Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperatures (CANDLE): Clinical Characterization and Initial Response To Janus Kinase Inhibition With Baricitinib

Gina A. Montealegre Sanchez¹, Adam L. Reinhardt², Paul Brogan³, Yackov Berkun⁴, Diane Brown⁵, Peter Chira⁶, Ling Gao⁷, Dawn C. Chapelle¹, Nicole Plass¹, Hanna Kim¹, Michael Davis⁸, Adriana Almeida de Jesus⁸, Yin Liu¹, Yan Huang¹, Colleen Hadigan⁹, Theo Heller¹⁰, Zlotogorski Zlotogorski¹¹, John J. O'Shea¹², Chyi-chia Lee¹³, Suvimol C. Hill¹⁴, Kristina Rother¹⁵, Massimo Gadina¹⁶ and Raphaela T. Goldbach-Mansky¹, ¹Translational Autoinflammatory Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ²Rheumatology, Children's Hosp of Omaha/UNMC, Omaha, NE, ³Paediatric Rheumatology International Trials Organization (PRINTO), Istituto Giannina Gaslini, Genova, Italy, ⁴Pediatrics, Hadassah Medical Center, Mount Scopus, Jerusalem, Israel, ⁵Division Of Rheumatology MS #60, Children's Hospital Los Angeles, Los Angeles, CA, ⁶Pediatric Rheumatology, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis, IN, ⁷Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR, ⁸Translational Autoinflammatory Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD, ⁹National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, ¹⁰National Institute of Diabetes and Digestive Kidney Diseases, NIH, Bethesda, MD, ¹¹Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Department of Dermatology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel., Jerusalem, Israel, ¹²NIAMS, Bethesda, MD, ¹³National Cancer Institute, National Institutes of Health, Bethesda, MD, ¹⁴Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD, ¹⁵Pediatric Diabetes & Metabolism, National Institute of Diabetes and Digestive Kidney Diseases, NIH, Bethesda, MD, ¹⁶National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Autoinflammatory Disease and Janus kinase (JAK)

Session Information

Title: Pediatric Rheumatology - Clinical and Therapeutic Aspects II: Autoinflammatory Disease and Systemic Juvenile Idiopathic Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose: CANDLE, a novel autoinflammatory syndrome presents with attacks of fever, annular cutaneous plaques, persistent periorbital edema, arthritis, lymphopenia and lipodystrophy since early childhood. CANDLE is caused by mutations in PSMB8 and other proteasome associated genes. Elevated serum IP-10 (CXCL10) levels and gene expression studies show a prominent “interferon (INF) signature”, and successful in vitro blocking studies with small molecules that inhibit Janus kinases (JAKs) signaling, raised the questions whether IFN could be a therapeutic target in CANDLE.

Objectives: The primary objective of this compassionate use study is to determine whether the treatment with the JAK1 and JAK2 inhibitor (baricitinib/Eli Lilly) allows a reduction in daily oral corticosteroid of at least 50%. The secondary objective is to determine whether treatment with baricitinib results in the reduction of the mean Autoinflammatory Diary Score (ADS) to below 0.5.

Methods: CANDLE patients with an ADS >0.5 who take at least 0.15mg/kg/day of oral prednisone are eligible. Paired t-test were used to compare baseline to last clinic visit data.

Results: We enrolled eight CANDLE patients, 62% males, 75% Caucasians, 37% Hispanics. Mean age at disease onset was 5 (SD±6) weeks. Most patients presented with annular lesions/periorbital erythema (88%), fever (85%) and failure to thrive (38%). At enrollment all patients had characteristic areas of lipodystrophy and joint contractures, growth delay (87%), increased intra-abdominal fat deposition (83%), and dyslipidemia (75%). Seven patients presented with anemia at baseline, mean of 11.6 g/dL, often also associated with thrombocytopenia and/or lymphopenia (the latter only patients not homozygous for PSMB8). MRI-confirmed myositis was present in 75% of patients. Other findings include: presence of basal ganglia calcifications (71%), peripheral calcinosis (25%), conjunctivitis/episcleritis (50%), pancreatic abnormalities (25%) and epididymitis (25%).

All patients were followed for at least 2 weeks (mean 8 months). The mean dose of baricitinib is 5 mg/day (SD±3), The mean daily autoinflammatory diary score at baseline of 1.33 dropped to 0.25 at the time of their last visit (p<0.05). The mean total prednisone dose of 17 mg/day (SD±7) dropped by 58% to 7 mg/day (SD±4) (~0.47 mg/kg/day), (p<0.05). Myositis improved in 4 out of the 5 patients and signs of bone marrow immunosuppression resolved in all patients, with improvement on Hgb, PLT and ALC counts. All other immunosuppressive medications were discontinued. Three SAEs were reported (rotavirus and CANDLE related severe neutropenia).

Conclusion: Preliminary data in eight patients with CANDLE treated with baricitinib are encouraging and suggest that targeting interferon signaling with a JAK1, JAK2 inhibitor may be a potential therapeutic regimen for CANDLE and possibly other IFN mediated autoinflammatory disorders but further data is needed.

Disclosure:

G. A. Montealegre Sanchez,
None;

A. L. Reinhardt,
None;

P. Brogan,
None;

Y. Berkun,
None;

D. Brown,
None;

P. Chira,
None;

L. Gao,
None;

D. C. Chapelle,
None;

N. Plass,
None;

H. Kim,
None;

M. Davis,
None;

A. Almeida de Jesus,
None;

Y. Liu,
None;

Y. Huang,
None;

C. Hadigan,
None;

T. Heller,
None;

Z. Zlotogorski,
None;

J. J. O’Shea,

Pfizer Inc,

US Patent,

C. C. Lee,
None;

S. C. Hill,
None;

K. Rother,
None;

M. Gadina,
None;

R. T. Goldbach-Mansky,
None.

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