Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci. In the early 70s, complement deficiencies led to the description of familial forms of SLE caused by a single gene defect. High-throughput sequencing has recently identified an increasing number of monogenic defects associated with lupus, shaping the concept of monogenic lupus and enhancing our insights into immune tolerance mechanisms. Monogenic lupus (moSLE) should be suspected in patients with either early-onset lupus or syndromic lupus, in male, or in familial cases of lupus. This review discusses the genetic basis of monogenic SLE and proposes its classification based on disrupted pathways. These pathways include defects in the clearance of apoptotic cells or immune complexes, interferonopathies, JAK-STATopathies, TLRopathies, and T and B cell dysregulations.

It is, so to say, not a prerogative authority assigned to SLE classification criteria that allow them to declare something definitively important about SLE. This is particularly true as criteria-based classification processes overrule the highly needed evolution of concise diagnostic criteria. It is classification criteria that allocate SLE patients into cohorts intended to describe the nature of their disease. Therefore, all major SLE classification criteria since the 1971 preliminary criteria usurp the role of diagnostic criteria. Today´s practice silently accept that the SLE classification process \"diagnose\" SLE patients despite the fact that classification criteria are not accepted as diagnostic criteria! This is a central paradox in contemporary SLE research strategies. Contemporary SLE cohorts are designed to investigate SLE´s etiological features. However, each cohort that is categorized by classification criteria has one central inherent problem. From theoretical and practical arguments, they embody multiple distinct clinical phenotypes. This raises the critical and principal question if phenotypically heterogenic SLE cohorts are useful to identify basic SLE-specific etiology(ies) and disease process(es). In times to come, we must prioritize development of firm diagnostic criteria for SLE, as the classification criteria have not contributed to reduce the enigmatic character of the syndrome. No radical improvements are visible in the horizon that may lead to concise investigations of SLE in well-defined homogenous SLE cohorts. We must develop new strategies where studies of phenotypically standardized cohorts of SLE must be central elements. Problems related to contemporary SLE classification criteria are contemplated, analyzed, and critically discussed in this study.

Systemic lupus erythematosus (SLE) is a complex disease with different genetic, immunologic, and environmental factors contributing to the pathogenesis. Monogenic SLE could help us understand the main phases of immune dysregulation in SLE. The aim of this review is to summarize the current knowledge on monogenic SLE with the implications of the respective genes on disease pathogenesis. A comprehensive literature search on monogenic SLE was conducted utilizing the Cochrane Library and MEDLINE/PubMed databases. The main affected pathways in disease pathogenesis are identified as follows: complement system, apoptosis, nucleic acid degradation, nucleic acid sensing, self-tolerance, and type I interferon production. Further studies on monogenic SLE can make precision medicine possible for SLE by increasing our understanding of disease pathogenesis.

Paediatric-onset systemic lupus erythematosus (SLE) is usually more severe than its adult counterpart. In particular, there is a higher incidence of renal and central nervous system involvement. Specific measures to assess disease activity and damage have been implemented. The disease is very rare before the fifth birthday and therefore the onset of an SLE picture in the first years of life should lead to the suspicion of the presence of one of the rare monogenic diseases that causes SLE or of one of those congenital diseases that has been showed to be closely associated with the SLE.