Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Sarcoidosis

A Publisher Correction to this article was published on 16 July 2019

This article has been updated

Abstract

Sarcoidosis is an inflammatory disorder of unknown cause that is characterized by granuloma formation in affected organs, most often in the lungs. Patients frequently suffer from cough, shortness of breath, chest pain and pronounced fatigue and are at risk of developing lung fibrosis or irreversible damage to other organs. The disease develops in genetically predisposed individuals with exposure to an as-yet unknown antigen. Genetic factors affect not only the risk of developing sarcoidosis but also the disease course, which is highly variable and difficult to predict. The typical T cell accumulation, local T cell immune response and granuloma formation in the lungs indicate that the inflammatory response in sarcoidosis is induced by specific antigens, possibly including self-antigens, which is consistent with an autoimmune involvement. Diagnosis can be challenging for clinicians because of the potential for almost any organ to be affected. As the aetiology of sarcoidosis is unknown, no specific treatment and no pathognomic markers exist. Thus, improved biomarkers to determine disease activity and to identify patients at risk of developing fibrosis are needed. Corticosteroids still constitute the first-line treatment, but new treatment strategies, including those targeting quality-of-life issues, are being evaluated and should yield appropriate, personalized and more effective treatments.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Incidence of sarcoidosis.
Fig. 2: Survival in sarcoidosis.
Fig. 3: Immunological features of granuloma formation in sarcoidosis.
Fig. 4: Histology of lymph node and granuloma in sarcoidosis.
Fig. 5: Granuloma resolution or progression in sarcoidosis.
Fig. 6: Whole body 18F-FDG-PET scan of a patient with sarcoidosis.
Fig. 7: Extrapulmonary manifestations of sarcoidosis.
Fig. 8: Proposed algorithm for diagnosing sarcoidosis.
Fig. 9: High-resolution CT imaging of pulmonary sarcoidosis.
Fig. 10: Proposed algorithm for choice of therapy or disease monitoring in sarcoidosis.

Similar content being viewed by others

Change history

  • 16 July 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

References

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

    CAS  PubMed  Google Scholar 

  2. Löfgren, S. Erythema nodosum: studies on etiology and pathogenesis in 185 adult cases. Acta Med. Scand. 124, 1–197 (1946).

    Google Scholar 

  3. Dubaniewicz, A. Mycobacterium tuberculosis heat shock proteins and autoimmunity in sarcoidosis. Autoimmun. Rev. 9, 419–424 (2010).

    CAS  PubMed  Google Scholar 

  4. Judson, M. A., Boan, A. D. & Lackland, D. T. The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States. Sarcoidosis Vasc. Diffuse Lung Dis. 29, 119–127 (2012).

    CAS  PubMed  Google Scholar 

  5. Arkema, E. V., Grunewald, J., Kullberg, S., Eklund, A. & Askling, J. Sarcoidosis incidence and prevalence: a nationwide register-based assessment in Sweden. Eur. Respir. J. 48, 1690–1699 (2016).

    PubMed  Google Scholar 

  6. Byg, K. E., Milman, N. & Hansen, S. Sarcoidosis in Denmark 1980–1994. A registry-based incidence study comprising 5536 patients. Sarcoidosis Vasc. Diffuse Lung Dis. 20, 46–52 (2003).

    PubMed  Google Scholar 

  7. Milman, N. & Selroos, O. Pulmonary sarcoidosis in the Nordic countries 1950–1982. Epidemiology and clinical picture. Sarcoidosis 7, 50–57 (1990).

    CAS  PubMed  Google Scholar 

  8. Baughman, R. P. et al. Sarcoidosis in America. Analysis based on health care use. Ann. Am. Thorac. Soc. 13, 1244–1252 (2016).

    PubMed  Google Scholar 

  9. Cozier, Y. C. et al. Sarcoidosis in black women in the United States: data from the Black Women’s Health Study. Chest 139, 144–150 (2011).

    PubMed  Google Scholar 

  10. Dumas, O., Abramovitz, L., Wiley, A. S., Cozier, Y. C. & Camargo, C. A. Jr Epidemiology of sarcoidosis in a prospective cohort study of U.S. women. Ann. Am. Thorac. Soc. 13, 67–71 (2016).

    PubMed Central  PubMed  Google Scholar 

  11. Morimoto, T. et al. Epidemiology of sarcoidosis in Japan. Eur. Respir. J. 31, 372–379 (2008).

    CAS  PubMed  Google Scholar 

  12. Yoon, H. Y., Kim, H. M., Kim, Y. J. & Song, J. W. Prevalence and incidence of sarcoidosis in Korea: a nationwide population-based study. Respir. Res. 19, 158 (2018).

    PubMed Central  PubMed  Google Scholar 

  13. Beghe, D. et al. Sarcoidosis in an Italian province. Prevalence and environmental risk factors. PLOS ONE 12, e0176859 (2017).

    PubMed Central  PubMed  Google Scholar 

  14. Kowalska, M., Niewiadomska, E. & Zejda, J. E. Epidemiology of sarcoidosis recorded in 2006–2010 in the Silesian voivodeship on the basis of routine medical reporting. Ann. Agric. Environ. Med. 21, 55–58 (2014).

    PubMed  Google Scholar 

  15. Deubelbeiss, U., Gemperli, A., Schindler, C., Baty, F. & Brutsche, M. H. Prevalence of sarcoidosis in Switzerland is associated with environmental factors. Eur. Respir. J. 35, 1088–1097 (2010).

    CAS  PubMed  Google Scholar 

  16. Arkema, E. V. & Cozier, Y. C. Epidemiology of sarcoidosis: current findings and future directions. Ther. Adv. Chronic Dis. 9, 227–240 (2018).

    PubMed Central  PubMed  Google Scholar 

  17. Rabin, D. L. et al. Sarcoidosis: social predictors of severity at presentation. Eur. Respir. J. 24, 601–608 (2004).

    CAS  PubMed  Google Scholar 

  18. Rabin, D. L., Richardson, M. S., Stein, S. R. & Yeager, H. Jr Sarcoidosis severity and socioeconomic status. Eur. Respir. J. 18, 499–506 (2001).

    CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Grunewald, J. & Eklund, A. Lofgren’s syndrome: human leukocyte antigen strongly influences the disease course. Am. J. Respir. Crit. Care Med. 179, 307–312 (2009).

    PubMed  Google Scholar 

  21. Rivera, N. V. et al. High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences. Am. J. Respir. Crit. Care Med. 193, 1008–1022 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Schurmann, M. et al. Results from a genome-wide search for predisposing genes in sarcoidosis. Am. J. Respir. Crit. Care Med. 164, 840–846 (2001).

    CAS  PubMed  Google Scholar 

  23. Grunewald, J., Spagnolo, P., Wahlstrom, J. & Eklund, A. Immunogenetics of disease-causing inflammation in sarcoidosis. Clin. Rev. Allergy Immunol. 49, 19–35 (2015).

    CAS  PubMed  Google Scholar 

  24. Rossides, M. et al. Familial aggregation and heritability of sarcoidosis: a Swedish nested case-control study. Eur. Respir. J. 52, 1800385 (2018).

    PubMed  Google Scholar 

  25. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Headings, V. E., Weston, D., Young, R. C. Jr & Hackney, R. L. Jr Familial sarcoidosis with multiple occurrences in eleven families: a possible mechanism of inheritance. Ann. NY Acad. Sci. 278, 377–385 (1976).

    CAS  PubMed  Google Scholar 

  28. 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).

    PubMed  Google Scholar 

  29. Vihlborg, P., Bryngelsson, I. L., Andersson, L. & Graff, P. Risk of sarcoidosis and seropositive rheumatoid arthritis from occupational silica exposure in Swedish iron foundries: a retrospective cohort study. BMJ Open 7, e016839 (2017).

    PubMed Central  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. Prezant, D. J. et al. The incidence, prevalence, and severity of sarcoidosis in New York City firefighters. Chest 116, 1183–1193 (1999).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  33. 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).

    PubMed  Google Scholar 

  34. Jordan, H. T. et al. Sarcoidosis diagnosed after September 11, 2001, among adults exposed to the World Trade Center disaster. J. Occup. Environ. Med. 53, 966–974 (2011).

    PubMed  Google Scholar 

  35. Esteves, T., Aparicio, G. & Garcia-Patos, V. Is there any association between Sarcoidosis and infectious agents? A systematic review and meta-analysis. BMC Pulm. Med. 16, 165 (2016).

    PubMed Central  PubMed  Google Scholar 

  36. Carlens, C. et al. Smoking, use of moist snuff, and risk of chronic inflammatory diseases. Am. J. Respir. Crit. Care Med. 181, 1217–1222 (2010).

    PubMed  Google Scholar 

  37. Ungprasert, P., Crowson, C. S. & Matteson, E. L. Smoking, obesity and risk of sarcoidosis: A population-based nested case-control study. Respir. Med. 120, 87–90 (2016).

    PubMed Central  PubMed  Google Scholar 

  38. Valeyre, D. et al. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax 43, 516–524 (1988).

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Cozier, Y. C. et al. Obesity and weight gain in relation to incidence of sarcoidosis in US black women: data from the Black Women’s Health Study. Chest 147, 1086–1093 (2015).

    PubMed  Google Scholar 

  40. Dumas, O., Boggs, K. M., Cozier, Y. C., Stampfer, M. J. & Camargo, C. A. Jr Prospective study of body mass index and risk of sarcoidosis in US women. Eur. Respir. J. 50, 1701397 (2017).

    PubMed Central  PubMed  Google Scholar 

  41. Versini, M., Jeandel, P. Y., Rosenthal, E. & Shoenfeld, Y. Obesity in autoimmune diseases: not a passive bystander. Autoimmun. Rev. 13, 981–1000 (2014).

    CAS  PubMed  Google Scholar 

  42. Cozier, Y. C. et al. Reproductive and hormonal factors in relation to incidence of sarcoidosis in US Black women: the Black Women’s Health Study. Am. J. Epidemiol. 176, 635–641 (2012).

    PubMed Central  PubMed  Google Scholar 

  43. Gerke, A. K., Judson, M. A., Cozier, Y. C., Culver, D. A. & Koth, L. L. Disease burden and variability in sarcoidosis. Ann. Am. Thorac. Soc. 14, S421–S428 (2017).

    PubMed Central  PubMed  Google Scholar 

  44. Gribbin, J. et al. Incidence and mortality of idiopathic pulmonary fibrosis and sarcoidosis in the UK. Thorax 61, 980–985 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Park, J. E. et al. Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003-2015: A nationwide population-based study. Respir. Med. 144S, S28–S34 (2018).

    PubMed  Google Scholar 

  46. Rossides, M. et al. Sarcoidosis mortality in Sweden: a population-based cohort study. Eur. Respir. J. 51, 1701815 (2018).

    PubMed Central  PubMed  Google Scholar 

  47. Tukey, M. H. et al. Mortality among African American women with sarcoidosis: data from the Black Women’s Health Study. Sarcoidosis Vasc. Diffuse Lung Dis. 30, 128–133 (2013).

    CAS  PubMed  Google Scholar 

  48. Ungprasert, P. et al. Epidemiology of sarcoidosis 1946-2013: a population-based study. Mayo Clin. Proc. 91, 183–188 (2016).

    PubMed  Google Scholar 

  49. Nardi, A. et al. Stage IV sarcoidosis: comparison of survival with the general population and causes of death. Eur. Respir. J. 38, 1368–1373 (2011).

    CAS  PubMed  Google Scholar 

  50. Ungprasert, P., Crowson, C. S. & Matteson, E. L. Sarcoidosis increases risk of hospitalized infection. A population-based study, 1976–2013. Ann. Am. Thorac. Soc. 14, 676–681 (2017).

    PubMed Central  PubMed  Google Scholar 

  51. Crawshaw, A. P., Wotton, C. J., Yeates, D. G., Goldacre, M. J. & Ho, L. P. Evidence for association between sarcoidosis and pulmonary embolism from 35-year record linkage study. Thorax 66, 447–448 (2011).

    CAS  PubMed  Google Scholar 

  52. Ungprasert, P., Crowson, C. S. & Matteson, E. L. Risk of cardiovascular disease among patients with sarcoidosis: a population-based retrospective cohort study, 1976–2013. Eur. Respir. J. 49, 1601290 (2017).

    PubMed Central  PubMed  Google Scholar 

  53. Yaqoob, Z. J., Al-Kindi, S. G. & Zein, J. G. Sarcoidosis and risk of VTE: validation with big data. Chest 151, 1398–1399 (2017).

    PubMed  Google Scholar 

  54. Ungprasert, P., Crowson, C. S. & Matteson, E. L. Association of sarcoidosis with increased risk of VTE: a population-based study, 1976 to 2013. Chest 151, 425–430 (2017).

    PubMed  Google Scholar 

  55. Wu, C. H. et al. Comorbid autoimmune diseases in patients with sarcoidosis: a nationwide case-control study in Taiwan. J. Dermatol. 44, 423–430 (2017).

    PubMed  Google Scholar 

  56. Bonifazi, M. et al. Sarcoidosis and cancer risk: systematic review and meta-analysis of observational studies. Chest 147, 778–791 (2015).

    PubMed  Google Scholar 

  57. Hunninghake, G. W. et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc. Diffuse Lung Dis. 16, 149–173 (1999).

    CAS  PubMed  Google Scholar 

  58. Facco, M. et al. Sarcoidosis is a Th1/Th17 multisystem disorder. Thorax 66, 144–150 (2011).

    PubMed  Google Scholar 

  59. Ramstein, J. et al. Interferon-gamma-producing Th17.1 Cells are increased in sarcoidosis and more prevalent than Th1 cells. Am. J. Respir. Crit. Care Med. 193, 1281–1291 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Broos, C. E. et al. Increased T-helper 17.1 cells in sarcoidosis mediastinal lymph nodes. Eur. Respir. J. 51, 1701124 (2018).

    PubMed  Google Scholar 

  61. Miedema, J. R. et al. Th17-lineage cells in pulmonary sarcoidosis and Lofgren’s syndrome: friend or foe? J. Autoimmun. 87, 82–96 (2018).

    CAS  PubMed  Google Scholar 

  62. Ostadkarampour, M. et al. Higher levels of interleukin IL-17 and antigen-specific IL-17 responses in pulmonary sarcoidosis patients with Lofgren’s syndrome. Clin. Exp. Immunol. 178, 342–352 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Kaiser, Y. et al. Expanded lung T-bet+RORgammaT+ CD4+ T cells in sarcoidosis patients with a favourable disease phenotype. Eur. Respir. J. 48, 484–494 (2016).

    CAS  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  65. 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).

    PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  67. Li, H., Zhao, X., Wang, J., Zong, M. & Yang, H. Bioinformatics analysis of gene expression profile data to screen key genes involved in pulmonary sarcoidosis. Gene 596, 98–104 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Zhou, T. et al. Identification of Jak-STAT signaling involvement in sarcoidosis severity via a novel microRNA-regulated peripheral blood mononuclear cell gene signature. Sci. Rep. 7, 4237 (2017).

    PubMed Central  PubMed  Google Scholar 

  70. Zhou, T. et al. Peripheral blood gene expression as a novel genomic biomarker in complicated sarcoidosis. PLOS ONE 7, e44818 (2012).

    PubMed Central  PubMed  Google Scholar 

  71. Celada, L. J. et al. PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-beta1 production. Sci. Transl Med. 10, eaar8356 (2018).

    PubMed Central  PubMed  Google Scholar 

  72. Damsky, W., Thakral, D., Emeagwali, N., Galan, A. & King, B. Tofacitinib treatment and molecular analysis of cutaneous sarcoidosis. N. Engl. J. Med. 379, 2540–2546 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Rotenberg, C. et al. Dramatic response of refractory sarcoidosis under ruxolitinib in a patient with associated JAK2-mutated polycythemia. Eur. Respir. J. 52, 1801482 (2018).

    PubMed  Google Scholar 

  74. Vega, L. E. & Espinoza, L. R. HIV infection and its effects on the development of autoimmune disorders. Pharmacol. Res. 129, 1–9 (2018).

    CAS  PubMed  Google Scholar 

  75. Foulon, G. et al. Sarcoidosis in HIV-infected patients in the era of highly active antiretroviral therapy. Clin. Infect. Dis. 38, 418–425 (2004).

    PubMed  Google Scholar 

  76. Morris, D. G. et al. Sarcoidosis following HIV infection: evidence for CD4+ lymphocyte dependence. Chest 124, 929–935 (2003).

    PubMed  Google Scholar 

  77. Linke, M. et al. Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression. Nat. Immunol. 18, 293–302 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Dubaniewicz, A. Microbial and human heat shock proteins as ‘danger signals’ in sarcoidosis. Hum. Immunol. 74, 1550–1558 (2013).

    CAS  PubMed  Google Scholar 

  79. 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).

    CAS  PubMed  Google Scholar 

  80. 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).

    PubMed Central  PubMed  Google Scholar 

  81. Chen, E. S. & Moller, D. R. Sarcoidosis—scientific progress and clinical challenges. Nat. Rev. Rheumatol. 7, 457–467 (2011).

    CAS  PubMed  Google Scholar 

  82. 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).

    CAS  PubMed  Google Scholar 

  83. Katchar, K., Wahlstrom, J., Eklund, A. & Grunewald, J. Highly activated T cell receptor AV2S3+ CD4+ lung T cell expansions in pulmonary sarcoidosis. Am. J. Respir. Crit. Care Med. 163, 1540–1545 (2001).

    CAS  PubMed  Google Scholar 

  84. Muller-Quernheim, J., Kronke, M., Strausz, J., Schykowski, M. & Ferlinz, R. Interleukin-2 receptor gene expression by bronchoalveolar lavage lymphocytes in pulmonary sarcoidosis. Am. Rev. Respir. Dis. 140, 82–88 (1989).

    CAS  PubMed  Google Scholar 

  85. Karakaya, B., Kaiser, Y., van Moorsel, C. H. M. & Grunewald, J. Lofgren’s syndrome: diagnosis, management, and disease pathogenesis. Semin. Respir. Crit. Care Med. 38, 463–476 (2017).

    PubMed  Google Scholar 

  86. Sakthivel, P., Grunewald, J., Eklund, A., Bruder, D. & Wahlstrom, J. Pulmonary sarcoidosis is associated with high-level inducible co-stimulator (ICOS) expression on lung regulatory T cells–possible implications for the ICOS/ICOS-ligand axis in disease course and resolution. Clin. Exp. Immunol. 183, 294–306 (2015).

    PubMed Central  PubMed  Google Scholar 

  87. Idali, F. et al. Reduced Th1 response in the lungs of HLA-DRB1*0301 patients with pulmonary sarcoidosis. Eur. Respir. J. 27, 451–459 (2006).

    CAS  PubMed  Google Scholar 

  88. Idali, F. et al. Altered expression of T cell immunoglobulin-mucin (TIM) molecules in bronchoalveolar lavage CD4+ T cells in sarcoidosis. Respir. Res. 10, 42 (2009).

    PubMed Central  PubMed  Google Scholar 

  89. Chen, E. S. & Moller, D. R. Etiology of sarcoidosis. Clin. Chest Med. 29, 365–377 (2008).

    CAS  PubMed  Google Scholar 

  90. Grunewald, J. et al. Restricted V alpha 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).

    CAS  PubMed  Google Scholar 

  91. Moller, D. R., Konishi, K., Kirby, M., Balbi, B. & Crystal, R. G. Bias toward use of a specific T cell receptor beta-chain variable region in a subgroup of individuals with sarcoidosis. J. Clin. Invest. 82, 1183–1191 (1988).

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Grunewald, J. et al. T cell receptor variable region gene usage by CD4+ and CD8+ T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients. Proc. Natl Acad. Sci. USA 91, 4965–4969 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Grunewald, J., Berlin, M., Olerup, O. & Eklund, A. Lung T-helper cells expressing T cell receptor AV2S3 associate with clinical features of pulmonary sarcoidosis. Am. J. Respir. Crit. Care Med. 161, 814–818 (2000).

    CAS  PubMed  Google Scholar 

  94. Ahlgren, K. M., Ruckdeschel, T., Eklund, A., Wahlstrom, J. & Grunewald, J. T cell receptor-Vbeta repertoires in lung and blood CD4+ and CD8+ T cells of pulmonary sarcoidosis patients. BMC Pulm. Med. 14, 50 (2014).

    PubMed Central  PubMed  Google Scholar 

  95. Grunewald, J. et al. T cell receptor-HLA-DRB1 associations suggest specific antigens in pulmonary sarcoidosis. Eur. Respir. J. 47, 898–909 (2016).

    CAS  PubMed  Google Scholar 

  96. Mitchell, A. M. et al. Shared alphabeta TCR usage in lungs of sarcoidosis patients with Lofgren’s syndrome. J. Immunol. 199, 2279–2290 (2017).

    CAS  PubMed  Google Scholar 

  97. Heckmann, J. G., Stefan, H., Heuss, D., Hopp, P. & Neundorfer, B. Isolated muscular sarcoidosis. Eur. J. Neurol. 8, 365–366 (2001).

    CAS  PubMed  Google Scholar 

  98. Heyder, T. et al. Approach for identifying human leukocyte antigen (HLA)-DR bound peptides from scarce clinical samples. Mol. Cell. Proteomics 15, 3017–3029 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Kveim, A. A new and specific cutaneous reaction in Boeck’s sarcoid [Norwegian]. Nord. Med. 9, 169 (1941).

    Google Scholar 

  100. Siltzbach, L. The Kveim test in sarcoidosis: a study of 750 patients. JAMA 178, 476–482 (1961).

    CAS  PubMed  Google Scholar 

  101. Chase, M. The preparation and standardization of Kveim testing antigen. Am. Rev. Respir. Dis. 84, 86–88 (1961).

    PubMed  Google Scholar 

  102. Eberhardt, C. et al. Proteomic analysis of Kveim reagent identifies targets of cellular immunity in sarcoidosis. PLOS ONE 12, e0170285 (2017).

    PubMed Central  PubMed  Google Scholar 

  103. Klein, J. T. et al. Selection of oligoclonal V beta-specific T cells in the intradermal response to Kveim-Siltzbach reagent in individuals with sarcoidosis. J. Immunol. 154, 1450–1460 (1995).

    CAS  PubMed  Google Scholar 

  104. Coulombe, P. A. & Wong, P. Cytoplasmic intermediate filaments revealed as dynamic and multipurpose scaffolds. Nat. Cell Biol. 6, 699–706 (2004).

    CAS  PubMed  Google Scholar 

  105. Mor-Vaknin, N., Punturieri, A., Sitwala, K. & Markovitz, D. M. Vimentin is secreted by activated macrophages. Nat. Cell Biol. 5, 59–63 (2003).

    CAS  PubMed  Google Scholar 

  106. Wahlstrom, J. et al. Identification of HLA-DR-bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J. Clin. Invest. 117, 3576–3582 (2007).

    PubMed Central  PubMed  Google Scholar 

  107. 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).

    PubMed  Google Scholar 

  108. Kinloch, A. J. et al. In situ humoral immunity to vimentin in HLA-DRB1*03+ patients with pulmonary sarcoidosis. Front. Immunol. 9, 1516 (2018).

    PubMed Central  PubMed  Google Scholar 

  109. Wegner, N. et al. Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev. 233, 34–54 (2010).

    CAS  PubMed  Google Scholar 

  110. Kinloch, A. J. et al. Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol. 66, 3359–3370 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Kaiser, Y., Eklund, A. & Grunewald, J. Moving target — shifting the focus to pulmonary sarcoidosis as an autoimmune spectrum disorder. Eur. Respir. J. https://doi.org/10.1183/13993003.021532018 (2019).

    Article  PubMed  Google Scholar 

  112. Chiang, C. H. & Lai, F. J. Sarcoidosis on the injection sites following treatment of interferon-alpha and ribavirin for hepatitis C. J. Formos. Med. Assoc. 113, 981–982 (2014).

    PubMed  Google Scholar 

  113. Jeon, E. K. et al. First reported case of interferon-alpha-induced sarcoidosis in an Asian patient with malignant melanoma. Asia Pac. J. Clin. Oncol. 12, e347–e349 (2016).

    Google Scholar 

  114. Viana de Andrade, A. C. et al. Development of systemic sarcoidosis and xanthoma planum during multiple sclerosis treatment with interferon-beta 1a: case report. Int. J. Dermatol. 54, e140–e145 (2015).

    CAS  PubMed  Google Scholar 

  115. Berthod, G. et al. Pulmonary sarcoid-like granulomatosis induced by ipilimumab. J. Clin. Oncol. 30, e156–e159 (2012).

    PubMed  Google Scholar 

  116. Spain, L., Diem, S. & Larkin, J. Management of toxicities of immune checkpoint inhibitors. Cancer Treat. Rev. 44, 51–60 (2016).

    CAS  PubMed  Google Scholar 

  117. Abdel-Wahab, N., Shah, M. & Suarez-Almazor, M. E. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLOS ONE 11, e0160221 (2016).

    PubMed Central  PubMed  Google Scholar 

  118. Chopra, A., Nautiyal, A., Kalkanis, A. & Judson, M. A. Drug-induced sarcoidosis-like reactions. Chest 154, 664–677 (2018).

    PubMed  Google Scholar 

  119. Broos, C. E. et al. Decreased cytotoxic T-lymphocyte antigen 4 expression on regulatory T cells and Th17 cells in sarcoidosis: double trouble? Am. J. Respir. Crit. Care Med. 192, 763–765 (2015).

    CAS  PubMed  Google Scholar 

  120. Celada, L. J. et al. Programmed death-1 inhibition of phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin signaling impairs sarcoidosis CD4+ T cell proliferation. Am. J. Respir. Cell. Mol. Biol. 56, 74–82 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Palmer, B. E. et al. Up-regulation of programmed death-1 expression on beryllium-specific CD4+ T cells in chronic beryllium disease. J. Immunol. 180, 2704–2712 (2008).

    CAS  PubMed  Google Scholar 

  122. Mack, D. G. et al. 4-1BB enhances proliferation of beryllium-specific T cells in the lung of subjects with chronic beryllium disease. J. Immunol. 181, 4381–4388 (2008).

    CAS  PubMed  Google Scholar 

  123. Birnbaum, M. R. et al. Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma. JAAD Case Rep. 3, 208–211 (2017).

    PubMed Central  PubMed  Google Scholar 

  124. Danlos, F. X. et al. Nivolumab-induced sarcoid-like granulomatous reaction in a patient with advanced melanoma. Chest 149, e133–e136 (2016).

    PubMed  Google Scholar 

  125. Montaudie, H., Pradelli, J., Passeron, T., Lacour, J. P. & Leroy, S. Pulmonary sarcoid-like granulomatosis induced by nivolumab. Br. J. Dermatol. 176, 1060–1063 (2017).

    CAS  PubMed  Google Scholar 

  126. Suozzi, K. C. et al. Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy. JAAD Case Rep. 2, 264–268 (2016).

    PubMed Central  PubMed  Google Scholar 

  127. Vogel, W. V. et al. Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission. J. Clin. Oncol. 30, e7–e10 (2012).

    PubMed  Google Scholar 

  128. Marijon, E., Mirabel, M., Celermajer, D. S. & Jouven, X. Rheumatic heart disease. Lancet 379, 953–964 (2012).

    PubMed  Google Scholar 

  129. Demirkok, S. S., Basaranoglu, M. & Akbilgic, O. Seasonal variation of the onset of presentations in stage 1 sarcoidosis. Int. J. Clin. Pract. 60, 1443–1450 (2006).

    CAS  PubMed  Google Scholar 

  130. Glennas, A. et al. Acute sarcoid arthritis: occurrence, seasonal onset, clinical features and outcome. Br. J. Rheumatol. 34, 45–50 (1995).

    CAS  PubMed  Google Scholar 

  131. Wilsher, M. L. Seasonal clustering of sarcoidosis presenting with erythema nodosum. Eur. Respir. J. 12, 1197–1199 (1998).

    CAS  PubMed  Google Scholar 

  132. Heyll, A. et al. Possible transmission of sarcoidosis via allogeneic bone marrow transplantation. Bone Marrow Transplant. 14, 161–164 (1994).

    CAS  PubMed  Google Scholar 

  133. 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).

    CAS  PubMed  Google Scholar 

  134. 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).

    CAS  PubMed  Google Scholar 

  135. 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).

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  137. Oswald-Richter, K. et al. Mycobacterial ESAT-6 and katG are recognized by sarcoidosis CD4+ T cells when presented by the American sarcoidosis susceptibility allele, DRB1*1101. J. Clin. Immunol. 30, 157–166 (2009).

    PubMed Central  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed Central  PubMed  Google Scholar 

  139. Ishige, I. et al. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 22, 33–42 (2005).

    PubMed  Google Scholar 

  140. Tebben, P. J., Singh, R. J. & Kumar, R. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment. Endocr. Rev. 37, 521–547 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Korenromp, I. H., Grutters, J. C., van den Bosch, J. M. & Heijnen, C. J. Post-inflammatory fatigue in sarcoidosis: personality profiles, psychological symptoms and stress hormones. J. Psychosom. Res. 72, 97–102 (2012).

    PubMed  Google Scholar 

  142. Braam, A. W. et al. Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis. Brain Behav. Immun. 33, 57–64 (2013).

    CAS  PubMed  Google Scholar 

  143. Korenromp, I. H. et al. Reduced Th2 cytokine production by sarcoidosis patients in clinical remission with chronic fatigue. Brain Behav. Immun. 25, 1498–1502 (2011).

    CAS  PubMed  Google Scholar 

  144. Korenromp, I. H. E., Heijnen, C. J., Vogels, O. J. M., van den Bosch, J. M. M. & Grutters, J. C. Characterization of chronic fatigue in patients with sarcoidosis in clinical remission. Chest 140, 441–447 (2011).

    PubMed  Google Scholar 

  145. Strookappe, B. et al. Predictors of fatigue in sarcoidosis: the value of exercise testing. Respir. Med. 116, 49–54 (2016).

    PubMed  Google Scholar 

  146. Valeyre, D. et al. Sarcoidosis. Lancet 383, 1155–1167 (2014).

    PubMed  Google Scholar 

  147. Wells, A. U. Sarcoidosis: a benign disease or a culture of neglect? Respir. Med. 144S, S1–S2 (2018).

    PubMed  Google Scholar 

  148. Heerfordt, C. Uber eine febris uveo-parotidea subchronica. Albrecht Von Graefes Arch. Ophthalmol. 70, 254–258 (1909).

    Google Scholar 

  149. Scadding, J. G. Sarcoidosis, with special reference to lung changes. Br. Med. J. 1, 745–753 (1950).

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Scadding, J. G. Prognosis of intrathoracic sarcoidosis in England. A review of 136 cases after five years’ observation. Br. Med. J. 2, 1165–1172 (1961).

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Abehsera, M. et al. Sarcoidosis with pulmonary fibrosis: CT patterns and correlation with pulmonary function. Am. J. Roentgenol. 174, 1751–1757 (2000).

    CAS  Google Scholar 

  152. Schupp, J. C. et al. Phenotypes of organ involvement in sarcoidosis. Eur. Respir. J. 51, 1700991 (2018).

    PubMed  Google Scholar 

  153. Sayah, D. M., Bradfield, J. S., Moriarty, J. M., Belperio, J. A. & Lynch, J. P. 3rd Cardiac involvement in sarcoidosis: evolving concepts in diagnosis and treatment. Semin. Respir. Crit. Care Med. 38, 477–498 (2017).

    PubMed  Google Scholar 

  154. Birnie, D. H., Nery, P. B., Ha, A. C. & Beanlands, R. S. Cardiac sarcoidosis. J. Am. Coll. Cardiol. 68, 411–421 (2016).

    PubMed  Google Scholar 

  155. Chau, E. M., Fan, K. Y. & Chow, W. H. Cardiac sarcoidosis: a potentially fatal but treatable form of infiltrative heart disease. Hong Kong Med. J. 12, 65–67 (2006).

    CAS  PubMed  Google Scholar 

  156. Culver, D. A., Ribeiro Neto, M. L., Moss, B. P. & Willis, M. A. Neurosarcoidosis. Semin. Respir. Crit. Care Med. 38, 499–513 (2017).

    PubMed  Google Scholar 

  157. Tabuena, R. P. et al. Diabetes insipidus from neurosarcoidosis: long-term follow-up for more than eight years. Intern. Med. 43, 960–966 (2004).

    PubMed  Google Scholar 

  158. Hoitsma, E. et al. Small fibre neuropathy in sarcoidosis. Lancet 359, 2085–2086 (2002).

    CAS  PubMed  Google Scholar 

  159. Saygin, D., Karunamurthy, A., English, J. & Aggarwal, R. Tattoo reaction as a presenting manifestation of systemic sarcoidosis. Rheumatology 58, 927 (2018).

    Google Scholar 

  160. Fallahi, P. et al. The association of other autoimmune diseases in patients with autoimmune thyroiditis: review of the literature and report of a large series of patients. Autoimmun. Rev. 15, 1125–1128 (2016).

    CAS  PubMed  Google Scholar 

  161. Costabel, U. & Hunninghake, G. W. ATS/ERS/WASOG statement on sarcoidosis. Sarcoidosis Statement Committee. American Thoracic Society. European Respiratory Society. World Association for Sarcoidosis and Other Granulomatous Disorders. Eur. Respir. J. 14, 735–737 (1999).

    CAS  PubMed  Google Scholar 

  162. Bargagli, E. & Prasse, A. Sarcoidosis: a review for the internist. Intern. Emerg. Med. 13, 325–331 (2018).

    PubMed  Google Scholar 

  163. James, W. E. et al. Clinical features of extrapulmonary sarcoidosis without lung involvement. Chest 154, 349–356 (2018).

    PubMed  Google Scholar 

  164. 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 

  165. Gilbert, S., Steinbrech, D. S., Landas, S. K. & Hunninghake, G. W. Amounts of angiotensin-converting enzyme mRNA reflect the burden of granulomas in granulomatous lung disease. Am. Rev. Respir. Dis. 148, 483–486 (1993).

    CAS  PubMed  Google Scholar 

  166. 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).

    CAS  PubMed  Google Scholar 

  167. Huitema, M. P. et al. Pulmonary artery diameter to predict pulmonary hypertension in pulmonary sarcoidosis. Eur. Respir. J. 47, 673–676 (2016).

    PubMed  Google Scholar 

  168. Walsh, S. L. et al. An integrated clinicoradiological staging system for pulmonary sarcoidosis: a case-cohort study. Lancet Respir. Med. 2, 123–130 (2014).

    PubMed  Google Scholar 

  169. Soussan, M. et al. Clinical value of a high-fat and low-carbohydrate diet before FDG-PET/CT for evaluation of patients with suspected cardiac sarcoidosis. J. Nucl. Cardiol. 20, 120–127 (2013).

    PubMed  Google Scholar 

  170. Vorselaars, A. D. et al. Effectiveness of infliximab in refractory FDG PET-positive sarcoidosis. Eur. Respir. J. 46, 175–185 (2015).

    PubMed  Google Scholar 

  171. Yatsynovich, Y. et al. Updates on the role of imaging in cardiac sarcoidosis. Curr. Treat. Opt. Cardiovasc. Med. 20, 74 (2018).

    Google Scholar 

  172. Adams, H., Keijsers, R. G., Korenromp, I. H. & Grutters, J. C. FDG PET for gauging of sarcoid disease activity. Semin. Respir. Crit. Care Med. 35, 352–361 (2014).

    PubMed  Google Scholar 

  173. Goktalay, T. et al. The role of endobronchial biopsy in the diagnosis of pulmonary sarcoidosis. Turk. Thorac. J. 17, 22–27 (2016).

    PubMed  Google Scholar 

  174. Heron, M. et al. Evaluation of CD103 as a cellular marker for the diagnosis of pulmonary sarcoidosis. Clin. Immunol. 126, 338–344 (2008).

    CAS  PubMed  Google Scholar 

  175. Bonifazi, M. et al. Conventional versus ultrasound-guided transbronchial needle aspiration for the diagnosis of hilar/mediastinal lymph adenopathies: a randomized controlled trial. Respiration 94, 216–223 (2017).

    PubMed  Google Scholar 

  176. von Bartheld, M. B. et al. Endosonography versus conventional bronchoscopy for the diagnosis of sarcoidosis: the GRANULOMA randomized clinical trial. JAMA 309, 2457–2464 (2013).

    Google Scholar 

  177. Baughman, R. P. et al. Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force. Sarcoidosis Vasc. Diffuse Lung Dis. 28, 56–64 (2011).

    CAS  PubMed  Google Scholar 

  178. Pereira, C. A., Dornfeld, M. C., Baughman, R. & Judson, M. A. Clinical phenotypes in sarcoidosis. Curr. Opin. Pulm. Med. 20, 496–502 (2014).

    PubMed  Google Scholar 

  179. Prasse, A. et al. Phenotyping sarcoidosis from a pulmonary perspective. Am. J. Respir. Crit. Care Med. 177, 330–336 (2008).

    CAS  PubMed  Google Scholar 

  180. James, W. E. & Baughman, R. Treatment of sarcoidosis: grading the evidence. Expert Rev. Clin. Pharmacol. 11, 677–687 (2018).

    CAS  PubMed  Google Scholar 

  181. Schutt, A. C., Bullington, W. M. & Judson, M. A. Pharmacotherapy for pulmonary sarcoidosis: a Delphi consensus study. Respir. Med. 104, 717–723 (2010).

    PubMed  Google Scholar 

  182. Atkins, C. & Wilson, A. M. Managing fatigue in sarcoidosis — a systematic review of the evidence. Chron. Respir. Dis. 14, 161–173 (2017).

    PubMed  Google Scholar 

  183. Dekhuijzen, P. N. & Decramer, M. Steroid-induced myopathy and its significance to respiratory disease: a known disease rediscovered. Eur. Respir. J. 5, 997–1003 (1992).

    CAS  PubMed  Google Scholar 

  184. Schreiber, T. & Windisch, W. Respiratory muscle involvement in sarcoidosis. Expert Rev. Respir. Med. 12, 545–548 (2018).

    CAS  PubMed  Google Scholar 

  185. O’Connell, K. et al. Neurosarcoidosis: clinical presentations and changing treatment patterns in an Irish Caucasian population. Ir. J. Med. Sci. 186, 759–766 (2017).

    PubMed  Google Scholar 

  186. Padala, S. K., Peaslee, S., Sidhu, M. S., Steckman, D. A. & Judson, M. A. Impact of early initiation of corticosteroid therapy on cardiac function and rhythm in patients with cardiac sarcoidosis. Int. J. Cardiol. 227, 565–570 (2017).

    PubMed  Google Scholar 

  187. Baughman, R. P., Winget, D. B. & Lower, E. E. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis Vasc. Diffuse Lung Dis. 17, 60–66 (2000).

    CAS  PubMed  Google Scholar 

  188. Müller-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).

    PubMed  Google Scholar 

  189. Hunninghake, G. W. et al. Outcome of the treatment of sarcoidosis. Am. J. Respir. Crit. Care Med. 149, 893–898 (1994).

    CAS  PubMed  Google Scholar 

  190. Gibson, G. J. et al. British Thoracic Society Sarcoidosis study: effects of long term corticosteroid treatment. Thorax 51, 238–247 (1996).

    CAS  PubMed Central  PubMed  Google Scholar 

  191. Drent, M. et al. Does the cellular bronchoalveolar lavage fluid profile reflect the severity of sarcoidosis? Eur. Respir. J. 13, 1338–1344 (1999).

    CAS  PubMed  Google Scholar 

  192. Ward, K., O’Connor, C., Odlum, C. & Fitzgerald, M. X. Prognostic value of bronchoalveolar lavage in sarcoidosis: the critical influence of disease presentation. Thorax 44, 6–12 (1989).

    CAS  PubMed Central  PubMed  Google Scholar 

  193. Ziegenhagen, M. W., Rothe, M. E., Schlaak, M. & Müller-Quernheim, J. Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis. Eur. Respir. J. 21, 407–413 (2003).

    CAS  PubMed  Google Scholar 

  194. Paramothayan, S. & Lasserson, T. Treatments for pulmonary sarcoidosis. Respir. Med. 102, 1–9 (2008).

    PubMed  Google Scholar 

  195. Broos, C. E. et al. No evidence found for an association between prednisone dose and FVC change in newly-treated pulmonary sarcoidosis. Respir. Med. 138S, S31–S37 (2018).

    PubMed  Google Scholar 

  196. Conron, M., Young, C. & Beynon, H. L. Calcium metabolism in sarcoidosis and its clinical implications. Rheumatology 39, 707–713 (2000).

    CAS  PubMed  Google Scholar 

  197. Baughman, R. P., Janovcik, J., Ray, M., Sweiss, N. & Lower, E. E. Calcium and vitamin D metabolism in sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 30, 113–120 (2013).

    CAS  PubMed  Google Scholar 

  198. Burke, R. R., Rybicki, B. A. & Rao, D. S. Calcium and vitamin D in sarcoidosis: how to assess and manage. Semin. Respir. Crit. Care Med. 31, 474–484 (2010).

    PubMed Central  PubMed  Google Scholar 

  199. Baughman, R. P., Nunes, H., Sweiss, N. J. & Lower, E. E. Established and experimental medical therapy of pulmonary sarcoidosis. Eur. Respir. J. 41, 1424–1438 (2013).

    PubMed  Google Scholar 

  200. Baughman, R. P., Barney, J. B., O’Hare, L. & Lower, E. E. A retrospective pilot study examining the use of Acthar gel in sarcoidosis patients. Respir. Med. 110, 66–72 (2016).

    PubMed  Google Scholar 

  201. Ziegenhagen, M. W., Rothe, M. E., Zissel, G. & Muller-Quernheim, J. Exaggerated TNFalpha release of alveolar macrophages in corticosteroid resistant sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 19, 185–190 (2002).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  203. Giv, M. J., Yoosuff, A. & Bazargan, A. Use of lenalidomide in 5q-myelodysplastic syndrome provides novel treatment prospects in management of pulmonary sarcoidosis. Chest 148, e35–e37 (2015).

    PubMed  Google Scholar 

  204. Moller, D. R. et al. Inhibition of human interleukin-12 production by pentoxifylline. Immunology 91, 197–203 (1997).

    CAS  PubMed Central  PubMed  Google Scholar 

  205. 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 

  206. Gomes, J. P., Watad, A. & Shoenfeld, Y. Nicotine and autoimmunity: the lotus’ flower in tobacco. Pharmacol. Res. 128, 101–109 (2018).

    PubMed  Google Scholar 

  207. Julian, M. W. et al. Nicotine treatment improves Toll-like receptor 2 and Toll-like receptor 9 responsiveness in active pulmonary sarcoidosis. Chest 143, 461–470 (2013).

    CAS  PubMed  Google Scholar 

  208. Saketkoo, L. A. & Baughman, R. P. Biologic therapies in the treatment of sarcoidosis. Expert Rev. Clin. Immunol. 12, 817–825 (2016).

    CAS  PubMed  Google Scholar 

  209. 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).

    CAS  PubMed  Google Scholar 

  210. Judson, M. A. et al. Safety and efficacy of ustekinumab or golimumab in patients with chronic sarcoidosis. Eur. Respir. J. 44, 1296–1307 (2014).

    CAS  PubMed  Google Scholar 

  211. Loza, M. J. et al. Inflammatory profile and response to anti-tumor necrosis factor therapy in patients with chronic pulmonary sarcoidosis. Clin. Vaccine Immunol. 18, 931–939 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  213. Hostettler, K. E., Studler, U., Tamm, M. & Brutsche, M. H. Long-term treatment with infliximab in patients with sarcoidosis. Respiration 83, 218–224 (2012).

    CAS  PubMed  Google Scholar 

  214. Perez-Alvarez, R., Perez-de-Lis, M. & Ramos-Casals, M. Biologics-induced autoimmune diseases. Curr. Opin. Rheumatol. 25, 56–64 (2013).

    CAS  PubMed  Google Scholar 

  215. Crouser, E. D. Role of imbalance between Th17 and regulatory T cells in sarcoidosis. Curr. Opin. Pulm. Med. 24, 521–526 (2018).

    CAS  PubMed  Google Scholar 

  216. Culver, D. A. et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest. Ophthalmol. Vis. Sci. 58, BIO52–BIO60 (2017).

    CAS  PubMed  Google Scholar 

  217. Lingner, H. et al. Short-term effects of a multimodal 3-week inpatient pulmonary rehabilitation programme for patients with sarcoidosis: the ProKaSaRe Study. Respiration 95, 343–353 (2018).

    PubMed  Google Scholar 

  218. Shlobin, O. A. & Nathan, S. D. Management of end-stage sarcoidosis: pulmonary hypertension and lung transplantation. Eur. Respir. J. 39, 1520–1533 (2012).

    PubMed  Google Scholar 

  219. Baughman, R. P. et al. Bosentan for sarcoidosis associated pulmonary hypertension: A double-blind placebo controlled randomized trial. Chest 145, 810–817 (2013).

    Google Scholar 

  220. Drent, M., Strookappe, B., Hoitsma, E. & De Vries, J. Consequences of sarcoidosis. Clin. Chest Med. 36, 727–737 (2015).

    PubMed  Google Scholar 

  221. Borrell-Carrio, F., Suchman, A. L. & Epstein, R. M. The biopsychosocial model 25 years later: principles, practice, and scientific inquiry. Ann. Fam. Med. 2, 576–582 (2004).

    PubMed Central  PubMed  Google Scholar 

  222. Judson, M. A. Strategies for identifying pulmonary sarcoidosis patients at risk for severe or chronic disease. Expert Rev. Respir. Med. 11, 111–118 (2017).

    CAS  Google Scholar 

  223. Judson, M. A., Chaudhry, H., Louis, A., Lee, K. & Yucel, R. The effect of corticosteroids on quality of life in a sarcoidosis clinic: the results of a propensity analysis. Respir. Med. 109, 526–531 (2015).

    PubMed Central  PubMed  Google Scholar 

  224. Saketkoo, L. A. et al. Feasibility, utility and symptom impact of modified mindfulness training in sarcoidosis. ERJ Open Res. 4, 00085-2017 (2018).

    PubMed Central  PubMed  Google Scholar 

  225. Shires, A., Sharpe, L. & Newton John, T. The relative efficacy of mindfulness versus distraction: the moderating role of attentional bias. Eur. J. Pain 23, 727–738 (2018).

    PubMed  Google Scholar 

  226. Moor, C. C. et al. Needs, perceptions and education in sarcoidosis: a live interactive survey of patients and partners. Lung 196, 569–575 (2018).

    CAS  PubMed Central  PubMed  Google Scholar 

  227. Smets, E. M., Garssen, B., Bonke, B. & De Haes, J. C. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J. Psychosom. Res. 39, 315–325 (1995).

    CAS  PubMed  Google Scholar 

  228. Minnock, P., Kirwan, J. & Bresnihan, B. Fatigue is a reliable, sensitive and unique outcome measure in rheumatoid arthritis. Rheumatology 48, 1533–1536 (2009).

    PubMed  Google Scholar 

  229. Petri, M. A., Martin, R. S., Scheinberg, M. A. & Furie, R. A. Assessments of fatigue and disease activity in patients with systemic lupus erythematosus enrolled in the Phase 2 clinical trial with blisibimod. Lupus 26, 27–37 (2017).

    CAS  PubMed  Google Scholar 

  230. Abad, S. et al. Association of peripheral multifocal choroiditis with sarcoidosis: a study of thirty-seven patients. Arthritis Rheum. 51, 974–982 (2004).

    CAS  PubMed  Google Scholar 

  231. De Boer, S. & Wilsher, M. L. Validation of the Sarcoidosis Health Questionnaire in a non-US population. Respirology 17, 519–524 (2012).

    PubMed  Google Scholar 

  232. De Vries, J., Michielsen, H., Van Heck, G. L. & Drent, M. Measuring fatigue in sarcoidosis: the Fatigue Assessment Scale (FAS). Br. J. Health Psychol. 9, 279–291 (2004).

    PubMed  Google Scholar 

  233. Wilsher, M. L. Psychological stress in sarcoidosis. Curr. Opin. Pulm. Med. 18, 524–527 (2012).

    PubMed  Google Scholar 

  234. Benn, B. S. et al. Sleep disturbance and symptom burden in sarcoidosis. Respir. Med. 144S, S35–S40 (2018).

    PubMed  Google Scholar 

  235. Bosse-Henck, A., Wirtz, H. & Hinz, A. Subjective sleep quality in sarcoidosis. Sleep Med. 16, 570–576 (2015).

    PubMed  Google Scholar 

  236. Hinz, A., Geue, K., Zenger, M., Wirtz, H. & Bosse-Henck, A. Daytime sleepiness in patients diagnosed with sarcoidosis compared with the general population. Can. Respir. J. 2018, 6853948 (2018).

    PubMed Central  PubMed  Google Scholar 

  237. Lal, C., Medarov, B. I. & Judson, M. A. Interrelationship between sleep-disordered breathing and sarcoidosis. Chest 148, 1105–1114 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  239. Ireland, J. & Wilsher, M. Perceptions and beliefs in sarcoidosis. Sarcoidosis Vasc. Diffuse Lung Dis. 27, 36–42 (2010).

    CAS  PubMed  Google Scholar 

  240. Elwyn, G., Cochran, N. & Pignone, M. Shared decision making — the importance of diagnosing preferences. JAMA Intern. Med. 177, 1239–1240 (2017).

    PubMed  Google Scholar 

  241. Dubovsky, A. N., Arvikar, S., Stern, T. A. & Axelrod, L. The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Psychosomatics 53, 103–115 (2012).

    CAS  PubMed  Google Scholar 

  242. Rees, J., O’Boyle, C. & MacDonagh, R. Quality of life: impact of chronic illness on the partner. J. R. Soc. Med. 94, 563–566 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  243. Sklenarova, H. et al. When do we need to care about the caregiver? Supportive care needs, anxiety, and depression among informal caregivers of patients with cancer and cancer survivors. Cancer 121, 1513–1519 (2015).

    PubMed  Google Scholar 

  244. Saketkoo, L. A. et al. Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases. J. Rheumatol. 41, 792–798 (2014).

    PubMed Central  PubMed  Google Scholar 

  245. Arkema, E. V., Eklund, A., Grunewald, J. & Bruze, G. Work ability before and after sarcoidosis diagnosis in Sweden. Respir. Med. 144S, S7–S12 (2018).

    PubMed  Google Scholar 

  246. Kawalec, P. P. & Malinowski, K. P. The indirect costs of systemic autoimmune diseases, systemic lupus erythematosus, systemic sclerosis and sarcoidosis: a summary of 2012 real-life data from the Social Insurance Institution in Poland. Expert Rev. Pharmacoecon. Outcomes Res. 15, 667–673 (2015).

    PubMed  Google Scholar 

  247. Rice, J. B. et al. Economic burden of sarcoidosis in a commercially-insured population in the United States. J. Med. Econ. 20, 1048–1055 (2017).

    PubMed  Google Scholar 

  248. Borgh, M., Eek, F., Wagman, P. & Hakansson, C. Organisational factors and occupational balance in working parents in Sweden. Scand. J. Public Health 46, 409–416 (2018).

    PubMed  Google Scholar 

  249. Markham, S. E. & Markham, I. S. Biometeorological effects on worker absenteeism. Int. J. Biometeorol. 49, 317–324 (2005).

    PubMed  Google Scholar 

  250. Muller, C. California State University catastrophic (Cat) leave donation program: demographics, economic security, and social equity. J. Health Hum. Serv. Adm. 38, 108–159 (2015).

    PubMed  Google Scholar 

  251. Alexanderson, H. et al. Resistive home exercise in patients with recent-onset polymyositis and dermatomyositis — a randomized controlled single-blinded study with a 2-year followup. J. Rheumatol. 41, 1124–1132 (2014).

    PubMed  Google Scholar 

  252. Bernardi, E., Pomidori, L., Cassutti, F. & Cogo, A. Home-based, moderate-intensity exercise training using a metronome improves the breathing pattern and oxygen saturation during exercise in patients with COPD. J. Cardiopulm. Rehabil. Prev. 38, E16–E18 (2018).

    PubMed  Google Scholar 

  253. Russell, A. M. et al. Daily home spirometry: an effective tool for detecting progression in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 194, 989–997 (2016).

    PubMed Central  PubMed  Google Scholar 

  254. Tuckson, R. V., Edmunds, M. & Hodgkins, M. L. Telehealth. N. Engl. J. Med. 377, 1585–1592 (2017).

    PubMed  Google Scholar 

  255. Bolat, M. S., Celik, B., Celik, H. K. & Akdeniz, E. The impact of thoracotomy on psychological and sexual function in men with lung cancer. Rev. Int. Androl. https://doi.org/10.1016/j.androl.2018.05.002 (2018).

    Article  PubMed  Google Scholar 

  256. Hassanin, A. M., Ismail, N. N., El Guindi, A. & Sowailam, H. A. The emotional burden of chronic skin disease dominates physical factors among women, adversely affecting quality of life and sexual function. J. Psychosom. Res. 115, 53–57 (2018).

    PubMed  Google Scholar 

  257. Ostlund, G., Bjork, M., Valtersson, E. & Sverker, A. Lived experiences of sex life difficulties in men and women with early RA — the Swedish TIRA Project. Musculoskeletal Care 13, 248–257 (2015).

    PubMed  Google Scholar 

  258. Fourie, S., Jackson, D. & Aveyard, H. Living with inflammatory bowel disease: a review of qualitative research studies. Int. J. Nurs. Stud 87, 149–156 (2018).

    PubMed  Google Scholar 

  259. Mittoo, S. et al. Patient perspectives in OMERACT provide an anchor for future metric development and improved approaches to healthcare delivery in connective tissue disease related interstitial lung disease (CTD-ILD). Curr. Respir. Med. Rev. 11, 175–183 (2015).

    PubMed Central  PubMed  Google Scholar 

  260. Cox, C. E., Donohue, J. F., Brown, C. D., Kataria, Y. P. & Judson, M. A. The Sarcoidosis Health Questionnaire: a new measure of health-related quality of life. Am. J. Respir. Crit. Care Med. 8, 8 (2003).

    Google Scholar 

  261. Patel, A. S. et al. The development and validation of the King’s Sarcoidosis Questionnaire for the assessment of health status. Thorax 68, 57–65 (2013).

    PubMed  Google Scholar 

  262. Judson, M. A. et al. Validation and important differences for the Sarcoidosis Assessment Tool. A new patient-reported outcome measure. Am. J. Respir. Crit. Care Med. 191, 786–795 (2015).

    PubMed  Google Scholar 

  263. Hendriks, C., Drent, M., Elfferich, M. & De Vries, J. The Fatigue Assessment Scale: quality and availability in sarcoidosis and other diseases. Curr. Opin. Pulm. Med. 24, 495–503 (2018).

    PubMed  Google Scholar 

  264. Fauchon, C. et al. Does an observer’s empathy influence my pain? Effect of perceived empathetic or unempathetic support on a pain test. Eur. J. Neurosci. 46, 2629–2637 (2017).

    CAS  PubMed  Google Scholar 

  265. Nixon, J. et al. Communicating actively responding empathically (CARE): comparison of communication training workshops for health professionals working in cancer care. J. Cancer Educ. https://doi.org/10.1007/s13187-018-1439-0 (2018).

    Article  Google Scholar 

  266. Buckley, L. et al. 2017 American College of Rheumatology Guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. 69, 1521–1537 (2017).

    PubMed  Google Scholar 

  267. Singh, J. A. et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 68, 1–26 (2016).

    PubMed  Google Scholar 

  268. Strookappe, B. et al. Physical activity and training in sarcoidosis: review and experience-based recommendations. Expert Rev. Respir. Med. 10, 1057–1068 (2016).

    CAS  PubMed  Google Scholar 

  269. Spagnolo, P. et al. Pulmonary sarcoidosis. Lancet Respir. Med. 6, 389–402 (2018).

    PubMed  Google Scholar 

  270. Moller, D. R. et al. Rationale and design of the genomic research in alpha-1 antitrypsin deficiency and sarcoidosis (GRADS) study. Sarcoidosis protocol. Ann. Am. Thorac. Soc. 12, 1561–1571 (2015).

    PubMed Central  PubMed  Google Scholar 

  271. Kaiser, Y. et al. Mass cytometry identifies distinct lung CD4+ T cell patterns in Lofgren’s syndrome and non-Lofgren’s syndrome sarcoidosis. Front. Immunol. 8, 1130 (2017).

    PubMed Central  PubMed  Google Scholar 

  272. Moller, D. R. et al. Genetic, immunologic, and environmental basis of sarcoidosis. Ann. Am. Thorac. Soc. 14, S429–S436 (2017).

    PubMed Central  PubMed  Google Scholar 

  273. Crouser, E. D. et al. Application of “omics” and systems biology to sarcoidosis research. Ann. Am. Thorac. Soc. 14, S445–S451 (2017).

    PubMed Central  PubMed  Google Scholar 

  274. Cinetto, F., Compagno, N., Scarpa, R., Malipiero, G. & Agostini, C. Rituximab in refractory sarcoidosis: a single centre experience. Clin. Mol. Allergy 13, 19 (2015).

    PubMed Central  PubMed  Google Scholar 

  275. Sweiss, N. J. et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur. Respir. J. 43, 1525–1528 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  276. Birring, S. S. et al. The Leicester Cough Monitor: preliminary validation of an automated cough detection system in chronic cough. Eur. Respir. J. 31, 1013–1018 (2008).

    CAS  PubMed  Google Scholar 

  277. Birring, S. S. et al. Treatment of interstitial lung disease associated cough: CHEST Guideline and Expert Panel Report. Chest 154, 904–917 (2018).

    PubMed  Google Scholar 

  278. Judson, M. A. Quality of life in sarcoidosis. Semin. Respir. Crit. Care Med. 38, 546–558 (2017).

    PubMed  Google Scholar 

  279. Judson, M. A. The diagnosis of sarcoidosis. Clin. Chest Med. 29, 415–427 (2008).

    PubMed  Google Scholar 

  280. Judson, M. A. The clinical features of sarcoidosis: a comprehensive review. Clin. Rev. Allergy Immunol. 49, 63–78 (2015).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank A. Eklund and Y. Kaiser for their help with this article as well as research nurses G. de Forest, M. Dahl and H. Blomqvist and biomedical analyst B. Dahlberg (all at Respiratory Medicine Unit, Karolinska University Hospital, Solna, Sweden) for skilful assistance in bronchoscopy and lavage and in sample preparation and processing. The authors thank C. A. Seldenrijk (Department of Pathology), R. G. M. Keijsers (Department of Nuclear Medicine) and H. W. van Es (Department of Radiology), all at St Antonius Hospital, Nieuwegein, Netherlands, for providing the histopathology, PET and CT images, respectively. J.G. is supported by the Swedish Heart Lung Foundation (HLF 20160354 and 20160300), the Swedish Research Council (2016–01209) and the US NIH (R01HL136137) through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and the Karolinska Institutet, The King Gustaf V and Queen Victoria’s Freemasons’ Foundation and the Karolinska Institutet.

Author information

Authors and Affiliations

Authors

Contributions

Introduction (J.G.); Epidemiology (E.V.A.); Mechanisms/pathophysiology (J.G. and D.R.M.); Diagnosis, screening and prevention (J.C.G.); Management (J.M.-Q.); Quality of life (L.A.S.); Outlook (J.G., J.C.G., E.V.A., L.A.S., D.R.M. and J.M.-Q.); Overview of the Primer (J.G.)

Corresponding author

Correspondence to Johan Grunewald.

Ethics declarations

Competing interests

D.R.M. is the Chairman and Chief Technology Officer of Sarcoidosis Diagnostic Testing, LLC. J.M.-Q. is supported by the German Research Foundation (Mu692/12) and Bristol-Myers-Squibb for investigator-initiated trials in sarcoidosis. All other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

MESARGEN: https://mesargen.wordpress.com

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Grunewald, J., Grutters, J.C., Arkema, E.V. et al. Sarcoidosis. Nat Rev Dis Primers 5, 45 (2019). https://doi.org/10.1038/s41572-019-0096-x

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-019-0096-x

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing