Systemic lupus erythematosus
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Systemic lupus erythematosus (SLE, lupus) is a systemic auto-immune disease and is associated with a wide range of autoantibodies, particularly anti-nuclear antibody (ANA) and anti-dsDNA (double-stranded DNA) antibodies. There are various subtypes, and manifestations can overlap with other connective tissue diseases.
Complex! There would appear to be an progressive accumulation of autoantibodies, particularly to degradation products of apoptosis, eg phospholipid, nuclear material. Anti-nuclear, anti-Ro, anti-La, and anti-phospholipid antibodies appear first, then anti-dsDNA and anti-nuclear ribonucleoprotein antibodies. This accumulation is evident up to 9 years before symptoms appear. At a certain point, however, symptoms become manifest, and this can be owing to direct toxic effects of these autoantibodies eg anti-dsDNA acting on the renal glomerulus.
Other parts of the jigsaw:
- Gene defects affecting early complement proteins esp., C1 complex and C4 are the strongest known predisposers to SLE.
- Role of EBV: increased viral load, increased latently infected peripheral B cells, altered immune responses found in patients with SLE (Current Opinion in Rheumatology. 18(5):462-7, 2006 Sep.)
- Dendritic cells (increased concentration seen in skin of SLE) seem to be important. They present antigen to other white cells, hence have an important role in tolerance. Fits with the poor clearance of apoptotic products idea mentioned above. If antigen is not recognised as self, immune complexes form which stimulate B cell response, leading to increased plasma cells and immunoglobulins.
- Genome-wide association studies have identified the variations in ATG5, a protein involved in autophagy, raising the possibility that defects in the processing of apoptotic bodies may contribute to the process.
The American College of Rheumatology criteria (devised 1982, revised 1997) require at least four of the following: 1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis 7. Renal disorder 8. Neurological disorder 9. Haematological disorder 10. Immunological disorder 11. Anti-nuclear antibodies
Signs can be diverse:
- Skin rashes (Discoid lupus can sometimes progress, and children who start with only cutaneous signs always do)
- Malar rash (gives rise to the name lupus, as looks like markings of a wolf)
- Vasculitic lesions
- Discoid lesions
- Mouth ulcers
- Symmetrical polyarthropathy
- Fever, fatigue, weight loss
- Restrictive lung defect - common, mostly asymptomatic
- Raynaud's phenomenon
- Renal (biopsy correlates poorly with clinical so scoring systems. Poorer prognosis if male, hypertensive, anaemia, nephrotic)
- Painful joints
- Chest pain
- About 90% female
- Slight risk disease flare with HRT but not with combined oral contraceptive
- Drugs (drug-induced lupus)
Consistent specific gene associations include:
- HLA (6p21.32) - antigen presentation
- Integrin alpha M (ITGAM) (16p11.2) - leukocyte adhesion
- Interferon regulatory factor 5 (IRF5) (7q32.1) - production alpha interferon
- Signal transducer and activator of transcription 4 (STAT4) (2q32) - cytokine modulation and activation macrophages by alpha interferon
There are several other associations that are likely to be important.
Initially directed at narrowing the differential diagnosis, a range of investigations is usually indicated to provide evidence of immune activation. Usually a non specific but sensitive autoimmune screen is ordered that will detect ANA and when positive the laboratory will do more specific antibodies.
- Autoantibodies (ANA, anti-dsDNA)
- C3/C4 (depressed, especially C3)
- U+Es (renal impairment)
- FBC (leucopenia, anaemia, thrombocytopenia)
- ESR/CRP (disproportionately high ESR with normal CRP)
Not necessarily benign, even with the best treatment. There appears to be up to a fourfold increased risk of death leading to 10 year survival rates of all presentations to between 92% to 83%. Malignancy, infection and nepropathy are significant contributers with thrombosis becoming more dominant on longer followup. Risk factors for poorer outcome appear to be:
- Renal presentations
- ↑ age
- Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index
- High-dose corticosteroids.
- Haematological manifestations
- ↑ Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis and rheumatism. 1982 Nov; 25(11):1271-7.
- ↑ Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis and rheumatism. 1997 Sep; 40(9):1725.(<1725::AID-ART29>3.0.CO;2-Y Link to article – subscription may be required.)
- ↑ Buyon JP, Petri MA, Kim MY, Kalunian KC, Grossman J, Hahn BH, Merrill JT, Sammaritano L, Lockshin M, Alarcón GS, Manzi S, Belmont HM, Askanase AD, Sigler L, Dooley MA, Von Feldt J, McCune WJ, Friedman A, Wachs J, Cronin M, Hearth-Holmes M, Tan M, Licciardi F. The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial. Annals of internal medicine. 2005 Jun 21; 142(12 Pt 1):953-62.
- ↑ Petri M, Kim MY, Kalunian KC, Grossman J, Hahn BH, Sammaritano LR, Lockshin M, Merrill JT, Belmont HM, Askanase AD, McCune WJ, Hearth-Holmes M, Dooley MA, Von Feldt J, Friedman A, Tan M, Davis J, Cronin M, Diamond B, Mackay M, Sigler L, Fillius M, Rupel A, Licciardi F, Buyon JP. Combined oral contraceptives in women with systemic lupus erythematosus. The New England journal of medicine. 2005 Dec 15; 353(24):2550-8.(Link to article – subscription may be required.)
- ↑ Crow MK. Collaboration, Genetic Associations, and Lupus Erythematosus N Eng J Med 2008 (10.1056/NEJMe0800096)registration/subscription may be required
- ↑ Moss KE, Ioannou Y, Sultan SM, Haq I, Isenberg DA. Outcome of a cohort of 300 patients with systemic lupus erythematosus attending a dedicated clinic for over two decades. Annals of the rheumatic diseases. 2002 May; 61(5):409-13.
- ↑ Cervera R, Khamashta MA, Font J, Sebastiani GD, Gil A, Lavilla P, Mejía JC, Aydintug AO, Chwalinska-Sadowska H, de Ramón E, Fernández-Nebro A, Galeazzi M, Valen M, Mathieu A, Houssiau F, Caro N, Alba P, Ramos-Casals M, Ingelmo M, Hughes GR. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine. 2003 Sep; 82(5):299-308.(Link to article – subscription may be required.)
- ↑ Mok CC, Mak A, Chu WP, To CH, Wong SN. Long-term survival of southern Chinese patients with systemic lupus erythematosus: a prospective study of all age-groups. Medicine. 2005 Jul; 84(4):218-24.
- ↑ Gladman DD, Goldsmith CH, Urowitz MB, Bacon P, Fortin P, Ginzler E, Gordon C, Hanly JG, Isenberg DA, Petri M, Nived O, Snaith M, Sturfelt G. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison. The Journal of rheumatology. 2000 Feb; 27(2):373-6.