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Systemic Lupus Erythematosus (SLE) (aka Lupus)

Systemic Lupus Erythematosus (SLE) (aka Lupus)

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systemic lupus erythematosus (aka lupus or SLE)
Overview
Demographics
  • In terms of its demographics, it is at least 10 times more common in women than in men and it’s 4 times more common in blacks than in whites: in the US, it affects 1/1,000 in white women vs 1/250 black women.
Environmental Triggers
  • Key environmental triggers include estrogen and UV light.
Pathology
  • Most of the pathology in SLE is due to class 3 hypersensitivity reactions, wherein an array of different antibodies can attack various cellular components to generate pathologic pro-inflammatory immune complexes.
Cells Under Attack
  • Cells under attack include:
    • Nucleic antigens and binding proteins (think: antinuclear antibodies (ANA)
    • Phospholipids (think: antiphospholipid antibody syndrome – a hypercoagulable, prothrombotic state)
    • Hematologic/immunologic cells (think: platelets, causing thrombocytopenia or erythrocytes, causing chronic anemia).
  • Knowing that many different autoantibodies can exist in SLE helps us understand the heterogeneity of its clinical manifestations.
Clinical Manifestations
Mucocutaneous Manifestations
Acute skin manifestations include:
  • Malar rash, which is an erythematous butterfly rash that spares the nasolabial folds (note that we can use this sparing to help distinguish it from the rash of dermatomyositis).
  • Photosensitive rash, which is a sunlight triggered flat, maculopapular erythematous rash: NSAIDS and thiazide diuretics are a trigger for this rash in patients with SLE.
Chronic skin manifestations include (for example):
  • Alopecia, which is a common finding, and manifests with hair thinning or patchy hair loss that may be related to a medication OR may improve with medication administration and disease reduction.
  • Chilblain lupus: a painful, violaceous frostbite-appearing rash that occurs in cold-exposed areas.
  • Discoid rash: a chronic, coin-shaped (hence: discoid), scarring form of rash with prominent central depigmentation – it occurs in sun-exposed skin surfaces.
  • Lupus tumidus: a photosensitive, erythematous, non-scarring urticarial form of rash.
  • Lupus profundus (aka panniculitis): a painful, nodular, subcutaneous inflammatory.
  • Painless oral and nasal uclers.
  • Seborrheic dermatitis: scaly, erythematous plaques in the face, including the eyebrows, nose, and nasolabial folds.
Arthritis
  • Next for arthritis, make note of Jaccoud arthropathy, which is tendon laxity that produces reversible deformities, such as swan-neck deformity (which we addressed in rheumatoid arthritis). A key distinguishing feature from RA is that the deformity is reversible.
Cardiopulmonary and Vascular manifestations
  • First, serositis (serous membrane inflammation), which can manifest with:
    • Pleuritis (in the lungs): presents with pleuritic pain or pleural effusion.
    • Pericarditis (in heart): presents with pericardial pain or effusion.
    • Note that peritonitis is another form of serositis that can occur but is less common.
  • From a strict pulmonary standpoint, include pneumonitis, alveolar hemorrhage, and pulmonary arterial hypertension.
  • From a strict cardiac standpoint, include mitral or aortic valvular thickening with or without Libman-Sacks endocarditis (these are non-bacterial valvular vegetations – we distinguish them from infectious endocarditis).
  • From a vascular standpoint, include atherosclerosis, which can cause thromboembolic events, and, most commonly, Raynaud’s phenomenon (a vasospastic phenomenon of the digits).
Renal
  • Renal disease, called lupus nephritis, can manifest with polyuria and nocturia, abnormal appearing urine (bloody or foamy), lower extremity edema, and hypertension.
  • We divide lupus nephritis into 6 classes, which range from minimal disease restricted to immune deposition in the mesangium, called Class I: minimal mesangial lupus nephritis, all the way to severe disease, requiring renal transplantion, called Class 6: advanced sclerosing lupus nephritis, manifesting with sclerosis of greater than 90% of the glomeruli.
  • For reference the disease classification is as follows:
    • Class I: Minimal Mesangial Lupus Nephritis
Normal glomeruli; mesangial immune deposits; normal renal function; no treatment required.
    • Class II: Mesangial Proliferative Lupus Nephritis
Mesangial hypercellularity; minimal renal impairment; Treatment involves angiotensin-converting-enzyme inhibitor (ACE inhibitor) when proteinuria is greater than 0.5 g/day.
    • Class III: Focal Proliferative Lupus Nephritis
    • Segmental lesions in less than half of the glomeruli; hypercellularity and immune complex deposition in the mesangium and extending into the subendothelial space and mesangium; renal failure is present with systemic manifestations of hypertension and lower extremity edema; immunosuppressive treatment is required.
    • Class IV: Diffuse Proliferative Lupus Nephritis
When Class 3 disease extends to greater than 50% of glomeruli it becomes Class 4 disease. As well, there are additional pathologic findings, including cellular glomerular crescent formation, a key finding of severe inflammatory glomerulonephritis. Immune suppression is required.
    • Class V: Membranous Lupus Nephritis
This is a distinct, less common, form of lupus nephritis that involves subepithelial immune deposition with resultant thickening of capillary loops and can occur in isolation or concomitantly with Class 3 or 4 disease. It notably manifests with severe proteinuria but a lack of anti-dsDNA antibodies.
    • Class VI: Advanced Sclerosing Lupus Nephritis
Greater than 90% of the glomeruli are already sclerotic with no ongoing active disease, so renal transplant is necessary and there is no role for immune suppression at this point.
Neuropsychiatric
  • Notable CNS manifestations include seizures and headaches and demyelination, albeit rare, a longitudinally extensive myelopathy (spinal cord demyelination) which we typically associate with neuromyelitis optica (NMO).
  • Importantly, include psychosis via a small-vessel vasculopathy (small-vessel thrombosis) rather than inflammatory vasculitis (which we might expect).
  • Albeit less dramatic, arguably the most common neuropsychatric manifestation is fatigue.
  • Notable PNS manifestations include various neuropathies.
Hematologic/Immunologic
  • Hematologic/Immunologic disorders include hemolytic anemia, leukopenia (or lymphopenia), and thrombocytopenia.
  • Essentially a reduction in blood and immunologic components.
Lupus Autoantibodies
ANA (antinuclear antibody test)
  • ANA (antinuclear antibody test) is a highly sensitive but non-specific test: a negative test can help exclude the diagnosis of SLE but a positive test is fairly unhelpful.
    • To help with its specificity of the test, we consider the degree of dilution at which the ANA is still positive, called the ANA titer; this reflects the degree of positivity (and thus specificity) of the test.
    • Antibody positivity at a dilution of 1:40 is common in the general population (est. 30% of the normal population) whereas positivity at a dilution of 1:320 is rare (est. 3% of the normal population).
Anti-dsDNA (double-stranded DNA) and Anti-Sm (Smith)
  • Both anti-dsDNA (double-stranded DNA) and anti-Sm (Smith) autoantibodies are highly specific for SLE.
  • Importantly, anti-dsDNA levels correlate with disease activity whereas anti-Sm levels do not.
Anti-histone antibodies
  • Histone autoantibodies are commonly associated with drug-induced lupus.
  • Although they are 90% sensitive for drug-induced lupus, up to 70% of SLE patients can also be positive for anti-histone antibodies, so we don’t use them to distinguish drug-induced lupus from systemic lupus erythematosus.
  • Common clinical manifestations of drug-induced lupus are cutaneous manifestations along with arthralgias, myalgias, and fever. Internal organ involvement (other than serositis) or neuropsychiatric manifestations are rare.
  • Common drug-induced lupus triggers:
    • Hydralazine, Isoniazid, Minocycline, Procainamide, Tumor necrosis factor alpha inhibitors (anti-TNF agents)
  • Many other drugs have also been shown to cause drug-induced lupus, including:
    • Chlorpromazine, Diltiazem, Methyldopa, and Quinidine.
Antiphospholipid antibodies
  • Antiphospholipid antibodies (antibodies directed at phospholipids or their binding plasma proteins) are present in roughly half of SLE patients and are an important marker of thromboembolism risk, including arterial thromboembolism, deep venous thrombosis, and they are an important cause of fetal loss (late-term miscarriages).
Additional lab tests
  • Before we address antiphospholipid antibody syndrome and antiphospholipid antibodies, themselves, in more detail, note that additional helpful lab laboratory tests to diagnose lupus include low complement levels and the findings of a positive direct Coombs test without evidence of hemolytic anemia.
Pathogenesis of immune complex-mediated hypersensitivity:
  • Immune complexes become deposited on the vessel wall (or, in some cases, in the tissues).
  • As a result, complement and neutrophil activation occurs, leading to the release of pro-inflammatory cytokines, enzymes, and reactive oxygen species.
  • Increased vessel permeability allows the inflammatory molecules to cause additional tissue damage outside of the vessel.

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