Upadacitinib as New Treatment for Giant Cell Arteritis

Giant cell arteritis (GCA) is a vasculitis of the large and medium-sized arteries, primarily the cranial branches of the aorta, affecting adults older than 50 years. Currently, there is an unmet need for steroid-sparing therapies for GCA, with only one glucocorticoid-sparing agent approved at this time, tocilizumab (an IL-6 receptor inhibitor). Interleukin-6 and interferon-y play a role in the pathogenesis of GCA through the Janus kinase (JAK)/signal transducer and activator of transcription signaling pathway. The SELECT-GCA study by Daniel Blockmans and colleagues evaluated the efficacy and safety of upadacitinib versus placebo, used in combination with a glucocorticoid taper, to treat patients with GCA. The study found that upadacitinib 15 mg daily with a 26-week steroid taper showed efficacy superior to that of placebo with a 52-week steroid taper in the treatment of GCA.

The study enrolled patients with GCA at 100 sites in 24 countries. Eligible patients included adults 50 years of age and older with a clinical diagnosis of new-onset or relapsing GCA confirmed by temporal artery biopsy or imaging (ultrasonography, PET, CT, MRI, or angiography). Investigators excluded patients with previous exposure to JAK inhibitors and those who had a disease flare while receiving an IL-6 inhibitor. Patients were randomly assigned, in a 2:1:1 ratio, to receive upadacitinib at a dose of 15 mg or 7.5 mg once daily in combination with a prespecified 26-week steroid taper or placebo with a prespecified 52-week steroid taper. The primary end point was sustained remission at week 52, defined by the absence of signs or symptoms of GCA from week 12 through week 52, and adherence to the protocol-specified steroid taper. Secondary end points included sustained complete remission, time to a flare of disease, cumulative exposure to glucocorticoids, and steroid-related adverse events, as well as patient-reported outcomes.

A total of 428 patients underwent randomization and treatment. Demographic and baseline characteristics were similar across the trial groups, with 70% having new-onset GCA and 30% having relapsing disease. All patients underwent temporal artery biopsy, which showed features consistent with GCA, or had evidence of large-vessel vasculitis on imaging, or both. The mean glucocorticoid dose at baseline was 35 mg/d across groups.

In the study a sustained remission at week 52 was observed in a significantly higher percentage of patients receiving upadacitinib 15 mg daily with a 26-week steroid taper than in those who received placebo with a 52-week steroid taper (46.4% vs 29%; P = 0.002). The 7.5-mg daily dose of upadacitinib did not lead to a significantly higher percentage of patients with a sustained remission versus placebo. The upadacitinib 15-mg daily dose was also superior to placebo in terms of the secondary end points including sustained complete remission, time to a disease flare, cumulative glucocorticoid exposure, and patient-reported outcomes. For example, patients in the group receiving the 15-mg upadacitinib dose had significantly lower total exposure to glucocorticoids over 52 weeks compared with those in the placebo group (median exposure, 1,615 mg vs 2,882 mg; P<0.001). Safety outcomes throughout the study were similar between the two groups. The most common adverse effects during treatment with the upadacitinib 15-mg dose included headache (16%), arthralgia (14%), hypertension (13%), and COVID-19 (13.4%).

This study highlights a phase 3 trial for use of the JAK inhibitor, upadacitinib, for GCA, demonstrating efficacy of a 15-mg once-daily dose with steroids over a placebo with a steroid taper. Almost half of the patients receiving upadacitinib 15 mg daily had a sustained remission at week 52, compared with 29% of patients receiving placebo. These results suggest upadacitinib would allow more rapid steroid tapering and less cumulative glucocorticoid toxicity. The incidence of adverse events, such as cancer and venous thromboembolic events, was reassuringly similar between the upadactinib and placebo groups. One limitation is the need for a long-term safety assessment via an extension period of the trial, especially for some potential long-term adverse effects, such as major adverse cardiovascular events. This study shows promising, exciting results for potential use of upadacitinib as another steroid-sparing agent in the GCA armamentarium.

Reference:

Blockmans D, et al. N Engl J Med. 2025. doi:10.1056/NEJMoa2413449