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Cutaneous Graft-versus-Host Disease
Sélim Aractingi, MD, PhD;
Olivier Chosidow, MD, PhD
Arch Dermatol. 1998;134:602-612.
ABSTRACT
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Graft-versus-host disease (GvHD) includes inflammatory and/or fibrosing manifestations that may arise at various times after transplantation of any organ containing lymphoid cells. For the dermatologist, the importance of GvHD is real and current. Indeed, because it has become easier to perform bone marrow transplantation (BMT), the indications of BMT have become broader, making follow-up of patients receiving grafts a widespread practice. Nonetheless, GvHD remains a frequent complication of BMT and its principal target organ is the skin. Furthermore, recent innovations, such as grafting of umbilical cord blood and the mobilization of peripheral blood progenitor cells, will be the source of new questions concerning the development of GvHD under these conditions. Finally, because of its analogies with other spontaneous idiopathic skin diseases, GvHD constitutes a model that may lead to a better understanding of the pathophysiological features of these diseases. In this review, the cutaneous aspects of GvHD are emphasized.
INTRODUCTION
The initial definition of graft-versus-host disease (GvHD), proposed by Billingham,1 grouped under the term graft-versus-host reaction the manifestations arising when the 3 following conditions were met: (1) the organ grafted contained immunologically competent cells, (2) the tissue antigens of the host differed from those of the donor, and (3) the recipient was immunocompromised. Thus, the primary situation in which GvHD can be observed is allogeneic bone marrow transplantation (BMT). However, GvHD has also been reported after heart or liver transplantation and after blood transfusion, especially into an immunodeficient host, when the cells have not been irradiated or depleted of leukocytes.
Graft-versus-host disease is divided into 2 forms: acute GvHD, which occurs during the first 3 months following BMT, and chronic GvHD, which includes all the manifestations that develop after the third month following transplantation. Acute GvHD is of short duration, involves only the epithelia, and is induced by the recognition of host-specific antigens. In contrast, chronic GvHD evolves via relapsing episodes, has multiple targets, and its pathophysiological features remain poorly understood, with a conjunction of alloimmunity and autoimmunity.
CUTANEOUS ACUTE GvHD
A Common Complication
Acute GvHD is characterized by a selective epithelial inflammation that can affect the skin, digestive tract, and liver. Cutaneous involvement is the most common. Some exocrine glands and the bronchi are rarely affected. The frequency of acute GvHD varies between 6% and 90% of graft recipients as a function of patient age, HLA type, and the prevention protocols applied.2 In adults receiving an HLA-identical graft, the mean frequency is 35%. Based on multivariate analyses of cohorts receiving allografts, several studies have identified the following as factors associated with an increased risk of acute GvHD: age of recipient, HLA mismatch, sex mismatch with the donor being female (especially those receiving transfusions or who are multigravida) and the recipient male, use of irradiation in the conditioning, and a suboptimal dose of immunosuppressive drugs.
Clinical Features
The disease usually begins between day 7 and day 21 following grafting. Nevertheless, an earlier onset is possible. At the beginning, a sensation of skin pain or itching may occur. The lesions are afterward characterized by the development of disseminated maculopapular exanthema (Figure 1), with sudden onset, resembling measles. The extent of this eruption varies (Table 1). Perifollicular papular lesions may be seen and are considered by some a good indicator of the diagnosis.3 Acral involvement is also suggestive of GvHD, characterized by an erythematous rash of the palms and soles and a violaceous discoloration of the ears (Figure 2 and Figure 3). Initial involvement of the cheeks or sides of the neck may also be observed. Mucosal involvement is poorly documented because it is difficult to distinguish from chemotherapy-induced mucitis. In 6% of cases, epidermal necrosis occurs, which can remain localized to pressure sites or can spread (Figure 4).4 In these cases, the Nikolsky sign is positive and skin flaps slough off. Acute GvHD may also present as a scarlatiniform rash with confluent sheets of erythema that desquamate and leave areas of hyperpigmentation, and it may even present as a clinical picture suggestive of varicella. Cutaneous GvHD is classified into 4 stages as a function of the extent of involvement and the prognosis is correlated with the stage (Table 1). The epidermal necrosis described earlier is the most severe (GvHD grade 4+).
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Figure 1. Maculopapular disseminated exanthema in a patient with acute graft-versus-host disease.
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Table 1. Clinical Staging of Acute Graft-versus-Host Disease
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Figure 2. Erythema of the ears in a patient with acute graft-versus-host disease.
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Figure 3. Redness of the palms in a patient with acute graft-versus-host disease.
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Figure 4. Grade IV acute graft-versus-host disease.
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Extracutaneous symptoms of acute GvHD may concern the gastrointestinal tract and/or liver. These symptoms are usually associated with concomitant cutaneous signs, although they may sometimes be isolated. Involvement of the gastrointestinal tract is responsible for various degrees of nausea, vomiting, anorexia, and diarrhea, graded 1+ to 4+. Malabsorption, abdominal pain, ileus, and ascites are manifestations of severe involvement. Acute GvHD of the liver is reflected mainly by increases in levels of aspartate aminotransferase and conjugated bilirubin, which are also graded 1+ to 4+. Moderate hepatomegaly and jaundice may be found. The diagnosis of GvHD in these organs is usually evoked when skin signs are present. If not, histopathologic examination of specimens from the gastrointestinal tract or rectum may be needed. Finally, an overall grading of GvHD is also used in the literature and correlated with the prognosis of the disease (Table 1).
Histological Aspects
Lymphocytic infiltration and cytopathic changes of keratinocytes are the major features of acute GvHD (Figure 5). The infiltrating lymphocytes are located in the superficial dermis, and in most cases, scattered lymphocytes are in the epidermis. Epithelial changes are resumed by focal or diffuse vacuolar degeneration of epidermal basal cells. Focal or diffuse spongiosis may occur. Characteristically, there are clustered lymphocytes around dyskeratotic and/or dead keratinocytes, referred to as satellite cell necrosis. This sign usually has been considered illustrative of the pathogenesis of GvHD, with the presence of an activated donor lymphocyte recognizing a host cell. In more severe forms, clefts and spaces after necrosis of the basal cell layer result in separation of the dermoepidermal junction. As for clinical manifestations, histological signs are classified into 4 grades, as follows: grade I, basal cell vacuolization; grade II, basal cell vacuolization and single necrotic keratinocytes; grade III, superepidermal clefts and numerous necrotic keratinocytes; and grade IV, necrosis of the entire epidermis and complete separation from the dermis.
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Figure 5. Skin section showing typical features of acute graft-versus-host disease with lymphocyte infiltration and keratinocyte vacuolization (hematoxylin-eosin, original magnification x200).
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Several reports have emphasized the importance of follicular involvement. In murine GvHD, Murphy et al5 found that follicular infiltrates preferentially affected the bulge regions of anagen follicles. These infiltrates often preceded invasion of the neighboring interfollicular dermis. Because epidermal stem cell density is higher in these sites, these authors suggested that hair follicle stem cells could represent a selective target in acute GvHD. Indeed, a retrospective analysis of a series of acute human GvHD cases found that the parafollicular bulge was involved in all patients who could be evaluated.6 Finally, direct immunofluorescence labeling of skin demonstrated granular deposits of IgM and/or C3, similar to a lupus band test, in 39% of biopsy specimens from patients with acute GvHD, whereas this pattern was seen in only 11% of BMT recipients without GvHD.7
Two recent in situ studies were able to confirm that the death of keratinocytes in mice8 and humans9 occurred via apoptosis. Gilliam et al8 even showed that in mice there were 2 waves of apoptosis: one prior to the lymphocytic infiltration and a later one concomitant with the presence of T cells in the skin. The authors hypothesized that the first wave could be secondary to the production of tumor necrosis factor (TNF)  , whereas the second could be induced by infiltrating cytotoxic lymphocytes (CTLs).
Composition of the Infiltrate
Many studies have been conducted to determine which lymphocyte subpopulations are found in the skin of patients with acute GvHD. Unfortunately, the results do not always agree, as seen in Table 2.8, 10-22 Briefly, the infiltrate is composed of T cells, with either both CD4+ and CD8+ or with 1 of these subsets predominating. Two investigations indicated that natural killer (NK) cells were present in acute GvHD skin lesions.8, 22 B cells are not found and cells expressing the   T-cell receptor (TCR) represented only a minority of infiltrating cells.
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Table 2. Immunophenotype of Lymphoid Infiltrate in Acute Graft-versus-Host Disease*
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Differential Diagnosis
A major problem in diagnosing acute GvHD arises because the clinical symptoms, histological aspects, and composition of the lymphocytic infiltrate are not specific. Also, similar aspects can be observed in cutaneous reactions to chemotherapy or radiation therapy, in adverse drug reactions, and even in some viral infections. Using 13 criteria, 3 pathologists blindly evaluated tissue sections from patients who received allografts considered to have acute GvHD or eruptions attributable to the conditioning regimen and from patients who had received autografts or allografts from a monozygotic twin.23 No differences were found between these groups in terms of vacuolization of keratinocytes, pyknosis, eosinophil bodies, or satellite cell necrosis. A consensus among the 3 pathologists was noted in only 31% of the slides, illustrating the difficulty of making conclusions in transplant recipients. Similarly, other authors have shown that the histological characteristics of the skin, HLA-DR expression, and composition of the skin infiltrate were similar in BMT recipients with GvHD and in patients not undergoing transplantation who had adverse drug reactions. A group from France retrospectively analyzed 9 cases of grade IV acute GvHD; 4 of them had no extracutaneous involvement of GvHD and therefore theoretically appeared more like a drug reaction.4 Also, some clinical pictures suggestive of GvHD could correspond to viral infections, particularly human herpesvirus 6. However, Horn et al24 demonstrated in rodents that the presence of a dermal lymphocytic infiltrate was useful in distinguishing GvHD from preparative regimen toxicity. In conclusion, absolute criteria for acute GvHD diagnosis are still poor and the possibility of conditioning regimen toxicity or even viral infection must be always taken into account when examining BMT recipients with a skin eruption. The presence of extracutaneous involvement can help support the diagnosis of acute GvHD. In the absence of such symptoms, the approach depends on the transplant unit's procedures, weighing the benefit-risk ratio of giving immunosuppressive treatment with the likelihood of the diagnosis of acute GvHD.
MECHANISMS OF SKIN LESIONS IN ACUTE GvHD
Induction by Mature Donor T Cells Recognizing Host Antigens
In mice and in humans, depletion experiments of mature T cells—or of subsets of these—from the donor bone marrow have shown a reduction in the frequency of acute GvHD.25 In the same way, the severity of the GvHD parallels the number of T cells transfused, demonstrating that T cells are responsible for the induction of GvHD.
Furthermore, several groups have shown that primary cultures of T cells derived from the skin biopsy samples of acute GvHD lesions displayed cytolytic and/or helper activity only against the recipient cells.26 All these studies demonstrate that acute GvHD occurring in humans is induced by donor T cells reactive against recipient cells expressing different tissue antigens.
Role of Minor Antigens
Minor antigens are peptides that are not encoded by the genes of the major histocompatibility complex but are nevertheless implicated in allogeneic reactions. Studies of GvHD have allowed major advances in the understanding of human minor antigens. One minor antigen, HA-2, was recently sequenced,27 and the target role of minor antigens was confirmed by a recent study in which a mismatch in minor antigen HA-1 was shown to be associated with acute GvHD, demonstrating that the recognition of a difference in this system can be responsible for triggering acute GvHD.28
Effector Cells in Acute GvHD
Although acute GvHD is induced by host-specific T cells, the nature of the cells producing lesions in target organs is still controversial. Some authors, noticing that the lymphoid infiltrate seen on histological sections of acute GvHD lesions was usually discrete, postulated that the epithelial cell lesions could be secondary to the secretion of cytokines by T cell–activated macrophages, mainly TNF-. Nevertheless, the presence of macrophages in the lesional tissues was rarely shown.29 The theory that the lesions were induced by NK cells was also suggested, essentially because of results of mouse studies. However, only a few studies conducted in humans found NK cells.10-11 In contrast, T cells CD4+ and/or CD8+ were always present (Table 2). The role of T cells as effectors of cutaneous lesions, although still debatable, seems highly probable. These cells produce perforin and this cytotoxic pathway could be implicated in acute GvHD.30
T-Cell Repertoire
The comparison of the repertoire of GvHD lesional skin to peripheral blood mononuclear cells (PBMCs) did not find evidence of selective recruitment of certain populations. However, later analysis of the junctional diversity in one patient demonstrated that a unique recurrent transcript represented 81% of the in-phase V transcripts in the skin and 59% of the in-phase V transcripts in PBMC.31 Therefore, arguments were made for the selective use of certain TCR cells, probably as a consequence of an antigen-induced process. Other studies have reported similar indications.32
Locally Produced Cytokines and Inflammatory Phenomena
The ability of keratinocytes to induce or amplify inflammatory phenomena has been demonstrated for several cutaneous disorders. In skin biopsy specimens of murine acute GvHD, reverse transcription–polymerase chain reaction detected TNF- and interleukin (IL) 1 messenger RNA.33 The treatment of grafted mice with anti–TNF- antibodies or an antagonist of the IL-1 receptor considerably reduced the mortality of the animals and the occurrence of skin lesions.33-34 Finally, Abhyankar et al35 noted 200-fold more IL-1 messenger RNA and approximately 6-fold more TNF- messenger RNA in the spleen and skin of animals with acute GvHD. All these observations suggest that in GvHD, keratinocytes produce TNF- and IL-1, maybe in response to the conditioning regimen. In turn, these cytokines would induce endothelial cells to synthesize adhesion molecules and allow a chemotactic effect on donor T cells, thereby triggering the onset of acute GvHD lesions.29
Major Histocompatibility Complex Class II Antigens and Expression of Intercellular Adhesion Molecule 1
In addition to cytokines, keratinocytes express intercellular adhesion molecule 1 (ICAM-1 or CD54) throughout the course of acute GvHD and even before the lymphocyte infiltration.36 Similar abnormalities have been observed in the digestive tract. Thus, expression of ICAM-1 during acute GvHD would enable the epidermis to "retain" lymphocytes. Keratinocytes express HLA class II antigens in the majority of patients with acute GvHD.12 This expression occurs early and also has been detected before the lymphocyte infiltration.13 A correlation has been found between the number of cells expressing HLA-DR and the number of those bearing ICAM-1. Therefore, keratinocyte activation and the use of the ICAM-1–lymphocyte-function associated antigen pathway are implicated in the pathogenesis of acute GvHD.
Endothelial Cells as Targets
Several studies indicate that modifications of endothelium are involved in acute GvHD, probably under the influence of proinflammatory cytokines. Indeed, histological abnormalities of endothelium have been found in acute GvHD.37 In addition, vascular adhesion molecules, such as E-selectin+ and vascular cellular adhesion molecule 1+, are expressed in acute GvHD.38 Furthermore, a recent study demonstrated that when the platelet endothelial cell adhesion molecule (PECAM or CD31) isoforms differed between donor and receptor, the risk of acute GvHD was significantly increased.39 The PECAM is an adhesion molecule allowing homophilic adhesion between a PECAM on the lymphocyte surface and another on the endothelial cell membrane. That a mismatch between PECAMs is associated with the development of acute GvHD suggests that circulating donor lymphocyte recognition of different endothelial molecules is involved in the pathogenesis of GvHD. Thus, immunological recognition phenomena could also involve vessels.
CUTANEOUS CHRONIC GvHD
Chronic GvHD develops after a mean delay of onset of 4 months, but manifestations resembling chronic GvHD can appear as early as day 40 following transplantation. The skin is involved in almost all cases of chronic GvHD and the mouth in 90%. Chronic GvHD may appear in the continuity of previous acute GvHD (32% of cases) after a variable symptom-free period in patients who experienced an acute episode (36% of cases) or de novo (30% of cases). The 2 main types of cutaneous manifestations are lichenoid or sclerodermatous lesions. Both can develop spontaneously or be triggered by several events, notably UV irradiation, physical trauma, zoster, or even Borrelia infections.
Cutaneous lichenoid lesions usually occur early in the course of the disease and are easy to recognize.40-41 These lesions are erythematous or violaceous papules or plaques, with a squamous surface, sometimes able to form larger confluent areas. The periorbital region, ears, palms, and soles are the typically affected sites (Figure 6). In some cases lichenoid papules can occur around hair follicles. Less typically the lesions center blisters leading to a vesicle, resembling dyshidrosis when present on the hands. Lichen planus–like GvHD can also affect the nails, with onychatrophia and pterygium, and the genital organs, with a risk of phimosis and vaginal strictures. Recently, lichenoid GvHD restricted to a dermatoma has been reported.42
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Figure 6. Lichenoid lesions of the face in a patient with chronic graft-versus-host disease.
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Chronic GvHD can also present as sclerodermatous lesions, which develop usually later.43 These appear as indurated, sclerotic, shiny, white-yellow plaques of poorly defined contours, usually with the early development of patchy hyperpigmentation or a poikilodermal aspect. Initially the lesions may present as inflammatory plaques. Sclerodermoid GvHD can be generalized and therefore extremely disabling or remain localized (Figure 7 and Figure 8). Localized sclerodermatous GvHD may develop on the legs and the skin can become so adherent to deeper tissues that mechanical ulcers can develop. Peripheral axonal neuropathy in the same site as the sclerosis has been reported in the legs of individuals with GvHD,44 which would be the consequence of entrapment of the nerve endings. When sclerodermatous plaques are located over the joints the fibrosis can involve the ligaments, causing a retraction. Of note, acrosclerosis and Raynaud phenomenon are uncommon in chronic sclerodermatous GvHD, in contrast to systemic sclerosis. In addition, sclerodermatous GvHD can, very rarely, be bullous without a clear understanding of the mechanisms of these lesions.
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Figure 7. Sclerodermoid late phase of chronic graft-versus-host disease.
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Figure 8. Disseminated sclerodermatous graft-versus-host disease.
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Rarer features of cutaneous GvHD are important to recognize. Fasciitis constitutes a rare form of chronic GvHD45 that presents initially as cellulitis with palpable subcutaneous infiltrated edema. The sides of the body and the proximal part of the limbs are the preferential affected sites. Then, as the disease progresses, the cellulitic area hardens and retracts and the lesion becomes visible and depressed without epidermal signs. Trauma or unusual physical exertion is noted in half of the cases. The evolution of fasciitis is remarkable by its resistance to treatment. De novo diffuse melanoderma, without underlying sclerosis, is another rare form of chronic GvHD observed in genetically pigmented transplant recipients. Although the significance of these lesions is not clearly established, the demonstration that postinflammatory mechanisms are implicated and the similarities with pure morphea pigmentosa suggest that this form indicates progressive cutaneous GvHD.46
Oral Involvement
The cheeks and often the tongue, palate, and lips can be involved in chronic GvHD. This involvement is characterized by diffuse or focal enhanced redness of the mucosa47 with atrophy. Atrophy of the dorsal area of the tongue is associated with shortened or totally absent lingual papillae. Lichenoid reticular or papular hyperkeratotic patterns may develop anywhere in the mouth and are usually interspersed with atrophic erythematous areas. In addition, in severe forms, ulcerative lesions may develop, which are responsible for pain and difficulties with eating (Figure 9). In one series, the severity of oral abnormalities appeared to reflect that of the systemic chronic GvHD. Oral and ocular Sjögren syndrome is almost always present and responsible for frequent Candida superinfections. Esophageal mucositis may also occur. Finally, the extent of lymphocyte infiltration of the accessory salivary glands is another indicator of severity.
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Figure 9. Oral lesions in a patient with chronic graft-versus-host disease.
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The Importance of Extracutaneous Involvement
Chronic GvHD is often a systemic disease with multiple organ involvement.48 When confronted with cutaneous chronic GvHD, it is important to ascertain the presence of other visceral signs. Aside from mucocutaneous disease, chronic GvHD may lead to variable degrees of keratoconjunctivitis sicca, liver disease resembling primary biliary cirrhosis with obstructive jaundice, diarrhea with or without malabsorption, bronchiolitis obliterans, polymyositis, or peripheral entrapment neuropathy.
The Role of Histological Examination
The so-called early phase of chronic GvHD is seen in lichenoid lesions, and the histological aspect resembles that of acute GvHD. There is a lymphocytic infiltrate of the superficial dermis with moderate exocytosis. In the dermis the infiltrate is sometimes perineural. The epidermis is thickened with acanthosis, parakeratotic hyperkeratosis, and hypergranulosis and includes a variable degree of keratinocyte necrosis, sometimes with satellite cell necrosis. It was recently shown that patients with all the histological criteria of lichenoid GvHD were more likely to die of GvHD.
The late phase corresponds to sclerodermatous lesions. At that time there is marked epidermal atrophy, progressive destruction of appendageal structures, linearization of the dermoepidermal junction, and superficial collagen fibrosis. Keratinocytes are small, flattened, and loaded with melanin. Vacuolized or necrotic keratinocytes are few and found in the basal cell layer. The dermis is the site of discrete pericapillary infiltrates. There is no pericapillary sclerosis.49 Ultrastructural analysis demonstrates several tangible differences between sclerodermatous GvHD and progressive systemic sclerosis.50 Differences between these diseases are summarized below.
Finally, granular IgM deposits at the dermoepidermal junction are found in 86% of biopsy specimens from patients with chronic GvHD.7
Diagnosis
The diagnosis of chronic GvHD usually can be made easily based on the clinical examination of lichenoid or sclerodermatous lesions in a BMT recipient. The blood cell count may help when demonstrating associated findings as eosinophilia or thrombocytopenia. Histological examination, immunoglobulin deposits at the dermoepidermal junction, the presence of autoantibodies, and/or involvement of another organ are other criteria to support the diagnosis of chronic GvHD.
Classification of Chronic GvHD
Unlike the classification of acute GvHD, that of chronic GvHD is relatively obsolete and, as deduced from the literature, is not applied to correlate symptoms and prognosis.51 Most authors recommend the use of the Karnofsky scale.
Principal Factors Associated With Increased Risk of Developing Chronic GvHD
The risk of chronic GvHD is 11 times higher if patients had prior acute GvHD.52 In addition, a multivariate analysis performed on a group of patients with de novo chronic GvHD identified other risk factors: recipient age (>20 years), a female donor (having received transfusion or been pregnant) for a male recipient, and the use of non–T-cell depleted bone marrow. When these 3 factors were present, the probability of developing chronic GvHD was 55% at 3 years.53
Evolution of Cutaneous Chronic GvHD
Chronic GvHD is linked to both morbidity and mortality in patients undergoing transplantation. In the absence of any treatment, in 13 patients with disseminated chronic GvHD, 5 died and 6 of the 9 survivors had severe disability.54 Another series shows that mortality in chronic GvHD may reach 40%.51 Death is usually a consequence of infection, cachexia, or liver dysfunction.51 In fact, the risk of infection is higher in patients with chronic GvHD. The main factor associated with the occurrence of infections in BMT recipients after the sixth month following transplantation is chronic GvHD. This increased risk is due to several causes: the immunodeficiency associated with chronic GvHD (with CD4 leukocytopenia and hypogammaglobulinemia); the immunodeficiency induced by the immunosuppressive therapy that patients receive for GvHD; the mucosal atrophy with Sjögren syndrome that reduces lubrication; the cutaneous and mucosal erosions; and the diminished IgA level. The principal sites of infections include the ear, nose, and throat (34%), skin (20%), and blood (7%). In addition, of 114 infections from which the pathogen could be isolated, 42% were viral (mostly varicella zoster virus), 33% bacterial (pneumococcal and staphylococcal), and 23% fungal (Candida). Finally, BMT recipients have an increased risk of cutaneous malignant tumors, mainly oral squamous cell carcinoma (ratio of observed to expected cases, 11:1) and melanoma (ratio, 5:1).55
Chronic GvHD Associated With a Beneficial Effect
When grafting was performed in the context of leukemia therapy, the presence of GvHD was associated with a notably lower risk of leukemia relapse. Follow-up of patients who had received T-cell–depleted bone marrow demonstrated the almost total absence of GvHD but, in contrast, a considerably higher risk of leukemia relapse. In addition, if grafting was done between identical twins, the rate of leukemia relapse was higher than when the graft was from an HLA-identical family member. Finally, multivariate analyses of several series showed that the presence of chronic GvHD was the most significant factor correlated to a reduced risk of leukemia relapse.56 This antileukemic effect associated with chronic GvHD is even a function of the severity of GvHD. This beneficial effect is referred to as graft versus leukemia.
MECHANISMS OF SKIN LESIONS IN CHRONIC GvHD
Chronic GvHD Associated With "Antirecipient" T Cells
The role of donor T cells against the recipient's tissues has been well demonstrated. In a study of phenotypically HLA-identical BMT recipients, Tsoi et al57 found that grafted lymphocytes proliferated in response to host cells in two thirds of the patients with chronic GvHD vs only 9% without chronic GvHD. In another series, a high frequency of helper T cell precursors against the host was present in the peripheral blood of all patients with chronic GvHD but not in patients without chronic GvHD.58 Furthermore, antihost CTL lymphocytes were found in a skin biopsy specimen from a patient with chronic GvHD. These studies clearly demonstrate that T cells recognizing host-specific antigens are present in the blood and the skin of patients with chronic GvHD.
Autoreactivity Phenomena
Autoreactivity has been suggested by the demonstration in chronic GvHD of antibodies targeting cell lines of donor origin with hemolytic anemia, thrombocytopenia, antilymphocyte antibodies,48, 59 or antibodies targeting antigens common to host and donor (nucleus, nucleoli, smooth muscle, thyroid, and skin).48, 59 In addition, the functional studies of chronic GvHD described earlier do not exclude autoreactivity since analyses by Tsoi et al57 found that helper T cells reacting against donor cells were discovered in 7 of 22 patients with chronic GvHD vs 1 of 12 without chronic GvHD. These percentages were not statistically different, probably because of the small number of patients evaluated. In the same manner, in the study by Bunjes et al58 8% to 21% of the clones recognized the donor or donor and host. Therefore, these investigations indicate preponderant but not exclusive alloreactivity in human chronic GvHD. Finally, important studies in mice have revealed the presence of autoreactive clones in chronic murine GvHD.60
What conclusions can be drawn from all these data? It is difficult to answer since the models and the situations are quite different. Nevertheless, there is a strong tendency in mice suggesting that chronic GvHD is associated with the development of alloreactive and autoreactive clones. Since the major risk factor for chronic GvHD is previous acute GvHD and since acute GvHD can involve the thymus and induce clonal deletion abnormalities,61 it is tempting to hypothesize that the chronic GvHD autoreactive clones may arise as a consequence of prior thymic disease.
Effector Cells of Chronic GvHD
Chronic GvHD is characterized by a T-cell infiltrate without B or NK cells.62 Most immunohistochemical studies have shown that CD8+ lymphocytes predominate (Table 3). Only 2 studies showed dense CD4+ infiltrates.12, 22 A recent reverse transcription–polymerase chain reaction analysis of messenger RNA derived from skin biopsy specimens demonstrated the quasi-constant presence of interferon . These observations suggest that the infiltrate in chronic GvHD could be composed of T helper 1 cells.
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Table 3. Immunophenotype of Lymphoid Infiltrate in Chronic Graft-versus-Host Disease*
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Epidermal Cytokines and Inflammatory Phenomena
Tumor necrosis factor and IL-1 are constantly produced by keratinocytes in the lesional skin of patients with chronic GvHD.62 Thus, these 2 cytokines may be implicated in the inflammatory phenomena seen in chronic GvHD. In contrast, the expression of IL-8 was comparable with that of the controls, and this cytokine does not seem to be implicated in chronic GvHD lesions.
Keratinocytes as the Usual Target
In one study, T-cell phenotype, cytokine expression patterns, and cell adhesion molecule expression profiles (with the exception of VCAM-1) were similar in lichenoid GvHD and de novo sclerodermatous chronic GvHD.62 Therefore, sclerodermatous GvHD exhibited the same epidermal abnormalities as those seen in lichenoid GvHD, but to a lesser extent. These findings suggest that the sclerosis of sclerodermatous GvHD could be secondary to scarring of the same keratinocytic abnormalities as those seen in lichenoid GvHD. The observation that sclerosis is superficial in chronic GvHD and that the collagen produced is similar to that of scarring50 strengthens the hypothesis of a common initial mechanism followed in some individuals by a fibrosing evolution. Similarly, analysis of skin specimens obtained from areas of diffuse hyperpigmentation that may develop in genetically pigmented individuals after BMT has demonstrated features of postinflammatory hyperpigmentation,46 suggesting that melanoderma was secondary to keratinocyte death induced by GvHD and followed by intense postinflammatory hyperpigmentation. However, in contrast to these results, another study has suggested that melanocytes could be a direct target for lymphocytes in GvHD.
The Mechanism of Fibrosis
Ultrastructural analysis of lesional skin in chronic GvHD has shown the presence of active fibroblasts with a developed Golgi apparatus, numerous vesicles in the rough endoplasmic reticulum, and the presence of procollagen fibrils in contact with their cell membrane. Fibroblasts proliferate. Mastocytes have been considered by some to play a key role in the development of sclerosis. This role is supported by results of studies on mouse models characterized by generalized sclerosis in which mastocytes lose granules or disappear.63 Thus, these authors concluded that the mastocytes had been activated by a mediator produced by lymphocytes and secreted into the circulation. In turn, mastocyte secretion products would induce fibroblasts to synthesize collagen. This theory is in contradiction with the findings reported by De Clerck et al,64 who showed that the supernatants of autoreactive CD4+ clones derived from mice with chronic GvHD directly stimulated the production of collagen by fibroblasts. These observations must be interpreted cautiously because the presence of activated mastocytes has not been confirmed in other reports, particularly in humans.
TREATMENT
Evaluation of the Risk of GvHD Before Transplantation
Although the risk factors for acute and chronic GvHD have been demonstrated in cohort studies, several in vitro models predictive of acute GvHD have been developed: coculture of recipient's skin with sensitized donor lymphocytes, mixed epidermal cell–lymphocyte reaction, and measurement of the frequency of host-specific donor T-cell precursors secreting IL-2.65-66 The objective of these tests is to evaluate, prior to transplantation, the individual risk of GvHD and to attempt to adapt the prophylaxis to this risk. However, these assays are difficult to perform on a routine basis.
Prophylaxis of Acute GvHD
Preventive treatment is key. At present cyclosporine and methotrexate are used together, their combined efficacy better than each drug alone.52 Cyclosporine is given at a dosage of 2 to 5 mg/kg per day, with monitoring of drug levels in the blood, starting 1 day before grafting until the end of the sixth month. Methotrexate is given on days 1, 3, and 6; the day 11 injection can be omitted. This strategy lowers the incidence of acute GvHD by 15% to 40% but does not alter that of chronic GvHD. Other modalities have been proposed, including total lymphoid irradiation, administration of a methylprednisolone bolus, and the triple association of cyclosporine, methotrexate, and glucocorticoids.67 Ex vivo depletion of mature T cells from the bone marrow of the donor has been discontinued by most groups because of the major risks of nonengraftment and leukemia relapse. In addition, various approaches (sterile environment, intestinal decontamination, use of intravenous immunoglobulins, and antiviral therapy) are useful to prevent infections.
CURATIVE THERAPY
Acute GvHD
Treatment of moderate cutaneous acute GvHD primarily consists of high-dose corticosteroids (1-3 mg/kg per day), sometimes given as a bolus. Cutaneous hydration and antihistamines are commonly prescribed. Cyclosporine (3-5 mg/kg per day), cyclophosphamide, or antithymocyte globulins are given as second-line treatments. In the case of refractory GvHD, use of antibodies, anti–IL-2 receptors, anti–TNF-, or human IL-1 receptor antagonists has been suggested.68-69 Deferoxamine mesylate (50 mg/kg per day) was able to resolve cutaneous GvHD in 16 patients (89%) in a series of 18 cases.
Mortality attributable to grade IV GvHD is very high (80%-100%).4 Compared with classic toxic epidermal necrolysis, in which mortality is only 30%, the factors of poorer prognosis in grade IV GvHD are the increased risk of infection and the severe extracutaneous involvement. In addition, corticosteroids are not used in classic toxic epidermal necrolysis because their potential role in facilitating infection, hypercatabolism, and retardation of healing might contribute to a poorer outcome. Also, as mentioned earlier, some clinical pictures suggestive of grade IV GvHD are obviously drug-induced toxic epidermal necrolysis, complicating the treatment of patients. The administration of anti–IL-2 receptor antibodies, active against GvHD but without the disadvantages of corticosteroid therapy, might be a therapeutic hope. The results, to date anecdotal, appear equally promising for hepatic and BMTs (O.C., unpublished data, 1990). In addition, in grade IV GvHD, symptomatic treatments, including macromolecular infusions, skin cleansing, treatment of the mucosa, and a balanced diet, are needed.
Chronic GvHD
Lichenoid chronic GvHD is generally well controlled with a combination of corticosteroids and immunosuppressors. The recommended treatment is 1 mg/kg per day of oral prednisone in combination with cyclosporine (monitored by blood levels) for a period varying as a function of the disease severity (usually 9-12 months). Alternating cyclosporine (12 mg/kg per day) and corticosteroids (1 mg/kg per day) may be helpful in severe GvHD and/or sclerodermatous disease that is refractory to classic treatment.43 Cyclophosphamide, methotrexate, or azathioprine may be proposed if first-line therapy fails. The beneficial effect of high-dose thalidomide (200-800 mg/d) on chronic GvHD has been described in several case reports and small series but remains difficult to assess because of some missing details.70 In addition, only a few isolated case reports of severe sclerodermatous GvHD treated with thalidomide have been published, and even then they were contradictory. Nevertheless, a recent study showed a favorable response in about one third of the patients with cutaneous and/or mucosal signs of chronic GvHD that was resistant to corticosteroid therapy.71 In all cases, clinical and electromyographical follow-up of patients is mandatory.
Phototherapy can play a role in the treatment of cutaneous chronic GvHD. Several isolated case reports and subsequent open trials of psoralen–UV-A (PUVA) therapy have described patients with generalized lichenoid chronic GvHD incompletely controlled by systemic treatments.72 Despite the efficacy of PUVA therapy in more than 50% of the patients studied, the small number of participants in each treatment group did not allow a definitive conclusion to be drawn. In addition to the effect on the skin, PUVA therapy can also attenuate lesions on the oral mucosa and thereby allow tapering of immunosuppressive regimens. In contrast, extracutaneous chronic GvHD, especially hepatic, obtained no benefit from PUVA therapy. The efficacy of PUVA therapy in sclerodermatous chronic GvHD is much more controversial. In lichenoid GvHD, in which the response to PUVA therapy is poor, UV-B or TL01 irradiation can be prescribed. Many recent case reports and small series have described the efficacy of extracorporeal photochemotherapy in cutaneous as well as systemic chronic GvHD, and this treatment may well be a promising alternative, maybe as a second-line treatment. Finally, the use of D-penicillamine, total lymphoid irradiation, plasma exchanges, ketotifen, and intravenous immunoglobulins is still of poorly documented efficacy.
Among the topical treatments available, topical cyclosporine used in solution as a mouthwash or applied with a finger73 can be useful in disabling oral erosive lichen planus. A kinetic study of plasma levels conducted in patients not undergoing transplantation with genital and/or oral erosive lichen planus showed almost no systemic diffusion of cyclosporine. However, therapeutic results have been variable, with relapse possible under treatment. Local high-potency corticosteroids are useful to treat phimosis. We have also prescribed local corticosteroids to treat patients with localized chronic GvHD, with sometimes very satisfactory responses. Finally, prevention of infections, physical therapy, a high-protein diet, the use of artificial tears and sunscreen, and cutaneous hydration are warranted.
Acute complications of therapy are not described herein. However, a higher occurrence of secondary cancers, especially squamous cell carcinoma of the skin and mouth,74 cutaneous Bowen disease, and melanoma have been demonstrated in these patients. Because of these findings and the intrinsic risks of PUVA therapy, this regimen should be reevaluated and closely monitored.75
CONCLUSIONS
Graft-versus-host disease is a frequent complication of transplantation and is responsible for the death of 12% to 20% of graft recipients. It causes more or less intense and prolonged inflammatory tissue lesions and a marked immunodeficiency, usually in association with a graft-versus-leukemia effect. Future research should be directed to obtain a better knowledge of the mechanisms involved in GvHD, especially the chronic form, devise better prophylaxis, and analyze the contributions of new donor sources. Because skin represents a highly informative and strongly implicated organ in GvHD, the continuation of biological and clinical dermatological studies is essential.
AUTHOR INFORMATION
Accepted for publication November 20, 1997.
We wish to thank Edgardo Carosella, MD, Eliane Gluckman, MD, and Anne Janin, MD, for their important contributions and Veronique Leblond, MD, for helpful criticism of the manuscript.
Reprints not available from the authors.
From the Department of Dermatology, Hôpital Tenon (Dr Aractingi), and the Department of Internal Medicine, Hôpital Pitié-Salpêtrière (Dr Chosidow), Paris, France.
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