Graft Versus Host Disease

Question 1

In what setting does graft versus host disease usually occur?

Answer 1

Allogeneic hematopoietic stem cell transplants

• Can also occur in transfusion of non-irradiated blood to immunocompromised hosts, maternal-fetal transmission and solid organ transplant (small intenstin>lier>kindey>heart)

Question 2

What is the most important predictor of graft versus host disease occurring?

Answer 2

HLA compatibility

Question 3

Why is the rate of graft versus host disease increasing in recent years?

Answer 3

There is increasing use of matched unrelated donors.

These pts are more likely to have small differences in HLA mismatch compared to matched related donors

Question 4

What sources of stem cells most increase the risk for graft versus host disease?

Answer 4

Peripheral blood (PB-HSCT) > bone marrow > cord blood

• There is increased popularity of the peripheral blood HSCT in the US due to ease of collection, but need to consider GVHD risk

Question 5

How can the pre-conditioning technique affect the risk for graft versus host disease?

Answer 5

Myeloablative preconditioning increases the risk of GVHD due to damage to host tissues.

• Many centers now do non-myeloablative reduced-intensity conditioning but this can also delay the onset of GVHD to beyond the classic 100 days (delayed-onset acute GVHD)

Question 6

What are the risks of developing graft versus host disease in HSCT recipients?

Answer 6

HLA-matched = 40%

HLA-mismatched = 60-70%

Question 7

What organ is most affected by graft versus host disease?

Answer 7

The skin

Question 8

How is a periphereal blood HSCT done?

Answer 8

The patient is treated with a colony-stimulating factor (filgrastim) which mobilizes the donor stem cells into the peripheral blood and then this can be aphoresed off and infused into the recipient

Question 9

What is the pathogenesis of acute graft versus host disease?

Answer 9

1. Activation of host antigen-presenting cells
2. Host antigen-presenting cells bind altered host proteins/neo-antigens
3. Donor lymphocytes recognize altered host protein antigen-presenting cell complexes and proliferate and target host tissue in skin, GI tract, and liver

Question 10

What is the pathogenesis of chronic graft versus host?

Answer 10

Largely unknown

• Early: IFN-gamma, increased regulatory T-cells, and T-cell cytokine response (IL-2Ralpha).
• Late: Lack of Th2 shift, B-cell activation via soluble BAFF, induction of Toll-like receptor 9 highly expressing B cells, and autoantibody formation
• Chronic lichenoid GVHD shows some Th1/th17 signature suggesting these treatments could be helpful

Question 11

What is the timing of acute GVHD?

Answer 11

Occurring within the first 100 days after transplant (this is considered not essential for diagnosis now)

Question 12

What is the typical timing of acute graft versus host disease after HSCT?

Answer 12

2-6 weeks after (peak incidence is 30 days after)

Question 13

What is the most common presenting morphology of acute graft versus host disease?

Answer 13

Morbilliform eruption on the acral surfaces (hands, feet, ears)

Clues: Acral erythema, violaceous hue on-ear, follicular/peri-eccrine erythema (darker punctate lesions help distinguish from simple morbilliform eruptions)

Question 14

What systemic effects can be seen in acute graft versus host disease?

Answer 14

GI tract: nausea, voluminous diarrhea, abdominal pain

Liver: transaminitis, cholestasis, bilirubin elevation)

Question 15

What are the 3 components of acute graft versus host disease staging?

Answer 15

• Skin: severity assessed by % BSA
• GI: severity assessed by the volume of diarrhea (and severe abdominal pain)
• Liver: severity assessed by the degree of bilirubin elevation

Note that there are also histologic gradings of acute graft versus host disease

Question 16

How many grades of acute graft versus host disease are there?

Answer 16

There are 4 stages ranging from 1-4.

Question 17

What are the 4 stages of histologic acute graft versus host disease?

Answer 17

1. focal vacuolar change of basal keratinocytes
2. Grade I plus necrotic keratinocytes in the epidermis and/or hair follicles and dermal lymphocytic infiltrate
3. Grade II plus a fusion of basilar vacuoles to form clefts and microvesicles
4. Grade III plus large areas of separation of the epidermis from the dermis

Question 18

What is the classic definition for the timing of chronic graft versus host disease?

Answer 18

>100 days (now considered to be arbitrary and not part of diagnosis)

Question 19

How often is chronic graft versus host disease preceded by acute graft versus host disease?

Answer 19

50% of the time

Question 20

What are the two classifications of clinical graft versus host disease?

Answer 20

Non-sclerotic GVHD vs sclerotic GVHD

Question 21

What are the clinical features of non-sclerotic chronic graft versus host disease?

Answer 21

Often but not always precedes sclerotic chronic graft versus host disease

• Most common presentation is the lichenoid eruption (80% of cases): coalescent, slightly scaly, violacious-to-pink papules arranged in a reticulate pattern. Most common sites for this are dorsal hands/feet, forearms, and trunk
• Other forms include atopic dermatitis-like psoriasiform, poikilodermatous, lupus-like and keratosis pilaris-like

Question 22

What is the most common clinical morphology of non-sclerotic chronic graft versus host disease?

Answer 22

Lichenoid: dorsal hands/feet, forearms, trunk –> coalescent, slightly scaly violaceous -to-pink papules arranged in reticulate pattern

Question 23

What is the clinical presentation of sclerotic graft versus host disease?

Answer 23

Favors areas of pressure, many morphologies

• Lichen sclerosis-like
• sclerodermoid/morphea-like plaques: unlike true scleroderma, the distribution is more patchy and lacks classic features of scleroderma (bird faces, puffy/indurated hands, sclerodactyly)
• eosinophilic fasciitis like

Question 24

What can help distinguish GVHD from drug reactions?

Answer 24

Apoptotic cells in adnexal structures (hair follicles and sweat ducts)

Question 25

What epidermal changes are seen in acute GVHD?

Answer 25

Epidermal dysmaturation (looks like Bowenoid AK or chemotherapy effect)

Question 26

Histologic findings in chronic GVHD?

Answer 26

Lichenoid: similar to LP but less dense of an infiltrate

Sclerotic: dermal sclerosis plus-minus subcutaneous and fascial fibrosis, may see overlying vacuolar or lichenoid interface

Question 27

What workup should be performed for graft versus host disease?

Answer 27

Tissue biopsy in both

Acute: bilirubin, CMP (liver enzymes), diarrhea volume measured

Chronic: MRI can detect fasciitis and may eliminate need for fascial biopsy

Question 28

What prophylaxis is used for graft versus host disease?

Answer 28

Often MTX + cyclosproin or tacrolimus

Question 29

Treatment of acute graft versus host disease?

Answer 29

If it is limited/skin only disease can use topical steroids, TCIs, and phototherapy

• For most cases that have skin + internal organ involvement) systemic steroids are the first line and are added to existing immunosuppressants

Question 30

How effective are systemic steroids for graft versus host disease involving skin + internal organs?

Answer 30

Only 50% tend to respond, in those that don’t respond mortality is high (70%)

Question 31

What is the treatment for chronic graft versus host disease?

Answer 31

Very difficult to treat, can try topical and systemic corticosteroids added to the immunosuppressive regimen, but again only 50% respond

• Second line, nothing shown to be effective, can try ECP, PUVA +/- isotretinoin, imatinib, and mTOR inhibitors

Question 32

What is the prognosis of acute graft versus host disease?

Answer 32

Overall: 30-50% mortality if moderate to severe dz

• If steroid-resistant 70% mortality

Question 33

What is the most common cause of death in chronic graft versus host disease?

Answer 33

Infection

Question 34

What medication can decrease the incidence of visceral graft versus host disease and how does it do it?

Answer 34

Maraviroc (CCR5 inhibitor) can decrease visceral GVHD by blocking CCR5 mediated CD8+ T-cell recruitment to the liver and gut

• Can be considered in pt’s with high risk for GVHD

Question 35

Does the addition of Maraviroc decrease the incidence of graft versus host disease?

Answer 35

No, only decreases the incidence of visceral involvement

Question 36

What other organs can be involved in chronic graft versus host disease?

Answer 36

Eyes (keratoconjunctivitis sicca, blepharitis, corneal erosions), salivary glands (sicca syndrome), and lungs (bronchiolitis obliterans)

Less commonly: esophagus (strictures/webs, less common), liver and pancreas (exocrine insufficiency)