PMID- 34492165 OWN - NLM STAT- MEDLINE DCOM- 20220217 LR - 20230202 IS - 2326-5205 (Electronic) IS - 2326-5191 (Print) IS - 2326-5191 (Linking) VI - 74 IP - 2 DP - 2022 Feb TI - Excess Serum Interleukin-18 Distinguishes Patients With Pathogenic Mutations in PSTPIP1. PG - 353-357 LID - 10.1002/art.41976 [doi] AB - 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-gamma 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. CI - (c) 2021, American College of Rheumatology. FAU - Stone, Deborah L AU - Stone DL AD - National Human Genome Research Institute, NIH, Bethesda, Maryland. FAU - Ombrello, Amanda AU - Ombrello A AD - National Human Genome Research Institute, NIH, Bethesda, Maryland. FAU - Arostegui, Juan I AU - Arostegui JI AUID- ORCID: 0000-0003-4757-504X AD - Hospital Clinic de Barcelona, Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain. FAU - Schneider, Corinne AU - Schneider C AD - University of Pittsburgh and UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. FAU - Dang, Vinh AU - Dang V AD - University of Pittsburgh and UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. AD - The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. FAU - de Jesus, Adriana AU - de Jesus A AD - National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland. FAU - Girard-Guyonvarc'h, Charlotte AU - Girard-Guyonvarc'h C AD - University of Geneva, Geneva, Switzerland. FAU - Gabay, Cem AU - Gabay C AD - University of Geneva, Geneva, Switzerland. FAU - Lee, Wonyong AU - Lee W AUID- ORCID: 0000-0003-4412-8519 AD - National Human Genome Research Institute, NIH, Bethesda, Maryland. FAU - Chae, Jae Jin AU - Chae JJ AD - National Human Genome Research Institute, NIH, Bethesda, Maryland. FAU - Aksentijevich, Ivona AU - Aksentijevich I AD - National Human Genome Research Institute, NIH, Bethesda, Maryland. FAU - Goldbach-Mansky, Raphaela T AU - Goldbach-Mansky RT AD - National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland. FAU - Kastner, Daniel L AU - Kastner DL AD - National Human Genome Research Institute, NIH, Bethesda, Maryland. FAU - Canna, Scott W AU - Canna SW AUID- ORCID: 0000-0003-3837-5337 AD - University of Pittsburgh and UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. AD - The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. LA - eng GR - R01 HD098428/HD/NICHD NIH HHS/United States GR - the RK Mellon Institute for Pediatric Research/ GR - the National Institute of Allergy and Infectious Disease/ GR - National Institute of Allergy and Infectious Disease, NIH/ GR - Intramural Research Programs of the National Human Genome Research Institute/ GR - Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH/ GR - the Institut d'Investigacions Biomediques August Pi i Sunyer/ GR - the University Hospital of Geneva/ PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20220103 PL - United States TA - Arthritis Rheumatol JT - Arthritis & rheumatology (Hoboken, N.J.) JID - 101623795 RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Cytoskeletal Proteins) RN - 0 (IL18 protein, human) RN - 0 (Interleukin-18) RN - 0 (PSTPIP1 protein, human) RN - Pyogenic arthritis, pyoderma gangrenosum, and acne SB - IM MH - Acne Vulgaris/*blood/*genetics MH - Adaptor Proteins, Signal Transducing/*genetics MH - Adolescent MH - Adult MH - Arthritis, Infectious/*blood/*genetics MH - Child MH - Child, Preschool MH - Cytoskeletal Proteins/*genetics MH - Female MH - Humans MH - Infant MH - Interleukin-18/*blood MH - Male MH - Middle Aged MH - *Mutation MH - Pyoderma Gangrenosum/*blood/*genetics MH - Retrospective Studies MH - Young Adult PMC - PMC8855702 MID - NIHMS1738472 EDAT- 2021/09/08 06:00 MHDA- 2022/02/19 06:00 PMCR- 2023/02/01 CRDT- 2021/09/07 17:31 PHST- 2021/08/04 00:00 [revised] PHST- 2021/02/02 00:00 [received] PHST- 2021/09/02 00:00 [accepted] PHST- 2021/09/08 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2021/09/07 17:31 [entrez] PHST- 2023/02/01 00:00 [pmc-release] AID - 10.1002/art.41976 [doi] PST - ppublish SO - Arthritis Rheumatol. 2022 Feb;74(2):353-357. doi: 10.1002/art.41976. Epub 2022 Jan 3.