Neonatal-Onset Multisystem Inflammatory Disease Responsive to Interleukin-1 Inhibition
Raphaela Goldbach-Mansky, M.D., Natalie J. Dailey, M.D., Scott W. Canna, M.D., Ana Gelabert, M.S.N., Janet Jones, B.S.N., Benjamin I. Rubin, M.D., H. Jeffrey Kim, M.D., Carmen Brewer, Ph.D., Christopher Zalewski, M.A., Edythe Wiggs, Ph.D., Suvimol Hill, M.D., Maria L. Turner, M.D., Barbara I. Karp, M.D., Ivona Aksentijevich, M.D., Frank Pucino, Pharm.D., Scott R. Penzak, Pharm.D., Margje H. Haverkamp, M.D., Leonard Stein, M.D., Barbara S. Adams, M.D., Terry L. Moore, M.D., Robert C. Fuhlbrigge, M.D., Ph.D., Bracha Shaham, M.D., James N. Jarvis, M.D., Kathleen O'Neil, M.D., Richard K. Vehe, M.D., Laurie O. Beitz, M.D., Gregory Gardner, M.D., William P. Hannan, M.D., Robert W. Warren, M.D., Ph.D., William Horn, M.D., Joe L. Cole, M.D., Scott M. Paul, M.D., Philip N. Hawkins, M.D., Tuyet Hang Pham, B.S., Christopher Snyder, B.S., Robert A. Wesley, Ph.D., Steven C. Hoffmann, M.S., Steven M. Holland, M.D., John A. Butman, M.D., Ph.D., and Daniel L. Kastner, M.D., Ph.D.
Background Neonatal-onset multisystem inflammatory disease ischaracterized by fever, urticarial rash, aseptic meningitis,deforming arthropathy, hearing loss, and mental retardation.Many patients have mutations in the cold-induced autoinflammatorysyndrome 1 (CIAS1) gene, encoding cryopyrin, a protein thatregulates inflammation.
Methods We selected 18 patients with neonatal-onset multisysteminflammatory disease (12 with identifiable CIAS1 mutations)to receive anakinra, an interleukin-1–receptor antagonist(1 to 2 mg per kilogram of body weight per day subcutaneously).In 11 patients, anakinra was withdrawn at three months untila flare occurred. The primary end points included changes inscores in a daily diary of symptoms, serum levels of amyloidA and C-reactive protein, and the erythrocyte sedimentationrate from baseline to month 3 and from month 3 until a diseaseflare.
Results All 18 patients had a rapid response to anakinra, withdisappearance of rash. Diary scores improved (P<0.001) andserum amyloid A (from a median of 174 mg to 8 mg per liter),C-reactive protein (from a median of 5.29 mg to 0.34 mg perdeciliter), and the erythrocyte sedimentation rate decreasedat month 3 (all P<0.001), and remained low at month 6. Magneticresonance imaging showed improvement in cochlear and leptomeningeallesions as compared with baseline. Withdrawal of anakinra uniformlyresulted in relapse within days; retreatment led to rapid improvement.There were no drug-related serious adverse events.
Conclusions Daily injections of anakinra markedly improved clinicaland laboratory manifestations in patients with neonatal-onsetmultisystem inflammatory disease, with or without CIAS1 mutations.(ClinicalTrials.gov number, NCT00069329
[ClinicalTrials.gov]
.)
Source Information
From the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R.G.-M., N.J.D., S.W.C., A.G., J.J., I.A., T.H.P., C.S., D.L.K.), National Eye Institute (B.I.R.), National Institute on Deafness and Other Communication Disorders (H.J.K., C.B., C.Z.), National Institute of Neurological Disorders and Stroke (E.W., B.I.K.), Clinical Center (S.H., F.P., S.R.P., S.M.P., R.A.W., J.A.B.), National Cancer Institute (M.L.T.) National Institute of Allergy and Infectious Disease (M.H.H., S.M.H.), and National Institute of Diabetes and Digestive and Kidney Diseases (S.C.H.), National Institutes of Health, Bethesda, Md.; University of North Carolina, Chapel Hill (L.S.); University of Michigan, Ann Arbor (B.S.A.); Saint Louis University, St. Louis (T.L.M.); Children's Hospital, Boston (R.C.F.); Children's Hospital, Los Angeles (B.S.); University of Oklahoma College, Oklahoma City (J.N.J., K.O.); University of Minnesota, Minneapolis (R.K.V.); Children's Hospital and Regional Medical Center, Seattle (L.O.B.); University of Washington Bone and Joint Center, Seattle (G.G.); State University of New York Hospital, Syracuse (W.P.H.); Texas Children's Hospital Baylor College of Medicine, Houston (R.W.W.); Watauga Medical Center, Boone, N.C. (W.H.); Adult and Pediatric Rheumatology, San Antonio, Tex. (J.L.C.); and Royal Free University College Medical School, London (P.N.H.).
Address reprint requests to Dr. Goldbach-Mansky at NIAMS, Bldg. 10, Rm. 9S-205, 10 Center Dr., Bethesda, MD 20892, or at goldbacr{at}mail.nih.gov.
Crow, Y. J., Rehwinkel, J.
(2009). Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity. Hum Mol Genet
18: R130-R136
[Abstract][Full Text]
Aksentijevich, I., Masters, S. L., Ferguson, P. J., Dancey, P., Frenkel, J., van Royen-Kerkhoff, A., Laxer, R., Tedgard, U., Cowen, E. W., Pham, T.-H., Booty, M., Estes, J. D., Sandler, N. G., Plass, N., Stone, D. L., Turner, M. L., Hill, S., Butman, J. A., Schneider, R., Babyn, P., El-Shanti, H. I., Pope, E., Barron, K., Bing, X., Laurence, A., Lee, C.-C. R., Chapelle, D., Clarke, G. I., Ohson, K., Nicholson, M., Gadina, M., Yang, B., Korman, B. D., Gregersen, P. K., van Hagen, P. M., Hak, A. E., Huizing, M., Rahman, P., Douek, D. C., Remmers, E. F., Kastner, D. L., Goldbach-Mansky, R.
(2009). An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist. NEJM
360: 2426-2437
[Abstract][Full Text]
Dinarello, C. A.
(2009). Interleukin-1β and the Autoinflammatory Diseases. NEJM
360: 2467-2470
[Full Text]
Lachmann, H. J., Lowe, P., Felix, S. D., Rordorf, C., Leslie, K., Madhoo, S., Wittkowski, H., Bek, S., Hartmann, N., Bosset, S., Hawkins, P. N., Jung, T.
(2009). In vivo regulation of interleukin 1{beta} in patients with cryopyrin-associated periodic syndromes. JEM
206: 1029-1036
[Abstract][Full Text]
Nold-Petry, C. A., Nold, M. F., Zepp, J. A., Kim, S.-H., Voelkel, N. F., Dinarello, C. A.
(2009). IL-32-dependent effects of IL-1{beta} on endothelial cell functions. Proc. Natl. Acad. Sci. USA
106: 3883-3888
[Abstract][Full Text]
Netea, M. G., Nold-Petry, C. A., Nold, M. F., Joosten, L. A. B., Opitz, B., van der Meer, J. H. M., van de Veerdonk, F. L., Ferwerda, G., Heinhuis, B., Devesa, I., Funk, C. J., Mason, R. J., Kullberg, B. J., Rubartelli, A., van der Meer, J. W. M., Dinarello, C. A.
(2009). Differential requirement for the activation of the inflammasome for processing and release of IL-1{beta} in monocytes and macrophages. Blood
113: 2324-2335
[Abstract][Full Text]
Lord, C. A., Savitsky, D., Sitcheran, R., Calame, K., Wright, J. R., Ting, J. P.-Y., Williams, K. L.
(2009). Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-1. J. Immunol.
182: 2948-2958
[Abstract][Full Text]
Dinarello, C. A.
(2009). Targeting the Pathogenic Role of Interleukin 1{beta} in the Progression of Smoldering/Indolent Myeloma to Active Disease. Mayo Clin Proc.
84: 105-107
[Full Text]
Granell, M., Urbano-Ispizua, A., Pons, A., Arostegui, J. I., Gel, B., Navarro, A., Jansa, S., Artells, R., Gaya, A., Talarn, C., Fernandez-Aviles, F., Martinez, C., Rovira, M., Carreras, E., Rozman, C., Juan, M., Yague, J., Montserrat, E., Monzo, M.
(2008). Common variants in NLRP2 and NLRP3 genes are strong prognostic factors for the outcome of HLA-identical sibling allogeneic stem cell transplantation. Blood
112: 4337-4342
[Abstract][Full Text]
Sidiropoulos, P I, Goulielmos, G, Voloudakis, G K, Petraki, E, Boumpas, D T
(2008). Inflammasomes and rheumatic diseases: evolving concepts. Ann Rheum Dis
67: 1382-1389
[Abstract][Full Text]
Li, S. C.
(2008). Characteristics of Patients With Systemic-Onset JIA Who Respond to Anti-Interleukin-1 Treatment. AAP Grand Rounds
20: 32-33
[Full Text]
Botsios, C., Sfriso, P., Furlan, A., Punzi, L., Dinarello, C. A.
(2008). Resistant Behcet Disease Responsive to Anakinra. ANN INTERN MED
149: 284-286
[Full Text]
Kadhim, H. J., Duchateau, J., Sebire, G.
(2008). Cytokines and Brain Injury: Invited Review. J Intensive Care Med
23: 236-249
[Abstract]
Yao, Q., Furst, D. E.
(2008). Autoinflammatory diseases: an update of clinical and genetic aspects. Rheumatology (Oxford)
47: 946-951
[Abstract][Full Text]
Kastbom, A., Verma, D., Eriksson, P., Skogh, T., Wingren, G., Soderkvist, P.
(2008). Genetic variation in proteins of the cryopyrin inflammasome influences susceptibility and severity of rheumatoid arthritis (The Swedish TIRA project). Rheumatology (Oxford)
47: 415-417
[Abstract][Full Text]
Farasat, S., Aksentijevich, I., Toro, J. R.
(2008). Autoinflammatory Diseases: Clinical and Genetic Advances. Arch Dermatol
144: 392-402
[Abstract][Full Text]
Maksimovic, L., Stirnemann, J., Caux, F., Ravet, N., Rouaghe, S., Cuisset, L., Letellier, E., Grateau, G., Morin, A.-S., Fain, O.
(2008). New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes. Rheumatology (Oxford)
47: 309-310
[Abstract][Full Text]
Saito, M., Nishikomori, R., Kambe, N., Fujisawa, A., Tanizaki, H., Takeichi, K., Imagawa, T., Iehara, T., Takada, H., Matsubayashi, T., Tanaka, H., Kawashima, H., Kawakami, K., Kagami, S., Okafuji, I., Yoshioka, T., Adachi, S., Heike, T., Miyachi, Y., Nakahata, T.
(2008). Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Blood
111: 2132-2141
[Abstract][Full Text]
Singh-Grewal, D., Chaitow, J., Aksentijevich, I., Christodoulou, J.
(2007). Coexistent MEFV and CIAS1 mutations manifesting as familial Mediterranean fever plus deafness. Ann Rheum Dis
66: 1541-1541
[Full Text]
Kuijk, L. M, Govers, A. M A P, Hofhuis, W. J D, Frenkel, J.
(2007). Effective treatment of a colchicine-resistant familial Mediterranean fever patient with anakinra. Ann Rheum Dis
66: 1545-1546
[Full Text]
Kaizer, E. C., Glaser, C. L., Chaussabel, D., Banchereau, J., Pascual, V., White, P. C.
(2007). Gene Expression in Peripheral Blood Mononuclear Cells from Children with Diabetes. J. Clin. Endocrinol. Metab.
92: 3705-3711
[Abstract][Full Text]
Lauro, C. F., Goldbach-Mansky, R., Schmidt, M., Quezado, Z. M. N.
(2007). The Anesthetic Management of Children with Neonatal-Onset Multi-System Inflammatory Disease. Anesth. Analg.
105: 351-357
[Abstract][Full Text]
Zeft, A., Bohnsack, J. F
(2007). Cryopyrin-associated autoinflammatory syndrome: a new mutation. Ann Rheum Dis
66: 843-844
[Full Text]
Duncan, J. A., Bergstralh, D. T., Wang, Y., Willingham, S. B., Ye, Z., Zimmermann, A. G., Ting, J. P.-Y.
(2007). Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc. Natl. Acad. Sci. USA
104: 8041-8046
[Abstract][Full Text]
Kummer, J. A., Broekhuizen, R., Everett, H., Agostini, L., Kuijk, L., Martinon, F., van Bruggen, R., Tschopp, J.
(2007). Inflammasome Components NALP 1 and 3 Show Distinct but Separate Expression Profiles in Human Tissues Suggesting a Site-specific Role in the Inflammatory Response. J. Histochem. Cytochem.
55: 443-452
[Abstract][Full Text]
Remick, D. G.
(2007). Pathophysiology of Sepsis. Am. J. Pathol.
170: 1435-1444
[Abstract][Full Text]
Mastronardi, C., Whelan, F., Yildiz, O. A., Hannestad, J., Elashoff, D., McCann, S. M., Licinio, J., Wong, M.-L.
(2007). Caspase 1 deficiency reduces inflammation-induced brain transcription. Proc. Natl. Acad. Sci. USA
104: 7205-7210
[Abstract][Full Text]
Larsen, C. M., Faulenbach, M., Vaag, A., Volund, A., Ehses, J. A., Seifert, B., Mandrup-Poulsen, T., Donath, M. Y.
(2007). Interleukin-1-Receptor Antagonist in Type 2 Diabetes Mellitus. NEJM
356: 1517-1526
[Abstract][Full Text]
Jin, Y., Mailloux, C. M., Gowan, K., Riccardi, S. L., LaBerge, G., Bennett, D. C., Fain, P. R., Spritz, R. A.
(2007). NALP1 in Vitiligo-Associated Multiple Autoimmune Disease. NEJM
356: 1216-1225
[Abstract][Full Text]
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