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  • Review Article
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Sarcoidosis—scientific progress and clinical challenges

Abstract

Sarcoidosis is an uncommon systemic inflammatory disorder characterized by noncaseating granulomatous inflammation that most commonly affects the lungs, intrathoracic lymph nodes, eyes and skin. One-third or more of patients with sarcoidosis have chronic, unremitting inflammation with progressive organ impairment. Findings of family and genetic studies indicate a genetic susceptibility to sarcoidosis, with genes in the MHC region having a dominant role. Immunologic hallmarks of the disease include highly polarized expression of cytokines produced by type 1 T helper cells and tumor necrosis factor (TNF) at sites of inflammation. Increasing evidence obtained within the past decade suggests the etiology of sarcoidosis predominantly involves microbial triggers, with the most convincing data implicating mycobacterial or propionibacterial organisms. Innate immune mechanisms, possibly involving misfolding and aggregation of serum amyloid A, might have a critical role in the pathobiology of sarcoidosis. Despite these advances, there are no clinically useful biomarkers that can assist the clinician in diagnosis, prognosis or assessment of treatment effects. Corticosteroids remain the cornerstone of therapy when organ function is threatened or progressively impaired. The role of immunosuppressive drugs and anti-TNF agents in the treatment of sarcoidosis remains uncertain, and there are no FDA-approved therapies. Meaningful progress in developing clinically useful tools and new therapies will depend on further advances in understanding the pathogenesis of sarcoidosis and its disease-specific pathways.

Key Points

  • Sarcoidosis is a multisystem disease characterized by noncaseating granulomatous inflammation with striking heterogeneity in its clinical manifestations

  • Results of immunologic and clinical association studies indicate that a highly polarized type 1 T helper cell immune response is a hallmark of sarcoidosis

  • Sarcoidosis is thought to result from both genetic susceptibility and specific environmental triggers

  • No useful diagnostic, prognostic or therapeutic biomarkers are currently available to assist in the clinical management of patients with sarcoidosis

  • Further clinical trials are needed to establish the role of immunosuppressive drugs, anti-tumor necrosis factor therapies and other biologic immunomodulators in the treatment of sarcoidosis

  • Improved understanding of the pathogenic mechanisms in sarcoidosis might provide new strategies to treat and potentially cure this disease

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Figure 1: Serum amyloid A misfolding hypothesis of the pathobiology of sarcoidosis.

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Johan Grunewald, Jan C. Grutters, … Joachim Müller-Quernheim

References

  1. Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999. Am. J. Respir. Crit. Care Med. 160, 736–755 (1999).

  2. Baughman, R. P. et al. Clinical characteristics of patients in a case control study of sarcoidosis. Am. J. Respir. Crit. Care Med. 164, 1885–1889 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Iannuzzi, M. C., Rybicki, B. A. & Teirstein, A. S. Sarcoidosis. N. Engl. J. Med. 357, 2153–2165 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Rybicki, B. A. & Iannuzzi, M. C. Epidemiology of sarcoidosis: recent advances and future prospects. Semin. Respir. Crit. Care Med. 28, 22–35 (2007).

    Article  PubMed  Google Scholar 

  5. Rybicki, B. A., Major, M., Popovich, J. Jr, Maliarik, M. J. & Iannuzzi, M. C. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am. J. Epidemiol. 145, 234–241 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Grunewald, J. & Eklund, A. Sex-specific manifestations of Löfgren's syndrome. Am. J. Respir. Crit. Care Med. 175, 40–44 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. Judson, M. A. et al. Two year prognosis of sarcoidosis: the ACCESS experience. Sarcoidosis Vasc. Diffuse Lung Dis. 20, 204–211 (2003).

    PubMed  Google Scholar 

  8. Girard, N. et al. Opportunistic infections and sarcoidosis [French]. Rev. Mal. Respir. 21, 1083–1090 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Romagnani, S. Regulation of the T cell response. Clin. Exp. Allergy 36, 1357–1366 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Welker, L., Jorres, R. A., Costabel, U. & Magnussen, H. Predictive value of BAL cell differentials in the diagnosis of interstitial lung diseases. Eur. Respir. J. 24, 1000–1006 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Zissel, G., Prasse, A. & Muller-Quernheim, J. Sarcoidosis--immunopathogenetic concepts. Semin. Respir. Crit. Care Med. 28, 3–14 (2007).

    Article  PubMed  Google Scholar 

  12. Moller, D. R. et al. Enhanced expression of IL-12 associated with TH1 cytokine profiles in active pulmonary sarcoidosis. J. Immunol. 156, 4952–4960 (1996).

    CAS  PubMed  Google Scholar 

  13. Greene, C. M. et al. Role of IL-18 in CD4+ T lymphocyte activation in sarcoidosis. J. Immunol. 165, 4718–4724 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Larousserie, F. et al. Expression of IL-27 in human TH1-associated granulomatous diseases. J. Pathol. 202, 164–171 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Ehrt, S. et al. Reprogramming of the macrophage transcriptome in response to interferon-γ and Mycobacterium tuberculosis: signaling roles of nitric oxide synthase-2 and phagocyte oxidase. J. Exp. Med. 194, 1123–1140 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Agostini, C. et al. Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis. J. Immunol. 157, 910–918 (1996).

    CAS  PubMed  Google Scholar 

  17. Rosenbaum, J. T. et al. Hypothesis: sarcoidosis is a STAT1-mediated disease. Clin. Immunol. 132, 174–183 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Walker, C. et al. Activated T cells and cytokines in bronchoalveolar lavages from patients with various lung diseases associated with eosinophilia. Am. J. Respir. Crit. Care Med. 150, 1038–1048 (1994).

    Article  CAS  PubMed  Google Scholar 

  19. Hauber, H. P., Gholami, D., Meyer, A. & Pforte, A. Increased interleukin-13 expression in patients with sarcoidosis. Thorax 58, 519–524 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wiken, M. et al. No evidence of altered alveolar macrophage polarization, but reduced expression of TLR2, in bronchoalveolar lavage cells in sarcoidosis. Respir. Res. 11, 121 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Facco, M. et al. Sarcoidosis is a TH1/TH17 multisystem disorder. Thorax 66, 144–150 (2011).

    Article  PubMed  Google Scholar 

  22. Lenner, R., Bregman, Z., Teirstein, A. S. & DePalo, L. Recurrent pulmonary sarcoidosis in HIV-infected patients receiving highly active antiretroviral therapy. Chest 119, 978–981 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Airaghi, L., Montori, D., Zorzi, F., Miadonna, A. & Tedeschi, A. Sarcoidosis in a patient with 5q-myelodysplasia. A possible pathogenetic link between the two diseases. Monaldi Arch. Chest Dis. 55, 378–380 (2000).

    CAS  PubMed  Google Scholar 

  24. Moller, D. R. Involvement of T cells and alterations in T cell receptors in sarcoidosis. Semin. Respir. Infect. 13, 174–183 (1998).

    CAS  PubMed  Google Scholar 

  25. Grunewald, J. et al. Restricted V α 2.3 gene usage by CD4+ T lymphocytes in bronchoalveolar lavage fluid from sarcoidosis patients correlates with HLA-DR3. Eur J. Immunol. 22, 129–135 (1992).

    Article  CAS  PubMed  Google Scholar 

  26. Strausz, J. et al. Spontaneous monokine release by alveolar macrophages in chronic sarcoidosis. Int. Arch. Allergy Appl. Immunol. 96, 68–75 (1991).

    Article  CAS  PubMed  Google Scholar 

  27. Baughman, R. P. et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am. J. Respir. Crit. Care Med. 174, 795–802 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Culver, D. A. et al. Peroxisome proliferator-activated receptor gamma activity is deficient in alveolar macrophages in pulmonary sarcoidosis. Am. J. Respir. Cell Mol. Biol. 30, 1–5 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Miyara, M. et al. The immune paradox of sarcoidosis and regulatory T cells. J. Exp. Med. 203, 359–370 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Taflin, C. et al. FoxP3+ regulatory T cells suppress early stages of granuloma formation but have little impact on sarcoidosis lesions. Am. J. Pathol. 174, 497–508 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Idali, F., Wahlstrom, J., Muller-Suur, C., Eklund, A. & Grunewald, J. Analysis of regulatory T cell associated forkhead box P3 expression in the lungs of patients with sarcoidosis. Clin. Exp. Immunol. 152, 127–137 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Prasse, A. et al. Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis. Am. J. Respir. Crit. Care Med. 182, 540–548 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Ho, L. P., Urban, B. C., Thickett, D. R., Davies, R. J. & McMichael, A. J. Deficiency of a subset of T-cells with immunoregulatory properties in sarcoidosis. Lancet 365, 1062–1072 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Mathew, S., Bauer, K. L., Fischoeder, A., Bhardwaj, N. & Oliver, S. J. The anergic state in sarcoidosis is associated with diminished dendritic cell function. J. Immunol. 181, 746–755 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Veltkamp, M. et al. Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis. Clin. Exp. Immunol. 149, 453–462 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wiken, M., Grunewald, J., Eklund, A. & Wahlstrom, J. Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis. J. Clin. Immunol. 29, 78–89 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Chen, E. S. et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am. J. Respir. Crit. Care Med. 181, 360–373 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Elias, J. A., Freundlich, B., Kern, J. A. & Rosenbloom, J. Cytokine networks in the regulation of inflammation and fibrosis in the lung. Chest 97, 1439–1445 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Zissel, G., Prasse, A. & Muller-Quernheim, J. Immunologic response of sarcoidosis. Semin. Respir. Crit. Care Med. 31, 390–403 (2010).

    Article  PubMed  Google Scholar 

  40. Henry, M. T. et al. Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. Eur. Respir. J. 20, 1220–1227 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Prasse, A. et al. A vicious circle of alveolar macrophages and fibroblasts perpetuates pulmonary fibrosis via CCL18. Am. J. Respir. Crit. Care Med. 173, 781–792 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Fernandez Fabrellas, E. Epidemiology of sarcoidosis [Spanish]. Arch. Bronconeumol. 43, 92–100 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rybicki, B. A. et al. Familial aggregation of sarcoidosis. A case–control etiologic study of sarcoidosis (ACCESS). Am. J. Respir. Crit. Care Med. 164, 2085–2091 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Sverrild, A. et al. Heredity in sarcoidosis: a registry-based twin study. Thorax 63, 894–896 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Muller-Quernheim, J. et al. Genetics of sarcoidosis. Clin. Chest Med. 29, 391–414, viii (2008).

    Article  PubMed  Google Scholar 

  46. Rossman, M. D. et al. HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites. Am. J. Hum. Genet. 73, 720–735 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Voorter, C. E. et al. HLA class II amino acid epitopes as susceptibility markers of sarcoidosis. Tissue Antigens 70, 18–27 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Berlin, M., Fogdell-Hahn, A., Olerup, O., Eklund, A. & Grunewald, J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am. J. Respir. Crit. Care Med. 156, 1601–1605 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Sato, H. et al. HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am. J. Respir. Cell Mol. Biol. 27, 406–412 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Voorter, C. E., Drent, M. & van den Berg-Loonen, E. M. Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602-DRB1*150101. Hum. Immunol. 66, 826–835 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. Medica, I., Kastrin, A., Maver, A. & Peterlin, B. Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis. J. Hum. Genet. 52, 836–847 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Zorzetto, M. et al. Complement receptor 1 gene polymorphisms in sarcoidosis. Am. J. Respir. Cell Mol. Biol. 27, 17–23 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Schurmann, M. et al. CARD15 gene mutations in sarcoidosis. Eur. Respir. J. 22, 748–754 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Spagnolo, P. et al. A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Lofgren's syndrome. J. Intern. Med. 264, 433–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Sato, H. et al. CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis. Eur. Respir. J. 35, 324–330 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Campo, I. et al. Expression of receptor for advanced glycation end products in sarcoid granulomas. Am. J. Respir. Crit. Care Med. 175, 498–506 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Kruit, A., Ruven, H. J., Grutters, J. C. & van den Bosch, J. M. Angiotensin II receptor type 1 1166 A/C and angiotensin converting enzyme I/D gene polymorphisms in a Dutch sarcoidosis cohort. Sarcoidosis Vasc. Diffuse Lung Dis. 27, 147–152 (2010).

    CAS  PubMed  Google Scholar 

  58. Rybicki, B. A., Maliarik, M. J., Poisson, L. M. & Iannuzzi, M. C. Sarcoidosis and granuloma genes: a family-based study in African-Americans. Eur. Resp. J. 24, 251–257 (2004).

    Article  CAS  Google Scholar 

  59. Valentonyte, R. et al. Sarcoidosis is associated with a truncating splice site mutation in BTNL2. Nat. Genet. 37, 357–364 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Rybicki, B. A., Walewski, J. L., Maliarik, M. J., Kian, H. & Iannuzzi, M. C. The BTNL2 gene and sarcoidosis susceptibility in African Americans and Whites. Am. J. Hum. Genet. 77, 491–499 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Spagnolo, P. et al. Analysis of BTNL2 genetic polymorphisms in British and Dutch patients with sarcoidosis. Tissue Antigens 70, 219–227 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Hofmann, S. et al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for sarcoidosis. Nat. Genet. 40, 1103–1106 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Franke, A. et al. Genome-wide association analysis in sarcoidosis and Crohn's disease unravels a common susceptibility locus on 10p12.2. Gastroenterology 135, 1207–1215 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Rossman, M. D. et al. HLA and environmental interactions in sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 25, 125–132 (2008).

    CAS  PubMed  Google Scholar 

  65. Westney, G. E. & Judson, M. A. Racial and ethnic disparities in sarcoidosis: from genetics to socioeconomics. Clin. Chest Med. 27, 453–462, vi (2006).

    Article  PubMed  Google Scholar 

  66. Newman, L. S. et al. A case control etiologic study of sarcoidosis: environmental and occupational risk factors. Am. J. Respir. Crit. Care Med. 170, 1324–1330 (2004).

    Article  PubMed  Google Scholar 

  67. Shaykhiev, R. et al. Smoking-dependent reprogramming of alveolar macrophage polarization: implication for pathogenesis of chronic obstructive pulmonary disease. J. Immunol. 183, 2867–2883 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Kern, D. G., Neill, M. A., Wrenn, D. S. & Varone, J. C. Investigation of a unique time-space cluster of sarcoidosis in firefighters. Am. Rev. Respir. Dis. 148, 974–980 (1993).

    Article  CAS  PubMed  Google Scholar 

  69. Izbicki, G. et al. World Trade Center “sarcoid-like” granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest 131, 1414–1423 (2007).

    Article  PubMed  Google Scholar 

  70. Crowley, L. E. et al. “Sarcoid like” granulomatous pulmonary disease in World Trade Center disaster responders. Am. J. Ind. Med. 54, 175–184 (2011).

    Article  PubMed  Google Scholar 

  71. Milman, N., Lisby, G., Friis, S. & Kemp, L. Prolonged culture for mycobacteria in mediastinal lymph nodes from patients with pulmonary sarcoidosis. A negative study. Sarcoidosis Vasc. Diffuse Lung Dis. 21, 25–28 (2004).

    PubMed  Google Scholar 

  72. Gupta, D., Agarwal, R., Aggarwal, A. N. & Jindal, S. K. Molecular evidence for the role of mycobacteria in sarcoidosis: a meta-analysis. Eur. Respir. J. 30, 508–516 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Song, Z. et al. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J. Exp. Med. 201, 755–767 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Teirstein, A. S. Kveim antigen: what does it tell us about causation of sarcoidosis? Semin. Respir. Infect. 13, 206–211 (1998).

    CAS  PubMed  Google Scholar 

  75. Ng, V. H., Cox, J. S., Sousa, A. O., MacMicking, J. D. & McKinney, J. D. Role of KatG catalase-peroxidase in mycobacterial pathogenesis: countering the phagocyte oxidative burst. Mol. Microbiol. 52, 1291–1302 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Zhang, Y., Garbe, T. & Young, D. Transformation with katG restores isoniazid-sensitivity in Mycobacterium tuberculosis isolates resistant to a range of drug concentrations. Mol. Microbiol. 8, 521–524 (1993).

    Article  CAS  PubMed  Google Scholar 

  77. Chen, E. S. et al. T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J. Immunol. 181, 8784–8796 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Drake, W. P. et al. Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect. Immun. 75, 527–530 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Dubaniewicz, A., Trzonkowski, P., Dubaniewicz-Wybieralska, M., Singh, M. & Mysliwski, A. Mycobacterial heat shock protein-induced blood T lymphocytes subsets and cytokine pattern: comparison of sarcoidosis with tuberculosis and healthy controls. Respirology 12, 346–354 (2007).

    Article  PubMed  Google Scholar 

  80. Oswald-Richter, K. A. et al. Multiple mycobacterial antigens are targets of the adaptive immune response in pulmonary sarcoidosis. Respir. Res. 11, 161 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Saltini, C. et al. M. avium binding to HLA-DR expressed alleles in silico: a model of phenotypic susceptibility to sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 25, 100–116 (2008).

    CAS  PubMed  Google Scholar 

  82. Zhou, Y. et al. Differentiation of sarcoidosis from tuberculosis using real-time PCR assay for the detection and quantification of Mycobacterium tuberculosis. Sarcoidosis Vasc. Diffuse Lung Dis. 25, 93–99 (2008).

    CAS  PubMed  Google Scholar 

  83. Eishi, Y. et al. Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis. J. Clin. Microbiol. 40, 198–204 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Ebe, Y. et al. Proliferative response of peripheral blood mononuclear cells and levels of antibody to recombinant protein from Propionibacterium acnes DNA expression library in Japanese patients with sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 17, 256–265 (2000).

    CAS  PubMed  Google Scholar 

  85. Nishiwaki, T. et al. Indigenous pulmonary Propionibacterium acnes primes the host in the development of sarcoid-like pulmonary granulomatosis in mice. Am. J. Pathol. 165, 631–639 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  86. McCaskill, J. G. et al. Pulmonary immune responses to Propionibacterium acnes in C57BL/6 and BALB/c mice. Am. J. Respir. Cell Mol. Biol. 35, 347–56 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tchaptchet, S. et al. Innate, antigen-independent role for T cells in the activation of the immune system by Propionibacterium acnes. Eur. J. Immunol. 40, 2506–2516 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Wahlstrom, J. et al. Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. Clin. Immunol. 133, 353–363 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Munro, C. S. & Mitchell, D. N. The Kveim response: still useful, still a puzzle. Thorax 42, 321–331 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mana, J. et al. Löfgren's syndrome revisited: a study of 186 patients. Am. J. Med. 107, 240–245 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Tremblay, A., Stather, D. R., Maceachern, P., Khalil, M. & Field, S. K. A randomized controlled trial of standard vs endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis. Chest 136, 340–346 (2009).

    Article  PubMed  Google Scholar 

  92. Turner-Warwick, M., McAllister, W., Lawrence, R., Britten, A. & Haslam, P. L. Corticosteroid treatment in pulmonary sarcoidosis: do serial lavage lymphocyte counts, serum angiotensin converting enzyme measurements, and gallium-67 scans help management? Thorax 41, 903–913 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Beirne, P. et al. Multiplex immune serum biomarker profiling in sarcoidosis and systemic sclerosis. Eur. Respir. J. 34, 1376–1382 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Mana, J. Magnetic resonance imaging and nuclear imaging in sarcoidosis. Curr. Opin. Pulm. Med. 8, 457–463 (2002).

    Article  PubMed  Google Scholar 

  95. Bradley, B. et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 63 (Suppl. 5), v1–v58 (2008).

    PubMed  Google Scholar 

  96. Baughman, R. P. & Lower, E. E. Steroid-sparing alternative treatments for sarcoidosis. Clin. Chest Med. 18, 853–864 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Bachelez, H., Senet, P., Cadranel, J., Kaoukhov, A. & Dubertret, L. The use of tetracyclines for the treatment of sarcoidosis. Arch. Dermatol. 137, 69–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Park, M. K. et al. Steroid-sparing effects of pentoxifylline in pulmonary sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 26, 121–131 (2009).

    CAS  PubMed  Google Scholar 

  99. Lower, E. E. & Baughman, R. P. The use of low dose methotrexate in refractory sarcoidosis. Am. J. Med. Sci. 299, 153–157 (1990).

    Article  CAS  PubMed  Google Scholar 

  100. Muller-Quernheim, J., Kienast, K., Held, M., Pfeifer, S. & Costabel, U. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur. Respir. J. 14, 1117–1122 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Moravan, M. & Segal, B. M. Treatment of CNS sarcoidosis with infliximab and mycophenolate mofetil. Neurology 72, 337–340 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Majithia, V., Sanders, S., Harisdangkul, V. & Wilson, J. G. Successful treatment of sarcoidosis with leflunomide. Rheumatology (Oxford) 42, 700–702 (2003).

    Article  CAS  Google Scholar 

  103. Baughman, R. P., Judson, M. A., Teirstein, A. S., Moller, D. R. & Lower, E. E. Thalidomide for chronic sarcoidosis. Chest 122, 227–232 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Doty, J. D., Mazur, J. E. & Judson, M. A. Treatment of corticosteroid-resistant neurosarcoidosis with a short-course cyclophosphamide regimen. Chest 124, 2023–2026 (2003).

    Article  PubMed  Google Scholar 

  105. Judson, M. A. et al. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur. Respir. J. 31, 1189–1196 (2008).

    Article  CAS  PubMed  Google Scholar 

  106. Utz, J. P. et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 124, 177–185 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. ClinicalTrials.gov. NIH[online], (2011).

  108. Sharma, O. P. Vitamin D and sarcoidosis. Curr. Opin. Pulm. Med. 16, 487–488 (2010).

    Article  PubMed  Google Scholar 

  109. Lagana, S. M., Parwani, A. V. & Nichols, L. C. Cardiac sarcoidosis: a pathology-focused Review. Arch. Pathol. Lab. Med. 134, 1039–1046 (2010).

    PubMed  Google Scholar 

  110. Uemura, A. et al. Histologic diagnostic rate of cardiac sarcoidosis: evaluation of endomyocardial biopsies. Am. Heart J. 138, 299–302 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Mehta, D. et al. Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing. Chest 133, 1426–1435 (2008).

    Article  PubMed  Google Scholar 

  112. Arcasoy, S. M. et al. Characteristics and outcomes of patients with sarcoidosis listed for lung transplantation. Chest 120, 873–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Barnett, C. F. et al. Treatment of sarcoidosis-associated pulmonary hypertension. A two-center experience. Chest 135, 1455–1461 (2009).

    Article  PubMed  Google Scholar 

  114. Nunes, H. et al. Pulmonary hypertension associated with sarcoidosis: mechanisms, haemodynamics and prognosis. Thorax 61, 68–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  115. Keating, D. et al. Lung transplantation in pulmonary fibrosis: challenging early outcomes counterbalanced by surprisingly good outcomes beyond 15 years. Transplant. Proc. 41, 289–291 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Zaidi, A. R., Zaidi, A. & Vaitkus, P. T. Outcome of heart transplantation in patients with sarcoid cardiomyopathy. J. Heart Lung Transplant. 26, 714–717 (2007).

    Article  PubMed  Google Scholar 

  117. Scott, T. F., Yandora, K., Valeri, A., Chieffe, C. & Schramke, C. Aggressive therapy for neurosarcoidosis: long-term follow-up of 48 treated patients. Arch. Neurol. 64, 691–696 (2007).

    Article  PubMed  Google Scholar 

  118. Voorter, C. E., Drent, M., Hoitsma, E., Faber, K. G. & van den Berg-Loonen, E. M. Association of HLA DQB1 0602 in sarcoidosis patients with small fiber neuropathy. Sarcoidosis Vasc. Diffuse Lung Dis. 22, 129–132 (2005).

    PubMed  Google Scholar 

  119. Chang, B. et al. Depression in sarcoidosis. Am. J. Respir. Crit. Care Med. 163, 329–334 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Goracci, A. et al. Quality of life, anxiety and depression in sarcoidosis. Gen. Hosp. Psychiatry 30, 441–445 (2008).

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by the Hospital for the Consumptives of Maryland (Eudowood) and the Life and Breath Foundation.

C. P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article.

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E. S. Chen and D. R. Moller contributed equally to all aspects of preparation of this manuscript.

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Correspondence to David R. Moller.

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D. R. Moller declares that an appeal against a rejection for a patent for using mKatG in diagnosis of sarcoidosis is ongoing. E. S. Chen declares no competing interests.

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Chen, E., Moller, D. Sarcoidosis—scientific progress and clinical challenges. Nat Rev Rheumatol 7, 457–467 (2011). https://doi.org/10.1038/nrrheum.2011.93

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