Pathology-SLE

Question 1

Criteria required for diagnosis of lupus

Answer 1

4 of 8 criteria: 1) Malar rash 2) Discoid rash 3) Photosensitivity 4) Oral ulcers 5) Non-erosive Arthritis 6) Serositis (pleuritis and pericarditis) 7) Renal disorder (massive proteinuria) 8) Neurologic disorder (seizures and psychosis) 9) Hematologic disorder (hemolytic anemia) 10) Immunologic disorder (Anti-ds DNA, anti-Smith, anti-phospholipid, lupus anticoagulant, anti-cardiolipin) 11) Antinuclear antibody seen in 100% of Lupus proteins

Question 2

Why is it important to note that the malar rash of lupus spares the nasolabial folds?

Answer 2

Seborrheic dermatitis does not spare the nasolabial folds

Question 3

Antibodies that are highly specific for lupus

Answer 3

Anti-ds DNA (associated with lupus nephritis) and anti-smith antibodies.

Question 4

Antibodies seen in lupus and Sjogren’s syndrome

Answer 4

Anti-SS-A (Ro) and anti-SS-B (La) antibodies, note that when associated with lupus it is typically subacute cutaneous lupus

Question 5

What are ANAs targeted against?

Answer 5

DNA, histones, non-histone proteins bound to RNA and nucleolar antigens.

Question 6

Antibodies that are commonly seen in drug-induced lupus

Answer 6

Anti-histone antibodies

Question 7

How do we determine if a patient has ANAs?

Answer 7

Incubate patient’s serum overnight -> Add fluorescing anti-IgG antibody that glows if ANAs are present.

Question 8

Immunohistochemical analysis of a patient with suspected lupus is shown below. What are the likely antibodies present in this patient’s serum and what diseases are they associated with?

Answer 8

Homogenous pattern = anti-histone (drug-induced lupus) and anti-dsDNA (SLE)

Question 9

Immunohistochemical analysis of a patient with suspected lupus is shown below. What are the likely antibodies present in this patient’s serum and what diseases are they associated with?

Answer 9

Peripheral (rim) pattern = anti-dsDNA (SLE w/renal involvement). Note that his is highly specific for SLE.

Question 10

Immunohistochemical analysis of a patient with suspected lupus is shown below. What are the likely antibodies present in this patient’s serum and what diseases are they associated with?

Answer 10

Speckled pattern = anti-smith, anti-RNP, anti-SSA(Ro), anti-SSB(La) antibodies against ribonucleoproteins. These are not highly specific, but are associated with SLE, RA, systemic sclerosis and Sjogren syndrome.

Question 11

How can we follow disease activity in patients with lupus?

Answer 11

Anti-dsDNA titers fluctuate parallel with disease activity

Question 12

Immunohistochemical analysis of a patient with suspected lupus is shown below. What are the likely antibodies present in this patient’s serum and what diseases are they associated with?

Answer 12

Nucleolar pattern = anti-topoisomerase I and anti-SCL-70 antibodies associated with diffuse systemic sclerosis.

Question 13

Immunohistochemical analysis of a patient with suspected lupus is shown below. What are the likely antibodies present in this patient’s serum and what diseases are they associated with?

Answer 13

Centromere pattern = anti-centromere antibody against the kinetochore that is associated with limited scleroderma (CREST syndrome)

Question 14

Antibodies that are present in 30-40% of lupus patients that target prothrombin, annexin V, B2 glycoprotein I and protein C/S? What other condition will these be present in?

Answer 14

Anti-phospholipid antibodies. Antibodies to phospholipid-beta2 glycoprotein bind cardiolipin and result in a false positive test for syphilis (+VDRL with a - FTA-ABS).

Question 15

People at highest risk for SLE

Answer 15

Females in childbearing years (2-4th decade)

Question 16

What alleles are associated with anti-dsDNA, anti-Sm antibodies?

Answer 16

HLA-DQ

Question 17

Complement deficiencies that may contribute to development of lupus

Answer 17

C2, C4 or C1q: deficiency results in failure to clear immune complexes and apoptotic cells that results in immunogenicity of apoptotic debris. Note that there is a lupus genetic component, but the environmental component is the largest factor.

Question 18

Environmental triggers for lupus

Answer 18

UV light: induces keratinocyte apoptosis and IL-1 release which can generate anti-nuclear antibodies. Females: sex hormones/genes on X chromosome. Drugs: hydralazine, procainamide, D-penicillamine and INH (isoniazid for Tb).

Question 19

What differentiates drug induced lupus from SLE?

Answer 19

There is no renal involvement

Question 20

How does self tolerance fail in lupus?

Answer 20

Pathogenic IgG antibodies = CD4+ T-cell and B-cell peripheral tolerance impairment. TLR activation by DNA/RNA immune complex promotes expansion of autoreactive B cells. Type I IFN: produced in response to immune complex binding to TLRs on dendritic cells -> production of IFN-alpha. Increased BAFF increases B cell survival.

Question 21

Belumimab

Answer 21

Anti-BAFF used to decrease B-cell survival in patients with lupus.

Question 22

Pathogenic model for lupus

Answer 22

Susceptibility genes impair self tolerance and produce B and T cells specific for self nuclear antigens -> external environmental agent triggers increased burden of nuclear antigens -> ANA-antigen complex endocytosis, nuclear antigen engages TLRs -> Stimulation of B-cells and dendritic cells -> Release of type 1 IFNs -> Stimulation of B cells and T cells -> Persistent high levels of ANA IgG

Question 23

What mediates tissue injury in lupus?

Answer 23

Immune complex deposition in glomeruli, small blood vessels and blood brain barrier. This causes fixation of complement and inflammation. Anti-RBC/WBC/Platelet antibodies bind to hematopoietic elements directly, complement fixes and hemolytic anemia ensues.

Question 24

Cells you might see that are indicative of lupus

Answer 24

LE cells: apoptosis allows ANA to bind nuclei, fix complement and attract PMNs and macrophages to engulf them. This results in nuclear material within the phagocytes.

Question 25

Antibody responsible for miscarriages and DVTs in patients with lupus

Answer 25

Anti-phospholipid antibodies

Question 26

What would you expect to see on biopsy of a young woman who has a malar rash?

Answer 26

IgG deposition along the dermal-epidermal junction, although not specific for SLE, it is highly suggestive. You would also see liquefactive vacuolar degeneration of the basal layer of the epidermis with edema at the dermal-epidermal junction. Perivascular inflammation and vasculitis with fibrinoid necrosis can also be seen.

Question 27

A woman presents with facial and scalp rash that is scaly, atrophic, scarred, edematous and erythematous. She has no other systemic symptoms. The rash on her hands are shown below. Labs reveal a + ANA, but anti-dsDNA is negative. What is your diagnosis?

Answer 27

Chronic discoid lupus erythematosus. Only 5-10% of these patients will develop systemic symptoms.

Question 28

A woman presents with facial and scalp rash that is scaly, atrophic, scarred, edematous and erythematous. She has no other systemic symptoms. The rash on her hands are shown below. Labs reveal a + ANA, but anti-dsDNA is negative. What would you expect to see on histologic examination?

Answer 28

Chronic discoid lupes erythematosus is characterized by striking hyperkeratosis, dermal fibrosis and lymphocytic infiltrate.

Question 29

A woman presents with multiple skin lesions with red raised borders and central clearing on sun-exposed areas. She has had mild pleuritic chest pain in the past but no other symptoms. Labs show anti-SSA(Ro) antibody and an HLA-DR3 genotype. What is likely causing her condition?

Answer 29

Subacute cutaneous lupus erythematosus is associated with Sjogren’s syndrome.

Question 30

A woman presents with multiple skin lesions with red raised borders and central clearing on sun-exposed areas. She has had mild pleuritic chest pain in the past but no other symptoms. Labs show anti-SSA(Ro) antibody and an HLA-DR3 genotype. What do you need to warn her of if she gets pregnant?

Answer 30

Anti-Ro (SSA) antibody-induced neonatal congenital heart block. These antibodies are IgG antibodies and cross the placenta and bind to the conduction system in the heart. Note that the child may also have the typical malar rash, mucosal ulcerations, alopecia, Raynaud’s and vasculitis.

Question 31

Where do females have alopecia from SLE?

Answer 31

The front of the head where hairs are short

Question 32

Skin manifestations of lupus

Answer 32

Malar rash, mucosal ulcerations, alopecia, Raynaud’s and vasculitis.

Question 33

MSK manifestations of lupus

Answer 33

Non-erosive, symmetric arhtralgias in small joints with pain out of proportion to physical exam and myopathy (make sure it’s not due to polymyositis or corticosteroids).

Question 34

Renal manifestations of lupus

Answer 34

Proteinuria, hematuria, elevated serum creatinine and high titers of anti-dsDNA when renal disease is active. Note that damage is immune complex mediated and renal failure is the most common cause of mortality.

Question 35

5 classes of lupus nephritis

Answer 35

I) Minimal Mesangial: normal histology, immune complex in mesangium II) Mesangial Proliferative: increased mesangial cells and matrix with granular Ig and complement deposition, glomeruli appear normal. III) Focal proliferative: 50% of glomeruli involved, endothelial proliferation with sub-endothelial deposits that form wire loops, renal insufficiency. IV) Diffuse proliferative: \> 90% sclerosed glomeruli. V) Membranous nephritis: sub-epithelial immune complex and thickened capillary walls w/severe proteinuria and nephrotic syndrome

Question 36

How does immunofluorescence differ in the glomeruli of a patient with SLE vs someone with Goodpasture’s syndrome?

Answer 36

Since the antigen in Goodpasture’s syndrome is the glomerular basement membrane, the fluorescence is more uniform than the lumpy bumpy deposition of SLE immune complexes.

Question 37

Neuropsychiatric symptoms of lupus

Answer 37

Seizures and psychosis, anti-phospholipid antibody-induced endothelial damage and occlusion of small blood vessels.

Question 38

Optic symptoms of lupus

Answer 38

CN III palsy and cytoid bodies (hemorrhage and exudate)

Question 39

Other significant features of lupus

Answer 39

Splenomegaly, pleuritis, myocarditis, endocarditis (Leibmann-Sacks cardiac valve venation made up of fibrin and clot shown below)

Question 40

A patient presents with fever, arthritis and serositis. Labs show ANA+ but no anti-dsDNA and presence of anti-histone antibodies. What drugs could cause this condition?

Answer 40

Hydralazine, procainamide, isoniazid and D-penicillamine can cause drug-induced lupus, note that no renal or CNS involvement occurs with this condition.

Question 41

Treatment and prognosis of lupus

Answer 41

If kidneys and CNS are involved, treat aggressively with cyclophosphamide/cytoxin. If joints and skin are all that are involved treat with corticosteroids.

Question 42

Most common causes of death in patients with lupus

Answer 42

1) Renal failure 2) Intercurrent infection 3) Coronary artery disease from atherosclerosis