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Erschienen in: Arthritis Research & Therapy 1/2010

01.04.2010 | Review

Type 1 interferons and myositis

verfasst von: Steven A Greenberg

Erschienen in: Arthritis Research & Therapy | Sonderheft 1/2010

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Abstract

Recent studies suggest a mechanistic role for molecules induced by type 1 interferons in the pathogenesis of some forms of myositis. For dermatomyositis, evidence that these molecules injure myofibers seems especially strong. In the group of disorders known as polymyositis, the study of blood samples suggests a potential role. It is unknown what drives the sustained presence of type 1 interferon-inducible molecules in these diseases, as the type 1 interferons themselves have not been specifically detected along with their downstream biomarkers. Therapeutic development for blockade of IFNα is in progress aided by the identification of blood genomic biomarkers.
Literatur
1.
Zurück zum Zitat Greenberg SA: Inflammatory myopathies: disease mechanisms. Curr Opin Neurol. 2009, 22: 516-523. 10.1097/WCO.0b013e3283311ddf.CrossRefPubMed Greenberg SA: Inflammatory myopathies: disease mechanisms. Curr Opin Neurol. 2009, 22: 516-523. 10.1097/WCO.0b013e3283311ddf.CrossRefPubMed
2.
Zurück zum Zitat Salajegheh M, Kong SW, Pinkus JL, Walsh RJ, Liao A, Nazareno R, Amato AA, Krastins B, Morehouse C, Higgs BW, Jallal B, Yao Y, Sarracino DA, Parker KC, Greenberg SA: Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy. Ann Neurol. 2009, 67: 53-63. 10.1002/ana.21805.CrossRef Salajegheh M, Kong SW, Pinkus JL, Walsh RJ, Liao A, Nazareno R, Amato AA, Krastins B, Morehouse C, Higgs BW, Jallal B, Yao Y, Sarracino DA, Parker KC, Greenberg SA: Interferon-stimulated gene 15 (ISG15) conjugates proteins in dermatomyositis muscle with perifascicular atrophy. Ann Neurol. 2009, 67: 53-63. 10.1002/ana.21805.CrossRef
3.
Zurück zum Zitat Greenberg SA: Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Neurology. 2007, 69: 2008-2019. 10.1212/01.WNL.0000291619.17160.b8.CrossRefPubMed Greenberg SA: Proposed immunologic models of the inflammatory myopathies and potential therapeutic implications. Neurology. 2007, 69: 2008-2019. 10.1212/01.WNL.0000291619.17160.b8.CrossRefPubMed
4.
Zurück zum Zitat Isenberg DA, Rowe D, Shearer M, Novick D, Beverley PC: Localization of interferons and interleukin 2 in polymyositis and muscular dystrophy. Clin Exp Immunol. 1986, 63: 450-458.PubMedCentralPubMed Isenberg DA, Rowe D, Shearer M, Novick D, Beverley PC: Localization of interferons and interleukin 2 in polymyositis and muscular dystrophy. Clin Exp Immunol. 1986, 63: 450-458.PubMedCentralPubMed
5.
Zurück zum Zitat Emslie-Smith AM, Arahata K, Engel AG: Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies. Hum Pathol. 1989, 20: 224-231. 10.1016/0046-8177(89)90128-7.CrossRefPubMed Emslie-Smith AM, Arahata K, Engel AG: Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies. Hum Pathol. 1989, 20: 224-231. 10.1016/0046-8177(89)90128-7.CrossRefPubMed
6.
Zurück zum Zitat Lundberg I, Brengman JM, Engel AG: Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne dystrophy, and non-weak controls. J Neuroimmunol. 1995, 63: 9-16. 10.1016/0165-5728(95)00122-0.CrossRefPubMed Lundberg I, Brengman JM, Engel AG: Analysis of cytokine expression in muscle in inflammatory myopathies, Duchenne dystrophy, and non-weak controls. J Neuroimmunol. 1995, 63: 9-16. 10.1016/0165-5728(95)00122-0.CrossRefPubMed
7.
Zurück zum Zitat Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF: Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve. 2003, 28: 659-682. 10.1002/mus.10462.CrossRefPubMed Figarella-Branger D, Civatte M, Bartoli C, Pellissier JF: Cytokines, chemokines, and cell adhesion molecules in inflammatory myopathies. Muscle Nerve. 2003, 28: 659-682. 10.1002/mus.10462.CrossRefPubMed
8.
Zurück zum Zitat Salomonsson S, Lundberg IE: Cytokines in idiopathic inflammatory myopathies. Autoimmunity. 2006, 39: 177-190. 10.1080/08916930600622256.CrossRefPubMed Salomonsson S, Lundberg IE: Cytokines in idiopathic inflammatory myopathies. Autoimmunity. 2006, 39: 177-190. 10.1080/08916930600622256.CrossRefPubMed
9.
Zurück zum Zitat Schmidt J, Barthel K, Wrede A, Salajegheh M, Bahr M, Dalakas MC: Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain. 2008, 131 (Pt 5): 1228-1240.PubMedCentralPubMed Schmidt J, Barthel K, Wrede A, Salajegheh M, Bahr M, Dalakas MC: Interrelation of inflammation and APP in sIBM: IL-1 beta induces accumulation of beta-amyloid in skeletal muscle. Brain. 2008, 131 (Pt 5): 1228-1240.PubMedCentralPubMed
10.
Zurück zum Zitat Banker BQ: Dermatomyostis of childhood, ultrastructural alteratious of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol. 1975, 34: 46-75. 10.1097/00005072-197501000-00005.CrossRefPubMed Banker BQ: Dermatomyostis of childhood, ultrastructural alteratious of muscle and intramuscular blood vessels. J Neuropathol Exp Neurol. 1975, 34: 46-75. 10.1097/00005072-197501000-00005.CrossRefPubMed
12.
Zurück zum Zitat Grimley PM, Davis GL, Kang YH, Dooley JS, Strohmaier J, Hoofnagle JH: Tubuloreticular inclusions in peripheral blood mononuclear cells related to systemic therapy with alpha-interferon. Lab Invest. 1985, 52: 638-649.PubMed Grimley PM, Davis GL, Kang YH, Dooley JS, Strohmaier J, Hoofnagle JH: Tubuloreticular inclusions in peripheral blood mononuclear cells related to systemic therapy with alpha-interferon. Lab Invest. 1985, 52: 638-649.PubMed
13.
Zurück zum Zitat Rich SA, Owens TR, Bartholomew LE, Gutterman JU: Immune interferon does not stimulate formation of alpha and beta interferon induced human lupus-type inclusions. Lancet. 1983, 1: 127-128. 10.1016/S0140-6736(83)91771-3.CrossRefPubMed Rich SA, Owens TR, Bartholomew LE, Gutterman JU: Immune interferon does not stimulate formation of alpha and beta interferon induced human lupus-type inclusions. Lancet. 1983, 1: 127-128. 10.1016/S0140-6736(83)91771-3.CrossRefPubMed
14.
Zurück zum Zitat Grimley PM, Rutherford MN, Kang YH, Williams T, Woody JN, Silverman RH: Formation of tubuloreticular inclusions in human lymphoma cells compared to the induction of 2'-5'-oligoadenylate synthetase by leucocyte interferon in dose-effect and kinetic studies. Cancer Res. 1984, 44: 3480-3488.PubMed Grimley PM, Rutherford MN, Kang YH, Williams T, Woody JN, Silverman RH: Formation of tubuloreticular inclusions in human lymphoma cells compared to the induction of 2'-5'-oligoadenylate synthetase by leucocyte interferon in dose-effect and kinetic studies. Cancer Res. 1984, 44: 3480-3488.PubMed
15.
Zurück zum Zitat Kuyama J, Kanayama Y, Mizutani H, Katagiri S, Tamaki T, Yonezawa T, Tarui S, Morise H, Arimura H, Suyama T: Formation of tubuloreticular inclusions in mitogen-stimulated human lymphocyte cultures by endogenous or exogenous alpha-interferon. Ultrastruct Pathol. 1986, 10: 77-85. 10.3109/01913128609015565.CrossRefPubMed Kuyama J, Kanayama Y, Mizutani H, Katagiri S, Tamaki T, Yonezawa T, Tarui S, Morise H, Arimura H, Suyama T: Formation of tubuloreticular inclusions in mitogen-stimulated human lymphocyte cultures by endogenous or exogenous alpha-interferon. Ultrastruct Pathol. 1986, 10: 77-85. 10.3109/01913128609015565.CrossRefPubMed
16.
Zurück zum Zitat Feldman D, Goldstein AL, Cox DC, Grimley PM: Cultured human endothelial cells treated with recombinant leukocyte A interferon. Tubuloreticular inclusion formation, antiproliferative effect, and 2',5' oligoadenylate synthetase induction. Lab Invest. 1988, 58: 584-589.PubMed Feldman D, Goldstein AL, Cox DC, Grimley PM: Cultured human endothelial cells treated with recombinant leukocyte A interferon. Tubuloreticular inclusion formation, antiproliferative effect, and 2',5' oligoadenylate synthetase induction. Lab Invest. 1988, 58: 584-589.PubMed
17.
Zurück zum Zitat Greenberg SA, Amato AA: Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol. 2004, 17: 359-364. 10.1097/00019052-200406000-00018.CrossRefPubMed Greenberg SA, Amato AA: Uncertainties in the pathogenesis of adult dermatomyositis. Curr Opin Neurol. 2004, 17: 359-364. 10.1097/00019052-200406000-00018.CrossRefPubMed
18.
Zurück zum Zitat Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, Tawil R, Barohn RJ, Saperstein DS, Briemberg HR, Ericsson M, Park P, Amato AA: Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol. 2005, 57: 664-678. 10.1002/ana.20464.CrossRefPubMed Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, Tawil R, Barohn RJ, Saperstein DS, Briemberg HR, Ericsson M, Park P, Amato AA: Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis. Ann Neurol. 2005, 57: 664-678. 10.1002/ana.20464.CrossRefPubMed
19.
Zurück zum Zitat Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, Beggs AH, Amato AA, Greenberg SA: Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Arthritis Rheum. 2007, 56: 3784-3792. 10.1002/art.22928.PubMedCentralCrossRefPubMed Walsh RJ, Kong SW, Yao Y, Jallal B, Kiener PA, Pinkus JL, Beggs AH, Amato AA, Greenberg SA: Type I interferon-inducible gene expression in blood is present and reflects disease activity in dermatomyositis and polymyositis. Arthritis Rheum. 2007, 56: 3784-3792. 10.1002/art.22928.PubMedCentralCrossRefPubMed
20.
Zurück zum Zitat Kea B, Pesich R, Chung LS, Brown PO, Fiorentino D: Genomic analyses identify lipid metabolism abnormalities in dermatomyositis patients [abstract]. J Invest Dermatol. 2007, 127 (Suppl 1): S12- Kea B, Pesich R, Chung LS, Brown PO, Fiorentino D: Genomic analyses identify lipid metabolism abnormalities in dermatomyositis patients [abstract]. J Invest Dermatol. 2007, 127 (Suppl 1): S12-
21.
Zurück zum Zitat Greenberg SA, Fiorentino D: Similar topology of injury to keratinocytes and myofibres in dermatomyositis skin and muscle. Br J Dermatol. 2009, 160: 464-465. 10.1111/j.1365-2133.2008.08967.x.CrossRefPubMed Greenberg SA, Fiorentino D: Similar topology of injury to keratinocytes and myofibres in dermatomyositis skin and muscle. Br J Dermatol. 2009, 160: 464-465. 10.1111/j.1365-2133.2008.08967.x.CrossRefPubMed
22.
Zurück zum Zitat Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, Fujita T, Kuwana M: RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum. 2009, 60: 2193-2200. 10.1002/art.24621.CrossRefPubMed Sato S, Hoshino K, Satoh T, Fujita T, Kawakami Y, Fujita T, Kuwana M: RNA helicase encoded by melanoma differentiation-associated gene 5 is a major autoantigen in patients with clinically amyopathic dermatomyositis: association with rapidly progressive interstitial lung disease. Arthritis Rheum. 2009, 60: 2193-2200. 10.1002/art.24621.CrossRefPubMed
23.
Zurück zum Zitat Baechler EC, Bauer JW, Slattery CA, Ortmann WA, Espe KJ, Novitzke J, Ytterberg SR, Gregersen PK, Behrens TW, Reed AM: An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity. Mol Med. 2007, 13: 59-68. 10.2119/2006-00085.Baechler.PubMedCentralCrossRefPubMed Baechler EC, Bauer JW, Slattery CA, Ortmann WA, Espe KJ, Novitzke J, Ytterberg SR, Gregersen PK, Behrens TW, Reed AM: An interferon signature in the peripheral blood of dermatomyositis patients is associated with disease activity. Mol Med. 2007, 13: 59-68. 10.2119/2006-00085.Baechler.PubMedCentralCrossRefPubMed
24.
Zurück zum Zitat Hooks JJ, Jordan GW, Cupps T, Moutsopoulos HM, Fauci AS, Notkins AL: Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis. Arthritis Rheum. 1982, 25: 396-400. 10.1002/art.1780250406.CrossRefPubMed Hooks JJ, Jordan GW, Cupps T, Moutsopoulos HM, Fauci AS, Notkins AL: Multiple interferons in the circulation of patients with systemic lupus erythematosus and vasculitis. Arthritis Rheum. 1982, 25: 396-400. 10.1002/art.1780250406.CrossRefPubMed
25.
Zurück zum Zitat Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL: Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979, 301: 5-8. 10.1056/NEJM197907053010102.CrossRefPubMed Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL: Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med. 1979, 301: 5-8. 10.1056/NEJM197907053010102.CrossRefPubMed
26.
Zurück zum Zitat Preble OT, Black RJ, Friedman RM, Klippel JH, Vilcek J: Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science. 1982, 216: 429-431. 10.1126/science.6176024.CrossRefPubMed Preble OT, Black RJ, Friedman RM, Klippel JH, Vilcek J: Systemic lupus erythematosus: presence in human serum of an unusual acid-labile leukocyte interferon. Science. 1982, 216: 429-431. 10.1126/science.6176024.CrossRefPubMed
27.
Zurück zum Zitat Ytterberg SR, Schnitzer TJ: Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 1982, 25: 401-406. 10.1002/art.1780250407.CrossRefPubMed Ytterberg SR, Schnitzer TJ: Serum interferon levels in patients with systemic lupus erythematosus. Arthritis Rheum. 1982, 25: 401-406. 10.1002/art.1780250407.CrossRefPubMed
28.
Zurück zum Zitat Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA. 2003, 100: 2610-2615. 10.1073/pnas.0337679100.PubMedCentralCrossRefPubMed Baechler EC, Batliwalla FM, Karypis G, Gaffney PM, Ortmann WA, Espe KJ, Shark KB, Grande WJ, Hughes KM, Kapur V, Gregersen PK, Behrens TW: Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci USA. 2003, 100: 2610-2615. 10.1073/pnas.0337679100.PubMedCentralCrossRefPubMed
29.
Zurück zum Zitat Hua J, Kirou K, Lee C, Crow MK: Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum. 2006, 54: 1906-1916. 10.1002/art.21890.CrossRefPubMed Hua J, Kirou K, Lee C, Crow MK: Functional assay of type I interferon in systemic lupus erythematosus plasma and association with anti-RNA binding protein autoantibodies. Arthritis Rheum. 2006, 54: 1906-1916. 10.1002/art.21890.CrossRefPubMed
30.
Zurück zum Zitat Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T: Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000, 13: 539-548. 10.1016/S1074-7613(00)00053-4.CrossRefPubMed Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T: Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000, 13: 539-548. 10.1016/S1074-7613(00)00053-4.CrossRefPubMed
31.
Zurück zum Zitat Sato M, Tanaka N, Hata N, Oda E, Taniguchi T: Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene. FEBS Lett. 1998, 425: 112-116. 10.1016/S0014-5793(98)00210-5.CrossRefPubMed Sato M, Tanaka N, Hata N, Oda E, Taniguchi T: Involvement of the IRF family transcription factor IRF-3 in virus-induced activation of the IFN-beta gene. FEBS Lett. 1998, 425: 112-116. 10.1016/S0014-5793(98)00210-5.CrossRefPubMed
32.
Zurück zum Zitat Marie I, Durbin JE, Levy DE: Differential viral induction of distinct interferonalpha genes by positive feedback through interferon regulatory factor-7. Embo J. 1998, 17: 6660-6669. 10.1093/emboj/17.22.6660.PubMedCentralCrossRefPubMed Marie I, Durbin JE, Levy DE: Differential viral induction of distinct interferonalpha genes by positive feedback through interferon regulatory factor-7. Embo J. 1998, 17: 6660-6669. 10.1093/emboj/17.22.6660.PubMedCentralCrossRefPubMed
33.
Zurück zum Zitat Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N: Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 1998, 441: 106-110. 10.1016/S0014-5793(98)01514-2.CrossRefPubMed Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N: Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 1998, 441: 106-110. 10.1016/S0014-5793(98)01514-2.CrossRefPubMed
34.
Zurück zum Zitat Niewold TB, Kariuki SN, Morgan GA, Shrestha S, Pachman LM: Elevated serum interferon-alpha activity in juvenile dermatomyositis: associations with disease activity at diagnosis and after thirty-six months of therapy. Arthritis Rheum. 2009, 60: 1815-1824. 10.1002/art.24555.PubMedCentralCrossRefPubMed Niewold TB, Kariuki SN, Morgan GA, Shrestha S, Pachman LM: Elevated serum interferon-alpha activity in juvenile dermatomyositis: associations with disease activity at diagnosis and after thirty-six months of therapy. Arthritis Rheum. 2009, 60: 1815-1824. 10.1002/art.24555.PubMedCentralCrossRefPubMed
35.
Zurück zum Zitat Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J: Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA. 2005, 102: 3372-3377. 10.1073/pnas.0408506102.PubMedCentralCrossRefPubMed Palucka AK, Blanck JP, Bennett L, Pascual V, Banchereau J: Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA. 2005, 102: 3372-3377. 10.1073/pnas.0408506102.PubMedCentralCrossRefPubMed
36.
Zurück zum Zitat Mavragani CP, Niewold TB, Moutsopoulos NM, Pillemer SR, Wahl SM, Crow MK: Augmented interferon-alpha pathway activation in patients with Sjogren's syndrome treated with etanercept. Arthritis Rheum. 2007, 56: 3995-4004. 10.1002/art.23062.PubMedCentralCrossRefPubMed Mavragani CP, Niewold TB, Moutsopoulos NM, Pillemer SR, Wahl SM, Crow MK: Augmented interferon-alpha pathway activation in patients with Sjogren's syndrome treated with etanercept. Arthritis Rheum. 2007, 56: 3995-4004. 10.1002/art.23062.PubMedCentralCrossRefPubMed
37.
Zurück zum Zitat Hengstman GJ, De Bleecker JL, Feist E, Vissing J, Denton CP, Manoussakis MN, Slott Jensen H, van Engelen BG, Hoogen van den FH: Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate. Eur Neurol. 2008, 59: 159-163. 10.1159/000114036.CrossRefPubMed Hengstman GJ, De Bleecker JL, Feist E, Vissing J, Denton CP, Manoussakis MN, Slott Jensen H, van Engelen BG, Hoogen van den FH: Open-label trial of anti-TNF-alpha in dermato- and polymyositis treated concomitantly with methotrexate. Eur Neurol. 2008, 59: 159-163. 10.1159/000114036.CrossRefPubMed
38.
Zurück zum Zitat Dastmalchi M, Grundtman C, Alexanderson H, Mavragani CP, Einarsdottir H, Helmers SB, Elvin K, Crow MK, Nennesmo I, Lundberg IE: A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis. 2008, 67: 1670-1677. 10.1136/ard.2007.077974.CrossRefPubMed Dastmalchi M, Grundtman C, Alexanderson H, Mavragani CP, Einarsdottir H, Helmers SB, Elvin K, Crow MK, Nennesmo I, Lundberg IE: A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies. Ann Rheum Dis. 2008, 67: 1670-1677. 10.1136/ard.2007.077974.CrossRefPubMed
Metadaten
Titel
Type 1 interferons and myositis
verfasst von
Steven A Greenberg
Publikationsdatum
01.04.2010
Verlag
BioMed Central
Erschienen in
Arthritis Research & Therapy / Ausgabe Sonderheft 1/2010
Elektronische ISSN: 1478-6362
DOI
https://doi.org/10.1186/ar2885

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