Sclerotic chronic GVHD: you may WANT to block WNT.
Ontology highlight
ABSTRACT:
SUBMITTER: Lee SJ
PROVIDER: S-EPMC8085478 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oral chronic GVHD (cGVHD) is a serious complication of alloSCT. Scales and instruments to measure oral cGVHD activity and severity have not been prospectively validated. The objective of this study was to describe the characteristics of oral cGVHD and determine the measures most sensitive to change. Patients enrolled in the cGVHD Consortium with oral involvement were included. Clinicians scored oral changes according to the National Institutes of Health (NIH) criteria, and patients completed symptom and quality-of-life measures at each visit. Both rated change on an eight-point scale. Of the 458 participants, 72% (n=331) had objective oral involvement at enrollment. Lichenoid change was the most common feature (n=293; 89%). At visits where oral change could be assessed, 50% of clinicians and 56% of patients reported improvement, with worsening reported in 4-5% for both the groups (weighted kappa=0.41). Multivariable regression modeling suggested that the measurement changes most predictive of perceived change by clinicians and patients were erythema and lichenoid, NIH severity and symptom scores. Oral cGVHD is common and associated with a range of signs and symptoms. Measurement of erythema and lichenoid changes and symptoms may adequately capture the activity of oral cGVHD in clinical trials but require prospective validation.
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Project description:In 2005, the National Institutes of Health sponsored a Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host (cGVHD) to achieve consensus about key elements of cGVHD research, including definitions for diagnosis, severity scoring, and response measures. To test these proposed definitions, a multicenter prospective cohort study of people with cGVHD is ongoing. This study will evaluate the performance of proposed prognostic factors, measures of disease activity, and surrogate endpoints for therapeutic response. Data are collected at 6-month intervals in a heterogeneous population of patients reflecting modern transplant techniques and posttransplantation clinical management (target enrollment 672 with cGVHD from 10 transplantation centers). This report describes the rationale, design, and methods of the cGVHD cohort study, and invites other investigators to collaborate with the Consortium to analyze data or specimens.
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Project description:Biologic markers of chronic GVHD may provide insight into the pathogenesis of the syndrome, identify molecular targets for novel interventions, and facilitate advances in clinical management. Despite extensive work performed to date largely focused on prediction and diagnosis of the syndrome, little synthesis of findings and validation of promising candidate markers in independent populations has been performed. Studies suggest that risk for subsequent chronic GVHD development may be associated with donor-recipient genetic polymorphism, deficiency in regulatory immune cell populations (NK, Treg, DC2), and variation in inflammatory and immunoregulatory mediators post-HCT (increased TNF?, IL-10 and BAFF, and decreased TGF? and IL-15). Established chronic GVHD is associated with alteration in immune cell populations (increased CD3(+) T cells, Th17, CD4(+) and CD8(+) effector memory cells, monocytes, CD86 expression, BAFF/B cell ratio, and deficiency of Treg, NK cells, and naïve CD8(+) T cells). Inflammatory and immunomodulatory factors (TNF?, IL-6, IL-1?, IL-8, sIL-2R, and IL-1Ra, BAFF, anti-dsDNA, sIL-2R?, and sCD13) are also perturbed. Little is known about biologic markers of chronic GVHD phenotype and severity, response to therapy, and prognosis.
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Project description:The International Chronic Ocular GVHD Consensus Group held 4 working meetings to define new diagnostic metrics for chronic ocular graft-versus-host disease (GVHD). After considering the factors currently used to diagnose chronic ocular GVHD, the Consensus Group identified 4 subjective and objective variables to measure in patients following allogeneic hematopoietic stem cell transplantation (HSCT): OSDI, Schirmer's score without anesthesia, corneal staining, and conjunctival injection. Each variable was scored 0-2 or 0-3, with a maximum composite score of 11. Consideration was also given to the presence or the absence of systemic GVHD. On the basis of their composite score and the presence or absence of systemic GVHD, patients were assigned to one of three diagnostic categories: NO, PROBABLE, or DEFINITE ocular GVHD. New diagnostic criteria for chronic ocular GVHD are presented by the Consensus Group. Validation studies are needed to identify the best combination of the proposed metrics to maximize diagnostic sensitivity and specificity.
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Project description:Skin biomechanical parameters (dynamic stiffness, frequency, relaxation time, creep, and decrement) measured using a myotonometer (MyotonPRO) could inform management of sclerotic disease. To determine which biomechanical parameter(s) can accurately differentiate sclerotic chronic graft-versus-host disease (cGVHD) patients from post-hematopoietic cell transplant (post-HCT) controls, 15 sclerotic cGVHD patients and 11 post-HCT controls were measured with the myotonometer on 18 anatomic sites. Logistic regression and two machine learning algorithms, LASSO regression and random forest, were developed to classify subjects. In univariable analysis, frequency had the highest overfit-corrected area under the receiver operating characteristic curve (AUC 0.91). Backward stepwise selection and random forest machine learning identified frequency and relaxation time as the optimal parameters for differentiating sclerotic cGVHD patients from post-HCT controls. LASSO regression selected the combination of frequency and relaxation time (overfit-corrected AUC 0.87). Discriminatory ability was maintained when only the sites accessible while the patient is supine (12 sites) were used. We report the distribution of values for these highly discriminative biomechanical parameters, which could inform assessment of disease severity in future quantitative biomechanical studies of sclerotic cGVHD.
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