Preliminary Response to JAK1/2 Inhibition with Baricitinib in “Candle”,“Savi” and “Candle-like” Diseases. a New Therapeutic Approach for Type I IFN Mediated Autoinflammatory Diseases

Gina A. Montealegre Sanchez¹, Adam Reinhardt², Paul Brogan³, Dawn C. Chapelle⁴, Hanna Kim⁴, Samantha Judd⁴, Bahar Kost⁴, Michelle O'Brien⁴, Wendy Goodspeed⁵, Robert A. Colbert⁴, Meryl Waldman⁶, Deborah L. Stone⁷, Ling Gao⁸, JA Dare⁸, Susanne Schalm⁹, Thomas L. Klausmeier¹⁰, Sara Murias¹¹, Yackov Berkun¹², Diane Brown¹³, John D. Carter¹⁴, Fehime K Eroglu¹⁵, A. Zlotogorski¹⁶, Philip Hashkes¹⁷, Helmut Wittkowski¹⁸, Suzanne Ramsey¹⁹, Seza Ozen²⁰, Adriana Almeida de Jesus²¹ and Raphaela Goldbach-Mansky²², ¹NIAID/NIH, Bethesda, MD, ²Rheumatology, Children's Hosp of Omaha/UNMC, Omaha, NE, ³UCL Institute of Child Health and Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom, ⁴NIAMS/NIH, Bethesda, MD, ⁵Office of the Clinical Director, NIAMS/NIH, Bethesda, MD, ⁶NIDDK/NIH, Bethesda, MD, ⁷NHGRI/NIH, Bethesda, MD, ⁸University of Arkansas for Medical Sciences, Little Rock, AR, ⁹LMU Munich, Munich, Germany, ¹⁰Riley Hospital for Children, Indianapolis, IN, ¹¹Hospital Infantil La Paz, Madrid, Spain, ¹²Hadassah-Hebrew University Medical Center, Jerusalem, Israel, ¹³Children's Hospital Los Angeles, Los Angeles, CA, ¹⁴Division of Rheumatology, University of South Florida, Tampa, FL, ¹⁵Department of Pediatrics, Hacettepe University Hospitals, Ankara, Turkey, ¹⁶Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, ¹⁷Pediatric Rheumatology, Shaare Zedek Medical Center, Jerusalem, Israel, ¹⁸Pediatrics, University of Muenster, Muenster, Germany, ¹⁹Pediatric Rheumatology, IWK Health Centre, Halifax, NS, Canada, ²⁰Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey, ²¹National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD, ²²Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Autoinflammatory Disease, interferons and pediatric rheumatology, Janus kinase (JAK)

Session Information

Date: Wednesday, November 16, 2016

Title: Pediatric Rheumatology – Clinical and Therapeutic Aspects III: Autoinflammatory Diseases and Juvenile Dermatomyositis

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Chronically elevated serum IP-10 (CXCL10) levels, and a prominent “interferon (IFN)-response gene signature” in patients with chronic neutrophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE), CANDLE-like diseases or with gain-of-function mutations in TMEM173/STING with STING-associated vasculopathy with onset in infancy (SAVI), suggested modulation of IFN signaling might be a therapeutic option for patients with some autoinflammatory interferonopathies. The compassionate use program was developed to provide baricitinib (JAK1/JAK2 inhibitor) to CANDLE, CANDLE-like and SAVI patients who have no other comparable or satisfactory treatment options. Potential efficacy of treatment was assessed by a reduction in mean Autoinflammatory Diary Scores (ADS) to < 0.5 (CANDLE and CANDLE-like pt.) and to <1.0 (SAVI pt.) and reduction of steroid doses to <0.15mg/kg/day or by at least 50% reduction from baseline.

Methods: Paired t-tests were used to compare mean ADS and prednisone doses at the last clinic visit to baseline data

Results: Between October 2011 and March 4^th, 2016, 18 patients (pt.) have been treated (mean duration 2.3 years, SD±1). 9 of 11 CANDLE pt. and 3 of 4 SAVI pt. achieved an ADS of < 0.5 and < 1.0 at the time of their last visit, respectively. None of 3 CANDLE-like pt. achieved an ADS of < 0.5 (mean ADS for all cohorts decreased from 1.5 ± 0.8 to 0.5 ± 0.5) (p< 0.005), 8 of 10 CANDLE pt. and 2 of 3 CANDLE-like pt. achieved a reduction in steroid doses > than 50% from baseline. 4 of 10 CANDLE pt. discontinued oral steroids completely and continued to have an ADS of <0.5. The only SAVI pt. on steroids at baseline continues at the same dose. Mean total prednisone dose decreased in patients receiving steroids at baseline from 0.7 mg/kg/day (0.2-1.8) to 0.2 mg/kg/day (0-0.8) (p< 0.005). The mean baricitinib dose at last patient visit was 6.9 ± 3.3 mg/day (0.2 mg/kg/day). 13 pt. reported at least 1 serious adverse event (SAE), infection being the most common. 2 CANDLE pt. have been discontinued due to SAEs (avascular necrosis; BK viremia and azotemia). Both pt. subsequently died: the first patient due to underlying liver and kidney disease 18 months after discontinuation of baricitinib, the second patient due to worsening interstitial lung disease with development of respiratory failure 4 months after discontinuation of baricitinib and initiation of another JAK inhibitor. 1 pt. required temporary interruption of baricitinib due to neutropenia, and 4 other pt. had their dose electively reduced after testing positive for BK viremia; patients were asymptomatic. The most common adverse events were upper respiratory infections, cough, and BK viruria (baseline BK virus screening was not performed).

Conclusion: Preliminary efficacy and safety data in 18 patients with autoinflammatory type I Interferonopathies treated with baricitinib are encouraging and suggest that targeting IFN signaling with a JAK1/JAK2 inhibitor may be a successful therapeutic strategy. Monitoring BK viral titers in blood and urine, in addition to other measures of safety and efficacy, may be important in dose selection and the benefit-risk assessment of baricitinib for these patients.

Disclosure: G. A. Montealegre Sanchez, baricitinib, 9; A. Reinhardt, None; P. Brogan, None; D. C. Chapelle, None; H. Kim, None; S. Judd, None; B. Kost, None; M. O'Brien, None; W. Goodspeed, None; R. A. Colbert, Baricitinib, 9; M. Waldman, None; D. L. Stone, None; L. Gao, None; J. Dare, None; S. Schalm, None; T. L. Klausmeier, None; S. Murias, None; Y. Berkun, None; D. Brown, None; J. D. Carter, None; F. K. Eroglu, None; A. Zlotogorski, None; P. Hashkes, None; H. Wittkowski, None; S. Ramsey, None; S. Ozen, None; A. Almeida de Jesus, None; R. Goldbach-Mansky, Baricitinib, 9.

To cite this abstract in AMA style:

Montealegre Sanchez GA, Reinhardt A, Brogan P, Chapelle DC, Kim H, Judd S, Kost B, O'Brien M, Goodspeed W, Colbert RA, Waldman M, Stone DL, Gao L, Dare J, Schalm S, Klausmeier TL, Murias S, Berkun Y, Brown D, Carter JD, Eroglu FK, Zlotogorski A, Hashkes P, Wittkowski H, Ramsey S, Ozen S, Almeida de Jesus A, Goldbach-Mansky R. Preliminary Response to JAK1/2 Inhibition with Baricitinib in “Candle”,“Savi” and “Candle-like” Diseases. a New Therapeutic Approach for Type I IFN Mediated Autoinflammatory Diseases [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/preliminary-response-to-jak12-inhibition-with-baricitinib-in-candlesavi-and-candle-like-diseases-a-new-therapeutic-approach-for-type-i-ifn-medi/. Accessed .

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