Systemic Lupus Erythematosus (SLE)

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Definition: Systemic lupus erythematosus (SLE), also called lupus, is an autoimmune disorder in which the body’s immune system (the cells in the body that fight infection) incorrectly attack the body’s own tissues and organs, leading to inflammation and damage

Pathogenesis and Etiology: There are incredible interactions between susceptibility genes as well as environmental factors which result in an abnormal immune response (all of which differ among different patients).

Some responses may include:

(1) Activation of innate immunity [dendritic cells, monocytes/macrophages) by CpG DNA, DNA in immune complexes, viral RNA and RNA/protein self antigens.

(2) Lowered activation thresholds and abnormal activation pathways in adaptive immunity cells (T and B lymphocytes).

(3) Ineffective regulatory CD4+ and CD8+ T cells.

(4) Reduced clearance of immune complexes and of apoptotic cells.

Self antigens RNA/protein in Sm, Ro, and La; phospholipids are available for recognition by the immune system in surface blebs of apoptotic cells; thus antigens, auto-antibodies, and immune complexes persist for prolonged periods of time allowing disease and inflammation to develop.

This immune cell activation is also accompanied by an increased secretion of proinflammatory type 1 and 2 Interferons (IFNs), as well as tumor necrosis factor a (TNF-a), Interleukin 17 (IL-17). Upregulation of genes induced by IFN is a genetic “signature” which we find in the peripheral blood cells of SLE in approximately 50% of patients.

What is also interesting to note is that decreased production of cytokines also contributes to SLE: Lupus T and natural killer (NK) cells fail to produce enough IL-2 and transforming  growth factor b (TGF- b) to induce and sustain regulatory CD4+ and CD8+ T cells. The result of this is abnormality is a continuous production of autoantibodies and immune complexes.

Risk Factors: Female sex is permissive for SLE with evidence for hormone effects, genes on the X chromosome and epigenic differences between gender plays a role in disease. For example females make higher antibody responses than males. Women exposed to estrogen-containing oral contraceptives or hormone replacement have an increased risk of developing SLE. Estradiol binds to receptos on T and B lymphocytes, increasing activation and survival of those cells, thus favoring prolonged immune responses. Genes on the X chromosome influence SLE, such as TREX-1 possible because some genes on the second X in females are not silent. People with XXY karyotype (Klinefelters) have a significantly increased risk for SLE. Several environmental factors may influence SLE i.e. exposure to ultraviolet light causes flares of SLE in about 70% of patients (either through apoptosis or altering DNA and intracellular proteins to make them antigenic).

Pathology: In SLE, biopsies of affected skin show deposition of Ig at the dermal-epidermal junction (DEJ), injury to basal keratinocytes, and inflammation dominated by T lymphocytes in the DEJ and around blood vessel.

TABLE 1 Autoantibodies in SLE (a short list*)

Antibody                                                                        Prevalence                  Notes

Antinuclear antibodies                                                   98%   *                               Best screening test

Anti-dsDNA                                                                         70%                                    High titers are specific for SLE

Anti-Sm                                                                                 25%                                    Specific for SLE

Antihistone                                                                          70%                                    More frequent in drug induced lupus

Antiphospholipid                                                              50%                                    Predisposes to clotting, fetal loss, thrombocytopenia

Diagnosis:The diagnosis of SLE is based on characteristic clinical features and autoantibodies.

TABLE 1:  Diagnostic Criteria for Systemic Lupus Erythematosus (any combination of ³ 4 of 11 criteria)

Malar rash           Discoid rash           Photosensitivity           Oral ulcers           Arthritis

Serositis               Renal disorders    Neurologic disorder   Hematologic disorder

Immunologic disorder                       Antinuclear antibodies

Laboratory Tests: In the laboratory we have three objectives: (1) to establish or to rule out SLE (2) to follow the course of the disease i.e. is the medication helping? Is their a flare occurring? What about organ damage? (3) to identify the adverse effects of therapies.

A. Diagnostically, the best test to confirm is an ANA as it is positive in 95% of patients, usually at the onset of symptoms.

B. Flare: titers of anti-dsDNA increases during a flare particularly of nephritis or vasculitis, especially when associate with declining levels of C3 or C4 complements.

C. Test for following disease course: the typical urinalysis for hematuria and proteinuria, hemoglobin levels, platelet counts and serum levels of Creatinine or albumin are all helpful in assessing the patients disease course. The physician should determine for each individual patient whether certain laboratory test are required.

Treatment: Unfortunately, there is no cure for SLE and complete sustained remissions are rare. Therefore, the best strategy is to plan to induce improvement of acute flares and then to maintain these improvements with strategies that suppress symptoms to an acceptable level and prevent organ damage.

Analgesics and antimalarials (hydroxychloroquine, quinacrine etc…) are the mainstay treatment regimens. NSAIDS are useful analgesics and anti-inflammatories, particularly for SLE arthritis/arthralgias.

Systemic glucocorticoids (methylprednisone) is the mainstay of treament for any inflammatory life-threatening or organ-threatening manifestations of SLE. Cytotoxic immunosuppressive agents can be added to glucocorticoids and are recommended when needed to treat critical SLE – either cyclophosphamide or mycophenolate is an acceptable choice for induction of improvement in severely ill patients.

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