Head-to-head trial data in rheumatoid arthritis scant, offer ‘shaky evidence’
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SAN DIEGO — Rheumatology research still offers too few head-to-head clinical trials of biologic medications to help clinicians manage rheumatoid arthritis, according to data presented at the 2023 Congress of Clinical Rheumatology West.
Addressing the attendees, Jeffrey A. Sparks, MD, MMSc, director of immuno-oncology and autoimmunity at the Brigham and Women’s Hospital division of rheumatology, inflammation and immunity, additionally raised an important question about choice and hierarchy of treatment: Does it matter?
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“This is probably the crux of rheumatology right now — this is the billion-dollar question,” he said. “I could have had one slide that says, ‘Maybe,’ but that would not really be helpful.”
For the most part, treatment choice is “algorithmic or trial and error,” according to Sparks. For moderate or severe patients, which account for approximately 90% of the RA population, methotrexate is the first line choice. For the remaining 10% with mild disease, hydroxychloroquine may be effective.
However, the most important — yet unresolved — questions pertain to therapeutic choice beyond methotrexate, Sparks said.
Although many clinicians will begin biologic therapy with a TNF inhibitor, Sparks suggested that challenges begin with loss of response to these medications.
“After primary non-response, putting them on a second TNF inhibitor is going to yield a pretty low response,” he said. “For the most part, we are switching to a different mechanism of action.”
Those mechanisms include interleukin (IL)-6 inhibition, Janus kinase (JAK) inhibition, the prevention of T-cell activation with abatacept (Orencia, Bristol Myers Squibb) or B-cell depletion with rituximab (Rituxan, Genentech) or other agents.
According to Sparks, the ORAL Strategy study — a head-to-head trial with the JAK inhibitor tofacitinib (Xeljanz, Pfizer) set against adalimumab (Humira, AbbVie) with or without methotrexate — found that tofacitinib plus methotrexate was noninferior to adalimumab plus methotrexate, and that tofacitinib monotherapy “underperformed” compared to other groups.
However, these data provide “shaky evidence” related to JAK inhibitor use, he said.
Meanwhile, in the RA-BEAM study, baricitinib (Olumiant, Eli Lilly) was statistically superior to adalimumab at 12 weeks, according to Sparks. However, the baricitinib dose in that study was 4 mg, while only the 2 mg dose is approved by the FDA, meaning that U.S. rheumatologists are unable to use the dose reported in the trial. Sparks argued this compounds the concerns clinicians have regarding the need for clear answers or guidance from clinical trial data.
In the SELECT-COMPARE trial, the JAK inhibitor upadacitinib (Rinvoq, Abbvie) bested adalimumab in terms of “signs, symptoms, and clinical function,” according to Sparks.
“That was a surprise,” he added.
Although all of these findings can offer some perspective for rheumatologists, Sparks called on the research community to conduct more head-to-head trials.
“It is unfortunate that there have been so few head-to-head randomized, clinical trials to help us make very important decisions with our patients,” he said.
If there is a silver lining, it is that there are clear answers with regard to TNF inhibition. “
Despite the current “shaky evidence,” Sparks said more studies and real-world data are likely to point toward a bright future for JAK inhibition.
“You can see why there is a lot of enthusiasm for JAK inhibitors,” he said.
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Sparks J. Biologic & tsDMARDs Choices for Rheumatoid Arthritis: Does it Matter? Presented at The Congress of Clinical Rheumatology West; Sept. 7-10, 2023 (hybrid meeting).
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