Graft-versus-host disease: part II. Management of cutaneous graft-versus-host disease.
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ABSTRACT:
SUBMITTER: Hymes SR
PROVIDER: S-EPMC7357210 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
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Graft-versus-host disease: part II. Management of cutaneous graft-versus-host disease.
Hymes Sharon R SR Alousi Amin M AM Cowen Edward W EW
Journal of the American Academy of Dermatology 20120401 4
Dermatologists are ideally suited to manage the various cutaneous sequelae of graft-versus-host disease (GVHD) outlined in part I of this review. However, the complexity of the patient with GVHD, including comorbidities, potential drug interactions related to polypharmacy, and the lack of evidence-based treatment guidelines, are significant challenges to optimizing patient care. In this section, we will provide an outline for the role of the dermatologist in a multispecialty approach to caring f ...[more]
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Project description:BackgroundSkin biopsies are often used in daily practice for the diagnosis of acute (aGvHD) or chronic graft versus host disease (cGvHD). With the latest understanding in pathogenesis and new National Institute of Health (NIH) classifications for aGvHD and cGvHD, there is a need to evaluate the current prognostic value of histological grading cutaneous GvHD and its correlation to the clinical grade.MethodsIn a retrospective study with 120 skin biopsies (all taken for suspected GvHD) from 110 patients (all classified according to the NIH), biopsies were revised and graded, blinded for clinical information, for either acute of chronic features. Morphological grades were compared for concordance with the clinical grade and survival analyses were done for clinical and histological grading.ResultsCorrelation for histologic vs. clinical grading was (very) poor for aGvHD and cGvHD (weighted κ - 0.038 and 0.0009, respectively). Patients with clinical aGvHD had worse prognosis compared to cGvHD. However, at time of biopsy neither clinical nor histological grading predicted the eventual survival for either aGvHD (p = 0.9739 and p = 0.0744, respectively) or cGvHD (p = 0.2149 and p = 0.4465, respectively).ConclusionsConfirming the diagnosis of GvHD is still a valuable reason for taking a skin biopsy, but this study shows that histologic grading of GvHD in the skin biopsy has no additional value for clinicians in current practice.
| S-EPMC6457000 | biostudies-literature
Project description:Allogeneic hematopoietic stem cell transplantation is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40-70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In this study, we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n = 5, stages 1-3) and healthy volunteers (n = 4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n = 8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n = 17), pre-HSCT skin biopsies (n = 6) and normal controls (n = 6) for their association with aGvHD. Expression of let-7c (p = 0.014), miR-503-5p (p = 0.003), miR-365a-3p (p = 0.02), miR-34a-5p (p < 0.001) and miR-34a-3p (p = 0.006) were significantly differentially expressed between groups and significantly associated with survival outcome in post-HSCT patients (miR-503-5p ROC AUC = 0.83 p = 0.021, Log Rank p = 0.003; miR-34a-3p ROC AUC = 0.93, p = 0.003, Log Rank p = 0.004). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p = 0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2 = 0.44, p = 0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p = 0.001), miR-34a-5p (p = 0.005), and miR-34a-3p (p = 0.004) was significantly elevated in the sera of patients who developed aGvHD versus no-aGvHD (n = 30) and miR-503-5p was associated with overall survival (OS) (ROC AUC = 0.80, p = 0.04, Log Rank p = 0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for OS. In addition, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes.
| S-EPMC6048189 | biostudies-literature
Project description:The kinetics of gene expression associated with the development of cutaneous graft-versus-host disease (GVHD) were examined in a mouse model of MHC-matched allogeneic hematopoietic stem cell transplantation. Ear skin was obtained from recipient mice with or without GVHD between 7 and 40 days after transplantation for histopathological analysis and gene expression profiling. Gene expression patterns were consistent with early infiltration and activation of CD8(+) T and mast cells, followed by CD4(+) T, natural killer, and myeloid cells. The sequential infiltration and activation of effector cells correlated with the histopathological development of cutaneous GVHD and was accompanied by up-regulated expression of many chemokines and their receptors (CXCL-1, -2, -9, and -10; CCL-2, -5, -6, -7, -8, -9, -11, and -19; CCR-1 and CCR-5), adhesion molecules (ICAM-1, CD18, Ly69, PSGL-1, VCAM-1), molecules involved in antigen processing and presentation (TAP1 and TAP2, MHC class I and II, CD80), regulators of apoptosis (granzyme B, caspase 7, Bak1, Bax, and BclII), interferon-inducible genes (STAT1, IRF-1, IIGP, GTPI, IGTP, Ifi202A), stimulators of fibroblast proliferation and matrix synthesis (interleukin-1beta, transforming growth factor-beta1), and markers of keratinocyte proliferation (keratins 5 and 6), and differentiation (small proline-rich proteins 2E and 1B). Many acute-phase proteins were up-regulated early in murine cutaneous GVHD including serum amyloid A2 (SAA2), SAA3, serpins a3g and a3n, secretory leukocyte protease inhibitor, and metallothioneins 1 and 2. The kinetics of gene expression were consistent with the evolution of cutaneous pathology as well as with current models of disease progression during cutaneous GVHD.
| S-EPMC1615752 | biostudies-literature
Project description:Chronic graft-versus-host disease (cGVHD) is the most common cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (alloHCT). Cutaneous cGVHD is characterized by thickening of the skin and connective tissues, causing discomfort and limited mobility. Current assessment of these skin lesions is based on physical examination of their thickening, pinchability, and movability. Optical coherence tomography (OCT) is a noninvasive, high-resolution technique using near-infrared light to interrogate tissues and image the microstructure without the use of contrast agents. We determined the applicability of OCT to human cutaneous cGVHD. Seven patients with varying degrees of cutaneous cGVHD, including 3 controls who underwent autologous HCT were prospectively examined using the cGVHD Skin (Vienna) Scale and imaged with OCT. Analysis of OCT images and clinical exams revealed that stratum corneum thickness, epidermal thickness, and depth of light transmission were correlated with cutaneous cGVHD severity in the hands, forearms, upper arms, legs, thighs, and upper back (P ≤ .03). Longitudinal OCT changes during cGVHD treatment paralleled clinical changes in the arm and upper back. OCT changes were observed in the absence of clinical changes. OCT imaging reflects the severity of cutaneous cGVHD and can be used to follow these lesions. OCT may facilitate the design of therapeutic trials in cGVHD by providing a quantitative measurement of cGVHD severity. Additional studies are needed.
| S-EPMC8010224 | biostudies-literature
Project description:Cutaneous erythema is used in diagnosis and response assessment of cutaneous chronic graft-versus-host disease (cGVHD). The development of objective erythema evaluation methods remains a challenge. We used a pre-trained neural network to segment cGVHD erythema by detecting changes relative to a patient's registered baseline photo. We fixed this change detection algorithm on human annotations from a single photo pair, by using either a traditional approach or by marking definitely affected ("Do Not Miss", DNM) and definitely unaffected skin ("Do Not Include", DNI). The fixed algorithm was applied to each of the remaining 47 test photo pairs from six follow-up sessions of one patient. We used both the Dice index and the opinion of two board-certified dermatologists to evaluate the algorithm performance. The change detection algorithm correctly assigned 80% of the pixels, regardless of whether it was fixed on traditional (median accuracy: 0.77, interquartile range 0.62-0.87) or DNM/DNI segmentations (0.81, 0.65-0.89). When the algorithm was fixed on markings by different annotators, the DNM/DNI achieved more consistent outputs (median Dice indices: 0.94-0.96) than the traditional method (0.73-0.81). Compared to viewing only rash photos, the addition of baseline photos improved the reliability of dermatologists' scoring. The inter-rater intraclass correlation coefficient increased from 0.19 (95% confidence interval lower bound: 0.06) to 0.51 (lower bound: 0.35). In conclusion, a change detection algorithm accurately assigned erythema in longitudinal photos of cGVHD. The reliability was significantly improved by exclusively using confident human segmentations to fix the algorithm. Baseline photos improved the agreement among two dermatologists in assessing algorithm performance.
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Project description:BackgroundGraft-versus-host disease (GvHD) is a major life-threatening complication of allogeneic haematopoietic stem cell transplantation (HSCT), limiting the broad application of HSCT for haematological malignancies. Cutaneous GvHD is described as a post-transplant inflammatory reaction by skin-infiltrating donor T cells and remaining recipient tissue-resident memory T cells. Despite the major influence of lymphocytes on GvHD pathogenesis, the complex role of mononuclear phagocytes (MNPs) in tissues affected by GvHD is increasingly appreciated.ObjectivesTo characterize the identity, origin and functions of MNPs in patients with acute cutaneous GvHD.MethodsUsing single-cell RNA sequencing and multiplex tissue immunofluorescence, we identified an increased abundance of MNPs in skin and blood from 36 patients with acute cutaneous GvHD. In cases of sex-mismatched transplantation, we used expression of X-linked genes to detect rapid tissue adaptation of newly recruited donor MNPs resulting in similar transcriptional states of host- and donor-derived macrophages within GvHD skin lesions.ResultsWe showed that cutaneous GvHD lesions harbour expanded CD163+ tissue-resident macrophage populations with anti-inflammatory and tissue-remodelling properties including interleukin-10 cytokine production. Cell-cell interaction analyses revealed putative signalling to strengthen regulatory T-cell responses. Notably, macrophage polarization in chronic cutaneous GvHD types was proinflammatory and drastically differed from acute GvHD, supporting the notion of distinct cellular players in different clinical GvHD subtypes.ConclusionsOverall, our data reveal a surprisingly dynamic role of MNPs after HSCT. Specific and time-resolved targeting to repolarize this cell subset may present a promising therapeutic strategy in combatting GvHD skin inflammation.
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Project description:Graft versus host disease (GVHD) is initiated by donor allo-reactive T cells activated against recipient antigens. Chronic GVHD (cGVHD) is characterized by immune responses that may resemble autoimmune features present in the scleroderma and Sjogren's syndrome. Unfortunately, ocular involvement occurs in approximately 60-90% of patients with cGVHD following allo-hematopoietic stem cell transplants (aHSCT). Ocular GVHD (oGVHD) may affect vision due to ocular adnexa damage leading to dry eye and keratopathy. Several other compartments including the skin are major targets of GVHD effector pathways. Using mouse aHSCT models, the objective was to characterize cGVHD associated alterations in the eye and skin to assess for correlations between these two organs. The examination of multiple models of MHC-matched and MHC-mismatched aHSCT identified a correlation between ocular and cutaneous involvement accompanying cGVHD. Studies detected a "positive" correlation, i.e., when cGVHD-induced ocular alterations were observed, cutaneous compartment alterations were also observed. When no or minimal ocular signs were detected, no or minimal skin changes were observed. In total, these findings suggest underlying cGVHD-inducing pathological immune mechanisms may be shared between the eye and skin. Based on the present observations, we posit that when skin involvement is present in aHSCT patients with cGVHD, the evaluation of the ocular surface by an ophthalmologist could potentially be of value.
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Project description:Genital chronic graft-versus-host disease (GVHD) in women posthaematopoietic cell transplantation may cause vaginal mucosal sclerosis. Human papillomavirus (HPV) reactivation, also common post-transplantation, limits local immunosuppressive, but not oestrogen treatment. A 36-year-old nulliparous woman developed coincidental genital chronic GVHD and HPV 22 months after transplant for aplastic anaemia. Topical immunosuppression for GVHD led to an eruption of warts successfully treated with laser surgery and cone biopsy. She maintained normal ovarian function and used extended cycle combined hormonal contraception. A vaginal oestrogen ring used continuously limited most scarring for 8?years. Progressive apical vaginal scarring obstructed menstrual flow leading to haematocolpos and haematometra. Normal anatomy was restored with a cruciate incision in the cervicovaginal scar performed during menses. When HPV disease limits use of topical immunosuppression in women with vaginal GVHD, the local scar-reducing effect of a vaginal oestrogen ring is limited, and surgery may be needed and can be successful in treating haematocolpos.This study was registered in ClinicalTrials.gov with trial registration number of NCT00003838.
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Project description:The significance of upper gastrointestinal tract (UGI) acute GVHD (aGVHD) compared with other grade II aGVHD is not clearly defined. We compared the outcomes of patients with grade II aGVHD with or without biopsy-proven UGI involvement in three groups: grade II aGVHD without UGI (n=178), grade II aGVHD with UGI and other sites (n=102) and isolated UGI aGVHD (n=32). The overall response (ORR) to steroids at day 28 differed among the three groups (76, 67 and 91%, respectively, P=0.01), but was only marginally different in direct comparison with those without or with UGI aGVHD (P=0.07) or with isolated UGI aGVHD (P=0.06). In multivariate analysis, as compared with grade II aGVHD patients without UGI involvement, those with UGI involvement and those with isolated UGI aGVHD had similar risks of chronic GVHD, relapse and non-relapse mortality and similar disease-free survival and overall survival. Our data suggest that patients with UGI aGVHD have similar outcomes as those without UGI involvement, supporting the view that UGI aGVHD should still be included as a grade II-defining event.
| S-EPMC5744262 | biostudies-literature
Project description:Sclerotic skin manifestations of chronic graft-versus-host disease (ScGVHD) lead to significant morbidity, including functional disability from joint range of motion (ROM) restriction. No superior second-line therapy has been established for steroid-refractory disease. Imatinib mesylate is a multikinase inhibitor of several signaling pathways implicated in skin fibrosis with in vitro antifibrotic activity. We performed an open-label pilot phase II trial of imatinib in children and adults with corticosteroid-refractory ScGVHD. Twenty patients were enrolled in a 6-month trial. Eight received a standard dose (adult, 400 mg daily; children, 260 mg/m(2) daily). Because of poor tolerability, 12 additional patients underwent a dose escalation regimen (adult, 100 mg daily initial dose up to 200 mg daily maximum; children, initial dose 65 mg/m(2) daily up to 130 mg/m(2) daily). Fourteen patients were assessable for primary response, improvement in joint ROM deficit, at 6 months. Primary outcome criteria for partial response was met in 5 of 14 (36%), stable disease in 7 of 14 (50%), and progressive disease in 2 of 14 (14%) patients. Eleven patients (79%), including 5 with partial response and 6 with stable disease, demonstrated a positive gain in ROM (range of 3% to 94% improvement in deficit). Of 13 patients with measurable changes at 6 months, the average improvement in ROM deficit was 24.2% (interquartile range, 15.5% to 30.5%; P = .011). This trial is registered at http://clinicaltrials.gov as NCT007020689.
| S-EPMC4425991 | biostudies-literature