graft-versus-host disease - american academy of dermatology · 2017-07-21 · • dorsal pterygium...

Graft-versus-Host Disease

Kathryn Martires, MD & Silvina Pugliese, MD

Stanford University School of Medicine

Stanford Hospitals & Clinics, Stanford Cancer Center

Palo Alto, CA

FOR THE DERMATOLOGIST

Roadmap

• Terms in transplantation

• Acute GvHD and mimickers

• Chronic GvHD potpourri

• Skin-directed management of GvHD

Terms in Transplantation

T H E B A S I C S

Fine balance in graft-versus-host disease

GvHD

GvM

GvHD

GvM

Immunosuppression

Immune system activation

Typical Transplant Course Timeline

Induction

Chemo

RemissionDx

Days- weeks Weeks

Consolidation

Chemo

Weeks- Months

Pre-

conditioning

chemo/TBI

Transplant= day 0

GvHD prophylaxis

Donor lymphocyte infusion

Maintenance chemo if not high risk

Find donor using HLA-matching

Infection prophylaxis- when

ANC dips after induction

chemo

(+) Engraftment

Days

Days- 2

weeks

GvHD

Infection

Graft failure

Remission

Day 28

Disease Indications for Transplantation

Leukemias

Acute myeloid leukemia

Acute lymphocytic leukemia

Chronic lymphocytic leukemia

(ibrutinib)

Chronic myeloid leukemia

(imatinib)

Lymphomas

Non-Hodgkin

Hodgkin

Others

Aplastic anemia

Myelodysplastic syndrome

Primary immunodeficiency

Metabolic disorders

Factors that affect likelihood of GvHD

Cell source

Type of transplant

Donor relationship

Histocompatibility

Pre-transplant conditioning regimen

GvHD prophylaxis

Infectious prophylaxis

Cell source

Peripheral blood

Bone marrow

Umbilical cord blood

Risk of GvHD Time to engraftment

Type of Transplant

Allogeneic

Syngeneic

Autologous

Risk of GvHD

Donor relationship

Unrelated

Related

Haploidentical (child)

Risk of GvHD

Histocompatibility

Haplocompatible

6/6 HLA-matched

8/8 HLA-matched

10/10 HLA-matched

Risk of GvHD

Pre-transplant conditioning regimen

Non-myeloablative

Reduced intensity conditioning

MyeloablativeRisk of GvHD

Martires et al. (Blood 2011) NIH cohort, TBI in the context of reduced-intensity conditioning (RIC) was

strongly associated with ScGVHD (p=.0014)

Inamoto et al. Fred Hutch Cancer Res Ctr (Blood 2013)

TBI dose in conditioning regimen (MV analysis): HR (95% CI) 1.62 (1.14–2.31) p = .008

Total body irradiation

Chemotherapy

GvHD prophylaxis

T-cell depletion

Pre- or post-transplantation

Cyclosporine

Methotrexate

Tacrolimus

Cellcept

Anti-thymocyte globulin

cyclophosphamide

anti CD-52 antibody (campath)

Ex-vivo T-cell depletion

Combinations

Cyclosporine + MTX +/- ATG

CsA or Tacrolimus + MTX

CsA or Tacrolimus + MMF

Pre-transplant ATG

+post-transplant Cytoxan, anti CD-52

(campath)

Infectious prophylaxis

Acute

Cefepime

Vancomycin

Zosyn

Chronic

Bactrim

Mepron

Acyclovir, Valacyclovir

Voriconazole, fluconazole, posaconazole

Acute GvHD

15

Fine balance in graft-versus-host disease

GvHD

GvM

GvHD

GvM

Immunosuppression

Immune system activation

Acute GVHD

Incidence:

• 30 – 50% in patients with sibling donors

• 65% in patients with unrelated donors

Mortality:

• 60 – 80% for severe acute

Acute GVHD

Classic Late/Persistent/Recurrent

Skin, GI, Liver

<100 days post-

transplant/DLI

>100 days post-

transplant/DLI

Does not meet criteria for chronic GVHD

Harris et al., Biol Blood Marrow Transplant. 2016;22(1).

Wound care

• Dermatology involvement is crucial to manage wound care

• Bleach soaks

• Triamcinolone ointment to intact skin

• Vaseline to eroded skin

• Silver dressings

• Vaseline-impregnated gauze

• Occlusion w/ Saran wrap

• Avoidance of tape/adhesive

• Kerlix

• Stockinettes to arms/legs

Classic findings in aGVHD

Clinical:

• Erythema, edema, pruritus

• Morbilliform eruption,

folliculocentric, bullae

• Check eyes

• Check MM

Path:

• Interface dermatitis

• Vacoulization of basal layer at

DEJ

• Necrotic epidermal cells

• Satellite cell necrosis

• Cleft formation/separation of

epidermis from dermis

Acute GVHD Mimickers

22

Transplant

Eruption of Lymphocyte Recovery

Day 14 Day 21 Day 28Day 7

Engraftment syndrome

Hyperacute GvHD Acute GvHD

Toxic erythema of chemotherapy

Drug reaction

Viral exanthem

Differential diagnosis acute GvHD

Engraftment syndrome

• Auto (7-10%) >>> allo HCT

• Follows neutrophil recovery, 7-10 days post-transplant, cytokine storm

• Symptoms:

• Shortness of breath due to noncardiogenic pulmonary edema, hemorrhage,

pneumonitis

• Fever

• Morbilliform eruption

• Diarrhea

• Increases transplant-related mortality (pulm, organ failure)

• Histologically similar to acute GvHD

• Treatment: steroids

24

Eruption of lymphocyte recovery

• Incidence 50-60% after chemotherapy

• Morbilliform eruption 7-21 days after chemotherapy

• Transient fever

• No GI abnormalities (e.g. diarrhea, LFT abnormalities)

• Histopathology can be similar to aGvHD

• Self-limited

Toxic erythema of chemotherapy

• Painful/pruritic eruption

• Acral and/or intertriginous skin

• Cytotoxic chemotherapy has toxic effect on eccrine ducts,

acrosyringium, and epidermis

• 2-3 weeks post-chemo initiation

• HSCT patients may receive chemotherapy as:

• Treatment (years prior)

• Induction (weeks to months prior)

• Conditioning (days prior)

• GvHD prophylaxis (days prior)

• Post-transplant

• Generally develops early in post-transplant course (~1-2

wks)

Bolognia et al., JAAD.

2008;59(3).

Viral exanthem

• Screened for in donor

• Treatment with antivirals can hinder cell counts

• Common viruses:

• HHV-6

• HHV-7

• CMV

• EBV

• HSV

• VZV

• Parvovirus

• Enterovirus

• Rhinovirus

• Parainfluenza

27

DRESS/DIHS

• Morbilliform eruption, 2-6 wks post med initiation

• Fever

• Facial swelling

• Lymphadenopathy

• Eosinophilia

• Leukocytosis

• Organ involvement including:

• Liver

• Kidney

• Lung

• Heart

• Neuro

• GI

• Endocrine

28

Husain et al, JAAD 2013.

Voriconazole

• Broad-spectrum triazole antifungal agent

• Well-known to induce phototoxicity

• In addition of photo-distributed erythema, these patients may develop bullous eruptions,

cheilitis, lentigines, dermatoheliosis

• Phototoxic effects may be compounded by concomitant medications (e.g. Bactrim, HCTZ,

methotrexate)

• MOA: N-oxide is major metabolite of voriconazole, absorbs in UVA/UVB and may serve as

chromophore

• At increased risk of skin cancer, particularly SCCs

29

To biopsy or not to biopsy?

• There is some evidence to suggest that:

• Biopsies in early GVHD may be non-diagnostic1

• Biopsy results may not change management2

• Despite a lack of strong evidence:

• Biopsy can be useful to establish alternative diagnosis

• Biopsy can be helpful to support a diagnosis of acute GVHD

• Can biopsy provide prognostic information?

• Higher histologic grade may be associated with a lower likelihood of treatment response and

a higher risk of non-relapse mortality and all-cause mortality at one year3

• Histologic grade LOWER than clinical grade may be associated with better treatment

response and improved non-relapse mortality at one year3

1. Kuykendall et al., JAAD. 2003; 49(6).

2. Zhou et al, Arch Dermatol. 2000; 136(6).

3. Nerkhede et al., Am J Hematol. 2017; 92(7).

Chronic GvHD Potpourri

T I P S A N D T R I C K S

“Conventional wisdom”

< 100 days: Acute GVHD (aGVHD)

> 100 days: Chronic GVHD (cGVHD)

Quiescent

Acute GvHD Chronic GvHD

How did we get here?




de Novo

Chronic GvHD





Progressive

Acute GvHD Chronic GvHD


#1 risk factor cGVHD: history of aGVHD

Common “triggers” of cGVHD

• Recent decrease in immunosuppression

• Donor lymphocyte infusion or CAR-T cell therapy

• UV exposure - acute sunburn

• Systemic infection

• Drug eruption

Clues to “flare” or onset of cGVHD

• Generalized fatigue/loss of appetite

• New onset limb edema

• Muscle cramps

• At night

• After physical activity

• “Charley horse”

• Decreased “flexibility”

• Difficulty getting dressed, climbing stairs, driving car

Filipovich et al. Biol Blood Marrow Transplant 2005;11:945-56.

NIH Scoring of Organ Systems

4-point scale (0-3)

9 elements

Skin

Mouth

Joints/Fascia

Genital

Performance Score

Eyes

GI

Liver

Lung

39

Establish the

presence of

chronic

GVHD

without the

need for

further

testing or

evidence of

other organ

involvement

Not

considered

sufficient to

establish

diagnosis

without further

testing (i.e., a

biopsy) or

additional

organ

involvement

Poikiloderma

Lichen planus-like

Sclerotic

Morphea-like

Lichen sclerosis-like

Epidermal cGVHDLichen planus-likeDyspigmentationPapulosquamousIchthyosiformKeratosis pilaris-likePoikiloderma

Dermal cGVHDLichen sclerosus-likeMorpheaScleroderma

Subcutaneous cGVHDSubcutaneous sclerosisFasciitis

cGVHD: a polymorphous skin disorder


Dermal cGVHDLichen-sclerosus-likeMorpheaScleroderma



Patel et al. Arch Dermatol 2008;144:1229.

Isomorphic response of Koebner

Arch Dermatol. 2011;147(9):1081-1086Arch Dermatol. 2011;147(9):1081-1086


Dermal cGVHDLichen-sclerosus-likeMorpheaScleroderma



cGVHD-related fasciitis

Eosinophilic fasciitis-like

Hidebound= not pinchable

Delayed onset (1-3 yrs post-Tx)

Overlying skin may appear unaffected

Sudden painful skin swelling, cramps

Polymyositis, arthritis

Groove sign

50% functionally disabled

Range-of-motion limitation

Joint contractures

Overlying skin may appear unaffected

Janin et al., Ann Intern Med 1994;122(2):155.

Sbano et al., Bone Marrow Transplant 2004;33:869.

Nail changes

• Longitudinal ridging thin, easily broke, brittle nails

• Onycholysis

• Partial or complete anonychia

• Dorsal pterygium

• Periungual erythema

• Paronychia

Other GVHD features

Kaffenberger et al., JAAD. 2014;71(4):745-53.

Zuo et al., JAMA Derm.

2015;151(1):23-32

Park JH et al., J Cutan Pathol. 2016;43:236-241.

Other GVHD features

5 patients with butterfly malar rash

2/5 patients with +ANA

No systemic SLE, no photosensitivity

Poor prognosis? 3/5 with sclerotic GVHD, 2/5 with relapse

51

Erythema, LP

or LSetA Erosions,

fissures

labial fusion,

fibrinous

adhesions, vaginal

shortening,

synechia, sclerosis,

and dense vaginal

stenosis

Discomfort= Vulvar pain elicited by the

gentle touch of a qtip on vestibular gland

openings, labia majora/minora

Palpate the vaginal walls with a single

digit to detect bands, shortening,

narrowing or other signs of vaginal scarring

Vulvo-vaginal GVHD

Erythema

LSetA-like

Fissures, ulceration, scarring, stenosis

NIH Scoring

53

4 Maneuvers

Shoulder

Lock elbows to 180°at sides tightly

Raise arms above the head with palms facing anteriorly

until as close to the ears as possible

Look for skin tightening, dimpling, Groove sign

4 Maneuvers

Elbow

Turn palms inward, drop shoulders so that upper arm is

parallel to ground

Then keep elbow still, slowly lower forearm until 180°

Look for skin tightening, dimpling, Groove sign

4 Maneuvers

Wrists and Fingers= Prayer Sign

Appose palms as close as possible while raising elbows

until parallel to ground

Volar tightening of forearms, clawing of the fingers

4 Maneuvers

Foot dorsiflexion

Ask patient to dorsiflex and extend

Hold your hand there to provide resistance

Tightening of Achilles tendon

Tips and tricks

If unsure if feel textural abnormalities,

tightening, compare both sides, and

compare with normal skin

Ask kids to sit cross-legged on exam

table reveals limitation

in ROM at hips

Have patient lie down and

palpate abdomen to look for subtle rippling

or pseudocellulite

NIH Scoring

Mucosal exam Erythema

Lichenoid lesions

Atrophy, Ulcers

Mucoceles

Buccal mucosa= 40%

Lips, lower labial mucosa=

20%

Dorsal tongue= 20%

Soft palate and ventrolateral

tongue=20%

Gingivae and hard palate do

not contribute to scoring

Filipovich et al. Biol Blood Marrow Transplant 2005;11:945-56.

NIH Scoring of Organ Systems

Mild: 1 or 2 organs or sites with no clinically significant functional impairment (maximum

of score 1)

Moderate: at least 1 organ or site with clinically significant but no major disability

(maximum score of 2)

3 or more organs or sites with no clinically significant functional impairment (maximum

score of 1 in all affected organs or sites)

Lung score of 1

Severe: major disability (score of 3 in any organ or site)

Lung score of 2

Cornejo et al., JAAD. 72(4).

Skin-directed therapy

R O L E O F T H E

D E R M A T O L O G I S T I N

M A N A G E M E N T

NIH cGVHD Natural History

Study

cGVHD

Hematology/Oncology

Dermatology Dentistry/Oral Surgery

Pulmonary

Gynecology

Ophthalmology

Pain/Palliative Care

Nutritional Support Rehabilitation Medicine

NIH Basic Laboratory Research

EndocrineGI

ID

Renal

Slide: c/o Ed Cowen

Stanford

cGVHD

Hematology/Oncology

DermatologyDentistry/Oral Surgery

Pulmonary

Gynecology

Ophthalmology

Pain/Palliative Care

Nutritional Support Rehabilitation Medicine

Laboratory Research

EndocrineGI

ID Renal

Role of dermatology

Diagnose skin GvHD or other skin disease

Carefully assess the subtype and extent of skin involvement with GvHD

Provide periodic dermatologic monitoring while understanding other organ

system activity, infection risk, and relapse risk

Differentiate other new skin disease from GVHD

Assess cutaneous disease response to treatment

Monitor for infection and skin malignancy

Skin-directed therapy

67

Credit: Gun Ho Lee,

MD Candidate

Topical steroidsNo studies or series examining the use of topical steroids alone in cGVHD patients

Types of GvHD

Predominantly epidermal

Icthyotic

Papulosquamous

Lichen planus-like

Lichen sclerosus-like

Focal morphea-like

Active areas ScGvHD

*Once epidermal GvHD becomes PIH, ensure

patients are aware to discontinue

*Chronic use on subcutaneous sclerotic GvHD not

beneficial

Intralesional steroids

Types of GvHD

Lichen sclerosus-like

Focal morphea-like

Active areas ScGvHD

Nodular sclerotic GvHD

Subcutaneous sclerosis

Ulcerative oral GvHD

Mucosal therapy

Hymes, et al.:2012 vol:66 iss:4 pg:535.e1 -16

Oral

Fluocinonide gel 0.05%, clobestasol gel 0.05%

Dexamethasone or prednisolone oral rinses (combine with nystatin)

Triamcinolone 0.1% orabase (dental paste)

Tacrolimus 0.1% in orabase

Cyclosporine and azathioprine solution

Avoid antihistamines, TCAs sicca sx

Genital

Clobetasol 0.05% ointment

Fluocinolone 0.025% ointment

Tacrolimus 0.1% ointment

Estrogen cream

Lubrication during intercourse

Topical Calcineurin Inhibitors

Supplement the use of topical steroids and serve as maintenance

Patients feel comfortable with topical tacrolimus because of the familiarity with oral tacrolimus

Elad et al.: 7/10 with limited skin improvement with 0.03-0.1% tacrolimus ointment

response as early as 2 weeks

lichenoid GVHD responded better than sclerodermatous GVHD

Choi et al.: 13/18 with reduction of pruritus, erythema with tacrolimus 0.1% ointment

within hours to days

all required systemic corticosteroids, PUVA, or ECP

Concern regarding systemic absorption

Bioavailability of 0.3% tacrolimus ointment

less than 5% of oral tacrolimus

less than 0.5% that of IV tacrolimus

Choi, et al. Arch Dermatol. 2001.

Elad, et al. Transpl. Int. 2003.

Topical Calcineurin inhibitors

Pimecrolimus

Ziemer et al. reported a nearly complete resolution of cutaneous lesions

of a pediatric patient experiencing early stage of chronic GVHD

Schmook et al. reported a complete resolution of pruritus and lichenoid

cGVHD

Zangrilli reported a >50% improvement of erythematous, hyperpigmented

and pruritic plaques

Additional skin-directed therapy

Relief of pruritus- dry skin, neuropathy from chemo, drug, shingles;

diabetes; bile salts in liver failure, uric acid in kidney failure, opiates

Low-potency topical steroids

Menthol-based creams, doxepin

Ice packs

SSRI’s, gabapentin

Maintain skin integrity- sclerosis around nerves, chemo, radtx, nutrition

Regular moisturization- ample amounts, especially to skin folds

Maintain ambient humidity >40%

Hydrate

Strict photoprotection

UVA-1 phototherapy

Long-wave UVA (UVA1: 340-400nm, UVA:

320-400nm)

Deeper penetration than UVB

Activate apoptosis pathways in T and B

lymphocytes, immediately triggering

cell death (<20 minutes); UVB causes

delayed cell death reliant on newly

synthesized proteins

UVA1 may increase the synthesis of

matrix metalloproteinases, and

decrease the synthesis of pro-

collagen though IL-1 and IL-6

UVA1 may reduce levels of TGF-beta,

TNF, IL-8 and IL-10

UVA-1 phototherapy protocol

Low dose (20-40J/cm2)

Medium dose (40-80J/cm2)

High dose (80-120J/cm2)

Three to five times a week starting with 10-50J/cm2 of irradiation

Average cumulative irradiation ranges from 787.5-1464.7J/cm2

Recommended Max Duration of Treatment = 40 sessions/year

UVA-1 phototherapy

Wetzig, et al. Bone Marrow Transplantation (2005) 35, 515–519

Connolly et al Photodermatol Photoimmunol Photomed. 2015 Nov;31(6):289-95.

cGVHD: Complete response in 6/10,

PR in 3/10, able to taper steroids,

aGVHD: CR In 5/7

Improvement in 21/21 patients on

medium- and high-dose UVA; 0/3

improved on low dose UVA

Calzavera et al.: 3 of 5 ScGvHD patients with

complete stable remission after UVA1 therapy;

4 lichenoid GvHD patients with initial response

and later relapse after one month Hematologica 2003 Oct;88(10):1169-75.

UVA-1 phototherapy

No significant adverse side effects

Theoretical risk of photodamage and skin cancers

Average cumulative irradiation dosage much higher given higher number

of treatment sessions require

Available at very few treatment centers

UVA-1 Centers

West

UC Davis

Mayo Arizona

U Utah

Vancouver Coastal Health

East

Weill Cornell

North Atlantic

Johns Hopkins

Walter Reed Military Medical Center

Midwest

Henry Ford Health System

Mayo Clinics

U Michigan

Southwest

UT Southwestern

Southeast

Mayo Jacksonville

UVA-1 Centers and Home Phototherapy

Daavlin ML2400

UVA-1 Centers and Home Phototherapy

80

PANOSOL II and 3D

Home phototherapy with

UVA-1 and NB-UVB lamps

Power output 30-

50mW/cm2

Narrow band UVB

Paucity of data

Brazzelli et al. 8/10 pediatric patients with lcGVHD and overlap GVHD

with CR; 2/10 with PR

Ballester-Sanchez et al. 4/6 adults with lcGvHD and ScGvHD with CR

Enk et al. 1 patient with lcGVHD with CR for 18 months; 2 scGvHD with

only reduction in dryness and pruritus

UVB does not penetrate dermis

Caution as sunburn can trigger flares of GvHD

PUVA

82 patients across 8 PUVA studies

32 (39.0%) experienced complete remission of their skin lesions

34 (41.5%) experienced partial remission- more often ScGvHD

Majority of patients could reduce their immunosuppression post-therapy

Caution with phototoxicity and risk of skin cancer

Extracorporeal Photophoresis

Modulate alloreactive T cell and dendritic cell activity

Particularly useful for sclerosis and fasciitis

Abu-Dalle, I. et al. Pooled analysis: overall response

84% in acute skin GvHD and 71% for chronic

skin GvHD

Alousi, A. M. et al. RCT: randomized trial, the

addition of ECP to systemic steroids resulted in

higher response rates, particularly for skin-only

acute GVHD

Couriel et al. large retrospective analysis: of 71

patients, response seen in 61%; 14 patients

experienced complete responses, best in the

skin

Abu-Dalle, I. et al. Biol. Blood Marrow Transplant. J. Am. Soc. Blood Marrow Transplant. 20, 1677–1686 (2014)

Alousi, A. M. et al. Blood 126, 854–854 (2015)

Couriel, D. R. et al. Blood 107, 3074–3080 (2006)

White cell compartment of the blood is removed from

the patient via pheresis, mixed with 8-

methyoxypsoralen, irradiated with UVA light, and

then returned to the patient

Limitations of photophoresis

A dedicated pheresis center– 138 centers in the U.S.

http://www.therakos.com/treatment-center-locator

Time commitment— several hours on two consecutive days for one cycle

Starting weekly

Prolonged vascular access– risks of stenosis, thrombus, infection

Risks: dizziness, nausea, photophobia, redness of skin immediately after

treatment, fever, hypotension, fluid and electrolyte imbalances,

hypocalcemia, infection

Avoidance of sun-sensitizing medications

Voriconazole

Methotrexate

Azathioprine

Tetracyclines

Fluoroquinolones

Hydrochlorothiazide

Trimethoprin-sulfamethoxazole

SSRI’s

Fractionated laser and contractions from morphea

Fractional ablative 10.6- μm carbon dioxide laser

Single pass, single pulse, no overlap, 50-mJ pulse energy, and 5% density, with a forced cooling system

Kineston, et al. Arch Dermatol. 147 (10), 2011

27 year-old woman with one year of progressive generalized morphea with 20°

improvement of plantar flexion after one treatment four months later

Laser resurfacing

Scarring

Morphea

CO2 laser

UVA-1

Wound care and prevention of infectionSystemic steroids, sirolimus, GvHD, prior cancer therapy

Prevention- prosthetics, treatment of edema

Specialized wound careVaseline, Aquaphor, Xeroform

Topical steroids- inflamed areas

Silvadene

Silver-impregnanted foam: Aquacel Ag, Acticoat, Mepilex Ag, Dermacol

Other antimicrobial: Mupirocin, Gentian violet, Medihoney

Exudative wounds: Duoderm, Mepilex

Deep: Punch grafting, Apligraf, Regranex, maggot therapy

Unna boots

Lower threshold for culture than stasis ulcers

Caution with any trauma to the skin, i.e. skin cancer therapy

Muscle spasms/cramping

More commonly present in sclerotic patients

Precede sclerotic skin changes

Activity-related, nocturnal

Cause of these cramps is unclear, multifactorial

Electrolyte imbalances- hypomagnesemia, hypocalcemia

Diarrhea associated in cases of concomitant GI GvHD, medications

Medications- imatinib, hydroxychloroquine, thalidomide

Associated with other autoimmune disease and neoplastic disorders

Voltage-gated calcium channel antibodies triggering hyperexcitability

Grazko et al. Neurology. 1995.

Muscle spasms/cramping

Electrolyte imbalances should be corrected

Medications should be reviewed

Reduction of hyperexcitability of peripheral nerves

Ca2+ channel blocking agents- amlodipine, diltiazem, quinine, dantrolene

Quinine (Qualaquin)- QT prologation, immune thrombocytopenic purpura, renal

insufficiency

Dantrolene- muscle weakness, diarrhea, LFT elevation, phototoxicity

Muscle relaxants: baclofen, benzodiazapenes, cyclobenzaprine, amitryptiline

Reduce neuronal repetitive firing:

Anticonvulsants: Phenytoin, carbamazepine, valproic acid, lamotrigine


Muscle spasms/crampingCannabis topical- balms, salves, lotions, oils infused with active cannabinoids

Not psychoactive

CB2 receptors in the skin

Cannibinoids are more permeable to skin than THC

Botulinum toxin- management of focal spasticity

Reduce afferent input caused by blocking fusimotor synapse

Hands and feet-5-10U per muscle

Chest wall- 25U in 2-3 locations of muscle


Systemic therapy

Prednisone 1mg/kg/d

Tacrolimus

Cyclosporine

Photophoresis

Mycophenolate mofetil

Sirolimus

Rituximab

Methotrexate

Imatinib

Ruloxitinib

Azthioprine

Etanercept

Etretinate

Mesencymal stem cells

Thalidomide/ Penalidomide

Ibrutinib

Vismodegib

Knowing when systemic therapy is indicated

>50% body surface area of skin involvement or any signs of skin

sclerosis

Involvement of 3 or more organ sites, with at least one organ with an NIH

score of 2 (moderate)

Any lung involvement of GvHD

Development of GvH while on >0.5mg/kg prednisone

Systemic therapy

Prednisone 1mg/kg/d

Tacrolimus

Cyclosporine

Photophoresis

Mycophenolate mofetil

Sirolimus

Rituximab

Methotrexate

Imatinib

Ruloxitinib

Azathioprine

Etanercept

Etretinate

Mesenchymal stem cells

Thalidomide/ Penalidomide

Ibrutinib

Vismodegib

Vismodegib

University of Utah- partial response 3/3 patients

Started at 150mg daily, now QOD, tolerating well

Limiting factor: cramping

Blood. 2012 Oct 04;120(14):2909-17.

Ibrutinib

Inhibition of Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase; which may

play a role in disease pathogenesis

420 mg daily in chronic GvHD patients with >25%BSA and <3 prior regimens

28 patients, ORR 67%; 21% experiencing CR

48% sustained response ≥32 weeks

75% had corticosteroid doses <0.15 mg/kg/d

NIH severity score decreased from 7 to 3 at week 49 (n=15)

Fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%)

Pneumonia (n=6), septic shock (n=2), and pyrexia (n=2)

Miklos et al., Blood 2016Dubovsky, J Clin Invest 2014

Ruloxitinib

Breakthrough therapy designation for acute gvhd

Modification of T cells and dendritic cells.

Zeiser et al. 2015: 54 acute, grade III or IV and 41 chronic, moderate- severe

ORR 81.5% (44/54) aGvHD, 25 CR (46.3%)

ORR 85.4% (35/41) for cGvHD

Cytopenias, CMV reactivation

IL-17 pathway in GvHD?

Th17 pathways also play a role in the pathogenesis of both acute and

chronic GvHD

Donor IL-17A, derived from Th17 cells, has been shown to promote skin

fibrosis

Demonstration of increased IL-17 mRNA in skin of cGVHD patients

Higher levels of Th-17 promoting cytokines including IL-6 and IL-21, and

transcription factor STAT3

Gartlan, K. H. et al. Blood 126, 1609–1620 (2015).

Harris, T, et al. J Immunol. 179. 4313-7 (2007).

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