Sources of Complexity and Clinical Heterogeneity in SLE

Clearly, SLE is a clinically complex disease such that two patients may share no common feature and yet still be diagnosed as having the illness. This fact is exemplified in the classification criteria, for which presence of any 4 of 11 criteria allows classification as SLE (1). SLE may involve almost any organ system with the mucocutaneus, musculoskeletal, neurological, hematological, immunological, cardiovascular, pulmonary, and renal systems all included in the criteria. Thus, the pattern of manifestations varies greatly between indi viduals, making the disease as clinically diverse as any single entity in modern medicine. So, it can easily be imagined that the complex clinical picture will have an impact on and produce an equally complex genetic etiology.

In general, SLE may range from not much more than a nuisance to an immediately life-threatening illness. Mortality in SLE is associated with several disease features, including thrombocytopenia most prominently (15,16). Nonetheless, prediction of severity of disease or mortality in an individual remains virtually impossible. Thus, the disease has marked heterogeneity regarding its severity as assessed by mortality.

Another area in which there is great heterogeneity in SLE is the immuno-logical manifestations. Although almost every patient has ANAs, the specificity of these autoantibodies varies widely. There are four prominent protein autoantigen specificities. Anti-Ro (or SSA) is found in the sera of about 40% of patients with SLE, some of whom also have anti-La (or SSB), which is never found without the simultaneous presence of anti-Ro. An analogous situation exists for anti-RNP and anti-Sm. Anti-RNP is found in the sera of about 40-50% of patients with SLE, and anti-Sm is found in 5-20% of sera but is always found in conjunction with anti-RNP. There are many clinical, immuno-logical, and immunogenetic associations for each of these autoantibodies. For example, anti-Ro is strongly associated with genetic deficiency of early complement components, such as C2 and C4 (reviewed in ref. 17), and is associated with neutropenia (18). Of course, the other prominent autoantibody system in SLE is that binding native (double-stranded) DNA. The presence of anti-dsDNA is associated with kidney disease.

Overall, the large variety of clinical/immunological changes noted and the variability seen across subjects imply that SLE is an etiologically heterogeneous disease phenotype. In addition, the number of major anomalies observed in different body organs or systems demonstrates a very likely complex etiology for SLE. Because SLE is an extremely complex disease, genetic susceptibility to SLE is likely to be polygenic, involving several genes of low penetrance with allelic (different variants within the same gene) as well as locus (genetic variants in separate genes) heterogeneity and complicated epitasis, gene-environmental interactions.

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