypersensitivity reaction – I wouldn’t go there, and I wouldn’t think that you could.”

Another attendee asked if there is a role for adding another biologic to vedolizumab. “We hope to initiate a study soon looking at combination of biologics, such as vedolizumab with adalimumab, with and without an immunomodulator, Dr. Sands replied. They cover somewhat different targets – so it’s sort of a ‘belts and suspenders approach’ … but there are no data whatsoever [yet].”

Dr. Siegel wrapped up the case discussion with the patient’s outcomes. “We did move him on to ustekinumab. He felt better and his arthralgias went away.”

The meeting was sponsored by the Crohn’s & Colitis Foundation of America.

Dr. Siegel and Dr. Rubin disclosed ties with AbbVie, Janssen, and Takeda. Dr. Sands disclosed ties with AbbVie, Janssen Biotech, and Takeda. Dr. Lichtenstein disclosed ties with AbbVie, Janssen Orthobiotech, and Takeda.

Systemic inflammation expands clinical challenge in IBD