Safety of Combo Therapy for IMIDs Requires Caution

Preliminary safety data from a French registry on combination therapy in immune-mediated inflammatory diseases (IMIDs) show a concerning rate of serious infections and illustrate the need for controlled research before the use of combination therapy picks up significant speed, Eric M. Ruderman, MD, professor of medicine in the Division of Rheumatology at the Northwestern University Feinberg School of Medicine, Chicago, said at the Rheumatology Winter Clinical Symposium (RWCS) 2025.

Data reported in a poster at the American College of Rheumatology 2024 Annual Meeting and were highlighted at the RWCS 2025 in a year-in-review session on psoriatic arthritis (PsA) led by Ruderman and Arthur Kavanaugh, MD, professor of medicine in the Division of Rheumatology, Autoimmunity, and Inflammation at the University of California, San Diego.

“One of the hottest topics over the past year and going forward is combination therapy,” said Kavanaugh. “I think combination therapy is coming; it’s just a question of which combinations,” he added.

The French COMBATT registry is an academic, observational, nationwide registry that aims to enroll at least 1000 patients with IMIDs who are treated with combined targeted therapy. In their abstract, the researchers reported on the first 79 patients — three of whom were treated with more than one combination — and on 97 combinations of therapies. Of the 79 patients, nine developed serious infections.

Although the researchers said in their abstract that their preliminary findings suggest “an acceptable short-term safety profile,” Ruderman urged caution. “I think we need to move really carefully. I look at this [preliminary data] and I see more than 10% serious infections,” he said. “That’s not what we’re used to seeing with these drugs.”

Combination therapy was initiated for one refractory IMID in 46 patients, for two related IMIDs in 16 patients, and for two unrelated IMIDs in 17 patients. Refractory IMIDs were mainly rheumatoid arthritis (43.5%), spondyloarthritis (19.6%), and PsA (10.8%). A median of six targeted therapies were tried before a combination approach was initiated, according to the abstract.

The severe infections occurred in four patients taking tumor necrosis factor (TNF) + Janus kinase (JAK) inhibitors; two patients taking TNF + interleukin (IL)-23 inhibitors; one taking CTLA4-Ig (abatacept) + JAK inhibitor; one taking IL-23 + JAK inhibitors; and one taking CD20 inhibitor + B-cell–activating factor inhibitor, Kavanaugh and Ruderman shared.

“A TNF inhibitor and JAK inhibitor is a combination I’m not really happy about trying because you’re hitting too many places in the pathways,” said Ruderman.

“On the other hand, some of the newer agents, like an IL-17 or an IL-23 inhibitor, are so specific that combining them with something else may be doable,” he said. “But we need to do it thoughtfully and see if we can do it in a way that actually targets complementary pathways without increasing risk.”

Roots and Future of Combination Therapy

Rheumatology’s current interest in combination therapy has its roots in gastroenterology, where the Janssen-sponsored phase 2 VEGA trial of ulcerative colitis induction therapy found that a combination of guselkumab, an IL-23 inhibitor, and golimumab, a TNF inhibitor, might be more effective for ulcerative colitis than either drug alone — without added toxicity, Kavanaugh said.

Results of a phase 2 trial of the same combination in PsA — the AFFINITY trial — are now awaited. Other trials are being considered by industry, and “there are some ongoing investigator-initiated trials” on combination therapy for PsA, Ruderman added in an email interview after the meeting.
 

The COMBATT registry data and other open, observational data can provide useful information on safety, he said, “but we need controlled data to confirm the true safety and efficacy of combination therapy.”

In the meantime, in practice, he said in the interview, “given the low risk of infection with IL-23 inhibitors, some clinicians are starting to consider combining these with other biologics.” Vedolizumab, a gut-specific immune-modulating agent for inflammatory bowel disease, is increasingly used in combination with other biologics for skin and joint disease, he noted.

Reports of combination therapy in IMIDs often involve apremilast, a phosphodiesterase 4 inhibitor, but given that “we think of apremilast as a potent anti-inflammatory and not necessarily immunosuppressive,” it’s not the type of combination therapy needing investigation, he said in the interview. “Most people are comfortable using it in combination.”

Ruderman said at the meeting that his caution about combination therapy “goes back 20 years to early combinations of TNF inhibitors and other biologics in RA [rheumatoid arthritis].” Published studies showed a doubling of the risk for serious infection.

But again, “given the targeted nature of newer biologics, I think we can begin to think about combinations after avoiding them for so many years,” he said in the interview.

Preliminary Effectiveness

Initial findings from the COMBATT registry suggest that combination therapies may reduce disease activity in some refractory patients, the investigators reported in their abstract. Of 80 combinations that involved at least one follow-up visit, 41 were discontinued because of primary failure (n = 20), secondary loss of efficacy (n = 9), remission (n = 6), intolerance (n = 5), or unevaluated cause (n = 1).

Of 46 combination therapies for 36 of the patients who had one refractory IMID and at least one follow-up visit, 20 were effective, six were partially effective, and two were initially effective with subsequent loss of effectiveness, according to the abstract.

In addition to the nine serious infections, two patients developed cytopenia and one had a thromboembolic event, they reported.

Study investigators reported financial relationships with AbbVie, Gilead Sciences, Eli Lilly company, Pfizer, and other companies. At the RWCS meeting, Kavanaugh reported consulting for Amgen, BMS, Eli Lilly company, Janssen, and other companies. Ruderman reported consulting for and/or serving on data safety monitoring boards for Janssen, Eli Lilly company, Merck, and other companies.