elafin and Graft-vs-Host-Disease

Acute GVHD remains an important complication after allogeneic hematopoietic cell transplantation (HCT). Many efforts have been devoted to identifying potential noninvasive peripheral blood biomarkers to help improve the diagnosis or management of acute GVHD while avoiding invasive tissue biopsies. Early attempts to identify biomarkers focused on inflammatory cytokines, especially IL-2 or TNF-α, however, both of these and others were not specific for GVHD, often being elevated in the setting of generalized inflammation, accompanying other major complications of HCT as well. More recent efforts have focused on additional cytokines and other cell-surface molecules, which function in leukocyte trafficking and activation with the hope that these can also serve as targets for novel therapeutic approaches. Modern proteomic methods have allowed the screening of large numbers of patient samples and yielded several novel candidate biomarkers, including elafin and reg3α, which may not be directly involved in the immunological pathogenesis of GVHD, but may be unique biomarkers for end-organ injury. Combining these new molecules with traditionally identified cytokines to form an acute GVHD biomarker panel has recently shown the ability to predict outcomes in patients who develop acute GVHD. The ultimate goals of identifying a specific biomarker are to refine diagnosis, guide therapy and develop risk-adapted approaches in order to better treat patients and improve outcomes after allogeneic HCT. These approaches include differential treatment for patients who develop acute GVHD with a high-risk biomarker profile as well as pre-emptive therapy in patients after HCT prior to the development of symptoms. With the recent progress summarized below, these goals may soon be realized.

Topics: Acute Disease; Allografts; Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Elafin; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-2; Lectins, C-Type; Pancreatitis-Associated Proteins; Proteomics; Tumor Necrosis Factor-alpha

Hematopoietic stem cell transplantation (HSCT) can cause serious transplant-related complications such as graft-versus-host disease (GVHD). Acute GVHD (aGVHD) has been diagnosed by clinical manifestations, laboratory data and pathological effects until now, but recently the discovery of specific biomarkers such as suppression of tumorigenicity 2 (ST2), elafin and regenerating islet-derived 3α (REG3α) is challenging this approach.. We investigated the expression of aGVHD-related markers (regulated on activation normal T-cell expressed and secretes: RANTES, elafin, REG3α and ST2) and endothelial cell activation markers (soluble vascular cell adhesion molecule: sVCAM-1 and plasminogen activator inhibitor: PAI-1) in patients undergoing allogeneic HSCT. Additionally, we studied the effects of recombinant soluble thrombomodulin (rTM) on the expression of these markers. Our study cohort included 225 patients who underwent allogeneic HSCT at several institutions in Japan.. RANTES, sVCAM-1, PAI-1, elafin, REG3α and ST2 exhibited significant increases in patients not receiving rTM after HSCT. When we examined patients with confirmed complications, the frequencies of aGVHD and VOD were significantly lower in the rTM-treated group. In addition, aGVHD-related biomarkers such as elafin, REG3α, and ST2 were elevated significantly in patients with aGVHD.. Our findings suggest that endothelial cell activation might be linked to aGVHD, and that rTM might act to prevent aGVHD, at least in part, through its effect on endothelial cells.

Topics: Acute Disease; Adolescent; Adult; Aged; Allografts; Biomarkers; Chemokine CCL5; Elafin; Endothelial Cells; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Vascular Cell Adhesion Molecule-1

Bone marrow mesenchymal stromal cells (BMSCs) have been used to treat acute graft-versus-host disease (GVHD) and other complications following allogeneic hematopoietic stem cell transplantation (SCT). We conducted a phase I trial using third party, early passage BMSCs for patients with steroid-refractory GVHD, tissue injury, or marrow failure following SCT to investigate safety and efficacy. To identify mechanisms of BMSC immunomodulation and tissue repair, patients were serially monitored for plasma GVHD biomarkers, cytokines, and lymphocyte phenotype. Ten subjects were infused a fixed dose of 2 × 10(6) BMSCs/kg intravenously weekly for three doses. There was no treatment-related toxicity (primary endpoint). Eight subjects were evaluable for response at 4 weeks after the last infusion. Five of the seven patients with steroid-refractory acute GVHD achieved a complete response, two of two patients with tissue injury (pneumomediastinum/pneumothorax) achieved resolution but there was no response in two subjects with delayed marrow failure. Rapid reductions in inflammatory cytokines were observed. Clinical responses correlated with a fall in biomarkers (Reg 3α, CK18, and Elafin) relevant for the site of GVHD or tissue injury. The GVHD complete responders survived significantly longer and had higher baseline absolute lymphocyte and central memory CD4 and CD8 counts. Cytokine changes also segregated with survival. These results confirm that BMSCs are associated with rapid clinical and biomarker responses in GVHD and tissue injury. However, BMSCs were ineffective in patients with prolonged GVHD with lower lymphocyte counts, which suggest that effective GVHD control by BMSCs requires a relatively intact immune system.

Topics: Adult; Aged; Antigens, Neoplasm; Biomarkers, Tumor; Bone Marrow Cells; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Elafin; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Keratin-18; Lectins, C-Type; Lymphocyte Count; Male; Mediastinal Emphysema; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Pancreatitis-Associated Proteins; Pneumothorax; Survival Analysis; Transplantation, Homologous; Treatment Outcome; Young Adult

Diagnosis of acute graft-vs-host disease (aGVHD) based on clinical symptoms and biopsy of involved organ was not satisfactory; reliable plasma biomarkers or their panels would be of great value to increase the sensitivity and specificity for such a fatal complication.. One hundred two patients who received allogeneic hematopoietic stem cell transplantation in our center were included in this study. Systemic biomarkers of ST2, IP10, IL-2Rα, TNFR1, and organ-specific biomarkers of Elafin, REG-3α, and KRT-18F in plasma were tested by ELISA. The correlation of each biomarker or selected panel of some systemic and organ-specific biomarker with aGVHD was investigated.. The level of each systemic biomarker in aGVHD patients was significantly higher than that in patients without aGVHD. Organ-specific biomarker of Elafin, REG-3α, and KRT-18F also had predictive value for aGVHD of skin, gastrointestinal tract, and liver, respectively. Combination of ST2 with one of the 3 organ-specific biomarkers could provide more accurate prediction for aGVHD with skin, gastrointestinal tract, and liver, respectively.. All the biomarkers tested in our study correlated with the severity and clinical course of aGVHD. Combination of each systemic biomarker with organ-specific biomarker could increase the sensitivity and specificity for the diagnosis of aGVHD, whereas ST2 with organ-specific biomarker is more sensitive for the diagnosis of organ-specific aGVHD.

Topics: Acute Disease; Biomarkers; Elafin; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-1 Receptor-Like 1 Protein; Sensitivity and Specificity

Acute graft-versus-host disease (GVHD) is a major cause of mortality in patients undergoing hematopoietic cell transplantation (HCT) for hematologic malignancies. The skin is the most commonly involved organ in GVHD. Elafin, a protease inhibitor overexpressed in inflamed epidermis, was previously identified as a diagnostic biomarker of skin GVHD; however, this finding was restricted to a subset of patients with isolated skin GVHD. The main driver of nonrelapse mortality (NRM) in HCT recipients is gastrointestinal (GI) GVHD. Two biomarkers, Regenerating islet-derived 3a (REG3α) and Suppressor of tumorigenesis 2 (ST2), have been validated as biomarkers of GI GVHD that predict long-term outcomes in patients treated for GVHD. We undertook this study to determine the utility of elafin as a prognostic biomarker in the general population of acute GVHD patients in whom GVHD may develop in multiple organs. We analyzed serum elafin concentrations as a predictive biomarker of acute GVHD outcomes and compared it with ST2 and REG3α in a large group of patients treated at multiple centers. A total of 526 patients from the Mount Sinai Acute GVHD International Consortium (MAGIC) who had received corticosteroid treatment for skin GVHD and who had not been previously studied were analyzed. Serum concentrations of elafin, ST2, and REG3α were measured by ELISA in all patients. The patients were divided at random into equal training and validation sets, and a competing-risk regression model was developed to model 6-month NRM using elafin concentration in the training set. Additional models were developed using concentrations of ST2 and REG3α or the combination of all 3 biomarkers as predictors. Receiver operating characteristic (ROC) curves were constructed using the validation set to evaluate the predictive accuracy of each model and to stratify patients into high- and low-risk biomarker groups. The cumulative incidence of 6-month NRM, overall survival (OS), and 4-week treatment response were compared between the risk groups. Unexpectedly, patients in the low-risk elafin group demonstrated a higher incidence of 6-month NRM, although the difference was not statistically significant (17% versus 11%; P = .19). OS at 6 months (68% versus 68%; P > .99) and 4-week response (78% versus 78%; P = .98) were similar in the low-risk and high-risk elafin groups. The area under the ROC curve (AUC) was 0.55 for elafin and 0.75 for the combination of ST2 and REG3α. The addition of elafin to

Topics: Biomarkers; Elafin; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Prognosis

Topics: Adult; Aged; Biomarkers; Cyclophosphamide; Disease-Free Survival; Elafin; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Skin; Transplantation, Haploidentical; Young Adult

Acute cutaneous graft-versus-host disease (acGVHD) following haematopoietic stem cell transplant (HSCT) is common but difficult to distinguish from other causes of rash. Plasma elafin has been proposed as a diagnostic and prognostic biomarker of skin GVHD.. To evaluate the role of plasma elafin as a biomarker in acGVHD in an Indian population.. Plasma elafin was evaluated in a prospective study of HSCT recipients, conducted over 2 years, taking measurements at baseline and at onset of skin rash after HSCT. Patients were categorized into those with GVHD rash, those with non-GVHD rash and those with no rash and the three groups were compared.. Two hundred and sixty-one patients with a median age of 16 years (range 1-61 years) and a male predominance (175 : 86 M/F) underwent HSCT during the study period: 56 patients in the GVHD group, 49 in the non-GVHD group and 156 in the no-rash group. The median baseline elafin was similar in all three groups. At the onset of rash, median elafin level was similar between GVHD and non-GVHD rash (34 549 vs. 32 077 pg/mL; P = 0.58) and between GVHD and no rash (34 549 vs. 26 197 pg/mL; P = 0.08). A rise in elafin from baseline was significantly different between GVHD and no rash (P < 0.001) but not between GVHD and non-GVHD rash (P = 0.44).. The utility of plasma elafin as a biomarker of skin GVHD is very limited. Plasma elafin, although elevated in cutaneous GVHD, is not helpful in distinguishing between GVHD rash and other causes of rash following HSCT.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Diagnosis, Differential; Elafin; Exanthema; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Middle Aged; Young Adult

The skin is the most common organ involved in acute graft-versus-host disease (GvHD). Because histopathology has limited utility in ruling out clinical mimics of acute skin GvHD, more accurate diagnostic techniques are required.. To evaluate the utility of elafin expression in skin by immunohistochemistry (IHC) for accurate diagnosis of acute skin GvHD.. Consecutive allogeneic haematopoietic stem cell transplant (HSCT) recipients during a 6-month period who developed rash within the first 100 days post-transplant were recruited. Skin biopsies were taken on the day the rash developed. IHC for epidermal elafin was performed and interpreted by a pathologist blinded to the histopathological diagnosis. Staining of ≥ 50% of epidermis was considered positive. Final diagnosis of the rash was assigned using clinical features supported by histopathology. The accuracy of elafin IHC in predicting the final diagnosis of acute GvHD was evaluated.. In total, 23 patients (20 male, 3 female; median age 16 years, range 3-53 years) with 27 episodes of skin rash were recruited. Skin rash post-HSCT occurred at a median of 20 days (range 5-45 days). A diagnosis of GvHD was made in 16 episodes (59.26%) while the remaining 11 episodes (40.74%) were judged to be non-GvHD rash. Elafin IHC was positive in all patients with GvHD. Of the 11 episodes of non-GvHD rash, elafin was negative in 8. Thus, the sensitivity and specificity of elafin IHC for predicting acute skin GvHD was 100% and 75%, respectively.. Tissue elafin is a useful immunohistochemical marker for acute skin GvHD. However, larger studies are needed to validate these results.

Topics: Adolescent; Adult; Biomarkers; Child; Child, Preschool; Elafin; Female; Graft vs Host Disease; Humans; Male; Middle Aged; Pilot Projects; Skin; Skin Transplantation; Young Adult

Severe cutaneous adverse reactions (SCARs) are frequent in inpatient oncology. Early intervention might reduce morbidity, mortality, and hospitalization costs; however, current clinical and histologic features are unreliable SCAR predictors. There is a need to identify rational markers of SCARs that could lead to effective therapeutic interventions.. To characterize the clinical and serologic features of hospitalized patients with cancer who developed SCARs.. Retrospective review of 49 hospitalized cancer patients with a morbilliform rash, recorded testing for serum cytokines (interleukin [IL] 6, IL-10, and tumor necrosis factor [TNF] α) or elafin, and a prior dermatology consultation. Patients were categorized as having a simple morbilliform rash without systemic involvement or complex morbilliform rash with systemic involvement.. Fifteen out of 49 patients (30.6%) were deceased at 6 months from time of dermatologic consultation. Elafin, IL-6, and TNF-α were significantly higher in patients who died compared with patients who were still alive at 6 months. IL-6 and IL-10 were significantly higher in patients with a drug-related complex rash.. Retrospective design, limited sample size, and high-risk patient population.. In cancer patients with SCARs, elafin, IL-6, and TNF-α levels might predict a poor outcome. Agents directed against these targets might represent rational treatments for the prevention of fatal SCARs.

Topics: Adult; Antineoplastic Agents; Biomarkers; Body Surface Area; Cytokines; Drug Hypersensitivity Syndrome; Edema; Elafin; Eosinophilia; Face; Female; Fever; Graft vs Host Disease; Hospital Mortality; Hospitalization; Humans; Interleukin-10; Interleukin-6; Lymphocytes; Male; Neoplasms; Purpura; Retrospective Studies; Stevens-Johnson Syndrome; Tumor Necrosis Factor-alpha

Topics: Aged; Biomarkers; Diagnosis, Differential; Elafin; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Skin; Stevens-Johnson Syndrome

Graft-versus-host disease (GVHD) is associated with kidney injury after hematopoietic cell transplantation (HCT). Because plasma elafin levels correlate with skin GVHD, this study examined urinary elafin as a potential marker of renal inflammation and injury.. Urine was collected prospectively on 205 patients undergoing their first HCT from 2003 to 2010. Collections were done at baseline, weekly through day 100, and monthly through year 1 to measure elafin and urine albumin-to-creatinine ratio (ACR). Associations between urinary elafin levels and microalbuminuria, macroalbuminuria, AKI and CKD, and mortality were examined using Cox proportional hazards or linear regression models. Available kidney biopsy specimens were processed for immunohistochemistry.. Mean urinary elafin levels to day 100 were higher in patients with micro- or macroalbuminuria (adjusted mean difference, 529 pg/ml; P=0.03) at day 100 than in those with a normal ACR (adjusted mean difference, 1295 pg/ml; P<0.001). Mean urinary elafin levels were higher in patients with AKI compared with patients without AKI (adjusted mean difference, 558 pg/ml; P<0.01). The average urinary elafin levels within the first 100 days after HCT were higher in patients who developed CKD at 1 year than in patients without CKD (adjusted mean difference, 894 pg/ml; P=0.002). Among allogeneic recipients, a higher proportion of patients with micro- or macroalbuminuria at day 100 also had grade II-IV acute GVHD (80% and 86%, respectively) compared with patients with a normal ACR (58%; global P<0.01). Each increase in elafin of 500 pg/ml resulted in a 10% increase in risk of persistent macroalbuminuria (hazard ratio, 1.10; 95% confidence interval [95% CI], 1.06 to 1.13; P<0.001) and a 7% increase in the risk of overall mortality (95% CI, 1.02 to 1.13, P<0.01). Renal biopsy specimens from a separate cohort of HCT survivors demonstrated elafin staining in distal and collecting duct tubules.. Higher urinary elafin levels are associated with an increased risk of micro- and macroalbuminuria, AKI and CKD, and death after HCT.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Albuminuria; Biomarkers; Biopsy; Case-Control Studies; Child; Child, Preschool; Creatinine; Elafin; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunohistochemistry; Kidney; Linear Models; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Up-Regulation; Young Adult

Graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. In the skin, GVHD can present in an acute (aGVHD), chronic lichenoid (clGVHD), or chronic sclerotic form (csGVHD). Measuring peripheral blood levels of the keratinocyte-derived protease inhibitor elafin has recently emerged as a promising tool for the diagnosis of cutaneous aGVHD. We evaluated whether the analysis of elafin expression in skin would allow distinguishing aGVHD from drug hypersensitivity rashes (DHR) and whether cutaneous elafin expression would correlate with disease severity or altered prognosis of aGVHD and clGVHD/csGVHD. Skin biopsies from aGVHD (n=22), clGVHD (n=15), csGVHD (n=7), and DHR (n=10) patients were collected and epidermal elafin expression and its association with diverse clinical/histological parameters were analyzed. Acute GVHD and DHR displayed varying degrees of elafin expression. No elafin was detectable in csGVHD, whereas the molecule was increased in clGVHD as compared with aGVHD. Elafin-high aGVHD/clGVHD lesions presented with epidermal thickening and were associated with poor prognosis-i.e., decreased overall survival in aGVHD and corticosteroid resistance in clGVHD. Although cutaneous elafin does not seem to discriminate aGVHD from DHR lesions, our study strongly suggests an association between cutaneous elafin expression and poor prognosis for patients with cutaneous GVHD.

Topics: Adult; Biopsy; Cohort Studies; Elafin; Epidermis; Female; Gene Expression Profiling; Gene Expression Regulation; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Microscopy, Fluorescence; Middle Aged; Prognosis; Real-Time Polymerase Chain Reaction; Transforming Growth Factor beta; Treatment Outcome; Tumor Necrosis Factor-alpha

Topics: Aged; Biomarkers; Biopsy, Needle; Central Nervous System Neoplasms; Elafin; Erythema; Follow-Up Studies; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunohistochemistry; Lymphoma; Male; Neoplasm Recurrence, Local; Risk Assessment; Sensitivity and Specificity; Syndrome; Treatment Outcome

Topics: Adolescent; Adult; Bone Marrow; Child; Child, Preschool; Elafin; Enzyme-Linked Immunosorbent Assay; Female; Graft vs Host Disease; Humans; Interleukin-2 Receptor alpha Subunit; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Monitoring, Immunologic; Prognosis; Receptors, Tumor Necrosis Factor, Type I; Young Adult

Acute graft-versus-host disease (GVHD) is the primary limitation of allogeneic hematopoietic cell transplantation, and once it develops, there are no reliable diagnostic tests to predict treatment outcomes. We hypothesized that 6 previously validated diagnostic biomarkers of GVHD (IL-2 receptor-α; tumor necrosis factor receptor-1; hepatocyte growth factor; IL-8; elafin, a skin-specific marker; and regenerating islet-derived 3-α, a gastrointestinal tract-specific marker) could discriminate between therapy responsive and nonresponsive patients and predict survival in patients receiving GVHD therapy. We measured GVHD biomarker concentrations from samples prospectively obtained at the initiation of treatment, day 14, and day 28, on a multicenter, randomized, 4-arm phase 2 clinical trial for newly diagnosed acute GVHD. We found that at each of 3 time points, GVHD onset, 2 weeks into treatment, and 4 weeks into treatment, a 6-protein biomarker panel predicted for the important clinical outcomes of day 28 posttherapy nonresponse and mortality at day 180 from onset. GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment nonresponsiveness or death, and they may provide opportunities for early intervention and improved survival after hematopoietic cell transplantation. The study was registered in clinicaltrials.gov as NCT00224874.

Topics: Acute Disease; Adult; Aged; Biomarkers; Bone Marrow Transplantation; Elafin; Female; Graft vs Host Disease; Hepatocyte Growth Factor; Humans; Immunosuppressive Agents; Interleukin-8; Logistic Models; Male; Middle Aged; Pancreatitis-Associated Proteins; Predictive Value of Tests; Prognosis; Proteins; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Tumor Necrosis Factor-alpha; Young Adult

Unbiased discovery proteomics strategies have the potential to identify large numbers of novel biomarkers that can improve diagnostic and prognostic testing in a clinical setting and may help guide therapeutic interventions. When large numbers of candidate proteins are identified, it may be difficult to validate candidate biomarkers in a timely and efficient fashion from patient plasma samples that are event-driven, of finite volume and irreplaceable, such as at the onset of acute graft-versus-host disease (GVHD), a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we describe the process of performing commercially available ELISAs for six validated GVHD proteins: IL-2Rα(5), TNFR1(6), HGF(7), IL-8(8), elafin(2), and REG3α(3) (also known as PAP1) in a sequential fashion to minimize freeze-thaw cycles, thawed plasma time and plasma usage. For this procedure we perform the ELISAs in sequential order as determined by sample dilution factor as established in our laboratory using manufacturer ELISA kits and protocols with minor adjustments to facilitate optimal sequential ELISA performance. The resulting plasma biomarker concentrations can then be compiled and analyzed for significant findings within a patient cohort. While these biomarkers are currently for research purposes only, their incorporation into clinical care is currently being investigated in clinical trials. This technique can be applied to perform ELISAs for multiple proteins/cytokines of interest on the same sample(s) provided the samples do not need to be mixed with other reagents. If ELISA kits do not come with pre-coated plates, 96-well half-well plates or 384-well plates can be used to further minimize use of samples/reagents.

Topics: Antigens, Neoplasm; Biomarkers; Biomarkers, Tumor; Elafin; Enzyme-Linked Immunosorbent Assay; Graft vs Host Disease; Hepatocyte Growth Factor; High-Throughput Screening Assays; Humans; Interleukin-2 Receptor alpha Subunit; Lectins, C-Type; Pancreatitis-Associated Proteins; Receptors, Tumor Necrosis Factor, Type I

To analyze the specificity, sensitivity and receiver operating characteristic (ROC) curve of plasma elafin for diagnosis of skin acute graft-versus-host disease (aGVHD), and to explore its clinical diagnostic value.. Incidence of skin aGVHD from fifty-three patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) were observed prospectively in Guangdong General Hospital from Apr 2010 to Aug 2011. The plasma concentrations of elafin were detected by enzyme-linked immunosorbent assay (ELISA). Skin biopsies were taken from 28 patients with skin rash, and elafin expression in the skin was detected by immunohistochemistry. Positive expression was defined as significant staining of at 50% of the depth of the epidermis, excluding the granular cell layer and the acrosyringium.. Among 28 patients with skin rash, twenty-five were considered as skin aGVHD by clinical diagnosis, seventeen were confirmed as skin aGVHD by pathological biopsy. 11 cases were elafin positive by immunohistochemical staining. Elafin protein was overexpressed in aGVHD skin tissue (P = 0.001). Plasma concentrations of elafin were significantly higher in patients with skin aGVHD (positive) group than in those without skin aGVHD (negative) group (P = 0.005), among which there being no statistically significant difference in plasma elafin level between patients with grade I skin aGVHD group and negative group(P = 0.971), but being statistically significant difference compared patients with grade II-IV skin aGVHD group with those with grade I skin aGVHD group (P = 0.02) and with negative group (P = 0.008). Using the pathological diagnosis as the gold standard, the estimated specificity and the sensitivity of clinical diagnosis criteria were 27.3% and 100%, respectively, and those of tissue elafin protein level were 100% and 64.7%, respectively. The area under the ROC curve was 0.909 (0.797 - 1.021) when plasma concentrations of elafin was used in diagnosis of skin aGVHD. The sensitivity was 82.4% and the specificity was 81.8 % when the critical value was set at 1456.043 µg/L.. Plasma concentration of elafin is significantly higher at the onset of skin aGVHD. It can be used as biochemical marker of skin aGVHD and has higher value in diagnosis of skin aGVHD.

Topics: Adolescent; Adult; Elafin; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; ROC Curve; Sensitivity and Specificity; Skin Diseases; Young Adult

Graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation, affects the skin, liver, and gastrointestinal tract. There are no plasma biomarkers specific for any acute GVHD target organ. We used a large-scale quantitative proteomic discovery procedure to identify biomarker candidates of skin GVHD and validated the lead candidate, elafin, with enzyme-linked immunosorbent assay in samples from 492 patients. Elafin was overexpressed in GVHD skin biopsies. Plasma concentrations of elafin were significantly higher at the onset of skin GVHD, correlated with the eventual maximum grade of GVHD, and were associated with a greater risk of death relative to other known risk factors (hazard ratio, 1.78). We conclude that elafin has significant diagnostic and prognostic value as a biomarker of skin GVHD.

Topics: Adolescent; Adult; Aged; Biomarkers; Child; Child, Preschool; Elafin; Enzyme-Linked Immunosorbent Assay; Graft vs Host Disease; Humans; Infant; Infant, Newborn; Middle Aged; Prognosis; Skin