Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome

Abstract

Objectives Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. Methods We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. Results We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid Stefano Volpi and Antonella Insalaco contributed equally.Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10875-019-00645-0) contains supplementary material, which is available to authorized users. treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. Conclusions We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

Familial Interstitial Lung Disease Caused by Mutation of the STING1 Gene

“…However, in another study, the author reported a patient with SAVI (p.ser102pro and p.phe279leu, two variants of STING1) who was treated with another Janus kinase inhibitor, tofacitinib, and the patients' skin lesions improved but the pulmonary defects remained unchanged (7). In another report, involving treatment with a JAK1/2 inhibitor, ruxolitinib, in a patient with severe pulmonary involvement of SAVI (c.842G>A p.Arg281Gln mutation in TMEM173), at 18 months of therapy, a CT scan revealed a worsening of the interstitial disease (21). JAK inhibition may be worth considering as a therapeutic approach for some subtypes of SAVI.…”

“…Currently, therapeutic options for SAVI are limited, and traditional immunosuppressive medications and biologic therapies have disappointing efficacy (16). No standard immunosuppressive treatment approach is able to control disease progression (21).…”

Biological and Clinical Changes in a Pediatric Series Treated with Off-Label JAK Inhibitors

“…However, since IFNs are crucial in the immune response to viruses and mycobacteria, the inhibition of these cytokines may be harmful. Interestingly, the risk of infections seems only slightly increased in subjects with monogenic interferonopathies despite treatment with high doses JAKinhibs, probably because a complete inhibition of the IFN signaling is not achieved, as indicated by the little or partial reduction of the IFN score observed in treated patients [ 21 , 22 ]. Thus, a high baseline IFN score might predict a safer profile of JAKinhibs.…”

Efficacy and Safety of Tofacitinib for Immunemediated Inflammatory Rheumatic Diseases (Part Ii)

“…Как видно из таблицы, ТОФА обладает способностью подавлять развитие клинических проявлений нефрита, кожи, нарушение функции сосудов (эндотелий-зависимую вазодилатацию) и иммунологическую активность болезни (антитела к ДНК), что ассоциируется с подавлением синтеза ФНОα, ИФНα, ИЛ17, ИЛ6, ИЛ2 и генов, участвующих в сигнализации ИФН (Ifit3, lsg15), и Mx1, STAT1, Isg15, Ifit1. Недавно была продемонстрирована эффективность ТОФА при семейной ознобленной (chilblain) волчанке [55,56], связанной с гетерозиготной мутацией белка STING (Stimulator of interferon genes), а также синдроме SAVI [57]. У пациента, страдающего РА, осложненным СКВ, применение ТОФА привело к снижению титров анти-ДНК [58].…”