medwireNews: The SELECT-GCA trial suggests that upadacitinib 15 mg once daily, combined with a 26-week glucocorticoid taper, may be more effective than placebo with a 52-week taper for inducing sustained remission in patients with giant cell arteritis (GCA).
“Nearly half the patients (46%) receiving upadacitinib at a dose of 15 mg had a sustained remission at week 52, as compared with 29% of the patients receiving placebo,” the authors write in The New England Journal of Medicine.
Sustained remission was defined as the absence of GCA signs or symptoms from week 12 and adherence to glucocorticoid taper.
The superiority over placebo for clinical remission with the Janus kinase (JAK) inhibitor at the 15 mg dose, was not seen at a 7.5 mg dose, however, with a rate of 41.1%, which was numerically but not significantly greater than the 29.0% rate with placebo, the authors report.
Daniel Blockmans, from University Hospital Gasthuisberg in Leuven, Belgium, and colleagues enrolled 428 adults aged 50 years or older (mean age 71 years, 73.1% women, 93.7% White) who had new-onset GCA (70%) or relapsing GCA (30%), confirmed by temporal artery biopsy or vascular imaging. Relapsing disease was defined as reactivation after at least one failed glucocorticoid taper, and all the patients had active disease in the 8 weeks prior to baseline.
Patients with previous exposure to JAK inhibitors or who had disease flare while receiving an interleukin-6 inhibitor were excluded.
The participants were randomly assigned to receive once-daily oral upadacitinib at a dose of 15 mg (n=209) or 7.5 mg (n=107) and to discontinue their concomitant glucocorticoids within 26 weeks, or placebo (n=112) with glucocorticoids discontinued within 52 weeks. The mean daily glucocorticoid dose at baseline was 35 mg across the groups.
The positive primary findings for upadacitinib 15 mg over placebo were consistent and significant across secondary endpoints. Glucocorticoid-free complete remission at week 52 was achieved in 50.2% of patients versus 19.6%, while sustained complete remission – defined by normalized erythrocyte sedimentation rate and C-reactive protein levels between weeks 12 and 52 – was achieved by 37.1% versus 16.1%.
The proportion of patients experiencing at least one disease flare was also significantly lower with upadacitinib 15 mg than placebo (34.3 vs 55.6%), and the treatment was associated with significant reductions in fatigue, and improvements in quality of life.
The researchers note that upadacitinib 15 mg allowed for “more-rapid glucocorticoid tapering and less cumulative exposure than treatment with glucocorticoids alone,” with the cumulative 52-week glucocorticoid dose a median of 1615 mg, which was significantly less than the 2882 mg with placebo.
In all, 69.9% of patients completed the 52-week regimen. Discontinuation was less frequent in the upadacitinib 15 mg group than the placebo group, at 25.8 versus 36.6%. Reasons included adverse events (20.5 vs 15.3%) and lack of efficacy (7.1 vs 3.3%).
The authors report that “[s]afety outcomes over the course of 52 weeks were generally similar in the upadacitinib groups and the placebo group.”
Serious adverse events (AEs) occurred in a comparable 22.5% of patients in the upadacitinib 15 mg group and 21.4% of those in the placebo group, although patients in the upadacitinib 15 mg group had a higher incidence of herpes zoster (5.3 vs 2.7%) and creatine kinase elevation (2.9 vs 0.0%).
The incidence of AEs of special interest was generally similar between the upadacitinib 15 mg and placebo groups, including venous thromboembolism (3.3 vs 3.6%) and cancer (1.9 vs 1.8%).
The researchers note that although cardiovascular risk is a known potential consideration with JAK inhibitors, “no major adverse cardiovascular events occurred in the upadacitinib group.” This compared with two events in the placebo group.
The authors stress, however, that “longer follow-up will be necessary to assess the relative effect on cardiovascular disease risk,” adding that this will be provided by additional safety data collected during the ongoing 52-week extension phase of the trial.
The researchers acknowledge limitations to their study, including the higher-than-expected discontinuation rate and the exclusion of patients previously unresponsive to interleukin-6 inhibitors. They also caution that glucocorticoid-related events were investigator-assessed, rather than formally adjudicated.
Nevertheless, Blockmans et al conclude that upadacitinib may offer a glucocorticoid-sparing oral option for the treatment of GCA, noting that “[o]ral therapies are generally preferred by most patients over injectable options, particularly by patients with barriers to injections such as older adults with reduced dexterity or impaired vision.”
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