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Epidemiology
Introduction
Systemic lupus erythematosus (SLE) is a complex multisystemic autoimmune disease characterized by a wide spectrum of clinical manifestations, overabundant immunological and laboratory abnormalities, and a variable course and outcome. Descriptive, observational and experimental studies, and a few population-based ones have used classification criteria to include patients with similar clinical and laboratory abnormalities and are the basis for the epidemiological data currently available.
In 1982 the American College of Rheumatology (ACR) developed and validated classification criteria to consistently define SLE for research and epidemiological surveillance; these criteria were updated but never validated in 1997 and are used for case definition nowadays. In 2012 the Systemic Lupus International Collaborating Clinics (SLICC) group revised these criteria establishing a more precise and clinically relevant set; in fact, clinical relevance and sensitivity increased but not specificity. These criteria allow the inclusion of patients with biopsy-proven nephritis in the presence of autoimmunity markers [antinuclear antibodies (ANA) and/or anti-dsDNA antibodies]. By including alopecia and other neurological manifestations and by separating acute and chronic cutaneous lupus manifestations improved clinical relevance was attained. More recently, the European League Against Rheumatism (EULAR) and the ACR have developed a new set of criteria using a four-phase process that present two main differences with the previous criteria sets: (1) the premise is that to enter the classification criteria, a patient had to be ANA positive, and (2) that different criteria exert a different weight toward their fulfillment; the overarching goal of these new criteria is to be able to classify patients as having lupus earlier than with the ACR or the SLICC criteria. The overarching goal of any set of criteria is to identify potential participants for clinical research studies, which requires some degree of homogeneity across subjects, while simultaneously dealing with the extreme heterogeneity of SLE. Thus using a system that achieves the maximum combination of sensitivity and specificity for SLE while retaining face validity.
While the use of the EULAR/ACR criteria may be advantageous for clinical trials as a more homogeneous group of patients are identified, all being ANA positive, conversely, for longitudinal observational studies, adhering to this entry-criterion may distort the natural history of the disease as ANA negative patients will, by definition, be excluded. The proof of this is that among patients with established lupus, the frequency of ANA negativity can vary from approximately 5%–30% depending on the assay kit used. The lack of extensive data on the longitudinal expression of ANA could affect the application of classification criteria in which ANA positivity is the entry point, especially without indication of the time point in the disease for ANA testing or the kit used for any historical value. Moreover, the ANA 1:80 criteria may also be in detriment of the specificity of SLE diagnosis. Further utilization of the 2019 EULAR/ACR criteria across the world will yield important information over the next few years determining how useful they may be in the clinical and research settings.
Incidence and prevalence
Using, for the most part, the ACR criteria (1982 or 1997) to classify patients, the overall incidence rates for SLE have varied around the globe from approximately 0.3–23.7 per 100,000 person-years, whereas prevalence rates have ranged from 6.5 to 178.0 per 100,000. Detailed data on the incidence and prevalence of SLE around the world from 1975 to 2016 and from 2017 onwards have been published. Herein we will describe the most salient studies.
There is no consensus related to temporal changes of SLE incidence and prevalence rates. Uramoto et al. demonstrated in a US population-based study that the disease has more than tripled in the past 40 years, which likely reflects not only an actual increase in disease occurrence but a more accurate case ascertainment, the inclusion of milder cases and the use of ANA testing. However, a recent UK cohort study using a clinical practice research data link has shown a decline of 1.8% in SLE annual incidence while its prevalence increased from 64.9 per 100,000 in 1999 to 97.04 in 2012.
The wide variations in the SLE incidence and prevalence rates most likely represent differences in patient characteristics such as age, gender, ethnic/racial group, geographic region, national origin, socioeconomic status (SES), and environmental exposures. However, differences in case ascertainment (self-reported, physician diagnosed, inclusion of serology), study type and time when the study was conducted may also explain these differences. A practical example of differences according to case ascertainment comes from different US CDC-funded SLE registries using capture–recapture analyses that were conducted to assess case under ascertainment and found a capture–recapture adjustment increased prevalence and incidence rates.
Distribution according to gender
SLE is more frequent in women than in men, in particular in females of child-bearing age, with a female to male ratio of 8–15:1. In prepuberal and late-onset lupus the ratio is 2.0–8:1. In the California Lupus Surveillance Project, the age-standardized incidence and prevalence was up to 12 times higher among women (8.6 and 155.6, respectively) than among men (0.7 and 19.3, respectively). Nevertheless, prevalence and incidence rates tend to be similar before puberty diverging sharply thereafter, with a maximum ratio difference during the childbearing years until approximately the seventh decade of life where rates again become similar. Importantly, the peak incidence/prevalence rates among women occur approximately 10–20 years earlier than in men.
Hormones, primarily estrogens, and candidate risk genes for SLE in the X chromosome that are crucial in determining sex hormone levels, and some immunologically relevant genes (interferon-related and CD40 ligand) probably explain the preponderance of lupus among women.
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