Thymus And Activation-regulated Chemokine Levels Research Articles

Changes in the composition of molecular species of covalently bound and free ceramides [EOS], and their correlation with disease severity in atopic dermatitis.

Ceramides are major constituents of stratum corneum (SC) intercellular lipids involved in skin barrier function. The ratio of molecular species of ceramides and their correlation with disease severity was examined in patients with atopic dermatitis (AD). Thirty-eight patients with AD and 32 healthy controls (HCs) were assessed for transepidermal water loss, SC collection and clinical assessment. The ceramide content of different molecular species in the samples was quantified using high-performance liquid chromatography coupled with tandem mass spectrometry. Unsaturated acyl chains of both covalently bound and free ceramides [EOS] were higher in AD lesional skin than those in AD non-lesional or normal HC skin. The proportion of unsaturated acyl chains (C30:1, C32:1 and C34:1) was higher than other ceramide molecular species among covalently bound and free ceramides [EOS] in patients with AD. The proportion of unsaturated acyl chains in covalently bound ceramides was positively correlated with transepidermal water loss (r = 0.600) when considering the total number of non-lesional and lesional skin. Additionally, thymus and activation-regulated chemokine (TARC) showed a positive correlation with unsaturated acyl chains proportion in AD non-lesional (r = 0.676) and lesional (r = 0.503) skin. Our study is the first to show the increase in unsaturated acyl chains of both covalently bound and free ceramides [EOS] in lesional and non-lesional skin in AD for each molecular species. This increase is associated with dryness and impaired barrier function, which correlates with TARC levels, a marker for the degree of type 2 inflammation. We speculate that type 2 inflammation exacerbation leads to abnormal epidermal lipid metabolism in the skin of patients with AD.

Effects of Dupilumab on Itch-Related Events in Atopic Dermatitis: Implications for Assessing Treatment Efficacy in Clinical Practice.

Dupilumab attenuates itch and skin inflammation in patients with atopic dermatitis (AD). However, itch-related events that are improved by dupilumab remain unclear. Therefore, the present study investigated changes in clinical scores, serum biomarkers, and the number of intraepidermal nerve fibers (IENFs) using skin biopsies and blood samples from 12 patients with moderate to severe AD before and after treatment with dupilumab. Clinical manifestations were assessed using eczema area and severity index (EASI) and visual analogue scale (VAS) scores at baseline and after 8 and 16 weeks of treatment. Serum levels of total immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), interleukin (IL)-4, IL-13, IL-22, and IL-31 were examined by electrochemiluminescence, chemiluminescent enzyme immunoassays, ProQuantum immunoassays, and enzyme-linked immunosorbent assays (ELISA) at baseline and after 8 and 16 weeks of treatment. In skin biopsies from AD patients at baseline and after 16 weeks of treatment, IENFs were examined immunohistochemically with the anti-protein gene product (PGP) 9.5 antibody. The dupilumab treatment significantly improved EASI and VAS scores and decreased serum levels of TARC, IgE, and IL-22, whereas those of IL-13 and IL-31, and the number of IENFs remained unchanged and those of IL-4 increased. VAS scores were positively correlated with serum TARC, IL-22, and IgE levels and the degree of epidermal thickening. Serum IL-31 levels were positively correlated with the number of IENFs. These results suggest that serum TARC, IL-22, and IgE levels and epidermal thickness are itch-related events associated with dupilumab treatment and that serum IL-31 levels may reflect the degree of IENF density in AD patients. Therefore, dynamic changes may be used to assess the efficacy of dupilumab treatment to treat itching and inflammation in patients with AD.

The influence of <i>Aspergillus fumigatus</i> micromycetes on immune response regulation in patients with asthma

Introduction. Aspergillus fumigatus is able not only to sensitize patients with atopy, but also to colonize the respiratory tract, remaining a constant source of allergens due to the small spore size and thermal tolerance. Currently, the role of micromycetes in the immunopathogenesis of asthma has been poorly studied. The objective was to evaluate the features of the immune response regulation in patients with allergic bronchopulmonary aspergillosis (ABPA) or asthma with sensitization to A. fumigatus. Materials and methods. There were enrolled 15 patients with ABPA, 10 patients with asthma with sensitization to A. fumigatus, 16 patients with asthma without sensitization to A. fumigatus. The control group consisted of 16 apparently healthy volunteers. All patients underwent a clinical and functional examination. The subpopulations of blood lymphocytes were assessed by flow cytometry. The A. fumigatus allergen was added to peripheral blood samples to evaluate the production of IFN, IL-10 and IL-13. The serum cytokine levels in cell culture supernatants, as well as total IgE, A. fumigatus-specific IgE (sIgE) as well as thymus and activation-regulated chemokine (TARC) level were measured by enzyme-linked immunosorbent assay. Results. Significantly higher serum levels of total IgE, A. fumigatus-specific sIgE and TARC were found in patients with ABPA and asthma with sensitization to A. fumigatus compared to patients with asthma without sensitization to A. fumigatus. The results of lymphocyte immunophenotyping revealed significant excess of memory Th2 cells and T-regulatory cells in all patients with asthma compared to the control group. The count of Tfh2 was higher but memory Th17.1 cells were lower in patients with sensitization to A. fumigatus compared to those of apparently healthy volunteers. Patients with ABPA had significantly higher count of memory Th2 cells and TARC level compared to patients with asthma sensitized to A. fumigatus. The increased activity of memory Th2 cells is confirmed by increased secretion of IL-13 and IL-10 following along with decreased IFN production in response to specific fungal allergen stimulation of blood cells compared to the patients with asthma and the control group. A positive correlation was revealed between the count of memory Th2 cells and the levels of sIgE, IgE, TARC, a negative correlation with FEV1. Conclusion. Thus, exposure to A. fumigatus significantly enhances the activity of memory Th2 cells in patients with asthma which can lead to severe disease course and development of allergic bronchopulmonary aspergillosis. The features of the immune response identified dictate a need for a personalized approach to choose therapeutic tactics in such patients.

Two‐sided influence of dupilumab on alopecia areata co‐existing with severe atopic dermatitis: A case series and literature review

AbstractObjectivesAlopecia areata (AA) often coexists with atopic dermatitis (AD). Recently, several reports suggested that dupilumab, an interleukin 4 receptor α‐antagonist, administration could be a promising medication not only for severe AD but also for AA concomitant with AD (AD‐AA). At the same time, dupilumab has also been reported to exacerbate AA in AD‐AA cases. Thus, the efficacy of dupilumab on AA in AD‐AA cases remains controversial.MethodsIn this study, we retrospectively analyzed four AD‐AA cases treated with dupilumab to evaluate its influence on AD and AA.ResultsAll cases had suffered from severe AD since childhood and their average eczema area and severity index (EASI) scores prior to dupilumab administration was 43.2 ± 15.0. Three of four cases had moderate to severe multifocal AA, which successfully recovered in response to dupilumab, accompanied by the decrease in serum thymus and activation‐regulated chemokine (TARC) levels and significant improvement of AD, achieving approximately 90% improvement of EASI scores within 3 months. In contrast, the remaining one case developed rapidly progressive hair loss 8 months after the initiation of dupilumab. In this case, AD was incompletely controlled by dupilumab with the elevation of serum TARC level despite AD improvement. The literature review found 39 dupilumab‐treated AD‐AA cases with elaborate description of clinical course; 24 cases with AA improvement, 15 cases with AA exacerbation, or new onset.ConclusionsThese findings alert physicians that use of dupilumab in expectation of AA improvement in AD‐AA cases can lead to unfortunate consequence in some patients.

054 Combination of thymus and activation-regulated chemokine and soluble OX40 as a diagnostic biomarker for DIHS/DRESS

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe drug-induced adverse reaction with fever, cutaneous eruptions, hematological abnormalities, organ dysfunction, and reactivation of human herpesvirus 6 (HHV-6). Although rapid diagnosis is necessary for the management of DIHS/DRESS, it is difficult to distinguish the early phase of DIHS/DRESS from other drug eruptions. We have previously reported that thymus and activation-regulated chemokine (TARC), which plays an important role in Th2-mediated immune-inflammatory processes such as atopic dermatitis, and serum soluble OX40 (CD134), which has an important role in allergic inflammation and functions as a cellular receptor for HHV-6 entry, can be a useful diagnostic marker for DIHS/DRESS. The sensitivity and specificity of sOX40 (cut-off value 213 pg/ml) for the diagnosis of DIHS/DRESS were 67% and 80%, respectively. Those of TARC (cut-off value 4000 pg/ml) were 72% and 77%, respectively. In this study, in order to reveal the relationship between serum soluble OX40 and TARC levels in the acute phase of DIHS/DRESS as well as the sensitivity and specificity of serological test using both soluble OX40 and TARC for diagnosis of DIHS/DRESS, we analyzed the sera of DIHS/DRESS patients presenting to our department. We found that the two markers were significantly correlated, and the combination of sOX40 and TARC significantly increased sensitivity to 85% but decreased specificity to 73%. The combined determination using sOX40 and TARC levels may be useful to increase the detection rate of DIHS/DRESS.

Immune Signature of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

Introduction: In our phase II study (Moskowitz AJ et al, JCO 2021), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (P-GVD) was found to be highly effective as salvage for patients (pts) with relapsed or refractory (R/R) classic Hodgkin lymphoma (cHL) proceeding to high dose therapy and autologous hematopoietic cell transplantation (AHCT). We present analyses assessing immunologic changes associated with P-GVD treatment as well as updated clinical outcome. Methods: Transplant eligible pts with R/R cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of P-GVD followed by AHCT. Peripheral blood samples were collected at baseline, after 2 cycles of P-GVD, before AHCT, 3 and 9 months after AHCT. Peripheral blood was analyzed for serum thymus and activation-regulated chemokine (TARC) and immune cell subsets. TARC was measured by enzyme-linked immunosorbent assay. Immune cell subsets, including T-cells and myeloid-derived suppressor cells (MDSC), were measured by multi-parametric flow cytometry (FC). Metabolic tumor volume (MTV) was evaluated at baseline. Changes in MDSC and TARC levels were assessed using Wilcoxon rank sum and Friedman tests, respectively. Correlations between MTV and either TARC or MDSC were assessed using Pearson's R. Results: Of 38 evaluable pts, the complete response (CR) rate after 2 or 4 cycles of P-GVD was 95%. Two pts declined AHCT and 36 proceeded to AHCT. After a median follow-up of 30 months (range: 2-43), only 1 pt experienced disease progression 23 months after AHCT. The estimated 30-month progression-free survival (PFS) is 96%. The median baseline MTV value was 37 cm3 (range 4- 845). 36/38 and 27/38 pts had sufficient correlative samples to perform analysis for TARC and MDSC analysis, respectively. The median baseline TARC level was 526 pg/mL (range: 12-4017). TARC levels decreased significantly after 2 cycles of P-GVD (p < 0.001) and increased post-AHCT. Circulating MDSCs were 0.05% of total mononuclear cells (range: 0.003-0.59%) and significantly increased after 2 cycles of P-GVD (p<0.001). Higher baseline TARC and circulating MDSC levels correlated with higher baseline MTV (r=0.45, 95% CI: 0.11-0.70, p<0.01 and r=0.46, 95%CI 0.03-0.76, p=0.03, respectively). High-dimensional analysis of FC data revealed several distinct immune clusters (Figure 1), of which non-proliferating PD-1+ CD4+ T-cells decreased most significantly following treatment (Figure 2). Additional markers (ICOS, CTLA-4, LAG-3, FOXP3) of immune exhaustion showed only a mild decrease over the treatment course. Conclusions: After a median of 30-months follow-up, second-line P-GVD continues to be associated with durable remissions after AHCT. These analyses provide insights into key immune changes associated with chemoimmunotherapy in HL. Baseline TARC correlated with baseline MTV and was significantly lower after P-GVD, illustrating its role as a marker of tumor bulk. The subsequent rise in serum TARC post AHCT suggests immune reconstitution of TARC-secreting cells. Higher circulating levels of MDSCs correlated with baseline MTV, which may reflect an association between immune suppression and tumor bulk. MDSC levels unexpectedly increased after P-GVD, indicating that a rise in MDSCs after treatment may not necessarily predict for poor outcomes. Ongoing single-cell RNA sequencing analysis of peripheral blood mononuclear cells (PBMC) may provide further understanding into immune dynamics associated with P-GVD treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real‐world effectiveness and safety of dupilumab in patients with moderate and severe atopic dermatitis: 2‐year experience

AbstractObjectiveDupilumab has been deemed highly effective for atopic dermatitis (AD). However, there have been no reports performing a combination analysis with hematological data and improvement rates pertaining to the continued use of dupilumab for up to 2 years in real world. In this study, we evaluated the effectiveness and safety of using dupilumab for up to 2 years in 9 patients with AD at our hospital.MethodsThirty‐six patients with moderate‐to‐severe AD treated by dupilumab, and 9 of them treated for 2 years. Changes in the severity scoring, pruritus numerical rating scale (NRS), patient‐oriented eczema measure (POEM), serum levels of immunoglobulin E (IgE), thymus and activation‐regulated chemokine (TARC), eosinophils, and lactate dehydrogenase (LDH) at Week 0, 2, 4, 16, 48, 72, and 96 of those patients were investigated, and we studied features of the patients who had any adverse events (AEs).ResultsInvestigator’s global assessment (IGA), eczema area and severity index (EASI), body surface area (BSA), NRS, POEM, and serum levels of LDH were significantly decreased from Week 4 onwards to Week 96 compared with baseline condition. Serum levels of TARC and LDH were significantly decreased from Week 4 onwards to Week 96. Regarding 9 patients who were treated with dupilumab for up to 2 years, serum levels of TARC and eosinophils decreased without statistical significance. The serum levels of IgE significantly decreased at Week 72, 96 compared with the baseline. Regarding as AEs, ocular symptoms were the most frequently observed (15/36, 41.2%), and there were no cases of discontinuation due to AEs.ConclusionsTreatment with dupilumab was well tolerated and showed improvements in AD for at least 2 years.

Comparison of Acute Phase Thymus and Activation-Regulated Chemokine (TARC) Levels in Food Protein-Induced Enterocolitis Syndrome and IgE-Dependent Food Allergy.

Introduction: Patients with food protein-induced enterocolitis syndrome (FPIES) have elevated thymus and activation-regulated chemokine (TARC) levels in the acute phase. However, to the best of our knowledge, no study has evaluated TARC levels in the acute phase of immunoglobulin E-dependent food allergy (IgE-FA). If TARC elevation is a specific response to FPIES among FAs, TARC measurement may help distinguish between FPIES and IgE-FA. Thus, we investigated acute phase TARC levels in patients with FPIES and IgE-FA. Methods: Thirty-one episodes in 16 patients with FPIES and 20 episodes (13 were anaphylaxis) in 20 patients with IgE-FA were included. Patients with eczema were excluded. Serum TARC levels within 6 h of allergic reaction onset and age-adjusted TARC ratios (TARC levels divided by age-specific normal TARC values) were compared between the groups. Results: The median age was 1.1 and 3.6 years in the FPIES and IgE-FA groups, respectively (P < 0.001). The median (range) serum TARC (pg/mL) levels were significantly higher in the FPIES group than in the IgE-FA group [1,283 (410-3,821) versus 377 (109-1,539); P < 0.001]. The median (range) age-adjusted TARC ratios were also significantly higher in the FPIES group [2.56 (0.57-7.86) versus 1.08 (0.15-2.17); P < 0.001]. The area under the curve (AUC) for TARC to distinguish FPIES from IgE-FA was 0.926, and the AUC for the age-adjusted TARC ratio was 0.850. The odds ratio for FPIES diagnosis per 1,000 pg/mL increase in TARC was 31.6 (P = 0.002), and the odds ratio adjusted by age was 17.1 (P = 0.016). Conclusion: Acute phase TARC levels were higher in patients with FPIES than in patients with IgE-FA. The increase in acute phase TARC levels was considered to be a specific response to FPIES among FAs. Measurement of TARC levels in the acute phase may help differentiate FPIES from IgE-FA.

Serum thymus and activation-regulated chemokine (TARC) levels correlate with atopic dermatitis disease severity in patients < 6 months.

Background: Atopic dermatitis (AD) may develop by 6 months of age, and its severity assessment is essential for appropriate treatments. Scoring Atopic Dermatitis (SCORAD) is suggested to evaluate the severity of AD but is cumbersome for routine clinical use. The serum thymus and activation-regulated chemokine (TARC) is used as a marker of AD severity. However, the normal range of the TARC levels varies by age, and its usefulness for the evaluation of AD severity has not been established in patients ages < 6 months. Here, we evaluated the correlation between serum TARC levels and SCORAD scores in early infancy and sought the optimal cutoff level to indicate AD severity. Methods: The subjects were 35 patients with AD (16 girls and 19 boys; 3-5 months of age) who visited our clinic between April 2015 and March 2017. All the patients were physically examined by a board-certified allergist. The AD severity was determined by using the SCORAD, together with serum levels of TARC, total immunoglobulin E (IgE), lactate dehydrogenase, and peripheral eosinophil counts. Receiver operating characteristic curve analysis was performed to determine the cutoff levels of serum TARC to indicate AD severity. Results: Significant correlations were observed between SCORAD scores and the serum TARC levels, peripheral eosinophil counts, and serum IgE levels (r = 0.640, r = 0.723, r = 0.533, respectively). The optimal cutoff levels of serum TARC to indicate mild and severe AD were <3523 pg/mL (area under the curve [AUC] = 0.856) and >6192 pg/mL (AUC = 0.833), respectively. Conclusion: Although this study had limitations, we suggest that serum TARC is useful as a marker of AD severity in patients <6 months of age.

TARC/CCL17 Expression Is Associated with CD8+ T Cell Recruitment in Abacavir-Induced Skin Hypersensitivity in HLA-Transgenic Mice.

Abacavir (ABC)-induced hypersensitivity (AHS) is strongly associated with human leukocyte antigen (HLA)-B*57 : 01 expression. Previous studies have demonstrated the feasibility of applying the HLA-transgenic mouse model in this context. ABC-induced adverse reactions were observed in HLA-B*57 : 01 transgenic (B*57 : 01-Tg) mice. Moreover, regulating immune tolerance could result in severe AHS that mimics symptoms observed in the clinical setting, which were modeled in CD4+ T cell-depleted programmed death-1 receptor (PD-1) knockout B*57 : 01-Tg (B*57 : 01-Tg/PD-1-/-) mice. Here, we aimed to examine whether thymus and activation-regulated chemokine (TARC)/CCL17 level can be used as a biomarker for AHS. Serum TARC levels increased in HLA-B*57 : 01-transgenic mice following oral administration of ABC; this increase was associated with the severity of skin toxicity. In ABC-fed CD4+ T cell-depleted B*57 : 01-Tg/PD-1-/- mice, TARC was detected in the epidermal keratinocytes of the ear. Skin toxicity was characterized by the infiltration of CD8+ T cells partially expressing C-C chemokine receptor type 4, which is the primary receptor for TARC. In vivo TARC neutralization effectively alleviated the symptoms of ear skin redness and blood vessel dilatation. Moreover, TARC neutralization suppressed the infiltration of CD8+ T cells to the ear skin but did not affect the ABC-induced adaptive immune response. Therefore, TARC was involved in ABC-induced skin toxicity and contributed to the recruitment of CD8+ T cells to skin. This evidence suggests that serum TARC level may be a functional biomarker for AHS.

Differences in Thymus and Activation-Regulated Chemokine and Squamous Cell Carcinoma Antigen 2 Levels in Food Protein-Induced Enterocolitis Syndrome and Atopic Dermatitis

Introduction: We previously reported that thymus and activation-regulated chemokine (TARC) levels measured after vomiting are useful predictors of a food protein-induced enterocolitis syndrome (FPIES) diagnosis. However, interpreting TARC levels in patients with eczema is difficult, as the levels are similarly elevated in patients with eczema caused by atopic dermatitis (AD). Therefore, we aimed to investigate whether it is possible to predict whether FPIES or AD is responsible for elevated TARC levels by simultaneously measuring TARC and squamous cell carcinoma antigen 2 (SCCA2), another T-helper type 2 biomarker. Methods: Twenty-one episodes in 11 patients with FPIES (FPIES group) and 42 age-matched patients with AD (AD group) were included in this study. Serum TARC and SCCA2 levels were measured, and those values and relative ratios were compared between groups. Results: The median age was 1.1 years in the FPIES group and 1.6 years in the AD group (p = 0.492). The median (interquartile range [IQR]) serum TARC concentration was significantly higher in the FPIES group than in the AD group (2,486 [1,815–4,097] pg/mL and 1,451 [1,201–1,751] pg/mL, respectively; p = 0.002). The median (IQR) SCCA2 concentration was significantly higher in the AD group than in the FPIES group (1.9 [1.3–2.9] pg/mL and 0.8 [0.6–1.5] pg/mL, respectively; p < 0.001). After matching, the analysis using stratified TARC values revealed no significant difference in TARC values between the FPIES and AD groups; however, the TARC/SCCA2 ratio was significantly higher in the FPIES group. Conclusion: Assessing the relative TARC/SCCA2 ratio may help predict whether elevated TARC levels measured after vomiting are caused by FPIES or AD.

Poor prognostic factors of Sézary syndrome: A retrospective single‐center study from Japan

AbstractObjectivesAlthough the prognosis of Sézary syndrome (SS) is highly unfavorable, the prognostic factors have not been fully understood. In this study, we tried to investigate the prognostic factors in Japanese SS patients for the first time.MethodsWe performed a retrospective cohort study of 19 SS patients who visited our hospital between January 1, 1999, and December 31, 2019. The collected clinical findings were age, gender, performance status (PS), and TNMB staging at diagnosis. TNMB staging was determined according to the International Society for Cutaneous Lymphomas and the cutaneous task force of the European Organization of Research and Treatment of Cancer criteria. The collected hematological findings were serum levels of soluble IL‐2 receptor (sIL‐2R), lactate dehydrogenase (LDH), thymus and activation‐regulated chemokine (TARC), and immunoglobulin E (IgE), Sézary cell count, Sézary cell ratio among white blood cells, and eosinophil count in peripheral blood at diagnosis.ResultsWe analyzed the correlations between overall survival and various clinical and hematological findings. In the log‐rank test, PS1‐3, N2‐3 stage, higher serum levels of LDH (≥355 IU/L), sIL‐2R (≥1729 U/ml) and TARC (≥19,867 pg/ml), and higher Sézary cell count (≥7480/μl) and Sézary cell ratio among white blood cells (≥52%) at diagnosis were associated with decreased overall survival.ConclusionsThis is the first report evaluating prognostic factors in Asian SS patients. This study may contribute to selecting the treatment strategy and improving survival and quality of life of Asian SS patients.

Serum thymus and activation-regulated chemokine level is associated with the severity of chronic kidney disease-associated pruritus in patients undergoing peritoneal dialysis

Thymus and activation-regulated chemokine (TARC), which induces a Th2-dominated inflammation, is a well-known biomarker that reflects the severity of atopic dermatitis. The present study aimed to evaluate TARC as a Th2-associated marker with chronic kidney disease-associated pruritus (CKD-aP) in patients with peritoneal dialysis (PD). This single-centre cross-sectional study included patients who underwent PD in our hospital between August 2020 and July 2021. The severity and impaired quality of life (QOL) of CKD-aP were assessed using the visual analogue scale (VAS) and Japanese version of the 5-D itch scale (5D-J), respectively. A total of 48 patients with PD were included in the present study. Age and dialysis vintage were (mean ± SD) 64.8 ± 12.0 year and (median (IQR)) 38.5 (11.5-91.5) month, respectively. VAS and 5D-J scores were 3.3 ± 2.0 and 10.5 (9.0-12.0), respectively. Serum TARC level was 481.5 (278.9-603.4) pg/mL (upper limits of normal 450 pg/mL) and significantly correlated with VAS (r = 0.39, p = 0.006) and 5D-J score (r = 0.37, p = 0.009). Multivariate linear analysis revealed that higher serum TARC level was significantly associated with VAS (p < 0.001) and 5D-J score (p < 0.001). Furthermore, the serum brain natriuretic peptide level tended to be associated with VAS (p = 0.060) and 5D-J score (p = 0.029). Serum TARC level is an independent predictor of the severity and impaired QOL of CKD-aP in patients with PD, and TARC might be involved in the pathogenesis of CKD-aP.

Correlation between lactate dehydrogenase and other laboratory data in patients with atopic dermatitis

Serum lactate dehydrogenase (LDH) can be a clinical marker for assessment of the severity and clinical course of atopic dermatitis (AD). One hundred twenty-eight patients with AD who visited Hirosaki University Hospital were included in this study. There are positive correlations between LDH and IgE, thymus and activation-regulated chemokine (TARC), and eosinophils, while TARC and eosinophils are used in evaluating type I-allergic disease, especially AD, and it is considered that LDH is also useful for evaluation of the severity of AD. Dear Editor, Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic and eczematous lesions.1 AD is associated with elevated serum immunoglobulin (Ig) E levels, specific IgE environmental allergens such as house dust mites, and tissue and peripheral blood eosinophilia.1 Since AD is thought to be a Th2-dominant inflammatory skin disease, especially in the acute phase, thymus and activation-regulated chemokine (TARC) is assumed to be involved in its pathogenesis.2, 3 Lactate dehydrogenase (LDH) is an enzyme present in most cells. Previous studies4 found that elevated serum LDH5 levels are correlated with epidermal cell damage in eczema-associated erythroderma and changes in serum LDH levels can serve as a clinical marker for assessing the severity and clinical course of AD.2 The aim of the present study was to explore the correlation between LDH levels and other laboratory data such as IgE and TARC levels and eosinophil count in patients with AD who visited Hirosaki University Hospital. This study was approved by the Committee of Medical Ethics of Hirosaki University Graduate School of Medicine in Aomori, Japan. This study included 128 patients with AD who visited Hirosaki University Hospital. The following variables were measured: LDH; white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, and basophils); platelet count; and levels of hemoglobin, TARC, total IgE, and C-reactive protein (CRP). Laboratory data were retrieved from medical records. We investigated the correlation between LDH levels and each laboratory variable using Pearson's test. The Pearson correlation coefficient is a measure of linear correlation between two sets of data. The result always has a value between −1 and 1. The significance level was set at p < .05, and the correlation coefficient ±.4 to ±.7 was considered as correlation. Only total IgE and TARC levels were positively correlated with LDH levels. The correlation coefficient for IgE and LDH levels was .54 (p < .001) (Figure 1A). The correlation coefficient for TARC and LDH levels was .57 (p < .001) (Figure 1B). Eosinophil count was weakly correlated with LDH levels (correlation coefficient, .41; p < .001) (Figure 1C). There was no correlation between TARC and IgE levels, TARC levels and eosinophil count, or IgE levels and eosinophil count. In this study, LDH levels were positively correlated with total IgE levels, TARC levels, and eosinophil count, respectively. Although the correlation between serum IgE levels and disease severity of AD is controversial, a previous study reported that IgE is significantly correlated with EASI score.5 LDH is also considered useful for evaluating disease severity of AD. Since TARC measurement is costly and should be performed only once a month for AD under the Japanese health insurance system, LDH levels and eosinophil count, which are more convenient markers than TARC levels, could be useful in daily clinical evaluation of patients with AD. The limitation of this study is that we did not compare LDH and disease severity of AD directly. So, we cannot conclude yet, and further study is needed. The authors express their gratitude to the study patients, their families, and caregivers, and the investigators who participated in the study; Ms. Haruka Sasaki and Mr. Tatsuto Inoue, Hirosaki University Graduate School of Medicine, in Aomori, Japan, for data analysis. This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (project 20k08684, to S. Minakawa), and by the 2021 Hirosaki University Research Support System. Approval of the research protocol: The protocol for this research project has been approved by a suitably constituted Ethics Committee of the institution, and it conforms to the provisions of the Declaration of Helsinki. The study protocol was approved by the Committee of Medical Ethics of Hirosaki University Graduate School of Medicine. Approval No. 2021-025. Informed Consent: All informed consent was obtained from the subjects or guardians. Registry and the Registration No. of the study/trail: The study outline was registered and published in the Japan Registry of Clinical Trials (trial ID no. jRCT1020210017). Animal Studies: N/A. The authors declare no conflict of interest. Management of the peer review process, and all editorial decision making, for this article was undertaken by Editor in Chief, Prof. Manabu Fujimoto.

Combined prognostic role of TARC and interim 18F-FDG PET/CT in patients with Hodgkin lymphoma-real world observational study.

Although the majority of patients with Hodgkin lymphoma (HL) has recently become long-term survivors, 20%-30% of HL patients have primary refractory disease or relapse. It is essential to identify patients at risk of treatment failure during first-line therapy. To objective of the present study was to investigate the combined prognostic role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging and thymus and activation-regulated chemokine (TARC) levels in Hodgkin lymphoma. Between 01/01/2013 and 01/03/2019 77 HL patients were enrolled in this study where serum TARC levels were measured by an immunoassay and 18F-FDG PET/CT scans were performed at baseline, after the second cycle of ABVD treatment (interim) and at the end of first-line therapy. Twenty-six patients (34%) had early-stage HL, while 51 patients presented with advanced-stage disease. Fifteen patients had primary refractory HL, while 1 patient relapsed after first-line therapy. Optimal TARC cut-off value for progression-free survival (PFS) was 700pg/mL based on receiver operating characteristic (ROC) curve analysis. With Cox regression analysis, 18F-FDG PET/CT with Deauville scores of 3, 4, or 5 and TARC levels above 700pg/mL predicted treatment failure at interim assessment. Inclusion of HL patients with a Deauville score of 3 to the high-risk population resulted in a 7-fold increase in the estimated risk of relapse compared to patients with Deauville score 4-5 with TARC levels above 700pg/mL. Patients with interim 18F-FDG PET/CT Deauville scores 3-5 had a significant survival benefit if their TARC levels were 700pg/mL. Positive predictive value (PPV) of interim 18F-FDG PET/CT scans with a Deauville score 3-5 was 47.8%, while combined PPV of a similar 18F-FDGPET/CT assessment and elevated TARC levels was 88.8%. Interim 18F-FDG PET/CT and TARC analyzed together accurately identify HL patients who do not respond sufficiently to treatment and who need an early change of therapy.

Serum thymus and activation-regulated chemokine (TARC) levels in newly diagnosed patients with Hodgkin lymphoma: a new promising and predictive tool? Preliminary report

Thymus and activation-regulated chemokine (TARC) is expressed on Reed-Sternberg cells of patients with classical Hodgkin lymphoma (HL) and may serve as a marker in response assessment. In our study, we correlated serum TARC levels with early response to treatment measured by PET/CT in 19 newly diagnosed patients with HL who received ABVD (Adriblastin, Bleomycin, Vinblastine, Dacarbazine) regimen. Finally, 17 patients were analyzed and six of them (35%) achieved PET/CT negativity defined as Deauville (D) 1 or 2 after 2 cycles of ABVD; 11 pts (65%) had D3 on PET/CT. None of the patients presented D 4/5. Median serum TARC levels at diagnosis were significantly higher when compared with healthy controls: 5718 pg/ml vs 76.1 pg/ml (p < 0.001). All study patients were treated with ABVD regimen and there was a significant decrease of baseline serum TARC levels after 2 cycles of therapy. No significant difference of baseline serum TARC levels was demonstrated between patients with D1/2 and D3 whereas levels were significantly decreased after 2 cycles of ABVD in patients D1/2 vs D3; p = 0.049. There was a tendency to higher baseline serum TARC levels in patients with an increased LDH (lactate dehydrogenase) activity (p = 0.08) and in those who progressed when compared with those who maintained response (p = 0.09). Serum TARC levels decrease after chemotherapy and may serve as a marker of response assessment.

Association study of transition of laboratory marker levels and transition of disease activity of atopic dermatitis patients treated with dupilumab.

Dupilumab, a fully human monoclonal antibody that blocks signalling pathways of interleukin (IL)-4 and IL-13, is effective in treating patients with atopic dermatitis (AD). We previously showed that transitions of serum thymus and activation-regulated chemokine (TARC) levels and eosinophil numbers were strongly associated with that of AD activity and that the transitions of serum lactate dehydrogenase (LDH) and immunoglobulin E (IgE) levels were weakly and not associated with that of AD activity, respectively, in patients treated without dupilumab. The purpose of this study was to elucidate whether the association of the transition of laboratory marker levels and transition of disease activity in dupilumab-treated AD patients (present study) was different from that in patients who are not treated with dupilumab (previous study). Sixty AD outpatients treated with dupilumab were included in this study. Associations between the transition of the eczema area and severity index (EASI) score and those of above-mentioned laboratory marker levels were evaluated using a mixed effects model of EASI as the response variable, laboratory markers as fixed effects and patients as random effects. The transitions of serum TARC and LDH levels were associated strongly with that of AD activity, but the transitions of serum IgE level and eosinophil numbers were associated with that of AD activity intermediately and weakly, respectively. Laboratory markers are useful for evaluating the effects of treatments for AD, but the meaning of each laboratory marker depends on the drugs used for treatment.

Dupilumab suppresses type 2 inflammatory biomarkers across multiple atopic, allergic diseases.

BackgroundType 2 inflammation is common in numerous atopic/allergic diseases and can be identified by elevated biomarker levels. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin‐4 and interleukin‐13, key and central drivers of type 2 inflammation.ObjectiveAssessment of dupilumab effect on type 2 inflammatory biomarkers in atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps (CRSwNP) and eosinophilic esophagitis (EoE).MethodsData were extracted from three randomized placebo‐controlled trials of dupilumab in AD (NCT02277743, N = 671; NCT02277769, N = 708; NCT02260986, N = 740); and one each in asthma (NCT02414854, N = 1902); CRSwNP (NCT02898454, N = 448); and EoE (NCT02379052, N = 47). Biomarkers assessed were serum thymus and activation‐regulated chemokine (TARC), plasma eotaxin‐3, serum total immunoglobulin E (IgE), serum periostin and blood eosinophil count.ResultsDupilumab versus placebo significantly suppressed most type 2 inflammatory biomarker levels across all studies/indications where data were assessed. Reductions in serum TARC, plasma eotaxin‐3 and serum periostin occurred rapidly, whereas reductions in serum total IgE were more gradual. Across diseases, at the end of treatment, median percentage change from baseline in TARC levels ranged from −24.8% to −88.6% (placebo +2.6% to −53.6%); −38.2% to −51.5% (placebo +8.3% to −0.16%) in eotaxin‐3; −24.8% to −76.7% (placebo +8.3% to −4.4%) in total IgE; and −13.6% to −41.1% (placebo +10.1% to −6.94%) in periostin levels. Blood eosinophil responses to dupilumab varied by disease, with minimal changes in AD in the SOLO studies (median percentage change from baseline to end of treatment: 0% [95% CI: −15.8, 0]); transient increases followed by decreases to below‐baseline levels in asthma (−14.6% [−20.0, −7.7]) and CRSwNP (−29.4% [−40.0, −16.3]); and significant decreases in EoE (−50.0% [−50.0, −33.3]).Conclusion and clinical relevanceDupilumab reduced levels of type 2 biomarkers across clinical studies in patients with AD, asthma, CRSwNP and EoE.

EVALUATION OF THE RELATIONSHIP BETWEEN THE SEVERITY OF SOLID FOOD PROTEIN-INDUCED ENTEROCOLITIS SYNDROME AND POST-EMETIC SERUM THYMUS AND ACTIVATION-REGULATED CHEMOKINE LEVELS

We reported that post-emetic serum thymus and activation-regulated chemokine (TARC) levels may be a potential biomarker to diagnose solid food protein-induced enterocolitis syndrome (FPIES). However, there are no reports on the relationship between FPIES severity and serum TARC levels. The subjects were 13 cases of FPIES (hen's egg=10, Wheat=1, rice=1, short-neck clam=1) for a total of 22 events (7 emergency outpatient visits, 9 positive and 6 negative results of oral food challenge test). Serum TARC levels at 6 and 24 h after antigen ingestion were compared between the symptomatic and asymptomatic events and the mild-moderate and severe events. We also evaluated the correlation between vomiting duration and serum TARC levels. The median serum TARC (pg/ml) in the asymptomatic, mild-moderate, and severe events were 546, 1093, and 3127 at 6 h after ingestion, and 910, 2053, and 6496 at 24 h after ingestion, respectively. The serum TARC level was significantly higher in the symptomatic events than the asymptomatic events, and it was significantly higher in the severe events than the mild-moderate events (p < 0.01). There was a moderate correlation between serum TARC levels and vomiting duration. Post-emetic serum TARC correlates with the severity of FPIES. It is expected that this information will lead to an objective evaluation of the severity of FPIES.

Infantile atopic dermatitis: Serum vitamin D, zinc and TARC levels and their relationship with disease phenotype and severity.

Several markers that influence the clinical course of atopic dermatitis (AD) have been investigated so far. Thymus and activation regulated chemokine (TARC) - a Th2-related cytokine - increase in various atopic diseases. It has been shown that vitamin D affects Treg cells and immune responses. Zinc as an essential trace element for cell-cell interactions, cellular differentiation, and proliferation. However, the effect of these markers on infantile AD and disease severity are mostly unknown. The aim of this study was to investigate the relationship between TARC, vitamin D, zinc levels, and the disease severity in infants with AD. AD patients (n = 160) with age and sex that matched healthy controls (n = 79) were included in the study. The diagnosis of AD was made based on the Hanifin-Rajka criteria. The objective SCORAD index was used for the assessment of disease severity. A total of 160 patients (male 71.9%) with AD were included in the study. The median age of onset of symptoms was 2 (1.0-3.5) months. The lesions initially started on face 76.9%, neck 6.9%, extremities 7.5%, and body 8.8%. Nearly 40% of the patients were found to be atopic. Food allergy was found in 39.4%. The median of objective SCORAD index was 27.5 (17.5-40) in the study group. The TARC levels of AD patients were higher than control group [1803 pg/ml (1006- 3123) vs 709 pg/ml (504-1147), p < 0.001] There was a significant correlation between objective SCORAD scores and TARC values in subjects with AD (r = 0.363, p < 0.001). As the severity of AD increased, vitamin D levels decreased (p for trend 0.015) and TARC values increased (p for trend < 0.001). Serum zinc levels did not change with the severity of the disease. The presence of atopy did not have an influence on serum TARC, zinc, and vitamin D levels. In infants with AD, disease severity is positively related with TARC levels; and inversely proportional to vitamin D levels. TARC levels differ between patients and healthy controls. The presence of atopy has not been shown to affect these markers. © 2021 Codon Publications. Published by Codon Publications.