Dermatologic Manifestations of Graft Versus Host Disease

Updated: Jun 10, 2021
  • Author: Ricardo Guerra, MD; Chief Editor: Dirk M Elston, MD  more...
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Dermatologic manifestations are an important aspect of graft versus host disease (GVHD). Because the skin often is the earliest organ affected in GVHD, dermatologists are crucial members of the patient's treatment team.

GVHD occurs when donor immune cells recognize and attack host antigens. GVHD refers to the immunologic insult and consequences to the host. The leading cause of GVHD is hematopoietic stem cell transplantation (HSCT), most commonly allogeneic (between two individuals) rather than autologous (from the same individual). In allogeneic HSCT, donor T cells target malignant hematopoietic cell populations, creating a graft-versus-tumor effect. [1] If nonhematopoietic tissues of the recipient are targeted, however, GVHD occurs. Many factors affect the balance between a graft-versus-tumor effect and GVHD, including genetic differences between donor and host and the magnitude of the T-cell response.

The incidence of GVHD can be as high as 40-60% of patients receiving HSCT. [2] Solid-organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD. [3, 4, 5, 6, 7] Various sorting mechanisms remove putative GVHD effector cells from donor marrow before transplantation but do not significantly reduce rates of GVHD. Despite attempts to manipulate the immune response before, during, and after transplantation, GVHD remains a primary cause of morbidity and mortality after HSCT.


Clinical Overview

Previously, acute graft versus host disease (GVHD) required symptoms within the first 100 days of transplantation and chronic GVHD after day 100. More recently, the aforementioned National Institutes of Health Working Group developed consensus criteria using clinical findings to distinguish between the two entities instead of the 100-day cutoff. [8] Classically, acute GVHD consists of the triad of dermatitis, enteritis, and hepatitis, while chronic GVHD consists of an autoimmune syndrome directed toward multiple organs.

Acute GVHD usually starts as scattered erythematous macules and papules that involve a greater percentage of total body surface area as the severity of GVHD increases. Erythroderma and bullae may occur in the most severe form of acute GVHD. The degree of liver and gastrointestinal tract involvement in acute GVHD affects patient outcomes. Evidence of liver and/or gastrointestinal tract GVHD without skin involvement is rare.

Chronic GVHD may occur as either a late phase of acute GVHD or a distinct entity. The skin is the primary organ involved in chronic GVHD, which can manifest as a lichen planus–like eruption or as scleroderma. Sclerodermatous GVHD has a broad clinical spectrum and presents therapeutic challenges. [9]

See the image below.

Boy who developed stage 3 skin involvement with ac Boy who developed stage 3 skin involvement with acute graft versus host disease (GVHD) despite receiving prophylaxis with cyclosporin A. The donor was a sister matched for human leukocyte antigen. The sex disparity increased the risk of GVHD. Courtesy of Mustafa S. Suterwala, MD.

Treatment and diagnosis considerations

Patients who undergo bone marrow transplantation usually are hospitalized until marrow engrafting is established and blood counts are within the reference range. Treatment for acute GVHD, which occurs during the transplantation recovery phase, is performed in an inpatient setting.

Patients who develop chronic GVHD sometimes are hospitalized for pulse steroid therapy, but more often they are treated as outpatients.

In acute GVHD, CXCL10 and B-cell–activating factor may be predictive biomarkers. In chronic GVHD and acute GVHD, CXCL10, CXCL11, and B-cell–activating factor can be used as diagnostic biomarkers. [10] Other factors studied include T-cell immunoglobulin, mucin-domain–containing-3, interleukin (IL)–6, and soluble tumor necrosis factor receptor–1. [11] However, there is limited evidence for using these biomarkers in clinical practice. [12]

Some patients develop stage 1 GVHD that responds to therapy and never progresses further. Other patients develop a fulminant form that quickly evolves from erythroderma to a lichen planus–like eruption.



Acute graft versus host disease (GVHD) has been described as a three-step process. In the first step, chemotherapy and radiotherapy during the conditioning process create tissue damage that activates the host antigen-presenting cells. Second, donor T cells start proliferating after interacting with these activated antigen-presenting cells. Finally, T-cytotoxic cells among other factors begin destroying target tissue, including skin, liver, and gastrointestinal tract. [11]

Chronic GVHD has been described as an autoimmune disorder in which human donor–derived T-cell clones recognize nonpolymorphic antigens expressed on both donor and recipient. B cells may also have a role in chronic GVHD. B cells constitutively express class II major HLA types that might trigger activity on T-cell receptors such as CD80 and CD86. B-cell activating factor (BAFF) might play a role as well. [13] Signaling involving toll-like receptor 4 has also been involved with the skin in cases of chronic GVHD. [14]

Multiple T-cell responses have been implicated in acute and chronic GVHD. In lesional skin biopsies of acute GVHD, increased interleukin (IL)–22-producing CD4+ T cells were present. Thymic stromal lymphopoietin, a cytokine promoting a T-helper (Th)–2 response, was elevated on days 20-30 post allogeneic hematopoietic stem cell transplantation (HSCT) in the skin of patients who later developed acute GVHD. [15] Donor T cells interact with host antigen-presenting cells in the early post HSCT phase, leading to an expansion of T cells into Th1, T-cytotoxic, and Th17/Tc17 types. [16]

In chronic lichenoid GVHD, T cells showed a mixture of Th1/Th17 signature. This was accompanied by the up-regulation of Th1/Th17 cytokine/chemokine transcripts and increased amounts of IL-17–producing and interferon-gamma–producing, and CD8+ T cells. An up-regulation of Th2 and down-regulation of regulatory T cells has also been shown in chronic GVHD. [17] In 2020, macrophages were reported to have been implicated in playing a pathogenic role in skin GVHD. [18]



A staging system for skin involvement in acute graft versus host disease (GVHD) has been outlined as follows [12] :

  • Stage 1 - Involvement of less than 25% of the body surface

  • Stage 2 - Involvement of 25-50% of the body surface

  • Stage 3 - Involvement of 50-100% of the body surface (erythroderma)

  • Stage 4 - Generalized erythroderma with bullous formation, often with desquamation

The National Institutes of Health Working Group report for staging chronic GVHD established clinical criteria for diagnosis. Diagnostic findings include poikiloderma, lichen planus–like skin changes, skin sclerosis, morphealike features, and lichen sclerosus–like skin changes. [8]


Patient History

The type of transplant, pretransplantation ablative therapy, marrow preparation, and concurrent medications can affect the presentation of graft versus host disease (GVHD). The likelihood of developing GVHD is affected by the malignancy being treated by the transplant. Acute GVHD typically occurs 10-30 days after transplantation, and chronic GVHD typically occurs after day 100. There is a category of acute GVHD, however, that persists after 100 days called persistent, recurrent, late-onset acute GVHD. [8]

In 70-90% of cases of chronic GVHD, the condition evolves from the acute form of the disease. The risk of chronic GVHD increases with the severity of acute GVHD; patients with stage 3 or stage 4 acute GVHD are more likely to develop chronic GVHD than are patients with stage 1 or stage 2 acute GVHD.

Patients with GVHD are at increased risk for a variety of bacterial, viral, and fungal infections; immunosuppressed patients with a suspected infection should be transferred to a tertiary care center. Human herpesvirus type 6 reactivation is significantly associated with the occurrence of GVHD, as is coinfection with Epstein-Barr virus. [19] Grover disease after bone marrow transplantation has also been associated with GVHD. [20]


Physical Examination

Acute graft versus host disease (GVHD) consists of tender, erythematous macules that may coalesce over time. Patients with chronic GVHD exhibit skin changes that resemble either lichen planus or scleroderma, sometimes simultaneously or sequentially. Patients with chronic GVHD may have alopecia, nail dystrophy, and thickening of the skin (hyperkeratosis). An interesting report notes the development of psoriasis with GVHD in a 4-year-old child, 3 months after bone marrow transplantation. [21] Epidermolysis bullosa acquisita can be a manifestation of GVHD. [22]

Acute GVHD

Eruptions usually begin as faint, tender erythematous macules on any part of the body, although they usually affect the palms and soles first (see the image below). When erythematous macules form on the trunk or limbs, erythema preferentially forms around the hair follicle.

Acute graft versus host disease involving desquama Acute graft versus host disease involving desquamating skin lesions in a patient who underwent allogeneic bone marrow transplantation for myelodysplasia. Courtesy of Romeo A. Mandanas, MD, FACP.

As the disease progresses, more erythematous macules form and may coalesce to form confluent erythema. The erythematous macules may evolve into papules. In the most severe cases, subepidermal bullae form and the disease may resemble toxic epidermal necrolysis.

In the oral cavity, erythema, erosions, ulcers, lichenoid lesions, xerostomia, and pain have been reported.

Chronic GVHD

As erythema subsides in acute GVHD, violaceous lichenified papules arise; these lesions are indistinguishable from those of lichen planus. Typical lacy, white patches on the buccal mucosa of lichen planus are often present. Lichenoid papules have a predilection for flexural surfaces. There are patients with atopic dermatitis (AD)–like GVHD, and these patients had increased eosinophils and regulatory T cells compared with lichen planus–like GVHD. [23]

Sclerodermatous changes occur in chronic GVHD. Some patients have few, scattered sclerodermatous plaques. Other patients develop widespread disease that results in ulcerations, joint contractures, and esophageal dysmotility. Hematocolpos has been noted as a complication of chronic GVHD. [24] Ulcers on sclerodermatous plaques of chronic GVHD can occur and are disabling. [25]

As compared to systemic sclerosis, in sclerosis of chronic GVHD, Raynaud disease is rare. [13] Whereas the fibrosis of chronic GVHD can be dermal, subcutaneous, and fascial, the fibrosis of systemic sclerosis is dermal. The face is more commonly involved in systemic sclerosis, but this is rare and usually is patchy in chronic GVHD. The “impaired prayer sign,” marked by limited wrist and finger flexibility, is an indication of fascial involvement, and the nails are involved in 50% of cases (showing pterygium, thickening, dystrophy, thinning, onycholysis, and/or vertical ridging). [13] There can also be a "groove sign" on limbs, showing sclerosis of fascial bundles as well as a rippled, cellulitelike appearance of the legs. [13] Calcinosis cutis was found in a small retrospective case series diagnosed on average 7.5 years after transplantation and 5.5 years after the onset of chronic GVHD, most commonly on the lower extremities. [26] GVHD-associated angiomatoses are vascular lesions that have been documented a median of 44 months after transplantation and similarly occur on the lower extremities in patients with sclerotic-type chronic GHVD, but the exact incidence is unknown. [27]

Nonscarring alopecia and scarring alopecia can occur and have been associated with medications and internal findings of chronic GVHD. In a prospective cohort of hematopoietic stem cell transplant recipients with cutaneous GVHD, patterns of hair loss observed included patchy nonscarring (41.2%), diffuse nonscarring (11.8%), diffuse sclerotic (11.8%), and patchy sclerotic (5.9%). [28] Angiomatous papules, poikiloderma, sweat impairment, erosions, ulcerations, and stenosis of the vagina and vulva also are findings. [29]

Diagnostic findings of the oral mucosa in chronic GVHD include keratotic plaques, lichen planus–like lesions, and restriction of oral opening from sclerosis. The genital mucosa develops lichen planus–like lesions and vaginal scarring and/or stenosis. [8]


Differential Diagnosis

The diagnosis of graft versus host disease (GVHD) is challenging, as other eruptions, such as engraftment syndrome, viral exanthems, and drug eruptions, can also occur after transplantation and have similar histopathologic findings, making clinical correlation necessary and complex. [30] For example, zoster can occur after a stem cell transplantation and can be confused with acute GVHD. [31]

See the image below.

Autologous graft versus host disease involving the Autologous graft versus host disease involving the skin on a patient's arm shortly after signs of engraftment appeared after autologous peripheral blood stem cell transplantation for ovarian cancer. Courtesy of Romeo A. Mandanas, MD, FACP.

Engraftment syndrome is associated with an erythematous eruption, fever, and pulmonary edema. If there is palmoplantar involvement 2-6 weeks following hematopoietic stem cell transplantation (HSCT), the diagnosis of toxic erythema of chemotherapy should be considered.

Regimens used to ablate marrow (eg, cyclophosphamide, busulfan, [32] and etoposide in various combinations, with or without total body irradiation) should be considered when GVHD is diagnosed. [33]

Do not mistake hyperpigmentation of palms and soles that cyclophosphamide and busulfan can cause for early GVHD. Busulfan has been associated with a widespread bullous eruption, and etoposide has been associated with hypersensitivity reactions. Characteristic histopathologic findings are present that can help the practioner to differentiate busulfan and etoposide reactions from GVHD.

After HSCT, patients usually take multiple medications. Eruptions related to these medications can have a clinical presentation similar to that of GVHD. The timing and administration of all medications are important when a diagnosis of GVHD is considered.

In 2006, Zenz et al [34] noted an autologous GVHD-like syndrome that followed an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation to treat chronic lymphocytic leukemia.

Kuskonmaz et al [35] noted fatal GVHD mimicking contact dermatitis in an infant who underwent 5/6 HLA-matched bone marrow transplantation from his mother for malignant infantile osteopetrosis. The initial rash on day 32 of life simulated diaper rash. The rash evolved into a belt-shaped rash, and then the child developed hyperkeratotic nodules on the hand.

In 2006, Ozdemir and Molldrem [36] reported a hookworm infection of the sigmoid colon mimicking GVHD in an immunosuppressed patient following allogeneic stem cell transplantation; the patient had received a donor lymphocyte infusion for refractory acute promyelocytic leukemia. In 2007, Nakagiri et al [37] noted thymoma-associated GVHD-like erythroderma. Vidal et al noted a case of cutaneous toxoplasmosis histologically mimicking GVHD. [38]

Conditions to consider in the differential diagnosis of GVHD include the following:


Histologic Findings

Skin biopsy with routine hematoxylin and eosin staining is the primary tool for evaluating skin eruptions in suspected graft versus host disease (GVHD). [39]

Histologic grading for acute GVHD is as follows [13] :

  • Grade 0 - Normal skin

  • Grade 1 - Basal cell layer diffuse or focal vacuolar alteration

  • Grade 2 - Grade 1 with epidermis and/or hair follicle necrotic keratinocytes with a dermal lymphocytic infiltrate

  • Grade 3 - Grade 2 with subepidermal vesicle formation

  • Grade 4 - Grade 3 with large areas of dermal and epidermal separation

Chronic GVHD exhibits basement membrane changes similar to those of acute GVHD (eg, vacuolar changes, necrotic epidermal cells, presence of lymphocytes). In addition, chronic disease can result in features such as thickened epidermis (acanthosis), thickened granular layer (hypergranulosis), thickened stratum corneum (hyperkeratosis), and rete ridges with a pointed or sawtooth appearance.

Horn et al reported that the lichen planus–like histologic changes (acanthosis, hypergranulosis, sawtooth rete ridges) believed to represent chronic GVHD occur before the 100th day after transplantation in approximately 15% of patients. In addition, lichen planus–like histologic changes, seen in either the acute or chronic clinical setting of GVHD, portend a poor patient prognosis. Several sequential biopsies are often needed because the rash evolves to establish the diagnosis; histologic changes during the early stage of the disease can be nonspecific.

Hematoxylin-eosin–stained punch biopsy specimens of the scalp in patients with chronic GVHD demonstrate an inflammatory infiltrate around the bulb in nonscarring cases and around the bulge in sclerotic cases. [28] Fluorescence in situ hybridization has shown that female patients with male donors had green Y chromosomes only in areas of the hair follicle with an inflammatory infiltrate.

GVHD-associated angiomatosis represents a vascular proliferation composed of thin-walled vessels that are D2-40 and HHV8 negative. [40]


Prevention of GVHD

Prophylaxis for acute graft versus host disease (GVHD) usually consists of methotrexate with or without prednisone, cyclosporine, cyclophosphamide, or tacrolimus. Topical tacrolimus may be helpful for mucosal disease [41] ; however, Prot-Labarthe et al [42] noted toxic serum levels of tacrolimus after topical administration of the drug in an infant with severe cutaneous GVHD. Bortezomib, a proteasome and NF-κB inhibitor, has been shown to be important for T-cell proliferation, [43] and evidence has shown its effectiveness in preventing acute GVHD in mice. [44] Interestingly, prebiotics reduced the incidence of acute GVHD in allogeneic hematopoietic stem cell transplantation patients. [45]

Marrow T-cell depletion can substantially reduce the incidence and severity of acute GVHD, but these results are offset by an increase in graft failure and recurrent leukemia. A randomized clinical study showed that a preinfusion single dose of mesenchymal stem cells decreases the rate of grade II or above acute GVHD, although there was no significant difference in survival. [46]

One prospective open-label study showed that inclusion of antihuman T-lymphocyte immune globulin (ATG) in the conditioning regimen led to a lower rate of chronic GVHD after allogeneic transplantation, [47] and another phase 3 trial showed decreased use of immunosuppressive therapy, chronic GVHD, and improved overall survival when ATG was added to standard GVHD prophylaxis. [48] Because B cells play a role in the pathophysiology of chronic GVHD, rituximab, an anti-CD-20 antibody targeting B cells, may be effective for prevention. [43] In one phase 3 randomized trial, tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide led to the best GVHD-free, relapse-free survival. [49]


Acute GVHD Treatment

Complex treatment of graft versus host disease (GVHD) is sometimes still the standard, with topical agents, systemic agents, and physical modalities (eg, phototherapy, extracorporeal photopheresis) needed, and with the coordination of many types of physicians and providers working to help the patient. [50]

Once the diagnosis of GVHD is established, treatment consists of continuing the original immunosuppressive agent and adding methylprednisolone. Chronic GVHD requires continued immunosuppressive therapy plus other modifying agents. Sirolimus compared with prednisone may offer similar initial treatment efficacy, avoid steroid-associated toxicity, and improve patient-reported quality of life. [51]

Monoclonal antibodies directed either against activated T cells (visilizumab, murine anti-CD147 monoclonal antibody [ABX-CBL]) or against cytokines (infliximab, etanercept) have had promising preliminary results. [52, 53] In a phase 1 trial of steroid-refractory acute GVHD, patients treated with brentuximab vedotin, an anti-CD30 monoclonal antibody, 14.7% showed complete response and 23.5% showed partial response. [54]

A 2013 report noted tofacitinib, a Janus kinase (JAK) inhibitor, reversed CD8 T-cell–mediated mucocutaneous GVHD in a mouse model. [55] Ruxolitinib, a JAK 1/2 inhibitor, had a 45% response rate in children with steroid-refractory acute GVHD in a retrospective study. [56] In a randomized phase 3 trial, ruxolitinib led to greater response rates compared with placebo in steroid-refractory acute GVHD. [57]

Topical tacrolimus can ameliorate GVHD. However, when applied under occlusion, systemic absorption, which is toxic, can occur. [58] One retrospective study of chronic GVHD treated with sirolimus or everolimus (MTOR inhibitors) showed a 76% response rate when given in combination with corticosteroids. [59]

Perfetti et al [60] and Flowers et al [61] found that extracorporeal photopheresis can be a treatment for steroid-refractory acute and chronic GVHD. Creamer et al [62] noted that eczematoid GVHD responded to psoralen plus ultraviolet (UV)–A phototherapy.

New techniques in transplantation might alter the findings in GVHD. Microtransplantation is a novel paradigm for parsing of GVHD and graft versus tumor. [63] Narrowband UVB therapy (311 nm) can be a helpful treatment for GVHD. [64]


Chronic GVHD Treatment

Halofuginone, a topically applied inhibitor of collagen type I synthesis, is beneficial in patients with sclerodermatous graft versus host disease (GVHD). Thalidomide has been used for chronic GVHD with reported benefit, but the high rate of adverse effects (including granulocytopenia) precludes its use in many patients. [65] Administration of interleukin (IL)–2, which plays an essential role in regulatory T-cell function, resulted in clinical response in 61% of steroid-refractory chronic GVHD patients in a phase 2 study. [66]

Abatacept, a drug with extracellular domain CTLA-4, blocks T-cell activation and led to clinical response in steroid-refractory chronic GVHD patients in a phase 1 trial. [67] Ibrutinib is an inhibitor of tyrosine kinase in B cells and IL-2–inducible kinase in T cells that was effective in both steroid-dependent and steroid-resistant chronic GVHD, showing a best overall response rate of 67%. [68]

Patients who develop sclerodermatous changes of chronic GVHD may require surgical release of a contracted joint. Patients who develop nonhealing ulcerations secondary to sclerodermatous GVHD may require wound debridement and skin grafting. A randomized phase 2 study showed that 36% of patients with sclerotic chronic GVHD showed improvement of skin symptoms and joint motion after treatment with imatinib, an inhibitor of platelet-derived growth factor and other kinases. [69]

Treatment for oral GVHD consists of topical steroids and calcineurin inhibitors. Severe and generalized lesions may require higher frequency and potency of the medication. [70] Vulvovaginal GVHD is treated with topical immunosuppression (steroids or tacrolimus), dilator use, and topical estrogen. Female patients of allogeneic hematopoietic stem cell transplantation (HSCT) are also at increased risk of condyloma, cervical dysplasia, and neoplasia and should receive appropriate cytology screening. [71]



Patients recovering from bone marrow transplantation are routinely hospitalized in specialized units for weeks after the procedure and continuously monitored for the development of infectious complications secondary to their immunosuppressed status. If the initial outcomes of bone marrow transplantations are successful, patients need close follow-up monitoring of their immunosuppressive regimens and primary tumor status.

Because patients usually require lifelong immunosuppressive therapy, long-term, continual monitoring is required. [72] In general, immunosuppressed patients should receive annual screening by a dermatologist as they are at increased risk for skin cancer.



Subspecialists are often consulted for the management of graft versus host disease (GVHD) and include the following:

  • Hematologist and oncologist: The most common indication for hematopoietic stem cell transplantation (HSCT) remains hematologic malignancy; other indications include treatment of aplastic anemia and restoration of marrow after attempts at ablating solid tumors (most patients who undergo HSCT are treated primarily by the hematologist or oncologist).
  • Dermatologist: A dermatologist may be the best specialist to differentiate the various skin eruptions that can occur in patients who are taking multiple medications and who are at risk for GVHD; skin biopsy remains the primary tool for differentiating the skin eruptions, and a dermatopathologist with clinical and dermatopathology training is the best specialist for interpreting the results.
  • Gastroenterologist: Patients with GVHD may have hepatic and gastrointestinal mucosal involvement; input from gastroenterologists is important in treating these complications.
  • Physical medicine/rehabilitation specialist: Patients who develop chronic GVHD are at risk for joint contractures and pressure ulcerations.
  • Transplantation medicine specialist and transplantation surgeon: Patients who receive solid organ transplants are treated by these specialists; GVHD is rare, but it has been reported, in patients who receive solid organ transplants.