Lupus

Question 1

Two types of hypersensitivity reactions we see with lupus

Answer 1

Type II - Cell type-specific autoantibodies

Type III - Immune complexes (most common)

Question 2

What defines a malar rash?

Answer 2

Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

Question 3

What defines a discoid rash?

Answer 3

Erythematous raised patches with adherent keratotic scaling and follicular plugging

Atrophic scarring may occur in cider lesions

Question 4

What defines the lupus criterion of serositis?

Answer 4

Pleuritis - convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion

or

Pericarditis - documented by ecg or rub or evidence of pericardial effusion

Question 5

What signs will we see with renal disorders related to lupus

Answer 5

Persistent proteinuria > 0.5 g/dL or >3 if quantitation not performed

or

cellular casts - may be RBC, hemoglobin, granular, tubular, or mixed

Question 6

What neurologic signs of lupus will we see?

Answer 6

Seizures - in the absence of offending drugs or known metabolic derangements (uremia, ketoacidosis, or electrolyte imbalance)

or

Psychosis - in the absence of offending drugs or known metabolic derangements

Question 7

When do we typically see anti-histone ANAs?

Answer 7

Drug induced SLE, relatively specific

Question 8

When do we typically see Anti SS-A (Ro) and Anti SS-B (La) ANAs?

Answer 8

Subacute cutaneous lupus and congenital heart block (these autoAbs also seen in majority of Sjogren’s syndrome patients)

Question 9

What does a homogenous antibody fluorescence pattern indicate?

Answer 9

On the microscope, the whole nucleus will light up. This could be histone, dsDNA, and/or chromatin.

Question 10

A peripheral or rim pattern on fluorescence indicates what?

Answer 10

Much more specific, it means you have an actively mitotic cell and are targeting the dsDNA, and occasionally nuclear envelope proteins

We see this with renal involvement of SLE

Question 11

A speckled fluorescence pattern indicates what?

Answer 11

This is the most commonly observed pattern and therefore the least specific. It reflects the presence of antibodies to non-DNA nuclear material like Sm antigen, ribonucleoprotein, and SS-A and SS-B reactive antigens. It looks essentially like the homogeneous pattern but with holes.

So we see it with SLE, RA, Systemic Sclerosis, and Sjogrens

Question 12

Another fluorescence pattern is nucleolar pattern. What does this indicate?

Answer 12

This looks like small specks in the very center, associated with antibodies to RNA.

We associate this with Diffuse Systemic Sclerosis

Question 13

The final pattern of fluorescence is the centromere pattern. What does this indicate?

Answer 13

This is an anti-centromere ab that targets the kinetochores. This is associated with limited scleroderma (CREST sdr) and systemic sclerosis.

Question 14

Although uncommon, there are certain genetic deficiencies that can lead to lupus. What are they?

Answer 14

Losses of complement C2, C4, or C1q - Lead to failure to clear immune complexes and apoptotic cells, leading to immune activation of apoptotic debris and loss of B-cell self tolerance

Question 15

What leads to the skin changes we see in Lupus?

Answer 15

Ig/complement at dermal epidermal junction

• Lymphocytic infiltration at dermal-epidermal junction
• Liquefaction of basal layer of epidermis
• Edema and perivascular lymphocytes in dermis

Question 16

How bad is the chronic discoid lupus erythematosus? What tests come back positive/negative?

Answer 16

Usually more benign, with only 5-10% developing multisystem features after many years.

We see depigmentation with coin and round-shaped erythematous plaques with adherent scales.

Ana positive, ds-DNA negative, + lupus band test

Question 17

The third type of epidermal manifestation of lupus, subacute cutaneous LE, is associated with what markers?

Answer 17

• anti Ro
• HL-DR3 genotype

This guy comes out with central clearing, like a rash of just peripheral areas of a scar.

Question 18

We see neonatal defects with what lupus type and serum marker?

Answer 18

Heart defects in subacute cutaneous with positive anti-Ro

Question 19

Raynaud’s phenomenon is seen in LE. How does this present?

Answer 19

Expose to cold:

1. Fingers turn white
2. Fingers turn blue
3. Very red once re-perfuson and cold is gone.

Everyone gets this, but we worry about this when its not that cold or the response is asymmetrical.

Also seen in smokers!

Question 20

There are 6 stages of lupus nephritis. Discuss the first 3

Answer 20

Stage 1 - Minimal mesangial - Very uncommon. Immune complexes in the mesangium that look normal under light microscopy

Stage 2 - Mesangial proliferation. Increase in mesangial cells and matrix with granular Ig, complement deposition. Still have a normal glomerulus

Stage 3 - Less than 50% of the glomerulus involved. We see segmented or global glomerular issues. WBCs are present. Look for crescents, necrosis, hematuria, proteinuria, RBC casts.

Question 21

Discuss the final 3 stages of Lupus nephritis

Answer 21

Stage 4 - Diffuse - This is the most common, and is exactly like stage 3 but way more extensive. You will see crescents, sub-endo deposits, thickened capillary wall (wire loop), and renal insufficiency will begin.

Stage 5 - Membranous - Sub epithelial immune complexes - Diffusee thickened capsule walls with severe proteinuria, nephrotic syndrome.

Stage 6 - Advanced sclerosing where more than 90% of the glomerulus is sclerosed.

Question 22

Glomerular immunofluorescence for Goodpastures vs. SLE

Answer 22

“Lumpy bumpy” for SLE, smooth linear for GP syndrome

Question 23

The prevalence of lupus is higher in these groups of people:

Answer 23

• 9:1 female to male

- Hispanics and blacks = 2-3x more likely

Question 24

Virtually diagnostic for SLE is:

Answer 24

Antibodies to double stranded DNA and the so called Smith (Sm) antigen

Question 25

In addition to ANAs, lupus patients have autoantibodies to a host of things, such as platelets, RBCs, lymphocytes, etc.

30 - 40% of patients with lupus have this second large category of autoantibodies:

Answer 25

Antiphospholipid antibodies, directed against epitopes of plasma membranes that are revealed when the proteins are in complex with phospholipids. Proteins included are:

• Prothrombin
• Annexin V
• B2 glycoprotein I ***
• Protein S
• Protein C

Antibodies against the B2 glycoprotein I complex also bind cardiolipin, which can yield a false positive for syphillis.

Question 26

Why are lupus antibodies sometimes referred to as lupus anti-coagulant? Are lupus patients hypocoagulable?

Answer 26

Some of the antiphospholipid complexes interfere with in vitro clotting tests such as partial thromblastin time (complex with prothrombin).

Although delayed in clotting for the test, however, lupus patients with antiphospholipid antibodies have issues related to too much clotting, such as thrombosis.

Question 27

Can lupus be inherited?

Answer 27

As many as 20% of clinically unaffected first degree relatives of SLE patients have autoantibodies and other immune issues.

Question 28

What environmental factors are linked to lupus?

Answer 28

• UV light - Exacerbates the disease by mutating genomes in exposed area and inducing certain reactions such as IL-1 production by keratinocytes to induce inflammation
• Gender bias - Not just female hormones can stimulate Lupus! Certain genes on the X-chromosome are linked to Lupus
• Drugs - Hydralazine, procainamide, D-penicillamine can induce SLE-response in humans

Question 29

So many ideas have been proposed for what causes Lupus. Funnel all of that into one basic mechanism of disease

Answer 29

To begin, you need susceptible genes that lead to production of B and T cells specific for self nuclear antigens. Then you need increased burden of nuclear antigens for them to grab on to, which is caused by external triggers such as UV radiation, which apoptose cells. Defective clearance of apoptotic bodies further increases the nuclear burden.

With nuclear antigens around and B and T cells ready to attack, we get formation of anti-nuclear antibody complexes, which bind to the Fc portion of B cells and dendritic cells, possibly getting internalized.

This engages TLRs, and stimulates the B cells to make more autoantibodies, and the dendritic cells to make more interferons and cytokines to further enhance the response, causing more cell death. This cycle leads to the persistence of high level anti-nuclear IgG antibody production.

Question 30

Most systemic lesions of Lupus are caused by:

Answer 30

Immune complexes (Type III hypersensitivity)

Question 31

What is an LE cell and what does it indicate?

Answer 31

So there is no evidence that ANAs can cross an intact cell membrane, but if the nuclei is exposed, they can bind to nuclear material.

In damaged cells, nuclei react with ANAs and lose their chromatin structure to become homogenous LE bodies, or hematoxylin bodies.

Phagocytic leukocytes (neutrophis and macrophages) eat these bodies and become LE cells.

Question 32

What is antiphospholipid antibody syndrome?

Answer 32

Patients with antiphospholipid antibodies may develop venous and arterial thromboses, associated with miscarriages and focal cerebral or ocular ischemia.

Lupus present with these findings = Secondary APA syndrome
No lupus = Primary APA syndrome

Question 33

Discuss the progression of pericarditis or involvement of other serosal cavities involved with lupus?

Answer 33

During the acute phases of inflammation of serosal linings, the mesothelial surfaces will be covered with fibrinous exudate. Later they become thickened, opaque, and coated with a shaggy fibrous tissue that may lead to partial or total obliteration of the serosal cavity.

Pleural and pericardia effusions may be present.

Question 34

Discuss cardiovascular findings we see in Lupus

Answer 34

• Damage to any layer of the heart
• Mitral and aortic valves can become thickened causing stenosis or regurgitation (valvular endocarditis, also called Libman Sacks, was more common before the use of steroids, and presents as non-bacterial warts on leaflets)