Eruption of lymphocyte recovery or autologous graft-versus-host disease?

Maculopapular exanthemas have a particular high incidence among patients treated with autologous hematopoietic stem cell transplantation (HSCT). In most cases, a viral or drug induced origin is easily identified. However, the transplantation itself may also induce similar skin changes. These exanthemas are known under various names, such as autologous graft-versus-host disease (GVHD), engraftment syndrome (ES) or eruption of lymphocyte recovery (ELR). Given the clinical and histopathological similarities of these disorders, it can prove difficult to establish a diagnosis. Here, we describe a patient who developed a maculopapular exanthema after autologous stem cell transplantation for multiple myeloma, diagnosed as autologous GVHD. We also briefly review the current knowledge of the pathogenesis of autologous GVHD, ES, and ELR. Based on these data we would like to suggest that the latter two do not reflect own disease entities but rather different presentations of autologous GVHD.     

移植物抗宿主病皮肤表现 (附 3例报告 )

报道3例外周血干细胞移植后致移植物抗宿主病（GVHD），皮疹具本病临床和组织学特点，皮损的严重性与供体有相关性，典型的皮疹及组织浓助于GVHD诊断。     

A case of sclerodermatous graft-versus-host disease following autologous peripheral blood stem cell transplantation

We report a 65-year-old woman with chronic graft-versus-host disease (GVHD) who developed severely sclerotic skin on the fingers, hand and trunk following autologous peripheral blood stem cell transplantation (APBSCT). The patient had suffered from breast cancer and been treated with surgery and chemotherapy. She showed pancytopenia and was treated with APBCST. Four years after APBSCT, she developed the severe sclerotic changes on the fingers, hands, extremities and trunk. The skin biopsy showed a flattened epidermis and a proliferation of collagen bundles in the dermis. No anti-nucleolar DNA titers were detected in the serum. She was diagnosed with chronic GVHD. Despite treatment with oral prednisolone, the skin sclerotic change developed and the breast cancer recurred. She died due to pericarditis. This is a rare case of sclerodermatous GVHD following APBSCT. The serum interleukin (IL)-12 levels were examined during the treatment.     

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.     

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.     

Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease

Graft-versus-host disease (GVHD) is a T cell-mediated disease seen most commonly after hematopoietic stem cell transplantation. Rarely, a GVHD-like disease can be seen in patients with malignant thymoma. We describe a 50-year-old man with malignant thymoma who developed skin, liver, and intestinal manifestations similar to that seen in GVHD. We also review other reported cases of GVHD-like manifestations in the setting of thymoma and propose "thymoma-associated multiorgan autoimmunity" as a name for this novel disease. Specifically, thymoma-associated multiorgan autoimmunity is defined as a disease of the liver, intestine, or skin, which on histopathology resembles GVHD but is seen in the setting of malignant thymoma and not after hematopoietic stem cell transplantation.     

Risk factors and clinical characteristics of acute and chronic cutaneous graft-versus-host disease in pediatric patients undergoing hematopoietic stem cell transplantation

Acute and chronic cutaneous graft-versus-host disease (GVHD) are common complications following hematopoietic stem cell transplantation (HSCT) in pediatric patients. In this retrospective study, we explored the risk factors and clinical characteristics of acute and chronic cutaneous GVHD in a case series of children undergoing HSCT at a tertiary referral hospital. We found that 36% of acute cutaneous GVHD was severe and these patients were more likely to have an unrelated donor, and that children with acute cutaneous GVHD who progressed to chronic cutaneous GVHD had a higher proportion of malignant diseases, total body irradiation, and bronchiolitis obliterans compared to those who did not progress to chronic cutaneous GVHD. Our study highlights the importance of identifying and monitoring these high-risk patients to improve the clinical management and outcomes of cutaneous GVHD in pediatric HSCT recipients.     

Role of skin biopsy to confirm suspected acute graft-vs-host disease: results of decision analysis

OBJECTIVE: To estimate the value of skin biopsy in the evaluation of suspected acute cutaneous graft-vs-host disease (GVHD) after allogeneic stem cell transplantation. DESIGN: Decision analysis using parameters specified by expert opinion for skin biopsy characteristics, prevalence of acute GVHD, and value of potential outcomes. One-, 2-, and 3-way sensitivity analyses were performed. SETTING: Major stem cell transplantation centers in the United States. PATIENTS: Hypothetical cohort of patients with suspected acute cutaneous GVHD after stem cell transplantation. INTERVENTIONS: The following 3 interventions were compared: treat immediately for GVHD without performing a skin biopsy, perform a skin biopsy and treat immediately but stop treatment if skin biopsy specimen findings are inconsistent with GVHD, and perform a skin biopsy and await results of the skin biopsy specimen before treating. MAIN OUTCOME MEASURES: Number of patients appropriately and inappropriately treated with each intervention, consistency of physician-reported behavior, individualized decision analyses, and preferred intervention based on the aggregate estimates of respondents. RESULTS: The decision to treat immediately for GVHD without performing a skin biopsy yielded the best clinical outcome for the specified clinical setting and under the parameters specified by expert opinion. One-way sensitivity analyses showed that these conclusions are robust if the prevalence of acute cutaneous GVHD in stem cell recipients with rash is greater than 50%, if the sensitivity of skin biopsy specimen is less than 0.8, and the specificity of skin biopsy specimen is less than 0.9. Only 25% of physicians interviewed chose an intervention consistent with their estimates of prevalence, test characteristics, and outcome evaluations, indicating an opportunity to improve management of this important clinical condition. CONCLUSIONS: This decision analysis modeling technique predicts that in patient populations in which the prevalence of GVHD is 30% or greater (typical for allogeneic stem cell transplantation), the best outcomes were obtained with treatment for GVHD and no skin biopsy. In populations with prevalence of GVHD of 30% or less, obtaining a skin biopsy specimen to guide treatment was predicted to provide the best patient outcomes.     

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.     

A case of acute cutaneous graft-versus-host disease mimicking psoriasis vulgaris

Graft-versus-host disease (GVHD) is a frequent complication occurring after allogenic hematopoietic stem cell transplantation and is divided into acute and chronic type. Cutaneous involvement is the most frequent manifestation of acute GVHD, with maculopapular exanthema and perifollicular papular lesions. We describe the first case to develop acute cutaneous GVHD mimicking psoriasis vulgaris shortly after allogenic peripheral blood stem cell transplantation. The patient's rash resembled psoriasis vulgaris and showed histologic features of both psoriasis and acute GVHD. Despite various immunosuppressant therapies, the skin lesion was drug-resistant. Therefore, we administered psoralen-UVA (PUVA) therapy and achieved the desired therapeutic effect. As far as we know, this is the first case of psoriasiform skin eruption as a manifestation of acute GVHD.     

Autologous Graft‐Versus‐Host Disease in a Child with Stage IV Neuroblastoma

Graft‐versus‐host disease (GVHD) is an underappreciated complication of autologous hematopoietic stem cell transplantation (AHSCT) that can affect the skin, gastrointestinal tract, and liver. The development of this rare condition is probably due to an impairment of immunologic tolerance that can occur spontaneously through T‐cell dysregulation, possibly from intensive conditioning chemotherapy regimens, or intentionally through administration of cyclosporine in the hopes of promoting an antitumor response. We present the case of a 2‐year‐old boy with metastatic neuroblastoma who spontaneously developed autologous GVHD after AHSCT. Severe pruritus and an inability to taper his oral steroids without a disease flare marked his disease. Eventually partial relief was achieved with initiation of cyclosporine and a strict soak and smear protocol using topical triamcinolone 0.1% ointment.     

银屑病样表现的移植物抗宿主病1例

患儿男,5岁。躯干、四肢皮疹伴瘙痒1周。7个月前,因患"急性B淋巴细胞白血病"行异基因造血干细胞移植术,术后发生两次急性移植物抗宿主病,临床表现为绿豆大鲜红色丘疹,压之退色,疹间皮肤正常,曾予糖皮质激素或免疫抑制剂治疗,丘疹可消退。皮肤科情况:面、颈、躯干及四肢伸侧可见散在分布大小不一的圆形或椭圆形干燥性红斑,上覆白色鳞屑,指/趾甲无受累,Auspitz’s征阴性。皮损组织病理示:表皮不规则增厚,浆痂形成,灶性海绵水肿,灶性基底细胞液化,表皮内可见个别坏死角质形成细胞,真皮浅中层血管周围可见稀疏的单一核细胞浸润。诊断:银屑病样表现的慢性移植物抗宿主病。     

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.     

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.     

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.     

Acute graft-vs-host disease. Development following autologous and syngeneic bone marrow transplantation

Graft-vs-host disease (GVHD) is a frequent complication of allogeneic bone marrow transplantation but has been infrequently reported following autologous or syngeneic bone marrow transplantation. Ninety-six autologous and 19 syngeneic marrow transplants were performed at our institution between July 1977 and March 1984. We report acute cutaneous GVHD occurring in seven patients who received autologous marrow and two patients who received marrow from an identical twin. All nine patients had clinically detectable eruptions and had skin biopsy specimens with histologic changes of grade 2 acute GVHD. Although most cases were mild and self-limiting, four patients required systemic corticosteroids to treat their disease. Thus, acute cutaneous GVHD was seen in approximately 8% of patients receiving autologous or syngeneic bone marrow transplants at our institution.     

Immunohistochemical Study of Graft-versus-Host Reaction (GVHR)-Type Drug Eruptions

Skin biopsies of graft-versus-host reaction (GVHR)-type drug eruptions in the acute phase were compared immunohistochemically with those in the chronic phase and also with non-GVHR type drug eruptions in the acute phase. Predominance of CD8⁺ T cells in the epidermal infiltrates, reduction in the number of epidermal OKT6⁺ dendritic cells (Langerhans cells), and increased expression of HLA-DR and ICAM-1 on keratinocytes were observed in the acute phase of GVHR-type, but not in either the chronic phase of GVHR-type or the acute non-GVHR type. These findings were similar to those of previous reports on skin lesions of acute GVH disease (GVHD) seen after bone marrow transplantation. Therefore, immunohistochemistry is not useful for differential diagnosis between acute GVHR-type drug eruptions and acute cutaneous GVHD. These findings also indicate that similar immunomechanisms may be involved in the pathogenesis of both GVHR-type drug eruptions and cutaneous GVHD.     

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...     

Psoralen plus ultraviolet-A-bath photochemotherapy as an adjunct treatment modality in cutaneous chronic graft versus host disease

BACKGROUND: Cutaneous chronic graft versus host disease (GVHD) is a severe complication following allogeneic stem cell (PBSCT) and bone marrow transplantation (BMT). Immunosuppressive therapy consists of prednisone, cyclosporine-A, azathioprine or mycophenolate mofetil (MMF). Treatment of patients refractory to immunosuppression represents a major problem. METHODS: We report six patients suffering from severe chronic GVHD of the skin who did not respond to immunosuppressive therapy or relapsed after reduction of glucocorticosteroids. Patients were treated with psoralen plus ultraviolet (PUVA)-bath photochemotherapy three times weekly following a standardized treatment protocol under continued treatment with prednisone and/or MMF. One patient was additionally pretreated with ultraviolet-A1 (UV-Al). RESULTS: After a median of 14, 5 treatment sessions, skin lesions improved. Out of six patients, three showed a complete remission. In all patients, systemic immunosuppressive therapy could be reduced. In sclerodermic lesions, skin thickness returned to the levels of normal skin after 25 treatments confirmed by 20 MHz ultrasound evaluation. In a follow-up ranging from 2 to 21 months (median 10, 3 months), skin conditions remained stable. CONCLUSION: Psoralen plus ultraviolet-A-bath represents an effective adjunct treatment option for extensive chronic and sclerodermic cutaneous GVHD offered by dermatologists. This is of high interest in patients suffering from cutaneous GVHD resistant to conventional immunosuppressive therapy and should be included to the menu of topical treatment options for chronic cutaneous GVHD.     

Very late appearance of acute graft-versus-host disease after tapering immunosuppression.

Graft-versus-host disease (GVHD) is a major complication of stem cell transplantation. Here we report a 40-year-old woman who developed an acute GVHD 30 months after transplantation. Late and very late appearance of acute GVHD has only been described in rare cases.