Systemic lupus erythematosus

The central defect in SLE is a loss of immune tolerance, leading to aberrant activation of T and B lymphocytes and the production of pathogenic autoantibodies, particularly against double-stranded DNA (anti-dsDNA) and other nuclear components. These autoantibodies form immune complexes that deposit in tissues, triggering complement-mediated inflammation and organ damage. Key mechanisms include defective clearance of apoptotic debris, dysregulation of type I interferons, and abnormal signaling through Toll-like receptors. Genetic susceptibility involves multiple loci, including HLA-DR2 and HLA-DR3, as well as genes such as IRF5, STAT4, and PTPN22, which influence immune responses. Epigenetic modifications, such as DNA hypomethylation in T cells, also contribute to disease pathogenesis.

SLE can affect virtually any organ, with common features including malar rash, photosensitivity, oral ulcers, non-erosive arthritis, serositis (pleuritis or pericarditis), and hematologic abnormalities such as leukopenia, lymphopenia, and thrombocytopenia. Renal involvement, termed lupus nephritis, occurs in about 40% of patients and is a major predictor of morbidity and mortality. Neuropsychiatric lupus can present with seizures, psychosis, or cognitive dysfunction. Diagnosis relies on the 2019 EULAR/ACR classification criteria, which require a positive antinuclear antibody (ANA) test and weighted clinical and immunological domains. Anti-dsDNA and anti-Smith antibodies are highly specific, while low complement levels (C3, C4) indicate active disease.

Management of SLE is individualized, aiming to control disease activity and prevent organ damage. Hydroxychloroquine is recommended for all patients unless contraindicated, as it reduces flares and improves survival. Corticosteroids and immunosuppressants such as mycophenolate mofetil, azathioprine, and cyclophosphamide are used for moderate-to-severe disease, particularly lupus nephritis. Belimumab, a monoclonal antibody against B-lymphocyte stimulator (BLyS), is approved for active, autoantibody-positive SLE, and anifrolumab, targeting type I interferon receptor, is used for moderate-to-severe disease. Emerging therapies include CAR-T cell therapy and proteasome inhibitors, which have shown promise in refractory cases. Non-pharmacologic measures include sun protection, smoking cessation, and vaccination (excluding live vaccines in immunosuppressed patients).

Beyond the classic presentation, SLE has several underrecognized facets. The disease was first described by Moritz Kaposi in 1872, and the term 'lupus' (Latin for wolf) was used earlier to describe skin lesions that resembled a wolf's bite. A notable historical case is that of the American singer Seal, who has discoid lupus, a form limited to the skin. In terms of epidemiology, SLE is more common and severe in people of African, Hispanic, and Asian descent, and it is associated with a higher risk of cardiovascular disease, even in young women. Pregnancy in SLE is high-risk, with increased rates of miscarriage, pre-eclampsia, and neonatal lupus (which can cause congenital heart block). Environmental triggers include ultraviolet light, infections, and certain drugs (e.g., hydralazine, procainamide) that can induce a lupus-like syndrome. Additionally, the gut microbiome may modulate disease activity, and vitamin D deficiency is common and linked to worse outcomes.

Antinuclear antibody (ANA)

An autoantibody that targets components of the cell nucleus; a hallmark of SLE.

Lupus nephritis

Inflammation of the kidneys caused by SLE, a major cause of morbidity.

Malar rash

A butterfly-shaped rash across the cheeks and nose, characteristic of SLE.

Anti-dsDNA

Antibodies against double-stranded DNA, highly specific for SLE and associated with nephritis.

Hydroxychloroquine

An antimalarial drug used as a cornerstone of SLE treatment.