Dataset Information

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 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.

SUBMITTER: Volpi S

PROVIDER: S-EPMC7086512 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Publications

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

Volpi Stefano S Insalaco Antonella A Caorsi Roberta R Santori Elettra E Messia Virginia V Sacco Oliviero O Terheggen-Lagro Suzanne S Cardinale Fabio F Scarselli Alessia A Pastorino Claudia C Moneta Gianmarco G Cangemi Giuliana G Passarelli Chiara C Ricci Margherita M Girosi Donata D Derchi Maria M Bocca Paola P Diociaiuti Andrea A El Hachem May M Cancrini Caterina C Tomà Paolo P Granata Claudio C Ravelli Angelo A Candotti Fabio F Picco Paolo P DeBenedetti Fabrizio F Gattorno Marco M

Journal of clinical immunology 20190529 5

<h4>Objectives</h4>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.<h4>Methods</h4>We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxo ...[more]

PMID: 31144250

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Project description:IntroductionIn Australia, there is an unmet need for improved treatments for rheumatoid arthritis (RA). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. To provide an overview of key study outcomes for tofacitinib in Australian patients, we analyzed the efficacy and safety of tofacitinib in the Australian subpopulation of global RA phase III and long-term extension (LTE) studies.MethodsData were pooled from the Australian subpopulation of four phase III studies and one LTE study (database not locked at cut-off date: January 2016). Patients in the phase III studies received tofacitinib 5 or 10 mg twice daily (BID), placebo (advancing to tofacitinib at months 3 or 6), or adalimumab, with background methotrexate or conventional synthetic disease-modifying antirheumatic drugs. Patients in the LTE study received tofacitinib 5 or 10 mg BID. Efficacy endpoints were American College of Rheumatology (ACR) 20/50/70 response rates, and change from baseline in the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Safety endpoints included incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs. AEs of special interest and laboratory parameters were analyzed in the LTE study.ResultsAcross phase III studies (N = 100), ACR response rates and improvements in DAS28-4(ESR) and HAQ-DI scores were numerically greater with tofacitinib vs. placebo at month 3, and increased until month 12. The results were sustained in the LTE study (N = 99) after 60 months' observation. In general, the efficacy and safety profiles of tofacitinib were similar to those of the global RA population.ConclusionsIn Australian patients with RA, tofacitinib therapy demonstrated sustained efficacy and consistent safety over ≥ 60 months' treatment.FundingPfizer Inc. TRIAL REGISTRATION NUMBERS (ALL CLINICALTRIALS.GOV): NCT00960440; NCT00847613; NCT00856544; NCT00853385; NCT00413699.

Dataset Information

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

Objectives

Methods

Results

Conclusions

Publications

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

Similar Datasets

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