title: Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome.
abstract: To provide a rationale for anti-IL-1 treatment in pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) by defining whether IL-1β secretion is enhanced; requires NLRP3; and correlates with proline-serine-threonine phosphatase-interacting protein 1 mutations, disease activity and/or the clinical picture in PAPA.
  
  
  
  Monocytes were isolated from 13 patients and 35 healthy donors and studied at baseline and following activation. Secretion pattern of IL-1β, IL-1α, IL-1Ra, IL-6, IL-18 and TNF-α was assessed in supernatants by ELISA. The NLRP3 requirement for IL-1β secretion was investigated by silencing technique in PAPA and healthy donor monocytes. Long-term follow-up (mean 26 months, range 4-38) was performed in five patients enrolled in an anti-IL-1 regimen.
  
  
  
  IL-1β secretion in PAPA is increased, requires NLRP3 and correlates with disease activity. Patients with a history of osteoarticular flares release more IL-1β, IL-6 and TNF-α compared with those with predominant cutaneous recurrences. Monocytes from patients in anti-IL-1 treatment dramatically reduced IL-1β secretion after ex vivo activation, and long-term follow-up demonstrated decreased frequency of flares and normalization of acute phase reactants in all the patients. A straightforward correlation between genotype and IL-1β signalling was not observed suggesting that factors other than mutation itself may play a role in regulating IL-1β secretion and response to treatment in PAPA.
  
  
  
  PAPA patients with active lesions display increased NLRP3-mediated IL-1β secretion, and long-term efficacy of IL-1 blockade was demonstrated. Even if other mechanisms related to the complex proline-serine-threonine phosphatase-interacting protein 1 protein networking might play additional roles, this study further supports the potential of IL-1 blockade as an effective therapeutic strategy in PAPA syndrome.
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infant Sciences (DINOGMI), University of Genoa.
authors.forename: Alessia
authors.initials: A
authors.lastname: Omenetti
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro.
authors.forename: Sonia
authors.initials: S
authors.lastname: Carta
authors.affiliation: Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Caorsi
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infant Sciences (DINOGMI), University of Genoa.
authors.forename: Martina
authors.initials: M
authors.lastname: Finetti
authors.affiliation: Ambulatorio aziendale di Reumatologia, ASL 2, Olbia and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Marotto
authors.affiliation: UO Pediatric Division, AOU Ospedali Riuniti 'Salesi Children's Hospital', Ancona, Italy.
authors.forename: Bianca
authors.initials: B
authors.lastname: Lattanzi
authors.affiliation: UO Pediatric Division, AOU Ospedali Riuniti 'Salesi Children's Hospital', Ancona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Jorini
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro.
authors.forename: Laura
authors.initials: L
authors.lastname: Delfino
authors.affiliation: Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Penco
authors.affiliation: Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Picco
authors.affiliation: Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Buoncompagni
authors.affiliation: Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal-Infant Sciences (DINOGMI), University of Genoa, Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.affiliation: Cell Biology Unit, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, marcogattorno@ospedale-gaslini.ge.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Rubartelli
authors.affiliation: Pediatrics II Unit and Laboratory of Immunology of Pediatric Rheumatology, G. Gaslini IRCCS, Genoa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
mesh_terms: D000152:Acne Vulgaris / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D001170:Arthritis, Infectious / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007155:Immunologic Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology; D017511:Pyoderma Gangrenosum / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D007375:Interleukin-1; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014409:Tumor Necrosis Factor-alpha
keywords: IL-1; IL-1 receptor antagonist; NLRP3 inflammasome; PAPA syndrome; PSTPIP1; anti-IL-1 monoclonal antibody