Review Article
Influence of the environment, gender, and hormones on systemic lupus erythematosus: A narrative reviewLa influencia del ambiente, el género y las hormonas en el lupus eritematoso sistémico: revisión narrativa de la literatura

https://doi.org/10.1016/j.rcreu.2021.02.008Get rights and content

Abstract

Systemic lupus erythematosus (SLE) is a multi-systemic inflammatory autoimmune disease whose etiology is incompletely understood. It is thought that certain environmental exposures’trigger’ or accelerate the disease in genetically predisposed individuals. The aim of this narrative review is to provide an overview of the latest findings on established environmental factors related to the pathophysiology of SLE and a brief summary of those for which evidence is beginning to be gathered on their role in SLE.

Resumen

El lupus eritematoso sistémico es una enfermedad autoinmune inflamatoria multisistémica de etiología todavía no claramente dilucidada. Se cree que ciertas exposiciones ambientales pueden desencadenar o acelerar la aparición de la enfermedad en individuos genéticamente predispuestos. Esta revisión narrativa de la literatura aborda los hallazgos más recientes en factores ambientales relacionados con la fisiopatología del lupus eritematoso sistémico y resume brevemente aquellos para los cuales se está comenzando a reunir evidencia sobre su papel en esta enfermedad.

Introduction

Systemic lupus erythematosus (SLE) is a complex multisystemic, chronic autoimmune disease that can affect virtually any organ system of the body. The etiology remains unknown, but it is likely due to loss of immune tolerance to self-antigens and induced autoimmunity in genetically predisposed individuals; this is driven by a complex interplay of defective clearance of apoptotic waste and immune complexes along with neutrophil extracellular traps, sensing of nucleic acids, disrupted lymphocyte biology, and interferon pathways which are triggered by exposure to some environmental factors.

The association of many genes with a predisposition to develop SLE has been clearly established; these genes usually encode for immune components such as HLA-DRB1*B8, HLA-DRB1*DR3, HLA-DRB1*DR2, IRF5, ITGAM, STAT4, BLK and CTLA4, among others.1 Genome-wide association studies (GWAS) have identified more than 1002 single nucleotide polymorphisms (SNPs) that play a role in SLE pathogenesis as well as contribute to disease onset and clinical manifestations.3, 4 Together, they explain the heritability of SLE in up to 47% of the patients and a pairwise concordance rate ranging from 11% to 50% in monozygotic twins.5, 6, 7, 8, 9 The penetration of the disease has been determined in multiple studies. A population-based family study carried out in the Taiwan National Health Insurance Research Database including 23,658,577 individuals, found that having an affected first-degree family member with SLE resulted in an adjusted risk ratio (RR) of 16.92 [95% Confidence Interval (CI) 15.23 to 18.80], while twins of SLE patients have a RR of 315.94 (95% CI 210.66 to 473.82) to develop the disease. Having parents affected had a RR to develop SLE of 14.42 (95% CI 12.45 to 16.70) and siblings of 23.68 (95% CI 20.13 to 27.84).9 The relatively low penetrance of the disease implies that environmental factors and epigenetic changes play important roles in the etiology of SLE.10 It is remarkable that in the same study, spouses were found to have a RR of 4.44 (95% CI 2.38 to 8.30) while sharing environmental but not genetic factors. Anti-double-stranded DNA (dsDNA) antibodies are also more frequently present in laboratory workers handling blood from patients with SLE, in comparison with low exposure groups.11 In another study conducted in Taiwan, a small, but statistically significant higher frequency of lupus in dogs owned by patients with SLE was found.12 These observations further support the role of an environmental and, possible transmissible factor in the development of SLE.

Some of the established environmental factors involved in the pathophysiology of SLE include hormones and gender, drugs, UV light exposure, and certain viral infections such as Epstein-Bar Virus (EBV), Retrovirus and Human Endogenous Retrovirus (HERV) (Table 1, Table 2).

This monograph will focus on the latest findings on established hormonal, and other environmental factors related to the pathophysiology of SLE.

Section snippets

Methods

We conducted a literature search in PubMed using the following Medical Subject Headings (MeSH) terms “systemic lupus erythematosus” AND “Environment” OR “Hormones” OR “Sex”. Articles in English were considered. No restrictions regarding the date of publication were applied. References of included articles were scrutinized for additional relevant literature.

Epidemiology

Lupus is distributed worldwide with a significant predilection for women of childbearing age with a female to male ratio up to 13:1 in this age group while it is only 2:1 in children and in older individuals.13, 14, 15 SLE is present across ethnicities, but it is more prevalent in non-Caucasians. While prevalence in Europe and United States is higher in people of African descent, SLE is infrequent in Africa16, 17; this has been called the African gradient for which not a clear explanation has

Sex, hormonal, and reproductive factors

While mechanism are not completely understood, epidemiologically, SLE development and severity appear to be influenced by steroid hormones, as 90% of patients with SLE are women, especially during their childbearing years; SLE is also more frequent in men with Klinefelter syndrome (14 times more frequently in comparison with men without SLE).23 Patients with Klinefelter syndrome exhibit some typical biochemical findings, including low serum total and free testosterone, and high

Infections

Infections caused by EBV, Parvovirus B19, and HERV have been linked to the pathogenesis of SLE, while data for other infectious agents, such as cytomegalovirus, Hepatitis C virus and some bacterial agents such as vibrio cholera and group A streptococcus, are being gathered at the present time. The data suggest that may all have a role in the pathogenesis of SLE by inducing aberrant innate and adaptative immunity, leading to a loss of tolerance toward autoantigens; however, the associations of

Ultraviolet irradiation (UVR)

It has been established that UVR exacerbates pre-existing and new cutaneous lesions, and photosensitivity is one of the classification criteria established by the ACR for SLE. However it remains unclear whether UVR induces the development of the disease.95 Only a few studies have examined exposure to UVR and the risk of SLE, with potential inaccuracy of exposure assessment and time bias, given that photosensitivity due to SLE can be present well before its diagnosis is made.96

UVR strength is

Conclusions

Significant progress has been made disentangling some clues of the SLE etiology, determining the hormonal and environmental factors whose exposure could lead to the onset or activation of SLE. Female sex and hormonal influence are significant risk factors for SLE. The use of estrogen OC and postmenopausal HRT can cause flares in SLE patients and have been associated with a higher incidence of SLE. Elevated levels of prolactin are seen in patients with SLE. Several viral infections have been

Conflict of interests

None declared.

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