Based on emerging evidence and multidisciplinary and international input, a steering committee nominated by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) has developed new classification criteria for systemic lupus erythematosus (SLE). Designed to increase classification sensitivity and specificity, these criteria were indicated for inclusion in SLE research studies and trials rather than for diagnostic purposes. This report was published in Annals of the Rheumatic Diseases.
Investigators performed a systematic review and meta-regression of literature focused on the validity of positive antinuclear antibody (ANA) as a new entry criterion, and improving on the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria, which required at least 1 immunologic criterion to be present. After conducting the Delphi exercise, new candidate criteria were nominated, reviewed, refined, and weighted; consensus was achieved through unanimous endorsement by the steering committee.
Recommendations for ANA as Entry Criterion
EULAR/ACR recommends that the positive presence of ANA be used as an entry criterion required for SLE classification, in which ANA performed as a highly sensitive screening test for SLE. In the review of literature, 13,080 patients demonstrated ANA ≥1:80 with a sensitivity of 97.8% (range, 96.8%-98.5%; 95% CI). A total of 99.5% of patients with early SLE were ANA positive.
The panel highly recommends testing by immunofluorescence on human epithelial type 2 (HEp-2) cells or a solid phase ANA screening immunoassay with equivalent performance in which ANA positivity is defined at a titer of ≥1:80. If ANA is persistently negative in patients, then they cannot be classified as SLE.
Recommendations for Additive Criteria
EULAR/ACR suggests that criterion not be counted toward SLE classification if there is a more likely diagnosis than SLE. The single occurrence of a criterion is sufficient to count as SLE; where multiple criteria occur, they need not be present simultaneously. To improve sensitivity, an SLE classification requires at least 1 clinical criterion. Criteria are weighted according to their relative contribution to an individual’s classification of SLE; only the highest weighted criterion within a domain is counted. Renal biopsy with class 3 or 4 lupus nephritis carries the most weight for SLE; this criterion along with the presence of a positive ANA can be classified as SLE.
Recommendations for Clinical Domains and Criteria
Unexplained fever, defined as a temperature >38.3°C, was counted as a new clinical criterion as fever is common and quite characteristic especially in new-onset SLE.
The hematologic domain includes the presence of leukopenia, defined as a white blood cell count <4.0×109/L at least once, with a slightly higher combined sensitivity and specificity than previous definitions of white blood cell counts of leukopenia (1.944 vs 1.942); thrombocytopenia, defined as a platelet count <100×109/L; and autoimmune hemolysis, defined as evidence of reticulocytosis, low haptoglobin, elevated indirect bilirubin or lactate dehydrogenase and positive Coombs test.
Neuropsychiatric manifestations of SLE were added in the 2012 SLICC classification criteria; disease definitions were refined to include delirium, psychosis, or seizure in the 2019 EULAR/ACR recommendations, and were evaluated for their sensitivity.
Similarly, mucocutaneous manifestations were also added in the 2012 SLICC classification criteria. EULAR/ACR improved on the sensitivity of existing criteria by refining the definitions of mucocutaneous manifestations to include nonscarring alopecia, oral ulcers, subacute cutaneous or discoid lupus, and acute cutaneous lupus.
Criteria in the serosal domain include pleural or pericardial effusion and acute pericarditis defined through imaging (ultrasound, x-ray, computed tomography scan, or magnetic resonance imaging) and/or clinical evidence (pericardial chest pain, pericardial rub, and electrocardiogram [EKG]).
Joint involvement, defined as synovitis involving 2 or more joints characterized by swelling or effusion, or as tenderness in 2 or more joints with at least 30 minutes of morning stiffness, had higher combined sensitivity and specificity compared with the definition of arthritis as synovitis of 2 or more joints (1.944 vs 1.900).
Renal manifestations included in SLE classification criteria are the presence of proteinuria >0.5 g/24 hours, renal biopsy class 2 or 5 lupus nephritis, and renal biopsy class 3 or 4 lupus nephritis. The goal was to increase sensitivity to the high sensitivity of the SLICC criteria, and significant renal histology in the presence of positive ANA is enough to classify a patient as SLE.
Recommendations for Immunologic Domains and Criteria
Antiphospholipid Antibodies Criteria
Antiphospholipid antibody tests were added to the 2012 SLICC classification criteria, and the presence of any 1 of the following are included in the EULAR/ACR recommendations to increase sensitivity: anticardiolipin antibodies (immunoglobulin [Ig]A, IgG, or IgM) at medium or high titers, positive anti-β2GP1 antibodies (IgA, IgG, or IgM), or positive lupus anticoagulant.
Presence of complement proteins C3 or C4 below their normal limit is included as an immunology criterion; if both low C3 and low C4 levels are present simultaneously, the contribution of complement proteins is increased.
Anti-dsDNA antibody presence (in an assay with ≥90% specificity against a relevant disease control group) or anti-Smith antibody presence is counted toward SLE classification.
EULAR/ACR recommends the use of ANA positivity as an entry criterion. The new classification criteria demonstrated excellent sensitivity and specificity compared with the sensitivity and specificity of ACR 1997 and SLICC 2012 criteria for SLE classification (96.1% and 93.4%, 82.8% and 93.4%, 96.7% and 83.7%, respectively).
Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151-1159.