GVHD - tutorial.pptx

1. GRAFT VS HOST DISEASE PRESENTER - DR. VIKAS PURUSHOTTAM MODERATOR – DR. RAM SINGH MEENA SIR

2. CONTENTS • Introduction • Classification • Pathophysiology • Clinical features • Histopathology • Differential diagnosis • Management

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%

4. • PRIMARY DISORDERS TREATED WITH ALLOGENIC HEMATOPOIETIC STEM CELL TRANSPLANTATION • Leukemia • Lymphoma • Bone marrow failure • Immunodeficiencies • Myeloproliferative disorders • Hematologic disorders • Metabolic disorders • Autoimmune diseases

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 .

10. GASTROINTESTINAL • Abdominal pain • Anorexia • Ileus • Vomiting • Secretory diarrhoea LIVER pale urine , dark coloured stools, upper quadrant tenderness • Pericholangitis • Cholestatic hyperbilirubinemia • Endothelithiasis

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

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

23. EOSINOPHILIC FASCIITIS-LIKE Rippled appearance & irregular ,nodular texture indicative of involvement of subcutaneous tissue SCLERODERMA LIKE POIKILODERMATOUS LIKE

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)

28. occular Keratoconjunctivitis sicca Blepharitis Photophobia Cicatricial conjunctivitis GIT Esophageal web -Strictures or stenosis in the upper to mid third of the esophagus Pancreas- exocrine insufficiency HEART Cardiac effusion Cardiomyopathy Conduction defect

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

31. DIFFERENTIAL DIAGNOSIS EPIDERMAL INVOLVEMENT • Drug eruption • Demodex folliculitis • Eczematous drug eruption • Lichen planus • Pityriasis lichenoides chronica • Pityrosporum folliculitis • Psoriasis SCLEROTIC INVOLVEMENT • Eosinophilic fasciitis • Lichen sclerosus • Morphea • Nephrogenic systemic brosis • Radiation dermatitis • Systemic sclerosis

32. CHRONIC GVHD-MANAGEMENT • Nonsclerotic lichen planus like and other papulosquamous chronic GVHD features – topical steroids • Topical emollients • Topical pimercrolimus 0.1% • Treatment with prednisolone and azathioprine for atleast 9-12 months – generalized chronic GVHD

33. First line • Corticosteroids, e.g. prednisolone 1 mg/kg oral or IV • Oral calcineurin inhibitors – ciclosporin as a steroid sparing Second line • Extracorporeal photopheresis • Imatinib • Sirolimus • Pentostatin • Rituximab Third line • Mycophenolate mofetil • Pulsed high‐dose corticosteroids • Methotrexate Others • Hydroxychloroquine, clofazemine, cyclophosphamide, alemtuzumab, anti‐TNF antibodies, thalidomide, alefacept, retinoids, azathioprine, mesenchymal stem cells

34. THANK YOU

GVHD - tutorial.pptx

GVHD - tutorial.pptx

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