Aetiology
The aetiology of SLE is not known but the interaction of an environmental agent in a genetically susceptible host is thought to be fundamental. The strong female preponderance also suggests a role for hormonal factors.[12][13]
Genetic factors
Familial aggregation and higher-than-expected rates of concordance in twin studies suggest that genetic factors are important.[14][15] The heritability of SLE has been estimated to be 43.9%.[16]
Genome-wide association studies have identified more than 60 genetic risk loci.[17] Predisposing genes may activate the innate or adaptive immune response, or have a potential role as self-antigen for autoreactive B cells.[18] Consistently reported SLE-associated loci include:[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 may be non-infectious or infectious.
The most important non-infectious causative agents are drugs.[25] The first reported association was with procainamide, but other commonly implicated drugs include minocycline, terbinafine, sulfasalazine, isoniazid, phenytoin, and carbamazepine.[26][27][28][29][30][31][32][33]
Pathogens most frequently associated with SLE include Epstein-Barr virus, parvovirus B19, cytomegalovirus, and human immunodeficiency virus type 1.[34][35][36] Potential mechanisms facilitating autoreactivity remain unclear; immunological changes subsequent to infection and molecular mimicry have been proposed.[34] Further studies are required to determine whether infectious agents are causative agents.
Pathophysiology
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.[37]
Rapid clearance of cells through apoptosis typically prevents 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.[37][38] Loss of immune tolerance in this manner is evidenced by the presence of antinuclear antibodies.
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.[39]
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.
Classification
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.
1997 update of the 1982 American College of Rheumatology revised criteria for the classification of SLE[2][3]
These criteria were initially developed to identify patients for clinical studies and were based on a white population. Any ≥4 of the 11 criteria are required to classify a patient as having SLE. These criteria can be present serially or simultaneously during any interval of observation.
Malar rash
Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds.
Discoid rash
Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions.
Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation.
Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by physician.
Arthritis
Non-erosive arthritis involving ≥2 peripheral joints, characterised by tenderness, swelling, or effusion.
Serositis (one of the following):
Pleuritis: convincing history of pleuritic pain, pleural rubs on auscultation, or evidence of pleural effusion
Pericarditis: documented by ECG, pericardial rub, or evidence of pericardial effusion.
Renal disorder (one of the following):
Persistent proteinuria >0.5 g/day or >3+ if quantification not performed
Cellular casts: may be red cell, haemoglobin, granular, tubular, or mixed.
Neurological disorder (one of the following):
Seizures: in the absence of offending drugs or known metabolic derangements (e.g., uraemia, ketoacidosis, or electrolyte imbalance)
Psychosis: in the absence of offending drugs or known metabolic derangements (e.g., uraemia, ketoacidosis, or electrolyte imbalance).
Haematological disorder (one of the following):
Haemolytic anaemia: with reticulocytes
Leukopenia: <4000/mm³ on ≥2 occasions
Lymphopenia: <1500/mm³ on ≥2 occasions
Thrombocytopenia: <100,000/mm³ in the absence of offending drugs.
Immunological disorder (one of the following):
Anti-DNA: presence of antibody to native DNA in abnormal titre
Anti-Smith: presence of antibody to Smith nuclear antigen
Positive findings of antiphospholipid antibodies based on:
An abnormal serum level of IgG or IgM anticardiolipin antibodies
Positive test result for lupus anticoagulant using a standard method
A false-positive serological test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilisation or fluorescent treponemal antibody absorption test.
Antinuclear antibody
An abnormal titre of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome.
2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for systemic lupus erythematosus[4]
The SLICC criteria for SLE classification requires:
Fulfilment of at least 4 criteria, with at least one clinical criterion AND one immunological criterion
OR
Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies.
Clinical criteria:
Acute cutaneous lupus
Chronic cutaneous lupus
Oral ulcers: palate
Non-scarring alopecia (diffuse thinning or hair fragility with visible broken hairs)
Synovitis involving two or more joints, characterised by swelling or effusion OR tenderness in two or more joints and 30 minutes or more of morning stiffness
Serositis
Renal
Neurological
Haemolytic anaemia
Leukopenia (<4000/mm³ at least once)
Thrombocytopenia (<100,000/mm³) at least once.
Immunological criteria:
ANA above laboratory reference range
Anti-dsDNA above laboratory reference range, except enzyme-linked immunosorbent assay: twice above laboratory reference range
Anti-Smith
Antiphospholipid antibody: any of the following
Low complement
Direct Coombs test in the absence of haemolytic anaemia.
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[5]
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.
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