J B Kuemmerle-Deschner1, D Verma2, T Endres1, L Broderick2, A A de Jesus3, F Hofer1, N Blank4, K Krause5, C Rietschel6, G Horneff7, I Aksentijevich8, P Lohse9, R Goldbach-Mansky4, H M Hoffman2, S M Benseler10. 1. University Hospital Tuebingen, Tuebingen, Germany. 2. Rady Children's Hospital and University of California at San Diego, San Diego, California. 3. National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland. 4. Universitaetsklinikum Heidelberg, Heidelberg, Germany. 5. Charité Medical University, Berlin, Germany. 6. Clementine-Kinderhospital, Frankfurt, Germany. 7. Asklepios-Klinik Sankt Augustin, Sankt Augustin, Germany. 8. National Human Genome Research Institute, NIH, Bethesda, Maryland. 9. Institute of Laboratory Medicine and Human Genetics, Singen, Germany. 10. University Hospital Tuebingen, Tuebingen, Germany, and Alberta Children's Hospital, University of Calgary, Calgary, Alberta, Canada.
Abstract
OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1β (IL-1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants. METHODS: A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1β release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. RESULTS: The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. CONCLUSION: Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1β and non-IL-1β-mediated inflammatory pathway activation.
OBJECTIVE: Cryopyrin-associated periodic syndromes (CAPS) result from gain-of-function mutations in the NLRP3 gene, which causes excessive release of interleukin-1β (IL-1β) and systemic inflammation. While pathogenetic NLRP3 variant phenotypes are well-characterized, low-penetrance NLRP3 variants represent a significant clinical challenge. The aims of this study were to determine the clinical phenotype, the in vitro biologic phenotype, and the effect of anti-IL-1 treatment in patients with low-penetrance NLRP3 variants. METHODS: A multicenter study of consecutive symptomatic patients with low-penetrance NLRP3 variants recruited from 7 centers between May 2012 and May 2013 was performed. The observed findings were transferred into a study database, from which they were extracted for analysis. Controls were patients with a known pathogenetic NLRP3 variant. Clinical presentation and CAPS markers of inflammation were captured. Functional assays of inflammasome activation, including caspase 1 activity, NF-κB release, cell death, and IL-1β release, were performed. Treatment effects of IL-1 were determined. Comparisons between low-penetrance and pathogenetic NLRP3 variants were performed. RESULTS: The study included 45 patients, 21 of which were female (47%); 26 of the patients (58%) were children. NLRP3 low-penetrance variants identified in the patients were Q703K (n = 19), R488K (n = 6), and V198M (n = 20). In the controls, 28 had pathogenetic NLRP3 variants. Patients with low-penetrance NLRP3 variants had significantly more fever (76%) and gastrointestinal symptoms (73%); eye disease, hearing loss, and renal involvement were less common. Functional inflammasome testing identified an intermediate phenotype in low-penetrance NLRP3 variants as compared to wild-type and pathogenetic NLRP3 variants. All treated patients responded to IL-1 inhibition, with complete response documented in 50% of patients. CONCLUSION:Patients with low-penetrance NLRP3 variants display a distinct clinical phenotype and an intermediate biologic phenotype, including IL-1β and non-IL-1β-mediated inflammatory pathway activation.
Authors: Micol Romano; Z Serap Arici; David Piskin; Sara Alehashemi; Daniel Aletaha; Karyl Barron; Susanne Benseler; Roberta A Berard; Lori Broderick; Fatma Dedeoglu; Michelle Diebold; Karen Durrant; Polly Ferguson; Dirk Foell; Jonathan S Hausmann; Olcay Y Jones; Daniel Kastner; Helen J Lachmann; Ronald M Laxer; Dorelia Rivera; Nicola Ruperto; Anna Simon; Marinka Twilt; Joost Frenkel; Hal M Hoffman; Adriana A de Jesus; Jasmin B Kuemmerle-Deschner; Seza Ozen; Marco Gattorno; Raphaela Goldbach-Mansky; Erkan Demirkaya Journal: Arthritis Rheumatol Date: 2022-05-27 Impact factor: 15.483
Authors: Adriana A de Jesus; Yangfeng Hou; Stephen Brooks; Louise Malle; Angelique Biancotto; Yan Huang; Katherine R Calvo; Bernadette Marrero; Susan Moir; Andrew J Oler; Zuoming Deng; Gina A Montealegre Sanchez; Amina Ahmed; Eric Allenspach; Bita Arabshahi; Edward Behrens; Susanne Benseler; Liliana Bezrodnik; Sharon Bout-Tabaku; AnneMarie C Brescia; Diane Brown; Jon M Burnham; Maria Soledad Caldirola; Ruy Carrasco; Alice Y Chan; Rolando Cimaz; Paul Dancey; Jason Dare; Marietta DeGuzman; Victoria Dimitriades; Ian Ferguson; Polly Ferguson; Laura Finn; Marco Gattorno; Alexei A Grom; Eric P Hanson; Philip J Hashkes; Christian M Hedrich; Ronit Herzog; Gerd Horneff; Rita Jerath; Elizabeth Kessler; Hanna Kim; Daniel J Kingsbury; Ronald M Laxer; Pui Y Lee; Min Ae Lee-Kirsch; Laura Lewandowski; Suzanne Li; Vibke Lilleby; Vafa Mammadova; Lakshmi N Moorthy; Gulnara Nasrullayeva; Kathleen M O'Neil; Karen Onel; Seza Ozen; Nancy Pan; Pascal Pillet; Daniela Gp Piotto; Marilynn G Punaro; Andreas Reiff; Adam Reinhardt; Lisa G Rider; Rafael Rivas-Chacon; Tova Ronis; Angela Rösen-Wolff; Johannes Roth; Natasha Mckerran Ruth; Marite Rygg; Heinrike Schmeling; Grant Schulert; Christiaan Scott; Gisella Seminario; Andrew Shulman; Vidya Sivaraman; Mary Beth Son; Yuriy Stepanovskiy; Elizabeth Stringer; Sara Taber; Maria Teresa Terreri; Cynthia Tifft; Troy Torgerson; Laura Tosi; Annet Van Royen-Kerkhof; Theresa Wampler Muskardin; Scott W Canna; Raphaela Goldbach-Mansky Journal: J Clin Invest Date: 2020-04-01 Impact factor: 14.808