Systemic lupus erythematosus (SLE) is associated with substantial heterogeneity in terms of clinical manifestations and immunological profile, presenting significant challenges in the diagnosis and classification of the disease.
Criteria developed by the American College of Rheumatology (ACR), initially published in 1982 and revised in 1997, have been used for decades for the classification of SLE in research.1,2 In addition, the ACR criteria have been used as a diagnostic tool in clinical practice, although their use can be problematic as they may be too stringent to detect SLE in individuals with a milder phenotype or non-classical features.3
The Systemic Lupus International Collaborating Clinics (SLICC) group introduced a new set of classification criteria in 2012.4 However, these criteria have been found to have higher sensitivity but decreased specificity in both adult and juvenile cohorts compared with the ACR criteria. “In part, this may be a consequence of the choice of the SLICC group to maintain the overall structure of the ACR criteria,” wrote the investigators in a recent article published in Arthritis Care & Research.5 “Currently, a new international effort to develop a novel and potentially more accurate set of classification criteria is under way, which is jointly supported by the European League Against Rheumatism (EULAR) and the ACR.”6
Two new items were introduced in the SLICC criteria: (1) the requirement of proof of autoantibodies, and (2) histology-proven immune complex nephritis as a criterion, but only in the presence of positive results on antinuclear antibody (ANA) testing and/or the anti-double stranded DNA (anti-dsDNA) test.
While ANA testing has high sensitivity for SLE and can be useful in early diagnosis, ANA specificity is low due to its presence in numerous other patient groups, including patients with other autoimmune diseases as well as infectious and malignant diseases.7 ANA positivity is also encountered in healthy individuals — for example, up to 23% of patients over the age of 85, according to one set of findings.8
In contrast to the ACR and SLICC criteria, the new approach in development proposes the use of positive indirect immunofluorescence ANA (IIF-ANA) as an entry criterion for SLE classification. Although IIF using Hep-2 cells (IIF HEp2) is considered the gold standard for ANA testing, findings regarding the optimal titer and sensitivity in patients with SLE have been mixed.9 To elucidate these matters, the investigators in the present study conducted a systematic review and meta-regression analysis of articles published between 1990 and 2015 regarding the use of IIF-HEp-2 ANA for SLE.
“We wanted to know if we could use positive ANA by HEp2 immunofluorescence as an entry criterion for the classification of SLE — meaning that the other criteria would be applied only if the entry criterion is positive,” explained co-investigator Nicolai Leuchten, MD, of the University Medical Center Carl Gustav Carus at Tecknische Universität in Dresden, Germany. The investigators also aimed to determine which titer would constitute a reasonable cut-off, Dr Leuchten told Rheumatology Advisor.
The final analysis included 66 articles with a total of 13,080 patient with SLE and 7539 controls. IIF-ANA positivity was detected at various titers in 95.9% (12,542) of patients with SLE.
The findings were as follows for the different titers:
- titer of 1:40: sensitivity 98.4% (95% CI, 97.6%-99.0%), specificity 66.9% (95% CI, 57.8%-74.9%)
- titer of 1:80: sensitivity 97.8% (95% CI, 96.8%-98.5%), specificity 74.7% (95% CI, 66.7%-81.3%)
- titer of 1:160: sensitivity 95.8% (95% CI, 94.1%-97.1%), specificity 86.2% (95% CI, 80.4%-90.5%)
- titer of 1:320: sensitivity 86.0% (95% CI, 77.0%-91.9%), specificity 96.6% (95% CI, 93.9%-98.1%)
Taken together, these results show that the sensitivity of IIF-ANA at a titer of 1:80 is adequate to be used as an entry criterion for other SLE classification criteria, including in pediatric patients and patients in early disease stages. It should be noted that a small number of patients may have ANA-negative SLE, and a “negative ANA test in the context of high clinical suspicion for SLE is both a clinical challenge and of immunological interest” that requires further investigation, according to the paper.
As for next steps in the development of the new classification system, the “empiric and consensus process for the other proposed classification criteria is being completed,” said Dr Leuchten. “The next step is the testing of the criteria in a validation cohort.”
Summary and Clinical Applicability
This systematic literature review and meta-regression determined that IIF-ANA testing has adequate sensitivity for SLE at a titer of 1:80 to be used as an entry criterion for SLE classification criteria.
Several variables may have increased the risk of bias in the studies analyzed, including a lack of information regarding the patient selection process, ANA testing methodology, and blinding of the testers.
- Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis & Rheumatology. 1997;40(9):1725. doi:10.1002/1529-0131(199709)40:9<1725::AID-ART29>3.0.CO;2-Y
- Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis & Rheumatology. 1982;25(11):1271-1277. doi:10.1002/art.1780251101
- Aggarwal R, Ringold S, Khanna D, et al. Distinctions between diagnostic and classification criteria? Arthritis Care & Research. 2015;67(7):891-897. doi:10.1002/acr.22583
- Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis & Rheumatology. 2012;64(8):2677-2686. doi:10.1002/art.34473
- Leuchten N, Hoyer A, Brinks R, et al; SLE Classification Criteria Steering Committee. Performance of anti-nuclear antibodies for classifying systemic lupus erythematosus: a systematic literature review and meta-regression of diagnostic data [published online May 23, 2017]. Arthritis Care Res (Hoboken). doi:10.1002/acr.23292
- Aringer M, Dorner T, Leuchten N, Johnson SR. Toward new criteria for systemic lupus erythematosus-a standpoint. Lupus. 2016;25(8):805-811. doi:10.1177/0961203316644338
- Tan EM, Feltkamp TE, Smolen JS, et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis & Rheumatology. 1997;40(9):1601-1611. doi:10.1002/1529-0131(199709)40:9<1601::AID-ART9>3.0.CO;2-T
- Nilsson BO, Skogh T, Ernerudh J, et al. Antinuclear antibodies in the oldest-old women and men. J Autoimmun. 2006;27(4):281-288. doi:10.1016/j.jaut.2006.10.002
- Agmon-Levin N, Damoiseaux J, Kallenberg C, et al. International recommendations for the assessment of autoantibodies to cellular antigens referred to as anti-nuclear antibodies. Ann Rheum Dis. 2014;73(1):17-23. doi:10.1136/annrheumdis-2013-203863