5th June 2025

Aetiology

The aetiology of SLE is not understood, but it is generally agreed that an environmental factor affecting a genetically susceptible individual is fundamental in its pathogenesis. The high female preponderance also suggests hormonal factors may play a role. 

The importance of genetic factors is confirmed by familial aggregation and higher-than-expected rates of concordance in twin studies, with the heritability of SLE estimated at 43.9%. Genome-wide association studies have identified more than 60 genetic risk loci, with the one most consistently associated with SLE shown below:

• IRF5 (interferon regulatory factor 5) codes a transcription factor involved in the regulation of pro-inflammatory cytokines 
• STAT4 (signal transducer and activator of transcription 4) acts as a transcription activator and helps mediate responses to interleukin-12 in lymphocytes and regulate T helper cell differentiation
• BANK1 (B-cell scaffold protein with ankyrin repeats 1) codes for a B-cell-specific scaffold protein and may contribute to SLE by altering B-cell signalling
• ITGAM (integrin alpha M) – polymorphism of this gene has a significant association with SLE in multiple ethnic populations
• PTPN22 (protein tyrosine phosphatase, non-receptor type 22) inhibits T-cell receptor signalling and selectively promotes type I interferon responses; a missense single-nucleotide polymorphism of this is associated with an increased risk for SLE 

Related environmental factors may be non-infectious or infectious. 

• Infectious agents include Epstein-Barr virus (EBV), parvovirus B19, cytomegalovirus (CMV) and human immunodeficiency virus 1 (HIV1).
• Non-infectious agents can include exposure to sunlight, drugs, hormones, toxins such as cigarette smoke or stress and emotional upset. 
• Drugs can either be an environmental factor triggering a flare or unmasking of latent LE, or can specifically cause drug-induced lupus erythematosus, which is a lupus-like syndrome different from idiopathic LE. 

Drug-induced LE has a time relationship with the causative drug, with symptoms beginning after starting treatment with the causative drug. However, the latent time between starting the medication and the symptoms beginning can range between 1 month and 10 years, which can make it very difficult to establish a causative relationship. Unlike idiopathic LE, drug-induced LE resolves once the causative agent is stopped. Some of the drugs commonly associated with LE are procainamide, minocycline, terbinafine, sulfasalazine, isoniazid, phenytoin and carbamazepine