Exam #3- Systemic Lupus Erythematous

4 types of lupus

- Discoid Lupus Erythematosus
- Systemic Lupus Erythematosus
- Drug-Induced
- Neonatal

Discoid Lupus

- cutaneous
- always limited to skin
- rash on face, neck, scalp
- does not generally involve internal organs
- can evolve to systemic lupus
- 10% of all lupus cases

Systemic Lupus

- more severe form
- multi-system: affects skin, joints, almost any organ/body system
- 70% of all lupus cases
- 50% of cases have a major organ affected (kidneys, stomach, heart, lungs)
- flare (active) and remission (fewer symptoms)

Drug-Induced Lupus

- occurs after use of certain prescribed drugs
- symptoms usually fade when drug is stopped
- hydralazine hydrochloride (antihypertensive) & procainamide hydrochloride ( antiarrhythmic)
4% of patients who take drug get this

Neonatal Lupus

- rare condition
- associated w/ rash appearing within 1st several weeks of life
- not systemic
- may persist for 6 months

2 most common drugs that can cause drug-induced lupus

- hydralazine hydrochloride (antihypertensive)
- procainamide hydrochloride ( antiarrhythmic)

Epidemiology of Systemic Lupus

- 10-15x more frequent in women than men (link with estrogen)
- 2-3x more prevalent among people of color (west African< African American)
- highest mortality rate in pts w/ progressive renal involvement/CNS disease
- 2 most frequent causes of death are renal failure & infectious complications

Signs & Symptoms of Systemic Lupus (General)

- elevated anti-dsDNA & anti-ribosomal P antibodies
- reduced levels of complement & leukopenia
- damage by immune complexes to renal system
- Wide range of manifestations
- ↑Infections if on immunesuppresents

Immunologic Manifestations of SLE

- B lymphs: state of spontaneous B lymphocyte hyperactivity—leads to uncontrolled production of a wide variety of antibodies to host and exogenous antigens
-T lymphs: lack of or reduced generalized suppressor T cell function and hyperproduction of helper T cells occurs
- dendritic cells also involved in pathogenesis
- loss of tolerance to nuclear antigens, deposition of immune complexes (hallmark of SLE) in tissues, and multi-organ involvement
- production of multiple autoantibodies (no autoantibody = not SLE)
- monocyte phagocyte system unable to eliminate all immune complexes —> accumulate in blood circulation -> deposited in tissues

Diagnostic Evaluation of SLE (histological, renal, hematological)

- histologic changes (vasculitis)
- renal: proliferative glomerulonephritis and membranous nephritis
- hematologic findings (moderate anemia, lymphocytopenia, thrombocytopenia)

Laboratory evaluation of antinuclear antibodies

ANAs have no organ or species specificity and are capable of cross-reacting with nuclear material from humans or various animal tissues

-31.7% of all normal individuals were ANA positive at 1:40 dilution; Negative cutoff titer of 1:160
- antigens recognized are mainly proteins, protein macromolecular complexes, protein-nucleic acid complexes, and nucleic acids
- Anti-dsDNA antibodies are the only autoantibodies that may be used to monitor disease activity of SLE

Etiology of Lupus

• Cause is unclear

• Development of autoantibodies in SLE due to defective B cell tolerance for self antigens

• Known to occur in families-- 10% of lupus patients have a parent or sibling with it but No identified gene or genes yet

• environmental triggering associated: UV light, smoking

• Gut microbes: Antibiotics can remove gut bacteria—may trigger lupus - sulfa drugs, tetracycline-related, and penicillin-related 

• Vitamins found to modulate lupus onset or flares:

  • Vitamin D, Vitamin A, and omega-3 polyunsaturated fatty acids

Cutaneous Symptoms

• butterfly rash worsened by UV (65% of patients get this) ; can extend to trunk and arms

• alopecia

• Raynaud phenomenon　（1/3 of patients)

• Urticaria, angioedema, nonthrombocytopenic purpura, scale formation, ulcerations of oral and genital mucous membranes

Renal and lymphatic Symptoms

• Complement mediated injury to the renal system—high levels of immune complexes

  • Renal disease progression is unpredictable

  • Acute and chronic glomerulonephritis possible

• Lymphoadenopathy - enlargement of peripheral and axial lymph nodes
  

GI and Serositis Symptoms

• Non-specific GI issues common

• Inflammation of the mesothelium (thin layer of connective tissue enclosing the body cavity)

  • sterile peritonitis (abdomen), pleuritis (lungs) , or pericarditis (membrane around heart); frequently accompanied by severe pain

    • inflammation of tissue with no infection

    • antibiotics will not help

Cardiopulmonary and Musculoskeletal Symptoms

• Inflammation of myocardium can produce persistent tachycardia —> congestive heart failure

• occult diffusion and obstructive abnormalities in high proportion of SLE patients

• Characteristic arthritis—transient and peripheral polyarthritis, symmetrical involvement of small and large joints

  • Chronic can result in disability and deformity

  • 10%--rheumatoid like hand deformities

  • 25%-- osteonecrosis  

Neuropsychiatric Symptoms

• Develop secondary to involvement of central and peripheral nervous systems

• Disturbances of mental function: mild confusion, memory deficiency and impairment of orientation and perception

  • psychiatric disturbances like hypomania, delirium, and schizophrenia possible

Late-Onset Lupus

• Can occur: at any age, gender, or race

• Average age: 62; women 8x more than men; primarily in Caucasian

• Symptoms relatively mild—mimic other diseases—makes it hard to diagnose

DIagnostic: Hemostatic testing

• Lupus anticoagulants—inhibitor or prothrombin activator—often see thrombosis instead of bleeding

• Antiphospholipid antibodies –20% 

• Circulating anticoagulants may cause false positive for syphilis

• Prolonged prothrombin time (PT) and partial thromboplastin time (PTT)

Diagnostic : serological

• High levels of anti-DNA antibodies

• Reduced complement levels

• Presence of complement breakdown products of C3 (C3d and C3b)

• Marked increase in igG (hyperviscosity syndrome or renal tubular acidosis)

• Serum cryoglobulins of mixed IgG-IgM type—levels correlate with severity of SLE

ANA classification (5)

1. Antibodies to DNA

2. Antibodies to centromere

3. Antibodies to histone

4. Antibodies to nonhistone proteins

5. Antibodies to nucleolar antigens

Homogeneous or Diffused

• Characterizes anti-DNA nucleoprotein antibodies 

  • nDNA, dsDNA, ssDNA, DNP, or histones

• High titers: SLE

• Low titers: SLE, RA Sjogren syndrome, mixed connective tissue disease (MCTD)

Speckled Pattern

• Detected against saline extractable nuclear antigens

  • anti-RNP, anti-Sm

• Anti-Sm: highly specific for SLE

• Anti-RNP: SLE, RA, Sjogrens, PSS, MCTD, dermatomyositis

Nucleolar Pattern

Reflects an antibody to nucleolar RNA (4-6S RNP)

Present in approx. 50% of patients with scleroderma, Sjögrens, and SLE. Also seen in Raynaud phenomenon

Centromere

Anticentromere antibody reacts with centromeric chromatin

Highly selected for CREST variant of PSS
Found infrequently in SLE, MCTD, PSS
- CREST: variant of systemic sclerosis haracterized by Calcinosis, Raynaud phenomenon, Esophageal motility abnormalities, Sclerodactyly, and Telangectasis