番茄社区

On April 1, 2021, 番茄社区 reported on a study on the successful treatment of psoriatic arthritis (PsA) with upadacitinib (Rinvoq), with 24 weeks of follow-up. As a review of the year's top stories, we follow up on what has happened since this study was published.

At the virtual annual meeting of the American College of Rheumatology (ACR) in November, the from that trial -- again showing beneficial effects of the selective JAK1 inhibitor for PsA -- were presented by lead investigator Iain McInnes, MD, PhD, of the University of Glasgow.

In the meantime, however, the FDA had raised concerns about potentially serious adverse events for a drug in the same class of JAK inhibitors, tofacitinib (Xeljanz), issuing a suggesting that similar risks may exist for JAK inhibitors in general.

The Data

The upadacitinib trial, known as SELECT-PsA 1, took place at 281 sites in 45 countries, and was sponsored by AbbVie.

In SELECT-PsA 1, published on April 1 in the New England Journal of Medicine, 1,704 patients with PsA that had not responded adequately to non-biologic treatment received oral upadacitinib (15 or 30 mg once daily), placebo, or subcutaneous adalimumab (40 mg every other week).

At week 12, the percentages of patients who had 20% improvements on the ACR criteria (ACR20) were:

• 70.6% for the upadacitinib 15-mg dose
• 78.5% for the 30-mg dose
• 65% for the adalimumab group
• 36.2% for the placebo group

Both upadacitinib groups were considered noninferior to adalimumab, and the 30-mg dose was considered superior.

Adverse events included serious infections in 1.2%, 2.6%, 0.9%, and 0.7% of the 15 mg, 30 mg, placebo, and adalimumab groups, respectively. Hepatic disorders were observed in 9.1% of the 15-mg group and in 12.3% of the 30-mg group.

The 56-week follow-up in SELECT-PsA 1 was completed by 1,419 participants. At that time point, ACR20 responses were observed in 74.4% of the upadacitinib 15-mg group, 74.7% of the 30-mg group, and 68.5% of the adalimumab group. Patients who had initially been randomized to placebo and then switched to one of the two upadacitinib groups had rates of ACR20 response by week 56 that were similar to rates seen among patients on upadacitinib throughout the trial.

Herpes zoster was reported more commonly in the upadacitinib groups, while malignancies were reported at similar rates across all treatment groups.

Major adverse cardiovascular events were seen in 0.4%, 0.2%, and 0.5% of the upadacitinib 15 mg, 30 mg, and adalimumab groups, respectively, while venous thrombotic events occurred in 0.4%, 0.5%, and 0.3%.

In a parallel trial, , 641 patients who were refractory to biologic therapy were randomized to upadacitinib 15- or 30-mg daily, or to placebo and then switched to one of the two upadacitinib doses at week 24.

At week 12, 56.9% of the 15-mg group and 63.8% of the 30-mg group achieved ACR20 responses compared with 24.1% of the placebo group (P<0.001). At week 24, minimal disease activity was seen in 25.1% of the 15-mg group and 28.9% of the 30-mg group compared with only 2.8% of the placebo group (P<0.001 for both).

Rates of serious infections were 0.5% for the 15-mg group, 2.8% for the 30-mg group, and 0.5% for the placebo group.

The Safety Concerns

In September, the FDA issued a drug safety communication explaining that when the first JAK inhibitor, tofacitinib, was approved, manufacturer Pfizer was required to conduct a safety trial for patients with rheumatoid arthritis being treated with tofacitinib plus methotrexate to further assess the risks of serious adverse events.

That trial, which included more than 4,300 patients, compared tofacitinib, 5 mg or 10 mg twice daily, with a tumor necrosis factor (TNF) inhibitor. Participants were 50 years or older and had one or more risk factors for heart disease.

The FDA in its review of the final trial results found "a higher rate of serious heart-related events such as heart attack and stroke, cancer, blood clots, and death in patients treated with both doses of Xeljanz compared to those treated with TNF blockers." Higher rates of lymphoma and lung cancer also were observed among the tofacitinib patients.

Other JAK inhibitors had not been evaluated in large safety studies, but because the mechanisms of action are similar, the risks may also be similar, according to the FDA safety communication. Therefore, the agency required revisions to the boxed warnings of tofacitinib, baricitinib (Olumiant), and upadacitinib concerning risks of serious cardiac events, cancer, blood clots, and death. Upadacitinib has a preexisting label for its indication in rheumatoid arthritis.

Despite that cautionary note, AbbVie announced in mid-December the approval of upadacitinib, 15-mg once daily, for the treatment of adults with active PsA who had an inadequate response or intolerance to one or more TNF inhibitors.

"Many adults still struggle to find a treatment option that helps them lower their disease activity," said McInnes in a press release. "With this FDA approval, Rinvoq has the potential to help more people find meaningful relief from the signs and symptoms of PsA that they see and feel and to help reach their treatment goals."

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