6. Conclusion

SLE is a chronic and highly progressive autoimmune disease that carries a high risk of early death [1–3]. The incidence and prevalence of SLE are highly influenced by many factors such as race, ethnicity, age, gender, and patients' demographics [6]. Although informative reporting on SLE epidemiology is inconsistent among the different countries, it is recognized as a global disease that faces so many clinical challenges in its diagnosis, prognosis, monitoring, and management [1]. The challenging nature of SLE originates from its chaotic immunopathology in which the affected stage in the immune cascade and the extent of deregulation are highly variable among SLE patients who as a consequence express a wide array of nonhomogeneous highly protean clinical and serological manifestations making them impossible to be recognized as a single cohort of patients that can be managed equally [1, 4]. Consequently, setting specific diagnostic criteria is very challenging, and until now no defined diagnostic guidelines have been established for SLE [51, 89]. However, as a reference, clinicians have used SLE classification criteria for diagnostic purposes such as the ACR or the more recent SLICC [48, 49, 92]. Nevertheless, using classification criteria for diagnosis is problematic because they are set to include the most prevalent manifestations of the disease that occur during late or severe stages and neglect many of the early or mid-stage symptoms making them highly specific but not sensitive [89, 91]. This cannot be well suited for SLE owing to its progressive nature where many of its pathologies accrue overtime and therefore referring to classification criteria for diagnosis can dismiss many SLE patients specifically those at the early stages of the disease [1, 89, 91]. Another challenge facing SLE is the insufficient availability of reliable and specific biomarkers which are highly needed for the highly heterogeneous nature of SLE where it is highly improbable that only a single biomarker can be indicative of the wide array of manifestations [5]. Therefore, the search for distinct and specific biomarkers that can accurately mediate early diagnosis, predict disease development and emergence of disease flares, monitor disease activity, indicate specific organ damage, and guide therapies, guide reliable inclusion in eligibility criteria for conducting clinical trials, and evaluate patients' responses to novel therapeutics is highly needed and never ceased [5, 43]. Conventionally, ANAs and anti-DNA antibodies are routinely used as biomarkers for SLE as they occur in at least 70 and 95% of SLE patients, respectively, and their detection is included in the classification criteria for SLE [48, 50, 51]. However, ANAs are highly unspecific for SLE as they are detected in other autoimmune diseases in addition to a not so small proportion of the general population [44]. Anti-DNA antibodies are currently the most specific biomarkers for SLE, and their detection outside SLE is not yet found [27]. Nevertheless, anti-DNA antibodies are poor predictors for SLE activity as it happens that elevated levels of anti-DNA antibodies accompany patients in remission while normal levels accompany flared disease activity [45, 59, 61, 62]. Many promising novel biomarkers are emerging such as type I INFs which are highly elevated in a subset of SLE patients or some epigenetic biomarkers that are associated with SLE progression such as DNA methylation pattern, microRNA expression, and various histone modifications [5]. However, efforts devoted to overcome the abovementioned challenges of SLE along those employed at the discovery of novel biomarkers will not be possible without being rivaled with developments in state-of-the-art technologies that can accurately detect and monitor biomarkers with high sensitivity and specificity and in a manner that is cost-effective, rapid, easy to perform, and amenable to high-throughput screening [27, 44]. Currently, many of the technologies available for SLE diagnosis and monitoring are set to detect ANAs and anti-DNA antibodies [27, 44]. According to many investigators, the Farr assay is considered the gold standard for being able to detect high-affinity autoantibodies which are described to be more reflective of mature immune responses [27]. Nevertheless, a variety of techniques are available that all set to measure the formation of autoantibody-antigen immune complexes but differ in the source of the antigenic substrates, the way that such substrates are being exposed to the autoantibodies in the sample, the employed reaction conditions, and in the principle of detection [27, 54]. These discrepancies in the setup of the distinct assays render the differential sensitivities and specificities toward the recovered or detected autoantibodies in which a particular autoantibody can be tested positive in one assay and negative in another for the same sample [94–96]. The most important contributor for such conflicting results is the affinity of autoantibodies where some assays employ reaction settings that favor the recovery of lowaffinity antibodies such as ELISA, while others favor the recovery of high-affinity antibodies such as the Farr assay [27, 97]. Therefore, the results obtained from different assays are difficult to compare and add to the confusion already facing SLE diagnosis. With the emergence of novel biomarkers, the need for multiplex technologies that permit the simultaneous detection of many antigens in just a single test in a rapid, cost-effective, and high-throughput fashion intensifies to accommodate the multiple parameters introduced with the increased variability of detected biomarkers [112, 113, 134]. Many multiplex technologies such as autoantigen arrays, nanobarcodes, microfluidics, and addressable laser immunoassays are strongly emerging with a highly promising potential for clinical diagnosis and monitoring of SLE [93, 112]. Finally, SLE most accurately exemplifies a disease model that in crucial need for the development of personalized therapies owing to the highly versatile clinical manifestations of SLE patients who are not possible to be treated equally [3, 118]. Potent immunosuppressants are currently employed for the nonspecific management of SLE patients, but they are associated with many adverse side effects that can even be more aggressive than the disease itself [41]. The better understanding of SLE pathophysiology has helped in stratifying SLE patients into subsets that share common immune-pathologies and thus can guide many of the emerging highly promising personalized therapeutic approaches [3, 118].
