Raphaela T. Goldbach-Mansky, M.D., M.H.S.

Translational Autoinflammatory Diseases Section

Established in 2016

NIH Main Campus, Bethesda, MD

Raphaela T. Goldbach-Mansky, M.D., M.H.S. (She/Her/Hers)

Senior Investigator
Chief, Translational Autoinflammatory Diseases Section

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Raphaela T. Goldbach-Mansky, M.D., M.H.S.

Major Areas of Research

  • Study pathogenesis and immune-dysregulatory mechanisms of interleukin (IL)-1-mediated autoinflammatory diseases including NOMID, DIRA, and the IL-1/IL-18-mediated disease NLRC4-MAS
  • Study pathogenesis and immune-dysregulatory mechanisms of Type I interferon (IFN)-mediated autoinflammatory diseases including CANDLE and SAVI
  • Identify molecular and genetic causes (using next-generation sequencing methods) of yet undifferentiated autoinflammatory diseases
  • Translate the knowledge gained from the pathogenesis evaluations into finding drug targets for better treatment approaches
  • Implement pilot treatment studies with targeted therapeutics to evaluate efficacy (control of organ inflammation and prevention of organ damage) and drug safety

Program Description

Autoinflammatory diseases are a group of rare immune dysregulatory syndromes that present with unexplained fevers, rashes, joint pain, and inflammation in multiple organs, such as the central nervous system, the eyes, inner ears, bones, fat, blood vessels, lungs and muscles. Many of the disease symptoms present very early in life and patients do not have infections or malignacies. The discovery of single gene mutations, which modify the regulation of inflammatory pathways that are triggered by exogenous and endogenous "danger" molecules, has provided new concepts to understand this disease group. It also continues to provide us with new targets for intervention.

Dr. Goldbach-Mansky's translational autoinflammatory research program focuses on clinical and translational studies in children with early-onset autoinflammatory diseases. Her research team conducts studies in patients with IL-1-mediated autoinflammatory diseases (including Neonatal Onset Multisystem Inflammatory Disease [NOMID] and Deficiency of the IL-1 Receptor Antagonist [DIRA] and in patients with IFN-mediated autoinflammatory diseases (including Chronic Atypical Neutophilic Dermatosis with Lipodystrophy and elevated Temperatures [CANDLE]), STING- Associated Vasculopathy with onset in Infancy [SAVI]) and other autoinflammatory interferonopathies. 

The research team also evaluates and studies patients with as yet undifferentiated autoinflammatory diseases who are difficult to treat. Their conditions are often uncharacterized, but may be clinically similar to known autoinflammatory diseases.

The team applies a diagnostic approach that includes careful clinical evaluation, and genetics and immune evaluations to characterize the immune dysregulation with the ultimate goal of finding better treatments for these patients. Clues from the pathogenic and genetic studies in patients with NOMID pointed to dysregulation in an innate immune pathway that regulates the release of the proinflammatory cytokine, IL-1, and our clinical studies have led to the Food and Drug Administration's approval of the IL-1 blocking agent anakinra in the treatment of this condition in December 2012. Other molecular defects identified in our patients have become the target for new drug development and these rare diseases have become models to understand the pathogenesis of more common inflammatory diseases.

Our program is part of the NIAID Clinical Genomics Program. Our goal is to use genetics as a diagnostic test for all patients seen to diagnose known diseases and to identify novel genetic variants that result or modify inflammatory disease phenotypes.

Our efforts to integrate insights gained from the disease pathogenesis with finding novel treatments. 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.  The TADS has established collaborations with specialists 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. NIH facilities including the Center of Human Immunology, provide access to high-throughput technologies to study autoinflammatory disease pathways, all of which are necessary clinical and research tools to evaluate patients with complex autoinflammatory diseases. 

For a more detailed description of the autoinflammatory diseases we study, see Autoinflammatory Alliance.

Biography

Dr. Raphaela Goldbach-Mansky received her medical degree from the University Witten-Herdecke, Germany, in 1990 and completed a combined residency in internal medicine and pediatrics at Case Western Reserve University, Metro Health Medical Center. She completed her rheumatology fellowship training at NIAMS in 1999 and served as a staff clinician at NIAMS through 2008. Dr. Goldbach-Mansky is chief of the NIAID Translational Autoinflammatory Disease Studies (TADS) Section. She leads the NIAID autoinflammatory disease clinic and has built a translational research program focusing on clinical and translational studies in children with early-onset autoinflammatory diseases. Together with Dr. Daniel Kastner (NHGRI) she founded the Translational Autoinflammatory Research Initiative (TARI) at NIH to improve research in patients with rare autoinflammatory diseases.

Dr. Goldbach-Mansky's research focus is on applying a systematic approach to the clinical and immunological study of autoinflammatory diseases. Her group uses targeted interventions to understand the role of specific inflammatory pathways in the pathogenesis of autoinflammatory diseases.

Selected Publications

Cetin Gedik K, Lamot L, Romano M, Demirkaya E, Piskin D, Torreggiani S, Adang LA, Armangue T, Barchus K, Cordova DR, Crow YJ, Dale RC, Durrant KL, Eleftheriou D, Fazzi EM, Gattorno M, Gavazzi F, Hanson EP, Lee-Kirsch MA, Montealegre Sanchez GA, Neven B, Orcesi S, Ozen S, Poli MC, Schumacher E, Tonduti D, Uss K, Aletaha D, Feldman BM, Vanderver A, Brogan PA, Goldbach-Mansky R. The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS. Ann Rheum Dis. 2022 May;81(5):601-613 and Arthritis Rheumatol. 2022 May;74(5):735-751.The 2021 European Alliance of Associations for Rheumatology/American College of Rheumatology points to consider for diagnosis and management of autoinflammatory type I interferonopathies: CANDLE/PRAAS, SAVI and AGS. Ann Rheum Dis. 2022 May;81(5):601-613. 

de Jesus AA, Hou Y, Brooks S, Malle L, Biancotto A, Huang Y, Calvo KR, Marrero B, Moir S, Oler AJ, Deng Z, Montealegre Sanchez GA, Ahmed A, Allenspach E, Arabshahi B, Behrens E, Benseler S, Bezrodnik L, Bout-Tabaku S, Brescia AC, Brown D, Burnham JM, Caldirola MS, Carrasco R, Chan AY, Cimaz R, Dancey P, Dare J, DeGuzman M, Dimitriades V, Ferguson I, Ferguson P, Finn L, Gattorno M, Grom AA, Hanson EP, Hashkes PJ, Hedrich CM, Herzog R, Horneff G, Jerath R, Kessler E, Kim H, Kingsbury DJ, Laxer RM, Lee PY, Lee-Kirsch MA, Lewandowski L, Li S, Lilleby V, Mammadova V, Moorthy LN, Nasrullayeva G, O'Neil KM, Onel K, Ozen S, Pan N, Pillet P, Piotto DG, Punaro MG, Reiff A, Reinhardt A, Rider LG, Rivas-Chacon R, Ronis T, Rösen-Wolff A, Roth J, Ruth NM, Rygg M, Schmeling H, Schulert G, Scott C, Seminario G, Shulman A, Sivaraman V, Son MB, Stepanovskiy Y, Stringer E, Taber S, Terreri MT, Tifft C, Torgerson T, Tosi L, Van Royen-Kerkhof A, Wampler Muskardin T, Canna SW, Goldbach-Mansky R. Distinct interferon signatures and cytokine patterns define additional systemic autoinflammatory diseases. J Clin Invest. 2020 Apr 1;130(4):1669-1682.
 
de Jesus AA, Brehm A, VanTries R, Pillet P, Parentelli A-S, Montealegre Sanchez GA, Deng Z, Koné-Paut I, Goldbach-Mansky R*, Krüger E*. (2018). Novel Proteasome Assembly Chaperone mutations in PSMG2/PAC2, cause the autoinflammatory interferonopathy, CANDLE/PRAAS4. J Allergy Clin Immunol. 2019 Jan 18. Novel Proteasome Assembly Chaperone mutations in PSMG2/PAC2, cause the autoinflammatory interferonopathy, CANDLE/PRAAS4. 2019 Jan 18. 

Montealegre Sanchez GA, Reinhardt A, 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, Dill S, Colbert, RA, Failla F, Kim H, O’Brien M, Kost B, Reynolds JC, Folio LR, Calvo KR, Paul SM, Weir N, Brofferio A, Soldatos A, Biancotto A, Cowen EW, DiGiovanna, JJ, Gadina, G, 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) JAK 1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies: results from a compassionate use program. J Clin Invest. 2018 Jul 2;128(7):3041-3052. JAK 1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies: results from a compassionate use program. 2018 Jul 2;128(7):3041-3052. 

Brehm A, Liu Y, Sheikh A, Marrero, B, Omoyinmi E, Zhou Q, Montealegre Sanchez MA, Biancotto A, Reinhardt A, Jesus AA, Pelletier M, Tsai WL, Remmers EF, Kardava L, Hill S, Kim H, Lachmann HL, Megarbane A, Chae JJ, Brady J, Castillo RD, Brown D, Casano AV, Gao L, Chapelle D, Huang Y, Stone D, Chen Y, Sotzny F, Lee C-CR, Kastner DL, Torrelo A, Zlotogorski A, Moir S, Gadina M, McCoy P, Wesley R, Rother K, Hildebrand PW, Brogan P, Krüger E, Aksentijevich I, Goldbach-Mansky R. (2015). Additive Loss-of-Function Proteasome Subunit Mutations in CANDLE/PRAAS promote Type-I-interferon production. J Clin Invest. Nov 2;125(11):4196-211. Additive Loss-of-Function Proteasome Subunit Mutations in CANDLE/PRAAS promote Type-I-interferon production. J Clin Invest. Nov 2;125(11):4196-211. 2015 

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. N Engl J Med. 2014;371(6):507-18.

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