Autoinflammatorische Erkrankungen als wichtige Differenzialdiagnosen in der Rheumatologie – ein Update

Zusammenfassung

Die autoinflammatorischen Syndrome sind eine Gruppe von prädispositionsbedingten Erkrankungen, die durch das intermittierende oder chronische Auftreten einer multisystemischen Inflammation – oft mit Gelenk- und Hautbeteiligung – charakterisiert sind. Ihnen liegt zumeist eine Störung der angeborenen Immunregulation mit konsekutiver Überproduktion von proinflammatorischen Zytokinen und neutrophiler Inflammation zugrunde. Zentrales Steuerelement sind sog. Inflammasome, intrazelluläre makromolekulare Proteinkomplexe, die insbesondere die Aktivierung von Interleukin (IL)-1β vermitteln. Typische Kranheitsvertreter sind die monogen vererbten Erkrankungen Familiäres Mittelmeerfieber (FMF), Tumornekrosefaktor-Rezeptor-1-assoziiertes periodisches Syndrom (TRAPS), Hyperimmunglobulinämie D- und periodisches Fieber-Syndrom (HIDS) und die Cryopyrin-assoziierten periodischen Syndrome (CAPS), die charakteristischerweise mit rekurrierenden Fieberepisoden einhergehen. Eine Spätkomplikation kann die SAA-Amyloidose sein. Dass Fieber aber nicht immer das führende Leitsymptom sein muss, zeigen die Defizienz des IL-1-Rezeptor-Antagonisten (DIRA) und der funktionelle Mangel des IL-10-Rezeptors, bei denen es zu einem gestörten Gleichgewicht von pro- und antiinflammatorisch wirkenden Zytokinen kommt und die vor allem mit Haut- sowie Gelenks- bzw. Darmaffektionen einhergehen. Mit zunehmender Kenntnis endogener und exogener Triggerfaktoren der Inflammasome bzw. der zugrundeliegenden molekularen Pathomechanismen konnte die Liste autoinflammatorischer Erkrankungen um wesentlich häufiger vorkommende, polygen vererbte Krankheitsentitäten wie Gicht, Pseudogicht, Diabetes mellitus Typ 2, die systemische juvenile idiopathische Arthritis, den adulten Morbus Still und das im Kindesalter am häufigsten vorkommende Fiebersyndrom PFAPA (periodisches Fieber, aphthöse Stomatitis, Pharyngitis, Adenitis) erweitert werden. Diese Erkenntnisse haben bereits den effektiven Einsatz einer gezielten IL-1-Blockade bei zahlreichen dieser Erkrankungen erlaubt und werden zur Identifikation weiterer Zielmoleküle für eine rationale Therapie führen.

Abstract

Autoinflammatory syndromes are a group of disorders with a genetic predisposition for an intermittent or chronic multisystemic inflammation, which often involves joints and skin. They are caused by a dysregulation of the innate immune response with a subsequently increased production of proinflammatory cytokines and neutrophilic inflammation. Central players are so-called inflammasomes, intracellular macromolecular protein complexes, which mediate especially the activation of interleukin (IL)-1β. Prototypic representatives are the monogenic autoinflammatory diseases familial Mediterranean fever (FMF), tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), and the cryopyrin-associated periodic syndromes (CAPS) which characteristically present with recurrent fever episodes. A long-term complication can be the development of a systemic amyloidosis. Fever, however, does not need to be present in each case, as demonstrated by the recently discovered deficiency of the IL-1 receptor antagonist (DIRA) and the functional deficiency of the IL-10 receptor, which are caused by an inherited imbalance of pro- and anti-inflammatory cytokines and mainly present with skin or joint and gastrointestinal manifestations, respectively. Our increasing knowledge of exogenous and endogenous triggers of inflammasomes and of the molecular pathways involved have led to the unexpected discovery that a growing number of genetically complex conditions such as, e. g., gout, pseudogout, diabetes mellitus type 2, systemic onset juvenile idiopathic arthritis, adult-onset Still’s disease and the most common fever syndrome in childhood, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis) syndrome, are also autoinflammatory diseases. These insights have already resulted in an effective treatment of a variety of these disorders by anti-IL-1 blockade and will most certainly lead to the identification of further target molecules for a rational drug therapy.

Schlüsselwörter

autoinflammatorische Erkrankung - periodisches Fiebersyndrom - Inflammation - Interleukin 1ß

Keywords

autoinflammatory disease - periodic fever syndrome - inflammation - interleukin 1ß

• Literatur

• 1 Kallinich T, Haffner D, Rudolph B et al. „Periodic fever“ without fever: two cases of non-febrile TRAPS with mutations in the TNFRSF1A gene presenting with episodes of inflammation or monosymptomatic amyloidosis. Ann Rheum Dis 2006; 65: 958-960
• 2 Morbach H, Richl P, Stojanov S et al. Tumor necrosis factor receptor 1-associated periodic syndrome without fever: cytokine profile before and during etanercept treatment. Rheumatol Int 2009; Apr 19 [Epub ahead of print]
• 3 Kastner DL, Aksentijevich I, Goldbach-Mansky R. Autoinflammatory diseases reloaded: a clinical perspective. Cell 2010; 140: 784-790
• 4 Masters SL, Simon A, Aksentijevich I et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 2009; 27: 621-668
• 5 McGonagle D, Aziz A, Dickie LJ et al. An integrated classification of pediatric inflammatory diseases, based on the concepts of autoinflammation and the immunological disease continuum. Pediatr Res 2009; 65: 38R-45R
• 6 Stojanov S, Lapidus S, Chitkara P et al. Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci USA. 2011 , Apr 8. [Epub ahead of print]
• 7 Lohse P. Autoinflammatorische (Fieber-)Syndrome – Klinik, Genetik und Therapie. Akt Rheumatol 2007; 32: 155-162
• 8 Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatrica 2010; 99: 178-184
• 9 Padeh S, Stoffman N, Berkun Y. Periodic fever accompanied by aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA syndrome) in adults. Isr Med Assoc J 2008; 10: 358-360
• 10 Cavuoto M, Bonagura VR. Adult-onset periodic fever, aphthous stomatitis, pharyngitis, and adenitis. Ann Allergy Asthma Immunol 2008; 100: 170
• 11 Cochard M, Clet J, Le L et al. PFAPA syndrome is not a sporadic disease. Rheumatology (Oxford) 2010; 49: 1984-1987
• 12 Caorsi R, Pelagatti MA, Federici S et al. Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome. Curr Opin Rheumatol 2010; 22: 579-584
• 13 Gattorno M, Sormani MP, D’Osualdo A et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum 2008; 58: 1823-1832
• 14 Tasher D, Stein M, Dalal I et al. Colchicine prophylaxis for frequent periodic fever, aphthous stomatitis, pharyngitis and adenitis episodes. Acta Paediatr 2008; 97: 1090-1092
• 15 Yalcinkaya F, Ozen S, Ozcakar ZB et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009; 48: 395-398
• 16 Padeh S, Livneh A, Pras E et al. Familial Mediterranean fever in the first two years in life: a unique phenotype of disease in evolution. J Pediatr 2010; 156: 985-989
• 17 Booty MG, Chae JJ, Masters SL et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit?. Arthritis Rheum 2009; 60: 1851-1861
• 18 Marek-Yagel D, Berkun Y, Padeh S et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum 2009; 60: 1862-1866
• 19 Ryan J, Masters SL, Booty MG et al. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein. Ann Rheum Dis 2010; 69: 1360-1363
• 20 Kallinich T, Wittkowski H, Keitzer R et al. Neutrophil-derived S100A12 as novel biomarker of inflammation in familial Mediterranean fever. Ann Rheum Dis 2010; 69: 677-682
• 21 Chae JJ, Cho Y-H, Cheng J et al. Familial Mediterranean fever (FMF)-associated B30.2 (PRYSPRY) mutations activate a NLRP3-independent inflammasome and induce autoinflammatory disease in mice. Arthritis Rheum 2009; 60: S463
• 22 Meinzer U, Quartier P, Alexandra JF et al. Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum. 2011 Jan 28 [Epub ahead of print]
• 23 Lainka E, Neudorf U, Lohse P et al. Incidence of TNFRSF1A mutations in German children: epidemiological, clinical and genetic characteristics. Rheumatology (Oxford) 2009; 48: 987-991
• 24 Pelagatti MA, Meini A, Caorsi R et al. Long-term follow-up of children with the low penetrance R92Q mutation of TNFRSF1A gene. Arthritis Rheum. 2011 Jan 10. [Epub ahead of print]
• 25 Simon A, Park H, Maddipati R et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci USA 2010; 107: 9801-9806
• 26 Bulua AC, Simon A, Maddipati R et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS) . J Exp Med. 2011 Jan 31 [Epub ahead of print]
• 27 Stojanov S, Dejaco C, Lohse P et al. Clinical and functional characterization of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with TNF receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment. Ann Rheum Dis 2008; 67: 1292-1298
• 28 Gattorno M, Martini A. Treatment of autoinflammatory syndromes. Curr Opin Pediatr 2010; 22: 771-778
• 29 Gattorno M, Pelagatti MA, Meini A et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 2008; 58: 1516-1520
• 30 Ammouri W, Cuisset L, Rouaghe S et al. Diagnostic value of serum immunoglobulinemia D level in patients with a clinical suspicion of hyper IgD syndrome. Rheumatology (Oxford) 2007; 46: 1597-1600
• 31 Steichen O, van der Hilst J, Simon A et al. A clinical criterion to exclude the hyperimmunoglobulin D syndrome (mild mevalonate kinase deficiency) in patients with recurrent fever. J Rheumatol 2009; 36: 1677-1681
• 32 van der Hilst JC, Bodar EJ, Barron KS et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 2008; 87: 301-310
• 33 Lainka E, Neudorf U, Lohse P . Analysis of cryopyrin-associated periodic syndromes (CAPS) in German children: epidemiological, clinical and genetic characteristics. Klin Padiatr 2010; 222: 356-361
• 34 Neven B, Marvillet I, Terrada C et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum 2010; 62: 258-267
• 35 Lepore L, Paloni G, Caorsi R et al. Follow-up and quality of life of patients with cryopyrin-associated periodic syndromes treated with anakinra. J Pediatr 2010; 157: 310.e1-315.e1
• 36 Kümmerle-Deschner JB, Tyrrell PN, Kötter I et al. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome. Arthritis Rheum 2010; Nov 15 [Epub ahead of print]
• 37 Lachmann HJ, Kone-Paut I, Kümmerle-Deschner JB et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009; 360: 2416-2425
• 38 Hoffman HM, Throne ML, Amar NJ et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 2008; 58: 2443-2452
• 39 Lachmann HJ, Kümmerle-Deschner JB, Hachulla E et al. Canakinumab provides rapid response and sustained remission in patients with cryopyrin associated periodic syndrome (CAPS) across different severity phenotypes. Ann Rheum Dis 2010; 69 (Suppl. 03) 112
• 40 Hoffman HM, Nadler DR, Brooks WP et al. Rilonacept: long-term safety profile in patients with cryopyrin-associated periodic syndromes (CAPS). Arthritis Rheum 2009; 60: S463
• 41 Rose CD, Arostegui JI, Martin TM et al. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain. Arthritis Rheum 2009; 60: 1797-1803
• 42 Aksentijevich I, Masters SL, Ferguson PJ et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 2009; 360: 2426-2437
• 43 Reddy S, Jia S, Geoffrey R et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med 2009; 360: 2438-2444
• 44 Glocker EO, Kotlarz D, Boztug K et al. Inflammatory bowel disease due to mutations in the IL-10 receptor. N Engl J Med 2009; 361: 2033-2045
• 45 Tinazzi E, Puccetti A, Patuzzo G et al. Schnitzler syndrome, an autoimmune-autoinflammatory syndrome: Report of two new cases and review of the literature. Autoimmun Rev. 2011 Jan 20 [Epub ahead of print]
• 46 Loock J, Lamprecht P, Timmann C et al. Genetic predisposition (NLRP3 V198M mutation) for IL-1-mediated inflammation in a patient with Schnitzler syndrome. J Allergy Clin Immunol 2010; 125: 500-502
• 47 Kötter I, Schedel J, Kümmerle-Deschner JB. Periodische Fiebersyndrome/autoinflammatorische Fiebersyndrome. Z Rheumatol 2009; 68: 137-149
• 48 Cantarini L, Lucherini OM, Iacoponi F et al. Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders. Int J Immunopathol Pharmacol 2010; 23: 1133-1141
• 49 Piram M, Frenkel J, Gattorno M et al. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Ann Rheum Dis 2011; 70: 309-314