The Importance of Sex Stratification in Autoimmune Disease Biomarker Research: A Systematic Review

Abstract

The immune system is highly dynamic and regulated by many baseline characteristic factors. As such, significant variability may exist among different patient groups suffering from the same autoimmune disease (AD). However, contemporary research practices tend to take the reductionist aggregate approach: they do not segment AD patients before embarking on biomarker discovery. This approach has been productive: many novel AD biomarkers have recently been discovered. Yet, subsequent validation studies of these biomarkers tend to suffer from a lack of specificity, sensitivity, and reproducibility which hamper their translation for clinical use. To enhance reproducibility in validation studies, an optimal discovery-phase study design is paramount: one which takes into account different parameters affecting the immune system biology. In this systematic review, we highlight need for stratification in one such parameter, i.e., sex stratification. We will first explore sex differences in immune system biology and AD prevalence, followed by reported sex-bias in the clinical phenotypes of two ADs—one which more commonly affects females: systemic lupus erythematosus, and one which more commonly affects males: ankylosing spondylitis. The practice of sex stratification in biomarker research may not only advance the discovery of sex-specific AD biomarkers but more importantly, promote reproducibility in subsequent validation studies, thus easing the translation of these novel biomarkers from bench to bedside to improve AD diagnosis. In addition, such practice will also promote deeper understanding for differential AD pathophysiology in males and females, which will be useful for the development of more effective interventions for each sex type.

Clinical characteristics and survival of 413 patients with systemic lupus erythematosus in southeastern areas of South Korea: A multicenter retrospective cohort study

“…Gender exerts an effect on the prevalence as well as the clinical phenotype and outcome in SLE . Male patients with SLE tended to have higher mortality than their female counterparts in previous studies, which was also found in our cohort (Table ). Nevertheless, contradictory results have been reported .…”

“…Because of the overall low number of deaths in previous studies and our study, larger prospective studies are warranted to conclusively determine whether male gender is associated with increased mortality in SLE. In addition, previous studies reported that men with SLE showed serositis, renal diseases, and cardiovascular complications more frequently, but less frequently with arthritis and photosensitivity compared with their female counterparts . However, except for arthritis, these findings were not observed in our data, and this may be due to the small number of male patients in our cohort (Table ).…”

An Intergenic rs9275596 Polymorphism on Chr. 6p21 Is Associated with Multiple Sclerosis in Latvians

“…In the Latvian population, rs9275596 rare allele (C) was identified as a risk factor in the MS common cohort (p < 0.001) and appears to be disease-susceptible in the female group (p < 0.01, Figure 4). Sex-specific differences in incidence, prevalence, and severity are well-known features of autoimmune disease epidemiology [36], including MS [2]. Stratification of the MS cohort in the Latvian population by sex revealed significant differences in alleles (p < 0.01, multiplicative model) and genotypes frequency (p < 0.001, recessive model; Table 1).…”

Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation

“…This was not observed in wild-type mice or in response to individual p110a or p110d deletion in the same cohort. It is interesting to note that females were more susceptible than male mice as this is often the case in human autoimmune disorders and indicate that the mechanisms underlying this phenotype could be relevant to human disease (56). Spontaneous peripheral neuropathy has been described in females aged 99-100 wk from several mouse strains, including C57BL/6 mice (57).…”