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.)
Recent research underlies the diversity of the T-cell response in acute GVHD, chronic lichenoid GVHD, and sclerotic GVHD. In acute GVHD interleukin (IL)–22 messenger RNA and increased of IL-22–producing CD4+ T cells were present. Thymic stromal lymphopoietin, a cytokine tilting the immune response to a Th2 response, from days 20 to 30 was elevated post allogeneic hematopoietic stem cell transplantation in patients' cutaneous systems, who then went on to develop acute GVHD. In chronic lichenoid GVHD, T cells showed a mixture of Th1/Th17 signature. This was accompanied by up-regulation of Th1/Th17 cytokine/chemokine transcripts and increased amounts of IL-17–producing and interferon-gamma–producing and CD8+ T cells. 
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.) [2, 3, 4, 5, 6]
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 as either 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.  The 5-year accumulated incidence for chronic GVHD appears to be 9-75% based on a number of risk factors.
A number of theories have tried to provide a basis for chronic GVHD, including chronic GVHD as an autoimmune disorder in which human donor–derived T-cell clones recognize nonpolymorphic antigens expressed on both donor and recipient, but have not yet been found. B cells may also have a role in chronic GVHD. B cells have constitutive expression of class II major HLA types that might trigger activity on T-cell receptors such as CD80 and CD86. B-cell activating factor might play a role as well. 
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.
Histologic staging for acute GVHD is as follows  :
Grade 0 - Normal skin
Grade 1 - Basal cell layer diffuse or focal vacuolar alteration
Grade 2 - Grade 1 with epidermis and/or hair follicle dyskeratotic squamous cells
Grade 3 - Grade 2 with subepidermal vesicle formation
Grade 4 - Complete dermal and epidermal separation
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  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).
In acute GVHD, CXCL10 and BAFF are predictive biomarkers. In chronic GVHD and acute GVHD, CXCL10, CXCL11, and BAFF are diagnostic biomarkers. 
Signaling involving toll-like receptor 4 is involved with the skin in cases of chronic GVHD. 
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.  Grover disease after bone marrow transplantation has also been associated with GVHD. 
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.  Epidermolysis bullosa acquisita can be a manifestation of 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.
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. Hematocolpos has been noted as complication of chronic GVHD.  Ulcers on sclerodermatous plaques of chronic GVHD can occur and are disabling. 
As compared to systemic sclerosis (SS), in sclerosis of chronic GVHD, Raynaud disease is rare.  Whereas the fibrosis of chronic GVHD can be dermal, subcutaneous, and fascial, the fibrosis of SS is dermal. The face is more commonly involved in SS, but this is rare and is usually 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).  There can also be a "groove sign" on limbs, showing sclerosis of fascial bundles as well as a rippled, cellulitelike appearance of the legs. 
Nonscarring alopecia and scarring can occur and can be associated with medications and internal findings of chronic GVHD. Angiomatous papules, poikiloderma, sweat impairment, erosions, ulcerations, and stenosis of the vagina and vulva are also findings. 
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.  For example, zoster can occur after a stem cell transplant and can be confused with acute GVHD. (See the image below.) 
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  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  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  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  noted thymoma-associated GVHD-like erythroderma. Vidal et al noted a case of cutaneous toxoplasmosis histologically mimicking GVHD. 
Conditions to consider in the differential diagnosis of GVHD include the following:
Eruption of lymphocyte recovery
Skin biopsy with routine hematoxylin and eosin staining is the primary tool for evaluating skin eruptions in suspected graft versus host disease (GVHD). 
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.  (However, Prot-Labarthe et al  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. 
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. [32, 33] Large-scale studies evaluating their effectiveness are not yet available.
Complex treatment of GVHD is sometimes still the standard in 2012, 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. 
A 2013 report noted tofacitinib, a JAK inhibitor, reversed CD8 T-cell–mediated mucocutaneous GVHD in a mouse model. 
Topical tacrolimus can ameliorate GVHD. However, when applied under occlusion, systemic absorption, which is toxic, can occur. 
Additional Treatment Options
Perfetti et al  and Flowers et al  found that extracorporeal photopheresis can be a treatment for steroid-refractory acute and chronic graft versus host disease (GVHD). Creamer et al  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.
New techniques in transplantation might alter the findings in GVHD. Microtransplantation is a novel paradigm for parsing of GVHD and graft versus tumor. 
Narrowband UVB therapy (311 nm) can be a helpful treatment for GVHD. 
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. 
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