Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies

Abstract

Purpose: A causal role of type-I interferons (IFN-I) in autoinflammatory type-I interferonopathies such as SAVI (STING-associated vasculopathy with onset in infancy) and CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) is suggested by elevated expression of IFN-I stimulated genes (ISGs). Hitherto, the lack of specific inhibitors of IFN-I signaling has prevented the verification of a causal role for IFN-I in these conditions. Commonly used inhibitors of the JAK/STAT pathway exert broad effects on multiple signaling pathways leading to more general immunosuppression beyond IFN-I signaling.

Methods: Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone. In two patients with SAVI, monotherapy with Anifrolumab is sufficient to retain a suppressed IFN-I signature and clinical improvement.

Results: Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies. In two patients Anifrolumab was used successfully as monotherapy. Addition of Anifrolumab enabled steroid tapering and cessation with reduced overall immunosuppression and lower risks of opportunistic infections and improved metabolic states and growth which is highly beneficial in these young patients.

Conclusion: These results verify a causal role of IFN-I signaling in type-I Interferonopathies SAVI and CANDLE and suggests Anifrolumab as an important new treatment option in autoinflammatory diseases with elevated IFN-I induced gene expression. Genia Kretzschmar, Laura Piñero Páez, and Ziyang Tan are shared-first authors. Sara Alehashemi, AnnaCarin Horne, and Petter Brodin are co-senior author.

Keywords: IFN-I, type I IFN, IFNAR1, Interferonopathies, Anifrolumab.

Fig. 1

Immunomodulatory therapy in patients with type-I interferonopathy SAVI. (A) Pedigree of family 1 with STING-associated vasculopathy in infancy (SAVI) due to the indicated STING1 gain-of-function mutation. (B) Immunomodulatory therapy and (doses in mg/kg/day) and IFN-I-stimulated gene (ISG) expression as measured by Nanostring nCounter and presented as geometric mean (geomean) of normalized counts across n = 30 ISGs in whole blood stabilized in PaxGene at the time of blood collection. (C) Mother of index patient in family 1 also affected by SAVI and interstitial lung disease. (D) Pedigree of family 2 with SAVI due to the indicated STING1 gain-of-function mutation. (E) Immunomodulatory therapy and (doses in mg/kg/day) and IFN-I-stimulated gene (ISG) expression as measured by Nanostring nCounter and presented as geometric mean (geomean) of normalized counts across n = 30 ISGs in whole blood stabilized in PaxGene at the time of blood collection in affected daughter and, (F) father of the index case in family 2

Fig. 2

Immunomodulatory therapy in a child with CANDLE syndrome. (A) Photos taken shortly after birth showing distended abdomen and necrotic skin lesions in a newborn girl with hyperinflammation and multiorgan involvement. (B) digenic cause of disease with probable loss of function variants in two proteasomal genes.(C) Immunomodulatory therapy and IFN-I stimulated gene expression (ISG) in fourteen consecutive blood samples shown as geometric mean (geomean) of normalized counts across n = 30 ISGs shown over time. Samples from unaffected parents shown and shaded area represent ISG levels in healthy contol samples. The indicated immunomodulatory medication and doses in mg/kg/day. Vertical pink lines represent infusions of Anifrolumab. (D) Episodes of infection or possible infection/disease flare as indicated by Neutrophil count (10⁹/L of blood) and C-reactive protein (CRP)

Fig. 3

Responsiveness to IFN-I in vitro during Anifrolumab treatment. (A) ISG measure by Nanostring nCounter using untreated blood from healthy controls (green), Unstimulated healthy donor blood cultured in vitro, IFNb stimulated blood from healthy controls, and blood from Patient 1 (SAVI) collected during daily Baricitinib (0.5 mg/kg/d) and 9 days following Anifrolumab infusion (5.5 mg/kg). The sample was either IFNb stimulated or unstimulated prior to ISG measurement revealing no upregulation of ISG following IFNb stimulation in patient blood. (B) Patient 5 (CANDLE) during Baricitinib (0.1 mg/k- g/d), steroids (0.2 mg/kg/d of prednisolone eqvivalent) and 5.5 mg/kg Anifrolumab therapy on April 5th, 2023 (27 days post infusion) or (C) April 21st, 2023 (14 days post infusion)