Page 62 - EJMO-9-3

Eurasian Journal of
Medicine and Oncology An update on SLE

that SLE patients have a 2 to 3 times higher risk of death Genetically, susceptibility to SLE is significantly influenced
compared to the general population, with cardiovascular by polymorphisms in key immune regulatory genes,
disease (CVD) and lupus nephritis being primary particularly within the human leukocyte antigen (HLA)
contributors to mortality. Lupus nephritis, a major region, including HLA-DR2 and HLA-DR3, which are
complication of SLE that affects the kidneys, is particularly critically involved in antigen presentation. Mutations in
common in Middle Eastern populations, including Saudi genes encoding complement components (e.g., C1q, C2,
Arabia. Studies show that 30% to 60% of SLE patients in and C4) that are essential for the clearance of immune
the region may develop nephritis, which significantly complexes and apoptotic cells further contribute to a
35
worsens long-term outcomes. 31 pathogenic milieu. In addition, non-HLA genes also
CVD is a significant cause of death among SLE patients. play a critical role in disrupting immune tolerance and
In Saudi Arabia, where the overall burden of CVD is already promoting autoimmunity in SLE. For example, genes
high – with 37% of all deaths from non-communicable involved in toll-like receptor (TLR) signaling pathways,
diseases linked to cardiovascular complications, SLE such as TLR7 and TLR9, as well as genes regulating B-cell
32
patients face an increased risk. A global study found receptor signaling, such as BLK and BANK1, contribute
36
that individuals with SLE are 10 times more likely to to the breakdown of immune regulation. This genetic
suffer from premature atherosclerosis, heart attacks, predisposition is exacerbated by environmental triggers,
and strokes compared to the general population. This with ultraviolet (UV) radiation being a prominent factor
risk is exacerbated by the high prevalence of associated that induces cell damage and the release of nuclear
37
conditions, such as hypertension, diabetes, and obesity antigens, facilitating autoantibody production. Infections,
within the Saudi population. particularly with Epstein-Barr virus (EBV), have also been
linked to SLE pathogenesis. Studies suggest that molecular
Because of its long-term impacts, SLE is considered mimicry – where EBV antigens resemble the body’s own
a significant obstacle to achieving optimal health care nuclear antigens – may lead to the production of harmful
standards. According to the World Health Organization, autoantibodies. In addition, hormonal influences,
38
stroke mortality rates in the Kingdom of Saudi Arabia especially estrogen, help explain why SLE is more common
range from 55 to 95/100,000, whereas ischemic heart in women. Estrogen is believed to enhance B-cell survival,
disease mortality rates range from 191 to 541/100,000. increase autoantibody production, and promote the
33
While SLE may not be included in these figures, they do expression of pro-inflammatory cytokines, all of which
indicate a troubling trend in both SLE-related and non- exacerbate the autoimmune response. Together, these
39
SLE public health disorders, which significantly elevate the genetic, environmental, and hormonal factors create a
overall level of illness in the community. perfect storm that drives the development and progression
Another factor contributing to SLE-related mortality of SLE.
in Saudi Arabia is the relatively late diagnosis and A major breakdown in immune regulation is central
limited access to specialized care. Early intervention to the pathogenesis of SLE, leading to the production of
and comprehensive disease management are critical a wide range of autoantibodies, particularly ANAs. These
for improving outcomes; however, many patients may antibodies target components of the cell nucleus, such as
present with advanced disease due to delays in diagnosis, dsDNA, histones, and ribonucleoproteins. This aberrant
particularly in rural areas where healthcare resources are antibody production is precipitated by defective clearance
scarcer. The severity of the issue in the kingdom is further of apoptotic cells and immune complexes, resulting in the
compounded by the high prevalence of obesity and low persistent presence of nuclear antigens in the extracellular
levels of physical activity, which are major risk factors for milieu. Dendritic cells play a key role in this regard by
the SLE. 34 picking up these antigens and presenting them to T-cells,
40
3. Pathogenesis of SLE which then activate and help autoreactive B-cells. This
chain of events leads to the formation of germinal centers in
SLE is a complex autoimmune disease characterized by the secondary lymphoid organs, where B-cells undergo somatic
abnormal production of autoantibodies that target nuclear hypermutation and class-switch recombination, ultimately
antigens. This results in widespread tissue inflammation churning out high-affinity autoantibodies. A critical part
and damage, often affecting multiple organs. While of this process involves TLRs, especially TLR7 and TLR9,
the exact cause of SLE remains not fully understood, its which are activated by nucleic acids. This triggers signaling
development involves a complex interaction between pathways, such as nuclear factor kappa B and interferon
genetic factors, environmental triggers, hormonal regulatory factors, leading to the production of type I
influences, and dysregulation of the immune system. interferons (IFNs). Type I IFNs, particularly IFN-α, are
41

Volume 9 Issue 3 (2025) 54 doi: 10.36922/EJMO025090042