Chapter 2.4 Autoimmune Disorders (Part 2)

Question 1

Describe SLE.

Describe the demographics of those most commonly affected.

Are men and women affected equally? Why/why not? What is an exception?

Answer 1

chronic systemic autoimmune disease

flares and remissions are common

middle-aged female (10 to 1 more likely involved in females)
more common in African Americans and Hispanics

Can occur in children and older adults but the female bias less dramatic (2:1)

(estrogen reduces apoptosis of self-reactive B cells…)

Question 2

Describe the hypersensitivity of SLE. Will CH50, C3 and C4 be increased or decreased in patients with SLE?

Answer 2

antigen-antibody complexes deposit in multiple tissues, results in activation of complement, which damages those tissues

(bc using more complement patients will have decreased CH50, decreased C3, decreased C4)

CH50 tests patients complement C1-C9, decrease indicates complement being used

Type III hypersensitivity

Question 3

In SLE, what are antibodies often directed against?

Answer 3

antibodies are often directed against host nuclear material (result in antigen antibody complexes, activate complement, cause tissue damage)

Question 4

Describe in detail the current paradigm of how patients might develop Lupus.

Answer 4

UV light hits keratinocyte, damages DNA, apoptosis of cells

cytoplasm shrinks, nucleus shrinks, apoptotic bodies/debris released and is taken up by macrophages

if poor clearance of apoptotic debris and it hangs out then a self reactive B cell may get exposed to that debris (sees nuclear material) and prod. Ab vs nuclear antigens… so next time UV light hits keratinocyte and causes apoptosis again and release of nuclear material, so Ab can bind nuclear material and have Antigen Ab complexes at low levels, can be taken up by DC cells, then antigen can activate TLR present in DC… TLR will amplify immune response and further activate the B cells, then additional Ab produced and now have high levels of Antigen Ab complexes forming… these can enter into blood and deposit in multiple tissues and result in activation of complement and damage tissues

Question 5

Why do patients with early complement deficiency (C1q, C4, C2) have an increased risk of developing Lupus?

Answer 5

Ab formed against host nuclear material

with antigen-antibody complexes … complement is essential for clearing antigen antibody complexes

IgG-nuclear material (C1 attach, c4 then will come and be cleaved, c2 attach, c2 cleaved, c4c2 complex is c3 convertase that will cleave c3 to c3a and c3b… c3b will attach to complex and act as opsonin to allow for removal of complex.

macrophages can recognize c3b and take it up.
if complex in blood, erythrocytes have receptor CR1 that can bind to C3b and will take complex to spleen to eat and remove the complex

Question 6

What is most common complement deficiency of early complement deficiencies leading to SLE?

Answer 6

deficiency of C2

Question 7

What are clinical features of SLE that are more nonspecific?

Answer 7

nonspecific symptoms:
Fever, weight loss, fatigue, LAD (big lymph nodes bc of activation of immune system),

Raynaud= patients get arterial vasospasm cuts blood supply for few minutes turns finger white, ischemia turns blue, as spasm releases turns back to red,

change in color on fingertips or tip of nose where change white to blue to red…)

Question 8

What are the 11 clinical criteria of SLE?

Answer 8

1. Malar ‘butterfly’ or
2. discoid rash (circular,
   erythematous, scaling, can scar),
3. (rash) especially upon exposure to sunlight
4. oral or nasopharyngeal ulcers
5. arthritis
6. serositis (can result in pleurtic pain when breathe in, pericarditis can occur)
7. CNS problems, psychosis or seizures
8. renal damage
9. anemia (ab against RBC), thrombocytopenia (Ab against platelets), leukopenia (ab against WBC) ….Type II hypersensitivity
10. antinuclear antibody
11. anti-dsDNA, anti-Sm or antiphospholipid Ab

Libman-Sacks endocarditis (Lupus can affect any layer of the heart…pericardium, myocardium or endocardium… patients get small vegetations on both sides of mitral valve. )

(11 criteria for lupus, need 4 for diagnosis)

Question 9

What are the damages to the kidney that can occur with SLE?

Answer 9

nephritic syndrome (hypertension and hematremia )
-diffuse proliferative glomerulonephritis

nephrotic syndrome (high levels of protein leaking into urine=protinuria…leads to membranous glomerulonephritis)

Question 10

Which clinical feature of SLE is actually a type II hypersensitivity?

Answer 10

anemia (ab against RBC), thrombocytopenia (Ab against platelets), leukopenia (ab against WBC) ….Type II hypersensitivity

Question 11

What is not a clinical criteria for diagnosing SLE but can occur in patients with SLE?

Answer 11

Libman-Sacks endocarditis (Lupus can affect any layer of the heart…pericardium, myocardium or endocardium… patients get small vegetations on both sides of mitral valve.)

not really seen now bc of treatment with immunosuppressives

Question 12

If patient had a positive ANA and you were worried about SLE, what would be the next step of testing?

Answer 12

test for anti-dsDNA and anti-Sm

antinuclear antibody (present in serum of patients, good for screening, however is nonspecific bc 5% can be seen in normal invididuals and in many patients with other autoimmune disorders, can have anti-dsDNA or anti-Sm are v specific for Lupus

Question 13

If patient tested and had high titers of anti-dsDNA what might that indicate?

Answer 13

patient may be about to relapse so treat.

associated with disease activity

Question 14

What is anti-dsDNA associated with? Why is it used for prognosis?

Answer 14

(associated with disease activity and with renal nephritis)

prognosis bc predicts renal involvement which is a common cause of death

Question 15

What is an antiphospholipid antibody?

Answer 15

auto antibody against proteins bound to phospholipids

when protein bound to phospholipids, epitopes releaved that are antigenic and that results in phospholipid antibody

Question 16

What are three antiphospholipid Ab commonly tested for Lupus?

Answer 16

anticardiolipin (can produce false positive test for syphilis: VDRL and RPR tests…in syphilis there is tissue damage, lipids released, develop anticardiolipin)

lupus anticoagulant (falsely-elevated PTT)

Anti-beta2 glycoprotein I

Question 17

Patients with lupus anticoagulant can also have what other syndrome? What will PTT test show?

What can occur clinically with this syndrome? How is it treated?

Answer 17

lupus anticoagulant (falsely-elevated PTT)

APA syndrome (associated with Lupus but more commonly as primary disorder)

antiphospholipid antibody plus hypercoagulable state

deep venous, hepatic vein, placental (would result in pregnancy loss), and cerebral thrombosis

requires lifelong anticoagulation

Question 18

What antibody will patients with drug-induced SLE likely have?

Answer 18

antihistone antibody

drugs can induce

Question 19

What drugs can induce Lupus?

What will ANA test show in drug induced Lupus?

Answer 19

hydralazine, procainamide, and isoniazid

ANA+ test (specific to antihistone antibodies)

develop rash, etc
CNS and renal involvement rare

removal of drug results usually in remission of Lupus

Question 20

What does treatment of Lupus include?

Answer 20

• avoid sunlight
• glucocorticoids (if patient undergoes flare)
• other immunosuppresive agents

Question 21

What is the prognosis for SLE?

What are most common causes of death?

Answer 21

> 90% 5 year survival

renal failure and infection are most common causes of death (infection bc treating w immunosuppressives and also can generate antibodies to WBC)

accelerated coronary atherosclerosis (late)

Question 22

Describe the etiology of Sjogren syndrome. What type of HSR?

Answer 22

autoimmune destruction of lacrimal and salivary glands

lymphocyte-mediated damage (type IV HSR) with fibrosis

Question 23

What is the clinical presentation of Sjogren syndrome?

What type of patient is typically affected?

Answer 23

dry eyes (destruction of lacrimal glands) 
dry mouth (destruction of salivary glands) 

recurrent dental caries in older women (salivary gland usually prod. fluid that washes over teeth and maintains some level of cleanliness

“can’t chew a cracker, dirt in my eyes” (lacrimal gland not prod fluid to wash away dirt that may come in from environment)

extraglandular manifestations common (joint problems, skin, CNS problems)

Question 24

Sjogren’s can be primary or can be associated with another autoimmune disorder? What disorders are common?

Answer 24

Rhematoid arthritis

Rheumatoid factor often present in blood, even in primary disease
(even if patient does not have RA they often also have RF in blood)

Question 25

How is Sjogren’s Syndrome characterized? Antibodies against what?

Describe association of SSA and pregnancy.

Answer 25

characterized by ANA and anti-ribonucleoproteins (RNA and proteins =ribosomes)

Anti-SSA and anti SSB
(sjogren’s syndrome=SS and A and B for antibodies but patients with Lupus can also have SSA and SSB without Sjogren’s)

patients with SSA and SSB often have extraglandular manifestations

(SSA can cross placenta so risk of neonatal lupus and congenital heart block) !!!

-also seen in subset of SLE patients; so risk of neonatal lupus, so important when someone with SLE gets pregnant screen for SSA or SSB then watch for neonatal lupus w feared complication of congenital heart block

Question 26

Describe additional diagnositic criteria besides SSA and SSB for Sjogren’s Syndrome.

Answer 26

biopsy of minor salivary glands (lip)

look for lymphocytes attacking minor salivary glands = lymphocytic sialadenitis

Question 27

Dry eyes and dry mouth can be due to causes other than Sjogren’s syndrome. What else could cause these symptoms?

Answer 27

• amyloidosis (no amyloid deposition)
• sarcoidosis (noncaseating granulomas throughout multipe system tissues)
• drugs
• prior radiation

Question 28

What three clinical criteria are necessary to diagnosis Sjogren’s syndrome?

Answer 28

1. dry eyes (test clinically with looking for decrease in tear production)
2. ANA but SSA or SSB or RF
3. presence of lymphocytic sialadenitis

(need 2/3 to diagnose)

Question 29

A patient has had Sjogren’s Syndrome for 10 or 15 years. Suddenly they come to you and one parotid gland is bigger than the other. What might this indicate, if anything?

Answer 29

inflammation of parotid glands on both sides is usual for Sjogren’s S.

presents as unilateral enlargement of parotid late in disease

increased risk for B cell lymphoma (can cause enlargement)

Question 30

What is Systemic Sclerosis? (Scleroderma) Describe.

What patients are most commonly affected?

Answer 30

autoimmune disorder

sclerosis (hardening of tissue) of skin and visceral organs

middle aged females

Question 31

Describe the etiology of Systemic Sclerosis. Why does hardening of tissue occur?

Answer 31

fibroblasts activation leads to deposition of collagen in multiple tissues

have immune reaction against mesenchymal antigen (antigen in connective tissue or endothelial cells, when get immune reaction, get dysfunction of endothelial cells which leads to increased expression of adhesion molecules that allows inflammatory cells into tissue

increased expression of endothelin (v strong vasoconstrictor) decreased NO

endothelial cells will produce platelet derived growth factor and TGF beta…activate fibroblasts and result in fibrosis around blood vessel

then ischemia, fibrosis… then get end organ damage and get system sclerosis

Question 32

Describe the limited type of Systemic Sclerosis.

Answer 32

shows limited skin with late visceral involvement

Calcinosis (deposition of Ca in subcutaneous connective tissues/anti-centromere

Raynaud phenomenon (fingertips, tip of nose, ear, exposed to cold or stress, arterial vasospasm, white blue then red…earliest signs seen in the limited type…can be seen in normal or Lupus patients too)

Esophageal dysmotility (can get fibrosis of wall of lower portion of esophagus, can lead to difficulty swallowing liquids and solids…don’t have normal peristalsis and need peristalsis to swallow liquids or solids, can be disruption of gastroesophageal junction and then reflux of acid from stomach into esophagus leading to GERD)

Sclerodactyly (fibrosis of skin of hands..makes skin tight, lose wrinkles, can constrict blood vessels leading to necrosis and ulceration of fingertips )

Telangiectasias of skin (dilated capillaries, results in red marks on skin)

overall prognosis is good

Question 33

Describe skin, vessels, GI tract, lungs, kidney, heart involvement in Systemic Sclerosis.

Answer 33

diffusely involves skin with early visceral involvement

Vessels

GI tract (esophagus is classic site, dysphagia, GERD

Lungs (most common cause of death, interstitial fibrosis or pulmonary hypertension)

Kidney (2nd most common cause of death, splenoderma renal crisis= sudden onset of acute renal failure and severe hypertension..if treat with ACE inhibitors and normalize high bp can resolve crisis)

Heart (heart failure bc of pulmonary hypertension or fibrosis of cardiac tissue itself)

Will have antibodies against DNA topoisomerase I antibodies

Question 34

Which antibodies will be present in the limited vs diffuse type of Systemic Sclerosis?

Answer 34

limited type -anti centromere antibodies

diffuse type- antibodies against DNA topoisomerase I

Question 35

What is mixed connective tissue disease? Mixed features of what conditions? What type of antibodies are seen?

Answer 35

autoimmune

mixed features of SLE, systemic sclerosis, and polymyositis

(patients can have arthritis-like SLE, can have GERD like patient with systemic sclerosis, can have myalgia or inflammation of muscles like seen in polymyositis)

…patients usually begin v nonspecific (fatigue, low grade fever… over time they develop overlapping features of these other conditions which allows you to classify them as mixed connective disease)

ANA with serum antibodies against U1 ribonucleoprotein (RNP)

Question 36

What are the hallmarks of Mixed Connective Tissue Disease? (How can it be distinguished from other autoimmune disorders?)

Answer 36

usually have Reynaud’s

usually lack renal CNS involvement,

usually have severe arthritis and pulmonary hypertension (major cause of death)

Question 37

Patients with mixed connective tissue disease will have what serum antibodies?

Answer 37

ANA with serum antibodies against U1 ribonucleoprotein (RNP)