JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

Gina A. Montealegre Sanchez, Adam L Reinhardt, Suzanne Ramsey, Helmut Wittkowski, Philip J. Hashkes, Yackov Berkun, Susanne Schalm, Sara Murias, Jason A. Dare, Diane Brown, Deborah L. Stone, Ling Gao, Thomas Klausmeier, Dirk Foell, Adriana A. De Jesus, Dawn C. Chapelle, Hanna Kim, Samantha Dill, Robert A. Colbert, Laura Failla & 35 others Bahar Kost, Michelle O’Brien, James C. Reynolds, Les R. Folio, Katherine R. Calvo, Scott M. Paul, Nargues Weir, Alessandra Brofferio, Ariane Soldatos, Angelique Biancotto, Edward W. Cowen, John J. Digiovanna, Massimo Gadina, Andrew J. Lipton, Colleen Hadigan, Steven M. Holland, Joseph Fontana, Ahmad S. Alawad, Rebecca J. Brown, Kristina I. Rother, Theo Heller, Kristina M. Brooks, Parag Kumar, Stephen R. Brooks, Meryl Waldman, Harsharan K. Singh, Volker Nickeleit, Maria Silk, Apurva Prakash, Jonathan M. Janes, Seza Ozen, Paul G. Wakim, Paul A. Brogan, William L. Macias, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.

Original languageEnglish (US)
Pages (from-to)3041-3052
Number of pages12
JournalJournal of Clinical Investigation
Volume128
Issue number7
DOIs
StatePublished - Jul 2 2018

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Therapeutics
Biomarkers
Viremia
Adrenal Cortex Hormones
baricitinib
Quality of Life
Inflammation
Azotemia
Lipodystrophy
Safety
Gastroenteritis
Prednisone
Skin Diseases
Respiratory Tract Infections
Bone Density
Temperature
Mortality
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Montealegre Sanchez, G. A., Reinhardt, A. L., Ramsey, S., Wittkowski, H., Hashkes, P. J., Berkun, Y., ... Goldbach-Mansky, R. (2018). JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. Journal of Clinical Investigation, 128(7), 3041-3052. https://doi.org/10.1172/JCI98814

JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. / Montealegre Sanchez, Gina A.; Reinhardt, Adam L; Ramsey, Suzanne; Wittkowski, Helmut; Hashkes, Philip J.; Berkun, Yackov; Schalm, Susanne; Murias, Sara; Dare, Jason A.; Brown, Diane; Stone, Deborah L.; Gao, Ling; Klausmeier, Thomas; Foell, Dirk; De Jesus, Adriana A.; Chapelle, Dawn C.; Kim, Hanna; Dill, Samantha; Colbert, Robert A.; Failla, Laura; Kost, Bahar; O’Brien, Michelle; Reynolds, James C.; Folio, Les R.; Calvo, Katherine R.; Paul, Scott M.; Weir, Nargues; Brofferio, Alessandra; Soldatos, Ariane; Biancotto, Angelique; Cowen, Edward W.; Digiovanna, John J.; Gadina, Massimo; Lipton, Andrew J.; Hadigan, Colleen; Holland, Steven M.; Fontana, Joseph; Alawad, Ahmad S.; Brown, Rebecca J.; Rother, Kristina I.; Heller, Theo; Brooks, Kristina M.; Kumar, Parag; Brooks, Stephen R.; Waldman, Meryl; Singh, Harsharan K.; Nickeleit, Volker; Silk, Maria; Prakash, Apurva; Janes, Jonathan M.; Ozen, Seza; Wakim, Paul G.; Brogan, Paul A.; Macias, William L.; Goldbach-Mansky, Raphaela.

In: Journal of Clinical Investigation, Vol. 128, No. 7, 02.07.2018, p. 3041-3052.

Research output: Contribution to journalArticle

Montealegre Sanchez, GA, Reinhardt, AL, Ramsey, S, Wittkowski, H, Hashkes, PJ, Berkun, Y, Schalm, S, Murias, S, Dare, JA, Brown, D, Stone, DL, Gao, L, Klausmeier, T, Foell, D, De Jesus, AA, Chapelle, DC, Kim, H, Dill, S, Colbert, RA, Failla, L, Kost, B, O’Brien, M, Reynolds, JC, Folio, LR, Calvo, KR, Paul, SM, Weir, N, Brofferio, A, Soldatos, A, Biancotto, A, Cowen, EW, Digiovanna, JJ, Gadina, M, Lipton, AJ, Hadigan, C, Holland, SM, Fontana, J, Alawad, AS, Brown, RJ, Rother, KI, Heller, T, Brooks, KM, Kumar, P, Brooks, SR, Waldman, M, Singh, HK, Nickeleit, V, Silk, M, Prakash, A, Janes, JM, Ozen, S, Wakim, PG, Brogan, PA, Macias, WL & Goldbach-Mansky, R 2018, 'JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies', Journal of Clinical Investigation, vol. 128, no. 7, pp. 3041-3052. https://doi.org/10.1172/JCI98814
Montealegre Sanchez, Gina A. ; Reinhardt, Adam L ; Ramsey, Suzanne ; Wittkowski, Helmut ; Hashkes, Philip J. ; Berkun, Yackov ; Schalm, Susanne ; Murias, Sara ; Dare, Jason A. ; Brown, Diane ; Stone, Deborah L. ; Gao, Ling ; Klausmeier, Thomas ; Foell, Dirk ; De Jesus, Adriana A. ; Chapelle, Dawn C. ; Kim, Hanna ; Dill, Samantha ; Colbert, Robert A. ; Failla, Laura ; Kost, Bahar ; O’Brien, Michelle ; Reynolds, James C. ; Folio, Les R. ; Calvo, Katherine R. ; Paul, Scott M. ; Weir, Nargues ; Brofferio, Alessandra ; Soldatos, Ariane ; Biancotto, Angelique ; Cowen, Edward W. ; Digiovanna, John J. ; Gadina, Massimo ; Lipton, Andrew J. ; Hadigan, Colleen ; Holland, Steven M. ; Fontana, Joseph ; Alawad, Ahmad S. ; Brown, Rebecca J. ; Rother, Kristina I. ; Heller, Theo ; Brooks, Kristina M. ; Kumar, Parag ; Brooks, Stephen R. ; Waldman, Meryl ; Singh, Harsharan K. ; Nickeleit, Volker ; Silk, Maria ; Prakash, Apurva ; Janes, Jonathan M. ; Ozen, Seza ; Wakim, Paul G. ; Brogan, Paul A. ; Macias, William L. ; Goldbach-Mansky, Raphaela. / JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 7. pp. 3041-3052.
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abstract = "BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.",
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TY - JOUR

T1 - JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies

AU - Montealegre Sanchez, Gina A.

AU - Reinhardt, Adam L

AU - Ramsey, Suzanne

AU - Wittkowski, Helmut

AU - Hashkes, Philip J.

AU - Berkun, Yackov

AU - Schalm, Susanne

AU - Murias, Sara

AU - Dare, Jason A.

AU - Brown, Diane

AU - Stone, Deborah L.

AU - Gao, Ling

AU - Klausmeier, Thomas

AU - Foell, Dirk

AU - De Jesus, Adriana A.

AU - Chapelle, Dawn C.

AU - Kim, Hanna

AU - Dill, Samantha

AU - Colbert, Robert A.

AU - Failla, Laura

AU - Kost, Bahar

AU - O’Brien, Michelle

AU - Reynolds, James C.

AU - Folio, Les R.

AU - Calvo, Katherine R.

AU - Paul, Scott M.

AU - Weir, Nargues

AU - Brofferio, Alessandra

AU - Soldatos, Ariane

AU - Biancotto, Angelique

AU - Cowen, Edward W.

AU - Digiovanna, John J.

AU - Gadina, Massimo

AU - Lipton, Andrew J.

AU - Hadigan, Colleen

AU - Holland, Steven M.

AU - Fontana, Joseph

AU - Alawad, Ahmad S.

AU - Brown, Rebecca J.

AU - Rother, Kristina I.

AU - Heller, Theo

AU - Brooks, Kristina M.

AU - Kumar, Parag

AU - Brooks, Stephen R.

AU - Waldman, Meryl

AU - Singh, Harsharan K.

AU - Nickeleit, Volker

AU - Silk, Maria

AU - Prakash, Apurva

AU - Janes, Jonathan M.

AU - Ozen, Seza

AU - Wakim, Paul G.

AU - Brogan, Paul A.

AU - Macias, William L.

AU - Goldbach-Mansky, Raphaela

PY - 2018/7/2

Y1 - 2018/7/2

N2 - BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.

AB - BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease. METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed. RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia. CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.

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