Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation.

Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (P = .11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.

Fractional CO2 laser for the treatment of sclerodermatous cGVHD.

Sclerodermatous graft versus host disease (sclGVHD) is a debilitating complication of hematopoietic stem cell transplant and is characterized by skin thickening and fibrosis that can result in severe contractures. While immunosuppressive therapy remains a mainstay of treatment, the disease course often progresses and, in severe cases, renders patients immobile and wheelchair-bound. Lasers that can target sclerotic lesions to improve tissue pliability and restore range of motion are a promising potential treatment for sclGVHD. Fractional CO2 lasers promote selective collagen remodeling by creating microcolumns of thermal injury that stimulate a wound healing response. Here, we present 2 patients with sclGVHD who underwent treatment with fractional ablative CO2 laser. In this pilot case series demonstrating the novel use of CO2 laser for severe, refractory sclGVHD, two patients were treated with fractional ablative CO2 laser to a focal area of sclerosis. One patient also received clobetasol ointment under occlusion in between treatments. Both patients reported marked subjective improvement in pain and mobility. Objective measurements were recorded for patient 2 who gained roughly 10 degrees of extension and 2 degrees of flexion, as well as a 10% reduction in skin thickness in the treated area. CO2 laser therapy with or without clobetasol ointment under occlusion is a promising treatment modality for sclGVHD.

[Sclerodermatous changes revealing porphyria cutanea tarda]. / État scléreux révélant une porphyrie cutanée tardive.

BACKGROUND: Porphyria cutanea tarda (PCT) is associated with cutaneous accumulation of porphyrins. This accumulation results from a deficiency of uroporphyrinogen decarboxylase occurring only in the liver. The classical presentation is blistering on sun-exposed areas. PATIENTS AND METHODS: A 59-year-old woman presented at the dermatology consultation for sclerotic lesions that had been present for one year. The remainder of the clinical examination and further investigations did not indicate systemic scleroderma. The sun-exposed nature of the lesions led us to perform an assay of urinary porphyrin, which was found to be elevated. Uroporphyrinogen decarboxylase levels were normal, confirming the diagnosis of type 1 PCT. Screening for a hepatic etiology revealed a heterozygous mutation H63D/C282Y of the hemochromatosis gene responsible for this clinical picture. The patient underwent regular bleeding, which led to complete disappearance of cutaneous sclerosis. DISCUSSION: Sclerodermatous lesions are an unusual presentation of PCT and cause delays in diagnosis. The accumulation of uroporphyrins in the dermis stimulates fibroblasts, which then synthesize collagen, resulting in cutaneous sclerosis.

Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole treatment option for highly malignant hematologic disease; however, the major complication-graft-versus-host disease (GVHD)-still hinders its clinical application. In addition, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HSCT. Previously we showed that bortezomib, a proteasome inhibitor, can ameliorate the sclerodermatous GVHD response while maintaining graft-versus-tumor (GVT) effects. Here we report that pevonedistat (MLN4924), an inhibitor of the Nedd8-activating enzyme, which functions upstream of the proteasome in the ubiquitin-proteasome pathway, can also show similar protective effects. Recipient mice treated with pevonedistat demonstrated inhibitory effects on sclerodermatous GVHD pathogenesis. The beneficial effect of pevonedistat was observed to be temporally dependent. Whereas treatment given at the time of allo-HSCT administration or before the onset of symptoms worsened the scleroderma response, therapeutic administration starting at 20 days post-transplantation ameliorated the sclerodermatous GVHD. Flow cytometry analysis revealed differential effects on immune subsets, with inhibition of only antigen-presenting cells and not of donor T cells. Finally, pevonedistat preserved GVT effects in a sclerodermatous murine model of B cell lymphoma. Taken together, these data suggest that inhibition of neddylation with pevonedistat can serve as an alternative approach for the treatment of GVHD while maintaining GVT effects in a murine model of sclerodermatous GVHD.

Eruptive angiokeratomas and porokeratosis in the setting of sclerodermatous graft-vs.-host disease.

Porokeratosis and angiokeratomas are both seen in the setting of chronic graft-vs.-host disease (GVHD), but rarely occur together. We present a case of a patient with lichen planus-like (LPL) and sclerodermatous chronic GVHD manifesting after allogeneic bone marrow transplant with concomitant eruptive angiokeratomas and porokeratosis.

Sclerodermatous Graft-Versus-Host Disease: A Rare Sequela of Hematopoietic Stem Cell Transplantation.

Although graft-versus-host disease (GVHD) is a common immunologic reaction after an allogeneic hematopoietic stem cell transplant (HSCT), progression into sclerodermatous GVHD is a rare sequela. It can present locally or generalized with various cutaneous and mucocutaneous manifestations, resulting in loss of skin elasticity and reduced functional capabilities. One of the most debilitating consequences of sclerodermatous GVHD is its effect on a range of motion due to fibrosis of the skin and subcutaneous fat. We present the case of a 54-year-old male with a medical history of acute myeloid leukemia and an allogeneic stem cell transplant who was diagnosed with sclerodermatous GVHD. We review the characteristic clinical and histopathological findings of sclerodermatous GVHD, as well as its treatment. Early recognition and intervention are crucial to prevent complications, such as joint contractures.

Targeting Bcl-6 prevents sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation in mice.

BACKGROUND: Chronic graft-versus-host disease (cGVHD) is the most common cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). CD4+ follicular helper T (Tfh) cells, specialized providers of T cell help to B cells, play a vital role in GVHD pathogenesis. B-cell lymphoma-6 (Bcl-6) transcription factor has been shown to be required for Tfh-mediated germinal center reactions. In this study, we would like to evaluate the effect of Bcl-6 on Tfh function in sclerodermatous cGVHD and the efficacy of Bcl-6 inhibitors (Bcl-6i) for treating a minor histocompatibility complex (miHC) mismatch model of sclerodermatous cGVHD (scl-cGVHD). METHODS: A minor histocompatibility haploidentical model of scl-cGVHD was established and received intraperitoneal injection of 79-6, a small-molecule inhibitor of Bcl-6. The clinical manifestations and survival times of cGVHD mice were recorded. The histological assessment was performed by hematoxylin-eosin (HE) and Masson's trichrome staining on the skin and lung tissues. Tfh cells and germinal center B cells in the spleen and peripheral blood were detected by flow cytometry. The cellular markers were immunostained in different organs. ELISA was performed to detect cytokine secretion. RESULTS: Bcl-6 inhibition by 79-6 improved the clinical manifestation of scl-cGVHD mice and prolonged their survival. The histopathologic damage, particular the fibrotic changes of scl-cGVHD mice was significantly relieved after 79-6 treatment. Furthermore, 79-6 treatment not only suppressed the development and function of Tfh and Tph cells in the peripheral blood, but also reduced the survival of Tfh cells in the spleen. Moreover, 79-6 decreased the frequency of GC plasmocytes accompanied by a reduction in IL-21. CONCLUSIONS: Our study demonstrates that Bcl-6 inhibitor could prevent murine sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation and suppressing the function of GC B cells, indicating that Bcl-6 inhibition may be a potential treatment for patients with cGVHD.

Mesenchymal stem cell-based therapy for autoimmune-related fibrotic skin diseases-systemic sclerosis and sclerodermatous graft-versus-host disease.

BACKGROUND: Systemic sclerosis (SSc) and sclerodermatous graft-versus-host disease (Scl-GVHD)-characterized by similar developmental fibrosis, vascular abnormalities, and innate and adaptive immune response, resulting in severe skin fibrosis at the late stage-are chronic autoimmune diseases of connective tissue. The significant immune system dysfunction, distinguishing autoimmune-related fibrosis from mere skin fibrosis, should be a particular focus of treating autoimmune-related fibrosis. Recent research shows that innovative mesenchymal stem cell (MSC)-based therapy, with the capacities of immune regulation, inflammation suppression, oxidation inhibition, and fibrosis restraint, shows great promise in overcoming the disease. MAIN BODY: This review of recent studies aims to summarize the therapeutic effect and theoretical mechanisms of MSC-based therapy in treating autoimmune-related fibrotic skin diseases, SSc and Scl-GVHD, providing novel insights and references for further clinical applications. It is noteworthy that the efficacy of MSCs is not reliant on their migration into the skin. Working on the immune system, MSCs can inhibit the chemotaxis and infiltration of immune cells to the skin by down-regulating the expression of skin chemokines and chemokine receptors and reducing the inflammatory and pro-fibrotic mediators. ​Furthermore, to reduce levels of oxidative stress, MSCs may improve vascular abnormalities, and enhance the antioxidant defenses through inducible nitric oxide synthase, thioredoxin 1, as well as other mediators. The oxidative stress environment does not weaken MSCs and may even strengthen certain functions. Regarding fibrosis, MSCs primarily target the transforming growth factor-ß signaling pathway to inhibit fibroblast activation. Here, miRNAs may play a critical role in ECM remodeling. Clinical studies have demonstrated the safety of these approaches, though outcomes have varied, possibly owing to the heterogeneity of MSCs, the disorders themselves, and other factors. Nevertheless, the research clearly reveals the immense potential of MSCs in treating autoimmune-related fibrotic skin diseases. CONCLUSION: The application of MSCs presents a promising approach for treating autoimmune-related fibrotic skin diseases: SSc and Scl-GVHD. Therapies involving MSCs and MSC extracellular vesicles have been found to operate through three primary mechanisms: rebalancing the immune and inflammatory disorders, resisting oxidant stress, and inhibiting overactivated fibrosis (including fibroblast activation and ECM remodeling). However, the effectiveness of these interventions requires further validation through extensive clinical investigations, particularly randomized control trials and phase III/IV clinical trials. Additionally, the hypothetical mechanism underlying these therapies could be elucidated through further research.

Sclerodermiform Dermatitis After Coronary Artery Bypass Graft With an Internal Thoracic Artery Conduit.

Coronary artery bypass grafting is a common surgical procedure that often uses the saphenous vein, internal thoracic artery, or radial artery as a conduit to improve blood circulation to the heart. When a blockage or impediment to arterial flow is noted, this procedure is undertaken to ensure the myocardium receives the blood it needs to function optimally. Infrequently, dermatoses overlying the conduit site may be observed, notably with the saphenous vein harvest site. Here we report the first case of sclerodermiform dermatitis occurring at the internal thoracic artery donor graft site. This unique case is important for providers to be aware of when evaluating a patient post-operatively who presents with new-onset dermatologic changes at the site of previous donor harvesting to ensure optimal treatment and management.

Efficacy of manual lymph drainage plus exercise on range of motion and flexibility in refractory chronic cutaneous graft-versus-host disease: A case report.

Graft-versus-host disease (GvHD) is a common complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with high morbidity and mortality rates. The purpose of this study was to demonstrate the efficacy of Manual Lymph Drainage (MLD) and a home-based exercise programme on range of motion (ROM) and flexibility in a patient diagnosed with chronic cutaneous GvHD. A 29-year-old male who was diagnosed as acute lymphoblastic leukemia underwent allo-HSCT after induction chemotherapy. He developed extended chronic cutaneous skin GvHD. He received systemic immunosuppressive treatment and Psoralen and ultraviolet radiation (PUVA) for 20 sessions. He was then consulted to physiotherapy department for the limitation of multiple ROM due to severe GvHD. The range of motions of shoulder, elbow, hip, knee and ankle joints were evaluated with universal goniometer. The chair sit, reach and back scratch tests were performed. MLD was applied for 2 weeks. Additionally, exercise recommendations were maintained as a home-programme. After the therapy, ROM values were better in wrist extension and hip abduction/adduction and the back scratch test result improved. According to chair sit and reach tests, the results decreased from 25 to 22cm distance after 2 weeks. With MLD treatment with exercise, ROM has been preserved and even improved in this refractory case. In addition, the flexibility test results were found to be increased. The efficacy of MLD and exercise in chronic cutaneous GvHD should be investigated in further studies.

CCL1 blockade alleviates human mesenchymal stem cell (hMSC)-induced pulmonary fibrosis in a murine sclerodermatous graft-versus-host disease (Scl-GVHD) model.

BACKGROUND: Human chronic graft-versus-host disease (CGVHD) shares clinical characteristics with a murine sclerodermatous GVHD (Scl-GVHD, B10.D2 → BALB/c) model that is characterized by skin and lung fibrosis. In this study, bone marrow- or adipose tissue-derived human mesenchymal stem cells (hMSCs) were injected into the Scl-GVHD mice to address their therapeutic effect on CGVHD. METHODS: Lethally irradiated BALB/c mice were transplanted with B10.D2 T cell-depleted bone marrow with or without spleen cells to generate Scl-GVHD. hMSCs were intravenously treated on days 3, 5, and 7 post-transplantation, and the control antibody or CCL1 blocking antibody was subcutaneously injected according to the same schedule as the hMSCs. Fourteen days after transplantation, the recipient mice were sacrificed, and their skin and lungs were analyzed. RESULTS: After the early injection of hMSCs after transplantation, the clinical and pathological severity of Scl-GVHD in the skin was significantly attenuated, whereas the pathological score was exacerbated in the lungs. hMSCs had migrated into the lungs, but not into the skin. CD11b monocyte/macrophages and CD4 T cells were markedly decreased in skin tissues, whereas there was an early recruitment of CD11b cells, and subsequently increased infiltration of CD4 T cells, in the lungs. Importantly, hMSCs persistently upregulated the expression of CCL1 in the lungs, but not in the skin. Concurrent treatment of hMSCs with a CCL1-blocking antibody alleviated the severity of the lung histopathology score and fibrosis with the preservation of the cutaneous protective effect against CGVHD. Infiltration of CD3 T cells and CD68 macrophages and upregulation of chemokines were also decreased in lung tissues, along with the recruitment of eosinophils and tissue IgE expression. In the skin, chemokine expression was further reduced after CCL1 blockade. CONCLUSIONS: These data demonstrate that despite a protective effect against Scl-GVHD in the skin, administration of hMSCs exacerbated lung fibrosis associated with eosinophilia and airway inflammation through persistent CCL1 upregulation. CCL1 blockade offers a potential treatment of pulmonary complications induced after treatment with hMSCs.

H Syndrome - A Case Report.

This case report describes a case of H syndrome with characteristic cutaneous hyperpigmentation, hypertrichosis, sclerodermatous thickening, and multisystem involvement such as hearing loss and heart anomaly in an Indian patient. There are around 100 cases of this rare, autosomal recessive genodermatosis reported in the literature, out of which 10 cases are from the Indian population. The aim of this paper is to increase awareness about this novel inherited form of histiocytosis and insist on the role of dermatologists to identify such patients in our population where consanguinity is prevalent.

Niclosamide: Beyond an antihelminthic drug.

Niclosamide is an oral antihelminthic drug used to treat parasitic infections in millions of people worldwide. However recent studies have indicated that niclosamide may have broad clinical applications for the treatment of diseases other than those caused by parasites. These diseases and symptoms may include cancer, bacterial and viral infection, metabolic diseases such as Type II diabetes, NASH and NAFLD, artery constriction, endometriosis, neuropathic pain, rheumatoid arthritis, sclerodermatous graft-versus-host disease, and systemic sclerosis. Among the underlying mechanisms associated with the drug actions of niclosamide are uncoupling of oxidative phosphorylation, and modulation of Wnt/ß-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways. Here we provide a brief overview of the biological activities of niclosamide, its potential clinical applications, and its challenges for use as a new therapy for systemic diseases.

Sclerodermatous Chronic Graft-versus-Host Disease Treated With Imatinib: A Dermatological Perspective. / Tratamiento de la enfermedad de injerto contra huésped crónica esclerodermiforme con imatinib: una perspectiva dermatológica.

INTRODUCTION: Chronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor. OBJECTIVE: To evaluate the response of cutaneous sclerodermatous cGVHD to imatinib. MATERIALS AND METHODS: Retrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians' assessment and patients' subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible. RESULTS: In our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months). CONCLUSIONS: This study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD.

Imatinib for sclerodermatous graft-versus-host disease in lung transplantation.

Imatinib has been proposed as a treatment for sclerodermatous chronic graft-versus-host disease (GVHD) due to its antifibrotic activity. Because imatinib has a potentially adverse effect on wound healing, the safety of its perioperative use in lung transplantation is unknown. Herein, we present a patient who underwent bilateral living-donor lobar lung transplantation for pulmonary complications after bone marrow transplantation, who had also received treatment with imatinib for sclerodermatous GVHD. Imatinib was discontinued 3 weeks before lung transplantation, but was resumed 1 week postoperatively for an exacerbation of sclerodermatous GVHD. Seven months after the postoperative the patient continues to do well without complications.