Ustekinumab for the Treatment of Giant Cell Arteritis

Abstract

Objective To evaluate the efficacy and safety of ustekinumab (UST) in giant cell arteritis (GCA). Methods We conducted a prospective, open‐label trial of UST in patients with active new‐onset or relapsing GCA. Active disease was defined as the presence of GCA symptoms and elevation of erythrocyte sedimentation rate (ESR) or C‐reactive protein (CRP) level within 6 weeks of baseline. All patients received a 24‐week prednisone taper and subcutaneous UST 90 mg at baseline and at weeks 4, 12, 20, 28, 36, and 44. The primary endpoint, prednisone‐free remission, was defined as the absence of relapse through week 52 and normalization of the ESR and CRP level. Relapse was defined as the recurrence of GCA symptoms requiring treatment intensification. A sensitivity analysis excluding ESR/CRP level normalization from the prednisone‐free remission definition was performed. Results The study enrolled 13 patients (target sample size 20). Enrollment was closed prematurely after 7 of the initial 10 patients relapsed. Five patients (39%) had new‐onset disease. The initial prednisone doses were 20 mg (1 patient), 40 mg (9 patients), and 60 mg (3 patients). All patients entered disease remission within 4 weeks of baseline. Only 3 (23%) achieved the primary endpoint. Of the 10 patients (77%) who failed to achieve the primary endpoint, 7 relapsed after a mean period of 23 weeks. The remaining 3 patients met the alternative definition of prednisone‐free remission that did not require ESR/CRP level normalization. One serious adverse event occurred. Conclusion UST combined with 24 weeks of prednisone was associated with a high rate of treatment failure in this prospective GCA trial.

Innate and Adaptive Immunity in Giant Cell Arteritis

“…Ustekinumab, a monoclonal antibody that inhibits both IL-12 and IL-23 signaling by binding to the common p40 subunit, has been tested in patients with GCA and Takayasu arteritis ( 114 , 115 ). A prospective, open-label trial of ustekinumab in 13 patients with active new-onset or relapsing GCA was prematurely closed because patients could not reach prednisone-free remission ( 116 ). Blocking IL-12/IL-23 should interfere with the differentiation program of naïve into memory/effector T cells, a process that may precede the onset of vasculitis.…”

The Immunopathology of Giant Cell Arteritis Across Disease Spectra

“…When data from GCA and TAK studies were combined in a meta-analysis, the only non-HLA SNP that reached significance was in IL12B, encoding the p40 portion of the IL-12 (p35p40)/IL-23 (p19p40) heterodimeric proteins that is shared by both cytokines ( 47 ). Yet, clinically targeting p40 with ustekinumab in two open-label trials has shown mixed results in GCA ( 49 , 50 ). Collectively, epidemiologic data emphasizes the importance of old age, female sex, and genetics with GCA though how these factors contribute to disease pathogenesis remains largely unclear.…”

“…Notably, of 10 patients with LV disease in this study, eight underwent reimaging by CT angiography, which demonstrated not only a halt to further vascular damage but improvement of wall thickening in all patients and complete resolution in four ( 49 ). In the American trial, both newly diagnosed and relapsing patients were recruited and all patients were required to end GC at 6 months, resulting in clinical flare across the majority of patients with elevated inflammatory markers and PMR symptoms; though data was not shown for relapse between newly diagnosed vs/ relapsing patients they were stated not to be different ( 50 ). Vascular imaging follow up was not reported ( 50 ).…”

“…In the American trial, both newly diagnosed and relapsing patients were recruited and all patients were required to end GC at 6 months, resulting in clinical flare across the majority of patients with elevated inflammatory markers and PMR symptoms; though data was not shown for relapse between newly diagnosed vs/ relapsing patients they were stated not to be different ( 50 ). Vascular imaging follow up was not reported ( 50 ). Consistent with molecular studies, these differing trial results suggest a degree of independence between systemic symptoms of flare downstream of IL-6 and vascular damage in relapsing patients downstream of IL-12.…”

Biologic Therapies for Giant Cell Arteritis

“…A second prospective, single centre, open-label pilot study was subsequently performed. 58 This study enrolled both new onset and relapsing GCA patients with active disease. Diagnosis required either a positive temporal artery biopsy or evidence of large vessel vasculitis on imaging.…”