Translational Autoinflammatory Disease Section

Raphaela T. Goldbach-Mansky, M.D., M.H.S.
Acting Chief
Phone: 301-435-6243
E-mail: goldbacr@mail.nih.gov 

The Translational Autoinflammatory Disease Section (TADS) evaluates patients with autoinflammatory diseases with the goal to:

  • understand the underlying immune dysregulation
  • identify the molecular and genetic cause (using next generation sequencing methods)
  • translate the knowledge gained into better treatment approaches to improve patients’ disease outcomes, and
  • implement pilot studies with targeted treatment to safely evaluate their effects in patients with autoinflammatory diseases.

Patients with autoinflammatory diseases often experience their first symptoms of disease early in life, even in the neonatal period. They present with unexplained fevers, rashes, joint pain, and inflammation in various organs such as the central nervous system (CNS), the eyes, inner ears, bones, fat and muscles and vessels. Almost any other organ can be involved.

Our past studies identified patients with disorders that are caused by increased production of the inflammatory mediator interleukin-1 (IL-1). One of these disorders is called NOMID (Neonatal-onset Multisystem Inflammatory Disease) a severe manifestation of CAPS (Cryopyrin Associated Periodic Syndromes). Another rare disease is DIRA (Deficiency of the IL-1 Receptor Antagonist). TADS conducted seminal treatment studies that provided proof-of-concept for the role of the IL-1 blocking agent anakinra in NOMID and DIRA that helped to establish IL-1 blockade as standard therapy for these conditions. Our studies in NOMID led to the Food and Drug Administration’s approval of anakinra for the treatment of NOMID in 2012. We currently follow cohorts of patients with NOMID and DIRA to assess long-term outcomes on treatment with a number of IL-1 blocking agents.

The evaluations of patients with IL-1 refractory diseases led to the discovery of dysregulation of another pro-inflammatory mediator, interferon, in two novel autoinflammatory diseases—CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperatures) and SAVI (STING-Associated Vasculopathy with onset in Infancy). The genetic and molecular insights gained from CANDLE and SAVI patients allowed us to target interferon signaling and to develop a compassionate use treatment protocol using a novel class of drugs, the Jak inhibitor, baricitinib. (www.clinicaltrials.gov, NCT01724580).

There are many children with undifferentiated inflammatory disease whom we are still unable to adequately diagnose and treat. The TADS clinical and laboratory groups integrate efforts in finding the cause of the patients’ disease, in finding novel treatments and in making a difference in the life of patients and families. (www.clinicaltrials.gov, NCT00059748).

The Clinical Center at the NIH is uniquely suited to accommodate patients with rare autoinflammatory diseases by providing in- and outpatient care facilities, laboratory support, and first-class imaging modalities. TADS has established collaborations with subspecialists in other NIH institutes including the National Eye Institute, National Institute on Deafness and other Communication Disorders, the dermatology branch at the National Cancer Institute, the National Human Genome Research Institute, and the radiology and physical therapy department at the Clinical Center. Core facilities at NIAMS, including the Office of Science and Technology, and the Center of Human Immunology, provide access to high-throughput technologies to study autoinflammatory disease pathways, all of which are necessary clinical research tools to evaluate our patients.

View a more detailed description of the autoinflammatory diseases we study.


Selected Publications

Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014 Oct;46(10):1140-6. doi: 10.1038/ng.3089. Epub 2014 Sep 14. PubMed Icon

Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Montealegre Sanchez GA, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CC, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a Vascular and Pulmonary Syndrome. The New England Journal of Medicine 2014 Aug 7;371(6):507-18. doi: 10.1056/NEJMoa1312625. Epub 2014 Jul 16. PubMed Icon

Sibley CH, Chioato A, Felix S, Colin L, Chakraborty A, Plass N, Rodriguez-Smith J, Brewer C, King K, Zalewski C, Kim HJ, Bishop R, Abrams K, Stone D, Chapelle D, Kost B, Snyder C, Butman JA, Wesley R, Goldbach-Mansky R. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis. 2014 Jun 6. pii: annrheumdis-2013-204877. doi: 10.1136/annrheumdis-2013-204877. [Epub ahead of print] PubMed Icon

Sanchez GA, de Jesus AA, Goldbach-Mansky R. Monogenic autoinflammatory diseases: disorders of amplified danger sensing and cytokine dysregulation. Rheum Dis Clin North Am. 2013 Nov;39(4):701-34. doi: 10.1016/j.rdc.2013.08.001. Epub 2013 Sep 21. PubMed Icon

Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: Concept and clinical manifestations. Clin Immunol. 2013 Jun;147(3):155-74. doi: 10.1016/j.clim.2013.03.016. Epub 2013 Apr 9. PubMed Icon

Goldbach-Mansky R. Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol. 2012 Mar;167(3):391-404. doi: 10.1111/j.1365-2249.2011.04533.x. PubMed Icon

Sibley CH, Plass N, Snow J, Wiggs E, Brewer C, King K, Zalewski C, Kim HJ, Bishop R, Hill S, Kicker P, Phillips Z, Dolan JG, Widemann B, Jayaprakash N, Pucino F, Stone D, Chapelle D, Snyder C, Butman JA, Wesley R, Goldbach-Mansky R. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease (NOMID) treated with anakinra. Arthritis Rheum. 2012 Jul;64(7):2375-86. doi: 10.1002/art.34409. PubMed Icon

Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, Kim PW, Sheikh A, Lee CC, Chen Y, Vera A, Zhang X, Goldbach-Mansky R, Zlotogorski A. Mutations in PSMB8 cause CANDLE syndrome with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012 Mar;64(3):895-907. doi: 10.1002/art.33368. PubMed Icon

Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgård U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.The New England Journal of Medicine 2009 Jun 4;360(23):2426-37. doi: 10.1056/NEJMoa0807865. PubMed Icon

Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. The New England Journal of Medicine 2006 Aug 10;355(6):581-92. PubMed Icon

See extended list of publications

 

Updated December 1, 2014