Abstract
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is a rare autosomal-dominant autoinflammatory disease of incomplete penetrance and variable expression. PAPA syndrome is the result of a mutation in the proline serine threonine phosphatase-interacting protein 1 (PSTPIP1/CD2BP1) gene located on chromosome 15, which results in an abnormal overproduction of the pro-inflammatory cytokine interleukin-1β (IL-1). This syndrome clinically manifests as early onset of recurrent episodes of acute aseptic inflammation of the joints, generally occurring in the first two decades of life, followed by manifestation of characteristic skin lesions in the third decade, after an obvious decline in the joint symptoms. Although uncommon, the potential clinical implications of PAPA syndrome warrant an appropriate diagnosis in a timely fashion.
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Demidowich AP, Freeman AF, Kuhns DB et al (2012) Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). Arthritis Rheum 64:2022–2027
Wise CA, Gillum JD, Seidman CE et al (2002) Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet 11:961–969
Yeon HB, Lindor NM, Seidman JG et al (2000) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome maps to chromosome 15q. Am J Hum Genet 66:1443–1448
Wang D, Höing S, Patterson HC et al (2013) Inflammation in mice ectopically expressing human pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome-associated PSTPIP1 A230T mutant proteins. J Biol Chem 288:4594–4601
Lindor NM, Arsenault TM, Solomon H et al (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 72:611–615
Online Mendelian Inheritance in Man (2018) National Center for Biotechnology Information website. http://www.ncbi.nlm.nih.gov/omim. Accessed 1 March 2018
Tallon B, Corkill M (2006) Peculiarities of PAPA syndrome. Rheumatology 45:1140–1143
Smith EJ, Allantaz F, Bennet L et al (2010) Clinical, molecular, and genetic characteristics of PAPA syndrome: a review. Curr Genomics 11:519–527
Loffler W, Lohse P, Weihmayr T et al (2017) Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome: differential diagnosis of septic arthritis by regular detection of exceedingly high synovial counts. Infection 45:395–402
Holzinger D, Roth J (2016) Alarming consequences — autoinflammatory disease spectrum due to mutations in proline-serine threonine phosphatase-interacting protein 1. Curr Opin Rheumatol 28:550–559
Fathalla BM, Al-Wahadneh AM, Al-Mutawa M et al (2014) A novel de novo PSTPIP1 mutation in a boy with pyogenic arthritis, pyoderma gangrenosum, acne (PAPA) syndrome. Clin Exp Rheumatol 32:956–958
Wise CA, Bennet LB, Pascual V et al (2000) Localization of a gene for familial recurrent arthritis 43:2041–2045
Cortis E, Benedetti DF, Insalaco A et al (2004) Abnormal production of the tumor necrosis factor inhibitor etanercept and clinical efficacy of tumor in a patient with PAPA syndrome. J Pediatr 145:851–855
Dierselhuis MP, Frenkel J, Wulffraat NM et al (2005) Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology 44:406–408
Brenner M, Ruzicka G, Plewig G (2009) Targeted treatment of pyoderma gangrenosum in PAPA (pyogenic arthritis, pyoderma gangrenosum and acne) syndrome with the recombinant human interleukin-1 receptor antagonist anakinra. Br J Dermatol 161:1199–1201
Tofteland ND, Shaver TS (2010) Clinical efficacy of etanercept for treatment of PAPA syndrome. J Clin Rheumatol 16:244–245
Schellevis MA, Stoffels M, Hoppenreijs EPAH et al (2011) Variable expression and treatment of PAPA syndrome. Ann Rheum Dis 70:1168–1170
Caorsi R, Picco P, Buoncompagni A et al (2014) Osteolytic lesion in PAPA syndrome responding to anti-interleukin 1 treatment. J Rheumatol 41:2333–2334
Omenetti A, Carta S, Caorsi R et al (2016) Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome. Rheumatology 55:1325–1335
Jacobs JC, Goetzi EJ (1975) Streaking leukocyte factor, arthritis, and pyoderma gangrenosum. Pediatrics 56:570–578
Shoham NG, Centola M, Mansfield E et al (2003) Pyrin binds PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A 100:13501–13506
McDermott MF (2004) A common pathway in periodic fever syndromes. Trends Immunol 25:457–460
Omenetti A, Caorsi R, Carta S et al (2013) PW02-006-PAPA syndrome clinical spectrum and IL1B release. Pediatr Rheumatol 11:A146
Caorsi R, Marotto D, Insalaco A et al (2015) The phenotypic variability of PAPA syndrome: evidence from the Eurofever registry. Pediatr Rheumatol 13:08
Yang H, Reinherz EL (2006) CD2BP1 modulates CD2-dependent T cell activation via linkage to protein tyrosine phosphatase (PTP)-PEST. J Immunol 176:5898–5907
Starnes TW, Bennin DA, Bing X et al (2014) The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages. Blood 123:2703–2714
Yu JW, Wu J, Zhang Z et al (2006) Cryopyrin and pyrin activate caspase-1, but not NF-kappa B, via ASC oligomerization. Cell Death Differ 13:236–249
Arostegui JI, Yagüe J (2008) Hereditary systemic autoinflammatory diseases. Part II: cryopyrin-associated periodic syndromes, pediatric systemic granulomatosis and PAPA syndrome. Med Clin 130:429–438
Braun-Falco M, Kovnerystyy O, Lohse P et al (2012) Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH) a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol 66:409–415
Lambertucci JR (2014) Fever of undetermined origin in a patient with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA syndrome). Rev Soc Bras Med Trop 47:122
Marzano AV, Borghi A, Meroni PL et al (2016) Pyoderma gangrenosum and its syndromic forms: evidence for a link with autoinflammation. Br J Dermatol 175:882–891
Varga G, Gattorno M, Foell D et al (2015) Redox distress and genetic defects conspire in systemic autoinflammatory diseases. Nat Rev Rheumatol 11:670–680
Löhrer R, Eming R, Wolfrum N et al (2011) Autoinflammatory diseases as cause of wound healing defects. Hautarzt 62:524–533
Verbsky JW (2012) Monogenic causes of inflammatory disease in rheumatology. Curr Opin Rheumatol 24:506–514
Caso F, Rigante D, Vitale A (2013) Monogenic autoinflammatory syndromes: state of the art on genetic, clinical, and therapeutic issues. Int J Rheumatol 2013:513782
Thacker PG, Binkovitz LA, Thomas KB (2012) Deficiency of interleukin-1-receptor antagonist syndrome: a rare auto-inflammatory condition that mimics multiple classic radiographic findings. Pediatr Radiol 42:495–498
Aksentijevich I, Masters SL, Ferguson PJ et al (2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 360:2426–2437
Stenerson M, Dufendach K, Aksentijevich I (2011) The first reported case of compound heterozygous IL1RN mutations causing deficiency of the interleukin-1 receptor antagonist. Arthritis Rheum 63:4018–4022
Daldrup-Link HE, Steinbach L (2009) MR imaging of pediatric arthritis. Magn Reson Imaging Clin N Am 17:451–467
Macaubas C, Nguyen K, Milojevic D et al (2009) Oligoarticular and polyarticular JIA: epidemiology and pathogenesis. Nat Rev Rheumatol 5:616–626
Oberle EJ, Harris JG, Verbsky JW (2014) Polyarticular juvenile idiopathic arthritis-epidemiology and management approaches. J Clin Epidemiol 6:379–393
Monsalve J, Kan JH (2015) Septic arthritis in children: frequency of coexisting unsuspected osteomyelitis and implications on imaging work-up and management. AJR Am J Roentgenol 204:1289–1295
Karchevsky M, Schweitzer ME, Morrison WB et al (2004) MRI findings of septic arthritis and associated osteomyelitis in adults. AJR Am J Roentgenol 182:119–122
Funk SS, Copley LAB (2017) Acute hematogenous osteomyelitis in children. Pathogenesis, diagnosis and treatment. Orthop Clin N Am 48:199–208
Guillerman RP (2013) Osteomyelitis and beyond. Pediatr Radiol 43:S193–S203
Ferguson PJ, Sandu M (2012) Current understanding of the pathogenesis and management of chronic recurrent multifocal osteomyelitis. Curr Rheumatol Rep 14:130–141
Ferguson PJ, Chen S, Tayeh MK et al (2005) Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J Med Genet 42:551–557
Chen W, Obermayer-Pietsch B, Hong JB (2011) Acne-associated syndromes: models for better understanding of acne pathogenesis. J Eur Acad Dermatol Venereol 25:637–646
Stichweh DS, Punaro M, Pascual V (2005) Dramatic improvement of pyoderma gangrenosum with infliximab in a patient with PAPA syndrome. Pediatr Dermatol 22:262–265
Khatibi K, Heit JJ, Telischak NA (2015) Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm. BMJ Case Rep. https://doi.org/10.1136/bcr-2015-011753
Horiuchi I, Fukatsu Y, Ushijima J et al (2016) A pregnancy-associated nonfamilial case of PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, acne) syndrome. Clin Case Rep 4:989–991
Hong J, Su Y, Chiu H (2009) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome): report of a sporadic case without an identifiable mutation in the CD2BP1 gene. J Am Acad Dermatol 61:533–535
Nguyen MT, Borchers A, Selmi C et al (2012) The SAPHO syndrome. Semin Arthritis Rheum 42:254–265
Basmaci R, Bonacorsi S (2017) Kingella kingae: from carriage to infection. Commentary on Canadian Medical Association Journal. CMAJ 189:E1105–E1106
Edrees AF, Kaplan DL, Abdou NI (2002) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) associated with hypogammaglobulinemia and elevated serum tumor necrosis factor-a levels. J Clin Rheumatol 8:273–275
Finetti M, Caorsi R, Marotto D et al (2015) Long-term efficacy of IL-1 blockers in PAPA patients. Pediatr Rheumatol 13:P207
Gattorno M, Tassi S, Carta S et al (2007) Pattern of interleukin-1 beta secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Arthritis Rheum 56:3138–3148
Geusau A, Mothes-Luksch N, Nahavandi H et al (2013) Identification of a homozygous PSTPIP1 mutation in a patient with a PAPA-like syndrome responding to canakinumab treatment. JAMA Dermatol 149:209–215
Ter Haar N, Lachmann H, Özen S et al (2013) Treatment of autoinflammatory diseases: results from the Eurofever registry and a literature review. Ann Rheum Dis 72:678–685
Stone D, Ombrello A, Almeida ADJ et al (2015) Use of TNF inhibitors in the treatment of PAPA syndrome. Pediatr Rheumatol 13:P138
Lee H, Park SH, Kim SK (2012) Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA syndrome) with E250K mutation in CD2BP1 gene treated with the tumor necrosis factor inhibitor adalimumab. Clin Exp Rheumatol 30:452
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Dr. R. M. Laxer has acted as a consultant for Sobi (manufacturer of anakinra) and Novartis (manufacturer of canakinumab). These relationships are not related to the development of this manuscript.
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Martinez-Rios, C., Jariwala, M.P., Highmore, K. et al. Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature. Pediatr Radiol 49, 23–36 (2019). https://doi.org/10.1007/s00247-018-4246-1
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DOI: https://doi.org/10.1007/s00247-018-4246-1