Background/Purpose: Autoinflammatory Type I Interferonopathies (IFNopathies) include SAVI (STING-associated vasculopathy with onset in infancy), CANDLE/PRASS (Chronic atypical neutrophilic dermatosis, with lipodystrophy and elevated temperature), and AGS (Aicardi-Goutieres syndrome). A high blood IFN-I signature/score correlates with disease activity and response to treatment² and is used together with a ratio (IFN-I score/NFKB score) to characterize patients with yet genetically uncharacterized diseases³. JAK inhibitors (JAKi), which block the signaling of the IFN receptor, have been the mainstay of treatment,¹ but suppression of the IFN-I score is only achieved in a subset of CANDLE/PRAAS patients. We treated patients with ongoing active disease and elevated IFN-I scores with the anti- type I IFN receptor (IFNAR) monoclonal antibody, anifrolumab to achieve better disease control and reduce side effects from high-dose JAKi treatment.

Methods: Pts (n=12), enrolled in NCT02974595, with type I IFNopathies (SAVI=3, CANDLE=6, Undifferentiated=3) and persistently elevated type I IFN score in the blood on optimized treatment with the JAKinhibitor, baricitinib, (n=11), were started on anifrolumab infusions every 4 wks (300 mg or 5.5 mg/kg) either as monotherapy (n=1) or in combination with the baseline JAKi treatment (n=11). The median length of treatment with anifrolumab (range 2-20, median 8 months). Table 1. All patients received zoster prophylaxis. Patient-reported outcomes (daily diaries and questionnaires, n=10) and clinical biomarkers, safety labs including BK viral titers were monitored (n=12).

Results: Treatment with anifrolumab resulted in a median change in IFN-I score from 142 to -16 and normalized in all patients treated (n=12) (Figure1). Clinical flares did not occur. The baricitinib dose was tapered down by median of 3 mg/day (0.2 mg/kg/day) in 10/11 pts of the starting dose. Pts on systemic steroids (n=9) could taper down by median of 0.5 mg/kg (n=7) or discontinued steroids (n=2). Inflammatory markers, CRP, and ESR significantly improved on anifrolumab (2/3 SAVI patients continue to have high CRP). Anemia resolved in all patients. Urine BK viral load dropped in (n=6) who had baseline high BK viral titers. Two pts on the combination of anifrolumab and JAKi developed systemic viral infections (Enterovirus n=1, Human Herpesvirus-6 =1 complicated with encephalopathy), and two patients had a long course of rhinovirus and parainfluenza infections that were resolved after tapering down the dose of JAKi and supportive therapy. Evaluation of cytokines and biomarkers is ongoing.

Conclusion: Anifrolumab effectively suppressed the IFN-1 signature/score in all patients, including in SAVI pts; this was associated with improved serum CRP and ESR in the context of tapering doses of baricitinib and corticosteroids. BK viral titers dropped. Long-term follow-up to assess treatment efficacy in controlling inflammatory organ manifestations and progression of organ damage is critical in determining the impact of IFN-I blockade on the diseases manifestations of the autoinflammatory interferonopathies.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anifrolumab-normalizes-the-type-i-interferon-signature-in-a-cohort-of-patients-with-type-i-interferonopathies/