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 manifestations of graft‐versus‐host disease: role of the dermatologist

Graft‐versus‐host disease (GVHD) is the major complication of hematopoietic stem cell transplantation and is associated with high mortality in severe cases. The skin is one of the major organs affected in both acute and chronic GVHD. This review aims to elucidate the basic characteristics of GVHD, and the role and contribution of dermatologists in the care of patients with this condition.     

A question of persistence: Langerhans cells and graft‐versus‐host disease

Langerhans cells (LCs) have been scrutinized many times in studies of the pathogenesis of graft‐versus‐host disease (GVHD). As migratory dendritic cells, LCs are capable of direct antigen presentation to cytotoxic T cells. Their self‐renewal capacity has led to speculation that persistent recipient LCs could provide a continuous source of host antigen to donor T cells infused during hematopoietic stem cell transplantation (HSCT). In this issue of Experimental Dermatology, a new study examines at the relationship between recipient LCs and chronic GVHD.     

Endothelial chimerism in chronic sclerotic‐type chronic graft‐versus‐host disease (GVHD) and GVHD‐associated angiomatosis

Graft‐versus‐host disease‐associated angiomatosis (GVHD‐AA) is an uncommon manifestation of chronic GVHD consisting of friable vascular proliferations. Using fluorescence in situ hybridization, we demonstrate the presence of donor‐derived endothelial cells within areas of GVHD‐AA. This is the first documented occurrence of a benign neoplastic growth in relationship to a form of chronic GVHD.     

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.     

Narrowband ultraviolet B phototherapy in the treatment of cutaneous graft‐versus‐host disease in oncohaematological paediatric patients

Background Graft‐versus‐host disease (GVHD) represents an important complication following allogeneic bone marrow transplantation. In recent years, narrowband ultraviolet B (NB‐UVB, 311–313 nm) has been found to be a beneficial adjuvant treatment in patients refractory to first‐line immunosuppressive drugs. Objectives The aim of this study is to analyse retrospectively the clinical outcome of 10 GVHD paediatric patients treated with NB‐UVB therapy. Patients and methods Ten paediatric patients (six girls and four boys: median age 12·5 years, range 4–20) with cutaneous GVHD were enrolled in the study: five patients with chronic GVHD and five patients with an overlap syndrome GVHD. All patients had already been shown to be resistant to first‐choice immunosuppressive protocols, and were treated with NB‐UVB phototherapy until a clinical remission of skin lesions occurred. Results A complete response (absence of lesions) was achieved in 80% of the cases (eight patients) after a median number of 29 treatments, corresponding to a median of 7·5 weeks (52 days) of treatment (range 3–13 weeks), with an average cumulative dose of 28·71 J cm^?2 (range 1·02–70·38 J cm^?2). Only two patients reported a partial remission (< 18% of body surface area involved). During the follow‐up period, a complete remission after 1 year was observed in 75% of patients and after 2 years in 71% of the evaluable patients. Conclusions This study provides evidence that NB‐UVB phototherapy represents a valid second‐line treatment in paediatric patients affected by GVHD and refractory to immunosuppressive first‐line treatment.     

Graft‐versus‐Host‐Disease: Ein interdisziplinäres Problem aus der Sicht des Dermatologen

Graft‐versus‐host disease (GVHD) is a frequent complication following hematopoietic stem cell transplantation. Acute and chronic GVHD are identified based on the onset of clinical symptoms and signs. Whereas acute GVHD is relatively uniform in its appearance, chronic GVHD is characterized by a broad spectrum of clinical manifestations. The aim of this review is to introduce the reader to the pathophysiologic processes underlying GVHD, to demonstrate its manifestations in the skin and to review current therapeutic options.     

Thymoma‐associated multi‐organ autoimmunity: A case of graft‐versus‐host disease‐like erythroderma complicated by Good syndrome successfully treated by thymectomy

Thymoma‐associated multi‐organ autoimmunity disease (TAMA) is a rare paraneoplastic disorder, clinicopathologically similar to graft‐versus‐host disease (GVHD). Many reported cases follow a difficult course; half of them die from serious infectious diseases subsequent to immunosuppression induced by chemotherapy for unresectable thymoma, or intensive therapies including systemic steroids for complicating autoimmune diseases and GVHD‐like symptoms. We report a patient whose skin symptoms were improved subsequently to total thymectomy. The patient also presented with hypogammaglobulinemia, which led to the diagnosis of complicated Good syndrome. Taking account of her immunodeficient condition, antibiotics and i.v. immunoglobulin were administrated promptly on onset of bacterial pneumonia, which was successfully treated. According to a review of the published work, treatments with systemic steroids for skin symptoms have limited effects and may contribute to serious infection. Our case indicates that successful treatment of thymoma itself may lead to the amelioration of the disease. The management priority should be given to the treatment of thymoma and the control of subsequent immune abnormality other than GVHD‐like erythroderma.     

Case of thymoma‐associated cutaneous graft‐versus‐host disease‐like disease successfully improved by narrowband ultraviolet B phototherapy

Thymoma‐associated graft‐versus‐host disease (GVHD)‐like disease is a rare paraneoplastic disease seen in patients with thymoma. Here, we describe the first case of thymoma‐associated GVHD‐like disease localized to the skin that was successfully improved by a combination of systemic corticosteroids and whole‐body narrowband ultraviolet (UV)‐B phototherapy. The patient had developed toxic epidermal necrolysis‐like erosive skin lesions over the whole body. Although systemic corticosteroids were effective up to a point, we were unable to begin the steroid taper. The addition of systemic narrowband UV‐B phototherapy improved the skin manifestation of this disease, allowing corticosteroids to be reduced to a third of the original dose. Histopathologically, it was confirmed that the proportion of Foxp3‐positive lymphocytes in the skin increased after narrowband UV‐B irradiation. We propose that whole‐body narrowband UV‐B phototherapy is a good therapeutic option for the skin manifestation of thymoma‐associated GVHD‐like disease.     

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.     

Basiliximab treatment of severe GVHD induced by donor lymphocyte infusion with interferon‐a

The development of acute graft‐versus‐host‐disease (GVHD) in recipients of donor lymphocyte infusion (DLI) is not rare and the complication is quite often fatal. We describe a severe skin GVHD patient who responded well to basiliximab. A 20‐year‐old male who received a hematopoietic stem cell transplantation at his age of 18. His fusion gene Aml1/Eto remained positive, so he was administered with DLI combined with interferon‐a (IFN‐a). Forty days after the therapy, he presented with severe skin rashes with multiple mucous membrane involvement. The skin and mucous lesions recovered after basiliximab treatment. So far, severe type of erythema multiforme in GVHD patients after DLI with IFN‐a injection is firstly reported here, together with a new alternative therapy.     

Chronic cutaneous lichenoid graft‐versus‐host disease at the area of herpes zoster infection and at a vaccination site

Cutaneous graft‐versus‐host disease (GVHD) is a frequent complication of allogeneic bone marrow transplant and haematopoietic cell transplantation, but it is rarely presented as a Wolf's isotopic response. We report a patient who developed chronic lichenoid GVHD following the dermatomes previously affected by varicella zoster virus (VZV) infection. Nineteen months later, the same patient suffered from reactivation of GVHD at the injection site of an influenza vaccination. We review the literature concerning GVHD appearing after VZV infection and discuss the possible implications of this case and the pathogenic hypotheses.     

A Pediatric Case of Sclerodermatous Graft‐Versus‐Host Disease Responsive to Ultraviolet A1 Phototherapy

Graft‐versus‐host disease (GVHD) is one of the major complications after hematopoietic stem cell transplantation and is responsible for post‐therapeutic morbidity, mortality, and poor quality of life of recipients. Sclerodermatous graft‐versus‐host disease (sGVHD) is a rare variant of chronic GVHD characterized by deposition of collagen in the skin and other soft tissues and resulting in loss of range of motion and functional capabilities. Treatment of sGVHD is challenging and largely limited by systemic side effects. Ultraviolet A1 phototherapy has been reported to be effective in connective tissue disorders, including sGVHD. We report a case of sGVHD in a 15‐year‐old girl that was resistant to traditional therapy but showed improvement in cutaneous symptoms with ultraviolet A1 phototherapy three times a week for 6 weeks (10 J/cm² single dose, 180 J/cm² cumulative dose).     

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.     

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.     

Immunohistochemical Staining of Pediatric Solitary Angiokeratomas

The precise etiology and subtype of vessels constituting angiokeratomas is poorly understood. We sought to characterize the vessels by studying prospero‐related homeobox gene‐1 and D2‐40 expression in 22 pediatric solitary angiokeratomas. Routine histologic examination demonstrated a mix of lymph‐containing vessels and erythrocyte‐filled small vessels. Our results suggest that angiokeratomas may in part be comprised of vessels with lymphatic differentiation.     

Fabry disease: Case report with emphasis on enzyme replacement therapy and possible future therapeutic options

A 38‐year‐old male Caucasian with Fabry disease presented with angiokeratomas and tortuous conjunctival and retinal vessels. Additionally, the patient showed characteristic skin lesions of psoriasis and seborrheic dermatitis. His past medical history revealed anhidrosis, acral paresthesias, myocardial infarction, phlebothrombosis, hypertension, antithrombin III deficiency, factor V Leiden disease, chronic obstructive lung disease, tinnitus, diarrhea, recurrent abdominal pain, headache, and depressive mood. He was treated with intravenous substitution of the deficient enzyme α‐galactosidase A. Possible future options in treatment of Fabry disease are discussed.     

Laser treatment of cutaneous angiokeratomas: A systematic review

Angiokeratomas can present therapeutic challenges, especially in cases of extensive lesions, where traditional surgical methods carry high risks of scarring and hemorrhage. Argon, pulsed dye (PDL), neodymium‐doped yttrium aluminum garnet (Nd:YAG), copper vapor, potassium titanyl phosphate, carbon dioxide, and erbium‐doped yttrium aluminum garnet (Er:YAG) lasers have emerged as alternative options. To review the use and efficacy of lasers in treating angiokeratomas. A PubMed search identified randomized clinical trials, cohort studies, case series, and case reports involving laser treatment of cutaneous angiokeratomas. Twenty‐five studies were included. Quality ratings were assigned using the Oxford Centre for Evidence‐Based Medicine scheme. Several laser modalities are effective in treating multiple variants of angiokeratomas. Vascular lasers like PDL, Nd:YAG, and argon are the most studied and of these, PDL offers the safest side effect profile. Nd:YAG may be more effective for hyperkeratotic angiokeratomas. Combination treatment with multiple laser modalities has also demonstrated some success. Lasers are a promising treatment option for angiokeratomas, but current use is limited by the lack of treatment guidelines. There are limited high quality studies comparing laser treatments to each other and to non‐laser options. Additional studies are needed to establish guidelines and to optimize laser parameters.     

Doxepin in difficult‐to‐treat chronic urticaria: A retrospective,cross‐sectional study from Turkey

Doxepin is an old tricyclic antidepressant, whose efficacy in chronic urticaria had been well documented until 1990. However, over the past three decades, there has been limited data on its use. We aimed to assess the efficacy and safety of doxepin in the treatment of patients with chronic urticaria who were poorly responsive to antihistamines. In this retrospective, cross‐sectional, single‐center study from Turkey, data were examined from patients with chronic urticaria who had poor antihistamine responses and received doxepin therapy from 1998 to 2017. Patient data were analyzed with regard to the duration of the disease, age, sex, treatment outcomes using a weekly urticaria activity score (UAS7), and adverse effects of doxepin therapy. A reduction of ≥90% in UAS7 was defined as “complete response,” 30–89% as “partial response” and <30% as “no significant response.” Thirty‐six patients were included in this study. Doxepin was effective in a majority (n = 27, 75%) of the patients with a short onset time. Sixteen patients (44.4%) showed a complete response. Mild sedative and anticholinergic side effects were well tolerated. Doxepin seems to be a reasonable, efficient, and affordable alternative for the treatment of chronic urticaria in patients who respond poorly to antihistamine therapy.     

Granulocyte‐macrophage colony‐stimulating factor enhances wound healing in diabetes via upregulation of proinflammatory cytokines

Summary Background Chronic ulceration, especially in diabetes, remains a substantial clinical problem. Exogenous granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) is efficacious in the treatment of chronic wound healing in both animal models and patients, but its role in diabetic wounds remains to be explored. Objectives Using a diabetic mouse model, to investigate the role of GM‐CSF in wound healing. Methods Clinical observation, histopathology, immunohistochemistry and cytokine assays. Results There was a significant reduction (50%) in GM‐CSF production in the wounds of the diabetics compared with nondiabetics. Exogenous GM‐CSF substantially enhanced the wound healing in diabetic mice, accompanied by increased interleukin‐6 and monocyte chemoattractant protein‐1 production. The elevated cytokines correlated with increased neovascularization, and infiltration of macrophages and neutrophils. GM‐CSF showed no beneficial effects in nondiabetic wound healing. Conclusions Our results provide useful guidelines for the clinical management of chronic ulceration in diabetes.