Pneumologie 2016; 70(04): 231-240
DOI: 10.1055/s-0041-108311
Serie: Translationale Forschung in der Pneumologie
© Georg Thieme Verlag KG Stuttgart · New York

Neue pathogenetische Konzepte und frühe pharmakologische Studien bei der Sarkoidose

New Pathogenetic Concepts and Early Pharmacological Studies in Sarcoidosis
J. C. Schupp
Klinik für Pneumologie, Department Innere Medizin, Universitätsklinikum Freiburg
,
B. C. Frye
Klinik für Pneumologie, Department Innere Medizin, Universitätsklinikum Freiburg
,
G. Zissel
Klinik für Pneumologie, Department Innere Medizin, Universitätsklinikum Freiburg
,
J. Müller-Quernheim
Klinik für Pneumologie, Department Innere Medizin, Universitätsklinikum Freiburg
› Author Affiliations

Subject Editor: M. Witzenrath, Berlin
Further Information

Publication History

eingereicht 14 August 2015

akzeptiert nach Revision 16 October 2015

Publication Date:
03 March 2016 (online)

Zusammenfassung

Ziel dieser Übersichtsarbeit ist es, einen Überblick über aktuelle pathogenetische Konzepte und klinische Studien zur Sarkoidose zu geben. Es haben sich neue Erkenntnisse zu Pathomechanismen der Sarkoidose im Bereich der Granulombildung, der immunologischen Prozesse, der Autoimmunität und der Genetik ergeben. Neue Daten weisen Serum Amyloid A und/oder mykobakteriellen Antigenen als Nidus eine wichtige Rolle bei der Granulomentstehung zu. Auf der anderen Seite sind neue potenzielle Autoantigene gefunden worden, die auf eine mögliche wichtige Rolle der Autoimmunität hinweisen. Durch große genomweite Assoziationsstudien konnten diverse Risikogene gefunden werden, die auf völlig neue Aspekte der Pathogenese der Sarkoidose hinweisen.

Aktuell laufende und kürzlich abgeschlossene klinisch-pharmakologische Studien bei Patienten mit Sarkoidose lassen auf neue Möglichkeiten in der Therapie der Sarkoidose hoffen. In letzter Zeit wurden einige positive Studien zu gut charakterisierten und homogenen Patientensubgruppen veröffentlicht, bei denen mehrere Medikamente bei der Sarkoidose-assoziierten Fatigue, der Hautsarkoidose und der pulmonalen Hypertonie bei Sarkoidose positive Wirkungen zeigten. Es scheint, dass die Bildung homogener Subkohorten bei einer heterogenen Erkrankung wie der Sarkoidose notwendig dafür ist, dass klinische Studien erfolgreich sein können.

Abstract

The etiology of sarcoidosis is still elusive, yet there has been considerable progress in various areas of basic and clinical research. This review focuses on mechanisms of granuloma formation and on new findings in autoimmunity and genetics of sarcoidosis. A new promising concept arose, where serum amyloid A and/or mycobacterial antigens serve as nidus for granuloma formation. Furthermore, autoimmunity in sarcoidosis was neglected for a long time, yet new studies found autoantigens and abnormalities in antigen presentation in sarcoidosis. Last but not least, large genome-wide association studies discovered several new predisposing genes, leading to new hypotheses on pathomechanisms of sarcoidosis.

In the second part, we focus on ongoing or recently completed clinical-pharmacological studies in patients with sarcoidosis: Positive studies were published in well characterized and homogenous subcohorts of sarcoid patients. Several drugs have shown a positive effect on sarcoidosis-associated fatigue, on sarcoidosis of the skin and on pulmonary hypertension in sarcoid patients. It seems that the generation of clinically closely defined subcohorts is necessary to achieve positive outcomes in studies on sarcoidosis.

 
  • Literatur

  • 1 Chen ES, Moller DR. Etiologic role of infectious agents. Semin Respir Crit Care Med 2014; 35: 285-295
  • 2 Chen ES, Song Z, Willett MH et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 2010; 181: 360-373
  • 3 Song Z, Marzilli L, Greenlee BM et al. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005; 201: 755-767
  • 4 Chen ES, Wahlström J, Song Z et al. T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol 2008; 181: 8784-8796
  • 5 Dubaniewicz A, Dubaniewicz-Wybieralska M, Sternau A et al. Mycobacterium tuberculosis complex and mycobacterial heat shock proteins in lymph node tissue from patients with pulmonary sarcoidosis. J Clin Microbiol 2006; 44: 3448-3451
  • 6 Oswald-Richter KA, Beachboard DC, Seeley EH et al. Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL. J Clin Immunol 2012; 32: 1129-1140
  • 7 Maertzdorf J, Weiner J, Mollenkopf H-J et al. Common patterns and disease-related signatures in tuberculosis and sarcoidosis. Proc Natl Acad Sci U S A 2012; 109: 7853-7858
  • 8 Homma JY, Abe C, Chosa H et al. Bacteriological investigation on biopsy specimens from patients with sarcoidosis. Jpn J Exp Med 1978; 48: 251-255
  • 9 Eishi Y. Etiologic link between sarcoidosis and Propionibacterium acnes. Respir Investig 2013; 51: 56-68
  • 10 Schupp JC, Tchaptchet S, Lützen N et al. Immune response to Propionibacterium acnes in patients with sarcoidosis – in vivo and in vitro. BMC Pulm Med 2015; 15: 75
  • 11 Zissel G, Prasse A, Müller-Quernheim J. Immunologic response of sarcoidosis. Semin Respir Crit Care Med 2010; 31: 390-403
  • 12 Zissel G. Cellular activation in the immune response of sarcoidosis. Semin Respir Crit Care Med 2014; 35: 307-315
  • 13 Müller-Quernheim J, Zissel G, Prasse A. Sarcoidosis. In: Oxford Textbook of Rheumatology 2013; 1434-1441
  • 14 Wahlström J, Dengjel J, Persson B et al. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest 2007; 117: 3576-3582
  • 15 Wahlström J, Dengjel J, Winqvist O et al. Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. Clin Immunol 2009; 133: 353-363
  • 16 Hunninghake GW, Crystal RG. Mechanisms of hypergammaglobulinemia in pulmonary sarcoidosis. Site of increased antibody production and role of T lymphocytes. J Clin Invest 1981; 67: 86-92
  • 17 Häggmark A, Hamsten C, Wiklundh E et al. Proteomic profiling reveals autoimmune targets in sarcoidosis. Am J Respir Crit Care Med 2015; 191: 574-583
  • 18 Grunewald J. Genetics of sarcoidosis. Curr Opin Pulm Med 2008; 14: 434-439
  • 19 Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients. Am J Respir Crit Care Med 2004; 169: 696-702
  • 20 Schürmann M, Reichel P, Müller-Myhsok B et al. Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med 2001; 164: 840-846
  • 21 Valentonyte R, Hampe J, Huse K et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat Genet 2005; 37: 357-364
  • 22 Hofmann S, Franke A, Fischer A et al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat Genet 2008; 40: 1103-1106
  • 23 Hofmann S, Fischer A, Nothnagel M et al. Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis. Eur Respir J 2013; 41: 888-900
  • 24 Hofmann S, Fischer A, Till A et al. A genome-wide association study reveals evidence of association with sarcoidosis at 6p12.1. Eur Respir J 2011; 38: 1127-1135
  • 25 Hosokawa N, Kamiya Y, Kamiya D et al. Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation, recognizes mannose-trimmed N-glycans. J Biol Chem 2009; 284: 17061-17068
  • 26 Evans TM, Simpson F, Parton RG et al. Characterization of Rab23, a negative regulator of sonic hedgehog signaling. Methods Enzymol 2005; 403: 759-777
  • 27 Bartee E, Mansouri M, Hovey Nerenberg BT et al. Downregulation of Major Histocompatibility Complex Class I by Human Ubiquitin Ligases Related to Viral Immune Evasion Proteins. J Virol 2004; 78: 1109-1120
  • 28 Zissel G, Ernst M, Schlaak M et al. Accessory function of alveolar macrophages from patients with sarcoidosis and other granulomatous and nongranulomatous lung diseases. J Investig Med 1997; 45: 75-86
  • 29 Adrianto I, Lin CP, Hale JJ et al. Genome-wide association study of African and European Americans implicates multiple shared and ethnic specific loci in sarcoidosis susceptibility. PLoS One 2012; 7: e43907
  • 30 Fischer A, Ellinghaus D, Nutsua M et al. Identification of Immune-relevant Factors Conferring Sarcoidosis Genetic Risk. Am J Respir Crit Care Med 2015; 192: 727-736
  • 31 Fischer A, Grunewald J, Spagnolo P et al. Genetics of sarcoidosis. Semin Respir Crit Care Med 2014; 35: 296-306
  • 32 Fischer A, Zissel G, Nebel A et al. [Genetic risk profile of sarcoidosis]. Internist (Berl) 2014; 55: 135-140
  • 33 Lower EE, Harman S, Baughman RP. Double-blind, randomized trial of dexmethylphenidate hydrochloride for the treatment of sarcoidosis-associated fatigue. Chest 2008; 133: 1189-1195
  • 34 Lower EE, Malhotra A, Surdulescu V et al. Armodafinil for sarcoidosis-associated fatigue: a double-blind, placebo-controlled, crossover trial. J Pain Symptom Manage 2013; 45: 159-169
  • 35 Baughman RP, Judson MA, Ingledue R et al. Efficacy and safety of apremilast in chronic cutaneous sarcoidosis. Arch Dermatol 2012; 148: 262-264
  • 36 Pariser RJ, Paul J, Hirano S et al. A double-blind, randomized, placebo-controlled trial of adalimumab in the treatment of cutaneous sarcoidosis. J Am Acad Dermatol 2013; 68: 765-773
  • 37 Heij L, Niesters M, Swartjes M et al. Safety and efficacy of ARA 290 in sarcoidosis patients with symptoms of small fiber neuropathy: a randomized, double-blind pilot study. Mol Med 2012; 18: 1430-1436
  • 38 Dahan A, Dunne A, Swartjes M et al. ARA 290 improves symptoms in patients with sarcoidosis-associated small nerve fiber loss and increases corneal nerve fiber density. Mol Med 2013; 19: 334-345
  • 39 Baughman RP, Culver DA, Cordova FC et al. Bosentan for sarcoidosis-associated pulmonary hypertension: a double-blind placebo controlled randomized trial. Chest 2014; 145: 810-817
  • 40 Judson MA, Highland KB, Kwon S et al. Ambrisentan for sarcoidosis associated pulmonary hypertension. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 139-145
  • 41 Vorselaars ADM, Wuyts WA, Vorselaars VMM et al. Methotrexate vs azathioprine in second-line therapy of sarcoidosis. Chest 2013; 144: 805-812
  • 42 Judson MA, Baughman RP, Costabel U et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur Respir J 2014; 44: 1296-1307
  • 43 Ford HJ, Baughman RP, Aris R et al. Tadalafil For Sarcoidosis Associated Pulmonary Hypertension. Am Thorac Soc Int Conf Meet Abstr 2014; 189: A4798
  • 44 Droitcourt C, Rybojad M, Porcher R et al. A randomized, investigator-masked, double-lind, placebo-controlled trial on thalidomide in severe cutaneous sarcoidosis. Chest 2014; 146: 1046-1054
  • 45 Sweiss NJ, Lower EE, Mirsaeidi M et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J 2014; 43: 1525-1528
  • 46 Dick AD, Tugal-Tutkun I, Foster S et al. Secukinumab in the treatment of noninfectious uveitis: results of three randomized, controlled clinical trials. Ophthalmology 2013; 120: 777-787
  • 47 Letko E, Yeh S, Foster CS et al. Efficacy and safety of intravenous secukinumab in noninfectious uveitis requiring steroid-sparing immunosuppressive therapy. Ophthalmology 2015; 122: 939-948
  • 48 Maya JR, Sadiq MA, Zapata LJ et al. Emerging therapies for noninfectious uveitis: what may be coming to the clinics. J Ophthalmol 2014; 2014 310329
  • 49 Gettig J, Cummings JP, Matuszewski K. H.p. Acthar gel and cosyntropin review: clinical and financial implications. P T 2009; 34: 250-257
  • 50 Drake W, Richmond BW, Oswald-Richter K et al. Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2013; 30: 201-211
  • 51 Palinski W. Immunomodulation: a new role for statins?. Nat Med 2000; 6: 1311-1312
  • 52 Dalm VASH, van Hagen PM, Krenning EP. The role of octreotide scintigraphy in rheumatoid arthritis and sarcoidosis. Q J Nucl Med 2003; 47: 270-278
  • 53 Siepmann K, Huber M, Stübiger N et al. Mycophenolate mofetil is a highly effective and safe immunosuppressive agent for the treatment of uveitis : a retrospective analysis of 106 patients. Graefes Arch Clin Exp Ophthalmol 2006; 244: 788-794
  • 54 Buenestado A, Grassin-Delyle S, Guitard F et al. Roflumilast inhibits the release of chemokines and TNF-α from human lung macrophages stimulated with lipopolysaccharide. Br J Pharmacol 2012; 165: 1877-1890
  • 55 Julian MW, Shao G, Schlesinger LS et al. Nicotine treatment improves Toll-like receptor 2 and Toll-like receptor 9 responsiveness in active pulmonary sarcoidosis. Chest 2013; 143: 461-470