Scleroderma and GVHD

Question 1

What is Limited Cutaneous Scleroderma?

Answer 1

• no skin sclerosis proximal to knees or elbows
• longstanding Raynaud’s phenomenon (typical)

Question 2

Define Diffuse Cutneous Scleroderma

Answer 2

• cardinal features: skin sclerosis proximal to the kness and elbows
• Raynaud’s phenomenon

Question 3

What is CREST syndrome?

Answer 3

also known as limited cutaneous form of systemic sclerosis. Multisystem CT disorder.
Calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia.

Question 4

Autoantibodies associated with scleroderma and CREST and their pattern

Answer 4

60% have antinuclear antibodies (ANA)

pattern: speckled, nucleolar, centromere, or diffuse

Question 5

Which antibody is very specific for proximal scleroderma? Which is a common antibody found in CREST patients?

Answer 5

Specific for proximal scleroderma (20-40%, CREST = 4%): Anti-topoisomerase I

CREST (40%), Prox scleroderma=12%: Anticentromere Antibody (ACA)

Question 6

Antibodies to topoisomerase I are associated with the following (3)

Answer 6

1) tight skin (proximal scleroderma) = sclerodactyly
2) severe dieases (i.e. pulm fibrosis)
3) cancer development

[antibodies to centromere (ACA) are associated with the features of CREST]

Question 7

In terms of the pathogenesis of scleroderma, what are the 3 major components? Which is the most important?

Answer 7

• vascular **most important**
• fibrotic
• immune

Question 8

Describe the vasculopathy component of Scleroderma.

Answer 8

• loss of endothelial lining layer with intimal proliferation and vascular occlusion
• thinning of muscular layer
• adventitial cuff of connective tissue

Question 9

Hypothesis of early disease of scleroderma, and following progression

Answer 9

• early disease: activation of endothelial cells, fibroblasts and perivascular inflammatory infiltrate
• endothelial loss, intimal proliferation, luminal narrowing, thrombosis and periadventitial fibrosis of small arteries and capillaries.

Question 10

which IL has been associated ith pulmonary endothelial injury? What does it react with?

Answer 10

IL-1 ; it reacts with endothelium through expression of ECAM-1 and ICAM-1

these in turn, lead to adhesion of lymphocytes to endothelium and endothelial damage.

Question 11

Sclerdoerma is a fibortic disease. While the vasculature is a major component, the fibrosis is key. What is the mechanisms of this fibrosis?

Answer 11

Fibroblast activation and proliferation leads to deposition of ECM. Increased collagen production may happen without necesarily fibroblast proliferation, and this may be mediated by TGF-beta.

Question 12

in patients with diffuse scleroderma, there has been a significant positive correlation between anti-endothelial cell antibodies and these 4 things

Answer 12

1. decreased dLCO
2. increased pulmonary artery pressures
3. digital ulcers
4. nail fold capillaroscopy abnormalities

Question 13

Three main treatment classes for Scleroderma

Answer 13

1, Phosphodiesterase inhibitors: Sildenafil

2. Endothelin Rececptor Antagonists: Bosentan, Ambrisentan
3. Prostacyclins: Epoprostenol, Iloprost, Treprostenil

Question 14

What drug was found to be useful in softening the skin in scleroderma?

Answer 14

Cyclophosphamide (immunosuppression), useful in alveolitis.

Question 15

8 steps for pathogenesis of scleroderma summary

Answer 15

1. Unidentified trigger
2. Endothelial injury and activation
3. Platelet Activation
4. Release of PDGF and TGF-B
5. Fibroblast activation
6. Overproduction of collagen and fibronectin in the dermis
7. Fibrosis in skin and organs
8. Activation of the immune system

Question 16

PDGF and TGF-beta, what are their actions?

Answer 16

PDGF: chemo attractant for fibroblasts and smooth mnuscle cells

TGF-beta: most potent inducer of collagen and fibronectin synthesis by FIBROBLASTS.

Question 17

side effect of scleroderma often misdiagnosed and mistreated to look out for

Answer 17

SCLERODERMA ALVEOLITIS: if misdx as cogestive heart failure, diuresing them is the worst thing you can do– precipitates renal HTN and renal crisis (due to occlusion of renal lumen and inflammation)

Question 18

Definition of Graft Vs. Host Disease (GVHD)

Answer 18

A syndrome occurring in immune compromised hosts exposed to immunocompetent donor T cells (i.e. bone marrow transplant patients, patients with congenital deficiencies of T lymphocytes)

Question 19

3 essential requirements for GVHD:

Answer 19

1. Graft must contain immunologically COMPETENT T cells
2. host must express tissue antigens not present in the donor (or must have an inappropriate response to self)
3. The host most be incapable of mounting an immune response that can destroy the transplanted cells.
   (recall: in GVHD, the ptmust be immunocompromised)

Question 20

ACUTE Graft Vs. Host Disease

Answer 20

Triad of complaints: dermatitis, hepatitis, gastroenteritis occurring within the first 100 days following transplantation

Question 21

CHRONIC Graft Vs. Host Disease

Answer 21

A multi-organ disease occurring more than 100 days after transplantation

Question 22

GVHD is a consequence of an outpouring of _______

Answer 22

CYTOKINES (TNF-a, IL-1, -2, -3, -4, -6. -11, IFN-B, IFN-gamma, LPS, GM-CSF)

Question 23

In Acute GVHD, what is essential for this disease? What does target cell injury reveal?

Answer 23

Mature DONOR T cells

Target cell injury reveals: dyskeratotic epithelial cells, mast cell degranulation and lymphocyte infiltration

Question 24

Satellitosis

Answer 24

Effective lymphocytes surrounding a central degenerating epithelial cell, seen in Acute GVHD

Question 25

What 3 features in Chronic GVHD are similar to auto immune disease?

Answer 25

1. Skin disease: pigment changes and scleroderma like lesions with dermal fibrosis, atrophy, ulceration, fibrosis, and limitation of joint movement
2. Liver disease: cholestasis with primary billiary cirrhosis like histopathology
3. Sjogrens-like sicca complaints with lymphocytic infiltrates in glandular tissues