This document provides information about graft-versus-host disease (GVHD), including its classification, pathophysiology, clinical features, histopathology, differential diagnosis, and management. GVHD is a complication of allogeneic hematopoietic stem cell transplantation where donor T cells attack the recipient's organs. It can be acute (occurring within 100 days of transplant) or chronic (after 100 days). The main organs affected are the skin, liver, and gastrointestinal tract. Risk factors include HLA mismatch and donor/recipient gender combinations. Management involves immunosuppression with corticosteroids, calcineurin inhibitors, or other agents depending on the severity.
3. INTRODUCTION
• Graft‐versus‐host disease (GvHD) is a multiorgan disease process
• Results from the action of donor‐derived immunocompetent T lymphocytes
against antigens expressed on the cells of the immunocompromised recipient
host.
• GvHD is a major complication of allogeneic haematopoietic stem
cell transplantation, with an incidence of 25–80%
5. MAIN ORGANS AFFECTED ARE –
1. Skin (1st and m/c)
2. Liver
3. Git tract
RISK FACTORS-
1. HLA incompatibility
2. Patient age (elderly > adult > pediatric)
3. Female donor (especially miltiparous) / male recipient
4. Stem cell source (peripheral blood>bone marrow>cord blood)
5. T cell replete graft
6. Unrelated donor
7. Donor leukocyte infusion
6. GvHD
Acute
≤ 100 days
post - HSCT
Classic
Acute GvHD
> 100 Days
post HSCT
Persistent Recurrent Delayed
Chronic
Overlap
syndrome
Classic
Chronic GvHD
7. HSCT conditioning by
chemotherapy or radiotherapy
causes tissue damage
in the host
release of numerous
inflammatory cytokines
cytokine storm
TISSUE INJURY PHASE
Activation of host antigen
presenting cells ( APCs)
Donor T cells proliferate
In response to contact with
activated APCs
Alloreactive T cells expand to
form cytotoxic effector T cells
release more inflammatory
cytokines
Tissue injury –skin , liver , GIT
DONOR T CELL PRIMING
PHASE EFFECTOR PHASE
8. ACUTE GvHD- clinical features
• Most commonly occur 4-6 weeks post
HSCT
• Pruritis or burning sensation precede the
skin lesions
• Erythematous blanching macules
develop on the palms, soles or ears.
• Photo aggravated in distribution
affecting neck ,upper back and face or it
may be folliculocentric
9. • Lesions become more confluent with a
morbilliform appearance.
• In severe cases, there may be
generalized erythroderma , bullae
• Extensive Nikolsky sign positive
• Epidermal skin loss with a TEN like
picture .
11. ACUTE GvHD staging
STAGE SKIN RASH GIT - DIARRHEA( ml/day ) LIVER - BILIRUBIN mg/dl
1 < 25% BSA ≥ 500 or persistent anorexia,
nausea, vomiting
2- 3
2 25%- 50 % BSA ≥ 1000 3-6
3 > 50 % BSA ≥ 1500 6- 15
4 Generalised Erythroderma with bulla
or desquamation
≥ 2000 or severe abdominal
pain with or without ileus
≥15
GRADE SKIN RASH GIT LIVER
I Stage 1-2 None None
II Stage 1-3 Stage 1 Stage 1
III Stage 2-3 Stage 2-3 Stage 2-3
IV Stage1- 4 stage 2-4 Stage 4-4
GLUCKSBERG SCORE AND GRADING FOR ACTE GvHD
12.
13. • Hallmark change,
although not
pathognomonic, is
satellite cell necrosis
consisting of apoptotic
keratinocytes with
tightly associated
lymphocytes seen in
the epidermis and
associated interface
vacuolar change.
14. HISTOLOGICAL
SEVERITY
DESCRIPTION
Grade I Basal cell vacuolation with or
without mononuclear cell
infiltration
Grade II Solitary epidermal cell necrosis
surrounded by mononuclear cells
Grade III Regional epidermal cell necrosis
with bulla
Grade IV Complete dermal and epidermal
separation
15. DIFFERENTIAL DIAGNOSIS
• Drug eruption
• Eruption of lymphocyte recovery
• Rash of engraftment syndrome
• Transient acantholytic dermatosis
• Toxic epidermal necrolysis (for stage IV disease)
• Toxic erythema of chemotherapy
• Viral exanthem
16. MANAGEMENT
• Skin sloughing –skin care, Rx infection, fluid management
• Prophylactic use of cyclosporine, methotrexate and prednisolone (combination of these
agents) has reduced the incidence of acute GvHD
• Grade1 skin involvement(without hepatic and GI symptoms) – high potency topical steroids
and emollients
• Topical tacrolimus in refractory cases
• More severe skin involvement with internal organ involvement – systemic corticosteroids
• Grade2 – oral prednisolone 1mg/kg
• Grade 3-4 – iv methylprednisolone 2mg/kg
17. SYSTEMIC TREATMENT FOR ACUTE CUTANEOUS GVHD
FIRST LINE
• Corticosteroids (IV methylprednisolone 2mg/kg/day)
• Tacrolimus (usually on prophylactic treatment)
• Cyclosporine (usually on prophylactic treatment)
SECOND LINE
• Mycophenolate mofetil (2 – 3 g/day)
• Etanercept(0.4mg/kg upto max of 25mg per dose s.c twice a week)
• Infliximab(10mg/kg iv once a week)
• Pentostatin (1.5 mg/m2 /d for 3 days)
18. OTHER SALVAGE THERAPY
• Extracorporeal photopheresis
• Mesenchymal stem cell therapy
• Alemtuzumab
• PUVA
• Narrowband UVB
FUTURE TREATMENTS/TRIALS
• Anti-thymocyte globulin (if not given during preconditioning)
• T‐regulatory adoptive immunotherapy strategies
19. PATHOGENESIS OF CHRONIC GvHD
• TWO THEORIES-
• 1.autoimmune model-
• decrease immune tolerance - allow activation and proliferation of
donor T cells directly at self antigen shared between host and
donor
• 2. chronic donor t cell activation – and role of B cells
20. CHRONIC GvHD
• CUTANEOUS FEATURES-
1. Sclerotic –
• sclerodermoid , deep sclerosis/ eosinophilic fascitis like
• Lichen sclerosus like
• Morphoeoform
2. Lichenoid
3. Epidermal – eczematoid, papulosquamous , prp like
21. erythematous–violaceous lichenoid papules &plaques
manifest in early disease, predominantly over the
dorsal aspects of the hands, forearms and trunk,
LICHEN PLANUS LIKE LICHEN SCLEROSUS LIKE
Shiny wrinkled porcelain white atrophic plaques
m/c seen over upper back
22. Localised or generalised areas of sclerosis
MORPHE LIKE
Diffuse dermal involvement may result in ‘pipe- stem’
appearance of extremities with
Marked reduction in limb volume
Overlying shiny hidebound skin
Loss of hair
24. • Fibrosis of subcutaneous fat
with cellulite-like appearance
Groove’s sign is the result of
increased fibrosis around tendons
25. OTHER ATYPICAL MANIFESTATIONS
• Psoriasiform
• Eczematous/dyshidrotic
• Keratotic follicular papules
• Pityriasis rosea-like lesions
• Erythema multiforme- like lesions
• SCLE like eruption
• Psoriasiform like
• Vitiligo like
26. ORAL CAVITY
• Lichen planus like
• Mucocele
• Erythema
• Gingivitis
• Hyperkeratotic plaques
• Mucosal atrophy
• Restriction of oral opening
from sclerosis
• Ulcer
• Xerostomia
27. NAIL
• Longitudnal ridging or
splitting
• Brittleness
• Partial or complete
anonychia
• Onycholysis
• pterygium
HAIR
• Scarring alopecia
• Loss of body hair
GENITAL MUCOSA
• Lichen planus-like features
• Lichen sclerosis-like
features
• Vaginal scarring or
clitoral/labial agglutination
(female)
• Phimosis or
urethral/meatus scarring
or stenosis (male)
29. • RESPIRATORY SYSTEM
• Bronchiolitis obliterans diagnosed with lung biopsy
• Air trapping and+ bronchiectasis on chest CT
• Pleural effusion
• MUSCULOSKELETON
• Arthralgia,Arthritis ,Edema , Myalgia
• Myositis /polymyositis
• OTHERS
▫ Peripheral neuropathy , nephrotic syndrome
▫ Thrombocytopenia ,Eosinophilia ,Hypo/hypergammaglobinemia
,Lymphopenia
▫ Elevated transaminases ,Elevated total bilirubin ,Elevated ALP
30. COMPLICATIONS
• Skin erosions and ulceration due to chronic GVHD - Secondary infection
• Sclerotic changes – functional disability and joint contracture
• HCT survivors are at increased risk for melanoma and nonmelanoma skin cancers
due to previous exposure to ionizing radiation, immunosuppressive treatment
indications of HSCT are varied and include hematologic
malignancies, congenital immunodeficiencies, and inborn errors
of metabolism.
Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic option for a variety of malignant and nonmalignant conditions [1]. The indication for its use has expanded, especially among older patients, over the last several years through novel strategies utilizing donor leukocyte infusions, non-myeloablative conditioning and umbilical cord blood (UCB) transplantation
For aGVHD, skin histopathology shows a lichenoid infl ammatory
process with a linear arrangement of lymphocytes along
the basement membrane zone. The hallmark change, although
not pathognomonic, is satellite cell necrosis consisting of apoptotic
keratinocytes with tightly associated lymphocytes seen in
the epidermis and associated interface vacuolar change. Histology
can be indistinguishable from a lichenoid drug eruption
For aGVHD, skin histopathology shows a lichenoid infl ammatory
process with a linear arrangement of lymphocytes along
the basement membrane zone. The hallmark change, although
not pathognomonic, is satellite cell necrosis consisting of apoptotic
keratinocytes with tightly associated lymphocytes seen in
the epidermis and associated interface vacuolar change. Histology
can be indistinguishable from a lichenoid drug eruption
associated with a nonspecific
erythematous skin eruption, fever, and pulmonary edema at the
time of neutrophil engraftment; the pulmonary edema is associated
with increased levels of B-type natriuretic peptide (BNP).
Both pathways inhibit calcineurin and
result in decreased T cell proliferation via the inhibition of IL-2
Production
Mycophenolate mofetil exerts selective antiproliferative
effects on lymphocytes by acting as a reversible inhibitor
of inosine monophosphate dehydrogenase.
PENTOSTATIN antineoplastic antimetabolite ..potent inhibitor of ADENOSINE DEAMINASE induce lymphocyte apoptosis
Extracorporeal photopheresis44 is a simple, safe, and mildly
invasive treatment that can be used in both acute and chronic
GVHD. This treatment has been shown to increase Tregs and
to help in mediating a state of immune tolerance
Treatment consists of exposure
of the peripheral blood mononuclear cells collected by
apheresis to the photosensitizing compound 8-methoxypsoralen,
and ultraviolet (UV) A radiation, which cause
cross-linking of DNA in cell nuclei, inducing apoptosis.
Apoptotic cells are re-infused to the patient and are thought
to promote immune tolerance by modulating cytokine
production and inducing T-regulatory cells.
Inolimumab – monoclonal antibody targets interleukin 2 receptor
Basi- il2 , alem- cd52 antibody
By contrast, a clear understanding of cGVHD is still lacking and
available murine models recapitulate only select features of human
disease (e.g. sclerotic skin involvement, autoantibodies).
Imatinib mesylate is an inhibitor of several tyrosine
kinases and has recently been reported to be used for the
treatment of steroid-refractory sclerotic chronic GVHD due
to its inhibitory activity against platelet-derived growth
factor
