PUVA therapy for chronic cutaneous graft-vs-host disease

Chronic graft-vs-host disease (GVHD) is an immunologic disorder frequently occurring as a late sequelae of allogeneic bone marrow transplantation and characterized in the skin with lichenoid or sclerodermoid lesions. Systemic immunosuppressive agents such as corticosteroids or cyclosporine are usually required to control the disease. Therapy with psoralen and UVA (PUVA) has recently been shown to be effective for skin and oral mucosa in a few cases of GVHD. We present our experience with PUVA in six patients, five with lichenoid and one with sclerodermoid GVHD. None of these patients had significant systemic involvement. All five patients with lichenoid GVHD showed clinical improvement after PUVA therapy. Three of these patients had complete clearance of skin lesions. Clinical clearance of the disease was accompanied by microscopic clearance. The patient with sclerodermoid GVHD did not respond to therapy. No significant complications or exacerbation of systemic disease occurred. We confirm that PUVA is an effective and safe therapy for the cutaneous manifestations of lichenoid chronic GVHD. We postulate that PUVA therapy clears chronic lichenoid GVHD by selective cytotoxicity for the activated lymphoid cells in the inflammatory infiltrate.     

Graft versus host disease

Graft versus host disease (GVHD) occurs in 50% to 70% of patients receiving bone marrow transplants. It can also develop in immunosuppressed patients with malignancies who receive nonirradiated blood transfusions. Most work indicates that the primary mechanism of GVHD is cell-mediated. It is likely that humoral factors are involved as well. Cutaneous manifestations are the earliest and most frequent sign of the disease. These may be morbilliform, scarlatiniform, lichenoid, or sclerodermoid lesions. In acute GVHD, the skin, gastrointestinal tract, and liver are commonly affected. In chronic GVHD, findings similar to collagen vascular disorders are present. A skin biopsy establishes the diagnosis.     

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.     

Nailfold capillary abnormalities are prevalent in sclerodermoid graft‐versus‐host disease and readily detected with dermatoscopy

Background Well‐recognized videocapillaroscopic patterns have been described in systemic sclerosis (SS). However, no studies have described the capillary abnormalities of sclerodermoid chronic graft‐versus‐host disease (Scl GVHD) developed after allogeneic haematopoietic stem cell transplantation (allo‐HSCT). Objectives The aims of this study were to find the characteristics of nailfold capillary changes in Scl GVHD after allo‐HSCT. Patients and methods Eighteen patients affected by Scl GVHD and a control group of 15 patients with lichenoid GVHD were evaluated. Duration and type of sclerodermoid GVHD, Raynaud phenomenon (RP), dysphagia, joint contractures, antinuclear antibodies (ANA), anti‐Scl‐70 and anticentromere (ACA) antibodies were investigated parameters. A nailfold capillary examination using a standard dermatoscope was performed on all fingers of each subject. Results Twelve patients were male and six were female with a mean age of 37 ± 11·6 years. Joint retractions and dysphagia developed in 27·8% and 38·9% of the patients, respectively. Three (16·7%) patients had RP. Autoimmune markers like anti‐Scl‐70 and ACA were negative in all. Capillaroscopy was abnormal in 15 patients with Scl GVHD. A regular disposition of the capillary loops along with avascular whitish linear areas at the level of the last row, neovascularization with reticular pattern, capillary disorganization, haemorrhages, enlarged capillaries and avascular areas were the main features. No capillary abnormalities were observed in patients with lichenoid GVHD. There was no statistically significant correlation between ANA positivity, RP, joint retractions, dysphagia, extensiveness of Scl GVHD, duration of sclerodermoid lesions and nailfold capillaroscopy analysis. Conclusions This study shows the identification of distinct nailfold capillaroscopy patterns in patients with Scl GVHD but it does not confer special risk for any other specific clinical symptoms of the disease.     

Lichen sclerosus and eosinophilic fasciitis as manifestations of chronic graft-versus-host disease: expanding the sclerodermoid spectrum

Chronic cutaneous graft-versus-host disease (GVHD) is classically divided into two major clinical categories--lichenoid and sclerodermoid. Although diffuse areas of sclerosis as in scleroderma characterize the more advanced stages of the sclerodermoid form, the initial circumscribed plaques would be more correctly described as morpheaform. Eosinophilic fasciitis (EF) (a fibrosing disorder related to deep morphea) and lichen sclerosus (LS) have also been reported as manifestations of sclerodermoid GVHD. However, these two presentations of GVHD have not been emphasized in the dermatologic literature. We describe 6 patients, all of whom developed LS and two of whom also developed EF in the context of chronic GVHD. Each patient presented clinically with hypopigmented plaques that exhibited wrinkling, scaling, and follicular plugging. These lesions demonstrated the classic histologic features of LS including epidermal atrophy; a subepidermal zone of pale-staining, homogenized collagen; and a bandlike lymphocytic infiltrate. Although all patients eventually developed morpheaform and/or sclerodermoid GVHD, LS was a prominent part of the initial presentation of chronic cutaneous GVHD in every case. The LS lesions tended to occur on the neck and upper to mid aspect of the trunk, whereas morpheaform lesions favored the lower aspect of the trunk. EF involved the extremities (sparing the hands and feet), and was characterized clinically by an acute onset of pain and edema followed by induration with a rippled appearance. This case series serves to expand the spectrum of sclerodermoid GVHD, with LS as the most superficial and EF as its deepest manifestation.     

Cutaneous graft-versus-host disease: a guide for the dermatologist

Graft-versus-host disease (GVHD) is defined by the aggregation of clinical and pathological manifestations in a recipient of allogeneic stem cells or bone marrow transplantation in which specific immunological as well as nonspecific phenomena lead to characteristic features. GVHD is one of the major complications after hematopoietic stem cell transplantations and responsible for posttherapeutic morbidity, mortality and decrease in quality of life of those patients. GVHD is critically induced and maintained by donor immunocompetent cells that particularly attack epithelia of fast proliferating tissues such as those from the liver, gastrointestinal tract and skin. On the basis of the time of presentation, cutaneous GVHD has been originally divided into an acute and chronic disease. The latter has traditionally been further subclassified into a more epithelial or lichenoid and a predominantly dermal or sclerodermoid form. With respect to the growing importance of this therapeutic procedure and increasing numbers of outpatients presenting with chronic GVHD, this article summarizes the updated knowledge on this disease focused for the dermatologist, and additionally it emphasizes the recent consensus documents on the various aspects of chronic GVHD of the National Institute of Health.     

Chronic cutaneous sclerodermoid graft-versus-host disease: evaluation by 20-MHz sonography

BACKGROUND: Chronic graft-versus-host disease (GVHD) is an immunological disorder frequently occurring as a late consequence of allogeneic bone marrow transplantation. Two variants, cutaneous lichenoid and sclerodermoid, have been described, based on clinical and histopathological examinations. It is, however, difficult to determine non-invasively the degree of cutaneous GVHD in vivo. Ultrasonographic methods have recently provided us with the means for objective and non-invasive monitoring of the dynamics of many chronic skin diseases. AIM, PATIENTS AND METHODS: In five patients with chronic cutaneous sclerodermoid GVHD skin thickness was measured with a 20-MHz B-mode ultrasound scanner (DUB 20S, taberna pro medicum, Lüneburg, Germany) in a clinically well-defined target skin lesion. Additionally cutaneous GVHD was assessed histologically before and after treatment. RESULTS: In all patients before treatment the corium of sclerotic skin was thicker than the corresponding areas of healthy skin. The skin thickness was increased from 45% to 83%. In the subcutaneous tissue proper echo-rich reflexes were prominent, representing the correlate of subcutaneous fibrotic trabeculae. In all patients ultrasonographic evidence of regression was shown (decrease of skin thickness by 18-83%). Moreover, it was demonstrated that quantitative assessment of skin thickness is feasible. CONCLUSIONS: In this paper we describe the detailed sonographic features of cutaneous sclerodermoid GVHD for the first time. As the method is simple and non-invasive, repeated examinations are possible. This provides the basis for monitoring treatment effects and efficient follow-up in these chronically progressive clinical conditions after bone marrow transplantation.     

Bullous scleroderma-like changes in chronic graft-versus-host disease

Cutaneous graft-versus-host disease (GVHD) is the most common clinical setting for GVHD after bone marrow transplantation. Chronic cutaneous GVHD is categorized according to the type of skin lesions into lichenoid and sclerodermoid variants, but bullous scleroderma-like changes are exceptional. Recently, we studied a patient with these alterations. This is the second case described in the literature.     

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.     

Dermatologic Treatment of Cutaneous Graft Versus Host Disease

Cutaneous involvement in graft versus host disease (GVHD) after allogeneic hematopoietic cell transplant can be separated into acute GVHD (aGVHD), lichenoid chronic GVHD (cGVHD) and sclerodermatous cGVHD. It seems clear that these syndromes result from different mechanisms and entail different treatment approaches. Standard treatment of cutaneous aGVHD involves the intensification of immunosuppressive therapy with adequate topical supportive management. In skin-limited disease, phototherapy has shown promising results. In cutaneous cGVHD, the combination of corticosteroids and cyclosporine (ciclosporin) is the recommended therapy, and other immunosuppressants may be added depending on whether lichenoid or sclerodermatous lesions are present. High response rates to phototherapy have been found in lichenoid disease, while sclerodermatous disease responds better to etretinate or extracorporeal photochemotherapy. Localized cutaneous cGVHD may be treated with topical corticosteroids alone. Few reports on the effect of treatments in GVHD clearly describe the cutaneous involvement and the influence of the treatment on the skin. Therefore, dermatologists should be deeply involved in the diagnosis and treatment of GVHD, and good dermatologic grading systems should be developed. Theses changes will increase our knowledge of cutaneous GVHD, and relevant data in the evaluation of the effect of therapy in the disease will be obtained.     

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.     

Chronic graft-versus-host disease: clinical presentation of multiple lesions of lichenoid and atrophic pattern

Graft-versus-host disease is observed mainly in recipients of hematopoietic cell transplantation and is expressed by cutaneous or systemic signals and symptoms. Graft-versus-host disease is clinically classified as acute or chronic. Chronic Graft-versus-host disease occurs in up to 70% of hematopoietic cell transplanted patients and its clinical manifestations have important impact on morbidity and quality of life. The authors report an expressive cutaneous, oral and adnexal involvement in a patient with chronic Graft-versus-host disease with multiple lesions of lichenoid and atrophic pattern.     

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.     

Histochemical and ultrastructural study of diffuse melanoderma after bone marrow transplantation

Summary Hyperpigmentation is a well-recognized feature of cutaneous graft-versus-host disease (GVHU). and is usually restricted to sites where lichenoid or sclerodermiform lesions have occurred. Since 1975, two of 745 patients treated by allogeneic bone marrow transplantation in our institution have developed diffuse melanoderma which differed considerably from the classic presentations. They both developed acute GVHD. then lichen planus-like chronic lesions and diffuse melanoderma. Histology of biopsies of the pigmented skin showed intense pigment deposition in the basal and suprabasal layers, and in dermal macrophages. On split-dopa, melanocyte counts were 98 and 93 per Held, respectively. Electron microscopy showed melanocytes protruding into the dermis, and dark melanosomes in all epidermal layers and in macrophages. These findings were suggestive of post-inflammatory hyperpigmentation. In bone marrow recipients, de nova melanoderma is a rare event which could represent a feature of cutaneous GVHD in pigmented subjects.     

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.     

Chronic cutaneous graft-versus-host disease simulating hypertrophic lupus erythematosus--a case report of a new morphologic variant of graft-versus-host disease

The spectrum of clinical and histopathologic features associated with chronic graft-versus-host disease (GVHD) is broad, with recognized variants simulating scleroderma, lichen sclerosus, eosinophilic fasciitis, and de novo diffuse melanoderma. We report a case of a patient with multiple myeloma who presented approximately 1 year after his allogeneic hematopoietic stem cell transplantation with lesions of chronic lichenoid GVHD that harbored features of hypertrophic lupus erythematosus (LE) and that was initially mistaken for a superficial well-differentiated squamous cell carcinoma (SCC). However, in 4 years of follow-up, the patient failed to develop any evidence of cutaneous or systemic LE, actinic damage, or SCC, and the lesions cleared with topical and systemic treatments appropriate for chronic GVHD. For proper interpretation of the histologic findings of GVHD, it is important for the dermatopathologist to be aware of unusual manifestations. Knowledge of the occurrence of hypertrophic LE and familiarity with its histologic features is also important to avoid an erroneous diagnosis of SCC in immunosuppressed patients.     

硬皮病样皮肤移植物抗宿主病24例临床特征分析

目的:分析异基因造血干细胞移植后硬皮病样皮肤移植物抗宿主病（GVHD）的临床特征和危险因素。方法:回顾2014—2019年间就诊于北京大学人民医院皮肤科硬皮病样皮肤GVHD患者24例的临床资料,分析临床特征、治疗、预后及发展为硬皮病样皮肤GVHD的可能因素。结果:24例硬皮病样皮肤GVHD患者中男11例,女13例,年龄...     

Lichenoid graft vs. host disease following liver transplantation

BACKGROUND: Graft vs. host disease (GVHD) is a common complication of bone marrow transplantation (BMT) but is rarely seen after solid organ transplantation. METHODS: We report a case of lichenoid GVDH arising in a 60-year-old man 10 weeks after orthotopic liver transplantation. RESULTS: Skin biopsies revealed changes suggestive of lichenoid GVHD, but histological features differed from those described in post bone marrow (stem cell) transplant GVHD, in that a dense lymphoid infiltrate was present. The brisk infiltrate contained eosinophils that initially led to concern for a lichenoid drug eruption. The patient developed multiorgan GVHD after reduction in immunosuppression. The diagnosis of chronic GVHD was confirmed by the demonstration of chimerism in the patient's peripheral blood. The generalized cutaneous eruption and systemic manifestations responded to salvage therapy including intravenous immunoglobulin infusion, increased immunosuppression with high-dose steroids, mycophenolate mofetil, and systemic and topical tacrolimus. CONCLUSIONS: In interpreting skin biopsies, it is important to recognize that brisk inflammation may be seen in GVHD in the setting of solid organ transplantation, in contrast to the more sparse inflammation typical of GVHD following BMT. The clinical and histologic differential diagnosis included the eruption of lymphocyte recovery, drug reaction, and viral exanthem. We provide a conceptual framework for evaluating generalized cutaneous changes that may occur post transplantation.     

Comedonal graft‐vs‐host disease: a distinct clinical expression of a lichenoid follicular GVHD

We report two cases of chronic follicular graft‐vs‐host disease (GVHD) that resemble closed and open acne‐like comedones. We propose the term ‘comedonal GVHD’ for this variant. A 47‐year‐old man presented with multiple 2–4‐mm acne‐like follicular papules in facial areas on day 82 status post bone marrow transplantation. A biopsy showed follicular infundibular dilation with keratotic plugs, hypergranulosis and vacuolar alteration (hydropic degeneration) of the basal layer, with dyskeratotic (apoptotic) keratinocytes, scattered lymphocytes and vascular ectasia of the superficial dermal plexus. We diagnosed chronic follicular lichenoid GVHD. The second patient was a 53‐year‐old female. On day 420 after transplantation, she presented with generalized dark to grayish, confluent, indurated lesions with confluent papules and unevenly distributed comedo‐like lesions. Skin biopsy showed sclerotic dermis and also dilated follicular infundibula with keratotic plugging, hypergranulosis and vacuolar alteration (hydropic degeneration) of the basal layer of the epidermis. We established the diagnosis of chronic sclerodermoid GVHD with follicular lichenoid involvement. The presence of open and closed comedones on the trunk and facial region of an adult raises several differential diagnosis but in our patients, histopathologic study demonstrated typical features of GVHD, which led to this diagnoses despite the peculiar clinical findings.