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Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1)  Kornvalee Meesilpavikkai,

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Presentation on theme: "Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1)  Kornvalee Meesilpavikkai,"— Presentation transcript:

1 Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1)  Kornvalee Meesilpavikkai, MD, Willem A. Dik, PhD, Benjamin Schrijver, BSc, Nicole M.A. Nagtzaam, BSc, Sandra J. Posthumus-van Sluijs, BSc, P. Martin van Hagen, MD, PhD, Virgil A.S.H. Dalm, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 142, Issue 1, Pages e2 (July 2018) DOI: /j.jaci Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Recurrent oral ulcers in the patient. Multiple shallow ulcers with erythematous borders were found at the upper lip, lower lip, and tongue. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Immunologic responses of peripheral blood cells obtained from the patient before and during baricitinib treatment. Blood samples were collected just before baricitinib was started and after 2, 4, 8, and 12 weeks of treatment. A and B, Kinetics of STAT1 (Fig 1, A) and STAT3 (Fig 1, B) phosphorylation in fresh whole blood CD3+ T lymphocytes on stimulation with IFN-α, IFN-β, IFN-γ, or IL-6 for the indicated time periods. Enhanced pSTAT1 levels in the patient observed before baricitinib treatment (solid red bars) were decreased after treatment (red striped bars depict the average MFI from the 4 time points of blood sampling after baricitinib initiation because samples from all time points showed comparable results). Inducible pSTAT3 in the patient also decreased under baricitinib treatment (gray bars in Fig 1, A and B, indicate average MFI from healthy control subjects; n = 5). C, Bar graph depicting mRNA expression levels of CXCL9 and CXCL10 in the patient's PBMCs relative to expression in healthy control subjects (n = 5) determined by using real-time quantitative TaqMan PCR (qRT-PCR). Data were normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). D, PBMCs from the patient and healthy control subjects (n = 5) were stimulated with phorbol 12-myristate 13-acetate and ionomycin (PMA+I) or HKCA. IL-17A, IL-17F, and IL-22 production was measured (by means of ELISA) in culture supernatants after 5 days of culture. BRN, Baricitinib; MFI, mean fluorescence intensity; US, unstimulated. All the results with error bars indicate average values with SEMs. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig E1 In vitro baricitinib efficacy studies. A and B, Kinetics of STAT1 phosphorylation (Fig E1, A) and STAT3 phosphorylation (Fig E1, B) in fresh whole blood CD3+ T lymphocytes on stimulation with IFN-α, IFN-β, IFN-γ, or IL-6 for the indicated time periods. Samples were preincubated with baricitinib for 1 hour before stimulation. C, Bar graph with statistical curve fit analysis depicting IL-17A production in culture supernatants from the patient's PBMCs after 5 days of stimulation with HKCA. The x-axis shows the baricitinib concentration used in the experiment in log scale. Samples were preincubated with baricitinib for 1 hour before stimulation. D, Long-term T-lymphocyte cultures were established, preincubated with baricitinib for 1 hour, and stimulated for 24 hours with IL-27. mRNA expression levels of the STAT1-regulated genes CXCL9, CXCL10, and PD-L1 (CD274) were determined by using real-time quantitative TaqMan PCR (qRT-PCR) and normalized to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In Fig E1, C and D, data depicted are means of 3 replicate experiments. Error bars indicate SEMs. BRN, Baricitinib; MFI, mean fluorescence intensity; US, unstimulated. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2018 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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