Sensitivity and specificity of serum soluble interleukin-2 receptor for diagnosing sarcoidosis in a population of patients suspected of sarcoidosis

Autoři: Laura E. M. Eurelings aff001;  Jelle R. Miedema aff003;  Virgil A. S. H. Dalm aff001;  Paul L. A. van Daele aff001;  P. Martin van Hagen aff001;  Jan A. M. van Laar aff001;  Willem A. Dik aff002
Působiště autorů: Departments of Internal Medicine and Immunology, Section Clinical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands aff001;  Department of Immunology, Laboratory Medical Immunology, Erasmus University Medical Center, Rotterdam, The Netherlands aff002;  Department of Pulmonology, Erasmus University Medical Center, Rotterdam, The Netherlands aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223897



The soluble interleukin 2 receptor (sIL-2R) has been proposed as a marker of disease activity in patients with sarcoidosis. However, no studies have evaluated whether serum sIL-2R measurement is of use in establishing the diagnosis of sarcoidosis in patients who are suspected of sarcoidosis among other diseases.


A cohort study was conducted, consisting of new patients who visited the immunology outpatient clinic and whose serum sIL-2R levels were available before a definitive diagnosis was established between February 2011 and February 2016. All patients underwent standard diagnostic testing for sarcoidosis (e.g. laboratory tests, radiographic and/or nuclear imaging and/or affected site biopsy). This resulted either in the diagnosis of sarcoidosis or the exclusion of sarcoidosis with the diagnosis of another disease. Results of sIL-2R and angiotensin-converting enzyme (ACE) levels, radiographic and nuclear imaging and histology results were collected and definitive diagnoses were recorded. Sensitivity, specificity, the concordance statistic from the receiver operating characteristic curve and Youden’s Index were calculated to assess the performance of sIL-2R in the diagnosis of sarcoidosis and were compared to ACE, currently one of the most used diagnostic biomarkers in the diagnosis of sarcoidosis.


In total 983 patients were screened for inclusion, of which 189 patients met the inclusion criteria. A total of 101 patients were diagnosed with sarcoidosis after diagnostic workup, of whom 79 were biopsy-proven. In 88 patients a diagnosis other than sarcoidosis was made. The sensitivity and specificity of serum soluble interleukin 2 receptor levels to detect sarcoidosis were 88% and 85%. The sensitivity and specificity of ACE were 62% and 76%. Receiver operating characteristic curve analysis revealed that sIL-2R receptor is superior to ACE (p<0.0001).


Serum sIL-2R is a sensitive biomarker and superior to ACE in establishing the diagnosis of sarcoidosis and can be used to rule out sarcoidosis in patients suspected of sarcoidosis.

Klíčová slova:

Biomarkers – Diagnostic medicine – Immunology – Interleukins – Ophthalmology – Rheumatoid arthritis – Sarcoidosis – T cells


1. Govender P, Berman JS. The Diagnosis of Sarcoidosis. Clin Chest Med. 2015;36(4):585–602. Epub 2015/11/26. doi: 10.1016/j.ccm.2015.08.003 26593135.

2. 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. 1999;160(2):736–55. doi: 10.1164/ajrccm.160.2.ats4-99 10430755.

3. Baughman RP, Lower EE, Kaufman AH. Ocular sarcoidosis. Semin Respir Crit Care Med. 2010;31(4):452–62. Epub 2010/07/29. doi: 10.1055/s-0030-1262213 20665395.

4. Kim JS, Judson MA, Donnino R, Gold M, Cooper LT Jr, Prystowsky EN, et al. Cardiac sarcoidosis. American Heart Journal. 2009;157(1):9–21. 19081391

5. Ungprasert P, Carmona EM, Crowson CS, Matteson EL. Diagnostic Utility of Angiotensin-Converting Enzyme in Sarcoidosis: A Population-Based Study. Lung. 2016;194(1):91–5. Epub 2015/11/14. doi: 10.1007/s00408-015-9826-3 26563332.

6. Rossi GA, Sacco O, Cosulich E, Damiani G, Corte G, Bargellesi A, et al. Pulmonary sarcoidosis: excess of helper T lymphocytes and T cell subset imbalance at sites of disease activity. Thorax. 1984;39(2):143–9. Epub 1984/02/01. doi: 10.1136/thx.39.2.143 6230751.

7. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180–90. Epub 2012/02/22. doi: 10.1038/nri3156 22343569.

8. Karim AF, Eurelings LEM, Bansie RD, van Hagen PM, van Laar JAM, Dik WA. Soluble Interleukin-2 Receptor: A Potential Marker for Monitoring Disease Activity in IgG4-Related Disease. Mediators Inflamm. 2018;2018:6103064. Epub 2018/04/25. doi: 10.1155/2018/6103064 29686532.

9. Rubin LA, Snow KM, Kurman CC, Nelson DL, Keystone EC. Serial levels of soluble interleukin 2 receptor in the peripheral blood of patients with rheumatoid arthritis: correlations with disease activity. J Rheumatol. 1990;17(5):597–602. 2359067.

10. ter Borg EJ, Horst G, Limburg PC, Kallenberg CG. Changes in plasma levels of interleukin-2 receptor in relation to disease exacerbations and levels of anti-dsDNA and complement in systemic lupus erythematosus. Clin Exp Immunol. 1990;82(1):21–6. Epub 1990/10/01. doi: 10.1111/j.1365-2249.1990.tb05398.x 2208793.

11. Vorselaars AD, van Moorsel CH, Zanen P, Ruven HJ, Claessen AM, van Velzen-Blad H, et al. ACE and sIL-2R correlate with lung function improvement in sarcoidosis during methotrexate therapy. Respir Med. 2015;109(2):279–85. doi: 10.1016/j.rmed.2014.11.009 25496652.

12. Witkowska AM. On the role of sIL-2R measurements in rheumatoid arthritis and cancers. Mediators Inflamm. 2005;2005(3):121–30. Epub 2005/08/18. doi: 10.1155/MI.2005.121 16106097.

13. Rubin LA, Kurman CC, Fritz ME, Biddison WE, Boutin B, Yarchoan R, et al. Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol. 1985;135(5):3172–7. Epub 1985/11/01. 3930598.

14. Lindqvist CA, Christiansson LH, Simonsson B, Enblad G, Olsson-Stromberg U, Loskog AS. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell malignancies. Immunology. 2010;131(3):371–6. Epub 2010/06/04. doi: 10.1111/j.1365-2567.2010.03308.x 20518821.

15. Caruso C, Di Lorenzo G, Modica MA, Candore G, Portelli MR, Crescimanno G, et al. Soluble interleukin-2 receptor release defect in vitro in elderly subjects. Mech Ageing Dev. 1991;59(1–2):27–35. Epub 1991/06/14. doi: 10.1016/0047-6374(91)90071-7 1890884.

16. Kobayashi H, Tagaya Y, Han ES, Kim IS, Le N, Paik CH, et al. Use of an antibody against the soluble interleukin 2 receptor alpha subunit can modulate the stability and biodistribution of interleukin-2. Cytokine. 1999;11(12):1065–75. Epub 2000/01/07. doi: 10.1006/cyto.1999.0509 10623432.

17. Yang ZZ, Grote DM, Ziesmer SC, Manske MK, Witzig TE, Novak AJ, et al. Soluble IL-2Ralpha facilitates IL-2-mediated immune responses and predicts reduced survival in follicular B-cell non-Hodgkin lymphoma. Blood. 2011;118(10):2809–20 21719603.

18. Ziegenhagen MW, Benner UK, Zissel G, Zabel P, Schlaak M, Muller-Quernheim J. Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med. 1997;156(5):1586–92. doi: 10.1164/ajrccm.156.5.97-02050 9372680.

19. Ziegenhagen MW, Rothe ME, Schlaak M, Muller-Quernheim J. Bronchoalveolar and serological parameters reflecting the severity of sarcoidosis. Eur Respir J. 2003;21(3):407–13. doi: 10.1183/09031936.03.00010403 12661993.

20. Gungor S, Ozseker F, Yalcinsoy M, Akkaya E, Can G, Eroglu H, et al. Conventional markers in determination of activity of sarcoidosis. Int Immunopharmacol. 2015;25(1):174–9. doi: 10.1016/j.intimp.2015.01.015 25623898.

21. Rothkrantz-Kos S, van Dieijen-Visser MP, Mulder PG, Drent M. Potential usefulness of inflammatory markers to monitor respiratory functional impairment in sarcoidosis. Clin Chem. 2003;49(9):1510–7. Epub 2003/08/21. 12928233.

22. Kiko T, Yoshihisa A, Kanno Y, Yokokawa T, Abe S, Miyata-Tatsumi M, et al. A Multiple Biomarker Approach in Patients with Cardiac Sarcoidosis. Int Heart J. 2018;59(5):996–1001. Epub 2018/08/14. doi: 10.1536/ihj.17-695 30101857.

23. Uysal P, Durmus S, Sozer V, Gelisgen R, Seyhan EC, Erdenen F, et al. YKL-40, Soluble IL-2 Receptor, Angiotensin Converting Enzyme and C-Reactive Protein: Comparison of Markers of Sarcoidosis Activity. Biomolecules. 2018;8(3). Epub 2018/08/30. doi: 10.3390/biom8030084 30154391.

24. Gundlach E, Hoffmann MM, Prasse A, Heinzelmann S, Ness T. Interleukin-2 Receptor and Angiotensin-Converting Enzyme as Markers for Ocular Sarcoidosis. PLoS One. 2016;11(1):e0147258. Epub 2016/01/23. doi: 10.1371/journal.pone.0147258 26799486.

25. Groen-Hakan F, Eurelings L, ten Berge JC, van Laar J, Ramakers CRB, Dik WA, et al. Diagnostic Value of Serum-Soluble Interleukin 2 Receptor Levels vs Angiotensin-Converting Enzyme in Patients With Sarcoidosis-Associated Uveitis. JAMA Ophthalmol. 2017;135(12):1352–8 29121154.

26. Thi Hong Nguyen C, Kambe N, Kishimoto I, Ueda-Hayakawa I, Okamoto H. Serum soluble interleukin-2 receptor level is more sensitive than angiotensin-converting enzyme or lysozyme for diagnosis of sarcoidosis and may be a marker of multiple organ involvement. J Dermatol. 2017;44(7):789–97. Epub 2017/03/16. doi: 10.1111/1346-8138.13792 28295528.

27. Crommelin HA, van der Burg LM, Vorselaars AD, Drent M, van Moorsel CH, Rijkers GT, et al. Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab. Respir Med. 2016;115:72–7. doi: 10.1016/j.rmed.2016.04.011 27215507.

28. Costabel U, Hunninghake GW. 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. 1999;14(4):735–7. Epub 1999/11/26. doi: 10.1034/j.1399-3003.1999.14d02.x 10573213.

29. Scadding JG. The late stages of pulmonary sarcoidosis. Postgrad Med J. 1970;46(538):530–6. Epub 1970/08/01. doi: 10.1136/pgmj.46.538.530 5481107.

30. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61(4):344–9. doi: 10.1016/j.jclinepi.2007.11.008 18313558.

31. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez J-C, et al. pROC: an open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011;12(1):1–8. doi: 10.1186/1471-2105-12-77 21414208

32. Wessendorf TE, Bonella F, Costabel U. Diagnosis of Sarcoidosis. Clinical Reviews in Allergy & Immunology. 2015;49(1):54–62. doi: 10.1007/s12016-015-8475-x 25779004

33. Bunting PS, Szalai JP, Katic M. Diagnostic aspects of angiotensin converting enzyme in pulmonary sarcoidosis. Clin Biochem. 1987;20(3):213–9. doi: 10.1016/s0009-9120(87)80123-6 2820616.

34. Rohrbach MS DR. Serum angiotensin converting enzyme activity in sarcoidosis as measured by a simple radiochemical assay. Am Rev Respir Dis. 1979;(119):761–7.

35. Denyer M Fau—Denyer M. Medical Statistics at a Glance.

36. Fawcett T. An introduction to ROC analysis. Pattern Recognition Letters. 2006;27(8):861–74.

37. Pepe MS. The statistical evaluation of medical tests for classification and prediction 2004.

38. Zhou X-H, McClish DK, Obuchowski NA, Electronic Book C, Wiley I. Statistical methods in diagnostic medicine Hoboken, N.J.: Wiley; 2011.

39. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3(1):32–5. doi: 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>;2-3 15405679.

40. Pannucci CJ, Wilkins EG. Identifying and Avoiding Bias in Research. Plast Reconstr Surg. 2010;126(2):619–25. doi: 10.1097/PRS.0b013e3181de24bc 20679844.

41. Fluss R, Faraggi D, Reiser B. Estimation of the Youden Index and its Associated Cutoff Point. Biometrical Journal. 2005;47(4):458–72. doi: 10.1002/bimj.200410135 16161804

42. Sato H, Woodhead FA, Ahmad T, Grutters JC, Spagnolo P, van den Bosch JM, et al. Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups. Hum Mol Genet. 2010;19(20):4100–11. Epub 2010/08/06. doi: 10.1093/hmg/ddq325 20685690.

43. Mann CJ. Observational research methods. Research design II: cohort, cross sectional, and case-control studies. Emerg Med J. 2003;20(1):54–60. doi: 10.1136/emj.20.1.54 12533370.

Článek vyšel v časopise


2019 Číslo 10
Nejčtenější tento týden