By Dara G. Jamieson, MD
Synopsis: The SELECT-GCA Study trial of patients with giant cell arteritis found that upadacitinib at 15 mg daily combined with a 26-week glucocorticoid taper showed efficacy superior to placebo treatment with a 52-week glucocorticoid taper. The 15-mg dose of oral upadacitinib added to a shorter steroid treatment regimen was well-tolerated and appeared to be safe, as compared to placebo treatment with a longer period of steroid treatment.
Sources: Blockmans D, Penn SK, Setty AR, et al; SELECT-GCA Study Group. A Phase 3 trial of upadacitinib for giant-cell arteritis. N Engl J Med. 2025;392(20):2013-2024.
Koster MJ, Warrington KJ. Upadacitinib — an up-and-comer for treatment of giant-cell arteritis. N Engl J Med. 2025;392(20):2062-2064.
Giant cell arteritis (GCA) is a primary inflammatory disease of large- and medium-sized cranial branches of the aorta that causes headaches, facial and scalp pain, and cerebral ischemic deficits in older patients, predominantly women. Glucocorticoids, at high doses for prolonged treatment periods, are the usual treatment for GCA; however, disease relapses with glucocorticoid tapering and medication-related side effects are common. The interleukin-6 (IL-6) receptor antagonist tocilizumab (Actemra and biosimilars) is an approved therapy for GCA that was reported to induce a sustained remission in about half of patients and to reduce the dosage of prednisone by about half.
The Janus kinase (JAK) family of enzymes plays a key role in the JAK-signal transducers and activators of transcription (STAT) signaling pathway and are activated in the temporal artery and aorta in patients with GCA. This overactivation of the JAK-STAT pathway, which triggers inflammation, represents a potential therapeutic target. Upadacitinib, an orally administered selective JAK-1 inhibitor (Rinvoq), was approved by the U.S. Food and Drug Administration (FDA) in April 2025 for the treatment of GCA based on the results of the pharmaceutical company (AbbVie)-sponsored SELECT-GCA Study. The glucocorticoid-sparing treatment already was approved for rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, axial spondylarthritis, ulcerative colitis, and Crohn’s disease.
Blockmans and colleagues reported the primary efficacy and safety results of the SELECT-GCA Phase III trial in patients with GCA who were treated through week 52 with upadacitinib as compared with placebo. The treatment with oral upadacitinib at a dose of 15 mg or 7.5 mg daily was combined with a 26-week glucocorticoid taper in 209 and 107 patients, respectively. The active, randomized treatment was compared with oral placebo with a 52-week glucocorticoid taper in 112 patients. The primary endpoint was a sustained remission at week 52, without signs or symptoms of GCA from week 12 through week 52 and adherence to the protocol-specified glucocorticoid taper.
The medication was relatively well-tolerated and efficacious as compared to placebo. Premature discontinuation of upadacitinib or placebo was higher in the placebo group (36.6%) than in the 7.5-mg upadacitinib group (31.8%) and the 15-mg upadacitinib group (25.8%). A higher percentage of patients receiving placebo, rather than upadacitinib at a dose of 7.5 mg or 15 mg, discontinued upadacitinib or placebo because of adverse events (20.5% vs. 16.8% and 15.3%, respectively) or because of a lack of efficacy (7.1% vs. 3.7% and 3.3%, respectively).
The 15-mg dose of upadacitinib, but not the 7.5-mg dose, showed significant treatment benefit as compared to placebo treatment with safety outcomes similar to placebo. A sustained remission at week 52 was observed with upadacitinib at a dose of 15 mg with a 26-week glucocorticoid taper as compared to the placebo with a 52-week glucocorticoid taper (46.4% vs. 29.0%; P = 0.002). A sustained remission was not found with the 7.5-mg dose as compared to placebo. A significantly greater treatment effect than placebo with the sustained complete remission (sustained remission with normalization of the erythrocyte sedimentation rate [ESR] and the C-reactive protein [CRP] level from week 12 through week 52) endpoint was found in 37.1% of the patients in the 15-mg upadacitinib group as compared with 16.1% of the patients in the placebo group (P < 0.001).
Common adverse events associated with upadacitinib at 15 mg included headache (16.3%), arthralgia (13.9%), hypertension (13.4%), and COVID-19 (13.4%). Herpes zoster was diagnosed in 2.7% of the placebo patients and in 5.3% of the patients taking 15 mg of upadacitinib. The authors noted the discontinuation rate of 26% of the patients in the 15-mg upadacitinib group and 37% of the patients in the placebo group, with these high percentages of discontinuation attributed to the timing of the trial during the COVID-19 pandemic and to the approval of tocilizumab treatment for GCA in 2017. The first study patient was enrolled in February 2019, with data cutoff five years later.
The editorial by Koster and Warrington noted that the Giant Cell Arteritis Actemra (GiACTA) trial in 2017 resulted in the widespread use of subcutaneous tocilizumab for the treatment of GCA.1 A sustained remission with tocilizumab occurred by week 52 in 56% of patients treated weekly and 53% of patients treated every other week. The editorial stated, “However, an unmet therapeutic need remains, because up to 30% of affected patients can have a flare while receiving tocilizumab, 6% to 25% of affected patients discontinue therapy because of adverse events, and more than 50% of affected patients have a relapse after discontinuation.”
In comparing the results of the two trials, the percentage of patients in the SELECT-GCA placebo group who had a sustained remission (29.0%) was higher than that observed in the GiACTA trial placebo groups (14% to 18%). The editors wrote that the data from the SELECT-GCA trial suggest that upadacitinib is an effective agent in the management of GCA.
Commentary
The diverse presentations and the myriad neurological deficits associated with GCA are being recognized in an aging population. The standard treatment with glucocorticoids has imperfect efficacy and significant side effects. Upadacitinib and tocilizumab both are immunomodulatory drugs used in the treatment of GCA by reducing inflammation by inhibition of JAK1-modulated cytokine signaling and blockage of the IL-6 receptor, respectively.
As compared to placebo, upadacitinib and tocilizumab both reduce the remission rate of the disease at 52 weeks by 46% and 56%, respectively, in combination with a tapering dose of steroids. Both treatments were relatively well-tolerated, although JAK inhibitors may increase the risk of thromboembolic events. Tocilizumab is a parenteral medication, with subcutaneous administration weekly or every other week, that may be less expensive monthly than a month of the daily oral dose of upadacitinib, which the Medical Letter estimates to cost about $6,750 for a 30-day supply.2
A comparative clinical trial is needed to determine the relative efficacy and tolerability of the two medications, which have comparable clinical trial results in patients with GCA. A head-to-head, randomized, and blinded controlled trial directly comparing upadacitinib and tocilizumab in patients with GCA would be logistically challenging given the difference in drug administration. Since the efficacy of the two steroid-sparing medications may be relatively similar, for now the choice of a steroid-sparing medication for the treatment of GCA should be based on drug administration, side effects, and cost. However, having a choice of steroid-sparing therapies for GCA, which for decades could only be managed by chronic steroid use, is a major advancement in the treatment of this chronic, age-related, debilitating disease.
Dara G. Jamieson, MD, is Clinical Associate Professor of Neurology, Weill Cornell Medical College.
References
1. Stone JH, Tuckwell K, Dimonaco S, et al. Trial of tocilizumab in giant-cell arteritis. N Engl J Med. 2017;377(4):317-328.
2. [No authors listed]. Upadactinib (Rinvoq) for giant cell arteritis. Med Lett Drugs Ther. 2025;67(1733):114-115.
