• CTCL
• Cutaneous T-cell lymphoma
• Mycosis fungoides
• Skin barrier
• Sézary syndrome

• Humans
• Lymphoma, T-Cell, Cutaneous/pathology
• Lymphoma, T-Cell, Cutaneous/therapy
• Skin/pathology
• Skin Neoplasms/pathology
• Skin Neoplasms/therapy

• atopic dermatitis
• epigenomics
• genomics
• lipidomics
• multi‐omics
• proteomics
• transcriptomics

• Dermatitis, Atopic/therapy
• Dermatitis, Atopic/genetics
• Dermatitis, Atopic/immunology
• Humans
• Genomics/methods
• Epigenomics/methods
• Proteomics/methods
• Metabolomics/methods
• Lipidomics
• Precision Medicine/methods
• Transcriptome
• Animals
• Gene Expression Profiling
• Multiomics

• cancer
• interleukin-31
• interleukin-31 receptor α
• oncostatin-M receptor
• pruritus

• Humans
• Pruritus/metabolism
• Pruritus/immunology
• Pruritus/etiology
• Neoplasms/metabolism
• Neoplasms/complications
• Neoplasms/immunology
• Interleukins/metabolism
• Animals
• Signal Transduction
• Inflammation/metabolism

• Cutaneous T-cell lymphoma
• IL-31
• Mast cells
• Mycosis fungoides
• Pruritus
• Tryptase

• Humans
• Pruritus
• Male
• Female
• Middle Aged
• Lymphoma, T-Cell, Cutaneous/complications
• Aged
• Adult
• Quality of Life
• Interleukins/blood
• Aged, 80 and over
• Skin Neoplasms/complications
• Skin Neoplasms/pathology
• Cytokines/blood

• 428144812 This study was supported by intramural funding. Outside of it, Carolin Steinert was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) as part of a clinical research unit (CRU) 339 "food allergy and tolerance" - 428144812.
• This study was supported by intramural funding. Outside of it, Carolin Steinert was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) as part of a clinical research unit (CRU) 339 “food allergy and tolerance” – 428144812.
• Charité - Universitätsmedizin Berlin (3093)

• Pruritus
• chronic itch
• novel treatments
• quality of life
• targeted therapy
• unmet needs

• Humans
• Pruritus/therapy
• Pruritus/etiology
• Pruritus/diagnosis
• Eczema/therapy
• Eczema/complications
• Quality of Life
• Chronic Disease

• Sezary syndrome
• cutaneous T cell lymphoma
• dupilumab
• interleukin 13
• interleukin 4
• lebrikizumab
• mycosis fungoides
• nemolizumab
• tezepelumab
• tralokinumab

• Humans
• Antipruritics/therapeutic use
• Quality of Life
• Skin Neoplasms/complications
• Skin Neoplasms/diagnosis
• Skin Neoplasms/drug therapy
• Lymphoma, T-Cell, Cutaneous/complications
• Lymphoma, T-Cell, Cutaneous/diagnosis
• Lymphoma, T-Cell, Cutaneous/drug therapy
• Pruritus/therapy
• Pruritus/drug therapy
• Dermatitis/complications

• Atopic dermatitis
• Cytokines
• Itch
• Neuroimmune
• Prurigo nodularis
• Pruritus

• Humans
• Transcriptome
• Skin Neoplasms/genetics
• Skin Neoplasms/pathology
• Lymphoma, T-Cell, Cutaneous/pathology
• CD4-Positive T-Lymphocytes/metabolism
• Receptors, Antigen, T-Cell/genetics

• T35 DK104689 NIDDK NIH HHS
• T35 HL007649 NHLBI NIH HHS
• UL1 TR001863 NCATS NIH HHS

• Diagnosis and therapy
• Gastric cancer
• Immune cell interactions
• Interleukin-31
• Interleukin-33
• Interleukin32

Atopic dermatitis (AD) is a chronic and relapsing cutaneous disorder characterized by compromised immune system, excessive inflammation, and skin barrier disruption. Post-translational modifications (PTMs) are covalent and enzymatic modifications of proteins after their translation, which have been reported to play roles in inflammatory and allergic diseases. However, less attention has been paid to the effect of PTMs on AD. This review summarized the knowledge of six major classes (including phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, o-glycosylation, and glycation) of PTMs in AD pathogenesis and discussed the opportunities for disease management.

• National Natural Science Foundation of China
• National Key Research and Development Program of China

Interleukin 31 belongs to the IL-6 superfamily, and it is an itch mediator already studied in several diseases, comprising atopic dermatitis, allergic pathologies, and onco-hematological conditions. This research aims to assess the role of this cytokine in the pathogenesis of these conditions and its potential therapeutic role. The research has been conducted on articles, excluding reviews and meta-analysis, both on animals and humans. The results showed that IL-31 plays a crucial role in the pathogenesis of systemic skin manifestations, prognosis, and itch severity. Traditional therapies target this interleukin indirectly, but monoclonal antibodies (Mab) directed against it have shown efficacy and safety profiles comparable with biological drugs that are already available. Future perspectives could include the development of new antibodies against IL-31 both for humans and animals, thus adding a new approach to the therapy, which often has proven to be prolonged and specific for each patient.

• IL-31
• allergic diseases
• biological drugs
• cancer
• hematological diseases
• interleukin-31
• interleukins
• itch
• respiratory diseases
• skin diseases

Keloids are scars that extend beyond the margins of an insulting cutaneous injury. Keloids are often thought to be primarily a cosmetic issue, as they are typically quite raised and pigmented. However, these scars also present with functional symptoms of pruritus and pain that significantly impact quality of life. The symptom of pruritus is frequently overlooked by dermatologists, and treatments are often primarily focused on the gross appearance of the scar. This review describes the prevalence and importance of pruritus in keloids. In addition, the putative mechanisms underlying the development of keloid pruritus, which include neuronal and immunological mechanisms, are discussed. Furthermore, this review describes keloid treatments that have been shown to reduce pruritus, treatments that specifically target the itch, and emerging therapies.

• asthma
• atopic dermatitis
• interleukin-31
• interleukin-31 receptor A
• oncostatin M receptor

• disease
• itch
• pediatric
• pruritus
• systemic

The itch associated with cutaneous T-cell lymphoma (CTCL), including Mycosis Fungoides (MF) and Sézary syndrome (SS), is often severe and poorly responsive to treatment with antihistamines. Recent studies have highlighted the possible role of interleukins in nonhistaminergic itch. We investigated the role of IL-31 and IL-8 in CTCL, concerning disease severity and associated itch. Serum samples of 27 patients with CTCL (17 MF and 10 SS) and 29 controls (blood donors) were analyzed for interleukin- (IL-) 31 and IL-8; correlations with disease and itch severity were evaluated. IL-31 serum levels were higher in CTCL patients than in controls and higher in SS than in MF. Also, serum IL-31 levels were higher in patients with advanced disease compared to those with early disease, and they correlated positively with lactate dehydrogenase and beta 2-microglobulin levels, as well as with the Sézary cell count. Itch affected 67% of CTCL patients (MF: 47%; SS: 100%). Serum IL-31 levels were higher in itching patients than in controls and in patients without itching. There was no association between serum IL-8 and disease severity, nor with itching. Serum IL-8 levels correlated positively with peripheral blood leukocyte and neutrophil counts in CTCL patients. Our study suggests a role for IL-31 in CTCL-associated itch, especially in advanced disease and SS, offering a rational target for new therapeutic approaches. Increased serum IL-8 observed in some patients may be related to concomitant infections, and its role in exacerbating itch by recruiting neutrophils and promoting the release of neutrophil proteases deserves further investigation.

Pruritus is one of the most common symptoms experienced by neoplastic patients. The pathogenesis of neoplastic itch is complex and multifactorial and could be due to an unbalanced production of humoral mediators by altered immune effector cells. IL-31 is a pro-inflammatory cytokine produced by CD4 + T helper cells. The aim of this review was to evaluate the role of this Th2 cytokine and its receptor IL-31RA, in the onset of neoplastic pruritus. We analysed scientific literature looking for the most relevant original articles linking IL-31to itch in oncologic diseases. Interleukin-31 seems to be a main itch mediator in several hematologic disease such as Cutaneous T cells lymphomas. In these patients IL-31 was positively linked to itch level, and IL-31 matched with disease stage. IL-31 seems to play an important role in the signalling pathway involved in pruritus, but it is also suggested to play a proinflammatory and immunomodulatory role which could play a part in the progression of the neoplastic disease. Further studies will be fundamental in facing pruritus in oncologic patients, since this problem compromise their quality of life worsening an already critic picture.

• Cancer
• Cytokines
• IL-31
• IL-33
• Itch
• Malignancies
• Pruritus
• Skin

• IL-31
• Th2 cell
• atopic dermatitis
• dendritic cell
• itch
• macrophage
• nemolizumab
• prurigo nodularis
• pruritus

Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus might have a tremendous impact on patients’ quality of life and strongly interfere with sleep, social, and work activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-31, IL-25, and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes, and type 2 T lymphocytes, and are master regulators of chronic itch. These cytokines might act as direct pruritogen on primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation- and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2 inflammation and immunity evolved to protect against parasites, and thus, the scratching response evoked by pruritus might have developed to alert about the presence and to remove parasites from the skin surface.

• T-helper type 2 cells
• atopic dermatitis
• chronic pruritus
• dupilumab
• interleukin 31
• interleukin-13
• interleukin-4
• itch
• prurigo
• pruritogenic mediator
• skin diseases

• CTCL
• Sézary syndrome
• cutaneous T cell lymphoma
• dermatologic oncology
• drug response
• immune deficiency
• immunopathogenesis
• immunotherapy
• mycosis fungoides

• Antineoplastic Agents, Immunological/pharmacology
• Antineoplastic Agents, Immunological/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/pharmacology
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Disease Progression
• Humans
• Immune Checkpoint Inhibitors/pharmacology
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Reconstitution
• Immunity, Cellular/drug effects
• Microbiota/immunology
• Mycosis Fungoides/drug therapy
• Mycosis Fungoides/immunology
• Mycosis Fungoides/mortality
• Mycosis Fungoides/pathology
• Progression-Free Survival
• Sezary Syndrome/drug therapy
• Sezary Syndrome/immunology
• Sezary Syndrome/mortality
• Sezary Syndrome/pathology
• Skin/drug effects
• Skin/immunology
• Skin/microbiology
• Skin/pathology
• Skin Neoplasms/drug therapy
• Skin Neoplasms/immunology
• Skin Neoplasms/mortality
• Skin Neoplasms/pathology
• Th2 Cells/drug effects
• Th2 Cells/immunology
• Tumor Escape/drug effects
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/immunology

• TL1 TR001880 NCATS NIH HHS

• Apoptosis modulating therapies
• Cutaneous T-cell lymphomas
• Inhibitors and small molecule inhibitors
• Macrophage checkpoint blockade
• Tyrosine-kinase

• Atopic dermatitis
• Chemokine
• Cutaneous T-cell lymphoma (CTCL)
• Dermatomyositis
• Dupilumab
• IL-13: Interleukin-13
• IL-31: Interleukin-31
• IL-33: Interleukin-33
• IL-4: Interleukin-4
• ILC2 cells: Type 2 innate immune cells
• Interleukin-31 receptor
• Lokivetmab
• Mycosis fungoides
• Nemolizumab
• Oclacitinib
• Sézary syndrome
• Th2: Type 2 helper T cell

• cutaneous T-cell lymphoma
• fibroblasts
• keratinocytes
• malignant T cells
• tumor microenvironment

Tenalisib (RP6530), a dual phosphoinositide 3-kinase δ/γ inhibitor was evaluated in a phase I/Ib study for maximum tolerated dose (MTD), pharmacokinetics, and efficacy in patients with relapsed/refractory peripheral and cutaneous T-Cell Lymphoma (TCL). Histologically confirmed (TCL) patients, with ≥1 prior therapy received Tenalisib orally in a 28-day cycle in doses of 200 to 800 mg twice daily (800 mg in fasting and fed state) in escalation phase (n = 19) and 800 mg twice daily (fasting) in expansion phase (n = 39). The most frequently reported treatment emergent adverse events (TEAE) and related TEAE were fatigue (45%) and transaminase elevations (33%), respectively. Most frequently reported related Grade ≥3 TEAE was transaminase elevation (21%). Two dose-limiting toxicities occurred in the 800 mg fed cohort; hence, 800 mg fasting dose was deemed MTD. Tenalisib was absorbed rapidly with a median half-life of 2.28 h. Overall response rate in 35 evaluable patients was 45.7% (3 complete response (CR); 13 partial response (PR)) and median duration of response was 4.9 months. Responding tumors showed a marked downregulation of CD30, IL-31 and IL-32α. With an acceptable safety and promising clinical activity, Tenalisib can be a potential therapeutic option for relapsed/refractory TCL. Currently, a phase I/II combination study with romidepsin is ongoing.

• CTCL
• PTCL
• dose limiting toxicity
• maximum tolerated dose

• atopic dermatitis
• itch
• neurogenic inflammation
• pruritus
• quality of life

• Animals
• Humans
• Neurons/physiology
• Pruritus/metabolism
• Pruritus/physiopathology
• Skin/innervation
• Spinal Cord/cytology
• Spinal Cord/physiology

• R01 CA094025 NCI NIH HHS
• R21 AR067399 NIAMS NIH HHS

• Cancer
• Epigenetic therapy
• Histone deacetylase (HDAC) Inhibitors
• Histone deacetylases
• Mechanisms
• Signaling pathways.

• Itch
• management
• mechanism
• pathophysiology
• pruritus
• treatment

• Clinical and pathologic features
• Cutaneous T-cell lymphoma
• Immunotherapies
• Molecular hallmarks
• Mycosis fungoides
• Sézary syndrome
• Treatment strategies
• Tumor microenvironment

• Humans
• Mycosis Fungoides/diagnosis
• Mycosis Fungoides/drug therapy
• Neoplasm Recurrence, Local
• Sezary Syndrome/diagnosis
• Sezary Syndrome/drug therapy
• Skin Neoplasms/diagnosis
• Skin Neoplasms/drug therapy

• cutaneous T-cell lymphoma
• lenalidomide
• pruritus
• romidepsin

• Biological agents
• Cutaneous
• Lymphoma
• Novel agents
• Sézary
• T cell

Primary cutaneous lymphomas comprise a group of lymphatic malignancies that occur primarily in the skin. They represent the second most common form of extranodal non-Hodgkin’s lymphoma and are characterized by heterogeneous clinical, histological, immunological, and molecular features. The most common type is mycosis fungoides and its leukemic variant, Sézary syndrome. Both diseases are considered T-helper cell type 2 (Th2) diseases. Not only the tumor cells but also the tumor microenvironment can promote Th2 differentiation, which is beneficial for the tumor cells because a Th1 environment enhances antitumor immune responses. This Th2-dominant milieu also underlies the infectious susceptibility of the patients. Many components, such as tumor-associated macrophages, cancer-associated fibroblasts, and dendritic cells, as well as humoral factors, such as chemokines and cytokines, establish the tumor microenvironment and can modify tumor cell migration and proliferation. Multiagent chemotherapy often induces immunosuppression, resulting in an increased risk of serious infection and poor tolerance. Therefore, overtreatment should be avoided for these types of lymphomas. Interferons have been shown to increase the time to next treatment to a greater degree than has chemotherapy. The pathogenesis and prognosis of cutaneous T-cell lymphoma (CTCL) differ markedly among the subtypes. In some aggressive subtypes of CTCLs, such as primary cutaneous gamma/delta T-cell lymphoma and primary cutaneous CD8⁺ aggressive epidermotropic cytotoxic T-cell lymphoma, hematopoietic stem cell transplantation should be considered, whereas overtreatment should be avoided with other, favorable subtypes. Therefore, a solid understanding of the pathogenesis and immunological background of cutaneous lymphoma is required to better treat patients who are inflicted with this disease. This review summarizes the current knowledge in the field to attempt to achieve this objective.

• Sézary syndrome
• adult T-cell leukemia/lymphoma
• cutaneous T-cell lymphoma
• mycosis fungoides
• primary cutaneous CD30+ T-cell lymphoproliferative disorders

• Endometrial cancer
• interleukin-31
• single nucleotide polymorphisms

• cell surface marker
• cutaneous T-cell lymphoma
• gene expression
• screening
• secretory protein

• Biomarkers/blood
• Gene Expression
• Humans
• Mycosis Fungoides/blood
• Mycosis Fungoides/diagnosis
• Sezary Syndrome/blood
• Sezary Syndrome/diagnosis

• P50 CA121973 NCI NIH HHS

• allergy
• cancer growth
• cytokine

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous and relatively rare group of non-Hodgkin lymphomas arising from neoplastic skin-homing memory T cells. There is no known cure for CTCL, and current treatments focus on achieving and maintaining remission, controlling symptoms, limiting toxicities and maintaining or improving quality of life. Patients with CTCL often suffer from pruritus (itching), which can be debilitating and can have a significant impact on physical well-being and quality of life. Although progress has been made towards understanding the mechanisms of pruritus, the pathophysiology of CTCL-related pruritus remains unclear. Currently, there is neither a step-wise treatment algorithm for CTCL nor a standardized approach to treating pruritus in patients with CTCL. Treatments which specifically target pruritus have been reported with varying effectiveness. However, systemic treatments that target CTCL have the potential to alleviate pruritus by treating the underlying disease. Several systemic CTCL treatments have reported anti-pruritic properties, some in both objective responders and nonresponders, but the lack of a standardized method to measure and report pruritus makes it difficult to compare the effectiveness of systemic treatments. In this review, we provide an overview of approved and investigational systemic CTCL treatments that report anti-pruritic properties. For each study, the methods used to measure and report pruritus, as well as the study design are examined so that the clinical benefits of each systemic treatment can be more readily evaluated.

Funding: Financial support for medical editorial assistance and article processing charge were provided by Celgene Corporation.

• Cutaneous T-cell lymphoma
• Itch
• Pruritus
• Therapy

Traffic-related air pollution (TRAP) may affect immune responses, including those in the T_H2 and T_H17 pathways. To examine whether TRAP is associated with plasma level of T_H17-, T_H1-, and T_H2-related cytokines in children with and without asthma, a cross-sectional study of 577 children (ages 6–14 years) with (n = 294) and without (n = 283) asthma in San Juan (Puerto Rico) was performed. Residential distance to a major road was estimated using geocoded home addresses for study participants. A panel of 14 cytokines, enriched for the T_H17 pathway, was measured in plasma. Asthma was defined as physician-diagnosed asthma and current wheeze. Multivariable linear regression was used to examine the association of residential distance to a major road (a marker of TRAP), asthma, and cytokine levels. Among all participating children, residential proximity to a major road was significantly associated with increased plasma level of IL-31, even after adjustment for relevant covariates and correction for multiple testing. The presence of asthma modified the estimated effect of the residential distance to a major road on plasma TNF-α (P for interaction = 0.00047). Although living farther from a major road was significantly associated with lower TNF-α level in control subjects, no such decrease was seen in children with asthma. In a direct comparison of cases and control subjects, children with asthma had significantly higher levels of IL-1β, IL-22, and IL-33 than control subjects. TRAP is associated with increased levels of proinflammatory cytokines among Puerto Rican children, who belong to an ethnic group with high risk for asthma.

• K08 HL125666 NHLBI NIH HHS

• Epidermis
• IL-17
• Netherton syndrome
• TNF-α
• autosomal recessive congenital ichthyosis
• congenital ichthyosiform erythroderma
• epidermolytic ichthyosis
• ichthyosis
• inflammation
• lamellar ichthyosis
• skin

• Adolescent
• Adult
• Aged
• Child
• Dermatitis, Atopic/genetics
• Dermatitis, Atopic/immunology
• Female
• Gene Expression
• Humans
• Ichthyosis/genetics
• Ichthyosis/immunology
• Interleukin-17/genetics
• Interleukin-17/immunology
• Interleukin-23/genetics
• Interleukin-23/immunology
• Male
• Middle Aged
• Psoriasis/genetics
• Psoriasis/immunology
• RNA, Messenger/metabolism
• Severity of Illness Index
• Skin/immunology
• Young Adult

• P30 AR057216 NIAMS NIH HHS
• R01 AR068392 NIAMS NIH HHS