Characterization of cells and mediators associated with pruritus in primary cutaneous T-cell lymphomas

Abstract

Patients with primary cutaneous T-cell lymphoma (CTCL) often experience severe and difficult-to-treat pruritus that negatively affects their quality of life (QoL). However, the mechanisms of pruritus in CTCL, including mycosis fungoides (MF), remain largely unknown, and detailed characteristics of CTCL-associated pruritus is not fully elucidated. To characterize pruritus in CTCL, cutaneous B-cell lymphoma (CBCL), and large plaque parapsoriasis (LPP), and to identify potential itch mediators involved in the pathogenesis of pruritus in CTCL patients. Clinical data and blood samples were collected from 129 healthy subjects and 142 patients. Itch intensity, QoL impairment, psychological distress, and sleep quality were assessed using validated questionnaires and instruments. Blood levels of BDNF, CCL24, GRP, IL-31, IL-33, sST2, substance P, TSLP, tryptase and total IgE were measured using ELISA or ImmunoCAP. Pruritus was prevalent in CTCL, LPP and CBCL patients, with higher prevalence and severity observed in CTCL. In CTCL, pruritus correlated with significant impairment in QoL, sleep, psychological distress. Compared to healthy controls, elevated levels of IL-31, IL-33, substance P, total IgE, tryptase, and TSLP were found in MF patients. A comparison of MF patients with and without pruritus revealed higher levels of IL-31, substance P, GRP, and CCL24 in the former. Itch intensity positively correlated with IL-31, GRP, CCL24, and tryptase levels. Pruritus significantly burdens CTCL patients, necessitating appropriate therapeutic management. Our findings suggest that various non-histaminergic mediators such as tryptase and IL-31 could be explored as novel therapeutic targets for managing pruritus in MF patients.

Keywords: Cutaneous T-cell lymphoma; IL-31; Mast cells; Mycosis fungoides; Pruritus; Tryptase.

Fig. 1

Characteristics and intensity of pruritus. a The intensity of worst itch in the last week in patients who reported pruritus in the last week of their respective disease. Data is presented as mean with error bars indicating standard deviation. The number below each group refers to the number of participants involved. b The intensity of current itch in patients who reported current pruritus in the morning during blood collection of their respective disease. Data is presented as mean with error bars indicating standard deviation. The number below each group refers to the number of participants involved. c The frequency (daily or not daily) and type (constant or in attacks) of itch in each group. d The effectiveness of antipruritic treatments in each group, the treatments mainly included antihistamines, topical steroids, and keratolytic agents. The values refer to valid data only (excluding missing data). CBCL, cutaneous B cell lymphoma; LPP, large plaque parapsoriasis; MF, mycosis fungoides; n, number; SS, Sézary syndrome; VAS, visual analogue scale.

Fig. 2

In MF patients who reported having pruritus in the last week, worst itch intensity in the last week correlates with higher levels of anxiety and depression, impairment of sleep quality and overall quality of life. The correlation of HADS-anxiety a, HADS-depression b, global sleep quality c, EORTC- global health score d, SF-12 physical component e, SF-12 mental component f, with worst itch intensity in the last week. The values refer to valid data only (excluding missing data). EORTC, European Organisation for Research and Treatment of Cancer; HADS, hospital anxiety and depression scale; MF, mycosis fungoides; PSQI, Pittsburgh Sleep Quality Index; SF-12, 12-item Short-Form Health Survey. Spearman’s rank correlation was used for analyzing the correlation between two independent variables.

Fig. 3

Differentially upregulated mediators in the blood of MF patients with current pruritus in the morning during blood collection compared to patients without current pruritus. The levels of serum IL-31 a, plasma IL-33 b, plasma sST2 c, plasma TSLP d, serum substance P be, serum BDNF f, plasma GRP g, serum CCL24 h, serum tryptase i, and serum total IgE j in healthy controls, MF patients, MF patients with and without pruritus. The values refer to valid data only (excluding missing data). The number below each group refers to the number of participants involved. Data is presented as mean with error bars indicating Standard Error of the Mean (SEM). BDNF, brain-derived neurotrophic factor; CCL24, chemokine (C–C motif) ligand 24; GRP, gastrin-releasing peptide; HC, healthy controls; IL: interleukin; MF, mycosis fungoides; n, number; sST2, soluble suppression of tumorigenicity 2; TSLP, thymic stromal lymphopoietin. Two- sample t test or Mann–Whitney U test was used for testing the differences between two independent categories of parametric and non-parametric variables, respectively.

Fig. 4

Correlation of potential itch mediators with intensity of current itch in the morning during blood collection in all MF patients. The correlation of current itch intensity with IL-31a, substance P b, GRP c, CCL24 d, tryptase e, IL-33 f. The values refer to valid data only (excluding missing data). CCL24, chemokine (C–C motif) ligand 24; GRP, gastrin-releasing peptide; IL: interleukin; MF, mycosis fungoides; VAS, visual analogue scale. Spearman’s rank correlation was used for analyzing the correlation between two independent variables.