Sclerodermatous graft-versus-host disease: clinical spectrum and therapeutic challenges

Sclerodermatous graft-versus-host disease (GVHD) is a rare complication of bone marrow transplantation. While GVHD is often associated with the beneficial graft vs. tumour effect, it also contributes towards significant morbidity and mortality. No reliably effective treatment has yet been established. We present 10 patients with haematological malignancies who underwent an allogeneic stem cell transplant and developed sclerodermatous GVHD. Donor lymphocyte infusion administered for relapse or reducing donor T-cell chimerism was a known trigger for sclerodermatous GVHD in four of the patients. Treatment with immunosuppressants, psoralen plus ultraviolet A (PUVA) and extracorporeal photopheresis has been largely unsuccessful in their management. Intensive immunosuppression including the use of anti-CD20 monoclonal antibody may have contributed to relapse of leukaemia in one patient 10 years after her transplant. Sclerodermatous GVHD may occur without a preceding lichenoid stage. Clinical heterogeneity is common, although sclerodermatous GVHD has a predilection for the limbs. Treatment options are largely unsatisfactory if conventional immunosuppression fails. PUVA may give some symptomatic benefit and extracorporeal photopheresis seems to be less efficacious than previously published work suggests.     

Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity

Transfer of donor immunity has been demonstrated in animal models of both allogeneic and syngeneic bone marrow transplantation (BMT). Clinical case reports have suggested that human autoimmune disease may be similarly transferred. However, it is difficult to completely exclude autoimmune phenomena associated with graft-versus-host disease (GVHD) as previously reported cases are of allogeneic BMT. In addition, the onset of autoimmunity has been distantly related to the timing of the transplant, perhaps because of the immunosuppression used for prophylaxis and treatment of GVHD. We describe a patient in whom the development of psoriasis shortly after receiving syngeneic bone marrow from a psoriatic donor and its recurrence with arthropathy following a second syngeneic BMT provide more direct evidence for the adoptive transfer of human autoimmune disease, probably by T cells.     

Depletion and repopulation of epidermal dendritic cells after allogeneic bone marrow transplantation in humans

We have observed marked depletion of epidermal dendritic cells, defined by monoclonal antibodies directed against HLA-DR (Ia-like) and T6 antigens, after allogeneic bone marrow transplantation. To more precisely characterize this observation, we examined a total of 39 sequential biopsies from 15 patients both before and after allogeneic bone marrow transplantation. Profound depletion of HLA-DR and T6-positive epidermal dendritic cells was observed early after transplantation (1-4 weeks), followed by gradual and variable repopulation. Transmission electron microscopy confirmed absence of dendritic cells in selected biopsies. Depletion of dendritic cells did not appear to be related to development of clinical or histologic evidence of graft-versus-host disease, suggesting that depletion may relate to pretransplant conditioning regimens. The rate of return of these cells, however, may be influenced by the presence or persistence of clinical disease. Repopulation of epidermal dendritic cells after initial depletion in bone marrow transplantation represents a human model relevant to studies concerned with the origin and kinetics of Langerhans cells.     

白癜风负压吸疱自体表皮移植的影响因素

负压吸疱自体表皮移植是目前广泛使用的稳定期白癜风治疗方法之一,具有成功率高,并发症少的优点,其疗效受多种因素影响.主要包括:负压吸疱条件如吸疱部位、温度、压力、吸疱时间等;受皮区的磨削技术;术中、术后汴意事项;术前或术后选择联合的不同治疗方法.这些因素之间亦相互作用,影响皮片内黑素细胞的含量和成活率,进而影响皮肤移植区着色程度和色素扩展范围.     

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.     

The lymphocytic infiltrate in acute cutaneous allogeneic graft-versus-host reactions lacks evidence for phenotypic restriction in donor-derived cells

The lymphocytic subtypes effecting allogeneic graft-versus-host disease (GVHD) are unknown. We studied 35 skin biopsy specimens from 19 women transplanted with bone marrow from men for patterns and time course of infiltration of the skin by Y chromosome-bearing lymphocytes using in situ hybridization. Immunophenotypic analysis was performed on serial sections. Significant numbers of donor cells were first observed by day 13 after bone marrow transplantation (BMT), although a few cells were noted at earlier time points. The quantity of donor lymphocytes in the dermis correlated with the diagnosis of GVHD. For specimens with grade 1 features, only rare cells bore the Y chromosome, whereas the majority of lymphocytes in grade 2 tissues, whether heavily inflamed or not, contained the Y chromosome. These lymphocytes were predominantly CD4+ with fewer CD8+ and CD56+ cells in the dermis and epidermis. No concentration of a specific subtype in the epidermal compartment was observed. These data do not support the observation that a cutaneous graft-versus-host reaction (GVHR) is mediated primarily by CD8+ lymphocytes. Several effector cell populations may mediate a cutaneous GVHR with further variation over time and in BMTs between different individuals.     

Rash and pancytopenia as initial manifestations of acute graft-versus-host disease after liver transplantation

Acute graft-versus-host disease is mainly a complication of allogeneic bone-marrow transplantation, and rarely seen after transplantation of solid organs. We describe a 68-year-old man who developed a maculopapular eruption and fever approximately 15 days after orthotopic liver transplantation for cryptogenic cirrhosis. At day 19, the patient developed abrupt neutropenia and diarrhea. Skin biopsy was performed and the specimen revealed basal cell layer vacuolization, necrotic keratinocytes, and satellite cell necrosis. Bone-marrow aspiration performed after the patient became pancytopenic revealed aplastic marrow with scattered lymphocytes and rare megakaryocytes. A diagnosis of acute graft-versus-host disease was made and an immunosuppressive drug regimen was initiated. Unfortunately, the patient died after support was withdrawn because of total ablation of his bone marrow and multiorgan failure. This report describes the rare presentation of acute graft-versus-host disease after solid organ transplantation, and that skin manifestations may be an early presenting sign.     

Overview of the progress on haploidentical hematopoietic transplantation

Allogeneic hematopoietic stem cell transplant (HSCT) remains the only potentially curative option for variety of hematologic disorders. Lack of a suitable fully HLA-matched donor limits this option for many patients. Without a suitable related or unrelated HLA-matched donor, umbilical cord blood and haploidentical family members provide a potential source of stem cells. Timely donor availability makes haploidentical donors an attractive alternative donor source. Initial attempts at haploidentical HSCT was associated with significantly increased mortality owing to high rates of graft rejection and severe graft-versus-host disease caused by major donor-recipient HLA-disparity. However, over the past decade, outcomes of haploidentical HSCT have improved significantly. Here, we review the advantages and challenges of haploidentical transplantation. We also discuss new developments to attempt to overcome the challenges to a successful haploidentical transplantation.     

Successful Repigmentation of Vitiligo after Allogeneic Bone Marrow Transplantation for Hodgkin's Lymphoma by Autologous Noncultured Melanocyte-keratinocyte Transplantation

The treatment of vitiligo is derisory since the pathogenesis of vitiligo is not clear at present. Most conservative treatments are difficult to approach satisfactory therapy. So transplantation is the only way left when the disease becomes insensitive to those conservative treatments. Here we describe an 18-year-old patient who developed vitiligo, which was triggered by graft-versus-host disease after a allogeneic bone marrow transplantation for the treatment of Hodgkin''s lymphoma from his sister. In the following treatment to vitiligo, the patient successfully performed the transplantation of autologous uncultured melanocyte on the premise of poor reaction to other conservative methods. We infer that transplantation can be a treatment of the vitiligo after allogeneic bone marrow transplantation.     

Dermal dendrocytes participate in the cellular pathology of experimental acute graft-versus-host disease

In a well established murine model relevant to human disease, graft-versus-host disease results from recognition of recipient minor histocompatibility antigens by donor bone marrow-derived T lymphocytes. Previous studies suggest that factor XIIIa-positive dermal dondrocytes may be involved in the pathogenesis of disorders involving antigen presentation to T cells and dermal fibrosis. This study was undertaken to determine (i) whether normal murine skin contains factor XIIIa-positive dermal dendrocytes, and (ii) whether such cells participate in the pathophysiology of acute graft-versus-host disease. Graft-versus-host disease was produced using B10.BR CD8+ donor T cells administered to CBA recipients. Skin samples were collected weekly for a 5-week period and evaluated by immunohistochemistry and electron microscopy. Our data indicate that normal murine dermis contains factor XIIIa-positive cells localized primarily around deep dermal microvessels. Ultrastructural analyses reveal these cells to have long processes, pinocytotic vesicles, fibronexuses, and intimate associations with mast cells. During graft-versus-host disease, factor XIIIa-positive dendrocytes appeared within the superficial dermis. By ultrastructure, the dendrocytes were hypertrophic and highly branched, and demonstrated an intimate relationship with neighboring cells. In conclusion, factor XIIIa-positive dendrocytes comprise a normal component of the murine dermis and undergo alterations in experimental acute graft-versus-host disease consistent with participation in disease pathophysiology.     

Extracorporeal photochemotherapy as an effective treatment modality in chronic graft-versus-host disease

Background In chronic graft-versus-host disease (cGvHD) cytotoxic and suppressor T lymphocytes probably play a decisive pathogenetic role. The efficacy of conventional immunosuppressive therapy is often insufficient, and drug side effects may produce further complications. Photochemotherapy with orally administered photosensitizer 8-methoxypsoralen (8-MOP) followed by UV-A irradiation of the skin (PUVA) has been reported as an advantage. Extracorporeal photochemotherapy (ECP) was introduced as an improved method of photochemotherapy compared with PUVA. ECP selectively affects autoreactive as well as malignant T lymphocytes and implies repeated ex vivo UV-A irradiation of chemically photosensitized leukocytes, followed by reinfusion. The treatment efficacy depends essentially on sufficient plasma levels of 8-MOP. In cases of considerable gastrointestinal malabsorption, however, therapeutic levels of 8-MOP are rarely achieved when the drug is administered orally. Objective In a case of severe cGvHD, ECP was used because of disease progression, despite massive conventional immunosuppressive therapy. Patient and method After bone marrow transplantation a 13-year-old girl developed acute Gv HD, which turned later to severe c Gv HD with massive involvement of the skin, oral mucosa, liver and gastrointestinal tract. The treatment with prednisolone, cyclosporin A (Cs A), azathioprine and thalidomide was without success. When the patient was 15 we started ECP with individually adapted modifications. Especially because of severe gastrointestinal malabsorption, a liquid preparation of 8-MOP was administered directly into the leukocyte (buffy coat) fraction, received by leukapheresis. Results After 15 treatment cycles within 12 months immunosuppressive drugs were omitted because of noticeable improvement in cutaneous changes, liver function parameters and general condition (Karnofsky score 85–90% compared with 30–40% at the beginning). Conclusion It seems to us that this modification of ECP is a very effective and safe treatment modality for cGvHD without any side effects.     

PUVA therapy prevents sensitization to mechlorethamine in patients with psoriasis

Two groups of 20 patients with psoriasis were treated with mechlorethamine applied topically (group A) or with PUVA combined with mechlorethamine (group B). In group B mechlorethamine was started after six PUVA treatments. Results showed a significant decrease of the incidence of contact dermatitis in group B (30%) compared with group A (75%). Allergic dermatitis, demonstrated by a positive patch test to mechlorethamine with an histology of eczema, was observed in 55% of patients in group A and 20% in group B. The incidence of irritant dermatitis was not significantly different in the two groups. Allergic dermatitis was observed later in group B: after an average of 32.2 applications of mechlorethamine compared with 25 applications in group A. Possible mechanisms responsible for these results are reduction of epidermal Langerhans cells by PUVA therapy and induction of antigen-specific suppressor T cells. Patients living far from a specialized centre might be treated initially with PUVA therapy then with mechlorethamine alone, at home. This schedule may reduce the incidence of contact dermatitis to mechlorethamine.     

Development of mycosis fungoides after bone marrow transplantation for chronic myeloid leukaemia: transmission from an allogeneic donor

We report on a patient who developed donor‐derived cutaneous T‐cell lymphoma (CTCL) 4 years after successful treatment of chronic myeloid leukaemia with an allogeneic bone marrow transplant. The patient developed an eczematous rash unresponsive to topical therapy and immunosuppression. When CTCL was diagnosed in the recipient, his sibling donor had been attending his local dermatology unit with a maculosquamous rash, which proved subsequently to be mycosis fungoides. An identical pattern of donor and recipient clonality assessment and T‐cell receptor gene sequencing indicated that the CTCL was probably transmitted in the bone marrow harvest. This suggests that CTCL cells circulate in the marrow at an early subclinical stage in this disease. This is the second case of donor‐derived CTCL reported to date.     

Generalized vitiligo after lymphocyte infusion for relapsed leukaemia

Vitiligo is an autoimmune disease caused by T-lymphocyte-mediated destruction of melanocytes. We describe two patients with generalized vitiligo caused iatrogenically after donor lymphocyte infusion (DLI) for leukaemia relapse over 3 years after bone marrow transplantation (BMT). Neither the sibling donor nor the recipient had vitiligo or other autoimmune diseases, and vitiligo did not occur after the first BMT. DLI was accompanied by skin graft-versus-host disease in both cases, which was controlled with immunosuppression. However, over several months, progressive generalized and persistent skin depigmentation occurred in both patients. Peripheral blood molecular studies showed the complete disappearance of host haematolymphopoiesis. The specific destruction of melanocytes in both patients was therefore probably mediated by new alloreactive lymphocytes infused from the donors.     

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.     

Acral erythemas induced by chemotherapy and graft-versus-host disease in adults with hematogenous malignancies

Acral erythema is being seen with increasing frequency in patients with hematologic malignancies, because of the administration of more aggressive high-dosage chemotherapy and the increasing use of allogeneic bone marrow transplantation, which may be followed by the development of cutaneous graft-versus-host disease. The varieties induced by both drugs and graft-versus-host disease are grossly similar but can be differentiated on the basis of symptoms, medical history, and response to therapy. Each also has to be differentiated from the painless palmar erythema commonly associated with pregnancy and with chronic liver disease. When making such a diagnosis, attention to the clinical history and an awareness of the points of distinction will help the physician to determine the precipitating cause and initiate appropriate treatment promptly.     

Specificity of antinuclear antibodies in scleroderma-like chronic graft-versus-host disease: clinical correlation and histocompatibility locus antigen association

Summary Chronic graft-versus-host disease after bone marrow transplantation presents, in a few cases, as mild to severe scleroderma-like changes. Patients with chronic graft-versus-host disease with and without sclerodermatous skin changes were analysed for antinuclear autoantibodies (ANA) and antinucleolar autoantibodies (ANoA) and the results correlated with disease symptoms and histocompatibility locus antigen (HLA) pattern. Nineteen patients with chronic graft-versus-host disease and scleroderma-like skin changes. 18 with chronic graft-versus-host diseae without scleroderma. and 17 controls on immunosuppressive treatment were screened for ANA and ANoA using enzyme-linked immunosorbent assay, immunodiffusion and immunoblot techniques. Four patients with severe scleroderma had antibodies to topoisomerase I. two had antibodies against PM-Scl. both characteristic serological findings in idiopathic systemic scleroderma. One patient had La/SSB antibodies and, in three cases, antibodies to the nucleolar antigen C23 (nucleolin) could be identified. A possible correlation between antinucleolin antibodies and disease activity was observed. HLA-Al. -B1. and -B2 were found significantly more often in patients with scleroderma-like symptoms in comparison to patients without scleroderma-like symptoms. Chronic graft-versus-host disease with seleroderma-like manifestations can be associated with the occurrence of ANA specific for idiopathic scleroderma. The development of seleroderma after bone marrow transplantation might have a HLA-linked genetic background.     

Papular urticaria and transfer of allergy following bone marrow transplantation

Skin rashes following allogeneic hone marrow transplantation are common. The majority are either drug reactions or manifestations of acute or chronic graft-versus-host disease (GVHD). We describe a previously unreported manifestion of a donor allergic response pattern in the recipient of an allogeneic hone marrow transplant who presented with papular urticaria in the post-transplant period.     

Latency-associated peptide prevents skin fibrosis in murine sclerodermatous graft-versus-host disease, a model for human scleroderma

Murine sclerodermatous graft-versus-host disease (Scl GVHD), produced by transplanting B10.D2 bone marrow and spleen cells to lethally irradiated BALB/cJ mice, is a model for human scleroderma. Mice with Scl GVHD have skin thickening, lung fibrosis, cutaneous mononuclear cell infiltration, and upregulation of cutaneous transforming growth factor beta1 (TGF-beta1) and type I collagen mRNAs by day 21 after bone marrow transplantation. Elevated TGF-beta1 appears to be the critical cytokine driving fibrosis in Scl GVHD, which can be prevented with antibodies to TGF-beta administered early in disease. Here we demonstrate that we can also prevent skin thickening in mice with Scl GVHD with a naturally occurring antagonist to TGF-beta1, human latency-associated peptide (LAP). By quantitative real-time PCR analysis and immunostaining, LAP treatment also abrogates the upregulation of cutaneous TGF-beta1 and connective tissue growth factor mRNAs and type I collagen synthesis in Scl GVHD. In contrast to anti-TGF-beta antibodies, LAP at 4 ng total per mouse has no significant suppressive effect on cutaneous influx of T cells and monocytes or immune cell activation. LAP may be a potential new therapy in scleroderma and other TGF-beta-driven fibrosing disease that targets TGF-beta more specifically, without affecting systemic critical roles of TGF-beta on immune cell function.     

A pediatric case of sclerodermatous chronic graft-versus-host disease

We report a rare case of sclerodermatous chronic graft-versus-host disease (GVHD) in a 6-year-old boy that occurred after bone marrow transplantation for his aplastic anemia. The clinical manifestation and histopathologic findings were typical of scleroderma. Although various kinds of treatment have been tried for scleroderma, no established therapy exists. Furthermore, treating this disease is even more difficult in children. In the future, clarification of the pathogenesis of chronic GVHD and establishment of therapy will be necessary.