Dermatologic Manifestations of Graft Versus Host Disease 

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. (See the image below.)

GVHD occurs when immunologically competent cells are introduced into an immunoincompetent host. GVHD refers to the immunologic insult and to the consequences to the organism. The leading cause of GVHD is hematopoietic cell transplantation (HCT), both allogeneic (between 2 individuals) and autologous (from the same individual). Solid organ transplants, blood transfusions, and maternal-fetal transfusions also reportedly cause GVHD. (See the diagram below.)^{[1, 2, 3, 4, 5]}

Acute GVHD occurs within the first 100 days of transplantation and consists of the triad of dermatitis, enteritis, and hepatitis. Chronic GVHD develops after day 100 and 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 outcome. Evidence of liver and/or gastrointestinal tract GVHD without skin involvement is rare.

Chronic GVHD may occur either as a late phase of acute GVHD or as 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.^[6]

Patients with GVHD are at increased risk for a variety of bacterial, viral, and fungal infections. (Immunosuppressed patients with suspected infection should be transferred to a tertiary care center.) Despite attempts to manipulate the immune response before, during, and after transplantation, GVHD remains the primary cause of morbidity and mortality after HCT.

Because of the complex immune status of patients with GVHD, other eruptions that can mimic GVHD must remain under consideration. Drug reactions are the most common in this regard, but other eruptions are also mimics of GVHD.

Various sorting mechanisms remove putative GVHD effector cells from donor marrow before transplantation but do not significantly reduce rates of GVHD.

Staging and scoring systems

A staging system for the skin involvement in acute GVHD has been outlined as follows (see the images below):

• 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 - Vesicles and bullaeBoy 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. Boy in whom graft versus host disease (GVHD), which progressed to stage 4. High-dose cyclosporin A and methylprednisolone had been administered intravenously. The patient later died from chronic pulmonary disease resulting from chronic GVHD. Courtesy of Mustafa S. Suterwala, MD.

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.

In 2007, Greinix et al^[7] reported a single-center pilot validation study of a new chronic GVHD skin scoring system. It combines the percentage of involved body surface area divided into 10 separate anatomic regions, with manifestations of chronic GVHD coded from 0 (normal skin) to 4 (hidebound skin, unmovable sclerosis).

The study used trained physicians who observed 3 times on 2 consecutive days for a total of 192 individual skin assessments. They (1) calculated results; (2) obtained good to excellent intraclass correlation coefficients in almost all scores, including erythematous lesions in areas with scores 3 and 4 for all observers; (3) saw moderate to good interrater reliability for observers 1 to 4 in lesions with scores 0, 3, and 4, respectively; and (4) noted marked improvement of interrater reliability in all scores and examinations when intraclass correlation coefficients were calculated only for the more experienced observers (1 to 3).

Treatment considerations

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

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

The type of transplant, pretransplantation ablative therapy, marrow preparation, and concurrent medications can affect the presentation of graft versus host disease (GVHD). Acute GVHD occurs 10-30 days after transplantation, whereas chronic GVHD occurs after day 100.

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.

Human herpesvirus type 6 reactivation is significantly associated with the occurrence of GVHD, as is coinfection with Epstein-Barr virus.^[8] Grover disease after bone marrow transplantation has also been associated with GVHD.^[9]

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).

Acute GVHD

Acute GVHD is observed 10-30 days after transplantation. 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.

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 resembles toxic epidermal necrolysis.

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. 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.

The diagnosis of graft versus host disease (GVHD) is complicated by the fact that other eruptions, such as engraftment syndrome, autologous GVHD, viral exanthems, and drug eruptions, can also occur after transplantation and can have histopathologic findings similar to those of GVHD, making clinical correlation necessary and complex.^[10] For example, zoster can occur after a stem cell transplant and can be confused with acute GVHD. (See the image below.)^[11]

Regimens used to ablate marrow (eg, cyclophosphamide, busulfan,^[12] and etoposide in various combinations, with or without total body irradiation) should be considered when GVHD is diagnosed.^[13]

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 physician to differentiate busulfan and etoposide reactions from GVHD.

After HCT, 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 is important when a diagnosis of GVHD is considered.

In 2006, Zenz et al^[14] 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^[15] 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^[16] 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^[17] noted thymoma-associated GVHD-like erythroderma. Vidal et al noted a case of cutaneous toxoplasmosis histologically mimicking GVHD.^[18]

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

• Allergic contact dermatitis
• Irritant contact dermatitis
• Drug eruptions
• Erythroderma (generalized exfoliative dermatitis)
• Lichen planus
• Morphea
• Staphylococcal scalded skin syndrome
• Stevens-Johnson syndrome and toxic epidermal necrolysis
• Toxic shock syndrome
• Eruption of lymphocyte recovery
• Scleroderma
• Viral exanthem

Skin biopsy with routine hematoxylin and eosin staining is the primary tool for evaluating skin eruptions in suspected graft versus host disease (GVHD).^[19]

A grading system describes the histologic changes of acute GVHD as follows:

• Grade 0 - Normal skin or changes not consistent with GVHD
• Grade 1 - Basal vacuolization of the dermal-epidermal junction
• Grade 2 - Basal vacuolization, necrotic epidermal cells, and lymphocytic infiltrate in superficial dermis, as in the image below.
• Grade 3 - Changes of grade 2 plus clefting at the basement membrane
• Grade 4 - Changes of grade 2 plus bullae formationAcute graft versus host disease. Tissue stained with hematoxylin and eosin shows dyskeratosis of individual keratinocytes and patchy vacuolization of the basement membrane. A moderate superficial dermal and perivascular lymphocytic infiltrate is also seen. Courtesy of Melanie K. Kuechle, MD.

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.

The best treatment for graft versus host disease (GVHD) is prevention. Prophylaxis for GVHD usually consists of methotrexate (MTX) with or without prednisone, cyclosporine, cyclophosphamide, or tacrolimus. Topical tacrolimus may be helpful for mucosal disease.^[20] (However, Prot-Labarthe et al^[21] noted toxic serum levels of tacrolimus after topical administration of the drug in an infant with severe cutaneous GVHD.)

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.

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. Immune modalities such as treatment with antibodies against the interleukin 2 receptor or antithymocyte globulin are not beneficial in treating acute GVHD.

Halofuginone, a topically applied inhibitor of collagen type I synthesis, is beneficial in patients with sclerodermatous 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.^[22]

Monoclonal antibodies directed either against activated T-cells (daclizumab, visilizumab, murine anti-CD147 monoclonal antibody [ABX-CBL]) or against cytokines (infliximab, etanercept) have had promising preliminary results.^{[23, 24]} Large-scale studies evaluating their effectiveness are not yet available.

Perfetti et al^[25] and Flowers et al^[26] found that extracorporeal photopheresis can be a treatment for steroid-refractory acute and chronic graft versus host disease (GVHD). Creamer et al^[27] noted that eczematoid GVHD responded to psoralen plus UV-A (PUVA).

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.

Patients recovering from bone marrow transplant are routinely hospitalized in specialized units for weeks after the procedure and continuously monitored for the development of infectious complications secondary to the 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.^[28]

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 HCT remains hematologic malignancy; other indications include treatment of aplastic anemia and restoration of marrow after attempts at ablating solid tumors (most patients who receive HCT 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 has been reported, in patients who receive solid organ transplants