Abstract
Innate immunity is a critical partner in the regulation of inflammation and some mutations in genes implied in innate immunity pathways can cause genetic disorders characterized by seemingly unprovoked self-limited inflammatory attacks. These rare conditions are collectively named “hereditary periodic fever syndromes” (HPFS), and protean pathogenetic mechanisms combined with several clinical phenotypes characterize at least four distinct conditions: (1) familial Mediterranean fever, which is the prototype and the most widely recognized among HPFS, inherited as an autosomal recessive disorder showing recurrent dysregulated inflammatory processes, caused by an abnormal interaction between cytoskeleton and inflammasome, a key-signaling platform that releases interleukin-1β (IL-1β); (2) the group of cryopyrin-associated periodic syndrome, which upsets directly the production of IL-1β, with a dominant pattern of inheritance; (3) tumor necrosis factor receptor-associated periodic syndrome, which is an autosomal dominant disorder subverting the functions and traffic of a cell membrane protein; and (4) mevalonate kinase deficiency, which is an autosomal recessive metabolic disorder halting the biosynthesis of cholesterol. MEFV, NLRP3, TNFRSF1A, and MVK are respectively the four causing genes of these conditions, all resulting in excessive IL-1β signaling, though the encoded proteins act at different levels in cytoskeletal filament organization, apoptosis, and activation of the IL-1β-structured inflammasome. The differential diagnosis of HPFS can be challenging, as there are no universally accepted diagnostic algorithms, and near half of patients may have a specific disease without any genetic pathogenetic variant identified. Herein, we outline the most relevant aspects of HPFS at the crossroads between clinical medicine and immunology and all the most recent advances in their treatment, as the increasing use of IL-1 antagonists has achieved unexpected clinical results in a large number of patients.
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References
Cooper EL (2010) Evolution of immune systems from self/not self to danger to artificial immune systems (AIS). Phys Life Rev 7(1):55–78. doi:10.1016/j.plrev.2009.12.001
Dzik JM (2010) The ancestry and cumulative evolution of immune reactions. Acta Biochim Pol 57(4):443–466
Buchmann K (2014) Evolution of innate immunity: clues from invertebrates via fish to mammals. Front Immunol 23(5):459. doi:10.3389/fimmu.2014.00459
Rigante D, Lopalco G, Vitale A et al (2014) Untangling the web of systemic autoinflammatory diseases. Mediat Inflamm 2014:948154. doi:10.1155/2014/948154
Aksentijevich I, Kastner DL (2011) Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol 7(8):469–478. doi:10.1038/nrrheum.2011.94
Lamkanfi M, Dixit VM (2012) Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol 28:137–161. doi:10.1146/annurev-cellbio-101011-155745
Cantarini L, Lopalco G, Cattalini M, Vitale A, Galeazzi M, Rigante D (2015) Interleukin-1: ariadne’s thread in autoinflammatory and autoimmune disorders. Israel Med Assoc J 17(2):93–97
Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA (1984) Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A 81(24):7907–7911
Mariathasan S, Monack DM (2007) Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7(1):31–40
Vitale A, Rigante D, Lucherini OM et al (2013) Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediat Inflamm 2013:939847. doi:10.1155/2013/939847
Ben-Chetrit E, Levy M (1998) Familial Mediterranean fever. Lancet 351(9103):659–664
Centola M, Wood G, Frucht DM et al (2000) The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 95(10):3223–3231
Touitou I, Lesage S, McDermott M et al (2004) Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat 24(3):194–198. doi:10.1002/humu.20080
Rigante D, Vitale A, Lucherini OM, Cantarini L (2014) The hereditary autoinflammatory disorders uncovered. Autoimmun Rev 13(9):892–900. doi:10.1016/j.autrev.2014.08.001
Balci B, Tinaztepe K, Yilmaz E et al (2002) MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol Dial Transplant 17(11):1921–1923
Bilginer Y, Akpolat T, Ozen S (2011) Renal amyloidosis in children. Pediatr Nephrol 26(8):1215–1227. doi:10.1007/s00467-011-1797-x
Livneh A, Langevitz P, Zemer D et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40(10):1879–1885
Jéru I, Hentgen V, Cochet E et al (2013) The risk of familial Mediterranean fever in MEFV heterozygotes: a statistical approach. PLoS One 8(7):e68431. doi:10.1371/journal.pone.0068431
Marek-Yagel D, Berkun Y, Padeh S et al (2009) Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum 60(6):1862–1866. doi:10.1002/art.24570
Rigante D, La Torraca I, Avallone L, Pugliese AL, Gaspari S, Stabile A (2006) The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever. Eur Rev Med Pharmacol Sci 10(4):173–178
Rigante D, Frediani B, Galeazzi M, Cantarini L (2013) From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases. Biomed Res Int 2013:485103. doi:10.1155/2013/485103
Aksentijevich I, Galon J, Soares M et al (2001) The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet 69(2):301–314
Caso F, Cantarini L, Lucherini OM et al (2014) Working the endless puzzle of hereditary autoinflammatory disorders. Mod Rheumatol 24(3):381–389. doi:10.3109/14397595.2013.843755
Cantarini L, Rigante D, Merlini G et al (2014) The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum 43(6):818–823. doi:10.1016/j.semarthrit.2013.12.002
Savic S, Dickie LJ, Wittmann M, McDermott MF (2012) Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives. Best Pract Res Clin Rheumatol 26(4):505–533. doi:10.1016/j.berh.2012.07.009
Rigante D, Lopalco G, Vitale A et al (2014) Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome. Clin Rheumatol 33(9):1197–1207. doi:10.1007/s10067-014-2722-z
Stojanov S, McDermott MF (2005) The tumour necrosis factor receptor-associated periodic syndrome: current concepts. Expert Rev Mol Med 7(22):1–18
Rigante D, Cantarini L, Imazio M et al (2011) Autoinflammatory diseases and cardiovascular manifestations. Ann Med 43(5):341–346. doi:10.3109/07853890.2010.547212
Ravet N, Rouaghe S, Dodé C et al (2006) Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann Rheum Dis 65(9):1158–1162
Aksentijevich I, D Putnam C, Remmers EF et al (2007) The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 56(4):1273–1285
Cantarini L, Lucherini OM, Frediani B et al (2011) Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes. Int J Immunopathol Pharmacol 24(4):827–836
Tanaka N, Izawa K, Saito MK et al (2011) High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum 63(11):3625–3632. doi:10.1002/art.30512
Hoffman HM, Wanderer AA, Broide DH (2001) Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 108(4):615–620
Aganna E, Martinon F, Hawkins PN et al (2002) Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum 46(9):2445–2452
Prieur AM, Griscelli C, Lampert F et al (1987) A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol 66:57–68
Rigante D (2010) The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci 14(1):1–18
Esposito S, Ascolese B, Senatore L et al (2014) Current advances in the understanding and treatment of mevalonate kinase deficiency. Int J Immunopathol Pharmacol 27(4):491–498
Mendey SH, Kuijk LM, Frenkel J, Waterham HR (2006) A role for geranylgeranylation in interleukin-1β secretion. Arthritis Rheum 54(11):3690–3695
Mendey SH, Schneiders MS, Koster J, Waterham HR (2006) Mutational spectrum and genotype-phenotype correlations in mevalonate kinase deficiency. Hum Mutat 27(8):796–802
van der Burgh R, ter Haar NM, Boes ML, Frenkel J (2013) Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol 147(3):197–206. doi:10.1016/j.clim.2012.09.011
Berody S, Galeotti C, Koné-Paut I, Piram M (2015) A restrospective survey of patients journey before the diagnosis of mevalonate kinase deficiency. Joint Bone Spine 82(4):240–244. doi:10.1016/j.jbspin.2014.12.011
Bader-Meunier B, Florkin B, Sibilia J et al (2011) Mevalonate kinase deficiency: a survey of 50 patients. Pediatrics 128(1):e152–159. doi:10.1542/peds.2010-3639
Ammouri W, Cuisset L, Rouaghe S et al (2007) Diagnostic value of serum immunoglobulinaemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology (Oxford) 46(10):1597–1600
Rigante D, Emmi G, Fastiggi M, Silvestri E, Cantarini L (2015) Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clin Rheumatol 34(8):1333–1339. doi:10.1007/s10067-015-2923-0
Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A (2003) The contribution of genotypes at the MEFV and SSA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 48(4):1149–1155
Ben-Zvi I, Livneh A (2011) Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 7(2):105–112. doi:10.1038/nrrheum.2010.181
Hentgen V, Grateau G, Kone-Paut I et al (2013) Evidence-based recommendations for the practical management of familial Mediterranean fever. Semin Arthritis Rheum 43(3):387–391. doi:10.1016/j.semarthrit.2013.04.011
Roldan R, Ruiz AM, Miranda MD, Collantes E (2008) Anakinra: new therapeutic approach in children with familial Mediterranean fever resistant to colchicine. Joint Bone Spine 75(4):504–505. doi:10.1016/j.jbspin.2008.04.001
Meinzer U, Quartier P, Alexandra JF, Hentgen V, Retornaz F, Koné-Paut I (2011) Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum 41(2):265–271. doi:10.1016/j.semarthrit.2010.11.003
Bulua AC, Mogul DB, Aksentijevich I et al (2012) Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study. Arthritis Rheum 64(3):908–913. doi:10.1002/art.33416
Nedjai B, Hitman GA, Quillinan N et al (2009) Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 60(2):619–625. doi:10.1002/art.24294
Grimwood C, Despert V, Jeru I, Hentgen V (2015) On-demand treatment with anakinra: a treatment option for selected TRAPS patients. Rheumatology (Oxford) 54(9):1749–1751. doi:10.1093/rheumatology/kev111
Federico G, Rigante D, Pugliese A, Ranno O, Catania S, Stabile A (2003) Etanercept induces improvement of arthropathy in chronic infantile neurological cutaneous articular (CINCA) syndrome. Scand J Rheumatol 32(5):312–314
Koné-Paut I, Galeotti C (2014) Anakinra for cryopyrin-associated periodic syndrome. Expert Rev Clin Immunol 10(1):7–18. doi:10.1586/1744666X.2014.861325
Rigante D, Ansuini V, Caldarelli M, Bertoni B, La Torraca I, Stabile A (2006) Hydrocephalus in CINCA syndrome treated with anakinra. Childs Nerv Syst 22(4):334–337
Kuemmerle-Deschner JB, Hachulla E, Cartwright R et al (2011) Two-years results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis 70(12):2095–2102. doi:10.1136/ard.2011.152728
Blech M, Peter D, Fischer P et al (2013) One target-two different binding modes: structural insights into gevokizumab and canakinumab interactions to interleukin-1β. J Mol Biol 425(1):94–111. doi:10.1016/j.jmb.2012.09.021
Lachmann HJ, Koné-Paut I, Kuemmerle-Deschner JB et al (2009) Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360(23):2416–2425. doi:10.1056/NEJMoa0810787
Koné-Paut I, Lachmann HJ, Kuemmerle-Deschner JB et al (2011) Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther 13:R202. doi:10.1186/ar3535
Anton J, Calvo I, Fernández-Martin J et al (2015) Efficacy and safety of canakinumab in cryopyrin-associated periodic syndromes: results from a Spanish cohort. Clin Exp Rheumatol 33(6 Suppl 94):S67–71
Steichen O, van der Hilst J, Simon A, Cuisset L, Grateau G (2009) A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol 36(8):1677–1681. doi:10.3899/jrheum.081313
Bodar EJ, Kuijk LM, Drenth JP, van der Meer JW, Simon A, Frenkel J (2011) On-demand anakinra treatment is effective in mevalonate kinase deficiency. Ann Rheum Dis 70(12):2155–2158. doi:10.1136/ard.2011.149922
Galeotti C, Meinzer U, Quartier P et al (2012) Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford) 51(10):1855–1859
Neven B, Valayannopoulos V, Quartier P et al (2007) Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med 356(26):2700–2703
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Rigante, D., Frediani, B. & Cantarini, L. A Comprehensive Overview of the Hereditary Periodic Fever Syndromes. Clinic Rev Allerg Immunol 54, 446–453 (2018). https://doi.org/10.1007/s12016-016-8537-8
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DOI: https://doi.org/10.1007/s12016-016-8537-8