State of the Art REVIEW
lupus erythematosus, 1 although differences in methodology between studies could also contribute. Nevertheless, the consensus is that systemic lupus erythematosus disproportionately affects women, with a female to male ratio of about 9:1, and certain populations, including African Americans, Amerindians, and Asians. 1 2 In the United States, the overall prevalence of systemic lupus erythematosus was estimated to be 72.8 per 100 000, with an overall incidence of 5.1 per 100 000 person years from 2002 to2009. 2 3 An upward trend in both incidence and prevalence of systemic lupus erythematosus was recently identified in a US population study in Minnesota, in which the prevalence of systemic lupus erythematosus increased from 30.6 per 100 000 in 1985 to 97.4 in 2015, with a 2% annual increase in incidence over 43 years (1976-2018). 4 This increase could relate to increased recognition. Similar patterns of increased prevalence of systemic lupus erythematosus over time have also been identified in other geographic regions, including Europe and Asia. 1 5 6 Sources and selection criteria We searched PubMed and Medline for publications on systemic lupus erythematosus from 2010 to2022 in two parallel search strategies. For clinical studies, we used the search term “lupus” and the filters “clinical study”, “clinical trial”, and “randomized controlled trial”, yielding 1238 reports. Case reports, purely descriptive studies, uncontrolled trials, and studies with few participants were excluded. For studies of pathogenesis, we used the search terms “systemic lupus erythematosus” AND “human” AND “English” AND “molecular pathogenesis” NOT “review”, which returned 1272 results. Studies that were exclusively in vitro or in experimental animals, or with findings of limited reproducibility within the report or between reports, were excluded. Clinical studies that were prioritized included large double blind randomized controlled trials (including both lupus and lupus nephritis trials), those with large numbers of subjects or comprehensive scope, and for basic and translational science, we prioritized those with robust or replicated supporting data, or multiple parallel lines of evidence supporting the conclusions. Classification and diagnosis The diagnosis of systemic lupus erythematosus remains a clinical one. 7 However, the use of classification criteria has been widely adopted for research purposes, enabling consistency between studies. Classification criteria for systemic lupus erythematosus have latterly evolved from the widely used American College of Rheumatology criteria that were last updated in 1997, 8 and a competing classification system produced by an international group of expert clinicians, the systemic lupus international collaborating clinics (SLICC), intended to increase sensitivity while retaining specificity. 9 Both sets of criteria determine if the number of
defined manifestations exceeds a threshold, which would be a testament to the implicit assumption of multisystem involvement in systemic lupus erythematosus. Recently, a joint effort between the American College of Rheumatology and the European Alliance of Associations for Rheumatology (EULAR) produced new classification criteria, 10 centered around an entry requirement for a positive antinuclear antibody test and scored using weighted domains for various clinical and laboratory findings. The sensitivity of these criteria is reflective of the SLICC criteria, while retaining the specificity of the earlier American College of Rheumatology criteria. Classification criteria have been used in virtually all studies discussed in this review. Importantly though, unlike malignant or infectious diseases where a causal mutation or microorganism is implicit to the diagnosis, classification of a patient as having systemic lupus erythematosus does not imply a specific causal pathology. The pooling of clinically dissimilar cases under a single diagnostic rubric reinforces the concept that systemic lupus erythematosus is heterogeneous, in a sort of taxonomic vicious cycle. As outlined in subsequent sections, evidence is mounting for considerable biological heterogeneity among patients classified clinically as having systemic lupus erythematosus, posing the possibility that classifying dissimilar pathologies under a single umbrella term is an error. 11 This possibility complicates all research in the lupus field, from clinical measurement and trials through to genetic and biological analysis. Knowledge of the pathogenesis of systemic lupus erythematosus has advanced considerably in the past two decades, accelerated by a move towards studying human systemic lupus erythematosus instead of murine models, and technologies allowing studies of gene sequencing and gene expression in large cohorts. We consider certain aspects of pathogenesis to now represent settled science, while many unanswered questions remain (table 1). Genetics Pathogenesis of systemic lupus erythematosus: susceptibility Systemic lupus erythematosus is characterized by a strong familial concordance, including greater concordance in monozygotic twins than dizygotic twins (24-56% in monozygotic v 2-4% in dizygotic 12 13 ), and a risk in first degree relatives similar to that of dizygotic twins. The pattern of inheritance generally fits that of a genetically complex disease with multiple moderate risk factors. 14 15 Recent genome wide association scans have supported this idea, with many genetic risk loci identified with odds ratios for disease between 1.2 and 1.7, and some that fall above or below this range. 15-17 The HLA region is the strongest common risk factor for systemic lupus erythematosus, including alleles of HLA-DR. A recent study identified that the HLA class II genetic association appears to
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doi: 10.1136/bmj-2022-073980 | BMJ 2023;383:073980 | the bmj
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