Definitions
Classification and diagnostic criteria
When in the mid-19th century Cazenave first used the name lupus erythematosus, SLE was a rare and life-threatening illness.2 3 A century later, as new technologies identified more patients,4–10 physicians found SLE to be more clinically diverse, and often less severe, than they once believed. To improve homogeneity of patient populations identified for clinical studies, investigators developed classification criteria that are specific, binary (SLE is present or not) and time limited (valid only for the extent of a study). The homogeneity of classification criteria is implied but not real. The American College of Rheumatology (ACR) criteria allow 330 different combinations of symptoms and laboratory tests to affirm a diagnosis of SLE.11 Classification criteria are insensitive; they exclude patients who, despite disabling and treatable symptoms, fall below criteria thresholds and those who have overlapping or changing forms of SLE, whom practising physicians treat according to rules established for typical SLE.12–21 Diagnostic criteria, which would be more sensitive, if less specific, time independent and scalar rather than binary, do not exist for SLE. (An internet search (23 September 2018) for SLE diagnostic criteria identified references only to classification criteria. Many published papers fail to distinguish diagnostic from classification criteria.21)
Exclusive and inclusive definitions
Many clinical and basic science investigators use an exclusive definition of SLE that accepts only classification criteria-defined patients and rejects (for ethical and practical reasons) patients with dementia, pregnancy, comorbid illness or specific forms of treatment.22–24 Practising physicians use an inclusive definition that gathers under one name all patients with lupus spectrum illness, including those with typical SLE (criteria fulfilling), overlap syndromes (typical SLE associated with another definable autoimmune illness), undifferentiated autoimmune syndrome (UAS) (lupus-like illness that does not fulfil criteria),25–27 SLE-associated antibodies only (diagnostic autoantibodies but no clinical illness)28 and cutaneous SLE (skin disease without systemic manifestations).29
In rheumatology practice, only 35% of patients with lupus spectrum have typical SLE. Compared with patients with atypical forms of lupus spectrum disease, patients with typical SLE differ demographically, have different involved organ systems and receive different treatments.30 31 Although differences between typical and atypical patients may result in different disease mechanisms and outcomes, many SLE studies include atypical patients with neither comment nor subanalysis.32
Studies differ in how they define onset of SLE, which may be first appearance of ANA, anti-DNA antibody, symptoms, ACR criteria or diagnosis by a physician. In animal model studies, onset may be first appearance of glomerulonephritis, anti-DNA antibodies, biomarkers, gene expression profiles or disease-inducing intervention.33–35 A study that defines SLE as first appearance of arthralgia or ANA may enrol patients more than a decade earlier than does one that defines SLE as first fulfilment of ACR criteria.36 Although both studies will speak of SLE, their results cannot be compared.
Stakeholders who use different definitions describe different patients (figure 1). Clinical and basic science investigators usually use exclusive definitions (clear area, centre and bottom); by study design, they include only patients whom a practising physician has already diagnosed to have SLE, that is, after time 2. Patients, practising physicians and some investigators consider SLE to begin at time 1 (shaded area on the left). Symptoms and laboratory abnormalities first occur at the earlier date, when social, environmental and/or endogenous inducers may determine which patient will remain well, develop typical SLE or fall ill with a different lupus spectrum illness (shaded area at the top). Exogenous factors may also determine if, how, and when the clinical phenotype may change (time 4, shaded area at the right). Outcomes are measurable after a diagnosis is assigned, throughout time 3.
Most administrators, patients, practising physicians and some clinical investigators ask the question what. The answer, for which the exclusive definition works best, is the diagnosis name. Most basic and some clinical science investigators ask how, the answer being disease mechanisms, for which the exclusive definition also functions best. Some epidemiological, clinical and basic science investigators, and practising physicians ask why—the aetiology. For this question the inclusive definition is preferred.