OBJECTIVE: Dominantly inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.). The connections between PSTPIP1 and PAPA syndrome are poorly understood, although evidence suggests involvement of pyrin inflammasome activation. Interleukin-18 (IL-18) is an inflammasome-activated cytokine associated with susceptibility to macrophage activation syndrome (MAS). This study was undertaken to investigate an association of IL-18 with PAPA syndrome. METHODS: Clinical and genetic data and serum samples were obtained from patients referred to institutions due to symptoms indicative of PAPA syndrome. Serum IL-18, IL-18 binding protein (IL-18BP), and CXCL9 levels were assessed by bead-based assay, and free IL-18 levels were assessed by enzyme-linked immunosorbent assay. RESULTS: The symptoms of PSTPIP1-positive patients with PAPA syndrome overlapped with those of mutation-negative patients with PAPA-like conditions, but mutation-positive patients had earlier onset and a greater proportion had a history of arthritis. We found uniform elevation of total serum IL-18 in treated PAPA syndrome patients at levels nearly as high as those seen in NLRC4-associated autoinflammation with infantile enterocolitis patients, and well above levels found in most familial Mediterranean fever patients. Serum IL-18 elevation in PAPA syndrome patients persisted despite fluctuations in disease activity. Levels of the soluble IL-18 antagonist IL-18BP were modestly elevated, and PAPA syndrome patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon-γ activity, but no PAPA syndrome patients had a history of MAS. CONCLUSION: PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 levels but not with risk of MAS. These findings affect our understanding of the diseases in which IL-18 is overproduced and suggest a link between pyrin inflammasome activation, IL-18, and autoinflammation, without susceptibility to MAS.
OBJECTIVE: Dominantly inherited PSTPIP1 mutations cause a spectrum of autoinflammatory manifestations epitomized by PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome.). The connections between PSTPIP1 and PAPA syndrome are poorly understood, although evidence suggests involvement of pyrin inflammasome activation. Interleukin-18 (IL-18) is an inflammasome-activated cytokine associated with susceptibility to macrophage activation syndrome (MAS). This study was undertaken to investigate an association of IL-18 with PAPA syndrome. METHODS: Clinical and genetic data and serum samples were obtained from patients referred to institutions due to symptoms indicative of PAPA syndrome. Serum IL-18, IL-18 binding protein (IL-18BP), and CXCL9 levels were assessed by bead-based assay, and free IL-18 levels were assessed by enzyme-linked immunosorbent assay. RESULTS: The symptoms of PSTPIP1-positive patients with PAPA syndrome overlapped with those of mutation-negative patients with PAPA-like conditions, but mutation-positive patients had earlier onset and a greater proportion had a history of arthritis. We found uniform elevation of total serum IL-18 in treated PAPA syndrome patients at levels nearly as high as those seen in NLRC4-associated autoinflammation with infantile enterocolitis patients, and well above levels found in most familial Mediterranean fever patients. Serum IL-18 elevation in PAPA syndrome patients persisted despite fluctuations in disease activity. Levels of the soluble IL-18 antagonist IL-18BP were modestly elevated, and PAPA syndrome patients had detectable free IL-18. PAPA syndrome was rarely associated with elevation of CXCL9, an indicator of interferon-γ activity, but no PAPA syndrome patients had a history of MAS. CONCLUSION: PAPA syndrome is a refractory and often disabling monogenic autoinflammatory disease associated with chronic and unopposed elevation of serum IL-18 levels but not with risk of MAS. These findings affect our understanding of the diseases in which IL-18 is overproduced and suggest a link between pyrin inflammasome activation, IL-18, and autoinflammation, without susceptibility to MAS.
Authors: Eric S Weiss; Charlotte Girard-Guyonvarc'h; Dirk Holzinger; Adriana A de Jesus; Zeshan Tariq; Jennifer Picarsic; Eduardo J Schiffrin; Dirk Foell; Alexei A Grom; Sandra Ammann; Stephan Ehl; Tomoaki Hoshino; Raphaela Goldbach-Mansky; Cem Gabay; Scott W Canna Journal: Blood Date: 2018-01-11 Impact factor: 22.113
Authors: Alexandra Laberko; Vasiliy Burlakov; Sarah Maier; Mario Abinun; Roderick Skinner; Anna Kozlova; Deepti Suri; Kai Lehmberg; Ingo Müller; Dmitry Balashov; Galina Novichkova; Dirk Holzinger; Andrew R Gennery; Anna Shcherbina Journal: J Allergy Clin Immunol Date: 2020-12-15 Impact factor: 10.793
Authors: Paul Tsoukas; Emily Rapp; Lauren Van Der Kraak; Eric S Weiss; Vinh Dang; Corinne Schneider; Edwin Klein; Jennifer Picarsic; Rosalba Salcedo; C Andrew Stewart; Scott W Canna Journal: Blood Date: 2020-11-05 Impact factor: 22.113
Authors: Yael Gernez; Adriana A de Jesus; Hanouf Alsaleem; Claudia Macaubas; Amitava Roy; Daniel Lovell; Karthik A Jagadeesh; Sara Alehashemi; Laura Erdman; Michael Grimley; Susanna Talarico; Rosa Bacchetta; David B Lewis; Scott W Canna; Ron M Laxer; Elizabeth D Mellins; Raphaela Goldbach-Mansky; Katja G Weinacht Journal: J Allergy Clin Immunol Date: 2019-07-02 Impact factor: 10.793
Authors: Carol A Wise; Joseph D Gillum; Christine E Seidman; Noralane M Lindor; Rose Veile; Stavros Bashiardes; Michael Lovett Journal: Hum Mol Genet Date: 2002-04-15 Impact factor: 6.150
Authors: Charlotte Girard; Jürgen Rech; Michael Brown; Danièle Allali; Pascale Roux-Lombard; François Spertini; Eduardo J Schiffrin; Georg Schett; Bernhard Manger; Sylvette Bas; Greg Del Val; Cem Gabay Journal: Rheumatology (Oxford) Date: 2016-09-10 Impact factor: 7.580
Authors: Ariane S I Standing; Dessislava Malinova; Ying Hong; Julien Record; Dale Moulding; Michael P Blundell; Karolin Nowak; Hannah Jones; Ebun Omoyinmi; Kimberly C Gilmour; Alan Medlar; Horia Stanescu; Robert Kleta; Glenn Anderson; Sira Nanthapisal; Sonia Melo Gomes; Nigel Klein; Despina Eleftheriou; Adrian J Thrasher; Paul A Brogan Journal: J Exp Med Date: 2016-12-19 Impact factor: 14.307
Authors: Michael T Lam; Simona Coppola; Oliver H F Krumbach; Giusi Prencipe; Antonella Insalaco; Mohammad R Ahmadian; Jordan S Orange; Fabrizio De Benedetti; Marco Tartaglia; Cristina Cifaldi; Immacolata Brigida; Erika Zara; Serena Scala; Silvia Di Cesare; Simone Martinelli; Martina Di Rocco; Antonia Pascarella; Marcello Niceta; Francesca Pantaleoni; Andrea Ciolfi; Petra Netter; Alexandre F Carisey; Michael Diehl; Mohammad Akbarzadeh; Francesca Conti; Pietro Merli; Anna Pastore; Stefano Levi Mortera; Serena Camerini; Luciapia Farina; Marcel Buchholzer; Luca Pannone; Tram N Cao; Zeynep H Coban-Akdemir; Shalini N Jhangiani; Donna M Muzny; Richard A Gibbs; Luca Basso-Ricci; Maria Chiriaco; Radovan Dvorsky; Lorenza Putignani; Rita Carsetti; Petra Janning; Asbjorg Stray-Pedersen; Hans Christian Erichsen; AnnaCarin Horne; Yenan T Bryceson; Lamberto Torralba-Raga; Kim Ramme; Vittorio Rosti; Claudia Bracaglia; Virginia Messia; Paolo Palma; Andrea Finocchi; Franco Locatelli; Ivan K Chinn; James R Lupski; Emily M Mace; Caterina Cancrini; Alessandro Aiuti Journal: J Exp Med Date: 2019-10-10 Impact factor: 14.307