SELECT-GCA suggests JAKis may be the new kid on the block Save

Clinicians treating giant cell arteritis (GCA) have long had to contend with a disappointingly limited selection of drugs from which to select. Glucocorticoids were until relatively recently our sole method of managing symptoms, the side-effects of which are well-known. Given the demographic of the typical patient with GCA, long-term use of glucocorticoids poses risks in terms of steroid-induced diabetes mellitus, osteoporosis and metabolic syndrome, to name a few, in an already multimorbid and elderly population (1). Methotrexate has offered an alternative for some but not all patients (2). The dawn of tocilizumab for GCA was a game-changer, reducing the overall steroid burden (and as a consequence, their adverse effects) as well as proving highly efficacious in achieving sustained glucocorticoid-free remission (3).

Fast-forward six years or so, and a new group of drugs is finally showing promise in the treatment of GCA.

The Janus kinase (JAK)-1 selective drug, upadacitinib (UPA) is the focus of two oral presentations at this year’s ACR among the non-ANCA vasculitis abstracts (abstract 0770 and abstract 1695).

SELECT-GCA is a double-blinded, randomised, placebo (PBO)-controlled phase 3 trial conducted across 24 countries and comprising two 52-week periods. The trial aimed to assess the efficacy and safety of UPA vs PBO, alongside a tapering regime of glucocorticoids, in patients with GCA. The primary endpoint was sustained remission (i.e. the absence of signs or symptoms of GCA from week 12 through 52, and adherence to the glucocorticoid taper regimen). Patients received UPA 7.5mg or 15mg once a day, with a 26-week glucocorticoid tapering regime or PBO with a 52-week glucocorticoid tapering regime. Crucially, patients included in the trial were ≥50 years of age. All had been diagnosed with new-onset or relapsing GCA, and previously received ≥40mg prednisone or equivalent daily before baseline.

428 patients were randomised to the trial, with 112 given PBO, 107 given UPA 7.5mg, and 209 given UPA 15mg. sustained remission was observed at week 52 with UPA 15mg, when compared to PBO. UPA 15mg also led to a decreased risk of flare and decreased fatigue, as per the FACIT-Fatigue score, when compared to PBO. A significant reduction in cumulative glucocorticoid use was also seen. While UPA at a dose of 7.5mg was also more efficacious than PBO, results were not statistically significant.

Readers may be wondering, as I was, as to the safety profile of such a regimen, given the age of this group of patients and concerns regarding major adverse cardiovascular events (MACE) and cancers reported in the ORAL surveillance study with tofacitinib, hailing from the same broad class as UPA (4). Herpes zoster also remains an active concern for patients commencing JAKis. It is worth remembering that, unlike tofacitinib, UPA benefits from greater selectivity in its mechanism of action, targeting JAK-1 over JAK-2/3 and TYK-2. Reassuringly, SELECT-GCA reported numerically higher rates of serious infections and MACE in the PBO cohort, with no MACE reported among patients randomised to UPA. However, numerical rates of herpes zoster and non-melanoma skin cancers were higher in the UPA 15mg group. Venous thromboembolism (VTE) was comparable across all patients.

In conclusion, UPA at 15mg, combined with a tapering course of glucocorticoids, was highly efficacious for the treatment of GCA and reduced the glucocorticoid burden. In addition, no new safety signals were noted. These are undoubtedly positive results for patients and clinicians alike.

However, how these results play out in real life, if and when the drug is licensed, will be interesting to observe. In the wake of the results of ORAL surveillance and the subsequent FDA blackbox warning, clinicians remain wary of the use of JAKi in older people, the exact population affected by GCA. Pre-existing MACE, cancers, VTE and infections are also greater in this population. The European Medicines Agency summary of product characteristics for Rinvoq (upadacitinib) states UPA should only be used if no suitable treatment alternatives are available in patients older than 65 years, patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors, and/or patients with malignancy risk factors (5). One may wonder therefore if UPA will really be the next piece in the rheumatologist’s GCA armamentarium. For now, however, results from this phase 3 study appear promising. UPA may yet prove to take off as the new kid on the block.

References

1. Buttgereit F, Matteson EL, Dejaco C, Dasgupta B. Prevention of glucocorticoid morbidity in giant cell arteritis. Rheumatology (Oxford, England). 2018;57:ii11-ii21.

2. Mahr AD, Jover JA, Spiera RF, Hernández‐García C, Fernández‐Gutiérrez B, Lavalley MP, et al. Adjunctive methotrexate for treatment of giant cell arteritis: An individual patient data meta‐analysis. Arthritis & Rheumatism. 2007;56(8):2789-97.

3. Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, et al. Trial of Tocilizumab in Giant-Cell Arteritis. The New England journal of medicine. 2017;377(4):317-28.

4. Ytterberg SR, Bhatt DL, Mikuls TR, Koch GG, Fleischmann R, Rivas JL, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. New England Journal of Medicine. 2022;386(4):316-26.

5. RINVOQ 15 mg prolonged-release tablets Electronic Medicines Compendium2024 [Available from: https://www.medicines.org.uk/emc/product/10972/smpc.