Baricitinib Outperforms TNF Inhibitors in Pragmatic RA Trial

Baricitinib may be the superior choice to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) for whom conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have failed, according to a new study.

After 12 weeks, patients taking baricitinib achieved a 50% improvement in RA symptoms according to American College of Rheumatology response criteria (ACR50) at twice the rate as in patients assigned to receive TNF inhibitors. In addition, 75% of the baricitinib group achieved a 28-joint Disease Activity Score with C-reactive protein under 2.6, compared with less than half of patients taking TNF inhibitors.

Putting Safety Into the Equation

However, safety concerns also need to be considered when prescribing medication, noted Andrew Wang, MD, PhD, a rheumatologist at Yale School of Medicine in New Haven, Connecticut. He was not involved with the study, called PERFECTRA.

“This category of drugs — JAK-STAT [inhibitors] — are much newer than TNF inhibitors, CTLAs, B-cell depleters, and the other tools we have,” he said, “with relatively less real-world experience and potential downsides in the future,” he said.

Both the ACR and European Alliance of Associations for Rheumatology guidelines recommend that patients who have not achieved target disease activity with csDMARDs can be prescribed either a Janus kinase (JAK) inhibitor or a TNF inhibitor as a treatment option, yet many physicians favor TNF inhibitors because of extensive clinical experience with the drug class and other factors such as biosimilar availability and cost, Celine van de Laar, MSc, of Erasmus University in Rotterdam, the Netherlands, and coauthors explained.

There are also notable safety concerns for using JAK inhibitors: Results from a large postmarketing clinical trial of tofacitinib prompted the US Food and Drug Administration to issue a boxed warning for the medication due to an increased risk for cardiovascular events, cancer, blood clots, and death, in comparison with TNF inhibitors. That warning now includes two other medications in the same drug class: Baricitinib and upadacitinib. The European Medicines Agency has also issued guidance to minimize the risk for side effects for these medications.

Some randomized controlled trials have demonstrated that baricitinib “showed significant clinical improvements” in patients with RA compared with adalimumab and placebo, but these trials do not always reflect treatment in the real world, the study authors wrote. The results were published in RMD Open on May 30.

Study Details

In the study, researchers enrolled 199 patients with active RA for which previous use of at least one csDMARD had failed and randomly assigned 97 patients to receive baricitinib and the remainder to receive a TNF inhibitor: 64% started on adalimumab, 33% started on etanercept, and the rest used golimumab or infliximab.

For all patients, the suggested treatment allocation was provided via randomization lists, but physicians and patients ultimately decided treatment via shared decision-making.

Patients were diagnosed less than 5 years ago, had received no previous treatment with biologics or targeted synthetic DMARDs, and had no contraindications for TNF inhibitors or baricitinib. Researchers recruited patients from September 2019 through February 2022 across 15 health centers in the Netherlands and Belgium. The study was funded by Eli Lilly, which manufactures baricitinib, although the study was investigator initiated.

Patients were on average aged 55 years, and about two thirds were women. The average disease duration was 2 years.

At 12 weeks, 42% of the baricitinib group achieved ACR50, compared with 20% of the TNF inhibitor group. All patient-reported outcome measures showed improvement over the study period, favoring baricitinib. More patients receiving baricitinib remained on the medication overall than patients on a TNF inhibitor: At 48 weeks, 70% of patients receiving a TNF inhibitor and 80% of patients receiving baricitinib had continued taking their assigned treatment.

These results are not surprising, Wang noted, as “JAK inhibitors hit many arms of immune signaling, whereas TNF blockers just hit TNF.” However, there is a trade-off between potent, effective drugs and toxicity, he added.

“I would not be as bullish on starting baricitinib in a patient off the bat, in the same way that nobody would want to keep patients on glucocorticoids [any longer than is] minimally necessary.”

While the study was not powered to compare safety between the two drugs, there were no adverse events during the study that had not been previously reported.

“Prescribers have to be aware that cardiovascular and malignant [serious adverse events] are more frequently reported” with JAK inhibitors than with TNF inhibitors, the authors wrote. “Obviously, this has to be considered carefully in risk-benefit discussions with any individual patient.”

Wang noted that, in general, he and his colleagues would not start with a JAK inhibitor first except for special circumstances: For example, if a patient will not use an injectable medication, or for some reason, it’s impractical for the patient’s lifestyle to use medication that requires constant refrigeration.

“I think the take-home message here is these are, in general, lifelong diseases, and so a rheumatologist and their patients have to develop good relationships to monitor whether or not we’re hitting the sweet spot of keeping disease under control” while also avoiding overmedication and toxicity, he said.

One potential solution, which Wang has also done in his clinical practice, is to initiate a JAK inhibitor in patients who need it but then switch to a different modality after achieving disease control.

“You can imagine a scenario where you get them to a very low [Disease Activity Score] with baricitinib, for example, and then you switch them to a TNF inhibitor,” he said. “I can imagine that there would be ways that you could get the best of both worlds.”

PERFECTRA was financially supported by an unrestricted grant from Eli Lilly. The authors reported financial relationships with AbbVie, Eli Lilly, Galapagos, and Janssen-Cilag. Wang serves on NGM Bio’s science advisory board, consults for TCG Labs-Soleil and Seranova Bio, and has received funding from AstraZeneca.