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Systemic Lupus Erythematosus (SLE)

A. History

1. Systemic lupus erythematosus (SLE) is a prototype multisystem autoimmune disease.

2. Chronic inflammatory disease with remissions and exacerbations of lupis.

3. First description of the systemic manifestations of SLE was in 1895 by Osier.

a. Prior to this, lupus was thought to be a disfiguring but nonfatal skin disease.

B. Epidemiology

1. Incidence of SLE overall is 7 cases per 100,000 per year.

2. Incidence of SLE in childhood is 0.6 cases per 100,000 per year.

3. Incidence highest in females Of childbearing age.

a. F:M, 9:1 overall. Ratio 4:1 for children.

b. Greater % Of males in younger children and elderly.

4.Incidence higher in blacks and Hispanics than whites.

5.Onset is rare before 5 years of age and in the elderly.

6.Prevalence is about 1 in 2,000 in general.

C. Etiology

1. Genetic factors.

a. Familial tendencies.

(1) High concordance in monozygotic twins (frequency in dizygotic twins is similar to other first-degree relatives.

(2) SLE patients often have relatives with SLE or other autoimmune and immunological diseases.

(3) Autoantibodies are inherited in an autosomal dominant pattern with  incomplete penetrance. 

b. Racial factors: Blacks have increased frequency and severity Of nephritis. 

c. MHC Class II genes: HLA-BS/DR2 and DR3 are associated with SLE.

1) Decrease HLA-DR4 in SLE.

d. MHC Class III genes: Complement abnormalities are associated with SLE.

(1) C2 deficiency.

(2) C4 deficiency or C4A deletions (null) (associated in whites and DR3 +). 

(3) Cytokine abnormalities, TNF-a?

e. Receptors

(1) May be related to ability to remove potentially pathogenic immune complexes.

(2) Fcylla bind to IgG2.

(a) Two codominant alleles:. H131 or high affinity and R131 or low affinity.

(b) Lack of expression of H131 allele is associated with lupus nephritis in blacks.

(3) FcyRLLa bind to IgG1 and IgG3.

(a) Low affinity allele associated with SLE in ethnically diverse patients.

f. Acetylator phenotype?

2. Hormonal factors.

a. Predominance of incidence in females of childbearing status suggests that hormones are important.

b. SLE is less severe in males and postmenopausal females.

c. Various inbred strains of SLE mice have sex predilections.

(1) NZB/NZW F1 hybrid mice develop a disease similar to human SLE.

(a) Disease course can be modified by hormonal manipulation.

3. Infection

a. Household pets of SLE patients have an increased incidence of +ANA.

b. Laboratory personnel who handle SLE serum have an increased incidence of +ANA.

4. Environmental factors.

a. Drugs - procainamide, hydralazine and isoniazid are most commonly associated with SLE syndrome.

(1) In children the drugs most commonly associated with SLE syndrome are anticonvulsants.

(2) Must remember that seizures may be an initial manifestation of SLE and, therefore, some of these patients may have idiopathic SLE.

(3) Anticonvulsants frequently cause +ANA.

b. Toxins?

III. Clinical manifestations

A. Systemic symptoms.

1. Fatigue, malaise - 80%, related to disease activity.

2. Weight loss - 65%, especially early in course.

3. Fever - 85%, especially with acute flares. Must rule out infection.

B. Skin involvement - 85%.

1. Malar rash - 50% at diagnosis. 

a. Frequently after sun exposure. 

b. Heals completely.

2. Discoid lupus erythematosus (DLE) - 20% in adults, much less common in children. 

a. Erythematous papules - hyperkeratosis with plaques, edema, erythema and telangiectasias - atrophy with central hypopigmentation, peripheral hyperpigmentation and hair loss.

3. Photosensitivity - 35% in adults, 15% in children.

a. Maculopapular, erythematous, scaly eruption.

(1) Occasionally urticarial or bullous.

b. Not always localized to sun exposed areas.

4. Cutaneous vasculitis - 20%.

a. Nodules - extensor surface of forearms and hands. 

b. Ulceration - especially over malleoli. 

c. Palpable purpura. d. Splinter hemorrhages.

5.Alopecia, 60-70% in adults, 20% in children

a. Usually diffuse, occasionally patchy.

6.Other lesions - livedo reticularis, fingertip and palmar lesions (common in children), urticaria or angioedema, bulbous lesions, lupus profundus, atrophic blanche lesions, nail deformities.

C. Mucosal ulcers - 35% in adults, 15% in children.

1. Often asymptomatic. Palate, nasal septum, vagina.

D. Musculoskeletal involvement.

1. Arthritis - 80-90% (less common in children); Arthralgias - 95%.

a. Deformity may occur from ligamentous laxity.

2. Rheumatoid nodules - 5%.

3. Tenosynovitis 5-10%.

4. Myositis- 15%.

E. Renal disease - 50% in adults, 80% or more in children. Histologic changes in patients with SLE approaches 100%.

1. Lupus nephritis is more frequent and more severe in children.

2.Kidney biopsies are helpful in determining type of renal lesion and activity and chronicity index. Helps determine treatment protocol.

3.Mesangial nephritis.

a. Usually subclinical but may have minimal proteinuria or hematuria.

b. Light microscopy - normal or mild mesangial hypercellularity. IF - Mesangial deposits of Ig and C3. EM- deposits in mesangium.

c. Mild serological abnormalities (anti-dsDNA and C3). d. May have transition to other types of lupus nephritis. e. Prognosis - excellent.

4. Focal proliferative glomerulonephritis

a. Renal lesion is mild but often associated with severe extrarenal disease.

b. Mild proteinuria and hematuria. Occasionally nephrotic syndrome or renal insufficiency.

c. Light microscopy - hypercellularity of less than 50% of GTO nerular tufts. Local lesions in glomeruli tend to be in peripheral loops. IF - lumpy, bumpy staining for Ig and C3 along basement membrane. EM - subendothetial deposits.

d. Marked serological abnormalities.

e. Steroid responsive, prognosis is excellent.

5. Diffuse proliferative glomerulonephritis.

a. Severe renal lesion with extrarenal manifestations.

b. Moderate to heavy proteinuria, hematuria, red cell casts, renal insufficiency, hypertension.

c. Light microscopy - hypercellularity of more than 50% of glomerular tufts. May have scarring. Activity and chronicity index. IF - lumpy, bumpy staining for Ig and C3 along capillary walls. EM- subendothetial and subepithelial deposits. 

d. Marked serological abnormalities. 

e. Prognosis - fair to poor. Requires steroids and often immunosuppressive agents.

6. Membranous glomerulonephritis.

a. Mild to moderate renal disease with mild extrarenal manifestations.

b. Heavy proteinuria, hematuria, nephrotic syndrome, may progress to renal insufficiency late.

c. Light microscopy - thickened basement membrane, minimal hypercellularity. IF -granular deposits of Ig and C3 along basement membrane. EM - intrabasement membrane deposits. 

d. Mild serological abnormalities. 

e. Prognosis - good, may progress to renal failure over years, not usually responsive to treatment.

7.Interstitial nephritis - usually occurs with diffuse proliferative glomerulonephritis. Worsens prognosis.

8.Rapidly progressive glomerulonephritis (crescentic) and membranoproliferative glomerulonephritis may also occur.

F. Neurologic disease (*associated with antiphospholipid antibodies).

1. Diffuse manifestations.

a. Organic brain syndromes including cognitive dysfunction; 35-60%. 

b. Psychiatric-psychosis; 10%. 

c. Others - headaches, aseptic meningitis, pseudotumor cerebri.

2.Seizures* - usually generalized or focal, occasionally petit mal or complex partial seizures; 15-35%.

3.Focal manifestations (* associated with aPL). 

a. Cerebrovascular accident*. 

b. Transverse myelitis*; 1%.

c. Cranial neuropathies including 2, 3, 4, 5, 6, 7; 10%. 

d. Movement disorders* - chorea; 4%.  

e. Peripheral neuropathies; 10-20%.

4.CNS disease often occurs in the absence of other manifestations of active SLE. 

a. Serological abnormalities may be absent or mild.

5.Evaluation includes - eye exam (optic neuritis or signs of retinal vasculitis are associated with CNS disease) CSF examination, EEG, CT scan or MRI, SPECT scan, neuropsychiatric testing, consider aPL testing.

G. Cardiac manifestations.

1. Pericarditis - 25%. Subclinical effusions much more frequent.

2. Myocarditis- 25%, CHF, arrhythmias.

3. Endocarditis - Libman-Sacks often asymptomatic.

4. EKG - often shows abnormalities such as ST-T changes and long PR interval.

H. Pulmonary manifestations.

1. Pleuritis - 45%. Fever, chest pain, chest x-ray changes. 

2. Acute pneumonitis- must differentiate from pneumonia. 

3. Chronic interstitial pulmonary fibrosis.

4. Vanishing lung (diaphragmatic dysfunction).

5. Alveolar hemorrhage - often fatal

I. Hematologic manifestations.

1. Anemia- 50%

a. Anemia of chronic disease.

b. Severe nonhemolytic anemia.

c. Hemolytic anemia, Coomb's positive - 10%.

2.Leukopenia - lymphopenia with active SLE.

3.Thrombocytopenia- 15%, often mild.

4.Antiphospholipid antibodies - thrombosis, thrombocytopenia.

J. Vascular manifestations.

1. Raynaud's phenomenon - 20%. May be associated with digital gangrene.

2. Thrombosis is more common in patients with SLE.

3. Antiphospholipid antibodies are present in up to 50% of SLE patients.

a. Moderate to high titers associated with clinical features of antiphospholipid antibody syndrome (APS); venous and arterial thrombosis, recurrent fetal loss, thrombocytopenia, hemolytic anemia, atypical neurologic syndromes, certain cardiopulmonary disorders.

K. GI manifestations.

1. Anorexia, nausea, vomiting, dysphagia.

2. Abdominal pain frequent in children - must rule out mesenteric vasculitis. 

3. Mesenteric vasculitis. 

4. Pancreatitis.

L. Liver - hepatomegaly with mild hepatitis occurs frequently early in the course of SLE, especially in children.

M. Overlap with autoimmune hepatitis.

N. Lymphadenopathy - 50%, more common in children.

O. Splenomegaly - 20%.

P. Ocular manifestations.

1. Conjunctivitis, episcleritis, vasculitis (hemorrhages, exudates, infarcts).

2. Parotid swelling.

Q. Pregnancy.

1.SLE does not in general affect fertility or incidence of congenital malformations. 

a. Severe disease (end stage renal disease) may affect fertility and therapy may be associated with infertility and congenital malformations.

b. Anti-SSA (Ro) is associated with neonatal lupus.

2. Increased incidence of fetal loss, prematurity, preeclampsia.

a. Pregnancy complications associated with antiphospholipid antibodies.

3.Pregnant SLE patient requires careful follow up with art obstetrician and rheumatologist as pregnancy can aggravate lupus nephritis and SLE flares may negatively impact on pregnancy.

R. Neonatal SLE - children born to mother with +ANA or SLE.

1. Typically associated with transplacental transmission of anti-SSA (Ro) antibodies. 

2. Discoid-like lesions on face, trunk and extremities. Histologically identical to DLE. 

3. Cytopenias.

4. +ANA, + anti-SSA antibodies.

5.Cardiac abnormalities - AV conduction delays such as third-degree heart block, PDA, ASD, transposition of great vessels, endocardial fibroelastosis.

6.All manifestations except cardiac abate with time, usually 6-9 months as maternal antibodies disappear. Only the cardiac manifestations may require treatment with prenatal dexamethasone or postnatal pacemaker.

IV. Diagnosis

A. Diagnostic criteria 

1. Malar rash 

2. Discoid LE

3. Photosensitivity 

4. Oral ulcers 

5. Arthritis

6. Serositis - pleuritis or pericarditis.

7. Renal disorder - proteinuria >0.5 gm/day or cellular casts.

8. Neurologic disorder - seizures or psychosis.

9. Hematologic disorder - hemolytic anemia, leukopenia, lymphopenia or thrombocytopenia.

10. Autoantibodies - +LE celt prep, anti-dsDNA, anti-Sin or false + STS.

11. + ANA.

a. Four or more in one patient is highly specific for a diagnosis of SLE.

B. Laboratory evaluation

1. General

a. CBC, platelets. 

b. Chemistries - renal and liver tests. 

c. Urinalysis. 

d. PT, P-IF. 

e. Chest x-ray and EKG.

2. Rheumatologic

a. ESR - correlates with disease activity. 

b. ANA- screening test - >99% + in SLE patients. 

c. Anti-ssDNA - commonly + but not specific. 

d. Anti-dsDNA - 50-60%. Specific and level often correlates with disease activity.

e. Anti-Sm - 30%. Very specific for SLE, correlates with photosensitivity, CNS disease, leukopenia, vasculitis.

f. Anti-RNP - 50%. Correlates with Raynaud's phenomenon, arthritis and serositis.

g. Anti-SSA (Ro) 30-40%, Anti-SSB (La) - 15%. Associated with SCLE, neonatal lupus, C2 deficiency with SLE-like syndrome.

h. Rheumatoid factor- 33%. 

i. LE prep - 60%. Specific but not sensitive. 

j. STS -false positive in 15%. 

k. Antiphospholipid antibodies -found in up to 50%.

(1) Anticardiolipin antibodies, Lupus anticoagulant.

l.C3, C4 and CH50 - depressed complement activity often correlates with disease activity

m. Lupus band test- IF staining for tgG and C3 in normal skin.

(1) + in 80% of active SLE, 30-40% of inactive SLE patients.

(2) Also positive in RA, MCTD, rosacea.

(3) + in involved skin - 100% of SLE and also leprosy, scleroderma, rosacea, porphyria cutanea tarda, DLE.

V. Prognosis

A. Prognosis improving because of improve treatment regimens and 

VI. Management of SLE

B. Minor organ involvement - constitutional symptoms, skin, joints, serositis.

1. Treat symptomatically as needed.

2. ASA and NSAIDs - arthritis,, fevers, serositis.

3. Topical corticosteroids - DLE.

4. Antimalarials - hydroxychloroquine, chloroquine - arthritis, rash.

5. Methotrexate- arthritis, skin involvement.

6. Minor organ involvement may require corticosteroids to control symptoms.

7. Skin involvement.

a. Topical corticosteroids and antimalarial drugs are first line therapy.

b. For resistant skin involvement consider intralesional corticosteroid injections (by dermatologist), methotrexate, dapsone, azathioprine, thalidomide.

C. Major organ involvement- renal, CNS, hematologic.

1. Use corticosteroids and immunosuppressive agents to prevent organ damage.

2. High-dose corticosteroids, starting at 0.5-1 mg/kg/day in divided doses or give large IV bolus of methylprednisolone, 30 mg/kg/day for 3 days followed by high-dose oral prednisone.

a. When clinical signs stabilize or improve begin to taper slowly.

3. Immunosuppressive drugs.

a. Cyclophosphamide.

(1) IV pulse (lupus nephritis protocol) or low dose oral.

(2) Toxicity- hematologic, GI, hair loss, infection, GU, lymphoid and bladder malignancies, infertility, teratogenic.

b. Azathioprine.

(1) Less potent, better tolerated agent than cyclophosphamide.

(2) Toxicity- hematologic, infection, hepatotoxicity, lymphoid malignancy. 

c. Cyclosporine has been used.

(1) Major concern is nephrotoxicity.

4.Other immunomodulatory therapies - Danazol for cytopenias, Dapsone for rashes, IVIG for cytopenias, plasmapheresis for severe SLE, ie, transverse myelitis.

5.Ancillary medications - antihypertensives, anticonvulsants, antipsychotics, anticoagulants, vasodilators, antibiotics, sun screen.

6.Rehabilitation and surgery.

7.Dialysis or renal transplantation for end stage renal disease.

8.Experimental.

a. Nonspecific antiinflammatory agents.

(1) PGE1 analogue.

(2) DP-1904; thromboxane A2 synthetase inhibitor.

(3) Zileuton; selective 5-1ipoxygenase inhibitor.

(4) Roquinimex; nitric oxide (NO) synthetase inhibitor.

b. Hormonal agents.

(1) Dehydroepiandrosterone (DHEA).

(2) Tamoxifen.

(3) Selective estrogen receptor modulation.

(4) Bromocriptine.

c. Nonspecific immunomodulatory agents.

(1) 2'-Chtorodeoxyadenosine; purine analogue.

(2) Mycophenolate mofetil; purine synthesis inhibitor.

(3) Leflunomide; pyrimidine synthesis inhibitor.

(4) Methimazole.

d. Specific immunomodulatory agents.

(1) Anti-CD40L monoclonal antibodies; block T cell-B cell interactions inhibiting autoantibody production.

(2) CTLA-41g fusion protein; inhibit T cell activation and T cell dependent El cell function.

(3) Anti-B7 monoctonat antibodies;, suppress production of anti-DNA antibodies.

(4) Anti-dsDNA monoctonat antibody (3E10) vaccination; induce anti-idiotypic antibodies.

(5) LJP 394; inactivate anti-DNA producing B cells by cross-linking anti-DNA on cell surface (B cell tolerogen).

(6) Anti-dsDNA binding peptides; inhibit anti-dsDNA deposition in kidneys.

(7) Recombinant human DNase; remove antigen stimulus for anti-DNA antibody production?

(8)Anti-C5a monoclonal antibody; inhibit production of inflammatory mediators via complement cascade.

(9) Anti-lL-10 monoclonal antibodies; suppress IL-10 driven autoantibody production.

(10) Stem cell transplantation