Sustained Interferon Signature Suppression With Anifrolumab in a Patient With STING-Associated Vasculopathy with Onset in Infancy Refractory to JAK Inhibitor and Dazukibart Therapy

Abstract

Objective: The objective was to report the safety and efficacy of an anti-IFNAR1 antibody (anifrolumab) in a patient with STING-associated vasculopathy with onset in infancy (SAVI) who presented with vasculitic ulcers and systemic inflammation refractory to JAK inhibition (JAKi) and to the interferon-β-neutralizing monoclonal antibody dazukibart.

Methods: A patient with SAVI and a de novo STING1 p.(Asn154Ser) mutation, a known pathogenic variant, and uncontrolled disease received 21 doses of dazukibart under a compassionate use investigational new drug protocol, which was followed by treatment with the anti-IFNAR1 antibody anifrolumab. Clinical and laboratory parameters, including wound healing, whole-blood type I interferon (IFN I) signature, and safety markers were closely monitored throughout both treatment periods.

Results: Despite initial reductions in C-reactive protein levels and IFN I scores following dazukibart administration, the patient experienced rebound inflammation and recurrent vasculitic lesions. Dazukibart dose adjustments failed to sustainably control IFN I signaling. Subsequent combination therapy of baricitinib and tocilizumab proved partially effective. Treatment with anifrolumab, an IFNAR1 blocker, in conjunction with tocilizumab led to sustained suppression of IFN I scores, allowed discontinuation of JAKi, and resulted in significant improvement in vasculitic wounds.

Conclusion: This case underscores the challenges in treating patients with SAVI and highlights the utility of IFN I scores as a theragnostic biomarker. Although high-dose JAKi and dazukibart failed to achieve sustained control of IFN I signaling, treatment with anifrolumab durably suppressed IFN scores and demonstrated promising efficacy, which allows for the investigation of the role of IFN I signaling in the disease pathogenesis of SAVI and other interferonopathies in future clinical trials.

Figure 1

(A) Schematic of SAVI pathogenesis and targeted treatments. In SAVI, constitutive activation of stimulator of interferon genes (a dinucleotide sensor) initiates IFNB1 transcription, leading to increased production of IFNβ. IFNβ signals through the IFNAR‐1, triggering upregulation of IFNα and interferon‐stimulated genes, which contribute to the 28‐gene IFN I score. The targeted treatments used in this patient are depicted: (1) Baricitinib, a JAKi, blocks JAK/STAT signaling downstream of the IFNAR‐1; (2) dazukibart, a neutralizing monoclonal antibody against IFNβ, prevents IFNβ from binding to and signaling through IFNAR‐1; (3) anifrolumab, an anti–IFNAR‐1 monoclonal antibody, blocks downstream IFN I signaling at the receptor level. (B–E) Clinical images of vasculitic lesions on the right knee (B) and right lateral thigh (C) at baseline, which improved with dazukibart but did not fully close (D and E). (F) Plot showing the associations between CRP levels and IFN I scores. (G) Plot depicting serum levels of bound‐to‐drug‐IFNβ (black) and free IFNβ (purple) during dazukibart treatment. Although bound IFNβ rose, fluctuating levels of free IFNβ were still detectable in the serum. (H) Serum levels of IFNα (green) levels were elevated during dazukibart treatment. Black stars indicate IV infusions of dazukibart; the doses are specified. Green stars indicate subcutaneous injections of dazukibart, which were all administered at a 200 mg dose. The pink star indicates the tocilizumab injection. The purple block denotes the period of systemic steroid administration due to severe flare following the thrombosed port access. CRP, C‐reactive protein; IFN I, type I interferon; IL, interleukin; ISG, interferon‐stimulated gene; IV, intravenous; JAKi, JAK inhibitor; SAVI, STING‐associated vasculopathy with onset in infancy; TNF, tumor necrosis factor.

Figure 2

Impact of anifrolumab on IFN I scores, vasculitic lesions, and clinical outcomes: (A) The IFN I score in the blood was persistently elevated at baseline, despite over ten years of treatment with baricitinib. Attempts to suppress IFN I signaling with dazukibart in combination with baricitinib, followed by the addition of tocilizumab to baricitinib, failed to achieve effective suppression, with levels continuing to fluctuate. In contrast, treatment with anifrolumab led to sustained and remarkable normalization of IFN I scores in the context of continued tocilizumab treatment but tapering and discontinuation of baricitinib. (B) Serum levels of free IFNα and IFNβ were measured on anifrolumab and presented alongside the observed ranges of IFNα and IFNβ levels that were measured when the patient was on treatment with dazukibart. (C–F) Anifrolumab treatment resulted in marked improvement in vasculitic skin lesions, leading to complete closure of all wounds. Shown are the lateral right thigh and both knees before and after anifrolumab. (G–H) Anifrolumab treatment allowed for the tapering of baricitinib, which ultimately led to clearance of the facial molluscum lesions. The area marked on the left palpebral region demonstrates significant improvement. IFN I, type I interferon; JAKi, JAK inhibitor.