The changing face of graft-versus-host disease

Despite advances in the procedure and posttransplantation immunosuppressive therapy, more than half of allogeneic hematopoietic stem cell transplant (HSCT) recipients develop graft-versus-host disease (GVHD), which remains a major cause of morbidity and mortality. Modern HSCT protocols have resulted in substantial alterations in the timing and relative incidences of acute and chronic GVHD, making traditional classification schemes obsolete. This article reviews major changes in HSCT during the past decade, evolving concepts of acute and chronic GVHD (including new diagnostic criteria) and the expanding spectrum of cutaneous GVHD. It focuses on observations that have led to a better delineation of the full constellation of skin findings in chronic cutaneous GVHD, including lichen sclerosus, morpheaform lesions, and eosinophilic fasciitis. Recent insights into pathogenesis of GVHD, lessons from GVHD arising in settings outside HSCT, and therapeutic advances also are highlighted.     

Efficacy of Acitretin for Porokeratosis in a Child with Chronic Cutaneous Graft Versus Host Disease

Abstract: Porokeratosis is a rare disorder of epidermal keratinization that is regarded as a precancerous. Recipients of hematopoietic stem cell transplantation (HSCT) have a greater risk of skin cancer; chronic graft versus host disease (GVHD) is an additional risk factor. A 16‐year‐old boy who had received HSCT for acute myelogenous leukemia was referred to us for sclerodermoid chronic cutaneous GVHD. Two years later, he developed disseminated porokeratosis with a few atypical lesions. Despite cryotherapy, numerous lesions of porokeratosis recurred rapidly. Acitretin resulted in good clinical response and reduced the rate of onset of new lesions.     

Fotoféresis extracorpórea en enfermedad injerto contra huésped en una población pediátrica

BackgroundExtracorporeal photopheresis (ECP) is an immunomodulatory therapy used to treat graft-vs-host disease (GVHD) in adults and children. Few studies have examined its use in children.ObjectiveTo describe demographic characteristics, clinical response, adverse effects, and outcomes in a series of pediatric patients with acute or chronic GVHD treated with ECP.Material and methodsWe included all pediatric patients with acute or chronic GVHD treated with ECP by the Dermatology Department of Hospital Italiano de Buenos Aires between January 2012 and December 2018. We used the UVAR-XTS™ system (2 patients) and the CELLEX system (7 patients). Patients with acute GVHD received 2 sessions a week and were reassessed at 1 month, while those with chronic GVHD received 2 sessions every 2 weeks and were reassessed at 3 months. Treatment duration in both scenarios varied according to response.ResultsWe evaluated 9 pediatric patients with corticosteroid-refractory, -dependent, and/or -resistant GVHD treated with ECP. Seven responded to treatment and 2 did not. Response was complete in 1 of the 9 patients with skin involvement and partial in 7. Complete response rates for the other sites of involvement were 60% (3/5) for the liver, 50% (1/2) for the gastrointestinal system, and 80% (4/5) for mucous membranes. Two patients died during the study period.ConclusionECP is a good treatment option for pediatric patients with acute or chronic GVHD.     

Clinical manifestations of cutaneous graft-versus-host disease after allogeneic haematopoietic cell transplantation: long-term follow-up results in a single Turkish centre

The aim of this study was to evaluate the clinical manifestations of cutaneous graft-versus-host disease (GVHD) developed after allogeneic haematopoietic cell transplantation. In all, 67 patients were evaluated: 49 patients developed acute GVHD, 17 patients developed de novo chronic GVHD and 29 developed secondary chronic (15 limited, 14 progressive) GVHD following acute cutaneous GVHD. Of the 46 patients with chronic GVHD, lichenoid lesions were observed in 32 and sclerodermoid lesions were observed in 12. In four patients with sclerodermoid cutaneous GVHD, these lesions occurred after a lichenoid phase. Oral lesions were present in 61% of the patients and six of them had only oral mucosal involvement without any skin lesions. Nail lesions were observed in 31% of the patients. During the follow-up period 15 patients with GVHD died and in 7 of them the cause of death was related to chronic GVHD. In conclusion, GVHD has a wide spectrum of cutaneous manifestations, which can be used as an important tool for the early diagnosis of the disease.     

Hyperacute graft-versus-host disease: histological assessment of skin biopsy specimens from 19 cases

Background. Hyperacute graft‐versus‐host disease (GVHD) is defined as GVHD occurring within 14 days after haematopoietic stem‐cell transplantation (HSCT). Aim. To evaluate the usefulness of skin biopsy in assessing hyperacute GVHD. Methods. We examined 19 cases of hyperacute GVHD from a total of 134 consecutive HSCT cases at Shinshu University Hospital between 1999 and 2008. Results. Exanthemas were seen in all patients, which were mainly disseminated maculopapular erythemas, commonly present in acute GVHD as well. Most patients presented with a high fever, and a few had mild hepatic dysfunction and/or diarrhoea. The clinical grade of GVHD was 1–2 in all patients; there were no cases of clinical grades 3–4. The histological findings of skin biopsy were divided into three groups: (i) eight had grade 2 changes, characterized by diffuse vacuolization of basal cells, with dyskeratotic bodies; (ii) five had grade 1 changes, characterized by vacuolization of epidermal basal cells (all these cases were diagnosed as acute GVHD with grade 2 histological changes at subsequent biopsy); (iii) and six had no significant changes (these cases were also diagnosed as acute GVHD with grade 2 (four cases) or grade 1 (one case) histological changes on the second biopsy). Many of the patients developed acute and later chronic GVHD. Conclusion. Skin biopsy should be considered when eruption develops after HSCT even before engraftment, especially when other organ involvement is minimal. If the first skin biopsy is inconclusive, follow‐up biopsy within a short time is helpful in the diagnosis of hyperacute GVHD.     

Clinical significance of skin biopsies in the diagnosis and management of graft-vs-host disease in early postallogeneic bone marrow transplantation

OBJECTIVE: To determine the value of skin biopsies in the management of suspected graft-vs-host disease (GVHD) within 30 days of allogeneic bone marrow transplantation (BMT). DESIGN: Retrospective study based on review of a BMT database. SETTING: Leukemia/BMT ward of a tertiary care, university teaching hospital. PATIENTS: One hundred and eighty-seven consecutive patients who received allogeneic BMT between January 1, 1994, and June 30, 1997, at Vancouver General Hospital, Vancouver, British Columbia. MAIN OUTCOME MEASURES: (1) Skin biopsy frequency for patients with rashes suggestive of acute GVHD; (2) clinical significance of skin biopsy in the management of patients with suspected acute GVHD after BMT; (3) relationship between severity of clinical GVHD and the likelihood to receive GVHD therapy; and (4) relationship between biopsy status or biopsy result and outcome of BMT (acute and chronic GVHD, transplant-related mortality, and overall and event-free survival). RESULTS: During the early post-BMT period (<30 days after BMT), 88 patients had rashes suggestive of acute GVHD; of these, 51 (58%) underwent skin biopsy to confirm the diagnosis. Skin biopsies were performed more often for higher clinical stages of cutaneous GVHD. There was no significant difference between the patients with positive biopsy findings and those with negative findings, either in the clinical severity of acute GVHD or in likelihood to receive treatment for GVHD. Most (85%) of the patients who underwent biopsies and received GVHD therapy had treatment initiated before skin biopsies were performed or before the results were available. The higher the clinical grade of overall acute GVHD, the more likely it was that the patients were treated for GVHD (P<.001). The outcome of BMT was not influenced by the skin biopsy status or biopsy result. CONCLUSIONS: The biopsy findings correlated poorly with the clinical severity of skin rash suggestive of acute GVHD soon after BMT. The decision to treat suspected acute GVHD depended not on skin biopsy findings but rather on clinical severity of acute GVHD. In this regard, skin biopsy has a limited role in the management of patients early after allogeneic BMT.     

Isomorphic cutaneous graft-versus-host disease reaction after ultraviolet exposure: clinical, histological and direct immunofluorescence studies of four allo-transplanted patients

Background  Acute and chronic graft-versus-host disease (GVHD) continues to be a major limitation to successful haematopoietic stem cell transplantation. If experimental studies and clinical observations could partially elucidate the pathophysiology of acute GVHD, the biology of chronic GVHD is still much less well understood.
Objectives  The aim of this study is to describe a peculiar photoinduced rash which triggered acute and then chronic lesions of GVHD in four allogenic haematopoietic-transplated patients and discuss the possible aetiology and treatment.
Patients/methods  Four patients, two children and two adults affected by either mild or severe chronic GVHD, developed an erythematous rash on sun- or narrow-band ultraviolet B-exposed area, which triggered the onset of acute lesions of GVHD. Any of the patients presented neither a history of photosensitivity nor circulating autoantibodies nor urinary/fecal porphyrine.
Results  The histopathologic findings were characterized by an interface dermatitis with sparse perivascular infiltrate of lymphocytes and scattered necrotic keratinocytes, especially in the upper part of epidermis. Direct immunofluorescence studies excluded lupus-like pattern, revealing nests of fluorescent bodies at the dermal–epidermal junction and in papillary dermis.
Conclusions  This peculiar isomorphic reaction of cutaneous GVHD after sun or narrow-band ultraviolet B exposures is described, and the possible mechanism involved is discussed. It may represent an interesting model of progression of chronic GVHD, starting with an acute stage and ending up with chronic clinical and histological findings, especially considering that there is no animal model that fully replicates all of the features of chronic GVHD in humans.

Conflicts of interest

None declared.     

Photo‐induced graft‐versus‐host disease

Overlap chronic graft‐versus‐host disease (GVHD) associates both features of acute and chronic GVHD. Trigger factors for chronic GVHD are unclear. We describe two patients who received allogenic haematopoietic stem‐cell transplantation, and who later developed overlap chronic GVHD after sun exposure. Available data from in vivo investigations suggest ultraviolet B radiation (UVB) has a beneficial effect on acute and chronic GVHD. The role of sun irradiation as a trigger for isomorphic cutaneous GVHD has been rarely reported in the literature. Herein, we demonstrate for the first time, using repetitive broadband phototesting, that UVB triggers chronic GVHD.     

Eczematoid graft-vs-host disease: a novel form of chronic cutaneous graft-vs-host disease and its response to psoralen UV-A therapy

BACKGROUND: Chronic cutaneous graft-vs-host disease (GVHD) is generally classified by whether lesions have a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the features of dermatomyositis and lupus erythematosus. Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed. OBSERVATIONS: We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5 months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk factors for chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the histologic features of GVHD coexisting with the changes of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six patients also received psoralen-UV-A. Four patients achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia. CONCLUSIONS: The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that we named eczematoid GVHD. Eczematoid GVHD is an aggressive, chronic dermatosis that requires substantial immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be transmitted to an individual from a hematopoietic stem cell transplant, none of the donors in this series gave a history of an atopic disorder. Therefore, other factors must be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic graft-vs-host activity.     

Cutaneous graft-versus-host reaction: prognostic features seen by light microscopy

Acute graft-versus-host disease (GVHD) is a severe complication of bone marrow transplantation. The diagnosis may be made and its course followed by serial skin biopsies. The degree of epidermal change has been used as a guideline in grading each biopsy, but great variation may be found within each grade, especially grade 2 (basal cell vacuolization and dyskeratosis). To find a histologic parameter that is prognostic of more severe acute GVHD, we examined retrospectively the serial biopsies of 54 patients. When we studied early cutaneous graft-versus-host reaction (GVHR), represented by the grade 2 biopsies, the number of dermal and epidermal mononuclear inflammatory cells correlated positively with the probability of developing more severe acute GVHD. In addition, the patients who had more severe acute GVHD tended to have an earlier appearance of cutaneous histologic changes. None of the other histologic parameters examined in these grade 2 biopsies were found to be predictive of GVHD progression. In addition, no histopathologic parameters in these grade 2 biopsies were predictive of the subsequent development of chronic GVHD.     

Analysis of risk factors for acute cutaneous graft-versus-host disease after allogeneic stem cell transplantation

BACKGROUND: Although skin is typically the first site of involvement of acute graft-versus-host disease (GVHD), most standard recommended staging and grading criteria allow enrolment of patients with involvement of GVHD target organs other than the skin in studies analysing risk factors for acute GVHD after stem cell transplantation (SCT). OBJECTIVES: To determine the risk factors for developing histologically confirmed acute cutaneous GVHD in patients who underwent allogeneic SCT for different haematological disorders. METHODS: This retrospective study was based on review of clinical files and databases from 300 consecutive patients with several haematological disorders who received allogeneic SCT between 1 January 1984 and 31 December 1999 at Hospital Universitario de la Princesa, Madrid, Spain. Variables evaluated included diagnosis of haematological disorder, age and gender (donor and recipient), HLA matching, female donor to male recipient, donor and recipient viral serology (cytomegalovirus), conditioning regimen, GVHD prophylaxis, blood counts at day of engraftment, mortality, cause of death, and survival at 100 days, 5 years and 10 years following SCT. RESULTS: In multivariate analysis, risk factors for acute cutaneous GVHD were type of haematological disease (P = 0.006), HLA disparity (P = 0.006), number of transplants per patient (P = 0.017), conditioning regimen (P = 0.001), and GVHD prophylaxis (P = 0.025). Survival rates did not differ significantly for cases and controls. CONCLUSIONS: Risk factors for acute cutaneous GVHD were a diagnosis of chronic myeloid leukaemia, HLA disparity, receipt of more than one SCT, conditioning regimens including total body irradiation, and GVHD prophylaxis regimens other than ciclosporin plus methotrexate. Other common risk factors for acute GVHD without specific target organ involvement showed no significant association with the risk for developing acute GVHD affecting the skin as primary target organ.     

Late appearance of acute graft-vs-host disease after suspending or tapering immunosuppressive drugs

BACKGROUND: Graft-vs-host disease (GVHD) is divided into acute and chronic phases based on time and clinical and histological features. The criterion of 100 days after transplantation for separating acute GVHD from chronic GVHD has been challenged on the following points: (1) the lichenoid rash of chronic GVHD may be observed as early as day 31 and acute GVHD may persist after day 100 in some cases, and (2) specific histological features do not consistently separate acute from chronic GVHD defined as the number of days after transplantation. However, the appearance of acute cutaneous GVHD after day 100 is not well established. OBSERVATIONS: Three patients developed a rash with clinical and histological features of acute GVHD between days 153 and 192 after allogeneic bone marrow transplantation or peripheral blood stem cell transplantation. In all patients, the late flare of acute GVHD occurred after tapering or suspending the immunosuppressive regimen with cyclosporine or corticosteroids, and was accompanied by stigmata of chronic GVHD in other target organs. CONCLUSIONS: The rash of acute GVHD may be observed as late as 192 days after transplantation, especially after tapering or suspending the immunosuppressive drugs, and should be considered in the differential diagnosis of late erythematous eruptions after transplantation.     

Hematopoietic stem cell transplantation in advanced cutaneous T‐cell lymphoma

We retrospectively reviewed data pertaining to five patients with cutaneous T‐cell lymphoma (CTCL) who had received hematopoietic stem cell transplantation (HSCT) between 2004 and 2015 at Kurume University Hospital, along with their clinical data until March 2016. For patients with advanced CTCL eligible for HSCT, autologous HSCT was performed when they responded well to chemotherapy, and allogeneic HSCT was selected for patients with advanced mycosis fungoides (MF)/Sézary syndrome (SS) and CTCL other than MF/SS with poor chemosensitivity. Two patients (primary cutaneous anaplastic large cell lymphoma and primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T‐cell lymphoma) who responded well to chemotherapy received autologous HSCT: one patient was alive in partial remission and the other died due to therapy‐related acute myeloid leukemia without disease relapse. In the remaining three patients with MF or SS, allogeneic HSCT was performed. Although one patient with MF died due to disease progression, the remaining two patients were alive in complete remission. Although there were two deaths in this study, the outcomes were considered satisfactory.     

A Case of Eczematoid Graft‐Versus‐Host Disease

A 13‐year‐old boy underwent allogeneic hematopoietic stem cell transplantation (HSCT) for underlying acute lymphoblastic leukemia and achieved neutrophil engraftment 28 days after HSCT. He developed ichthyosis 6 weeks after HSCT and then keratotic follicular papules, palmoplantar keratoderma, and a seborrheic dermatitis–like eruption 18 weeks after HSCT. From skin biopsies he was diagnosed with eczematoid graft‐versus host disease (GVHD), which showed spongiosis with scattered necrotic keratinocytes. He responded to oral and topical steroids and an increase in cyclosporine dose. Although uncommon, eczematoid GVHD must be considered in children who have undergone HSCT and then develop an atypical eczematous eruption, especially in the absence of a history of atopy.     

Clinicopathologic characteristics of cutaneous chronic graft-versus-host diseases: a retrospective study in Korean patients

Background Chronic graft‐versus‐host disease (cGVHD) is a major complication in long‐term survivors of hematopoietic stem cell transplantation (HSCT). Cutaneous manifestations are frequently the presenting features; therefore, the dermatologist needs to be aware of the wide spectrum of cutaneous cGVHD. Methods We retrospectively evaluated patients’ characteristics, clinical, and histological features of cutaneous cGVHD and analyzed factors influencing the severity of cutaneous cGVHD in 100 Korean HSCT recipients between January 1, 1995, and December 31, 2007. Results Clinical manifestations of cutaneous cGVHD mainly presented as lichenoid (60.0%), sclerodermoid (12.0%), or erythematous maculopapular (22.0%) patterns. Other less common findings included xerosis, dyspigmentation, acquired ichthyosis, eczema, exfoliative dermatitis, alopecia, erythema multiforme‐like or keratosis pilaris‐like eruption. Among 100 patients, 46 patients were investigated for nail involvement, and 29 (63.0%) of them were accompanied with nail abnormalities. Histologically, characteristic lichenoid lesions were observed in 53%, sclerodermoid in 9%, and acute/chronic overlap syndrome in 28% of patients. We also discovered that HSCT from female donors to male recipients increased the severity of cutaneous cGVHD. Conclusions We report a large study about cutaneous cGVHD in Asian patients. Cutaneous cGVHD presented with a wide spectrum of clinical and histological manifestations.     

Cutaneous immunological studies in diagnosis of acute graft-versus-host disease

A comparative study of the healthy skin of patients who had undergone bone marrow grafting and not developed graft-versus-host disease (GVHD) and of patients with cutaneous lesions of acute GVHD has been carried out. The aim of this study was to assess the diagnostic value of cutaneous immunopathology in the diagnosis of acute GVHD. A double-labelling immunofluorescence technique was used with a panel of monoclonal antibodies. The results showed a lack of specificity for GVHD in the distribution of Langerhans cells, but confirmed the diagnostic value of HLA-DR staining of epidermal keratinocytes. Cellular polymorphism of the T cell infiltrate in the dermis was observed (T helpers 40% and T suppressors 20%). The expression of the 55-57 Kd keratin polypeptide and of bullous pemphigoid antigen showed modification during acute GVHD while that of pemphigus antigen remained unchanged.     

Immunohistochemistry of cutaneous graft-versus-host disease after allogeneic bone marrow transplantation

Graft-versus-host disease (GVHD) is an immunologically mediated disease occurring most frequently after allogeneic bone marrow transplantation. The aim of this study was to evaluate the contribution of immunohistochemistry in the diagnosis of cutaneous GVHD. Patients transplanted for either leukemia or beta-thalassemia were included in the study. Skin lesions of acute and chronic GVHD were examined both by direct immunofluorescence to detect immunoglobulin deposits and by an avidin-biotin-peroxidase complex technique to evaluate the inflammatory cell infiltrate. Epidermal and dermal fluorescent bodies (IgG and IgM) were frequently found in both acute and chronic GVHD. Most of the infiltrating cells were CD3+ T lymphocytes, with CD8+ cells representing the major cell population invading the epidermis both in acute GVHD and in chronic lichenoid GVHD. A small proportion of the dermal cells were CD14+ macrophages; no B cells were detected. HLA-DR, but not HLA-DQ antigens, were variably expressed by keratinocytes in all cases of acute GVHD and in chronic lichenoid GVHD. KL-1, a monoclonal antikeratin antibody specific for the 56.5 KD acidic polypeptide usually present in suprabasal keratinocytes, stained all epidermal layers, including the basal layer. Langerhans cells were dramatically reduced in number in the epidermis of both acute and chronic lichenoid GVHD. It is concluded that immunohistologic analysis may be supportive in the diagnosis of acute and early chronic lichenoid cutaneous GVHD.