Elucidating pathogenesis and improving clinical management of benign cutaneous inflammation in urticaria and malignant inflammation in cutaneous T-cell lymphomas
Bibliographic record
Abstract
Introduction: Chronic urticaria (CU) is defined when hives occur for at least 6 weeks. When no identifiable cause can be found, it is classified as chronic spontaneous urticaria (CSU). Approximately 50% of patients are now considered to have an autoimmune etiology which can be established in vivo with the use of the autologous serum skin test (ASST) or in vitro with the Basophil Activation Test (BAT) measuring CD63 expression. Because of its chronicity, CU in children results in substantial impairment of health-related quality of life (QoL). While urticaria represents benign inflammation, Cutaneous T-Cell Lymphomas (CTCL) represents malignant inflammation that is driven by neoplastic CD4+ T cells in the skin. About 20% of patients with early stage will progress and succumb to their disease. Currently, it is not possible to predict which patients will progress. It is also challenging to diagnose CTCL as it mimics benign inflammatory dermatoses. It may be possible to identify a set of molecular markers that may be used to help prognosticate and diagnose this disease. Methods: We have created a cohort of 139 children affected by CSU. All patients were followed for 2 years. We have studied the utility of BAT to help diagnose and monitor response to treatment, evaluated the natural history and assessed for predictors of disease resolution using established validated tools including the weekly urticaria activity score (UAS7) and the Chronic Urticaria quality of life questionnaire (CU-Q2oL). For CTCL research we used the RT-PCR and tested gene expression in 60 CTCL skin biopsy samples and in 11 patient-derived cell lines to discover diagnostic and prognostic markers and to gain additional insight in the molecular etiology of CTCL. We also tested the expression of Embryonic Stem Cell (ESC) genes in this cancer. Results: Based on the log-normal distribution of CD63 values in control subjects, the reference range and the cut-off for positive CD63 BAT values was established to be 1.2% to 1.8% (95%CI) and 1.8%, respectively. Children with CSU showed significantly elevated and significantly more increased BAT values as compared to healthy controls (Wilcoxon rank test p-value <0.001). In contrast, no difference was found between BAT results in controls and PU patients. Higher disease activity and treatment resistance were associated with higher BAT values. Using the BAT we documented that 57% of children in our cohort had autoimmune CSU. The rate of disease resolution was 10.3% per year. Positive BAT and basopenia were statistically associated with earlier disease resolution. CU-Q2oL at time of recruitment suggested that itch, sleep impairment and physical appearance were the most important factors affecting QoL. The mean UAS7 at first follow up was 8.23 and reduced to 3.62 on next follow up suggesting an overall good control of symptoms with current management strategies.Our research findings on CTCL demonstrated that 17 genes (CCL18, CCL26, FYB, T3JAM, MMP12, LEF1, LCK, ITK, GNLY, IL2RA, IL26, IL22, CCR4, GTSF1, SYCP1, STAT5A, and TOX) are able to both identify patients who are at risk of progression and also distinguish CTCL from benign mimickers. Our findings for the first time demonstrated that many critical ESC genes are expressed in CTCL. Select ESC genes (OCT4, EED, TCF3, THAP11, CHD7, TIP60, TRIM28) were preferentially expressed in CTCL samples when compared to benign skin biopsies. Conclusions: Relative frequency of autoimmune urticaria in children is similar to adults and if proven in the future, may be a good prognostic factor predicting earlier disease resolution. BAT may serve as an effective laboratory tool to help diagnose autoimmune CSU and monitor response to treatment in moderate/severe cases.Our gene expression findings in CTCL, combined with other gene expression analyses, prepare the foundation for the development of personalized molecular approach toward diagnosis and prognostication of this cancer.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".