Upadacitinib bumps up GCA treatment armamentarium

The primary results of the phase III SELECT-GCA trial underpin the potential of upadacitinib plus a glucocorticoid taper (GC-T) for the treatment of giant-cell arteritis (GCA).

“In this trial involving patients with GCA, the efficacy of upadacitinib 15 mg with a 26-week GC-T was superior to that of placebo with a 52-week GC-T,” the researchers said.

Nearly half (46.4 percent) of participants in the upadacitinib 15-mg arm achieved sustained remission* at week 52, vs 29 percent in the placebo arm. A comparison between arms yielded a p-value of 0.002. [N Engl J Med 2025;392:2013-2024]

Upadacitinib 7.5 mg produced a numerically greater treatment effect vs placebo (41.1 percent vs 29 percent).

Secondary outcomes

Week 52 also saw more patients on upadacitinib 15 mg vs placebo achieving sustained complete remission** (CR) from week 12 (37.1 percent vs 16.1 percent; p<0.001) and CR without glucocorticoids after completing GC-T (50.2 percent vs 19.6 percent; p<0.001).

The proportion of participants experiencing ≥1 disease flare through week 52 was lower in the upadacitinib 15-mg vs placebo arm (34.3 percent vs 55.6 percent; p=0.001), as were the total cumulative exposure to glucocorticoids over 52 weeks (median, 1,615 vs 2,882 mg; p<0.001) and cumulative additional glucocorticoid dose received beyond the prespecified taper (median, 20 vs 512.5 mg).

Safety profile

The rates of adverse events leading to drug discontinuation were lower with upadacitinib vs placebo (15.9 percent [7.5 mg] and 14.8 percent [15 mg] vs 19.6 percent [placebo]), as were the incidences of serious infections (5.6 percent and 5.7 percent vs 10.7 percent).

Compared with placebo, the higher upadacitinib dose was tied to increased risks of herpes zoster (5.3 percent vs 2.7 percent) and creatine kinase elevation (2.9 percent vs 0 percent). These align with the findings of prior studies on Janus kinase (JAK) inhibitors. [RMD Open 2023;9:e002735; Front Pharmacol 2023;14:1241954]

Despite the potential cardiovascular (CV) risk with a JAK inhibitor, the study showed no major adverse cardiovascular events with upadacitinib. [Ann Rheum Dis 2023;82:1130-1141; N Engl J Med 2022;386:316-326; Nat Rev Rheumatol 2024;20:101-115] “However, longer follow-up will be necessary to assess the relative effect on CV disease risk,” the investigators noted.

Effective glucocorticoid-sparing Tx warranted

“GCA is a systemic vasculitis with limited treatment options,” the investigators said. Tocilizumab is the only approved drug for GCA treatment. [N Engl J Med 2017;377:317-328]

“[G]lucocorticoids remain the primary treatment option despite the high risk of glucocorticoid-related toxic effects. Approximately 50–80 percent of patients with GCA have a disease relapse when glucocorticoids are tapered. Thus, there is an unmet need for effective glucocorticoid-sparing treatments for this disease,” they said.

Most patients – particularly older adults with impaired vision or reduced dexterity – generally prefer oral over injectable treatment alternatives. Upadacitinib – an oral, targeted therapy – would allow for more rapid GC-T and less cumulative exposure than glucocorticoids alone, the investigators noted.

A total of 428 patients (mean age 71.1 years) with new-onset (~70 percent) or relapsing GCA who had not received interleukin-6 inhibitors were randomized 2:1:1 to upadacitinib 15 or 7.5 mg QD plus a 26-week GC-T or placebo plus a 52-week GC-T.

Reaching new heights

In a linked editorial, Dr Matthew Koster and Dr Kenneth Warrington from the Mayo Clinic, Rochester, Minnesota, US, noted that the results support the efficacy of against GCA. [N Engl J Med 2025;392:2062-2064]

“The long and arduous climb to the development of glucocorticoid-sparing therapy for GCA is reaching new heights,” they said. “An exciting time is ahead as we endeavour to evaluate the efficacy of upadacitinib in specific subgroups of patients with GCA, as well as the long-term safety and effects on vascular complications of GCA of this new oral therapeutic option.”