Skip to main content

Thank you for visiting 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.

Diagnostic criteria for systemic lupus erythematosus: has the time come?


Systemic lupus erythematosus (SLE) is a multiorgan disease with protean manifestations. Because SLE is uncommon and heterogeneous, its diagnosis can pose a considerable challenge, especially for clinicians with limited expertise of the disease. This is particularly true at the early stages of SLE, when an inadequate number of features to secure the diagnosis might be present, and for patients presenting with uncommon features, which can nonetheless be severe and require prompt treatment. Furthermore, the suboptimal performance of immunological testing in patients referred for possible SLE has been highlighted. As a result, SLE remains largely a clinical diagnosis that is made after excluding alternative diagnoses. Diagnostic criteria can expedite diagnosis and treatment, but are not available for SLE. Thus, SLE classification criteria are often used, but strict adherence to these criteria could delay diagnosis. Therefore, while eagerly awaiting diagnostic criteria for this disease, we propose interim potential solutions to facilitate its diagnosis.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Diagnostic steps in patients presenting with features suggestive of SLE.


  1. 1

    Uttenthal, B. J., Layton, D. M., Vyse, T. J. & Schreiber, B. E. Clinical problem-solving. The wolf at the door. N. Engl. J. Med. 366, 2216–2221 (2012).

    CAS  Article  Google Scholar 

  2. 2

    Alonso, M. D. et al. Late-onset systemic lupus erythematosus in Northwestern Spain: differences with early-onset systemic lupus erythematosus and literature review. Lupus 21, 1135–1148 (2012).

    CAS  Article  Google Scholar 

  3. 3

    Pons-Estel, G. J., Alarcon, G. S., Scofield, L., Reinlib, L. & Cooper, G. S. Understanding the epidemiology and progression of systemic lupus erythematosus. Semin. Arthritis Rheum. 39, 257–268 (2010).

    Article  Google Scholar 

  4. 4

    Kamphuis, S. & Silverman, E. D. Prevalence and burden of pediatric-onset systemic lupus erythematosus. Nat. Rev. Rheumatol. 6, 538–546 (2010).

    CAS  Article  Google Scholar 

  5. 5

    Uramoto, K. M. et al. Trends in the incidence and mortality of systemic lupus erythematosus, 1950–1992. Arthritis Rheum. 42, 46–50 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Alonso, M. D. et al. Systemic lupus erythematosus in northwestern Spain: a 20-year epidemiologic study. Medicine (Baltimore) 90, 350–358 (2011).

    Article  Google Scholar 

  7. 7

    Feldman, C. H. et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000–2004. Arthritis Rheum. 65, 753–763 (2013).

    Article  Google Scholar 

  8. 8

    Lerang, K., Gilboe, I., Garen, T., Thelle, D. S. & Gran, J. T. High incidence and prevalence of systemic lupus erythematosus in Norway. Lupus 21, 1362–1369 (2012).

    CAS  Article  Google Scholar 

  9. 9

    Bresnihan, B. Outcome and survival in systemic lupus erythematosus. Ann. Rheum. Dis. 48, 443–445 (1989).

    CAS  Article  Google Scholar 

  10. 10

    Rivest, C. et al. Association between clinical factors, socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J. Rheumatol. 27, 680–684 (2000).

    CAS  PubMed  Google Scholar 

  11. 11

    Alarcon, G. S. et al. Systemic lupus erythematosus in three ethnic groups. III. A comparison of characteristics early in the natural history of the LUMINA cohort. LUpus in MInority populations: NAture vs. Nurture. Lupus 8, 197–209 (1999).

    CAS  Article  Google Scholar 

  12. 12

    Alarcon, G. S. et al. Systemic lupus erythematosus in three ethnic groups. II. Features predictive of disease activity early in its course. LUMINA Study Group. Lupus in minority populations, nature versus nurture. Arthritis Rheum. 41, 1173–1180 (1998).

    CAS  Article  Google Scholar 

  13. 13

    Hiraki, L. T. et al. Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US Medicaid beneficiary population. Arthritis Rheum. 64, 2669–2676 (2012).

    Article  Google Scholar 

  14. 14

    Cervera, R. et al. Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus. Medicine (Baltimore) 72, 113–124 (1993).

    CAS  Article  Google Scholar 

  15. 15

    Nossent, J. et al. Disease activity and damage accrual during the early disease course in a multinational inception cohort of patients with systemic lupus erythematosus. Lupus 19, 949–956 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Cerovec, M., Anic, B., Padjen, I. & Cikes, N. Prevalence of the American College of Rheumatology classification criteria in a group of 162 systemic lupus erythematosus patients from Croatia. Croat. Med. J. 53, 149–154 (2012).

    Article  Google Scholar 

  17. 17

    Cross, L. S., Aslam, A. & Misbah, S. A. Antinuclear antibody-negative lupus as a distinct diagnostic entity—does it no longer exist? QJM 97, 303–308 (2004).

    CAS  Article  Google Scholar 

  18. 18

    Mosca, M., Tani, C. & Bombardieri, S. Defining undifferentiated connective tissue diseases: a challenge for rheumatologists. Lupus 17, 278–280 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Calvo-Alen, J. et al. Systemic lupus erythematosus: predictors of its occurrence among a cohort of patients with early undifferentiated connective tissue disease: multivariate analyses and identification of risk factors. J. Rheumatol. 23, 469–475 (1996).

    CAS  PubMed  Google Scholar 

  20. 20

    Nimelstein, S. H., Brody, S., McShane, D. & Holman, H. R. Mixed connective tissue disease: a subsequent evaluation of the original 25 patients. Medicine (Baltimore) 59, 239–248 (1980).

    CAS  Article  Google Scholar 

  21. 21

    Gendi, N. S. et al. HLA type as a predictor of mixed connective tissue disease differentiation. Ten-year clinical and immunogenetic followup of 46 patients. Arthritis Rheum. 38, 259–266 (1995).

    CAS  Article  Google Scholar 

  22. 22

    Cappelli, S. et al. “To be or not to be,” ten years after: evidence for mixed connective tissue disease as a distinct entity. Semin. Arthritis Rheum. 41, 589–598 (2012).

    Article  Google Scholar 

  23. 23

    Amezcua-Guerra, L. M. et al. Presence of antibodies against cyclic citrullinated peptides in patients with 'rhupus': a cross-sectional study. Arthritis Res. Ther. 8, R144 (2006).

    Article  Google Scholar 

  24. 24

    Aringer, M. & Smolen, J. S. Efficacy and safety of TNF-blocker therapy in systemic lupus erythematosus. Expert Opin. Drug Saf. 7, 411–419 (2008).

    CAS  Article  Google Scholar 

  25. 25

    Sjowall, C. et al. Abnormal antinuclear antibody titers are less common than generally assumed in established cases of systemic lupus erythematosus. J. Rheumatol. 35, 1994–2000 (2008).

    Google Scholar 

  26. 26

    Meroni, P. L. & Schur, P. H. ANA screening: an old test with new recommendations. Ann. Rheum. Dis. 69, 1420–1422 (2010).

    CAS  Article  Google Scholar 

  27. 27

    Craig, W. Y. & Ledue, T. B. The antinuclear antibody assay: developing criteria for reflexive anti-dsDNA antibody testing in a laboratory setting. Clin. Chem. Lab. Med. 49, 1205–1211 (2011).

    CAS  Article  Google Scholar 

  28. 28

    Compagno, M. et al. Low diagnostic and predictive value of anti-dsDNA antibodies in unselected patients with recent onset of rheumatic symptoms: results from a long-term follow-up Scandinavian multicentre study. Scand. J. Rheumatol.

  29. 29

    Swaak, T. & Smeenk, R. Detection of anti-dsDNA as a diagnostic tool: a prospective study in 441 non-systemic lupus erythematosus patients with anti-dsDNA antibody (anti-dsDNA). Ann. Rheum. Dis. 44, 245–251 (1985).

    CAS  Article  Google Scholar 

  30. 30

    Danieli, M. G., Fraticelli, P., Salvi, A., Gabrielli, A. & Danieli, G. Undifferentiated connective tissue disease: natural history and evolution into definite CTD assessed in 84 patients initially diagnosed as early UCTD. Clin. Rheumatol. 17, 195–201 (1998).

    CAS  Article  Google Scholar 

  31. 31

    Arbuckle, M. R. et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N. Engl. J. Med. 349, 1526–1533 (2003).

    CAS  Article  Google Scholar 

  32. 32

    Wandstrat, A. E. et al. Autoantibody profiling to identify individuals at risk for systemic lupus erythematosus. J. Autoimmun. 27, 153–160 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Mariz, H. A. et al. Pattern on the antinuclear antibody-HEp-2 test is a critical parameter for discriminating antinuclear antibody-positive healthy individuals and patients with autoimmune rheumatic diseases. Arthritis Rheum. 63, 191–200 (2011).

    CAS  Article  Google Scholar 

  34. 34

    Ahearn, J. M., Liu, C. C., Kao, A. H. & Manzi, S. Biomarkers for systemic lupus erythematosus. Transl. Res. 159, 326–342 (2012).

    CAS  Article  Google Scholar 

  35. 35

    Li, Q. Z. et al. Risk factors for ANA positivity in healthy persons. Arthritis Res. Ther. 13, R38 (2011).

    Article  Google Scholar 

  36. 36

    Li, Q. Z. et al. Interferon signature gene expression is correlated with autoantibody profiles in patients with incomplete lupus syndromes. Clin. Exp. Immunol. 159, 281–291 (2010).

    CAS  Article  Google Scholar 

  37. 37

    Braunstein, I., Klein, R., Okawa, J. & Werth, V. P. The interferon-regulated gene signature is elevated in subacute cutaneous lupus erythematosus and discoid lupus erythematosus and correlates with the cutaneous lupus area and severity index score. Br. J. Dermatol. 166, 971–975 (2012).

    CAS  Article  Google Scholar 

  38. 38

    Sood, R., Wong, W., Gotlib, J., Jeng, M. & Zehnder, J. L. Gene expression and pathway analysis of immune thrombocytopenic purpura. Br. J. Haematol. 140, 99–103 (2008).

    CAS  PubMed  Google Scholar 

  39. 39

    Feng, X. et al. Type I interferon signature is high in lupus and neuromyelitis optica but low in multiple sclerosis. J. Neurol. Sci. 313, 48–53 (2012).

    CAS  Article  Google Scholar 

  40. 40

    Mackay, M. et al. Molecular signatures in lupus: untangling infection from inflammation. Arthritis Rheum. 64, S1088 (2012).

    Google Scholar 

  41. 41

    Li, Q. Z. et al. Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes. Clin. Exp. Immunol. 147, 60–70 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Silverman, G. J. et al. Genetic imprinting of autoantibody repertoires in systemic lupus erythematosus patients. Clin. Exp. Immunol. 153, 102–116 (2008).

    CAS  Article  Google Scholar 

  43. 43

    Grimes, D. A. & Schulz, K. F. Refining clinical diagnosis with likelihood ratios. Lancet 365, 1500–1505 (2005).

    Article  Google Scholar 

  44. 44

    Somers, E. C., Antonsen, S., Pedersen, L. & Sorensen, H. T. Parental history of lupus and rheumatoid arthritis and risk in offspring in a nationwide cohort study: does sex matter? Ann. Rheum. Dis. 72, 525–529 (2013).

    CAS  Article  Google Scholar 

  45. 45

    Kassirer, J. P. Teaching clinical reasoning: case-based and coached. Acad. Med. 85, 1118–1124 (2010).

    Article  Google Scholar 

  46. 46

    Tan, E. M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982).

    CAS  Article  Google Scholar 

  47. 47

    Hochberg, M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997).

    CAS  Article  Google Scholar 

  48. 48

    Calvo-Alen, J. et al. Identification of patient subsets among those presumptively diagnosed with, referred, and/or followed up for systemic lupus erythematosus at a large tertiary care center. Arthritis Rheum. 38, 1475–1484 (1995).

    CAS  Article  Google Scholar 

  49. 49

    Petri, M. et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 64, 2677–2686 (2012).

    Article  Google Scholar 

  50. 50

    Alarcon, G. S., McGwin, G. Jr, Madger, L. & Petri, M. Comparing the ACR and the SLICC criteria for the classification of SLE patients using data from an existing multi-ethnic cohort. Arthritis Rheum. 64, S262 (2012).

    Article  Google Scholar 

Download references


We wish to thank D. Vassilopoulos, I. Gergianaki and M. Drandaki for their thoughtful comments.

Author information




All authors contributed to researching data for the article, discussing its content, writing the article and reviewing/editing it before publication.

Corresponding author

Correspondence to Dimitrios T. Boumpas.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

The ACR and SLICC classification criteria for SLE. (DOCX 31 kb)

Supplementary Table 2

Diagnostic performance of individual features for established SLE patients seen in academic referral centers. (DOCX 27 kb)

Supplementary Table 3

Common cognitive biases and flaws in SLE diagnosis and management. (DOCX 24 kb)

Supplementary Figure 1

Fagan's normogram for calculating post-test probability after considering lupus laboratory tests. (DOCX 62 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bertsias, G., Pamfil, C., Fanouriakis, A. et al. Diagnostic criteria for systemic lupus erythematosus: has the time come?. Nat Rev Rheumatol 9, 687–694 (2013).

Download citation

Further reading


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