3. Diagnosis

Diagnosis of SLE, according to the majority of clinicians, is best established upon combinatorial approach. Thus, a combination of patients' clinical manifestations and laboratory investigations that can comprise autoantibody assays, blood tests, cell cultures, certain functional tests such as echocardiogram, or imaging such as neuroimaging must be adopted [1, 51, 89]. The decision upon any of the aforementioned investigations is guided by the patient's clinical presentations [51]. In addition, other important factors must be examined including patient's history, risk factors, SLE prevalence within the patient's demographic population, and other epidemiological data. Clinical expertise is also crucial as a highly heterogeneous disease such as SLE can be easily missed or misdiagnosed [1, 51, 89]. Some clinical manifestations are strongly associated with SLE and are therefore of high diagnostic significance such as alopecia, leukopenia, neurological involvement, oral ulcers, and serositis [51].

Nevertheless, until now no diagnostic criteria have been established for SLE due to extreme disease heterogeneity where no consistent clinical presentation or degree of disease severity appears within the cohort of SLE patients [51, 89]. Therefore, clinicians had to refer to a sort of guidelines to aid proper diagnosis and relied on SLE classification criteria such as the revised American College of Rheumatology (ACR) classification criteria for SLE for clinical diagnosis [48, 49].

The ACR classification encompasses a total of 11 criteria for defining SLE including an individual criterion for abnormally elevated titers of antinuclear antibodies that are detected by immunofluorescence immunoassay, which will be described later, or any other equivalent assay and another criterion specifying immunologic abnormalities that include the release of aberrant titers of anti-DNA antibodies or anti-Sm antibodies [48]. Based on ACR, at least 4 of the 11 criteria must be met for a patient to be classified with SLE disease [48]. However, ACR criteria are more suited for severe cases of SLE and not patients with mild or moderate conditions as it includes the most pronounced manifestations and excludes some of the clinical presentations shown by patients at early or mid-stages which are considered important. Clinical presentations need to be taken in consideration as SLE is known to be a progressive disease that tends to exacerbate over time and establish many of the clinical and serological manifestations in an accumulating manner [1, 90]. Therefore, the ACR classification criteria have a specificity reaching 96% but with a suboptimal sensitivity of 83% [89]. Specificity here is defined as the percentage of individuals who are known to be devoid of the disease and test negative for it, while sensitivity refers to the percentage of patients who are known to have the disease and test positive for it [91]. With the aim of overcoming the limitations of the ACR classification, the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria have been set in 2012 to encompass many of the clinical manifestations overlooked by ACR to reach a total of 17 criteria instead of 11 where at least 4 out of the 17 criteria must be met for a patient to be classified with SLE [50]. In SLICC, the antinuclear antibody criterion was not changed. However, the immunologic abnormalities criterion in ACR has been separated into individual criteria including a separate criterion for abnormal titers of anti-DNA antibodies but with a more strict cutoff value and a separate criterion for anti-Sm antibodies highlighting the importance of such autoantibodies in the diagnosis of SLE [50]. Nevertheless, despite an increase in sensitivity to reach 97% in SLICC compared to 83% in ACR, the specificity has been reduced to 84% compared to 96% in ACR [50]. Moreover, SLICC criteria did not improve the inclusion of SLE patients at early stages except for patients with renal nephritis damage [92].

However, it should be noted that relying on classification criteria for diagnosis is actually problematic as both disease classification and diagnosis do not generally share the ultimate aim [89, 91]. Diagnosis aims at identifying a patient's illness in terms of its causes and nature and is based on a set of diagnostic criteria that include a number of clinical symptoms and investigations that are used routinely for guiding the clinical care of patients [91]. Therefore, diagnostic criteria should have nearly 100% specificity and sensitivity [89, 91]. On the other hand, classification criteria are basically established to define a total population of patients having a specific disease that can be recruited for clinical research. They, therefore, encompass the most prominent and prevalent manifestations dropping out the rarer or less common symptoms and thus typically enjoy high specificity but at the expense of sensitivity. Consequently, using classification criteria for diagnosis can easily miss or overlook patients with the disease [1, 89, 91].

With the emergence of new biomarkers that are strongly associated with SLE pathogenesis as described above, it is highly suggested that these biomarkers will reserve their places in future developments and optimization in diagnostic criteria next to autoantibodies which will not only aid accurate diagnosis but will significantly guide patients' clinical care and management. The increasingly accumulating data in SLE biomarkers will need to be paralleled with the development of new sensitive and reliable detection technologies that are able to simultaneously detect disease biomarkers in a rapid, cost-effective, and sensitive manner [93]. In the next section, current and new trends in diagnostic technologies for SLE will be discussed.
