Ätiologie und Pathogenese der Polymyalgia rheumatica und Riesenzellarteritis

Zusammenfassung

Der Polymyalgia rheumatica (PMR) und die Riesenzellarteritis (RZA) sind eng assoziierte Krankheitsbilder unklarer Ätiologie. Neben genetischen Faktoren wie weibliches Geschlecht, Polymorphismen im HLA Klasse II Gen sowie Varianten in Genen für Adhäsionsmoleküle und Chemokine spielen vermutlich auch Infektionen eine zentrale Rolle. Serologische Untersuchungen und Gewebeanalysen auf diverse virale und bakterielle Erreger (insbesondere Parvovirus B19 und Chlamydia pneumoniae) lieferten bisher aber widersprüchliche Ergebnisse. Alterungsprozesse des Immun- und Gefäßsystems wie die Ansammlung pro-inflammatorischer Zytokine und die Häufung oxidativer Endprodukte, sowie Störungen der endokrinen Achsen (z. B. inadäquat niedrige endogene Kortisolproduktion, Verlust von Androgenen) könnten zusätzlich zur Entstehung der PMR und RZA beitragen. Entscheidend für die Entzündungsreaktion ist die abnorme Reifung dendritischer Zellen in der Gefäßwand. Aktivierte dendritische Zellen rekrutieren bei der RZA (nicht aber bei der PMR) IFN-γ produzierenden CD4+ T-Zellen und Makrophagen in die Gefäßwand, welche durch Produktion von Matrix Metalloproetinasen eine Zerstörung der glatten Muskelzellen und eine Fragmentierung der Membrana elastica interna hervorrufen. Wachstumsfaktoren wie Platelet-derived growth factor (PDGF) und Vascular endothelial growth factor (VEGF) welche im nachfolgenden Reparationsprozess sezerniert werden, rufen einen Intimahyperplasie hervor, die schlussendlich zum Verschluss des betroffenen Gefäßes führt.

Abstract

Polymyalgia rheumatica (PMR) and giant-cell arteritis (GCA) are closely related conditions with unclear aetiology. Genetic factors including female sex and polymorphisms in the HLA II gene, adhesion molecules and chemokines, as well as infections may play important roles in the pathogenesis of the disease. Serological and tissue analyses for viral and bacterial agents (including Parvovirus B19 and Chlamydia pneumoniae), however, revealed conflicting results. Age-related changes of the immune and vascular system with the accumulation of pro-inflammatory cytokines and oxidative end-products as well as abnormalities in the endocrine axes (e. g., inadequate low endogenous cortisol production, loss of androgens) may all together contribute to the disease process. In GCA but not in PMR, abnormal maturation of dendritic cells leads to the recruitment of IFN-γ producing CD4+ T-cells and macrophages into the vessel wall. Macrophages produce matrix metalloproteinases causing a destruction of small muscle cells and the internal elastic membrane. They also release growth factors including platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) leading to intima hyperplasia and vascular occlusion.

Schlüsselwörter

Polymyalgia rheumatica - Riesenzellarteritis - T-Zellen - Ätiologie

Key words

polymyalgia rheumatica - giant cell arteritis - T-cells - etiology

• Literatur

• 1 Weyand CM, Goronzy JJ. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol 2013; 9: 731-740
• 2 Duftner C, Dejaco C, Schirmer M. Polymyalgia rheumatica. Internist (Berl) 2009; 50: 51-59
• 3 Cimmino MA, Zaccaria A. Epidemiology of polymyalgia rheumatica. Clin Exp Rheumatol n. d. 18: S9-S11
• 4 Dejaco C, Duftner C, Schirmer M. Recent advances in polymyalgia rheumatica. MMW. Fortschr Med 2012; 154: 54-57
• 5 Combe B, Sany J, Le Quellec A et al. Distribution of HLA-DRB1 alleles of patients with polymyalgia rheumatica and giant cell arteritis in a Mediterranean population. J Rheumatol 1998; 25: 94-98
• 6 Dababneh A, Gonzalez-Gay MA, Garcia-Porrua C et al. Giant cell arteritis and polymyalgia rheumatica can be differentiated by distinct patterns of HLA class II association. J Rheumatol 1998; 25: 2140-2145
• 7 Haworth S, Ridgeway J, Stewart I et al. Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404. Br J Rheumatol 1996; 35: 632-635
• 8 Salvarani C, Casali B, Boiardi L et al. Intercellular adhesion molecule 1 gene polymorphisms in polymyalgia rheumatica/giant cell arteritis: association with disease risk and severity. J Rheumatol 2000; 27: 1215-1221
• 9 Coll-Vinent B, Vilardell C, Font C et al. Circulating soluble adhesion molecules in patients with giant cell arteritis. Correlation between soluble intercellular adhesion molecule-1 (sICAM-1) concentrations and disease activity. Ann Rheum Dis 1999; 58: 189-192
• 10 Remahl AIMN, Bratt J, Möllby H et al. Comparison of soluble ICAM-1, VCAM-1 and E-selectin levels in patients with episodic cluster headache and giant cell arteritis. Cephalalgia 2008; 28: 157-163
• 11 Makki RF, al Sharif F, González-Gay MA et al. RANTES gene polymorphism in polymyalgia rheumatica, giant cell arteritis and rheumatoid arthritis. Clin Exp Rheumatol n. d. 18: 391-393
• 12 Doran MF, Crowson CS, O’Fallon WM et al. Trends in the incidence of polymyalgia rheumatica over a 30 year period in Olmsted County, Minnesota, USA. J Rheumatol 2002; 29: 1694-1697
• 13 Salvarani C, Gabriel SE, O’Fallon WM et al. The incidence of giant cell arteritis in Olmsted County, Minnesota: apparent fluctuations in a cyclic pattern. Ann Intern Med. 1995. 123. 192-194
• 14 Lidar M, Lipschitz N, Langevitz P et al. Infectious serologies and autoantibodies in Wegener’s granulomatosis and other vasculitides: novel associations disclosed using the Rad BioPlex 2200. Ann N Y Acad Sci 2009; 1173: 649-657
• 15 Hemauer A, Modrow S, Georgi J et al. There is no association between polymyalgia rheumatica and acute parvovirus B19 infection. Ann Rheum Dis 1999; 58: 657
• 16 Duhaut P, Bosshard S, Calvet A et al. Giant cell arteritis, polymyalgia rheumatica, and viral hypotheses: a multicenter, prospective case-control study. Groupe de Recherche sur l’Artérite à Cellules Géantes. J Rheumatol 1999; 26: 361-369
• 17 Helweg-Larsen J, Tarp B, Obel N et al. No evidence of parvovirus B19, Chlamydia pneumoniae or human herpes virus infection in temporal artery biopsies in patients with giant cell arteritis. Rheumatology (Oxford) 2002; 41: 445-449
• 18 Cimmino MA, Grazi G, Balistreri M et al. Increased prevalence of antibodies to adenovirus and respiratory syncytial virus in polymyalgia rheumatica. Clin Exp Rheumatol n. d. 11: 309-313
• 19 Uddhammar A, Boman J, Juto P et al. Antibodies against Chlamydia pneumoniae, cytomegalovirus, enteroviruses and respiratory syncytial virus in patients with polymyalgia rheumatica. Clin Exp Rheumatol 15: 299-302
• 20 Gabriel SE, Espy M, Erdman DD et al. The role of parvovirus B19 in the pathogenesis of giant cell arteritis: a preliminary evaluation. Arthritis Rheum 1999; 42: 1255-1258
• 21 Salvarani C, Farnetti E, Casali B et al. Detection of parvovirus B19 DNA by polymerase chain reaction in giant cell arteritis: a case-control study. Arthritis Rheum 2002; 46: 3099-3101
• 22 Helweg-Larsen J, Tarp B, Obel N et al. No evidence of parvovirus B19, Chlamydia pneumoniae or human herpes virus infection in temporal artery biopsies in patients with giant cell arteritis. Rheumatology (Oxford) 2002; 41: 445-449
• 23 Rodriguez-Pla A, Bosch-Gil JA, Echevarria-Mayo JE et al. No detection of parvovirus B19 or herpesvirus DNA in giant cell arteritis. J Clin Virol 2004; 31: 11-15
• 24 Wagner AD, Gérard HC, Fresemann T et al. Detection of Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating dendritic cells. Arthritis Rheum 2000; 43: 1543-1551
• 25 Njau F, Ness T, Wittkop U et al. No correlation between giant cell arteritis and Chlamydia pneumoniae infection: investigation of 189 patients by standard and improved PCR methods. J Clin Microbiol 2009; 47: 1899-1901
• 26 Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature 1998; 392: 245-252
• 27 Steinman RM, Nussenzweig MC. Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 2002; 99: 351-358
• 28 Pryshchep O, Ma-Krupa W, Younge BR et al. Vessel-specific Toll-like receptor profiles in human medium and large arteries. Circulation 2008; 118: 1276-1284
• 29 Raffeiner B, Dejaco C, Duftner C et al. Between adaptive and innate immunity: TLR4-mediated perforin production by CD28null T-helper cells in ankylosing spondylitis. Arthritis Res Ther 2005; 7: R1412-R1420
• 30 Mohan SV, Liao YJ, Kim JW et al. Giant cell arteritis: immune and vascular aging as disease risk factors. Arthritis Res Ther 2011; 13: 231
• 31 Wagner AD, Björnsson J, Bartley GB et al. Interferon-gamma-producing T cells in giant cell vasculitis represent a minority of tissue-infiltrating cells and are located distant from the site of pathology. Am J Pathol 1996; 148: 1925-1933
• 32 Weyand CM, Hicok KC, Hunder GG et al. Tissue cytokine patterns in patients with polymyalgia rheumatica and giant cell arteritis. Ann Intern Med 1994; 121: 484-491
• 33 Dejaco C, Duftner C, Dasgupta B et al. Polymyalgia rheumatica and giant cell arteritis: management of two diseases of the elderly. Aging Health 2011; 7: 633-645
• 34 Deng J, Younge BR, Olshen RA et al. Th17 and Th1 T-cell responses in giant cell arteritis. Circulation 2010; 121: 906-915
• 35 Kaiser M, Weyand CM, Björnsson J et al. Platelet-derived growth factor, intimal hyperplasia, and ischemic complications in giant cell arteritis. Arthritis Rheum 1998; 41: 623-633
• 36 Kaiser M, Younge B, Björnsson J et al. Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. Am J Pathol 1999; 155: 765-774
• 37 Rittner HL, Hafner V, Klimiuk PA et al. Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis. J Clin Invest 1999; 103: 1007-1013
• 38 Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008; 372: 234-245
• 39 Uddhammar A, Sundqvist KG, Ellis B et al. Cytokines and adhesion molecules in patients with polymyalgia rheumatica. Br J Rheumatol 1998; 37: 766-769
• 40 Roche NE, Fulbright JW, Wagner AD et al. Correlation of interleukin-6 production and disease activity in polymyalgia rheumatica and giant cell arteritis. Arthritis Rheum 1993; 36: 1286-1294
• 41 Straub RH, Herfarth HH, Rinkes B et al. Favorable role of interleukin 10 in patients with polymyalgia rheumatica. J Rheumatol 1999; 26: 1318-1325
• 42 Chatelain D, Duhaut P, Loire R et al. Small-vessel vasculitis surrounding an uninflamed temporal artery: a new diagnostic criterion for polymyalgia rheumatica?. Arthritis Rheum 2008; 58: 2565-2573
• 43 Campisi J, d’Adda di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 2007; 8: 729-740
• 44 Lee H-Y, Oh B-H. Aging and arterial stiffness. Circ J 2010; 74: 2257-2262
• 45 Gouspillou G, Bourdel-Marchasson I, Rouland R et al. Alteration of mitochondrial oxidative phosphorylation in aged skeletal muscle involves modification of adenine nucleotide translocator. Biochim Biophys Acta 2010; 1797: 143-151
• 46 Sawabe M. Vascular aging: from molecular mechanism to clinical significance. Geriatr Gerontol Int 2010; 10 (Suppl. 01) S213-S220
• 47 Straub RH, Cutolo M. Further evidence for insufficient hypothalamic-pituitary-glandular axes in polymyalgia rheumatica. J Rheumatol 2006; 33: 1219-1223
• 48 Nilsson E, de la Torre B, Hedman M et al. Blood dehydroepiandrosterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell arteritis and primary fibromyalgia. Clin Exp Rheumatol n. d. 12: 415-417
• 49 Zietz B, Reber T, Oertel M et al. Altered function of the hypothalamic stress axes in patients with moderately active systemic lupus erythematosus. II. Dissociation between androstenedione, cortisol, or dehydroepiandrosterone and interleukin 6 or tumor necrosis factor. J Rheumatol 2000; 27: 911-918
• 50 Van den Brink HR, Blankenstein MA, Koppeschaar HP et al. Influence of disease activity on steroid hormone levels in peripheral blood of patients with rheumatoid arthritis. Clin Exp Rheumatol n. d. 11: 649-652
• 51 Johnson EO, Vlachoyiannopoulos PG, Skopouli FN et al. Hypofunction of the stress axis in Sjögren’s syndrome. J Rheumatol 1998; 25: 1508-1514
• 52 Narváez J, Bernad B, Díaz Torné C et al. Low serum levels of DHEAS in untreated polymyalgia rheumatica/giant cell arteritis. J Rheumatol 2006; 33: 1293-1298
• 53 Späth-Schwalbe E, Born J, Schrezenmeier H et al. Interleukin-6 stimulates the hypothalamus-pituitary-adrenocortical axis in man. J Clin Endocrinol Metab 1994; 79: 1212-1214
• 54 Ehrhart-Bornstein M, Hinson JP, Bornstein SR et al. Intraadrenal interactions in the regulation of adrenocortical steroidogenesis. Endocr Rev 1998; 19: 101-143
• 55 Bhatt AS, Manzo VE, Pedamallu CS et al. In search of a candidate pathogen for giant cell arteritis: Sequencing based characterization of the giant cell arteritis microbiome. Arthritis Rheumatol (Hoboken, NJ) 2014; [Epub ahead of print]
• 56 Brusca SB, Abramson SB, Scher JU. Microbiome and mucosal inflammation as extra-articular triggers for rheumatoid arthritis and autoimmunity. Curr Opin Rheumatol 2014; 26: 101-107
• 57 Nadkarni S, Dalli J, Hollywood J et al. Investigational analysis reveals a potential role for neutrophils in giant-cell arteritis disease progression. Circ Res 2014; 114: 242-248
• 58 Mihm B, Bergmann M, Brück W et al. The activation pattern of macrophages in giant cell (temporal) arteritis and primary angiitis of the central nervous system. Neuropathology 2013; [Epub ahead of print]
• 59 Van der Geest KSM, Abdulahad WH, Chalan P et al. Disturbed B cell homeostasis in patients with newly-diagnosed giant cell arteritis and polymyalgia rheumatica. Arthritis Rheumatol (Hoboken, NJ) 2014; [Epub ahead of print]
• 60 Dejaco C, Duftner C, Al-Massad J et al. NKG2D stimulated T-cell autoreactivity in giant cell arteritis and polymyalgia rheumatica. Ann Rheum Dis 2013; 72: 1852-1859
• 61 Unizony S, Stone JH, Stone JR. New treatment strategies in large-vessel vasculitis. Curr Opin Rheumatol 2013; 25: 3-9
• 62 Kermani TA, Warrington KJ. Advances and challenges in the diagnosis and treatment of polymyalgia rheumatica. Ther Adv Musculoskelet Dis 2014; 6: 8-19