Systemic lupus erythematosus

The aetiology of systemic lupus erythematosus (SLE) is not known but the interaction of an environmental agent in a genetically susceptible host is thought to be fundamental.[10] The strong female preponderance also suggests a role for hormonal factors.[11][12]

Genetic factors

Familial aggregation and higher-than-expected rates of concordance in twin studies suggest that genetic factors are important.[13][14] The heritability of SLE has been estimated to be 43.9%.[15]

Genome-wide association studies have identified more than 60 genetic risk loci.[16] Predisposing genes may activate the innate or adaptive immune response, or have a potential role as self-antigen for autoreactive B cells.[17] Consistently reported SLE-associated loci include:[18][19][20][21][22][23][24]

IRF5 (interferon regulatory factor 5), which codes a transcription factor involved in the regulation of the expression of pro-inflammatory cytokines by several cell types
STAT4 (signal transducer and activator of transcription 4), which acts as a transcription activator; essential for mediating responses to interleukin-12 in lymphocytes, and regulating the differentiation of T helper cells
BANK1 (B-cell scaffold protein with ankyrin repeats 1), which encodes a B-cell-specific scaffold protein; may contribute to lupus by altering B-cell signalling
ITGAM (integrin alpha M); significant association between ITGAM gene polymorphism and SLE in multiple ethnic populations
PTPN22 (protein tyrosine phosphatase, non-receptor type 22), a regulator of immune homeostasis through inhibition of T-cell receptor signalling and by selectively promoting type I interferon responses; associated with autoimmune disease; a missense single-nucleotide polymorphism is associated with increased risk for SLE.

Environmental factors

The association of environmental factors with SLE may be due to non-infectious or infectious factors.

Non-infectious environmental factors

Exposure to ultraviolet (UV) radiation can exacerbate skin lesions in lupus erythematosus patients (photosensitivity).[25] Prospective, methodologically robust studies are required to evaluate the relationship between UV-B and incident SLE.

Smoking has been demonstrated to increase the risk of SLE, and worsen the course and outcome of disease; it is also associated with cumulative chronic damage.[26][27][28][29]

Clinical and serological manifestations can occur in patients taking certain drugs.[30][31] The first reported association was with procainamide, but other commonly implicated drugs include minocycline, terbinafine, sulfasalazine, isoniazid, phenytoin, and carbamazepine.[32][33][34][35][36][37][38][39]

Other non-infectious environmental factors that may be associated with SLE include air pollution, and occupational exposure to free crystalline silica.[40][41] One meta-analysis of six studies suggests that 6 days of exposure to increased particulate matter 2.5 significantly increases scores on the Systemic Lupus Erythematosus Disease Aactivity Index.[40] Results from one systematic review and meta-analysis of epidemiological studies support the hypothesis of a possible association between occupational exposure to free crystalline silica and SLE, in particular at higher exposure levels, known to induce silicosis.[41]

Infectious environmental factors

Pathogens most frequently associated with SLE include Epstein-Barr virus, parvovirus B19, cytomegalovirus, and human immunodeficiency virus type 1.[42][43][44] Potential mechanisms facilitating autoreactivity remain unclear; immunological changes subsequent to infection and molecular mimicry have been proposed.[42] Further studies are required to determine whether infectious agents are causative agents.

SLE is primarily an antigen-driven immune-mediated disease characterised by high-affinity immunoglobulin G antibodies to double-stranded DNA, as well as nuclear proteins. Genes implicated in SLE may contribute to pathology by breaching immune tolerance and promoting auto-antibody production.[45]

Rapid clearance of cells through apoptosis normally minimises exposure of nuclear antigens to the immune system. However, failure of this process, and that of other mechanisms that confer immune tolerance to nuclear antigens, may provoke an immune response.[45][46] Loss of immune tolerance in this manner is evidenced by the presence of antinuclear antibodies.

Type I interferons, such as interferon alfa, are produced by plasmacytoid dendritic cells in response to damaged cells or viral infections. Their production is elevated in SLE patients and is linked to disease activity.[47][48]

NETosis, cell death in which neutrophil extracellular traps are released, is increasingly recognised as a source of nuclear antigens and bioactive molecules that may facilitate autoimmunity in SLE.[49]

While animal models have been used to illustrate how genes that affect autoantigen clearance can promote the production of antinuclear auto-antibodies, evidence in humans remains limited.

Several mechanisms have been proposed, by which T-cell dysregulation of B cells may arise, resulting in autoimmunity.

2019 European League Against Rheumatism/American College of Rheumatology classification system[1]

Entry criterion

Antinuclear antibodies (ANA) at a titre of ≥1:80 on HEp-2 cells or an equivalent positive test (ever)
If absent, do not classify as SLE; if present, apply additive criteria

Additive criteria

Additive criterion should not be counted if there is a more likely explanation than SLE
Occurrence of a criterion on at least one occasion is sufficient
SLE classification requires at least one clinical criterion and ≥10 points
Criteria need not occur simultaneously
Within each domain, only the highest criterion is counted toward the score*

Clinical domains and criteria

Constitutional

Fever, 2 points

Haematological

Leukopenia, 3 points
Thrombocytopenia, 4 points
Autoimmune haemolysis, 4 points

Neuropsychiatric

Delirium, 2 points
Psychosis, 3 points
Seizure, 5 points

Mucocutaneous

Non-scarring alopecia, 2 points
Oral ulcers, 2 points
Subacute cutaneous OR discoid lupus, 4 points
Acute cutaneous lupus, 6 points

Serosal

Pleural or pericardial effusion, 5 points
Acute pericarditis, 6 points

Musculoskeletal

Joint involvement, 6 points

Renal

Proteinuria >0.5 g/24 hours, 4 points
Renal biopsy class II or V lupus nephritis, 8 points
Renal biopsy class III or IV lupus nephritis, 10 points

Immunology domains and criteria

Antiphospholipid antibodies

Anticardiolipin antibodies OR anti-beta2-glycoprotein 1 antibodies OR lupus anticoagulant, 2 points

Complement proteins

Low C3 OR low C4, 3 points
Low C3 AND low C4, 4 points

SLE-specific antibodies

Anti-double-stranded (ds)DNA antibody** OR anti-Smith antibody, 6 points

Total score

Scores of 10 or more are classified as systemic lupus erythematosus if the entry criterion has been fulfilled.

* Additional criteria items within the same domain will not be counted.

** In an assay with ≥90% specificity against relevant disease controls.

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices[2]

Class I: minimal mesangial lupus nephritis
Class II: mesangial proliferative lupus nephritis
Class III: focal lupus nephritis
Class III (A): active lesions - focal proliferative lupus nephritis
Class III (A/C):
- Active and chronic lesions: focal proliferative and sclerosing lupus nephritis class III (C)
- Chronic inactive lesions: focal sclerosing lupus nephritis
Class IV: diffuse lupus nephritis
Class V: membranous lupus nephritis
Class VI: advanced sclerosis lupus nephritis.

Pathophysiology

Classification

2019 European League Against Rheumatism/American College of Rheumatology classification system[1]

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices[2]