Graft Versus Host Disease

Most commonly due to allogenic hematopoietic stem cell transplant (HSCT)

Previous classification based on disease onset post-HSCT (≤ 100 or > 100 days); however, features of aGVHD and cGVHD may coexist and changes in treatment practices have altered traditional disease time periods (see Epidemiology/pathogenesis); hence, classification is often based on clinical features

  • Skin = most frequently affected organ in GVHD
  • Causes of GVHD:
    • Allogenic HSCT *most common
    • Non-irradiated blood transfusion to immunocompromised hosts
    • Maternal-fetal transmission
    • Solid organ transplantation
  • Risk factors for GVHD:
    • Donor factors: 
      • HLA incompatibility *most important
      • Donor unrelated to recipient
      • Female
    • Recipient factors:
      • Age: higher in elderly
    • Stem cell source:
      • Peripheral blood > bone marrow > cord blood
  • T-cell-replete graft
    • Myeloablative conditioning regimen (for aGVHD only)
  • Most important predictor of GVHD = HLA compatibility 
    • 40% of HLA-identical and 60-70% in HLA-mismatched recipients will develop GVHD
  • Cord blood transplantation associated with decreased GVHD incidence, but increased non-engraftment rates
  • Peripheral blood HSCTs are often preferred due to rapid engraftment relative to bone marrow HSCTs; however, increased GVHD risk
  • T-cell depletion (removal of donor T-cells) significantly decreases GVHD risk, but increased cancer relapse risk
  • Total body irradiation may increase risk for delayed fibrosing form of cGVHD
  • Donor lymphocyte infusions post-HSCT may induce aGVHD at any time (ie. even after 100 days), alterating traditional 100-day benchmark of acute versus chronic disease

Pathogenesis of aGVHD:

  • Damage to host tissue from HSCT → host antigen-presenting cells activation → donor T-cell proliferation → target tissue destruction (skin, liver, GIT)

*donor T-cell responsible for ultimate destruction

Pathogenesis of cGVHD: 

  • Not fully understood
  • Alloreactive T- and B-cells thought to play most important role
  • Multiple autoantibodies (antinuclear, anti-dsDNA, and anti-smooth muscle) found with unknown functional significance
  • B-cell activation marker (marker of B-cell activation) correlates with cGVHD disease
  • Antibodies against platelet-derived growth factor receptor (PDGFR) found in cGVHD, suggesting that imatinib mesylate may improve disease
  • cGVHD can be characterized into “early” and “late” onset with noted immunologic profile differences:
    • Early onset cGVHD (3-9 months): IFN-γ, ↑regulatory T cells, and T-cell cytokine response (IL2Rα)
    • Late onset cGVHD (>9 months): lack of Th2 shift, BAFF-mediated B-cell activation, induction of B-cells with high Toll-like receptor 9 (TLR9) expression, autoantibody formation
  • Chronic lichenoid GVHD: mixed Th1/Th17 signature profile with ↑IFN-γ and IL-17-producing T-cells

Donor-derived, skin-infiltrating macrophages that produce TGF-β may explain skin fibrosis

aGVHD:

  • Morbilliform exanthem 
  • Initial predilection: acral sites, upper trunk
  • Lesions appear 4-6 weeks post-HSCT
  • ± Pruritus
  • May have folliculocentric pattern or hemorrhagic pattern (if patient is thrombocytopenic)
  • GI and liver involvement: cholestasis, transaminitis, diarrhea 
  • Stage IV: generalized skin involvement with bullae may lead to skin sloughing, with very low survival likelihood

cGVHD:

  • Almost any organ can be involved
  • Skin and mucosa are most involved (with much variability)
  • Other organs’ involvement: keratoconjunctivitis sicca, blepharitis, corneal erosions, salivary glands (sicca syndrome), lungs (bronchiolitis obliterans), esophagus (strictures), liver, pancreas (exocrine insufficiency) 
  • cGVHD phenotypes:
    • Lichen planus-like: reticular pink-violet papules and plaques with overlying scale, ± patterned post-inflammatory hyperpigmentation *most characteristic

      *NB: the term “lichenoid” should be reserved for histologic description

    • Lichen sclerosus-like: shiny, wrinkled, gray–white plaques on the upper back ± follicular plugging
    • Morphea-like: occur anywhere but commonly in trauma/friction sites 
    • Eosinophilic fasciitis-like: subcutaneous rippling of the skin with joint contractures; hypereosinophilia with edematous in the earlier phase may diagnostic clue
    • Also: scleroderma-like, poikiloderma, psoriasiform plaques, eczematous/dyshidrotic, subacute cutaneous lupus erythematosus-like, pityriasis rosea-like, eczema craquelé, ichthyosis-like, keratosis pilaris-like follicular erythema, hypo- or hyper-pigmentation, vitiligo, angiomatous nodules 
  • To differentiate lichen sclerosus-like cGVHD from systemic sclerosis: pulmonary hypertension, renal crisis, Raynaud disease and sclerodactyly are features seen in systemic sclerosis but less likely in GVHD; also, the pattern of skin involvement in systemic sclerosis is acral to proximal with facial involvement being common (scleroderma facies), while that of lichen sclerosus-like GVHD is patchy with facial involvement being rare
  • Fibrosis of subcutis and fascia may present with decreased range-of-motion, and nonspecific myalgias/ cramping
  • Groove sign: linear depressions seen in involved fascial sites (secondary to linear vascular/fascial bundles)
  • Chronic fibrosis can 🡪 ulceration (especially in legs and high friction sites) 🡪 benign angiomatous nodules
  • Other cutaneous involvement: 
    • Oral mucosa: resembles lichen planus with keratotic plaques on non-attached mucosa, ulceration, gingivitis; mucocele; restriction of oral opening from sclerosis
    • Genital mucosa: affects up to 50% of females, male genitalia involvement less common; burning, pruritis, dyspareunia common; fissures, erosions, ulcers, balanitis, phimosis, vaginal scarring/ stenosis can occur
    • Nails: ridging, thinning/brittle, distal splitting, onycholysis, dorsal pterygium, anonychia

Hair: new-onset alopecia, alopecia areata, premature graying

Diagnostic mucocutaneous manifestations of cGVHD:

  • Skin: 
    • Lichen planus-like
    • Lichen sclerosus-like
    • Morphea-like
    • Scleroderma-like
    • Fasciitis 
    • Poikiloderma
  • Oral mucosa:
    • Keratotic plaques
    • Lichen planus-like
    • Restricted oral cavity opening due to sclerosis
  • Genital mucosa:
    • Lichen planus-like
    • Vaginal scarring and/or stenosis
  • “Distinctive” cGVHD criteria (eg. papulosquamous lesions, alopecia): require biopsy to confirm and exclude all other possibilities

Histologic features:

  • aGVHD: widespread keratinocyte necrosis, basal layer hydropic degeneration, upper dermis band-like lymphohistiocytic infiltrate
  • Epidermal cGVHD: resembles aGVHD + epidermal orthokeratosis and hypergranulosis
  • Sclerotic cGVHD: sclerosis of dermis, subcutaneous tissue and fascia ± aGVHD
    • Subcutaneous fat septae thickening suggests deep sclerosis *magnetic resonance imaging can help identify fascial involvement

Differential diagnosis: 

  • Viral/drug exanthem
  • Engraftment syndrome: presents with erythematous skin eruption, fever, pulmonary edema (through neutrophil engraftment), increased B-type natriuretic peptide (BNP)
  • Toxic erythema of chemotherapy: if palmoplantar involvement in first 2-6 weeks post-HSCT
  • Many others: lichenoid drug eruption, autoimmune connective tissue diseases (lupus, dermatomyositis, morphea, systemic sclerosis), papulosquamous disorders
  • Reports of transient acantholytic dermatosis and voriconazole-associated photosensitivity misdiagnosed as cGVHD highlight value of biopsy confirmation if unclear clinical presentation
Stage Skin Liver Gut Grade Histologic
1 Erythematous macules and papules (<25% BSA) Bilirubin 2 to <3 mg/dl Diarrhea (500–1000 ml/ day) or persistent nausea I Focal vacuolar change of basal keratinocytes
2 Erythematous macules and papules (25–50% BSA) Bilirubin 3–6 mg/dl Diarrhea, 1000–1500 ml/ day II Grade I plus necrotic keratinocytes in the epidermis and/or hair follicle and a dermal lymphocytic infiltrate
3 Erythematous macules and papules (>50% BSA) to generalized erythroderma Bilirubin 6–15 mg/dl Diarrhea, >1500 ml/day III Grade II plus fusion of basilar vacuoles to form clefts and microvesicles
4 Generalized erythroderma with bulla formation Bilirubin >15 mg/dl Severe abdominal pain with or without ileus IV Grade III plus large areas of separation of epidermis from dermis

aGVHD:

  • If limited to cutaneous, can try control with topical corticosteroids
  • If not controlled with topicals:
    • 1st line: oral Prednisone or IV methylprednisolone (1mg/kg BID) + ongoing prophylactic GVHD therapy with systemic calcineurin inhibitor eg, tacrolimus, cyclosporine *controls 50% of patients
    • 2nd line: immunosuppressive agents eg. mycophenolate mofetil and TNF-α antagonists

cGVHD:

  • Therapeutic challenge as no single therapy is superior
  • LP-like eruption or pruritus: medium- to high-potency topical corticosteroids + topical calcineurin inhibitors
  • Phototherapy (PUVA, UVB, NB-UVB, UVA1) have shown some benefit
  • First-line systemic therapy: systemic corticosteroids *but 50% do not respond adequately
  • Other options: hydroxychloroquine, mycophenolate mofetil, imatinib mesylate, rituxumab, ruxolitinib, acitretin, extracorporeal photophoresis
  • Ocular symptoms: special contact lenses
  • Long-term: physical therapy, sun protection